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24/9/2015 Ethanolamineoleateversusbotulinumtoxininthetreatmentofidiopathicachalasia

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367212/ 1/8

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AnnGastroenterol.2015AprJun28(2):229235. PMCID:PMC4367212

EthanolamineoleateversusbotulinumtoxininthetreatmentofidiopathicachalasiaJavadMikaeli, ArashKazemiVeisari, NargesFazlollahi, NargesMehrabi, HosseinAslSoleimani, ShapoorShirani, andRezaMalekzadeh

DepartmentofGastroenterology,DigestiveDiseaseResearchInstitute,ShariatiHospital,TehranUniversityofMedicalSciences(JavadMikaeli,ArashKazemiVeisari,NargesFazlollahi,NargesMehrabi,HosseinAslSoleimani,RezaMalekzadeh),Tehran,IranDepartmentofRadiology(ShapoorShirani),TehranHeartCenter,TehranUniversityofMedicalSciences,Tehran,Iran

Correspondenceto:JavadMikaeli,DepartmentofGastroenterology,DigestiveDiseaseResearchInstitute,ShariatiHospital,TehranUniversityofMedicalSciences,KaregarShomaliAve,Tehran1411713135,Iran,Tel.:+98218241500,Fax:+982182415400,email:[email protected]

Received2014Mar21Accepted2014May30.

Copyright:HellenicSocietyofGastroenterology

ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNoncommercialShareAlike3.0Unported,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

Abstract

Background

Botulinumtoxin(BT)injectionreducesloweresophagealsphincterpressureandalleviatessymptomsinidiopathicachalasia(IA).Ethanolamineoleate(EO)hasalsobeenintroducedforthetreatmentofIA.WecomparedthelongtermefficacyofBTandEOinjectionsinthetreatmentofIA.

Methods

Atotalof189IApatientswereevaluatedprospectively,ofwhom21wereunwillingtoundergoorwerepoorcandidatesforpneumaticballoondilationandHellermyotomyandwereenrolledinthestudy.ElevenpatientsweretreatedbyBT,and10byEOinjections.Patientswerefollowedupbyachalasiasymptomscore(ASS),timedbariumesophagogram(TBE),andhighresolutionmanometryatbaselineandposttreatment.AgoodinitialresponsewasdefinedasadecreaseinASSto4orless,andareductioninbariumcolumnheightandvolumeinTBEby>50%.

Results

All10EOgrouppatientsand10of11BTgrouppatientsshowedagoodinitialresponse.FourEOgrouprelapsersand6BTgrouprelapsersweremanagedeffectivelybyreinjections.Meandurationoffollowupwas27.38months.Oncompletionofthestudy,asustainedgoodresponsewasseenin9and6patientsinEOandBTgroups,respectively(P=0.149).

Conclusion

ThisstudyrevealedthatBTandEOhavecomparableefficacyinthetreatmentofIA.However,thecostofEOisabout2timeslowerthanBT.

Keywords:Achalasia,botulinumtoxin,ethanolamineoleate,esophagus

Introduction

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Idiopathicachalasia(IA)isachronicdiseaseoftheesophaguscharacterizedbyabsenceofperistalsisandincompleterelaxationoftheloweresophagealsphincter(LES).EsophagealemptyingisimpairedinIAduetotheinflammatorydegenerationofinhibitoryganglioncellsinthemyentericesophagealplexus.Thiscausesanimbalancebetweentheexcitatoryandinhibitoryneurons,leadingtoaperistalsis,increasedbasalLESpressure,andincompleterelaxationofLES[1,2].

Thetreatmentofthediseaseisonlypalliative,aimingtoreduceLESpressuretherebyfacilitatingesophagealemptyingbygravity.Currenttherapeuticmodalitiesincludepharmacologictreatment,pneumaticballoondilation(PBD)ofLES,Hellermyotomy,andintrasphinctericinjectionofbotulinumtoxin(BT)[1,2]orethanolamineoleate(EO)[4,5].

IntrasphinctericinjectionofBTasanalternativetoPBDorHellermyotomywasintroducedbyPasricha[6].BTisapotentinhibitorofacetylcholinereleasefromnerveendings.InjectionofBTintotheLESunderdirectendoscopicvisionisasafeandeffectivetreatmentanddecreasesLESpressurebyinhibitingacetylcholinereleasefromexcitatoryneuronsandrelaxingthemusclefibers[68].

EO,asclerosantagent,hasbeenintroducedasaneffectivealternativetreatmentofachalasia[9].EOisasalt,asyntheticmixtureofethanolamineandoleicacid,withanempiricalformulaofC H NO .EOinjectionhasbeenusedinthetreatmentofbleedingesophagealvarices,varicoseveinsinthelegsandreactivevascularlesions[1012].EOisasclerosantagentinducinginflammatoryresponseandfibrosisinthetissuesthus,theinjectionofEOintotheLEScausesexcitatoryneurondamageanddecreasestheLESpressure[4,5].

Tothebestofourknowledge,thereisnostudyintheliteraturecomparingsclerotherapywithBTinjectionforthetreatmentofIA.Therefore,wedecidedtocomparethelongtermefficacyofthesetreatmentoptionsinIApatients.

Patientsandmethods

Studypopulationanddesign

Inthisprospectivestudy,weevaluated189patientswithIA,referredtoourcenteroveraperiodof4years,i.e.from2009to2013.

ThediagnosisofIAwasbasedonclinicalsymptomsaswellasradiologicandendoscopicfindings,andconfirmedbymanometriccriteria.PatientswhowerepoorcandidatesforPBD(duetopresenceofsigmoidesophagus,epiphrenicdiverticula,orseverecomorbidities)orHellermyotomy(duetohighperioperativerisk),andthoseunwillingtoundergothelatterprocedureswereenrolledinthisstudy.Exclusioncriteriacomprised:beingagoodcandidateforPBDorHellermyotomysecondaryachalasiapoorcooperationpregnancybreastfeedingage



offoodmaterialfromtheesophagusactiveinstandingorsitting,andpassiveinsupineorlyingpositions.TheASSwascalculatedforeachpatientatthefollowingintervals:pretreatment,1.5,3,6,9,and12monthsafterthelastinjection,thenevery6months,andfinallyattheendofthefollowup.Thepatientswereaskedtocomebackforareevaluationiftheyfeltseveredysphagiaorregurgitationbetweenfollowupperiods.AgoodclinicalresponsewasdefinedasadecreaseinASStoascoreof4orless,whileaclinicalrelapsewasdefinedasanincreaseintheseverityscoreofdysphagiaofabout2ormorepointsaftertheinitialgoodresponsewasachieved.Asustainedgoodresponsewasdefinedasclinicalremission(ASS4)atthefollowupintervalswithoutrequiringanyreinjectionoverthelast6months.

Table1Cardinalsymptomscore

Table2Severityscoreofdysphagiaforeveryswallow

TBE

TBEwasusedasanobjectivetooltoassessesophagealemptying.AllpatientsunderwentTBEatbaselineand1.5monthsposttreatment.Patientsswallowed200mLofbariumsulfatesuspension(81%weight/volume)[13]intheuprightposition,andthenradiographiesweretakenat1,3,and5minafterswallowingfromtheleftposteriorobliqueview.Thebariumcolumnheight,i.e.thedistancefromthemostdistalpartoftheesophagustothemostproximalbariumlevel,wasmeasuredincentimeters.Thevolumeofretainedbariuminmilliliter(mL)wascalculatedasfollows:(meanradius)3.14heightofthecolumn.Thesecalculationshavebeenusedinsimilarstudies[5,13].

TheinitialTBEinourpatientsshowedbariumretentionat1,3,and5min,adilatedesophagusandbeaklikenarrowingatgastroesophageal(GE)junction.Severedilationandtortuosityoftheesophaguswereseenin9patients.Thedifferenceintheretainedbariumheightandvolumeat5minwascalculatedbetweenthepretreatmentandposttreatmentTBEs.Agoodresponsewasdefinedasareduction>50%fromthebaselineinthebariumcolumnheightandvolumeat1.5monthsafterthelastinjection,whereasifthementionedoutcomeswerenotachievedpatientswereconsideredaspoorresponders.

Endoscopy

EndoscopicevaluationwasperformedinallpatientstoconfirmIAandexcludemalignancies.Inourstudygroup,theendoscopicfindingsincludeddilatedesophagus,retainedfoamysecretionand/orfoodparticlesintheesophagus,hypertonicLESthatdidnotopenspontaneouslybutcouldbetraversedbygentlepressureoftheendoscope,andsomeerythemaandirritationofesophagealmucosaincaseswithsigmoidesophagus.

Highresolutionmanometry(HRM)

TheHRM(SolarGastrointestinal[GI]HRM,MedicalMeasurementSystemsMMS,TheNetherlands)wasdonewith22waterperfusedcatheter.AbnormalLESrelaxationwasdefinedasameanintegratedrelaxationpressure(meanIRP)>15mmHg.PatientswereclassifiedinthreeIAtypesbasedonHRM.IntheBTgroup,1patienthadtypeI,8patientshadtypeII,and2patientshadtypeIIIIA.IntheEOgroup,2patientshadtypeI,7patientshadtypeII,and1patienthadtypeIIIIA.AllpatientsunderwentHRMatbaselineand1.5monthsposttreatment.

Endoscopicinjections



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Patientswererandomlyassignedintotwogroups.ElevenpatientsweretreatedintwosessionsofBTinjection(Dysport,Ipsen,UK)withanintervalof4weeks.Aftera1dayliquiddietandanovernightfasting,patientsweresedatedusingintravenousdiazepam(510mg)andmeperidine(2550mg)andtheesophagogastricjunctionwasidentifiedthroughupperGIendoscopy.Dysportpowder(onevialof500U)wasdissolvedin5mLofnormalsaline,andanaliquotof0.5mLwasusedineachinjection.TeninjectionswereperformedintotheLESaroundtheGEjunctionupto1cmaboveit,usinga5mmsclerotherapyneedle.BTinjectionwasrepeated4weekslater.Thenumberofinjectionsessionswasdeterminedusingdatafromapreviousmulticenterstudy[7].

Inthesecondgroup,onevialofEO(5%,5mL)(MartindalePharmaLtd.,HaroldHill,UK)wasdilutedby5mLofnormalsalineandanaliquotof1mLwasusedineachinjection.TeninjectionsofdilutedEO(2.5%)wereperformedintotheLESaroundtheGEjunctionupto1cmaboveit,usinga5mmsclerotherapyneedle.PatientsreceivedidenticaldosesofEO2and4weekslater.Thenumberofinjectionsessionswasdeterminedbasedonpreviousstudies[4,59].Patientswereobservedfor3haftertheprocedureandwerethendischarged.Theywereallowedtostarteatingsoftfoodonthesameday.

Ethicalconsiderations

ThestudywasapprovedbytheDigestiveDiseaseResearchCenterEthicsCommitteeandwasconductedaccordingtotheethicalguidelinesofthedeclarationofHelsinki.Thisstudywasnotblinded.PossiblebenefitsandrisksofEOorBTinjectionswereexplainedtothepatients.Informedconsentwasobtainedfromallpatientsandtheirparticipationinthestudywasvoluntary.ThisstudywasregisteredinIranianRegistryCenterofClinicalTrials.RegistrationnumberwasIRCT201108157335N1.

Studyendpoints

TheprimarystudyendpointwasthereductioninASSandTBEvalues6weeksafterthelastinjectioncomparedwithbaselinevalues.Thesecondaryendpointwasdefinedasasustainedgoodresponseduringfollowupperiods.Furthermore,voluntarywithdrawalforanyreason,developmentofseverecomplicationsorsideeffectsleadingtothediscontinuationoftheinjection,poorcooperation,poorornoresponsetotreatmentprotocols,recurrencesofmorethan3times,anddeathwereconsideredasafailureoftreatment.

Statisticalanalysis

Thisstudyisaparallelrandomizedcontrolled,openlabel,notblindedtrial.AcentralrandomizationcenterusedevennumbersforEOandoddnumbersforBTtreatment.TheresultswereanalyzedusingSPSSversion19.00forWindows.Continuousvariableswereexpressedasmeanstandarddeviation.ComparisonsineachgroupwereperformedusingthepairedttestforsymptomscoresandheightofbariumandWilcoxonsignranktestforthevolumeofbarium.Categoricaldatawassummarizedasrelativeandabsolutefrequency,andthedifferencesbetweengroupsweretestedbytheindependentttestforsymptomscoresandheightofbariumcolumn,andtheMannWhitneytestforbariumvolume.WeusedchisquarebasedonFishersexacttestforevaluationoftheendoffollowup.AP



Table3Baselinecharacteristicofthepatients

Inbothgroups,thetreatmentprotocols(BTandEOinjection)werecompleted.Themeandurationoffollowupwas27.3816.49months(range:1264).

All10patientsintheEOgroupand10of11patientsintheBTgroupshowedagoodinitialresponse.Onepatient,whoinitiallyrefusedtoundergoPBDorHellermyotomy,laterchangedhisdecisionandoptedforthesurgeryowingtothepoorinitialresponseinBTtreatment(>Fig.1).

Figure1Flowdiagramofthestudy

Ageandsexwerenotcorrelatedwiththeresponsesofthetreatment(P=0.120,P=0.180,respectively).

InBTtreatedpatients,themeansymptomscoresatbaselineandat1.5monthsposttreatment(secondinjection)was10.092.80vs.3.552.77,respectively(P=0.0001).IntheEOgroup,themeansymptomscoredecreasedfrom113.8atbaselineto3.83.8at1.5monthsposttreatment(thirdinjection)(P=0.001).Themeansymptomscoresinbothgroupswerealsocalculatedat3,6,9,and12monthsafterthelastinjections(Table4).

Table4ThecomparisonofASSatbaselineandposttreatment

InTBEoftheBTgroup,themeanretainedbariumvolumeat5thmin,atbaselineandat1.5monthsposttreatmentwere78.5070.12mLvs.37.9261.79mL,respectively(P=0.051),while,intheEOgroup,thesevalueswere130.44106.54mLvs.29.5664.23mL,respectively(P=0.028)(Table5).

Table5Thecomparisonofretainedbariumvolume(mL)andcolumnheight(cm),in5 minofTBE,atbaselineandposttreatment

ThemeanIRPdecreasedfrom31to25mmHginBTgroup,andfrom27to15mmHginEOgroup(P=0.764vs.0.008).

Arelapsewasdefinedasanincreaseintheseverityscoreofdysphagiaby2ormorepointsafteraninitialgoodresponse.

Inthefollowupperiod,symptomsrelapsedin4patientsintheEOgroup(1patient3times,1patient2times,and2patients1time)and6patientsintheBTgroup(1patient3times,1patient2times,and4patients1time)(P=0.24).Allofthemunderwentreinjections(7timesintheEOgroupand9timesintheBTgroup).Themediandurationtothefirstrelapsewas15and10monthsintheEOandBTgroups,respectively(P=0.432).

Transientchestpainaftertheinjectionwasreportedby5patientsintheBTand3patientsintheEOgroup(P=0.020).Someerosions(



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secondarytoGErefluxorlocalinjuryofthepreviousinjections.Wedidnotperformcomplementarystudies(e.g.24hesophagealpHmetry)todifferentiatethem.Alloftheseminorcomplicationsweremanagedconservatively.Noseverecomplications(perforation,bleeding,ulcer,andfibroticstenosis)werenoticed.

Intheshortterm,neitherBTnorEOhadanysignificanttherapeuticadvantagesovereachother(Tables4and5).However,attheendofthefollowup,intheBTgroup,6patientshadgoodsustainedresponse,and5patientshadpoorresponses(



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Attheendoffollowup,9patientsintheEOgroupversus6patientsintheBTgroupwereinsustainedgoodresponseaccordingtoASS,butthisdifferencewasnotstatisticallysignificant(P=0.149).

SincebothBTandEOinjectionsmaycausefibrosisintheesophagealwall,weenrolledthepatientswhowerepoorcandidatesforPBDandHellermyotomywithlowprobabilitytoundergotheseinvasiveproceduresinthefuture.Only3patientswhodidnotaccepttoundergoHellermyotomyorPBDwereenrolledinthisstudy.

Fibroticstricturewasnotdevelopedinanyofourpatients,anditcouldbetheadvantageofdeepinjectionsofdilutedEO(2.5%)butthedurationofthefollowupinthisstudymaynothavebeenlongenoughtoruleoutthispossibility.

Ontheotherhand,BTismoreexpensivethanEO(Table6).BTcostsapproximately20timesmorethanEO(foreachinjectionsession),andthisisanimportantadvantageofEOoverBT.Exceptfortheinitialinjectionprotocolincluding3sessionsforEOand2sessionsforBT,additionalendoscopiesandinjectionsforrelapseswerecomparableinbothgroups.

SinceIAisachronicandprogressivedisease,itwouldbereasonabletochoosethemostpracticalmethodforitslifelongtreatment.

Giventhatthecomparisonbetweenthesetwogroupshasbeenperformedforthefirsttime,itcanbeaclueforfurtherstudiestofindbetterwaystotreatIAandimprovethequalityoflifeinIApatients.

AsaresultoftherarityofIAandthelimitedinclusioncriteria,onlyasmallnumberofpatientswereenrolledinthisstudy.Thestudieswithlargesamplesizesmayrevealmoredetailsincomparisonbetweenthesetreatments.

SummaryBox

Whatisalreadyknown:

Botulinumtoxin(BT)andethanolamineoleate(EO)havecomparableefficacyinthetreatmentofidiopathicachalasia(IA)ThecostofEOisapproximately20timeslowerthanBTBothEOandBTgroupshadcomparablerelapserates,butmediandurationtothefirstrelapsewaslongerintheEOgroupcomparedtotheBTgroup

Whatthenewfindingsare:

EOandBThavecomparableefficacyinthetreatmentofIA

Biography

DigestiveDiseaseResearchInstitute,ShariatiHospital,TehranUniversityofMedicalSciences,Tehran,Iran

FootnotesConflictofInterest:None

References



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