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Restless legs syndrome (RLS) is characterized by a compelling, often insatiable, need to move the legs, accompanied by unpleasant sensations located mainly in the ankles and calves. Because symptoms are brought on by inactivity, distress intrudes upon everyday activities such as air travel, car rides, attending school, meetings, or the theatre, and sleep. The first comprehensive description of RLS in 1945 by Ekbom noted its key features: (1) a prevalence of at least 5%; (2) a diurnal preference for the evening and night; (3) a subpopulation with pain; (4) a proclivity to affect pregnant women; (5) heritability; and (6) a favorable response to iron supplementation. A second advance came with recognition that periodic limb movements in sleep (PLMs) are present in the anterior tibialis muscles of the legs in 85–95% of RLS subjects. Coincident with PLMs are elevations of heart rate and blood pressure, and peripheral vasoconstriction that are increasingly viewed as causal to cardio- and cerebrovascular morbidity. A third major advance has come with demonstration that pharmacologic agents acting at D2 and D3dopamine receptors relieve both the sensory (RLS) and motor (PLMs) symptoms. A fourth advance has been demonstration of brain iron reductions in a subpopulation of RLS cases. The fifth seminal advance has been the identification of five genetic loci in four genes that account for a majority of the population attributable risk of RLS.

RLS is conventionally defined by a symptom complex that includes (1) an intense urge to move the legs that is often uncomfortable or painful; (2) a worsening at rest; (3) relief with movement; and (4) a circadian preference to emerge in the evening and at night.1 Variability in symptom expressivity is the rule rather than exception.25 Symptoms begin as mild and infrequent and slowly progress, thereby delaying most diagnoses until the fourth to sixth decades of life. RLS prevalence in populations of European descent ranges from 3–15%.612 “Clinically significant” RLS, that is, symptoms that are deemed frequent or severe enough to require treatment, is less common, occurring in about 1.6% to 2.8% of these populations.7,8,13

Symptoms of RLS and PLMs exhibit a genuine circadian pattern,1418 and are influenced by age, sex, pregnancy, genetic factors, and common medical conditions. RLS affects 2% of school-aged children,1920 3% of 30 year-olds, and 20% aged 80 and older.10 Women are affected more often than men are in a roughly 2:1 ratio, and exhibit greater night-to-night variability in PLMs.21 Nearly one-in-three pregnant women experience RLS in their third trimester2223 and the risk of RLS increases linearly with the number of live births (OR = 3.57 for >3 births).24 Familial aggregation of RLS is well documented,25 and the proportion of phenotypic variation attributable to genes, that is, heritability, is 54–83%.2629 Prevalence in non-European ethnic groups are notably low: ...

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