Restless legs syndrome

The restless legs syndrome (RLS, also known as Ekbom's syndrome) (1) is a common sensorimotor disorder - the adult prevalence figures for this syndrome are between 5 and 29 per cent (2)

Patients complain of unpleasant sensations experienced predominantly in the legs and rarely in the arms. The symptoms occur only at rest and become more pronounced in the evening or at night.

There is often a strong urge to move the limbs, resulting in only temporary relief of symptoms. The disorder is characterised by periodic leg movements during sleep. These movements may interfere with sleep.

The disorder is associated with a condition known as periodic leg movements during sleep (PLMS). Around 80% of the patients with RLS have PLMS (although less than 50% of PLMS patients have RLS) (3). These movements may interfere with sleep and patients may present with complains of insomnia or fatigue as initial symptoms (1).

The underlying pathophysiology of RLS is not fully recognized. It appears to be associated with

• abnormalities of the dopaminergic neurons
• reduced iron stores specially in the brain (4)

Large-scale study groups in Europe and the US have identified several factors which are associated with RLS:

• high body-mass index
• lower income
• smoking
• lack of exercise
• low alcohol consumption
• diabetes mellitus (5)

Note that dopamine agonists are no longer used as first-line treatment for RLS, because the of complications associated (6,7):

• augmentation (suggested by a worsening of RLS accompanied by the need to increase the dose of dopamine agonist) (7)
  • augmentation refers to a drug-induced paradoxical worsening of RLS symptoms, often presenting as an earlier onset of symptoms in the day, increased symptom severity, or spread to other body parts
  • risk of augmentation increases with higher doses (>0.5 mg/day for pramipexole or >4 mg/day for ropinirole), prolonged use, and evening or multiple daily dosing
  • 10-year cumulative incidence of augmentation with dopamine agonists has been reported to exceed 60% in some cohorts
• risk of developing impulse control disorder (ICD)
  • recognized ICDs in this setting include pathologic gambling, hypersexuality, compulsive eating, compulsive shopping and compulsive medication use
  • dopamine agonists used in RLS have high selective affinity for the D2/D3 receptor subtypes, which are expressed predominantly in the brain limbic areas, regions that are implicated in addiction and ICDs
    • unclear why some RLS patients develop these complications while others do not
  • prevalence estimates for ICDs and/or addictive behaviors ranging from 5-17% (8,9)
    • however Heim B et al noted, albeit via a retrospective case-control study, that patients with RLS with augmentation with dopamine agonist therapy have an almost 6-fold increased risk of exhibiting ICD symptoms (10)
    • dopamine agonist dose does not correlate with the incidence of ICDs in RLS patients (10)

Reference:

• (1) Earley C.J. Restless legs syndrome. NEJM 2003;348:2103-210.
• (2) Prescriber (2003), 14 (18).
• (3) Bayard M et al. Restless legs syndrome. AFP 2008;78(2)
• (4) Merlino G. et al. Restless legs syndrome: differential diagnosis and management with rotigotine. Neuropsychiatr Dis Treat. 2009;5:67–80
• (5) RLS-UK/Ekbom Syndrome Association. What is Restless legs syndrome?
• (6) Winkelman JW et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025 Jan 1;21(1):137-152.
• (7) Xu Y, Guan Y, Lang B. Unraveling Restless Legs Syndrome: A Comprehensive Review of Current Research and Future Directions. Int J Gen Med. 2025 Jul 23;18:4041-4055.
• (8) Dang D, Cunnington D, Swieca J. The emergence of devastating impulse control disorders during dopamine agonist therapy of the restless legs syndrome. Clin Neuropharmacol 2011;34:66-70.
• (9) Voon V, Schoerling A, Wenzel S, et al. Frequency of impulse control behaviours associated with dopaminergic therapy in restless legs syndrome. BMC Neurol 2011;11:117
• (10) Heim B et al. Augmentation and impulsive behaviors in restless legs syndrome: Coexistence or association?Neurology. 2016 Jul 5;87(1):36-40