What are the diagnostic criteria and recommended work‑up and treatment plan for restless‑leg syndrome, including evaluation for iron deficiency and medication options?

Restless Legs Syndrome: Diagnosis and Management

Diagnostic Criteria

Diagnose RLS when all five essential criteria are met: (1) urge to move the legs with or without uncomfortable sensations, (2) symptoms begin or worsen with rest/inactivity, (3) symptoms relieved by movement, (4) symptoms worse in evening/night, and (5) symptoms not better explained by another condition—this fifth criterion requiring exclusion of mimics is critical because without proper differential diagnosis, 16% of patients will be misdiagnosed. 1, 2

Essential Clinical Features

• Urge to move the legs is mandatory, usually accompanied by uncomfortable sensations described variably as crawling, tingling, or aching 1, 3
• Rest-induced worsening occurs during sitting or lying down 1, 4
• Movement provides relief that persists during activity (walking, stretching) 1, 4
• Circadian pattern with predictable evening/nighttime predominance 1, 4
• Bilateral involvement is typical, though asymmetry in severity is common 2

Critical Differential Diagnosis

The following mimics must be actively excluded through history and examination 1, 5:

• Leg cramps: Sudden, painful muscle contractions (not urge to move); lack circadian pattern 5
• Venous stasis: Look for visible varicosities, dependent edema, skin changes; discomfort lacks circadian pattern 5
• Peripheral neuropathy: Perform neurological exam for sensory deficits, diminished reflexes, dermatomal distribution 2, 5
• Arthritis: Pain localized to joints on examination; lacks circadian pattern; joint abnormalities present 2, 5
• Vascular disease/claudication: Exercise-induced pain relieved by rest (opposite of RLS); check for diminished pulses 5
• Positional discomfort: Resolves with position change alone, not requiring sustained movement 5
• Akathisia: Generalized whole-body restlessness, not leg-specific 5

Recommended Work-Up

Mandatory Iron Studies

Check serum ferritin AND transferrin saturation in ALL patients with clinically significant RLS, drawn in the morning after avoiding iron-containing supplements for at least 24 hours. 2, 3

• Ferritin alone is insufficient because inflammation falsely elevates it independent of true iron stores 2
• Both parameters required: Transferrin saturation <20% indicates functional iron deficiency even when ferritin appears adequate 2
• RLS-specific thresholds differ from general population: Supplement if ferritin ≤75 ng/mL OR transferrin saturation <20% 2, 3

Additional Laboratory Tests

• Complete blood count (CBC) to assess for iron-deficiency anemia requiring more aggressive repletion 2
• Electrolytes and renal function to identify chronic kidney disease (24% prevalence in end-stage renal disease) 2, 3
• Thyroid function (TSH) as part of endocrine screening 2
• HbA1c to screen for diabetes (21.5% prevalence with diabetic neuropathy) 2, 3
• Pregnancy test where applicable (22% prevalence in third trimester) 3

What NOT to Order

Do not order polysomnography or periodic limb movement studies for routine RLS diagnosis—reserve for uncertain diagnoses or research settings only. 2

Treatment Algorithm

First-Line: Iron Repletion (When Indicated)

Initiate iron supplementation for ferritin ≤75 ng/mL or transferrin saturation <20% before or concurrent with pharmacologic therapy. 1, 3

• Oral iron: Ferrous sulfate 325-650 mg daily or every other day 1, 3
• Pediatric patients: Use ferrous sulfate even with "appropriate" iron status 1
• IV iron (1000 mg): Consider for ferritin 75-100 ng/mL, intolerance to oral iron, or augmentation with severe symptoms 1, 6, 3
• End-stage renal disease: IV iron sucrose for ferritin <200 ng/mL AND transferrin saturation <20% 1

First-Line: Pharmacologic Therapy

Gabapentinoids are first-line pharmacologic treatment, with approximately 70% of patients achieving much or very much improved symptoms versus 40% with placebo. 1, 3

• Gabapentin, gabapentin enacarbil, or pregabalin are preferred initial agents 1, 3
• Dopamine agonists (pramipexole, ropinirole, rotigotine) are NO LONGER first-line due to 7-10% annual risk of augmentation—an iatrogenic worsening with earlier symptom onset, increased severity, and spread to arms 1, 3

Medications to Discontinue

Stop exacerbating medications when possible: serotonergic antidepressants, dopamine antagonists, centrally acting H1 antihistamines (diphenhydramine). 3

Second-Line: Refractory or Augmented RLS

Low-dose opioids (methadone 5-10 mg daily, tramadol, oxycodone) for patients not improving with first-line treatment or experiencing augmentation. 1, 6, 3

Medications to AVOID

• Strongly recommend AGAINST cabergoline (moderate certainty evidence) 1
• Suggest AGAINST: Carbamazepine, clonazepam, valproic acid, valerian 1
• Levodopa and rotigotine in ESRD: Only for patients prioritizing short-term symptom reduction over long-term augmentation risk 1

Common Pitfalls

• Failing to exclude mimics leads to 16% misdiagnosis rate when only assessing symptom criteria 1, 5
• Using ferritin alone without transferrin saturation misses functional iron deficiency 2
• Drawing iron studies without proper preparation (not morning, recent iron intake) yields falsely elevated results 2
• Starting dopamine agonists as first-line increases augmentation risk unnecessarily 1, 3
• Ordering polysomnography routinely wastes resources without diagnostic benefit 2
• Missing secondary causes: Check for renal disease, neuropathy, pregnancy, iron deficiency 2, 3