sleep disturbance in autism
TRANSCRIPT
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Sleep Disturbance In Autism
Eman Alluwaimi General Paediatric Clinical Fellow McMaster Children’s Hospital
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Objectives 1. General Overview; neurobiological
factors, complications, prognosis 2. Systematic review of Melatonin 3. Overview of other agents
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Prevalence of sleep disorders in ASD • 40% to 80% 1 • Rank as one of the most common concurrent clinical disorders among children with ASD 2
• Peak onset: second year of life 3
(1) M. Souders, et al. Sleep behaviors and sleep quality in children with autism
spectrum disorders, Sleep,(2009) (2) X. Ming, et.al. Autism spectrum disorders: concurrent clinical disorders J
Child Neurol (2008) (3) Gianno6 F, et.al. An open-‐label study of controlled release melatonin in treatment
of sleep disorders in children with auBsm. J AuBsm Dev Disord (2006)
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ASD related Sleep disturbances Most common: • late onset sleep: More than an hour • Frequent waking : Lasts 2-3 Hours • Reduced sleep duration
Kotagal S, et.al. Sleep in children with autism spectrum disorder. Pediatr Neurol 2012
Cortesi F, et.al. Sleep in children with auBsBc spectrum disorder. Sleep Med 2010
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Others: • Non-rapid eye movement (REM) arousal disorders
• REM sleep behaviour disorder • Rhythmic movement disorder
Kyle P. Johnson,et.al. Assessment and Pharmacologic Treatment of Sleep
Disturbance in AutismChild and Adolescent Psychiatric Clinics of North America (2008)
ASD related Sleep disturbances
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Sleep disturbance: Comparison
Sleep paMerns in children with and without auBsm spectrum disorders: Developmental comparisons, Danelle Hodge,et.al. Research in Developmental DisabiliBes (2014)
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Sleep disturbance: Comparison
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Neuropathology of Sleep disturbance in ASD
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Normal sleep
Excitatory neurons from brain stem and hypothalamus send signals to brain cortex along with other areas of the brain to keep us awake and alert
When awake
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Normal sleep
GABA
Melatonin +
• Inhibitory neurons from ventro-lateral preoptic area send their signals to these areas resulting in sleep
• An example of an inhibitory neurotransmitter is GABA • This process is controlled by many mechanisms one is through
Melatonin a hormone secreted from the pineal gland
In sleep
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Melatonin Regulation • Melatonin is made from
the amino acid tryptophan which is absorbed from blood into the pineal glad
• Tryptophan is then utilized through enzymatic reactions to yield seretonin
• During day light seretonin is stored inside the pinealocyte unavailable for further enzymatic reactions
Serotonin
5-Hydroxytryptophan
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Melatonin Regulation
Serotonin
5-Hydroxytryptophan
With the onset of darkness, postganglionic sympatheBc ouWlow to the pineal increases And the consequent release of norepinephrine onto pinealocytes Causes stored serotonin to become accessible for intracellular metabolism
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Serotonin
N-Acetylserotonin
Melatonin
5-Hydroxytryptophan
ASMT
Melatonin Regulation
With the onset of darkness, postganglionic sympatheBc ouWlow to the pineal increases And the consequent release of norepinephrine onto pinealocytes Causes stored serotonin to become accessible for intracellular metabolism
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Serotonin
N-Acetylserotonin
Melatonin
5-Hydroxytryptophan
ASMT
Melatonin Regulation
• Serotonin is converted to melatonin
• Consequently pineal melatonin level rises many-‐folds
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Serotonin
N-Acetylserotonin
Melatonin
5-Hydroxytryptophan
ASMT
In ASD
Many theories suggesBng different disrupBon mechanisms in melatonin pathway, one is a geneBc defect leading to reduced funcBon of ASMT enzyme
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Neurobiological abnormaliBes in ASD: Melatonin/seretonin • AbnormaliBes in ASMT gene with low ASMT acBvity leading to increased synthesis and asymmetry in serotonin producBon
• In one study (Makkonen I,2008) reduced serotonin transporter binding capacity was idenBfied in children with ASD.
• At least four independent studies have demonstrated abnormal melatonin regulaBon in individuals with ASD compared with controls, including elevated dayBme melatonin and significantly lower nocturnal melatonin
• loss of effect as tolerance
Flavia Cortesia,et.al. Sleep in children with autistic spectrum disorder, Advances in Pediatric Sleep Medicine. (2010)
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Neurobiological abnormaliBes in ASD: GABA
• Hypothesis: GABAergic interneurons migraBon and maturaBon could be affected
• A region of geneBc suscepBbility has been idenBfied on chromosome 15q that contains GABA-‐related genes
Levitt P, et.al. Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders. Trends Neurosci
2004
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Neurobiological abnormaliBes in ASD
• AlteraBon in hormone/neurotransmiMer (melatonin/serotonin) producBon
• Imbalance of excitaBon–inhibiBon • AbnormaliBes in the hypothalamic–pituitary–adrenal axis regulaBng circadian rhythms
Flavia Cortesia,et.al. Sleep in children with autistic spectrum disorder,
Advances in Pediatric Sleep Medicine. (2010)
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• Biological • Psychological • Social/environmental • Family factors • Behavioural
Richdale AL, Schreck KA. Sleep problems in autistim spectrum disorders: prevalence, nature and possible biopsychosocial etiologies.
Sleep Med Rev (2009) Flavia Cortesia,et.al. Sleep in children with autistic spectrum disorder,
Advances in Pediatric Sleep Medicine. (2010)
Risk factors for sleep disturbance
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Risk factors for sleep disturbance
• Anxiety • Autism symptom severity • Sensory sensitivities • Gastrointestinal problems • Intelligence quotient
Grigg-Damberger,et.al. Treatment strategies for complex behavioral insomnia in children with neurodevelopmental disorders, Current Opinion in Pulmonary
Medicine. (2013)
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Risk factors for sleep disturbance • Impaired emotional regulation • Difficulty transitioning • Impaired communication skills
Hollway JA, et.al. Correlates and risk markers for sleep disturbance in participants of the Autism Treatment Network. J Autism Dev Disord (2013)
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Complications • May exacerbate disturbed social interactions, repetitive behaviours, affective problems, and inattention/hyperactivity1
• Worsen Social skills deficits, stereotypic behaviour, and increased overall autism scores 2
(1) Gabriels et al. 2005; Goldman et al. 2012, 2009; Malow et al. 2006; Schreck
et al. 2004 (2) Schreck KA,et.al. Sleep problems as possible predictors of intensified
symptoms of autism. Res Dev Disabil 2004
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Complications
• Poor sleep quality and shorter total sleep time among parents
Meltzer LJ. et.al sleep in parents of children with autism spectrum disorders. J Pediatr Psychol (2008)
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Assessment/Management • Screening for sleep problems:
• Pediatric Sleep QuesBonnaire, Children's Sleep Habits QuesBonnaire
• History: • Screen for obstructive apnea and other sleep disorders • Insomnia: sleep environment/behaviour, Sleep diaries
• Referral to specialist: • (sleep specialist, neurologist, otolaryngologist)
• Treatment: • Non-Pharmacological: Behavioral • Pharmacological
Kyle P. Johnson,et.al, Assessment and Pharmacologic Treatment of Sleep Disturbance in Autism. Child and Adolescent Psychiatric Clinics of North America (2008)
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Pharmacological use • Melatonin • Other agents:
• Niaprazine • Mirtazapine • Clonidine
• Clonazepam
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Melatonin
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1. Rossignol DA,et.al. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol (2011)
2. Fabian Guénolé a, et.al. Melatonin for disordered sleep in individuals with autism spectrum disorders: Systematic review and discussion. Sleep Medicine Reviews (2011)
Melatonin Systematic reviews
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First systematic review
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Method • Search engine: PubMed, Google Scholar,
CINAHL,EMBASE, Scopus, and ERIC (untill Oct 2010) • Two reviewers independently assessed 35 (out of 68)
studies that met the inclusion criteria • Meta-analysis was performed on five randomized double-
blind, placebo-controlled studies • Quality assessed using the Downs and Black checklist
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Results: Characteristics and trial designs
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Result: Sleep duration
73 - 44 minutes longer
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Result: Sleep onset Latency
66 and 39 minutes shorter
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Result: Awakenings
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Genetic bases of sleep deprivement
daniel a rossignol, richard e frye, Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Developmental Medicine & Child Neurology (2011)
Melatonin receptors Enzymes involved in melatonin synthesis
Five studies
MTNR1A, MTNR1B GPR50 alkylamine N-acetyltransferase ASMT
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Genetic bases of sleep deprivement
daniel a rossignol, richard e frye, Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Developmental Medicine & Child Neurology (2011)
Melatonin receptors Enzymes involved in melatonin synthesis
Five studies
MTNR1A, MTNR1B GPR50 alkylamine N-acetyltransferase ASMT
Four studies One study reported a partial duplication of ASMT in 6 to 7% of individuals with ASD compared with 2% of healthy individuals (Cai G 2008) One study reported that two single-nucleotide polymorphisms in ASMT were significantly more frequent (Jonsson L 2010)
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Genetic bases of sleep deprivement
daniel a rossignol, richard e frye, Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Developmental Medicine & Child Neurology (2011)
Melatonin receptors Enzymes involved in melatonin synthesis
Five studies
MTNR1A, MTNR1B GPR50 alkylamine N-acetyltransferase ASMT
Four studies
No abnormality
One study (Jonsson L 2010)
Found abnormality
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Genetic bases of sleep deprivement
daniel a rossignol, richard e frye, Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Developmental Medicine & Child Neurology (2011)
Melatonin receptors Enzymes involved in melatonin synthesis
Five studies
MTNR1A, MTNR1B GPR50 alkylamine N-acetyltransferase ASMT
Four studies
No abnormality
One study (Jonsson L 2010)
two studies (Chaste P 2010 Jonsson L 2010)
Variant genes Found abnormality
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Genetic bases of sleep deprivement
daniel a rossignol, richard e frye, Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Developmental Medicine & Child Neurology (2011)
Melatonin receptors Enzymes involved in melatonin synthesis
Five studies
MTNR1A, MTNR1B GPR50 alkylamine N-acetyltransferase ASMT
Four studies
No abnormality
One study (Jonsson L 2010)
two studies (Chaste P 2010 Jonsson L 2010)
Variant genes
two studies (Chaste P 2010 Jonsson L 2010)
No significance Found abnormality
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Metabolism of Melatonin • Four studies: night-‐Bme urinary excreBon of 6-‐SM was inversely correlated with: • The severity of impairments in verbal communicaBon and play (Tordjman S, 2005)
• DayBme sleepiness (Leu RM, 2010) • Abnormal electroencephalogram (Nir I, 1995) • HyperacBvity
• These studies suggest that melatonin metabolism is directly or indirectly related to certain auBsBc behavior
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Prevalence of Melatonin usage
• Three survey studies (1071 individuals) • 2.98 -‐ 10.8%70, mean of 7.2% (95% CI 5.6–8.7%)
Polimeni MA (2005), Aman MG (2003), Green VA (2006)
Rossignol DA,et.al. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol(2011)
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Prevalence of physician recommendaBons Three survey studies (2483 physicians)
(Two studies also included several pediatric condiBons other than ASD)
• 32.4% (95% CI 30.6–34.2%) with a range of 24.982 to 39%.60 recommend melatonin usage
• In one study,Golnik AE (2009) • 22% of physicians did not feel ‘knowledgeable’ enough about melatonin to recommend its use
• 14% discouraged melatonin use • 39% were accepBng of its use if the child was already taking melatonin.
Owens JA(2010), Golnik AE(2009), Owens JA(2003)
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Effects of melatonin treatment on sleep 18 studies,( one: >18y, another: 3-28y, 16: 2-18y)
• Dose: 0.75mg – 15mg (rare use of 25mg) • 14days - 4years • Measurement of effect: subjecBve (parent report quesBonnaires and sleep diaries), objecBve (acBgraphy)
• All of these studies reported improvements in sleep parameters, including improvements in overall sleep, sleep duration, sleep onset latency, and night-time awakenings.
Rossignol DA,et.al. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol(2011)
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Safety • Side effects: difficulty waking, dayBme sleepiness, and enuresis • Seven studies :no side-‐effects • Remaining studies: transient or mild side-‐effects in a small number of individuals.
• Tolerated when combined • Seizure acBvity: No increase (one study reported an abnormal EEG with lower mean serum melatonin)
Rossignol DA,et.al. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol(2011)
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Effect on daytime behavior • Six studies : improvements in dayBme behavior in some children with ASD • less behavioural rigidity, ease of management for parents and teachers, beMer social interacBon, fewer temper tantrums, less irritability, more playfulness, beMer academic performance, and increased alertness.
• One study (Wright B,2010) noted a significant improvement in overall dayBme behaviour as measured by the Developmental Behaviour Checklist when comparing melatonin with placebo.
Rossignol DA,et.al. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol(2011)
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Loss of Melatonin effect Four studies (Andersen IM. 2008, Ishizaki A. 1999, Jan JE. 1996, McArthur AJ. 1998) • Some attributed the loss of effect to Tolerance: leading to melatonin dose overtime
• Others attributed it to Slow Melatonin Metabolism: • Evident by daytime melatonin level In ASD individuals, even
when melatonin was not recently given, leading to the loss of normal melatonin circadian rhythm (Nir I. 1995, Ritvo ER. 1993)
• This problem responds to a reduction in melatonin dose rather than an increase in dose (Braam W. 2010)
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Second systematic review:
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Melatonin Systematic review • 12 citaBons (4 case reports, 3 retrospecBve studies, 2 open-‐label clinical trials, and 3 placebo-‐controlled trials)
• literature supports the existence of a beneficial effect of melatonin on sleep in individuals with ASD, with only few and minor side effects
Fabian Guénolé a, et.al. Melatonin for disordered sleep in
individuals with autism spectrum disorders: Systematic review and discussion. Sleep Medicine Reviews (2011)
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Other agents
• Niaprazine • Mirtazapine • Clonidine • Clonazepam
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Niaprazine
Rossi PG1,et.al. Niaprazine in the treatment of autistic disorder. J Child Neurol.(1999)
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Mirtazapine
Posey DJ1,et.al. A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders, Child Adolesc Psychopharmacol. (2001)
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Clonidine
Xue Ming, et.al. Use of clonidine in children with auBsm spectrum disorders. Brain and Development (2008)
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Clonazepam • Severe NREM parasomnias, such as sleep terrors and sleepwalking
• Rhythmic movement disorder • REM sleep behaviour disorder
Kyle P. Johnson, et.al. Sleep Patterns in Autism Spectrum Disorders, Child Adolesc Psychiatric Clin N Am 18 (2009)
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PROGNOSIS • Persist past mid-puberty (Sivertsen B 2012) • Last for many years, continue into adulthood (A.M. Robinson 2004)
• In one study, 63% of children with ASD and sleep problems experienced persistence of sleep difficulties over time (L. Wiggs,2004)
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Conclusion
• Melatonin proven to be effecBve • More data needed on:
• Dosing, Bming, type (slow vs. fast release preparaBons)
• Long-‐term side effect and follow-‐up
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Take Home Message • Children and adolescents with an ASD are at substanBal risk for experiencing sleep problems, parBcularly insomnia
• The clinician assessing a child with an ASD should screen carefully for sleep disorders and make referrals as indicated
• Consider slow melatonin metabolism that needs to be managed by lower melatonin levels rather than increasing it
• IdenBfying and treaBng sleep disorders may result not only in improved sleep, but also impact favourably on dayBme behaviour and family funcBoning
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2. Hodge D, et.al. Sleep patterns in children with and without autism spectrum disorders: Developmental comparisons, Research in Developmental Disabilities (2014)
3. Hollway JA, et.al. Correlates and risk markers for sleep disturbance in participants of the Autism Treatment Network. J Autism Dev Disord (2013)
4. Kotagal S, et.al. Sleep in children with autism spectrum disorder. Pediatr Neurol (2012)
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