What is the best course of management for a patient with lethargy, dizziness, and restless leg syndrome, who has a history of low iron (Fe) levels and is currently taking iron supplements?

Management of Lethargy, Dizziness, and Restless Leg Syndrome with History of Low Iron

Order morning fasting serum ferritin and transferrin saturation immediately (after holding iron supplements for 24 hours), and if ferritin ≤75 ng/mL or transferrin saturation <20%, continue oral iron supplementation while simultaneously initiating gabapentin, gabapentin enacarbil, or pregabalin as first-line pharmacological therapy. 1

Immediate Diagnostic Workup

• Check serum iron studies including ferritin and transferrin saturation in the morning after avoiding iron-containing supplements for at least 24 hours 1
• The threshold for iron supplementation in RLS differs from general population guidelines: supplement if ferritin ≤75 ng/mL or transferrin saturation <20% (not the typical anemia thresholds) 1
• Measure transferrin saturation and ferritin before continuing iron therapy to rule out hemochromatosis or iron overload, as iron therapy can unmask hereditary hemochromatosis 2
• Re-measure serum iron parameters once or twice yearly during ongoing iron therapy 2

The American Academy of Sleep Medicine specifically recommends higher ferritin targets for RLS patients because brain iron deficiency plays a key role in pathophysiology even when serum iron appears normal 1. This patient's lethargy and dizziness may be multifactorial—related to both iron deficiency and RLS-associated sleep disruption, as insomnia occurs in approximately 90% of RLS patients and represents the primary morbidity 1.

Iron Supplementation Strategy

• Continue oral ferrous sulfate if ferritin ≤75 ng/mL or transferrin saturation <20% (conditional recommendation, moderate certainty) 1
• If no response to oral therapy after adequate trial, consider IV ferric carboxymaltose (strong recommendation, moderate certainty) 1
• Iron supplementation should be continued indefinitely with ongoing monitoring, as RLS symptoms may recur if iron stores decline below therapeutic thresholds 1
• Maintenance surveillance with iron studies every 6-12 months is necessary even with symptom resolution 1

Critical caveat: Iron supplementation alone is insufficient for clinically significant RLS—one Cochrane review found no clear benefit of iron monotherapy for RLS symptoms (mean difference in IRLS severity scores of -3.79,95% CI: -7.68 to 0.10, p = 0.06) 3. However, a network meta-analysis showed iron supplement significantly alleviates RLS symptoms in patients with iron deficiency (MD -5.15,95% CI -8.99 to -1.31) but not in those with normal ferritin 4. This underscores why checking iron levels is essential before making treatment decisions.

First-Line Pharmacological Treatment

• Initiate alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line therapy regardless of iron status (strong recommendation, moderate certainty of evidence) 1
• Gabapentin dosing: start 300mg three times daily (900mg/day total), titrate up to 1800-2400mg/day divided three times daily if symptoms persist after 3-7 days 1
• Pregabalin allows twice-daily dosing and may have superior bioavailability compared to gabapentin 1
• Alpha-2-delta ligands are now preferred over dopamine agonists because they avoid augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread 1

The American Academy of Sleep Medicine strongly recommends against standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to high risk of augmentation 1, 5. Common side effects of gabapentin include somnolence and dizziness, which are typically transient and mild 1.

Addressing Exacerbating Factors

• Review and discontinue medications that worsen RLS: antihistaminergic medications, serotonergic medications (SSRIs, tricyclic antidepressants), antidopaminergic medications (antipsychotics), and lithium 1, 6
• Eliminate alcohol and caffeine, especially in the evening, as even moderate amounts can significantly worsen RLS symptoms 1
• Screen for and treat untreated obstructive sleep apnea if present 1
• Avoid heavy meals or drinking within 3 hours of bedtime 1

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months during treatment 1
• Monitor for side effects of alpha-2-delta ligands including dizziness and somnolence 1
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1
• Prior to initiating alpha-2-delta ligands, evaluate risk factors for misuse, as there is increasing evidence these agents may be misused in certain populations 1

Alternative Considerations

• Do not trial unproven supplements like thiamine, vitamin B12, or magnesium as monotherapy, as the American Academy of Sleep Medicine guidelines do not recommend these as standard treatments for RLS 5
• Melatonin can be safely used for sleep-related issues without concern for RLS symptom exacerbation 6
• For refractory cases after failure of first-line treatment, consider extended-release oxycodone or other low-dose opioids (conditional recommendation, moderate certainty) 1

The key pitfall to avoid: Do not delay evidence-based treatment by trialing unproven supplements or relying solely on iron supplementation without concurrent pharmacological therapy 5. The combination of correcting iron deficiency and initiating alpha-2-delta ligands addresses both the underlying pathophysiology (brain iron insufficiency affecting dopaminergic function) and provides symptomatic relief 7, 8.