What is the most likely diagnosis for a patient with a 2-month history of gradual onset of nocturnal discomfort in the calves, thighs, and arms, relieved by stretching or movement, with no other medical problems or reported symptoms?

Restless Legs Syndrome (RLS)

The most likely diagnosis is Restless Legs Syndrome (RLS), based on the classic presentation of nocturnal leg discomfort relieved by movement and stretching. 1, 2

Diagnostic Reasoning

This patient meets all five essential diagnostic criteria for RLS established by the American Academy of Sleep Medicine 1, 2:

1. Urge to move with discomfort: The patient describes discomfort in calves, thighs, and arms (RLS can involve upper extremities, not just legs) 1

2. Worsening with rest/inactivity: Symptoms occur nightly when the patient is at rest 1

3. Relief with movement: Stretching or getting up provides temporary relief, which is pathognomonic for RLS 1, 2

4. Circadian pattern: Symptoms occur specifically at night, demonstrating the characteristic evening/nocturnal worsening 1

5. Not explained by another condition: No other medical problems or symptoms are reported 1

The diagnosis is made by history alone without need for polysomnography in the majority of cases 1

Critical Next Steps

Immediate Laboratory Evaluation

Check serum ferritin immediately - this is the single most important initial test 2, 3:

• Ferritin levels <50 ng/mL are consistent with RLS diagnosis and indicate need for iron supplementation 1, 2
• Iron deficiency is a critical secondary cause even when hemoglobin is normal 2, 3

Perform Thorough Neurological Examination

While the physical exam is usually unremarkable in primary RLS, you must exclude secondary causes 1:

• Look for sensory deficits, diminished reflexes, or radiculopathy suggesting peripheral neuropathy 1, 3
• Check for visible varicosities, dependent edema, and skin changes suggesting venous stasis 3
• Assess for diminished peripheral pulses indicating vascular disease 3

Key Differential Diagnoses to Exclude

The American Academy of Sleep Medicine warns that 16% of subjects without RLS will be misclassified if you only ask about symptoms without excluding mimics 3:

• Venous stasis: Look for visible varicosities and edema; unlike RLS, lacks circadian pattern 3
• Peripheral neuropathy: Presents with sensory deficits in dermatomal distribution 1, 3
• Vascular disease/claudication: Pain is exercise-induced and relieved by rest (opposite of RLS) 1, 3
• Arthritis: Pain localized to joints, not diffuse leg discomfort 3
• Leg cramps: Sudden, painful muscle contractions, distinct from RLS urge to move 3

Treatment Algorithm

If Ferritin <50 ng/mL:

Start iron supplementation first 2, 3

If Ferritin ≥50 ng/mL or Inadequate Response to Iron:

First-line pharmacologic treatment: Dopamine receptor agonists 2, 4

Ropinirole dosing 2:

• Start 0.25 mg orally 1-3 hours before bedtime
• Increase to 0.5 mg after 2-3 days
• Increase to 1 mg after 7 days
• Weekly titration by 0.5 mg increments to maximum 4 mg

Pramipexole dosing 2:

• Start 0.125 mg orally 2-3 hours before bedtime
• Double every 4-7 days to maximum 0.5 mg

Alternative first-line options: Gabapentin or pregabalin 4

Second-line therapies: Intravenous iron infusion (for those intolerant of oral iron or with augmentation), opioids including tramadol, oxycodone, methadone 4

Critical Pitfalls to Avoid

The American Academy of Sleep Medicine and American Geriatrics Society identify these key errors 2:

• Missing iron deficiency: Always check ferritin even with normal hemoglobin 2, 3
• Overlooking venous stasis: Particularly important in patients with prolonged standing history 2, 3
• Using levodopa-carbidopa: High risk of augmentation (worsening symptoms with earlier onset and spread to arms) 2, 4
• Abruptly discontinuing dopaminergic therapy: Can cause severe rebound 2
• Ignoring medication review: Tricyclic antidepressants, SSRIs, lithium, and dopamine antagonists exacerbate RLS 1