Iron deficiency with normal ferritin levels in restless legs syndrome
Shaun T. O’Keeffe*
Department of Geriatric Medicine, Unit 4, Merlin Park Regional Hospital, Galway, Ireland
Received 22 September 2004; received in revised form 20 October 2004; accepted 21 October 2004
This report describes a patient with iron deficiency in bone marrow examination and iron-responsive restless legs syndrome (RLS), in
whom serum ferritin levels were well above the conventional cutofffor considering iron deficiency. The predictive value of serum ferritin for
iron deficiency in RLS depends on the cutoff employed, on the pre-test likelihood of iron deficiency and on coexisting inflammatory
conditions. Bone marrow examination is helpful when ferritin levels are equivocal.
q 2004 Elsevier B.V. All rights reserved.
Keywords: Iron deficiency; Restless legs syndrome; Ferritin levels
There is convincing evidence that iron status is an
important factor in the pathogenesis of restless legs
syndrome (RLS) . Iron deficiency is common in RLS
patients, and iron therapy can lead to considerable
improvement in symptoms . Radiographic and autopsy
studies have found reduced iron in the basal ganglia of RLS
subjects [3,4]. Altered dopaminergic neurotransmission
seems important in RLS, and iron is an essential cofactor
for tyrosine hydoxylase, the rate-limiting enzyme for
Serum ferritin is the best screening test for iron
deficiency . O’Keeffe et al. reported an inverse
relationship between ferritin levels and the severity of
restless legs in older patients and that patients with a serum
ferritin less than 45 mcg/L were most likely to respond to
iron therapy .Sun et al.found that almost all patients with
severe RLS attending a referral centre had serum ferritin
levels of 50 mcg/L or less .
Based on these studies, serum ferritin measurement,
using a cutoff of 50 mcg/L is now recommended as a
screening test for iron deficiency in RLS . However, use
of a single cutoff point for serum ferritin to distinguish
normal from abnormal is not always appropriate. In this case
report, I discuss a patient with iron deficiency in bone
marrow examination and iron-responsive RLS, in whom
serum ferritin levels were potentially misleading.
1. Case report
The subject was an 83-year-old man with a 2-year history
of severe RLS. At the time of presentation, he was
experiencing symptoms for several hours every night. His
severity score on the International RLS Study Group
(IRLSSG) rating scale was 29 out of 40, corresponding to
severe restless legs . He was not aware of any relative
with similar symptoms.
The patient had a history of ischaemic heart disease and
of bronchiectasis secondary to old tuberculosis. Medications
on admission were aspirin 150 mg daily, ranitidine 150 mg
daily, enalapril 5 mg daily and bendrofluazide 2.5 mg daily.
On physical examination, neurological and abdominal
examinations were normal with a negative stool test for
occult blood. Blood tests were essentially normal. In
particular, hemoglobin was 12.7 g%, mean corpuscular
volume was 89, transferrin saturation was 25% and serum
ferritin was 93 mcg/L. ESR was slightly elevated at 52.
Temazepam had been tried without success before
presentation. Trials of treatment with low doses
of pramipexole, pergolide and levodopa all caused
unacceptable nausea. There was a limited response to
clonazepam 0.25 mg nocte, but this also caused some
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daytime drowsiness. Repeat serum ferritin at this time was
84 ng/mL, and ESR was 45.
A bone marrow aspirate was performed. Iron stores were
absent on staining with Prussian blue. There were no other
abnormalities. A diagnosis of iron deficiency was made. The
patient was commenced on iron and vitamin C and on a
proton pump inhibitor. Ferrous fumarate 140 mg twice daily
after food was well tolerated. The patient refused gastro-
intestinal investigation. On review 6 weeks later, restless
legs symptoms had improved and IRLSSG score was 22.
Serum ferritin was now 114 ng/mL. On review at 4 months,
serum ferritin was 136 and IRLSSG score was 16,
corresponding to mild RLS.
The gold standard for determining iron deficiency is
examination of the bone marrow for absent iron stores. This
is an unpleasant procedure, and blood tests are usually
preferred. Studies comparing blood tests with bone marrow
examination in people with suspected iron deficiency have
shown that serum ferritin is the best screening blood test in
older people, although serum soluble transferrin receptor
(or the ratio of transferrin receptor to ferritin or to log
ferritin) has emerged as potentially better in younger
The predictive value of serum ferritin, as with any
diagnostic test, varies with the cutoff employed and with the
prior probability of disease. The greater the pre-test
probability of iron deficiency, the greater is the likelihood
of iron deficiency at any level of serum ferritin. Serum
ferritin is also an acute phase reactant, and levels are
increased in patients with acute and chronic inflammatory
conditions or with liver disease. In such patients, the
likelihood of iron deficiency does not start to drop until
serum ferritin levels are higher than 70 mcg/L, compared
with 45 mcg/L in the general population .
These considerations can be applied to the patient
reported here. He had nonfamilial, very late onset RLS, a
plausible risk factor for iron deficiency (aspirin treatment), a
chronic inflammatory condition (bronchiectesis) and serum
ferritin levels around 90 mcg/L. Secondary causes of RLS,
including iron deficiency, seem most common in those who
develop the condition at an older age . Our previous work
suggests a conservative estimate for pre-test probability of
iron deficiency in this group of about 30% . The
likelihood ratio for iron deficiency is 0.57 for a patient
with an inflammatory condition who has a serum ferritin of
90 mcg/L ; in other words, this test result is 0.57 times
as likely to come from patients with iron deficiency as from
patients without. This corresponds to a post-test probability
of iron deficiency of 20%. Thus, the ferritin levels in this
patient, while well within the conventional normal range,
did not in fact exclude the possibility of iron deficiency. In
contrast, in a younger patient with familial RLS, no
inflammatory disease and, say, an estimated pre-test
probability of iron deficiency of 10%, a serum ferritin of
90 mcg/L would give a likelihood ratio of 0.34 and a post-
test probability of 4% and would effectively rule out iron
Individual clinical factors must be taken into account
when interpreting serum ferritin levels in RLS patients.
Recognition of iron deficiency is important in such patients
because they are likely to benefit from iron therapy and
because investigations may show a serious cause for iron
deficiency . Bone marrow examination is definitive and
should be considered when ferritin results are equivocal
such as in those with an elevated ESR or C-reactive protein
or when there is a strong likelihood of iron deficiency.
Examination of the bone marrow may also help to clarify
the relationship between systemic and regional brain iron
status in RLS in future research.
 Earley CJ, Allen RP, Beard JL, Connor JR. Insight into the
pathophysiology of restless legs syndrome. J Neurosci Res 2000;62:
 O’Keeffe S, Gavin K, Lavan J. Iron status and restless legs syndrome
in the elderly. Age Ageing 1994;23:200–3.
 Allen RP, Barker PB, Wehrl F, et al. MRI measurement of brain iron
in patients with restless legs syndrome. Neurology 2001;23:263–5.
 Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological
examination suggests impaired brain iron acquisition in restless legs
syndrome. Neurology 2003;61:304–9.
 Guyatt GH, Patterson C, Ali M, et al. Diagnosis of iron-deficiency
anemia in the elderly. Am J Med 1990;88:205–9.
 Sun ER, Chen CA, Ho G, et al. Iron and the restless legs syndrome.
 Restless legs syndrome. Detection and management in primary care.
NIH Publication No. 00-3788; 2000.
 Walters AS, LeBrocq C, Dhar A, et al. Validation of the International
Restless Legs Syndrome Study Group Rating Scale for restless legs
syndrome. Sleep Med 2003;4:121–32.
 Joosten E, Van Loon R, Billen J, et al. Serum transferrin receptor in
the evaluation of the iron status in elderly hospitalized patients with
anemia. Am J Hematol 2002;69:1–6.
 Guyatt GH, Oxman AD, Ali M, et al. Laboratory diagnosis of iron-
deficiency anemia: an overview. J Gen Intern Med 1992;7:145–53.
S.T. O’Keeffe / Sleep Medicine 6 (2005) 281–282282