­­Diagnosis: Restless Sleep Disorder

A pediatric sleep specialist at Seattle Children’s Hospital, Lourdes DelRosso, MD, PhD, had long noted that many parents would come to a consultation with concerns that their children “moved a lot in their sleep, were tired during the day, or had problems in school.” The parents attributed the daytime symptoms to “poor sleep quality,” Dr. DelRosso recalls.

However, the children’s symptoms did not meet the criteria for a sleep movement disorder such as periodic limb movement disorder (PLMD), restless legs syndrome (RLS), or repetitive and rhythmic (i.e., stereotypic) movements during sleep such as headbanging or body rocking. The children instead had frequent movements involving the large muscles (e.g., repositioning) or sleep disruptions caused by body movements (e.g., falling out of bed, movement-related arousals).

In 2018, Dr. DelRosso proposed a novel pediatric sleep disorder, called restless sleep disorder (RSD).¹ The following year she was involved in a task force of international sleep experts that aimed to establish diagnostic criteria for RSD, .² One goal was to distinguish RSD from other movement disorders.

In 2020, the task force published a journal paper that provides a consensus on a definition and diagnostic criteria for RSD, based on a comprehensive literature review and expert clinical experience.² It was a huge step in raising awareness of this newly defined sleep disorder, and

In this article, we’ll delve into the characteristics and diagnostic markers that set RSD apart from common pediatric sleep movement disorders, look at links between iron deficiency and RSD, and touch on key areas for future research.

Distinguishing Characteristics of RSD

Although RSD involves increased movements during sleep, it differs from PLMD, RLS, and sleep-related rhythmic movement disorders in the following ways:

Periodic Limb Movement Disorder

In PLMD, a person’s limbs—usually the lower limbs—contract involuntarily and rhythmically (typically every 20–40 seconds) for intermittent periods during sleep.³ The movements occur at least four times per hour of sleep and can cause arousals, thereby interrupting sleep and contributing to excessive daytime sleepiness and fatigue. By contrast, the movements in RSD have no rhythmicity, although they can cause arousals and contribute to impaired daytime function.

Restless Leg Syndrome

RLS is characterized by an irrepressible urge to move the legs because of uncomfortable crawling, itching, or tingling sensations.^3-5 Symptoms are most noted when a person is at rest and briefly relieved by walking or moving, stretching, or rubbing the legs. Symptoms are worse during the evening, which can delay going to sleep at a desired time. The sensations typically resolve immediately before sleep onset. Symptoms occur at least three times weekly and persist for at least three months.

To qualify as a diagnosis of RLS, the latest edition of the American Academy of Sleep Medicine’s International Classification of Sleep Disorders further requires the symptoms to cause significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning.⁵ By contrast, body movements in RSD occur only during sleep.

Sleep-related Rhythmic Movement Disorders

A sleep-related rhythmic movement disorder involves stereotyped motor activity (e.g., body rocking and headbanging) that involves the large muscle groups, occurs predominantly during sleep, interferes with normal sleep, and contributes to significant impairment in daytime functioning or self-inflicted bodily injury, and is not better explained by another movement disorder or epilepsy.⁵ RSD involves large-muscle movements, but the movements are not stereotyped.

Criteria for Diagnosis

The task force’s recommended diagnostic criteria are as follows (all criteria need to be met for a diagnosis):⁶

1. The patient or the patient’s parent, caregiver, or bedpartner complains the patient has “restless sleep.”
2. Restless sleep movements involve large-muscle groups of the whole body (i.e., all four limbs, arms only, legs only, or head).
3. The movements occur only during sleep or when the individual appears to be asleep.
4. Video-polysomnography shows a total movement index of ≥5 movements per hour of sleep.
5. Restless sleep occurs at least three times weekly.
6. Restless sleep has occurred for at least three months.
7. Restless sleep causes clinically significant impairment in behavioral, educational, academic, social, occupational, or other important areas of functioning (e.g., daytime sleepiness, irritability, fatigue, mood disturbance, impaired concentration, or impulsivity), as reported by the patient or the patient’s parent, caregiver, or bedpartner.
8. The restless sleep is not better explained by another sleep disorder (e.g., RLS, PLMD, sleep-related rhythmic movement disorder); medical disorder (e.g., seizures); mental disorder; behavior disorder (e.g., attention deficit-hyperactivity disorder); environmental factor; or physiological effects of a substance.

Video-polysomnography is particularly beneficial for a diagnosis because it allows clinicians to objectively view and assess the sleep of a child with suspected RSD and distinguish this disorder from other sleep-related movement disorders such as RLS and PLMD. In addition, polysomnographic differences in sleep parameters, such as movement patterns, sleep stages, and arousals, may be beneficial in differentiating between RSD and RLS or PLMD. For example, some research indicates that body and arm movements are higher in children with RSD than in children with RLS and alterations in the amount of certain sleep stages such as slow wave sleep may be predictive of .^7-8

The task force’s effort to establish diagnostic guidelines for RSD that are consistent with The AASM International Classification of Sleep Disorders guidelines remains a work in progress.

Links with Iron Deficiency

A factor that is not mentioned in the aforementioned criteria but has been noted in people with RSD is low levels of blood iron or ferritin, an iron-storing protein that releases iron as needed from the body’s tissues.¹

Iron is involved in the production of the neurotransmitter dopamine, which is involved in movement, wakefulness, and some aspects of sleep, including the sleep–wake transition. notes, “Ferritin levels were low in children with RSD, and symptoms improved significantly or resolved after iron supplementation. We still need to elucidate the cause; we suspect it is related to brain iron deficiency, as in the case of restless legs syndrome, but maybe in a different brain region causing frequent movements. Iron deficiency, with or without anemia, can cause many symptoms.”

Iron deficiency is treated with oral or intravenous (IV) iron supplementation. However, even with appropriate treatment, a child’s iron levels may not increase. Some indicates that the efficacy of iron supplementation for RSD may depend on whether a child is a treatment responder or nonresponder.⁹ For example, Dr. DelRosso and colleagues examined treatment responses in children ages 2 to 18 with suspected RLS, RSD, and/or PLMD.⁹ Children with a ferritin level <50 µg/L received oral iron supplements for two to six months. They were classified as “responders” if their ferritin increased by ≥10 µg/L. After treatment, nonresponders had a higher rate of reporting “no change” in symptoms (71.4%) than did responders (26.2%). Treatment duration and ferritin level change were correlated in responders but not in nonresponders. Thus, the status of “responder” and “nonresponder” may be important when treating children with RSD.

Most studies have subjectively assessed symptom changes after iron treatment.^9-10 To determine whether subjective findings could be corroborated objectively, Chu and colleagues used actigraphy to objectively measure activity changes after iron supplementation in three children with RSD and low ferritin levels.¹¹ All received IV iron supplementation. Sleep features were measured via polysomnography.

Chu noted that after treatment, patient 1 had decreased day and night activity; patient 2 had increased activity during the day, which further increased dramatically at night; and patient 3 had decreased activity during the day but slightly increased activity. After IV treatment, ferritin levels increased by 99 µg/L (patient 1), 57 µg/L (patient 2), and 94 µg/L (patient 3), and RSD symptoms subjectively “very much” in patients 1 and 3 but “minimally” in patient 2. In light of these findings, Chu proposes that actigraphy could potentially be used to monitor treatment response to IV iron supplementation.

Beyond Pediatrics

Significant strides have been made in defining the characteristics of RSD as a primary sleep disorder and developing diagnostic criteria in the pediatric population. Promising research in RSD continues, with a focus on exploring this disorder in the adult population.

According to Dr. DelRosso, the International Restless Legs Study Group has formed a task force that she will be co-chairing with neurologist Daniel Picchietti, MD, to explore RSD in adults. “I expect to have more answers in the next two years,” she says.

Neurologist Merve Aktan, MD, has also been conducting research in this area in collaboration with Dr. DelRosso. Earlier this year, she was the lead author of a study looking at an analysis of large-muscle movements (LMMs) in the diagnosis of possible RSD (pRSD) in adult populations.¹⁰ They aimed to define pRSD features in adults by using clinical, electrophysiological, and biochemical data to analyze LMMs in patients complaining of restless sleep who did not fit the diagnostic criteria for other sleep disorders. They wanted to analyze the parameters with the strongest predictive power for LMMs and to determine LMM cutoff values that correspond to pRSD in adults.¹⁰

Their analyses demonstrated that the total LMM index in total sleep time ≥7.2/hour and the arousal-related LMM index in total sleep time ≥4.6/hour were significantly discriminative for pRSD from healthy controls with high sensitivity (with 78.6% accurately detected as having RSD) and specificity (72.3% accurately detected as not having RSD).

In patients with pRSD, the most significant predictors of LMMs were serum ferritin and transferrin saturation, the percentage of slow wave sleep, and the high-frequency band of heart rate variability during sleep.¹⁰ According to Dr. Aktan Suzgun, additional findings showed a 1% decrease in slow wave sleep percentage of total sleep time causes a 0.4/hour increase in the LMM index in the total sleep time and a 1 ng/mL decrease in the ferritin level causes a 0.2/hour increase in LMM index in total sleep time. Such findings are intriguing and encouraging because they offer potential targets for personalized treatment strategies for managing pRSD.

The Next Frontier in RSD

Adults who have RSD may have had symptoms since childhood.¹² In a recent study published in April, Xiaoli Wang states: “Adult patients also suffer from severe RSD, and the RSD that originates in childhood tends to persist into adulthood.”¹² However, clinicians often do not recognize RSD in children or adults, leaving individuals with RSD untreated and struggling with the effects of impaired sleep. Continued research in RSD may soon establish definitive diagnostic guidelines, further clarify RSD mechanisms, enhance clinicians’ recognition of this disorder, and improve treatment options.

By: Regina Patrick, RPSGT, RST

Source: SleepWorld Magazine September/October 2024

References

1. DelRosso LM, Bruni O, Ferri R. Restless sleep disorder in children: a pilot study on a tentative new diagnostic category. Sleep. 2018;41(8):1-7.
2. DelRosso LM, Ferri R, Allen RP, et al. Consensus diagnostic criteria for a newly defined pediatric sleep disorder: restless sleep disorder (RSD). Sleep Med. 2020;75:33540.
3. World Health Organization (WHO). International Statistical Classification of Diseases and Related Health Problems. 10th edition. WHO: Geneva, Switzerland; 1992.
4. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders. 5th edition. APA: Arlington, VA; 2013.
5. American Academy of Sleep Medicine (AASM). International Classification of Sleep Disorders. 3rd edition. AASM: Darien, IL; 2014.
6. DelRosso LM, Mogavero MP, Ferri R, et al. Restless sleep disorder (RSD): a new sleep disorder in children. A rapid review. Curr Neurol Neurosci Rep. 2022;22(7):395-404.
7. DelRosso LM, Jackson CV, Trotter K, Bruni O, Ferri R. Video-polysomnographic characterization of sleep movements in children with restless sleep disorder. Sleep. 2019;42(4):zsy269.
8. Aktan Suzgun M, Benbir Senel G, DelRosso L, Karadeniz D. Analysis of large-muscle movements in the diagnosis of possible restless sleep disorder in adult population. Sleep. 2024;47(7):zsae102.
9. DelRosso LM, Yi T, Chan JHM, et al. Determinants of ferritin response to oral iron supplementation in children with sleep movement disorders. Sleep. 2020;43(3):zsz234.
10. DelRosso LM, Picchietti DL, Ferri R. Comparison between oral ferrous sulfate and intravenous ferric carboxymaltose in children with restless sleep disorder. Sleep. 2021;44(2):zsaa155.
11. Chu ZYB, DelRosso LM, Mogavero MP, Ferri R. Actigraphy evaluation before and after intravenous ferric carboxymaltose in 3 children with restless sleep disorder. J Clin Sleep Med. 2023;19(3):633-7.
12. Wang X, Pan Y, Marcuse LV, Yuan N, Liu Y. Clinical and video-polysomnographic characterization of restless sleep disorder in adult patients. Sleep Biol Rhythms. 2024;22(3):395-402.