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Evaluation of oral iron treatment in pediatric restless legs syndrome (RLS)
Sleep Medicine 13 (2012) 429–432
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Brief Communication
Evaluation of oral iron treatment in pediatric restless legs syndrome (RLS) Ikuko Mohri a,b,c, Kumi Kato-Nishimura b,c,d, Kuriko Kagitani-Shimono a,b,c, Shihoko Kimura-Ohba c, Keiichi Ozono c, Naoko Tachibana e, Masako Taniike a,b,c,⇑ a
Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka, Japan Department of Mental Health and Environmental Effects Research, The Research Center for Child Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan c Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan d Sleep Medical Center, Osaka Kaisei Hospital, Osaka, Japan e Center for Sleep-related Disorders, Kansai Electric Power Hospital, Osaka, Japan b
a r t i c l e
i n f o
Article history: Received 6 January 2011 Received in revised form 19 December 2011 Accepted 23 December 2011 Available online 15 February 2012 Keywords: Restless legs syndrome Children Ferritin Iron Dopamine agonist Japanese
a b s t r a c t Objective: We conducted a retrospective chart review of children with restless legs syndrome (RLS) to evaluate the efficacy of oral iron treatment, which was administered open-label during the course of clinical care. In addition, we provided detailed clinical information about RLS in this pediatric cohort. Patients and methods: The study included 30 consecutive Japanese children with RLS who visited the Pediatric Sleep Clinic at Osaka University Hospital, and consisted of 17 boys and 13 girls, aged 2–14 years (mean ± SD, 6.5 ± 2.8). All-night polysomnography was performed in 18 patients and serum ferritin levels were measured in all the patients. After the diagnosis of RLS, iron was administered at doses between 1.6 and 7.8 mg/kg/day (3.2 ± 1.3). Serum ferritin was re-evaluated 3–6 months after iron treatment, or when RLS symptoms had disappeared. Results: The patient age at onset of RLS symptoms ranged from six months to 13 years (4.3 ± 3.6). A positive family history was recognized in 19 children (63.3%). Serum ferritin levels before therapy were 9– 62 ng/ml (26.6 ± 12.8) and oral iron supplementation was reported to be highly effective in 17 children, effective in 10, and ineffective in three. The serum ferritin level at follow-up was 23–182 ng/ml (83.5 ± 49.8). The onset of treatment effect was within approximately three months. Conclusions: Iron treatment could be effective in Japanese pediatric RLS. Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction Restless legs syndrome (RLS) is a sensorimotor disorder characterized by the prototypical complaint of a strong, nearly irresistible urge to move the legs [1]. The International Restless Legs Syndrome Study Group (IRLSSG) proposed consensus criteria for the diagnosis of definite RLS in pediatric populations [1]. In addition to the four essential features of adult RLS, the pediatric RLS criteria are (1) the child relates a description in his or her own words that is consistent with leg discomfort, or (2) the child has two of the three following supportive criteria: sleep disturbance for age; a biological parent or sibling with definite RLS; a periodic leg movements during sleep (PLMS) index of more than five per hour. In school-aged children the prevalence of pediatric RLS has been estimated at 1.9–3.6% [2–4]. ⇑ Corresponding author at: Department of Child Development, United Graduate School of Child Development, Osaka University, 2-2 D-5 Yamadaoka, Suita-shi, 5650871 Osaka, Japan. Tel./fax: +81 6 6879 3863. E-mail addresses: [email protected], [email protected] (M. Taniike). 1389-9457/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2011.12.009
The pathophysiology of RLS has recently been elucidated in significant detail, including the genetic features, dopaminergic dysfunction, and low iron storage status [5,6]; however, some aspects of the disorder remain unclear. Ekbom reported a high prevalence of iron deficiency among his patients and discussed the effectiveness of iron treatment for RLS [7]. Many conditions that compromise the patient’s iron status may increase the risk of RLS, and iron supplementation has been shown to reduce the risk of RLS, and, in some cases, effect a cure [6]. Moreover, autopsies, analyses of cerebrospinal fluid, and brain imaging studies have all documented the low brain iron status of adult RLS patients [8]. Wang et al. reported a randomized double-blind study showing that oral iron is an effective treatment for adult RLS patients with low-normal ferritin [9]. Here, we retrospectively report the results of oral iron treatment of 30 Japanese children with RLS, including ferritin levels and other clinical characteristics. Although there are three published case reports of iron therapy in pediatric RLS [10–12] and a review [13], to our knowledge this is the first clinical study to address the efficacy of iron therapy in pediatric RLS.
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2. Subjects and methods All patients were seen in the Pediatric Sleep Clinic at Osaka University Hospital between 2005 and 2009. The RLS diagnosis was made if the patient satisfied the IRLSSG consensus criteria [1]. To judge the presence of ‘‘the urge to move’’ we gave verbal instructions to the parents to request their children stay still at bedtime, and to ask them what they were feeling. Children over the age of four explained that they could not stop moving their legs (or limbs), although they were sleepy. The three children under the age of four (#17, #26, #28) were unable to report their urge to move, so this was estimated based on hyperactive behavior at bedtime that caregivers were unable to stop. Therefore, these three patients were diagnosed as having probable RLS based on the IRLSSG criteria [1]. The patients consisted of 17 boys and 13 girls, aged 2–14 years (6.8 ± 2.9). The children and their biological parents were all Japanese. Relevant information for patients #1, #11, #13, #14, #15, #16, and #17 have been previously described [12,14]. Details of the sleep history, symptoms, family history, and comorbidity of the 30 patients in this study are presented in Supplemental Table 1. All-night polysomnography (PSG) was performed in 18 patients to rule out comorbidity with other sleep disorders. PLMS was scored and the PLMS index (PLMSI) was calculated according to the American Academy of Sleep Medicine criteria [15]. All patients received blood cell count and blood chemistry work-ups, as well as measurements of serum iron and ferritin concentrations. Patients took ferrous sulfate twice in a day and the dose is ranged 1.6– 7.8 (3.2 ± 1.3) mg/kg/day in elemental iron. In the case of very young children who were unable to swallow the big tablet of fer-
rous sulfate, ferric pyrophosphate in a syrup format was prescribed. The efficacy of iron treatment was judged by monthly visits to record bedtime behaviors, leg movements, bedtime irritability, sleep latency, awakenings during sleep, and daytime behavior, in addition to the patient’s own descriptions of their leg discomfort. In this study, the effectiveness of iron treatment was assessed at three months after the initiation of treatment and was classified as ‘‘highly effective’’ when RLS symptoms were reported to have disappeared, ‘‘effective’’ when the frequency and severity of RLS symptoms had decreased, and ‘‘ineffective’’ when RLS symptoms remained unchanged. Ferritin levels were re-evaluated 3–6 months after iron treatment or when RLS symptoms were reported to disappear.
3. Results 3.1. Characteristics of RLS symptoms A positive family history was recognized in 19 of 30 patients (63.3%). In these 19 familial cases RLS was seen in the paternal line, the maternal line, and not definite (only identified in brothers and sisters) in five, 12, and two patients, respectively. Information from caregivers revealed that the onset of symptoms such as severe bedtime irritability, leg restlessness at night, and touching and gripping the legs dated back to infancy in seven patients (Table 1). The average age at onset of symptoms was 4.3 ± 3.7 years (range 0–13). The RLS symptoms are summarized in Supplemental Table 1. Our patients expressed unpleasant feelings in a variety of ways, with the most common expressions being ‘‘creeping feelings in the legs’’ and ‘‘discomfort in the legs.’’ How-
Table 1 Summary of RLS treatment. No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 ⁄
Sex
M F F M F M M M M M M F F F M F F M M F M F M F F M M M M F
Age of Diagnosis
Age of Onset
Serum iron level (lg/dl)
Serum ferritin level (ng/ml) Before iron treatment
After iron treatment
5 7 7 7 6 9 7 8 7 14 4 7 5 6 4 4 2 5 11 5 13 6 4 9 9 3 5 3 8 6
4 5 0 3 5 8 7 8 7 13 0 (10 M) 7 0 (6 M) 6 2 3 0 (10 M) 2 5 1 12 0 2 3 9 2 5 1 5 5
188 64 115 58 136 38 95 120 75 89 132 37 96 105 101 183 12 65 121 80 136 24 34 43 100 34 110 84 77 126
26 22 20 37 31 12 31 44 20 35 9 36 19 35 21 14 9 9 17 28 62 39 49 44 25 19 22 15 21 26
56 132 109 104 92 94 182 100 N/P 35 34 114 24 131 N/P 23 37 N/P 38 37 N/P N/P N/P 151 178 N/P 52 N/P 67 46
++; highly effective, +; effective, –; ineffective. CZP; clonazepam, (+ indicates ‘‘additional’’). N/P; not performed.
Dose of iron (mg/ kg/day)
Effectiveness of iron treatment⁄
2.8 3.8 4.8 3.2 3.9 4.2 4 3.3 3.5 1.9 3 2.5 1.6 7.8 3.3 2.3 4.5 2.7 1.6 1.8 2.7 2.6 2.7 3.5 4.2 2.6 2.3 2.4 5 2.7
++ + + ++ ++ + ++ + + + ++ ++ ++ ++
Alternative or additional medication
CZP Pramipexole + CZP
+CZP Pramipexole +Pramipexole +Pramipexole +CZP
+Pramipexole ++ ++ ++ + + + + ++ ++ ++ ++ ++ ++
+CZP
I. Mohri et al. / Sleep Medicine 13 (2012) 429–432
ever, they sometimes complained of pain, tickles, or hot sensations. RLS symptoms were recognized almost every day in 19 children (63.3%), and at least once a week in 28 (93.3%). The caregivers reported that daytime irritability or sleepiness was observed in 13 (43.3%) and 20 (66.7%) patients, respectively. On PSG, PLMSI of more than five per hour was documented in four of the 18 patients (22.2%) in whom PSG was performed. The detailed indices are shown in Supplemental Table 2. 3.2. Treatment process and iron status Table 1 shows the serum iron and ferritin levels before and after iron treatment and the treatment doses, for each of the 30 patients. Before iron therapy, serum ferritin levels were between 26.6 ± 12.8 ng/ml (range 9–62). All except one patient (#21) had ferritin levels below 50 ng/ml. No tolerance or adverse effects were seen in our 30 children. Treatment was reported to be highly effective in 17 patients, effective in 10, and ineffective in three. Serum ferritin levels after iron therapy were available in 22 of 30 children showing 23– 182 ng/ml (83.5 ± 49.8). For the patients in whom iron treatment was effective, serum ferritin levels before and after treatment were 28.1 ± 12.4 ng/ml (range 9–62) and 85.6 ± 49.9 ng/ml (range 23– 182), respectively. Conversely, for patients in whom the treatment was ineffective, serum ferritin levels before and after treatment were 12.6 ± 6.4 ng/ml (range 9–20) and 60.0 ± 42.5 ng/ml (range 34–109), respectively. Patient #21 had a pre-treatment ferritin level of 62 ng/ml and showed a partial response to iron supplementation. In patients with a favorable response the reported time to therapeutic effect after initiating iron treatment was 1–3 months (1.7 ± 0.7). The duration of iron treatment was 1–36 months (8.6 ± 8.1). The three patients who were refractory to iron therapy were infantile-onset and exhibited severe symptomatology (#3, #11, and #17). The follow-up period after treatment was 8.4 ± 4.1 months. There has been no recurrence of RLS symptoms in 14 patients with good responses since iron supplementation was stopped. In patients #8 and #19 symptoms recurred transiently in the summer or during febrile illness, respectively. An immediate recurrence of symptoms was reported after iron supplementation was stopped in patients #1, #26, and #28. Serum ferritin in patient #1 was elevated from 26 to 56 ng/ml by iron supplementation, but this decreased to 37 ng/ml when his symptoms relapsed after the cessation of iron treatment. In the cases in which iron supplementation was partially effective or ineffective the patients were changed to or given add-on pramipexole (#3, #9, #10, #11, and #17) or clonazepam (#2, #3, #7, #12, and #21).
431
tients were low-normal (less than 50 ng/ml) and rose from 40.6 to 65.7 ng/ml [9]. Because the efficiency of iron absorption is dependent on the individual’s iron status, the ineffectiveness of iron therapy in the former study could be due to inadequate absorption. To circumvent this problem, several trials have been performed in which iron was administered intravenously [21–23]. Three randomized, double-blind, placebo-controlled trials of intravenous iron sucrose showed contradictory results; one failed to demonstrate benefit [22] while the other showed significant improvement of RLS symptoms [23,24]. Ondo reported on the efficacy of intravenous iron supplementation in severe refractory RLS, but the results were inconsistent and not predicted by patient demographics [23]. Allen conducted a randomized, placebo-controlled trial of intravenous administration of ferric carboxymaltose and revealed its effectiveness. This study indicates that the transport system for iron should be kept in mind in addition to the iron compound characteristics, because iron storage did not correlate with the iron input regardless of intravenous administration which could bypass poor iron absorption in the upper gastrointestinal tract. A higher baseline ferritin level can (at least partially) account for the differences. Other factors such as inflammation and iron formulation may also play a role. There may be some differences in absorption or metabolism of iron between adults and children. In addition, the demand for iron as a cofactor for tyrosine hydroxylase activity, which is responsible for dopamine biosynthesis, is higher in younger children [25], suggesting they might require higher ferritin levels. Simakajornboon et al. [26] reported that patients with high PLMI had serum ferritin levels of less than 50 ng/ml. In patients who responded to iron therapy, PLMI and efficacy correlated with increased serum ferritin levels above 50 ng/ml. Konofal et al. [27] reported that iron supplementation improved core symptoms in ADHD patients who had serum ferritin below 30 ng/ml. Thus, serum ferritin levels of 50 ng/ml may be used as a threshold for treatment; however, this requires further investigation. Two of the patients (#3 and #11) with onset of RLS in infancy did not respond to iron therapy to the same extent. Therefore, patients with very early onset of RLS tended to need add-on treatments such as pramipexole. Fulda and Wetter reported that 20–25% of RLS patients were at increased risk for daytime sleepiness [28]. In our study, parents reported irritability in 13 patients (43.3%) and daytime sleepiness in 20 (66.7%). Sleep disturbance due to RLS could influence childhood development; evidence has accumulated to suggest widespread deterioration of neural function, which may cause permanent neuronal damage [29]. In addition, a recent epidemiological study indicated that sleep problems in early childhood (between ages two and four) are an indicator of subsequent attention problems that may persist into adolescence [29]. In this regard, the longterm follow up of pediatric RLS patients is crucial.
4. Discussion 4.1. Limitations We present here 30 Japanese children with RLS. Their average age at onset of symptoms was 4.3 years. Oral iron supplementation, administered in an open-label manner, was reported to be effective in 27 of the children. Previous studies examining iron insufficiency have consistently suggested an association between abnormal iron metabolism and some RLS cases [16–19]. However, the efficacy of iron treatment in adult RLS patients has been underexplored. There have been only two randomized, double-blind, placebo-controlled studies of oral iron therapy in RLS, with conflicting results [9,20]. One study showed no benefit of iron therapy in RLS patients with average baseline serum ferritin levels of approximately 134.8 ng/ml [20]. In contrast, improvement in RLS symptoms was observed in the second study, where the average baseline ferritin levels of RLS pa-
There are several limitations to this study. First, this is an openlabel and retrospective study that had no structured outcome measures, non-uniform times of reassessment, and included only a small number of children of different ages. Therefore, we cannot definitively conclude that iron therapy is effective for children with RLS. Second, there is placebo effect on dopamine and opioids for treatment of adult RLS [30], so the results obtained here in pediatric RLS must be cautiously interpreted. Finally, the patients were followed up for less than 36 months with incomplete repeated ferritin measurements, which may be inadequate to observe the longterm effects and consequences of iron therapy. Although limited and preliminary, our results suggest a favorable response to oral iron in Japanese children with RLS. From a
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child development standpoint, we should try to make an accurate diagnosis of RLS as early as possible. To maximize the range of treatments available to RLS patients, systematic, well-controlled studies are warranted to investigate the best use of iron supplementation for pediatric RLS patients. Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.12.009.
References [1] Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4(2):101–19. [2] Picchietti D, Allen RP, Walters AS, Davidson JE, Myers A, Ferini-Strambi L. Restless legs syndrome: prevalence and impact in children and adolescents – the Peds REST study. Pediatrics 2007;120(2):253–66. [3] Turkdogan D, Bekiroglu N, Zaimoglu S. A prevalence study of restless legs syndrome in Turkish children and adolescents. Sleep Med 2011;12(4):315–21. [4] Yilmaz K, Kilincaslan A, Aydin N, Kor D. Prevalence and correlates of restless legs syndrome in adolescents. Dev Med Child Neurol 2011;53(1):40–7. [5] Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010;6(6):337–46. [6] Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004;5(4):385–91. [7] Ekbom K. Restless legs: a clinical study. Acta Med Scand 1945;121(S158):1–123. [8] Allen RP, Earley CJ. The role of iron in restless legs syndrome. Mov Disord 2007;22(Suppl. 18):S440–8. [9] Wang J, O’Reilly B, Venkataraman R, Mysliwiec V, Mysliwiec A. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: a randomized, double-blind, placebo-controlled study. Sleep Med 2009;10(9):973–5. [10] Kryger MH, Otake K, Foerster J. Low body stores of iron and restless legs syndrome: a correctable cause of insomnia in adolescents and teenagers. Sleep Med 2002;3(2):127–32. [11] Starn AL, Udall Jr JN. Iron deficiency anemia, pica, and restless legs syndrome in a teenage girl. Clin Pediatr (Phila) 2008;47(1):83–5.
[12] Mohri I, Kato-Nishimura K, Tachibana N, Ozono K, Taniike M. Restless legs syndrome (RLS): an unrecognized cause for bedtime problems and insomnia in children. Sleep Med 2008;9(6):701–2. [13] Simakajornboon N, Kheirandish-Gozal L, Gozal D. Diagnosis and management of restless legs syndrome in children. Sleep Med Rev 2009;13(2):149–56. [14] Mohri I, Kato-Nishimura K, Kagitani-Shimono K, Tachibana N, Ozone K, Taniike M. Restless-legs syndrome – possible unrecognized cause for insomnia and irritability in children. No To Hattatsu 2008;40(6):473–7. [15] International Classification of Sleep Disorders neDacm. Westchester, IL: American Academy of Sleep Medicine; 2005. [16] Allen RP, Barker PB, Wehrl F, Song HK, Earley CJ. MRI measurement of brain iron in patients with restless legs syndrome. Neurology 2001;56(2):263–5. [17] Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003;61(3):304–9. [18] Earley CJ. The importance of oral iron therapy in restless legs syndrome. Sleep Med 2009;10(9):945–6. [19] Schmidauer C, Sojer M, Seppi K, et al. Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome. Ann Neurol 2005;58(4):630–4. [20] Davis BJ, Rajput A, Rajput ML, Aul EA, Eichhorn GR. A randomized, doubleblind placebo-controlled trial of iron in restless legs syndrome. Eur Neurol 2000;43(2):70–5. [21] Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord 2009;24(10):1445–52. [22] Earley CJ, Horska A, Mohamed MA, Barker PB, Beard JL, Allen RP. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med 2009;10(2):206–11. [23] Ondo WG. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med 2010;11(5):494–6. [24] Allen RP, Adler CH, Du W, Butcher A, Bregman DB, Earley CJ. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multicentred, placebo-controlled preliminary clinical trial. Sleep Med 2011. [25] McGeer EG, McGeer PL. Some characteristics of brain tyrosine hydroxylase. In: Mandel J, editor. New concepts in neurotransmitter regulation. New York, London: Plenum; 1973. p. 53–68. [26] Simakajornboon N, Gozal D, Vlasic V, Mack C, Sharon D, McGinley BM. Periodic limb movements in sleep and iron status in children. Sleep 2003;26(6):735–8. [27] Konofal E, Cortese S, Marchand M, Mouren MC, Arnulf I, Lecendreux M. Impact of restless legs syndrome and iron deficiency on attention–deficit/ hyperactivity disorder in children. Sleep Med 2007;8(7–8):711–5. [28] Fulda S, Wetter TC. Is daytime sleepiness a neglected problem in patients with restless legs syndrome? Mov Disord 2007;22(Suppl. 18):S409–13. [29] Jan JE, Reiter RJ, Bax MC, Ribary U, Freeman RD, Wasdell MB. Long-term sleep disturbances in children: a cause of neuronal loss. Eur J Paediatr Neurol 2010;14(5):380–90. [30] Fulda S, Wetter TC. Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies. Brain 2008;131(Pt 4):902–17.
Contents lists available at SciVerse ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Brief Communication
Evaluation of oral iron treatment in pediatric restless legs syndrome (RLS) Ikuko Mohri a,b,c, Kumi Kato-Nishimura b,c,d, Kuriko Kagitani-Shimono a,b,c, Shihoko Kimura-Ohba c, Keiichi Ozono c, Naoko Tachibana e, Masako Taniike a,b,c,⇑ a
Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka, Japan Department of Mental Health and Environmental Effects Research, The Research Center for Child Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan c Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan d Sleep Medical Center, Osaka Kaisei Hospital, Osaka, Japan e Center for Sleep-related Disorders, Kansai Electric Power Hospital, Osaka, Japan b
a r t i c l e
i n f o
Article history: Received 6 January 2011 Received in revised form 19 December 2011 Accepted 23 December 2011 Available online 15 February 2012 Keywords: Restless legs syndrome Children Ferritin Iron Dopamine agonist Japanese
a b s t r a c t Objective: We conducted a retrospective chart review of children with restless legs syndrome (RLS) to evaluate the efficacy of oral iron treatment, which was administered open-label during the course of clinical care. In addition, we provided detailed clinical information about RLS in this pediatric cohort. Patients and methods: The study included 30 consecutive Japanese children with RLS who visited the Pediatric Sleep Clinic at Osaka University Hospital, and consisted of 17 boys and 13 girls, aged 2–14 years (mean ± SD, 6.5 ± 2.8). All-night polysomnography was performed in 18 patients and serum ferritin levels were measured in all the patients. After the diagnosis of RLS, iron was administered at doses between 1.6 and 7.8 mg/kg/day (3.2 ± 1.3). Serum ferritin was re-evaluated 3–6 months after iron treatment, or when RLS symptoms had disappeared. Results: The patient age at onset of RLS symptoms ranged from six months to 13 years (4.3 ± 3.6). A positive family history was recognized in 19 children (63.3%). Serum ferritin levels before therapy were 9– 62 ng/ml (26.6 ± 12.8) and oral iron supplementation was reported to be highly effective in 17 children, effective in 10, and ineffective in three. The serum ferritin level at follow-up was 23–182 ng/ml (83.5 ± 49.8). The onset of treatment effect was within approximately three months. Conclusions: Iron treatment could be effective in Japanese pediatric RLS. Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction Restless legs syndrome (RLS) is a sensorimotor disorder characterized by the prototypical complaint of a strong, nearly irresistible urge to move the legs [1]. The International Restless Legs Syndrome Study Group (IRLSSG) proposed consensus criteria for the diagnosis of definite RLS in pediatric populations [1]. In addition to the four essential features of adult RLS, the pediatric RLS criteria are (1) the child relates a description in his or her own words that is consistent with leg discomfort, or (2) the child has two of the three following supportive criteria: sleep disturbance for age; a biological parent or sibling with definite RLS; a periodic leg movements during sleep (PLMS) index of more than five per hour. In school-aged children the prevalence of pediatric RLS has been estimated at 1.9–3.6% [2–4]. ⇑ Corresponding author at: Department of Child Development, United Graduate School of Child Development, Osaka University, 2-2 D-5 Yamadaoka, Suita-shi, 5650871 Osaka, Japan. Tel./fax: +81 6 6879 3863. E-mail addresses: [email protected], [email protected] (M. Taniike). 1389-9457/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2011.12.009
The pathophysiology of RLS has recently been elucidated in significant detail, including the genetic features, dopaminergic dysfunction, and low iron storage status [5,6]; however, some aspects of the disorder remain unclear. Ekbom reported a high prevalence of iron deficiency among his patients and discussed the effectiveness of iron treatment for RLS [7]. Many conditions that compromise the patient’s iron status may increase the risk of RLS, and iron supplementation has been shown to reduce the risk of RLS, and, in some cases, effect a cure [6]. Moreover, autopsies, analyses of cerebrospinal fluid, and brain imaging studies have all documented the low brain iron status of adult RLS patients [8]. Wang et al. reported a randomized double-blind study showing that oral iron is an effective treatment for adult RLS patients with low-normal ferritin [9]. Here, we retrospectively report the results of oral iron treatment of 30 Japanese children with RLS, including ferritin levels and other clinical characteristics. Although there are three published case reports of iron therapy in pediatric RLS [10–12] and a review [13], to our knowledge this is the first clinical study to address the efficacy of iron therapy in pediatric RLS.
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I. Mohri et al. / Sleep Medicine 13 (2012) 429–432
2. Subjects and methods All patients were seen in the Pediatric Sleep Clinic at Osaka University Hospital between 2005 and 2009. The RLS diagnosis was made if the patient satisfied the IRLSSG consensus criteria [1]. To judge the presence of ‘‘the urge to move’’ we gave verbal instructions to the parents to request their children stay still at bedtime, and to ask them what they were feeling. Children over the age of four explained that they could not stop moving their legs (or limbs), although they were sleepy. The three children under the age of four (#17, #26, #28) were unable to report their urge to move, so this was estimated based on hyperactive behavior at bedtime that caregivers were unable to stop. Therefore, these three patients were diagnosed as having probable RLS based on the IRLSSG criteria [1]. The patients consisted of 17 boys and 13 girls, aged 2–14 years (6.8 ± 2.9). The children and their biological parents were all Japanese. Relevant information for patients #1, #11, #13, #14, #15, #16, and #17 have been previously described [12,14]. Details of the sleep history, symptoms, family history, and comorbidity of the 30 patients in this study are presented in Supplemental Table 1. All-night polysomnography (PSG) was performed in 18 patients to rule out comorbidity with other sleep disorders. PLMS was scored and the PLMS index (PLMSI) was calculated according to the American Academy of Sleep Medicine criteria [15]. All patients received blood cell count and blood chemistry work-ups, as well as measurements of serum iron and ferritin concentrations. Patients took ferrous sulfate twice in a day and the dose is ranged 1.6– 7.8 (3.2 ± 1.3) mg/kg/day in elemental iron. In the case of very young children who were unable to swallow the big tablet of fer-
rous sulfate, ferric pyrophosphate in a syrup format was prescribed. The efficacy of iron treatment was judged by monthly visits to record bedtime behaviors, leg movements, bedtime irritability, sleep latency, awakenings during sleep, and daytime behavior, in addition to the patient’s own descriptions of their leg discomfort. In this study, the effectiveness of iron treatment was assessed at three months after the initiation of treatment and was classified as ‘‘highly effective’’ when RLS symptoms were reported to have disappeared, ‘‘effective’’ when the frequency and severity of RLS symptoms had decreased, and ‘‘ineffective’’ when RLS symptoms remained unchanged. Ferritin levels were re-evaluated 3–6 months after iron treatment or when RLS symptoms were reported to disappear.
3. Results 3.1. Characteristics of RLS symptoms A positive family history was recognized in 19 of 30 patients (63.3%). In these 19 familial cases RLS was seen in the paternal line, the maternal line, and not definite (only identified in brothers and sisters) in five, 12, and two patients, respectively. Information from caregivers revealed that the onset of symptoms such as severe bedtime irritability, leg restlessness at night, and touching and gripping the legs dated back to infancy in seven patients (Table 1). The average age at onset of symptoms was 4.3 ± 3.7 years (range 0–13). The RLS symptoms are summarized in Supplemental Table 1. Our patients expressed unpleasant feelings in a variety of ways, with the most common expressions being ‘‘creeping feelings in the legs’’ and ‘‘discomfort in the legs.’’ How-
Table 1 Summary of RLS treatment. No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 ⁄
Sex
M F F M F M M M M M M F F F M F F M M F M F M F F M M M M F
Age of Diagnosis
Age of Onset
Serum iron level (lg/dl)
Serum ferritin level (ng/ml) Before iron treatment
After iron treatment
5 7 7 7 6 9 7 8 7 14 4 7 5 6 4 4 2 5 11 5 13 6 4 9 9 3 5 3 8 6
4 5 0 3 5 8 7 8 7 13 0 (10 M) 7 0 (6 M) 6 2 3 0 (10 M) 2 5 1 12 0 2 3 9 2 5 1 5 5
188 64 115 58 136 38 95 120 75 89 132 37 96 105 101 183 12 65 121 80 136 24 34 43 100 34 110 84 77 126
26 22 20 37 31 12 31 44 20 35 9 36 19 35 21 14 9 9 17 28 62 39 49 44 25 19 22 15 21 26
56 132 109 104 92 94 182 100 N/P 35 34 114 24 131 N/P 23 37 N/P 38 37 N/P N/P N/P 151 178 N/P 52 N/P 67 46
++; highly effective, +; effective, –; ineffective. CZP; clonazepam, (+ indicates ‘‘additional’’). N/P; not performed.
Dose of iron (mg/ kg/day)
Effectiveness of iron treatment⁄
2.8 3.8 4.8 3.2 3.9 4.2 4 3.3 3.5 1.9 3 2.5 1.6 7.8 3.3 2.3 4.5 2.7 1.6 1.8 2.7 2.6 2.7 3.5 4.2 2.6 2.3 2.4 5 2.7
++ + + ++ ++ + ++ + + + ++ ++ ++ ++
Alternative or additional medication
CZP Pramipexole + CZP
+CZP Pramipexole +Pramipexole +Pramipexole +CZP
+Pramipexole ++ ++ ++ + + + + ++ ++ ++ ++ ++ ++
+CZP
I. Mohri et al. / Sleep Medicine 13 (2012) 429–432
ever, they sometimes complained of pain, tickles, or hot sensations. RLS symptoms were recognized almost every day in 19 children (63.3%), and at least once a week in 28 (93.3%). The caregivers reported that daytime irritability or sleepiness was observed in 13 (43.3%) and 20 (66.7%) patients, respectively. On PSG, PLMSI of more than five per hour was documented in four of the 18 patients (22.2%) in whom PSG was performed. The detailed indices are shown in Supplemental Table 2. 3.2. Treatment process and iron status Table 1 shows the serum iron and ferritin levels before and after iron treatment and the treatment doses, for each of the 30 patients. Before iron therapy, serum ferritin levels were between 26.6 ± 12.8 ng/ml (range 9–62). All except one patient (#21) had ferritin levels below 50 ng/ml. No tolerance or adverse effects were seen in our 30 children. Treatment was reported to be highly effective in 17 patients, effective in 10, and ineffective in three. Serum ferritin levels after iron therapy were available in 22 of 30 children showing 23– 182 ng/ml (83.5 ± 49.8). For the patients in whom iron treatment was effective, serum ferritin levels before and after treatment were 28.1 ± 12.4 ng/ml (range 9–62) and 85.6 ± 49.9 ng/ml (range 23– 182), respectively. Conversely, for patients in whom the treatment was ineffective, serum ferritin levels before and after treatment were 12.6 ± 6.4 ng/ml (range 9–20) and 60.0 ± 42.5 ng/ml (range 34–109), respectively. Patient #21 had a pre-treatment ferritin level of 62 ng/ml and showed a partial response to iron supplementation. In patients with a favorable response the reported time to therapeutic effect after initiating iron treatment was 1–3 months (1.7 ± 0.7). The duration of iron treatment was 1–36 months (8.6 ± 8.1). The three patients who were refractory to iron therapy were infantile-onset and exhibited severe symptomatology (#3, #11, and #17). The follow-up period after treatment was 8.4 ± 4.1 months. There has been no recurrence of RLS symptoms in 14 patients with good responses since iron supplementation was stopped. In patients #8 and #19 symptoms recurred transiently in the summer or during febrile illness, respectively. An immediate recurrence of symptoms was reported after iron supplementation was stopped in patients #1, #26, and #28. Serum ferritin in patient #1 was elevated from 26 to 56 ng/ml by iron supplementation, but this decreased to 37 ng/ml when his symptoms relapsed after the cessation of iron treatment. In the cases in which iron supplementation was partially effective or ineffective the patients were changed to or given add-on pramipexole (#3, #9, #10, #11, and #17) or clonazepam (#2, #3, #7, #12, and #21).
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tients were low-normal (less than 50 ng/ml) and rose from 40.6 to 65.7 ng/ml [9]. Because the efficiency of iron absorption is dependent on the individual’s iron status, the ineffectiveness of iron therapy in the former study could be due to inadequate absorption. To circumvent this problem, several trials have been performed in which iron was administered intravenously [21–23]. Three randomized, double-blind, placebo-controlled trials of intravenous iron sucrose showed contradictory results; one failed to demonstrate benefit [22] while the other showed significant improvement of RLS symptoms [23,24]. Ondo reported on the efficacy of intravenous iron supplementation in severe refractory RLS, but the results were inconsistent and not predicted by patient demographics [23]. Allen conducted a randomized, placebo-controlled trial of intravenous administration of ferric carboxymaltose and revealed its effectiveness. This study indicates that the transport system for iron should be kept in mind in addition to the iron compound characteristics, because iron storage did not correlate with the iron input regardless of intravenous administration which could bypass poor iron absorption in the upper gastrointestinal tract. A higher baseline ferritin level can (at least partially) account for the differences. Other factors such as inflammation and iron formulation may also play a role. There may be some differences in absorption or metabolism of iron between adults and children. In addition, the demand for iron as a cofactor for tyrosine hydroxylase activity, which is responsible for dopamine biosynthesis, is higher in younger children [25], suggesting they might require higher ferritin levels. Simakajornboon et al. [26] reported that patients with high PLMI had serum ferritin levels of less than 50 ng/ml. In patients who responded to iron therapy, PLMI and efficacy correlated with increased serum ferritin levels above 50 ng/ml. Konofal et al. [27] reported that iron supplementation improved core symptoms in ADHD patients who had serum ferritin below 30 ng/ml. Thus, serum ferritin levels of 50 ng/ml may be used as a threshold for treatment; however, this requires further investigation. Two of the patients (#3 and #11) with onset of RLS in infancy did not respond to iron therapy to the same extent. Therefore, patients with very early onset of RLS tended to need add-on treatments such as pramipexole. Fulda and Wetter reported that 20–25% of RLS patients were at increased risk for daytime sleepiness [28]. In our study, parents reported irritability in 13 patients (43.3%) and daytime sleepiness in 20 (66.7%). Sleep disturbance due to RLS could influence childhood development; evidence has accumulated to suggest widespread deterioration of neural function, which may cause permanent neuronal damage [29]. In addition, a recent epidemiological study indicated that sleep problems in early childhood (between ages two and four) are an indicator of subsequent attention problems that may persist into adolescence [29]. In this regard, the longterm follow up of pediatric RLS patients is crucial.
4. Discussion 4.1. Limitations We present here 30 Japanese children with RLS. Their average age at onset of symptoms was 4.3 years. Oral iron supplementation, administered in an open-label manner, was reported to be effective in 27 of the children. Previous studies examining iron insufficiency have consistently suggested an association between abnormal iron metabolism and some RLS cases [16–19]. However, the efficacy of iron treatment in adult RLS patients has been underexplored. There have been only two randomized, double-blind, placebo-controlled studies of oral iron therapy in RLS, with conflicting results [9,20]. One study showed no benefit of iron therapy in RLS patients with average baseline serum ferritin levels of approximately 134.8 ng/ml [20]. In contrast, improvement in RLS symptoms was observed in the second study, where the average baseline ferritin levels of RLS pa-
There are several limitations to this study. First, this is an openlabel and retrospective study that had no structured outcome measures, non-uniform times of reassessment, and included only a small number of children of different ages. Therefore, we cannot definitively conclude that iron therapy is effective for children with RLS. Second, there is placebo effect on dopamine and opioids for treatment of adult RLS [30], so the results obtained here in pediatric RLS must be cautiously interpreted. Finally, the patients were followed up for less than 36 months with incomplete repeated ferritin measurements, which may be inadequate to observe the longterm effects and consequences of iron therapy. Although limited and preliminary, our results suggest a favorable response to oral iron in Japanese children with RLS. From a
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child development standpoint, we should try to make an accurate diagnosis of RLS as early as possible. To maximize the range of treatments available to RLS patients, systematic, well-controlled studies are warranted to investigate the best use of iron supplementation for pediatric RLS patients. Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.12.009.
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