Restless Legs Syndrome: From Pathophysiology to Clinical ...

Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian ... Articles AurelPopa-Wagner UniversityofMedicineandPharmacyofCraiova,Romania AntónBarreiro-Iglesias UniversityofSantiagodeCompostela,Spain JunC.Su DepartmentofNeurology,TangduHospital,theFourthMilitaryMedicalUniversity, ShuqinZhan XuanwuHospital,CapitalMedicalUniversity,China Theeditorandreviewers'affiliationsarethelatestprovidedontheirLoopresearchprofilesandmaynotreflecttheirsituationatthetimeofreview. Abstract Background Epidemiology ClinicalPresentationsandDiagnosticCriteria DifferentialDiagnosis SecondaryRLS Pathophysiology Treatment Conclusion AuthorContributions Funding ConflictofInterestStatement Abbreviations References SuggestaResearchTopic> DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex totalviews ViewArticleImpact SuggestaResearchTopic> SHAREON OpenSupplementalData REVIEWarticle Front.AgingNeurosci.,02June2017 |https://doi.org/10.3389/fnagi.2017.00171 RestlessLegsSyndrome:FromPathophysiologytoClinicalDiagnosisandManagement ShiyiGuo1†,JinshaHuang1†,HaiyangJiang1,ChaoHan1,JieLi1,XiaoyunXu1,GuoxinZhang1,ZhichengLin2,3,NianXiong1andTaoWang1* 1DepartmentofNeurology,UnionHospital,TongjiMedicalCollege,HuazhongUniversityofScienceandTechnology,Wuhan,China 2DepartmentofPsychiatry,HarvardMedicalSchool,Belmont,MA,UnitedStates 3DivisionofAlcoholandDrugAbuse,MailmanNeuroscienceResearchCenter,McLeanHospital,Belmont,MA,UnitedStates Restlesslegssyndrome(RLS),acommonneurologicalsensorimotordisorderinwesterncountries,hasgainedmoreandmoreattentioninAsiancountries.TheprevalenceofRLSishigherinolderpeopleandfemales.RLSismostcommonlyrelatedtoirondeficiency,pregnancyanduremia.TheRLSsymptomsshowasignificantcircadianrhythmandacloserelationshiptoperiodiclimbmovements(PLMs)inclinicalobservations,whilethepathophysiologicalpathwaysarestillunknown.Thediagnosticcriteriahavebeenrevisedin2012toimprovethevalidityofRLSdiagnosis.RecentstudieshavesuggestedanimportantroleofirondecreaseofbraininRLSpathophysiology.Dopaminergic(DA)systemdysfunctioninA11cellgroupshasbeenrecognizedlongagofromclinicaltreatmentandautopsy.Nowadays,itisbelievedthatirondysfunctioncanaffectDAsystemfromdifferentpathwaysandopioidshaveaprotectiveeffectonDAsystem.SeveralsusceptiblesinglenucleotidepolymorphismssuchasBTBD9andMEIS1,whicharethoughttobeinvolvedinembryonicneuronaldevelopment,havebeenreportedtobeassociatedwithRLS.Severalpharmacologicalandnon-pharmacologicaltreatmentarediscussedinthisreview.First-linetreatmentsofRLSincludeDAagentsandα2δagonists.Augmentationisverycommoninlong-termtreatmentofRLSwhichmakespreventionandmanagementofaugmentationveryimportantforRLSpatients.Acombinationofdifferenttypesofmedicationiseffectiveinpreventingandtreatingaugmentation.TheknowledgeonRLSisstilllimited,thepathophysiologyandbettermanagementofRLSremaintobediscovered. Background ThesymptomsoftheRLSwerefirstdescribedbyWillis(1685)andthenpublishedbyEkbom(1960).Despitebeingintroducedhundredsofyearsago,it’sstillapoorlyrecognizeddisorderbecauseoftheunclearpathophysiologyandrelativelylowmorbidity,resultinginlimitedrecognitionbyprimarycarephysiciansandcommonmisdiagnosisandunder-diagnosis.RLSisconsideredasacommonneurologicalsensorimotordisorderthatmanifestsasanirresistibleurgetomovethebodytorelievetheuncomfortablesensations.There’sasignificantcircadianrhythmoftheRLS,asitcommonlyworsensatnight. Epidemiology Ithasbeenconcludedthattheprevalenceraterangedfrom3.9to15%ofthegeneralpopulation(Ohayonetal.,2012)fromrecentepidemiologicanalysesofdifferentcountries.TheestimatedprevalenceoftheRLSisaround7–10%inCaucasians(Ohayonetal.,2012)whilethereisamuchlowerincidencerangingfrom0.1to12%amongAsianpopulation(Choetal.,2009;Tsuboietal.,2009;Chenetal.,2010;Pandaetal.,2012;Shietal.,2015).Comparedwithothercountries,RLSismuchmorecommoninwesterncountries.Asnumerousstudiesinwesterncountriesindicatedtheprevalenceof10,10–15,and5.5%inUnitedStates,Canada,andEurope(UnitedKingdom,Spain,Germany,Italy),respectively(Phillipsetal.,2000;OhayonandRoth,2002).Ontheotherhand,studiesfromAsiancountriesshowedaprettylowprevalencerateofRLS.ThefirstIndianpopulationstudyonRLSrevealedaprevalenceof2.9%(Pandaetal.,2012)whileaprevalenceof0.96%amonginhabitantsofAjimuinJapanwhowereolderthan65yearsold(Tsuboietal.,2009).AnotherRLSstudyinShanghai,Chinarevealedaprevalencerateof1.4%among2941eligibleindividualsolderthan18yearsold(Shietal.,2015).Thesignificantdifferencebetweendifferentethnicpopulationsmaybeduetodifferentgeneticbackground,ethnicity,geography,andenvironmentalinfluencesincludingnaturalenvironmentanddiethabits.Thedifferentpopulationstargeted,researchmethodologiesanddiagnosiscriteriausedmaycontributetothisresultaswell. MostsurveyshaveconcludedthattheprevalenceandseverityoftheRLSbothincreasewithage(Phillipsetal.,2000;OhayonandRoth,2002),suggestingthattheneurodegenerativeprocessmayplayanimportantroleinRLS.LifestyleofolderpeopleandthesenilechangesincludingcardiovascularchangesandmetabolismchangesisalsorelatedtoRLS(Kohetal.,2015;Casseletal.,2016).Inadults,theincidenceofRLSistwiceashighinwomenthaninmen(Bergeretal.,2004),whichmayresultfromthehormonessuchasestrogenandprogesteroneanddifferentsocialroles. Theageofonsetvarieswidelyfromchildhoodtoover90yearsofage.Thoughmostpatientsinclinicalpracticearemiddle-agedorolder,juvenileonsetisnotrare.38–45%ofadultpatientscomplainaboutfirstsymptomsbeforetheageof20(Waltersetal.,1996;Montplaisiretal.,1997).Astudyin2007foundratesof1.9and2.0%in8–11yearsoldand12–17yearsoldchildrenandadolescence,respectively.AnotherstudyusingadifferentdiagnosticcriteriaforRLSinchildrenthatpublishedin2003revealedaprevalenceof5.9%(KotagalandSilber,2004).AnewestpediatricRLSdiagnosticcriteriathatincludeconsiderationoftypicalwordsusedbychildren,differentialdiagnosisandcomorbiditywaspublishedin2013(Picchiettietal.,2013).ButnogenderdifferenceisfoundinpediatricRLS(Peretal.,2017).ThisgenderdifferenceinadultbutnotinchildrenmightbeduetopregnancybecausenulliparouswomenhaveaboutthesameprevalenceofRLSasmales(Bergeretal.,2004).ThedifferentclassificationsofRLSincludingprimaryandsecondaryRLSmayalsocontributetothesefindings.Sleep,mood,cognition,andqualityoflifearesignificantlyaffectedinpediatricRLSpatients(PicchiettiandPicchietti,2010).AndADHD,depressivesymptoms,andanxietyareverycommoncomorbiditiesofpediatricRLSpatients(Pullenetal.,2011). ClinicalPresentationsandDiagnosticCriteria ClinicalPresentations Restlesslegssyndromemanifestsasanoverwhelmingurgetomovethebodytorelievetheuncomfortablesensations,primarilywhenresting,sitting,orsleeping.Theuncomfortablefeelingsarealwaysdescribedbythepatientsas“creeping,crawlingtingling,tingling,pulling,orpainful”deepinsidethelimbs(Trenkwalderetal.,2005),unilaterallyorbilaterallyoccurringwiththeknees,theanklesoreventhewholelowerlimbs(Trenkwalderetal.,2005).Sometimeseventhephantomlimbscanbeinvolved(Skidmoreetal.,2009).Commonlyitaffectsthepatient’ssleep.InsomniaisthemostcommonreasonforapatientwithRLStosearchforconsultinclinicalpractice.ThemostcommonbedtimeproblemscausedbyRLSisdifficultyinitiatingsleep(Mohrietal.,2008).Ithasasignificantcircadianpatternwhichpresentsasworseningsymptomsintheeveningandshortremissioninthemorningafterwakingup(Kushidaetal.,2007).Thelongerthecourseofthedisease,themorelikelythesymptomsaffectthearmsortheotherplacesofthebodybesidesthelegs.It’snotuncommonthatpatientsdevelopedarmrestlesssyndromewithprogressivedisease(FreedomandMerchut,2003).Movementsuchaswalking,stretching,orbendingthelegsrelievesthediscomfortatleasttemporarilyandpartially(Trenkwalderetal.,2005). Restlesslegssyndromeaffectsthepatient’sHRQoLtodifferentdegreesaccordingtovariousseveritiesofthesymptoms.HRQoLismeasuredby36-ItemShortFormHealthSurvey(SF-36),a36itemsurveyusedtoconstructeightscalesamongphysicalandmentalhealthandhealthtransition.Mostpatientshavemildsymptoms,only11.9%ofthemseekforconsult,whileabout3.4%ofallthepatientsneeddrugtreatment(Hening,2004).Themainmorbiditiesexceptforextremediscomfortweresleeplossanddisruptionofnormalactivities(Trenkwalderetal.,2005).Patientswithmildormoderatesymptomsmanifesteddiscomfortwithlessfrequency,lowerseverity,andlessinfluenceofthesymptomsontheirsleep.Comparingwiththegeneralpopulation,patientswithsevereorverysevereRLSsymptomsalwaysreportedapparentdeficits(10–40pointson100-pointsscales)inphysicalfunctioning,bodilypain,generalhealth,vitality,socialfunctioning,role-physical,androle-emotion(Trenkwalderetal.,2005).Withdeficientsleepatnight,severelyaffectedpatientsmightcomplainabouthavingdifficultyintheirdailylifeincludingtheirjobsandsocialactivities(Kushidaetal.,2007).Asignificanthigherprobabilityof25%withADHDwerefoundinRLSpatientscomparedtogeneralpopulation(Pullenetal.,2011).Ontheotherhand,20%ofADHDpatientsmeetcriteriaforRLSaswell(Zaketal.,2009;Yilmazetal.,2011).PathophysiologicalpathwaysofADHDremainspoorlyunderstood,butthemostpopulartheoryisthedopaminedeficittheory,whichcouldbeasharedpathwaywithRLS(Swansonetal.,2007).BTBD9,aRLSriskallele,mayberelatedtocertainsubtypesofADHD,whichrespondswelltoironsupplementationtreatment(Schimmelmannetal.,2009).Disruptionofsleeplengthandquality,daytimealertnesscancontributetodepressionandanxiety.IncreasingsympathetictoneduetoPLMSmayleadtocardiovasculardiseaseandhighbloodpressure(Stevens,2015). Differentfrominadults,painisacommonpresentationinpediatricRLS.45%ofchildrenusethetermspainandhurtsorhurtingwhichmakesgrowingpainsacommonmisdiagnosisinpediatricRLS(Picchiettietal.,2013).Andchildrenalwaysusetheirownwordslike“needtomove,wanttomoveandgottokick(Picchiettietal.,2011)”todescribe“urge”.ADHDisalsoaverycommoncomorbidityinpediatricRLS.Exceptforbadimpactonsleep,moodandcognition,behavioralandeducationalchangesareverycommoninpediatricRLS(Picchiettietal.,2013).Itmightbeduetodisruptionofhomeworkandabilitytoconcentrate. AssociatedFeatures CircadianRhythm BothsensoryandmotorsymptomsshowsignificantcircadianrhythminRLS,whichdisplayasapeakatsimilartimeatnight.AstudyshowedtheincreaseinmelatoninsecretiontobetheonlychangesprecedingthesensoryandmotorsymptomsinRLSpatients,indicatingmelatoninmightaffectthesymptomsbyitsinhibitoryeffectondopaminesecretionincentralnervoussystem(Michaudetal.,2004).TheintensityofRLSsymptomspeaksonthefallingphaseofthecorebodytemperature,anotherendogenousmarkerofcircadianrhythm,whileitdecreaseswhencoretemperatureincreases(Heningetal.,1999;Barriereetal.,2005). Previousstudieshaveshownthatplasmadopamineanditsmetaboliteschangeswithcircadianrhythmnotonlyjustinhumans(SowersandVlachakis,1984),butalsoinCSFinprimateanimals(Perlowetal.,1977)andinthestriatumofrat(Schadeetal.,1995;Castanedaetal.,2004).AnotherstudyindicatedthatthedopaminereceptorresponsivenessismodulatedbythecircadianrhythmatthelevelofspinalcordindecapitatedDrosophilamelanogaster(AndreticandHirsh,2000).Moreover,ithasbeenrevealedthatsensitivityofdopaminereceptorsincreasedatnightattheleveloftubero-infundibular-dopaminergicsystem(Garcia-Borregueroetal.,2004).Additionally,acircadianvariationofserumironparalleledtheCSFdopamine,aswellastheseverityofsymptoms(Garcia-Borregueroetal.,2004).However,itisunclearwhetherthebrainironconcentrationschangeswouldfollowthispattern. PeriodicLimbMovementDisorder Periodiclimbmovementdisorder,previouslyknownasnocturnalmyoclonus,isdefinedasinvoluntarymovementsofthepatient’slimbortorsoduringawakeorsleepwhichthepatientisnotawareof,differentfromthevoluntarymovementofthelimbtorelievethediscomfortinRLSpatients(Heningetal.,1999;Trenkwalderetal.,2005).Nevertheless,it’saverycommonphenomenoninRLSpatients.ApreviousstudyindicatedthatPLMSwasfoundinaround80%ofRLSpatients(Montplaisiretal.,1997).Onthecontrary,notalargepercentageofpatientshavingPLMSpresentedRLS.PLMS,whichisnotaspecificfeatureforRLSpatients,canbeassociatedtomanyotherconditions.ThePSGisusuallyemployedtomeasurethemovements,whileactigraphyisahelpfulmethodfordiagnosingandmeasuringPLMWorPLMS.PLMSisdiagnosedonPSGbyatleastcontinuousfourmusclecontractionslasting0.5–10sandrecurringduringintervalsof5–90s.Theminimumamplitudeofalegmovementeventisan8μVincreasesinEMGvoltageaboverestingEMG(Iberetal.,2007)indiagnosticcriteriaforPLMD. AmovementinPLMSstartinginsleepcancontinuewhenwakingupandviceversa.Ontheotherhand,arousalshappeningbeforeorduringamovementeventdonotchangetheassessmentofthatevent(Iberetal.,2007).ImmobilizationtestistomeasurePLMWinwhichthepatientisaskedtolieperfectlystill.ThePSGrecordsthetimethepatientcanstaystillandthelimbmovementsduringanhour.ItcanbeusedtoquantifytheseverityofRLS,tofollowupthepatient’scourseofdiseaseandtomonitortreatmentresponse(Trenkwalderetal.,2005). DiagnosticCriteria Thediagnosticcriteriahaveexperiencedalotofimprovementsandrevisionsinthehistory,includingtheearliestinformalEkbom’s“criteria”forRLSin1960,thenDCSADrestlesslegsDIMSorDOESsyndrome–essentialfeaturesin1979,ICSDdiagnosticcriteriaforRLSin1990,IRLSSG“minimal”criteriafordiagnosisofRLSin1995andNIH/IRLSSG(NIH)“essential”criteriafordiagnosisofRLSin2003(Allenetal.,2014).Onthebasisofpreviousdiagnosticcriteria,thefouressentialdiagnosticcriteriaofRLSpublishedbyNIH/IRLSSGin2003emphasizedtheimportanceoftheurgetomovethelegsindiagnosingRLS.Thefouressentialcriteriaareshownbelow(Table1). TABLE1 TABLE1.2003NIH/IRLSSGdiagnosticcriteria. Although,2003NIH/IRLSSGdiagnosticcriteriahavedefinedRLSinamuchmoredetailedwaythanthosepreviouscriteria.Thesamedisadvantagestillexistinthiscriteria,RLS“mimics”can’tbeexcludedaccordingtothisdiagnosticcriteria.Suchasconditionslikecramps,positionaldiscomfortandlocallegpathology.ThenthediagnosticcriteriawererecentlyrevisedagainbytheIRLSSGin2012(InternationalRestlessLegsSyndromeStudyGroup,2012).Comparingwith2003NIH/IRLSSGdiagnosticcriteria,2012revisedRLSdiagnosticcriteriahaveaddedanimportantessentialcriterion,notingthatRLSshouldbedifferentiatedwithotherconditionswithsimilarsymptomssuchasmyalgia,venousstasis,legedema,arthritis,habitualfoottapping,andsoon(InternationalRestlessLegsSyndromeStudyGroup,2012).2012revisedRLSdiagnosticcriteriaalsostatedthestipulationofclinicalcourseandclinicalsignificanceofRLSaspresented(InternationalRestlessLegsSyndromeStudyGroup,2012).Thenewestdiagnosticcriteria(Table2)ismuchmorerigorousthan2003IRLSSGdiagnosticcriteria. TABLE2 TABLE2.2012revisedIRLSSGdiagnosticcriteria(InternationalRestlessLegsSyndromeStudyGroup,2012). SpecifierforclinicalsignificanceofRLSemphasizesthattheinfluenceofRLSonthepatient’sfunctioninsocial,occupational,educational,orotherimportantareasshouldbeevaluated.Differentfrominadults,functionalconsequencesofRLSinchildrenaremainlybehavioralandeducationaldomains(Arbuckleetal.,2010).ThenewdiagnosticcriteriasetupamorerigorousmethodtoascertainaRLScasewithmorespecificcriteriaandexcludingstandards.IthasimprovedthevalidityofRLSdiagnosis.Ontheotherhand,ithelpstoclassifythepatient’sclinicalcourseandclinicalsignificancewhichhelpsthephysiciantobettermonitortheprogressionofRLSandsupportbettercasesforresearchsamples(Allenetal.,2014).ThespecifierforclinicalcoursedoesnotapplyforpediatricRLSorspecialcasesofRLSsecondarytopregnancyormedication(Picchiettietal.,2013).Generally,mildRLSseveritywithnofamilyhistory,andyoungageatRLSonsetarepredictorsofRLSremission.WhilemostpatientswithsevereRLSshowachronicclinicalcourse(Leeetal.,2016). PeriodiclimbmovementduringsleepisaveryidentifiedsigninRLSpatients.Itisfoundthat80–89%ofRLSpatientshaveexcessivePLMSthansameagedpeople(Montplaisiretal.,1997).PLMSisnotveryspecificforRLSsinceitisafrequentconditionamongadultsagedover45years(Hornyaketal.,2007).WhenPLMSpresentinapatterndifferentthanexpectedforageexcludingthestatesofotherdiseaseormedication,PLMScansupportthediagnosisofRLS. Consideringthatchildrenmightnotunderstandtheterm“urge”,simplestraightforwardpromptsshouldbeasked,like“Doyourlegsbotheryou?”or“Doyourlegsbotheryouatnight?”AndcommondescriptionsusedbychildrenaboutRLSsensationsare“needtomove,wanttomoveandgottokick(Picchiettietal.,2011)”.RLSmimicslikeADHD,sorelegmuscles,growingpainsanddermatitisshouldbecarefullyconsideredwhendiagnosingpediatricRLS(Picchiettietal.,2013). Comparingwiththepreviousdiagnosticcriteria,2012revisedRLSdiagnosticcriteriaistheonlycriteriathatdevelopedbyalargeinternationalnumberofRLSclinicalandresearchexpertsthroughaninterdisciplinary,internationalandevidence-basedapproachwhichensureittobeaworld-wideconsensuscriteriawhichreducestheriskofculturalbiasandavoidsarbitraryandimprovethevalidity.Thespecifiersforclinicalcourseandsignificanceareabletoprovideamethodtodefinedifferenttargetpopulationwhichwouldhelpcliniciansandresearcherstoofferbetterpreventionandtreatmentstrategiesforspecificgroupsofpatientsandtobetterelucidateetiopathogenesis(Allenetal.,2014). Ontheotherhand,somedisadvantagesstillexistsincethediagnosticcriteriaforRLSaresubjective,somemoreobjectiveandreliablediagnosticcriterianeedtobebroughtupforafurtherdiagnosisandclassificationofRLS,suchasbiologicalmarkers,geneticfeatures,PLMSmeasuring,polysomnography,andactigraphychanges.Somenewtoolsaretobedevelopedforstandardizecaseascertainment(Allenetal.,2014).Acase-controlstudyinGermanyrevealsthatinositolmetabolitesincreasedspecificallyinRLSpatients(Schulteetal.,2016).ThismightbeadiscoveryapproachusingserummetaboliteprofilinginRLS. Classification TheRLSincludestwogroupsingeneral:primaryRLSandsecondaryRLS. PrimaryRLSisconsideredtobeidiopathicwhenthecauseistrulyunknown.AmongtheidiopathicRLS,40.9–92%ofwhomhadafamilyhistoryofRLS,indicatingtheimportantroleofgeneticfactorsindevelopingRLS(Winkelmanetal.,1996;Winkelmannetal.,2002;Tisonetal.,2005). MostsecondaryRLScaseshaveanonsetafter40yearsold.SecondaryRLSarethoseassociatedwithavarietyofneurologicaldisorders,irondeficiency,pregnancy,orchronicrenalfailure(Winkelmanetal.,1996;Curgunluetal.,2012;Srivanitchapoometal.,2014).AstudyinTurkeyrevealedthatseverityofRLSsymptomsisverycloselyrelatedtolowferritinlevel(Curgunluetal.,2012).IntheearlieststudiesofRLS,somerevealedthat25%ofRLSpatientshaveirondeficiencycondition.Theothercorrelatedfactorswerediabeticperipheralneuropathy(ZobeiriandShokoohi,2014),painfulneuropathies(Rutkoveetal.,1996),ADHD(Royetal.,2015),migraine(Zanignietal.,2014),AS(TekatasandPamuk,2015),leprosy(PadhiandPradhan,2014),inflammatorychronicdemyelinatingneuropathieslikemultiplesclerosis(Deriuetal.,2009)andGuillain–Barrésyndrome(Marinetal.,2010),thyroiddisease(RodriguezMartinetal.,2015),poliomyelitis(Kumruetal.,2014),chronicvenousdisorder(McDonaghetal.,2007),autoimmunediseaseincludingSjögren’ssyndrome(Theanderetal.,2010),rheumatoidarthritis(HeningandCaivano,2008),inflammatoryboweldisease(Beckeretal.,2015),andCrohn’sdisease(Hoeketal.,2015).EpidemiologystudiesalsoshowedthattheprevalenceofRLSsignificantlyincreasedinpost-strokepatients,mainlyinpatientswhosestroketopographyliedonpyramidaltractandthebasalganglia-brainstemaxiswhichwereprimarilyinvolvedinmotorfunctions(SechiandSechi,2013).SomecertaindrugscancauseorworsenRLSsymptoms,suchaspsycotropicslikeantidepressantsandneuroleptics,dopaminergicdrugs,andsomeotherdrugs(Giudice,2010)suchascumulativedopaminergicagonistseffectsinParkinson’sdiseasepatients(McDonaghetal.,2007).Astudyrevealedthatthestrongestevidencefordrug-inducedRLSareforthefollowing:escitalopram,fluoxetine,L-dopa/carbidopaandpergolide,L-thyroxine,mianserin,mirtazapine,olanzapine,andtramadol(HoqueandChesson,2010). Accordingtotheonsetageofthesymptoms,RLSisdividedintoearly-onsetRLSandlate-onsetRLS.Early-onsetRLSreferstothosewhofirstlyhavethesymptomsbefore45yearsold.Whilelate-onsetRLSpatientshavethesymptomsfromorafter45yearsold.Ahigherfamilialhistoryratewasfoundinearly-onsetRLScomparingtolate-onsetRLS(KotagalandSilber,2004).Variousclinicalcourseswithperiodicremissionsarecommoninearly-onsetRLS.Whileachronicprogressiveclinicalcoursewithmoreseveresymptomsareseeninlate-onsetRLS.PediatricRLSarealwaysmisdiagnosedas“growingpain”.CurrentresearchesdemonstratearelativelyirondeficiencyandrenalfailuretobeexacerbatingfactorsforpediatricRLS(KotagalandSilber,2004;Davisetal.,2005;Applebeeetal.,2009;Sinhaetal.,2009).CommonlypediatricRLSshouldbedifferentiatedfromADHDwhileonlyRLSpatientspresentstheneedtomovebecauseoflegdiscomfortbutnotdifficulty“sittingstill”(Trenkwalderetal.,2005). DifferentialDiagnosis VerycommonconditionswhichshouldbedifferentiatedwithRLSincludelegcramps,positionaldiscomfort,localleginjury,arthritis,legedema,venousstasis,peripheralneuropathy,radiculopathy,habitualfoottapping/legrocking,anxiety,myalgia,anddrug-inducedakathisia(Allenetal.,2014).TheycanmimicRLSindifferentways.Legcrampsarepresentedasknotofthemuscle.Positionaldiscomfortcanberelievedbyapositionalshift.Arthritispatientshavealimitationofthejointsorjointerythema.Myalgiaspresentasmusclesoreness.NumbnesshappentoneuropathypatientsaswellasRLSpatients,andbothvenousstasisandlegedemacanmanifestasswellinginthelimbs(Davisetal.,2005;Applebeeetal.,2009;Sinhaetal.,2009;Karroumetal.,2012).Lesscommondifferentialdiagnosticconditionsincludedmyelopathy,myopathy,vascularorneurogenicclaudication,hypotensiveakathisia,orthostatictremor,painfullegs,andmovingtoes(Allenetal.,2014).DifferentialdiagnosisisreallyimportanttoRLSpatientsfortheirfurthertreatment.ThereforeclinicalphysicianshavecreatedadditionaldiagnosticquestionnairesandscalestoimprovethediagnosisofRLSinclinicalpractice(Popatetal.,2010).RLS-NIHquestionnaire,developedin2002withthreemandatoryquestions,showedsensitivityandspecificityof86and45%respectively(Popatetal.,2010).Onthebasisofthis,antheRLS-EXPshowedthesensitivityandspecificityof81and73%respectively(Popatetal.,2010).TheCH-RLSqismorecommonlyusedinclinicalpracticeandbyresearchers. SecondaryRLS IronDeficiency Earlyin1953,Nordlander(1953)firstproposedthatirondeficiencymightbeanimportantpartofthepathophysiologicalprocessinRLSwhichwassupportedbyconsistentprevalencestudiesandrecentpharmacologicalresearches.Lowserumironlevels(normalrange:50–170μg/dLformen;65–176μg/dLforwomen;50–120μg/dLforchildren)presentedin25%ofpatientswithsevereRLS(Ekbom,1960).While43%ofpatientscomplainingof“legrestless”werefoundtobeintheconditionofirondeficiency(Matthews,1976).Theseverityofthesymptomswasfoundtobecorrelatedwithserumferritinlevels(normalrange:15–200ng/mLformen;12–150ng/mLforwomen;7–140ng/mLforchildren)(O’Keeffeetal.,1994;Mizunoetal.,2005).NumbersofpharmacologicalstudiesofironsupplementforRLSgainedtherapeuticeffects(Nordlander,1953).CSFbiologicalstudiesshowedlowerironandferritinlevelsinRLSpatients,alongwithhighertransferrinlevels(Mizunoetal.,2005).However,acurrentstudyhassuggestedthatinnormalcircumstances,thebraindoesnotrespondtoperipheralvariationsinironstatus(Wardetal.,2014).ThismightexplainwhysomeRLSpatientshadanormalorover-loadedserumironlevelwhiletheirCSFironlevelwasdecreased.VariousmedicalimagingstudiesincludingultrasoundstudiesandMRIstudiesrevealedadecreasedironlevelsinthesubstantianigraandputamen,especiallyintheveryseverepatients(Schmidaueretal.,2005;Moonetal.,2014).Otherstudiesdemonstratedirondecreaseintherednucleus,thalamusandthepallidum(Haba-Rubioetal.,2005;Rizzoetal.,2013).However,MRIwasnotcapableoflocatingtheirondeficiencyconditiontoparticularcellsuptonow.Autopsystudiesalsoreportedadecreaseinironconcentrationinthesubstantianigra(Moonetal.,2014). Pregnancy 15–25%ofpregnantwomenhaveRLSinWesterncountriesaccordingtoprevalencestudies(Leeetal.,2001;Neauetal.,2010).ApeakprevalenceofRLSinpregnantwomenmainlyoccurredinthethirdtrimesterandgainedaremissionby1monthafterdelivery(Ismailogullarietal.,2010).SurveysmanifestedthatnulliparouswomenwereatthesameriskofRLSassameagedmen,whiletheriskforwomenwereincreasedafteronepregnancy(OR1.98)andtwopregnancies(OR3.04),evenmoreafterthreeormorepregnancies(OR3.57)(Bergeretal.,2004;Pantaleoetal.,2010).ThesefindingsmayexplainthegenderdifferenceinRLSprevalence.ThereasonwhypregnantwomenhavehigherriskofhavingRLSremainsunknown.Onereasonisthatanincreaseddemandofironinpregnantwomenresultsinrelativeirondeficiency.Theotherestablishedfactorsincludedhormonalstatus(prolactin,progesteroneandestrogen),folatedeficiencyandstretchorcompressionofnervesduetofetalgrowthconflicting(Pantaleoetal.,2010;Pereiraetal.,2013).Psychomotorbehavioralchangeduringthelastweeksofpregnancymightalsocontributetothesymptoms.Anxiety,insomnia,andfatiguearealwaysassociatedwithpregnancyinthelasttrimester. End-StageRenalDiseasePatientsonHemodialysis Studieshaverevealedapproximateprevalenceof20–30%RLSinhemodialysisthantheprevalenceof3.9–15%amongthegeneralpopulations(Ohayonetal.,2012).Astudyincluding166patientsinSerbianshowed22.7%ofpatientsonhemodialysiswereundertheconditionofRLS(Nikicetal.,2007).Otherstudiesindicatedaprevalenceof14.8%among176patientsonhemodialysisinBrazil(GoffredoFilhoetal.,2003)andaprevalenceof37.4%in163patientsonhemodialysisinIran(Rohanietal.,2015).SomeofthestudiesrevealedapredominanceoffemalepatientswithRLSratherthanmalepatientsonhemodialysis(Al-Jahdalietal.,2009;LaMannaetal.,2011;Haideretal.,2014),whilearecentstudyinSaudidisplayednostatisticallydifferencebetweentwogenders(WaliandAlkhouli,2015).MostoftheRLSpatientsamongend-stagerenaldiseaseindicatedmoderatetoseveresymptomscomparedtomostmildRLSsymptomsamonggeneralpopulations(WaliandAlkhouli,2015).Irondeficiencyinend-stagerenaldiseasepatientsmayleadtoanemiaandaffectthedopaminemetabolism,contributingtoRLS(Nikicetal.,2007),anduremia-relatedperipheralneuropathyandhighserumcalciumcanbepartofthephysiologyofRLS(Nikicetal.,2007).However,inarecentreport,irondeficiency,anemia,andcalciumwerenotfoundtobestatisticallyrelatedtoRLSinhemodialysispatients(WaliandAlkhouli,2015).PreviousstudiesshowedconflictsabouttheassociationbetweenBMIandRLSinend-stagerenaldiseasepatients.AstudywithalargecohortfoundthattheprevalenceofRLSinend-stagerenaldiseasepatientswaspositivelyrelatedtotheirBMI(Gaoetal.,2009).TheORforRLSwas1.42(95%CI:1.3–1.6;p<0.0001)forpatientswithBMIfrom23to30kg/m2and1.60(95%CI:1.5–1.8;p<0.0001)forpatientswithhighestBMIcomparedwithpatientswithlowestBMI(Gaoetal.,2009).Decreasednumberofdopaminereceptorsinobesepeople’sbrainwasconsideredtobethepossiblereason(Wangetal.,2001).However,anotherpreviousstudyrevealednosuchrelationships(Kimetal.,2008).Arecentcross-sectionalstudybetweencontrolgroup,renaltransplantationgroupandhemodialysisgroupfoundthatprevalenceinrenaltransplantationissignificantlylowerthaninhemodialysispatients(Kahveciogluetal.,2016).RLSisveryprevalentinend-stagerenaldiseasepatients,andhemodialysispatientswithRLSwerefoundtohaveahigherriskofmuscleatrophy(Giannakietal.,2011),cardio/cerebrovasculareventsandmortality(LinC.H.etal.,2015).Topreventmoremorbidityinend-stagerenaldiseasepatients,theirRLSshouldbediagnosedinearlystageandreceivestandardtreatmentofRLSorhavearenaltransplantationassoonaspossible. Pathophysiology ThepathophysiologyofRLSisstillpartiallyunderstood.Themostacceptedpathwaysincludegeneticsvariants,abnormalironmetabolisms,dopaminergicdysfunction,andcentralopiatesystem. Iron It’swidelyacceptedthatthelocalbrainironlevelplaysanimportantroleinRLSpathophysiology,however,themechanismisstillunclear.Recentstudiesdemonstratedthattheirondeficiencyinbrainwasrelatedtothefunctionofblood-braininterface,asBBBsendothelialcellsactedasanironreservoirforthebrain.AdysfunctionofironregulatoryproteininthemicrovasculatureinciteddysregulationofirontransportacrosstheBBB,resultinginadecreaseofironstorageinendothelialcells(Leeetal.,2001).Biochemicalstudiesontheeffectofironinbrainindicatedthatseveralproteinscontainingironwereincludedinvariousprocesseslikeoxidativephosphorylation,oxygentransportation,myelinproductionandthesynthesisandmetabolismofneurotransmitters(Wardetal.,2014).Therefore,irondeficiencycanleadtocellulardamagebyoxidationandmodificationofcellularcompoundssuchaslipids,carbohydrates,protein,andDNAfromhydroxylradicalproduction(Wardetal.,2014).Theinteractionsbetweenimpairedneuronalironuptakeandthefunctionsoftheneuromelanin-containinganddopamine-producingcellsplayimportantrolesinRLSpathophysiology(Michaudetal.,2004).Decreasedextracellulardopamine,DAT,D1andD2receptorsarefoundinirondeficiency,indicatingthatironaffectthebraindopaminergictransmissionindifferentways(DauvilliersandWinkelmann,2013). Dopamine AlargenumberofpharmacologicalstudiesandclinicalfindingshaveprovidedevidencefortheimportantroleofdopaminergicsystemdysfunctioninRLS(Winkelmannetal.,2001;PaulusandTrenkwalder,2006;Galbiatietal.,2015).AnimprovementofRLSsymptomswasfoundinpatientsreceivinglow-dosedopaminergicmedications(PaulusandTrenkwalder,2006;Galbiatietal.,2015)whileaworseningofRLSsymptomsinpatientsreceivingdopamineantagonists(Winkelmannetal.,2001).TheneedfordopaminergicagoniststocrosstheBBBtobeeffectiveinRLSsymptomsindicatedthatdopaminergicsystemincentralnervoussystemwasentailedinRLSpathophysiologyratherthaninperipheralnervoussystem(Garcia-BorregueroandWilliams,2014).Tyrosinehydroxylaseisarate-limitingstepenzymefortheconversionoflevodopatodopamine.Asironisacofactorofthisenzyme,irondeficiencycanalterthedopaminergicsysteminthebrain(DauvilliersandWinkelmann,2013).DopaminergicA11cells,locatedinthemidbrainandclosetohypothalamus,havelongaxonsandprojectdiffuselythroughoutthespinalcord(ClemensandHochman,2004).Theyarethemajorsourceofdopamineinspinalcord.A11cellsarriveinthedorsalhorn,thenprojecttothemotoneuronalsite(Holstegeetal.,1996).It’sfoundthatstereotaxicbilateral6-hydroxydopaminelesionsintotheA11nucleuscanresultinanincreasedaveragenumberofstandingepisodesandtotalstandingtimecomparingtotheshamrats(Ondoetal.,2000),suggestinganimportantroleofA11dopaminergiccellsinpathophysiologicalpathwaysinRLS.AsignificantlydecreasedN-acetylaspartate,creatinineratio,andN-acetylaspartateconcentrationswerefoundinthemedialthalamusofRLSpatientsinarecentstudyusingprotonmagneticresonancespectroscopy(Rizzoetal.,2012).FunctionalMRIandPETstudiesconcludedanimportantroleofmedialthalamicnucleiinRLSpathophysiology.Themedialthalamicnucleiarepartofthelimbicsystem,whichismodulatedbydopaminergicafferents.Anotherstudyfoundthalamicactivitychangesinthethalamocotricalcircuit(Goulartetal.,2014).Therefore,itwashypothesizedthatthedopaminergicdysfunctionmightleadtoanimpairmentofthemedialpainsystem(Garcia-BorregueroandWilliams,2014;Goulartetal.,2014)andthencausedtheuncomfortablesymptomsofRLS.PharmacologicalstudiesalsodemonstratedthatopioidshadaprotectiveeffectinsomeRLSpatients.Aninvitrostudyinratsfoundthatirondeficiencycancausecelldeath,mainlydopaminergiccellsinsubstantianigraandopioidscouldprotectthemfromcelldeathundertheconditionofirondeprivation(Sunetal.,2011).Theauthorsconcludedfromthisresultthatanintactendogenousopioidsystemandopioidtreatmentcouldpreventthedopaminesystemfromdysfunctioninirondeficiencypatients(Sunetal.,2011).AstudyoftsDCSinRLSpatientsshowedsupportiveevidenceofspinalcordhyperexcitability(Heideetal.,2014). Genes Studiesdemonstrateastrongrelationshipbetweengeneticpredispositionandearly-onsetRLS,ofwhichmorethan60%revealapositivefamilialhistory.Moreover,inheritancewasfoundtoberelatedtolate-onsetRLSandsecondaryRLS(Winkelmannetal.,2000;Xiongetal.,2010;Yangetal.,2011).Astudyamong249CanadianRLSpatientsfoundafamilyhistoryexistedin77.1%ofthemwhiletherest22.9%weresporadic(Yangetal.,2011).VariantsinMEIS1,BTBD9andMAP2K5/SKOR1resultedinamuchhigherriskofRLSamongaUSpopulation(Yangetal.,2011).Sofar,theGWASshavereportedthefollowingsusceptibleSNPsinassociationwithRLS:MEIS1(chromosome2p14),BTBD9(chromosome6p21.2),PTPRD(chromosome9p24.1-p23),MAP2K5/SCOR1(chromosome15q23)andchromosome16q12.1(Bergeretal.,2002;Hogletal.,2005;Stefanssonetal.,2007;Schormairetal.,2008).Mainfunctionofthesegeneswasrelatedtoembryonicneuronaldevelopmentandlimbdevelopment(DauvilliersandWinkelmann,2013;Garcia-BorregueroandWilliams,2014).InRLSautopsycases,MEIS1genewasfoundtobeassociatedwithanincreaseinH-ferritin,L-ferritinanddivalentmetaltransporter-1RNAexpressioninthethalamus(Catoireetal.,2011),suggestingMEIS1genemutantspredisposedtolowerironcondition.AnotherstudyusedRNAinterferencetechniquesinalymphoblastoidcelllineinwhichtheMEISmRNAexpressionwasblocked(Silveretal.,2010).Forty-eighthourslater,anincreaseintransferring-2receptor,ferroportinmRNAandBTBD9,andadecreaseinhepcidinmRNAexpressionwereobserved(Silveretal.,2010),indicatingthatMEIS1controlledcellularirontransfertomitochondria,cellularexportofironandpotentiallyaffectedBTBD9expressionanditsdownstreamironmodulation.TheeffectofMEIS1onironhomeostasiswasalsoshowninCaenorhabditiselegans(Catoireetal.,2011).AstudyusingdBTBD9mutantfliesshowedsignificantlydecreasedbraindopamineandabnormalsleepphenotypewhichwascompletelyretrievedbyadministeringwithpramipexole,adopamineD2receptoragonist(Freemanetal.,2012).Furthermore,RLSsymptomscanbereconstructedbyknocking-downdBTBD9expression.WhileoverexpressionofBTBD9inHEKcellsshowedthatthegenecontrolledironhomeostasisthroughtheregulationofIRP2(Freemanetal.,2012).TheauthorssuggestedthattheBTBD9proteinbelongedtoaproteinfamilywhichcontainedsubstrateadaptorsfortheCul3class(Freemanetal.,2012).Cul3classofE3ubiquitinligaseswasshowntoregulatesleepinflies(StavropoulosandYoung,2011).AsusceptibleviewpointwasthatBTBD9playedaroleindopaminebiosynthesisbyunclearmechanisms(ShawandDuntley,2012).TheseSNPshadstrongassociationwithPLMinRLSpatients(Mooreetal.,2014).Theexactpathophysiologicalpathwaysofthesegenesstillremainunclear.AnSNPstudyintheSpanishCaucasianpopulationsuggestedamodestbutsignificantassociationbetweenvitaminDreceptorrs731236SNPandtheriskforRLS.RLSpatientscarryingtheallelicvariantrs731236Ghadanearlieronsetagewhilethosecarryingtheallelicvariantrs731236GGhadmoreseveresymptoms(Jimenez-Jimenezetal.,2015).AweakassociationbetweenhemeoxygenasegeneticvariantsHMOX1rs2071746polymorphismandtheriskofdevelopingRLSwasfoundintheSpanishpopulation(Garcia-Martinetal.,2015).LinkageanalysesinfamiliesidentifiedseveralgeneticlociforRLS:RLS1(chromosome12q12–q21),RLS2(14q13–q21),RLS3(9p24–p22),RLS4(2q33),RLS5(20p13),RLS6(19p13),andRLS7(16p12.1)(Desautelsetal.,2001,2005;Bonatietal.,2003;Kemlinketal.,2007).TheauthorssuggestedtheinheritancemodeofRLScouldbearecessivemodeoradominantmodewithvariableofinheritance.ThemainSNPfindingsaresummarizedasbelow(Table3). TABLE3 TABLE3.MainSNPfindingsassociatedwithRLS. NervousSystemStructures PrevioustheoriesaboutdopaminergiceffectonRLSpathophysiologymainlyfocusedonsubstantianigraanddopaminergicA11cellgroup(Ondoetal.,2000;TrenkwalderandPaulus,2010),nevertheless,changesindopaminergicneuronsinbasalgangliainRLSpatientswerealsofoundinautopsystudies.Thisresultmightberelatedtoirondeficiencyinbrain(Connoretal.,2003).DopaminergicprojectionstothespinalcordoriginateexclusivelyfromA11cellgroup(Nogaetal.,2004).Dopamineactedasanexcitatoryandinhibitoryneurotransmitterinspinalcordtoregulatesensory,motoraswellasautonomicfunctions(DauvilliersandWinkelmann,2013).RecentstudiesreportedfrequentPLMSinpatientswithspinalcordinjury,indicatingthecenterroleofspinalcordinRLSpathophysiologyprocess(DauvilliersandWinkelmann,2013).Itmightalsoresultfromthedecreasingsupraspinalinhibitiontothespinalcord.FunctionalMRIstudiesshowedchangesofthalamicandcerebralactivationinRLS(Bucheretal.,1997).However,postmortemstudiesinRLSpatientsshowednoevidenceofchangesinthevolumeoftyrosinekinase(+)neuronsorgliosischangesinA11regionintheposteriorhypothalamus(Earleyetal.,2009).ThismightresultfromthefactthatonlysixcasesareincludedinthisstudyorthehypothesisthatthemanifestationsofRLSmaybesecondarytodopaminemetabolismorchangesinthedistalA11synapseswhichisnotaseasilydetectedasstructuralorquantitychangesinthecellbodies(Earleyetal.,2009).Anotherrecentstudyindicatedthatdomperidone,adopamineantagonistthatcannotcrosstheBBBincreasedthefrequencyofRLSinpatientswithParkinson’sDisease,proposingthatperipheraldopaminergicneuronsmightplayanimportantroleinRLS(RiosRomenetsetal.,2013).It’swidelybelievedthatirondeficiencyinbraincausesthedecreaseindopaminergicfunctionwhichthenmotivatesspinalhyperexcitability,leadingtothespontaneoussensoryandmotormovementsofRLS(Garcia-BorregueroandWilliams,2014). Treatment TreatmentbeforeRLS,threeaspectsshouldbeconsidered:lifestylechange,medicationeffectandirondeficiency(definedasferritin<75ng/mLoriron/TIBCratio<20%)(MackieandWinkelman,2015).Lifestylelikesleepdeprivation,alcoholortobaccouse,decreasedmotility,orinmedication(dopamineantagonists,antihistaminesorserotonergicantidepressants,opioiddiscontinuationorbloodloss)canresultinearlieronsetorincreaseseverityinRLSsymptoms.Adetailedinquiryforthepatientshouldbecarriedout.TreatmentofRLSmainlyincludepharmacologicalandnon-pharmacologicaltreatment. PharmacologicalTreatment Dopaminergicagentsareconsideredtobethefirst-linetreatmentforRLS,includingpramipexoleandropinirole(Garcia-Borregueroetal.,2013;Silberetal.,2013).Pergolideandcabergolinearenotrecommendedduetotheirassociationwithincreasedriskofvalvularheartdisease(Zanettinietal.,2007).Ropinirolehasafasteronsetwithshorterduration,whilerotigotineiscommonlyusedasatransdermalpatchwhichcontinuouslyprovidesstableplasmadrugconcentrations,resultinginitsparticulartherapeuticeffectonpatientswithsymptomsthroughouttheday(MackieandWinkelman,2015).α2δagonistshavebecomeincreasinglyimportantintreatingRLS,forbeingconsideredaspossiblefirst-lineagentsforRLS.Arecentdouble-blindstudyover12-weekperiodcomparedtheefficacyofpregabalin,pramipexoleandplacebo,demonstratingabetterefficacyofpregabalinratherthandopamineagonistorplacebo(Hubneretal.,2013).Moreover,thedifferenceoftheefficacyvariedwithdrugdoses(Hubneretal.,2013).OpioidshavebeenfoundtobeeffectiveintreatingRLS,butthepotentialdrugabuseandsideeffectsincludingrespiratorydepressionandconstipationlimititsuseinRLS,astheyarenotcommonlyadvisedasinitialtreatmentofchoice.Arecentstudyontreatingfirst-lineagentsrefractoryRLSwithextended-releaseoxycodone–naloxonecombinationshowedveryimpressiveandpersistenteffectofthiscombinationonRLSsymptoms(Trenkwalderetal.,2013).Otherpharmacologicaltreatmentsincludeironsupplement,someotheranticonvulsantsandbenzodiazepines.Thechoiceoftwomajorfirst-lineagentsshouldbeconsideredwiththeirsideeffects.DopamineagonistscancausesomnolenceandICDslikecompulsivegamblingorover-eating,whilecommonsideeffectsofα2δagonistsareweightgain,dizzinessandgaitinstability.Asaresult,forinitialtreatmentofRLSpatients,dopaminergicagentsareusedasfirst-lineagentsinpatientswithveryseveresymptoms,over-weighted,comorbiddepression,riskoffalls,orcognitiveimpairment(Garcia-Borregueroetal.,2013),whileα2δagonistsareadvisedasfirst-lineagentsinpatientswithseveresleepdisturbance,comorbidanxiety,RLS-relatedpain,orprevioushistoryofICDs(Garcia-Borregueroetal.,2013).Evidence-basedguidelinesontreatingRLSwerepublishedbyEFNSandIRLSSGin2012and2013respectively.ManyotherpharmacologicaltreatmentreviewsandresearchpapersofRLShavebeenpublishedrecently(Garcia-BorregueroandWilliams,2014;Hornyaketal.,2014).Aconclusionofseveralmedicationsisshownabove(Table4). TABLE4 TABLE4.RecommendationdrugsforRLS. Otherdrugssuchasdopaminergicagents(piribedil),anticonvulsants(gabapentin),opioids(tramadol,methodone),iron,hypnoticandsedativeagents,folate,vitaminB12,magnesium,vitaminE,botulinumtoxin,physiotherapy,phototherapy,andaerobicexercisesarenotrecommendedinclinicalpracticeduetoinsufficientevidence.However,theycanbeusedasauxiliarydrugsconcerningtothesymptomsandcomorbiditiesofthepatient. AsdepressionisaverycommoncomorbidityinRLSandmanyantidepressantssuchasselectiveserotoninreuptakeinhibitors(SSRIs)andtricyclicantidepressants(TCAs)canworsenthesymptomsofRLS,treatmentofdepressioninRLSpatientsshouldbecautious.Sincebupropion,anewerantidepressant,doesn’tshowanyevidenceofexacerbationofRLSsymptoms,itisusedasaneffectiveantidepressantinthesepatients(MackieandWinkelman,2015). Restlesslegssyndromeisverycommoninwomenduringpregnancyandlactation,withaprevalenceof15–25%(Hubneretal.,2013).GuidelinesontreatingRLSduringpregnancyandlactationhavebeenpublishedbyIRLSSGin2014(Picchiettietal.,2015)(Table5).OnceRLSisdiagnosedinpregnancy,non-medicinetreatmentshouldbeconsideredfirstly.PatientsshouldbeeducatedaboutthenaturalcourseofRLSduringpregnancy,inwhichRLScommonlyremitsordisappearsafterdelivery.Moderateexerciseandavoidanceofaggravatedfactorssuchasirondeficiency,long-termimmobility,serotonergicantidepressantsshouldbesuggested.Ironlevelshouldbemeasuredtodecidewhethertotreatthepatientwithiron.Irontherapy(oralorintravenous)shouldbegivenwhenserumferritin<75ug/L.Whenserumferritin>75ug/LwithrefractoryRLS,drugtreatmentshouldbeconsidered. TABLE5 TABLE5.MedicationtreatmentforRLSinwomenduringpregnancyandlactation. LossofefficacyandaugmentationaretwomaintreatmentfailuresafteralongcourseoftreatmentofRLS.TheprobablereasonsofthemmightbethenaturalworseningofRLSsymptomsovertimeorcompensatoryresponseofCNStochronicdrugtreatment(MackieandWinkelman,2015).Irondeficiencyshouldbetreatedwithironsupplement.BothoftheintravenousandoralironformulationsareprovedtobeeffectiveinsomeRLSpatients(Trottietal.,2012;Hornyaketal.,2014).FurtherstudyabouteffectofirontherapyinallRLSpatientsoronlyacertaintypeofRLSremainstobeinvestigated. AugmentationreferstoaworseningofthesymptomsthatoccursverycommonlyamongRLSpatientsafterlong-termtreatmentwithsomecertainmedications.Anoverallaugmentationrateof5.6%wasreported(Liuetal.,2016).Allthecurrentdopaminergicdrugsandanothernon-dopaminergicdrugtramadolhavebeenreportedtoshowsomedegreeofaugmentation(Trenkwalderetal.,2007;Vetrugnoetal.,2007;Hogletal.,2010;Oerteletal.,2011),whicharethoughttoberelatedtodoseanddurationofmedicationandindividualfactorssuchasirondeficiency(Garcia-Borregueroetal.,2013).Thehighestincidencerateofaugmentationoccurredwithlevodopawasupto60–80%inRLSpatients(Hogletal.,2010).Inaddition,incidenceratewasreportedtobehigherinpatientstreatingwithshorter-actingdopaminergicagents(pramipexole,ropinirole)thanlonger-actingdopaminergicagents(rotigotine,cabergoling).Apossibleexplanationisthemaskingofearliersymptomonsetbylonger-actingdopaminergicagents(Garcia-BorregueroandWilliams,2014).Topreventaugmentation,itisimportanttoinitiatethetreatmentwithα2δagonistsformilderRLSpatients(Silberetal.,2013),andalowesteffectivedoseofdopaminergicagentsshouldbeestablishedtodecreasetheincidenceanddelaytheoccurrenceofaugmentation(Silberetal.,2013).Managementofaugmentationisnottoincreasethedoseofdopaminergicagents,buttoaddanon-dopaminergicagentasacombinationstrategy(Silberetal.,2013).Moreover,lossofefficacyisthereductionofdrugefficacyovertime.Inthesecases,RLSsymptomsarenotworsethanbeforeinitiatingthetreatment(Garcia-BorregueroandWilliams,2014),acombinationtherapyisrecommendedinlossofefficacytodecreasethesideeffectsofcertainmedications,aswellastopreventaugmentation. Non-pharmacologicalTreatment Sleephygieneshouldbecorrectedbeforeallthepharmacologicaltreatment.Sleepdeprivation,sleepdisturbancesandfactorsthatcanresultininsomniashouldallbeavoided.AnothercommonbuteasilyneglecteddisorderisOSAS.EarlytreatmentforOSASisbeneficialforimprovingsleepforRLSpatients.Othernon-pharmacologicaltreatmentshavebeenproventobeeffectiveinRLS.tsDCSshowedashort-lastingclinicalimprovementinidiopathicRLSpatients(Heideetal.,2014),whilehigh-frequencyrTMSresultedinansignificantimprovementinthemotorsymptomsandsleepdisturbancesinRLSpatients(LinY.C.etal.,2015).Butthesenon-pharmacologicaltreatmentforRLSstudiesarescarce.TheyshowsomeadvantagesinsymptomaticRLSpatientswhodonotrespondtoordonottoleratetheclassicpharmacologicaltreatments.Itmaybringbrandnewsolutionstothesepatients.Ontheotherhand,thesemethodsarenon-invasiveandsafe,nosignificantsideeffectshavebeenobservedyet.DevelopingthesenewmethodscanbeagreatbenefitforRLSpatients. Conclusion TherehavebeenalotofadvancesinthefieldsofRLSinrecentyears,asthediagnosticcriteriahavebeenrevisedin2012.AdeeperinsightinpathophysiologyofRLShasputironmetabolismdysfunctioninanimportantposition,aswellasdopaminergicsystemdysfunction,hasbeendemonstrated.Guidelinesoflong-termtreatmentofRLSarepublishedbyIRLSSGin2013tohelpwiththetreatmentofRLSforclinicians.Preventionandmanagementofaugmentationforlong-termtreatmenthasbeenimprovedthroughclinicalexperienceandresearches.Moreresearchesshouldbedonetodiscoverthepathophysiology,andtofindbettertreatmentandmanagementofaugmentationofRLS. AuthorContributions SG:draftingthemanuscriptandthetables;HJ,CH,JL,XX,GZ:givingadviceonconceptionanddesign;JH,NX:revisingthemanuscript;ZL:givingadviceonconceptionanddesign;TW:conceptionanddesign.Givingfinalapprovaloftheversiontobepublished. Funding Thisworkwassupportedbygrants31171211and81471305fromtheNationalNaturalScienceFoundationofChina(toTW),grant81200983fromtheNationalNaturalScienceFoundationofChina(toNX),grant81301082fromtheNationalNaturalScienceFoundationofChina(toJH),grant2012B09fromChinaMedicalFoundation(toNX)andgrant0203201343fromHubeiMolecularImagingKeyLaboratory(toNX). ConflictofInterestStatement Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest. Abbreviations ADHD,attention-deficit/hyperactivitydisorder;AS,ankylosingspondylitis;BBBs,blood–brainbarriers;CH-RLSq,Cambridge–HopkinsdiagnosticquestionnaireforRLS;CI,confidenceinterval;CSF,cerebrospinalfluid;Cul3,Cullin-3;DA,dopaminergic;DAT,dopaminetransporter;DCSAD,DiagnosticClassificationofSleepandArousalDisorders;DIMS,disorderofinitiatingandmaintainingsleep;DOES,disorderofexcessivesomnolence;EFNS,EuropeanFederationofNeurologicalSocieties;EXP,expandedscreeningquestionnaire;GWASs,genome-wideassociationstudies;HRQoL,health-relatedqualityoflife;ICDs,impulsecontroldisorders;ICSD,InternationalClassificationofSleepDisorders;IRLS,internationalrestlesslegsscale;IRLSSG,InternationalRestlessLegsSyndromeStudyGroup;IRP2,ironregulatoryprotein-2;NIH,NationalInstitutesofHealth;OR,oddratio;OSAS,obstructivesleepapneasyndrome;PLMs,periodiclimbmovements;PLMS,periodiclimbmovementduringsleep;PLMW,periodiclimbmovementduringwakefulness;PSG,polysomnogram;RLS,restlesslegssyndrome;rTMS,repetitivetranscranialmagneticstimulation;SNPs,singlenucleotidepolymorphisms;tsDCS,transcutaneousspinaldirectcurrentstimulation. 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Editedby: AurelPopa-Wagner,UniversityofRostock,Germany Reviewedby: AntónBarreiro-Iglesias,UniversidadedeSantiagodeCompostela,Spain JunChangSu,FourthMilitaryMedicalUniversity,China ShuqinZhan,XuanWuHospitaloftheCapitalMedicalUniversity,China Copyright©2017Guo,Huang,Jiang,Han,Li,Xu,Zhang,Lin,XiongandWang.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).Theuse,distributionorreproductioninotherforumsispermitted,providedtheoriginalauthor(s)orlicensorarecreditedandthattheoriginalpublicationinthisjournaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionorreproductionispermittedwhichdoesnotcomplywiththeseterms. *Correspondence:TaoWang,[email protected] †Theseauthorshavecontributedequallytothiswork. COMMENTARY ORIGINALARTICLE Peoplealsolookedat SuggestaResearchTopic>