Abstract
Objective: To assess the prevalence and severity of restless legs syndrome (RLS) in the general community and to investigate its potential relationship with iron metabolism and other potential risk factors.
Methods: This was a cross-sectional study of a sex- and age-stratified random sample of the general population (50 to 89 years; n = 701). The diagnosis of RLS was established by face-to-face interviews; severity was graded on the RLS severity scale. Each subject underwent a thorough clinical examination and extensive laboratory testing.
Results: The prevalence of RLS was 10.6% (14.2% in women, 6.6% in men); 33.8% of all patients with RLS had mild, 44.6% had moderate, and 21.6% had severe disease expression. None had been previously diagnosed or was on dopaminergic therapy. Free serum iron, transferrin, and ferritin concentrations were similar in subjects with and without RLS. However, soluble transferrin receptor (sTR) concentrations were different in subjects with and without RLS (1.48 vs 1.34 mg/L; p < 0.001). Female sex and high sTR independently predicted the risk of RLS.
Conclusion: This large survey confirms the high prevalence, female preponderance, and underrecognition of restless legs syndrome in the general community. Although two-thirds of patients had moderate to severe disease, none was on current dopaminergic therapy.
In various adult white populations of Europe and the United States, remarkably similar prevalence rates of restless legs syndrome (RLS) of approximately 10% have been reported.1–6 There are only few studies from other geographic regions that indicate much lower frequencies of RLS in Singapore7 (<1%) and Turkey8 (3.2%). Prevalence estimates exceeding 10%9–11 have been attributed to sample selections or the application of less stringent diagnostic criteria. In contrast to the crude prevalence of RLS, the distribution of disease severity in the general population has not been investigated systematically. Although the negative impact of RLS on life quality is beyond doubt, it was proposed that only one-fourth of patients with RLS12 or 3% of the population presenting to a primary care physician13 may require drug therapy.
In this study, we investigated both the prevalence and severity of RLS in a large sample of the general population (Bruneck study) and assessed its association with parameters of iron metabolism and other potential risk factors.
Methods.
Survey area and study participants.
The survey area was Bruneck, a small city located in an Alpine region of northern Italy (South Tyrol) with an entirely white population. The genetic background was heterogeneous with sizable segments of the population having either northern Italian or Austro-German background. The Bruneck study is an ongoing prospective evaluation of the epidemiology of atherosclerosis and disorders of the brain and bone.14–18 It was launched in 1990 and has regular follow-up examinations every 5 years. The study population was recruited as a sex- and age-stratified random sample of all inhabitants aged 40 to 79 years such that 125 men and 125 women of each age decade were selected for inclusion.14 At the 1990 baseline, 936 (of the targeted 1,000) individuals participated. Data for the present study were collected as part of the 2000 follow-up examination when subjects were 50 to 89 years old. Between 1990 and 2000, 168 participants in the initial sample had died. A total of 701 of the remaining 768 persons participated in the 2000 follow-up, corresponding with a participation rate of approximately 92%.
Data acquisition and diagnostic procedures.
All clinical examinations of the Bruneck study cohort were performed over an 8-week period (Monday to Saturday, 8 am to 6 pm) according to a standardized protocol. The diagnosis of RLS was established based on the four minimal criteria of the International RLS Study Group as originally described in 1995.19 The same four questions, which strictly adhere to the wording of the minimal criteria, were posed to each study subject by the same investigator, a neurology resident experienced in sleep disorders (M.S.): 1) Did you experience a desire to move your legs associated with unpleasant sensations like crawling, paresthesias, and pain? 2) Did you sometimes notice motor restlessness? 3) Do symptoms occur or worsen at rest or during inactivity, and does moving improve them? 4) Are symptoms more pronounced in the evening or at night compared with the morning. All four responses had to be yes for the diagnosis of RLS to be established. The revised minimal criteria for RLS20, which were used in some recent evaluations and provide predefined questions, were not available in 2000 when our study was conducted.
In each patient with RLS, the International RLS Study Group Severity Scale score for RLS, termed the International RLS Severity Scale,21 was recorded. The RLS assessments were part of a standardized 20-minute interview on lifestyle behaviors and sleep disorders.
Each subject underwent a thorough neurologic examination done by experienced senior neurologists (A.G., G.R.). The diagnosis of polyneuropathy was established on clinical grounds and substantiated by EMG and nerve conduction studies in a majority of subjects (>90%).
Vascular risk factors and lifestyle behaviors were assessed by standard methods as extensively described previously.14–16,18 In brief, systolic and diastolic blood pressures were calculated as means of three independent measurements, each taken in the supine position after at least 10 minutes of rest. Hypertension was defined as a blood pressure ≥140/90 or the use of antihypertensive drugs. The average number of cigarettes smoked per day was noted for each smoker. Diabetes was diagnosed according to the American Diabetes Association criteria. The body mass index was computed as weight divided by the height squared. Physical activity was quantified by the Baecke score (indexes for leisure and sports activity).22
Blood samples were all drawn in the morning between 7:30 and 9:30 am after an overnight fast and 12-hour abstinence from smoking. Laboratory parameters including variables of iron metabolism, renal and hepatic function, markers of inflammation, endocrine function, and vitamins were measured by standard techniques.15,23 In particular, serum ferritin was assessed with a fluorometric enzyme immunoassay on a Stratus II Fluorometric Analyzer (Baxter Diagnostic Inc.) and the soluble transferrin receptor (sTR) with a nephelometric immunoassay (Dade Behring GmbH, Marburg, Germany). The concentration of sTR reflects the total body mass of cellular transferrin receptor.24 An increase of sTR is considered to be the initial response to declining body iron supply. Therefore, sTR is considered a measure of intracellular iron availability. According the upper limit of normal provided by the manufacturer, sTR levels exceeding 1.76 mg/L were regarded as high sTR concentrations. Anemia was defined as a hemoglobin level <140 g/L in men and <120 g/L in women. Renal insufficiency was coded present in the case of creatinine levels exceeding 114.4 μmol/L. The cutoff value for vitamin B12 was 148 pmol/L, and for folic acid deficiency, it was 5 nmol/L.
Statistics.
Prevalence rates were calculated by standard methods and directly standardized to the age and sex structure of the general community in Bruneck using 10-year categories.25,26 Of note, crude and standardized rates were very similar because after 10 years of follow-up, the age and sex structure of the study population (see above) had approximated that of the general community in Bruneck. Differences between proportions were calculated with the χ2 and Fisher exact test as appropriate (table 1) and a test for trend (table 2). Analysis of variance was performed to compare scores on lifestyle and laboratory variables between subjects with and without RLS while simultaneously controlling for age and sex (table 3). Variables with a skewed distribution including sTR were loge-transformed to satisfy the assumption of normality and constant variance of the residuals. Dichotomous variables were analyzed with age- and sex-adjusted logistic regression analyses. A two-sided p value of <0.05 was considered significant except for table 3, in which a Bonferroni adjustment was performed to account for the multiple (in all 33) comparisons performed, and a p value of <0.0015 was considered significant. Finally, a multivariable risk model of RLS was built by means of logistic regression analysis. Variables were selected for inclusion from all those listed in tables 1 and 3 applying standard inclusion and exclusion criteria (forward stepwise selection). The test procedure was based on the maximum likelihood estimator.27
Table 1 Severity of RLS according to the International RLS Rating Scale
Table 2 Sex- and age-specific prevalences of RLS
Table 3 Potential causes of RLS
Results.
Prevalence and severity of RLS.
The prevalence of RLS was high at 10.6% (95% CI 8.3% to 12.9%) in this population aged 50 to 89 years. The rate standardized to the age and sex distribution of the Bruneck population was nearly identical at 11.0% (8.6% to 13.4%). RLS was more than twice as frequent in women compared with men. Of 366 women, 52 satisfied the diagnostic criteria of RLS (14.2% [10.6% to 17.8%]) as opposed to 22 of 335 men (6.6% [4.0% to 9.2%]) (p < 0.001 for difference). Population-standardized rates were 14.3% (10.7% to 17.9%) for women and 7.0% (4.1% to 9.9%) for men. There was no effect of age on RLS frequency (table 2). The modest drop in the RLS rate among men in the highest decade (80 to 89 years) is explained by the comparatively low number of subjects in this group (n = 35) and fell short of significance. The distribution of RLS severity among individuals affected is shown in table 1. Two-thirds of subjects showed moderate to severe degrees of RLS severity corresponding with absolute frequencies of 3.6% (mild), 4.7% (moderate), and 2.3% (severe) in the general population. None of the 74 patients with RLS was on a first-line RLS therapy with dopaminergic drugs.
Secondary RLS.
Overall, potential causes of symptomatic RLS-like peripheral neuropathy, anemia, renal insufficiency, and vitamin B12 and folic acid deficiency were rare in this central European community (table 3). None of these conditions was more frequent in the patients with RLS, and mean levels of vitamin B12, folic acid, and creatinine were identical in subjects with and without RLS (table 4).
Table 4 Characterization of subjects with and without RLS
Risk factor associations.
Levels of hemoglobin, free serum iron, transferrin, and ferritin did not differ between subjects with and without RLS. In line, the proportions of subjects with ferritin and transferrin levels at the low end of distribution (bottom quintile) were similar in patients with RLS and those without (16.2% vs 20.4% and 20.3% vs 19.3%, p value for difference >0.05 each). However, the concentration of sTR was elevated in individuals with RLS (p < 0.001), and this finding held true after accounting for the multiple comparisons performed. The association was particularly strong in men (age-adjusted geometric mean sTR 1.47 vs 1.27 mg/L in subjects with and without RLS; p = 0.001) and somewhat less pronounced in women (age-adjusted geometric mean sTR 1.42 vs 1.34 mg/L in subjects with and without RLS; p = 0.086), even though from a statistical view point sex was not a significant effect modifier. The percentage of high sTR was also increased in patients with RLS (15.3% vs 6.2%; p = 0.004). In men, high sTR was found in 22.7% of patients with RLS and 3.8% of nonaffected individuals and vice versa, 29.5% of men with high sTR actually had RLS. In women, high sTR was found in 13.5% of patients with RLS and in 8.3% of the nonaffected group. Twenty-one percent of women with high sTR had RLS. Finally, age- and sex-adjusted geometric means of sTR gradually increased across severity categories of RLS (no [1.31], mild [1.39], moderate [1.43], and severe [1.45] RLS; p value for linear trend <0.001).
No significant differences between subjects with and without RLS were observed regarding all other lifestyle and laboratory variables assessed in this study. This includes vascular risk factors, hormone and vitamin levels, hepatic and renal function tests, smoking habits, measures of body composition like the body mass index, and physical inactivity. All the following types of medication were distributed equally among subjects with and without RLS: statins, hormone replacement therapy, aspirin, anticoagulants, digitoxin, angiotensin-converting enzyme inhibitors, diuretics, β-inhibitors, calcium antagonists, theophylline, β-mimetics, corticosteroids, nonsteroidal antirheumatics, iron supplements, neuroleptics, antidepressant drugs, H2-blockers, and antiepileptic drugs. Benzodiazepines were taken on a regular basis by 14.9% of patients with RLS as compared with 9.9% of subjects without RLS. This difference was not significant.
In a stepwise logistic regression analysis allowing for all variables listed in tables 1 and 3, only female sex (OR 2.2 [1.3 to 3.7] p = 0.004) and loge-transformed sTR (OR 1.4 [1.1 to 1.8] for a 1-SD unit increase in loge-transformed sTR, p = 0.002) emerged as significant and independent risk predictors of RLS.
Discussion.
The prevalence of RLS of 10.6% with a 2:1 female-to-male ratio in this random sample of the general community aged 50 to 89 years is in accordance with epidemiologic findings in various white populations in Germany,1 Sweden,2,3 and other regions.4–6,8 Age trends of RLS rates in middle-aged and elderly populations have been less consistent in previous evaluations. Although the majority of studies reported increasing rates, some suggested stable rates and one even a decline of RLS frequency in the older elderly.1 Increasing comorbidity in the very old (e.g., dementia, stroke), however, may interfere with an accurate identification of RLS and lead to an underestimation of the true prevalence. Our findings suggest that RLS prevalence does not substantially change in the general community aged 50 and older. To our knowledge, this is the first study to provide data on RLS severity in the general population using a validated scale of RLS symptom severity.21 Sixty-six percent of cases and 7.0% of the entire population had moderate or severe RLS, which convincingly underscores the substantial burden of RLS in populations of the Western hemisphere. Nevertheless, none of the patients with RLS in our survey had received first-line treatment of RLS with dopaminergic agents. This is in agreement with previous studies reporting marked underrecognition and undertreatment of RLS in the community.1,28 Potential causes of secondary RLS such as anemia, renal insufficiency, peripheral neuropathy, and vitamin B12 or folic acid deficiency were found in 9.5% of patients with RLS, but a causal relationship was difficult to establish in most of these cases. Overall, these potential causes occurred at similar frequencies in subjects with and without RLS, and the great majority of patients in the community seem to have idiopathic RLS. Symptomatic RLS has minor if any relevance in the general community.
An intriguing yet unproven concept of RLS etiology is in relation to brain iron deficiency. Decreased iron concentrations in the substantia nigra and nucleus ruber have been suggested in an MRI study of patients with RLS,29 and immunocytochemical autopsy studies have also produced evidence of impaired iron metabolism in neuromelanin cells of the substantia nigra.30,31 In addition, decreased levels of ferritin and increased transferrin levels were found in the CSF of patients with RLS.32 Very recently, a study on the expression of iron-handling proteins in neuromelanin cells found decreased levels of ferritin, ferroportin, and divalent metal transporter 1, a pattern consistent with intracellular iron deficiency. The finding of a significant association between high sTR concentrations, a sensitive marker of incipient systemic iron deficiency, and RLS in the Bruneck study lends the first epidemiologic support to the iron deficiency hypothesis. Our results, however, do not allow us to infer causality and are inconsistent with previous findings in a smaller population sample from Germany (n = 365).28 Several previous population studies attempted to identify further risk factors for RLS and have yielded highly variable results. Some studies reported associations with hypertension, physical inactivity, obesity, diabetes, and smoking, but none of these variables were consistently related to RLS in a majority of surveys.1–11 The Bruneck study, which has contributed important findings to epidemiologic atherosclerosis research14–16 and offers a high-quality assessment of all these potential risk factors, failed to identify significant associations other than female sex and high sTR.
Footnotes
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The Bruneck Study was supported by Pustertaler Verein zur Prävention von Herz- und Hirngefaesserkrankungen, Sanitaetseinheit Ost, and Assessorat fuer Gesundheit, Province of Bolzano, Italy.
Received December 21, 2004. Accepted in final form March 2, 2005.
References
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