What is the best course of treatment for a 21-year-old female with a history of chronic exertional compartment syndrome (CECS) versus shin splints, presenting with symptoms concerning for restless legs syndrome (RLS), iron deficiency anemia, and hypercholesterolemia, with lab results showing hypochromic microcytic anemia and low iron stores?

Iron Deficiency Anemia with Restless Legs Syndrome in a Young Female

Lab Interpretation

Your patient has clear iron deficiency anemia (IDA) with microcytic hypochromic features that strongly supports RLS as a secondary manifestation of iron deficiency. The hemoglobin of 10.7 g/dL, MCV of 77.5 fL (microcytic), and RDW of 18.3% (elevated, indicating mixed red cell populations) combined with the initial iron panel showing transferrin saturation of 8% and TIBC of 419 µg/dL definitively establish IDA 1, 2. The elevated RDW suggests ongoing iron-deficient erythropoiesis with a mixed population of older normocytic cells and newer microcytic cells 3.

The initial iron studies are particularly telling:

• Transferrin saturation of 8% is severely low (normal >20%), indicating inadequate iron delivery to tissues including the brain 1, 4
• TIBC of 419 µg/dL is elevated, reflecting the body's attempt to capture more circulating iron 1
• Iron of 34 µg/dL is frankly low 1

Additional Labs to Order

Wait for the pending ferritin before initiating treatment, but you can start addressing RLS symptoms immediately with non-iron therapies. The ferritin is the single most critical missing value because:

• Ferritin ≤75 ng/mL triggers iron supplementation in RLS (not the general population threshold of <15 ng/mL) 1, 4
• Ferritin can be falsely elevated by inflammation, so you need both ferritin AND transferrin saturation to assess true iron status 1, 5
• Given her transferrin saturation of 8%, her ferritin will almost certainly be low, but the exact value determines treatment intensity 1

Additional labs to order now:

• CRP or ESR to assess for inflammation that might falsely elevate ferritin 5
• Reticulocyte count to assess bone marrow response to anemia 3
• Comprehensive metabolic panel if not already done, to assess renal function (eGFR) since chronic kidney disease is a strong RLS predictor 1, 5
• TSH as part of standard RLS workup to exclude thyroid dysfunction 2
• Vitamin B12 and folate since macrocytic changes can coexist and folate may help RLS 6

Do NOT order polysomnography or periodic limb movement studies—these are not indicated for routine RLS diagnosis 2.

Treatment Approach

Immediate Management (Start Now)

Begin gabapentin 300 mg at bedtime as first-line RLS treatment while awaiting ferritin results. 1. Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line pharmacological therapy for RLS with moderate certainty of evidence 1. Titrate gabapentin by 300 mg every 3-7 days up to 1800-2400 mg/day divided three times daily if symptoms persist 1.

Address exacerbating factors immediately:

• Eliminate caffeine, alcohol, and nicotine, especially within 3 hours of bedtime 1
• Review all medications for RLS-worsening agents (antihistamines, SSRIs, antipsychotics, metoclopramide) 1
• Optimize sleep hygiene: dark, quiet room, regular sleep schedule, avoid heavy meals before bed 1

Iron Repletion Strategy (Once Ferritin Returns)

If ferritin ≤75 ng/mL or transferrin saturation <20% (which is virtually certain given TSAT 8%):

Start with oral ferrous sulfate 325 mg (65 mg elemental iron) daily on an empty stomach 1. This is conditionally recommended with moderate certainty for RLS patients with appropriate iron parameters 1. Take with vitamin C to enhance absorption 1.

However, given the severity of her anemia (Hgb 10.7) and very low transferrin saturation (8%), strongly consider IV iron instead:

• IV ferric carboxymaltose 750-1000 mg is strongly recommended for RLS with appropriate iron parameters and provides rapid correction 1, 3
• IV iron may be superior to oral iron, especially when ferritin is in the 75-100 ng/mL range 1, 4
• One study showed 76% of RLS-IDA patients improved with 1000 mg IV iron dextran, with 47% showing extended response >6 months 3
• Critical caveat: Some patients required higher doses than the standard 1000 mg to achieve hemoglobin >12.5 g/dL and sustained RLS improvement 3

Monitor response:

• Recheck CBC, iron studies, and ferritin in 8-12 weeks 1
• Continue iron supplementation indefinitely with surveillance every 6-12 months, as RLS symptoms recur if iron stores decline 1
• Target ferritin >75 ng/mL and transferrin saturation >20% 1, 4

What NOT to Do

Avoid dopamine agonists (ropinirole, pramipexole, rotigotine) entirely 1, 7. The American Academy of Sleep Medicine suggests against their standard use due to high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and spread to other body parts with long-term use 1. While ropinirole is FDA-approved for RLS 7, current guidelines prioritize gabapentin over dopaminergic agents 1.

Critical Pitfalls to Avoid

1. Do not use general population ferritin thresholds (<15 ng/mL) for RLS—the brain requires higher iron stores, so supplement if ferritin ≤75 ng/mL 1, 4

2. Do not assume 1000 mg IV iron is sufficient—patients with hemoglobin <12.5 g/dL after initial IV iron may need additional dosing for sustained RLS improvement 3

3. Do not start iron without checking ferritin first—you need baseline values to monitor response, and rare patients have hemochromatosis that would be worsened by iron therapy 8

4. Do not treat RLS with iron alone—start gabapentin now for symptom relief while addressing the underlying iron deficiency 1

5. Do not ignore the hypercholesterolemia (total cholesterol 223, LDL 104)—while not directly related to RLS, this young woman needs cardiovascular risk assessment and likely lifestyle modification 1

Underlying Pathophysiology

The connection between iron deficiency and RLS is well-established: brain iron deficiency, particularly in the substantia nigra, impairs dopamine transport and synthesis, which is the critical mechanism producing RLS symptoms 4, 6. Iron serves as a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine production 6. Even when serum iron appears borderline, brain iron can be severely depleted, explaining why RLS-specific ferritin thresholds (≤75 ng/mL) are higher than general population thresholds 1, 4.

Her CECS/shin splints history may reflect exercise-induced iron losses or increased iron demands, though this is speculative 1.