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Patients With RLS Often Describe the Following Symptoms:
  • Burning3
  • Creeping3
  • Crawling3
  • Tingling4
  • Tugging5

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Clinical Overview Epidemiology   Etiology   Morbidity

Etiology

Primary or idiopathic RLS

Primary RLS is a central nervous system disorder. While little is known about the pathophysiology of RLS, familial involvement is estimated in over 50% of idiopathic RLS cases.10,11 Recent familial aggregation studies indicate an autosomal dominant mode of inheritance with major susceptibility loci on chromosomes 9p and 12q.10,11

It is hypothesized that dopaminergic system dysfunction contributes to this condition.12 A study using positron emission tomography to measure nigostriatal terminal dopamine storage demonstrated a 13% reduction of mean caudate and putamen D2 receptor binding, as well as a reduction in dopamine uptake compared to control.12 Plasma dopamine levels are lowest at night, when RLS symptoms are most intense.12 This postsynaptic dopaminergic dysfunction could partially explain the long-term efficacy of dopaminergic agents in RLS treatment.12,13

Secondary RLS

Sometimes restless legs syndrome symptoms can occur due to an underlying condition. Successful treatment of the underlying condition may relieve this category of RLS symptoms.3

Causes:

  • Iron deficiency
    Restless legs syndrome can be associated with iron deficiency at sub-anemic levels.14 Serum ferritin levels less than 50 µg/L have been associated with more severe RLS symptoms.5 Like dopamine, serum iron concentrations are lowest at night, when RLS symptoms are exacerbated, decreasing up to 50% from daytime levels.7 A recent study demonstrated decreased ferritin, ferroportin, and transferrin receptor in neuromelanin cells from the substantia nigra, suggesting a basis for cellular iron deficiency in RLS.15
  • Hemodialysis/Uremia
    Studies report that up to 50% of patients with end-stage renal disease also suffer from RLS.5,14 While hemodialysis has no impact on RLS, an improvement in RLS symptoms has been reported after renal transplantation.5,16
  • Neurologic lesions
    Spinal cord and peripheral nerve lesions, as well as vertebral disc disease have been associated with RLS.5
  • Drug treatment
    The use of medications such as dopamine receptor antagonists, certain neuroleptics (risperidone, olanzapine), histamine-receptor antagonists, beta-blockers, tricyclic antidepressant drugs, some anticonvulsants (lithium, zonisamide), and selective serotonin reuptake inhibitors can initiate or aggravate RLS symptoms.5,17,18
  • Pregnancy
    The prevalence of RLS symptoms during pregnancy is estimated at 19% to 23%.18 Studies have associated reduced serum folate levels in pregnant women experiencing RLS symptoms.16 In most cases, RLS symptoms subside after delivery.18