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Udine Special Section
Dopamine and iron in the pathophysiology
of restless legs syndrome (RLS)
Richard Allen*
Neurology and Sleep Medicine, Johns Hopkins Bayview Medical Center, Asthma and Allergy Bldg 1B46b,
5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA
Received 1 January 2003; accepted 15 October 2003
Abstract
Background and purpose: The evaluation of the pathophysiology of restless legs syndrome (RLS) stems largely from recognition of the
information provided by both pharmacological treatment of the disorder and the secondary forms of the disorder. This article examines the
pathophysiological implications of each of these clinical aspects of RLS.
Patients and methods: The article reviews the existing literature in relation to possible pathology suggested by the clinical data. It will
then explore other data supporting each of the possible pathologies and examine the relationships between these pathologies.
Results: The pharmacological treatment data strongly support a dopaminergic abnormality for RLS. Other pharmacological data and some
imaging data also support this, although the data are not entirely consistent. The secondary forms of RLS strongly support an iron deficiency
abnormality for RLS, further documented by several other studies. Some animal studies have shown a relation between iron deficiency and
dopaminergic abnormalities that have some similarity to those seen in the RLS patient.
Conclusions: It is concluded that there may be an iron–dopamine connection central to the pathophysiology of RLS for at least some if not
most patients with this disorder.
q 2004 Elsevier B.V. All rights reserved.
Keywords: Restless legs syndrome; Dopamine; Iron; Pathophysiology; Ferritin; CSF
1. Introduction—development of the RLS program
at Johns Hopkins University
The involvement of the Johns Hopkins group in the study
of the restless less legs syndrome (RLS) started with a
review of our clinical sleep medicine cases that I conducted
in 1988–1989. When I reviewed the cases I found a large
number that had been diagnosed with periodic limb
movement disorder (PLMD) who had in general not
benefited from our treatment, which was entirely restricted
to the use of benzodiazepines and some behavioral sleep
treatments. Some complained of having an expensive test
and no help. More than half had discontinued their
medications. In the face of these discouraging results I did
a review of the literature regarding periodic limb move-
ments in sleep (PLMS) and PLMD and realized we had
failed in our sleep medicine program to appreciate that
the RLS could be a major cause of PLMS. We were all
aware that this connection had been made many years
earlier by Lugaresi et al. [1], but had simply considered the
PLMD diagnosis to be not only more common but also
clinically more significant. At that time, however, there was
no well-established diagnostic criterion for RLS and no
awareness of its prevalence or clinical significance. The
sleep education provided by the professional organization
now recognized as the American Academy of Sleep
Medicine provided little information or education about
RLS. The limited education provided about RLS (e.g. two
slides in a 1-h talk) recommended treatment based on
current literature with opiates [2], clonazepam [3] or
carbamazepine [4–7], specifically recommending avoid-
ance of dopaminergic agents because they were expected to
exacerbate the condition, based on reports of effects on
myoclonus [8]. Professional and scientific interest focused
on the periodic limb movements of sleep (PLMS). RLS was
a casual afterthought and the impression given was that it
was difficult to treat and not a common problem.
1389-9457/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.sleep.2004.01.012
Sleep Medicine 5 (2004) 385–391
www.elsevier.com/locate/sleep
* Tel.: þ1-410-550-2609; fax: þ1-410-550-3364.
E-mail address: [email protected].
The recent literature at the time of our review also
revealed that Akpinar [9,10], who was unaware of the
recommendation to avoid the use of levodopa to treat RLS,
had described a serendipitous finding to the contrary. He
reported that levodopa provided dramatic and almost
complete relief of RLS symptoms for his patients,
maintained with continued use of the medication. The
efficacy of this treatment had been further documented by
the excellent studies of Montplaisir and colleagues [11,12].
At the same time, however, Walters, Hening and Kavey
were reporting effective treatment of RLS with opioids
including propoxyphene [13]. My first goal, then, was to
determine which of these treatments we should use and
whether they were suitable for all patients with PLMD or
only those with RLS. We conducted a double-blinded
crossover pilot study to determine the relative efficacy of
carbidopa/levodopa and propoxyphene for treatment of
patients with PLMS, provided they had RLS or significant
daytime complaints indicating that PLMS disturbed their
normal functioning. We excluded patients with other sleep
disorders. Almost all selected patients had RLS, and to our
surprise all showed dramatic reduction in PLMS on a very
low dose of either 50/100 or 100/200 carbidopa/levodopa
and only marginally significant reductions on either 100 or
200 mg of propoxyphene [14,15]. We concluded that
dopaminergic medications should be considered as the
treatment of first choice for RLS, and possibly for PLMD
contingent on the patient showing significant daytime
dysfunction associated with the PLMS. Moreover, we
agreed with Montplaisir that the excellent pharmacological
response at a very low dose suggested specific dopaminergic
pathology for RLS. This appeared to be a potentially
significant area for further study. At that time we decided to
focus attention on RLS and its pathology, and this effort was
greatly enhanced when Dr Christopher J. Earley joined the
clinical and research team and committed to advancing
its work.
Further examination of all the data on RLS provided two
different bases for assessing potential pathophysiology:
pharmacological response and secondary forms of RLS. The
first strongly supports the dopaminergic abnormality, and
this has been the emphasis of most studies to date. The
second, however, fails to provide any support for RLS as a
primarily dopaminergic disorder, but rather posits the
clearly established secondary causes of RLS as iron
deficiency anemia, end stage renal disease, and pregnancy,
all involving iron insufficiency. (Note that although diabetes
and neuropathy are commonly given as causes for
secondary RLS, the data supporting this claim do not
currently exist.) There are also many other reported causes
of secondary RLS, but none aside from these three have
been clearly documented, with the possible exception of
gastric surgery. The following provides a review of the
evidence, separately for each of the suggested pathophy-
siologies for RLS, and then briefly examines some possible
connections between these two pathologies noting some
of the predictions and research gains from a putative
dopamine–iron connection in RLS.
2. Evidence for dopaminergic pathology in RLS
The strongest evidence for a dopaminergic pathology in
RLS comes from the pharmacological response to medi-
cations. To date, all evaluated agents that enhance dopamine
activity have been found to reduce RLS symptoms in open-
label uncontrolled trials. Double-blinded, placebo-con-
trolled studies have demonstrated the treatment benefit for
levodopa [12,16,17] and for the currently used major
dopamine agonists, i.e. pergolide [18,19], pramipexole
[20] and ropinirole [21]. These medications are effective
at remarkably low doses relative to that given for
Parkinson’s disease, sometimes at the minimum tablet size
available to the patient, e.g. carbidopa/levodopa at 25/100 or
pergolide at 12.5 mg. Moreover, they are effective immedi-
ately after the first therapeutic dose for virtually all patients
with RLS. The immediate, universal and almost complete
reduction of RLS symptoms by low doses of levodopa
provides strong support for a possible dopaminergic
abnormality in this disorder.
Dopamine antagonists generally exacerbate RLS symp-
toms, suggesting a primary role for the dopamine system.
In the first report of this effect, Pimozide, a dopamine
antagonist was shown to reverse treatment benefits of the
opioid Codeine in one patient [22]. In a later study,
Metoclopramide given IV produced increased RLS symp-
toms on a suggested immobilization test in five out of six
subjects evaluated [23] and produced an increase in
prolactin release [23] that was at least three times greater
than that expected from age-matched normals [24].
Dopaminergic abnormalities in the tuberoinfundibular
system have been further supported by the exaggerated
response of prolactin to levodopa [25].
It deserves note that all other types of medications used
to treat RLS require doses equivalent to those used to treat
other conditions. The doses for the opioids are usually in the
same range as that used for the analgesic treatments; e.g. the
average effective dose of oxycodone in one double-blind
controlled study was 15.7 mg (about three 5 mg tablets)
[26]. Similarly, the average effective dose of the antic-
onvulsant gabapentin in a double-blind controlled study was
1,855 mg [27], about the same as that used for seizure
control. The effects of these medications on RLS symptoms
may therefore be indirect, such as a non-specific effect on
nociception. Moreover, naloxone does not exacerbate RLS
symptoms, and when it was given IV did not produce
increased symptoms during a SIT test [23]. Thus, the
pharmacological evidence supports a dopaminergic
abnormality more than it does for any other neurotransmitter
system.
Imaging studies have produced mixed results. The one
PET study with an adequate sample size found decreased
R. Allen / Sleep Medicine 5 (2004) 385–391386
striatal D2R binding [28]. Two of four SPECT studies also
found decreased striatal D2R binding [29,30], but one of
these studies [30] was compromised by having significantly
younger controls than patients; thus the well established
decrease in D2R binding with age could explain these
results. The other study had no similar problem and was
particularly well controlled. Two other similarly well-
controlled SPECT studies, however, failed to find any
difference in striatal D2R binding [31,32]. Two SPECT
studies failed to find differences in striatal dopamine
transporter (DAT) [29,32]. But it should be noted that all
of these studies were conducted in the daytime when RLS
symptoms are minimal. It may be that evaluation of the
dopaminergic system when the patient has few symptoms
will produce variable results depending on the degree of
symptom expression, thus explaining the conflicting results
reported above. Evaluation during the symptomatic period
is needed, but has not yet been done. There is one report of a
PET study showing significant circadian changes in D1
receptor binding [33], and it seems reasonable to assume the
same may occur for D2 receptors. Moreover, DAT plays a
significant role in the substantia nigra in regulating the
nigrostriatal dopaminergic system, and this has not yet been
studied. There have also been two good studies using
F-dopa PET that both found significantly less uptake by
about 11% in the putamen for RLS patients compared to
normal controls [28,34]. One of these studies reported
approximately the same difference ðP , 0:05Þ for the
caudate [34], while the other found no significant difference
for the caudate [28]. These studies are somewhat difficult to
interpret. They suggest decreased pre-synaptic uptake, but it
deserves note that in Parkinson’s disease even patients with
significant cell loss have normal F-dopa striatal uptake. This
small decrease may reflect changes in the status of the
growth or integrity of the terminals of the dopaminergic
cells. Since fluorodopa is also taken up by serotonergic cells
there may be some uncertainty regarding the specificity of
this finding for the dopaminergic cells. Finally, there is a
problem with competitive binding for receptor uptake. An
increase in extracellular dopamine would produce a
decrease in dopamine receptor binding. The currently
available data do not permit controlling for this possibility.
Overall, the imaging data, while not entirely consistent,
support some mild reductions in the nigrostriatal dopamin-
ergic system, but further study is needed to confirm this and
better describe the characteristics of this abnormality.
3. Evidence for iron pathology in RLS
The potential central role of iron insufficiency to RLS is
indicated primarily by the secondary causes of RLS, but also
from some limited pharmacological study. Three causes of
secondary RLS have been well established. RLS develops
with the development of each of these disorders, is more
common for patients with these disorders than expected
for the population, and disappears when the disorders are
treated. End stage renal disease (ESRD) with dialysis is
perhaps the best studied of the secondary causes of RLS.
RLS develops with the disorder and occurs in 20–60% of
patients on dialysis [35–37], or about 2–6 times more
frequently than expected. The RLS symptoms with ESRD
have been related to increased mortality [35]. Kidney
transplants resolving the renal disease also lead to a
disappearance of all RLS symptoms within 1–21 days
after transplant for all patients who have been reported
[38,39]. RLS also develops in about 20–30% of pregnant
women [40,41]. Women with RLS before pregnancy
reported increased severity of RLS symptoms during
pregnancy [41]. The RLS symptoms are clinically reported
to usually resolve after pregnancy, and did so in 85% of the
cases in one study [40]. Ekbom [42] identified RLS as
commonly occurring with iron deficiency anemia and this
has gained wide clinical acceptance, although there have
been few studies documenting this relationship. O’keeffe
found that oral iron supplement treatment of iron deficiency
among older patients with RLS reduced or reversed the RLS
symptoms [43]. Data indicate that two other conditions
increasing the risk of RLS are gastric surgery and frequent
blood donations. The increased prevalence of RLS after
gastrectomy was described by Ekbom [44] and supported by
subsequent study [45]. More recent studies have documen-
ted the increased prevalence of RLS for frequent blood
donors [46]. Both neuropathy and diabetes have been
reported to be associated with the development of RLS, but
survey studies using full diagnostic criteria have failed to
find any significant increase in the prevalence of RLS for
either neuropathy [47] or diabetes [48].
All of the established causes of secondary RLS involve
compromise of iron sufficiency. Treatment with IV iron and
erythropoietin reduced the RLS symptoms of PLMS in one
study of patients on dialysis [49]. Iron deficiency commonly
occurs in pregnancy, and the pregnant women at risk of RLS
showed compromise in iron status before pregnancy [40],
although it was noted that folate may also be involved.
Correcting iron status in patients with iron deficiency has
been found to reduce RLS symptoms [43]. Both gastric
surgery and frequent blood donations have a
well-recognized increased risk of reduced iron sufficiency.
Virtually all the conditions clearly associated with common
occurrence of secondary RLS involve problems
with iron metabolism, and the obverse is also true; all
conditions involving iron insufficiency increase the risk of
developing RLS.
The relationship between iron and RLS was recognized
much earlier by Nordlander, who postulated that a tissue
deficiency in iron might be responsible for the occurrence of
RLS. He also used IV iron to treat RLS patients, including
several without clear anemia, and reported complete
remission of symptoms lasting several months for 21 of
the 22 patients. [50,51]. Thus, pharmacological data as well
R. Allen / Sleep Medicine 5 (2004) 385–391 387
as data from secondary RLS strongly support a relation
between iron deficiency and RLS.
4. Evaluation of iron status in RLS
If we assume that the primary pathology of RLS involves
iron insufficiency, then we want to measure the iron status
and relate it to the RLS status. Our group at Johns Hopkins
and Hershey School of Medicine has explored four different
methods for evaluating the iron status of RLS patients; i.e.
serum measures of ferritin, CSF measures of ferritin and
transferrin, magnetic resonance imaging (MRI) measures of
regional brain iron concentrations and autopsy evaluations
of brain iron status. All of these have supported the view that
there is a brain iron deficiency in RLS patients.
The serum ferritin had previously been found by
O’Keeffe to correlate with RLS symptoms for older
patients. O’Keeffe correctly recognized that serum ferritin
provides the best measure of peripheral iron stores. Serum
measures of iron and transferrin relate more to immediate
activity of iron transport and only very poorly to the status
of the body stores of iron. Even the serum measure of the
soluable transferrin receptor [52], when in the normal range,
relates to the rate of erythropoiesus more than to iron stores,
although when abnormal provides a more reliable measure
of the iron deficiency. Ferritin, in contrast, relates to iron
stores over a wider range with the exception of the elevated
values seen in response to disease states. We decided to
replicate the O’Keeffe finding and extend it to a full age
range of RLS patients. For our study we also developed and
validated a fairly simply clinical rating scale for RLS
severity, the Johns Hopkins Restless Legs Scale (JHRLSS).
This scale assessed RLS severity by the patients’ report of
the usual time of symptom onset, with 0 indicating no
symptoms, 1 symptoms only at or after bedtime, 2
symptoms in the evening (after 6 p.m.) but not earlier, and
3 symptoms earlier in the day. This scale correlated
significantly with the objective polysomnographic measures
of sleep disruption from RLS of PLMS/h of sleep and sleep
efficiency [53] and has been shown to be responsive enough
to detect treatment benefits in small-size, double-blinded
medication trials [54]. In a consecutive series of available
RLS patients we found approximately the same degree of
correlation between our subjective scale for RLS severity
and serum ferritin (r ¼ 0:48; P ¼ 0:02; see Fig. 1) [55] as
was reported by O’Keeffe for his older RLS patients.
In a subsequent study, morning CSF iron measures
were obtained from 16 consenting RLS patients and eight
age-matched normal controls. Studies with iron-deprived
rats indicate that low CSF ferritin and high transferrin can
be expected to occur with reduced brain iron. The RLS
patients compared to controls showed differences for both
iron status measures in the CSF ðP , 0:02Þ; despite having
normal serum levels for all iron measures, and all 16
patients were abnormal in at least one of these CSF
measures. Thus, all RLS patients in this study showed
abnormally reduced CNS iron status. A particularly striking
finding from that study was the positive correlation between
serum and CSF ferritin. Higher levels of ferritin in the serum
were associated with higher levels in the CSF for both
normal controls and RLS patients, but the slope of this
relationship was much lower for the RLS patients. Thus, for
RLS patients, higher levels of 200 mcg/l or greater for
serum ferritin tended to occur with CSF ferritin in the low
range of the usual normal levels.
The MRI has long been known to be altered by the
amount of iron in ferritin, and recent studies have developed
a valid MRI measure of regional brain iron concentration.
For this measure the transverse relaxation rates or the
inverses of the relaxation times are used, and it has been
found that R02; representing the relaxation resulting from
field inhomogeneities that can be reversed by an 1808 pulse,
provides the most specific measure of regional brain iron. R2
is measured as the irreversible transverse relaxation rate and
Rp2 represents the sum of R0
2 and R2: The images with Rp2 will
have the most sensitive measure of iron content and are used
for identification of significant regions, but the values of R02
are the most specific for iron since they will not be
contaminated by other factors affecting R2 relaxation rates
such as brain water content [56]. In our study of five RLS
patients and five age-matched controls the RLS patients
showed significant decreases in R02 in the substantia nigra,
which correlated significantly with the JHRLSS measure of
severity [57]. The much lower iron content in the substantia
nigra can be clearly seen for the RLS patient compared to
the control (shown in Fig. 2). Thus, the brain iron problems
for RLS involve particularly significant iron reduction in the
substantia nigra, which appears not only to be related to
occurrence of RLS but also to its severity.
Finally, a recent initial report of an autopsy analyses of
the substantia nigra for an RLS patient compared to controls
showed reduced iron content in the cells, an apparent
Fig. 1. Serum ferritin levels and RLS severity for a consecutive available
RLS patients. (reprinted with permission from Sun, et al. 1998).
R. Allen / Sleep Medicine 5 (2004) 385–391388
reduction in H-ferritin along with an abnormal cellular
distribution of L-ferritin [58].
The combined impact of all these studies can leave little
doubt that at least some, and probably most RLS patients
have an abnormality of iron metabolism that appears central
to the pathology of the disorder. The question remains about
the connection between these two pathologies for RLS: iron
and dopamine.
5. Possible connections between iron and dopamine
pathology in RLS
Iron is known to be a co-factor at the rate-limiting step in
the production of dopamine, and decreased iron may reduce
the tyrosine hydroxylase activity. This, however, was not
clearly shown in the autopsy study [58], and the role of iron
in this step may not be very sensitive to iron loss. Iron
deprived rats with brain iron deficiency have been found to
have decreased D1 and D2 receptors [59], decreased DAT
[60], and increased extra-cellular dopamine in the striatum
[61] and a more consistent decrease in H- than L-ferritin in
brain regions [62]. As noted above, two imaging studies of
RLS patients suggest a possible decrease in the D2R binding
[28,29], which could reflect a decrease in the D2 receptors,
an increase in extra-cellular dopamine, or both. The autopsy
studies have also shown a greater decrease in H- than
L-ferritin [58]. These results are in general consistent for
both the RLS patients and the effects of iron deprivation on
dopaminergic function in the rat brain. The findings for the
DAT are, however, not the same for the rat iron-deficiency
and human RLS, but the DAT studies for RLS patients
involved only daytime evaluations and did not use the more
sensitive PET measures. These need to be extended before it
is clear that this is a real difference. The similarities of the
dopaminergic abnormalities resulting from brain iron
deprivation in the rat and those observed to occur in RLS
patients indicate a possible strong iron-dopamine connec-
tion in RLS pathology that should be further explored.
It is particularly interesting to note that most of these
animal studies have neglected to examine the circadian
effects. One study evaluated changes in the extra-cellular
dopamine of normal and iron-deprived rats over the time
period from the last part of the rest period through the first
part of the active period (from light to dark periods). The
normal animal showed a significant increase in extra-
cellular dopamine, but the iron-deprived rat showed an
increase that was four times greater [61]. This is particularly
hard to explain given that motor activity is, if anything
generally decreased for these iron-deprived animals during
the active period. The issue of circadian variation in
dopamine function in relation to iron deficiency deserves
to be more carefully explored, especially given the
pronounced circadian pattern of RLS symptoms.
6. Conclusions
The data reviewed above provides support for the view
that iron and dopamine may be linked in producing RLS
symptoms. Further evaluation of the iron–dopamine
connection in general, and particularly in relation to RLS,
is needed.
Acknowledgements
This work was supported in part by US NIH grant
R01-NS38704.
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