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Editorial
Wrestling with restless legs
While most people take comfort in the knowledge that a
peaceful rest awaits them at the end of a weary day, the
many who suffer from restless legs syndrome (RLS) find no
such reward in recumbency. The therapeutic dilemma of
how to bring about resolution of symptoms for those
patients suffering from RLS has thus disturbed the slumber
of more than one neurologist, primary care physician, and
yes, even the lowly nephrologist.
In many disease states, serendipitous discoveries provide
clues that help unlock key pathophysiologic processes,
eventually providing satisfactory therapeutic solutions. So
appears to be the case with RLS, where iron seems to be
lynchpin to the disorder [1,2], serving as a probe that is
allowing pieces of the mechanistic puzzle to gradually fall
into place.
Iron is a critical element in healthy neuronal cell
function, acting as an essential co-factor for neurotransmit-
ter synthesis [3]. Dopamine synthesis in the substantia nigra
is dependent on iron acting as a co-factor for cytosolic
tyrosine hydroxylase. In particular, iron is a co-factor for the
rate-limiting step required to convert tyrosine to levodopa.
The latter is then decarboxylated to form dopamine. As
such, low levels of iron in the basal ganglia and other
‘movement centers’ of the brain can reduce levels of this
neurotransmitter critical to movement and cognition. The
presence of diminished iron stores in the substantia nigra of
individuals afflicted with RLS adds support to this
hypothesis [4]. Alternatively, studies in iron-deficient rats
have shown decreased activity of dopamine transporter
(DAT) in pre-synaptic neurons, perhaps mediated by
decreased D2 receptor expression [5]. The resultant decrease
in reuptake of dopamine from the synaptic cleft may trigger
ligand-induced down-regulation of D1 receptors and
aberrant neurotransmission. Some reversibility of DAT
and dopamine receptor levels has been demonstrated with
iron repletion in these animals [6].
Iron metabolism is tightly regulated within the neuron
owing not only to its importance in normal cellular
physiologic functioning, but the vulnerability of the cell to
excessive accumulation. Ferrous (FeC2) iron is lethal to
neuronal cell membranes given its capability of forming
intracellular hydroxyl radicals [7]. Transferrin receptors
expressed on the neuronal cell surface serve to transport
1389-9457/$ - see front matter q 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.sleep.2005.02.006
ferric iron (FeC3) transferrin complex into the cell [8].
Of note, neuronal transferrin receptor expression is
increased by iron deficiency. Once the iron-transferrin
complex is endocytosed, iron is released from transferrin
into endosomes, reduced again to its ferrous form, and
transported into the cytosol by divalent metal transport 1
(DMT1). Excessive cytosolic iron build-up is further
precluded by ferroportin1, a membrane-bound protein that
mediates ferrous iron egress from the cell. In concert with
the ferrous oxidase activity of hephastine, a ceruloplasmin-
like protein, ferrous iron is oxidized and exported into the
brain interstitium to be bound again by transferrin. Iron can
then be transported back into the blood, carried to other
tissues, or to serum ferritin for storage. Neural storage of
iron by intracellular ferritin occurs only in a few selected
areas of the brain, of which the substantia nigra, putamen,
and other basal ganglia nuclei are excluded. Conversely,
dopaminergic neurons in these areas contain neuromelanin,
an iron-storage pigment with less iron-binding capacity than
ferritin. The exact nature and function of neuromelanin is
currently not fully understood [9].
As noted above, a considerable body of evidence now
suggests that a defect in the metabolism of neurocellular
iron plays a causative role in RLS. Recent studies have
demonstrated salutary effects of high dose intravenous iron
in the treatment of subjects with both primary and secondary
RLS [10,11]. In this issue of Sleep Medicine, Earley et al.
report the effects of repetitive intravenous iron adminis-
tration to patients experiencing a relapse of RLS after
achieving a beneficial response to a previous dose of infused
iron. They observed an apparent attenuated rate of iron loss
measured by decelerated ferritin decay after each sequential
dose. Sustained serum ferritin levels and RLS response
might well be explained here by iron supersaturation of
neurocellular ferritin and neuromelanin, co-factor sites for a
neurotransmitter synthesis and D2 receptor expression, and
decreased expression of transferrin receptors and/or
increased ferroportin1 activity. This would be not all that
unexpected given the abundance of iron provided by
intravenous administration. Recent studies of leukocyte
iron dysmetabolism in end-stage renal disease [12], a
condition where secondary RLS reaches a prevalence of
20–57% [8], reveal up-regulated transferrin receptor and
down-regulated ferroportin1 activity. If these two iron
transporter defects also exist in neurons of ESRD patients,
Sleep Medicine 6 (2005) 295–296
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Editorial / Sleep Medicine 6 (2005) 295–296296
one would expect copious cytosolic iron available to
facilitate neurotransmitter synthesis. That ESRD patients
with RLS experience a beneficial response to administered
iron despite apparent normal or supranormal iron stores
implies the contrary, however. Assuming that defects are
similar in primary and secondary RLS, the above studies
taken together might imply that iron is not available in the
cytosol for neurotransmitter synthesis or D2 receptor
expression, perhaps due to abnormal offloading of iron
from DMT1 or subtle changes in microenvironmental pH
that preclude dissociation of iron from its carrier or storage
vehicle.
There is obviously more work to be done. However, the
sharing of experiences and information across subspecial-
ties should allow future collaborative efforts to pinpoint
single or multiple subcellular defects in this ubiquitous
disorder. One can only hope that this will translate
into successful, long lasting therapeutic interventions that
will guarantee both the patients with RLS and their care
providers a good night’s rest.
References
[1] Ekbom KA. Restless legs syndrome. Neurology 1960;10:868–73.
[2] Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and restless legs
syndrome. Sleep 1998;21:371–7.
[3] Blake D, Williams A, Pall H, Fonseca A, Beswick T. Iron and
akathisia. Br Med J 1986;292:1393.
[4] Allen RP, Barker PB, Wehrl F, Song HK, Early CJ. MRI measurement
of brain iron in patients with restless legs syndrome. Neurology 2001;
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[5] Erikson KM, Byron BC, Beard JL. Iron deficiency alters dopamine
transporter functioning in rat striatum. J Nutr 2000;130:2831–7.
[6] Beard J, Erikson KM, Byron BC. Neonatal iron deficiency results in
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[7] Nappi AJ, Vass E. Iron, metalloenzymes, and cytotoxic reactions. Cell
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[8] Moos T, Morgan EH. The metabolism of neuronal iron and its
pathogenic role in neurologic disease. Ann NY Acad Sci 2004;1012:
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[9] Zucca FA, Giaveri G, Gallorini M, et al. The neuromelanin of human
substantia nigra: physiological and pathogenic aspects. Pigment Cell
Res 2004;17:610–7.
[10] Earley CJ, Heckler D, Horska A, Barker PB, Allen RP. The treatment
of restless legs syndrome with intravenous iron dextran. Sleep Med
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[11] Sloand JA, Shelly MA, Feigin A, Bernstein P, Monk MD. A double-
blind, placebo-controlled trial of intravenous iron dextran therapy in
patients with end stage renal disease and restless legs syndrome. Am
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[12] Otaki Y, Nakanishi T, Hasuike Y, et al. Defective regulation of iron
transporters leading to iron excess in polymorphonuclear leukocytes
of patients on maintenance hemodialysis. Am J Kidney Dis 2004;43:
1030–9.
James A. Sloand
Nephrology Division,
University of Rochester, Rochester, NY, USA
E-mail address: [email protected]
Received 17 February 2005
Accepted 17 February 2005
