A Clinical Primer on Restless Legs Syndrome: What We Know, and What We Don’t Know

Characteristics and Epidemiology of RLS

Restless legs syndrome (RLS) is a sensorimotor disorder notable for its characteristic symptoms, including strong feelings of restlessness and distressing paresthesia-like sensations in the lower legs.¹ RLS typically manifests when the patient is at rest, and a state of relaxation or comfort is associated with a greater likelihood of symptom occurrence. Conversely, symptoms usually resolve when the patient initiates movement, and as symptoms arise, patients will experience an intense urge to begin moving in order to relieve the discomfort.¹ In addition, the symptoms have a circadian pattern and are worse in the evening. However, it must be emphasized that daytime symptoms that may require intervention may occur in up to 50% of patients.²

RLS is a common disorder; in the RLS Epidemiology, Symptoms, and Treatment (REST) study, 7.2% of US and European adults reported having experienced symptoms of RLS at some point during a 1-year period, and 5% reported experiencing symptoms on a weekly basis.³ Overall, RLS symptoms occur nearly twice as often in women compared with men: data from the REST study found that 9.0% of women and 5.4% of men had experienced RLS symptoms within the previous year. The gender difference increases when comparing the rates of symptoms experienced at least once per week. These more frequent symptoms were seen among 2.8% of men in the REST study versus 6.2% of women.³ Among the subgroup of persons with RLS who experienced symptoms at least twice a week (3.7% of women and 1.7% of men), 81% had sought treatment from a primary care physician at some time, and 61.3% had consulted a physician in the previous year.³ The prevalence of RLS in the pediatric population is somewhat lower, with approximately 2% of children between the ages of 8 and 17 years experiencing symptoms at least once a month, and 1.2% experiencing symptoms at least twice per week. Among pediatric patients, RLS is slightly more common in males than females overall (53.9% vs 46.1%), but the male preponderance is more striking when moderate-to-severe RLS (occurring at least twice a week) is measured (59.8% vs 40.2%).⁴

Etiology and Pathophysiology

RLS is delineated into primary and secondary forms. Primary RLS is, by definition, idiopathic, lacking comorbidities or physiologic context that can explain a patient’s symptoms.⁵ Patients with secondary RLS possess comorbidities or other recognizable causes—such as iron deficiency, medications, chronic renal failure, and iron deficiency anemia.^6,7 The pathophysiology of RLS is not fully understood. Dopaminergic dysfunction and brain iron deficiency have long been regarded as the key culprits in the pathophysiology of RLS.

Dopaminergic Dysfunction. The most persuasive argument in favor of dopaminergic dysfunction is the striking improvement in symptoms with dopaminergic drugs.⁸ However, the mechanism of this improvement has never been fully elucidated. Imaging of the nigrostriatal system has yielded conflicting results and the substantia nigra does not demonstrate cell loss at autopsy.^2,9 Most studies utilizing single-photon emission computed tomography (SPECT) scan to assess dopamine transporter density have shown normal results, but a recent positron emission tomography (PET) study showed a decreased number of dopamine transporters (DAT).¹⁰ The authors hypothesized that this was reflective of a decreased amount of membrane-bound DAT.¹⁰ However, this could also be a reflection of increased extracellular dopamine.

The number of D2/D3 receptors may be decreased in the mesolimbic areas as shown by raclopride binding.¹¹ Also, lesioning of the A11 area that gives rise to a dopaminergic pathway projecting to the spinal cord results in overactivity in mice.¹² However, an autopsy study did not show a dramatic cell loss in the A11 hypothalamic region of patients with RLS.¹³

Physiological studies have shown altered spinal excitability with decreased inhibition.¹⁴

Iron Deficiency. Iron deficiency has also been repeatedly shown to be associated with RLS. Several secondary causes of RLS (end-stage renal disease, iron deficiency, and pregnancy) are associated with problems maintaining adequate iron.¹⁵ In idiopathic RLS it is central nervous system (CNS) iron storage that may be impaired, while the systemic iron may be normal. The discordance between systemic and CNS iron is demonstrated by the observation that patients with hemochromatosis (iron overload disease) may develop RLS.¹⁶ Brain magnetic resonance imaging (MRI) studies of patients with RLS have demonstrated decreased iron in the midbrain, and a correlation between decreased brain iron and RLS severity has been demonstrated.¹⁷ An autopsy study found that H-ferritin was markedly reduced while L-ferritin was present but had a different morphology.⁹ In addition, another autopsy study found that iron regulatory protein (IRP) 1 levels were decreased in the brains of patients with RLS while IRP2 was upregulated.¹⁸

The mechanism by which iron deficiency leads to dopaminergic dysfunction is unclear. Iron has a complex effect on dopaminergic function. It is a cofactor for tyrosine hydroxylase and is integral to D2 receptor function.^9,15 However, iron deficiency does not lead to reduced dopamine levels. A study of rats deficient in iron showed an increase in extracellular dopamine.¹⁹