Restless Legs Syndrome (RLS) / Willis-Ekbom Disease

Definition & Epidemiology

• Adams and Victor's Principles of Neurology, 12th Edition, p. 420
• Bradley and Daroff's Neurology in Clinical Practice

Diagnostic Criteria (IRLSSG - 4 Essential Features)

1. Urge to move the legs, usually accompanied by uncomfortable sensations
2. Worse at rest - symptoms begin or worsen during inactivity (sitting, lying down)
3. Relieved by movement - walking or stretching provides temporary relief
4. Circadian pattern - symptoms worse in the evening and night

Clinical Features

• Unpleasant aching, drawing, or creeping/crawling sensations in the calves and thighs
• Descriptions include "worms," "internal itch," "coldness," heaviness, weakness
• Proximal leg location (distinguishes from peripheral acral paresthesias)
• The urge can be suppressed briefly but is ultimately irresistible
• Fatigue and warm weather worsen symptoms
• In severe/long-standing cases: symptoms may spread to arms, abdomen, and even spill into daytime hours
• May lead to severe sleep deprivation and daytime somnolence

Pathophysiology

• Decreased dopamine (DA) receptor expression and mild dopaminergic hypofunction in the basal ganglia
• Iron is a cofactor for tyrosine hydroxylase (rate-limiting enzyme in dopamine biosynthesis) - iron deficiency reduces dopamine production
• PET/SPECT studies show reduced dopamine binding by receptors and transporters in the basal ganglia

• Low serum ferritin and CSF iron levels are strongly associated with RLS
• Even if frank anemia is absent, reduced iron stores impair dopaminergic signaling
• This explains why iron supplementation alone can be therapeutic
• Adams and Victor's Principles of Neurology, 12th Edition, p. 420-421
• Goodman & Gilman's Pharmacological Basis of Therapeutics

Secondary Causes (Always Screen For)

Periodic Limb Movements of Sleep (PLMS) - Related Disorder

• Closely associated with RLS (most RLS patients have PLMS; reverse is less common)
• Repetitive stereotyped leg movements every 20-90 seconds, lasting several minutes to an hour
• Mainly involves tibialis anterior: dorsiflexion of foot and big toe, sometimes hip/knee flexion
• Resembles the triple-flexion (Babinski) response
• Diagnosed by polysomnography (unlike RLS which is a clinical diagnosis)
• Causes microarousals and disrupted sleep, often noticed first by a bed partner

Treatment

Step 1: Address Secondary Causes

• Check iron stores: serum ferritin, transferrin saturation
• If ferritin < 75 µg/L, supplement iron (ferrous sulfate 325 mg BID/TID) - correction alone may resolve or significantly reduce RLS

Step 2: Non-pharmacological Measures

• Sleep hygiene
• Reduce/eliminate alcohol, caffeine, nicotine
• Avoid aggravating drugs (antihistamines, antidepressants if possible)
• Moderate exercise, leg massage, warm/cool baths
• Pneumatic compression devices

Step 3: Pharmacotherapy

Current First-Line (2025 AASM Guidelines)

Key 2025 update: The AASM now recommends gabapentin over dopamine agonists as the primary pharmacotherapy (strong recommendation, moderate certainty evidence), given the well-documented problem of augmentation - a paradoxical worsening of RLS symptoms with long-term dopaminergic treatment, often with earlier onset, greater intensity, and spread to other body parts.

The AASM also recommends against the routine use of levodopa (augmentation risk) and against bupropion for RLS.

• Bradley and Daroff's Neurology in Clinical Practice, Table 10.1.11
• Adams and Victor's Principles of Neurology, p. 421
• 2025 AASM Clinical Practice Guideline (Winkelman et al., PMID 39324664)

Augmentation - Key Complication of Dopaminergic Therapy

• Symptoms appear earlier in the day than before treatment
• Increased intensity and spread to other body parts (arms, trunk)
• Occurs with L-dopa and dopamine agonists - higher doses carry higher risk
• Association with impulse control behaviors (gambling, hypersexuality, binge eating)
• Management: switch to gabapentinoid, reduce/taper dopaminergic agent, consider rotigotine patch as bridge

Prognosis

• Idiopathic RLS is typically chronic and progressive
• Secondary RLS may resolve if the underlying cause is treated (e.g., iron repletion, renal transplantation, postpartum)
• Severity fluctuates - fatigue, stress, and warm weather worsen symptoms
• With appropriate treatment, most patients achieve good symptom control

• The 2025 AASM systematic review and meta-analysis (PMID 39324664) formally established gabapentin as the preferred first-line agent over dopamine agonists with GRADE methodology.
• A 2026 systematic review and meta-analysis on neurostimulation for RLS (PMID 42001819) supports emerging non-pharmacological options including transcutaneous stimulation for medication-refractory cases.
• A 2024 meta-analysis on TOMAC (transcutaneous oxygen/CO2) therapy (PMID 39173210) showed efficacy in both naive and refractory RLS.