What laboratory tests are recommended for a patient presenting with restless legs syndrome?

Laboratory Testing for Restless Legs Syndrome

Check serum ferritin and transferrin saturation in all patients with suspected RLS—these are the only essential laboratory tests required for diagnosis. 1, 2

Core Iron Studies (Required for All Patients)

Serum ferritin and transferrin saturation must both be obtained because ferritin alone can be falsely elevated by inflammation, making transferrin saturation necessary to identify functional iron deficiency even when ferritin appears adequate. 1

Proper Collection Technique

• Draw blood in the morning after the patient has avoided all iron-containing supplements and foods for at least 24 hours prior 1, 2
• Ferritin has diurnal variation and recent iron intake falsely elevates results, making standardized timing critical 1

RLS-Specific Iron Thresholds (Different from General Population)

• Supplement iron if ferritin ≤75 ng/mL OR transferrin saturation <20% 1, 3
• Consider IV iron if ferritin is between 75-100 ng/mL 1
• These thresholds are higher than standard anemia cutoffs because RLS pathophysiology involves impaired dopamine transport in the substantia nigra due to reduced intracellular iron 4

Additional Laboratory Tests to Identify Secondary Causes

While not required for diagnosis, these tests help identify treatable secondary causes of RLS:

Renal Function

• Electrolytes and creatinine to screen for chronic kidney disease and end-stage renal disease, which causes RLS in 24% of affected patients 1, 4, 3
• Urine albumin-to-creatinine ratio for early renal disease detection 1

Metabolic Screening

• HbA1c to identify diabetes mellitus, which is associated with peripheral neuropathy that can trigger RLS (21.5% prevalence in diabetic neuropathy) 1, 3
• TSH for thyroid dysfunction screening 1
• Calcium as part of baseline metabolic assessment 1

Hematologic Assessment

• Complete blood count (CBC) to assess for iron-deficiency anemia, which has significantly higher prevalence in RLS patients and may require more aggressive iron repletion 1
• Note that approximately one-third of B12 deficiency cases lack macrocytic anemia, so severe neurological symptoms can occur with normal CBC findings 4

Special Populations

• Pregnancy test where applicable, as pregnancy causes RLS in 22% of cases, especially in the third trimester 1, 3
• Vitamin B12 level should be considered in patients with late-onset RLS (fifth to seventh decade) without family history, as B12 deficiency causes demyelination and axonal degeneration that overlaps substantially with RLS presentations 4

What NOT to Order

Polysomnography or periodic limb movement studies should NOT be ordered as part of routine RLS diagnosis—reserve these only for cases where the diagnosis is uncertain or when assessing treatment response in research settings. 1

Critical Clinical Pitfalls

• Without proper differential diagnosis, 16% of patients will be misclassified as having RLS if clinicians only assess the four symptom criteria without excluding mimics through thorough neurologic examination 1, 2
• A normal neurologic exam with appropriate iron studies supports primary RLS, while abnormal exam findings suggest peripheral neuropathy, radiculopathy, or vascular disease as alternative diagnoses 1
• Blood work helps distinguish RLS from mimics: renal function identifies uremia-related RLS, HbA1c identifies diabetic neuropathy, and iron studies with proper thresholds guide treatment 1