How does one choose the correct pharmacotherapy for a pediatric patient with restless legs syndrome and periodic limb movement disorder?: Expert Guidance

KEYWORDS:

• Pediatric RLS
• PLMD
• iron therapy
• α2δ-1 ligands
• dopaminergic medications

1. Introduction

Epidemiological studies have shown that restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are common in children and adolescents with an estimated prevalence of 2–4% [1,2]. The etiology of RLS and PLMD is not well understood. However, genetic factors, dopaminergic dysfunction, and iron deficiency have been proposed to play a role in the pathogenesis of RLS and PLMD [1]. In addition, other neurochemical systems including glutamate and opioid may be involved in the pathophysiology of RLS and PLMD. The diagnosis of RLS and PLMD is challenging, especially among young children, as they may not be able to describe specific RLS symptoms or these symptoms may not appear until later. Children often have non-specific symptoms such as restless sleep, insomnia, and daytime fatigue or sleepiness. The International RLS Study Group (IRLSSG) has developed specific diagnostic criteria for RLS and PLMD in children [3]. In addition to the five essential adult RLS criteria, several specific features should be considered in making a diagnosis of RLS in children. These features include language and cognitive development as related to ability to describe RLS symptoms, the effect of RLS on behavior and educational domain, and the close link between RLS and PLMD in children. Furthermore, certain clinical features including a periodic limb movement (PLM) index of more than 5/hr, a family history of RLS or PLMD among the first degree relatives, and a family history of PLMS (PLM index >5/hr) can be used to support the diagnosis of RLS in children.

There are increasing, albeit limited data indicating cardiovascular, autonomic, and neurocognitive changes associated with RLS and PLMD in children [1,2,4,5]. Therefore, early recognition and management are important. Management of RLS and PLMD in children involves non-pharmacologic and pharmacologic approaches [6]. Choosing a safe and effective pharmacotherapy for RLS and PLMD in children is challenging as current available data are limited in pediatric population. In this article, the choice of various pharmacologic therapy will be discussed based on current limited evidence and clinical experiences.

2. Pharmacology therapy for RLS and PLMD

2.1. Iron therapy

Iron plays a crucial role in the pathogenesis of RLS and PLMD. Iron is a cofactor for tyrosine hydroxylase, a rate-limiting enzyme for dopamine synthesis. Several studies have shown the role of iron insufficiency within the central nervous system (CNS) in the pathogenesis of RLS. Serum ferritin is often used as a reliable clinical markers of iron stores. However, there are wide ranges of normative data for serum ferritin in children. In addition, several factors can affect serum ferritin in children including common respiratory infections. There are several randomized controlled studies evaluating the effect of both oral and intravenous iron therapy in adult population [7]. In children and adolescents, four open-label retrospective studies and two open-label prospective studies were conducted to assess the effectiveness of oral iron therapy in the management of RLS and PLMD [8–13]. The dose of iron in these studies ranged from 3 to 8.5 mg/kg/day. All studies demonstrated short-term improvement of RLS symptoms and PLMI (periodic limb movement index) after iron therapy. Intravenous iron therapy was also evaluated in one open-label retrospective study in children and adolescents who failed oral iron therapy and found clinical improvement in 62.5% of subjects [14]. Although long-term outcome of iron therapy is limited, our recent retrospective study showed sustained clinical improvement with an adequate level of serum iron and ferritin over a period of 1–2 years when iron treatment was continued with slow weaning [12].

Based on these studies, the recommended dose of oral iron therapy in children is 3 mg of elemental iron/kg/day. The recommended dose in adolescents with RLS and PLMD is 65–130 mg of elemental iron. The addition of vitamin C may be beneficial in some children to improve iron absorption. Calcium and dairy product should be avoided within 2 h of taking iron supplements. Common side effects include constipation, gastric irritation (nausea, epigastric pain), dark stool, teeth staining (liquid iron). Iron treatment should be avoided in children with underlying hematologic disorders such as hemolytic anemia and hemochromatosis. The duration of iron treatment based on previous studies is three months followed by slow tapering over the period of 1–2 years. Oral iron therapy should be considered as the first line of treatment in children when serum ferritin is less than 50 µg/L. It is important to periodically check serum iron and ferritin and wean or adjust the dose of iron accordingly.

In those children with RLS/PLMD who do not tolerate or fail oral iron therapy, intravenous (IV) iron may be considered. Children who do not respond to oral iron therapy are likely to have systemic co-morbidities that impair iron absorption such as celiac disease, eosinophilic esophagitis, chronic gastritis, malabsorption syndrome, or bowel resection [7]. However, there is limited evidence as there is only one study using IV iron sucrose in children with RLS [14]. Based on this study and clinical experience and data in adult RLS, the IRLSSG task force states that IV iron sucrose (3–6 mg/kg) can be considered for pediatric RLS/PLMD in the following situations: (1) children who have prior oral iron treatment of at least 3 months without adequate benefit or adequate rise of serum ferritin (2) children who do not tolerate or develop adverse effects from oral therapy (3) children who have co-morbidity that will interfere with iron absorption and are unlikely to respond to oral iron therapy [7]. Side effects of IV iron therapy in children include difficulty with IV line placement and transient gastrointestinal disturbances (anorexia, nausea, and vomiting within 24 h of infusion). Intravenous iron therapy should be done in an infusion center with pediatric experience, preferably under the supervision of pediatric hematologist.

2.2. α2δ-1 ligands

After iron supplementation, α2δ-1 ligands including gabapentin, pregabalin, and gabapentin encarbil are increasingly considered to be the second line treatment option for pediatric RLS and PLMD. Despite their name, they are inactive at GABA receptors and instead selectively bind the α2δ-1 subunits of certain voltage gate calcium channels. Though the mechanism by which this improves RLS/PLMD symptoms has not been fully elucidated, it has been suggested that by decreasing the excitatory neurotransmission of glutamatergic neurons, α2δ-1 ligands decrease arousability, increase sleep continuity, and potentially reduce the hyperalgesic response of the limbs [15].

Multiple studies have demonstrated the efficacy of α2δ-1 ligands in improving RLS symptoms and reducing PLMS in adults, though similar studies do not exist in children. In our retrospective long-term iron study, α2δ-1 ligands were used as a concurrent medication in 12.4% of children treated with iron sulfate [12]. One study evaluating gabapentin for the treatment of insomnia in children used bedtime doses starting at 5 mg/kg/dose and titrating up to 15 mg/kg/dose based on efficacy [16].

No studies have evaluated pregabalin or gabapentin enacarbil for pediatric RLS or PLMD, though pregabalin doses of 2 to 3 mg/kg/dose have been used for painful neuropathy in the pediatric population [17]. As no medications are FDA approved for the treatment of pediatric RLS/PLMD, safety guidelines have not been established for α2δ-1 ligands. Trials examining the use of gabapentin and pregabalin for treatment of epilepsy have demonstrated that these drugs are generally safe and well tolerated with somnolence and dizziness being common adverse effects [18,19].

2.3. Dopaminergic medications

Dopaminergic medications, which include carbidopa/levodopa and dopamine receptor agonists (pramipexole, ropinirole), are commonly used to treat moderate to severe RLS/PLMD in the adult population. Although there is increasing evidence on the use of dopaminergic medications in children, the data are mostly based on retrospective studies and case series [6]. These studies have demonstrated both short and long-term effectiveness of dopaminergic medications in the managements of RLS and PLMD in children as evidenced by clinical improvement of RLS symptoms, reduction in PLM index and arousal associated with PLMS [6,20]. In children with co-existing ADHD and parasomnia, dopaminergic medications resulted in improvement of ADHD symptoms and resolution of parasomnia [20,21].

There are only two prospective studies evaluating the use of dopaminergic medications in children. One prospective double-blinded, placebo-controlled trial evaluated the effect of carbidopa-levodopa in 16 children diagnosed with both ADHD and RLS/PLMD. This study demonstrated significant improvement in RLS symptoms and a reduction of PLMS in carbidopa-levodopa group compared to placebo, but no change in the ADHD symptoms [22]. The other prospective study evaluated the effectiveness of a transdermal rotigotine in adolescents. This multicenter, open-label, prospective study included 24 subjects between 13 and 18 years of age with moderate to severe RLS. Significant improvements of RLS symptoms and reduction of PLMS were seen with rotigotine patch [23].

Reported adverse effects of dopaminergic medications included nausea, dizziness, vomiting, nasopharyngitis, headache and paradoxical alerting reaction [24]. Skin irritation at the patch site was reported for transdermal rotigotine [23]. Given the high incidence of augmentation and impulse control disorders associated with dopaminergic medication in the adult population [25], they are less frequently used in children. We have used these drugs sparingly, reserving them for the most severe, refractory cases of RLS/PLMD, or when other underlying neurologic conditions prompt their use.

2.4. Other pharmacotherapy

Other pharmacotherapy in adults with RLS and PLMD including benzodiazepine, α-2 adrenergic agonists, and opioid medications have not been adequately studied in pediatric population. Clonazepam, a long-acting benzodiazepine, is frequently used for treatment of RLS and PLMD in children. Two randomized controlled studies in adult population showed mixed results of clonazepam in treating mild to moderate RLS. Only a few pediatric case series have revealed the effectiveness of clonazepam especially when it was used in combination with iron therapy or dopaminergic medications in treating children with RLS and PLMD [6]. Clonazepam may aggravate hyperactivity in children with ADHD [26]. Other side effects include worsening of sleep-disordered breathing, paradoxical alerting, sleepiness and behavior changes. The recommended dose for school-aged children and adolescents is 0.125 to 1 mg. The low dose is preferred as higher dose can lead to increased risk for sleep-disordered breathing and morning sleepiness.

The α-2 adrenergic agonist such as clonidine has been used in children with RLS and PLMD, although the evidence is very limited. One retrospective case series showed that it was used alone or in combination with iron or other medications in children with RLS [10]. Side effects are usually mild and include dry mouth, sleepiness, constipation, headache, orthostatic hypotension, bradycardia, depression, and irritability. Clonidine should generally be considered in children with RLS/PLMD who have sleep onset insomnia. The recommended dose is 0.05 to 0.3 mg at bedtime. We usually start at a low dose and titrate slowly to avoid cardiovascular side effects.

Opioids have been shown to be effective for treatment of RLS and PLMD in adults. However, there is no available data to support the use of opioids in children with RLS and PLMD. The effectiveness of melatonin in treatment of RLS and PLMD is unclear. Melatonin has been used with other medications in management of RLS in children [10]. Vitamin D deficiency may play a role in the pathogenesis of growing pain, a condition which is closed related to RLS. Other medications including carbamazepine, valproic acid, valerian, and magnesium have been used in adults with RLS and PLMD, but there is no available data in children.

3. Conclusions

RLS and PLMD are relatively common in children and adolescents. If left untreated, RLS and PLMD may lead to cardiovascular and neurocognitive consequences. Therefore, early diagnosis and management are important. Pharmacologic therapy is the mainstay for management of RLS and PLMD in children. Although there is currently no FDA approved medication for RLS and PLMD in children, there is growing evidence of the use of pharmacologic therapy in this population. Most children with RLS and PLMD have low iron storages, and oral iron therapy should be considered as the first line of treatment when ferritin is less than 50 µg/L. In those children with low iron stores who do not tolerate or fail oral iron therapy, intravenous iron may be considered. After iron therapy, α2δ ligands are increasingly considered to be the second line treatment option, although there are very limited data evaluating the effectiveness in children with RLS and PLMD. Dopaminergic medications are commonly used in adults with moderate to severe RLS and PLMD. There is increasing evidence on the use of dopaminergic medications in children, and they may be considered as a second line of treatment. Due to concerns of side effects, especially augmentation and impulse control disorders, they are less frequently used in children. Benzodiazepines such as clonazepam and α-2 adrenergic agonist such as clonidine have been used in children with RLS and PLMD, although the evidence is limited. Other medications including opioids, melatonin, vitamin, anti-epileptic drugs, valerian, and magnesium have been used in adults, but there is no available data in children with RLS and PLMD.

4. Expert opinion

Choosing the correct pharmacology for children with RLS and PLMD is challenging as there are limited available data in pediatric population. Iron therapy is increasingly used in children with RLS and PLMD, although the effectiveness is based on retrospective and open labeled studies. Therefore, there is a need to conduct a prospective randomized study to confirm these findings. The duration of iron therapy is 3–6 months with slow tapering, though it needs further investigation since most studies are short-term studies. Other areas of research for iron therapy include indicators of low iron stores, optimal iron and ferritin levels, iron metabolism in children, and long-term outcome of iron therapy. Overall side effects of iron therapy are generally benign, and it should be considered as the first line of treatment in children with low iron stores.

Both α2δ-1 ligands and dopaminergic medications can be considered as the second line treatment. There is increasing evidence on the use of dopaminergic medications in children, but the concerns for side effects make it less frequently used in children. In our opinion, dopaminergic mediations should be reserved for older children and adolescents with severe refractory RLS and PMD. In contrast, α2δ-1 ligands such as gabapentin and pregabalin are increasingly considered as the second line of treatment in children with RLS and PLMD as these medications are generally safe and well tolerated based on experiences in children with epilepsy. However, there are very limited data on the effectiveness of α2δ-1 ligands in children with RLS and PLMD. In our practice, we typically begin treatment with gabapentin using 5 mg/kg/dose and titrating up to 15 mg/kg/dose based on efficacy, with the medication given approximately 1.5 h before bedtime when RLS symptoms are present and closer to bedtime when PLMD related symptoms are the only concern. We have used pregabalin at doses of 2 to 6 mg/kg/dose if an alternative to gabapentin is needed. Logistical and financial concerns have resulted in limiting the use of gabapentin enacarbil in our practice. There is limited evidence on the use of clonazepam and clonidine. Both clonazepam and clonidine are often used in young children with RLS and PLMD especially those with sleep onset or sleep maintenance insomnia.

In addition to clinical information, PSG findings and actigraphy can be particularly helpful when evaluating therapeutic options. For example, sleep fragmentation and excessive arousals may prompt treatment with α2δ-1 ligands or benzodiazepines, while the presence of PLMS and motor activities may suggest the benefit of dopaminergic medications. Further, well-designed studies are needed to evaluate both short and long-term efficacy and safety profiles of these medications in children.

Besides iron supplementation, pharmacologic therapy for children with RLS and PLMD involves the use of psychotropic medications. Further investigation of cardiovascular and neurocognitive consequences of RLS and PLMD is critically important before subjecting children to long-term effect of these medications. Until further evidence is available, physicians and health-care providers should be cautious in making a correct diagnosis and determining the proper pharmacologic therapy in children with RLS and PLMD based on limited data and their clinical experiences.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgments

Work for this study was performed at Cincinnati Children’s Hospital Medical Center. All authors have seen and approved the manuscript.

Additional information

Funding

Financial support was provided by the Cincinnati Children’s Hospital Research Fund.