sleep disturbance in autism

Sleep Disturbance In Autism

Eman Alluwaimi General Paediatric Clinical Fellow McMaster Children’s Hospital

Objectives 1.  General Overview; neurobiological

factors, complications, prognosis 2.  Systematic review of Melatonin 3.  Overview of other agents

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)

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

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

Sleep disturbance: Comparison

Sleep paMerns in children with and without auBsm spectrum disorders: Developmental comparisons, Danelle Hodge,et.al. Research in Developmental DisabiliBes (2014)

Sleep disturbance: Comparison

Neuropathology of Sleep disturbance in ASD

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

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

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

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

Serotonin

N-Acetylserotonin

Melatonin

5-Hydroxytryptophan

ASMT


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

Serotonin

N-Acetylserotonin

Melatonin

5-Hydroxytryptophan

ASMT


•  Serotonin is converted to melatonin

•  Consequently pineal melatonin level rises many-‐folds

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

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)

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

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)

• 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

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)

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)

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

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)

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)

Pharmacological use • Melatonin • Other agents:

•  Niaprazine •  Mirtazapine •  Clonidine

• Clonazepam

Melatonin

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

First systematic review

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

Results: Characteristics and trial designs

Result: Sleep duration

73 - 44 minutes longer

Result: Sleep onset Latency

66 and 39 minutes shorter

Result: Awakenings

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




Five studies


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)




Five studies


Four studies

No abnormality

One study (Jonsson L 2010)

Found abnormality




Five studies


Four studies

No abnormality


two studies (Chaste P 2010 Jonsson L 2010)

Variant genes Found abnormality




Five studies


Four studies

No abnormality



Variant genes


No significance Found abnormality

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

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)

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)

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.


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)


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.


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)

Second systematic review:

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)

Other agents

• Niaprazine • Mirtazapine • Clonidine • Clonazepam

Niaprazine

Rossi PG1,et.al. Niaprazine in the treatment of autistic disorder. J Child Neurol.(1999)

Mirtazapine

Posey DJ1,et.al. A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders, Child Adolesc Psychopharmacol. (2001)

Clonidine

Xue Ming, et.al. Use of clonidine in children with auBsm spectrum disorders. Brain and Development (2008)

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)

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)

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

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

Reference 1.  Weissman L, Augustyn M. Autism spectrum disorder in children and adolescents: Pharmacologic

interventions. Up to date (2014)

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)

5.  Rossignol DA,et.al. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol (2011)

6.  Guénolé a F, et.al. Melatonin for disordered sleep in individuals with autism spectrum disorders: Systematic review and discussion. Sleep Medicine Reviews (2011)

7.  Cortesi F, et.al. Sleep in children with autistic spectrum disorder. Sleep Med (2010)

8.  Tricoire H, Locatelli A, Chemineau P, Malpaux B. Melatonin enters the cerebrospinal fluid through the pineal recess. AU SO Endocrinology. (2002)

9.  Reichlin S, Baldessarini RJ, Martin JB. The pineal gland: A model of neuroendocrine regulation. In: The

Hypothalamus, Raven Press, New York (1978)

sleep disturbance in autism

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