Rev. bras. ortop. vol.51 número6

SOCIEDADE BRASILEIRA DE ORTOPEDIA E TRAUMATOLOGIA

w w w . r b o . o r g . b r

Review

Article

Femoroacetabular

impingement

夽

José

Batista

Volpon

UniversidadedeSãoPaulo,FaculdadedeMedicinadeRibeirãoPreto,DepartamentodeBiomecância,MedicinaeReabilitac¸ãodoAparelho Locomotor,RibeirãoPreto,SP,Brazil

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Articlehistory:

Received18December2015 Accepted7January2016 Availableonline19October2016

Keywords: Hip Anatomy

Femoroacetabularimpingement Arthroscopy

Osteotomy

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Thefemoroacetabularimpingement(FAI)isasconditionrecentlycharacterizedthatresults fromtheabnormalanatomicandfunctionalrelationbetweentheproximalfemurandthe acetabularborder,associatedwithrepetitivemovements,whichleadlabrumand acetabu-larcartilageinjuries.Suchalterationsresultfromanatomicalvariationssuchasacetabular retroversionordecreaseofthefemoroacetabularoffset.Inaddition,FAImayresultfrom acquiredconditionsasmalunitedfemoralneckfractures,orretrovertedacetabulumafter pelvicosteotomies.Theseanomaliesleadtopathologicalfemoroacetabularcontact,which inturncreateimpactandshearforcesduringhipmovements.Asaresult,thereisearly labruminjuryandacetabulumcartilagedegeneration.Thediagnosisisbasedonthetypical clinicalfindingsandimages.Treatmentisbasedonthecorrectionoftheanatomic anoma-lies,labrumdebridementorrepair,anddegeneratearticularcartilageremoval.However, thenaturalevolutionofthecondition,aswellastheoutcomefromlong-termtreatment, demandabetterunderstanding,mainlyintheasymptomaticindividuals.

©2016SociedadeBrasileiradeOrtopediaeTraumatologia.PublishedbyElsevierEditora Ltda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://

creativecommons.org/licenses/by-nc-nd/4.0/).

Impacto

femoroacetabular

Palavras-chave: Quadril Anatomia

Impactofemoroacetabular Artroscopia

Osteotomia

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O impacto femoroacetabular (FAI) é condic¸ão de caracterizac¸ão relativamente recente; decorre de relac¸ões anatômico-funcionais anormais entre a regiãoproximal dofêmur e oacetábulo, associadasa movimentos de repetic¸ão,queacarretam lesõesnolabrum e nacartilagem acetabular. As alterac¸ões sãorepresentadas pela retroversão acetabu-lar ou diminuic¸ão da altura entre a borda lateral da cabec¸a e o colo femoral. Além disso,oimpactofemoroacetabularpodesersecundárioafraturasdocolodofêmurcom consolidac¸ãoviciosaoudecorrerdeosteotomiaspélvicasqueprovocamo retrodireciona-mentodoacetábulo.Essasanomaliaslevamaocontatofemoroacetabularpatológicoque originaforc¸asdeimpactoecisalhamentoduranteosmovimentosdoquadril.Em consequên-cia,hálesãolabraleartroseprecoce.Odiagnósticoéfeitopelasintomatologiatípica,sinais

夽

StudyconductedattheDepartmentofMedicine,Biomechanics,andLocomotiveApparatusRehabilitation,FaculdadedeMedicinade RibeirãoPreto,UniversidadedeSãoPaulo,RibeirãoPreto,SP,Brazil.

E-mails:[email protected],[email protected] http://dx.doi.org/10.1016/j.rboe.2016.10.006

theinguinalregion,duringorafterphysicalactivitiesorafter longsittingperiods.Paradoxically,thephysicalexamination waspoorandtheradiographswereinterpretedasanormal aspector,insomecases,presentedalterationsconsistentwith sequelaefrompreviousillness,suchasLegg-Perthesorslipped capitalfemoralepiphysis,butthatdidnotexplainthe symp-tomsinthelightoftheknowledgeatthetime.Asaresult,there wasnospecificdiagnosisandtherapy;therecommendation wassymptomatictreatmentandrestrictionofphysical activi-ties.However,insomecases,therewaslongtermevolutionto articulardegeneration,1,2_{whichwasdiagnosedasprimary(or}

idiopathic)osteoarthritis.Nowadays,it isknownthatmany ofthesepeoplehadtheconditionnowtermed femoroacetab-ularimpingement(FAI).Atfirst,itwasonlydescribedbased onclinicalexamination,plainradiographs,andsurgical find-ings;currently,diagnosisisalsobasedonmagneticresonance imagingandarthroscopicfindings.3–6

ThecurrentconceptisthatFAIisaconditionthatresults from the abnormalcontactbetweenthe femoralhead and theacetabularrim,whichleadstoamechanicalconflictthat causesmicrotraumatotheacetabularlabrumandcartilage, whichinturninjuresthesestructures.7 _{Usually,theimpact}

iscausedbychanges inthehead-neckjunctionand/orthe acetabulum.However,itcanoccurinmorphologicallynormal hipsthataresubjectedtogreatphysicaldemandsassociated withrepeatedflexion.8,9

However,thenotionofhipimpingementisnotnew.One ofthe earliest references tothis conditionis attributed to Smith-Petersen,10 _{in 1936, who described it as a result of}

the femoral neckshock against the acetabulum and iden-tified thecauses as originating from femoralor acetabular changes.Theobservations that identified the cause ofthe pain asthe mechanical conflict betweenthe femoral neck and the edge of the acetabulum, which resulted in trau-maticarthritis,arevalid.Thatsameauthorcoinedtheterm impingementtoexplainthepathophysiologicalmechanism;he presentedaproposedtreatment,whosefoundationsarestill appliedtoday.10_{In1965,Murray}11_{identifiedcasesofprimary}

osteoarthritisassociatedwithabnormalrelationshipbetween femoralheadandneck,whichhetermedtiltdeformity. Subse-quently,theconditionwasthoroughlydescribedbyHarris.12

However,interestinthedisease wasrenewedin1991by Ganzetal.,13_{asacauseofhippainanddysfunction.These}

authors showedthat therewas anassociation ofpainand limitedmovementafterviciouslyconsolidatedfemoralneck

itwasobservedthattheconditioncouldoccurincaseswith nohistoryoftrauma,inpeoplewithoveruseofthehipflexion movementduetosportorwork.9

Currently, the conceptofFAIis well establishedand its treatment has evolved significantly.1,2,15–17 _{Since then, the}

numberofarticlesonthesubjecthasgrownexponentially.15,18

Inrecentyears,theissuehasbeenrepeatedlyaddressedinthe BrazilianJournalofOrthopedics.4,8,19–23

Pathophysiology

Thehipisaball-and-socketjoint,anditsmovementsrequire bearingofthefemoralheadintheacetabulum.Impingement ariseswhentheharmonyofthismovementisaltered,which resultsinmechanicalinterlockingofthelastdegreesofthe femoralhead movements,whichinturn makesthis struc-turestrikethelateraledgeoftheacetabulum,causingregional microtraumas.Themostaffectedstructuresare thelabrum and the anterolateral area ofthe articular cartilage of the acetabulum;thedetrimentalforcesarerepresentedby com-pressionandshear.

Inanormalhip,inadditiontoanadequatecoverageofthe femoralheadbytheacetabulum,thepresenceofthe cervico-cephalicoffsetisalsoimportant,i.e.,thedifferenceinheight betweentheneckofthefemurandthesphericaledgeofthe femoralhead(Fig.1A).Thisgapisimportant,asitensuresthe accommodationofthefemoralnecktotheperipheryofthe acetabulum,inordertoprovidethelastdegreesofmovement (Fig.1B).Thereductionintheoffsetcausedbylossof spheric-ityofthefemoralheadiscausedbyananomalousextension oftheproximalfemoralepiphysis,mainlyinthe anterosupe-riorregion(coxarecta).15_{Thisextensioncanbeaphylogenetic}

vestige24_{orarise asaresponsetoexcessivesporting}

activ-ityduringskeletalmaturation.25 _{Inothercases,theetiology}

ofFAImaybeevident,suchasincasesoffemoralneck frac-turesequelae,14_{Perthesdisease,}26_{epiphysiolysis,}27_andcoxa

vara,9_amongothers.

Theimpactmayarisewhentheoffsetisreduced,oreven reversed, bythepresenceofaprotuberanceofthefemoral neck, which willstrike the edgeofthe acetabulum during flexion and internal rotation of the hip (Fig. 2A). This is knownasthecameffect,whichoriginatesfromthepistolgrip deformity.9,22_{Inthecaseofsmallprotrusions,theinitial}

Fig.1–Illustrationoftheanatomicalandfunctionalfeaturesofthecervico-cephalicjunctionofthehip.(A)Femoralneck offsetinrelationtothefreeborderofthefemoralhead(d).(B)Normalmovementsoftheheadintheacetabulumoccurwhen thejointisconcentric,i.e.,thereisacoincidencebetweenthegeometricalcentersofthefemoralheadandacetabulum.This allowsforaharmonicbearingofthefemoralheadwithintheacetabulum.Thecervico-cephalicoffset(d)allowsforthe extensioninthelastdegreesofmovement.(DrawingadaptedfromEmary28_).

orlamination,asthe protrudedportionpenetrates intothe acetabulum,shearsthearticularcartilage,anddamagesthe labrumthroughthesamemechanism.28_Thus,most

acetab-ularorlabralchondrallesionsduetocamimpingementare locatedanterosuperiorly.1,2

Whenabnormalitiesarepredominantlyacetabular,there isapincerimpingement(Fig.2B).16,28,29_{Thesechangesresult}

fromcaseswithcoxaprofundaorprotrusioacetabuli,wherein thefemoralheadisexcessivelycontainedintheacetabulum duetoacetabularretroversion,whichcanbeconstitutional30

ororiginatefrompelvicosteotomies,suchasSalterortriple osteotomy.31 _{There is also the less frequent possibility of}

excessiveacetabularanteversion.

Finally,acetabularandfemoralchangescancoexist(mixed impact).5

Physical

examination

–

diagnosis

FAIcausedbyalterationsinthecephalocervical junctionis morecommon amongmenaged20–30years.16 _Conversely,

impingement caused by acetabular changes is more often observedinmiddle-agedwomen.32

Symptomatology

Paininthehipregion,whetheranteriororposterior,maybea manifestationofanumberofregionalproblems;forthe cor-rect diagnosis,adetailed historyand semiologicaltests,as wellasimages,areparamount.EarlydiagnosisofFAIcanbe achallengebecausemanypatientshaveinsidioussymptoms,

Fig.2–Illustrationofthetypesofmovementblockingincasesoffemoroacetabularimpact.(A)Intheabsenceof cervico-cephalicoffset,oritsinversion,thefemoralheadstrikesthelateraledgeoftheacetabuluminthelastdegreesof

flexionmovement,associatedwithinternalrotationand/oradduction(camimpingement).(B)Whentheacetabulumis

Fig.3–Clinicaltestsforimpingement.(A)Fortheanteriorimpingement,thehipisflexedat90◦_{,adducted,andinternally} rotated.(B)Forposteriorimpingement,thelowerlimbtobeevaluatedisplacedoutsideoftheexaminationtable,extended, abducted,andexternallyrotated.Bothmaneuversshouldtriggerthepatient’susualpain.

radiographsthatareapparentlynormalorhaveminor modifi-cations,andsymptomscancoexistwithconditionsofnearby structures.33

AnindividualwithanteriorFAIwouldcomplainmainlyof chronic painin the groin area, withinsidious onset, long-term, and progressive worsening.Acute exacerbations can occurwhentherearephysicalexcesses.Patientsaretypically youngadults,16_{manyofwhompracticeasportthatinvolves}

hipflexion.8,34_{Painmaybeconstant,intermittent,oratrest,}

andmayinterferewithsleep,eitherpreventingitorcausing waking.

In additionto the classic symptomsin the groin, there may beanassociationwith paininthe anteriorthigh, the trochantericregion,andevenontheinnerfaceoftheknee, triggeredorworsenedbyphysicalactivityinvolvinghipflexion orsittingforextendedperiods.33

A posterior impingement is manifested by pain in the gluteal,lumbosacral,orposteriorregionofthethigh,33

asso-ciated with movements or positions in hip extension and abduction.However,whenthereisalreadysecondary arthro-sis in both posterior and anterior impingement, the pain becomesmoresevere,moretypicalofjointdegeneration,and usuallyleadstotheabandonmentofphysicalactivity.

Onphysicalexamination,thighatrophyandaslight clau-dicationmaybeobserved.Thelastfewdegreesofmotionof thehiparelimited.TheTrendelenburgtestcanbepositive, andimpingementtestsarepositivein88.8%ofcases.33

Anobjectivephysicalexaminationshouldinvestigatethe involvementofvariousstructuresoftheregion.Whenpainis anterior,thefollowingshouldbeconsidered:inguinalhernia, iliopsoasbursitis, pubalgia,trochanteric bursitis, degenera-tionorruptureofthetendinousportionofthegluteusmedius, andFAI.Thereisapositiveassociationbetweeninguinal her-nia and FAI; the two conditions can coexist, especially in athletes.35

Tosearchforananteriorimpingement,atestthat repro-duces it should be performed: the individual is placed in supinepositionandtheaffectedhipisflexedat90◦_,adducted

atapproximately20◦_{,andinthisposition,theinternal}

rota-tionisdone. Forapositivetest,painnormally experienced

bythepatientshouldbereproduced(Fig.3A).23,28_The

over-all movementofthehipisusuallypreserved,exceptinthe lastdegreesofrotationandflexion.Incasesofgreatimpact, thereisagreaterlimitationofflexion,whichsometimesisonly possiblewhenassociatedwithexternalrotation(Drehmann sign).Incasesofarthrosisoracetabularprotrusion,various movementsmaybesignificantlyaffected.

Thesubsequentimpactscausepainintheglutealregion; the differential diagnosis includes the most common con-ditions in this location, such as sacroiliac arthritis, sacral stress fracture, injury to the hamstring muscles, greater trochantericpainsyndrome,piriformissyndrome,ischial bur-sitis, ischiofemoral impingement, and chronic pelvic floor dysfunction.36

Thetestforposteriorimpingementshouldbedonewith thehipinextension,slightabduction,andexternalrotation.28

To facilitatethese maneuvers, the lower limb tobe tested should beplaced,without support,out oftheexamination table(Fig.3B).

Images

Morphologicalalterationsoftheproximalfemur

Althoughplainradiographsdonotshowallcasesoflossof sphericityofthefemoralhead,ifseveralviewsaremade,that possibilityisreduced.

The moststriking aspectof the femoralchanges is the pistolgripdeformity,whichissynonymouswiththelossof sphericity ofthefemoralhead(coxarecta)and reductionof thecervico-cephalicoffset.Theseanomaliescannowbeseen ontheanteroposteriorradiographofthepelvis(Fig.4A),with caretokeepthehipininternalrotationat15◦ _toavoidfalse

positives.28

However,theneckprofileisthemostsuitablepositionto view theneck-headjunction(Fig.4B).Thiscanbeachieved using the classical Lauenstein view (frog position) or the extendedneckprofile(Dunnview)at45◦_or90◦_{offlexion(these}

areequivalent).37_{Dunn’sextendedviewcanbereplacedbythe}

crosstableview.38_{Generally,alltheseincidencesareneeded,}

Fig.4–AlterationsonhipX-raysincasesoffemoroacetabularimpact.(A)Intheproximalregionoftheleftfemur,thereisa typicalpistolgripdeformity,withrectificationofthesphericityoftheanteriorportionofthefemoralhead(blackarrow).In thisradiographthereisagreaterprominenceoftheischialspine,whichsuggestsanassociatedacetabularretroversion

(whitearrowhead).(B)ThesamepatientontheLauensteinview;thisradiographshowsthedecreaseinthehead-neck

offsetonbothsides,withalterationsthatpredisposetoimpingement(blackarrows).

Thecervico-cephalicoffsetcanbeassessedbymeasuring theNötzlialphaangle39_{;thisanglewasoriginallydescribedfor}

magneticresonanceimaging,butwasadaptedforradiographs inextendedprofile.Thisanglemayvarywithage,gender,and view,butitisgenerallyconsideredtobenormalwhenupto 50◦_.37 _{Fig.5 showsthe outlineofthat angle.Theposterior}

angle,namedbeta,maybesimilarlytraced.40

Thecompletionofradiographichipseriesismadeusing thefalseprofileofLequesneandSèze,41_{usedtovisualizethe}

anterosuperiorregionofthehip,afrequentsiteofinitialjoint degeneration.Someminorsignsmaybepresent,suchas ossi-ficationoftheacetabularrimandsmallcysticlesionsinthe cervix(casesofpincerimpingement).

Acetabularalterations

Assessmentoftheacetabulumismadewithanteroposterior hipradiographs.Awellpositionedpelvicradiographimplies, inadditiontothesymmetriesoftheiliacwingandobturator foramen,adistanceof2–3cmfromtheprojectionofthe coc-cyxtothepubicsymphysis.42_{Theanteriorandposteriorrims}

oftheacetabulum,whichshouldbedivergentinthecaudal direction,areidentified.Incasesofretroversion,theselines approximateandevenintersect(cross-oversign;Fig.6).30,40

However,afalsediagnosismaybeobtained,duetothepelvic tilt.43_{Itisalsopossibletoobserveanexcessiveprominenceof}

theischialspine44_{andasymmetryoftheobturatorforamen.}

Coxaprofundaandprotrusioacetabulicanbequantified in theanteroposteriorradiographofthepelvis,bymeasuringthe centrolateralangleofWiberg.Whenthisangleisabove40◦_,the

hipisconsideredtobeatriskofflexionimpingement(Fig.7A andB).7_{TheexcesscoveragecanbeseenintheLequesneand}

Sèzeview,whichallowsforagoodvisualizationoftheanterior regionofthefemoralhead,wherethefirstjointdegeneration arises.

Althoughcomputedtomographyisabletoassessthe head-neckjunction,itdoesnotshowthesofttissueandcartilage; furthermore,it impliesalargeradiation dose.Even in sub-tle bone changes in femoroacetabular junction, computed

Fig.5–Thesamepatientfromthepreviousfigure.Profile

radiographyofthefemoralneck,withameasurementof

thealphaangle.Thecenterofthefemoralheadis

Fig.6–Radiographyofahipmodelwithmetalrepairsto theacetabularrim.Ontherightside,aSalterosteotomy

wassimulated,witha20◦_{edge.Osteotomycauses}

retroversionoftheacetabulum,whichcanbeobservedby thecrossingoftheanteriorandposterioredgesofthe acetabulum(crossoversign;arrow),prominenceofthe

ischialspine(arrowhead),andasymmetryoftheobturator

foramen.

tomographyhasintrinsiclimitations.45_{Thus,itshouldnotbe}

usedroutinelytodiagnoseFAI.However,itisusefulwhenitis importanttoquantifytheacetabularversion.46

Magneticresonance imaging withradial sequences has becomevaluable,asitshowstheboneportionandthelabrum indetail,allowing foraccuratelytracingthe alpha angle.39

Italsoassesses thesphericity ofthe femoralheadandthe articularcartilage.

The protocol indicates that images should be obtained alongthehead-neckaxisatanintervalof10–30◦_.Anormal

labrumhasatriangularaspect,definedmargins,andlow sig-nalintensityonT1andT2;itiscontinuousandinsertedin theboneedgeoftheacetabulum,exceptforasmallgapin

ofosteoarthritis.15_{Treatmentswithmanipulation}

(chiroprac-tic)andphysicaltherapycanworsensymptoms.28_However,

it is difficult to establish a treatment when arthritis is already advanced.Inthiscondition, anarthroplastyshould be considered, depending on the patient’s profile, type of symptoms,anddegreeofdisability.Nonetheless,aless aggres-sive surgicaltreatment, usually arthroscopic,withremoval oftheblockades, debridementorrepairofthelabrum,and joint debridement,canproviderelief, especiallyinyounger patients.

There is no consensus whether to treat asymptomatic patientsbased onlyonimagingexams48 _{orthose inwhom}

asymptomaticisolatedlesionsofthelabrumweredetected.49

The morphology of FAI corresponds to a set of diagnostic parameters basedonstaticimages, whileFAIisadynamic complex resulting from morphological changes associated withactivitiesinvolvingspecifichipmovements.50_Thatisto

saythatmanypeoplehaveimagessuggestiveofFAIbutdonot presentanyclinicalsymptoms.51

Surgicaltreatment

Theprinciplesofsurgicaltreatmentaretocorrectanatomical deformities,debrideand/orreinsertthelabrum,andremove the degeneratedcartilage.29_{Surgicaltreatmentusually}

pro-videsgoodresults.6,8,49,52

Camimpingement

When the main deformity is coxa vara with secondary impingement,treatmentisbasedoncorrectionofthe cervico-diaphysealangle.Thisisusuallyenoughtoremovetheneck from theimpact region, but it isrecommended toaddress thehead-neckjunctionthroughthesamesurgicalapproach, anddirectlyobservewhethertheimpingementpersistswith aflexion–adduction–internalrotationhipmaneuver.Ifso,the protrudingportionshouldberemoved.

When theimpingementis causedprimarilybya protu-beranceintheneck-headjunction(coxarecta),theprotruding partshouldberesectedandthecervico-cephalicoffsetshould be carved (chondro-osteoplasty). During the same surgery, repairsand/ordebridementofthelabrumandofarticular car-tilagearemade.Theseprocedurescanbeachievedbythree mainapproaches:openaccesswithhip dislocation, associ-ationofarthroscopyandmini-arthrotomy,andarthroscopy. Thethreemethodsareeffectiveinimprovingpainand func-tion,andaresafeprocedures.52

Surgicalhipdislocation

ThistechniquewasdescribedbyGanzetal.13,53_andis

consid-eredthegoldstandardforthetreatmentofcamimpingement. However, it presents major complications related to the femoral osteotomy,52 _{requiring training and experience. It}

allowsapproachforallpathologicalcomponentspresent,with appropriatechondrocostal osteoplasty and debridement of thecartilage.However,thisdebridementshouldnotbe exag-gerated,asthelimitforneckthicknessresectionis30%;ifit isresectedanymorethanthat,afracturemayoccur.54 _The

labrumshouldbedebridedandreinserted;thisisimportant toitspreservation,asitperformsasealingeffectonthehip. Whenthelabrumisunrecoverableornon-existent, reconsti-tutionwithsubstitutessuchasfascia lata,knee flexors,or roundligamentmaybeattempted,55_{butthesetechniquesare}

consideredexperimental.

Arthroscopyandarthrotomybyanteriormini-access

In2005,Clohisyand McLure29 _{describedthe dualapproach}

forcasesofcamimpingement.First,anarthroscopic inspec-tion ofthe hipit is made,followed bydebridement ofthe articularcartilageandlabrum,ifnecessary.Afterarthroscopy, throughasmallanteriorincision,theSmith-Petersenspace isdeepened,10_{thecapsuleisopened,andosteoplastyis}

per-formed.Thistechniquegivesresultscomparabletoothers,but ithassignificantincidenceofinjurytothelateralcutaneous nerve of the thigh.52 _{Moreover, as training in arthroscopy}

advances,theauthorshavetendedtoabandonopenaccess.

Arthroscopictreatment

Thismethodhasbeenincreasinglyused,withsuccessrates rangingfrom67%to90%.7_{Thecorrectapproachofthe}

alter-ationsismadeonlyarthroscopically,followingthestandard stepsforthisprocedure.6 _{Withpracticeandfamiliarity,itis}

possibletodebridethelabrumandarticularcartilage,aswell asremoveexcessbone,inordertorecoverthesphericalshape ofthefemoralhead(coxarotunda).Complicationsarethose commontohiparthroscopyandincludeinjuryofthelateral cutaneousnerveofthethighandparesisofthesciaticnerve.

Pincerimpingement

Whentheimpactispredominantlycausedbypoororientation oftheacetabulum,thisshouldbecorrectedthrough periac-etabularosteotomy,whichisaquiteeffectiveprocedure,56_but

difficulttoperform,andshouldbereservedforexperienced professionals.Thereportsontheresultsusingthetechnique are scarce,becauseinacetabularretroversionimpingement thesymptomsaredelayed,sothatwhenthereissecondary osteoarthritis,treatmentisperformedthrougharthroplasty.

Final

considerations

FAIisawell-definedclinicalentityinwhichthereare mor-phological alterations, whether constitutional or acquired, associatedwithrepetitivemovementsofthehip;thesecan lead to injuryof the labrum and acetabular cartilage with subsequent arthrosis.Thesymptoms manifestaspain and movement limitation,which progressivelyworsen, and the effectivetreatmentissurgicalcorrectionofanatomical abnor-malities.However,morestudiesareneededtobetterdefine thepopulationatrisk,thosewhoshouldbetreated,andwhat is the best approach in terms oftreatment.52 _{Thus, larger}

follow-upperiodsarenecessarynotonlytoevaluateresults, butalsotobetterunderstandthenaturalcourseofthedisease.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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