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Alsunaid A, Spencer S, Bhandari S. Intravenous iron in chronic kidney disease without anaemia but iron deficiency: A scoping review. World J Nephrol 2025; 14:101576. [PMID: 40134647 PMCID: PMC11755244 DOI: 10.5527/wjn.v14.i1.101576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 12/30/2024] [Accepted: 01/09/2025] [Indexed: 01/20/2025] Open
Abstract
Iron deficiency (ID) is a prevalent complication of chronic kidney disease (CKD), often managed reactively when associated with anaemia. This scoping review evaluates the evidence supporting intravenous (IV) iron therapy in non-anaemic individuals with CKD and ID, focusing on safety, efficacy, and emerging therapeutic implications. Current diagnostic markers, including serum ferritin, transferrin saturation, and reticulocyte haemoglobin content, are reviewed alongside their limitations in the context of inflammation and variability. The pathophysiology of ID in CKD is explored, highlighting the roles of hepcidin, hypoxia-inducible factor pathways, and uraemic toxins. Comparative studies reveal that IV iron offers a more rapid correction of iron stores, improved compliance, and fewer gastrointestinal side effects compared to oral iron. Evidence from trials such as "iron and heart" and "iron and muscle" suggests potential benefits of IV iron on functional capacity and fatigue, though findings were statistically non-significant. Insights from heart failure trials support the safety and efficacy of IV iron in improving quality of life and reducing hospitalizations, with newer formulations like ferric derisomaltose demonstrating favourable safety profiles. This review underscores the need for standardized screening protocols for ID in CKD, even in the absence of anaemia, to facilitate earlier intervention. Future research should prioritise robust outcome measures, larger sample sizes, and person-specific treatment strategies to optimise dosing and administration frequency. Tailored approaches to IV iron therapy have the potential to significantly improve functional outcomes, quality of life, and long-term health in people with CKD.
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Affiliation(s)
- Abdulrahman Alsunaid
- Department of Medical Science, Hull York Medical School, Kingston Upon Hull HU6 7RU, United Kingdom
| | - Sebastian Spencer
- Department of Medical Science, Hull York Medical School, Kingston Upon Hull HU6 7RU, United Kingdom
- Department of Medical Science, University of Hull, Kingston Upon Hull HU6 7RU, United Kingdom
- Department of Academic Renal, Hull University Teaching Hospitals NHS Trust, Kingston Upon Hull HU3 2JZ, United Kingdom
| | - Sunil Bhandari
- Department of Medical Science, Hull York Medical School, Kingston Upon Hull HU6 7RU, United Kingdom
- Department of Academic Renal, Hull University Teaching Hospitals NHS Trust, Kingston Upon Hull HU3 2JZ, United Kingdom
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Silber MH, Block DR, St Louis EK. Serum ferritin measurements differ according to the assay used: implications for iron therapy in restless legs syndrome. J Clin Sleep Med 2025; 21:65-67. [PMID: 39172079 DOI: 10.5664/jcsm.11332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
STUDY OBJECTIVES Serum ferritin levels are used to determine the need for iron supplementation in patients with restless legs syndrome. The purpose of this study was to determine whether immunoassay measurement of serum ferritin yields varying levels according to different manufacturers' assays, with resultant variation in cutoff values. METHODS We compared serum ferritin levels using 116 clinical samples assessed by the Beckman and Roche methods. RESULTS Although there was a high correlation between results obtained from the 2 methods (R2 = 0.99), the absolute values differed. The equivalent ferritin measures determined by the Beckman and Roche methods were 50 μg/dl, 83 μg/dl; 75 μg/dl, 121 μg/dl; 100 μg/dl, 158 μg/dl; and 300 μg/dl, 457 μg/dl. CONCLUSIONS It is uncertain which assays were used to measure serum ferritin in the seminal studies on which current guidelines for iron therapy for restless legs syndrome are based. In view of this uncertainty, as well as the limited data on which current recommendations are based, clinicians should be flexible in using recommended serum ferritin cutoff values, also using percentage of transferrin saturation. Assuming that Beckman or equivalent assays were used, centers using the Roche method need to adjust the cutoffs for administration of oral iron and intravenous iron recommended by current practice guidelines to avoid withholding treatment for restless legs syndrome patients who might benefit from iron supplementation. CITATION Silber MH, Block DR, St. Louis EK. Serum ferritin measurements differ according to the assay used: implications for iron therapy in restless legs syndrome. J Clin Sleep Med. 2025;21(1):65-67.
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Affiliation(s)
- Michael H Silber
- Center for Sleep Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
- Department of Neurology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Darci R Block
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Erik K St Louis
- Center for Sleep Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
- Department of Neurology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
- Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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Winkelman JW, Berkowski JA, DelRosso LM, Koo BB, Scharf MT, Sharon D, Zak RS, Kazmi U, Carandang G, Falck-Ytter Y, Shelgikar AV, Trotti LM, Walters AS. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med 2025; 21:153-199. [PMID: 39324664 DOI: 10.5664/jcsm.11392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2024]
Abstract
INTRODUCTION This systematic review provides supporting evidence for the accompanying clinical practice guideline on the treatment of restless legs syndrome and periodic limb movement disorder. METHODS The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine. A systematic review was conducted to identify studies that compared the use of pharmacological or nonpharmacological treatment to no treatment to improve patient-important outcomes. Statistical analyses were performed to determine the clinical significance of using various interventions to treat restless legs syndrome and periodic limb movement disorder in adults and children. The Grading of Recommendations Assessment, Development, and Evaluation process was used to assess the evidence for making recommendations. RESULTS The literature search resulted in 3,631 studies out of which 148 studies provided data suitable for statistical analyses. The task force provided a detailed summary of the evidence along with the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. CITATION Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2025;21(1):153-199.
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Affiliation(s)
- John W Winkelman
- Departments of Psychiatry and Neurology, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | | | | | - Brian B Koo
- Department of Neurology, Yale University, New Haven, Connecticut
- Connecticut Veterans Affairs Healthcare System, West Haven, Connecticut
| | - Matthew T Scharf
- Comprehensive Sleep Center, Division of Pulmonary and Critical Care, Departments of Medicine and Neurology, Rutgers/Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Denise Sharon
- Keck Medical Center of University of Southern California Sleep Disorder Center, Division of Pulmonary, Critical Care and Sleep Medicine, Keck School of Medicine of University of Southern California, Los Angeles, California
- Adult and Children Sleep Disorders Center, Pomona Valley Hospital and Medical Center, Claremont, California
| | - Rochelle S Zak
- Sleep Disorders Center, University of California, San Francisco, San Francisco, California
| | - Uzma Kazmi
- American Academy of Sleep Medicine, Darien, Illinois
| | | | - Yngve Falck-Ytter
- Case Western Reserve University, Cleveland, Ohio
- Department of Gastroenterology and Hepatology, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, Ohio
| | - Anita V Shelgikar
- University of Michigan Sleep Disorders Center, University of Michigan, Ann Arbor, Michigan
| | - Lynn Marie Trotti
- Department of Neurology, Emory University School of Medicine, Atlanta, Georgia
| | - Arthur S Walters
- Department of Neurology, Vanderbilt University, Nashville, Tennessee
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Qadri SN, Jamil S, Zahid S, Asghar T, Gillani SM, Qasim SA, Kambar T, Abideen ZU, Brohi U, Tareen SK, Tareen PK, Kumari S, Kumar S, Khatri M. Clinical efficacy and safety of IV ferric carboxymaltose in restless legs syndrome: A meta-analysis of 537 patients. Sleep Med 2024; 124:244-253. [PMID: 39326219 DOI: 10.1016/j.sleep.2024.09.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 09/08/2024] [Accepted: 09/12/2024] [Indexed: 09/28/2024]
Abstract
BACKGROUND Recent research indicates that intravenous ferric carboxymaltose (IV FCM) presents a promising solution for Restless Legs Syndrome (RLS), distinguishing itself from other iron sources with minimal to no adverse effects. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety profile of administering IV FCM in patients with RLS, assuming that RLS and Iron deficiency anemia (IDA) are correlated. METHODOLOGY This study was conducted according to the PRISMA guideline, with search conducted on PubMed, Google Scholar, and the Medline library. Data was extracted from each study regarding RLS and the effect of IV FCM on it, while analysis was conducted on Review Manager Software. RESULTS This meta-analysis comprises of 7 randomized controlled trials (RCTs). All 7 studies reported international RLS severity scale (IRLS) and the pooled analysis revealed a significant reduction in IRLS score favoring IV FCM [WMD: -6.03, 95 % CI (-10.11, -1.96), p = 0.004]. 3 out of 7 studies reported short form-36 health survey (SF-36) and the pooled analysis revealed that the total score of SF-36 significantly favors the group taking IV FCM [WMD: 7.44, 95%CI (1.67, 13.20) p = 0.01]. 4 out of 7 studies reported visual analogue scale (VAS) for RLS severity and pooled analysis revealed that IV FCM significantly decreased VAS) of RLS severity score as compared to the control [MD -19.21, 95%CI (-31.90, -6.52) p0.003]. CONCLUSION The study findings support the efficacy of IVFCM in reducing the severity of RLS symptoms. Significant improvements in the IRLS scores were observed, alongside enhancements in overall quality of life measured by SF-36 scores.
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Affiliation(s)
- Syeda Nimra Qadri
- Medicine Department, Dow University of Health Sciences, Karachi, Pakistan.
| | - Saifullah Jamil
- Medicine Department, Dow University of Health Sciences, Karachi, Pakistan.
| | - Subhan Zahid
- Medicine Department, Dow University of Health Sciences, Karachi, Pakistan.
| | - Tehreem Asghar
- Medicine Department, Akhtar Saeed Medical & Dental College, Lahore, Pakistan.
| | - Syeda Muzna Gillani
- Medicine Department, Foundation University Medical College, Islamabad, Pakistan.
| | - Soban Ali Qasim
- Medicine Department, Multan Medical and Dental College, Multan, Pakistan.
| | - Tilyan Kambar
- Medicine Department, Ziauddin University, Karachi, Pakistan.
| | - Zain Ul Abideen
- Medicine Department, Quaid-e-Azam Medical College/Bahawal Victoria Hospital Bahawalpur Pakistan, Pakistan.
| | - Usama Brohi
- Medicine Department, Jinnah Sindh Medical University, Karachi, Pakistan.
| | | | - Palay Khan Tareen
- Medicine Department, University Hospitals Birmingham, United Kingdom.
| | - Sandhya Kumari
- Medicine Department, Ziauddin University, Karachi, Pakistan.
| | - Satesh Kumar
- Medicine Department, Shaheed Mohtarma Benazir Bhutto Medical College, Karachi, Pakistan.
| | - Mahima Khatri
- Medicine Department, Dow University of Health Sciences, Karachi, Pakistan.
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Trenkwalder C, Stefani A, Bachmann CG, Maihöfner C, Mathis J, Muntean L, Mollin J, Paulus J, Heidbreder A. Restless legs syndrome: abbreviated guidelines by the German sleep society and the German neurological society. Neurol Res Pract 2024; 6:53. [PMID: 39501372 PMCID: PMC11539677 DOI: 10.1186/s42466-024-00353-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 10/09/2024] [Indexed: 11/08/2024] Open
Affiliation(s)
- Claudia Trenkwalder
- Paracelsus-Elena Klinik, Center of Parkinsonism and Movement Disorders, Klinikstraße 16, Kassel, Germany.
- Department of Neurosurgery, University Medical Center, Goettingen, Germany.
| | - Ambra Stefani
- Department of Neurology, Medical University of Innsbruck, Anichstr. 35, Innsbruck, Austria
| | - Cornelius G Bachmann
- Department of Neurology, University Medical Center, Goettingen, Germany
- Somnodiagnostics, Martinistrasse 63-65, Osnabrück, Germany
| | | | | | - Lucia Muntean
- Paracelsus-Elena Klinik, Center of Parkinsonism and Movement Disorders, Klinikstraße 16, Kassel, Germany
| | - Julian Mollin
- Department of Paediatrics and Adolescents' Medicine, Klinikum Westbrandenburg, Charlottenstraße 72, Potsdam, Germany
| | - Joachim Paulus
- RLS e.V. - German Restless Legs Association, Schäufeleinstr. 35, Munich, Germany
| | - Anna Heidbreder
- Clinic for Neurology, Johannes Kepler University, Linz, Austria
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Burini A, Pellitteri G, Merlino G, Nilo A, Tereshko Y, Dolso P, Gigli GL, Valente M. Current and emerging pharmaceutical strategies for the treatment and management of restless legs syndrome. Expert Rev Neurother 2024; 24:997-1009. [PMID: 39082506 DOI: 10.1080/14737175.2024.2385947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/25/2024] [Indexed: 09/21/2024]
Abstract
INTRODUCTION Restless legs syndrome (RLS) is a sensory-motor sleep disorder that affects up to 13% of adults in the Western world and 2-4% of children. It impairs night sleep with an impact on daily performances and life quality. Thus, moderate-to-severe RLS requires pharmacological treatment. AREAS COVERED In the present review, which is based on PubMed searches with no time limits, the authors discuss the recommended pharmacotherapy for RLS in addition to other emerging treatment options. The authors provide coverage to the current recommendations for both adults and pediatric patients with RLS. EXPERT OPINION Current evidence suggests removing all causes of secondary RLS, including iron deficiency, chronic renal failure, drugs, and treating other sleep disorders that may worsen symptoms. Also, intermittent RLS should be addressed with behavioral measures and on-demand therapy. For chronic persistent RLS, α2δ calcium channel ligands are a first-line pharmacological approach, whereas dopamine agonists are associated with increased risk and should be spared. When RLS is refractory to first-line treatment, polytherapy, or opioid monotherapy should be considered. Nonetheless, some patients may not reach sustained symptom relief. Further research is needed to better understand the pathophysiology of RLS and to develop newer more effective drugs.
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Affiliation(s)
- Alessandra Burini
- Clinical Neurology, Department of Medicine (DMED), University of Udine, Udine, Italy
- Clinical Neurology, Department of Head-Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy
| | - Gaia Pellitteri
- Clinical Neurology, Department of Head-Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy
| | - Giovanni Merlino
- Clinical Neurology, Department of Head-Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy
- SOSD Stroke Unit, Department of Head-Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy
| | - Annacarmen Nilo
- Clinical Neurology, Department of Medicine (DMED), University of Udine, Udine, Italy
- Clinical Neurology, Department of Head-Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy
| | - Yan Tereshko
- Clinical Neurology, Department of Head-Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy
| | - Pierluigi Dolso
- Clinical Neurology, Department of Head-Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy
| | - Gian Luigi Gigli
- Clinical Neurology, Department of Medicine (DMED), University of Udine, Udine, Italy
| | - Mariarosaria Valente
- Clinical Neurology, Department of Medicine (DMED), University of Udine, Udine, Italy
- Clinical Neurology, Department of Head-Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy
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Earley CJ, García-Borreguero D, Falone M, Winkelman JW. Clinical efficacy and safety of intravenous ferric carboxymaltose for treatment of restless legs syndrome: a multicenter, randomized, placebo-controlled clinical trial. Sleep 2024; 47:zsae095. [PMID: 38625730 DOI: 10.1093/sleep/zsae095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 11/03/2023] [Indexed: 04/17/2024] Open
Abstract
STUDY OBJECTIVES Iron therapy is associated with improvements in restless legs syndrome (RLS). This multicenter, randomized, double-blind study evaluated the effect of intravenous ferric carboxymaltose (FCM) on RLS. METHODS A total of 209 adult patients with a baseline International RLS (IRLS) score ≥ 15 were randomized (1:1) to FCM (750 mg/15 mL) or placebo on study days 0 and 5. Ongoing RLS medication was tapered starting on Day 5, with the goal of discontinuing treatment or achieving the lowest effective dose. Co-primary efficacy endpoints were changed from baseline in IRLS total score and the proportion of patients rated as much/very much improved on the Clinical Global Impression (CGI)-investigator (CGI-I) scale at day 42 in the "As-Treated" population. RESULTS The "As-Treated" population comprised 107 FCM and 101 placebo recipients; 88 (82.2%) and 68 (67.3%), respectively, completed the day 42 assessment. The IRLS score reduction was significantly greater with FCM versus placebo: least-squares mean (95% confidence interval [CI]) -8.0 (-9.5, -6.4) versus -4.8 (-6.4, -3.1); p = .0036. No significant difference was observed in the proportion of FCM (35.5%) and placebo (28.7%) recipients with a CGI-I response (odds ratio 1.37 [95% CI: 0.76, 2.47]; p = .2987). Fewer patients treated with FCM (32.7%) than placebo (59.4%) received RLS interventions between day 5 and study end (p = .0002). FCM was well tolerated. CONCLUSIONS The IRLS score improved with intravenous FCM versus placebo, although the combination of both co-primary endpoints was not met. Potential methodological problems in the study design are discussed.
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Affiliation(s)
| | | | - Mark Falone
- American Regent, Inc., Clinical Research and Development, Shirley, NY, USA
| | - John W Winkelman
- Departments of Psychiatry and Neurology, Massachusetts General Hospital, Boston, MA, USA
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Makharia A, Agarwal A, Srivastava AK, Garg D. Current updates in Restless Legs Syndrome: A pragmatic review. ANNALS OF MOVEMENT DISORDERS 2024; 7:55-77. [DOI: 10.4103/aomd.aomd_48_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 08/01/2024] [Indexed: 01/03/2025] Open
Abstract
AbstractRestless legs syndrome (RLS), also called Willis–Ekbom disease (WED), affects approximately 3% of the global population, with higher incidence in Caucasians and women. This review explores the latest advancements in the diagnosis, pathophysiology, and management of RLS, and it highlights the recent changes in diagnostic criteria that improve specificity. The diagnostic spectrum now includes atypical presentations involving the upper limbs and other body parts. The new diagnostic specifiers categorize RLS more effectively into chronic-persistent or intermittent types, and a clinical significance specifier has been introduced to better address the disorder’s effects on daily life. RLS management has shifted toward a balanced approach with non-pharmacological strategies and lifestyle changes, supported by updated pharmacological treatment protocols including iron therapy designed to mitigate risks such as augmentation. Notably, gabapentinoids have emerged as a superior treatment option over dopamine agonists owing to their lower risk of augmentation and superior safety profile. Innovative treatments, such as the FDA-approved tonic motor activation device and new pharmacological agents, serve as alternatives for treating medication-refractory RLS, thereby expanding the therapeutic landscape. Additionally, this review addresses the specific considerations for managing RLS in special groups, including pregnant women, individuals with chronic kidney disease, and patients with comorbid conditions such as Parkinson’s disease and multiple sclerosis. We emphasizes the dynamic nature of RLS research and highlight the critical need for ongoing studies to further elucidate the complex mechanisms underlying RLS, as well as to refine the treatment modalities to enhance patient outcomes.
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Affiliation(s)
- Archita Makharia
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Ayush Agarwal
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Divyani Garg
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
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Chenini S, Barateau L, Dauvilliers Y. Restless legs syndrome: From clinic to personalized medicine. Rev Neurol (Paris) 2023; 179:703-714. [PMID: 37689536 DOI: 10.1016/j.neurol.2023.08.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/11/2023]
Abstract
Restless legs syndrome (RLS) is a common neurological sensorimotor disorder that impairs sleep, mood and quality of life. RLS is defined by an urge to move the legs at rest that increases in the evening and at night, and is frequently associated with metabolic and cardiovascular diseases. Symptoms frequency, age at RLS onset, severity, familial history and consequences of RLS vary widely between patients. A genetic susceptibility, iron deficiency, dopamine deregulation, and possible hypo-adenosinergic state may play a role in the pathophysiology of RLS. Polysomnographic recordings found often periodic leg movements during sleep and wakefulness in patients with RLS. RLS can be classified as primary or comorbid with major diseases: iron deficiency, renal, neurological, rheumatological and lung diseases. First-line treatments are low-dose dopamine agonists, and alpha-2-delta ligands depending on the clinical context, and second/third line opiates for pharmacoresistant forms of RLS. Augmentation syndrome is a serious complication of dopamine agonists and should be prevented by using the recommended low dose. Despite an increase in knowledge, RLS is still underdiagnosed, poorly recognized, resulting in substantial individual health burden and socioeconomic coast, and education is urgently needed to increase awareness of this disabling disorder.
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Affiliation(s)
- S Chenini
- National Reference Centre for Orphan Diseases Narcolepsy and Rare Hypersomnias, Sleep Unit, Department of Neurology, CHU Montpellier, University of Montpellier, Montpellier, France; Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France.
| | - L Barateau
- National Reference Centre for Orphan Diseases Narcolepsy and Rare Hypersomnias, Sleep Unit, Department of Neurology, CHU Montpellier, University of Montpellier, Montpellier, France; Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France
| | - Y Dauvilliers
- National Reference Centre for Orphan Diseases Narcolepsy and Rare Hypersomnias, Sleep Unit, Department of Neurology, CHU Montpellier, University of Montpellier, Montpellier, France; Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France.
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Restless Legs Syndrome and Periodic Limb Movements of Sleep: From Neurophysiology to Clinical Practice. J Clin Neurophysiol 2023; 40:215-223. [PMID: 36872500 DOI: 10.1097/wnp.0000000000000934] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023] Open
Abstract
SUMMARY This article summarizes restless legs syndrome (RLS), periodic limb movements of sleep, and periodic limb movement disorder. RLS is a common sleep disorder with a prevalence of 5% to 15% in the general population. RLS can present in childhood, and incidence increases with age. RLS can be idiopathic or secondary to iron deficiency, chronic renal failure, peripheral neuropathy, and medications such as antidepressants (with higher rates for mirtazapine and venlafaxine, while bupropion may reduce symptoms at least in the short term), dopamine antagonists (neuroleptic antipsychotic agents and antinausea medications), and possibly antihistamines. Management includes pharmacologic agents (dopaminergic agents, alpha-2 delta calcium channel ligands, opioids, benzodiazepines) and nonpharmacologic therapies (iron supplementation, behavioral management). Periodic limb movements of sleep are an electrophysiologic finding commonly accompanying RLS. On the other hand, most individuals with periodic limb movements of sleep do not have RLS. The clinical significance of the movements has been argued. Periodic limb movement disorder is a distinct sleep disorder that arises in individuals without RLS and is a diagnosis of exclusion.
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Heidbreder A, Trenkwalder C, Bachmann CG, Bartl M, Fulda S, Habersack L, Maihöfner C, Mathis J, Muntean L, Schneider B, Stefani A, Paulus J, Young P. Restless Legs Syndrom. SOMNOLOGIE 2023. [DOI: 10.1007/s11818-023-00399-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/19/2023]
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Gigli GL, de Biase S, Pellitteri G, Pez S, Garbo R, Tereshko Y, Valente M. Restless legs syndrome in internal medicine. ENCYCLOPEDIA OF SLEEP AND CIRCADIAN RHYTHMS 2023:743-756. [DOI: 10.1016/b978-0-12-822963-7.00146-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Dugan C, Cabolis K, Miles LF, Richards T. Systematic review and meta-analysis of intravenous iron therapy for adults with non-anaemic iron deficiency: An abridged Cochrane review. J Cachexia Sarcopenia Muscle 2022; 13:2637-2649. [PMID: 36321348 PMCID: PMC9745472 DOI: 10.1002/jcsm.13114] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 09/04/2022] [Accepted: 09/21/2022] [Indexed: 12/14/2022] Open
Abstract
Iron is an essential nutrient for oxygen supply and aerobic metabolism. Iron deficiency impacts cellular respiration and mitochondrial energy metabolism, which can lead to reduced skeletal muscle function and muscle mass, causing sarcopenia. Intravenous iron offers the ability to rapidly correct iron deficiency, but the functional impact on patient mental and physical health is unclear. We assessed the effects of intravenous iron therapy on physical function and quality of life in the treatment of adults with non-anaemic iron deficiency. An update and reanalysis of a previously published Cochrane systematic review was performed to assess randomized controlled trials that compared any intravenous iron preparation with placebo in adults. The primary functional outcome measure was physical performance as defined by the trial authors. Secondary outcome measures included fatigue and quality-of-life scores, and adverse effects at the end of follow-up. Biochemical efficacy was assessed by change in serum ferritin and haemoglobin concentration levels. Twenty-one randomized controlled trials, comprising 3514 participants, were included. Intravenous iron compared with placebo resulted in significantly increased physical function measured by mean peak oxygen consumption (mean difference [MD] 1.77 mL/kg/min, 95% confidence interval [CI] 0.57 to 2.97). An overall improvement in fatigue was seen (standardized MD 0.30, 95% CI -0.52 to -0.09) but no overall difference in quality of life (MD 0.15, 95% CI -0.01 to 0.31). Biochemically, intravenous iron resulted in improved serum ferritin (MD 245.52 μg/L, 95% CI 152.1 to 338.9) and haemoglobin levels (MD 4.65 g/L, 95% CI 2.53 to 6.78). There was a higher risk of developing mild adverse events in the intravenous iron group compared with the placebo group (risk ratio 1.77, 95% CI 1.10 to 2.83); however, no differences were seen in serious adverse events (risk difference 0, 95% CI -0.01 to 0.01). The quality of evidence was rated 'low' and 'very low' for all outcome variables, except for fatigue, mainly due to most studies being judged as having a high risk of bias. In non-anaemic iron-deficient adults, the use of intravenous iron compared with placebo improved physical function and reduced fatigue scores. However, we remain uncertain about the efficacy in this population due to low-quality evidence, and there is a need for further studies to address potential impact on overall quality of life.
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Affiliation(s)
- Cory Dugan
- Division of Surgery, Faculty of Health and Medical ScienceThe University of Western AustraliaPerthAustralia
| | - Katerina Cabolis
- Department of Neuroinflammation, UCL Queen Square Institute of NeurologyUniversity College LondonLondonUK
| | - Lachlan F. Miles
- Department of Critical Care, Faculty of Medicine, Dentistry and Health SciencesThe University of MelbourneMelbourneAustralia
| | - Toby Richards
- Division of Surgery, Faculty of Health and Medical ScienceThe University of Western AustraliaPerthAustralia
- Department of Neuroinflammation, UCL Queen Square Institute of NeurologyUniversity College LondonLondonUK
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Suwała S, Rzeszuto J, Glonek R, Krintus M, Junik R. Is Restless Legs Syndrome De Facto Thyroid Disease? Biomedicines 2022; 10:biomedicines10102502. [PMID: 36289762 PMCID: PMC9599059 DOI: 10.3390/biomedicines10102502] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/22/2022] [Accepted: 10/04/2022] [Indexed: 12/01/2022] Open
Abstract
While a primary role in the pathogenesis of restless legs syndrome (RLS) has been attributed to dysfunction of the dopaminergic system and impaired iron metabolism (particularly in the central nervous system), it has been hypothesized that an imbalance between thyroid hormones and dopaminergic activity may be the starting point for all aspects of RLS. Although this hypothesis was proposed more than a decade ago, it has not yet been verified beyond doubt. The main aim of this study is to compare the prevalence of RLS in a population of patients with the most common thyroid gland diseases with a population of individuals with a healthy thyroid gland. The study included 237 participants divided into smaller groups according to the thyroid disease concerning them. Each participant had a laboratory diagnosis, an ultrasound scan and an assessment of the fulfilment of RLS criteria according to the International Restless Legs Syndrome Study Group (IRLSSG) criteria. The results obtained were subjected to statistical analysis. RLS is significantly more common in patients with known thyroid disease; Hashimoto’s disease, among others, manifests a 2.56× higher risk of a positive diagnosis for RLS than the general population. The association of RLS with thyroid disease is notable, although it is difficult to conclude unequivocally that there is a cause-and-effect relationship between the two. Further investigation into a potentially autoimmune cause of restless legs syndrome should be considered.
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Affiliation(s)
- Szymon Suwała
- Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland
- Correspondence:
| | - Jakub Rzeszuto
- Evidence-Based Medicine Students Scientific Club of Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland
| | - Rafał Glonek
- Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland
| | - Magdalena Krintus
- Department of Laboratory Medicine, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland
| | - Roman Junik
- Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland
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15
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Park HR, Choi SJ, Joo EY. Does Repeated Dosing of Intravenous Ferric Carboxymaltose Alleviate Symptoms of Restless Legs Syndrome? J Clin Med 2022; 11:jcm11061673. [PMID: 35329998 PMCID: PMC8949271 DOI: 10.3390/jcm11061673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/07/2022] [Accepted: 03/15/2022] [Indexed: 12/03/2022] Open
Abstract
Background: Several studies have reported the efficacy of intravenous (IV) iron for patients with restless legs syndrome (RLS), but little is known about the efficacy or safety of repeated IV iron treatment. The aim of this study was to evaluate the effectiveness of repeated doses of IV ferric carboxymaltose (FCM) in treating RLS symptoms. Methods: Patients who received FCM more than twice for RLS from April 2016 to January 2020 were retrospectively reviewed. Patients who had shown positive response to initial IV FCM re-visited the clinic when their symptoms returned, and received repeated IV FCM (1000 mg). Blood iron panels were measured before initial and repeated IV FCM. We defined ‘responders’ as patients with a greater than 40% decrease in International Restless Legs Study Group Severity Scale (IRLS) compared with pre-treatment levels. Results: A total of 42 patients, including 26 with primary RLS, 5 with gastrectomy, and 11 with anemia, completed the evaluation. Patients received IV FCM infusion 2–4 times. A total of 21 of 26 (80.8%) primary cases of RLS, 4 of 5 (80.0%) patients with a history of gastrectomy, and 9 of 11 (81.8%) patients with anemia responded to repeated FCM treatment. Serum ferritin levels of patients with primary RLS were higher before the second treatment than the baseline levels. There were no serious adverse events observed in the study. Conclusions: Repeated IV FCM for recurring symptoms is an effective treatment for primary RLS and RLS associated with iron deficiency. Serum ferritin might not be a reliable factor to monitor the sustained effects of IV iron for RLS.
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Affiliation(s)
- Hea Ree Park
- Department of Neurology, Inje University College of Medicine, Ilsan Paik Hospital, Goyang 10380, Korea;
| | - Su Jung Choi
- Graduate School of Clinical Nursing Science, Sungkyunkwan University, Seoul 04514, Korea;
| | - Eun Yeon Joo
- Department of Neurology, Neuroscience Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 16419, Korea
- Correspondence: ; Tel.: +82-2-3410-3597; Fax: +82-2-3410-0052
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16
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Vlasie A, Trifu S, Lupuleac C, Kohn B, Cristea M. Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review). Exp Ther Med 2021; 23:185. [PMID: 35069866 PMCID: PMC8764906 DOI: 10.3892/etm.2021.11108] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/05/2021] [Indexed: 11/06/2022] Open
Affiliation(s)
- Andrei Vlasie
- Department of Psychiatry, ‘Prof. Dr. Alexandru Obregia’ Clinical Hospital of Psychiatry, Bucharest 041914, Romania
| | - Simona Trifu
- Department of Clinical Neurosciences, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020021, Romania
| | - Cristiana Lupuleac
- Department of Psychiatry, ‘Prof. Dr. Alexandru Obregia’ Clinical Hospital of Psychiatry, Bucharest 041914, Romania
| | - Bianca Kohn
- Department of Psychiatry, ‘Prof. Dr. Alexandru Obregia’ Clinical Hospital of Psychiatry, Bucharest 041914, Romania
| | - Mihai Cristea
- Department of Morphological Sciences, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020021, Romania
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Beatrix J, Piales C, Berland P, Marchiset E, Gerbaud L, Ruivard M. Non-anemic iron deficiency: correlations between symptoms and iron status parameters. Eur J Clin Nutr 2021; 76:835-840. [PMID: 34811510 DOI: 10.1038/s41430-021-01047-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/02/2021] [Accepted: 11/01/2021] [Indexed: 11/10/2022]
Abstract
OBJECTIVES To register all symptoms reported by non-anemic menstruating women, and examine the links between these symptoms and iron status parameters available including serum ferritin (SF) in primary care. SUBJECTS AND METHODS In this cross-sectional study, we collected clinical and biological data from 780 French menstruating women aged 18-50 years. The data included an anonymous questionnaire (biometric information, physical and cognitive symptoms, reduction in physical performance, current quality of life with SF-36 questionnaire) and seven biological parameters available in primary care. We excluded women with anemia (hemoglobin < 12 g/dl) or chronic disease. Correlations were studied for 554 participants in bivariate analysis (BVA) and multivariate analysis (MVA), with adjusted odds ratio (OR). Receiver operating characteristic (ROC) curves were established for significant correlations in MVA (p < 0.05). RESULTS Among these 554 non-anemic women included, 304 (54.9%) had SF level below 50 µg/l, 103 (18.6%) had SF level below 20 µg/l, and 60 (10.8%) had SF level below 15 µg/l. Iron deficiency was significantly correlated with recent hair loss for SF ≤ 15 µg/l (OR = 2.19 with p = 0.02 in MVA) and SF ≤ 20 µg/l (OR = 2.26 with p < 0.01 in MVA). SF ≤ 20 µg/l was also correlated with limitations due to emotional problems according to SF-36 questionnaire (p = 0.01 in MVA). SF ≤ 50 µg/l was significantly correlated with restless legs syndrome (OR = 2.82 with p = 0.01 in MVA). Only one ROC curve for restless legs syndrome could suggest an optimal SF cut-off point at 39 µg/l (sensitivity 73%, specificity 61%). CONCLUSION We identified two symptoms significantly more reported by non-anemic iron-deficient menstruating women: recent hair loss for serum ferritin (SF) ≤ 20 µg/l and restless legs syndrome for SF ≤ 50 µg/l. Non-anemic iron deficiency may also impact their quality of life, but further investigation is needed. If one of these symptoms is reported in primary care, the possibility of a symptomatic iron deficiency cannot be ruled out, and iron supplementation should be considered.
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Affiliation(s)
- Julien Beatrix
- Service Médecine Interne, CHU Estaing, Clermont-Ferrand, France.
| | - Claire Piales
- Service Hématologie, Gen-Bio, Clermont-Ferrand, France
| | - Pauline Berland
- Service Santé Publique, CHU Gabriel Montpied, Clermont-Ferrand, France
| | | | - Laurent Gerbaud
- Service Santé Publique, CHU Gabriel Montpied, Clermont-Ferrand, France.,UMR 6602 UCA/CNRS/SIGMA - T.G.I., Université Clermont Auvergne, Clermont-Ferrand, France
| | - Marc Ruivard
- Service Médecine Interne, CHU Estaing, Clermont-Ferrand, France.,UMR 6602 UCA/CNRS/SIGMA - T.G.I., Université Clermont Auvergne, Clermont-Ferrand, France
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18
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Shah AA, Donovan K, Seeley C, Dickson EA, Palmer AJR, Doree C, Brunskill S, Reid J, Acheson AG, Sugavanam A, Litton E, Stanworth SJ. Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis. JAMA Netw Open 2021; 4:e2133935. [PMID: 34767026 PMCID: PMC8590171 DOI: 10.1001/jamanetworkopen.2021.33935] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/13/2021] [Indexed: 12/22/2022] Open
Abstract
Importance Intravenous iron is recommended by many clinical guidelines based largely on its effectiveness in reducing anemia. However, the association with important safety outcomes, such as infection, remains uncertain. Objective To examine the risk of infection associated with intravenous iron compared with oral iron or no iron. Data Sources Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials (RCTs) from 1966 to January 31, 2021. Ongoing trials were sought from ClinicalTrials.gov, CENTRAL, and the World Health Organization International Clinical Trials Search Registry Platform. Study Selection Pairs of reviewers identified RCTs that compared intravenous iron with oral iron or no iron across all patient populations, excluding healthy volunteers. Nonrandomized studies published since January 1, 2007, were also included. A total of 312 full-text articles were assessed for eligibility. Data Extraction and Synthesis Data extraction and risk of bias assessments were performed according to the Preferred Reporting Items of Systematic Reviews and Meta-analyses (PRISMA) and Cochrane recommendations, and the quality of evidence was assessed using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. Two reviewers extracted data independently. A random-effects model was used to synthesize data from RCTs. A narrative synthesis was performed to characterize the reporting of infection. Main Outcomes and Measures The primary outcome was risk of infection. Secondary outcomes included mortality, hospital length of stay, and changes in hemoglobin and red blood cell transfusion requirements. Measures of association were reported as risk ratios (RRs) or mean differences. Results A total of 154 RCTs (32 920 participants) were included in the main analysis. Intravenous iron was associated with an increased risk of infection when compared with oral iron or no iron (RR, 1.17; 95% CI, 1.04-1.31; I2 = 37%; moderate certainty of evidence). Intravenous iron also was associated with an increase in hemoglobin (mean difference, 0.57 g/dL; 95% CI, 0.50-0.64 g/dL; I2 = 94%) and a reduction in the risk of requiring a red blood cell transfusion (RR, 0.93; 95% CI, 0.76-0.89; I2 = 15%) when compared with oral iron or no iron. There was no evidence of an effect on mortality or hospital length of stay. Conclusions and Relevance In this large systematic review and meta-analysis, intravenous iron was associated with an increased risk of infection. Well-designed studies, using standardized definitions of infection, are required to understand the balance between this risk and the potential benefits.
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Affiliation(s)
- Akshay A. Shah
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
- National Institute for Health Research Biomedical Research Centre Haematology Theme, Oxford, United Kingdom
- Adult Intensive Care Unit, Oxford University Hospitals National Health Service (NHS) Foundation Trust, Oxford, United Kingdom
| | - Killian Donovan
- Adult Intensive Care Unit, Oxford University Hospitals National Health Service (NHS) Foundation Trust, Oxford, United Kingdom
| | - Claire Seeley
- Department of Anaesthesia, Royal Berkshire Hospitals NHS Foundation Trust, Reading, United Kingdom
| | - Edward A. Dickson
- National Institute for Health Research Biomedical Research Centre in Gastrointestinal and Liver Diseases, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
- Department of Colorectal Surgery, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, United Kingdom
| | - Antony J. R. Palmer
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Carolyn Doree
- Systematic Review Initiative, NHS Blood & Transplant, Oxford, United Kingdom
| | - Susan Brunskill
- Systematic Review Initiative, NHS Blood & Transplant, Oxford, United Kingdom
| | - Jack Reid
- Department of Anaesthesia, Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom
| | - Austin G. Acheson
- National Institute for Health Research Biomedical Research Centre in Gastrointestinal and Liver Diseases, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
- Department of Colorectal Surgery, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, United Kingdom
| | - Anita Sugavanam
- Department of Anaesthesia, Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom
| | - Edward Litton
- Intensive Care Unit, Fiona Stanley Hospital, Perth, Australia
| | - Simon J. Stanworth
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
- National Institute for Health Research Biomedical Research Centre Haematology Theme, Oxford, United Kingdom
- Systematic Review Initiative, NHS Blood & Transplant, Oxford, United Kingdom
- Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
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19
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Silber MH, Buchfuhrer MJ, Earley CJ, Koo BB, Manconi M, Winkelman JW. The Management of Restless Legs Syndrome: An Updated Algorithm. Mayo Clin Proc 2021; 96:1921-1937. [PMID: 34218864 DOI: 10.1016/j.mayocp.2020.12.026] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 12/13/2020] [Accepted: 12/28/2020] [Indexed: 01/26/2023]
Abstract
Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.
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Affiliation(s)
- Michael H Silber
- Center for Sleep Medicine and Department of Neurology, Mayo Clinic College of Medicine and Science, Rochester, MN.
| | - Mark J Buchfuhrer
- Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford, CA
| | - Christopher J Earley
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Brian B Koo
- Department of Neurology, Yale University, New Haven, CT
| | - Mauro Manconi
- Sleep Medicine, Neurocenter of Southern Switzerland, Ospedale Civico, and Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland; Department of Neurology, University Hospital, Inselspital, Bern, Switzerland
| | - John W Winkelman
- Departments of Psychiatry and Neurology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Cambridge, MA
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20
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Bae H, Cho YW, Kim KT, Allen RP, Earley CJ. Randomized, placebo-controlled trial of ferric carboxymaltose in restless legs syndrome patients with iron deficiency anemia. Sleep Med 2021; 84:179-186. [PMID: 34157632 DOI: 10.1016/j.sleep.2021.05.036] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/20/2021] [Accepted: 05/31/2021] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Intravenous ferric carboxymaltose (FCM) has been shown to be efficacious in treating restless legs syndrome (RLS) symptoms in non-anemic patients. The aim of this study was to evaluate the effectiveness of FCM in treating RLS symptoms in patients who also had an iron deficiency anemia (IDA). METHODS This is a randomized, double-blinded, placebo-controlled study. Subjects with RLS and IDA were enrolled. Subjects received an infusion of either 1500 mg FCM or placebo in Phase I. The primary outcomes were a change-from-baseline at week six on the International Restless Legs Syndrome Study Group scale (IRLS). Phase II of the study involved long-term (52 weeks) follow-up, for those who responded to treatment in the prior phase, with the potential for further treatment if symptoms returned. RESULTS We enrolled 29 RLS patients with IDA (15 FCM and 14 placebo). At week six post-infusion, FCM compared to placebo group showed significant improvement from baseline in IRLS score (-13.47 ± 7.38 vs. 1.36 ± 3.59). Among secondary outcome variables, quality of sleep showed significant improvement from baseline in the FCM group. 61% of subjects remained off RLS medications at the Phase II, week-52 endpoint. There were no serious adverse events observed in the study. CONCLUSION The study showed significant efficacy and safety of FCM 1500 mg treatment both in the short term (6 weeks) and long term (52 weeks) in RLS patients with IDA.
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Affiliation(s)
- Hyoeun Bae
- Department of Neurology, Keimyung University School of Medicine, Daegu, South Korea
| | - Yong Won Cho
- Department of Neurology, Keimyung University School of Medicine, Daegu, South Korea.
| | - Keun Tae Kim
- Department of Neurology, Keimyung University School of Medicine, Daegu, South Korea
| | - Richard P Allen
- Department of Neurology, Johns Hopkins University, Hopkins Bayview Medical Center, Baltimore, MD, USA
| | - Christopher J Earley
- Department of Neurology, Johns Hopkins University, Hopkins Bayview Medical Center, Baltimore, MD, USA
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21
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Abstract
For a long time, dopaminergic treatment (DT) was the medication for restless legs syndrome. Although DT is effective and safe over the short-term, complications develop over longer periods, including augmentation, tolerance, and impulse control disorders. Nowadays, it is recommended that first-line treatment should be alpha-2 ligands, which are more effective in the absence of previous DT. As a second-line treatment, opioids, such as oxycodone extended-release with naloxone, are approved in Europe. Brain iron should be monitored before and during treatment and corrected if necessary. Two new promising non-DTs are being developed: perampanel and dipyridamole. More research is needed.
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22
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[Evidence-based iron therapy and consensus-oriented treatment of restless legs syndrome in practice-Routinely established or ignored?]. DER NERVENARZT 2021; 92:1068-1071. [PMID: 33688972 DOI: 10.1007/s00115-021-01095-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/15/2021] [Indexed: 10/22/2022]
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Lv Q, Wang X, Asakawa T, Wang XP. Pharmacologic Treatment of Restless Legs Syndrome. Curr Neuropharmacol 2021; 19:372-382. [PMID: 33380302 PMCID: PMC8033969 DOI: 10.2174/1570159x19666201230150127] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/24/2020] [Accepted: 12/19/2020] [Indexed: 01/14/2023] Open
Abstract
Restless legs syndrome (RLS)/Willis-Ekbom disease is a neurologic disorder characterized by a strong desire to move when at rest (usually in the evening) and paraesthesia in their lower legs. The most widely used therapies for first-line treatment of RLS are dopaminergic drugs; however, their long-term use can lead to augmentation. α2δ Ligands, opioids, iron, glutamatergic drugs, adenosine, and sleep aids have been investigated as alternatives. The pathogenesis of RLS is not well understood. Despite the efficacy of dopaminergic drugs in the treatment of this disorder, unlike in Parkinson's disease dopaminergic cell loss in the substantia nigra has not been observed in RLS. The etiology of RLS is likely complex, involving multiple neural pathways. RLS-related genes identified in genome-wide association studies can provide insight into the mechanistic basis and pathophysiology of RLS. Here we review the current treatments and knowledge of the mechanisms underlying RLS.
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Affiliation(s)
| | | | - Tetsuya Asakawa
- Address correspondence to these authors at the Department of Neurology, TongRen Hospital, Shanghai Jiao Tong University School of Medicine, No.1111 Xianxia Road, 200336, Shanghai, China; Tel: +86-021-52039999-72223; Fax: +86-021-52039999-72223; E-mail: and Department of Neurosurgery, Hamamatsu University School of Medicine, Handayama, 1-20-1, Higashi-ku, Hamamatsu-city, Shizuoka 431-3192, Japan; Tel: + 81-53-435-2283; Fax: + 81-53-435-2282;, E-mail:
| | - Xiao Ping Wang
- Address correspondence to these authors at the Department of Neurology, TongRen Hospital, Shanghai Jiao Tong University School of Medicine, No.1111 Xianxia Road, 200336, Shanghai, China; Tel: +86-021-52039999-72223; Fax: +86-021-52039999-72223; E-mail: and Department of Neurosurgery, Hamamatsu University School of Medicine, Handayama, 1-20-1, Higashi-ku, Hamamatsu-city, Shizuoka 431-3192, Japan; Tel: + 81-53-435-2283; Fax: + 81-53-435-2282;, E-mail:
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24
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Gossard TR, Trotti LM, Videnovic A, St Louis EK. Restless Legs Syndrome: Contemporary Diagnosis and Treatment. Neurotherapeutics 2021; 18:140-155. [PMID: 33880737 PMCID: PMC8116476 DOI: 10.1007/s13311-021-01019-4] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2021] [Indexed: 12/12/2022] Open
Abstract
Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination, and iron measures, including ferritin and transferrin saturation, should be checked at presentation and with worsened symptoms, especially when augmentation develops. Augmentation is characterized by more intense symptom severity, earlier symptom occurrence, and often, symptom spread from the legs to the arms or other body regions. Some people with RLS have adequate symptom control with non-pharmacological measures such as massage or temperate baths. First-line management options include iron-replacement therapy in those with evidence for reduced body-iron stores or, alternatively, with prescribed gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone. RLS significantly impacts patients' quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies.
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Affiliation(s)
- Thomas R Gossard
- Mayo Center for Sleep Medicine, 200 First Street SW, Rochester, MN, 55905, USA
| | | | | | - Erik K St Louis
- Mayo Center for Sleep Medicine, 200 First Street SW, Rochester, MN, 55905, USA.
- Departments of Neurology and Clinical and Translational Research, Mayo Clinic Southwest Wisconsin, La Crosse, Wisconsin, USA.
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Abstract
Restless legs syndrome (RLS), with a lifetime prevalence of up to 10%, is a frequent neurological disease and the most common movement disorder in sleep. A compulsive urge to move the legs with sensory symptoms and sleep disturbances can significantly impair the quality of life. Furthermore, RLS frequently occurs as a comorbidity to various internal and neurological diseases. It is diagnosed clinically based on the five essential diagnostic criteria. For treatment, an iron deficiency should first be excluded. Drugs approved for the treatment of RLS include dopaminergics (L-DOPA/benserazide) and dopamine agonists as well as oxycodone/naloxone, as a second-line treatment in severe cases. Augmentation as a deterioration of symptoms is a clinically defined complication of high-dose dopaminergic treatment, requiring special management strategies. Due to its high prevalence of up to 25%, RLS plays also an important role in the care of pregnant women.
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Restless-legs-Syndrom: ein Update. SOMNOLOGIE 2020. [DOI: 10.1007/s11818-020-00283-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Zhu XY, Wang HM, Wu TT, Liu T, Chen YJ, Li X, Chen TJ, Liu Y, Zhang XJ, Wang XX, Zhang Y, Ondo WG, Wu YC. SNCA-Rep1 polymorphism correlates with susceptibility and iron deficiency in restless legs syndrome. Parkinsonism Relat Disord 2020; 81:12-17. [PMID: 33035800 DOI: 10.1016/j.parkreldis.2020.09.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 09/05/2020] [Accepted: 09/08/2020] [Indexed: 01/31/2023]
Abstract
BACKGROUND Brain iron disequilibrium and dopaminergic dysfunction are key pathophysiological features of Restless Legs Syndrome (RLS). Rep1 polymorphism in the promotor region of SNCA is associated with risk of Parkinson's disease, however its association with RLS and iron status is unclear. OBJECTIVE To investigate SNCA-Rep1 polymorphism in RLS and its phenotypes. METHODS We recruited RLS patients as well as age and gender matched healthy controls. Demographic information and clinical features of RLS were recorded. Laboratory examinations were performed to exclude possible secondary causes. RESULTS 215 RLS patients and 369 healthy controls were included. We found that the Rep1 allele 0 homozygosity significantly decreased RLS risk (OR: 0.345; P < 0.0001, and remained significant after the Bonferroni correction). Phenotypic analysis demonstrated that longer Rep1 alleles were associated with increased susceptibility to iron deficiency (53.0% vs 36.1%, P = 0.017), however had no phenotypic significant effects on age, gender, onset age, duration, RLS family history, severity, laterality, extra body involvement and seasonal fluctuation. Multivariate logistic regression analyses confirmed long Rep1 allele was associated with higher risk of iron deficiency in RLS after adjusting for potential confounding factors. In detail, Rep1 allele 2 homozygosity was prone to a higher risk of peripheral iron deficiency in RLS (OR: 4.550, P = 0.006, remained significant after the Bonferroni correction). CONCLUSION The SNCA-Rep1 variability modified RLS risk and influenced peripheral iron deficiency in this group of Chinese RLS patients. Rep1 allele 0 homozygosity decreased the risk of RLS, while homozygous allele 2 increased the risk of nonanemic iron deficiency in RLS.
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Affiliation(s)
- Xiao-Ying Zhu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Hong-Ming Wang
- Department of Clinical Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Ting-Ting Wu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Te Liu
- Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200031, PR China
| | - Ya-Jing Chen
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Xuan Li
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Tian-Jiao Chen
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Ye Liu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Xiao-Jin Zhang
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Xi-Xi Wang
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Yue Zhang
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, PR China
| | - William G Ondo
- Department of Neurology, Methodist Neurological Institute, Weill Cornell Medical School, Houston, TX, USA
| | - Yun-Cheng Wu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China.
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Low risk of iron overload or anaphylaxis during treatment of restless legs syndrome with intravenous iron: a consecutive case series in a regular clinical setting. Sleep Med 2020; 74:48-55. [PMID: 32841843 DOI: 10.1016/j.sleep.2020.06.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/21/2020] [Accepted: 06/01/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To evaluate the incidence of iron overload and anaphylaxis following intravenous (IV) iron treatment of restless legs syndrome (RLS). METHODS A total of 58 consecutive RLS patients, meeting clinical requirements for IV iron treatment according to current IRLSSG guidelines were recruited. IV iron treatment consisted of two 500 mg infusions of ferric carboxymaltose (FCM) administered five days apart. During each of the three follow-up visits we obtained blood samples, substantia nigra echogenity index (SNEI) by means of transcranial sonography (TCS), and assessed the severity of RLS symptoms (IRLS scale). "Iron overload risk" was defined as transferrin saturation (TSAT) > 45% on two consecutive follow-up visits. In patients who had a reduction in systemic iron levels following treatment, an additional 500 mg of FCM was administered when feasible. In such cases an additional two follow-up visits were performed. RESULTS Among the total sample, only 2/58 participants met criteria for iron overload risk. They had no evidence of liver damage and did not require additional treatment. Among the 21 patients receiving an additional 500 mg infusion after, only one patient was diagnosed with iron overload risk. Among these three patients, only one was a hemochromatosis gene carrier. No anaphylaxis or other side-effects were reported. CONCLUSIONS In real-life clinical conditions, the risk of iron overload is low when IV FCM is administered according to the safety limits defined in the current RLS treatment guidelines. However, a close clinical follow-up with periodic blood sampling for iron status, is needed.
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Leung W, Singh I, McWilliams S, Stockler S, Ipsiroglu OS. Iron deficiency and sleep - A scoping review. Sleep Med Rev 2020; 51:101274. [PMID: 32224451 DOI: 10.1016/j.smrv.2020.101274] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 12/11/2019] [Accepted: 12/15/2019] [Indexed: 12/16/2022]
Abstract
Iron deficiency (ID) is associated with sleep disorders, but standardized assessment of iron status in the diagnostic work-up and iron supplementation as treatment have not been considered in clinical practice. We investigated associations of ID with type and severity of sleep disorders and whether iron supplementation improves sleep-related symptoms. In 2017, we conducted a scoping review for the period 1972-2016 using the terms "iron deficiency anemia" and "sleep" on biomedical database search engines, and in 2019, we updated our review with an ad-hoc search. Among the 93 articles meeting our inclusion criteria, 74/93 studies investigated restless legs syndrome (RLS), 8/93 periodic limb movements in sleep (PLMs), 3/93 sleep disordered breathing (SDB), 6/93 general sleep disturbances (GSD), and 2/93 attention-deficit/ hyperactivity disorder related sleep disorders (ADHD-SDs). A statistically supported positive association with ID was found in 22/42 RLS, 3/8 PLMs, 1/2 SDB, 3/4 GSD, and 1/2 ADHD-SDs association studies. The ad-hoc literature search revealed eight additional association studies with a statistically supported positive association in 2/5 RLS, 1/1 SDB, 1/1 ADHD-SDs, and 1/1 restless sleep disorder (RSD) studies. Iron supplementation was beneficial in 29/30 RLS (including five randomized controlled trials [RCTs]), 1/1 SDB, and 2/2 GSD treatment studies. Iron supplementation was also beneficial in 2/2 RLS (including two RCTs), 1/1 GSD (RCT), and 1/1 RSD studies identified in the ad-hoc search. In pediatric populations, 1/1 RLS, 1/1 SDB, 2/5 PLMs, 2/3 GSD and 1/2 ADHD-SDs studies found positive associations, and 6/6 RLS and 2/2 GSD studies demonstrated a benefit with iron supplementation. In conclusion, iron investigation and supplementation should be considered in patients presenting with sleep disorders. To investigate the role of ID in sleep in the future, a harmonization of study designs, including outcome measures and standardized iron and inflammation status is necessary.
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Affiliation(s)
- Wayne Leung
- H-Behaviours Research Lab (Previously Sleep/Wake-Behaviours Research Lab), BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Ishmeet Singh
- H-Behaviours Research Lab (Previously Sleep/Wake-Behaviours Research Lab), BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Scout McWilliams
- H-Behaviours Research Lab (Previously Sleep/Wake-Behaviours Research Lab), BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Sylvia Stockler
- H-Behaviours Research Lab (Previously Sleep/Wake-Behaviours Research Lab), BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, Canada; Division of Biochemical Genetics, BC Children's Hospital, Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - Osman S Ipsiroglu
- H-Behaviours Research Lab (Previously Sleep/Wake-Behaviours Research Lab), BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, Canada; Divisions of Developmental Pediatrics & Child and Adolescent Psychiatry, BC Children's Hospital, Department of Pediatrics, University of British Columbia, Vancouver, Canada.
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Didato G, Di Giacomo R, Rosa GJ, Dominese A, de Curtis M, Lanteri P. Restless Legs Syndrome across the Lifespan: Symptoms, Pathophysiology, Management and Daily Life Impact of the Different Patterns of Disease Presentation. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E3658. [PMID: 32456058 PMCID: PMC7277795 DOI: 10.3390/ijerph17103658] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 05/17/2020] [Accepted: 05/18/2020] [Indexed: 12/14/2022]
Abstract
Restless legs syndrome is a common but still underdiagnosed neurologic disorder, characterized by peculiar symptoms typically occurring in the evening and at night, and resulting in sleep disruption and daily functioning impairment. This disease can affect subjects of all age ranges and of both sexes, manifesting itself with a broad spectrum of severity and deserving special attention in certain patient categories, in order to achieve a correct diagnosis and an effective treatment. The diagnosis of restless legs syndrome can be challenging in some patients, especially children and elderly people, and an effective treatment might be far from being easy to achieve after some years of drug therapy, notably when dopaminergic agents are used. Moreover, the pathophysiology of this disorder offers an interesting example of interaction between genetics and the environment, considering strong iron metabolism involvement and its interaction with recognized individual genetic factors. Therefore, this syndrome allows clinicians to verify how lifespan and time can modify diagnosis and treatment of a neurological disorder.
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Affiliation(s)
- Giuseppe Didato
- Clinical and Experimental Epileptology and Sleep Disorders Unit, Foundation IRCCS Carlo Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy; (R.D.G.); (G.J.R.); (A.D.); (M.d.C.)
| | - Roberta Di Giacomo
- Clinical and Experimental Epileptology and Sleep Disorders Unit, Foundation IRCCS Carlo Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy; (R.D.G.); (G.J.R.); (A.D.); (M.d.C.)
| | - Giuseppa Jolanda Rosa
- Clinical and Experimental Epileptology and Sleep Disorders Unit, Foundation IRCCS Carlo Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy; (R.D.G.); (G.J.R.); (A.D.); (M.d.C.)
- Neurology Unit, University Hospital of Ferrara, 44100 Ferrara, Italy
| | - Ambra Dominese
- Clinical and Experimental Epileptology and Sleep Disorders Unit, Foundation IRCCS Carlo Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy; (R.D.G.); (G.J.R.); (A.D.); (M.d.C.)
| | - Marco de Curtis
- Clinical and Experimental Epileptology and Sleep Disorders Unit, Foundation IRCCS Carlo Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy; (R.D.G.); (G.J.R.); (A.D.); (M.d.C.)
| | - Paola Lanteri
- Neurophysiopathology Unit, Foundation IRCCS Carlo Besta Neurological Institute, 20133 Milan, Italy;
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Zhu XY, Wu TT, Wang HM, Li X, Ni LY, Chen TJ, Qiu MY, Shen J, Liu T, Ondo WG, Wu YC. Correlates of Nonanemic Iron Deficiency in Restless Legs Syndrome. Front Neurol 2020; 11:298. [PMID: 32425874 PMCID: PMC7205016 DOI: 10.3389/fneur.2020.00298] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 03/30/2020] [Indexed: 01/23/2023] Open
Abstract
Objective: Iron deficiency anemia (IDA) is a well-known cause of secondary restless legs syndrome (RLS). Iron deficiency without anemia (IDNA) is insidious, and its association with RLS is less evaluated. We investigate prevalence and features of IDNA in a consecutive cohort of patients with RLS. Methods: We included sequential primary RLS patients and RLS patients with IDA. We also recruited age- and gender-matched healthy controls. RLS mimics and other comorbidities were carefully excluded. Results: One-hundred and ninety-six RLS patients without anemia, 26 RLS patients with IDA, and 63 controls were included. 42.3% of RLS patients without anemia had iron deficiency. Women were much more susceptible for IDNA with a relative risk of 5.51 (p < 0.0001). Women with IDNA and RLS had younger age both at interview and at RLS onset compared to women with RLS without iron deficiency (NID) (P < 0.01). IDNA RLS patients showed a tendency to higher risk of severe/very severe tiredness or sleepiness during the day as compared to NID RLS patients. Furthermore, IDNA RLS patients had longer duration of RLS (P < 0.01 in men, P < 0.05 in women) and younger age at onset (only in men, P < 0.05) compared to IDA RLS patients. Conclusion: IDNA is frequent in RLS and iron deficiency may be severe despite a normal hemoglobin level. Women are at much higher risk for IDNA, and IDNA in women presents some specific clinical features. Features of IDNA RLS are different from IDA RLS. Regular screening of peripheral iron parameters even in patients with normal blood counts is recommended for timely optimal management.
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Affiliation(s)
- Xiao-Ying Zhu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ting-Ting Wu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong-Ming Wang
- Department of Clinical Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuan Li
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling-Yan Ni
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tian-Jiao Chen
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meng-Yao Qiu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Shen
- Department of Clinical Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Te Liu
- Geriatric Laboratory, Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - William G Ondo
- Department of Neurology, Methodist Neurological Institute, Weill Cornell Medical School, Houston, TX, United States
| | - Yun-Cheng Wu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Park HR, Choi SJ, Joo EY, Allen RP. Patient characteristics predicting responses to intravenous ferric carboxymaltose treatment of restless legs syndrome. Sleep Med 2020; 75:81-87. [PMID: 32853922 DOI: 10.1016/j.sleep.2020.02.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 11/19/2019] [Accepted: 02/27/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Significant benefit of intravenous ferric carboxymaltose (FCM) treatment for restless legs syndrome (RLS) has been well-established. However, no clinical indicators predicting treatment response of RLS have been established. This study aimed to determine factors predicting outcome of clinical FCM treatment of RLS patients. METHODS Data were retrospectively reviewed from all patients who received FCM treatment for RLS from April 2016 to April 2019. These data included: detailed history, international RLS scale score (IRLS), questionnaires, comorbidity, and previous RLS medication use. Morning fasting serum iron, ferritin, and total iron-binding capacity were measured before and at four weeks after treatment. RLS patients with possible secondary RLS were identified by reviewing the medical histories. This included patients with iron deficiency anemia, lumbosacral radiculopathy, and gastrectomy. Primary RLS included those with no indication of secondary medical factors contributing to RLS. Treatment response was assessed using the IRLS and clinical ratings at four weeks after FCM administration. Patients with a greater than 40% decrease in IRLS were classified as responders. RESULTS The study comprised 164 patients with IRLS and clinical ratings obtained before and at four weeks after intravenous (IV) iron. Treatment responses differed considerably between diagnostic groups of RLS. Percentage responding was: 64.7% (66 of 102) for patients with primary RLS, 90.9% (10 of 11) with gastrectomy, 91.3% (21 of 23) with iron deficiency anemia and 39.3% (11 of 28) with lumbosacral radiculopathy. When responders were compared to non-responders in primary RLS patients, responders had significantly lower serum iron (80.5 ± 26.7 vs. 95.8 ± 30.5 μg/dL, p = 0.022) and percentage transferrin saturation (%TSAT) (25.4 ± 9.6 vs. 30.5 ± 10.5%, p = 0.026) in females, but not males. Logistic regression controlling for major subject variables showed that %TSAT significantly predicted response. (odds ratio [OR]: 0.955, confidence interval: 0.913-0.998, p = 0.040). CONCLUSION Intravenous FCM in moderate to severe RLS patients is beneficial as a first-line or add-on treatment, particularly for patients with compromised peripheral iron state. Overall, lower %TSAT predicted better chance of responding to the IV iron treatment especially for females.
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Affiliation(s)
- Hea Ree Park
- Department of Neurology, Inje University College of Medicine, Ilsan Paik Hospital, Goyang, Republic of Korea
| | - Su Jung Choi
- Department of Nursing, Samsung Medical Center, Graduate School of Clinical Nursing Science, Sungkyunkwan University, Seoul, Republic of Korea
| | - Eun Yeon Joo
- Department of Neurology, Neuroscience Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Richard P Allen
- Department of Neurology, Johns Hopkins University, Hopkins Bayview Medical Center, Baltimore, MD, USA
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Abstract
BACKGROUND Iron deficiency is one of the most common nutritional deficiencies, and has a number of physiological manifestations. Early, or non-anaemic iron deficiency can result in fatigue and diminished exercise capacity. Oral iron preparations have a high incidence of intolerable side effects, and are ineffective in certain forms of iron deficiency. Consequently, intravenous iron preparations are increasingly used in the treatment of non-anaemic iron deficiency. The newer, more stable iron preparations in particular purport to have a lower incidence of side effects, and are now used across a range of different patient populations. OBJECTIVES To assess the effects of intravenous iron therapy in the treatment of adults with non-anaemic iron deficiency. SEARCH METHODS On 18 October 2019 we electronically searched CENTRAL, MEDLINE, Embase, two further databases and two trials registries 2019. We handsearched the references of full-text extracted studies, and contacted relevant study authors for additional data. SELECTION CRITERIA We included randomised controlled trials that compared any intravenous iron preparation to placebo in adults. We excluded other forms of comparison such as oral iron versus placebo, intramuscular iron versus placebo, or intravenous iron studies where other iron preparations were used as the comparator. We also excluded studies involving erythropoietin therapy or obstetric populations. DATA COLLECTION AND ANALYSIS Two review authors screened references for eligibility, extracted data and assessed risk of bias. We resolved differences in opinion through discussion and consensus, and where necessary, involved a third review author to adjudicate disputes. We contacted study authors to request additional data where appropriate. The primary outcome measures were haemoglobin concentration at the end of follow-up, and quality-of-life scores at end of follow-up. Secondary outcome measures were serum ferritin, peak oxygen consumption (as measured by cardiopulmonary exercise testing), adverse effects (graded as mild to moderate and severe) and bacterial infection. We pooled data for continuous outcomes, which we then reported as mean differences (MDs) with 95% confidence intervals (CIs). We reported quality-of-life metrics as standardised mean difference (SMD), and then converted them back into a more familiar measure, the Piper Fatigue Scale. We analysed dichotomous outcomes as risk ratios (RRs). Given an expected degree of heterogeneity, we used a random-effects model for all outcomes. We performed the analysis with the software package Review Manager 5. MAIN RESULTS This review includes 11 studies with 1074 participants. Outcome metrics for which data were available (haemoglobin concentration, quality-of-life scores, serum ferritin, peak oxygen consumption and mild to moderate adverse effects) were similar across the included studies. The incidence of severe adverse events across all studies was zero. None of the studies measured bacterial infection as a specific outcome metric. Substantial heterogeneity influenced the results of the meta-analysis, arising from differing patient populations, definitions of iron deficiency, iron preparations and dosing regimens, and time to end of follow-up. Consequently, many outcomes are reported with small group sizes and wide confidence intervals, with a subsequent downgrading in the quality of evidence. The level of bias in many included studies was high, further reducing confidence in the robustness of the results. We found that intravenous iron therapy may lead to a small increase in haemoglobin concentration of limited clinical significance compared to placebo (MD 3.04 g/L, 95% CI 0.65 to 5.42; I2 = 42%; 8 studies, 548 participants; low-quality evidence). Quality-of-life scores (Piper Fatigue Scale MD 0.73, 95% CI 0.29 to 1.18; I2 = 0%; studies = 3) and peak oxygen consumption (MD 2.77 mL/kg/min, 95% CI -0.89 to 6.43; I2 = 36%; 2 studies, 32 participants) were associated with very low-quality evidence, and we remain uncertain about the role of intravenous iron for these metrics. We were unable to present pooled estimates for the outcomes of serum ferritin at the end of follow-up or mild to moderate adverse effects due to extreme statistical heterogeneity. Ultimately, despite the results of the meta-analysis, the low- or very low-quality evidence for all outcomes precludes any meaningful interpretation of results beyond suggesting that further research is needed. We performed a Trial Sequential Analysis for all major outcomes, none of which could be said to have reached a necessary effect size. AUTHORS' CONCLUSIONS Current evidence is insufficient to show benefit of intravenous iron preparations for the treatment of non-anaemic iron deficiency across a variety of patient populations, beyond stating that it may result in a small, clinically insignificant increase in haemoglobin concentration. However, the certainty for even this outcome remains limited. Robust data for the effectiveness of intravenous iron for non-anaemic iron deficiency is still lacking, and larger studies are required to assess the effect of this therapy on laboratory, patient-centric, and adverse-effect outcomes.
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Affiliation(s)
- Lachlan F Miles
- The University of MelbourneCentre for Integrated Critical Care151 Barry StreetParkvilleVictoriaAustralia3010
| | | | - Georgina Imberger
- RigshospitaletCochrane AnaesthesiaBlegdamsvej 9,Afsnit 3342KøbenhavnDenmark2100
| | - David Story
- The University of MelbourneMelbourneAustralia
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Trenkwalder C, Paulus W. Pharmacological treatments of augmentation in restless legs syndrome patients. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2019; 84:255-265. [PMID: 31229175 DOI: 10.1016/bs.apha.2019.02.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Augmentation, a treatment-induced paradoxical worsening of the symptoms of restless legs syndrome (RLS) that is caused by long-term dopaminergic therapy, in particular with higher doses, remains the major challenge of RLS treatment. The mainstay of treatment continues to be preventing augmentation, either by starting RLS therapy with alternative drugs or by sensitizing physicians about the absolute necessity of respecting approved dosages of dopaminergic drugs when treating RLS and never exceeding the maximum recommended dosages. In the case of a positive diagnosis of augmentation, treatment consists of reducing or eliminating dopaminergic therapy, ensuring that serum ferritin is clearly higher than the level assumed to be necessary from a hematological point of view and/or switching treatment to alternative drugs such as α2δ ligands, opiates, or to combination therapy.
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Affiliation(s)
- Claudia Trenkwalder
- Department of Neurosurgery, University Medical Center, Göttingen, Germany; Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders, Kassel, Germany.
| | - Walter Paulus
- Department of Clinical Neurophysiology, University Medical Center Göttingen, Georg August University, Göttingen, Germany
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Chaiard J, Weaver TE. Update on Research and Practices in Major Sleep Disorders: Part II-Insomnia, Willis-Ekbom Disease (Restless Leg Syndrome), and Narcolepsy. J Nurs Scholarsh 2019; 51:624-633. [PMID: 31524329 DOI: 10.1111/jnu.12515] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/07/2019] [Indexed: 01/17/2023]
Abstract
PURPOSE This review (Part II of a series on sleep disorders) presents an update of the characteristics, epidemiology, assessment, and latest management of insomnia, restless legs syndrome (Willis-Ekbom disease; RLS/WED), and narcolepsy. Insomnia, the most common sleep disorder and most prevalent of all psychological health disorders, is a problem of difficulty initiating and maintaining sleep and early morning awakenings. RLS/WED is characterized by a crawling sensation or urge to move the legs in the evening and nighttime. Narcolepsy is a sleep disorder that commonly results in chronic daytime sleepiness and cataplexy. Nonpharmacological management, which includes education, cognitive behavioral therapy, and complementary therapy, is used as primary or adjunctive to pharmacotherapy for the treatment of these disorders. METHODS This narrative review utilized medical databases such as PubMed to identify relevant English-language original and systematic review articles predominantly from peer-reviewed journals from 2012 to 2019. However, as background, findings from classic articles prior to 2012 were also included. CLINICAL RELEVANCE Assessment of sleep problems, excessive sleepiness, and difficulty performing activities or being productive should be routine in the care of all patients. Utilization of behavioral interventions, including cognitive behavioral therapy, in addition to education and sleep hygiene, can promote sleep quality. Management of insomnia, RLS/WED, and narcolepsy should include helping patients adjust to treatment, managing cataplexy triggers in narcolepsy, and initiating strategies to live with chronic illness to improve quality of life.
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Affiliation(s)
- Jindarat Chaiard
- Assistant Professor, Faculty of Nursing, Chiang Mai University, Chiang Mai, Thailand
| | - Terri E Weaver
- Tau Xi and Alpha Lambda, Dean, College of Nursing, Professor of Biobehavioral and Health Science, College of Nursing, Professor of Nursing in the Department of Medicine, College of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Illinois at Chicago, Chicago, IL, USA
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Zhu XY, Wu TT, Wang HM, Ni LY, Li X, Liu Y, Zhang XJ, Chen YJ, Cui XX, Ondo WG, Wu YC. Clinical features and subtypes of restless legs syndrome in Chinese population: a study of 359 patients. Sleep Med 2019; 59:15-23. [DOI: 10.1016/j.sleep.2019.01.053] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/14/2019] [Accepted: 01/31/2019] [Indexed: 10/27/2022]
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Avni T, Reich S, Lev N, Gafter-Gvili A. Iron supplementation for restless legs syndrome - A systematic review and meta-analysis. Eur J Intern Med 2019; 63:34-41. [PMID: 30798983 DOI: 10.1016/j.ejim.2019.02.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 01/30/2019] [Accepted: 02/10/2019] [Indexed: 10/27/2022]
Abstract
BACKGROUND Iron supplementation, is recommended for the treatment of restless legs syndrome (RLS). We gathered evidence for the efficacy and safety of iron supplementation for RLS. METHODS A systematic review and meta-analysis of randomized controlled trials that compared iron supplementation versus no iron for patients with RLS was performed. Multiple databases were searched. The primary outcome was the effect of iron on the International Restless Legs Syndrome score (IRLSS) at 4 weeks after treatment. For dichotomous data, risk ratios (RR) with 95% confidence intervals (CIs) were estimated and pooled. For continuous data, weighted mean differences (WMD) were calculated. RESULTS Ten trials fulfilled the inclusion criteria. Iron therapy was associated with a significant decrease of the IRLSS of -3.55 [95% CI (-5.41) - (-1.68)] points and an increase in the percentage of patients with improvement of the IRLSS score, RR of 2.16 [95% CI 1.56-2.98]. IV FCM was associated with improvement in both the IRLSS (WMD of -2.79 (95% CI (-4.62) - (-0.96), 4 trials, I2 = 0%) and on the RLS-QOL by WMD of 8.67 (95% CI 1.68-15). Iron was associated with an increased rate of adverse events RR 2.04 (95% CI 1.46-2.85), which were not severe and not associated with increased rate of treatment discontinuation. CONCLUSION Iron supplementation is associated with improvement of the IRLSS score. Our meta-analysis supports the use of iron, oral or IV, as effective therapy for patients with RLS. Further studies should assess subgroups of patients most likely to benefit from iron supplementation.
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Affiliation(s)
- Tomer Avni
- Internal Medicine E, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
| | - Shelley Reich
- Internal Medicine A, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel and Sackler faculty of Medicine, Tel-Aviv University, Israel
| | - Nirit Lev
- Neurology Department, Meir Medical Center, Kfar Saba, Israel and Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Anat Gafter-Gvili
- Internal Medicine A, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel and Sackler faculty of Medicine, Tel-Aviv University, Israel
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Abstract
Intravenous ferric carboxymaltose (Ferinject®; Injectafer®) is a colloidal solution of nanoparticles which consist of a polynuclear iron (III)-(oxyhydr)oxide core stabilized by carboxymaltose and may be given as a single high-dose, 15-min infusion. This article reviews the clinical use of ferric carboxymaltose in various patient populations with iron deficiency (ID) [± anaemia] and briefly summarizes its pharmacological properties. Based on extensive experience in the clinical trial and real-world settings, ferric carboxymaltose is an effective and generally well tolerated treatment for rapidly replenishing iron stores and correcting anaemia in patients with ID (± anaemia) of various aetiologies, including patients with chronic heart failure (CHF), chronic kidney disease, inflammatory bowel disease or perioperative anaemia, and women with ID during pregnancy, postpartum or associated with heavy uterine bleeding. As it may be given as a single high-dose infusion, ferric carboxymaltose has the potential to provide cost savings from a healthpayer perspective. Thus, ferric carboxymaltose remains an important option for the treatment of ID in adults and, where approved, children aged ≥ 14 years, when oral iron preparations are ineffective or cannot be used.
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Affiliation(s)
- Lesley J Scott
- Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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Yang X, Yang B, Ming M, Li S, Wang F, Zhu Z, Ji C, Long J, Hu F, Xu Z, Ren H, Liu B. Efficacy and tolerability of intravenous iron for patients with restless legs syndrome: evidence from randomized trials and observational studies. Sleep Med 2019; 61:110-117. [PMID: 31395522 DOI: 10.1016/j.sleep.2019.01.040] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 11/11/2018] [Accepted: 01/08/2019] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Restless legs syndrome (RLS) is a common neurological disorder of unclear pathophysiology that appears to involve an iron deficiency in the brain. Some studies, but not others, suggest that intravenous injection of iron can reduce RLS severity. METHOD The databases Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed were searched for randomized controlled trials, cohort studies and case-control studies of intravenous iron therapy to treat RLS. Eligible studies were meta-analyzed using Stata 12.0. RESULTS This analysis indicated that IV iron was more efficacious than placebo in treating RLS (OR: 4.71,95%CI 4.21-5.21,p < 0.0001). According to sub-group analysis, either IV ferric carboxymaltose (FCM) or iron sucrose was more efficacious than placebo in treating RLS. Adverse events did not differ significantly between patients receiving intravenous iron or placebo (OR 1.68, 95%CI 0.92-3.07, p = 0.093). The present study also indicated after accepting IV iron treatment the IRLS score in RLS patients decreased (OR = 6.75,95%CI 4.02-9.49, p < 0.0001). The subgroup analysis showed that IV iron dextran, iron sucrose, and FCM could alleviate the IRLS score. CONCLUSION The available evidence suggests that intravenous iron is effective and tolerable for patients with RLS regardless of peripheral iron status.
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Affiliation(s)
- Xinglong Yang
- Department of Geriatric Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650032, PR China
| | - Baiyuan Yang
- Department of Neurology, Seventh People's Hospital of Chengdu, 610041, PR China
| | - Mao Ming
- Department of Emergency Internal Medicine Guang'an Men South Area Hospital, China Academy of Chinese Medical Sciences, 102600, PR China
| | - Shimei Li
- Department of Anesthesia, Kunming Xishan District People's Hospital, Kunming, Yunnan Province, 650100, PR China
| | - Fang Wang
- Department of Geriatric Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650032, PR China
| | - Zhigang Zhu
- Department of Geriatric Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650032, PR China
| | - Chang Ji
- Department of Geriatric Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650032, PR China
| | - Juan Long
- Department of Geriatric Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650032, PR China
| | - Fayun Hu
- Department of Neurology, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu, Sichuan Province, 610041, PR China
| | - Zhong Xu
- Department of Geriatric Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650032, PR China
| | - Hui Ren
- Department of Geriatric Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650032, PR China.
| | - Bin Liu
- Department of Geriatric Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650032, PR China.
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Abstract
BACKGROUND Restless legs syndrome (RLS) is a common neurologic disorder that is associated with peripheral iron deficiency in a subgroup of patients. It is unclear whether iron therapy is effective treatment for RLS. OBJECTIVES To evaluate the efficacy and safety of oral or parenteral iron for the treatment of restless legs syndrome (RLS) when compared with placebo or other therapies. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycNFO, and CINAHL for the time period January 1995 to September 2017. We searched reference lists for additional published studies. We searched Clinicaltrials.gov and other clinical trial registries (September 2017) for ongoing or unpublished studies. SELECTION CRITERIA Controlled trials comparing any formulation of iron with placebo, other medications, or no treatment, in adults diagnosed with RLS according to expert clinical interview or explicit diagnostic criteria. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and assessed trial quality, with discussion to reach consensus in the case of any disagreement. The primary outcome considered in this review was restlessness or unpleasant sensations, as experienced subjectively by the patient. We combined treatment/control differences in the outcomes across studies using random-effects meta-analyses. We analysed continuous data using mean differences (MDs) where possible and performed standardised mean difference (SMD) analyses when different measurements were used across studies. We calculated risk ratios (RRs) for dichotomous data using the Mantel-Haenszel method and 95% confidence intervals (CIs). We analysed study heterogeneity using the I2 statistic. We used standard methodological procedures expected by Cochrane. We performed GRADE analysis using GRADEpro. MAIN RESULTS We identified and included 10 studies (428 total participants, followed for 2-16 weeks) in this review. Our primary outcome was restlessness or uncomfortable leg sensations, which was quantified using the International Restless Legs Scale (IRLS) (range, 0 to 40) in eight trials and a different RLS symptom scale in a ninth trial. Nine studies compared iron to placebo and one study compared iron to a dopamine agonist (pramipexole). The possibility for bias among the trials was variable. Three studies had a single element with high risk of bias, which was lack of blinding in two and incomplete outcome data in one. All studies had at least one feature resulting in unclear risk of bias.Combining data from the seven trials using the IRLS to compare iron and placebo, use of iron resulted in greater improvement in IRLS scores (MD -3.78, 95% CI -6.25 to -1.31; I2= 66%, 7 studies, 345 participants) measured 2 to 12 weeks after treatment. Including an eighth study, which measured restlessness using a different scale, use of iron remained beneficial compared to placebo (SMD -0.74, 95% CI -1.26 to -0.23; I2 = 80%, 8 studies, 370 participants). The GRADE assessment of certainty for this outcome was moderate.The single study comparing iron to a dopamine agonist (pramipexole) found a similar reduction in RLS severity in the two groups (MD -0.40, 95% CI -5.93 to 5.13, 30 participants).Assessment of secondary outcomes was limited by small numbers of trials assessing each outcome. Iron did not improve quality of life as a dichotomous measure (RR 2.01, 95% CI 0.54 to 7.45; I2=54%, 2 studies, 39 participants), but did improve quality of life measured on continuous scales (SMD 0.51, 95% CI 0.15 to 0.87; I2= 0%, 3 studies, 128 participants), compared to placebo. Subjective sleep quality was no different between iron and placebo groups (SMD 0.19, 95% CI -0.18 to 0.56; I2 = 9%, 3 studies, 128 participants), nor was objective sleep quality, as measured by change in sleep efficiency in a single study (-35.5 +/- 92.0 versus -41.4 +/- 98.2, 18 participants). Periodic limb movements of sleep were not significantly reduced with iron compared to placebo ( SMD -0.19, 95% CI -0.70 to 0.32; I2 = 0%, 2 studies, 60 participants). Iron did not improve sleepiness compared to placebo, as measured on the Epworth Sleepiness Scale (data not provided, 1 study, 60 participants) but did improve the daytime tiredness item of the RLS-6 compared to placebo (least squares mean difference -1.5, 95% CI -2.5 to -0.6; 1 study, 110 participants). The GRADE rating for secondary outcomes ranged from low to very low.Prespecified subgroup analyses showed more improvement with iron in those trials studying participants on dialysis. The use of low serum ferritin levels as an inclusion criteria and the use or oral versus intravenous iron did not show significant subgroup differences.Iron did not result in significantly more adverse events than placebo (RR 1.48, 95% CI 0.97 to 2.25; I2=45%, 6 studies, 298 participants). A single study reported that people treated with iron therapy experienced fewer adverse events than the active comparator pramipexole. AUTHORS' CONCLUSIONS Iron therapy probably improves restlessness and RLS severity in comparison to placebo. Iron therapy may not increase the risk of side effects in comparison to placebo. We are uncertain whether iron therapy improves quality of life in comparison to placebo. Iron therapy may make little or no difference to pramipexole in restlessness and RLS severity, as well as in the risk of adverse events. The effect on secondary outcomes such as quality of life, daytime functioning, and sleep quality, the optimal timing and formulation of administration, and patient characteristics predicting response require additional study.
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Affiliation(s)
- Lynn M Trotti
- Emory University School of MedicineDepartment of Neurology12 Executive Park Drive NEAtlantaUSA30329
| | - Lorne A Becker
- SUNY Upstate Medical UniversityDepartment of Family Medicine475 Irving AveSuite 200SyracuseNew YorkUSA13210
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Ghorayeb I. Idiopathic restless legs syndrome treatment: Progress and pitfalls? PHARMACOLOGY OF RESTLESS LEGS SYNDROME (RLS) 2019; 84:207-235. [PMID: 31229172 DOI: 10.1016/bs.apha.2019.01.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Restless Legs Syndrome and Other Movement Disorders of Sleep-Treatment Update. Curr Treat Options Neurol 2018; 20:55. [PMID: 30411165 DOI: 10.1007/s11940-018-0540-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review article is to summarize and discuss the recent advances in the treatment of restless legs syndrome (RLS), as well as REM sleep behavior disorder (RBD), and periodic leg movement disorder (PLMD). RECENT FINDINGS Traditionally, dopaminergic therapy has been considered the sole option for first-line treatment of RLS due to their impressive acute efficacy. Dopamine agonists such as oral pramipexole and ropinirole, as well as transdermal rotigotine are all effective treatment options. However, augmentation of the RLS symptoms is a major limitation of oral dopaminergic therapy. Recently, gabapentinoid agents such as gabapentin enacarbil and pregabalin have shown comparable short-term efficacy to dopaminergics with lower risk of augmentation of the RLS symptoms. Recent evidence on the efficacy of oxycodone-naloxone in treatment-resistant RLS provides an additional therapeutic avenue. The increasing understanding of the role of iron in RLS pathophysiology has led to new options in iron supplementation therapy in RLS, including treatment with ferric carboxymaltose. With emerging evidence of augmentation being a side effect specific to dopaminergic treatment, gabapentinoids are considered a safer option as initial treatment. In severe refractory RLS, oxycodone-naloxone can be used. If iron stores are low, IV iron formulations should be the initial treatment choice. New treatment options are needed to address issues with current therapies.
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Haschka D, Volani C, Stefani A, Tymoszuk P, Mitterling T, Holzknecht E, Heidbreder A, Coassin S, Sumbalova Z, Seifert M, Dichtl S, Theurl I, Gnaiger E, Kronenberg F, Frauscher B, Högl B, Weiss G. Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome. Mov Disord 2018; 34:114-123. [DOI: 10.1002/mds.27482] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 07/11/2018] [Accepted: 07/16/2018] [Indexed: 12/11/2022] Open
Affiliation(s)
- David Haschka
- Department of Internal Medicine II Medical University of Innsbruck Innsbruck Austria
| | - Chiara Volani
- Department of Internal Medicine II Medical University of Innsbruck Innsbruck Austria
| | - Ambra Stefani
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
| | - Piotr Tymoszuk
- Department of Internal Medicine II Medical University of Innsbruck Innsbruck Austria
| | - Thomas Mitterling
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
- Department of Neurology Wagner‐Jauregg Hospital Linz Linz Austria
| | - Evi Holzknecht
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
| | - Anna Heidbreder
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
- Department of Neurology, Division of Sleep Medicine and Neuromuscular Disorders University Hospital Muenster Muenster Germany
| | - Stefan Coassin
- Department of Medical Genetics, Division of Genetic Epidemiology, Molecular and Clinical Pharmacology Medical University of Innsbruck Innsbruck Austria
| | - Zuzana Sumbalova
- Pharmacobiochemical Laboratory of the 3rd Department of Internal Medicine, Faculty of Medicine in Bratislava Comenius University Bratislava Slovakia
| | - Markus Seifert
- Department of Internal Medicine II Medical University of Innsbruck Innsbruck Austria
| | - Stefanie Dichtl
- Department of Internal Medicine II Medical University of Innsbruck Innsbruck Austria
| | - Igor Theurl
- Department of Internal Medicine II Medical University of Innsbruck Innsbruck Austria
| | - Erich Gnaiger
- Department of General and Transplant Surgery, D. Swarovski Research Laboratory Medical University of Innsbruck Innsbruck Austria
| | - Florian Kronenberg
- Department of Medical Genetics, Division of Genetic Epidemiology, Molecular and Clinical Pharmacology Medical University of Innsbruck Innsbruck Austria
| | - Birgit Frauscher
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
| | - Birgit Högl
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
| | - Guenter Weiss
- Department of Internal Medicine II Medical University of Innsbruck Innsbruck Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research Medical University of Innsbruck Innsbruck Austria
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Comorbidities, treatment, and pathophysiology in restless legs syndrome. Lancet Neurol 2018; 17:994-1005. [PMID: 30244828 DOI: 10.1016/s1474-4422(18)30311-9] [Citation(s) in RCA: 164] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 07/05/2018] [Accepted: 08/08/2018] [Indexed: 12/11/2022]
Abstract
Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation is affected by complex environmental and genetic interactions. Restless legs syndrome can occur on its own, mostly at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a difficult condition to properly diagnose. However, the concept of restless legs syndrome as being two entities, primary or secondary to another condition, has been challenged with genetic data providing further insight into the pathophysiology of the condition. Although dopaminergic treatment was formerly the first-line therapy, prolonged use can result in a serious worsening of symptoms known as augmentation. Clinical studies on pregabalin, gabapentin enacarbil, oxycodone-naloxone, and iron preparations have provided new treatment options, but most patients still report inadequate long-term management of symptoms. Studies of the hypoxic pathway activation and iron deficiency have provided valuable information about the pathophysiology of restless legs syndrome that should now be translated into new, more effective treatments for restless legs syndrome.
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Zucconi M, Galbiati A, Rinaldi F, Casoni F, Ferini-Strambi L. An update on the treatment of Restless Legs Syndrome/Willis-Ekbom Disease: prospects and challenges. Expert Rev Neurother 2018; 18:705-713. [PMID: 30095315 DOI: 10.1080/14737175.2018.1510773] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sleep disorder characterized by an urge to move the legs, frequently associated or triggered by unpleasant sensations in the lower limbs that affects approximately 2.5% of adults. Therapy and management of RLS/WED require long-term interventions, since the typical manifestation of this disorder is chronic. Areas covered: In this review, we provide an update regarding the treatment of RLS/WED with particular attention to future challenges for its management. We reviewed a large variety of treatments studied in clinical trials and supported by the most updated guidelines. Alongside with first-line interventions other pharmacological options including opioids, benzodiazepines, iron therapy, and newly studied drugs are discussed. Furthermore, due to the occurrence of augmentation and worsening of symptoms we also reviewed the development of non-pharmacologic alternatives. Expert commentary: The management of RLS/WED is a challenge because of different long-term issues. Several complications, such as loss of the therapeutic effect of dopaminergic or non-dopaminergic agents and augmentation, are still unsolved concerns. However, the development of new drugs acting on adenosinergic and glutamatergic neurotransmission seems promising. Randomized controlled trials are needed in order to recognize effectiveness of new drugs or non-pharmacological treatment strategies.
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Affiliation(s)
- Marco Zucconi
- a Department of Clinical Neurosciences, Neurology - Sleep Disorders Center , IRCCS San Raffaele Scientific Institute , Milan , Italy
| | - Andrea Galbiati
- a Department of Clinical Neurosciences, Neurology - Sleep Disorders Center , IRCCS San Raffaele Scientific Institute , Milan , Italy.,b Faculty of Psychology , "Vita-Salute" San Raffaele University , Milan , Italy
| | - Fabrizio Rinaldi
- a Department of Clinical Neurosciences, Neurology - Sleep Disorders Center , IRCCS San Raffaele Scientific Institute , Milan , Italy
| | - Francesca Casoni
- a Department of Clinical Neurosciences, Neurology - Sleep Disorders Center , IRCCS San Raffaele Scientific Institute , Milan , Italy
| | - Luigi Ferini-Strambi
- a Department of Clinical Neurosciences, Neurology - Sleep Disorders Center , IRCCS San Raffaele Scientific Institute , Milan , Italy.,b Faculty of Psychology , "Vita-Salute" San Raffaele University , Milan , Italy
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Ratneswaran C, Sagoo MK, Steier J. Preface for the 3rd Clinical Update Sleep, 23rd February 2018, Royal College of Physicians, London, UK: year in review. J Thorac Dis 2018; 10:S1-S23. [PMID: 29445524 PMCID: PMC5803052 DOI: 10.21037/jtd.2017.10.162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Culadeeban Ratneswaran
- Faculty of Life Sciences and Medicine, King's College London, London, UK
- Lane Fox Unit/Sleep Disorders Centre, Guy's & St Thomas' NHS Foundation Trust, London, UK
| | - Manpreet K Sagoo
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Joerg Steier
- Faculty of Life Sciences and Medicine, King's College London, London, UK
- Lane Fox Unit/Sleep Disorders Centre, Guy's & St Thomas' NHS Foundation Trust, London, UK
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Allen RP, Picchietti DL, Auerbach M, Cho YW, Connor JR, Earley CJ, Garcia-Borreguero D, Kotagal S, Manconi M, Ondo W, Ulfberg J, Winkelman JW. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med 2017; 41:27-44. [PMID: 29425576 DOI: 10.1016/j.sleep.2017.11.1126] [Citation(s) in RCA: 189] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 11/09/2017] [Accepted: 11/13/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND Brain iron deficiency has been implicated in the pathophysiology of RLS, and current RLS treatment guidelines recommend iron treatment when peripheral iron levels are low. In order to assess the evidence on the oral and intravenous (IV) iron treatment of RLS and periodic limb movement disorder (PLMD) in adults and children, the International Restless Legs Syndrome Study Group (IRLSSG) formed a task force to review these studies and provide evidence-based and consensus guidelines for the iron treatment of RLS in adults, and RLS and PLMD in children. METHODS A literature search was performed to identify papers appearing in MEDLINE from its inception to July 2016. The following inclusion criteria were used: human research on the treatment of RLS or periodic limb movements (PLM) with iron, sample size of at least five, and published in English. Two task force members independently evaluated each paper and classified the quality of evidence provided. RESULTS A total of 299 papers were identified, of these 31 papers met the inclusion criteria. Four studies in adults were given a Class I rating (one for IV iron sucrose, and three for IV ferric carboxymaltose); only Class IV studies have evaluated iron treatment in children. Ferric carboxymaltose (1000 mg) is effective for treating moderate to severe RLS in those with serum ferritin <300 μg/l and could be used as first-line treatment for RLS in adults. Oral iron (65 mg elemental iron) is possibly effective for treating RLS in those with serum ferritin ≤75 μg/l. There is insufficient evidence to make conclusions on the efficacy of oral iron or IV iron in children. CONCLUSIONS Consensus recommendations based on clinical practice are presented, including when to use oral iron or IV iron, and recommendations on repeated iron treatments. New iron treatment algorithms, based on evidence and consensus opinion have been developed.
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Affiliation(s)
- Richard P Allen
- Department of Neurology, Johns Hopkins University, Hopkins Bayview Medical Center, Baltimore, MD, USA.
| | - Daniel L Picchietti
- University of Illinois College of Medicine at Urbana-Champaign and Carle Foundation Hospital, Urbana, IL, USA
| | - Michael Auerbach
- Department of Medicine, Georgetown University, Washington DC, USA
| | - Yong Won Cho
- Department of Neurology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - James R Connor
- Department of Neurosurgery, Penn State Hershey Medical Center, Hershey PA, USA
| | - Christopher J Earley
- Department of Neurology, Johns Hopkins University, Hopkins Bayview Medical Center, Baltimore, MD, USA
| | | | - Suresh Kotagal
- Department of Neurology and the Center for Sleep Medicine, Mayo Clinic, Rochester, MN, USA
| | - Mauro Manconi
- Sleep and Epilepsy Center, Neurocenter of Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland
| | - William Ondo
- Methodist Neurological Institute, Weill Cornell Medical School Houston, TX, USA
| | - Jan Ulfberg
- Sleep Disorders Department, Capio Health Center, Örebro, Sweden
| | - John W Winkelman
- Departments of Psychiatry and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Wijemanne S, Ondo W. Restless Legs Syndrome: clinical features, diagnosis and a practical approach to management. Pract Neurol 2017; 17:444-452. [PMID: 29097554 DOI: 10.1136/practneurol-2017-001762] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2017] [Indexed: 11/04/2022]
Abstract
Restless legs syndrome (RLS) is a chronic neurological disorder that interferes with rest and sleep. It has a wide spectrum of symptom severity, and treatment is started when symptoms become bothersome. Dopamine agonists and calcium channel apha-2-delta antagonists (gabapentin, gabapentin enacarbil and pregabalin) are first-line treatments; calcium channel alpha-2-deltas are preferred over dopamine agonists because they give less augmentation, a condition with symptom onset earlier in the day and intensification of RLS symptoms. Dopamine agonists can still be used as first-line therapy, but the dose should be kept as low as possible. Iron supplements are started when the serum ferritin concentration is ≤75 µg/L, or if the transferrin saturation is less than 20%. For severe or resistant RLS, a combined treatment approach can be effective. Augmentation can be very challenging to treat and lacks evidenced-based guidelines.
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Affiliation(s)
- Subhashie Wijemanne
- Department of Neurology, University of Texas Health San Antonio, San Antonio, Texas, USA
| | - William Ondo
- Department of Neurology, Weill Cornell Medical School, Methodist Neurological Institute, Houston, Texas, USA
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