Why is iron testing recommended for patients with Restless Leg Syndrome (RLS)?

Iron Testing in Restless Leg Syndrome: Essential for Diagnosis and Treatment

Iron testing is essential in all patients with Restless Leg Syndrome (RLS) because iron deficiency is a key pathophysiological factor in RLS, and iron supplementation is a first-line treatment for patients with low iron parameters, which can significantly improve symptoms and quality of life. 1

Iron's Role in RLS Pathophysiology

Iron deficiency in the central nervous system appears to be a fundamental mechanism in RLS development, even when peripheral iron measures may be within normal population ranges. This is why iron testing is critical for proper management:

• Iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis
• Brain iron deficiency can lead to dopaminergic dysfunction, a key factor in RLS symptoms
• Iron status directly influences treatment decisions and outcomes

Specific Iron Parameters to Test

According to the 2025 American Academy of Sleep Medicine (AASM) clinical practice guideline, clinicians should test: 1

• Serum ferritin
• Transferrin saturation (calculated from iron and total iron binding capacity)

Testing Protocol

For accurate results: 1

• Test should be administered in the morning
• Patient should avoid all iron-containing supplements and foods for at least 24 hours prior to blood draw

Treatment Thresholds Based on Iron Testing

The AASM guideline provides specific thresholds for iron supplementation in RLS patients that differ from general population guidelines: 1

For adults with RLS:

• Oral or IV iron if serum ferritin ≤ 75 ng/mL or transferrin saturation < 20%
• IV iron only if serum ferritin is between 75 and 100 ng/mL

For children with RLS:

• Oral or IV iron if serum ferritin < 50 ng/mL

Treatment Recommendations Based on Iron Status

The AASM makes several recommendations regarding iron therapy for RLS: 1

• Strong recommendation: IV ferric carboxymaltose for adults with appropriate iron status parameters (moderate certainty of evidence)
• Conditional recommendations:
  • IV low molecular weight iron dextran (very low certainty of evidence)
  • IV ferumoxytol (very low certainty of evidence)
  • Ferrous sulfate (oral) (moderate certainty of evidence)

Clinical Implications of Iron Testing

Iron testing directly impacts clinical decision-making:

1. Identifies patients who may benefit from iron supplementation rather than other medications
2. Determines the appropriate route of iron administration (oral vs. IV)
3. Helps monitor treatment response and need for additional supplementation
4. May prevent unnecessary use of medications with higher side effect profiles

Common Pitfalls to Avoid

• Not testing iron parameters: Some clinicians may jump to prescribing dopamine agonists or alpha-2-delta ligands without checking iron status first
• Using general population iron thresholds: The thresholds for iron supplementation in RLS are higher than for the general population 1
• Not repeating iron studies: Iron parameters should be regularly monitored in RLS patients
• Overlooking iron status in patients on dopaminergic medications: Iron deficiency can worsen augmentation, a serious side effect of dopaminergic drugs

Treatment Algorithm

1. Test serum ferritin and transferrin saturation in all RLS patients
2. Address exacerbating factors (alcohol, caffeine, antihistamines, serotonergic and antidopaminergic medications, untreated sleep apnea) 1
3. If ferritin ≤ 75 ng/mL or transferrin saturation < 20%:
   • Begin with oral iron (ferrous sulfate) if tolerated
   • Consider IV iron if oral iron not tolerated or ineffective
4. If ferritin between 75-100 ng/mL:
   • Consider IV iron only
5. If iron parameters normal:
   • Consider alpha-2-delta ligands (gabapentin, pregabalin) as first-line pharmacologic therapy 1

Iron therapy has been shown to significantly reduce RLS symptoms and improve quality of life in multiple studies, with meta-analyses demonstrating meaningful reductions in RLS severity scores 2, 3.