How should I manage an elderly woman with restless‑legs syndrome whose ferritin is 39 ng/mL (borderline low) but iron saturation, total iron‑binding capacity, unsaturated iron‑binding capacity, serum iron, hemoglobin and hematocrit are normal?

Management of Elderly Woman with RLS and Borderline-Low Ferritin

You should supplement this patient's iron immediately, even though her ferritin is 39 ng/mL and other iron parameters appear normal, because RLS-specific iron thresholds are fundamentally different from general population guidelines. 1

Iron Supplementation is the Critical First Step

The American Academy of Sleep Medicine recommends iron supplementation when ferritin is ≤75 ng/mL or transferrin saturation is <20% in adults with RLS—thresholds substantially higher than those used for general iron deficiency. 1 This patient's ferritin of 39 ng/mL falls well below the RLS-specific threshold of 75 ng/mL, making iron repletion essential regardless of her normal hemoglobin, iron saturation, or serum iron. 1

Why RLS Requires Different Iron Thresholds

• Brain iron deficiency in the substantia nigra—not systemic iron stores—drives RLS pathophysiology by impairing dopamine synthesis and transport. 2
• Serum ferritin correlates inversely with RLS symptom severity in elderly patients, with lower ferritin predicting more severe disease. 3, 4
• Even ferritin levels between 75–100 ng/mL may warrant IV iron in RLS patients who fail to respond adequately to oral therapy. 1
• Low ferritin is independently associated with dopaminergic augmentation risk, making early correction doubly important. 5

Iron Repletion Options

Start with oral ferrous sulfate 325 mg daily (or every other day to improve tolerability), as this receives a conditional recommendation with moderate certainty of evidence. 1 Oral iron is the appropriate first-line approach given her ferritin of 39 ng/mL and absence of severe refractory symptoms. 1

• If oral iron is not tolerated or fails to improve symptoms after 3 months, transition to IV ferric carboxymaltose 750–1000 mg in one or two infusions, which carries a strong recommendation with moderate certainty. 1
• IV iron does not rely on gastrointestinal absorption and may be more effective even when ferritin is 75–100 ng/mL. 6, 1
• Recheck morning fasting ferritin and transferrin saturation after 3 months of oral therapy, ensuring the patient withholds iron supplements for ≥24 hours before the blood draw. 1

First-Line Pharmacologic Therapy: Alpha-2-Delta Ligands

While correcting iron status, initiate an alpha-2-delta ligand (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacologic therapy, which receives a strong recommendation with moderate certainty of evidence. 1

Gabapentin Dosing

• Start gabapentin 300 mg three times daily. 1
• Titrate by 300 mg/day every 3–7 days as tolerated. 1
• Target maintenance dose is 1800–2400 mg/day divided three times daily. 1
• Maximum studied dose is 3600 mg/day. 1
• Common side effects include somnolence and dizziness, which are typically transient and mild. 1

Pregabalin as an Alternative

• Pregabalin allows twice-daily dosing and may have superior bioavailability compared to regular gabapentin. 1
• Start 50 mg three times daily or 75 mg twice daily. 1
• After 3–7 days, increase to 300 mg/day, then by 150 mg every 3–7 days as tolerated. 1
• Maximum dose is 600 mg/day. 1

Avoid Dopamine Agonists as First-Line Therapy

The American Academy of Sleep Medicine now suggests against the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to a 7–10% annual risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and spread to the arms or trunk. 1 This represents a major shift from older 2012 guidelines that listed dopamine agonists as first-line agents. 1

• Augmentation occurs in a substantial proportion of patients on dopamine agonists and is associated with lower ferritin levels. 5
• Alpha-2-delta ligands do not cause augmentation and are now strongly preferred. 1

Address Exacerbating Factors

• Eliminate alcohol, caffeine, antihistaminergic medications, serotonergic antidepressants, and antidopaminergic agents. 1
• Screen for and treat obstructive sleep apnea if present. 1

Monitoring and Follow-Up

• Reassess RLS severity at 4–6 weeks after initiating treatment. 1
• Recheck iron studies every 6–12 months, as brain iron deficiency may persist despite clinical improvement. 1
• Evaluate both nighttime symptom relief and daytime functional outcomes (alertness, mood, quality of life). 1

Critical Pitfalls to Avoid

• Do not apply general-population ferritin cut-offs (<15 ng/mL for iron deficiency) to RLS; the disease-specific threshold is ≤75 ng/mL. 1
• Do not assume that "normal" serum iron, iron saturation, or hemoglobin exclude the need for iron supplementation in RLS. 1 These parameters reflect systemic iron availability for erythropoiesis, not brain iron stores critical for dopamine synthesis. 2
• Do not start dopamine agonists as first-line therapy given current evidence favoring alpha-2-delta ligands. 1
• Do not delay iron supplementation while waiting for pharmacologic therapy to take effect. 1 Iron repletion addresses the underlying pathophysiology and may reduce augmentation risk if dopaminergic agents are ever needed. 5