Restless sleep disorder in children

INTRODUCTION — Although restless sleep in children is a common clinical symptom and has been noted in the medical literature for decades, restless sleep disorder (RSD) was first defined as a specific disorder of sleep in children in 2018 [1-3]. Consensus diagnostic criteria for RSD emphasize a core clinical complaint of restless sleep accompanied by frequent large body movements on polysomnography, clinically significant impairment, and a lack of other causes for the restlessness [4]. While recognition of RSD was too recent to be considered for inclusion in the International Classification of Sleep Disorders, third edition [3], multiple publications provide substantial information on this disorder.

Data on pathophysiology, comorbidities, and treatment options are emerging. RSD has distinct features that separate it from other sleep-related movement disorders of childhood, such as restless legs syndrome, periodic limb movement disorder, or sleep-related rhythmic movement disorder, and is therefore presented as a separate disorder.

This topic review will focus on clinical features, diagnosis, and treatment of restless sleep disorder in children. Related topics that address movement and behaviors during sleep include:

●(See "Restless legs syndrome and periodic limb movement disorder in children".)

●(See "Sleep-related movement disorders in childhood".)

●(See "Approach to abnormal movements and behaviors during sleep".)

●(See "Parasomnias of childhood, including sleepwalking".)

EPIDEMIOLOGY — RSD has been studied and identified in children ages 6 to 18 years. It may also occur in younger children, but research is lacking. Restless sleep as a symptom has been described in adults, but restless sleep as a disorder has not [5].

RSD incidence, population prevalence, and remission rates are unknown. In a pediatric sleep clinic referral population, RSD accounted for 7.7 percent of diagnoses, with no difference in prevalence between males and females [6].

PATHOPHYSIOLOGY — Iron deficiency, sleep instability, and sympathetic activation have been implicated in the pathophysiology of RSD.

●Iron deficiency – Children with RSD typically have low or low-normal serum ferritin levels, with mean or median values between 16 and 22 mcg/L [1,7,8]. These values are similar to or lower than those observed in children with restless legs syndrome (RLS) [1,9] and slightly higher than typical levels in iron deficiency anemia (<15 mcg/L). While there is not consensus about ferritin levels in non-anemic iron deficiency, most data support the view that iron deficiency in the absence of anemia can occur with ferritin levels of 15 to 30 mcg/L [10,11]. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Definitions'.)

Iron deficiency, with or without anemia, alters neuronal dopaminergic neurotransmission in early development, impacting motor activity both during the day and at night [12]. These observations, together with studies showing that iron supplementation improves nighttime and daytime symptoms in children with RSD, support a brain iron deficiency hypothesis. (See 'Iron supplementation' below.)

Iron deficiency has also been implicated in the pathophysiology of other sleep movement disorders, such as RLS and periodic limb movement disorder (PLMD). (See "Restless legs syndrome and periodic limb movement disorder in children", section on 'Pathophysiology'.)

●Sleep instability – Cyclic alternating pattern (CAP) has long been recognized as a physiologic marker of sleep instability [13]. Studies in children with RSD suggest changes in the CAP A3 subtypes [14], shorter duration of the B phase of the CAP cycle, and shorter CAP cycle [15,16]. Interestingly, CAP events overlap with arousals [17] and contribute to sleep disruption [18].

●Sympathetic activation – Heart rate variability (HRV) provides information about balance in the autonomic nervous system and has been widely studied in sleep disorders to assess the interaction between the sympathetic and parasympathetic systems. The analysis of HRV includes two domains: the time domain and the frequency domain, which is further subdivided into high-frequency band (HF, a marker of parasympathetic activity) and low-frequency band (LF, a marker of sympathetic and parasympathetic modulation) [19].

Studies in children with RSD demonstrate a higher predominance of sympathetic activity during sleep compared with controls, particularly during rapid eye movement (REM) and N3 sleep, whereas no difference is found during wakefulness [20]. In the time domain, the RR interval during stage N3 is longer in children with RSD than in children with RLS. In the frequency domain, the LF band during N3 is higher in RSD compared with that in controls. During REM sleep, the LF/HF ratio is higher in both RSD and RLS compared with controls.

CLINICAL FEATURES

Sleep and daytime symptoms — Core clinical features of RSD include the following:

●Restless sleep – All children with RSD must have a concern of restless sleep reported by the patient’s parent, caregiver, or bed partner or by the patient [1,21]. Commonly used phrases include "moving all night," "all over the bed," "trashing the bed," and "moving like a helicopter" [4]. The child may be found in different positions, the bed sheets may end up on the floor, and sometimes the child may fall out of bed.

●Large body movements – Frequent, visible body movements are reported during sleep [1,21,22]. These movements involve the whole body, arms, legs, and/or head.

●Functional impairment – Daytime concerns associated with RSD include daytime sleepiness, irritability, fatigue, mood disturbance, impaired concentration, and impulsivity [21]. Parents and caregivers may report behavioral problems, poor school performance, or attention problems.

●Frequency and chronicity – Parents state that the movements occur almost every night and at any hour of the night. It may be reported that the child with RSD "has never been a good sleeper" [1]. Comparison of the child with RSD to siblings may be helpful since the parent may recognize that the child with RSD sleeps differently than siblings.

Surprisingly, insomnia symptoms are not the chief complaint. Although there are frequent movements and repositioning, children with RSD rarely wake up in the middle of the night and typically do not have difficulty falling asleep [1]. Similarly, there are no associated leg complaints.

Comorbidities — RSD has been found commonly in children with the following disorders:

●Non-rapid eye movement (NREM) parasomnias (eg, sleep terrors, sleepwalking, sleep enuresis) – RSD was found in 29 percent of children with the diagnosis of an NREM parasomnia [16].

●Attention-deficit/hyperactivity disorder (ADHD) – RSD was found in 9 percent of children with ADHD referred for polysomnography, which is slightly higher than the prevalence of RSD in a pediatric sleep clinic referred population (7.7 percent) [23].

Laboratory findings — All studies in children with RSD have found low or low-normal serum ferritin levels [1,7,8]. (See 'Pathophysiology' above.)

EVALUATION — The diagnosis of RSD is based on typical clinical features, exclusion of alterative disorders, and in-laboratory polysomnography.

History — RSD should be suspected in any child with concerns of restless sleep, frequent body movements during sleep, and daytime symptoms (see 'Sleep and daytime symptoms' above). The history is critical for confirming typical clinical features as well as distinguishing RSD from other sleep disorders. (See 'Differential diagnosis' below.)

The figure presents an algorithm that outlines a practical approach to the clinical complaint of restless sleep in childhood (algorithm 1).

Polysomnography — A polysomnogram is required in all children to confirm polysomnographic criteria for RSD and to rule out other causes of restless sleep, such as sleep-related breathing disorders or periodic limb movement disorder (PLMD) [18,24]. Clinical diagnosis is not sufficient.

Polysomnography in children with RSD demonstrates [1,25]:

●Frequent large muscle movements (at least five per hour) [18]

●Movements that occur throughout the night [1]

●No evidence for sleep-disordered breathing or increased periodic leg movement activity

The criteria for RSD recommend video polysomnography (at least one video frame per second) performed in agreement with the American Academy of Sleep Medicine (AASM) Scoring Manual standard [26].

To score large muscle movements with video polysomnography, careful video analysis must reveal clearly visible large body movements lasting for at least three seconds [18]. Movement types can include isolated arm or leg movements (not meeting the criteria for periodic limb movements of sleep [PLMS]); combined arm and leg movements without body repositioning; body position change; and head movements with or without limb movement. Movements must be scored, and an index per hour must be generated. PLMS should be marked and excluded before visual detection and measurement of large body movements.

To score large muscle movements when video is not available, criteria published by the International Restless Legs Syndrome Study Group (IRLSSG) might be a good alternative [24]. In this case, the technician uses the AASM-recommended leads for polysomnography. The movement must satisfy all of the following: present in at least two leads; EMG or movement artifact is at least twice the amplitude of the background signal amplitude; duration is ≥3 seconds with a maximum of 30 seconds for children and 45 seconds for adults; ends with return of amplitude to below twice the baseline signal amplitude for >1 second in the last of the channels involved.

In our practice, we score large muscle movements only when there is suspicion of RSD.

Iron studies — We suggest evaluating the iron status of all children with RSD because of the association between RSD and iron deficiency. Serum ferritin is the best single measure of iron stores. However, serum ferritin is an acute phase reactant, and false elevation can occur for up to four weeks after febrile illness [27]. As a result, we wait four weeks after acute illness before performing this test. If there is suspicion of chronic inflammation, we measure C-reactive protein (CRP). Less sensitive iron measures such as percent iron saturation (transferrin saturation) and total iron-binding capacity (TIBC) may also be helpful.

DIAGNOSIS

Diagnostic criteria — The International Restless Legs Syndrome Study Group (IRLSSG) has published consensus criteria for the diagnosis of RSD [4]. RSD has only been described in children and adolescents ages 6 to 18 years. Until there is further research, diagnosis outside of this age range should be approached with caution.

All of the following eight criteria must be met (algorithm 1) [4]:

●A complaint of "restless sleep" as reported by the patient's parent, caregiver, or bed partner or by the patient.

●Restless sleep movements involve large muscle groups of the whole body, all four limbs, arms, legs, or head.

●The movements occur during sleep or when the individual appears to be asleep.

●Video polysomnography shows a total movement index (by video analysis) of five or more per hour of sleep. An alternative method for scoring without video is described above. (See 'Polysomnography' above.)

●Restless sleep occurs at least three times per week.

●Restless sleep has been present for at least three months.

●Restless sleep causes clinically significant impairment in behavioral, educational, academic, social, occupational, or other important areas of functioning (eg, daytime sleepiness, irritability, fatigue, mood disturbance, impaired concentration, or impulsivity), as reported by the patient's parent, caregiver, or bed partner or by the patient.

●The condition is not better explained by another sleep disorder, medical disorder, mental disorder, behavior disorder, environmental factor, (eg, sleep-related breathing disorder, restless legs syndrome (RLS), periodic limb movement disorder (PLMD), sleep-related rhythmic movement disorder, chronic insomnia disorder, atopic dermatitis, seizure disorder), or the physiological effects of a substance (eg, caffeine).

There are two supportive features, which are typical but not necessary:

●The large body movements occur distributed throughout the night rather than clustering during the first half of the night, as is often seen with periodic limb movements of sleep (PLMS) and most non-rapid eye movement (NREM) parasomnias.

●Delayed sleep onset is uncommon. Significant differences in sleep latency were not seen between RSD patients and controls [1].

Differential diagnosis — Differentiating RSD from other disorders is essential. Conditions other than RSD should be identified and treated as the likely primary cause of restless sleep, with a diagnosis of RSD limited to cases where no other condition can better explain the restless sleep.

Important distinctions are [5]:

●RLS – RLS has been the most common condition compared to RSD. The essential and discriminating feature of RLS is an urge to move the legs, expressed by the child, often accompanied by uncomfortable or unpleasant sensations in the legs (table 1) [28,29]. Also, children with RLS can have PLMS, which is not a feature of RSD.

●PLMD – PLMD is a polysomnographic diagnosis characterized by frequent PLMS (index of five or more per hour (table 2)). This diagnosis supersedes the diagnosis of RSD [29,30].

●Sleep apnea – Sleep-related breathing disorders often present with frequent motor movements associated with the respiratory events, both of which resolve with effective treatment [31,32].

●Sleep-related rhythmic movement disorder – Sleep-related rhythmic movement disorder (SRRMD) has specific polysomnographic characteristics and scoring rules that differentiate it from RSD [30]. SRRMD is characterized by rhythmic movements of the head, neck, and/or trunk, most commonly manifesting as body rocking, head rolling (side to side), or head banging. (See "Sleep-related movement disorders in childhood", section on 'Rhythmic movement disorder'.)

●Chronic insomnia disorder – Insomnia can present with restless behaviors and movements during the night, but these usually occur during wakefulness, not during sleep as in RSD.

●Motor tics – Motor tics can persist during sleep and result in restless sleep. Tics are brief twitches and not large muscle movements, however, and they are also manifest during wakefulness [33].

●Atopic dermatitis – Atopic dermatitis is often accompanied by restless sleep, presumably due to pruritus during sleep [34].

●Others – Other conditions that may mimic RSD include asthma (especially if poorly controlled), nocturnal pain (including acute otitis media), sleep-related bruxism, sleep-related seizures, hypnagogic foot tremor, alternating leg muscle activation (ALMA), REM sleep behavior disorder, and the effect of a substance such as caffeine.

While it is very important to identify restless sleep caused by another medical, psychiatric, or sleep disorder, follow-up after treatment of these disorders is suggested to assess whether restless sleep persists. If it does, RSD should be considered as an additional diagnosis.

TREATMENT — There is very limited published evidence regarding treatment options for RSD. The treatment options discussed below are based upon RSD case series and our clinical experience in both RSD and pediatric restless legs syndrome (RLS). Individual risk versus benefit should be assessed. The focus of treatment is to improve sleep quality and, thereby, associated daytime symptoms.

Healthy sleep habits — All children with RSD should establish and maintain healthy sleep habits (table 3 and table 4). Recommendations include:

●Keep a regular sleep routine.

●Allow enough sleep opportunity for age (figure 1), including sleep extension if needed.

●Keep the sleep environment cool.

●Obtain regular exercise.

●Avoid caffeinated products.

●Avoid use of electronic devices at least one hour before bedtime.

Iron supplementation — For children with RSD who have a serum ferritin less than 50 mcg/L, we suggest iron supplementation. This is based on the consistent association between RSD and low or low-normal serum ferritin, as well as small studies reviewed below showing a clinical benefit of iron in children with RSD. We generally start with oral iron and offer intravenous (IV) iron if oral iron is not effective or tolerated.

We administer iron based on a regimen used by most pediatric sleep physicians for children with restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) [35]:

●Oral iron

•Adolescents 12 years and older – Ferrous sulfate 65 mg of elemental iron per tablet, one to two tablets once daily.

•Children younger than 12 years – Ferrous sulfate 3 mg/kg/day of elemental iron (to a maximum of 130 mg elemental iron daily), administered once daily.

•The rationale for these doses and strategies to avoid side effects and optimize adherence are discussed separately. (See "Iron requirements and iron deficiency in adolescents", section on 'Oral iron therapy' and "Iron deficiency in infants and children <12 years: Treatment", section on 'Oral iron therapy'.)

•Iron should not be taken with milk or other dairy and calcium-containing products, as these will lessen absorption.

•We also advise parents and caregivers about safe storage of iron supplements to prevent accidental ingestion, which can be lethal. (See "Acute iron poisoning".)

●IV iron

•The most-studied IV preparation for RSD is ferric carboxymaltose at a dose of 15 mg/kg (for children weighing <50 kg) and a dose of 750 mg (for children weighing >50 kg) [7].

•IV iron should be administered at an infusion center with pediatric experience and with care taken to avoid extravasation of iron subcutaneously. (See "Iron deficiency in infants and children <12 years: Treatment", section on 'Intravenous iron therapy'.)

●Monitoring and response – A clinical response can be expected by three months of adherent oral iron supplementation and by eight weeks after IV iron supplementation.

•We recheck serum ferritin in two to three months and adjust treatment as needed to target serum ferritin levels between 50 and 100 mcg/L. This range generally reflects optimal body iron stores, unless the value is falsely elevated by an inflammatory state. For treatment of RSD, it appears to be important to target optimal iron status rather than typically defined "normal" ranges for tests of iron sufficiency.

•Once iron stores have been replenished, we continue to monitor the child’s iron status by checking serum ferritin periodically. In many children, it may be difficult to attain and maintain a serum ferritin level >50 mcg/L due to growth, decreased iron absorption once levels get to the low-normal range, and blood loss with menses in adolescent girls. In some children, we continue therapeutic doses of oral iron in anticipation of growth spurts.

It is important to monitor children during treatment with therapeutic doses of iron to avoid the rare but serious complication of iron overload, which can occur in individuals who carry hemochromatosis genes [36]. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

●Evidence – Supporting evidence for iron in RSD consists of small observational studies [7,8,37]. In the largest retrospective study, 30 patients with RSD received either oral or IV iron supplementation as part of routine care, and a Clinical Global Impression (CGI) scale was assessed at baseline and post-treatment [7]. Among 15 children treated with oral iron, CGI scores improved at three months and serum ferritin rose from a median of 16 to 34 mcg/L. Among 15 children treated with IV ferric carboxymaltose, CGI scores were "much improved" and serum ferritin rose from a median of 16 to 124 mcg/L at eight weeks after iron infusion. Compared with oral iron, IV iron was associated with greater improvement in both CGI scores and serum ferritin levels. Similar results were reported in a retrospective study of IV iron in 17 children with RSD [8].

Other interventions — There is no evidence that medications used to treat other pediatric sleep-related movement disorders are effective in treating RSD. No medications have been approved by the US Food and Drug Administration (FDA) for pediatric RSD. This is also true for other pediatric sleep disorders, despite evidence of long-term negative impact when sleep problems in children are not treated [38]. Therefore, the interventions discussed below are off-label uses of medications based upon evidence extrapolated from other pediatric sleep disorders and limited experience in children with RSD.

We have found that medications used to improve sleep quality can be used to help RSD symptoms at the clinician’s and family’s discretion short term, while iron status improves. These medications include gabapentin and clonazepam at doses used for pediatric RLS. (See "Restless legs syndrome and periodic limb movement disorder in children", section on 'Medication'.)

REMAINING QUESTIONS — As a recently described sleep disorder, RSD requires further research in several key areas. Large muscle movement indices are needed for the diagnosis of RSD in children younger than 6 years of age and adults older than 18 years of age. Other diagnostic methods should be explored, such as home video or activity monitors. There is more to learn about the natural history of RSD across the lifespan, and treatment options beyond iron supplementation need to be studied.

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: Restless legs syndrome".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Restless sleep disorder (RSD) has been identified and characterized in children ages 6 to 18 years. The disorder was first described in 2018, and incidence and population prevalence are not yet known. (See 'Epidemiology' above.)

●Pathophysiology – Iron deficiency, sleep instability, and sympathetic activation have been implicated in the pathophysiology of RSD. Low or low-normal serum ferritin levels have been consistently identified in children with RSD. (See 'Pathophysiology' above.)

●Clinical features – The hallmarks of RSD are restless sleep, large body movements during sleep, and associated impairment of function. Children present with daytime symptoms of sleepiness, inattention, behavioral problems, or poor sleep performance. (See 'Sleep and daytime symptoms' above.)

●Evaluation – All children suspected of having RSD should undergo a history and physical examination, polysomnography, and serum iron studies. History and polysomnography help to exclude other disorders that can cause restless sleep, such as sleep apnea, restless legs syndrome (RLS), and periodic limb movement disorder (PLMD). (See 'Evaluation' above and 'Differential diagnosis' above.)

●Diagnosis – Diagnosis of RSD requires fulfillment of eight diagnostic criteria, including video polysomnography showing a large muscle movement index of five or more (algorithm 1). Scoring rules for large muscle movements have been published. (See 'Diagnostic criteria' above and 'Polysomnography' above.)

●Treatment – The focus of treatment is to improve sleep quality and, thereby, associated daytime symptoms.

•Healthy sleep habits – All children with RSD should establish and maintain healthy sleep habits (table 3 and table 4). (See 'Healthy sleep habits' above.)

•Assess and treat iron deficiency

-Serum ferritin should be measured in all patients with RSD. (See 'Iron studies' above.)

-For children with RSD who have a serum ferritin less than 50 mcg/L, we suggest iron supplementation (Grade 2C). We generally start with oral iron and offer intravenous (IV) iron if oral iron is not effective or tolerated. (See 'Iron supplementation' above.)

-Serum ferritin should be rechecked in two to three months and treatment adjusted as needed to target serum ferritin levels between 50 and 100 mcg/L. (See 'Iron supplementation' above.)

•Other interventions – There is no evidence that medications used to treat other pediatric sleep-related movement disorders are effective in treating RSD. Short-term use of selected medications to improve sleep quality may be appropriate for some children while iron status improves. (See 'Other interventions' above.)

●Remaining questions – Areas of future research for RSD include natural history across the lifespan, development of large muscle movement indices in children younger than 6 years of age and adults older than 18 years of age, and exploration of alternative diagnostic methods such as home video and activity monitors. (See 'Remaining questions' above.)