Restless legs syndrome in chronic obstructive pulmonary disease

Document Type: Review


1 Lung Disease Research Center ,Mashhad University Of Medical Sciences

2 Department of neurology


Restless legs syndrome (RLS) is a common chronic sensory motor disorder that prevents initiation and/or sleep staying. Patients with this syndrome have uncomfortable sensations in their legs (and sometimes arms or other parts of the body), with moving their legs to relieve this sensations. The symptoms of RLS are usually worse in the evening and at night. The diagnosis of RLS is primarily based on clinical evaluation and clinical history of the patient. International restless leg syndrome group study (IRLSSG) evaluates the symptoms and severity of RLS. RLS can be divided into two groups of primary and secondary. Iron deficiency, Parkinson’s disease, kidney failure, diabetes, peripheral neuropathy, and pregnancy may cause RLS. Antinausea, antipsychotic drugs, some antidepressants, and antihistamines may also worsen the symptoms. RLS is also observed in chronic obstructive pulmonary disease (COPD), which makes the outcomes  worse. COPD is a main preventable health problem that can lead to morbidity and mortality. Thus, RLS in COPD causes excessive daytime hypersomnolence, fatigue, poor quality of life, disability and neuropsychological complications such as social isolation, frequent daytime headaches, anxiety and depression.


 Restless leg syndrome (RLS) also called Willis-Ekbom disease (WED) is a sensory motor disorder that leads to an urge to move the limbs (1,2). Patients with this syndrome have uncomfortable sensations in their legs (and sometimes arms or other parts of the body), so with moving their limbs these sensations are relieved (3-5).The symptoms of RLS are usually worse in the evening and at night than at the day time (6-8). The diagnosis of RLS is based on clinical evaluation and the patient’s history. Clinical criteria for the diagnosis of RLS are based on those developed by the international restless legs syndrome study group (IRLSSG). The IRLSSG suggested following four features as minimal criteria for the diagnosis of RLS: 1- desire to move the extremities, often associated with discomfort and restlessness, 2- occurrence or worsening of symptoms at rest, 3- relief of symptoms completely or partly during activity, 4-occurrence or worsening of symptoms only in the evening or at night(9-11). Also, IRLSSG described the symptoms and severity of RLS (11). RLS is classified into primary (idiopathic) and secondary (1,12). People with RLS usually have problem to fall asleep and stay asleep. In addition, since they do not get enough sleep, they may feel tired and sleepy during the day. RLS can make it difficult to concentrate, and daily and social activities performance may also be affected by RLS. Lack of enough sleep can also make patients feel depressed or have mood swings (7-10). It should be noted that chronic obstructive pulmonary disease (COPD) characterized by airflow obstruction is not fully reversible (13).  COPD is a preventable and debilitating disease worldwide and till 2030 it would be the third cause for mortality (14,15). Shortness of breathing and chronic productive cough are the cardinal manifestation in COPD (16,17) Cigarette smoking is a main risk factor for COPD. Also occupational exposure to toxicants, biomass inhalation, and genetic predisposition were documented for pathogenesis of COPD (18-22) Sleep disordered breathing such as obstructive sleep apnea (OSA), and RLS are comorbidities in COPD (23,24).

Literature Review
A narrative review was conducted on RLS in COPD through literature search in the PubMed and google scholar databases. One hundred and eighty nine articles were found for full text review.

Restless legs syndrome and COPD
RLS of any severity occurs in 5 to 15 percent of adults. This syndrome can be observed at any ages and sexes, but its frequency is slightly more common in women. To this point, RLS is common in COPD patients (3-6). The incidence of COPD is over 10%-15% in adults with 40 years of ages or older (13,14,25). Since, the prevalence of COPD is increasing worldwide, the related morbidity and mortality such as RLS are important health problems that needs further attention (26-28). However, the accurate cause of RLS is unknown. Idiopathic RLS is observed in younger age and had a genetic predisposition. Inversely, the secondary RLS had more severe progression in symptoms and is observed in late onset (2,3,6,7). The effective treatment with dopaminergic drugs in RLS supports that malfunction in central nervous system (CNS) is responsible for pathogenesis rather than peripheral nervous system (2-12). In secondary RLS, predisposing factor that often include symptoms of RLS are iron deficiency, Parkinson’s disease, kidney failure, diabetes, and peripheral neuropathy. Antinausea drugs, antipsychotic drugs, some antidepressants, cold and allergy medications containing sedating antihistamines may worsen the symptoms. Pregnancy, alcohol use and sleep deprivation, may trigger symptoms or make them worsen (3-7). Low CNS iron is a persistent finding in RLS/WED. Therefore, decreased serum ferritin (
Obstructive sleep apnea
OSA is a common disorder defined by repeated closure upper air way during sleep that leads to a significant functional disability and end organ damage as well as mortality (51,52). Essential manifestations of OSA in adults include apneas, hypopneas, loud snoring, morning headache, daytime sleepiness, fatigue, low concentration, poor cognitive function, and restlessness (53-58). The incidence of OSA in male higher than female. Overweight is the most important risk facor, although aging, hypothyroidism, myopathy, craniofacial abnormalities and smoking are the predisposing factors (59-63).OSA is diagnosed when apnea hypopnea index (AHI) was ≥5 per hour.  Apnea is defined as the complete stop in respiratory flow over a period of ten seconds or more. Polysomnography measures the AHI, a measure of the number of apnea or hypopnea events per hour during sleep (64-69). The AHI is used to diagnose and assess the severity of OSA (70). OSA patients are at risk for profound hypoventilation, respiratory failure, chronic hypoxemia and cardiovascular complications (71-73). Patients with OSA, especially in untreated cases, are at risk for a major range of cardiovascular impairment, including systemic hypertension, pulmonary arterial hypertension, coronary artery disease, cardiac arrhythmias, heart failure, and stroke (74-77). OSA patients are prone to diabetes mellitus and resistance to insulin (78). Sleep overlap syndrome (concomitant COPD and OSA in an individual) leads to more severe nocturnal desaturations, and increases the risk for pulmonary hypertension, cardiac morbidity and mortality (79-88).

Periodic limb movements
PLMs are short involuntary movements that may occur during sleep at about 20-40 second intervals (5,88). They are characterized by a rhythmic and repetitive extension of the big toe and dorsiflexion of the ankle with occasion flexion at the knee and hip (88). The majority of RLS patients have PLM (80%-90%) (3-10). In addition, PLM is observed in OSA (50,61). Also, findings have documented a high incidence of PLMs in healthy people over the age of 40 years (88).

There is no specific diagnostic test for RLS, so its diagnosis is based on clinical evaluation.   The IRLSSG formulated four criteria defining RLS: 1) there is an urge to move the legs, usually accompanied by uncomfortable or unpleasant sensations in the legs; 2) the urge to move the legs begins or worsens during inactivity such as lying or sitting; 3) the urge to move is partially or totally relieved by movements; and 4) the urge to move is worse in the evening or at night .Thus ,diagnosis of RLS is based on  a medical history and does not need  a polysomnography  recording(1-4), although polysomnography confirmation would be considered  when sleep disordered breathing  is observed. OSA is diagnosed with polysomnography. Additionally, PLMs are recorded at night during sleep in polysomnography (80-88).

RLS treatment is based on the severity of RLS and degree of disability .In mild and intermittent symptoms, lifestyle improvement is recommended. Mild exercise, limited caffeine intake, leg message, hot baths may be beneficial .Up to 90% of patients with RLS relieve with dopaminergic agents. Benzodiazepines treat RLS symptoms, but in concomitant occurrence of RLS and OSA, benzodiazepines induce apneas and hypoventilations, and the sleep disordered breathing may also worsen (1-12). Some studies have shown that Continuous positive airway pressure treated OSA as well as RLS and PLMS. Weight reduction, using oral device, and nasal congestion relieve are the proper treatment for OSA (70-78).

RLS is a common neurological sensory motor disorder that interferes with sleep quality. Its prevalence is higher in COPD patients than in healthy controls; hence, the screening of RLS in patients with COPD is strongly recommended.

Conflict of Interest
The authors declare no conflict of interest.

 This study was supported by a grant from the Vice Chancellor for Research of the Mashhad University of Medical Sciences (Grant number:921045).

  1. Roux FJ.  Restless legs syndrome: impact on sleep-related breathing disorders. Respirology. 2013;18:238-245.
  2. Allen  RP, Picchietti  D, Hening  WA, et al. Restless legs syndrome: diagnostic  criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-119.
  3. Zucconi M, Ferini-Strambi L. Epidemiology and clinical findings of restless legs syndrome.Sleep Med. 2004;5:293-299.
  4. Kaplan Y, Inonu H, Yilmaz A, et al. Restless legs syndrome in patients with chronic obstructive pulmonary disease. Can J Neurol Sci. 2008;35:352-357.
  5. Gamaldo CE, Earley CJ. Restless legs syndrome:a clinical update.Chest. 2006;130:1596-1604.
  6. Glasauer FE. Restless Legs Syndrome. Spinal Cord. 2001;39:125-133.
  7. Trenkwalder C. The restless legs syndrome. Lancet Neurol. 2005;4:465-475.
  8. Sieminski  M. Restless legs syndrome-Secondary, Co morbid or Coincidental? Eur Neurol. 2013;69:150-151.
  9. Trenkwalder  C, Paulus W. Restless legs  syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol. 2010;6:337-346.
  10. Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome:results of general population survey in the United States. Mov Disord. 2011;26:114-120.
  11. Walters AS,  LeBrocq C, Dhar A , et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003;4:121-132.
  12. Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther. 2004;26:925-935.
  13. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung  Disease (GOLD) 2016. Available from:
  14. Miravitlles M, Soler-Cataluña JJ, Calle M, et al. A new approach to grading and treating COPD based on clinical phenotypes: summary of the Spanish COPD guidelines (GesEPOC). Prim Care Respir J. 2013;22:117-121.
  15. Rezaeetalab F, Alamdari HD, Dalili A. Oxidative stress in COPD, pathogenesis and therapeutic views. Rev Clin Med.2014;1:115-124.
  16. National Institute for Health and Clinical Excellence.NICE clinical guideline 101. Available: Accessed 2013 Jul 26.
  17. Rabinovich RA, Louvaris Z, Raste Y, et al. Validity of physical activity monitors during daily life in patients with COPD. EUR Respir J. 2013;42:1205-1215.
  18. Gupta N, Pinto LM, Morogan A, et al. The COPD assessment test: a systematic review. Eur Respir J. 2014;44:873-884.
  19. Lange P, Halpin DM, O’Donnell DE, et al. Diagnosis, assessment, and phenotyping of COPD: beyond FEV1. Int J Chron Obstruct Pulmon Dis. 2016 19;11 Spec Iss:3-12.
  20. Giraud V, Beauchet A, Gomis T, et al. Feasibility of spirometry in primary care to screen for COPD: a pilot study. Int J Chron Obstruct Pulmon Dis. 2016 12;11:335-340.
  21. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis,management,and prevention of chronic obstructive pulmonary disease:GoLD executive summary. Am J Respir Crit Care Med. 2013;187:347-365.
  22. Singh A, Kumar S, Mishra AK, et al. Correlation between clinical characteristics, spirometric indices and high resolution computed tomography findings in patients of chronic obstructive pulmonary disease. Lung India. 2016;33:42-48.
  23. Price D,West D,Brusselle G et al. Management of COPD in the UK primary –care setting: an analysis of real-life prescribing patterns. Int J Chron Obstruct Pulmon Dis. 2014;9:889-904.
  24. Smith MC,Wrobel JP. Epidemiology and clinical impact of major co morbidities in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2014;9:871-888.
  25. Molfino NA, Jeffery PK. Chronic Obstructive Pulmonary disease: Histopathology, inflammation and potential therapies. Pulm Pharmacol Ther. 2007;20:462-472.
  26. Sansores RH, Velázquez-Uncal M, Pérez-Bautista O, et al. Prevalence of chronic obstructive pulmonary disease in asymptomatic smokers. Int J Chron Obstruct Pulmon Dis. 2015;10:2357-2363.
  27. Garvey C. Recent updates in chronic obstructive pulmonary disease. Postgrad Med. 2016;128:231-238.
  28. Seemungal TA, Wedzicha JA. Update in Chronic Obstructive Pulmonary Disease 2014. Am J Respir Crit Care Med. 2015;192:1036-1044.
  29. de Marco R, Accordini S, Marcon A, et al. Risk factors for chronic obstructive pulmonary disease in a European cohort of young adults. Am J Respir Crit Care Med. 2011;183:891-897.
  30. Postma DS, Bush A, van den Berge M. Risk factors and early origins of chronic obstructive pulmonary disease. Lancet. 2015;385:899-909.
  31. Brinchault G, Diot P, Dixmier A, et al. Comorbidities of COPD. Rev Pneumol Clin. 2015;71:342-349.
  32. May SM, Li JT. Burden of chronic obstructive pulmonary disease: healthcare costs and beyond. Allergy Asthma Proc. 2015;36:4-10.
  33. Miniati M, Monti S, Pavlickova I, et al. Survival in COPD: impact of lung dysfunction and comorbidities. Medicine (Baltimore). 2014;93:e76.
  34. Tinkelman DG, Price D, Nordyke RJ, et al. COPD screening efforts in primary care :what is the yield? Prim Care Respir J. 2007;16:41-48.
  35. Bednarek M, Maciejewski J, Wozniak M, et al. Prevalence,severity and underdiagnosis of COPD in the primary care setting. Thorax. 2008;63:402-407.
  36. Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28:523-532.
  37. Agustí A, Jones PW, Vogelmeier C. Highlights and hot topics in the management of COPD: where are we heading? Int J Chron Obstruct Pulmon Dis. 2016;11 Spec Iss:1-2
  38. Restrepo RD. Year in Review 2014: COPD. Respir Care. 2015;60:1057-1060.
  39. Flenley  DC. Sleep in chronic obstructive lung disease. Clin Chest Med. 1985;6:651-661.
  40. Stansbury RC, Strollo PJ. Clinical manifestations of sleep apnea. J Thorac Dis. 2015;7:E298-310.
  41. Ezzie ME, Parsons JP, Mastronarde JG. Sleep and Obstructive Lung Disease. Sleep Med Clin. 2008;3:505-515.
  42. Rosario IC. Obstructive sleep apnea: a review and update. Minn Med. 2011;94:44-48.
  43. Jung da W, Hwang SH, Lee YJ, et al. Apnea-hypopnea index estimation using quantitative analysis of sleep macrostructure. Physiol Meas. 2016;37:554-563.
  44. Owens RL, Malhotra A. Sleep-disordered breathing and COPD: the overlap syndrome. Respir Care. 2010; 55: 1333-1344.
  45. McNicholas WT. Chronic obstructive pulmonary disease and obstructive sleep apnoea-the overlap syndrome. J Thorac Dis. 2016;8:236-242.
  46. Rezaeetalab F, Rezaeitalab F, Dehestani V. Inhaled steroids reduce apnea-hypopnea index in overlap syndrome. Pneumologia. 2013;62:212.
  47. Hiestand  D, Phillips  B. The overlap syndrome :chronic obstructive pulmonary disease and obstructive sleep apnea.Crit Care Clin. 2008;3:551-563.
  48. Koren D, Chirinos JA, Katz LE, et al. Interrelationships between obesity, obstructive sleep apnea syndrome and cardiovascular risk in obese adolescents. Int J Obes (Lond). 2015;39:1086-1093.
  49. Lo Coco D, Mattaliano A, Lo Coco A, et al. Increased frequency of restless legs syndrome in chronic obstructive pulmonary disease patients. Sleep Med. 2009;10:572-576.
  50. Bianchi MT, Goparaju B, Moro M. Sleep apnea in patients reporting insomnia or restless legs symptoms. Acta Neurol Scand. 2016;133:61-67.
  51. Rezaeitalab F, Moharrari F, Saberi S, et al. The correlation of anxiety and depression with obstructive sleep apnea syndrome. J Res Med Sci. 2014;19:205-210.
  52. Yaggi HK, Mittleman MA, Bravata DM, et al. Reducing cardiovascular risk through treatment of obstructive sleep apnea:2 methodological approaches. Am Heart J. 2016;172:135-143.
  53. Lee SA, Paek JH, Han SH. Sleep hygiene and its association with daytime sleepiness, depressive symptoms, and quality of life in patients with mild obstructive sleep apnea. J Neurol Sci. 2015;359:445-449.
  54. Miller JN, Berger AM. Screening and assessment for obstructive sleep apnea in primary care. Sleep Med Rev. 2016;29:41-51.
  55. Franklin KA, Lindberg E. Obstructive sleep apnea is a common disorder in the population-a review on the epidemiology of sleep apnea. J Thorac Dis. 2015;7:1311-1322.
  56. Hostler JM, Hostler DC, Holley AB. Diagnosis of obstructive sleep apnea in adults. Ann Intern Med. 2015;162:455-456.
  57. Ghandeharioun H, Rezaeitalab F, Lotfi R. Accurate Estimation of Obstructive Sleep Apnea Severity Using Non-Polysomnographic Features For Home-Based Screening. Iran J Public Health. 2015;44:1433-1435.
  58. Epstein LJ, Kristo D, Strollo PJ Jr,  et al. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5:263-276.
  59. Jennum P, Riha RL. Epidemiology of sleep apnoea/hypopnoea syndrome and sleep-disordered breathing. Eur Respir J. 2009;33:907-914.
  60. Young T, Palta M, Dempsey J, et al. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ. 2009;108:246-249.
  61. Dempsey JA, Veasey SC, Morgan BJ, et al. Pathophysiology of sleep apnea. Physiol Rev. 2010;90:47-112.
  62. Boostani R, Rezaeitalab F, Pourmokhtari B, et al. Sleep apnea headaches. Rev Clin Med. 2016;3:1-3.
  63. Bingol Z, Pıhtılı A, Cagatay P, et al. Clinical predictors of obesity hypoventilation syndrome in obese subjects with obstructive sleep apnea. Respir Care. 2015;60:666-672.
  64. Koehler U, Buchholz C, Cassel W, et al. Daytime sleepiness in patients with obstructive sleep apnea and severe obesity: prevalence, predictors, and therapy. Wien Klin Wochenschr. 2014;126:619-625.
  65. Kuna ST, Reboussin DM, Borradaile KE, et al. Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes. Sleep. 2013;36:641-649A.
  66. Russell MB. Sleep apnea headache: a growing concern in an increasingly obese population? Expert Rev Neurother. 2013;13:1129-1133.
  67. Pereira H, Xará D, Mendonça J, et al. Patients with a high risk for obstructive sleep apnea syndrome: postoperative respiratory complications. Rev Port Pneumol. 2013;19:144-151.
  68. Subramanian S, Guntupalli B, Murugan T, et al. Gender and ethnic differences in prevalence of self-reported insomnia among patients with obstructive sleep apnea. Sleep Breath. 2011;15:711-715.
  69. Sateia MJ. International International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014;146:1387-1394.
  70. Ghandeharioun H, Rezaeitalab F, Lotfi R. Accurate methods for home-based diagnosis of obstructive. Rev Clin Med. 2016;3:8-12.
  71. Kabir A, Ifteqar S, Bhat A. Obstructive sleep apnea in adults. Hosp Pract (1995). 2013;41:57-65.
  72. Wang X, Ouyang Y, Wang Z, et al. Obstructive sleep apnea and risk of cardiovascular disease and all-cause mortality: a meta-analysis of prospective cohort studies. Int J Cardiol. 2013;169:207-214.
  73. Lavie P, Herer P, Lavie L. Mortality risk factors in sleep apnoea:a matched case-control study. J Sleep Res. 2007;16:128-134.
  74. Dewan NA, Nieto FJ, Somers VK. Intermittent hypoxemia and OSA: implications for comorbidities. Chest. 2015;147:266-274.
  75. Badran M, Ayas N, Laher I. Insights into obstructive sleep apnea research. Sleep Med. 2014;15:485-495.
  76. Marin JM, Soriano JB, Carrizo SJ, et al. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med. 2010;182:325-331.
  77. Szaulińska K, Pływaczewski R, Sikorska O, et al. Obstructive sleep apnea in severe mental   disorders. Psychiatr Pol. 2015;49:883-895.
  78. Xu S, Wan Y, Xu M, et al. The association between obstructive sleep   apnea and metabolic syndrome: a systematic review and meta-analysis. BMC Pulm Med. 2015;15:105.
  79. McNicholas WT, Verbraecken J, Marin JM. Sleep disorders in COPD :the forgotten dimension. Eur Respir Rev. 2013;22:365-375.
  80. Lee R, McNicholas WT. Obstructive sleep apnea in chronic obstructive pulmonary disease patients. Curr Opin Pulm Med. 2011;17:79-83.
  81. Nakayama H. Sleep-disordered breathing. Nihon Rinsho. 2013;71:286-290.
  82. Heatley EM, Harris M, Battersby M, et al. Obstructive sleep apnoea in adults: a common chronic condition in need of a comprehensive chronic condition management approach. Sleep Med Rev. 2013;17:349-355.
  83. Aoki T, Akinori E, Yogo Y, et al. Sleep disordered breathing in patients with  chronic  obstructive disease. COPD. 2005;2:243-252.
  84. Greenberg-Dotan S, Reuveni H, Tal A, et al. Increased prevalence of obstructive lung disease in patients with obstructive sleep apnea. Sleep Breath. 2014;18:69-75.
  85. Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology. 2013;18:421-431.
  86. Franklin KA, Lindberg E.  Obstructive sleep apnea is a common disorder in the population-a review on the epidemiology of sleep apnea. J Thorac Dis. 2015;7:1311-1322.
  87. López-Acevedo MN, Torres-Palacios A, Elena Ocasio-Tascón M, et al. Overlap syndrome:an indication for sleep studies? a pilot study. Sleep Breath. 2009;13:409-413.
  88. Pennestri MH, Montplaisir J, Fradette L,  et al. Blood pressure changes associated  with periodic leg movements during sleep in healing subjects. Sleep Med. 2013;14:555-561.