Sleep-Wake Disorders in Childhood

REVIEW ARTICLE

Sleep-Wake Disorders in
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Childhood
By Amy Licis, MD, MSCI
ABSTRACT
PURPOSE OF REVIEW: The presentation of sleep issues in childhood differs from
the presentation in adulthood and may be more subtle. Sleep issues may
affect children differently than adults, and distinct treatment approaches
are often used in children.
RECENT FINDINGS: Sodium oxybate was approved by the US Food and Drug
Administration (FDA) in October 2018 for an expanded indication of
treatment of sleepiness or cataplexy in patients with narcolepsy type 1 or
narcolepsy type 2 aged 7 years or older, with side effect and safety
profiles similar to those seen in adults. Restless sleep disorder is a recently
proposed entity in which restless sleep, daytime sleepiness, and often
iron deficiency are observed, but children do not meet the criteria for
restless legs syndrome or periodic limb movement disorder.
SUMMARY: Children’s sleep is discussed in this article, including normal sleep

CITE AS: patterns and effects of insufficient sleep. Sleep disorders of childhood are
CONTINUUM (MINNEAP MINN)
2020;26(4, SLEEP NEUROLOGY):
reviewed, including insomnia, obstructive sleep apnea, restless legs
1034–1069. syndrome, parasomnias, narcolepsy, and Kleine-Levin syndrome. Children
with neurologic issues or neurodevelopmental disorders frequently have
Address correspondence to sleep disorders arising from an interaction of heterogeneous factors.
Dr Amy Licis, 660 S Euclid Ave,
Campus Box 8111, Department of Further attention to sleep may often be warranted through a
Neurology, Washington polysomnogram or referral to a pediatric sleep specialist. Sleep disorders
University School of Medicine, may cause indelible effects on children’s cognitive functioning, general
St Louis, MO 63110,
licisa@wustl.edu. health, and well-being, and awareness of sleep disorders is imperative for
neurologists who treat children.
RELATIONSHIP DISCLOSURE:
Dr Licis has received personal
compensation for serving as a
moderator for Pediatric Update.
INTRODUCTION
S
UNLABELED USE OF leep issues are highly prevalent in both typically developing children
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
and children with neurologic and neurodevelopmental disorders.
Dr Licis discusses the unlabeled/ Sleep and neurologic disorders may interact in a bidirectional manner,
investigational use of so that neurologic disorders may affect sleep and sleep issues may
medications, none of which are
approved by the US Food and affect neurologic disorders. Increased awareness of sleep issues can
Drug Administration for pediatric help neurologists appropriately refer patients for sleep evaluations, potentially
use except for sodium oxybate
and amphetamines for the
improving patients’ neurologic issues, general health measures, cognitive
treatment of narcolepsy. outcomes, and quality of life. In this article, the features of normal sleep in
childhood are reviewed, including recommended sleep duration by age,
© 2020 American Academy
age-related changes in sleep architecture, and the role of sleep in learning.
of Neurology. Potential mechanisms by which sleep issues may exert their effects on
1034 AUGUST 2020
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

development are delineated. Sleep disorders are also discussed, including
insomnia, obstructive sleep apnea (OSA), restless legs syndrome (RLS),
parasomnias, and disorders of hypersomnia. The associations of particular
neurodevelopmental disorders and neurologic conditions with sleep issues
are detailed.
NORMAL SLEEP
Sleep is a dynamic process with changes in pattern and architecture as
children grow and as sleep disorders or neurologic issues emerge or resolve.
Some features of sleep are particular to certain ages or stages of development. An
understanding of normal sleep processes in childhood provides context for the
pathophysiology of sleep disorders. TABLE 11-1 details changes in sleep
architecture during childhood.
Childhood sleep schedules vary by age, with sleep becoming more consolidated
and shorter in total daily duration with increasing age. Infant sleep is composed of
multiple separate sleep cycles in each diurnal period, with lengthening of the
nocturnal sleep period as infants age. Eventually, napping becomes limited to a
single daily nap in early childhood. A majority of 3- to 4-year-olds nap, with nap
rates decreasing over time so that nearly all 7-year-olds have stopped napping.
Also, the timing of sleep schedules varies by age. Environmental cues, homeostatic
sleep pressure, and individual differences in circadian rhythms help determine
sleep timing. Chronotype, which is an inherent preference for an early, typical, or
late sleep schedule, has an approximately 50% heritability1 and is reflective of
melatonin release patterns, with melatonin release occurring later in later
chronotypes.2 Early and late chronotypes have a relatively early and late preferred
sleep schedule, respectively, compared with the typical age-dependent preferred
sleep schedule. Interestingly, chronotypes have recently been linked to differences
in resting-state functional connectivity and attention.3 A trend toward an early
sleep schedule preference exists in young children. In contrast, bedtimes and wake
times are shifted later in adolescence, a delay that is not entirely driven by social
factors. Salivary dim light melatonin onset, a marker of circadian sleep timing,
occurs later in adolescence, indicating a biological preference for later sleep
schedules.4 The recommendations for sleep duration per age as determined by a
task force of the American Academy of Sleep Medicine are shown in TABLE 11-2.5
Changes in Sleep Architecture in Childhood TABLE 11-1
◆ At 27 to 28 weeks postconceptional age, 80% of sleep is active sleep (rapid eye movements,
mixed-frequency EEG, and irregular respirations)
◆ By 40 weeks postconceptional age, 50% of sleep time is active sleep
◆ By 2 to 3 months postconceptional age, sleep spindles and K complexes are apparent and
signify thalamocortical maturation
◆ By 3 to 4 years of age, rapid eye movement (REM) sleep percentage decreases to 20% to 25%
◆ N3 sleep occurs more in the first part of the night and is associated with growth hormone
release; a decrease in N3 sleep begins in puberty
EEG = electroencephalogram.
CONTINUUMJOURNAL.COM 1035

SLEEP-WAKE DISORDERS IN CHILDHOOD
Short sleep duration in childhood is associated with an increased likelihood of

attention, behavior and learning problems, injuries, hypertension, obesity,
diabetes mellitus, and depression.5 Conversely, associations have been described
between long sleep duration in childhood and mental health issues, hypertension,
diabetes mellitus, and obesity.5
The level of insufficient sleep among children is concerning. In a 2015 sample
of data from 52,356 children in middle school and high school analyzed by the
Centers for Disease Control and Prevention, 57.8% of 6- to 12-year-olds and
72.7% of 13- to 18-year-olds reported sleeping less than the recommended
minimum sleep duration on school nights.6 A reemergence of napping or longer
sleep times on weekends can be signs of sleep deprivation. Problematic sleep
hygiene habits can affect sleep. In a 2014 poll of 1103 parents or guardians of
children aged 6 to 17 years, the prevalence of electronic devices in the children’s
bedrooms was high and associated with shorter sleep duration.7 Exposure to light
on the blue light spectrum at bedtime has been linked to delays in circadian
rhythm markers such as dim light melatonin onset and core body temperature
nadir, as well as increased cortisol levels.8 Problems with children’s sleep
hygiene, sleep duration, and sleep timing are more prevalent in families of lower
socioeconomic status.9 In addition, school schedules can impose nonphysiologic
restriction of sleep times, such as by implementing early school start times for
adolescents. A delay in high school start times of as little as 30 minutes correlated
with longer sleep duration, improved attendance, less tardiness, less falling
asleep in class, better grades, and fewer motor vehicle crashes.10
Sleep facilitates learning and memory consolidation. The evolution in sleep
schedules may follow brain maturation, with the sleep schedules of younger
children providing more frequent opportunities for sleep-related memory
consolidation. Preschoolers were shown to better encode visuospatial
information after a nap, both immediately after the nap and 24 hours later.11 The
role of frequent sleep-facilitated memory processing may diminish with age.
Children 9 to 12 years old who obtained adequate nocturnal sleep did not
demonstrate improved learning after napping.12 In school-aged children, a
correlation has been found between sleep duration and grades.13 Sleep
deprivation has a number of cognitive effects including increased periods of
TABLE 11-2 Recommended Sleep Duration for Children by Age According to the
American Academy of Sleep Medicinea
Age Recommended Sleep Duration per 24 Hours
4–12 months 12–16 hours (including naps)
1–2 years 11–14 hours (including naps)
3–5 years 10–13 hours (including naps)
6–12 years 9–12 hours
13–18 years 8–10 hours
a
Modified with permission from Paruthi S, et al, J Clin Sleep Med.5 © 2016 American Academy of Sleep
Medicine.
1036 AUGUST 2020

inattention, increased error rates, cognitive slowing, and declines in short-term KEY POINTS
recall and working memory and behavioral effects including increased
● Environmental cues,
impulsivity and risk-taking.14,15 homeostatic sleep pressure,
and individual differences in
LONG-TERM IMPACT OF SLEEP DISRUPTION ON DEVELOPMENT circadian rhythms help
Sleep disturbances may have consequences for development, both for typically determine sleep timing.
developing children and children with neurodevelopmental disorders. The
● The evolution in sleep
combination of experimental sleep fragmentation and suppression of rapid eye schedules may follow brain
movement (REM) sleep in juvenile prairie voles was associated with impairment maturation, with the sleep
of long-term social bonding, with a predominance of symptoms in males.16 schedules of younger
Children with a short sleep duration at 2.5 years of age (9 hours of sleep or less) children providing more
frequent opportunities for
were shown to have increased levels of hyperactivity and impulsivity at 6 years of sleep-related memory
age, along with lower performance on cognitive assessments at 5 and 6 years of consolidation.
age, even if sleep time had later increased to recommended amounts.17 These
results suggest a critical developmental period that is sensitive to sleep disruption ● The mechanisms by which
sleep disorders or sleep
with potential long-term consequences. Adequate sleep remains important for restriction may impair
brain development later in childhood, as suggested by the correlation of shorter development remain
sleep time in early adolescence with smaller brain gray matter volumes in frontal, unclear.
anterior cingulate, and precuneus cortex regions, especially the prefrontal cortex,
a center for executive functions and one of the later-maturing regions.18
The mechanisms by which sleep disorders or sleep restriction may impair
development remain unclear. Sleep restriction, fragmented sleep, and especially
chronic intermittent hypoxia during sleep, as found in OSA, have been shown to
cause endoplasmic reticulum stress.19,20 Particularly of note for the developing
brain, myelinating cells are vulnerable to apoptosis during endoplasmic reticulum
stress, and extensive white matter alterations have been demonstrated in
patients with OSA, although disagreement among studies exists about the precise
brain structural effects of OSA.21,22 Chronic intermittent hypoxia provokes
hippocampal apoptosis and structural changes in a mouse model, with an
associated reduction in synaptic plasticity and impairment of long-term memory
formation.20 An inhibitor of endoplasmic reticulum stress lessened these
effects considerably, modeling the potential effects of sleep disorders and their
treatments on learning and memory.20 Poor or restricted sleep may affect synaptic
connections, especially during childhood when a high degree of plasticity exists.
Measures of worse sleep quality detected by actigraphy, including efficiency,
number of awakenings, and duration of awakenings, have been associated with a
weaker default mode network connectivity at rest in adolescents, and sleep
restriction has been associated with aberrant functional connectivity patterns in
the frontal limbic circuits in adolescents.23,24 In animal models, both REM sleep
and non-REM sleep contribute to synaptic plasticity and memory consolidation.25,26
Neurodevelopmental disorders may exert their effects on development partly
through impairment of sleep, among other factors. More research is needed to
investigate whether improving sleep may improve developmental trajectories.
SLEEP DISORDERS
Sleep issues occur frequently in children. The clinical features, pathophysiology,
diagnosis, and treatments of pediatric sleep disorders are reviewed, including
insomnia, OSA, RLS, parasomnias, and disorders of hypersomnia. In addition,
associations of particular neurologic conditions and neurodevelopmental
disorders with sleep issues are explored.

Insomnia
Insomnia is difficulty falling asleep, called sleep-onset insomnia, or difficulty
returning to sleep, called sleep-maintenance insomnia.
EPIDEMIOLOGY. Prevalence ranges have been reported at approximately 20% in a

community sample of school-aged children and 30% to 80% of children with
neurodevelopmental disorders, with estimates differing among studies.27,28
PATHOPHYSIOLOGY AND CLINICAL FEATURES. Insomnia is influenced by both

biological and psychological factors. Insomnia may be associated with
inappropriate sleep associations or inadequate limit setting for children.29
Heightened arousal appears to be a common mechanism underlying insomnia,
based on imaging and physiologic biomarkers. Patients with insomnia scored
higher on measures of depression, anxiety, neuroticism, arousal predisposition,
and stress perception and had higher 24-hour adrenocorticotropic hormone
(ACTH) and cortisol secretions than individuals without insomnia.30,31
Illustrating the concept that insomnia is not solely behavioral in nature,
genome-wide association data have shown that insomnia shares a genetic
background with RLS, aging, coronary artery disease, neurotic traits, smoking
behavior, and depression.32 Sleep disorders such as circadian rhythm disorder
(delayed-phase type), RLS, or OSA can exacerbate insomnia, as can medical
conditions such as asthma, psychiatric conditions such as depression or anxiety,
or medication side effects.28 The interplay of many complex factors contributes
to the significant insomnia often found in children with neurodevelopmental
disorders, including abnormalities in the sleep-wake cycle and circadian
rhythms, hypersensitivity to environmental factors, comorbid medical
conditions such as epilepsy, and side effects of medications used to treat
comorbid conditions.28 Nightmares can exacerbate insomnia and occur
frequently in 2% to 4% of children 29 months to 6 years old with a peak
occurrence at 41 months (3.9%).33
DIAGNOSIS. Diagnostic criteria of the International Classification of Sleep

Disorders, Third Edition29 (ICSD-3) require that one or more of the following
symptoms are present: difficulty initiating sleep, difficulty sleeping without a
caregiver, bedtime resistance, difficulty maintaining sleep, or waking earlier
than desired, along with fatigue/sleepiness, limitations to academic/occupational
functioning, impaired cognitive capabilities, mood disturbances, or behavior
problems.29 Information about sleep schedules should be noted, including
bedtime, wake time, estimated sleep latency, and naps, and a sleep log or diary
may be kept to record this information (FIGURE 11-1).
Diagnosis can be aided by objective measures such as actigraphy, especially
when sleep state misperception or circadian rhythm disorder is suspected or
when corroboration of parental reporting of sleep schedules in children with
neurodevelopmental disorders or in young children is desired (FIGURE 11-2).
Actigraphy is a wristwatchlike device that measures movement through an
accelerometer to provide quantified assessments of sleep patterns, sleep
duration, and quality. Actigraphy has been validated against the gold standard
polysomnogram in pediatric populations; it consistently identifies sleep
(sensitivity range for sleep, 82% to 90%) but is less accurate in identifying wake
after sleep onset in children (ie, specificity for sleep, 51% to 73%).34 Actigraphy
1038 AUGUST 2020

KEY POINT
● Sleep disorders such as

circadian rhythm disorder
(delayed-phase type),
restless legs syndrome, or
obstructive sleep apnea can
exacerbate insomnia, as can
medical conditions such as
asthma, psychiatric
conditions such as
depression or anxiety, or
medication side effects.
FIGURE 11-1
Example of a sleep diary.
cannot reliably distinguish sleep from stationary wakefulness and demonstrates a

tendency to overestimate sleep time.34 In addition, popularity is growing for
consumer wearable devices, including those that provide information about
sleep. A limited number of studies have been performed comparing consumer
wearable devices to polysomnography, with most involving adult participants
only and very few involving children. Similar patterns have been noted with
consumer wearable devices as with actigraphy, with an overestimation of sleep
and an underestimation of wake and a relatively high sensitivity (accuracy to
detect sleep) but relatively low specificity (accuracy to detect wake).35,36
TREATMENT. Treatments for insomnia in children include cognitive-behavioral

therapy and medications.
COGNITIVE-BEHAVIORAL THERAPY AND SLEEP HYGIENE. The mainstay of treating

insomnia in children is behavioral intervention, currently the most effective
treatment available. A review of 52 treatment studies showed that 94% of studies
found behavioral interventions effective, with more than 80% of children
maintaining improvement for 3 to 6 months.37 Particularly helpful strategies
included unmodified extinction (the approach of not providing parental attention
unless physical needs are present), parent education regarding habits conducive to
sleep, graduated extinction (the approach of a gradual withdrawal of parental
attention unless physical needs are present), and bedtime routines.37 Good
sleep hygiene should be discussed, such as maintaining relatively regular wake
times, bedtime routines, minimizing play at bedtime, screen-free time starting at
least 1 hour before bedtime, the use of blue light–blocking applications on
electronic devices in the evening, independent sleep, avoidance of clock watching,
and adoption of relaxation strategies. Efforts are underway to develop
internet-based pediatric sleep education tools as access to appointments with
pediatric sleep psychologists is sometimes limited. For example, a pediatric sleep
education program currently undergoing evaluation is Better Nights, Better
Days (betternightsbetterdays.ca), with promising results in the pilot study.38

KEY POINT
● No medications for the

treatment of insomnia in
children are approved by
the US Food and Drug
Administration, and the
literature on their efficacy is
limited.
FIGURE 11-2
Example of an actigraphy tracing.
SLEEP-PROMOTING MEDICATIONS. If insomnia is significant, referral for an

appointment with a pediatric sleep specialist, a sleep study, or both should be
considered to provide treatment and evaluate for other sleep disorders that may
be contributing to the insomnia. Some children have continued insomnia after
behavioral intervention or treatment of other sleep disorders. In particular, many
children with neurologic conditions have a biological basis for disrupted sleep
that can be caused by concurrent medical conditions, medication side effects, or
neurotransmitter abnormalities involving sleep-wake regulation. Due to the
significant insomnia these children may experience, consideration of sleep-
promoting medications for insomnia, called hypnotics, may be appropriate.
No medications for the treatment of insomnia in children are approved by
the US Food and Drug Administration (FDA), and the literature on their efficacy
1040 AUGUST 2020

is limited. Children’s metabolic needs are different from adults’ needs, and
direct extrapolation of weight-based dosing from adult studies may be incorrect.
When dosing is insufficient, children may have paradoxical reactions, resulting
in potential agitation or confusion rather than sleep. More studies, potentially
augmented by the creation of a registry, are needed to better determine
medication efficacy and dosing for children with insomnia.
General principles regarding the prescription of medications for insomnia in
children are reviewed here and in TABLE 11-3. Hypnotics have a range of
mechanisms of action, and various hypnotics act upon the melatonin,
γ-aminobutyric acid (GABA), norepinephrine, serotonin, dopamine, histamine,
and orexin (hypocretin) receptors. A reasonable initial medication option is
supplemental melatonin. Melatonin is an endogenous hormone produced by the
pineal gland and follows a nearly 24-hour circadian cycle controlled by the
suprachiasmatic nucleus. The suprachiasmatic nucleus is reset daily by diurnal
light inputs from the retina and nocturnal melatonin release. Melatonin begins to
increase 2 hours before habitual bedtime and remains elevated through the night.
Some medications that may be considered for use in children are reviewed in
TABLE 11-4. Medication use should be combined with a behavioral approach.
Adolescents should be cautioned against combining hypnotics with alcohol or
illicit drug use, and adolescent girls should be counseled about potential pregnancy
risks. In general, long-term side effects are not well studied, and possible effects on
the developing brain are unknown. Conversely, sleep deprivation due to insomnia
may also have effects on the developing brain, as reviewed in this article, so the
risk-benefit ratio of medications for insomnia should be carefully weighed.
Hypnotics may be a short-term tool to help children establish better sleep hygiene
and better psychological sleep associations that may perpetuate improved sleep
after the hypnotics are withdrawn. However, children with neurodevelopmental
disorders may exhibit a tendency toward insomnia indefinitely and may or may
not demonstrate long-lasting improvement after hypnotics are weaned.
Obstructive Sleep Apnea

Childhood sleep-related breathing disorders encompass a variety of disorders,
with onset from infancy to adolescence, including snoring, OSA, central sleep
apnea, and sleep-related hypoventilation.
Principles for Prescribing Hypnotic Medications for Insomnia in Children TABLE 11-3
◆ Shorter-acting medications for sleep-onset insomnia

◆ Shorter-acting medications are less likely to cause morning sleepiness
◆ Longer-acting medications for sleep-maintenance insomnia
◆ Consider adjusting the timing or dosage of medications prescribed for other indications
◆ Prescribe medications for the shortest duration possible
◆ Hypnotics should be weaned rather than stopped
◆ A slow wean may be successful when a faster wean is not
◆ Habituation may occur, and efficacy may be restored after a drug holiday
◆ Sedating medications may worsen obstructive sleep apnea

TABLE 11-4 Medications Used to Treat Insomnia in Children
Classification and Notable Side

Medication Dosage Effects Indications Comments
Melatonin39–48 Hypnotic dosing Sleepiness, Consider in Antioxidant and anti-inflammatory
when given close enuresis, children with properties; may improve sleep
to bedtime: 1 mg to headache, developmental partly by modulating pain or
3 mg 30 minutes dizziness, diarrhea; disorders, anxiety; little US Food and Drug
before bedtime for side effects could blindness, or Administration (FDA) oversight;
children who weigh be related to typical formulations confirmed by the
<40 kg (88 lb) or melatonin or development; can United States Pharmacopeial
5 mg to 6 mg for contaminants such be initial Convention Verification Services
children who weigh as its precursor pharmacotherapy may be more reliable; supplement
≥40 kg (88 lb); serotonin; studies for sleep-onset testing companies exist, but their
maximum dose: with a follow-up insomnia: hypnotic information is not independently
10 mg 30 minutes period of nearly effect at higher verified
before bedtime 4 years have not doses closer to
shown adverse bedtime; circadian
Chronobiotic effects, including rhythm disorder,
dosing, phase- no clear effect on delayed phase
shifting effects: puberty; type: can shift
0.2 mg to 0.5 mg supplemental circadian rhythm
3 to 4 hours before melatonin given earlier when given
habitual bedtime, over 6–12 months at lower doses
increasing to a does not appear to 3–4 hours prior to
maximum of 3 mg suppress bedtime;
3 to 4 hours before endogenous prolonged-release
habitual bedtime, melatonin formulations may
together with improve sleep-
morning light maintenance
exposure insomnia and
reduce wakings
Melatonin receptor agonists49
Ramelteon 8 mg at bedtime Dizziness, Insomnia, consider May be effective in some children

sleepiness, nausea, in autism/other even if melatonin was ineffective;
Acts on MT1 and headaches; use disorders in which lower risk for rebound insomnia,
MT2 melatonin with fluvoxamine is melatonin levels withdrawal symptoms, or
receptors contraindicated may be abnormal dependence compared to other
hypnotics
Tasimelteon 20 mg at bedtime Elevated Non–24-hour May be effective in some children

transaminases, sleep-wake rhythm even if melatonin was ineffective;
Greater affinity sleepiness, disorder, children lower risk for rebound insomnia,
for the MT2 headaches, with blindness, withdrawal symptoms, or
receptors than nightmares, Smith-Magenis dependence compared to other
the MT1 receptors, decreased syndrome, hypnotics
provides a strong hemoglobin and consider in autism/
circadian hematocrit other disorders in
entrainment which melatonin
effect levels may be
abnormal
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α-Adrenergic agonist50
Clonidine Most commonly Hypotension, Children with Caution in patients with cardiac
0.05 mg to 0.1 mg at bradycardia, autism, attention conditions, narrow therapeutic
bedtime; maximum sedation, rebound deficit index
dose in a child who hypertension if hyperactivity
weighs 27–40.5 kg abruptly disorder, tics
(44–89 lb): 0.2 mg discontinued
Benzodiazepine
Clonazepam 0.25 mg to 0.75 mg Sedation, Insomnia comorbid Caution in patients with epilepsy,
at bedtime rebound insomnia, with problematic may contribute to tolerance for
withdrawal anxiety or rescue benzodiazepines, advise
symptoms, parasomnias (likely against alcohol use
dependence acts by suppressing
arousals and
decreasing
slow-wave sleep)
Non–benzodiazepine receptor agonist51
Zolpidem
Short-acting: 2.5 mg to 10 mg at Hyperactivity in Immediate-release: Advise against alcohol use; better

immediate-release bedtime; maximum children with autism, Sleep-onset efficacy data in adults, boxed
dose: 0.25 mg/kg/ tolerance, sedation, insomnia in older warning for occasional serious
d (5 mg for girls, 10 parasomnias, rebound children injuries from parasomnias in adults,
mg for boys) insomnia, girls may no serious injuries in children
be more likely than reported to the FDA
boys to experience
sleepiness at
higher doses
Long-acting: 6.25 mg to 12.5 mg Extended-release:

extended-release at bedtime; Sleep-maintenance
maximum dose: insomnia in older
0.25 mg/kg/d children
(6.25 mg for girls,
12.5 mg for boys)
α2δ Ligands52
Gabapentin 5 mg/kg/d to Sedation, weight Sleep-onset or Consider in young children (due to

15 mg/kg/d given gain, nausea, mood sleep-maintenance pediatric experience for multiple
Ligand of voltage-
30–60 minutes prior changes, may insomnia comorbid indications)
dependent
to bedtime; may worsen generalized with restless legs
calcium channels
give 2 hours before epilepsy syndrome or focal
bedtime if restless onset seizures, may
legs symptoms are reduce nocturnal
significant; typical wakings,
maximum dose: neuropathic pain
600 mg
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Antidepressants
Doxepin53 1 mg to 6 mg at Sleepiness and Sleep-onset and At doses >25 mg, less effective for
bedtime; maximum nausea; few side sleep-maintenance insomnia, broader anticholinergic
Tricyclic
dose for insomnia: effects and no insomnia, autism and antiadrenergic effects
antidepressant;
10 mg at bedtime known QT
selective histamine
prolongation at low
H1 receptor
doses
antagonist at low
doses
Mirtazapine54,55 7.5 mg to 30 mg at Sleepiness, Insomnia, Increased noradrenergic

bedtime irritability, mood hyperactivity, neurotransmission at doses
Atypical
changes, anxiety, >30 mg may lessen efficacy for
antidepressant with
constipation, depression, insomnia
antagonism of
daytime sedation, Angelman
serotonergic (5-HT2
dry mouth, weight syndrome, autism,
and 5-HT3),
gain, QT interval especially in
adrenergic (α2), and
prolongation children with
histaminergic (H1)
self-injury
receptors
Trazodone56 25 mg to 100 mg at QT interval Insomnia comorbid A genetic polymorphism exists

bedtime prolongation, with depression, in which trazodone is metabolized
Atypical
priapism, mood efficacy unclear in to higher amounts of methyl-
antidepressant
changes, dizziness, children without chlorophenylpiperazine,
with antagonism
nausea, depression or associated with wake promotion,
of serotonergic
constipation, anxiety anxiety, and false-positive
(5-HT2), adrenergic
weight gain results for 3,4-
(α1), and
methylenedioxymethamphetamine
histaminergic (H1)
(MDMA) on drug screens
receptors; one of
the most sedating
antidepressants
Antihistamine
Diphenhydramine 1 mg/kg at bedtime Tolerance, sedation, Occasional short- Efficacy in older children unclear;
as needed for anticholinergic term use in younger limited role for long-term use due
Histamine H1
insomnia; maximum effects (dry mouth, children to significant potential for
receptor
dose: 50 mg at urinary retention, tolerance and sedation
antagonist
bedtime constipation, blurry
vision), hyperactivity
Orexin (hypocretin)-receptor antagonist57
Suvorexant 5 mg to 20 mg at Could exacerbate Persistent severe Should be weaned rather than

bedtime cataplexy in children insomnia in older stopped quickly due to the
Novel mechanism
with narcolepsy; children potential for rebound insomnia
of action
sleepiness,
nightmares,
hyperactivity,
interacts with
CYP3A4 inhibitors
1044 AUGUST 2020

EPIDEMIOLOGY. Snoring presents habitually in approximately 10% of children and
occasionally in approximately 54% of children.58 Primary snoring exclusive of
OSA has been associated with decrements in memory, attention, global and verbal
IQ, and school performance; increased behavioral issues; and elevated blood
pressure.58–60 This article focuses on OSA, which involves a narrowing of the upper
airway with preserved respiratory effort, causing a reduction or cessation of airflow.
OSA presents in about 1% to 5% of children, and the most common age of
presentation is 2 to 6 years, related to the tonsillar hypertrophy that is present
during these ages.61 Neurologic or medical conditions in which OSA is common
are shown in TABLE 11-5. Sleep in Down syndrome is reviewed in more detail
later in this article. In children with obesity, the prevalence of OSA is particularly
high, estimated at 21.5% to 39.5%, but is even higher in children who qualify as
having morbid obesity.67 In a study of adolescents undergoing evaluation for
bariatric surgery with qualifying criteria of a BMI of greater than 40 kg/m2 plus a
comorbidity, 73.5% of the patients had at least mild OSA and 55% had at least
moderate OSA.77
PATHOPHYSIOLOGY AND CLINICAL FEATURES. Many factors may interact to

produce OSA. Upper airway collapsibility results from a combination of mechanical
obstruction and reduced upper airway patency. Hypertrophy of the tonsils and
adenoids narrows the airway caliber, predisposing toward obstruction as the
pharyngeal dilator muscle tone lowers during sleep. Allergic rhinitis increases nasal
obstruction and upper airway resistance, likely contributing to the risk of OSA.78
Anatomical conditions that narrow the airway size, such as midface hypoplasia, a
high narrow arched palate, or micrognathia, or neurologic conditions that affect the
upper airway tone increase the likelihood of OSA. Obstructive respiratory events
can result in hypoxemia or hypercapnia, and frequently arousals occur as a
compensatory mechanism to restore airway tone, resulting in sleep fragmentation.
Symptoms of OSA include snoring, witnessed apneas, noisy breathing, labored
or paradoxical breathing, nocturnal sweating, headaches, restless sleep, dry mouth
on waking, enuresis, sleepiness, or fatigue. A majority of children with OSA have
Neurologic or Medical Conditions in Which Obstructive Sleep Apnea TABLE 11-5

Is Common
◆ Down syndrome62,63
◆ Neuromuscular disorders64
◆ Epilepsy65
◆ Cerebral palsy66
◆ Obesity67
◆ Chiari malformations68,69
◆ Headaches70
◆ Attention deficit hyperactivity disorder71
◆ Traumatic brain injury72–74
◆ Prader-Willi syndrome75
◆ Pierre Robin syndrome76

been reported to have symptoms of inattention.79 In addition, OSA has been shown
to adversely affect executive function, learning, memory, school performance, IQ,
behavior, and emotion regulation.80,81 OSA is linked to other health consequences
in children, including increased levels of inflammatory markers, blood pressure
elevation, endothelial dysfunction, and insulin sensitivity.82
DIAGNOSIS. Children with symptoms of OSA should have a polysomnogram

performed in a sleep laboratory with pediatric expertise or should be referred for a
clinical evaluation by a pediatric sleep specialist. The threshold for obtaining a
polysomnogram should be low because symptoms may be subtle in children.
According to the diagnostic criteria for pediatric OSA adapted from the ICSD-3,
OSA is typically diagnosed if the obstructive apnea-hypopnea index (AHI) is greater
than or equal to 1 event per hour, although alternative criteria specifying a pattern
of obstructive hypoventilation also exist.29 OSA is graded as mild if the AHI is 1.0
to 4.9 events per hour, moderate if the AHI is 5.0 to 9.9 events per hour, and severe
if the AHI is ≥10.0 events per hour. Apneas are scored if there is a ≥90% decrease in
airflow signal for ≥2 breath cycles in children and are classified as obstructive if
effort is preserved or central if there is a cessation of effort.83 Hypopneas are scored
CASE 11-1 A 5-year-old boy with autism and epilepsy presented to his pediatric
neurologist with an increased frequency of seizures and aggression for
5 months. In the same timeframe, he was also noted to have an increased
frequency of nocturnal waking and difficulty returning to sleep.
His examination was notable for poor eye contact and sparsity of
speech, although he answered questions appropriately. A sleep study
was obtained, showing an obstructive apnea-hypopnea index (AHI) of
10.5 events per hour, qualifying as severe obstructive sleep apnea (OSA).
He was referred to a pediatric otolaryngologist, who noted enlarged
tonsils (Mallampati class III airway, tonsils 2+ on the Brodsky grading
scale) and performed an adenotonsillectomy.86 Postsurgically, the
patient’s seizure frequency had lowered to baseline levels, and his
aggression improved, although he continued to have a prolonged sleep
latency.
A sleep study obtained 4 months after the adenotonsillectomy showed
an obstructive AHI of 3.5 events per hour of sleep, qualifying as mild OSA.
The use of a routine intranasal steroid spray was instituted as a treatment
for mild OSA, and his attention and sleep latency improved somewhat. He
began cognitive-behavioral therapy for insomnia and taking melatonin
3 mg 30 minutes before bedtime. Over the next 2 months, his sleep onset,
attention, and behavior improved.
COMMENT This case illustrates the concepts of OSA severity scoring being relatively
lower in children and the various effects of OSA in children with
neurodevelopmental disorders, including effects on seizure frequency
and behavior. Also, it shows the tendency for children with
neurodevelopmental disorders to have insomnia.
1046 AUGUST 2020

if there is a ≥30% decrease in airflow signal associated with cortical arousals, KEY POINTS
awakening, or a ≥3% oxygen desaturation and are classified as obstructive if
● The threshold for
snoring, increased effort, or other obstructive pattern is present.83 Central obtaining a polysomnogram
apneas can increase in the presence of OSA, but a central apnea index ≥5 should should be low because
prompt evaluation for a neurologic or cardiac disorder. Either adult or pediatric symptoms may be subtle in
scoring criteria may be applied to adolescents between 13 and 18 years of age, children.
because the evidence is insufficient to stipulate the optimal age at which adult
● The American Academy
scoring criteria should first be applied and maturation of airway dynamics does of Sleep Medicine advises
not relate directly with Tanner staging (sexual maturity rating).83,84 The American against the use of
Academy of Sleep Medicine advises against the use of ambulatory sleep studies in ambulatory sleep studies in
children because further research is required to assess whether factors likely to be children because further
research is required to
present in children, such as restless sleep, monitoring intolerance, frequency of assess whether factors
arousal-based respiratory events requiring EEG electrodes for detection, and sleep likely to be present in
fragmentation, may or may not reduce the validity of ambulatory sleep studies for children, such as restless
the pediatric population.85 sleep, monitoring
intolerance, frequency of
arousal-based respiratory
TREATMENT. The treatment choice depends on the severity of OSA, symptoms, events requiring EEG
and medical comorbidities. If adenotonsillar hypertrophy is present, electrodes for detection,
adenotonsillectomy is recommended as the first-line treatment (CASE 11-186), and and sleep fragmentation,
may or may not reduce the
continuous positive airway pressure may be considered if adenotonsillectomy validity of ambulatory sleep
is not performed or OSA persists following adenotonsillectomy.87 studies for the pediatric
Adenotonsillectomy may be reasonably performed in children with obesity, even population.
though they are predisposed to residual OSA, because they tend to have an
● A postoperative
enlargement of resectable pharyngeal lymphoid tissues.88 Estimates for residual
polysomnogram is advisable
OSA following adenotonsillectomy have varied widely, from 31% to 73% for OSA after adenotonsillectomy,
of any severity, and from 13% to 22% for moderate to severe OSA.87,89,90 A especially if presurgical
postoperative polysomnogram is advisable after adenotonsillectomy, especially if obstructive sleep apnea
presurgical OSA was moderate to severe or a child is overweight or has asthma.88 (OSA) was moderate to
severe.
CHAT (Childhood Adenotonsillectomy Trial) randomly assigned children 5 to
9 years old with OSA without significant oxygen desaturation (defined as less than
90% for 2% or more of the total sleep time) and not taking medications for
attention deficit hyperactivity disorder (ADHD) to adenotonsillectomy versus
watchful waiting and found that adenotonsillectomy improved behavior, quality
of life, and many OSA symptoms.91 In other studies, cognitive and behavioral
issues improved after adenotonsillectomy.92,93 Interestingly, in CHAT, nearly half
of the children randomly assigned to watchful waiting had a resolution of OSA
(46% versus 79% of the group that underwent adenotonsillectomy); this group
was limited to children without significant oxygen desaturations, and they were,
therefore, selected for milder OSA.91
Other treatments available for OSA in children include positive airway
pressure, either continuous or bilevel, which has been found to be highly effective
in treating childhood OSA, but adherence may sometimes be suboptimal.94 A
randomized trial of intranasal corticosteroids caused a significant reduction in the
AHI in children with mild OSA.95 Similarly, a randomized trial of oral montelukast
for 16 weeks effectively lowered the severity of OSA in children.96 Rapid maxillary
expansion, the use of an appliance to gradually expand the transverse diameter of
the hard palate, was effective in treating OSA for select children with maxillary
constriction and dental malocclusion.97 Additional surgical options exist to
address anatomical issues that may remain after adenotonsillectomy, including
lingual tonsillectomy, glossectomy, correction of a deviated nasal septum, and

correction of anatomical issues related to craniofacial abnormalities. A promising

surgical study is currently enrolling adolescents with Down syndrome for
hypoglossal nerve stimulator implantation; the pilot study results were favorable
with a 56% to 85% reduction in AHI, and 4 of 6 adolescents achieved an AHI of
fewer than 5 events per hour (signifying mild or no OSA).98 Myofunctional
therapy, a series of exercises that are intended to improve the strength and tone
of oral and oropharyngeal muscles to treat OSA, has shown favorable results in
small-scale pediatric studies and may help mild OSA.99 High-flow nasal cannula
therapy may also be a promising therapy for OSA, especially for young children
intolerant of positive airway pressure, but further study is needed.100 Children
should continue to be monitored for symptoms after OSA resolution, as
previously cured OSA can recur years later, perhaps due to other anatomical
issues that may remain. OSA can develop even when prior polysomnograms
were normal.101,102
Restless Legs Syndrome

RLS is generally described as nocturnally predominant leg discomfort that is
improved with movement. More specific criteria are listed below. Periodic limb
movement disorder is defined as an elevated PLM index and is associated
with daytime symptoms such as sleepiness but in which children do not meet
criteria for RLS.29 Finally, restless sleep disorder is a newly proposed entity, in
which restless sleep and daytime sleepiness are noted but children do not meet
the criteria for RLS or periodic limb movement disorder.103 Restless sleep
disorder is associated with iron deficiency, per the ferritin parameters described
below.103 This article focuses on RLS in children.
EPIDEMIOLOGY. An internet-based questionnaire study of 10,523 families in the

United States and United Kingdom found a prevalence of 1.9% for definite RLS in
8- to 11-year-olds and 2.0% in 12- to 17-year-olds.104 Parents retrospectively
reported the age of onset as younger than 5 years old in 15%, 5 to 7 years old in 63%,
and 8 years old or older in 22%.104 Elevated levels of periodic limb movements
TABLE 11-6 International Restless Legs Syndrome Study Group Definite Pediatric
Restless Legs Syndrome Diagnostic Criteriaa
◆ An urge to move the legs, usually accompanied by uncomfortable sensations in the legs
◆ The symptoms worsen during periods of rest
◆ The symptoms are at least partly relieved by movement
◆ The symptoms are worse in the evening or night than during the day
◆ In addition, there must be a description of leg discomfort in the child’s own words or at
least two supporting criteria:
a Sleep disturbance
b A biological parent or sibling has definitive restless legs syndrome
c Periodic limb movement index ≥5 on polysomnogram
a
Modified with permission from Picchietti DL, et al, Sleep Med.119 © 2013 The Authors.
1048 AUGUST 2020

(PLMs), defined in children as more than 5 PLMs per hour on polysomnogram,29 KEY POINTS
have been reported in 74% of children with RLS (normal is fewer than five per
● Restless sleep disorder is
hour for children).105 a newly proposed entity, in
which restless sleep and
PATHOPHYSIOLOGY AND CLINICAL FEATURES. RLS appears to have a strong daytime sleepiness are
genetic component, with more than 70% of children with RLS having at least one noted but children do not
meet the criteria for restless
parent with RLS in a large epidemiologic study.104 The causative genetic legs syndrome (RLS) or
mutations have not yet been identified, although familial inheritance patterns periodic limb movement
suggest an autosomal dominant inheritance with variable penetrance.106 Putative disorder. Restless sleep
mechanisms for RLS include dopaminergic dysfunction and iron deficiency. Iron disorder is associated with
iron deficiency.
is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine
synthesis. Patients with RLS have been shown to have low MRI-determined ● Putative mechanisms for
regional brain iron concentrations relative to controls.107 Brain iron levels RLS include dopaminergic
declined in the inactive phase but not the active phase in iron-deficient mice, dysfunction and iron
deficiency.
perhaps informative about the diurnal variation of RLS symptoms.108 Iron
deficiency is frequent in children with RLS, and children with iron deficiency ● Specific populations of
frequently have RLS; serum ferritin levels were <50 ng/mL in 83% of children children may have a high
with RLS, and correspondingly, 55% of children with serum levels <50 ng/mL rate of RLS or increased
exhibited RLS.109,110 Specific populations of children may have a high rate periodic limb movements,
including children taking
of RLS or increased PLMs, including children taking antidepressants, antidepressants,
antipsychotics, or antiepileptic medications or children predisposed to anemia or antipsychotics, or
uremia through chronic kidney disease, former preterm status, or autism.111–115 antiepileptic medications or
Other etiologic factors have not been fully elucidated but may include vitamin D children predisposed to
anemia or uremia through
deficiency. Vitamin D, or specifically the active metabolite 1α,25- chronic kidney disease,
dihydroxyvitamin D3, induces protein synthesis to reduce oxidative stress and former preterm status, or
protect dopaminergic neurons against glutamate-related cytotoxicity.116 More autism.
research is needed regarding the role of vitamin D deficiency in children with
● Vitamin D deficiency may
RLS, although a significant association was shown in a study of adults.117 Vitamin
be a particularly important
D deficiency may be a particularly important etiologic factor for RLS in children etiologic factor for RLS in
with skin tones with relatively higher concentrations of melanin.117 Childhood children with skin tones
RLS has been associated with negative impacts on mood, energy, and with relatively higher
attention.104 A study of 5374 children with RLS showed that RLS is highly concentrations of melanin.
comorbid with psychiatric disorders, with ADHD in 25%, mood disturbances in

29.1%, anxiety disorders in 11.5%, and behavioral disturbances in 10.9%.118
DIAGNOSIS. RLS is diagnosed clinically. Diagnostic criteria for definite pediatric

RLS are reviewed in TABLE 11-6,119 as developed by the International Restless Legs
Syndrome Study Group. In young children, RLS may be mistaken for growing
pains, which are common and often present nocturnally. Presumed growing pains
were reported in 80% of children later diagnosed with RLS compared with 63% of
children without RLS.119 Worsening with rest and amelioration with movement
are key distinguishing features that identify RLS. Diagnosis of RLS in young
children may be challenging, and the presenting complaint is often general sleep
disturbance or insomnia rather than RLS symptoms (CASE 11-2).109,119
TREATMENT. Iron supplementation is considered first-line therapy when iron

deficiency is found. Low serum ferritin levels are an early marker of iron
deficiency, although caution is advised with interpretation because ferritin is an
acute-phase reactant and may be elevated in the presence of inflammation. The
International Restless Legs Syndrome Study Group advised that oral iron therapy

be considered if serum ferritin is less than 75 ng/mL (or perhaps if less than
50 ng/mL in children).120 In one large-scale study, long-term oral iron
supplementation in children led to sustained improvements in RLS symptoms,
PLM index, and serum ferritin levels.121 In some patients, low absorption of oral
iron supplementation may limit its efficacy but perhaps can be improved by
coadministration with vitamin C and avoidance of dairy at the time of
administration. Constipation is a common side effect of oral iron
supplementation. Oral iron can be given at 3 mg to 6 mg elemental iron/kg/d,
with once-daily dosing preferred for better absorption. One study of IV iron in
children with RLS involved administration of iron sucrose to 16 children (mean
age, 6.6 years; range, 2 to 16 years) who had side effects or insufficient benefit
from oral iron therapy.122 No instances of anaphylaxis occurred, but two patients
experienced nausea and vomiting during the infusion. Eighty-three percent of
patients endorsed improved sleep, and the mean ferritin level rose significantly
from a pretreatment mean of 15.3 ng/mL to a postinfusion mean of 45.7 ng/mL.122
The International Restless Legs Syndrome Study Group task force proposes that
IV iron sucrose be considered in children with RLS if oral iron therapy produced
CASE 11-2 A 3-year-old girl without significant past medical history presented to her
pediatrician and then pediatric sleep specialist with insomnia. Her
parents stated that, for the past few months, she would take about 1 to
2 hours to fall asleep. She had a bedtime routine including bathing,
brushing her teeth, and reading a short book. After being put in her bed at
7:30 PM, she would repeatedly walk to her parents and request that they
play with her. A favorite activity involved participating in children’s races.
One parent noted that, a couple weeks ago, she started talking about
wanting to “run my race” and would run around the house every evening.
She did not verbalize any leg discomfort at bedtime. Once asleep, she
would tend to stay asleep until her wake time, although her parents noted
that her sleep seemed restless.
Her examination was normal, including her neurologic examination.
Her serum ferritin level was 20 ng/mL. Because of her symptoms and a
family history of restless legs syndrome (RLS) in her mother and maternal
grandmother, a diagnosis of likely RLS was made. A polysomnogram was
obtained, which was notable for an elevated periodic limb movement
index of 10 per hour of sleep. She was started on oral iron therapy but had
constipation, so she then received IV iron therapy. Her ferritin level
increased to 75 ng/mL. She and her parents also participated in
cognitive-behavioral therapy for insomnia. On her 6-month follow-up,
her insomnia and RLS symptoms had essentially resolved.
COMMENT This case illustrates that young children may have subtle presentations of
sleep issues and may reveal symptoms of sleep issues through actions
rather than words. Other sleep issues such as RLS may underlie insomnia,
even though insomnia may be the presenting symptom.
1050 AUGUST 2020

an inadequate response after 3 months, was not tolerated, or was not likely to be KEY POINTS
absorbed and if the ferritin level is ≤100 ng/mL.120
● Dopamine agonists should
Currently, no medication is FDA approved for RLS and periodic limb be used sparingly in
movement disorder in children. Beyond iron therapy, second-line treatment for children, because children
pediatric RLS is generally considered to be α2δ-1 ligands including gabapentin, appear to be even more
likely to experience
pregabalin, and gabapentin enacarbil, although efficacy has been established
augmentation than adults.
through adult rather than pediatric studies.123 The mechanism of the α2δ-1
ligands has been postulated to involve decreased excitatory neurotransmission ● Parasomnias seem to be
of glutamatergic neurons resulting in decreased arousability and lessening relatively common in
extremity hyperalgesia.124 Gabapentin could be initiated at 5 mg/kg/dose and children with autism.
titrated up to 15 mg/kg/dose based on efficacy, given about 1 hour before the ● Conditions that promote
typical start of RLS symptoms in the evening, or pregabalin at 2 mg/kg/dose to arousal or sleep drive can
6 mg/kg/dose if an alternative is indicated. If other options are needed, limited increase the likelihood of
data exist on the use of clonidine or clonazepam.123 Dopamine agonists are no parasomnias, such as OSA,
periodic limb movement
longer considered first-line therapy for adults with RLS because of their
disorder, sleep deprivation,
implication in a high rate of impulse control disorders and drug class–specific or sedating medications.
association with augmentation, which manifests as the eventual medication-
induced worsening of symptoms.123,125 Dopamine agonists should be used ● The frequency of
sparingly in children, because children seem to be even more likely to experience parasomnias can be
lessened by reducing sleep
augmentation than adults.123,125 fragmentation, such as by
treating OSA or periodic
Parasomnias limb movement disorder,
Parasomnias are abnormal behaviors in sleep and may occur in non-REM sleep and by obtaining adequate
sleep.
(eg, sleepwalking, confusional arousals, sleeptalking, or night terrors) or REM
sleep (eg, REM sleep behavior disorder). This section focuses on non-REM ● Safety measures should
parasomnias, which are the predominant parasomnia type in children. be discussed for patients
with parasomnias, such as
locking doors and windows,
EPIDEMIOLOGY. In a sampling of 1940 children in Quebec, night terrors peaked in
restricting access to
prevalence at 1.5 years of age (present in 34.4% of children of that age), and weapons or sharp objects,
sleepwalking peaked in prevalence at 10 years of age (present in 13.4% of placing gates on stairs, and
children of that age).126 About 22.5% of children have at least one sleepwalking possibly installing door
alarms to alert others in the
episode in their lifetime.126 By adulthood, most sleepwalking parasomnias
household.
resolve, with a large-scale meta-analysis showing an overall prevalence of
current sleepwalking of 1.5% in adults versus 5.0% in children.127 Parasomnias
seem to be relatively common in children with autism.128
PATHOPHYSIOLOGY AND CLINICAL FEATURES. Sleepwalking involves walking

and complex behaviors initiated during partial arousals from slow-wave sleep,
including disorientation and anterograde and retrograde memory impairment.
Sleep terrors are composed of partial arousals from slow-wave sleep and may
include screaming, manifestations of fear, crying, hyperventilation, and
tachycardia. Confusional arousals involve disorientation and agitation during an
arousal from sleep. Non-REM parasomnias tend to occur in slow-wave sleep,
when the arousal threshold is higher, and in the first third of the night, when
slow-wave sleep predominates. Daytime symptoms experienced by patients with
parasomnias include sleepiness, fatigue, insomnia, depressive and anxiety
symptoms, and altered quality of life.129 A high level of heritability exists in
sleepwalking, as 47.4% of children who sleepwalk have at least one parent who
sleepwalks.126 Linkage analysis in a large family of people who sleepwalk
identified a region of interest on chromosome 20, which cosegregated with the

sleepwalking phenotype and which contains the adenosine deaminase gene

(ADA).130 Inhibition of ADA activity is associated with increased slow-wave
activity and may confer a sleepwalking tendency.131 People who sleepwalk have
been shown to have more hypersynchronous delta activity than those who do not
sleepwalk, and it is increased even further following sleep deprivation.132
Conditions that promote arousal or sleep drive, such as OSA, periodic limb
movement disorder, sleep deprivation, or sedating medications can increase
the likelihood of parasomnias.133 In rare cases, a structural lesion may present
with an apparent parasomnia, as in a case of a dysembryoplastic neuroepithelial
tumor presenting in a 15-year-old with new-onset seizures in which the
symptomatology was sleepwalkinglike episodes.134 Suspicion for a structural lesion
could be raised if the parasomnialike spells have onset in an older child with no
parasomnia history, have a brief duration (less than 3 minutes), or are highly
stereotyped.134
DIAGNOSIS. According to the ICSD-3 criteria, parasomnias are behaviors that

involve incomplete awakening from sleep, inappropriate or lack of response to
others, and amnesia for the event.29 Parents can be advised to obtain videos of
the spells, which can be potentially helpful in differentiating among possible
diagnoses. In general, sleep-related hypermotor seizures (formerly known as
nocturnal frontal lobe seizures) are more stereotyped than parasomnias. The
Frontal Lobe Epilepsy and Parasomnias Scale may be useful in distinguishing
sleep-related hypermotor seizures from parasomnias, with the following features
being suggestive of a seizure diagnosis: duration of less than 2 minutes,
frequency of three or more episodes per night, occurrence within 30 minutes of
sleep onset, auras, dystonic posturing, a highly stereotyped appearance, and,
sometimes, clear recall. Features that are suggestive of a parasomnia diagnosis
include duration more than 10 minutes, walking more than a few feet,
performance of complex or directed behaviors, and a high degree of variability.
The absence of any feature cannot exclude a particular diagnosis.135
TREATMENT. The frequency of parasomnias can be lessened by reducing sleep

fragmentation, such as by treating OSA or periodic limb movement disorder,
and by obtaining adequate sleep. Safety measures should be discussed, such as
locking doors and windows, restricting access to weapons or sharp objects,
placing gates on stairs, and possibly installing door alarms to alert others in the
household. Clonazepam can be considered for frequent or potentially
dangerous parasomnias, with a response rate of about 74% as described in a
case series of 103 adult patients, and likely acts by suppressing arousals
and slow-wave sleep.136 If parasomnias are frequent or dangerous, a
polysomnogram can be considered to evaluate for OSA or periodic limb
movement disorder as contributing factors.
Narcolepsy
Narcolepsy is a disorder of hypersomnia, further classified as narcolepsy type 1
(with cataplexy) or narcolepsy type 2 (without cataplexy). Narcolepsy in the
pediatric age is most commonly a primary disorder but can also be secondary to
pathology involving the hypothalamus, whether from injury, tumor, or stroke.137
Idiopathic hypersomnia also manifests in children, with its primary features
being sleepiness, sleep inertia, and often prolonged sleep times; it is possibly
1052 AUGUST 2020

caused by endogenous modulators of GABAA, demonstrated in the CSF of adults KEY POINTS
with idiopathic hypersomnia.138 In children, it is unclear to what degree
● In children, it is unclear to
narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia are distinct what degree narcolepsy
entities. This section focuses on narcolepsy. type 1, narcolepsy type 2,
and idiopathic hypersomnia
EPIDEMIOLOGY. The prevalence varies worldwide; the lowest is in Israel (0.23 per are distinct entities.
100,000), and the highest is in Japan (160 per 100,000), likely influenced by the
● An autoimmune-induced
population frequency of the human leukocyte antigen (HLA)-DQB1*06:02 loss of orexin (hypocretin)
allele.139–141 The incidence of narcolepsy in the United States has been reported as neurons in the lateral
1.37 per 100,000 overall, highest in the second decade, followed by the third, hypothalamus is thought to
fourth, and first decades, with 5% of patients having symptoms before the age of be the primary cause of
narcolepsy, with resulting
5 years.137,142,143 Approximately 41% to 64% of patients with narcolepsy develop instability of sleep-wake
cataplexy.142,144 states.
PATHOPHYSIOLOGY AND CLINICAL FEATURES. An autoimmune-induced loss of ● The fundamental

complaint of patients with
orexin (hypocretin) neurons in the lateral hypothalamus is thought to be the narcolepsy is sleepiness that
primary cause of narcolepsy, with resulting instability of sleep-wake states. The exceeds expectations for a
primary function of orexin (hypocretin) is to activate orexin (hypocretin) neurons given sleep duration.
to maintain a long-consolidated wake phase, with projections to or from other
systems that regulate emotion, reward, energy homeostasis, and the autonomic
system.145 Supportive of the autoimmune theory, cytotoxic CD8+ T cells specific
for orexin (hypocretin) neurons have been discovered in both the serum and CSF
of some patients with narcolepsy.146 Other evidence for an autoimmune process
includes the HLA-DQB1*06:02 positivity that was demonstrated in approximately
85% to 95% of patients with classic cataplexy and 40% to 60% with mild, atypical,
or no cataplexy compared with 24% of controls, as well as the association of
narcolepsy with the influenza A (H1N1) virus and a monovalent adjuvanted
vaccine for the H1N1 virus.139,147,148 Less is known about the pathophysiology of
narcolepsy type 2. A predisposing genetic background is insufficient for the
development of narcolepsy because narcolepsy is far less prevalent than the
HLA-DQB1*06:02 haplotype, present in 12% to 38% of the population.147
The fundamental complaint of patients with narcolepsy is sleepiness that
exceeds expectations for a given sleep duration. Patients can also have
hypnagogic or hypnopompic hallucinations or sleep paralysis. Cataplexy involves
the sudden loss of muscle tone, either falling or loss of tone in the extremities,
face, trunk, or neck without impairment of consciousness, in response to
emotion. Cataplexy is usually brief, lasting seconds to minutes, but can be more
prolonged if episodes cluster. Particularly in children, cataplexy can be atypical,
with mouth opening, tongue protrusion, and stuttering speech, sometimes with
such frequent clustering that episodes present as apparent facial weakness and
sometimes lack a clear emotional trigger.149 Cataplexy most commonly presents
at the onset of sleepiness but could manifest 1 to 2 years or up to 12 years later as
described in a case series of children with narcolepsy.149 Occasionally, cataplexy
can be the presenting symptom of narcolepsy in children.143 Active motor
phenomena with a degree of emotional triggering have been described soon after
narcolepsy onset in children, including eyebrow-raising, perioral and tongue
movements, facial grimacing, body swaying, and stereotyped motor behavior,
sometimes in association with high antistreptolysin O titers.150 The mechanism of
cataplexy was further elucidated by a functional MRI (fMRI) study in children
that revealed concurrent blood-oxygenation-level–dependent (BOLD) signal

increases in the amygdala, nucleus accumbens, and ventromedial prefrontal

cortex, centers that process emotions and reward.151
Other associated features of narcolepsy in childhood may relate to the
projections of the orexin (hypocretin) system. Multiple comorbidities have been
associated with narcolepsy, including anxiety, depression, thyroid disorders,
hypertension, OSA, peripheral neuropathy, headaches, and glucose intolerance,
many of which were present both at diagnosis and long-term follow-up (mean,
9.9 years of follow-up; SD, 7.27 years).144 Also, a high rate of significant weight
gain has been described at the time of narcolepsy diagnosis, perhaps related to an
effect of orexin (hypocretin) deficiency on appetite or metabolism or decreased
caloric expenditure.144 Patients with narcolepsy frequently endorse symptoms of
dysautonomia, including photophobia, constipation, orthostasis, and insufficient
thermoregulation.152 REM sleep behavior disorder (dream enactment behaviors
with REM sleep without atonia demonstrated on polysomnogram) is common
in children with narcolepsy type 1, probably a reflection of sleep state
instability.153 In addition, children with narcolepsy often exhibit poor attention,
academic underperformance, memory deficits, social isolation, and emotional
lability.154
DIAGNOSIS. The first step in establishing a diagnosis of narcolepsy is recognizing

a concerning level of hypersomnia and referring patients to a pediatric sleep
specialist experienced in treating patients with narcolepsy. Hypersomnia is a
common complaint among children, endorsed by 11.7% of the adolescents who
report adequate sleep duration.155 Historical details that identify concerning
hypersomnia in children include falling asleep unintentionally, resuming
napping, taking multiple daily naps, or struggling to complete homework despite
adequate sleep duration. However, sometimes symptoms can be subtle early in
presentation or in the presentation of a young child, with sleepiness being less
prominent than expected or manifesting as irritability or hyperactivity. The
challenges of identifying which children should be referred for further
evaluation may result in a diagnostic delay. In a large survey of patients with
narcolepsy, diagnosis took longer than 5 years in 50% of patients, with a pediatric
onset of symptoms being the strongest predictor of a prolonged time to
diagnosis.156
Diagnosing narcolepsy in children can sometimes be challenging and confounded
by testing limitations. To evaluate for narcolepsy, an overnight polysomnogram
followed by a multiple sleep latency test (MSLT) is performed. The sleep-onset time
and presence of REM sleep are measured on five 20-minute nap opportunities,
spaced 2 hours apart. A mean sleep latency of 8 minutes or less and with at least two
naps containing REM periods on the MSLT (referred to as sleep-onset REM period)
can confirm a narcolepsy diagnosis when the clinical picture is also supportive.29
Alternatively, REM sleep occurring within 15 minutes of sleep onset on the
preceding nocturnal polysomnogram can replace a sleep-onset REM period on one
nap to confirm the diagnosis.29 Adequate sleep must be obtained prior to the study
as verified by sleep logs or actigraphy; otherwise, an MSLT may be unreliable.
REM-suppressing medications or soporific medications should be weaned if doing
so can be safely tolerated. Although mean sleep latencies have been shown to vary
by Tanner stage, no established adjustments exist for abnormal MSLT criteria based
on age or Tanner stage so the adult-derived criteria continue to be used.157 In a study
of patients with narcolepsy type 1 confirmed by low CSF orexin (hypocretin), 7%
1054 AUGUST 2020

had a false-negative MSLT result.158 The false-positive rate for narcolepsy and the KEY POINTS
false-negative rate for children with narcolepsy type 2 are not well defined.
● Particularly in children,
Consideration should be given to repeating the MSLT if false-negative or cataplexy can be atypical,
false-positive results are suspected.159 Ongoing work is being performed to refine with mouth opening, tongue
MSLT criteria for pediatric narcolepsy, such as a suggestion that sleep-onset protrusion, and stuttering
REM periods of ≥2 or a mean sleep latency of ≤8.2 minutes on the MSLT reliably speech, sometimes with
such frequent clustering
identifies narcolepsy, as validated in a sample of children aged 3 to 17 years with
that episodes present as
low orexin (hypocretin) levels or cataplexy.160 Age did not significantly affect apparent facial weakness,
the findings.160 and sometimes lacking a
Alternative diagnostic criteria for narcolepsy type 1 replace the MSLT findings clear emotional trigger.
with a CSF orexin (hypocretin)-1 concentration of 110 pg/mL or less.29 CSF
● Active motor phenomena
orexin (hypocretin) levels are low (<110 pg/mL) in 87% to 96% of patients with with a degree of emotional
narcolepsy type 1 and 24% of patients with narcolepsy type 2.159,161 African triggering have been
Americans are relatively likely to have a low orexin (hypocretin) level, even in described soon after
the absence of cataplexy.162 Orexin (hypocretin) assessment may be particularly narcolepsy onset in
children, including
helpful in children younger than 5 years old for whom the MSLT is less eyebrow-raising, perioral
interpretable, when REM-suppressing medications cannot be weaned, or when and tongue movements,
the patient is positive for haplotype HLA-DQB1*06:02 as are most patients with facial grimacing, body
low orexin (hypocretin) levels.159,161 CSF orexin (hypocretin) testing is now swaying, and stereotyped
motor behavior.
available clinically (mayocliniclabs.com).
● Multiple comorbidities
TREATMENT. Children with narcolepsy require adequate sleep and may benefit have been associated with
from scheduled naps. Documentation should be provided supporting narcolepsy, including
anxiety, depression, thyroid
accommodations at school. Although not FDA approved because of rare
disorders, hypertension,
reports of Stevens-Johnson syndrome in a few children, modafinil and OSA, peripheral neuropathy,
armodafinil may be effective and generally well-tolerated treatments for headaches, and glucose
narcolepsy in children.163 Also, amphetamine and methylphenidate intolerance.
derivatives can effectively reduce sleepiness in many children with
● The first step in
narcolepsy. The effects of these stimulants and wakefulness-promoting establishing a diagnosis of
medications are complex and involve dopamine reuptake inhibition and may narcolepsy is recognizing a
secondarily improve cataplexy.164 Other options address both sleepiness and concerning level of
cataplexy more directly. Sodium oxybate activates GABAB receptors and is hypersomnia and referring
patients to a pediatric sleep
thought to induce slow-wave sleep and REM sleep, reducing sleep specialist experienced in
fragmentation.164 In a multicenter trial involving 7- to 16-year-old children treating patients with
with narcolepsy, sodium oxybate was more effective than placebo in reducing narcolepsy.
sleepiness and cataplexy.165 The reported side effects and safety profiles were
● Historical details that
similar to what was described in adults and included enuresis, vomiting,
identify concerning
headache, decreased weight, decreased appetite, dizziness, and two adverse hypersomnia in children
events involving severe acute psychosis and suicidal ideation.165 Sodium include falling asleep
oxybate may confer an increased risk of both central sleep apnea and unintentionally, resuming
OSA.165,166 Sodium oxybate became FDA approved in October 2018 for an napping, taking multiple
daily naps, or struggling to
expanded indication of treatment of sleepiness or cataplexy in patients 7 years complete homework
old or older who have narcolepsy type 1 or narcolepsy type 2. Baclofen is also a despite adequate sleep
GABAB agonist with limited data supporting improvement of sleepiness in duration.
children with narcolepsy who did not tolerate or had little benefit from other
● Diagnosing narcolepsy in
therapies.167 Other options for treatment of cataplexy include selective children can sometimes be
serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake challenging and confounded
inhibitors (SNRIs), and tricyclic antidepressants. Finally, pediatric experience by testing limitations.
is currently lacking with the agents recently approved by the FDA for use in
adults, the selective dopamine and norepinephrine reuptake inhibitor

solriamfetol and the histamine receptor inverse agonist pitolisant; a trial

of pitolisant in children with narcolepsy is ongoing in Europe.168
Immunomodulatory therapies have been studied, and the results have been
conflicting, including IV immunoglobulins, plasmapheresis, corticosteroids,
and the lymphocyte-depleting monoclonal antibody alemtuzumab, suggesting
that further research is indicated.169
KLEINE-LEVIN SYNDROME
Kleine-Levin syndrome is a disorder of periodic hypersomnia and is illustrated in
CASE 11-3. The periods of hypersomnia and prolonged sleep may last 2 days to
5 weeks, occurring at least once every 18 months, and are associated with
cognitive dysfunction, anorexia or hyperphagia, disinhibited behavior, and
normal functioning in between episodes.29 The most common symptomatology
of Kleine-Levin syndrome encompasses the tetrad of hypersomnia, confusion,
apathy, and derealization.170 Menstrual-associated hypersomnia is considered a
variant of Kleine-Levin syndrome.29 Kleine-Levin syndrome has an estimated
prevalence of approximately 2.3 cases in 1 million, with onset in adolescence
being most common.170 Hypoperfusion of the parietotemporal junction has been
demonstrated on fMRI during episodes of hypersomnia, and the EEG may be
normal or show generalized slowing.171,172 Autopsy findings in a few patients
have shown inflammatory infiltrates in the midbrain, hypothalamus, or
CASE 11-3 A 16-year-old girl with a history of headaches and postural orthostatic
tachycardia syndrome presented to her pediatric neurologist with a
headache lasting 4 weeks and sleepiness. For the past 2 years, she had
episodes of headaches and sleepiness, lasting 4 to 12 weeks each,
occurring once per year in the winter. Her headaches were described as
pounding, bifrontal, and accompanied by photophobia. Aside from these
episodes, her headaches were otherwise mild. During the episodes of
prolonged headaches, she slept for 18 to 20 hours per day and was mildly
irritable when attempts were made to wake her. She had reduced food
intake but did drink sufficient liquids. She conversed little and seemed
apathetic. Completing schoolwork was difficult during the episodes
because she found it hard to concentrate, so she took a leave from
school; however, she performed well academically between the
episodes. She had no sleepiness between the episodes.
Her physical and neurologic examinations were normal. An EEG
showed diffuse slowing but no epileptiform discharges. A brain MRI was
normal. She was referred to a pediatric sleep specialist, and a diagnosis
of Kleine-Levin syndrome was made based on clinical assessment. When
she next entered an episode of hypersomnia, IV steroids were given, and
the episode resolved within 1 week.
COMMENT This case illustrates a presentation of Kleine-Levin syndrome. It is

important to have a high index of suspicion and understand the variety of
possible presentations.
1056 AUGUST 2020

thalamus.173,174 There is no definitive test for Kleine-Levin syndrome. The
natural history suggests eventual resolution in approximately 85% of cases, but
15% have a persistent disorder after more than 20 years of follow-up.175
Therapeutic reports have been inconsistent, but among the most promising
therapies are lithium as a preventative agent or amantadine or IV steroids to
shorten an episode.170,172,175
NEUROLOGIC AND PSYCHIATRIC DISORDERS AND EFFECTS ON SLEEP

Sleep issues are associated with many neurologic conditions. TABLE 11-7 provides
a list of common neurologic conditions and the described sleep issues, although
Some Common Neurologic Conditions Associated With Sleep Issues TABLE 11-7
Neurologic Condition Associated Sleep Issues Additional Comments
Headaches70,176 Insomnia, obstructive sleep apnea (OSA), Children should be screened for comorbid
sleepiness, parasomnias, restless legs sleep conditions, and sleep hygiene should
syndrome (RLS), bruxism be discussed
Attention deficit hyperactivity RLS, insomnia, OSA, sleep deprivation, High prevalence of RLS in children with
disorder71,177,178 circadian rhythm disorders attention deficit hyperactivity disorder
Epilepsy65,179,180 Insomnia, OSA, sleep fragmentation Vagal nerve stimulators associated with
OSA; more research on cannabidiol oil
needed; association of sudden unexpected
death in epilepsy and OSA
Traumatic brain Insomnia, increased awakenings, nightmares, Melatonin and light therapy may help sleep
injury72–74,181,182 fatigue, central sleep apnea and OSA, and recovery from traumatic brain injury
circadian rhythm disorders, hypersomnia
with low orexin (hypocretin) levels that may
improve over time
Chiari malformations68,69 OSA, central sleep apnea Some improvement may be noted after
decompression
Prematurity183–186 Immature sleep patterns, increased stage More organized sleep-wake transitions at
shifts, sleep-disordered breathing term-equivalent, more rapid eye movement
(REM) sleep, and more sustained sleep
associated with better cognitive
development
The developmental impact of synchronizing
hands-on care and sleep cycles should be
researched; arousals, awakenings, apneas,
and oxygen desaturations were more likely
with care during active sleep
Neuromuscular Nocturnal hypoventilation, OSA, central American Academy of Sleep Medicine

disorders64,83,187 sleep apnea, arousals, sleep fragmentation criteria for sleep-related hypoventilation:
>25% of total sleep time with PCO2 >50 mm Hg
Pediatric patients with neuromuscular
disorders can develop nocturnal
hypoventilation in the absence of clinical
symptoms or significant nocturnal oxygen
desaturation

sleep issues are associated with so many neurologic and psychiatric disorders that
the list is not exhaustive.
Sleep in Neurodevelopmental Disorders

Sleep issues are common in children with neurodevelopmental disorders because
of a variety of contributing factors as detailed below and in TABLE 11-8. Sleep in
children with select neurodevelopmental disorders is highlighted.
AUTISM. Sleep problems present in 50% to 80% of children with autism and
correlate with worsening of inattention, hyperactivity, and repetitive
behaviors.188 Sleep problems described in children with autism include
insomnia, circadian rhythm disorders, sleep-disordered breathing,
sleep-related movement disorders, and parasomnias.128 In children with
autism, RLS may be frequent although difficult to diagnose definitively in this
population. High rates of iron deficiency and vitamin D deficiency related to
restricted food intake, as well as the antidopaminergic effects of the
commonly prescribed medication risperidone, likely contribute to RLS.114,115
More research is needed to establish adequate sleep duration, which is often
short in children with autism.128
Medical or behavioral issues intrinsic to autism can compound sleep issues,
such as epilepsy or gastrointestinal issues, medication side effects, bedtime
resistance, or difficulty with self-soothing. Abnormalities in GABA-ergic and
serotonergic signaling have been found in both autism and insomnia and could
be causative factors for sleep problems in autism.128 Dysfunctional melatonin
synthesis resulting in lower melatonin levels has been demonstrated in some
individuals with autism, but not consistently, likely indicating genetic
heterogeneity.128 Low sleep spindle density has been described in adolescents
with autism and is perhaps a marker of lower plasticity because sleep spindles
have been associated with neuroplasticity.189
Regarding the treatment of insomnia in autism, behavioral therapy should be
considered. Melatonin has been shown to be effective and may act in children
with autism by improving melatonin deficiency and/or by reducing anxiety,
pain, and gastrointestinal dysfunction.41 In particular, prolonged-release
melatonin has been shown to shorten sleep latency and increase total sleep time
in children with autism.39 Guidelines for screening, diagnosis, and treatment of
TABLE 11-8 Contributing Factors for Sleep Issues in Children With

Neurodevelopmental Disorders
◆ Comorbid medical conditions

◆ Medication side effects
◆ Behaviors such as bedtime resistance or difficulty with self-soothing
◆ Abnormal melatonin synthesis
◆ Anatomical factors or abnormal muscle tone affecting the upper airway
◆ Abnormal circadian or neuronal signaling affecting sleep
◆ Structural brain lesions or loss of structural integrity in areas regulating sleep
1058 AUGUST 2020

insomnia in children with autism have been developed by committees of the KEY POINTS
Autism Treatment Network and the American Academy of Neurology,
● The most common
supporting cognitive-behavioral therapy and the use of melatonin.190,191 symptomatology of
Gabapentin, ramelteon, doxepin, mirtazapine, and clonidine have also been Kleine-Levin syndrome
shown to have a reasonable effect for the treatment of insomnia in children with encompasses the tetrad of
autism.49,50,52–54 The Autism Treatment Network has partnered with Autism hypersomnia, confusion,
apathy, and derealization.
Speaks to offer an educational toolkit for parents of children with autism
(autismspeaks.org/tool-kit/atnair-p-strategies-improve-sleep-children-autism). ● Menstrual-associated
hypersomnia is considered a
OTHER NEURODEVELOPMENTAL DISORDERS. Sleep issues in neurodevelopmental variant of Kleine-Levin
disorders may arise, in part, from anatomical factors or abnormal muscle tone syndrome.
that affect the upper airway. Children with Down syndrome have a high ● Medical or behavioral
prevalence of OSA, likely because of underlying anatomical factors such as issues intrinsic to autism can
hypotonia, macroglossia, glossoptosis, midface hypoplasia, and enlargement of the compound sleep issues,
adenoid or lingual tonsils.62 Also evident is a propensity toward hypoventilation such as epilepsy or
gastrointestinal issues,
and an increased prevalence of central sleep apnea, especially at young ages.62 medication side effects,
When children with Down syndrome were studied indiscriminately with bedtime resistance, or
polysomnograms, 66% had OSA and 52% with OSA had severe OSA, and 54% difficulty with self-soothing.
without noted snoring or witnessed apneas had OSA.63 Although OSA usually
improves significantly after adenotonsillectomy in patients with Down syndrome,
residual OSA is frequent and likely due to multiple sites of obstruction, and
treatment with positive airway pressure or multilevel surgery may be indicated.
Abnormal circadian signaling may contribute to sleep disruption in other
neurodevelopmental disorders. Smith-Magenis syndrome is caused by interstitial
deletions in chromosome 17p11.2, including the circadian regulator gene retinoic
acid–induced 1 gene (RAI1), impairing light-activated daytime melatonin
suppression with resulting high diurnal levels and low nocturnal levels of
melatonin.192,193 Children with Smith-Magenis syndrome commonly exhibit
early sleep onset, frequent awakenings, early wake times, and daytime sleep
attacks.194 A treatment approach for stabilization of sleep-wake patterns in
Smith-Magenis syndrome is the administration of evening melatonin to
supplement low endogenous nocturnal melatonin levels and a morning
beta-blocker to suppress abnormal daytime melatonin secretion.194 Angelman
syndrome is most commonly caused by deletions of the maternal copy of
chromosome 15 in the region of 15q11-q13, including the UBE3A gene. Reduction
in UBE3A modulates expression of the clock gene BMAL1 to lengthen and
delay the circadian phase, presumably inducing the short sleep duration and
increased sleep-onset latency frequently observed with Angelman syndrome.195
Children with neurofibromatosis type 1 (NF1) were found to have increased
rates of insomnia and sleep-wake transitions.196 Drosophila NF1 knockout
mutants had increased frequencies of arrhythmic light-dark cycles and
locomotor activity, indicating that NF1 mutations may produce circadian
rhythm disturbances.197
Brain lesions or injury can provoke sleep problems in children with
neurodevelopmental disorders. More than 40% of children with cerebral palsy
were found to have sleep issues, especially children with comorbid epilepsy or
with more limited motor function.66 Neurodegenerative disorders, many of which
can have a childhood onset including those discussed here, can cause a loss of
structural integrity to areas of the brain regulating sleep. Niemann-Pick disease
type C is associated with cataplexy in 5% to 30% of patients, not necessarily

accompanied by low orexin (hypocretin) levels or sleepiness and likely due to lipid
deposition-mediated loss of neuronal stimulation of the locus coeruleous.198,199
Patients with Wolfram syndrome were noted to have a high rate of OSA, likely
partly because of the syndrome’s effect on the cerebellum and brainstem, which
function in coordinating respiration.200–202 The nature of sleep issues associated
with neurodegenerative disorders can evolve. For example, in Rett syndrome,
sleep problems occurred in more than 80% of individuals, with laughing and
screaming during sleep being more common in younger individuals, but frequent
waking, OSA, and central sleep apnea were noted independently of age.203,204
An intrinsic complexity underlies the sleep issues observed in children with
neurodevelopmental issues, and multiple molecular mechanisms and sequelae
may act in synchronicity to affect sleep. In addition to the circadian rhythm
disturbances found in Angelman syndrome, dysregulation of the thalamic pacing
of GABA-ergic reticular neurons occurs, likely driven by the UBE3A deficiency
described earlier.205 This thalamocortical dysfunction putatively magnifies the
sleep architecture abnormalities noted in Angelman syndrome, such as reduced
sleep spindles and K complexes, reduced REM, and an increased percentage of
slow-wave sleep.206 Prader-Willi syndrome is caused by a loss of paternal gene
expression from chromosome 15q11.2-q13, and individuals with Prader-Willi
syndrome are highly predisposed to sleep issues because of a multiplicity of
factors including micrognathia, narrowing of the upper airway, obesity,
hypotonia, chemoreceptor insensitivity, and growth hormone therapy–related
acceleration of lymphoid tissue growth.75 Children with Prader-Willi syndrome
TABLE 11-9 Indications for Referral to Pediatric Sleep Clinic or for Obtaining a
Sleep Study
Potential Referral to Pediatric Sleep Clinic

◆ Significant insomnia, especially if not improving with behavioral measures
◆ Obstructive sleep apnea (OSA) or symptoms of OSA
◆ Suspected restless legs syndrome
◆ Parasomnias
◆ Significant sleepiness
◆ Disorders of hypersomnia
◆ Any sleep issue requiring guidance
Potential Referral for a Sleep Study
◆ Symptoms of OSA: snoring, witnessed apneas, noisy breathing, labored or paradoxical
breathing, nocturnal sweating, headaches, restless sleep, dry mouth on waking, enuresis,
sleepiness, fatigue, inattention
◆ Restless sleep or frequent extremity movements in sleep in association with impaired
functioning
◆ Neurologic condition not improving, such as headaches, seizures, or inattention
◆ Evaluation of efficacy of adenotonsillectomy or other treatment for OSA
◆ Comorbid condition highly associated with OSA, such as obesity, craniofacial abnormalities,
Down syndrome, other conditions
1060 AUGUST 2020

exhibit predominantly central sleep apnea in infancy and OSA in older KEY POINT
childhood.75 Also, hypothalamic dysfunction may act synergistically with other
● An intrinsic complexity
factors to produce a characteristic hypersomnia.75 underlies the sleep issues
observed in children with
neurodevelopmental issues,
CONCLUSION and multiple molecular
mechanisms and sequelae
Sleep is a critical process in childhood, and disruptions in sleep have important
may act in synchrony to
implications for health and development. Sleep issues associated with childhood affect sleep.
include insufficient sleep, poor sleep hygiene, insomnia, OSA, RLS, parasomnias,
and narcolepsy. Children with neurodevelopmental disorders have a high rate of
sleep issues and are particularly sensitive to their effects. Polysomnograms
should be obtained for a wide range of indications, as reviewed in TABLE 11-9.
Treatment of sleep issues is fundamentally important, and referral to a pediatric
sleep specialist may be considered for any sleep issues, whether complex or
simple (TABLE 11-9). Evaluation by a pediatric sleep specialist is encouraged
when guidance is sought for any issue or when a child has significant sleepiness,
intractable insomnia, problematic or frequent parasomnias, restless leg
symptoms, frequent awakenings during sleep, or persistent or severe OSA.
USEFUL WEBSITES
AUTISM SPEAKS BETTER NIGHTS, BETTER DAYS
This educational toolkit provides parents with This website provides online enrollment and study
strategies to improve sleep in their children participation for parents of children who have
affected by autism. sleeping problems.
autismspeaks.org/tool-kit/atnair-p-strategies- betternightsbetterdays.ca
improve-sleep-children-autism
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Sleep-Wake Disorders in Childhood

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SUMMARY: Children’s sleep is discussed in this article, including normal sleep

1034 AUGUST 2020

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Changes in Sleep Architecture in Childhood TABLE 11-1

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Short sleep duration in childhood is associated with an increased likelihood of

Age Recommended Sleep Duration per 24 Hours

4–12 months 12–16 hours (including naps)

1–2 years 11–14 hours (including naps)

3–5 years 10–13 hours (including naps)

6–12 years 9–12 hours

13–18 years 8–10 hours

1036 AUGUST 2020

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EPIDEMIOLOGY. Prevalence ranges have been reported at approximately 20% in a

PATHOPHYSIOLOGY AND CLINICAL FEATURES. Insomnia is influenced by both

DIAGNOSIS. Diagnostic criteria of the International Classification of Sleep

1038 AUGUST 2020

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● Sleep disorders such as

cannot reliably distinguish sleep from stationary wakefulness and demonstrates a

TREATMENT. Treatments for insomnia in children include cognitive-behavioral

COGNITIVE-BEHAVIORAL THERAPY AND SLEEP HYGIENE. The mainstay of treating

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● No medications for the

SLEEP-PROMOTING MEDICATIONS. If insomnia is significant, referral for an

1040 AUGUST 2020

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Obstructive Sleep Apnea

◆ Shorter-acting medications for sleep-onset insomnia

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TABLE 11-4 Medications Used to Treat Insomnia in Children

Classification and Notable Side

Melatonin receptor agonists49

Ramelteon 8 mg at bedtime Dizziness, Insomnia, consider May be effective in some children

Tasimelteon 20 mg at bedtime Elevated Non–24-hour May be effective in some children

CONTINUED ON PAGE 1043

1042 AUGUST 2020

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Classification and Notable Side

Non–benzodiazepine receptor agonist51

Short-acting: 2.5 mg to 10 mg at Hyperactivity in Immediate-release: Advise against alcohol use; better

Long-acting: 6.25 mg to 12.5 mg Extended-release:

Gabapentin 5 mg/kg/d to Sedation, weight Sleep-onset or Consider in young children (due to

CONTINUED ON PAGE 1044

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CONTINUED FROM PAGE 1043

Classification and Notable Side

Mirtazapine54,55 7.5 mg to 30 mg at Sleepiness, Insomnia, Increased noradrenergic

Trazodone56 25 mg to 100 mg at QT interval Insomnia comorbid A genetic polymorphism exists

Orexin (hypocretin)-receptor antagonist57

Suvorexant 5 mg to 20 mg at Could exacerbate Persistent severe Should be weaned rather than

1044 AUGUST 2020

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PATHOPHYSIOLOGY AND CLINICAL FEATURES. Many factors may interact to

Neurologic or Medical Conditions in Which Obstructive Sleep Apnea TABLE 11-5

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DIAGNOSIS. Children with symptoms of OSA should have a polysomnogram

1046 AUGUST 2020

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