What is the appropriate workup and treatment for an adult patient with restless leg syndrome (RLS), possibly with a history of neurological or sleep disorders, iron deficiency, kidney problems, or peripheral neuropathy?

Restless Leg Syndrome Workup

Initial Diagnostic Assessment

The diagnosis of RLS is purely clinical based on four essential criteria: (1) urge to move the legs with or without uncomfortable sensations, (2) symptoms begin or worsen during rest/inactivity, (3) symptoms are relieved by movement, and (4) symptoms worsen in the evening or at night. 1, 2 No objective test confirms RLS—a careful clinical history distinguishing RLS from mimics (neuropathy, akathisia, positional discomfort, nocturnal leg cramps) is imperative. 1, 3

Essential Laboratory Workup

• Check morning fasting serum ferritin and transferrin saturation in all patients with clinically significant RLS, ideally after avoiding iron-containing supplements for at least 24 hours. 2 Both parameters are required because ferritin alone can be falsely elevated by inflammation. 3

• Supplement iron if ferritin ≤75 ng/mL OR transferrin saturation <20%—these RLS-specific thresholds differ from general population guidelines. 2, 3 Transferrin saturation <20% indicates functional iron deficiency even when ferritin appears adequate. 3

• Obtain comprehensive metabolic panel (electrolytes, creatinine, calcium) to identify chronic kidney disease, which is a secondary cause of RLS and requires different treatment algorithms. 3

• Check TSH, HbA1c, and urine albumin-to-creatinine ratio to screen for thyroid dysfunction, diabetes mellitus, and renal disease—all associated with secondary RLS. 3

• Perform thorough neurologic examination to identify peripheral neuropathy, radiculopathy, or other conditions that may mimic or trigger RLS. 3 A normal neurologic exam with appropriate iron studies supports primary RLS. 3

What NOT to Order

• Do not routinely order polysomnography or periodic limb movement studies—these are reserved for cases where diagnosis is uncertain or when assessing treatment response in research settings, not for routine diagnosis. 3

Identifying Exacerbating Factors

Before initiating pharmacotherapy, address potential triggers: 2, 4

• Medications to avoid or discontinue: antihistamines (including OTC sleep aids), serotonergic antidepressants, antidopaminergic medications (antipsychotics like lurasidone, anti-nausea drugs). 2, 4

• Substances to eliminate: alcohol, caffeine (especially evening consumption), nicotine close to bedtime. 2, 4

• Screen for and treat untreated obstructive sleep apnea, which can exacerbate RLS symptoms. 2, 4

Treatment Algorithm

First-Line Pharmacological Treatment

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line therapy for moderate to severe RLS (strong recommendation, moderate certainty of evidence). 1, 2 These agents avoid the augmentation phenomenon—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread—that plagues dopaminergic agents with long-term use. 1, 2, 5

• Gabapentin: Start 300 mg three times daily (900 mg/day total), titrate by 300 mg/day every 3-7 days to maintenance dose of 1800-2400 mg/day divided three times daily. 2 Maximum doses up to 3600 mg/day are well-tolerated. 2

• Pregabalin: Allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin. 2

• Gabapentin enacarbil: Prodrug of gabapentin with improved pharmacokinetics. 2

• Monitor for common side effects: somnolence and dizziness, which are typically transient and mild. 2 Use caution in patients with untreated obstructive sleep apnea or COPD. 2

Iron Supplementation

If ferritin ≤75 ng/mL or transferrin saturation <20%: 2

• Oral ferrous sulfate is conditionally recommended (moderate certainty of evidence). 1, 2 Monitor for constipation, especially in pediatric patients. 2

• IV ferric carboxymaltose is strongly recommended for patients with appropriate iron parameters who don't respond to oral therapy (strong recommendation, moderate certainty of evidence). 2

• Continue iron supplementation indefinitely with ongoing monitoring—symptoms may recur if iron stores decline below therapeutic thresholds. 2 Recheck iron studies every 6-12 months. 2

Second-Line Options for Refractory Cases

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for refractory RLS or when treating augmentation from dopaminergic agents. 1, 2 Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients with only small dose increases over 2-10 years. 2

• Caution: Assess risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea. 2

• Bilateral high-frequency peroneal nerve stimulation is a newer non-pharmacological option (conditional recommendation, moderate certainty of evidence). 1, 2

Medications to AVOID

The American Academy of Sleep Medicine recommends AGAINST the standard use of dopamine agonists (levodopa, pramipexole, ropinirole, rotigotine) due to high risk of augmentation with long-term use. 1, 2 These may only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects. 1, 2

• Strongly recommend AGAINST cabergoline (strong recommendation, moderate certainty of evidence). 1, 2

• Suggest AGAINST: bupropion, carbamazepine, clonazepam, valproic acid, valerian. 1, 2

Special Populations

End-Stage Renal Disease (ESRD)

• Gabapentin: Conditionally recommended, start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily (very low certainty of evidence). 1, 2 Note: Gabapentinoids carry 31-68% higher hazard for altered mental status and falls in dialysis patients. 2

• IV iron sucrose: Conditionally recommended if ferritin <200 ng/mL AND transferrin saturation <20% (moderate certainty of evidence). 1, 2

• Vitamin C: Conditionally recommended (low certainty of evidence). 1, 2

Pediatric RLS

• Ferrous sulfate: Conditionally recommended if ferritin <50 ng/mL (very low certainty of evidence). 1, 2 Monitor for constipation. 2

Critical Pitfalls to Avoid

• Do not start dopamine agonists as first-line therapy—augmentation occurs in a significant proportion of patients and can produce progressively severe around-the-clock symptoms. 1, 2, 5

• Do not assume "normal" ferritin means adequate iron stores—RLS requires higher brain iron levels (ferritin >75 ng/mL) than general population thresholds. 2, 3

• Do not misdiagnose RLS mimics (arthritis, neuropathy, akathisia)—16% of patients will be misclassified without proper differential diagnosis. 3 Key distinguishing features: RLS has predictable circadian rhythm, responds to dopaminergic agents, and has unremarkable physical exam. 3

• Do not ignore medication-induced RLS—antipsychotics (including lurasidone), antihistamines, and serotonergic antidepressants can trigger or worsen symptoms through dopamine antagonism. 2, 4