Restless Legs Syndrome: Dopamine Dysregulation, Iron, and PLMS
RLS is characterized by urge to move legs at rest, with 80% of patients showing periodic limb movements during sleep (PLMS) every 20–40 seconds; ferritin below 50 ng/mL is linked to symptom severity and IV iron supplementation reduces PLMS by 70%.
| Measure | Value | Unit | Notes |
|---|---|---|---|
| Adult prevalence of RLS | 5–10 | % of population | Higher in women, older adults; clinically significant RLS ~2–3% of adults |
| PLMS prevalence in RLS patients | 80 | % of patients | Periodic limb movements during sleep; ≥15/hour threshold for PLMS disorder |
| PLMS interval | 20–40 | seconds between movements | Each movement causes arousal; arousals accumulate to fragment sleep |
| Ferritin threshold associated with severity | 50 | ng/mL | Below this level, RLS symptoms worsen; below 20 ng/mL is high-risk |
| IV iron reduction in PLMS index | 70 | % reduction | Wang et al. 2013; IV ferric carboxymaltose; most effective in iron-deficient patients |
Diagnostic Criteria (IRLSSG 2012)
Diagnosis requires all four criteria:
- Urge to move legs (or arms), usually accompanied by unpleasant sensations
- Symptoms worse at rest (lying, sitting)
- Partial or total relief with movement (walking, stretching)
- Circadian pattern: worse in the evening/night
Pathophysiology: Dopamine and Iron
The central model:
Iron deficiency (regional/brain) → Reduced dopamine synthesis → Reduced D2/D3 receptor activity in spinal cord and basal ganglia → Disinhibited sensorimotor processing → RLS symptoms
Evidence for this model:
- CSF ferritin lower in RLS patients regardless of serum iron
- Neuromelanin MRI shows reduced iron in substantia nigra in RLS
- Dopamine agonists (pramipexole, ropinirole) are highly effective
- IV iron supplementation produces sustained improvement
Periodic Limb Movements During Sleep (PLMS)
PLMS are stereotyped extensions of the big toe and dorsiflexion of the foot occurring every 20–40 seconds during NREM sleep. Each movement produces cortical arousal visible on EEG. A PLMS index (movements per hour) above 15 meets criteria for PLMS disorder.
Consequence: Sleep becomes fragmented, slow-wave sleep is disrupted, and patients wake unrefreshed. PLMS occurs without RLS in ~4% of adults and also in many other sleep disorders (sleep apnea, narcolepsy, REM behavior disorder).
Treatment
| Category | Agents | Notes |
|---|---|---|
| Dopamine agonists | Pramipexole, ropinirole, rotigotine | First-line pharmacotherapy; risk of augmentation |
| Iron | Oral (with vitamin C) or IV | First-line if ferritin <50 ng/mL |
| Alpha-2-delta ligands | Gabapentin, pregabalin | First-line if pain predominates |
| Opioids | Low-dose oxycodone | Third-line; severe refractory cases |
Augmentation: A major complication of dopamine agonist therapy — symptoms spread to arms, worsen earlier in the day, become more severe. Risk increases with higher doses and longer treatment duration. Managed by switching to alpha-2-delta ligands or IV iron.
Related Pages
Sources
- Earley CJ et al. — Abnormalities in CSF dopaminergic markers in restless legs syndrome. Neurology (2006)
- Trenkwalder C et al. — Restless legs syndrome: pathophysiology, clinical presentation, and management. Nat Rev Neurol (2010)
- Allen RP et al. — International Restless Legs Syndrome Study Group — diagnostic criteria. Sleep Med (2003)
- Wang J et al. — Iron therapy in restless legs syndrome. Ann Neurol (2013)
Frequently Asked Questions
What is the connection between iron deficiency and restless legs?
Iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. In RLS, brain iron deficiency — detectable in the substantia nigra and putamen via MRI or CSF ferritin — reduces dopaminergic tone in basal ganglia circuits that inhibit the spinal cord's sensorimotor system during rest. The result is disinhibited sensorimotor activity experienced as crawling, aching, or irresistible leg movement urges. Iron supplementation (oral if ferritin <50 ng/mL, IV if oral intolerant or severe) directly addresses the root mechanism and produces meaningful symptom improvement in many patients.
Why does RLS get worse at night?
RLS has a pronounced circadian pattern — symptoms peak in the evening and overnight, typically 10 PM–4 AM. This mirrors the circadian trough in dopaminergic activity and endogenous iron availability in the brain. Dopamine D2 receptor sensitivity oscillates across 24 hours, with lowest levels at night. The circadian system amplifies whatever underlying dopamine/iron deficiency exists. Additionally, the supine rest position typical of sleep onset maximizes sensory discomfort by eliminating the movement that temporarily relieves symptoms.