Common mimics
∙ Positional discomfort
∙ Sore leg muscles
∙ Ligament sprain/tendon strain
∙ Positional ischemia (numbness)
∙ Dermatitis
∙ Bruises
∙ Growing pains
Less common mimics
∙ Leg cramps
∙ Arthritis
∙ Other orthopedic disorders
∙ Peripheral neuropathy
∙ Radiculopathy
∙ Myelopathy
∙ Myopathy
∙ Fibromyalgia
∙ Complex regional pain syndrome
∙ Drug-induced akathisia
∙ Sickle cell disease
As RLS symptoms occur during bedtime they are most likely to interfere with sleep onset and these symptoms may be confused with bedtime resistance and limit setting-type behaviors.
Unlike RLS, leg cramps are very painful, typically affect only one leg, and are restricted to specific muscle groups. Symptoms are not relieved by leg movements (LMs) and are alleviated by rest and alternate use of ice packs and warm compresses. Electrolyte disturbances and neuromuscular disorders may be an underlying etiology, especially in severe cases.
Causes of secondary RLS include peripheral neuropathy and uremia. Medications, such as antidepressants, sedating antihistamines, and dopamine receptor antagonists, may worsen or precipitate cases of RLS.
It is important to evaluate the similarities and the differences between pediatric RLS and growing pains, a common benign condition in childhood characterized by intermittent bilateral leg pain that occurs in the late afternoon or evening [14]. A recent paper explored the relationship between pediatric RLS and growing pains showing the considerable overlap in the diagnostic criteria and the sharing of clinical symptoms. RLS and growing pains are common disorders, with criteria for definite RLS met by 1.9% of children ages 8–11 years and 2% of children and adolescents ages 12–17 years [2]. The prevalence of growing pains widely varies from study to study, but conservative estimates suggest a prevalence of 4.7% [15]. RLS and growing pains commonly occur together and the family histories of RLS and growing pains often are overlapping. Leg rubbing to obtain relief from leg discomfort is common to both disorders, though walking to obtain relief seems unique to RLS; on the other hand, childhood RLS has been reported to be painful in up to 45% of cases. Even experienced clinicians found difficult to differentiate the two conditions that could represent the different phenotypic expressions of the same disorder [16].
Furthermore, growing pains differ from RLS in that the unpleasant sensations are not partially or totally relieved by movements of the lower extremities. Typically, children may awaken in the middle of the night complaining of a “throbbing” pain in the legs. Onset usually occurs during early to late childhood, and the location of the pain is prominent in the front of the thighs, calves, or behind the knees. Symptoms may be alleviated with massage, ice packs, warm compresses, and acetaminophen or ibuprofen. To better evaluate the similarities and differences between the two disorders, a genome wide association study of all genes with particular attention to those genes identified as related to RLS need be performed in growing pain children.
There are no specific tests for RLS and the diagnosis is made through a complete medical history and physical examination. An overnight sleep study may be recommended to evaluate for other sleep disorders, especially periodic limb movement disorder.
The RLS diagnosis in children is often hampered because children may be unable to provide a good description of the symptoms. This clinical criteria constitutes the first obstacle for the clinician who examines a child compelling for a sleep disorder suggestive for RLS: spontaneous verbal expression of symptoms can be very limited, especially in preschoolers.
Establishing a good relationship with the child will greatly enhance chances of accurately assessing sensory symptoms, while the parents can refer other symptoms. It is very important to avoid leading questions and facilitate expression of the sensation in the child’s own words.
When exploring RLS diagnostic criteria in children, it is important to use age-specific vocabulary (e.g., “Do your legs bother you?”) and encourage the child to report symptoms in his/her own words; to define “urge” to move, children use more age-appropriate terms such as “need to move”, “want to move,” and “got to kick”.
Sensory symptoms are difficult to explain by children and simple description such as a funny feeling, pain, hurting, tickling, bugs, spiders, ants, goose bumps in the legs can be accepted.
Most children will not describe an ‘urge to move’ per se, but parents may report frequent stretching, kicking, pacing and running around and/or requests for leg massage. These symptoms may be perceived by parents as bedtime resistance behaviors: these children avoid being in bed and lying still as these symptoms may worsen by inactivity. Sometimes children may draw pins, needles, tiny sand particles, bugs, or a saw over their legs when asked to depict their symptoms.
The presence of RLS may be unrecognized, especially in infants and preschool children that may present clinically with sleep disturbance before the onset of any RLS feelings, months or years later [17]. Recently it has been described as typical of early RLS an awakening after 1–3 h of sleep accompanied from screaming, crying, kicking and slapping the legs or by verbally expressing that the legs ‘hurts’ [18].
RLS-related pain in children typically occurs from both knees down and especially involves the calves, although thigh pain may also appear. These pains can be symmetric or asymmetric. Partial or complete resolution by movement is a key feature when diagnosing RLS in children with pain complaints.
To decide on the appropriateness of a possible treatment, clinicians should assess not only the severity of symptoms but also the impact of RLS symptoms on sleep, cognition, and mood.
The above reported diagnostic criteria are intended for both clinical and research settings. However, due to some differences in the presentation of symptoms the pediatric RLS committee adopted two different diagnostic categories [9]:
Probable RLS
- (a)
The child meets all five essential criteria for RLS, except criterion 4 (occurrence only or worsening in the evening or night). A significant subset of children do not report worsening at evening and night, yet they meet all other diagnostic criteria and have supportive features for RLS including a positive family history [2, 17, 19].
- (a)
Possible RLS
- (b)
The child is observed to have behavior manifestations of lower extremity discomfort when sitting or lying, accompanied by motor movement of the affected limbs. The discomfort is characterized by RLS criteria 2–5 (is worse during rest and inactivity, relieved by movement, worse in the evening or night, and is not solely accounted for as primary to another medical or a behavioral condition). This diagnosis is based on behavioral observations rather than direct report by the child or adolescent and is particularly helpful for children younger than 6 years of age and in children with neurodevelopmental disabilities).
- (b)
The diagnosis of pediatric RLS is mostly based on clinical symptoms but in order to support the diagnosis the clinician should evaluate the presence of Periodic Limb Movements during sleep (PLMS) >5 per hour and, most importantly, a family history showing the presence of: (a) RLS among first-degree relatives; (b) PLMS >5 per hour; (c) Periodic Limb Movements Disorder (PLMD) among first-degree relatives.
RLS and ADHD
In literature several studies have shown a strict association between RLS and ADHD or ADHD symptoms both in clinical and in community samples. Sleep disruption associated with RLS may lead to ADHD symptoms, RLS may mimic the symptomatology of ADHD, or it may be comorbid with idiopathic ADHD [20–25].
About 25% of adults and school-age children with RLS meet the criteria for ADHD, whereas 12–35% of children with ADHD met the criteria for RLS [21, 26]. Several different studies showed that diurnal manifestations of RLS mimic ADHD and that RLS/PLMs are more prevalent in ADHD children [23]; in particular up to 44% of ADHD children have RLS and up to 26% of RLS children have ADHD [27].
The exact relationship of ADHD, RLS, and PLMD is not clear but we can hypothesize different possible explanations of this association:
RLS may might lead to symptoms of ADHD through sleep disruption, i.e. hyperactivity might lead to inattention through the mechanism of leg discomfort
RLS may mimic ADHD symptomatology in restrictive situations such as when seated in a classroom, movie theater, airplane, or car
RLS and ADHD may coexist as comorbid disorders
RLS, PLMD, and ADHD share a common dopamine dysfunction, which could be genetically determined, at least in subgroup of patients and respond to dopaminergic agents.
For these reasons, the association between RLS and ADHD symptoms may have relevant implications for treatment when these conditions coexist [27]. For example, stimulant medication has been found to not adversely affect RLS or PLMS and conversely may improve sleep and diminish ADHD symptoms [1].
Both ADHD and RLS have been found to be associated with iron deficiency (ID) [27]: The hypothesis of ID is not incompatible with the hypothesis of dopaminergic hypoactivity, since iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis. Children with ADHD are more likely to have ID and treatment with supplemental iron has been reported to help reduce their PLMD symptoms, improve sleep quality and subsequently decrease ADHD symptoms.
Furthermore, preliminary observational data suggest that RLS in parents of children with ADHD predicts lifetime occurrence of ADHD and anxiety disorders, especially agoraphobia, implying a genetically conveyed vulnerability for psychiatric disorders and RLS in families with ADHD [28]: a shared dysfunction in dopaminergic, adrenergic and serotoninergic neurotransmitter systems may explain this association.
It has been further demonstrated that ADHD symptom severity was higher in children with ADHD when RLS is present as comorbid disorder [29]. In children diagnosed with both RLS and ADHD, previously unsuccessfully treated with psychostimulants, low doses of dopaminergic agents (levodopa, pergolide, and ropinirole) has been effective [27] and also those children benefits of the concurrent administration of iron supplementation [30].
RLS and PLMS
Different reports showed that RLS and PLMS may occur in children [31, 32]. The relationship between RLS, PLMS, and PLMD is complex. Most individuals with RLS have PLMS [33] and PLMS are considered to be supportive of an RLS diagnosis in children and represents an objective measure for RLS and be an endophenotype for certain RLS cases [34]. Furthermore, PLMD is considered as a diagnostic entity related to RLS, particularly for children and that PLMD evolves to RLS in children over time [32]. Often a diagnosis of PLMD precede the diagnosis of RLS in young children less than 6 years of age who do not yet have well-developed language skills and therefore cannot adequately describe the sensory component of RLS and the development of a clear sensory component could appear only in early adolescence [32]. The clinical picture of an RLS child could be extremely variable: a child can have RLS with PLMS, but he or she cannot have RLS and PLMD.
The role and clinical significance of periodic leg movements during sleep (PLMS) are still under debate [35]; however, they remain the most important and constant objective finding in RLS and PLMD in adults.
Different studies have shown that periodicity of LMs develops with age and is unusual in normal children or children with RLS [36, 37] because LMs tend to show clear-cut periodicity in subjects with RLS only after the second decade and in normal controls after the fourth decade of life. Furthermore PLMS index increased up to age ages 15–25 years then plateaued until age 65 years when there was another increase, [2] periodicity index progressively increased up to the age of 35 years and then remained stable up to age 85, and [3] time of night decrement was evident at 15–75 years of age but not <15 or >75 years [36].
So, the classical PLMS Index does not seem to be sufficiently specific for the diagnosis and clinical significance of RLS. Ferri et al. [38] have suggested a new approach for the detection and analysis of LMs recorded from the anterior tibialis muscles during sleep in patients with RLS, with particular attention to their quantity, duration, amplitude and periodicity. They also have suggested that a synthesis of the features of LMs during sleep can be achieved by considering three main parameters including the total number of LMs per hour of sleep, the periodicity of the LMs and the distribution of the LMs throughout the night.
Furthermore, Manconi et al. [39] showed that only a subset of LMs during sleep corresponding to the periodic component of the whole leg motor activity during sleep (with intermovement intervals 6–46 s and duration of 2–4 s) responded to pramipexole treatment while the non periodic isolated LMs did not.
The primary findings of a recent study conducted from Ferri et al. [40] in a clinical sample of children with ADHD were an increased PLMS index in ADHD children compared to controls but a low periodicity index and little time of night decrement in both groups. For children the intermovement intervals may be short and variable in contrast to the typical 15–40 s intervals in adults [41–43]. However, although this was within the PLMS range, the peak was not prominent and most of the activity was quite irregular with lack of the fixed stereotypic pattern characteristic of adult RLS.
Treatment
Pediatric RLS therapy is really important since RLS’s associated sleep disturbances might determine significant developmental-behavioural and cardiovascular morbidity and impacts family well-being. Positive parental involvement and support is another important aspect in the treatment of pediatric RLS, nonetheless because RLS is highly familial and it is not unusual for a parent to be affected.
Treatment reviews and algorithms for RLS and PLMD have been recently published for adults but not for children [44]. For pediatric RLS and PLMD, the focus of treatment is not only to reduce leg symptoms but mainly to improve sleep. In patients who are thought to have secondary RLS, screening for renal disease, thyroid dysfunction, vitamin B12 and folic acid deficiency (peripheral neuropathy) should be considered.
Non-pharmacologic Interventions
Establishing healthy sleep habits is an important aspect of a comprehensive treatment plan. In milder cases, these interventions alone can be sufficient. Adequate sleep duration, regular bed timings and routine principles of good sleep hygiene are important.
Daily exercises in the daytime (avoid vigorous exercise and mind-stimulating activities around bedtime) can improve sleep quality and help to reduce RLS symptoms. Good sleep hygiene practices can be helpful for children with RLS. These include enforcing a regular sleep-wake schedule; avoiding caffeine, heavy meals, fluids, or exercise within a few hours of bedtime, and discouraging non-sleep-inducing activities such as watching television or playing games near bedtime. For legs symptoms relief, the use of local comfort aids is helpful: apply a heating pad, cold compress, or consider rubbing legs but also consider massage, acupressure, walking, stretching, or other relaxation techniques.
It is important to identify medications or other factors that could aggravate RLS and PLMD and examine ways of discontinuing these medications. For instance, selective serotonin reuptake inhibitors (SSRIs), tryciclic antidepressants (TCAs), metoclopramide, diphenhydramine, nicotine, caffeine, and alcohol has all been shown to either promote or aggravate RLS and PLMD.
Iron Hypothesis
The most common cause of secondary RLS in children appears to be iron deficiency (ID): ID is prevalent in human infants, especially in the late infancy/toddler period and there is mounting evidence that ID affects motor activity [45]. Typically, iron stores increase slowly with supplemental iron over weeks to months, and buildup is delayed by physical growth. The level of iron stores in humans is easily measured by serum ferritin that is the best indicator of early iron deficiency, but can be a challenging marker to interpret: cut-off values differ across centres and literature sources, and as an acute-phase reactant, false elevations can occur from infection or inflammation [46]. Saturation of peripheral iron stores typically occurs at ferritin levels of 80–100 ng/mL. Current evidence suggests that achieving and maintaining serum ferritin above 50 ng/mL can be of benefit [32, 46]. In children, therapeutic iron has been found to be of benefit for RLS, PLMS, and ADHD [29, 30, 47, 48].
The dopaminergic theory of RLS further support the ID hypothesis since iron is fundamental for the biosynthesis of dopamine and it is necessary for tyrosine hydroxylation, which is a rate-limiting step for dopamine production. Iron deficiency has been well documented from brain autopsy, magnetic resonance imaging and cerebrospinal fluid studies of adults with RLS [18, 49, 50].
Some authors have postulated that increased leg activity during the period of IDA might indicate a shared underlying mechanism with RLS [51, 52]. Peirano et al. [52] found that that 10-year-old children who experienced IDA in infancy showed a mild but significant increase of tibialis anterior EMG activity during sleep when compared to age-matched normal controls. The activity is characterized by a slightly but significantly higher periodicity due to a selective increase of muscle activations separated by an interval ranging approximately 10–50 s. Taken all together, these findings point to the possibility that long-term consequences of IDA in infancy, despite iron therapy, can be detected during sleep.
Whether increasing peripheral iron stores increases brain iron stores has not yet been definitively determined. The only placebo-controlled trial involving children with RLS was an RCT for ADHD [30] included 23 children with ADHD and serum ferritin levels <30 ng/mL, randomized with a 3:1 ratio to oral iron (ferrous sulfate: 80 mg/day; n = 18) or placebo (n = 5). After 12 weeks, although the reduction on the CPRS index score and on the CTRS index score failed to reach significance (p = 0.055 and p = 0.076, respectively), the authors found a significant decrease in the clinical global impression severity scale (p < 0.01).
A general recommendation for iron supplementation when ferritin level is <50 μg/L is to start with 3 mg elemental iron/kg/day or ferrous sulfate at a dose of 50–65 mg of elemental iron for three months and then recheck ferritin level. To enhance absorption, iron should ideally be taken in the morning on an empty stomach with a source of vitamin C such as orange juice. Some foods (e.g. milk, cereals, fiber, eggs) may decrease iron absorption for 2 h.
Children need monitoring over time for symptom recurrence. Although the risk of iron overload is very low parents should be asked for a personal and family history of hemochromatosis or unexplained liver disease, and it is recommended to measure transferrin saturation and ferritin levels at baseline and at least twice yearly while on iron. Finally consider that it may take weeks or months of treatment with iron supplementation to detect improvements in RLS symptoms.
Pharmacologic Treatment
Recently consensus-based guidelines for pharmacological treatment of adult RLS have been published [53, 54] but no specific papers or guidelines are available for children. Currently, either the US Food and Drug Administration or the European Medicines Agency (EMEA) have not approved medications for RLS in children.
However, several papers in literature have demonstrated the efficacy of specific pharmacological agents in children with moderate-to-severe RLS symptoms and PLMD who did not respond to the sleep hygiene and nutritional measures.
In children medication should be combined with non-pharmacological measures to achieve optimal results and should involve a detailed discussion of risks versus benefits with the family [1, 55].
Pharmacologic treatments for RLS have been serendipitously discovered and developed for adults and then applied to children. For the past decades a series of clinical studies investigated the therapeutic value and limitations of these medications whose effectiveness and safety are now better understood. The paucity of large-scale treatment studies may imply a difficulty in recruiting sufficient paediatric sample sizes that meet diagnostic criteria.
The best initial form of treatment is to reduce factors or conditions that may worsen or precipitate RLS and evaluate for the presence of iron deficiency. Careful monitoring for adverse events and periodic reassessment of treatment are recommended and family understanding of the pathology is crucial. When starting a drug for RLS in children it is prudent to begin with the lowest possible dose and slowly titrate upwards with close monitoring for adverse effects.
Dopaminergic Agents
Dopaminergic medications are considered the first line of treatment for RLS: these agents include carbidopa/levodopa and the selective dopamine agonists (pramipexole, ropinirole, pergolide). The use of dopaminergic medications has proved successful in numerous case reports and small open-label studies of children with RLS with and without ADHD, but no large-scale double-blind, placebo-controlled trial with dopaminergic medications in children has been performed [29, 56–63].
The use of dopaminergic medications is associated with an improvement in RLS symptoms and reduction of PLMS and associated arousals. In children with ADHD and RLS and PLMD, the use of dopaminergic medications can result in improvements and even resolution of ADHD symptoms.
Some studies exists about dopaminergic treatment in children with RLS, although with intrinsic limitations in methodology due to sample size, open labeling and absence of randomization: cardibopa/l-dopa and pergolide showed to improve sleepiness in 43% of ADHD patients [64], although the same authors in a successive recent study found that l-DOPA had no effect on Conners’ scales, sleep, or psychometric tests when all patients treated with the drug were compared to those on placebo or when patients with ADHD only were compared to those with ADHD and RLS/PLMS, indicating that l Dopa had effect on RLS/PLMS but not on ADHD symptoms [65].
Ropinirole was found effective in a case of RLS comorbid with depression, without side effects [59] and pramipexole has been successful in open studies, eliminating clinical symptoms [17, 66, 67]. Adjunctive therapy with iron in selected patients may improve resolution of symptoms [68].
In case of comorbid depression or anxiety, the adult literature indicates improved results with treatment of disordered sleep and the preference of noradrenergic medication (such as bupropion) over serotonergic medication for depression [69, 70].
The side effects of dopaminergic agents are limited, particularly at the low dosages usually prescribed for RLS treatment; in particular, inappropriate sleepiness and sleep attacks, or compulsive behavior have not been seen. Compared with the adverse reactions of levodopa, including tolerance, rebound, and augmentation phenomena in RLS, pramipexole had one of the best profiles.
Recent meta-analyses have found pramipexole to be effective and well tolerated in adult patients [53, 54].
Related posts:
Health-Related Quality of Life and Depression Symptom Measures for the Assessment of Treatment in Restless Legs Syndrome/Willis–Ekbom Disease
Cognitive Functioning
Long-Term Efficacy of Pharmacological Treatment
Outcome and Mortality in Renal Failure Related RLS
Sleep Impact: Insomnia, Hypersomnia, Sleep Attacks, and Circadian Disorders
Impulse Control Behavior in Movement Disorders: Focus on Restless Leg Syndrome
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