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Sleep disorders during and after cancer in children

Sleep disorders during and after cancer in children
Authors:
Valerie McLaughlin Crabtree, PhD
Merrill S Wise, MD
Section Editor:
Ronald D Chervin, MD, MS
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: May 18, 2021.

INTRODUCTION — Advances in treatment for childhood cancers have led to dramatic increases in survival, with overall five-year survival rates of nearly 85 percent by 2016 [1]. Rates of survival vary by the type of cancer; more than 90 percent of children with acute lymphoblastic leukemia survive to adulthood, while most children with diffuse intrinsic pontine glioma die within one year from diagnosis (table 1) [1]. With improved survival, it becomes important for providers to focus on optimizing quality of life and function during and after treatment, including addressing sleep problems and fatigue.

Sleep disturbances are among the most frequently reported symptoms experienced by oncology patients during cancer-directed therapy, and in some cases, these problems continue into survivorship [2,3]. These include excessive daytime sleepiness (EDS), as well as nighttime problems such as poor sleep efficiency, insomnia, obstructive sleep apnea (OSA), and restless legs syndrome (RLS) [3-7]. In addition, many patients experience cancer-related fatigue, which can be exacerbated by sleep disturbance, although it is not itself a sleep disorder [8]. Sleep disruption and fatigue often have adverse effects on mood, behavior, daily activities, social interaction, overall quality of life, and possibly on immune function [3,9-12]. Conversely, mood disruptions during hospitalizations may impact both sleep duration and sleep latency [13].

The clinical characteristics, consequences, and management of sleep problems in children with cancer, and in cancer survivors, will be discussed here. Other topic reviews with related content include:

(See "Behavioral sleep problems in children".)

(See "Overview of cancer survivorship in adolescents and young adults".)

(See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

DEFINITIONS

Excessive daytime sleepiness (EDS) – Daytime sleepiness is defined as excessive when it causes a subjective complaint or interferes with function. The American Academy of Sleep Medicine defines EDS as the inability to maintain wakefulness and alertness during the major waking episodes of the day, with sleep occurring unintentionally or at inappropriate times almost daily for at least three months [14].

Fatigue – Fatigue refers to a subjective lack of physical or mental energy. It is generally defined as the subjective feeling of physical, emotional, or cognitive tiredness that interferes with participation in physical or social activities.

In practice, patients often use terms such as sleepiness, tiredness, fatigue, and low energy interchangeably. The clinician should try to distinguish between these complaints to permit optimal management, although it may be difficult to do so. (See "Approach to the patient with excessive daytime sleepiness".)

OVERVIEW OF PATHOGENESIS — Mechanisms that can lead to sleep disturbance and fatigue in children with cancer include:

Effects of the cancer – Cancer may cause sleep disruption due to pain, or direct effects on sleep centers (in brain tumors). Cancers also contribute to fatigue through effects on metabolism, endocrine function, anemia, or systemic symptoms in certain cancers, such as lymphoma.

Treatment effects – Radiation therapy and/or chemotherapy (in addition to glucocorticoids) are often associated with sleep disruption or fatigue. In addition, sleep may be disrupted by treatment side effects, such as pain, anemia, or nausea [5,15-17].

Environmental effects – For inpatients, the hospital environment often disrupts sleep routine and continuity due to room entries and exits, taking vital signs, nighttime medication administration, etc. Cancer patients also are at risk for disrupted circadian sleep-wake cycles and for poor-quality sleep due to limited mobility and diminished physical activity [2].

Psychosocial effects – Insomnia, sleepiness, and fatigue can arise due to anxiety, mood problems, and stress associated with a cancer diagnosis, repeated hospitalizations, treatment, or disruption in typical routine [18].

Some of these effects occur primarily during the period of active cancer treatment. Others may persist or even increase over time and cause sleep disruption in cancer survivors. These include the anxiety and depression (any cancer); residual physical effects of the cancer, including chronic pain; and sometimes disruption to brain or endocrine function (primarily in patients with brain tumors). (See "Overview of cancer survivorship in adolescents and young adults", section on 'Psychiatric and psychosocial needs' and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)

COMMON SLEEP COMPLAINTS AND DISORDERS IN CHILDREN WITH CANCER

All cancers — Excessive daytime sleepiness (EDS) and fatigue are reported by a majority of pediatric oncology patients, and fatigue is often described as one of the most distressing symptoms for youth with cancer [19-22]. Insomnia, circadian rhythm disturbances, restless legs syndrome (RLS), and sleep-disordered breathing are also increased in this population compared with healthy children.

The prevalence of sleep problems is particularly high in children with malignancies of the central nervous system, in whom unique mechanisms contribute to the sleep disturbances, as discussed below. (See 'Central nervous system cancer' below.)

Excessive daytime sleepiness — EDS is present in many children undergoing cancer treatment and is substantially more common than in otherwise healthy children, including those with obesity [2,23]. EDS is especially common and severe among children with brain tumors. (See 'Central nervous system cancer' below.)

Symptoms of EDS include increased duration of sleep time, resumption of daytime napping, significant difficulty awakening in the morning, and difficulty remaining alert during daytime activities [19,24]. Clinicians should try to distinguish EDS from fatigue, which is the subjective feeling of tiredness that interferes with participation in physical or social activities and is also common in this population. (See 'Fatigue' below.)

Causes or contributors to EDS include direct effects of the cancer-directed therapy, poor quality or quantity of sleep due to sleep habits or insomnia, and circadian sleep-wake disturbances. In children with brain tumors, EDS is likely caused by direct effects on the hypothalamus or other centers involved in regulating sleep or circadian rhythms. (See 'Central nervous system cancer' below.)

Identifying the likely cause(s) of the EDS is an important step in management. Each of these sleep problems is outlined in the following sections.

Behavioral insomnia — Children with cancer can be prone to chronic insomnia disorder, manifested as delayed sleep onset, or awakenings. As an example, children with acute lymphocytic leukemia (ALL) experience longer sleep duration and increased daytime napping but also have more sleep disruption, manifested by difficulty with initiating and maintaining sleep, restlessness, bedtime resistance, recurrent nightmares, and changing sleep location during the night [15,16].

Behavioral conditioning often is an important contributor to insomnia in children with cancer, compounding any direct effects from the cancer and its treatment. In younger children, cancer care tends to promote behavioral conditioning because it requires a high level of involvement from the parents, including vigilance at night (eg, for monitoring children for fever or other medical problems). The vigilant parent can inadvertently reinforce behaviors, such as cosleeping or nighttime awakenings, that tend to interfere with sleep. Furthermore, if a parent is consistently present at sleep onset, this can reinforce the child's need for parental presence to initiate sleep. As sleep is a conditioned response, this type of sleep habit may persist and continue to disrupt sleep after cancer treatment has ended. (See 'Behavioral sleep interventions' below and "Behavioral sleep problems in children".)

Older children are also at risk for conditioned insomnia as older children and adolescents with cancer may require more parental monitoring and caretaking at night compared with their healthy peers. Even if parents have less direct involvement in nighttime care, the conditioned insomnia can be characterized by anxiety about falling or staying asleep and is more likely in children with underlying generalized or cancer-related anxiety or depression. This type of chronic insomnia disorder is referred to as the psychophysiologic subtype. Circadian rhythm shifts also may play a role. (See "Behavioral sleep problems in children", section on 'Older children and adolescents'.)

Circadian rhythm sleep-wake disturbances — Several mechanisms may contribute to circadian rhythm disturbances in cancer patients:

Limited exposure to light may contribute to circadian rhythm disturbance during cancer treatment [25]. Cancer patients may have less exposure to daylight because of reduced outdoor activities, or inpatient environments in which they sleep or spend time in darkened rooms during the day. A negative feedback loop can then become established in which children feel fatigued, engage in less activity, and have less exposure to daytime light; this dampens circadian rhythms and increases fatigue [26,27]. The cycle can be reversed by environmental interventions, such as engagement in more activity during the day and establishment of healthier light/dark cues. (See 'Environmental interventions' below.)

In some cases, cancer or its treatment contributes directly to the circadian rhythm disturbance. As an example, dexamethasone, which is an important component of treatment for ALL and some other cancers, tends to disrupt circadian rhythms, contributing to cancer-related fatigue [28-30]. Surprisingly, circadian rhythm disturbance is more prominent in ALL patients receiving low-dose dexamethasone compared with those on high-dose dexamethasone. The mechanism for this paradoxical effect is unclear. It is possible that high-dose dexamethasone causes an increased daytime activity level (hyperactivity), which manifests as an apparent improvement in circadian rhythmicity compared with low-dose dexamethasone [29].

Children with brain tumors are particularly prone to circadian rhythm disturbances. (See 'Central nervous system cancer' below.)

Restless legs syndrome — Children with cancer are probably at increased risk for RLS, which can delay sleep onset due to discomfort. Most of the evidence for this association comes from studies in adults with cancer who have double the prevalence rates (18 percent) of RLS in comparison with a healthy sample [31]; the association is not well studied in pediatric populations. A possible mechanism for the association is iron deficiency, which is a common consequence of chemotherapy and is thought to be an important contributor to RLS. Furthermore, children receiving medications that can cause peripheral neuropathy, such as vincristine [32,33], may be at increased risk for RLS symptoms. (See "Restless legs syndrome and periodic limb movement disorder in children".)

Fatigue — Fatigue is reported by up to 80 percent of youth receiving chemotherapy [34-38]. Fatigue related to cancer is distinct from typical fatigue in that it is more severe and not relieved by rest. Factors that can contribute to the fatigue include direct effects from chemotherapy or radiation therapy, side effects of certain medications (such as corticosteroids), medical problems due to treatment (such as anemia), disruptions in routine, circadian rhythm disturbance, stress and anxiety, and sleep disruption. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment".)

Fatigue is a complicated symptom to measure because there is no gold standard to objectively evaluate specific symptoms or severity of fatigue. Instead, clinicians must rely on either parent- or child-reported symptoms. The best approach is to ask patients and their parents directly about symptoms of fatigue, including cognitive, physical, or emotional tiredness. Clinicians should attempt to distinguish fatigue from sleepiness by inquiring about specific symptoms of EDS, as described above. (See 'Excessive daytime sleepiness' above.)

In the research setting, survey instruments are sometimes used to assess fatigue, including the Multidimensional Fatigue Scale [39,40], the Fatigue Scale (with versions for children [41] and adolescents [42]), or the Patient-Reported Outcomes Measurement Information System (PROMIS) measures [43]. Unfortunately, these instruments are used almost exclusively in the context of research and they yield very little clinical utility. In particular, no clear clinical cutoffs have been established to guide clinical intervention based on assessment results.

Fatigue can contribute to many adverse outcomes including poor treatment adherence, reduced social activities, depressive symptoms, and behavior problems [9,44-47]. Furthermore, adolescent and adult oncology patients have described substantial impact of fatigue on mood, physical well-being, social interactions, cognitive abilities (particularly concentration and attention), global distress, and overall quality of life [48-51]. Fatigue is a particularly distressing symptom for adolescents [52] because it interferes with their independence and social activities, which they tend to value highly [48]. Further, fatigue has been demonstrated to persist well into survivorship [53,54]. Thus, evaluation and management of fatigue has the potential to improve overall quality of life as well as social interactions and mood.

Central nervous system cancer — Youth with brain tumors are particularly prone to sleep disturbances, especially EDS, circadian rhythm sleep disturbances, and sleep-related breathing disorders such as obstructive or central sleep apnea. These children also may experience sleep-wake problems common to all children with cancer, such as fatigue and insomnia. Sleep problems may occur before the diagnosis of the cancer or, more commonly, just after diagnosis and during treatment. Some of the problems may persist into survivorship [55,56].

Brain tumors tend to cause sleep problems due to direct effects on brain structures involved with regulation of sleep or breathing during sleep, such as the hypothalamus or brainstem, as well as indirect effects due to hydrocephalus, elevated intracranial pressure, or dysregulation of the hypothalamic-pituitary-endocrine axis. Other factors may include surgical complications or damage to neural structures, or side effects of cranial radiation therapy or chemotherapy. In addition, these children are at risk for sleep problems due to the same treatment-related, psychosocial, and environmental mechanisms that mediate sleep disruption in all children with cancer, as outlined in the previous sections. (See 'Overview of pathogenesis' above.)

Recognition is growing that sleep problems are often under-identified and poorly addressed in children with brain tumors, leading to years of symptoms that may be disabling. There is a paucity of longitudinal studies to characterize and track these problems or to identify risk factors and mediating factors, and few studies address optimal therapeutic approaches in this population.

EDS – Children with brain tumors are particularly prone to EDS, which may be severe and may persist into survivorship. This problem is best documented in children with craniopharyngioma. These tumors are located in the sellar/suprasellar region and often involve or displace the hypothalamus, pituitary gland, and the optic chiasm, leading to vision deficits and a variety of endocrine problems due to disruption of the hypothalamic-pituitary adrenal axis. Symptoms can include rapid onset of obesity (due to hypothalamic dysfunction), behavioral changes, and EDS, including circadian rhythm sleep-wake disturbances and forms of narcolepsy [57]. In one study of children with recently diagnosed craniopharyngioma, 75 percent exhibited pathologic sleepiness as documented by a multiple sleep latency test (MSLT) [20]. In another study of children who had completed therapy, 80 percent reported "feeling drowsy" [58]. Persistent hypersomnolence was noted in a study of craniopharyngioma survivors that documented ongoing EDS and narcolepsy in a subset of survivors [59].

The prevalence and severity of EDS in this population is probably related to direct effects on the hypothalamus or other centers involved in regulating circadian rhythms, as sleepiness is associated with the degree of hypothalamic involvement and not serum or cerebrospinal fluid orexin levels [20,60]. Importantly, the higher the degree of hypothalamic involvement of the tumor, the greater risk for narcolepsy. In one polysomnographic study of survivors of pediatric craniopharyngioma, all patients who were overweight or obese met criteria for hypersomnia [61]. These findings suggest that the mechanism underlying hypersomnolence in certain pediatric brain tumor patients, and particularly those with hypothalamic-pituitary axis involvement, may be different from other causes of pathologic sleepiness, such as narcolepsy with cataplexy (narcolepsy type 1). (See "Clinical features and diagnosis of narcolepsy in children", section on 'Pathophysiology'.)

The profound and persistent EDS in children with brain tumors may have a significant negative impact on cognitive function, academic performance, psychosocial function, and quality of life [9,23,46,62-64]. Because medical efforts are initially focused on diagnosis and prompt intervention with surgery, radiation therapy, or both, sleepiness may not be an immediate source of concern by parents or health care providers. Nevertheless, early recognition, evaluation, and treatment of pathologic sleepiness in children with brain tumors are important components of the treatment program. As these patients are at high risk for pathologic EDS including narcolepsy, evaluation typically includes polysomnography (PSG) to evaluate for associated sleep-related breathing disorders, followed by an MSLT for characterization of EDS. Treatment with psychostimulants can improve daytime alertness [65]. (See "Craniopharyngioma" and "Approach to the patient with excessive daytime sleepiness".)

Circadian rhythm sleep-wake disturbances – Circadian rhythm sleep-wake disturbance is one mechanism that may contribute to EDS or insomnia in children with brain tumors. Several investigators have studied relationships between circadian rhythms and cancer [66,67] and, specifically, in patients with brain tumors [56,68]. A possible mechanism for the disruption is irregular melatonin secretion due to injury of the suprachiasmatic nuclei of the hypothalamus, which coordinate circadian rhythms [56]. Individuals with craniopharyngiomas, recipients of cranial radiation doses more than 3500 cGy, and those of younger age at the time of treatment experience more severe sleep dysfunction. Patients with brain tumors may experience major dysfunction in the hypothalamic-pituitary adrenal axis affecting both the homeostatic Process S and circadian Process C from the two-process model of sleep regulation [56]. (See "Sleep-wake disturbances in shift workers", section on 'Pathophysiology'.)

Limited clinical evidence from small case series supports the notion that melatonin has a role in mediating circadian rhythm disruption in children with brain tumors [57,69-72]. A few reports suggest that exogenous melatonin may help to improve circadian rhythm sleep-wake regulation and improve daytime alertness [57,70]. Further investigation of this approach is warranted in children with brain tumors and abnormal circadian regulation. (See 'Medications' below.)

Sleep-related breathing disorders – Sleep-related breathing disorders, including obstructive sleep apnea (OSA) and central sleep apnea, are more common in children with brain tumors than in children with other cancers. These disorders may contribute to EDS and may also impair daytime behavior and function, causing attentional difficulties, hyperactivity, and mood disturbance. (See 'Cognitive, emotional, and behavioral consequences' below.)

An increased risk for OSA in children with brain tumors has been documented in several studies. One of the largest studies used questionnaires to evaluate symptoms in pediatric brain tumor survivors at least five years after diagnosis and reported that 16 percent of survivors snored frequently or almost always, 6 percent snored loudly or very loudly, and 3 percent of survivors reportedly "struggled to breathe" when sleeping [55]. A separate study used PSG to evaluate adolescents with craniopharyngioma and obesity and found that 4 of 15 patients had at least moderate OSA (apnea-hypopnea index >15), which was significantly more than in otherwise healthy controls with obesity [73]. Because of this high prevalence of OSA, the investigators suggested that routine PSG evaluations be considered in craniopharyngioma patients with obesity. A systematic review of studies on adolescents with brain tumors and sleep disturbances reported the presence of sleep-related breathing disturbance, as well as insomnia, parasomnias, and daytime sleepiness and fatigue [74].

Central sleep apnea appears to be a less common complication of brain tumors. In a case series of 14 children with brain tumors who were referred for a sleep evaluation, central sleep apnea was identified in two children (14 percent); in both of these children, the tumor involved the medulla [19]. Conversely, a separate series of children with central sleep apnea reported brain tumors (gangliogliomas) in 17 percent [75]. Other small case series in children with a variety of brain tumors describe abnormal ventilatory control, characterized by hypercarbic periodic breathing, or alveolar hypoventilation [76-78].

Cancer survivors — Fatigue and sleep complaints, including EDS, often persist well into the survivorship period. Several studies document complaints of significant fatigue and sleep complaints among childhood cancer survivors five years after treatment and sometimes continuing into adulthood [4,10,62,79,80]. Among survivors, higher degrees of emotional distress are associated with more sleep problems and EDS [10]. In one report of cancer survivors referred to a pediatric sleep center, 60 percent presented with EDS, 40 percent with sleep-disordered breathing, 24 percent with insomnia (delayed sleep onset or awakenings), 4 percent with circadian rhythm dysfunction, and 9 percent with parasomnias [23]. EDS has been seen in up to 80 percent of youth who have survived brain tumors. Insomnia has been reported in one-third of all survivors and one-fourth of brain tumor survivors [81-83].

Increased risk for sleep-disordered breathing was also noted in a survey of survivors of pediatric non-central nervous system cancers, in which 19 percent reported symptoms of sleep-disordered breathing; this suggests a prevalence substantially higher than the 1 to 4 percent reported for OSA in children more generally [84,85]. It is possible that the increased risk for sleep-disordered breathing is mediated by obesity, which is more common among survivors of childhood cancer [86-88]; the risk for obesity among childhood cancer survivors is associated with corticosteroid treatment as well as younger age at diagnosis [89]. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Obesity'.)

IMPACT OF SLEEP DISORDERS ON CHILDREN WITH CANCER — In healthy children, sleep disturbances are associated with decreased cognitive functioning, increased anxiety and depression, and lower perceived well-being [90-93]. These effects are also relevant for children with cancer and can have important consequences for function and quality of life.

Cognitive, emotional, and behavioral consequences — Pediatric cancer survivors are at risk for poor school performance from extended school absences during treatment and from neurocognitive late effects of cancer treatments [94-96]. These problems may be exacerbated by sleep disturbance, which is known to affect cognition and attention [97-100]; behavior; and mood and social function in healthy children [97,101] (table 2). Similar mechanisms may contribute to the problems with executive functioning, anxiety, depression, and disturbances in social relationships experienced by many pediatric oncology patients [6,46,80,102,103]. These issues are discussed in detail in a separate topic review. (See "Cognitive and behavioral consequences of sleep disorders in children".)

Specific to youth with cancer, those with craniopharyngioma and EDS have been found to demonstrate on functional MRI greater activation of frontal brain regions, demonstrating greater attentional effort and likely less efficient processing, likely related to their sleepiness [20]. Survivors of pediatric cancer who have EDS, fatigue, and poor nighttime sleep were more likely to have worse cognitive efficiency, organization, and memory. By parent report, survivors of pediatric brain tumors who have more difficulties with nighttime sleep are also more likely to have worse executive function [64]. Taken together, it is likely that sleep disruption poses additional cognitive risk above and beyond that seen typically in pediatric cancer survivors.

Youth with cancer who report high fatigue are more likely to report depressive symptoms and negative affect with lower reporting of positive affect [104]. The combination of fatigue and sleep disruption has been associated with poorer interpersonal interactions and higher rates of anxiety and depression in youth with cancer [46]. Further, pediatric patients with brain tumors who reported worse daytime mood had longer sleep onset latency and shorter sleep that night [13]. Among pediatric cancer survivors, those with poorer sleep, EDS, and fatigue also reported higher rates of emotional distress [10].

Quality of life — As pediatric cancer survivorship rates have improved, quality of life has become an important goal in pediatric oncology research and treatment. Children and adolescents with cancer report poorer quality of life when compared with healthy peers, especially related to physical functioning and mood [105]. Some of these effects may be mediated by sleep disturbance during treatment for cancer [9,47] and in long-term cancer survivors [62]. The combined effects of sleep disturbance; excessive daytime sleepiness (EDS); and the physical, social, and emotional consequences of pediatric cancer may result in more negative quality of life than any of these symptoms in isolation [106]. As a result, interventions to address both sleep and fatigue are likely to improve quality of life.

MANAGEMENT — Because sleep disturbance and fatigue in the pediatric oncology population can have a negative impact on cognition, mood, behavior, and quality of life, it is crucial to manage these symptoms to facilitate healthy sleep and maintenance of daily activities [47]. Similarly, because mood may impact sleep, it is important to address significant mood concerns to promote healthier sleep in this population [13,107]. (See "Overview of cancer survivorship in adolescents and young adults".)

Little evidence is available to evaluate the effects of specific interventions in the management of sleep disturbance in children with cancer. However, interventions that have been validated and used clinically with other populations for improvement of sleep disturbance, anxiety, and mood disruption can be modified for use with childhood cancer patients and survivors as outlined below. It is also important to consider the role of illness management in addressing sleep problems. For example, pain management should be optimized, sleep-inducing medications should be given at bedtime to the extent possible, and obesity should be addressed [108].

Selection of interventions — Selection of interventions depends upon the clinician's analysis of the cause(s) or contributors to the sleep disruption, determined by a thorough clinical assessment. In many cases, a combination of factors may contribute to the sleep problem.

Key considerations for the most common sleep complaints are (table 3) [47]:

Excessive daytime sleepiness (EDS) – EDS is common among children undergoing cancer-directed therapy and also in children with brain tumors, before and after treatment. Recognition of EDS should prompt a thorough sleep and medical history, which is the foundation for establishing the diagnosis. It is not uncommon for more than one diagnosis to be identified, and each etiology should be addressed. The first step is to determine whether the child has a specific sleep disorder that can be diagnosed and treated, or has other evidence for interrupted or insufficient nighttime sleep. If so, any behavioral or environmental causes of this problem should be addressed, including circadian rhythm disturbance (see 'Behavioral sleep interventions' below and 'Environmental interventions' below). If insomnia or EDS persist despite intervention, pharmacotherapy may be needed. (See 'Medications' below.)

Children with brain tumors are particularly at risk for both circadian rhythm disturbances and EDS, both before and after treatment, and are more likely to require pharmacotherapy if other measures are not effective.

Insomnia – Selection of the intervention for insomnia depends upon patient characteristics:

Preschool- or school-aged children with insomnia related to inconsistent limit-setting, which is relatively common in parents of young children with cancer. Solutions include optimizing sleep hygiene and parental education about limit-setting and sleep-onset associations. (See 'Behavioral insomnia' above and 'Behavioral sleep interventions' below.)

Insomnia in school-aged children or adolescents associated with underlying generalized or cancer-related anxiety or depression. It is characterized by anxiety specifically about not being able to sleep (as opposed to symptoms of a more generalized anxiety or mood disorder) and sometimes by habitual inability to sleep at certain times of the night. Solutions include optimizing sleep hygiene, cognitive behavioral therapy for insomnia (CBT-I), and evaluation and treatment for any underlying anxiety or mood disorder that may contribute. Both in-person and internet-administered CBT-I have been shown to improve insomnia symptoms in adolescent and young adult cancer survivors [109,110]. (See 'Behavioral insomnia' above and 'Behavioral sleep interventions' below.)

Circadian rhythm disturbance – This is common in children on glucocorticoids, and in children with brain tumors during or after treatment. Other contributors include frequent or prolonged hospitalizations, low daytime activity or light exposure, or nighttime stimulation (eg, electronics) (see 'Circadian rhythm sleep-wake disturbances' above and 'Central nervous system cancer' above). Solutions include optimizing sleep hygiene and environmental conditions, and possibly melatonin and/or bright light therapy. (See 'Sleep hygiene' below and 'Environmental interventions' below and 'Insomnia' below.)

Snoring or breathing problems – Children presenting with complaints of snoring or difficulty breathing, or other clinical suspicion for sleep apnea (table 4), should be evaluated with polysomnography (PSG). A high index of suspicion is appropriate for children with brain tumors, adenotonsillar hypertrophy, or obesity. (See 'Central nervous system cancer' above and "Evaluation of suspected obstructive sleep apnea in children".)

Fatigue – Our approach to managing fatigue involves the following steps:

Determine whether a component of EDS is present (see 'Excessive daytime sleepiness' above and 'Fatigue' above) and, if so, evaluate and treat for EDS as outlined above. Review any medications (eg, sedative-hypnotics) that may contribute to the symptoms.

Assess and treat for any underlying sleep disorder (table 3). Untreated sleep disorders can cause fatigue, even in the absence of complaints about daytime sleepiness, and treatment for the sleep disorders can improve fatigue as much as sleepiness [111-113].

Ensure that sleep times and sleep conditions are optimized. (See 'Sleep hygiene' below.)

Encourage physical activity and offer bright light therapy since these are low-risk interventions and have been shown to be feasible and acceptable and show promise in reducing fatigue in youth with cancer [114,115]. (See 'Sleep hygiene' below and 'Environmental interventions' below.)

Behavioral sleep interventions — Maintaining healthy sleep habits is a necessary element to ensuring adequate sleep. This may be challenging for parents and caregivers of children undergoing cancer treatment because of physical side effects of treatment (nighttime pain or illness), distress or overprotectiveness, or disrupted routines as a result of medication schedules or hospitalizations.

Strategies to prevent or treat behavioral sleep problems in healthy children are particularly important for children with cancer. These include:

Sleep hygiene — The first step is to establish and maintain healthy sleep habits, which are summarized in the table (table 5). These include limiting caffeine intake (with no caffeine after lunchtime), establishing a relatively stable bedtime and wake time, as well as a stable bedtime routine with calming pre-bedtime activities, without television or other electronic devices, and ensuring a cool, quiet sleep environment [116,117]. It is useful to create a daily schedule with activity pacing that includes alternating periods of rest and activity [15,47,118]. Often, children receiving treatment for cancer may require daytime naps due to fatigue or sedating medications. Parents and caregivers should be encouraged to limit napping to the early afternoon to avoid interference with nighttime sleep onset. (See "Behavioral sleep problems in children".)

An increase in physical activity has shown promise in treating both sleep disruption and daytime fatigue [114,119]. Activity interventions have included endurance exercise (eg, pedaling, running, or walking at 40 to 70 percent heart rate reserve), resistance, strength/conditioning, stretching/flexibility, or yoga. Some studies have utilized professionally supervised exercise, while others focused on in-home activity. Of importance when prescribing activity for pediatric oncology patients with sleep problems and fatigue is the use of activity in general (aerobic, strength training, and/or flexibility) rather than specific exercises or whether or not they are supervised. Finally, in addition to improving overall sleep and fatigue, quality of life has been demonstrated to improve as a result of physical activity.

Specific behavioral strategies — Behavioral strategies depend on the type of behavioral insomnia, which varies with the child's age group:

Younger children – In younger children, insomnia is often related to inadequate or inconsistent parental/caregiver limit-setting (which tends to present with bedtime resistance), sleep-onset associations (which typically result in prolonged night awakenings), or a combination of these issues. Children with cancer are particularly at risk for insomnia, as mentioned above, due to nighttime monitoring and caretaking needs.

Important strategies to address these problems include establishing healthy sleep habits, as described above, and educating parents and caregivers about limit-setting. Specific behavioral techniques such as positive reinforcement and systematic ignoring (including "graduated extinction") also may be helpful [120-122]. Implementing these strategies may be difficult at first, especially for families dealing with the many stresses of cancer care. It may help to remind parents that short-term difficulties of implementing a behavioral intervention will likely be rewarded with the longer-term benefit of improved sleep, which can improve the child's quality of life, mood, and behavior. Some parents may elect to wait to implement systematic ignoring or graduated extinction until after their children have completed treatment, due to a need or desire to be present at sleep onset and throughout the night to monitor the child's medical status or provide medical intervention during the night. Details of these and other behavioral strategies are discussed separately. (See "Behavioral sleep problems in children", section on 'Young children with behavioral insomnia'.)

Inpatient admissions for cancer care offer an opportunity for parent and caregiver education about sleep hygiene and limit-setting [118]. Parents and caregivers are often most concerned about the child's difficulty initiating sleep and may not recognize the importance of sleep hygiene in addressing this problem [123]. Because families and providers may not always agree on the most important target of intervention, a shared decision-making model should be employed to ensure that the interventions selected best meet the family's needs.

Older children – In older children, chronic insomnia is often psychophysiologic (conditioned). It is characterized by anxiety about falling or staying asleep and is more likely in children with underlying generalized or cancer-related anxiety or depression. As with younger children, older children may require nighttime monitoring and caretaking by their parents, which may contribute to behavioral insomnia by conditioning the child to require parental presence for sleep. Implementing healthy sleep hygiene is an important step. In addition, underlying anxiety or depression should be addressed and treated.

For some children, CBT-I, and calming strategies that promote self-soothing behaviors after nighttime awakenings, may be beneficial [109,122]. Specifically, cognitive restructuring, which can be taught to younger children by having them "think like a detective," may be helpful in reducing negative cognitions related to sleep. Children can be taught to identify their negative thought, provide evidence for and against the thought, and then replace the negative thought with a more realistic belief [124]. For example, the thought "I will never go to sleep" can be evaluated to determine that there is little evidence to support this. Once this is determined, the child can replace the thought with "It may take me a while to go to sleep, but eventually I will be able to do so." Adding elements of relaxation training, including diaphragmatic breathing, progressive muscle relaxation, and guided imagery techniques can also reduce the child's distress while awaiting sleep onset, promote more rapid sleep onset, and improve the ability to return to sleep after nighttime awakenings [125]. These approaches are similar to those used for adults with and without cancer. Children with chronic insomnia, particularly when it interferes with daytime functioning or causes significant distress, may benefit from a referral to a specialist. This expertise is typically available from a behavioral health specialist at an accredited sleep disorders center; a pediatric oncology center also may be able to assist in accessing appropriate treatment [109]. Alternatively, there is support for online cognitive behavioral therapy for insomnia in pediatric cancer survivors. (See "Cognitive behavioral therapy for insomnia in adults".)

Environmental interventions

Home – In the home, general measures to improve sleep hygiene include establishing a quiet and comfortable sleep environment and avoiding television and screens near bedtime [126,127]. In addition, daytime exposure to light (especially daylight) and physical activity can help to maintain normal circadian rhythms. (See 'Circadian rhythm sleep-wake disturbances' above.)

Because fatigue has been associated with reduced exposure to bright light in adult breast cancer patients [25], bright light therapy has been used in adult cancer patients and survivors with some promising outcomes. Daily use of 30 minutes of bright light therapy upon awakening has been shown to protect the circadian rhythm and prevent increases in fatigue, with resulting improved quality of life among breast cancer patients [44], as well as to reduce rates of fatigue in adult cancer survivors [128]. Bright light therapy is a recommended treatment for children and adolescents with delayed circadian rhythm sleep-wake disorder [129] and has been shown to reduce depressive symptoms in youth with seasonal affective disorder, depression, bipolar disorder, and comorbid anorexia nervosa [130-133]. One trial demonstrated feasibility and acceptability of bright light therapy and promise in reducing fatigue in adolescents and young adults with cancer, indicating it may be an appropriate and noninvasive intervention [115].

Hospital – For children needing hospital admissions for cancer care, the hospital environment presents particular challenges to sleep due to noise or entries and exits by staff into the room for care. This can result in sleep deprivation and disruption of circadian rhythms if the hospitalizations are frequent or prolonged. As an example, in one study conducted on an inpatient pediatric oncology unit, there were an average of 11 room entries/exits by staff during the night shift, with a mean of 12 to 16 nighttime awakenings per night [2]. As would be expected, the child's self-reported levels of fatigue were associated with the number of room entries and increased with each night of admission.

To address this problem, hospitals wards can institute a variety of steps to improve the sleep environment, including noise mitigation, behavioral support, and minimizing the number of entries into the room during the night by "bundling" visits so that all scheduled care occurs during one room entry. A pilot study evaluated bundling as one of several environmental measures to improve sleep in hospitalized children with brain cancer [134]. In addition, the child and parent determined a pre-bedtime routine, bedtime, and wake time; used white noise machines and light-blocking blinds; and had out-of-bed activity during the day. Parents and patients reported appreciating the routine and asked for similar environmental measures with their subsequent admissions. Although no protocols have been rigorously tested, it seems likely that a hospital focus on lowering light and sound levels, bundling care, and promoting structured sleep-wake schedules can have a positive impact on sleep and daytime activity levels in patients. (See "Poor sleep and insomnia in hospitalized adults".)

Medications

Excessive daytime sleepiness — Management of EDS in children with cancer is similar to the management of sleepiness in otherwise healthy children. For children with narcolepsy due to a medical disorder (secondary narcolepsy) or hypersomnia due to a medical disorder, the mainstay of management is a combination of nonpharmacologic intervention (ensuring adequate sleep hygiene and sleep duration) and pharmacologic therapy [135]. The goal is to optimize alertness throughout the day, with a particular focus on class time and key social activities, while minimizing adverse side effects.

Medications that are useful for this purpose include traditional stimulants such as methylphenidate and dextroamphetamine [136,137] or wakefulness-promoting agents such as modafinil or armodafinil [135]. Of note, the latter two medications are approved by the US Food and Drug Administration (FDA) in adults only, and their use in children under 18 years of age is considered "off-label." There are no large systematic studies involving the use of these medications in children with cancer. However, a variety of small case reports and the authors' personal observations clearly support pharmacologic intervention in children with pathologic sleepiness and cancer, particularly for those with brain tumors. Close monitoring over time is required to adjust the timing and dose of medication and to monitor for adverse side effects or the emergence of other sleep disorders that may contribute to daytime sleepiness.

Insomnia — For children with insomnia, the first step is to optimize nonpharmacologic intervention, including the behavioral and environmental strategies described above. Sleep disorders that can be diagnosed and treated effectively, such as chronic insomnia and obstructive sleep apnea (OSA), should be considered [138]. The clinician should also explore the full range of potential medical causes or contributors to insomnia including chronic pain, gastroesophageal reflux, medication side effects, or nonmedical causes such as environmental sleep problems or psychologic problems such as anxiety or depression.

For children who have failed to respond to nonpharmacologic interventions, we offer one of the following medications. This is an off-label use since none of these are FDA-approved for treatment of chronic insomnia in children. Chronic use of "over-the-counter" medications such as diphenhydramine should be avoided because tolerance tends to develop. Selection of medication should be based on the clinician's judgment of the best match between the clinical circumstances (eg, type of sleep problem, patient characteristics, expected duration of therapy), the individual properties of available drugs (eg, onset of action, safety, and tolerability), and any comorbid disorders (eg, attention deficit hyperactivity disorder, anxiety, or depression). Specific considerations are discussed in a separate topic review. (See "Pharmacotherapy for insomnia in children and adolescents: A rational approach".)

Adult survivors have reported significantly greater "over-the-counter" sleep supplement use than their siblings, and those with emotional distress are significantly more likely to use sleep medications or supplements than their siblings [10].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Insomnia in children" and "Society guideline links: Parasomnias, hypersomnias, and circadian rhythm disorders" and "Society guideline links: Sleep-related breathing disorders including obstructive sleep apnea in children".)

SUMMARY AND RECOMMENDATIONS — Dramatic improvements in survival rates of childhood cancer, coupled with the common occurrence of sleep problems in this population, warrant focused efforts to diagnose and treat sleep disorders in children with cancer. This is especially important when disturbances in sleep-wake regulation lead to pathologic sleepiness and associated decrements in cognitive function, academic performance, behavioral or mood regulation, or social isolation.

Excessive daytime sleepiness (EDS) is present in many children undergoing cancer treatment or pediatric cancer survivors, especially among those with brain tumors. Causes or contributors to EDS can include insufficient or interrupted sleep due to obstructive sleep apnea (OSA), chronic insomnia disorder, restless legs syndrome (RLS), circadian rhythm sleep-wake disorders, or other sleep disorders. (See 'Excessive daytime sleepiness' above and 'Central nervous system cancer' above.)

Insomnia is another common clinical complaint among children with cancer. In many cases, there are behavioral contributors (eg, parental/caregiver limit-setting or conditioned insomnia). Other contributors may include direct effects of the cancer or its treatment (pain, radiation therapy, glucocorticoids, or chemotherapy) or circadian rhythm disturbances due to hospitalization or other environmental contributors. Chronic insomnia disorder and specific subtypes can often be diagnosed and treated effectively. (See 'Behavioral insomnia' above and 'Circadian rhythm sleep-wake disturbances' above.)

Children with brain tumors are at particularly high risk for pathologic and persistent EDS, including narcolepsy. Circadian rhythm sleep-wake disorders and sleep-disordered breathing (obstructive and/or central sleep apnea) also are common. As a result, evaluation of a child with a brain tumor and sleep complaints typically includes polysomnography (PSG), which may be followed by a multiple sleep latency test (MSLT). (See 'Central nervous system cancer' above.)

Fatigue is reported by most children during cancer-directed therapy; it is generally defined as the subjective feeling of physical, emotional, or cognitive tiredness that interferes with participation in physical or social activities. Clinicians should attempt to distinguish fatigue from sleepiness by inquiring about specific symptoms of EDS. However, treatable sleep disorders may well underlie fatigue, just as they often underlie sleepiness. Interventions that may help to improve fatigue include physical activity and light therapy. (See 'Fatigue' above and 'Environmental interventions' above.)

Selection of interventions for EDS or insomnia should be targeted at the cause(s) of the sleep disruption, determined by a thorough diagnostic assessment. In many cases, a combination of diagnoses and factors may contribute to the sleep problem (table 3). General management typically includes:

Establish and maintain healthy sleep habits (table 5). (See 'Sleep hygiene' above.)

Utilize behavioral strategies for behavioral insomnia (due to parental/caregiver limit-setting or sleep-onset associations in younger children or conditioned insomnia in older children). (See 'Specific behavioral strategies' above.)

Optimize the sleep environment and increase daytime exposure to light and physical activity to entrain circadian rhythms. (See 'Environmental interventions' above.)

For children who fail to respond to these interventions and to treatment for any underlying sleep disorder, adjunctive pharmacotherapy is often beneficial, particularly for children with EDS or insomnia due to brain tumors. (See 'Medications' above and "Pharmacotherapy for insomnia in children and adolescents: A rational approach".)

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Topic 97876 Version 15.0

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