What is the likely diagnosis and recommended evaluation and treatment for a patient with bilateral leg discomfort that worsens when supine, improves with standing or walking, and is not relieved by analgesics?

Restless Legs Syndrome (RLS)

This patient's presentation is classic for Restless Legs Syndrome (RLS), characterized by bilateral leg discomfort that worsens when lying down, improves with standing/walking, and is not relieved by standard analgesics.

Diagnostic Confirmation

The clinical presentation meets all five essential diagnostic criteria for RLS 1, 2:

• Urge to move the legs with uncomfortable sensations (often described as "crawling," aching, or tingling) 1, 3
• Symptoms worsen with rest/inactivity (lying down, sitting) 1, 4
• Relief with movement (standing, walking) that persists during activity 1, 5
• Circadian pattern with evening/nighttime predominance 1, 6
• Not explained by another condition after appropriate evaluation 2, 7

The bilateral nature of symptoms is typical—RLS characteristically affects both legs from onset, though severity may be asymmetric 2. The lack of response to standard analgesics is a key distinguishing feature 1.

Critical Differential Diagnoses to Exclude

Before confirming RLS, you must rule out important mimics 8, 2:

• Venous stasis: Look for history of prolonged standing, visible varicosities, edema, and signs of venous insufficiency. This is a critical mimic to exclude 1, 8
• Peripheral neuropathy: Perform thorough neurologic examination checking for sensory deficits, diminished reflexes, or radiculopathy 1, 2
• Peripheral arterial disease (PAD): Palpate femoral, popliteal, dorsalis pedis, and posterior tibial pulses bilaterally. Absence of all four posterior tibial and dorsalis pedis pulses suggests PAD 8, 9
• Spinal stenosis: Would present with bilateral symptoms, pain radiating down legs, relief with lumbar flexion (not just standing), and often motor weakness 8

Key distinguishing features: True RLS has predictable circadian rhythm, unremarkable physical examination, and responds to dopaminergic agents—unlike arthritis (joint abnormalities on exam, no circadian pattern) or PAD (abnormal pulses, claudication with walking distance) 2, 8.

Essential Laboratory Workup

Order the following tests immediately 1, 2:

• Serum ferritin (morning draw, avoid iron supplements for 24 hours prior): Iron deficiency is the most critical secondary cause. RLS-specific threshold is ≤75 ng/mL (not the general population cutoff) 1, 2
• Transferrin saturation: Supplement if <20%, as ferritin alone can be falsely elevated by inflammation 2
• Complete blood count (CBC): To assess for iron-deficiency anemia 9
• Renal function (creatinine, BUN): End-stage renal disease causes secondary RLS in 24% of patients 2, 6
• HbA1c: Diabetic neuropathy can mimic or coexist with RLS 2
• TSH: Thyroid dysfunction is part of standard endocrine screening 2

Do not order polysomnography—it is not indicated for routine RLS diagnosis 2.

Treatment Algorithm

Step 1: Iron Supplementation (if indicated)

• If ferritin ≤75 ng/mL or transferrin saturation <20%: Start ferrous sulfate 325-650 mg daily or every other day 6, 1
• If ferritin 75-100 ng/mL with severe symptoms: Consider IV iron 1000 mg 2, 6

Step 2: Medication Review

• Discontinue exacerbating medications if possible: serotonergic antidepressants, dopamine antagonists (antipsychotics, metoclopramide), centrally acting H1 antihistamines (diphenhydramine) 6, 1

Step 3: First-Line Pharmacologic Therapy

Gabapentinoids are now first-line (not dopamine agonists) 6, 1:

• Gabapentin: Start 300 mg 1-2 hours before bedtime, titrate to 600-1200 mg as needed 6
• Pregabalin: Alternative gabapentinoid option 4, 6
• Efficacy: Approximately 70% of patients achieve much or very much improved symptoms vs 40% with placebo 6

Step 4: Second-Line Options (if gabapentinoids fail)

• Dopamine agonists (now second-line due to augmentation risk) 6, 1:
  • Ropinirole: Start 0.25 mg 1-3 hours before bedtime, increase to 0.5 mg after 2-3 days, then 1 mg after 7 days, with weekly titration by 0.5 mg increments to maximum 4 mg 1, 10
  • Pramipexole: Start 0.125 mg 2-3 hours before bedtime, double every 4-7 days to maximum 0.5 mg 1
  • Warning: Annual augmentation risk of 7-10% (iatrogenic worsening of symptoms with earlier onset and spread to arms) 6, 4

Step 5: Refractory Cases

• Low-dose opioids (methadone 5-10 mg daily, tramadol, oxycodone) for patients who fail first-line treatment or develop augmentation 6, 4

Critical Pitfalls to Avoid

• Missing iron deficiency: Check ferritin even if hemoglobin is normal. Use RLS-specific threshold (≤75 ng/mL), not general population cutoff 1, 2
• Starting with dopamine agonists: These are no longer first-line due to augmentation risk 6
• Overlooking venous stasis: Particularly in patients with prolonged standing history 1
• Ignoring medication review: Many common medications exacerbate RLS 6, 1
• Abruptly discontinuing dopaminergic therapy: If patient is already on these agents, taper carefully 1