What is the recommended diagnostic work‑up and treatment algorithm for restless‑legs syndrome?

Restless Legs Syndrome: Diagnostic Work-Up and Treatment Algorithm

Diagnosis: Clinical Criteria

Diagnose RLS by asking four specific questions—all must be answered "yes": an urge to move the legs accompanied by uncomfortable sensations, symptoms beginning or worsening during rest or inactivity, symptoms partially or totally relieved by movement, and symptoms worsening or only occurring in the evening or night. 1, 2

• The diagnosis is entirely clinical and does not require polysomnography or periodic limb movement studies. 1
• Critical pitfall: Without proper differential diagnosis, 16% of patients who do not have RLS will be misclassified if you only assess the four symptom criteria without excluding mimics. 1, 2

Differential Diagnosis: Excluding Mimics

Perform a thorough neurologic examination to identify conditions that can mimic RLS, focusing on:

• Joint abnormalities (arthritis presents with pain localized to joints, lacks circadian pattern, and shows physical exam findings). 1
• Peripheral neuropathy signs (diabetic or idiopathic neuropathy may present with leg discomfort but lacks the circadian pattern and relief with movement). 1, 2
• Radiculopathy indicators (pain follows dermatomal distribution, lacks circadian pattern). 1, 2
• Leg cramps (sudden, painful muscle contractions rather than urge to move). 3
• Positional discomfort (relieved by position change, not continuous movement). 3

True RLS is distinguished by a predictable circadian rhythm, symptoms responding to dopaminergic agents, and a typically unremarkable physical examination. 1

Laboratory Work-Up

Essential laboratory tests to order:

• Serum ferritin and transferrin saturation (drawn in the morning after avoiding iron-containing supplements for ≥24 hours)—this is the only essential laboratory test. 1, 2, 4
• Complete blood count (CBC) to assess for iron-deficiency anemia. 4
• Electrolytes and renal function (BUN, creatinine) to identify chronic kidney disease. 1
• Thyroid function (TSH) as part of endocrine screening. 1
• HbA1c to screen for diabetes mellitus. 1
• Calcium as part of baseline metabolic assessment. 1
• Urine albumin-to-creatinine ratio to assess for renal disease. 1

Do NOT order polysomnography as part of routine RLS diagnosis—reserve it only for cases where the diagnosis is uncertain. 1

Iron Supplementation Thresholds (Different from General Population)

Supplement if ferritin ≤75 ng/mL OR transferrin saturation <20% in adults with RLS. 1, 4

• Both parameters are required because ferritin alone can be falsely elevated by inflammation. 1
• Transferrin saturation <20% indicates functional iron deficiency even when ferritin appears adequate. 1
• In children, supplement if ferritin <50 ng/mL. 2, 4

Iron supplementation options:

• Oral ferrous sulfate 325-650 mg daily or every other day (conditional recommendation, moderate certainty). 4, 5
• IV ferric carboxymaltose 1000 mg for rapid correction if oral iron is not tolerated or ineffective after 3 months (strong recommendation, moderate certainty). 4, 5

First-Line Pharmacological Treatment

Alpha-2-delta ligands are first-line therapy (strong recommendation, moderate certainty of evidence):

• Gabapentin: Start 300 mg three times daily; increase by 300 mg/day every 3-7 days; target maintenance 1800-2400 mg/day divided TID; maximum 3600 mg/day. 4
• Gabapentin enacarbil (prodrug with better bioavailability, allows once-daily dosing). 4
• Pregabalin (allows twice-daily dosing with superior bioavailability compared to regular gabapentin). 4

Approximately 70% of patients treated with gabapentinoids have much or very much improved RLS symptoms vs 40% with placebo. 5

Medications to AVOID as First-Line

Dopamine agonists (pramipexole, ropinirole, rotigotine) are NOT recommended for standard use due to high risk of augmentation—a paradoxical worsening of symptoms with annual incidence of 7-10%. 4, 5

• Augmentation presents as earlier symptom onset during the day, increased intensity, and spread to arms/trunk. 4, 6
• May be considered only for short-term use in patients who prioritize immediate relief over long-term safety. 4

Strong recommendation AGAINST:

• Cabergoline, bupropion, carbamazepine, clonazepam, valproic acid, valerian. 4
• Levodopa (very high augmentation risk). 4, 6

Second-Line Options for Refractory Cases

Extended-release oxycodone and other low-dose opioids (methadone 5-10 mg daily, buprenorphine) are conditionally recommended for moderate to severe refractory RLS, particularly when treating augmentation from dopamine agonists. 4, 5

• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years. 4

Other second-line options:

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty). 4
• Dipyridamole (conditional recommendation, low certainty). 4

Special Population: End-Stage Renal Disease

• Gabapentin: Start 100 mg post-dialysis or at bedtime; maximum 200-300 mg daily (conditional recommendation, very low certainty). 4
• IV iron sucrose if ferritin <200 ng/mL AND transferrin saturation <20% (conditional recommendation, moderate certainty). 4
• Vitamin C supplementation to enhance iron utilization (conditional recommendation, low certainty). 4
• Avoid pregabalin in ESRD due to increased hazard for altered mental status and falls. 4

Lifestyle Modifications and Exacerbating Factors

Address potential exacerbating factors:

• Avoid alcohol, caffeine, and nicotine too close to bedtime. 4
• Discontinue medications that worsen RLS: serotonergic antidepressants (SSRIs), dopamine antagonists (antipsychotics like lurasidone), centrally acting H1 antihistamines (diphenhydramine). 4, 5
• Treat untreated obstructive sleep apnea if present. 4
• Avoid heavy meals or drinking within 3 hours of bedtime. 4
• Regular exercise in morning/afternoon, but avoid vigorous exercise close to bedtime. 4

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months. 4
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence). 4
• Evaluate for improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood). 4
• If using dopamine agonists despite recommendations, monitor closely for augmentation signs. 4, 6