Clinical manifestations

Presentation and course

The most characteristic symptom of restless sleep disorder is frequent movements during sleep.

Parents usually describe these movements in various forms, for example, “moves like a helicopter,” “sleeps like a fish,” or “fights in his sleep.” In some cases, children have fallen out of bed and ended up sleeping on a mattress on the floor. These descriptions by the parents have been corroborated by video polysomnography analysis. In fact, in the very first restless sleep disorder descriptive study, video polysomnographic characterization of restless sleep disorder demonstrated that these children move through the night at a rate of approximately five large body movements or repositionings per hour (11). Restless sleep disorder is also a chronic disorder occurring at least three times a week and for at least 3 months. The chronicity of restless sleep disorder is an important consideration, particularly because restless sleep has also been associated with other disorders, and it is important to rule out temporary causes, such as eczema exacerbation, infection, or effect of the surrounding environment (eg, temperature). Parents are also concerned about daytime symptoms because children with restless sleep disorder can present with poor academic performance, excessive daytime sleepiness, behavioral problems, mood disorders, or difficulty with attention or hyperactivity (07). A study assessed cognitive and executive functions in children with restless sleep disorder and showed that selective attention was the most affected area (16).

Early studies compared children with restless sleep disorder to children with restless legs syndrome and identified a lack of leg kicks during sleep in children with restless sleep disorder, whereas children with restless legs syndrome are known to have an increased index of periodic limb movements of sleep in 70% of cases (19). Children with restless legs syndrome tend to present with symptoms of insomnia and the classic “urge to move the legs,” whereas children with restless sleep disorder do not typically present with concerns for insomnia (39). Another important consideration in the differential diagnosis is periodic limb movement disorder; however, identifying periodic limb movement disorder requires an index of periodic limb movements of at least five per hour. Periodic limb movements are characteristic movements that are excluded when counting the large body movements of restless sleep disorder (12).

The natural course of restless sleep disorder is currently unknown. It has been described in children but not adults. Table 1 summarizes the diagnostic criteria for restless sleep disorder.

Table 1. Diagnostic Criteria for Restless Sleep Disorder (A to H must be met)

Prognosis and complications

The long-term consequences of restless sleep disorder are unknown. Parents of children with restless sleep disorder report that the children present with excessive sleepiness, inattention, and behavioral problems. Currently, restless sleep disorder has not been described in adults.

Biological basis

Etiology and pathogenesis

Although the pathophysiology of restless sleep disorder is unknown, current research points towards iron deficiency as a main contributing mechanism. Other important findings that help elucidate the underlying mechanism include changes in cyclic alternating pattern and heart rate variability.

Early studies demonstrated that children with restless sleep disorder had low ferritin levels. On average, children with restless sleep disorder were found to have ferritin levels around 20 ng/dl; this finding was lower than the ferritin levels in children with restless legs syndrome (07). Nonanemic brain iron deficiency in patients with restless legs syndrome has been identified and defined as ferritin levels lower than 50 ng/dl. Low iron level represented by low ferritin level is a known contributor to sleep-related movement disorders, mainly by altering dopaminergic pathways involved in motor activity at night (02). Children with restless sleep disorder not only have low ferritin levels at presentation but also demonstrate improvement in sleep patterns and daytime symptoms after supplementation with iron, supporting the pathophysiologic mechanism of iron deficiency (15; 25).

Sleep instability was studied by analyzing a physiological electroencephalographic pattern detected in polysomnography during NREM sleep called cyclic alternating pattern, which is a marker of NREM sleep instability (11). Cyclic alternating pattern cycles include two subtypes (A3 and B). Children with restless sleep disorder had abnormal cyclic alternating pattern characterized by a lower percentage of A3 subtypes than controls, shorter duration of the B phase of the cyclic alternating pattern cycle, and shorter cyclic alternating pattern cycle suggesting abnormalities in sleep stability. Another interesting finding was that movements in children with restless sleep disorder occurred mainly during NCAP periods interrupting the sleep period (33), confirming that the large muscle group movements seen in children with restless sleep disorder during sleep are associated with significant sleep disruption.

During sleep, in particular, during NREM sleep, there is a predominance of parasympathetic activity responsible for slowing the heart rate and lowering blood pressure (40). Increased sympathetic activation has been demonstrated in sleep disorders that disrupt NREM, such as obstructive sleep apnea (17). Heart rate variability is a marker of sympathetic-to-parasympathetic balance (23). Children with restless sleep disorder have demonstrated subtle abnormalities in heart rate variability consistent with increased sympathetic activation during sleep compared to controls (21; 36).

Epidemiology

The incidence and prevalence of restless sleep disorder in the general population are unknown. The prevalence of restless sleep disorder in a pediatric sleep center referred population is 7.7% (09), which places it around the prevalence of insomnia in children. Studies have also reported that restless sleep disorder can coexist with other disorders or sleep-related complaints. In fact, the prevalence of restless sleep disorder in children with attention deficit hyperactivity disorder has been found to be 9.1% (26). Furthermore, when restless sleep disorder coexists with another disorder like parasomnia, the symptoms of sleep disruption are worse than those in children with parasomnia but without restless sleep disorder (36).

Prevention

Primarily, it is important to understand that children with normal hemoglobin levels can still be at risk of nonanemic iron deficiency (04). Prevention of iron deficiency is key in the prevention of restless sleep disorder. In a sleep medicine setting, every child evaluated in a sleep center should have an assessment of sleep quality and restless sleep. If restless sleep is present, a video polysomnogram must be performed in agreement with the American Academy of Sleep Medicine Scoring Manual standard, which recommends at least one video frame per second (05). The PSG diagnosis of restless sleep disorder includes five or more movements per hour during sleep (07). It is important to re-assess sleep quality after another sleep disorder has been treated. For example, a child with obstructive sleep apnea and restless sleep undergoes adenotonsillectomy; snoring and apnea resolve, but restless sleep and frequent movements could persist. Special attention is recommended to screen restless sleep disorder in patients known to be at high risk, including children with attention deficit hyperactivity disorder and parasomnia.

Differential diagnosis

Confusing conditions

It is important to identify restless sleep disorder from other sleep-related movement disorders that present with parental perception of restless sleep (Table 2). The most common disorders that present with restless sleep are obstructive sleep apnea and restless legs syndrome. Video polysomnography is, therefore, indicated to rule out obstructive sleep apnea, periodic leg movement disorder, and nocturnal seizures (43).

Restless legs syndrome can be easily differentiated in children who can express in their own words the urge to move the legs and the improvement in symptoms with the movement of the legs. The other two key diagnostic features of restless legs syndrome include worsening of symptoms in the evening and during periods of rest.

Sleep-related rhythmic movement disorders are repetitive, rhythmic movements that usually start early in infancy and rarely persist in children older than 5 years of age. These movements are quite typical and hard to miss. For example, the child rolls back and forth or bangs his head against the pillow repetitively. The movements are also more common during periods of sleep-wake transition and are postulated to be associated with self-soothing mechanisms prior to sleep (08).

Bruxism is another sleep-related movement disorder equally difficult to miss. The hallmark of bruxism is teeth grinding. A characteristic “grinding” sound is often heard.

Nocturnal epilepsy can present with dystonia, stereotypical movements, and myoclonic movements. These movements occur during the seizure and can be correlated with electroencephalographic findings. Although seizures can occur several times a night, they are usually rare during REM sleep (38).

Children with restless sleep disorder move through the night and in every sleep stage, including REM sleep, with an index of at least five movements per hour. Children with restless sleep disorder do not have leg movements characteristic of periodic leg movement disorder, and the prevalence of comorbid bruxism in other sleep-related movement disorders has not been studied.

Table 2. Differential Diagnosis of Restless Sleep Disorder

Associated or underlying disorders

Iron deficiency is the only disorder that has been associated with restless sleep disorder.

Diagnostic workup

The evaluation of restless sleep in children should start with a complete medical and sleep history and physical examination. Often conditions or medications that can contribute to restless sleep can be identified at this step, and appropriate measures to improve the disorder can be prescribed. A clear example is eczema. A skin evaluation can identify the typical lesions, and treatment recommendations can be prescribed. Follow-up should be established to ensure improvement in sleep after treatment of a primary medical, psychiatric, or sleep disorder. If a primary cause is not identified, a sleep study or polysomnogram should be ordered. At this stage, other sleep disorders can be identified, such as obstructive sleep apnea and periodic limb movement disorder. Large body movement index can be identified in polysomnography, and the International Restless Legs Study Group criteria should be used to score large muscle group movements (20). A large muscle group movement index of five or more is diagnostic of restless sleep disorder. A single case series report using actigraphy before and after intravenous iron administration in children with restless sleep disorder showed inconsistent results (06). Therefore, actigraphy or other home sleep monitors are currently not recommended for diagnosis of restless sleep disorder.

Management

Outcomes

Iron supplementation is the main treatment option for children with restless sleep disorder. Children with ferritin levels lower than 50 ng/dl are recommended to start oral iron supplementation in the form of ferrous sulfate 325 mg tablet or liquid given from 1 to 3 mg/kg/day for at least 3 months. Some considerations to side effects of oral iron supplementation include constipation and teeth staining (15). Children who can not take oral iron and those who experienced significant side effects or were not compliant with oral iron would be good candidates for intravenous iron administration. Ferric carboxymaltose in a single dose of 15 mg/kg if weighing less than 50 kg or 750 mg if weighing over 50 kg has shown significant improvement in iron levels and symptoms. When comparing both groups, it was found that serum ferritin increased with both oral and intravenous iron, and symptoms improved in both groups, but intravenous iron showed more improvement in ferritin and symptoms (13).