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Treatment of Pediatric Restless Legs Syndrome Louella B. Amos, Megan L. Grekowicz, Evelyn M. Kuhn, Jenna D. Olstad, Maureen M. Collins, Nan A. Norins and Lynn A. D'Andrea CLIN PEDIATR 2014 53: 331 originally published online 6 November 2013 DOI: 10.1177/0009922813507997 The online version of this article can be found at: http://cpj.sagepub.com/content/53/4/331
Published by: http://www.sagepublications.com
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507997
research-article2013
CPJXXX10.1177/0009922813507997Clinical PediatricsAmos et al
Article
Treatment of Pediatric Restless Legs Syndrome
Clinical Pediatrics 2014, Vol. 53(4) 331–336 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922813507997 cpj.sagepub.com
Louella B. Amos, MD1, Megan L. Grekowicz, APN1, Evelyn M. Kuhn, PhD2, Jenna D. Olstad, BA2, Maureen M. Collins, MS, RD2, Nan A. Norins, MD1, and Lynn A. D’Andrea, MD1
Abstract Objective. The primary aim was to determine if iron supplementation effectively treats children with restless legs syndrome (RLS), the time to improvement or resolution of symptoms, and patient characteristics (family history of RLS, secondary sleep disorders, medical diagnoses, and/or mental health diagnoses) that may affect outcome. Methods. This was a retrospective chart review of children between 5 and 18 years old who were diagnosed with RLS at the pediatric sleep disorders clinic at Children’s Hospital of Wisconsin in Milwaukee, Wisconsin. Documented RLS treatment approaches included supplemental iron, nonpharmacologic interventions, melatonin, gabapentin, clonidine, and dopamine agonists (pramipexole and ropinirole). Results. Ninety-seven children were diagnosed with RLS; 60.8% of children were between 5 and 11 years old. Most children (65%) received iron either as monotherapy or in combination with other treatments. Approximately 80% of the children who received iron and had follow-up had improvement or resolution of their symptoms. The median baseline ferritin level was 22.7 ng/mL, and 71% of children had a ferritin level less than 30 ng/mL. The median time to improvement or resolution of symptoms was 3.8 months. Conclusions. Supplemental iron as monotherapy or in combination with other treatments is effective in treating pediatric RLS. A prospective study could help determine if the initial ferritin level and degree of change in the ferritin level impact response to iron treatment. It is also important to study the long-term outcomes in these patients. Keywords pediatric, restless legs syndrome, iron, treatment, ferritin
Introduction Over the past 2 decades, pediatric restless legs syndrome (RLS) has received increasing attention among general pediatricians and various pediatric subspecialties.1 In adults, RLS is a clinical diagnosis based on patient report of nocturnal leg discomfort that worsens during rest or inactivity and is partially or totally relieved by movement.2 Recognition and treatment of pediatric RLS is problematic because of confounding diagnoses such as growing pains.3-5 In addition, young children may have difficulty describing their RLS symptoms, and clinical decisions may depend on parental observations and report. Therefore, in 2003, criteria for the definite and probable diagnosis of RLS in children were published.6 In 2007, a population-based study reported a 2% prevalence of RLS among children aged 8 to 17 years.7 Despite growing recognition of pediatric RLS, therapeutic outcomes have not been extensively studied, and treatment guidelines have not been established. Iron replacement has been suggested as an effective therapy for pediatric RLS based on the proposed
pathophysiology of RLS.8 In adults, a serum ferritin level 30 ng/mL. Iron was not prescribed in one child due to constipation issues; the other child clinically improved on melatonin alone. Forty-six percent (25 of 54) of children who improved or resolved used a non-pharmacologic intervention compared with only 19% (4 of 21) of those who did not improve or resolve (P = .03, χ2 test). No Improvement or Resolution. Twenty-one of the 75 children (28%) with at least one follow-up contact did not have documented improvement or resolution of symptoms; however, 19 of these 21 patients did not have follow-up on treatment or were lost to follow-up before treatment was initiated. Twelve of these patients were started on iron. Risk Factors. There was no statistically significant association between improvement or resolution of symptoms and family history of RLS, age of child, or mental health diagnosis, including the diagnosis of ADHD.
Discussion To our knowledge, this is the first study examining treatment outcomes of children with RLS with a focus on iron therapy. Previous publications have described the various pharmacotherapeutic options for pediatric RLS, but few have investigated the outcomes of such medications, and none have evaluated the efficacy of iron treatment.12-14 In addition, this study analyzed the impact of serum ferritin level and co-morbidities on treatment
outcomes. These findings may provide insight for pediatric RLS treatment guidelines.
Treatment Outcomes Children treated with iron were more likely to have a positive treatment outcome than those not treated with iron. All patients treated with dopaminergic agents improved/ resolved but had prior iron treatment. Overall, more children whose symptoms improved/resolved used a nonpharmacologic approach compared with those children who did not improve/resolve. These findings suggest that iron is often effective not only as monotherapy but also in combination with other medications, and as adjunct therapy for dopamine agonists. In addition, nonpharmacologic interventions are essential in the RLS treatment plan.
Serum Ferritin Levels Most children (71%) in our study had an initial ferritin level less than 30 ng/mL. In the majority of patients, iron treatment was initiated at 3 to 4 mg of elemental iron per kilogram divided twice daily if the ferritin level was less than 30 ng/mL. In adult RLS, the consensus is to start iron supplementation when the serum ferritin level is less than 50 ng/mL.16-18 In 1984, Milman and Cohn19 examined serum iron, transferrin, ferritin and transferrin saturation in 253 healthy children aged 4, 8, and 13 years without iron deficiency and showed that among 196 children with a serum ferritin ≥15 µg/L (equivalent to 15 ng/mL), the median serum ferritin was 25 µg/L. Ferritin levels were less than 15 µg/L in the remaining 57 children. In the same study, the median ferritin level in 60 healthy adults was 54 µg/L. These data imply that children inherently have lower iron stores than adults and that the serum ferritin threshold of 50 ng/mL in adult RLS treatment guidelines for iron replacement may not apply to pediatric RLS.
Downloaded from cpj.sagepub.com at GEORGIAN COURT UNIV on December 4, 2014
335
Amos et al Our study demonstrated that the children who experienced symptomatic relief with iron treatment had a lower median ferritin level than those who did not improve/resolve. Among those who improved/resolved on iron and who had follow-up ferritin levels, the median final ferritin level was 34.5 ng/mL, suggesting that targeting a ferritin level >30 ng/mL may result in a therapeutic response. Therefore, in contrast to adult RLS treatment guidelines, we propose starting iron therapy in children with RLS if the serum ferritin level is less than 30 ng/mL with a therapeutic goal of >30 ng/mL.
Comorbid Diagnoses Among the children with a comorbid medical diagnosis, a significant proportion had orthopedic problems, emphasizing the importance of monitoring for concurrent musculoskeletal issues. The most common mental health diagnosis was ADHD. The coexistence of ADHD and RLS in children has been well-described in the literature.20-22 In 2007, Konofal et al23 demonstrated that mean serum ferritin levels are low in children with ADHD (25 ng/mL) and are even lower in children with ADHD and RLS (16 ng/mL). In a double-blind, placebo-controlled, randomized pilot trial in 2008, Konofal et al24 treated 23 children with ADHD and serum ferritin levels 30 ng/mL would have benefited from iron supplementation. A significant number of children used various therapeutic modalities, and in some cases, it was difficult to discern if the outcome was related to the combination of therapies or one particular treatment. A prospective study design could address these limitations and provide additional information regarding pediatric RLS treatment guidelines.
Conclusions The majority (60.8%) of children in this study were between 5 and 11 years old, emphasizing the significant prevalence of RLS in young children. Because of the potential negative impact of RLS on daytime function and school performance, timely diagnosis and effective treatment is crucial during these early childhood years of academic development. These same children may have comorbid risk factors such as other secondary sleep, medical, or mental health disorders, although this does not seem to adversely affect response to treatment. The data from this study shows that iron as monotherapy or in combination with other treatments is effective in treating pediatric RLS. We also propose that a serum ferritin level of >30 ng/mL may be a more meaningful therapeutic goal in treating children with RLS. A prospective study may further elucidate the relationship between the initial ferritin level, follow-up ferritin levels, and clinical response to iron. Structured follow-up with repeat ferritin levels would also aid in monitoring long-term outcomes in these children. Authors’ Note This study was conducted at Children’s Hospital of Wisconsin, Milwaukee, Wisconsin.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
Downloaded from cpj.sagepub.com at GEORGIAN COURT UNIV on December 4, 2014
336
Clinical Pediatrics 53(4)
References 1. Walters AS, Picchietti DL, Ehrenberg BL, Wagner ML. Restless legs syndrome in childhood and adolescence. Pediatr Neurol. 1994;11:241-245. 2. American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. 3. Picchietti DL, Stevens HE. Early manifestations of restless legs syndrome in childhood and adolescence. Sleep Med. 2008;9:770-781. 4. Walters AS. Is there a subpopulation of children with growing pains who really have restless legs syndrome? A review of the literature. Sleep Med. 2002;3:93-98. 5. Rajaram SS, Walters AS, England SJ, Mehta D, Nizam F. Some children with growing pains may actually have restless legs syndrome. Sleep. 2004;27:767-773. 6. Allen RP, Picchietti D, Hening W, Trenkwalder C, Walters AS, Montplaisir J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-119. 7. 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;120:253-266. 8. 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;3:127-132. 9. Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep. 1998;21:371-377. 10. Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology. 2003;61:304-309. 11. Erikson KM, Jones BC, Hess EJ, Zhang Q, Beard JL. Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol Biochem Behav. 2001;69:409-418. 12. Walters AS, Mandelbaum DE, Lewin DS, Kugler S, England SJ, Miller M. Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD. Dopaminergic Therapy Study Group. Pediatr Neurol. 2000;22:182-186. 13. Picchietti MA, Picchietti DL. Restless legs syndrome and periodic limb movement disorder in children and adolescents. Semin Pediatr Neurol. 2008;15:91-99.
14. Simakajornboon N, Kheirandish-Gozal L, Gozal D. Diagnosis and management of restless legs syndrome in children. Sleep Med Rev. 2009;13:149-156. 15. Picchietti DL, Arbuckle RA, Abetz L, et al. Pediatric restless legs syndrome: analysis of symptom descriptions and drawings. J Child Neurol. 2011;26:1365-1376. 16. Hening WA, Allen RP, Earley C, Kushida C, Picchietti DL, Silber M. The treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 1999;22:970-999. 17. Chesson AL Jr, Wise M, Davila D, et al. Practice parameters for the treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine Report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 1999;22:961-968. 18. Oertel WH, Trenkwalder C, Zucconi M, et al. State of the art in restless legs syndrome therapy: practice recommendations for treating restless legs syndrome. Mov Disord. 2007;22(suppl 18):S466-S475. 19. Milman N, Cohn J. Serum iron, serum transferrin and transferrin saturation in health children without iron deficiency. Eur J Pediatr. 1984;143:96-98. 20. Picchietti DL, England SJ, Walters AS, Willis K, Verrico T. Periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. J Child Neurol. 1998;13:588-594. 21. Picchietti DL, Underwood DJ, Farris WA, et al. Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. Mov Disord. 1999;14:1000-1007. 22. Chervin RD, Archbold KH, Dillon JE, et al. Associations between symptoms of inattention, hyperactivity, restless legs, and periodic leg movements. Sleep. 2002;25:213-218. 23. Konofal E, Cortese S, Marchand M, Mouren M-C, Arnulf I, Lecendreux M. Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children. Sleep Med. 2007;8:711-715. 24. Konofal E, Lecendreux M, Deron J, et al. Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol. 2008;38:20-26. 25. Arbuckle R, Abetz L, Durmer JS, et al. Development of the Pediatric Restless Legs Syndrome Severity Scale (P-RLS-SS): a patient-reported outcome measure of pediatric RLS symptoms and Impact. Sleep Med. 2010;11: 897-906.
Downloaded from cpj.sagepub.com at GEORGIAN COURT UNIV on December 4, 2014
Treatment of Pediatric Restless Legs Syndrome Louella B. Amos, Megan L. Grekowicz, Evelyn M. Kuhn, Jenna D. Olstad, Maureen M. Collins, Nan A. Norins and Lynn A. D'Andrea CLIN PEDIATR 2014 53: 331 originally published online 6 November 2013 DOI: 10.1177/0009922813507997 The online version of this article can be found at: http://cpj.sagepub.com/content/53/4/331
Published by: http://www.sagepublications.com
Additional services and information for Clinical Pediatrics can be found at: Email Alerts: http://cpj.sagepub.com/cgi/alerts Subscriptions: http://cpj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Mar 5, 2014 OnlineFirst Version of Record - Nov 6, 2013 What is This?
Downloaded from cpj.sagepub.com at GEORGIAN COURT UNIV on December 4, 2014
507997
research-article2013
CPJXXX10.1177/0009922813507997Clinical PediatricsAmos et al
Article
Treatment of Pediatric Restless Legs Syndrome
Clinical Pediatrics 2014, Vol. 53(4) 331–336 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922813507997 cpj.sagepub.com
Louella B. Amos, MD1, Megan L. Grekowicz, APN1, Evelyn M. Kuhn, PhD2, Jenna D. Olstad, BA2, Maureen M. Collins, MS, RD2, Nan A. Norins, MD1, and Lynn A. D’Andrea, MD1
Abstract Objective. The primary aim was to determine if iron supplementation effectively treats children with restless legs syndrome (RLS), the time to improvement or resolution of symptoms, and patient characteristics (family history of RLS, secondary sleep disorders, medical diagnoses, and/or mental health diagnoses) that may affect outcome. Methods. This was a retrospective chart review of children between 5 and 18 years old who were diagnosed with RLS at the pediatric sleep disorders clinic at Children’s Hospital of Wisconsin in Milwaukee, Wisconsin. Documented RLS treatment approaches included supplemental iron, nonpharmacologic interventions, melatonin, gabapentin, clonidine, and dopamine agonists (pramipexole and ropinirole). Results. Ninety-seven children were diagnosed with RLS; 60.8% of children were between 5 and 11 years old. Most children (65%) received iron either as monotherapy or in combination with other treatments. Approximately 80% of the children who received iron and had follow-up had improvement or resolution of their symptoms. The median baseline ferritin level was 22.7 ng/mL, and 71% of children had a ferritin level less than 30 ng/mL. The median time to improvement or resolution of symptoms was 3.8 months. Conclusions. Supplemental iron as monotherapy or in combination with other treatments is effective in treating pediatric RLS. A prospective study could help determine if the initial ferritin level and degree of change in the ferritin level impact response to iron treatment. It is also important to study the long-term outcomes in these patients. Keywords pediatric, restless legs syndrome, iron, treatment, ferritin
Introduction Over the past 2 decades, pediatric restless legs syndrome (RLS) has received increasing attention among general pediatricians and various pediatric subspecialties.1 In adults, RLS is a clinical diagnosis based on patient report of nocturnal leg discomfort that worsens during rest or inactivity and is partially or totally relieved by movement.2 Recognition and treatment of pediatric RLS is problematic because of confounding diagnoses such as growing pains.3-5 In addition, young children may have difficulty describing their RLS symptoms, and clinical decisions may depend on parental observations and report. Therefore, in 2003, criteria for the definite and probable diagnosis of RLS in children were published.6 In 2007, a population-based study reported a 2% prevalence of RLS among children aged 8 to 17 years.7 Despite growing recognition of pediatric RLS, therapeutic outcomes have not been extensively studied, and treatment guidelines have not been established. Iron replacement has been suggested as an effective therapy for pediatric RLS based on the proposed
pathophysiology of RLS.8 In adults, a serum ferritin level 30 ng/mL. Iron was not prescribed in one child due to constipation issues; the other child clinically improved on melatonin alone. Forty-six percent (25 of 54) of children who improved or resolved used a non-pharmacologic intervention compared with only 19% (4 of 21) of those who did not improve or resolve (P = .03, χ2 test). No Improvement or Resolution. Twenty-one of the 75 children (28%) with at least one follow-up contact did not have documented improvement or resolution of symptoms; however, 19 of these 21 patients did not have follow-up on treatment or were lost to follow-up before treatment was initiated. Twelve of these patients were started on iron. Risk Factors. There was no statistically significant association between improvement or resolution of symptoms and family history of RLS, age of child, or mental health diagnosis, including the diagnosis of ADHD.
Discussion To our knowledge, this is the first study examining treatment outcomes of children with RLS with a focus on iron therapy. Previous publications have described the various pharmacotherapeutic options for pediatric RLS, but few have investigated the outcomes of such medications, and none have evaluated the efficacy of iron treatment.12-14 In addition, this study analyzed the impact of serum ferritin level and co-morbidities on treatment
outcomes. These findings may provide insight for pediatric RLS treatment guidelines.
Treatment Outcomes Children treated with iron were more likely to have a positive treatment outcome than those not treated with iron. All patients treated with dopaminergic agents improved/ resolved but had prior iron treatment. Overall, more children whose symptoms improved/resolved used a nonpharmacologic approach compared with those children who did not improve/resolve. These findings suggest that iron is often effective not only as monotherapy but also in combination with other medications, and as adjunct therapy for dopamine agonists. In addition, nonpharmacologic interventions are essential in the RLS treatment plan.
Serum Ferritin Levels Most children (71%) in our study had an initial ferritin level less than 30 ng/mL. In the majority of patients, iron treatment was initiated at 3 to 4 mg of elemental iron per kilogram divided twice daily if the ferritin level was less than 30 ng/mL. In adult RLS, the consensus is to start iron supplementation when the serum ferritin level is less than 50 ng/mL.16-18 In 1984, Milman and Cohn19 examined serum iron, transferrin, ferritin and transferrin saturation in 253 healthy children aged 4, 8, and 13 years without iron deficiency and showed that among 196 children with a serum ferritin ≥15 µg/L (equivalent to 15 ng/mL), the median serum ferritin was 25 µg/L. Ferritin levels were less than 15 µg/L in the remaining 57 children. In the same study, the median ferritin level in 60 healthy adults was 54 µg/L. These data imply that children inherently have lower iron stores than adults and that the serum ferritin threshold of 50 ng/mL in adult RLS treatment guidelines for iron replacement may not apply to pediatric RLS.
Downloaded from cpj.sagepub.com at GEORGIAN COURT UNIV on December 4, 2014
335
Amos et al Our study demonstrated that the children who experienced symptomatic relief with iron treatment had a lower median ferritin level than those who did not improve/resolve. Among those who improved/resolved on iron and who had follow-up ferritin levels, the median final ferritin level was 34.5 ng/mL, suggesting that targeting a ferritin level >30 ng/mL may result in a therapeutic response. Therefore, in contrast to adult RLS treatment guidelines, we propose starting iron therapy in children with RLS if the serum ferritin level is less than 30 ng/mL with a therapeutic goal of >30 ng/mL.
Comorbid Diagnoses Among the children with a comorbid medical diagnosis, a significant proportion had orthopedic problems, emphasizing the importance of monitoring for concurrent musculoskeletal issues. The most common mental health diagnosis was ADHD. The coexistence of ADHD and RLS in children has been well-described in the literature.20-22 In 2007, Konofal et al23 demonstrated that mean serum ferritin levels are low in children with ADHD (25 ng/mL) and are even lower in children with ADHD and RLS (16 ng/mL). In a double-blind, placebo-controlled, randomized pilot trial in 2008, Konofal et al24 treated 23 children with ADHD and serum ferritin levels 30 ng/mL would have benefited from iron supplementation. A significant number of children used various therapeutic modalities, and in some cases, it was difficult to discern if the outcome was related to the combination of therapies or one particular treatment. A prospective study design could address these limitations and provide additional information regarding pediatric RLS treatment guidelines.
Conclusions The majority (60.8%) of children in this study were between 5 and 11 years old, emphasizing the significant prevalence of RLS in young children. Because of the potential negative impact of RLS on daytime function and school performance, timely diagnosis and effective treatment is crucial during these early childhood years of academic development. These same children may have comorbid risk factors such as other secondary sleep, medical, or mental health disorders, although this does not seem to adversely affect response to treatment. The data from this study shows that iron as monotherapy or in combination with other treatments is effective in treating pediatric RLS. We also propose that a serum ferritin level of >30 ng/mL may be a more meaningful therapeutic goal in treating children with RLS. A prospective study may further elucidate the relationship between the initial ferritin level, follow-up ferritin levels, and clinical response to iron. Structured follow-up with repeat ferritin levels would also aid in monitoring long-term outcomes in these children. Authors’ Note This study was conducted at Children’s Hospital of Wisconsin, Milwaukee, Wisconsin.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
Downloaded from cpj.sagepub.com at GEORGIAN COURT UNIV on December 4, 2014
336
Clinical Pediatrics 53(4)
References 1. Walters AS, Picchietti DL, Ehrenberg BL, Wagner ML. Restless legs syndrome in childhood and adolescence. Pediatr Neurol. 1994;11:241-245. 2. American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. 3. Picchietti DL, Stevens HE. Early manifestations of restless legs syndrome in childhood and adolescence. Sleep Med. 2008;9:770-781. 4. Walters AS. Is there a subpopulation of children with growing pains who really have restless legs syndrome? A review of the literature. Sleep Med. 2002;3:93-98. 5. Rajaram SS, Walters AS, England SJ, Mehta D, Nizam F. Some children with growing pains may actually have restless legs syndrome. Sleep. 2004;27:767-773. 6. Allen RP, Picchietti D, Hening W, Trenkwalder C, Walters AS, Montplaisir J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-119. 7. 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;120:253-266. 8. 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;3:127-132. 9. Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep. 1998;21:371-377. 10. Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology. 2003;61:304-309. 11. Erikson KM, Jones BC, Hess EJ, Zhang Q, Beard JL. Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol Biochem Behav. 2001;69:409-418. 12. Walters AS, Mandelbaum DE, Lewin DS, Kugler S, England SJ, Miller M. Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD. Dopaminergic Therapy Study Group. Pediatr Neurol. 2000;22:182-186. 13. Picchietti MA, Picchietti DL. Restless legs syndrome and periodic limb movement disorder in children and adolescents. Semin Pediatr Neurol. 2008;15:91-99.
14. Simakajornboon N, Kheirandish-Gozal L, Gozal D. Diagnosis and management of restless legs syndrome in children. Sleep Med Rev. 2009;13:149-156. 15. Picchietti DL, Arbuckle RA, Abetz L, et al. Pediatric restless legs syndrome: analysis of symptom descriptions and drawings. J Child Neurol. 2011;26:1365-1376. 16. Hening WA, Allen RP, Earley C, Kushida C, Picchietti DL, Silber M. The treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 1999;22:970-999. 17. Chesson AL Jr, Wise M, Davila D, et al. Practice parameters for the treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine Report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 1999;22:961-968. 18. Oertel WH, Trenkwalder C, Zucconi M, et al. State of the art in restless legs syndrome therapy: practice recommendations for treating restless legs syndrome. Mov Disord. 2007;22(suppl 18):S466-S475. 19. Milman N, Cohn J. Serum iron, serum transferrin and transferrin saturation in health children without iron deficiency. Eur J Pediatr. 1984;143:96-98. 20. Picchietti DL, England SJ, Walters AS, Willis K, Verrico T. Periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. J Child Neurol. 1998;13:588-594. 21. Picchietti DL, Underwood DJ, Farris WA, et al. Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. Mov Disord. 1999;14:1000-1007. 22. Chervin RD, Archbold KH, Dillon JE, et al. Associations between symptoms of inattention, hyperactivity, restless legs, and periodic leg movements. Sleep. 2002;25:213-218. 23. Konofal E, Cortese S, Marchand M, Mouren M-C, Arnulf I, Lecendreux M. Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children. Sleep Med. 2007;8:711-715. 24. Konofal E, Lecendreux M, Deron J, et al. Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol. 2008;38:20-26. 25. Arbuckle R, Abetz L, Durmer JS, et al. Development of the Pediatric Restless Legs Syndrome Severity Scale (P-RLS-SS): a patient-reported outcome measure of pediatric RLS symptoms and Impact. Sleep Med. 2010;11: 897-906.
Downloaded from cpj.sagepub.com at GEORGIAN COURT UNIV on December 4, 2014
