ER

TstbcRbtGoa

Rtiitri

dtrfdr“siudmtslhvdc

J

0

©

d

5

DITORIAL

estless legs syndrome: The CNS/iron connection

mpmlmlp

dri

otflswtetdcR

pameInmlbmcncpmbhcm

he nicely done study by Clardy et al in thisissue is a welcome addition to growing evi-dence that restless legs syndrome (RLS) is

omehow related to iron misregulation at the level ofhe central nervous system (CNS). The finding thatoth H- and L-subunits of ferritin are reduced in theerebrospinal fluid (CSF) in early, but not late, onsetLS not only buttresses the CNS-iron relationship,ut also it offers additional evidence that there isruly a difference between early and late onset RLS.iven the high prevalence of RLS, these findings aref intense interest to basic scientists and clinicianslike.Although commonly thought of as a sleep disorder,LS is actually a neurologic sensory motor disorder

hat commonly presents as a sleep complaint—severensomnia. RLS is one of the most important causes ofnsomnia, both because of its prevalence (5%–15% ofhe general population) and because of the gratifyingesponse to treatment. RLS may begin in childhood, butt tends to be more prevalent with increasing age.1,2

RLS is characterized by a vague and difficult-to-escribe unpleasant sensation involving the lower ex-remities. This discomfort appears primarily during pe-iods of inactivity, particularly during the transitionrom wake to sleep in the evening. Patients often haveifficulty in describing the unpleasant sensations; theyarely use conventional terms of discomfort such asnumbness, tingling, or pain,” but rather bizarre termsuch as “pulling, searing, drawing, crawling, shimmer-ng, or boring,” which suggests that RLS sensations arenlike any experienced by unaffected persons. Theseistressing sensations are typically relieved only byovement or stimulation of the legs. Many different

echniques have been found by patients: walking about,tomping the feet; rubbing, squeezing or stroking theegs; taking hot showers or baths; or applying ointment,ot packs, or wraps to the legs. Although these maneu-ers are effective while they are being performed, theiscomfort usually returns as soon as the person be-omes inactive or returns to bed to try to sleep. The

Lab Clin Med 2006;147:56–57.

022-2143/$ – see front matter

2006 Mosby, Inc. All rights reserved.

soi:10.1016/j.lab.2005.08.012

6

otor restlessness often seems to follow a circadianattern, peaking between midnight and 4 AM.3 Thoseore severely affected may be unable to sit for pro-

onged periods of time such as during long perfor-ances, car trips, or airplane rides.4–6 There is abso-

utely no evidence that RLS is related to anysychological or psychiatric problems.The International RLS Study Group has developed

iagnostic criteria,7 and an RLS severity scale hasecently been validated,8 which greatly enhances clin-cal and research studies in RLS.

There seems to be a difference in early versus latenset RLS. Although they present with the same symp-oms, the early onset is more likely to have a positiveamily history, suggesting genetic factors, and has aesser relation to serum iron status.9,10 Recent studiesuggest there may be a susceptibility gene locus, whichould explain why RLS is often familial.11 The fact

hat the current study found reduced CSF ferritin inarly onset RLS is interesting and may represent addi-ional evidence that the CNS is the primary site of ironysmetabolism in RLS. That numerous neurologicalonditions may result in RLS underscores the fact thatLS is not a unitary condition.12

RLS is commonly observed in pregnancy, hemo- oreritoneal dialysis for renal failure, and iron deficiencynemia—all known to be associated with iron abnor-alities. Low ferritin levels may be associated with

ither the development or the exacerbation of RLS.mportantly, serum ferritin levels may be low despiteormal more conventional measures of iron status (he-oglobin, hematocrit, and serum iron values). Simi-

arly, serum ferritin may appear normal despite reducedone marrow iron.13 Patients with RLS have abnor-ally reduced CSF ferritin levels as compared with

ontrols, despite normal serum ferritin levels.14 Mag-etic resonance imaging (MRI) studies revealing de-reased iron concentrations in the substantia nigra andutamen support the concept of abnormal CNS ironetabolism in RLS.10 There is even evidence of local

rain iron deficiency by MRI scanning in patients withemochromatosis and RLS.15 These studies support theoncept that RLS is associated with a primary abnor-ality of CNS iron metabolism.Recent positron emission tomography (PET) studies

uggest central dopaminergic dysfunction in RLS,16

atgRnRft

pco

taTpppadaRLnF

rnsmsttpa

R

1

1

1

1

1

1

1

1

1

1

2

2

2

J Lab Clin MedVolume 147, Number 2 Mahowald 57

nd functional neuroimaging studies have identifiedhalamic, red nucleus, and brainstem involvement in theeneration of periodic limb movements in patients withLS.17 A recent FDOPA PET study indicated mildigrostriatal presynaptic dopaminergic hypofunction inLS.18 The relationship between dopaminergic dys-

unction and CNS iron metabolism remains to be de-ermined.

Demonstration of a continuous hypersensitivity toin-prick, but not to light touch, confirms a sensoryomponent to RLS19 and may explain the efficacy ofpiate medications in RLS.20

Most cases of RLS respond gratifyingly to medicalreatment including anti-Parkinsonian agents, benzodi-zepines, opiates, and anti-convulsant medications.21

he dopaminergic anti-Parkinsonian medications arearticularly effective.11 Iron supplementation is appro-riate if there is evidence of reduced iron stores. Onereliminary study suggests that intravenous iron ther-py may prove to be effective in some cases.22 Up-to-ate treatment information is available to practitionersnd patients at the National Center on Sleep Disordersesearch (NCSDR), located in the National Heart,ung, and Blood Institute website, http://www.nhlbi.ih.gov/about/ncsdr,and the Restless Legs Syndromeoundation, Inc. website, http://www.rls.org.In summary, RLS is an extremely prevalent condition

esulting in severe, occasionally incapacitating insom-ia. It is readily diagnosed by history alone. Formalleep studies are not indicated. Response to medicalanagement is usually most gratifying. Further studies

uch as the Clardy et al study of the relationship be-ween dopamine and central nervous system iron me-abolism will be of great interest and value to neuro-hysiologists, neurochemists, neuropharmacologists,nd of course, patients.

MARK W. MAHOWALDMN Regional Sleep Disorders Center

Hennepin County Medical Centerand Department of Neurology

University of MN Medical SchoolMinneapolis, Minnesota

EFERENCES

1. Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, BellTJ, et al. Restless legs syndrome prevalence and impact. RESTgeneral population study. Arch Intern Med 2005;165:1286–92.

2. Hogl B, Kiechl S, Willeit J, Saletu M, Frauscher B, Seppi K, etal. Restless legs syndrome. A community-based study of preva-

lence, severity, and risk factors. Neurology 2005;64:1920–4.

3. Trenkwalder C, Hening WA, Walters AS, Campbell SS, RahmanK, Chokroverty S. Circadian rhythm of periodic limb movementsand sensory symptoms of restless legs syndrome. MovementDisorders 1999;14:102–10.

4. Walters AS, Hickey K, Maltzman J, Verrico T, Joseph D, HeningW, et al. A questionnaire study of 138 patients with restless legssyndrome: the ‘night-walkers’ survey. Neurology 1996;46:92–5.

5. O’Keefe ST. Restless legs syndrome: a review. Arch Intern Med1996;156:243–8.

6. Silber MH. Restless legs syndrome. Mayo Clin Proc 1997;72:261–4.

7. Walters AS. Toward a better definition of the restless legs syn-drome. Movement Disorders 1995;10:634–42.

8. Allen RP, Earley CJ. Validation of the Johns Hopkins restlesslegs severity scale. Sleep Med 2001;2:239–42.

9. Winkelmann J, Wetter TC, Collado-Seidel V, Gasser T,Dichgans M, Yassouridis A, et al. Clinical characteristics andfrequency of the hereditary restless legs syndrome in a popula-tion of 300 patients. Sleep 2000;23:597–602.

0. Allen RP, Earley CJ. Defining the phenotype of the restless legssyndrome (RLS) using age-of-symptom-onset. Sleep Med 2000;1:11–9.

1. Desautels A, Turecki G, Montplaisir JLX, Walters AS, Ehren-berg BL, et al. Restless legs syndrome. Confirmation of linkageto chromosome 12q, genetic heterogeneity, and evidence ofcomplexity. Arch Neurol 2005;62:591–6.

2. Mahowald MW. Restless leg syndrome and periodic movementsof sleep. Curr Treat Opt Neurol 2003;5:251–60.

3. O’Keefe ST. Iron deficiency with normal ferritin levels in rest-less legs syndrome. Sleep Med 2005;6:281–2.

4. Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, AllenRP. Abnormalities in CSF concentrations of ferritin and trans-ferritin in restless legs syndrome. Neurology 2000;54:1698–700.

5. Haba-Rubio J, Staner L, Petiau C, Erb G, Schunck T, Macher JP.Restless legs syndrome and low brain iron levels in patients withhemochromatosis. J Neurol Neurosurg Psych 2005;76:1009–10.

6. Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic functionin restless legs syndrome. Neurology 1999;52:932–7.

7. Bucher SF, Seelos KC, Oertel WH, Reiser M, Trenkwalder C.Cerebral generators involved in the pathogenesis of the restlesslegs syndrome. Ann Neurol 1997;41:639–45.

8. Ruottinen HM, Partinen M, Hublin C, Bergman J, Haaparanta M,Solin O, et al. An FDOPA PET study in patients with periodiclimb movement disorder and restless legs syndrome. Neurology2000;54:502–4.

9. Stiasny-Kolster K, Magerl W, Oertel WH, Moller JC, TreedeR-D. Static mechanical hyperalgesia without dynamic tactileallodynia in patients with restless legs syndrome. Brain 2004;127:773–82.

0. von Spiczak S, Whone AL, Hammers A, Asselin M-C, Turk-heimer F, Tings T, et al. The role of opioids in restless legssyndrome: an [11C]diprenorphine PET study. Brain 2005;128:906–17.

1. Silber MH, Ehrenberg BL, Allen RP, Buchfuhrer MJ, Earley CJ,Hening WA, et al. An algorithm for the management of restlesslegs syndrome. Mayo Clin Proc 2004;79:916–22.

2. Earley C, Heckler D, Allen R. The treatment of restless legssyndrome with intravenous iron dextran. Sleep Med 2004;5:

231–5.