What is restless legs syndrome?
RLS, also called Willis-Ekbom disease, is a common chronic movement disorder in which patients have an irresistible urge to move the legs, often with abnormal non-painful sensations. Symptoms start at rest and improve with activity, with a diurnal pattern: worse in the evening and at night. Sleep disturbance and involuntary leg jerks during sleep follow.
- Prevalence: 5–15% of the population, women more than men; may start in childhood but is often diagnosed only in the third decade.
- Primary RLS is a central nervous system disorder, familial in 25–75% (autosomal dominant or recessive; genetic anticipation described). Familial cases present earlier (under 45 years) and progress more slowly. Gene polymorphisms include BTBD9 and MEIS1.
- Secondary RLS follows another disorder or drug (next section).
- Sensations are described as crawling, creeping, pulling, itching or stretching, deep in the limb rather than on the skin. Tingling paraesthesia of painful neuropathy is usually absent, and the skin is not tender to touch.
What are the diagnostic criteria for RLS?
RLS is diagnosed clinically. The International Restless Legs Syndrome Study Group (IRLSSG) requires all five essential criteria:
- An urge to move the legs, usually but not always accompanied by or felt to be caused by uncomfortable, unpleasant sensations in the legs.
- The urge and any sensations begin or worsen during rest or inactivity such as lying down or sitting.
- They are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.
- They occur or are worse in the evening or night than during the day.
- The features are not solely accounted for by another medical or behavioural condition (for example myalgia, venous stasis, leg oedema, arthritis, leg cramps, positional discomfort, habitual foot tapping).
| Finding | Detail |
|---|---|
| Periodic limb movements of sleep (PLMS) | Involuntary forceful dorsiflexion of the foot lasting 0.5–5 s, recurring every 20–40 s through sleep; present in about 80% of RLS patients |
| Examination | Usually normal; done to look for secondary causes, radiculopathy, neuropathy or Parkinson disease |
| Polysomnography | Not needed for diagnosis; quantifies leg movements and sleep pattern |
| Differential | Tardive dyskinesia, akathisia, leg cramps, vascular disease, muscle spasm, radiculopathy |
What is the link between RLS, iron and dopamine?
The pathogenesis is not fully known. In idiopathic RLS there is dysfunction of the dopaminergic system and diminished iron stores in specific brain regions. Neuropathologic and imaging studies show decreased iron in the substantia nigra and thalamus, with a state of relative dopamine excess in these areas. CSF studies show reduced ferritin.
| Point | Recommendation |
|---|---|
| Who is tested | All patients with clinically significant RLS: serum iron, ferritin and transferrin saturation (from iron and TIBC); at minimum, ferritin |
| How | Ideally morning sample, avoiding iron supplements and iron-rich food for at least 24 hours |
| Adults — oral or IV iron | Ferritin 75 ng/mL or less or transferrin saturation below 20% |
| Adults — IV iron only | Ferritin between 75 and 100 ng/mL |
| Children | Iron supplementation when ferritin is below 50 ng/mL, oral or IV |
| Re-test | When symptoms recur or augmentation appears |
What are the secondary causes of RLS?
| Group | Examples |
|---|---|
| Deficiency states | Iron deficiency, folate or magnesium deficiency, celiac disease |
| Renal | End-stage renal disease — 25–50% have RLS, worse during haemodialysis; may resolve after transplant |
| Pregnancy | 11–29% of pregnant women, three times the rate in non-pregnant women, highest in the third trimester; usually resolves after delivery, but RLS in pregnancy carries a four-fold risk of chronic RLS |
| Neuromuscular | Peripheral neuropathy, lumbosacral radiculopathy, amyloidosis |
| Other medical | Diabetes mellitus, rheumatic disease, venous insufficiency, fibromyalgia |
| Drugs that cause or worsen RLS | Antidopaminergics (neuroleptics), diphenhydramine, tricyclic antidepressants, SSRIs, SNRIs, alcohol, caffeine, lithium, beta-blockers |
Uraemic RLS involves calcium–phosphate imbalance, anaemia, functional iron deficiency and subclinical peripheral nerve changes. In pregnancy, vitamin D deficiency, pre-eclampsia, family history, low serum iron and ferritin and high oestrogen levels may play a role. The first investigations are blood count, urea, creatinine, glucose, magnesium, vitamin B12, TSH and folate; see anaemia for iron deficiency work-up.
How is RLS treated now?
Mild or occasional symptoms often need no drug. The 2024 AASM guideline (published 2025) reorganised treatment because years of use showed that dopamine agonists, while helpful in the short term, worsen symptoms over time (augmentation) and carry impulse-control risk. Older textbooks still list dopamine agonists as first line.
| Strength | Treatment |
|---|---|
| Strong — recommends | Gabapentin enacarbil, gabapentin, pregabalin; IV ferric carboxymaltose (if iron status appropriate) |
| Conditional — suggests for | IV low-molecular-weight iron dextran, IV ferumoxytol, oral ferrous sulfate (if iron status appropriate), dipyridamole, extended-release oxycodone and other opioids, bilateral high-frequency peroneal nerve stimulation |
| Conditional — suggests against standard use | Levodopa, pramipexole, ropinirole, transdermal rotigotine (may be used when short-term relief is valued over long-term augmentation risk) |
| Conditional — suggests against | Bupropion, carbamazepine, clonazepam, valerian, valproic acid |
| Strong — recommends against | Cabergoline |
| Population | AASM / StatPearls points |
|---|---|
| End-stage renal disease | Suggests gabapentin; IV iron sucrose if ferritin below 200 ng/mL and transferrin saturation below 20%; vitamin C; suggests against standard use of levodopa |
| Pregnancy | Consider the pregnancy-specific safety of each treatment; RLS usually resolves after delivery |
| Children | Iron if ferritin below 50 ng/mL; no adult drug is approved for children in the German guideline |
- Oral iron (StatPearls): ferrous sulfate 325 mg with vitamin C 250 mg on an empty stomach, nothing to eat for 60 minutes; parenteral iron if oral fails.
- Non-drug measures: sleep hygiene, exercise, hot or cold bath, limb massage, vibration or electrical stimulation, avoid caffeine before bed.
- Dopamine agonist adverse effects: gambling and impulse-control disorder, marked weight gain, and augmentation.
What is the course and what are the complications?
In about 70% of patients the symptoms progress to moderate or severe, and the arms may be affected. Progression is slower in idiopathic than in secondary RLS. Complications are mainly poor sleep, daytime fatigue and poor quality of life; RLS patients are also prone to hypertension, headaches and sleep difficulties, and anxiety and depression are common.
RLS is under-diagnosed and diagnosis is often delayed. It is a chronic condition with frequent relapses and poor long-term adherence, so team-based care with a neurologist, sleep physician and physician is recommended.