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Epidemiology of Restless Legs Syndrome

Ahmed Masood, Barbara Phillips

Prevalence Estimates
Restless legs syndrome (RLS) is a distinctive but often-misdiagnosed sensorimotor disorder.13 Persons with RLS often do not seek medical attention, even when their symptoms are troublesome or disabling. Furthermore, symptoms may be wrongly attributed by physicians to nervousness, insomnia, stress, muscle cramps, arthritis, or consequences of aging.4 Thus, poor recognition and frequent misdiagnosis have hampered epidemiologic studies of RLS. Early prevalence estimates of RLS were derived from clinical populations. Ekbom1 estimated that the prevalence of RLS in the general population was 5% based on a clinical review of 500 patients in his practice. On the other end of spectrum, Strang5 reported a prevalence of 2.5% in his investigation of 320 patients. More recent surveys of clinical populations have yielded much higher prevalence estimates of RLS. In a survey of outpatient veterans, 29% of 515 patients reported restless or crawling sensations in the legs at night.6 A subsequent study of Veterans Administration Hospital inpatients found that 21% of 222 consecutive inpatients endorsed symptoms of either restless legs or a combination of leg jerks and leg kicking or twitching during sleep, associated with a sleep complaint.7 Although motor restlessness and relief of symptoms by movements were not reported in these studies, they clearly raise the possibility that there may be a surprisingly high prevalence of this disorder. Although solid epidemiologic studies of large groups of people have not yet been published,
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several recent population-based surveys have lent insight into the prevalence of RLS in the general population.2 These data are somewhat difcult to interpret because diagnostic criteria differ from one study to another.8 In a 1994 Canadian survey by Lavigne and Montplaisir,9 15% of respondents reported leg restlessness at bedtime and 10% reported unpleasant leg muscle sensations associated with awakening during sleep and with the irresistible need to move or walk. This prevalence of RLS symptoms is double or triple that reported by Ekbom. In 1996, the Kentucky Behavioral Risk Factor Surveillance Survey (BRFSS) included a question regarding the present of RLS symptoms that was based on the four diagnostic criteria put forth by the International RLS study group.10,11 In this survey, 5.9% of more than 18,000 individuals surveyed reported experiencing RLS symptoms very often and another 4.1% reported experiencing symptoms often, for a total of 10%. This is remarkably similar to Lavignes estimate. Countrywide United States questionnaire studies conducted between 1995 and 1999 by the National Sleep Foundation found a similar range (10% to 15%) of adults complaining of restless legs related symptoms.1214 In more recent studies, similar prevalence levels have been found. A study of working age women in Sweden (aged 18 to 64 years) found that 11.4% of these young to middleaged adults reported symptoms of RLS that matched the IRLSSG diagnostic criteria,15 and a similar study among working-age men found a prevalence of 5.8%.16 In Chile, a Southern cone country with a predominant European population base, 13% of the relatives of hospital outpatients were found to meet diagnostic criteria for RLS.17

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Thus, prevalence estimates of RLS vary more than 10-fold, from 2.5% to more than 25%. Some of this difference is due to the varying populations investigated, some results from the difference between identifying RLS in clinical versus community populations, and some results from inadequate measurement tools (survey questions and clinical skills). The high end of prevalence estimates is based on the Canadian9 and Kentucky10,18 surveys that were population-based and did not include examination of patients. The low end estimates1,5 were based on clinical populations that did undergo physical examinations. So far, only one study16 has included population-based patients who were clinically examined. Because many people with RLS do not complain or seek medical advice, careful population-based estimates, such as that done by the Canadian or Swedish groups, are probably closest to the truth.

Age Effects
RLS is often considered to be a condition of middle to older age, because symptoms typically do not become troublesome until later in life.20 The Kentucky, Canadian, and Swedish surveys all found an increasing prevalence with age9,10,16 However, in a study of 133 patients with cliniciandiagnosed RLS, mean age at onset was found to be 27.2 years; symptom onset occurred before age 20 in 38.3% of patients.21 Clearly, RLS can occur in childhood and adolescence and may be more common than heretofore recognized.22 In some instances, it can be severe in children.22 When medical attention is sought at an early age, the diagnosis may be missed and the symptoms thought to be psychologically induced or attributed to growing pains or to attention decit hyperactivity disorder (ADHD).23 In fact, sleep disruption associated with periodic limb movement disorder (PLMD) and the motor restlessness of RLS while awake may contribute to the inattention and hyperactivity seen in subgroups of ADHD-diagnosed children.23

Genetics
Clinicians and patients with RLS have long noted that the disorder is often found in rst-degree relatives of aficted individuals.8,20,21,24 In one series, one or more rst-degree relatives were affected with RLS in at least 50% of cases.20 Because

of the high prevalence of RLS in offspring of RLS patients and the equal distribution of the syndrome in both genders, it is possible that RLS inheritance follows an autosomal dominant pattern.5,20,25.26 In a more recent survey of 300 families, the Munich group has found that patients with idiopathic RLS often have a positive family history (42.3% denite, 12.6% possible) compared with those with secondary RLS resulting from uremia.27 Patients with a positive family history were more likely to have a younger age of onset. An analysis of these families has found that a model of dominant inheritance best t the distribution of affected relatives in families in which individuals had an average age of onset of 30 or less.27a A family history study from Johns Hopkins using a validated telephone diagnostic interview to ascertain rst- and second-degree relatives found that there was an affected rstdegree relative in 18 of the 21 rst families completed (86%).28 Several studies have suggested that idiopathic RLS patients are more likely to have affected rstdegree relatives than secondary RLS patients, whether the secondary disorder is due to uremia27 or of peripheral neuropathy.29 More recently, the Hopkins group has suggested that there are likely to be two populations of RLS patients producing a bimodal age of onset distribution.30 Familial RLS has an earlier age of onset than secondary or acquired RLS. There are also biologic differences between the patient groups; familial RLS patients are more likely to have elevated hypocretin levels in the cerebrospinal uid, whereas the later onset, presumably secondary group, shows a greater relation of severity to serum ferritin levels (a marker of iron storage). There can be variable expressivity of the clinical features in familial RLS, and there are probably some relatively nonrestless patients with prominent periodic movements in sleep who are carriers of the RLS gene.31 Genetic studies, underway for more than a decade, have nally begun to yield candidate genetic loci. A search for candidate genes, focusing particularly on those involved in the dopamine system, has not yielded clear genetic markers.31a A major advance, however, is a linkage found using found using a recessive inheritance model in a French Canadian family.31b French Canadians have a high prevalence of RLS,9 and the disorder appears to be derived from only a restricted number of French

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immigrants. These factors may facilitate genetic analysis. In any case, this particular linkage is unlikely to provide an answer for all hereditary RLS.

Pregnancy
RLS often occurs initially or is exacerbated during pregnancy.2,32 Ekboms33 early nding of an 11% prevalence rate during pregnancy has been supported by subsequent reports showing rates of RLS ranging from 11% to 33%.2 Goodman, Brodie, and Ayida34 found that 97 of 500 women (19%) with singleton pregnancies had RLS. In 16 of these cases, the RLS symptoms antedated the pregnancies, and in 5 of those 16, the symptoms became much worse during the third trimester but returned to baseline postpartum. In a related study that looked at limb movements but did not report RLS symptoms, the presence of periodic limb movements was almost universal in pregnancy.35 The cause of increased incidence of RLS in pregnancy has been hypothesized to be related to anemia, hormonal changes, and vascular congestion.2 Botez3639 has described the correlation between the presence of RLS and folate deciency, with particular emphasis on pregnancy. In a recent report, Lee, Zaffke, and Baratte-Beebe40 found that pregnant women with initial low ferritin levels (a measure of iron stores) were more likely to develop RLS, although the critical value during the period of symptoms (third trimester) were the serum folate levels.

Association with Other Medical Conditions

In 1996, Callaghan41 described ve cases of uremia and RLS. RLS is more common in patients with end-stage renal disease than in the general population, and RLS occurs both before and after the institution of dialysis treatment.2,41,42 Prevalence rates have been described to be from 17% to 42% among this patient group.2,42a,43,44 Signicantly increased risk for mortality was observed in dialysis patients with RLS at a 2.5 year follow-up.45 A study investigating a possible relationship between RLS and anemia in hemodialysis patients has been described in which symptoms improved with the correction of anemia with epoetin alpha in uremic patients.44

RLS symptoms have also been linked to increased levels of urea and creatinine,46 peripheral neuropathy,43 and decreased levels of intact parathyroid hormone.47 In 1960 Ekbom33 noted iron deciency in 25% of patients with RLS. Iron deciency was found in a third of older patients with RLS in one study.48 Iron deciency, with or without anemia, is an important contributor to the development of RLS in older patients, and iron supplements can produce a signicant reduction in symptoms.49,50 Serum ferritin levels were inversely correlated with the severity of RLS symptom,50 and patients appear to have fewer symptoms if they have ferritin levels greater than 50 mg/L.51 In a series of 154 patients with clinical and electrical evidence of polyneuropathy, 8 (5.2%) had symptoms of RLS.52 Idiopathic RLS patients have a higher rate of positive family history than do those with neuropathic RLS (92% vs. 13.3%). Clinical characteristics, however, were similar across the group, except for an older age at onset and more rapid progression in sporadic/ neuropathic patients than in familial/idiopathic patients.31 RLS is a frequent and treatable cause of disabling sleep disturbance in spinocerebellar ataxia type 3 (SCA 3). RLS was rarely observed in patients with genetically different types of autosomal dominant cerebellar ataxias, such as SCA 1, SCA 2, or SCA 6. It appears that expanded CAG repeat (mutation) is a causative factor in the genesis of RLS in SCA 3 patients.53 The coexistence of Charcot-Marie-Tooth (CMT) neuropathy and RLS has been investigated in a series of 44 patients. RLS was present in 10 of 27 CMT 2 patients (37%) and in none of CMT 1 patients. The meaning of the association of CMT 2 and RLS is unclear. Axonal atrophy seems to represent a signicant nerve ber change in RLS, as demonstrated in patients with apparently idiopathic RLS. This may explain the high rate of occurrence of RLS in CMT 2, which is characterized by prominent axonal atrophy, compared with that in CMT 1.54 RLS symptoms were more frequent in rheumatoid arthritis (RA) patients (25%) than in nonRA controls with osteoarthritis or seronegative arthropathy (4%). RA disease severity and current disease activity were greater in patients with RLS than in RA patients unaffected by RLS.55

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Association with Lifestyle

In the Canadian study, there was no difference between smokers and nonsmokers for RLS prevalence.56 In a more recent study, a positive association was found between cigarette smoking and RLS for those individuals smoking at least one pack per day but not for lighter smokers.10 We hypothesized that there is a dose response relationship between cigarette smoking and RLS.18 In the same population-based study, RLS symptoms also appeared to be inversely associated with the level of exercise activity and with socioeconomic status. Furthermore, alcohol abstinence was more likely to be reported by individuals who endorsed RLS symptoms.

Conclusion
RLS may affect 2.5% to 15% of the population in varying degrees of severity. Prevalence appears to increase with age, although children can be aficted. It appears likely that some cases of RLS have a genetic basis and progress has been made through nding at least one genetic linkage. Pregnancy, renal failure, iron deciency, and RA are associated with an increased prevalence of RLS. Acknowledgment Supported by Grant K07 HL 03637-03 from the National Heart, Lung, and Blood Institute.
REFERENCES 1. Ekbom KA: Restless legs: A clinical study. Acta Med Scand Suppl 158:1, 1945. 2. RLS Medical Bulletin. Rochester, MN, Restless Leg Syndrome Foundation, 1999, p 1. 3. Shaun T, OKeefe ST: Restless legs syndrome. Arch Intern Med 156:243, 1996. 4. Chokroverty S, Jankovic J: Restless legs syndrome; a disease in search of identity. Neurology 52:907, 1999. 5. Strang RR: The symptoms of RLS. Med J Aust 1:1211, 1967. 6. Obler SK: Leg symptoms in outpatient veterans. West J Med 155:256, 1991. 7. Meissner H, Riemer A, Santiago SM, et al: Failure of physician documentation of sleep complaints in hospitalized patients. West J Med 169:146, 1998. 8. Wetter TC, Pollmacher T: Restless leg and periodic leg movements in sleep syndromes. J Neurol 244(Suppl 1):S37, 1997. 9. Lavigne GJ, Montplaisir JY: Restless legs syndrome and sleep bruxism: Prevalence and association among Canadians. Sleep 17:739, 1994. 10. Purvis C, Phillips B, Asher K, et al: The 1996 Kentucky behavioral risk factor surveillance survey. Sleep Res 26:474, 1997 (abstr). 11. Walters AS: Towards a better denition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord 10:634, 1995. 12. National Sleep Foundation: Sleep in America 1995. National Sleep Foundation Gallup Poll. Washington DC, National Sleep Foundation, 1995. 13. Johnson E: 1998 Omnibus Sleep in America Poll. Washington DC, National Sleep Foundation, 1998, p 89, 4143. 14. Johnson E: 1999 Omnibus Sleep in America Poll. Washington DC, National Sleep Foundation 1999. 15. Ulfberg J, Nystrm B, Carter N, Edling C: Restless legs syndrome among working-aged women. Eur Neurol 46:17, 2001.

Gender and Race

Most published studies indicate that RLS appears to affect both genders approximately equally,2,9,10 although women have had slightly higher prevalences. However, in a study of older Germans (ages 65 to 83 years), there appeared to be a higher prevalence in women.19 This same female preponderance has been found in studies of RLS in working-age (18 to 64 years old) women (11.4%)15 and men (5.8%)16 in Sweden. Only recently have there been studies in populations that are not derived primarily from European ethnic groups. Two recent studies from the Orient suggest a lower prevalence of RLS in Japan and Singapore, perhaps less than 1%.57,58 In contrast, one study of secondary RLS (induced by kidney failure) in China found that 62% of peritoneal dialysis patients had RLS.42a Nevertheless, there is not yet enough data about racial or ethnic differences to draw any rm conclusions at present.

Remission
RLS symptoms usually persist and may become more severe over time. However, some patients experience spontaneous remissions during which symptoms decrease signicantly or disappear for a period. This may be related to lifestyle, stress, or diet.2 Reversal of iron deciency has resulted in relief from RLS symptoms. RLS symptoms may worsen during pregnancy and improve after delivery of the child.34,49,50

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Botez MI: Folate deciency and neurological disorders in adults. Med Hypothesis 2:135, 1976. 39. Botez MI: Folate responsive neurological and mental disorders: Report of 16 cases. Neuropsychological correlates of computerized transaxial tomography and radionuclide cisternography in folic acid deciencies. Eur Neurol 16:230, 1977. 40. Lee KA, Zaffke ME, Baratte-Beebe K: Restless legs syndrome and sleep disturbance during pregnancy: The role of folate and iron. J Womens Health Gend Based Med 10:335, 2001. 41. Callaghan N: Restless legs syndrome in uremic neuropathy. Neurology 16:359, 1966. 42. Stepanski E, Faber M, Zorick F, et al: Sleep disorders in patients on continuous peritoneal dialysis. J Am Soc Nephrol 6:192, 1995. 42a. Hui DS, Wong TY, Ko FW, et al: Prevalence of sleep disturbances in Chinese patients with endstage renal failure on continuous ambulatory peritoneal dialysis. Am J Kid Dis 36(4):783, 2000. 43. 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