OfficialreprintfromUpToDate

2016UpToDate

Cervicalsubluxationinrheumatoidarthritis
Authors
PeterHSchur,MD
BradfordLCurrier,MD

SectionEditor
RavinderNMaini,BA,MBBChir,
FRCP,FMedSci,FRS

DeputyEditor
PaulLRomain,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:May2016.|Thistopiclastupdated:Feb25,2016.
INTRODUCTIONThediscovertebraljointsinthecervicalspinemaybeaffectedinpatientswithrheumatoidarthritis
(RA)withresultingosteochondraldestruction[1,2].Areviewoftheclinicalmanifestationsandtreatmentofatlantoaxial
(C1toC2)andsubaxialsubluxationinRAispresentedhere.Theclinicalfeaturesandgeneralmedicalmanagementof
RA,aswellasthedifferentialdiagnosisandgeneralevaluationofthepatientwithneckpainandofcervicalspine
disorders,arediscussedseparately.(See"Clinicalmanifestationsofrheumatoidarthritis"and"Generalprinciplesof
managementofrheumatoidarthritisinadults"and"Evaluationofthepatientwithneckpainandcervicalspinedisorders".)
CERVICALINVOLVEMENTCervicaljointdestructioninpatientswithrheumatoidarthritis(RA)mayleadtovertebral
malalignment(eg,subluxation),causingpain,neurologicaldeficit,anddeformity.Riskfactorsfordevelopmentofcervical
subluxationincludeolderageatonsetofRA,moreactivesynovitis,higherlevelsofCreactiveprotein,rapidlyprogressive
erosiveperipheraljointdisease,andearlyperipheraljointsubluxations[3,4].Bothatlantoaxialandsubaxial(belowC2)
jointsmaybeinvolved.
AtlantoaxialdiseaseAmongthejointsofthecervicalspine,theatlantoaxialjointispronetosubluxationinmultiple
directions,potentiallyleadingtocervicalmyelopathy[5].Theatlas(C1)canmoveanteriorly,posteriorly,vertically,laterally,
orrotationallyrelativetotheaxis(odontoidandbodyofC2):
Abnormalanteriormovementontheaxisisthemostcommontypeofsubluxation.Itoftenresultsfromlaxityofthe
transverseligamentinducedbyproliferativeC1toC2synovialtissue,butmayalsooccurasaresultoferosionor
fractureoftheodontoidprocess[6].
Posteriormovementontheaxiscanoccuronlyiftheodontoidpeghasbeenfracturedfromtheaxisorhasbeen
destroyed.
Verticalmovementinrelationtotheaxisisleastcommonitresultsfromdestructionofthelateralatlantoaxialjoints
orofbonearoundtheforamenmagnum[7].
Verticalatlantoaxialsubluxationmayoccurinthosewithinitialanteriorposteriorsubluxation.Verticalsubluxations
arebelievedtohaveaworseprognosisthantheothervarieties[8].
PathogenesisTherearetwopossiblemechanismsforinvolvementoftheintervertebraljointsinthecervicalspinein
RA:
Extensionoftheinflammatoryprocessfromadjacentneurocentraljoints(thejointsofLuschka,whicharelinedby
synovium)intothediscovertebralarea.
Chroniccervicalinstabilityinitiatedbyapophysealjointdestruction,subsequentlyleadingtovertebralmalalignment
orsubluxation[9].Thismayproducemicrofracturesofthevertebralendplates,discherniation,anddegenerationof
disccartilage.
Bursalspacesexistbetweenthecervicalinterspinousprocesses.Insomerheumatoidpatients,bursalproliferationhasled
toradiographicallydemonstrateddestructionofthespinousprocesses[10].
TheinvolvementandseverityofcervicalspinediseaseinRAparallelstheprogressionofperipheraljointerosions.Asa
result,cervicalsubluxationismorelikelyinthosewitherosionsofthehands,feet,hips,and/orknees[11,12].
Neurologicalfindingsmayoccurwhenthespaceavailableforthebrainstem,spinalcord,ornerverootsiscompromised
byvertebralsubluxation.

Asymmetricapophysealjointerosionmaycausescoliosismanifestedasheadtilt.Jointdestructionand/orspontaneous
fusionoftenleadtoreducedrangeofmotion.Anterioratlantoaxialorsubaxialsubluxationsmaycausetheheadtoprotrude
forward,leadingtopositivesagittalbalance.
PrevalenceAlthoughdecreasesinratesofhospitalizationsforcertainmanifestationsofsevereRA(eg,rheumatoid
vasculitis,splenectomyforFeltyssyndrome)wererecordedinCalifornia,nosignificantdecreaseinratesof
hospitalizationforcervicalspinesurgerywasnotedfrom1983to2001[13].However,theclinicalexperienceofexpertsin
spinalsurgeryisthattherateofoccipitalcervicalfusionhasdecreasedwiththeadventofmoreeffectivedisease
modifyingantirheumaticdrugs(DMARDs).TheprevalenceofcervicalinvolvementamongthosewithRAvarieswiththe
patientsubsetstudied.
Inoneseriesof113patientswithRAreferredforhiporkneearthroplasty,61percenthadroentgenographicevidence
ofcervicalspineinstability[12].
Aninceptioncohortstudyof103patientswithRA(ofwhom69survivedatleast20yearstohavelateralradiographs
ofthecervicalspine)documentedanterioratlantoaxialsubluxationandverticalsubluxationin23and26percent,
respectively[14].Noneofthesepatientsrequiredsurgicalproceduresonthecervicalspine.
Inagroupof476hospitalizedpatientswithRA,verticalsubluxationwasnotedin4percent[15].
Inagroupof165Greekpatientsinanoutpatientsetting,withmeanageof60yearsanddurationofdiseaseof12
years,theprevalenceofatlantoaxialsubluxationof2.5mmonlateralradiographwas21percent,butneurologic
impairmentwasonlypresentinonepatient[16].Subaxialsubluxation1mmatoneormorelevelswaspresentin44
percent.
Anincreasedriskofradiographiccervicalspineinvolvementhasbeenassociatedwiththepresenceinserumof
rheumatoidfactorandwithanelevatedCreactiveproteinlevel,buthasnotbeenassociatedwiththepresenceofhuman
leukocyteantigen(HLA)DR4[4,17].
SymptomsInvolvementofcervicaljointsmayresultinsignificantpain.However,passiverangeofmotionmaybe
normalintheabsenceofmusclespasm.Theearliestandmostcommonsymptomofcervicalsubluxationispainradiating
superiorlytowardstheocciput[18].Additionalsymptomsofsubluxationinclude:
Spasticquadriparesisisslowlyprogressive.
Sensoryfindingsarealsocommon,includingpainlesssensorylossinthehandsorfeet.
InpatientswithC1toC2subluxation,transientepisodesofmedullarydysfunction(suchasrespiratoryirregularity)
wereassociatedwithverticalpenetrationoftheodontoidprocessofC2andwithprobablevertebralartery
compression[19].Suddendeathmayoccur.Therate,reportedas10to20percentintheolderliterature,is
uncertain.
Neurologicfindingsinpatientswithatlantoaxialsubluxationmayalsoincludemyelopathy,sensoryloss,paresthesiasin
theC2area(greateroccipitalneuralgia),decreasedsensationinthedistributionofthefifthcranialnerve,andnystagmus.
Subaxialsubluxations,whichnarrowtheintervertebralforamina,maycauseradiculopathy.
Neurologicsignsandsymptomsoftenhavelittlerelationshiptothesizeoftheabnormallywidenedspacebetweenthe
archoftheatlasandtheanterioraspectofthedens(anterioratlantodentalinterval[AADI])ortotheamountofsubluxation
betweensubaxialvertebrae.Themagnitudeofthespaceavailableforthecord(SAC)inthesubaxialspineoratC1toC2,
whereitisknownastheposterioratlantodentalinterval(PADI),doescorrelatewiththeincidenceofneurological
compromise[20].Thesymptomsofspinalcordcompressionthatdemandimmediateattentionandinterventioninclude
[21]:

Asensationoftheheadfallingforwarduponflexionofthecervicalspine
Changesinlevelsofconsciousness
Dropattacks
Lossofsphinctercontrol
Respiratorydysfunction
Dysphagia,vertigo,convulsions,hemiplegia,dysarthria,ornystagmus

 Peripheralparesthesiaswithoutevidenceofperipheralnervediseaseorcompression
Lhermittesphenomenon,anelectricshocklikesensationintheneckradiatingdownthespineorintothearms,
producedbyforwardflexionoftheneck
However,insteadofcompressionofthespinalcord,someofthesesymptomsmaybeduetocompressionofthevertebral
arteries,whichmustwindthroughforaminawithinthelateralaspectsofC1andC2.Findingsonmagneticresonance
imaging(MRI)mayhelpdistinguishbetweenthesetwopossibilities.
PhysicalfindingsPhysicalfindingsrelatingtothespinewhicharesuggestiveofatlantoaxialsubluxationinclude:

Lossofcervicallordosis
Scoliosis
Resistancetopassivespinemotion
Abnormalprotrusionoftheanteriorarchoftheatlasfeltbytheexaminingfingerontheposteriorpharyngealwall

Inaddition,neurologicfindingsappropriatetothesymptomsdescribedabovemaybeseen,including:

Increaseddeeptendonreflexes(seeninmyelopathy)
Extensorplantarresponses
Hoffmanssign
Muscleweakness,spasticity,ormuscleatrophy
Gaitdisorders
Decreaseddeeptendonreflexes(seeninradiculopathy)

IMAGINGFINDINGSPatientswithmild,nonspecificneckoroccipitalpaincanbeevaluatedinitiallybyconventional
radiography,butpatientswithevidenceofsubluxationorofC1toC2synovitisrequirecarefulobservationandmagnetic
resonanceimaging(MRI)examinationifsymptomsorsignsprogress.Theuseofconventionalradiographs,computerized
tomography(CT),andMRIarediscussedbelow.(See'Symptoms'aboveand'Physicalfindings'aboveand'Conventional
radiography'belowand'CTscan'belowand'Magneticresonanceimaging'below.)
ConventionalradiographyAmongpatientswithatlantoaxialsubluxation,plainradiographicviewsofthecervicalspine
(anteroposterior,lateral,openmouth,flexion,andextension)mayrevealmorethan3mmofseparationbetweenthe
odontoidpegandtheC1arch(image1)[19,22].SeparationbetweenC1andC2(anteriorsubluxation)of9mmormoreor
aposterioratlantodentaldistanceoflessthan14mmisassociatedwithanincreasedincidenceofcordcompression
[20,23,24].Inaddition,ifthespaceavailableforthespinalcordislessthan13mmanywhereinthecervicalregion,there
isanincreasedriskforneurologicimpairment.Insymptomaticpatients,thefilmsinflexionshouldbetakenonlyafter
radiographs(includinganopenmouthview)haveexcludedanodontoidfractureorsevereatlantoaxialsubluxation.
Thesestructuresmaybedifficulttovisualizeeffectivelyusingconventionalradiographictechniquesbecauseof
osteopenia,thesmallsizeofthemultiplejointsinthecervicalspine,thelargemassofsofttissuesurroundingthespine,
andthelowerbordersoftheoccipitalbones.Inaddition,theusuallandmarksmaybeobliteratedinadvanceddisease[25].
Sinceneckpositioningrequiredforintubationpriortosurgerymaybefatalamongpatientswithrheumatoidarthritis(RA)
andunrecognizedC1toC2disease,andsincesubluxationisnotalwayssymptomatic,radiographicevaluationofthe
cervicalspineisadvisedforallpatientswithRAscheduledtoundergosurgeryrequiringmanipulationoftheneckforeither
anesthesiaorsurgery[26].
CTscanCTcandemonstratespinalcordcompressionbyrevealingthelossofsubarachnoidspace,attenuationofthe
transverseligament,andbonyandsofttissuechangesinpatientswithC1toC2subluxation(image2)[27,28].However,
notallstudieshavefoundthatCTishelpfulinthissetting.Inonestudyof12patients,forexample,CTprovidedadditional
usefulinformationinonlyonepatient[28].CTandCTangiographyareusefulforpreoperativeplanning.Thereformatted
sagittalCTscancanpreciselydocumentthepositionoftheodontoidwithrespecttotheforamenmagnum,thedegreeof
atlantoaxialdislocation,andtherelationshipsamongtheuppercervicalspinejoints[29].
CTisalsohelpfulinplanningthebestsurgicaltechniquetobeusedineachcaseandinassessingthesizeofthe
implantstobeused.Itisusedtodeterminethetypeoffixationthatcanbeused,suchasC1posteriorarchversuslateral
massscrewsorC2pars,pedicle,orlaminarscrews[30].AcontrastenhancedCTscancanbeusefultodiagnose
inflammatorysofttissueproliferationinpatientsunabletoundergoMRI(eg,thosewithaneurysmclips,bodyimplants,

wiresorplates,someheartvalves,someimplantedelectrodes)[31].
MagneticresonanceimagingMRIisparticularlyvaluableintheassessmentofcervicalspinediseaseinRA,because
itpermitsvisualizationofthepannusproducingcordcompression,thespinalcord,andbone(image3)[3235].MRIisthe
modalityofchoiceforearlydiagnosisofcervicalinvolvement,becauseithashighsensitivityindetectinginflammatory
changesinthejointsevenbeforeinstabilitydevelops[36].MRIcanprovideinformationaboutneuraltissue(spinalcord
andnerveroots)andthecontentsoftheepiduralspaceandistheradiologicalmodalityofchoiceinevaluatingforpossible
spinalcordcompression[37].
ThedevelopmentofneurologicaldysfunctionisstronglyassociatedwithMRIevidenceofspinalcanalstenosis,
particularlyinpatientswithevidenceofuppercervicalcordorbrainstemcompressionorofsubaxialmyelopathy[38].Bone
marrowedema(BME)canbeobservedbyMRIinpatientswithearlycervicalspineinvolvementtheedemamaybeseen
intheodontoidprocess,inthevertebralendplates,andinthesubaxialinterapophysealjoints[39].Highererythrocyte
sedimentationrateswereassociatedwithmoresevereatlantoaxialjointsynovitis.
Adynamic(flexionextension)MRIclearlydelineatestherelationshipbetweentheodontoid,foramenmagnum,and
cervicalspinalcord,butprolongedflexionshouldbeperformedwithcautionbecauseoftheriskofcordcompression[25].
Inaddition,gradientechoMRIpulsesequencesprovidereliablevisualizationofthetransverseatlantalligament,permitting
thecliniciantodistinguishrupturefromstretchingoftheligamentandtovisualizepannuscompressingthecord[40].
TheinformationgainedfromMRIissufficientlyadditivetowarranttheincreasedcostofthisprocedure,particularlyif
surgeryiscontemplated[33,41].However,onedrawbackofMRIisthatitoftenunderestimatesthedegreeofatlantoaxial
subluxationwhencomparedwithflexionextensionplainfilmradiography.Thiswasillustratedinaseriesof23patients
withRAorjuvenileidiopathicarthritis(JIA)whohadbothradiographsandMRIwithflexionandextensionviewsperformed
withinaonemonthtimeframe[42].Afteraccountingformagnificationontheplainfilms,themeasuredatlantoaxial
subluxationbyMRIwaslessthanthatnotedonradiographsin19ofthe23patientsintheworstcase,themeasured
distancedifferedby7mm.Thus,unlessflexionandextensionMRimagesdocumentexcessivesubluxation,plainfilm
flexionextensionradiographyisstillneededtoassessatlantoaxialstability,especiallyinpatientswithRAscheduledto
undergosurgeryrequiringmanipulationoftheneckforeitheranesthesiaorsurgery.(See'Conventionalradiography'
above.)
NATURALHISTORYAsnotedabove,theonsetofatlantoaxialsubluxationaloneisnotinexorablyassociatedwith
neurologicdysfunctionorwithanincreasedriskofdeath[43].Althoughradiographicprogressioniscommon,itdoesnot
alwayscorrelatewithneurologicdeterioration[18,4447].Patientswithplainfilmradiographicevidenceofcervical
subluxation,withorwithoutneurologicsymptoms,haveafiveyearmortalityrateof17percent[7].
However,somepatientswithseveredislocationmaybeatriskofdeath.Inoneseriesof104consecutiveautopsiesof
patientswithrheumatoidarthritis(RA),11casesofseveredislocationwerefound[48].Inall11,theodontoidprotruded
posterosuperiorlyandimpingedonthemedullawithintheforamenmagnum.Infive,spinalcordcompressionwas
determinedtobetheonlycauseofdeath.
Patientswithsubluxationandsignsofspinalcordcompressionhaveapoorprognosiswithoutsurgery.Inthissetting,
myelopathyprogressesrapidly,anddeathmayquicklyensue[49,50].Asanexample,inastudyof21patientswith
atlantoaxialsubluxationandwithsignsofmyelopathywhoweremanagedmedically,neurologicdeteriorationoccurredin
16of21(76percent),andallwereunabletowalkwithinthreeyearsoffollowup[51].Nonesurvivedmorethaneight
years.AsystematicreviewoftheliteraturerevealedneurologicdeteriorationwasalmostinevitableinRanawatII,IIIA,and
IIIBpatients(ie,thosewithfindingstoindicateaneurologicaldeficit)treatednonoperatively.The10yearoverallsurvival
ratewas40percent[50].
Magneticresonanceimaging(MRI)findingsmaybemorehelpfulthanplainfilmradiographyindeterminingprognosis.As
anexample,among82patientswithMRIevidenceofcordcompressionatthelevelofC1toC2,60percentdeteriorated
withconservativemanagementoveramedianof12months[52].Thosewithsubaxialcordcompressionfaredbetter,with
only18percentworseningwithtime.Amongallpatients,nineeventuallyrequiredsurgicalintervention(sixduetoa
combinationofpainandprogressiveneurologicdeficits,twoduetopainonly,andoneduetopainlessneurologic
deterioration).
Aninabilitytowalkpreoperativelyalsoconfersapoorprognosis.Inonestudy,only20percentofsuchpatientsimproved
aftertreatment[53].

PREVENTIONLimitedevidencesuggeststhattheadministrationofcombinationtherapyconsistingofdisease
modifyingantirheumaticdrugs(DMARDs)mayhelppreventthedevelopmentofcervicalspinesubluxation.Asan
example,195patientswithrheumatoidarthritis(RA)ofrecentonset(twoyearsorless)wererandomlyassignedtoa
regimenofsulfasalazine,methotrexate,hydroxychloroquine,andprednisoloneortosulfasalazinealone[54].Atlantoaxial
impactionoranteriorsubluxationdevelopedin2and7percentofthesulfasalazinealonegroup,respectively,butinnoneof
thosereceivingcombinationtherapyaftertwoyearsoftreatment.DMARDtreatmentwasunrestrictedaftertwoyears.
Atfiveyearsoffollowup,theoccurrenceofanterioratlantoaxialsubluxationswassignificantlyassociatedwithinitial
singleDMARDtherapy[55].Atlantoaxialimpactionoranteriorsubluxationdevelopedmoreoftenintheinitialsingle
therapygroupcomparedwiththeinitialcombinationtherapygroup(6and14percentversus1and3percent,respectively).
Inastudyof91patientswithRAtreatedwithbiologicals,the44patientswithoutneckinvolvementatbaselineweremuch
lesslikelytodevelopneckradiographicprogressionthanthose47RApatientswhohadalreadydevelopedneck
involvement(7versus72to79percent)[56].
AnoverviewofthemanagementofRAispresentedelsewhere.(See"Generalprinciplesofmanagementofrheumatoid
arthritisinadults".)
TREATMENTPatientswithcervicalsubluxationaretreatedmedicallyand/orsurgicallybasedlargelyuponthe
presenceorabsenceofsignsofspinalcordcompression.
MedicaltherapyPatientswithseveresubluxationbutwithoutsignsofcordcompressionareatriskforsevereinjury
andperhapsdeathduetoavarietyofinsults.Theseincludeminorfalls,whiplashinjuries,andintubation.Althoughthe
subjectofsomecontroversy,stiffcervicalcollarsmaybeprescribedforstabilityinonereport,morethan50percentof
suchpatientsbenefitedfromthismodality[57,58].Insomepatients,halotractionmaybeofbenefit,typicallyfollowedby
surgery.
Collarsthatarenotrigid(and,therefore,thataremorecomfortableforthepatient)givereassurancetoboththeclinician
andthepatientbutprovidelittlestructuralsupport.Spinalmanipulationiscontraindicated.
Theroleofneckmusclestrengtheningexercisesisuncertain.Adecreaseinanterioratlantoaxialsubluxationwasnotedin
asubgroupofsevenpatientswithrheumatoidarthritis(RA)andunstableatlantoaxialjointsduringactiveisometricneck
flexormusclecontraction[59].Whilethissuggeststhatisometricneckflexorexerciseisprobablysafe,theefficacyof
neckflexormusclestrengtheningforsymptomsrelatedtosubluxation,radiographicprogression,andotherimportant
patientoutcomeswerenotassessedinthisstudy.Incontrastwiththeneckflexors,isometricneckextensormuscle
tighteningworsenedradiographicallyapparentatlantoaxialsubluxationinthosewithunstablearticulations.Thus,while
furtherinvestigationofneckflexorstrengtheningmaybewarranted,isometricexerciseoftheneckextensorsshouldbe
avoided.
PatientswhohavepainduetoirritationofC2nerverootbutwhodonothaveevidenceofcordcompressionmaybenefit
fromagentsusedforchronicneuropathicpain(see"Overviewofthetreatmentofchronicpain").Thesepatientsmay
obtainsomebenefitfromlocalnerveblocks,althoughthereliefisgenerallytemporary.
SurgeryPatientswithsubluxationandsignsofspinalcordcompressionhaveagraveprognosiswithoutsurgical
interventiontoprovidestabilitytothespine[1,19,50].Althoughsurgeryforatlantoaxialsubluxationhasattendantrisks,
somedataindicatethatearlyoperativetreatmentmaydelaythedetrimentalcourseofcervicalmyelopathyinRA[50,60].
(See'Naturalhistory'above.)
Thebenefitsofferedbysurgicalmanagementofpatientswithatlantoaxialsubluxationwhohavemyelopathyincludean
improvedsurvivalrate,animprovementinmyelopathyinsomepatients,andadecreasedriskofneurologicprogression.
Thebeneficialeffectsofsurgerywereillustratedinanobservationalstudythatcompared19patientswithsymptomatic
atlantoaxialsubluxationwhounderwentlaminectomyandoccipitocervicalfusionwith21otherswhoweremanaged
conservatively[51].The5and10yearsurvivalratesforthosewhounderwentsurgerywere84and37percent,
respectively.Incontrast,noneofthe21patientsmanagedconservativelysurvivedmorethaneightyears.Neurologic
improvementwasnotedin68percentfollowingsurgery,while,inthenonoperativegroup,76percenthadneurologic
deterioration.
Surgeryisgenerallywelltolerated.Inaprospectivestudyof532patientswithRAandwithsubluxationsofthecervical
spineseenbetween1974and1999,217underwentsurgery,ofwhomonly11(5percent)experiencedresidualneckpainor

neurologicsymptoms[61].Suchsymptomswereassociatedwithincreasedriskofdeathduringthecourseofthestudy.
Therewerereducedsurvivalforpatientswithsubaxialsubluxationsandanassociationofincreasedverticalsettlingwith
suddendeath.Therewerefewperioperativeorpostoperativecomplications.
Surgeryshouldbeconsideredcarefullyandonanindividualizedbasisamongpatientswithsubluxationbutwithoutsignsor
symptomsofcordcompression.Inthissetting,operativestabilizationmaybeconsideredifsymptomsdevelop,whichis
notuncommon.Inoneseriesof84patientswithsomeformofsubluxationbutwithoutcordorbrainstemlesions,one
fourthworsened,andonefourthimprovedwithoutsurgeryover5to14yearsoffollowup[44].
SomedatasupportthehypothesisthatearlyC1toC2fusionforatlantoaxialsubluxation,beforethedevelopmentof
superiormigrationoftheodontoid,decreasestheriskoffurtherprogressionofcervicalspineinstability.Aretrospective
studyof110patientswithRAwhounderwentcervicalspinefusionnotedtwomajorfindingsonfollowup[62]:
Fifteenpercentdevelopedcervicalinstabilitythisoccurredin5.5percentofthosewithatlantoaxialsubluxationand
in36percentofthosewithatlantoaxialsubluxationandsuperiormigrationoftheodontoid.
NopatientwithC1toC2fusionforatlantoaxialsubluxationsubsequentlydevelopedsuperiormigrationofthe
odontoid.
Alimitingfactoristhattheincidenceofsustainedneurologicdeteriorationrelatedtosurgerymaybeashighas6percent
[63].Asaresult,askilledsurgicalteamandacarefulassessmentofeachpatientareimportantelementsofany
therapeuticregimen.
Fortunately,theprognosisforpatientswithsurgeryappearstobeimprovingdue,inpart,toearlierreferral,enhanced
technique,andbetterperioperativemanagement.Theoutcomesof27patientswithRAwhohadcervicalfusionsinthe
periodof1991to1996(latecohort)werecomparedwiththoseof32individualswhosesurgeryoccurredintheperiodof
1974to1982(earlycohort)[64].Only7percentofpatientsinthemorerecentgrouphadseverecervicalmyelopathyprior
tosurgery,versus34percentintheearliercohort.Comparedwiththeearlygroup,thelatecohorthadfewerearly
postoperativedeaths(0versus9percent),complications(22versus50percent),failedsurgeries(15versus28percent),
andreoperations(11versus20percent).Amongpatientsinthemorerecentcohortinwhomtherewassufficient
informationtojudgeachangeinneurologicstatuswithsurgery(18patients),improvementinandmaintenanceofthe
preoperativeleveloffunctionwerenotedthreemonthsaftersurgeryinonethirdandtwothirds,respectively.
Asystematicliteraturereviewidentified23observationalstudiesdescribingtheneurologicoutcomeaftersurgeryfor752
patients[50].PatientswithRanawatI(asymptomaticpatientswithnoneurologicdeficit)andII(patientswithsubjective
weaknesswithhyperreflexiaanddysesthesia)neurologicstatusrarelydeteriorated.RanawatIIIpatients(thosewith
objectiveweaknessandlongtractsigns)typicallydidnotrecovercompletely.The10yearsurvivalratesmirroredthe
Ranawatclassandrangedfrom77percentto30percentforRanawatI(nodeficit)andIIIB(nonambulatorypatientswith
objectiveweaknessandlongtractsigns),respectively[50].Outcomeswerebetterwithsurgerythanconservative
treatmentinallpatientswithneurologicinvolvement,butweresimilarforasymptomaticpatientswithnoneurologicdeficit
(RanawatI).Theevidenceisweak,however,andtheidealtreatmentforasymptomaticpatientswithradiographic
instabilityawaitstheresultsofarandomizedcontroltrial[65].
EventhoughRanawatIIIBpatientshaveasignificantlyworseoutcomethanallothergroups[50],surgerymaystilloffer
thebestqualityoflifeandsurvivalfortheseseverelydisabledpatients[66].Ideally,surgeryshouldbeofferedbeforea
significantneurologicdeficitoccurs.
Thedecompressionandstabilizationmayneedtoextendintothesubaxialspine.Inoneseries,histopathologicstudiesof
brainstemsandspinalcordsofninepatientswithendstageRArevealedsignificantsubaxialmyelopathyinthecervical
spinerelateddirectlytocompression,stretching,andmovementofthespinalcord[67].
Transpediclescrewfixationusingstereotacticguidancehasalsobeenusedforstabilization[68].Becausethediameterof
cervicalpediclesisverysmall,thisisconsideredaprocedurewithsignificantrisk.However,useoffullscale,three
dimensionalmodelsinpreoperativeplanningmaylessenmorbidity[69].
Occipitocervicalfixationhasalsobeenemployedtotreatpatientswithunstablecervicalspines.Whenthisprocedurewas
employedin163RApatients,88percentimproved,7percentremainedunchanged,and5percentprogressed[70].
Complicationsincludedinfection(10percent)andprogressivesubluxationthatrequiredreoperation(4percent).

SUMMARYANDRECOMMENDATIONS
Cervicaljointdestructioninpatientswithrheumatoidarthritis(RA)mayleadtovertebralmalalignment(eg,
subluxation),causingpain,neurologicaldeficit,anddeformity.Riskfactorsforcervicalsubluxationincludeolderage
atonsetofRA,moreactivesynovitis,higherlevelsofCreactiveprotein,rapidlyprogressiveerosiveperipheraljoint
disease,andearlyperipheraljointsubluxations.Bothatlantoaxialandsubaxial(belowC2)jointsmaybeinvolved.
EstimatesoftheprevalenceofcervicalinvolvementamongthosewithRAvarywidelyfewerpatientsappearto
requiresurgerysincethe1990s.(See'Cervicalinvolvement'aboveand'Prevalence'above.)
Theatlantoaxialjointispronetosubluxationinmultipledirections,potentiallyleadingtocervicalmyelopathy.The
atlas(C1)canmoveanteriorly,posteriorly,vertically,laterally,orrotationallyrelativetotheaxis(odontoidandbodyof
C2).Abnormalanteriormovementontheaxisisthemostcommontypeofsubluxationitoftenresultsfromlaxityof
thetransverseligamentinducedbyproliferativeC1toC2synovialtissue,butmayalsooccurasaresultoferosion
orfractureoftheodontoidprocess.(See'Atlantoaxialdisease'above.)
ThetwopossiblemechanismsforinvolvementoftheintervertebraljointsinthecervicalspineinRAare1)extension
oftheinflammatoryprocessfromadjacentneurocentraljoints(thejointsofLuschka,whicharelinedbysynovium)
intothediscovertebralareaand2)chroniccervicalinstabilityinitiatedbyapophysealjointdestruction,subsequently
leadingtovertebralmalalignmentorsubluxation.(See'Pathogenesis'above.)
Involvementofcervicaljointsmayresultinsignificantpain.However,passiverangeofmotionmaybenormalinthe
absenceofmusclespasm.Theearliestandmostcommonsymptomofcervicalsubluxationispainradiating
superiorlytowardtheocciput.Additionalsymptomsofsubluxationincludeslowlyprogressivespasticquadriparesis
sensoryfindings,includingpainlesssensorylossinthehandsorfeettransientepisodesofmedullarydysfunction
(suchasrespiratoryirregularity)andothers.Suddendeathmayoccur.Symptomsofspinalcordcompressionmay
alsoresultfromcompressionofthevertebralarteries.Thesymptomsofspinalcordcompressionthatdemand
immediateattentionandinterventioninclude(see'Symptoms'above):

Asensationoftheheadfallingforwarduponflexionofthecervicalspine
Changesinlevelsofconsciousness
Dropattacks
Lossofsphinctercontrol
Respiratorydysfunction
Dysphagia,vertigo,convulsions,hemiplegia,dysarthria,ornystagmus
Peripheralparesthesiaswithoutevidenceofperipheralnervediseaseorcompression
Lhermittesphenomenon,anelectricshocklikesensationintheneckradiatingdownthespineorintothearms,
producedbyforwardflexionoftheneck

Physicalfindingsrelatingtothespine,whicharesuggestiveofatlantoaxialsubluxation,includelossofcervical
lordosis,scoliosis,resistancetopassivespinemotion,andabnormalprotrusionoftheanteriorarchoftheatlasfelt
bytheexaminingfingerontheposteriorpharyngealwall.Neurologicfindingsappropriatetothesymptomsdescribed
abovemaybeseen,includingincreaseddeeptendonreflexes(seeninmyelopathy)extensorplantarresponses
Hoffmanssignmuscleweakness,spasticity,ormuscleatrophygaitdisordersanddecreaseddeeptendonreflexes
(seeninradiculopathy).(See'Physicalfindings'above.)
Patientswithmild,nonspecificneckoroccipitalpaincanbeevaluatedinitiallybyconventionalradiography,but
patientswithevidenceofsubluxationorC1toC2synovitisrequirecarefulobservationandmagneticresonance
imaging(MRI)examinationifsymptomsorsignsprogress.Radiographicevaluationofthecervicalspineisadvised
forallpatientswithRAscheduledtoundergosurgeryrequiringmanipulationoftheneckforeitheranesthesiaor
surgery.(See'Imagingfindings'above.)
Atlantoaxialsubluxationaloneisnotinexorablyassociatedwithneurologicdysfunctionorwithanincreasedriskof
death.Althoughradiographicprogressioniscommon,itdoesnotalwayscorrelatewithneurologicdeterioration.
However,somepatientswithseveredislocationmaybeatriskfordeath.Patientswithplainfilmradiographic
evidenceofcervicalsubluxation,withorwithoutneurologicsymptoms,haveafiveyearmortalityrateof17percent.
Patientswithsubluxationandsignsofspinalcordcompressionhaveapoorprognosiswithoutsurgery.(See'Natural
history'above.)

 Patientswithseveresubluxationbutwithoutsignsofcordcompressionareatriskforsevereinjuryandperhaps
deathduetoavarietyofinsults.Theseincludeminorfalls,whiplashinjuries,andintubation.Suchpatientsmay
benefitfromrigidcervicalcollars.Surgeryshouldbeconsideredcarefullyandonanindividualizedbasisamong
patientswithsubluxationbutwithoutsignsorsymptomsofcordcompression.Patientswithsubluxationandsignsof
spinalcordcompressionhaveagraveprognosiswithoutsurgicalinterventiontoprovidestabilitytothespine.(See
'Treatment'aboveand'Medicaltherapy'aboveand'Surgery'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1.BlandJ.Rheumatoidarthritisofthecervicalspine.JRheumatol19741:319.
2.BallJ.Enthesopathyofrheumatoidandankylosingspondylitis.AnnRheumDis197130:213.
3.NevaMH,IsomkiP,HannonenP,etal.Earlyandextensiveerosivenessinperipheraljointspredictsatlantoaxial
subluxationsinpatientswithrheumatoidarthritis.ArthritisRheum200348:1808.
4.PaimelaL,LaasonenL,KankaanpE,LeirisaloRepoM.Progressionofcervicalspinechangesinpatientswith
earlyrheumatoidarthritis.JRheumatol199724:1280.
5.SantavirtaS,KankaanpU,SandelinJ,etal.Evaluationofpatientswithrheumatoidcervicalspine.ScandJ
Rheumatol198716:9.
6.KauppiM,SakaguchiM,KonttinenYT,etal.Pathogeneticmechanismandprevalenceofthestableatlantoaxial
subluxationinrheumatoidarthritis.JRheumatol199623:831.
7.ChangDJ,PagetSA.Neurologiccomplicationsofrheumatoidarthritis.RheumDisClinNorthAm199319:955.
8.DavidsonRC,HornJR,HerndonJH,GrinOD.Brainstemcompressioninrheumatoidarthritis.JAMA1977
238:2633.
9.MartelW.Pathogenesisofcervicaldiscovertebraldestructioninrheumatoidarthritis.ArthritisRheum197720:1217.
10.BywatersEG.Rheumatoidandotherdiseasesofthecervicalinterspinousbursae,andchangesinthespinous
processes.AnnRheumDis198241:360.
11.WinfieldJ,YoungA,WilliamsP,CorbettM.Prospectivestudyoftheradiologicalchangesinhands,feet,and
cervicalspineinadultrheumatoiddisease.AnnRheumDis198342:613.
12.CollinsDN,BarnesCL,FitzRandolphRL.Cervicalspineinstabilityinrheumatoidpatientshavingtotalhiporknee
arthroplasty.ClinOrthopRelatRes1991:127.
13.WardMM.Decreasesinratesofhospitalizationsformanifestationsofsevererheumatoidarthritis,19832001.
ArthritisRheum200450:1122.
14.NevaMH,KaarelaK,KauppiM.Prevalenceofradiologicalchangesinthecervicalspineacrosssectionalstudy
after20yearsfrompresentationofrheumatoidarthritis.JRheumatol200027:90.
15.HendersonDR.Verticalatlantoaxialsubluxationinrheumatoidarthritis.RheumatolRehabil197514:31.
16.ZikouAK,AlamanosY,ArgyropoulouMI,etal.Radiologicalcervicalspineinvolvementinpatientswithrheumatoid
arthritis:acrosssectionalstudy.JRheumatol200532:801.
17.FujiwaraK,FujimotoM,OwakiH,etal.Cervicallesionsrelatedtothesystemicprogressioninrheumatoidarthritis.
Spine(PhilaPa1976)199823:2052.
18.StevensJC,CartlidgeNE,SaundersM,etal.Atlantoaxialsubluxationandcervicalmyelopathyinrheumatoid
arthritis.QJMed197140:391.
19.NakanoKK,SchoeneWC,BakerRA,DawsonDM.Thecervicalmyelopathyassociatedwithrheumatoidarthritis:
analysisofpatients,with2postmortemcases.AnnNeurol19783:144.
20.BodenSD,DodgeLD,BohlmanHH,RechtineGR.Rheumatoidarthritisofthecervicalspine.Alongtermanalysis
withpredictorsofparalysisandrecovery.JBoneJointSurgAm199375:1282.
21.MayerJW,MessnerRP,KaplanRJ.Brainstemcompressioninrheumatoidarthritis.JAMA1976236:2094.
22.MARTELW.Theoccipitoatlantoaxialjointsinrheumatoidarthritisandankylosingspondylitis.AmJRoentgenol
RadiumTherNuclMed196186:223.
23.WeissmanBN,AliabadiP,WeinfeldMS,etal.Prognosticfeaturesofatlantoaxialsubluxationinrheumatoidarthritis
patients.Radiology1982144:745.
24.LipsonSJ.Rheumatoidarthritisinthecervicalspine.ClinOrthopRelatRes1989:121.

25.BellGR,StearnsKL.FlexionextensionMRIoftheupperrheumatoidcervicalspine.Orthopedics199114:969.
26.NevaMH,HkkinenA,MkinenH,etal.Highprevalenceofasymptomaticcervicalspinesubluxationinpatients
withrheumatoidarthritiswaitingfororthopaedicsurgery.AnnRheumDis200665:884.
27.RaskinRJ,SchnapfDJ,WolfCR,etal.Computerizedtomographyinevaluationofatlantoaxialsubluxationin
rheumatoidarthritis.JRheumatol198310:33.
28.BraunsteinEM,WeissmanBN,SeltzerSE,etal.Computedtomographyandconventionalradiographsofthe
craniocervicalregioninrheumatoidarthritis.Acomparison.ArthritisRheum198427:26.
29.HolmesJF,AkkinepalliR.Computedtomographyversusplainradiographytoscreenforcervicalspineinjury:a
metaanalysis.JTrauma200558:902.
30.JoaquimAF,GhizoniE,AnderleDV,etal.Axisinstrumentation:surgicalresults.ArqNeuropsiquiatr201270:857.
31.CzernyC,GramppS,HenkCB,etal.Rheumatoidarthritisofthecraniocervicalregion:assessmentand
characterizationofinflammatorysofttissueproliferationswithunenhancedandcontrastenhancedCT.EurRadiol
200010:1416.
32.BreedveldFC,AlgraPR,VielvoyeCJ,CatsA.Magneticresonanceimagingintheevaluationofpatientswith
rheumatoidarthritisandsubluxationsofthecervicalspine.ArthritisRheum198730:624.
33.DAVISFWJr,MARKLEYHE.Rheumatoidarthritiswithdeathfrommedullarycompression.AnnInternMed1951
35:451.
34.StiskalMA,NeuholdA,SzolarDH,etal.RheumatoidarthritisofthecraniocervicalregionbyMRimaging:detection
andcharacterization.AJRAmJRoentgenol1995165:585.
35.GlewD,WattI,DieppePA,GoddardPR.MRIofthecervicalspine:rheumatoidarthritiscomparedwithcervical
spondylosis.ClinRadiol199144:71.
36.TehranzadehJ,AshikyanO,DascalosJ.Magneticresonanceimaginginearlydetectionofrheumatoidarthritis.
SeminMusculoskeletRadiol20037:79.
37.JoaquimAF,GhizoniE,TedeschiH,etal.Radiologicalevaluationofcervicalspineinvolvementinrheumatoid
arthritis.NeurosurgFocus201538:E4.
38.NarvezJA,NarvezJ,SerrallongaM,etal.Cervicalspineinvolvementinrheumatoidarthritis:correlationbetween
neurologicalmanifestationsandmagneticresonanceimagingfindings.Rheumatology(Oxford)200847:1814.
39.NarvezJA,NarvezJ,deAlbertM,etal.Bonemarrowedemainthecervicalspineofsymptomaticrheumatoid
arthritispatients.SeminArthritisRheum200938:281.
40.DickmanCA,MamourianA,SonntagVK,DrayerBP.Magneticresonanceimagingofthetransverseatlantal
ligamentfortheevaluationofatlantoaxialinstability.JNeurosurg199175:221.
41.MartelW.Fatalatlantoaxialluxationinrheumatoidarthritis.ArthritisRheum19636:224.
42.LaihoK,SoiniI,KautiainenH,KauppiM.Canwerelyonmagneticresonanceimagingwhenevaluatingunstable
atlantoaxialsubluxation?AnnRheumDis200362:254.
43.PellicciPM,RanawatCS,TsairisP,BryanWJ.Aprospectivestudyoftheprogressionofrheumatoidarthritisofthe
cervicalspine.JBoneJointSurgAm198163:342.
44.SmithPH,BennRT,SharpJ.Naturalhistoryofrheumatoidcervicalluxations.AnnRheumDis197231:431.
45.IsdaleIC,ConlonPW.Atlantoaxialsubluxation.Asixyearfollowupreport.AnnRheumDis197130:387.
46.MathewsJA.Atlantoaxialsubluxationinrheumatoidarthritis.A5yearfollowupstudy.AnnRheumDis1974
33:526.
47.WinfieldJ,CookeD,BrookAS,CorbettM.Aprospectivestudyoftheradiologicalchangesinthecervicalspinein
earlyrheumatoiddisease.AnnRheumDis198140:109.
48.MikulowskiP,WollheimFA,RotmilP,OlsenI.Suddendeathinrheumatoidarthritiswithatlantoaxialdislocation.
ActaMedScand1975198:445.
49.MeijersKA,CatsA,KremerHP,etal.Cervicalmyelopathyinrheumatoidarthritis.ClinExpRheumatol19842:239.
50.WolfsJF,KloppenburgM,FehlingsMG,etal.Neurologicoutcomeofsurgicalandconservativetreatmentof
rheumatoidcervicalspinesubluxation:asystematicreview.ArthritisRheum200961:1743.
51.MatsunagaS,SakouT,OnishiT,etal.Prognosisofpatientswithuppercervicallesionscausedbyrheumatoid
arthritis:comparisonofoccipitocervicalfusionbetweenc1laminectomyandnonsurgicalmanagement.Spine(Phila
Pa1976)200328:1581.
52.HamiltonJD,JohnstonRA,MadhokR,CapellHA.Factorspredictiveofsubsequentdeteriorationinrheumatoid
cervicalmyelopathy.Rheumatology(Oxford)200140:811.
53.CaseyAT,CrockardHA,BlandJM,etal.Surgeryontherheumatoidcervicalspineforthenonambulant

myelopathicpatienttoomuch,toolate?Lancet1996347:1004.
54.NevaMH,KauppiMJ,KautiainenH,etal.Combinationdrugtherapyretardsthedevelopmentofrheumatoid
atlantoaxialsubluxations.ArthritisRheum200043:2397.
55.KauppiMJ,NevaMH,LaihoK,etal.Rheumatoidatlantoaxialsubluxationcanbepreventedbyintensiveuseof
traditionaldiseasemodifyingantirheumaticdrugs.JRheumatol200936:273.
56.KaitoT,OhshimaS,FujiwaraH,etal.Predictorsfortheprogressionofcervicallesioninrheumatoidarthritisunder
thetreatmentofbiologicalagents.Spine(PhilaPa1976)201338:2258.
57.KauppiM,AnttilaP.Astiffcollarforthetreatmentofrheumatoidatlantoaxialsubluxation.BrJRheumatol1996
35:771.
58.AlthoffB,GoldieIF.Cervicalcollarsinrheumatoidatlantoaxialsubluxation:aradiographiccomparison.AnnRheum
Dis198039:485.
59.HakkinenA,MakinenH,YlinenJ,etal.Stabilityoftheupperneckduringisometricneckexercisesinrheumatoid
arthritispatientswithatlantoaxialdisorders.ScandJRheumatol200837:343.
60.SchmittSodyM,KirchhoffC,BuhmannS,etal.Timingofcervicalspinestabilisationandoutcomeinpatientswith
rheumatoidarthritis.IntOrthop200832:511.
61.PausAC,SteenH,RislienJ,etal.Highmortalityrateinrheumatoidarthritiswithsubluxationofthecervicalspine:
acohortstudyofoperatedandnonoperatedpatients.Spine(PhilaPa1976)200833:2278.
62.AgarwalAK,PeppelmanWC,KrausDR,etal.Recurrenceofcervicalspineinstabilityinrheumatoidarthritis
followingpreviousfusion:candiseaseprogressionbepreventedbyearlysurgery?JRheumatol199219:1364.
63.YonenobuK,HosonoN,IwasakiM,etal.Neurologiccomplicationsofsurgeryforcervicalcompressionmyelopathy.
Spine(PhilaPa1976)199116:1277.
64.HamiltonJD,GordonMM,McInnesIB,etal.Improvedmedicalandsurgicalmanagementofcervicalspinedisease
inpatientswithrheumatoidarthritisover10years.AnnRheumDis200059:434.
65.WolfsJF,PeulWC,BoersM,etal.RationaleanddesignofTheDelphiTrialI(RCT)2:internationalrandomized
clinicaltrialofrheumatoidcraniocervicaltreatment,aninterventionprognostictrialcomparing'early'surgerywith
conservativetreatment[ISRCTN65076841].BMCMusculoskeletDisord20067:14.
66.NannapaneniR,BehariS,ToddNV.SurgicaloutcomeinrheumatoidRanawatClassIIIbmyelopathy.Neurosurgery
200556:706.
67.HendersonFC,GeddesJF,CrockardHA.Neuropathologyofthebrainstemandspinalcordinendstagerheumatoid
arthritis:implicationsfortreatment.AnnRheumDis199352:629.
68.RathSA,MoszkoS,SchffnerPM,etal.Accuracyofpediclescrewinsertioninthecervicalspineforinternal
fixationusingframelessstereotacticguidance.JNeurosurgSpine20088:237.
69.MizutaniJ,MatsubaraT,FukuokaM,etal.Applicationoffullscalethreedimensionalmodelsinpatientswith
rheumatoidcervicalspine.EurSpineJ200817:644.
70.ZygmuntSC,ChristenssonD,SvelandH,etal.Occipitocervicalfixationinrheumatoidarthritisananalysisof
surgicalriskfactorsin163patients.ActaNeurochir(Wien)1995135:25.
Topic7518Version11.0

GRAPHICS
AnteriorsubluxationofC1onC2inrheumatoidarthritisonradiography

Alateralexaminationofthecervicalspine(A)showsanteriorsubluxationofC1onC2.Themagnifiedview(B)
showsa12mmseparationbetweentheposteriorborderofthearchofC1(arrowhead)andtheanteriorborder
oftheodontoidprocessofC2(arrow).
RA:rheumatoidarthritis.
Graphic100051Version2.0

AnteriordislocationofC1onC2inrheumatoidarthritisonCT

AsagittalreconstructionofaCTscan(A)showsa7.5mmseparationbetweentheposteriorpartof
thearchofC1(arrowhead)andtheanterioraspectofthedens(arrow).ImageBisacoronal
reconstructionofaCTscanandshowsalargeerosiononthelateralaspectofthedens(arrowhead).
ImageCisanaxialimageandshowsalargeerosion(arrowhead)ontheeccentricallypositioned
dens.ImageDisanaxialimageusingsofttissuewindowsthroughthesameregionasC,andshows
extensivepannusformationaroundthedens(asterisks),whichimpingesontheCSFspace(arrow)
surroundingthespinalcord(arrowhead).
CT:computedtomography.
Graphic100052Version2.0

AnteriorsubluxationofC1onC2inrheumatoidarthritiswithcordindentation
onMRI

AT2weightedimageofthecervicalspineinthesagittalplain(A)showsa5mmseparation(arrows)
betweentheposteriorborderofC1arch(anteriorarrow)andtheanteriorborderofthedens(posterior
arrow).MultilevelspondylosisisalsopresentbetweenC3andC7.ImageBisamagnifiedviewofimageA,
andshowstheC1C2separation(arrows),pannusformationposteriortothedens(asterisk),with
impingementonthecordandtheanteriorCSFspace(dashedarrow),andthecord(arrowhead).
MRI:magneticresonanceimaging.
Graphic100053Version2.0

ContributorDisclosures
PeterHSchur,MDNothingtodisclose.BradfordLCurrier,MDConsultant/AdvisoryBoards:ZimmerSpine[Spine
surgery(Cervicalspinalimplants)].PatentHolder:DePuySpine[Spinesurgery(Cervicalspinalimplants)].RavinderN
Maini,BA,MBBChir,FRCP,FMedSci,FRSPatentHolder:Inventor[Inventor'sshareofroyaltiesreceivedbythe
KennedyTrustforRheumatologyResearchforantiTNFtreatmentofRA:JanssenCentocor,AbbVie,Hospira,and
Celltrion].PaulLRomain,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedby
vettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.
AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy