w w w . e l s e v i e r . c o m / l o c a t e / b j i d
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
Original
article
Onabotulinumtoxin
type
A
improves
lower
urinary
tract
symptoms
and
quality
of
life
in
patients
with
human
T
cell
lymphotropic
virus
type
1
associated
overactive
bladder
Jose
Abraão
Carneiro
Neto
a,b,
Silvane
Braga
Santos
b,c,
Gloria
Orge
Orge
b,
Davi
Tanajura
a,
Lucia
Passos
b,
Cassius
José
Oliveira
a,
Rosana
Andrade
a,
Cláudio
Galeno
de
Melo
d,
Ubirajara
Barroso
Jr
d,
Edgar
M.
Carvalho
d,e,f,∗aUniversidadeFederaldaBahia(UFBA),ProgramadePós-Graduac¸ãoemCiênciasdaSaúde,Salvador,BA,Brazil
bUniversidadeFederaldaBahia(UFBA),HospitalUniversitárioProf.EdgardSantos,Servic¸odeImunologia,Salvador,BA,Brazil cUniversidadeEstadualdeFeiradeSantana,FeiradeSantana,BA,Brazil
dUniversidadeFederaldaBahia(UFBA),HospitalUniversitárioProf.EdgardSantos,Servic¸odeUrologia,Salvador,BA,Brazil eFiocruzBahia,InstitutoGonc¸aloMoniz,LaboratóriodePesquisaClínica,Salvador,BA,Brazil
fInstitutoNacionaldeCiênciaeTecnologiadeDoenc¸asTropicais(INCT-DT),Salvador,BA,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received2August2017 Accepted30October2017 Availableonline17February2018
Keywords:
Overactivebladder Onabotulinumtoxin HTLV-1
a
b
s
t
r
a
c
t
Aim: ToevaluatetheefficacyoftheonabotulinumtoxintypeAinthetreatmentofHTLV-1 associatedoveractivebladderanditsimpactonqualityoflife(QoL).
Methods:Caseserieswith10patientswithoveractivebladderrefractorytoconservative treatmentwithanticholinergicorphysicaltherapy.Theyreceived200Uiof onabotulinum-toxin type A intravesically and were evaluated by overactivebladder symptoms score (OABSS)andKing’sHealthQuestionnaire.
Results:Themean(SD)oftheagewas52+14.5yearsand60%werefemale.Allofthemhad confirmeddetrusoroveractivityonurodynamicstudy.SevenpatientshadHAM/TSP.The medianandrangeoftheOABSSwas13(12–15)beforetherapyanddecreasedto1.0(0–12) onday30andto03(0–14)onday90(p<0.0001).Therewasasignificantimprovementin8of the9domainsoftheKing’sHealthQuestionnaireaftertheintervention.Hematuria,urinary retentionandurinaryinfectionwerethecomplicationsobservedin3outof10patients.The meantimetorequestretreatmentwas465days.
Conclusion: OnabotulinumtoxintypeAintravesicallyreducedtheOABSSwithlastlongeffect andimprovedthequalityoflifeofHTLV-1infectedpatientswithsevereoveractivebladder. ©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).
∗ Correspondingauthor.
E-mailaddress:[email protected](E.M.Carvalho). https://doi.org/10.1016/j.bjid.2017.10.009
1413-8670/©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
ThehumanT cell lymphotropic virus type1is the causal agentofthe HTLV-1-associatedmyelopathy/tropicalspastic paraparesis(HAM/TSP).About10millionpeopleareinfected by HTLV-1 worldwide.1 HAM/TSP is characterized by back
pain,hyperreflexia,spasticparaparesis, andBabinskisign.2
Manifestationsofthegenitourinarysystemsuchaserectile dysfunction,increasedurinaryfrequencyandurgency,with or without incontinence, and nocturia are documented in virtuallyallpatientswithHAM/TSP.3–5Moreover,these
man-ifestationsmaybedetectedinalargepercentageofHTLV-1 subjects who do not fulfill criteria forHAM/TSP.5 The
uri-narycomplaints are responsible forserious impairment of quality of life, development of depression, and increased risk for upperurinary tract infection and kidney dysfunc-tionduetoincreasedintravesicalpressureandresidualurine volume.6–8 Themainurodynamicfindings inpatients with
urinarydysfunctionassociatedwithHTLV-1areoveractivity ofthedetrusor,sphincter-detrusordyssynergia,andimpaired bladdercontractility.8,9 Asonlyfewstudies haveaddressed
thetreatmentofsuchevents inthis population,itremains undefinedifthetherapeuticinterventionsusedinindividuals notinfectedwithHTLV-1havethesame responseinthose infectedbythevirus.TheonabotulinumtoxintypeAhasbeen usedwithsuccesstoimproveurinarysymptomsinpatients withoveractivebladdersymptomsduetomultiplesclerosisor spinalcordinjury.10,11 Wehadpreviouslyshowninalimited
numberofpatientswithurologicdysfunctionstheshort-term resultsoftheuseofonabotulinumtoxin.12Hereweextendthis
observationtoalargenumber ofpatients, besides evaluat-ingthelong-termtherapeuticresponsetoonabotulinumtoxin type A in HTLV-1 infected patients with overactive blad-derrefractorytoconservativetreatmentwithanticholinergic drugsorphysicaltherapy.
Theaimofthisstudywastodeterminetheeffectof onabo-tulinumtoxintypeAincontrollingsymptomsoflowerurinary tractinpatientsinfectedwithHTLV-1refractoryto conserva-tivetreatmentwithanticholinergicandpelvicfloorphysical therapy associated with parasacral or intracavitary neuro-modulation(vaginaloranal).
Methods
Patientsandcasedefinitions
Participantsofthestudywereselectedfromacohortstudy of 419 HTLV-1 infected subjects, of whom, 142 presented urinarysymptoms.Eighty-sixpatientswereonconservative treatmentforHTLV-1associatedoveractivebladder,34were notreceiving regular treatment and 22 of thesewere con-sidered refractory todrug therapy. Overactive bladder was definedaccording toInternationalContinence Society (ICS) criteria13 and refractory overactivebladder was defined as
failuretocontrolurgencyandincontinenceusingtwo differ-entanticholinergicdrugsinmaximaltolerateddosage.14–16All
patientsunderwentanurodynamicstudydonebefore treat-ment.
ThediagnosisofHAM/TSPandprobableHAM/TSPwas per-formedaccordingtoDeCastroCostacriteria.17Patientswith
probable HAM/TSP had urologic dysfunctions as the main symptoms.Theamountofonabotulinumtoxinavailablewas enoughforonly10patientsandthefirst10caseswhoagreedto usetheonabotulinumtoxintypeAwereenrolledinthestudy.
AdministrationofonabotulinumtoxintypeA
Patientswere anesthetizedandpositionedinlithotomy.All patientswereonfluoroquinoloneantibioticprophylaxis.They receivedspinalorgeneralanesthesiaand20mLoflidocaine gelintotheurethra.OnabotulinumtoxintypeA(Botox®, Aller-gan,Inc.,Irvine,CA)waspreparedaccordingtothefabricant recommendation: Astandard dose of 200UI was reconsti-tuted in30mLofNaCl 0.9%solution. Then,the medication wasinjectedinthedetrusormusclebycystoscopyin30 dif-ferentpointsofthesupratrigonalregion.Onemilliliterofthe solutionwasadministeredineachsiteofapplication.18
Thechoiceof200UIdosewasbasedinapreviousstudyby Cruzetal.whoshowedthatdosetohavethesameefficacyof 300UIinpatientswithurinaryincontinenceduetodetrusor overactivity.
Clinicalevaluation
The efficacy of the onabotulinumtoxin type A in control-ling overactive bladder symptoms inHTLV-1 patients were assessedbya3-dayvoidingdiaryandbytheoveractive blad-dersymptomscore(OABSS).Theseparameterswereassessed pre-andpost-treatment.Moreover,patientswereevaluated after30,90and365daysafterthetherapeuticintervention. TheimpactonqualityoflifewasmeasuredusingtheKing’s HealthQuestionnaire.19Weconsideredahighpostvoid
vol-umeasover50%oftheestimatedbladdercapacity(400mL), aspreviouslyestablishedbyAsimakopoulosetal.20
Statisticsanalysis
The demographics and clinical data are described as mean±standard deviation (SD) or median (range). The Wilcoxonpairedtestwasappliedtocomparepre-and post-intervention changes in frequency of voiding symptoms, OABSSandKing’sHealthQuestionnaire.p-Values<0.05were consideredstatisticallysignificant.
Results
Table 1 summarizes demographic and clinical features of patientsundergoingtreatmentwithonabotulinumtoxintype A.Allofthemhadalreadyusedatleasttwoanticholinergic drugs(oxybutyninandpropanthelinebromide),givenorallyin fulltolerateddosage.Ofthe10participantsofthestudy,three hadreceivedinadditiontooral,intravesicaloxybutynin,but remainedwithurgeincontinence.Twocasesalsohadphysical therapywithsacral,vaginalortrans-analelectrical stimula-tionwithnoimprovement.Themajorityofthepatientshad illnessdurationforalongperiod.Detrusoroveractivitywas
Table1–Demographic,urodynamicandcystoscopic dataofpatientswithrefractoryoveractivebladder infectedwithHTLV-1undergoingtreatmentwith onabotulinumtoxintypeA.
Demographicandclinicaldata
Age(mean±SD) 52±14.5
Gender
Male:female 4:6
Durationofdisease–years(mean±SD) 7±4.2 Starttimeoftreatment–years
(mean±SD)
6±3.0
Numberofdrugsused(mean±SD) 2±0.5
Urodynamicfindings
Detrusoroveractivity 10
Impairedcontractilityduringthe voidingphaseofurodynamicstudy
7
Acontractilebladder(voidingphase) 5
Bladderemptyingmode
Self-intermittentcatheterization 6 Credémaneuver 1 Cystoscopy Trabeculations 10 Diverticulum 7 Neurologicstatus HAM/TSP 7 ProbableHAM/TSP 3 EDSS(mean±SD) 5±2 Osame(mean±SD) 5±3.5
observedinall patientsbeforetherapy.Bladderempty dys-functionwas detectedinsevenpatients. Five ofthem had acontractile detrusor documented and six performed self-intermittentcatheterization.Themajorityofthesepatients (n=04)hadHAM/TSP,butinthreecasesurinarydysfunctions were the mainneurologic symptoms. Theimpact of treat-mentonurologicalsymptomsandOABSSafter30daysand90 daysofthetherapeuticinterventionisshowninTable2.After applicationofonabotulinumtoxintypeA,therewasa signifi-cantreductioninthefrequency(p=0.008),urgency(p=0.007) andnocturia (p=0.008). Inaddition, therewasasignificant
reductionofOABSSmeasured30,90and365daysafterthe applicationofonabotulinumtoxin(p<0.005).Nosurgical com-plicationwasobservedduringtheintraoperativeperiod.Three outof10patientspresentedcomplicationsdetectedafter ther-apycharacterizedbyurinarytractinfection andhematuria. Urinaryretentionwereobservedintwoofthesepatientswho were abletovoid spontaneouslybeforetreatmentthat per-sisted for31 and 65 daysafter therapy. In all three cases, theinfectionwasinthelowerurinarytractandthepatients responded promptly to ciprofloxacin. Inpatients who pre-sented hematuria the symptoms disappeared within two days.Thosepatientswhodevelopedurinaryretentionneeded touseself-intermittentcatheterization.Despitebeingableto voidspontaneouslybeforetherapy,thesepatientshad high voidresidualvolume.
Table3showstheimpactofthetreatmentonQoL.Ofthe ninedomainscomprisedintheKing’sHealthQuestionnaire,a statisticallysignificantreductionwasdemonstratedineightof them.Regardingthegeneralhealthperception,thestatistical significancewasnotachievedbutthep-valuewas0.05.
Thedurationofthetreatmenteffectwasassessedby sur-vivalanalysisandexpressedinaKaplan–Meiercurve(Fig.1). Theaveragetimeforrequiringretreatmentorreturningtothe previoustreatmentOABSSwas465.7±66.3days(Fig.1).
Discussion
Urinarytractdysfunction(UD)playsanimportantroleinthe morbidityrelatedtoHTLV-1infection.5,8,21,22Initially, itwas thoughtthaturinarysymptomswerecausedbyurinarytract infection,butonestudyfailedtoprovethishypothesis,and OABsymptomsareinfactduetoneurologicaldisease.8,23,24
Althoughseveralstudieshaveinvestigatedthe physiopathol-ogy of UD, there are few studies assessing the efficacy of therapeuticstrategiesinHTLV-1infectedsubjects.Inthisopen label clinical study,we assessedthe long-termtherapeutic responseofHTLV-1infectedsubjectstoonabotulinumtoxin type A. Thisdrug was able tocontrol the OAB symptoms,
Table2–ImpactoftreatmentwithonabotulinumtoxintypeAonOABSSaandcomplicationsin10HTLV-1binfected patientswithoveractivebladderrefractorytoconservativetreatment.
Beforetreatment 30daysaftertreatment 90daysaftertreatment pvaluec
Frequency(median–range) 10.0(4–20) 1.0(0–12) 4(3–8) 0.00
Urgency(median–range) 5.0(3–20) 0.0(0–4) 1(0–5) 0.00
Nocturia(median–range) 5.5(2–15) 1.0(0–4) 1(0–5) 0.00
OABSS(median–range) 13.0(12–15) 1.0(0–12) 3.0(0–14) 0.00
Hospitalization(meandays) 3.8
Numberofpatientswithcomplications
Urinarytractinfectiond 03cases
Hematuriad 03cases
Retention 02cases
a Overactivebladdersymptomscore. b HumanTcelllymphotropicvirustype1. c Wilcoxontestforpairedsamples.
Table3–ImpactofonabotulinumtoxintypeAtreatmentinqualityoflifeevaluatedbyKing’sHealthQuestionnaire.
Domain King’sHealthQuestionnairescore pvaluea
Beforeintervention(mean±SD) Postintervention(mean±SD)
Generalhealthperception 55.5(30.0) 28.1(20.8) 0.05
Incontinenceimpact 81.5(33.8) 33.3(43.6) 0.04
Dailyactivitieslimitations 81.5(29.4) 22.9(35.6) 0.01
Physicallimitations 72.2(34.3) 14.3(26.2) 0.02 Sociallimitations 61.7(28.4) 11.1(27.2) 0.01 Personalrelationship 83.3(28.9) 8.3(20.4) 0.03 Emotions 82.7(20.1) 19.4(32.4) 0.01 Sleep/energy 82.7(20.11) 18.7(27.4) 0.01 Severitymeasures 80.4(19.2) 16.7(35.6) 0.01
a Wilcoxonsigntest(Wicoxonsignedranktest).
Fig.1–Kaplan–Meiercurve.SurvivalanalysisinHTLV-1 infectedpatientswithrefractoryoveractivebladder submittedtointravesicalapplicationofonabotulinumtoxin A.Timetorequestretreatmentortoreturntoprevious treatmentOABSS.
mainlyurgencyandincontinenceforalongperiod(meanof 466days)andimprovedQoLofthepatients.
Thecasesenrolledinthisstudyhaveexperienced conser-vativetreatmentforameanperiodofsixyearsandhadnot achievedtotalcontrolofthesymptoms.Inadditiontotheuse ofmorethanonedrugorally,intravesicaltherapyhadbeen appliedintwopatients.Althoughsevenpatientshad impair-mentofdetrusorcontractility,wepreferredtouseastandard doseoftheonabotulinumtoxintypeAinallpatients(200UI), asrecommendedbyCruzetal.10
In the present study, OABSS was used to measure the OAB severity. This score evaluatesthe main symptoms of OAB giving different weights for each question related to thesymptoms.Therefore,urgencyandincontinencetranslate intomorepointsinthe scorethan frequencyand nocturia. Thisscorewasalsoappliedinarandomizedcontrolledtrial evaluating onabotulinumtoxin A in patients with multiple sclerosis.10 Ourdata show asignificant decrease ofOABSS
inall periodsofevaluation afterthe applicationof onabo-tulinumtoxintypeA,whichpersistedforalongtime(Fig.1). Thetimeforretreatmentofthepatientswashigherthan pre-viouslydocumented25 and severalfactors mayexplainthis
finding.Itisknownthattheresponsetointravesicalinjections
ofonabotulinumtoxintypeAisquitevariableanddependent ontheneurologicaldiseaserelatedtourinarydysfunction.26
Moreover, we only offered retreatment when the patients requesteditorwhentheypresentedthesameorhigherOABSS comparedtothescoreobservedbeforetherapy.
UTI,hematuriaandurinaryretentionwerethemost com-moncomplications,buttheirfrequenciesweresimilartorates reported for patients withother neurologic diseases.10,27,28
Aspreviousreported,UTImayoccuraftertherapy.12,29 This
factmaybeexplainedbyurinecolonizationinpatientsusing self-intermittentcatheterizationduetohighvoidresidual vol-ume orbyendoscopictreatment.AnywayUTIisfrequently documentedinHTLV-1infectedpatients.Regarding urinary retention,thiscomplicationwasmorefrequentthantherate observed inother series.30 However,this wasa predictable
event,asallpatientswhopresentedurinaryretentionwere notvoidingnormally,astheyemptythebladderby involun-tarycontraction.Insuchcases,patientsshouldbeinformed thaturinaryretentionmaybeobservedaftertherapy.
Gotoh et al. foundeda directrelationship betweenOAB severity andimpairment onqualityoflife(QoL).Theyalso found that the symptoms with the highest bother score wasfrequencyandurgencyamongpatientsunder50years, urgency in the age range of 50–70year, and incontinence inthoseover80years.31Inourstudy,incontinencewasthe
symptom withthe highestimpact on QoL,but we didnot investigatebyagegroups.
Thelimitationsofthepresentstudyincludethesmall sam-plesize,theabsenceofacontrolgroup,andlackofcontinuity ofcareandtheimpossibilitytoapplyalltherapeutic arma-mentarium, such asposterior tibial stimulationand sacral neuromoduation.Also,wedidnotperformurodynamicstudy in the post-treatment evaluationfor ethical reasons. First, therewasnodoubtabouttheclinicalimprovementand sec-ond the conduction ofan urodynamic study by minimally invasivetechniquewasnotavailableinourservice.
Werecentlyshowedthatendocavitary(vaginalandanal) electrical stimulation combined with pelvic physiotherapy is an effective treatment of HTLV-1 associated urinary dysfunction.32 Herewe foundthatonabotulinumtoxintype
A promoted improvement in urinary symptoms and on QoL with acceptable rates of complications and may be usedinpatientsinfectedwithHTLV-1withurinary inconti-nence.
Conclusion
OnabotulinumtoxintypeAshouldbeconsideredinthe treat-mentofoveractivebladderassociatedtoHTLV-1refractoryto anticholinergicdrugsandphysicaltherapy.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgment
ToCristianoFrancofortheassistanceinmanuscript transla-tionandrevision.
ToPauloLessaandMariaEmiliaPedreiraFreiredeCarvalho Foundation.
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