Sleep disturbances in Rett syndrome 6 European Rett

Sleep disturbances in Rett syndrome 6. European Rett Syndrome Conference, Tampere, Finland 27. – 28. September 2019 Anne-Marie Bisgaard, M. D. , Ph. D Center for Rett syndrome, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark

Why are we talking about sleep today? • Nearly every person with RTT experiences sleep disturbances at some point in their lives • Both in children, adolescents and in adults • Problems might have impact on the whole family’s quality of life • We want to learn more about it Center for Rett syndrome 2

• why is it important to have a good night’s sleep? • what is happening in the brain during sleep? • what has research taught us about RTT and sleep? • the different kinds of sleep disturbances in RTT • other medical issues which can affect sleep • investigations and suggestions for behavioral management and medical treatment • recommendations, take home messages Center for Rett syndrome 4

Why is it important to have a good night’s sleep? • Important for development and cognition, growth, health, mood, behaviour and quality of life • Housekeeping – the brain clears out toxins • The brain works with our memories • Information is stored into long-term memory Center for Rett syndrome 5

Why is it important to have a good night’s sleep? • Important for development and cognition, our health, mood, behaviour and quality of life • The majority of growth hormone is released during sleep (is important for bones, muscles, organs and metabolism) Center for Rett syndrome 6

Why is it important to have a good night’s sleep? • Poor sleep over a longer period increases the risk of overweight, cardiovascular diseases and diabetes BUT • How much sleep do we need? • Needed hours decrease with age Center for Rett syndrome 7

National Sleep Foundation's updated sleep duration recommendations: final report. Sleep Health. 2015 Dec; 1(4): 233 -243. Center for Rett syndrome 8

• why is it important to have a good night’s sleep? • what is happening in the brain during sleep? • what has research taught us about RTT and sleep? • the different kinds of sleep disturbances in RTT • other medical issues which can affect sleep • investigations and suggestions for behavioral management and medical treatment • recommendations, take home messages Center for Rett syndrome 9

What is happening in the brain during sleep? • Melatonin is our sleep hormone • regulates our sleep-wake rhythm • it is secreted from corpus pineale in the brain and retina in the eye • The sleep is divided into 4 stages in a sleep cycle • Each cycle takes 90 -120 min. • Typically 4 to 5 cycles a night Center for Rett syndrome 10

What is happening in the brain during sleep? https: //www. tuck. com/stages/ Center for Rett syndrome 11

What is happening in the RTT brain during sleep? • It is normal to have small awakenings during the night • but in a person with RTT the periods might be prolonged and the person can have difficulties falling asleep again • Sleep studies in RTT – polysomnographies – have shown conflicting results, e. g • One has shown increased REM sleep and others have shown decreased duration of the REM period Center for Rett syndrome 12

• Why is it important to have a good night’s sleep? • what is happening in the brain during sleep? • what has research taught us about RTT and sleep? • the different kinds of sleep disturbances in RTT • other medical issues which can affect sleep • investigations and suggestions for behavioral management and medical treatment • recommendations, take home messages Center for Rett syndrome 13

What has research taught us about RTT and sleep? • Sleep abnormalities are • Study of adults from the frequent - up to 80% Australian Rett syndrome Database (ARSD) and the • There is a high degree of international database Inter. Rett sleepiness during the day in adults • 150 + 273 individuals, aged 18 – 54. 3 y • 24 countries represented Anderson A et al. Twenty years of surveillance in Rett syndrome: what does this tell us? Orphanet Journal of Rare Diseases 2014, 9: 87. Center for Rett syndrome 14

What has research taught us about RTT and sleep? • Longitudinal questionnaire study from the Australian Rett syndrome database • 320 participants both children and adults Results, frequency • Prevalence > 80% • Decreased with age • But for many it continued into adulthood • Night laughing 75% • Night screaming 40% Wong K, Leonard H, Jacoby P, Ellaway C, Downs J. The trajectories of sleep disturbances in Rett syndrome. Journal of sleep research 2015; 24: 223 -33. Center for Rett syndrome 15

What has research taught us about RTT and sleep? • Longitudinal questionnaire study from the Australian Rett syndrome database • 320 participants both children and adults Results, treatment • 16% received treatment • Treatment was associated with less than a 2% reduction in risk of further sleep problems Wong K, Leonard H, Jacoby P, Ellaway C, Downs J. The trajectories of sleep disturbances in Rett syndrome. Journal of sleep research 2015; 24: 223 -33. Center for Rett syndrome 16

What has research taught us about RTT and sleep? Results, frequency • Questionnaire study on impact and management • 364 participants from 7 countries • Aged from 2 to 57 years (median 14 y 4 m) • Ever having either difficulty falling asleep or night waking was reported for 93% • Almost half reported that their child was waking during the night more than once a week Boban S, Leonard H, Wong K, Wilson A, Downs J. Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices. American journal of medical genetics. Part A 2018. Center for Rett syndrome 17

What has research taught us about RTT and sleep? Results, impact • 364 participants from 7 countries • The impact of sleep problems was rated both on the child and on the family as moderate or major by the majority • Aged from 2 to 57 years (median 14 y 4 m) • Affected health and daily routines for the child • Questionnaire study on impact and management • Family routines and activities were often structured around the child's sleep patterns Boban S, Leonard H, Wong K, Wilson A, Downs J. Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices. American journal of medical genetics. Part A 2018. Center for Rett syndrome 18

What has research taught us about RTT and sleep? Results, impact on the child “when she is up through the night she has behavior issues the next day” “if she doesn’t sleep well she tends to have increased seizure activities” “…and is more difficult to feed her and give her drink on those days” Boban S, Leonard H, Wong K, Wilson A, Downs J. Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices. American journal of medical genetics. Part A 2018. Center for Rett syndrome 19

What has research taught us about RTT and sleep? Results, impact on the families “I have become very unhealthy because I don’t have energy to work out or take care of my self and my children when we are tired” “My husband I are currently sick. We have been sick for over 2 months, suffer from depression, and I’ve lost 30 pounds in 2 months. All of this is mainly due to lack of sleep. Marital conflict arises when we are tired. ” Boban S, Leonard H, Wong K, Wilson A, Downs J. Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices. American journal of medical genetics. Part A 2018. Center for Rett syndrome 20

What has research taught us about RTT and sleep? Results, treatment Definition of sleep hygiene • comprises a set of behaviors that expose the individual to activities and cues in preparation for a healthy sleep pattern High sleep hygiene scores in nearly two thirds • Usually went to bed at the same time every night • Their room was usually dark or dimly lit • Usually followed a regular bedtime routine (15 -30 min) Boban S, Leonard H, Wong K, Wilson A, Downs J. Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices. American journal of medical genetics. Part A 2018. Center for Rett syndrome 21

What has research taught us about RTT and sleep? • Improved sleep but did not fully treat it • Provided a more optimal background for other treatments Results, treatment High sleep hygiene scores in nearly two thirds • Usually went to bed at the same time every night • Their room was usually dark or dimly lit • Usually followed a regular bedtime routine (15 -30 min) Boban S, Leonard H, Wong K, Wilson A, Downs J. Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices. American journal of medical genetics. Part A 2018. Center for Rett syndrome 22

What has research taught us about RTT and sleep? Results, treatment • 75% did not use any pharmacological treatment • Melatonin was the most used medication • But they still had some sleep problems Boban S, Leonard H, Wong K, Wilson A, Downs J. Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices. American journal of medical genetics. Part A 2018. Center for Rett syndrome 23

What has research taught us about RTT and sleep? Results • Feasibility study of using actigraphy to characterize sleep • Sleep diary, questionnaire • Feasible • Most had appropriate onset latency (fall asleep from lights out) • 13 girls aged 20 month to 17 years • All but one had low sleep efficiency (percentage of time • Watchlike device worn in-home for being asleep) 7 days and nights • Individuals with active epilepsy had lower sleep efficiency • Several slept too little or too much • Daytime sleep continues into adolescence Merbler AM, Byiers BJ, Garcia JJ, Feyma TJ, Symons FJ. The feasibility of using actigraphy to characterize sleep in Rett syndrome. Journal of neurodevelopmental disorders 2018; 10: 8. Center for Rett syndrome 24

Video What has research taught us about RTT and sleep? Electro impulses from the brain Eye movements airflow Muscle activity • 17 girls aged 6 to 16 years Heart rate Respiration Pulse oximetry Box with wires • Polysomnography study Carbon dioxide • All had scoliosis • 88% had epilepsy Muscle activity Amaddeo A, De Sanctis L, Arroyo JO, Khirani S, Bahi-Buisson N, Fauroux B. Polysomnographic findings in Rett syndrome Eur J Paediatr Neurol. 2019 Jan; 23(1): 214 -221 Center for Rett syndrome 25

What has research taught us about RTT and sleep? Results • Only 2 children had a normal sleep efficiency • Poor sleep quality with alterations in sleep stages • Increase in stage 3 (deep sleep) • Decrease of REM sleep (dreaming) Amaddeo A, De Sanctis L, Arroyo JO, Khirani S, Bahi-Buisson N, Fauroux B. Polysomnographic findings in Rett syndrome Eur J Paediatr Neurol. 2019 Jan; 23(1): 214 -221 Center for Rett syndrome 26

What has research taught us about RTT and sleep? Results • Obstructive respiratory events were only seen in children with adenotonsilar hypertrophy • Central respiratory events were rare Amaddeo A, De Sanctis L, Arroyo JO, Khirani S, Bahi-Buisson N, Fauroux B. Polysomnographic findings in Rett syndrome Eur J Paediatr Neurol. 2019 Jan; 23(1): 214 -221 Center for Rett syndrome 27

What has research taught us about RTT and sleep? • Investigation of sleep-disordered breathing • Retrospective study Results 9/13 had obstructive sleep apnea One had central apnea • 13 children, mean age 10 years • Symptoms were snoring and apnea Sarber KM, Howard JJM, Dye TJ, Pascoe JE, Simakajornboon N. Sleep-Disordered Breathing in Pediatric Patients with Rett Syndrome J Clin Sleep Med. 2019 Aug 30 Center for Rett syndrome 28

What has research taught us about RTT and sleep? Summary • Falling asleep and staying asleep is problematic for the majority • Sleep disturbances are connected to more daytime sleepiness • Sleep disturbances are chronic • Sleep disturbances have a huge impact on the child’s and family’s quality of life • There might be breathing issues, apnea - mainly obstructive • Epilepsy plays a role Center for Rett syndrome 29

What has research taught us about RTT and sleep? Summary • Investigations • Polysomnography might be helpful but • Studies show conflicting results • Actigraphy is feasible • Treatment • 1. focus on other medical issues • 2. focus on sleep hygiene • 3. consider medication • 4. further evaluation, actigraphy, polysomnography Center for Rett syndrome 30

What has research taught us about RTT and sleep? Little is still known about • Melatonin cycles in individuals with RTT • Circadian activity rhythm/sleep-wake cycle • Sleep architecture • Epileptic activity under sleep • Efficient treatment Center for Rett syndrome 31

• why is it important to have a good night’s sleep? • what is happening in the brain during sleep? • what has research taught us about RTT and sleep? • the different kinds of sleep disturbances in RTT • other medical issues which can affect sleep • investigations and suggestions for behavioral management and medical treatment • recommendations, take home messages Center for Rett syndrome 32

The different kinds of sleep disturbances in RTT • Difficulties falling asleep • Difficulties staying asleep • Night laughing • Night screaming • Obstructive apnea • (central apnea) • Day time sleepiness • Sleep-wake dysregulation – shifting day and night Center for Rett syndrome 33

• why it is important to have a good night’s sleep? • what is happening in the brain during sleep? • what has research taught us about RTT and sleep? • the different kinds of sleep disturbances in RTT • other medical issues which can affect sleep • investigations and suggestions for behavioral management and medical treatment • recommendations, take home messages Center for Rett syndrome 34

Other medical issues which can affect sleep • Epilepsy • Gastrointestinal symptoms • Reflux -> pain and/or respiratory symptoms • Gas -> pain • Other causes of pain • Adenoids and enlarged tonsils • Medication • …. Center for Rett syndrome 35

• Why is it important to have a good night’s sleep? • what is happening in the brain during sleep? • what has research taught us about RTT and sleep? • the different kinds of sleep disturbances in RTT • other medical issues which can affect sleep • investigations and suggestions for behavioral management and medical treatment • recommendations, take home messages Center for Rett syndrome 36

Investigations and suggestions for behavioral management and medical treatment • Are there any medical issues which may affect sleep • Seizures • Gastrointestinal symptoms – reflux? • Adenotonsillar hypertrophy? • Sleep diary • Sleep questionnaire – different kinds depending on local experience • Actigraphy • Polysomnography Center for Rett syndrome 37

Investigations and suggestions for behavioral management and medical treatment • When shall we do a polysomnography? • Indications • When behavioural and medical treatment are ineffective • Suspicion on obstructive apnea – snoring • Suspicion on epileptic seizures under sleep • You cannot figure out what is happening Center for Rett syndrome 38

Suggestions for behavioral management and medical treatment • Insomnia – problems falling asleep and staying asleep • Sleep hygiene • Bedtime routine • Warm bath, reading, singing/music ect. or whatever makes she/he to relax • Regular bedtimes • Not too high temperature in bedroom, not too much light • Behavioural treatment of inappropriate behaviour • Tonsillectomy/adenotomy • Respiratory treatment – CPAP, NIV Center for Rett syndrome 39

Suggestions for behavioral management and medical treatment • Medication – lack of evidence • Melatonin – short-and long-time acting • Clonidin • Zolpidem • Risperidon (behavioral issues) • Sedative antihistamine • …. . Center for Rett syndrome 40

• why it is important to have a good night’s sleep? • what is happening in the brain during sleep? • what has research taught us about RTT and sleep? • the different kinds of sleep disturbances in RTT • other medical issues which can affect sleep • investigations and suggestions for behavioral management and medical treatment • recommendations, take home messages Center for Rett syndrome 41

Take home messages RTT and sleep • Sleep disturbances in RTT are common and chronic in children, young people and in adults • Sleep disturbances have a huge impact also on the family’s quality of life • Medical issues might influence sleep negatively • Investigation/treatment • 1. focus on other medical issues • 2. focus on sleep hygiene • 3. consider medication • 4. further evaluation, actigraphy, polysomnography Center for Rett syndrome 42

We owe everyone who are affected by Rett syndrome to do our very best Thank you for your attention Center for Rett syndrome