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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: þ 1-410-550-3364. E-mail address: [email protected].

Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)

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Page 1: Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)

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].

Page 2: Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)

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

Page 3: Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)

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

Page 4: Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)

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

Page 5: Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)

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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