Restless legs syndrome (formally Willis-Ekbom disease) is a sensorimotor disorder with characteristic clinical features. Prevalence is substantial — 5-10% of adults have RLS symptoms, with 2-3% having clinically significant disease. Often unrecognized despite producing substantial sleep disruption and daytime impact.
The diagnostic URGE criteria — all four required:
(U) Urge to move legs, usually accompanied by uncomfortable sensations (described variously as creepy-crawly, electric, aching, restless, throbbing). The sensations are typically in the legs but can occur in arms or trunk in severe cases.
(R) Rest worsens the symptoms. The patient experiences symptoms when lying down or sitting.
(G) Gets better with movement — walking, stretching, moving the legs temporarily relieves symptoms.
(E) Evening or night onset/worsening. Symptoms peak at night, especially at sleep onset.
The neurobiology: dopaminergic and iron-related mechanisms. Iron is a cofactor for tyrosine hydroxylase (rate-limiting enzyme in dopamine synthesis); CNS iron deficiency can impair dopamine signaling in striatal circuits implicated in RLS. The diurnal pattern (worse at night) suggests circadian dopaminergic regulation.
Iron evaluation is essential. Check ferritin — the threshold for repletion in RLS is ferritin <75 mcg/L, substantially higher than the threshold for treating iron-deficiency anemia. CNS iron stores can be inadequate even when serum iron is normal. Oral iron repletion (ferrous sulfate 325 mg with vitamin C for absorption); IV iron (ferric carboxymaltose) for severe symptoms or oral intolerance.
Pharmacotherapy hierarchy (modern approach):
First-line: gabapentinoids — gabapentin enacarbil (FDA-approved for RLS), gabapentin, pregabalin. Have largely replaced dopamine agonists as first-line due to augmentation risk. Generally well-tolerated.
Second-line: dopamine agonists — pramipexole, ropinirole, rotigotine patch. Highly effective short-term, but augmentation develops in 8-10% per year of long-term use — symptoms become more severe, occur earlier in the day, spread to other body parts. Iatrogenic worsening of the disorder. Use cautiously, monitor for augmentation, switch to gabapentinoid if augmentation emerges.
Third-line: low-dose opioids (methadone, low-dose buprenorphine, oxycodone) for refractory severe RLS. Effective but require careful patient selection given long-term opioid concerns.
Worsening factors to address: medications that worsen RLS — most antidepressants (mirtazapine particularly), antihistamines (diphenhydramine), antipsychotics, anti-nausea agents (metoclopramide, prochlorperazine). Caffeine, alcohol, nicotine. Sleep deprivation. Pregnancy (often substantially worsens). Iron deficiency. Treat comorbidities (sleep apnea, peripheral neuropathy).
When you encounter a patient with the URGE pattern, RLS is the diagnosis. Check ferritin first. Modern first-line is gabapentinoid, not dopamine agonist — the augmentation risk has shifted standard of care. Effective treatment substantially improves sleep and quality of life.