22 Sleep and Circadian Rhythms

Toluwalase A. Ajayi, Eric S. Zhou, and Valerie E. Rogers

Introduction

Sleep is a biological necessity, a time of healing, mending, and restoration. Lack of restful sleep can affect daytime functioning, increase pain, promote mood disturbances, alter immune function, negatively impact developmental outcomes in children, and contribute to cardiovascular and metabolic disease.^1,2,3 Healthy, or robust, circadian rhythms, likewise, are increasingly recognized as important to good health.⁴

Sleep and circadian rhythm disturbances are common among children and adolescents, particularly among those with life-threatening illnesses. This chapter reviews normal sleep and circadian rhythms, and common sleep and circadian disturbances in children. It further discusses current evidence for sleep and circadian disturbances in children with common life-threatening illnesses. Finally, assessment and interdisciplinary management strategies for sleep and circadian rhythm disorders are discussed.

Sleep and Circadian Rhythm Problems in Children

Sleep is regulated by two independent processes. The first is the homeostatic sleep drive, wherein the longer one is awake, the stronger the drive to sleep becomes. Sleep needs vary by developmental age group, and daily sleep recommendations have been established (Table 22.1).⁵ The second is the circadian timing system, which regulates the timing of diurnal physiological processes such as core body temperature, blood pressure, and hormone levels. Circadian rhythms are generated by clock genes controlled by the central circadian pacemaker in the hypothalamus. In contrast to the homeostatic sleep drive, the circadian timing system operates independently of time spent awake but can be modified by environmental cues (zeitgebers) such as light and noise exposure, physical and social activities, and food intake, with light being the most important.⁶

Sleep problems are common, reported in 20–50% of healthy children.⁷ The most common pediatric sleep disorder is insomnia, affecting nearly one-third of children. It is characterized by persistent problems with sleep initiation, maintenance, or quality despite age-appropriate opportunity for sleep and that result in daytime impairment.⁸ Behavioral insomnias are most common in children. They result from inadequate sleep training or caregiver difficulties with setting limits around sleep in younger children or from poor sleep hygiene habits such as excessive caffeine intake and use of electronic devices near bedtime in older children.⁹ Insomnia can also co-occur with medical or psychiatric disorders due to sleep-disrupting symptoms such as pain, mood disorders or depression, or sleep-related breathing disorders (SRBDs).^10,11,12

Parasomnias are undesirable events that occur when falling asleep or awakening from sleep (disorders of arousal) or during sleep. They involve bizarre sleep-related movements, behaviors and emotions.⁸ Parasomnias affect about 13% of children and are typically outgrown by adolescence.¹³ Although generally benign, they can result in injuries and further disrupted sleep, and their symptoms overlap those of nocturnal frontal lobe epilepsy.¹³ Disorders of arousal are the most common parasomnias and include confusional arousals, sleep walking, and sleep terrors. Sleep terrors, the most striking of these, are characterized by sudden onset of screaming, intense fear, and autonomic activation (e.g., increased heart and respiratory rates). They are distinguished from nightmares in that they occur earlier in the sleep cycle, and these children exhibit significant motor activity, are difficult to awaken during the terror, and have little memory of it.¹⁴

SRBDs range from primary snoring (snoring without significant upper airway obstruction), to obstructive sleep apnea (OSA) or central sleep apnea. OSA involves intermittent partial (hypopneas) or complete (apneas) cessation of airflow during sleep despite continued respiratory effort due to collapse of the upper airway on inspiration. An obstructive apnea-hypopnea index (AHI) of 1 or more per hour is diagnostic of pediatric OSA.⁸ Central nervous system (CNS)-mediated intermittent apneas without accompanying respiratory effort reflect central apneas and are diagnostic of central sleep apnea when the central AHI is 5 or more per hour.⁸ Snoring occurs in about 12% of children¹⁵ and OSA and central sleep apnea in about 5% each.^16,17 Both types of sleep apnea result in intermittent oxygen desaturations and sleep fragmentation.

Restless legs syndrome (RLS), or Willis-Ekbom disease, occurs in 2–4% of children. It is characterized by a strong urge to move affected limbs, accompanied by uncomfortable sensations in the limbs. Symptoms start or worsen during rest, are relieved with movement, and occur predominantly in the evening or at night.⁸ In children, sleep disruption is commonly the presenting complaint.¹⁸ Symptoms can occur in association with low iron stores, but are also seen in children with neurologically based disorders such as attention deficit-hyperactivity disorder and depression. The presence of periodic limb movements in sleep (PLMS)—episodes of repetitive, stereotyped movements of the limbs—are supportive of an RLS diagnosis but require polysomnography with limb electromyography for diagnosis.

Narcolepsy is a rare disorder characterized by an irresistible need to sleep or lapses into sleep during the day. Narcolepsy results from genetic and environmental factors,¹⁹ but tumors, surgery, or radiation of the brain can also play a role. Narcolepsy is the most common cause of excessive daytime sleepiness (EDS), but other symptoms may be present such as disturbed sleep, hypnagogic hallucinations (vivid dreams occurring during sleep–wake transitions), and sleep paralysis (temporary inability to move at sleep–wake transitions). The presence of cataplexy (brief, sudden loss of muscle tone while maintaining consciousness) is the key feature distinguishing type 1 from type 2 narcolepsy.⁸

The most common circadian rhythm disorder in pediatrics is delayed sleep–wake phase disorder, with a prevalence of 3% in adolescents.²⁰ Hormonal changes and physiological lengthening of the circadian period during adolescence, as well as external factors such as academic and social demands, can delay bedtime and contribute to its development. Adolescents are typically unable to fall asleep before midnight and have difficulty waking in the morning to meet school and social obligations.¹⁵ Delayed sleep–wake phase disorder is often confused with sleep onset insomnia. Importantly, it is highly associated with depression.²¹

Sleep and Circadian Rhythm Problems in Children with Life-Threatening Illnesses

Sleep disturbances are among the most commonly reported symptoms in pediatric palliative care (PPC) patients. However, the complex clinical presentations of many of these children, and the frequency of life-threatening symptoms may be so overwhelming to providers that problematic sleep may easily be dismissed as less important²² or may not be recognized.²³ Current evidence for sleep and circadian disorders in children with several life-threatening illnesses is presented. Table 22.2 presents definitions for sleep terms and normal values.

Cancer

Cancer, its treatment, and its late effects all impact the regulation of sleep and circadian rhythms. Children experience a high level of sleep fragmentation, demonstrated by frequent nighttime awakenings and daytime naps, and catch-up sleep on weekends in response to chronic sleep loss on school days (referred to as social jet lag).^24,25 Problems initiating and maintaining sleep have been described,²⁶ with insomnia reported by 24% of a sample of children with mixed tumors and 39% of those with leukemia.²⁷ Studies exploring symptoms of children during the last week or month of life, or children with advanced cancer, found that changes in sleep patterns or insomnia were among the most commonly reported problems.^28,29 Even still, medical teams referring children for palliative care consults significantly underdiagnose less clinically evident symptoms, including sleep disturbances.²³

Among the most frequent sleep-related problems are EDS and hypersomnolence.²⁷ Children with CNS tumors report significantly higher somnolence than children with other types of cancer,^26,30 and childhood brain tumor survivors have a prevalence of hypersomnia/narcolepsy up to 80 times higher than the general population.³¹ Among children and young adults with advanced cancer receiving palliative care, EDS was one of the most common and distressing symptoms, reported by 59%, with few differences by gender, age, ethnicity, or tumor type.^28,29,32

SRBDs have gained recognition as sleep disorders in children with cancer. One study reported that 40% of a sample of children with mixed tumor types had symptoms of SRBDs, which increased to 46% in children with tumors of the hypothalamus, thalamus, or brainstem, areas of the brain responsible for sleep and respiratory control.²⁷

Circadian rhythm disturbances have been little studied in children with cancer, unlike in the adult cancer population. In a sample of children with mixed tumor types, 4% had a circadian rhythm disorder,²⁷ while circadian activity rhythms measured by actigraphy became dysregulated during dexamethasone therapy in children with acute lymphoblastic leukemia.³³

Sickle Cell Disease

Children with sickle cell disease (SCD) and parents reporting on their children have reported frequent nighttime awakenings and poor quality sleep by questionnaire or sleep diary.^34,35 More than one-third of adolescents have reported moderate or severe sleep disturbances, and 18% required a sleeping medication at least three times per week.³⁶ Symptoms of insomnia are also common, with 29–50% reporting difficult or delayed sleep onset.^34,35,36 Studies using objective measures have also identified suboptimal sleep quality and duration in children with SCD.^37,38

Parasomnias are common, with a prevalence of 16% reported for night terrors, 27% for sleep talking, and 25% for nightmares,³⁴ and an overall prevalence of parasomnias of 26%.³⁹ Symptoms of RLS are also common, although underrecognized.^34,40,41 EDS with accompanying daytime dysfunction has been reported by 60% of children with SCD and 70% of parents reporting on their child.⁴²

Children with SCD have a high prevalence of SRBDs, with snoring reported in up to 54%.^34,43 OSA is also common, ranging from 11% in children with sickle cell anemia⁴⁴ to 41% in children with SCD recruited without regard to SRDB status.⁴³

Neuromuscular Disorders

Disease-related respiratory muscle weakness and decreased ventilatory responses common in neuromuscular disorders and associated obesity, scoliosis, and chest wall and upper airway abnormalities predispose to the development of SRBDs (OSA, central sleep apnea, nocturnal hypoxemia, and hypoventilation).^22,45 Their prevalence exceeds 40%.⁴⁶ Children with neuromuscular disorders who also have untreated SRBDs are at higher risk of developing complications of SRBDs compared to the general population. These include neurocognitive deficits, cardiac and metabolic dysfunction, and pulmonary hypertension.⁴⁷ SRBDs in Duchenne muscular dystrophy has a bimodal presentation, with OSA most common during the first decade of life and hypoventilation more common in the second decade. Among children and adolescents, 65% reported sleep-related symptoms (snoring, sleep disturbance) and 24% reported daytime symptoms⁴⁸ including EDS, fatigue, and headaches.⁴⁵

Prader-Willi syndrome is characterized by increased fat mass, hypotonia, appetite dysregulation, behavioral difficulties, and endocrinopathies, all of which predispose to sleep disorders. Compared to age- and sex-matched controls, these children demonstrate shorter sleep onset latency (SOL), higher wake after sleep onset (WASO), and higher EDS.⁴⁹ SRBDs include nocturnal hypoxemia, hypoventilation, central sleep apnea, and OSA, which has a prevalence in these children of 80%.⁵⁰ Respiratory failure during illness is the most common cause of death, with sleep apnea considered the likely cause of most deaths.⁵¹

Human Immunodeficiency Virus

Human immunodeficiency virus (HIV)-related sleep disturbances have been well studied in adults but are less well described in children. HIV-infected children experience significantly less total sleep time (TST), more WASO, lower sleep efficiency (SE), and more frequent awakenings during sleep than noninfected children,⁵² as well as significantly more EDS.⁵³ A high prevalence of insomnia (20%) was identified in HIV-infected adolescents and was significantly associated with age, fatigue, depression, and anxiety.⁵⁴ Adolescents also reported significantly higher scores on a SRBDs questionnaire compared to noninfected peers,⁵³ while 4 of 11 HIV-infected adolescents who underwent polysomnography had an AHI of 1 per hour or greater.⁵⁵

Cystic Fibrosis

While the prevalence of sleep disturbances in children with cystic fibrosis is unknown, they are common due to disease-related factors such as nocturnal hypoxemia, cough, SRBDs, medications, and pain.^56,57,58 On average, children with cystic fibrosis experience more frequent and longer nighttime awakenings, lower SE, longer SOL, and more WASO.^{57,58,59,60,61} Symptoms of insomnia are common, with 43% of children reporting problems with sleep onset and 39% reporting sleep maintenance problems,⁶⁰ while insomnia was reported by 38% of adolescents.⁶² EDS has been reported at a prevalence of 48–74%.^60,63

Children have a high prevalence of SRBDs, including snoring in 30–58% and witnessed apneas in 88%.^59,60 Shorter TST, lower SE, higher WASO, and more frequent awakenings during the night were associated with more severe lung disease,^57,60 while lower nocturnal oxygen saturation (SpO₂) was associated with poorer lung function and structural lung changes.⁶⁴ This is important, as progressive decline in lung function and recurrent lung infections lead to respiratory failure, the most common cause of death.

Heart Disease

Among children and adolescents with heart disease, only half achieve at least 8 hours of sleep per night, and adolescents report significant social jet lag, with only 18% reporting 8 hours or more of sleep on school nights versus 79% on weekends. TST did not differ by presence or absence of heart failure or by illness severity.⁶⁵ Adolescents and young adults with an implanted cardiodefibrillator report more trouble falling asleep, restless/disturbed sleep, and early morning awakenings compared to a normative sample.⁶⁶

Most studies of children with heart disease have focused on respiratory-related sleep disorders, reporting lower mean and nadir SpO₂ and greater sleep time with SpO₂ of less than 90% in children with congenital heart diseases compared to healthy children.^67,68 In a study of infants with congenital heart disease, three-quarters were found to have an AHI of 1 per hour or more,⁶⁷ while among children with clinically stable primary cardiomyopathy aged 1 month to 18 years, 9 out of 10 had an obstructive AHI of 1 per hour or more. A central AHI of 5 per hour or more on polysomnography was found in 5 of 10 children, and central sleep apnea was associated with severity of cardiac dysfunction.⁶⁹

Chronic Kidney Disease

Sleep disturbances in chronic kidney disease (CKD) are caused by a variety of disease-related factors including stress, pain, malnutrition, anemia, reduced airway muscle tone, and upper airway edema.⁷⁰ Among nondialyzed children with CKD, 39% of whom were post-renal transplant with a stable graft, 10% reported insomnia and 37% had a sleep disorder.⁷¹ One-quarter of children and adolescents on either peritoneal dialysis or hemodialysis slept less than 7 hours per night, and 86% endorsed sleep disturbing symptoms,⁷² with greater sleep disturbance associated with lower quality of life.⁷³ Children on hemodialysis for end-stage renal failure reported significantly more nighttime awakenings and difficult morning arousals, and a greater need for sleeping medications than age- and sex-matched controls; they also achieved significantly less deep sleep and more arousals on polysomnography.⁷⁴

One of the most common sleep disorders in children with CKD is RLS. Prevalence of RLS symptoms vary from 10% in children recruited regardless of dialysis or transplant status, to 30% in children on either peritoneal dialysis or hemodialysis, and 35% in children most of whom had mild CKD.^71,72,73 Importantly, only one-quarter of children with CKD and RLS had reported their symptoms to their healthcare provider.⁷⁵ EDS was reported by parents of 12% of children with CKD who were not dialysis-dependent,⁷¹ while 46% of children studied without regard to their dialysis or transplant status reported EDS or presence of daytime napping.⁷³

Studies of SRBDs in children with CKD are limited. Snoring has been reported in 46% of children on dialysis,⁷² while SRBDs were identified in 6% of nondialysis-dependent children with CKD⁷¹ and in 23% of children with CKD regardless of dialysis or transplant status.⁷³

Environmental and Psychosocial Factors Related to Sleep Problems

Identifying factors that influence sleep must move beyond individual-based models and examine sleep within a larger environmental context. Environments that promote a sense of safety and security also promote longer and higher quality sleep (Figure 22.1). Mental health, home and family dynamics, electronic media use, nutrition/diet, and hospital setting are discussed separately here, yet each of these factors is interrelated.

Mental Health

Fear, anxiety, depression, or anger at bedtime make it difficult for a child to transition to sleep at bedtime and at subsequent awakenings throughout the night. Children may worry about their health, their situation, and fears of the dark compounded by legitimate fears of death. For the transition to sleep to be smooth, a child must feel safe. Adolescents with a life-threatening illness also have concerns about growing up and planning for the future, combined with a grief relating to multiple losses including friendships, physical appearance, and modification of future aspirations. Supportive communication with their parents may be lacking, and, as a consequence, adolescents may remain awake in bed trying to deal with poorly understood anxieties.⁷⁶

Research and clinical experience support a relationship between childhood sleep problems and anxiety or other alterations in mood. Even modest sleep restriction results in difficulties regulating emotions and subsequent elevations in anxiety and depression. As many as 83% of anxious children experience significant sleep disturbance.⁷⁷ Difficulty falling asleep, refusing to sleep alone, and nightmares are common in children with anxiety, along with reduced TST on school nights, frequent nighttime awakening, and decreased deep sleep.⁷⁶ Children who require a high level of parental involvement at bedtime are more likely to have problems with nighttime awakenings and vice versa.⁷⁸ Thus, the interaction between anxiety, sleep problems, and parent–child bedtime interactions may be particularly complex in the palliative care context.

Sleep disturbances are reported in up to 90% of adolescents with major depression.⁷⁹ Among young people, depression is associated with symptoms of insomnia, with polysomnography studies identifying reduced TST, longer SOL, and shorter latency to rapid eye movement (REM) sleep.⁸⁰ Poor sleep quality and EDS are also frequently reported. Increasingly, there is evidence of a bidirectional relationship between sleep and emotional and behavioral functioning.

Home and Family Dynamics

Multiple aspects of family functioning in families of children with serious illness have been linked with child sleep problems. Taking care of a seriously or chronically ill child is one of the most difficult tasks a parent can endure, leading to extreme physical and emotional stress. Stress can lead to disturbed sleep of the primary caregiver, which can then affect the sleep of the child.⁸¹ The reciprocal nature of the child–parent sleep relationship has been well-studied, such that children’s sleep problems predict parent mental well-being, and parent sleep problems predict children’s behavior and functioning.^82,83

Family chaos can also impact the seriously ill child’s sleep. Family chaos is defined as family disorganization and environments that are unstructured, pressured for time, noisy, and unpredictable—themes commonly experienced when a child is diagnosed with a serious illness. Depending on illness severity and chronicity, there can also be significant employment and financial consequences⁸⁴ contributing to the sense of instability and leading to sustained family disorganization. Stressful family environments, lack of parental rules, and family conflict are all associated with sleep problems in children and adolescents.⁸⁵ High levels of family disorganization debilitate children from developing stable sleep onset and good quality sleep.^85,86

Electronic Media

Children and adolescents are growing up in a technological age, with 75% of children having electronic screen-based devices in their bedrooms and 60% of adolescents interacting with screens in the hour before bedtime.^87,88 Research is emerging on how blue light emitted by electronic devices contributes to hyperarousal and decreased sleepiness at bedtime.⁸⁹ Presence of a television and or computer/electronic gaming console in a child’s or adolescent’s bedroom has been related to delayed bedtimes, shorter time in bed and TST, increased bedtime resistance, sleep anxiety, parasomnias, more SRBDs and higher overall sleep disturbance.⁹⁰ This is particularly relevant in children receiving home-based hospice or palliative care, where the living room may become their bedroom to provide space to accommodate medical equipment.

Nutrition/Diet

Malnutrition and poor nutrition are common complications in infants and children with serious illnesses including heart disease, metabolic disorders, and cancer. Concerns of poor caloric or protein delivery and loss of ability to orally feed tend to center around growth, neurodevelopment, and family distress, but nutrition is also a significant factor in sleep. Research is emerging on how dietary patterns and specific foods impact sleep. Some studies, for example, highlight a potential effect of macronutrients on sleep, particularly alterations in slow wave sleep (deep sleep) and REM sleep with changes in carbohydrate and fat intakes.⁹¹

Caffeine, alcohol, and tobacco can also lead to sleep disturbances. Higher caffeine intake, occurring as early as 12 years of age, is associated with shorter TST, and increased SOL, WASO, and EDS.⁹² Alcohol, tobacco, and cannabis use are not uncommon in adolescents living with serious illness, and their use is well-documented in adolescent cancer survivors and those with active disease.^93,94 Large quantities of alcohol before falling asleep leads to decreased SOL early in the night when blood alcohol levels are high, with subsequent disrupted, poor-quality sleep later in the night as blood alcohol levels fall.⁹⁵

Hospital Setting

Reasons for disturbed sleep in the hospital are multifactorial. A systematic review of sleep in hospitalized pediatric cancer patients found that noise, light levels, and staff interruptions were associated with decreased TST and increased nighttime awakenings.⁹⁶ Additionally, as the complexity of a child’s illness increases, their sleep becomes increasingly fragmented, with increased awakenings.⁹⁷ Parents report sleep disruptions by nighttime nursing care such as vital signs, intravenous medications and procedures, and by sequelae of treatment such as nausea and vomiting, diarrhea, fever, and trips to the bathroom (Figure 22.2).⁹⁸ Children admitted to intensive care lost up to 50% of their usual sleep time.⁹⁹ In children with CNS tumors hospitalized for high-dose chemotherapy, only half achieved the recommended TST for age, and the longest continuous sleep period averaged 88 minutes,⁹⁸ about the length of a single sleep cycle. Changes in sleep in young children persisted for up to 7 weeks after discharge from intensive care.¹⁰⁰ Circadian rhythms can also become severely dysregulated during hospitalization.¹⁰¹

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Quality in Pediatric Palliative Care Program Development The Language of Pediatric Palliative Care Relationships with Children and Ensuring Their Voices in Decision-Making Advanced Heart Disease Children’s Voices: The Experience of Patients and Their Siblings

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