Restless Legs Syndrome: More Than Just an Annoyance

Restless legs syndrome (RLS) — also called Willis-Ekbom disease — affects approximately 5–10% of adults in Western populations, making it one of the more common neurological conditions, yet it is frequently unrecognised, misdiagnosed, or dismissed as anxiety, growing pains, or simple restlessness. People who live with significant RLS describe the experience as deeply distressing: an overwhelming, almost irresistible compulsion to move the legs precisely when stillness is required for sleep.

Diagnostic Criteria

RLS is diagnosed clinically based on four core criteria established by the International Restless Legs Syndrome Study Group:

1. An urge to move the legs, usually accompanied by or caused by uncomfortable or unpleasant sensations in the legs.
2. The urge begins or worsens during rest or inactivity — sitting, lying down, or periods of reduced movement.
3. The urge is partially or totally relieved by movement — walking, stretching, rubbing the legs — at least as long as the movement continues.
4. The urge is worse in the evening or night — this circadian pattern is a distinguishing feature. RLS symptoms typically worsen significantly after 6pm and peak in the late evening and early night, when the person is trying to rest or sleep.

The sensations people describe vary considerably: crawling, creeping, tingling, burning, aching, itching, or simply an indescribable urge to move. They are not typically described as painful, though in more severe cases they can be. The distinguishing feature is the compulsive quality — unlike normal restlessness, RLS symptoms feel like they cannot be ignored.

The Biology: Dopamine and Iron

The neurobiological basis of RLS is best understood through the relationship between iron and dopamine. Iron is an essential cofactor for the enzyme tyrosine hydroxylase, which catalyses the rate-limiting step in dopamine synthesis. Brain iron deficiency — which can occur even when systemic iron markers appear normal — impairs dopamine synthesis and alters the function of dopaminergic circuits in the striatum and spinal cord.

The dopaminergic dysfunction in RLS appears to involve the A11 nucleus in the hypothalamus, which sends dopaminergic projections to the spinal cord that normally suppress sensorimotor circuits active during rest. When this inhibitory pathway is disrupted, the spinal cord's sensorimotor circuits become hyperexcitable at rest — generating the characteristic urge to move.

The circadian pattern of RLS (worsening at night) reflects circadian variation in brain iron and dopamine availability: both reach their lowest levels in the evening and overnight, which explains why symptoms consistently worsen after dark even in people who are not sleep-deprived.

Primary and Secondary RLS

Primary (idiopathic) RLS is genetically influenced — first-degree relatives of people with RLS have a 3–5 times higher risk of developing it. Genome-wide association studies have identified several risk loci involved in neural development and dopamine signalling. Primary RLS often begins in middle age and tends to be progressive.

Secondary RLS occurs in the context of an underlying condition and may resolve if that condition is treated:

• Iron deficiency: The most important and treatable secondary cause. Even iron deficiency without frank anaemia — as reflected in low serum ferritin — is associated with RLS. Correcting iron stores (target ferritin >75–100 µg/L in RLS) often significantly improves symptoms.
• Pregnancy: RLS is common in the third trimester, likely due to the combination of iron depletion and hormonal changes. It usually resolves after delivery.
• Chronic kidney disease: High prevalence of RLS in patients on dialysis, with mechanisms involving iron deficiency, uremic toxin accumulation, and altered dopamine metabolism.
• Medications: Several commonly used drugs worsen RLS or precipitate it in susceptible individuals — antihistamines (diphenhydramine), antidopaminergic antiemetics (metoclopramide), antidepressants (particularly SSRIs and SNRIs), and antipsychotics.

Associated Condition: Periodic Limb Movement Disorder

Approximately 80% of people with RLS also have periodic limb movements during sleep (PLMS) — repetitive, stereotyped movements of the legs (and sometimes arms) occurring every 20–40 seconds during NREM sleep, often with brief EEG arousals. PLMS can occur without RLS (Periodic Limb Movement Disorder, PLMD), but the overlap is substantial. The micro-arousals caused by PLMS fragment sleep architecture, contributing to the non-refreshing sleep and daytime fatigue that many RLS sufferers report despite technically spending adequate time in bed.

Treatment

Iron supplementation should be the first consideration whenever RLS is diagnosed. A ferritin level below 75 µg/L in an RLS patient warrants iron supplementation. Oral iron (ferrous sulfate or bisglycinate) taken with vitamin C for absorption is the first approach; intravenous iron is used when oral supplementation is insufficient or not tolerated. Multiple studies have demonstrated that optimising iron stores reduces RLS symptom severity, particularly in patients with lower ferritin levels.

Dopaminergic medications are the most effective pharmacological treatment for moderate-to-severe RLS. Low-dose dopamine agonists — pramipexole and ropinirole — significantly reduce RLS symptoms and are FDA-approved for this indication. However, an important complication limits their long-term use: augmentation — a paradoxical worsening of RLS that develops with chronic dopamine agonist use, characterised by symptoms occurring earlier in the day, spreading to the arms, and intensifying in severity. Augmentation affects 30–50% of patients on long-term dopamine agonists and often requires dose escalation followed by medication discontinuation.

Alpha-2-delta calcium channel ligands — gabapentin and pregabalin — have emerged as preferred alternatives to dopamine agonists for long-term treatment, particularly when pain or sleep disturbance is prominent. They do not carry the augmentation risk and may be more appropriate for first-line long-term pharmacotherapy in many patients.

Low-dose opioids are used in refractory cases, particularly when augmentation has made dopamine agonist therapy untenable. Very low-dose extended-release oxycodone-naloxone is approved for severe RLS in some European countries.

Lifestyle measures: Avoiding caffeine (particularly in the evening), avoiding alcohol and nicotine, moderate exercise, warm baths before bed, and pneumatic compression devices can provide modest benefit. These are typically adjunctive to pharmacological treatment rather than primary therapies for significant RLS.