What is the treatment approach for restless legs syndrome (RLS) with low ferritin levels indicating iron deficiency?

Target Ferritin for Restless Legs Syndrome

For adults with RLS, target a serum ferritin level of at least 75 ng/mL, and consider iron supplementation when ferritin is ≤75 ng/mL or transferrin saturation is <20%. 1, 2

RLS-Specific Iron Thresholds (Different from General Population)

The iron requirements for RLS differ substantially from general population guidelines because brain iron deficiency plays a central pathophysiological role in RLS, even when serum iron appears normal by standard medical criteria. 2

Adult Targets:

• Ferritin ≤75 ng/mL or transferrin saturation <20%: Use either oral ferrous sulfate (65 mg elemental iron daily) or IV ferric carboxymaltose (1000 mg) as first-line iron therapy 1, 2
• Ferritin 75-100 ng/mL: Use IV iron formulations exclusively—oral iron is poorly absorbed and ineffective in this range 2, 3
• Ferritin >100 ng/mL: Iron supplementation generally not indicated based on current evidence 3

Pediatric Targets:

• Ferritin <50 ng/mL: Institute iron supplementation with oral or IV formulations 1, 2

Special Population - End-Stage Renal Disease:

• Ferritin <200 ng/mL AND transferrin saturation <20%: Use IV iron sucrose (this is the only population where iron sucrose has demonstrated efficacy) 2, 4

Critical Testing Requirements Before Treatment

• Always check serum ferritin AND transferrin saturation in all patients with clinically significant RLS before initiating any treatment 1, 2
• Timing matters: Draw blood in the morning, ideally after fasting 1, 2
• Avoid contamination: Patients must avoid all iron-containing supplements and foods for at least 24 hours prior to blood draw 1, 2, 3
• Monitor during treatment: Recheck iron studies once or twice yearly during ongoing iron therapy to ensure levels remain adequate and to screen for iron overload 5

Treatment Algorithm Based on Iron Status

Step 1: Ferritin ≤75 ng/mL or Transferrin Saturation <20%

• First-line option: Oral ferrous sulfate 65 mg elemental iron daily (conditional recommendation, moderate certainty) 2, 3
• Alternative first-line: IV ferric carboxymaltose 1000 mg (strong recommendation, moderate certainty) 2, 4
• Other IV options: Low molecular weight iron dextran or ferumoxytol (conditional recommendations) 4, 3

Step 2: Ferritin 75-100 ng/mL

• Use IV iron exclusively—oral iron will not work due to poor absorption in this range 2, 3
• Preferred: IV ferric carboxymaltose, ferumoxytol, or low molecular weight iron dextran (these slow-release, higher-dose formulations enable the H-ferritin binding and macrophage iron uptake necessary for CNS penetration) 3

Step 3: Monitor Response

• Reassess symptoms at 4-12 weeks using the International RLS Study Group Severity Rating Scale (IRLS) 6, 7
• Expect IRLS score reduction of approximately 3.5-10 points with effective iron therapy 8, 7
• Continue iron therapy indefinitely with ongoing monitoring, as RLS symptoms may recur if iron stores decline 4

Why Higher Ferritin Targets Matter in RLS

• Brain iron deficiency is central to RLS pathophysiology, requiring higher ferritin levels (≥50-75 ng/mL) for optimal neurological function and CNS iron availability 2
• Low ferritin increases augmentation risk: Patients with low serum ferritin who receive dopaminergic agents have significantly higher rates of augmentation (paradoxical worsening of symptoms), making iron repletion critical before or alongside pharmacological treatment 9
• General population cutoffs miss most RLS patients: Using standard ferritin thresholds (<15-30 ng/mL) will fail to identify the majority of RLS patients who would benefit from iron therapy 2, 3

Common Pitfalls to Avoid

• Don't use general population ferritin cutoffs (<15-30 ng/mL)—this misses most RLS patients who need iron 2, 3
• Don't assume all IV iron formulations are equivalent—iron sucrose lacks efficacy except in dialysis patients 2, 3
• Don't test iron studies while patients are taking supplements—wait at least 24 hours after the last iron-containing product 2, 3
• Don't use oral iron for ferritin 75-100 ng/mL—it will be ineffective due to poor absorption 2, 3
• Don't forget to screen for hemochromatosis—measure transferrin saturation and ferritin before initiating iron therapy, especially in patients of northern European ancestry, and evaluate elevated levels before treatment 5
• Don't start dopaminergic agents without correcting iron deficiency first—this increases augmentation risk 9

Expected Outcomes with Iron Therapy

• Meta-analysis demonstrates iron supplementation (oral or IV) reduces IRLS scores by approximately 3.55 points 8
• Response rate (≥50% reduction in IRLS score) is approximately 47% with iron monotherapy 6
• IV ferric carboxymaltose specifically improves IRLS scores by 2.79 points and RLS-Quality of Life scores by 8.67 points 8
• Adverse events with iron are typically mild (primarily gastrointestinal with oral formulations) and do not lead to increased treatment discontinuation 8