Can elevated ferritin (iron storage protein) levels cause Restless Legs Syndrome (RLS) and Periodic Limb Movements (PLMs) and how are they treated?

High Ferritin Does NOT Cause RLS or PLMs—Low Brain Iron Does

High serum ferritin levels do not cause restless legs syndrome (RLS) or periodic limb movements (PLMs); rather, RLS is fundamentally caused by brain iron deficiency, particularly in the substantia nigra, which disrupts dopaminergic neuron function regardless of peripheral iron stores. 1 The rare case reports of RLS with elevated ferritin likely represent coincidental findings or reflect that serum ferritin does not accurately reflect brain iron status. 2

Understanding the Iron Paradox in RLS

• Brain iron deficiency is the core pathophysiological mechanism in RLS, specifically affecting the substantia nigra where iron is essential for dopamine synthesis and transport. 1
• Serum ferritin can be falsely elevated by inflammation while brain iron remains deficient, which is why transferrin saturation must also be checked. 3
• The American Academy of Sleep Medicine uses higher ferritin thresholds for RLS (≤75 ng/mL) than for general iron deficiency precisely because brain iron requirements differ from peripheral stores. 4, 3
• One case series documented RLS patients with high serum ferritin (normal iron levels) who improved with dopaminergic treatment, suggesting the elevated ferritin was incidental and did not reflect adequate brain iron. 2

Diagnostic Approach to RLS with Elevated Ferritin

• Check morning fasting serum ferritin AND transferrin saturation after avoiding iron supplements for 24 hours—both parameters are required because ferritin alone is unreliable. 4, 3
• If ferritin is elevated but transferrin saturation <20%, functional iron deficiency exists and iron supplementation is indicated. 3
• Rule out inflammatory conditions (check CRP, ESR) that could falsely elevate ferritin while masking true iron deficiency. 3
• Perform a thorough neurologic examination to exclude RLS mimics such as peripheral neuropathy, radiculopathy, or arthritis. 5

Treatment Algorithm for RLS (Regardless of Ferritin Level)

Step 1: Address Iron Status First

• Supplement with oral ferrous sulfate if ferritin ≤75 ng/mL or transferrin saturation <20% (conditional recommendation, moderate certainty). 3
• Consider IV ferric carboxymaltose if ferritin is 75-100 ng/mL or if oral iron fails (strong recommendation, moderate certainty). 3, 6
• In children, supplement if ferritin <50 ng/mL. 4

Step 2: Eliminate Exacerbating Factors

• Discontinue or minimize alcohol, caffeine (especially evening), antihistamines, SSRIs/SNRIs, antipsychotics, and metoclopramide. 4, 3
• Treat untreated obstructive sleep apnea if present. 4

Step 3: First-Line Pharmacological Treatment

• Start alpha-2-delta ligands as first-line therapy (strong recommendation, moderate certainty): 4, 3
  • Gabapentin: 300 mg three times daily, titrate up to 1800-2400 mg/day divided TID
  • Gabapentin enacarbil: 600 mg once daily (extended-release formulation)
  • Pregabalin: 75-150 mg twice daily, titrate to 300-450 mg/day divided BID
• These agents avoid the augmentation phenomenon seen with dopamine agonists. 3

Step 4: Second-Line Options for Refractory Cases

• Extended-release oxycodone or low-dose opioids (methadone, buprenorphine) for refractory RLS (conditional recommendation, moderate certainty). 3
• Bilateral high-frequency peroneal nerve stimulation as a non-pharmacological alternative (conditional recommendation, moderate certainty). 3

Step 5: Avoid These Medications

• Do NOT use dopamine agonists (pramipexole, ropinirole, rotigotine) as standard treatment due to high augmentation risk (conditional recommendation against, moderate certainty). 4, 3
• Strongly avoid cabergoline (strong recommendation against, moderate certainty). 3
• Do NOT use clonazepam, valproic acid, carbamazepine, or bupropion for RLS treatment. 3

Understanding PLMs in the Context of RLS

• Approximately 90% of RLS patients exhibit PLMs during sleep, detected as brief (0.5-10 seconds) recurrent leg movements every 15-30 seconds on polysomnography. 4
• PLMs are particularly prominent during the first 4 hours of sleep and are invariably associated with heart rate and blood pressure elevations. 4
• Isolated PLMs without RLS symptoms (periodic limb movement disorder, PLMD) require >15 events/hour in adults (>5/hour in children) with clinically significant sleep disturbance not explained by other disorders. 4
• One case report documented a patient with isolated PLMS who developed severe RLS symptoms after starting dopaminergic treatment with low ferritin (31-61 mcg/L), suggesting isolated PLMS and RLS may share pathogenic mechanisms. 7

Critical Pitfalls to Avoid

• Do not assume high ferritin excludes the need for iron supplementation—check transferrin saturation and consider IV iron even with ferritin 75-100 ng/mL. 3, 6
• Do not start dopamine agonists as first-line therapy—augmentation occurs in a significant proportion of patients and worsens long-term outcomes. 4, 3
• Do not order polysomnography routinely for RLS diagnosis—it is reserved for uncertain diagnoses or research settings. 5
• Do not increase dopamine agonist doses if augmentation develops—this paradoxically worsens symptoms; instead, transition to alpha-2-delta ligands. 3
• Do not use clonazepam as monotherapy—it improves subjective sleep quality but does not reduce PLM index and has insufficient efficacy evidence. 3

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months even with symptom resolution, as brain iron deficiency may persist despite normal serum parameters. 3
• Monitor for side effects of alpha-2-delta ligands including dizziness and somnolence, which are typically transient and mild. 3
• Evaluate for improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood). 3