restless legs syndrome in patients on dialysis

R

●

Sttvtciassimcmt©

Il

Rtmbwqbmtceds

The Official Journal of the

National Kidney Foundation

VOL 43, NO 5, MAY 2004

AJKD American Journal ofKidney Diseases

A

EVIEWS

Restless Legs Syndrome in Patients on Dialysis

David Kavanagh, MRCP(UK), Samira Siddiqui, MRCP(UK), andColin C. Geddes, FRCP(Glasgow)

The past decade has seen an explosion of interest in both idiopathic and secondary restless legs syndrome (RLS).econdary RLS occurs in patients with uremia, pregnancy, and iron deficiency. Patients experience an irresistible urge

o move the legs that is worse during inactivity and at night. RLS affects 6.6% to 62% of patients on long-term dialysisherapy and is associated with a greater mortality risk. The wide range of reported prevalence is explained in part byariations in methods of diagnosis. The International Restless Legs Syndrome Study Group defined diagnostic criteriahat have improved the quality of RLS research. Advanced neurological imaging techniques suggest the pathophysiologi-al state of idiopathic RLS involves dysfunction of subcortical areas of the brain. Dopaminergic pathways and neuronalron handling have been implicated. Limited studies of patients with uremic RLS suggested similar mechanisms, butnemia, hyperphosphatemia, and psychological factors also may have a role. The few clinical trials in uremic RLSuggest that treatment should involve the reduction of potential exacerbating agents (tricyclic antidepressants,elective serotonin uptake inhibitors, lithium, and dopamine antagonists), correction of anemia (with erythropoietin andron), and use of levodopa or dopamine agonists. Other agents shown to be of benefit in idiopathic RLS can be tried, but

ay be limited by side effects in patients with uremia (benzodiazepines, opioids, gabapentin, carbamazepine, andlonidine). Symptoms of uremic RLS will disappear within a few weeks of successful renal transplantation. The progressade to date in unraveling the pathophysiological state of uremic RLS should stimulate additional research toward

argeted therapy. Am J Kidney Dis 43:763-771.2004 by the National Kidney Foundation, Inc.

NDEX WORDS: Dialysis; dopamine; hyperphosphatemia; iron deficiency; kidney failure; pathophysiology; restless
egs syndrome (RLS); treatment; uremia; levodopa (L-dopa); iron deficiency.
tt

1

GTR

J

gG

Related article, p. 900

ESTLESS LEGS syndrome (RLS) causesmuch distress to many patients on long-

erm dialysis therapy. Patients experience an al-ost irresistible urge to move their legs caused

y an unpleasant sensation in the legs that isorse during inactivity and at night. As a conse-uence, patients experience severe sleep distur-ance and, occasionally, daytime sleepiness. Ure-ic RLS is common, underdiagnosed,1 and

reatable. As well as outlining the epidemiologi-al characteristics of uremic RLS, this reviewxamines recent evidence that enhances our un-erstanding of the pathophysiological state andummarizes current evidence for therapeutic in-

merican Journal of Kidney Diseases, Vol 43, No 5 (May), 2004: p

erventions that now offer the potential for effec-ive symptom reduction.

HISTORY

Symptoms of RLS were described first in672 by Sir Thomas Willis.2 For more than 4

From the Department of Nephrology, Institute of Humanenetics, International Centre for Life, Newcastle-upon-yne, England; Renal Unit, Glasgow Royal Infirmary; andenal Unit, Western Infirmary, Glasgow, Scotland.Received September 17, 2003; accepted in revised form

anuary 12, 2004.Address reprint requests to Colin C. Geddes, FRCP(Glas-

ow), The Renal Unit, Western Infirmary, Glasgow, Scotland11 6NT. E-mail: [email protected]© 2004 by the National Kidney Foundation, Inc.0272-6386/04/4305-0001$30.00/0
doi:10.1053/j.ajkd.2004.01.007
p 763-771 763

cmmPcp

mwsinwitef1m

atqvct(tp

tsritt

terilssdascpnl

lhmc

pil

RWWCHHMSCK

K

FBTS

KAVANAGH, SIDDIQUI, AND GEDDES764

enturies, the syndrome was largely ignored,aking only fleeting appearances in literature,3

ost notably in Anton Chekhov’s The Weddingroposal.4 It was only in 1945 that Karl Ekbom5

omprehensively described the symptom com-lex that is RLS.

EPIDEMIOLOGICAL CHARACTERISTICS

Idiopathic RLS is one of the most commonovement disorders in the general population,ith a prevalence of 1.2% to 15%.6,7 Uremia is a

econdary cause of RLS. Other secondary causesnclude iron deficiency anemia, pregnancy, andeurological lesions. Drugs may precipitate ororsen RLS. Idiopathic RLS shows a high famil-

al tendency and high concordance for identicalwins.8 The genetic tendency remains to be fullylucidated, but linkage studies of individual largeamilies suggest susceptibility loci in 12q9 and4q.10 There also may be a genetic link betweenonoamine oxidase (11p) and RLS.11

The prevalence of RLS in dialysis populationsppears to be greater than in the general popula-ion, although there is wide variation, with ratesuoted from 6.6% to 62%12-23 (Table 1). Thisariation reflects in part the lack of standardizedriteria before 1995.24 Even with the introduc-ion of the International RLS Study GroupIRLSSG) diagnostic criteria,24 the method usedo screen dialysis patients can alter the apparent

Table 1. Geographic Variability in t

Reference Country

oger et al16 Australiaalker et al17 Canadainkelman et al18 United Statesollad-Seidel et al20 Germanyuigi et al14 Chinaui et al15 Chinairanda et al13 Chileabbatini et al21 Italyirignotta et al25 Italyutner andBliwise26

United States (Caucasian)

utner andBilwise26

United States (African American

ilho et al12 Brazilhowmik et al22 Indiaakaki et al23 Japaniddiqui et al19 United Kingdom

revalence. Questionnaires administered to long- d

erm dialysis patients have been less reliable forcreening compared with clinical review by neu-ologists.25 This is thought to reflect the highncidence of other leg symptoms, such as pares-hesia, itching, cramp, and peripheral neuropa-hy.

Despite the problems of accurate diagnosis,here appear to be some racial or ethnic differ-nces. In a study of Indian hemodialysis patientseviewed by clinicians and diagnosed with RLSn accordance with IRLSSG criteria, the preva-ence was only 6.6%22 and is less than that inimilar studies in developed countries using theame methods. The best evidence for ethnicifferences in uremic RLS comes from Kutnernd Bliwise.26 They showed that for older dialy-is patients, symptoms of RLS occurred lessommonly in those of African, rather than Euro-ean, descent. Although they used a question-aire approach, this is unlikely to explain thearge racial difference.

There appears to be no difference in preva-ence between patients on peritoneal dialysis andemodialysis therapy.27 The occurrence of ure-ic RLS also has been shown to predict in-

reased mortality.28,29

One study examined the difference betweenatients with uremic and idiopathic RLS.30 Thenvestigators found that the number of periodiceg movements, the periodic leg movement in-

valence of RLS in Dialysis Patients

PublicationYear

Prevalence(%)

IRLSSG Criteria Used toMake Diagnosis?

1991 40 No1995 57.4 No1996 20 No1998 23 Yes2000 34.2 Yes2000 62 Yes2001 25.9 Yes2002 37 No2002 33 Yes2002 68 No

2002 48 No

2003 14.8 Yes2003 6.6 Yes2003 12.2 Yes2003 49 Yes

he Pre

)

ex, and the periodic leg movement index while

aggaShbq

itRqpi1ur

dTr

thiRdi

a(maoPns

Tdf(td

tSgmtgswdaa

sgsb

staascpeBtsp

dt

A

T

T

T

RESTLESS LEGS SYNDROME IN DIALYSIS PATIENTS 765

wake (see Diagnosis of RLS) were significantlyreater in patients with uremic RLS. Polysomno-raphic measures of sleep continuity and sleeprchitecture were not different between groups.leep quality was worse in the uremic group. It isypothesized that motor symptoms are worseecause of increased excitability as a conse-uence of uremia.One of the other main differences between

diopathic and uremic restless legs is the familialendency. In a study of 300 index cases withLS, Winkelmann et al31 examined the fre-uency of familial RLS. They found a definiteositive family history in 42% of patients withdiopathic RLS and a possible family history in2.6% of patients with idiopathic RLS, but val-es were only 12% and 6% in uremic RLS,espectively.

DIAGNOSIS OF RLS

The diagnosis of RLS is a clinical one, and itsefinition was clarified by the IRLSSG in 1995.24

his recently was revised.32 Table 2 lists 4 crite-ia essential to the diagnosis of RLS.

Other clinical features may be supportive ofhe diagnosis of RLS. Although a positive familyistory is good supportive evidence of RLS indiopathic RLS, it is weaker for uremic RLS.31

esponse to dopaminergic drugs is strong evi-ence, with more than 90% of patients with

32

Table 2. Essential Diagnostic Criteria for RLS asDefined by the IRLSSG in 1995

n urge to move the limbs, usually accompanied orcaused by uncomfortable and unpleasant sensations inthe legs (sometimes the urge to move is presentwithout the uncomfortable sensations, and sometimesthe arms or other body parts are involved in addition tothe legs)

he urge to move or unpleasant sensations begin orworsen during periods of rest or inactivity, such as lyingor sitting

he urge to move or unpleasant sensations are partiallyor totally relieved by movement, such as walking orstretching, at least as long as the activity continues.

he urge to move or unpleasant sensations are worse inthe evening or night than during the day or only occur inthe evening or night (when symptoms are very severe,worsening at night may not be noticeable, but musthave been present previously)

Data from Walters.24

diopathic RLS responding. RLS frequently is t

ssociated with periodic limb movements in sleepPLMSs). These are repetitive stereotypic move-ents that affect 1 or both legs and involve the

rms in some patients. PLMSs are found in 80%f patients with RLS.33 Although the presence ofLMSs is not pathognomonic of RLS, the diag-osis should be made with caution in their ab-ence.32

PATHOPHYSIOLOGICAL STATE

The pathophysiological state is still unclear.he hypothesis that RLS involves dopaminergicysfunction in the central nervous system comesrom the chance finding that low-dose levodopaL-dopa) relieves the symptoms of RLS34,35 andhe exacerbating effect of such centrally activeopaminergic antagonists as metoclopramide.36

Functional studies have been performed to tryo characterize any dopaminergic dysfunction.ome single-photon emission computed tomo-raphic studies showed a decrease in D2 dopa-ine receptor function,37-39 whereas others failed

o confirm this.40,41 One positron emission tomo-raphic study using raclopride showed reducedtriatal binding,39 but a smaller study by Trenk-alder et al42 did not. Two other studies showedecreased flourodopa uptake in the putamen43

nd caudate and putamen.44 Thus, the dopaminebnormality currently remains ill defined.

Functional magnetic resonance imaging (MRI)tudies and electrophysiology studies have sug-ested a possible abnormality in the brain-tem,45-47 but these are challenged by negativelink reflex excitation studies.48,49

Transcranial magnetic stimulation studies havehown decreased inhibition of the corticospinalract at the level of the cortex.50,51 These studiesre consistent with subcortical dysfunction thatlters function of the motor pathways. However,tudies of the spinal flexor reflex showed in-reased spinal cord excitability during sleep com-ared with waking in contrast to the decreasedxcitability found in control subjects.52 Aksu andara-Jimenez53 also showed spinal cord dysfunc-

ion in patients with uremic RLS, suggestingimilar neuronal pathways are involved in idio-athic and uremic RLS.Iron metabolism also is linked to RLS. Iron

eficiency anemia is associated with RLS, andreatment with iron causes resolution of symp-

54,55
oms. The other main secondary causes of

RwRaauutbn

sfmwarptcstscadfiscctwfwTrsrnRhtm

iHshlta

atap

hRwcisic

agio

caR

psaecs

Rtl

trwtiwiwapDhe


LS, pregnancy and renal failure, are associatedith iron deficiency. Anemia has been linked toLS in 2 studies in uremia.16,23 Correction ofnemia with intravenous iron and erythropoietinlso has improved symptoms in patients withremic RLS.16,56 Other more recent studies inremia have failed to show an association be-ween anemia, iron, and RLS,13,19,20 but this maye caused by the routine use of high-dose intrave-ous iron in modern dialysis management.In idiopathic RLS, O’Keefe57 and Sun et al58

howed that RLS severity correlates with serumerritin level, even for ferritin levels in the nor-al range. O’Keefe57 also showed that treatmentith iron reduced symptoms of RLS. Earley et

l59 showed low cerebrospinal fluid (CSF) fer-itin levels and high CSF transferrin levels inatients with idiopathic RLS compared with con-rols. MRI measurement of regional brain ironontent showed reduced iron content in the sub-tantia nigra and putamen compared with con-rols, and level of abnormality correlated witheverity of symptoms.60 A recent neuropathologi-al examination by Connor et al61 also pointed tocrucial role for iron in RLS. They showed

ecreased staining for iron in the RLS brain, anding consistent with MRI data. They alsohowed decreased staining for ferritin and in-reased staining for transferrin in neuromelaninells of the substantia nigra that was similar tohat observed in CSF analysis. However, thereas a paradoxical decrease in staining for trans-

errin receptors in neuromelanin cells that other-ise had the phenotype of an iron-deficient cell.hey hypothesized that the lack of transferrin

eceptor expression or lack of increase in re-ponse to insufficient iron status suggested thategulation of transferrin receptor expression oneurons in the substantia nigra is abnormal inLS. Iron is a necessary cofactor for tyrosineydroxylase (the rate-limiting step in the produc-ion of dopamine), and it is suggested that thisay provide the iron-dopaminergic link.Uremic RLS is not improved by dialysis, but

s improved by transplantation.62 Interestinglyuiqi et al14 showed that the number of dialysis

essions per week in patients with RLS wasigher than in those without RLS. They specu-ated that this was caused by the loss of nutri-ional substances in dialysate. However, the aver-
ge number of sessions per week was low, with fi
n average of 2.5 for those with RLS and 2 forhose without RLS. Several other groups lookedt dialysis efficiency19,23 and duration of dialysiser week20,21,26 and failed to show a difference.

A recent study of patients on regular hospitalemodialysis therapy in Japan linked uremicLS with hyperphosphatemia.23 How this fitsith the iron-dopaminergic hypothesis is un-

lear. A separate study failed to show differencesn calcium and phosphate concentrations andhowed lower intact parathyroid hormone levelsn patients with uremic RLS compared withontrols.20

In the Japanese study, psychological factorslso were linked to uremic RLS. Anxiety and areater degree of emotion-orientated coping werendependently associated with RLS in patientsn hemodialysis therapy.23

The only study to show an association withause of renal failure and RLS was by Filho etl,12 which associated glomerulonephritis withLS.

TREATMENT OF RLS

The first step after diagnosis is a review of theatient’s medication. Tricyclic antidepressants,63

elective serotonin uptake inhibitors,64 lithium,65

nd dopamine antagonists36 have been shown toxacerbate or unmask RLS, although paradoxi-ally, some patients have been reported to re-pond favorably to antidepressants.66

Although dialysis does not improve uremicLS, cool dialysate fluid (36.5°C) has been linked

o symptomatic improvement compared with dia-ysate fluid at 37°C.67

As described, iron deficiency has been linkedo RLS. In nonuremic patients with serum fer-itin levels less than 18 ng/mL (�g/L), treatmentith oral iron resulted in improvement in symp-

oms,57 although this finding was not reproduc-ble in a study that was not limited to patientsith low serum ferritin levels.6 Use of high-dose

ntravenous iron has benefited patients with RLSith normal serum iron levels.69 Correction of

nemia with iron and erythropoietin has im-roved symptoms in hemodialysis patients.56

ialysis patients therefore should have theiremoglobin and iron stores optimized withrythropoietin and iron.

Dopaminergic agents should be considered
rst-line drug therapy for patients with uremic

Rhpwfrsr(qmaaes

tRctitfta

ml

ahtopfiap

abPimrotaga

D

D

A

O

�

B


LS (Table 3). Randomized controlled trialsave clearly shown the efficacy of L-dopa with aeripheral decarboxylase inhibitor in patientsith idiopathic RLS.70-72 There also is evidence

or L-dopa treatment in uremic RLS; 2 smallandomized studies and 1 small cohort studyupported the use of L-dopa.73-75 In the largestandomized controlled trial of uremic patientsn � 11), Trenkwalder et al73 showed improveduality of sleep and quality of life and decreasedovements with the use of L-dopa. Walker et

l75 showed a decrease in extent of movementsnd increased slow wave sleep, whereas Sandykt al74 also showed symptomatic relief from RLSymptoms.

The major problem with the use of L-dopa inhe general population is the development ofLS symptom augmentation. Symptoms be-ome more severe and start earlier in the dayhan before treatment began despite an increas-ng dose of L-dopa. Symptoms also may spreado different parts of the body. Earley and Allen76

ound that 50% of patients on long-term L-dopaherapy needed to be switched to a dopamine

Table 3. Pharmacological Ag

Agent Initial Dose (mg)

opamine precusorsL-dopa (with

carbidopa orbenserazide)

50 Higindlo

opaminergic agonistsPergolide 0.025 Hig

paL

ntiepilepticsGabapentin 200 after

hemodialysisCa

df

pioidsOxycodone 5 Ca

b

-Adrenergic blockerClonidine 0.075 twice daily Ant

enzodiazepinesClonazepam 0.5 Ma

gonist for adequate management. The develop- c

ent of augmentation has been shown to corre-ate with greater doses of L-dopa.77

In patients with idiopathic RLS, the dopaminegonists pergolide78-81 and pramipexole82 alsoave been effective in randomized controlledrials. A short open-label trial of ropinirole, an-ther dopamine agonist, in patients with idio-athic RLS also suggested efficacy.83 Evidenceor the use of dopamine agonists in uremic RLSs limited. Pergolide was shown to be effective insmall, double-blind, placebo-controlled trial ofatients with uremic RLS.84

There is scarce evidence comparing L-dopand dopamine agonists. Staedt et al85 showedetter subjective relief and greater decreases inLMSs with pergolide compared with L-dopa in

diopathic RLS. Current evidence suggests theajor benefit of dopamine agonists is the lower

ate of augmentation. With dopamine agonists,nly 20% to 30% of patients develop augmenta-ion79,86,87 compared with 80% with L-dopa,88

lthough it is possible that longer term use withreater doses may result in similar levels ofugmentation with L-dopa. When symptoms oc-

hown to Be of Benefit in RLS

dvantages Disadvantages

cacious; useful fortent RLS becausenergic agents takeo work

As many as 80% may developaugmentation; can causeinsomnia andgastrointestinal disturbance

cacious;lly lower rate oftation than

Role of long-term useunknown; nausea; slow doseincrease important

nsidered ifne agonists have

Accumulates in renal failure;gastrointestinal disturbance

ed on intermittent Accumulates in renal failure;constipation; drowsiness;tolerance and dependencepossible

tensive effects Dizziness; dry mouth;sleepiness

ve sleep Daytime sleepiness; cognitiveimpairment

ents S

A

hly effitermitopaminger t

hly effiotentiaugmen-dopa

n be coopamiailed

n be usasis

ihyper

y impro

ur only occasionally (eg, during hemodialysis

sort

ReUpnbfpoe

opbstlerRtbs

tpeuiRcRcmb

cbwCu

sas

da

RiRWotporgcwf

lrpednmeimupIts

sEaS

M

5

T

1

Sd


essions), L-dopa administered when symptomsccur is a reasonable choice because it has aapid onset of action (within 1 hour) and augmen-ation should not be a problem.

Opioids have been used to treat idiopathicLS. Walters et al89 showed oxycodone wasffective, but relatively high doses were needed.se of strong opioids typically is reserved foratients with refractory RLS. Use of opioids hasot been reported in patients with uremic RLS,ut is likely to be associated with a greaterrequency of side effects than in the generalopulation because of the known accumulationf active metabolites normally cleared by renalxcretion.

There are only 2 small, double-blind, cross-ver studies of clonazepam in patients with idio-athic RLS. One study showed no significantenefit compared with placebo,90 and the othertudy showed only a modest benefit in leg symp-oms and sleep.91 However, a long-term open-abel study showed significant benefit.92 Clonaz-pam was reported to give swift and completeelief in an open study of 15 patients with uremicLS.93 Although clonazepam may be useful in

he treatment of RLS, the effect may be causedy nonspecific effects of benzodiazepines onleep, rather than specific actions on RLS.88

A double-blind study showed carbamazepineo be superior to placebo in patients with idio-athic RLS,94 although a high percentage of sideffects was reported, and this is liable to limit itsse. Gabapentin has been shown to be effectiven 2 open-label studies of patients with idiopathicLS95,96 and a randomized, double-blind, pla-ebo-controlled trial of patients with idiopathicLS.97 A randomized, double-blind, placebo-ontrolled, crossover study of gabapentin in he-odialysis patients also was conducted, showing

oth safety and efficacy.98

The centrally acting �-adrenergic blockerlonidine has been used to treat RLS. One double-lind controlled study of clonidine in patientsith idiopathic RLS showed significant benefit.9

lonidine also was effective in patients withremic RLS in a double-blind study.100

Apparent success with several other drugs,uch as amantadine,101 baclofen,102 and ket-mine,103 has been reported in small open-label
tudies and case reports, but confirmatory evi-
ence is required before recommending thesegents.

The best treatment in patients with uremicLS is kidney transplantation. Yasuda et al104

nitially reported a case of resolution of uremicLS after kidney transplantation. Recently,inkelmann et al105 reported the long-term course

f RLS in dialysis patients after kidney transplan-ation. In this study, all patients’ symptoms disap-eared within 3 weeks of transplantation. Failuref the transplanted kidney was associated withecurrence of RLS. In 1 patient, failure of theraft resulted in the return of symptoms, whicheased with another transplant. Many patientsith good graft function remained symptom free

or up to 9 years of follow-up.

CONCLUSION

RLS is a common condition in patients onong-term dialysis therapy, but probably is under-ecognized. It is a cause of much distress toatients; however, it can be treated. The pathogen-sis is still uncertain, but recent studies suggestopamine and iron have a role in subcorticaleurones and may lead to targeted therapy. Opti-ization of iron and hemoglobin levels with

rythropoietin and iron appears to be beneficialn dialysis patients. Dopaminergic agents are theost appropriate first-line therapeutic agents in

remic RLS, but several other agents also haverovided relief of symptoms in published trials.n patients with uremic RLS, successful renalransplantation offers the potential for cure ofymptoms.

REFERENCES

1. Allen RP, Hening W, Montplaisir J, et al: Restless legsyndrome (RLS), a common disorder rarely diagnosed inurope or USA: The REST (RLS Epidemiology, Symptomsnd Treatment) study in primary care. Mov Disord 17:240A, 2002 (abstr, suppl 5)2. Cooke B: The London Practice of Physick, Boston,Ap 104, Milford House, 19733. Winkelman JW: Restless legs syndrome. Arch Neurol

6:1526-1527, 19994. Chekhov A: The wedding proposal, in Garnett C (ed):

he Russian. London, UK, Chatto & Windus, 1965, p 2575. Ekbom K: Restless legs syndrome. Acta Med Scand

58:S4-S122, 1945 (suppl 1)6. Ondo W, Jankovic J: Restless legs syndrome, in Appel(ed): Current Neurology. The Netherlands, IOS, Amster-

am, 1997, pp 207-235
7. Allen RP, Earley CJ: Restless legs syndrome: A review

op

m1

td1

Zs2

fr

Ric

Ag1

(h

doD

tL

c1

l2

ltS

Gfis

sD

Si2

pp2

lS

arK

AS

dsO

lsti

mr

wwD

Cl2

sedt

en1D

p

Rpc

sdS

lcC

ors

g9


f clinical and pathophysiologic features. J Clin Neuro-hysiol 18:128-147, 20018. Ondo W, Vuong K, Wang Q: Restless legs syndrome inonozygotic twins: Clinical correlates. Neurology 55:1404-

406, 20009. Desautels A, Turecki G, Montplaisir J, et al: Identifica-

ion of a major susceptibility locus for restless legs syn-rome on chromosome 12q. Am J Hum Genet 69:1266-270, 200110. Bonati M, Ferini-Strambi L, Aridon P, Oldani A,

ucconi M, Casari G: Autosomal dominant restless legsyndrome maps on chromosome 14q. Brain 126:1485-1492,00311. Desautels A, Turecki G, Montplaisir J, et al: Evidence

or a genetic association between monoamine oxidase A andestless legs syndrome. Neurology 59:215-219, 2002

12. Filho G, Gorini C, Purysko A, Silva H, Elias I:estless legs syndrome in patients on chronic hemodialysis

n a Brazilian city: Frequency, biochemical findings andomorbidities. Arq Neuropsiquiatr 61:723-727, 2003

13. Miranda M, Araya F, Castillo J, Duran C, Gonzalez F,ris L: Restless legs syndrome: A clinical study in adulteneral population and in uraemic patients. Rev Med Chil29:179-186, 200114. Huiqi Q, Shan L, Mingcai Q: Restless legs syndrome

RLS) in uraemic patients is related to the frequency ofaemodialysis sessions. Nephron 86:540, 200015. Hui D, Wong T, Ko F, et al: Prevalence of sleep

isturbances in Chinese patients with end-stage renal failuren continuous ambulatory peritoneal dialysis. Am J Kidneyis 36:783-788, 200016. Roger S, Harris D, Stewart J: Possible relation be-

ween restless legs and anaemia in renal dialysis patients.ancet 337:1551, 199117. Walker S, Fine A, Kryger M: Sleep complaints are

ommon in a dialysis unit. Am J Kidney Dis 26:751-758,99518. Winkelman JW, Chertow GM, Lazarus JM: Restless

egs syndrome in end-stage renal disease. Am J Kidney Dis8:372-378, 199619. Siddiqui S, Mak M, Kavanagh D, Geddes CC. Rest-

ess legs syndrome in haemodialysis patients. Presented athe Scottish Renal Association, May 9-10, 2003, Dumfries,cotland.20. Collad-Seidel V, Kohnen R, Samtleben W, Hillebrand

, Oertel W, Trenkwalder C: Clinical and biochemicalndings in uremic patients with and without restless legsyndrome. Am J Kidney Dis 31:324-328, 1998

21. Sabbatini M, Minale B, Crispo A, et al: Restless legsyndrome in maintenance haemodialysis patients. Nephrolial Transplant 17:852-856, 200222. Bhowmik D, Bhatia M, Gupta S, Agarwal S, Tiwari

, Dash S: Restless legs syndrome in haemodialysis patientsn India: A case controlled study. Sleep Med 4:143-146,00323. Takaki J, Nishi T, Nangaku M, et al: Clinical and

sychological aspects of restless legs syndrome in uremicatients on hemodialysis. Am J Kidney Dis 41:833-839,003
24. Walters AS: Towards a better definition of the restless
egs syndrome. The International Restless Legs Syndrometudy Group. Mov Disord 10:634-642, 199525. Cirignotta F, Mondini S, Santoro A, Ferrari G, Ger-

rdi R, Buzzi G: Reliability of a questionnaire screeningestless legs syndrome in patients on chronic dialysis. Am Jidney Dis 40:302-306, 200226. Kutner N, Bliwise D: Restless legs complaint in

frican-American and Caucasian hemodialysis patients.leep Med 3:497-500, 200227. De Vecchi A, Finazzi S, Padalino R, et al: Sleep

isorders in peritoneal and haemodialysis patients as as-essed by a self administered questionnaire. Int J Artifrgans 23:237-242, 200028. Winkelman JW, Chertow GM, Lagos L, et al: Rest-

ess legs syndrome is associated with reduced long termurvival in patients with end stage renal disease. Presented athe 10th Annual Associated Professional Sleep Studies Meet-ng, June 1996, Washington, DC

29. Pressman M, Benz RL, Paterson D: Periodic legovements in sleep index predicts mortality in end stage

enal disease patients. Sleep Res 24:416A, 1995 (abstr)30. Wetter T, Stiasny K, Kohnen R, Oertel W, Trenk-

alder C: Polysomnographic sleep measures in patientsith uraemic and idiopathic restless legs syndrome. Movisord 13:820-824, 199831. Winkelmann J, Wetter T, Collad-Seidel V, et al:

linical characteristics and frequency of the hereditary rest-ess legs syndrome in a population of 300 patients. Sleep3:597-602, 200032. Allen RP, Picchietti D, Hening W, et al: Restless legs

yndrome: Diagnostic criteria, special considerations, andpidemiology. A report from the restless legs syndromeiagnosis and epidemiology workshop at the National Insti-ute of Health. Sleep Med 101-119, 2003

33. Montplaisir J, Boucher S, Poirer G, Lavigne G, Lapi-rre O, Lesperance P: Clinical, polysomnography and ge-etic characteristics of restless legs syndrome: A study of33 patients diagnosed with new standard criteria. Movisord 12:61-65, 199734. Akpinar S: Treatment of restless legs with levodopa

lus benserazide. Arch Neurol 39:739, 198235. Montplaisir J, Godbout R, Poirer G, Bedard M:

estless legs syndrome and periodic movements in sleep;hysiology and treatment with L-dopa. Clin Neuropharma-ol 9:456-463, 1986

36. Winkelmann J, Schadrack J, Wetter T, Zieglgan-berger W, Trenkwalder C: Opioid and dopamine antagonistrug challenges in untreated restless legs syndrome patients.leep Med 2:57-61, 200137. Staedt J, Stoppe G, Kogler A, et al: Nocturnal myoc-

onus syndrome (periodic movements in sleep) related toentral dopamine D2-receptor alteration. Eur Arch Psychiatrlin Neurosci 245:8-10, 199538. Michaud M, Soucy J, Chabli A, et al: SPECT imaging

f striatal pre- and postsynaptic dopaminergic status inestless legs syndrome with periodic limb movements inleep. J Neurol 249:164-170, 2002

39. Turjanski N, Lees AJ, Brooks DJ: Striatal dopaminer-ic function in restless legs syndrome. Neurology 52:932-37, 1999
40. Tribl G, Asenbaum S, Klosch G, et al: Normal IPT

ap

Ip2

eM

d((

Pa

ai

lp

tA

a9

dM

a5

il

ls

il3

md

1

prd(

r2

a

s

f5

ms

cr

os(

pP

J

s1

tI

t1

rr

1

d

2

Tmt

Dd1

Bl

n2

lm8

l1

il


nd IBZM SPECT in drug naive and levodopa-treated idio-athic restless legs syndrome. Neurology 59:649-650, 200241. Eisensehr I, Wetter T, Linke R, et al: Normal IPT and

BZM SPECT in drug naive and levodopa- treated idio-athic restless legs syndrome. Neurology 57:1307-1309,00142. Trenkwalder C, Walters AS, Hening W, et al: Positron

mission tomographic studies in restless legs syndrome.ov Disord 14:141-145, 199943. Turjanski N, Lees AJ, Brooks DJ: Dopaminergic

ysfunction in patients with restless legs: (18F) Dopa and1C) raclopride PET studies. Neurology 50:S391A, 1998suppl 4; abstr)

44. Ruottinen H, Partinen M, Hublin C, et al: An FDOPAET study in patients with periodic limb movement disordernd restless legs syndrome. Neurology 54:502-504, 2000

45. Briellmann R, Rosler K, Hess C: Blink reflex excit-bility is abnormal in patients with periodic leg movementsn sleep. Mov Disord 11:710-714, 1996

46. Wechsler L, Stakes J, Shahani B, Busis N: Periodiceg movements of sleep (nocturnal myoclonus): An electro-hysiological study. Ann Neurol 19:168-173, 198647. Bucher S, Seelos K, Oertel W, et al: Cerebral genera-

ors involved in the pathogenesis of restless legs syndrome.nn Neurol 41:639-645, 199748. Bucher S, Trenkwalder C, Oertel W: Reflex studies

nd the MRI in the restless legs syndrome. Acta Med Scand4:145-150, 199649. Chokroverty S: Editor’s corner: Restless legs syn-

rome, a common disease uncommonly diagnosed. Sleeped 4:91-93, 200350. Tergau F, Wischer S, Paulus W: Motor system excit-

bility in patients with restless legs syndrome. Neurology2:1060-1063, 199951. Entezari-Taher M, Singleton J, Jones C, et al: Changes

n excitability of motor cortical circuitry in primary restlessegs syndrome. Neurology 53:1201-1205, 1999

52. Bara-Jimenez W, Aksu M, Graham B, et al: Periodicimb movements in sleep: State-dependent excitability of thepinal flexor reflex. Neurology 54:1609-1616, 2000

53. Aksu M, Bara-Jimenez W: State dependent excitabil-ty changes of spinal flexor reflex in patients with restlessegs syndrome secondary to chronic renal failure. Sleep Med:427-430, 200254. Fry J: Restless legs syndrome and periodic leg move-ents in sleep exacerbated or caused by minimal iron

eficiency. Neurology 36:S276A, 1986 (suppl 1; abstr)55. Matthews WB: Iron deficiency and restless legs. BMJ

:898, 197656. Benz RL, Pressman MR, Hovick ET, Peterson DD: A

reliminary study of the effects of correction of anemia withecombinant human erythropoietin therapy on sleep, sleepisorders, and daytime sleepiness in hemodialysis patientsThe SLEEPO study). Am J Kidney Dis 34:1089-1095, 1999

57. O’Keeffe ST, Gavin K, Lavan JN: Iron status andestless legs syndrome in the elderly. Age Ageing 23:200-03, 199458. Sun ER, Chen CA, Ho G, Earley CJ, Allen RP: Iron

nd the restless legs syndrome. Sleep 21:371-377, 199859. Earley CJ, Connor JR, Beard JL, Malecki EA, Ep-

tein DK, Allen RP: Abnormalities in CSF concentrations of

erritin and transferrin in restless legs syndrome. Neurology4:1698-1700, 200060. Allen R, Barker P, Wehr F, Song H, Earley C: MRIeasurement of brain iron in patients with restless legs

yndrome. Neurology 56:263-265, 200161. Connor JR, Boyer P, Menzies S, et al: Neuropathologi-

al examination suggests impaired brain iron acquisition inestless legs syndrome. Neurology 61:304-309, 2003

62. Richert A, Osuna E, Sateia M, Remillard B: A surveyf sleep and restless legs in haemodialysis, peritoneal dialy-is and renal transplant populations. Sleep 21:S91A, 1998suppl 1; abstr)

63. Garvey M, Tollefson G: Occurrence of myoclonus inatients treated with tricyclic antidepressants. Arch Gensychiatry 44:269-272, 198764. Bakshi R: Fluoxetine and restless legs syndrome.

Neurol Sci 142:151-152, 199665. Terao T, Terao M, Yoshimura R, Abe K: Restless legs

yndrome induced by lithium. Biol Psychiatry 30:1167-170, 1991

66. Dimmit S, Riley G: Selective serotonin receptor up-ake inhibitors can reduce restless legs symptoms. Archntern Med 160:712-715, 2000

67. Kerr PG, van Bakel C, Dawborn JK: Assessment ofhe symptomatic benefit of cool dialysate. Nephron 52:166-69, 198968. Davis B, Rajput A, Rajput M, Aul E, Eichhorn G: A

andomised double blind placebo controlled trial of ironestless legs syndrome. Eur J Neurosci 43:70-75, 1998

69. Norlander N: Restless legs. Br J Phys Med 17:160-62, 195470. Akpinar S: Restless legs syndrome treatment with

opaminergic drugs. Clin Neuropharmacol 10:69-79, 198771. Von Scheele C: Levodopa in restless legs. Lancet

:426-427, 198672. Brodeur C, Montplaisir J, Godbout R, Marinier R:

reatment of restless legs syndrome and periodic move-ents during sleep with L-dopa: A double blind controlled

rial. Neurology 38:1845-1848, 198873. Trenkwalder C, Stiasny K, Pollmacher T, et al: L-

opa therapy of uraemic and idiopathic restless legs syn-rome: Double blind, crossover trial. Sleep 18:681-688,99574. Sandyk R, Bernick C, Lee S, Stern L, Iacono R,

amford C: L-Dopa in uraemic patients with the restlessegs syndrome. Int J Neurosci 35:233-235, 1987

75. Walker S, Fine A, Kryger M: L-Dopa/carbidopa forocturnal movement disorders in uraemia. Sleep 19:214-18, 199676. Earley CJ, Allen RP: Pergolide and carbidopa/

evodpa treatment of restless legs syndrome and periodic legovements in a consecutive series of patients. Sleep 19:801-

10, 199677. Allen RP, Earley CJ: Augmentation of the restless

egs syndrome with carbidopa/levodopa. Sleep 19:205-213,99678. Wetter T, Stiasny K, Winkelman JW, et al: A random-

sed controlled study of pergolide in patients with restlessegs syndrome. Neurology 52:944-950, 1999

79. Silber M, Shepard J, Wisbey J: Pergolide in the

mS

bN

Aoc5

cd9

D

Es

SsAv

iaf

ed

DpS

trS

pcS

il

eo1

t2

sd2

g

l

Vls

gh

GcS

tfi

Hd

s1

t1

lt

wd


anagement of restless legs syndrome: An extended study.leep 20:878-882, 199780. Earley CJ, Yaffee J, Allen RP: Randomised, double-

lind controlled trial of pergolide in restless legs syndrome.eurology 51:1599-1602, 199881. Trenkwalder C, Brandenburg U, Hundemer H, et al:randomised long-term placebo controlled multicenter trial

f pergolide in the treatment of restless legs syndrome withentral evaluation of polysomnographic data. Neurology6:S5A, 2001 (suppl 3; abstr)82. Montplaisir J, Nicolas A, Denesle R, Gomez-Man-

illa B: Restless legs syndrome improved by pramipexole: Aouble blind randomised controlled trial. Neurology 52:938-43, 199983. Ondo W: Ropinirole for restless legs syndrome. Mov

isord 14:138-140, 199984. Pieta J, Millar T, Zacharias J, Fine A, Kryger M:

ffect of pergolide on restless legs and leg movements inleep in uraemic patients. Sleep 21:617-622, 1998

85. Staedt J, Wabmuth F, Ziemann U, Hajak G, Ruther E,toppe G: Pergolide: Treatment of choice in restless legsyndrome (RLS) and nocturnal myoclonus syndrome (NMS).

double blind randomized crossover trial of pergolideersus L-dopa. J Neural Transm 104:461-468, 199786. Staedt J, Hunerjager H, Ruther E, Stoppe G: Pergol-

de: Treatment of choice in restless legs syndrome (RLS)nd nocturnal myoclonus syndrome (NMS): Long termollow up on pergolide. J Neural Transm 105:265-268, 1998

87. Stiasny K, Wetter T, Winkelman JW, et al: Long termffects of pergolide in the treatment of restless legs syn-rome. Neurology 56:1399-1402, 200188. Hening W, Allen RP, Earley CJ, Kushida C, Picchietti

, Silber M: The treatment of restless legs syndrome anderiodic limb movement disorder: An American Academy ofleep Medicine review. Sleep 22:970-999, 199989. Walters AS, Wagner M, Hening W, et al: Successful

reatment of the idiopathic restless legs syndrome in aandomised double blind trial of oxycodone versus placebo.leep 16:327-332, 199390. Boghen D, Lamothe L, Elie R, Godbout R, Mont-

laisir J: The treatment of the restless legs syndrome withlonazepam: A prospective controlled study. Can J Neurolci 13:245-247, 198691. Montagna P, Sassoli de Bianchi L, Zucconi M, Cir-

gnotta F, Lugaresi E: Clonazepam and vibration in restless
egs syndrome. Acta Neurol Scand 69:428-430, 1984 1
92. Schenck CH, Mahowald MW: Long term, benzodiaz-pine treatment of injurious parasomnias and other disordersf disrupted nocturnal sleep in 170 adults. Am J Med00:333-337, 199693. Read DJ, Feest TG, Nassim MA: Clonazepam: Effec-

ive treatment for restless legs syndrome in uraemia. BMJ83:885-886, 198194. Telstad W, Sorensen O, Larsen S, Lillevold P, Sten-

rud P, Nyberg-Hansen R: Treatment of restless legs syn-rome with carbemazepine: A double blind study. BMJ88:444-446, 198495. Adler C: Treatment of restless legs syndrome with

abapentin. Clin Neuropharmacol 20:148-151, 199796. Mellick GA, Mellick LB: Management of restless

egs syndrome with gabapentin. Sleep 19:224-226, 199697. Garcia-Borreguero D, Larrosa O, de la Llave Y,

erger K, Masramon X, Hernandez G: Treatment of restlessegs syndrome with gabapentin. A double blind, cross overtudy. Neurology 59:1573-1579, 2002

98. Thorp M, Morris C, Bagby S: A crossover study ofabapentin in treatment of restless legs syndrome amongemodialysis patients. Am J Kidney Dis 38:104-108, 200199. Wagner M, Walters AS, Coleman R, Hening W,

rasing K, Chokroverty S: Randomised double blind pla-ebo controlled study of clonidine in restless legs syndrome.leep 19:52-58, 1996100. Ausserwinkler M, Schimdt P: Successful clonidine

reatment of restless legs syndrome in chronic kidney insuf-ciency. Schweiz Med Wochenschr 119:184-186, 1989101. Evidente V, Adler C, Caviness J, Hentz J, Gwinn-

ardy K: Amantadine is beneficial in restless legs syn-rome. Mov Disord 15:324-327, 2000102. Guilleminault C, Flagg W: Effect of baclofen on

leep related periodic movements. Ann Neurol 15:234-239,984103. Kapur N, Friedman R: Oral ketamine: A promising

reatment for restless legs syndrome. Anesth Analg 94:1558-559, 2002104. Yasuda T, Nishimura A, Katsuki Y, Tsuji Y: Restless

egs syndrome treated successfully by kidney transplanta-ion—A case report. Clin Transpl 1986:138, 1986

105. Winkelmann JW, Stautner A, Samtleben W, Trenk-alder C: Long term course of restless legs syndrome inialysis patients after kidney transplantation. Mov Disord
7:1072-1076, 2002

restless legs syndrome in patients on dialysis

Documents