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ORIGINAL ARTICLE
Five years follow-up study and failures analysis of Botulinum toxin repeated injections to treat
neurogenic detrusor overactivity 夽,夽夽
Injections intradétrusoriennes de toxine botulique A dans le traitement de l’incontinence urinaire par hyperactivité neurogène du détrusor : suivi d’une cohorte à cinq ans et analyse des échecs
S. Gaillet
a,b, P. Bardot
e, B. Bernuz
a,b,d, R. Boissier
a,b, K. Lenne-Aurier
b, I. Thiry-Escudier
a,b,d,
H. Tournebise
a,b,c, E. Lechevallier
a,b, G. Karsenty
a,b,∗aAixMarseilleuniversité,13284,Marseille,France
bAP—HM,LaConceptionhospital,urologyandkidneytransplantation,13385Marseille, France
cMédecinephysiqueetréadaptation,hôpitalRené-Sabran,HCL,83406Giens,France
dMédecinephysiqueetréadaptation,hôpitalLéon-Bérard,83400Hyères,France
eMédecinephysiqueetréadaptation,institutPomponiana-Olbia,83407Hyères,France
Received5September2012;accepted4October2012
KEYWORDS Botulinumtoxin;
Overactivebladder;
Urinaryincontinence;
Neurogenicbladder;
Treatmentfailure
Summary
Introduction.—Theaimofthisworkwastofollowprospectivelyacohortofpatientssuffering fromneurogenicoveractivebladder,treatedbybotulinumtoxinA,studytheefficiencyofthis treatment,analysetheprimaryfailures,secondaryandsurrender.
Patientsandmethods.—Thirty-onepatientssufferingfromneurogenicOABreceivedadetru- sorinjectionof300unitsofBotoxTM (ALLERGAN,Irvine,CA)andwerefollowedprospectively (median5years).Theywereevaluatedbyvoidingdiary,QualiveenTM questionnaryandurody- namicsbeforetreatment,2monthsafterthefirstinjectionandthelastre-injection.
Results.—Fiveyearsafterthebeginningofthetreatment,17patientsof31(54.8%)werestill injected,itmeans60.7%oftheprimaryresponders.Elevenpatientshadleftupthetreatment, afteratleastoneeffective injection. Weidentifiedthreereasonsofsurrender:echapment oftreatmentfor twopatients of11 (7.1%);cessationofselfcatheterize for sixpatients of
夽 Frenchversionofthisarticleisavailableonline.
夽夽Levelofevidence:4.
∗Correspondingauthor.
E-mailaddress:[email protected](G.Karsenty).
1166-7087/$—seefrontmatter©2012ElsevierMassonSAS.Allrightsreserved.
http://dx.doi.org/10.1016/j.purol.2012.10.006
11 (54.6%)andthe surrenderofthe treatmentwithoutclinicalorurodynamicalfailure, for threepatients of11 (27.3%).Although the cessationofselfcatheterize was more frequent forpatientssufferingfrommultiplesclerosis,nopredictivefactorofsurrenderwasstatically significant.
Conclusion.—Inthisseries,bladderBTAinjectionswasefficientatmiddletermtotreatneu- rogenicOAB.The echapmentwas arare event(7%).The majorcauseofsurrenderwasthe increasedifficultytoselfcatheterize,duetoprogressionofdisability,morefrequentforpatients sufferingofmultiplesclerosis.
©2012ElsevierMassonSAS.Allrightsreserved.
MOTSCLÉS Toxinebotulique; Hyperactivité vésicale; Incontinence urinaire;
Vessieneurologique; Échecdetraitement
Résumé
Introduction.—L’objectifdecetravailétaitdesuivreprospectivement,unecohortedepatients traitésparinjectionsdetoxinebotuliqueA (TBA)pourhyperactiviténeurogènedudétrusor (HND),d’étudierl’efficacitédutraitementaufildesréinjectionsetdecaractériserleséchecs primaires,leséchappementsetlesabandons.
Matérieletméthode.—Trenteetunpatientsconsécutifssouffrantd’HNDontrec¸u unepre- mièreinjectionintradétrusoriennede300unitésBotoxTM (Allergan,IrvineCA)etontétésuivis prospectivement(médiane cinqans).Ilsétaientévaluésparcalendriermictionnel,question- naireQualiveenTM eturodynamiqueavanttraitement,deuxmoisaprèspremièreinjectionet dernièreré-injection.
Résultats.—Cinq ans après début du traitement, 17patients sur 31 (54,8%) étaient tou- joursréinjectés, soit60,7%des répondeursprimaires. Onze patients avaient abandonnéle traitement,aprèsavoireuaumoinsuneinjectionefficace.Nousavonsidentifié troiscauses d’abandon: l’échappement au traitement chez deux patients sur 11 (7,1%); l’arrêt des autosondageschez six patients sur11 (54,6%) etl’abandondu traitementsans échec clin- ique ni urodynamique chez trois patients sur 11 (27,3%). Bien que l’on observe abandon des autosondagesplus fréquent chez les patients souffrantde SEP, aucun facteur prédictif d’abandonn’apuêtrecaractériséstatistiquement.
Conclusion.—LaTBA intradétrusorienneest efficaceàmoyen terme (cinqans) pourtraiter l’HND.L’échappementestunphénomènerare(7%).Laprincipalecaused’abandondutraite- mentestl’augmentationdeladifficultéàréaliserlesautosondagespropresintermittentsliée àl’évolutionduhandicapquipourraitêtreplusfréquentechezlespatientsatteintsdeSEP.
©2012ElsevierMassonSAS.Tousdroitsréservés.
Abbreviations
BtA botulinumtoxintypeA
NDO neurogenicdetrusoroveractivity ISC intermittentself-catherization MDP maximumdetrusorpressure
MCC maximumcystomanometriccapacity RV reflexvolume
MS multiplesclerosis
CBEU cytobacteriologicalexaminationofurine Ab-aBtA anti-BtAantibodies
Introduction
Theefficacyof intradetrusorinjectionsofbotulinumtoxin type A (BtA) has been shown in the second-line treat- ment of incontinenceby neurogenic detrusoroveractivity (NDO)afterfailureofanticholinergictreatmentinpatients performing intermittent self-catherization (ISC) [1]. Rec- ommended by the principal learned societies of urology andphysicalmedicine[2—4],BtAinjections(BotoxTM,Aller- gan, Irvine,CA) obtainedmarketing authorizationfor this indicationforpatientswithmedullarpathologyormultiple sclerosisinSeptember2011.
Thereductioninurinaryandurgeincontinenceanduri- naryinfections obtainedby thistreatment hasprovideda markedimprovementinthequalityoflifeforover 80%of thesepatients.Thetwokeyurodynamiccriteria,maximum detrusor pressure (MDP) and maximum cystomanometric capacity (MCC) were improved for a mean duration of 9 months,providing effective protection for the upper uri- narytract.Upto10reinjectionshavebeendocumentedas effective[5].
Uptothepresent,fewstudieshavefocusedonBtAtreat- mentfailure,primaryorsecondaryafteraninitialperiodof effectiveness,i.e.resistancetothetreatment.
The aim of this study was to prospectively follow up a cohort of patients treated by BtA injection for 5 years in order to evaluate the efficacy of repeated injections in responder patients and characterize the population of patientswhowerenon-responders,resistant totreatment orlosttofollow-upduringthisperiod.
Patients and methods
Between April 2004 and December 2005, 31 consecutive patients, including 30 toxin-naïve (vesical or extraves- ical), received an intradetrusor injection of 300 units
Botox® (Allergan, Irvine, CA) for urinary of incontinence owing to NDO refractory to anticholinergics (insufficient or poorly tolerated) and due to a chronic medullary lesion. Anticholinergic failure was defined by the per- sistence of urinary leakage and/or pressure NDO>40cm H2O despite treatment at the maximum dose tolerated by the patient. Only one patient had had his/her first injectioninanother center. ISCwasa prerequisitetothis treatment. Patients who had not done ISC before treat- mentweretrainedtodoitbeforeinjection.Injectionwas performedunderlocalanesthesiaafterinstillationofxylo- caineandbicarbonateunderendoscopiccontrol.Allofthe patientswhowereonanticholinergicsbeforetheinjection continued the treatment until the first follow-up consul- tation. Good responders recommended self-adjustment according to the reappearance of leaks or urge inconti- nence.These patientswere followedup prospectivelyfor 5years.
Evaluation criteria
WeevaluatedeachpatientbeforethefirstinjectionofBtA, twomonthsafterthefirstinjection,thentwomonthsafter thelast injectionby interview, QualiveenTM questionnaire (quality of life linked to urinary status in patients with medullarpathologyor multiple sclerosis (MS)[6],a 3-day voiding schedule and urodynamic examination performed accordingtoICSguidelines.
The following clinical criteria were collected: mean number of leakage episodes per 24hours and overall QualiveenTMscore(from0=normalqualityoflifeto4=very poor quality of life, minimum significant difference±0.5 [7]. Urodynamic criteria were MCC, MDP and reflex volume(RV).
Accordingtotheclinicalandurodynamicresponsesfol- lowingthefirstinjection,wedefinedthreetypesofpatients:
goodresponders,partialrespondersandnon-responders(or primaryfailure).
Clinicalresponsewasdefinedbyanabsenceofleakage betweenISC.
Urodynamicresponsewasdefinedbytheassociation of twocriteria: an increase in MCC of more than 30%and a reductioninMDPinferiorto40cmH20.
Apatientwasqualifiedasagoodresponderwhenhe/she hadaclinicalandurodynamicresponse,apartialresponder whentheclinical and/orurodynamicresponse waspartial (reductionin leakage or variations in subthresholdurody- namiccriteria),andanon-responderwhentherewasneither clinicalnorurodynamicresponse.
A non-respondercouldbe primaryifhe/she hadnever had a response to treatment or secondary after an ini- tialresponseperiodtotreatment.Secondarynon-response definedresistance. Non-responder status (primary or sec- ondary)wasconfirmedby asecond injection withneither clinicalnorurodynamicresponse.
Inpatientswhoresponded(goodandpartial)tothefirst injection,wenotedthenumberofreinjectionsperpatient andthetimeperiodbetweeneachinjection.
Fornon-responders,wespecifiedthealternativetherapy prescribed.
Statistical analysis
Thevariouscomparisonsofquantitativevariableswereper- formed by paired non-parametric tests (Wilcoxon paired test)andthesurvivalcurveswereevaluatedbytheKaplan- Meier technique and compared with the log-rank test.
StatisticalanalyseswereperformedonSPSSsoftware.
Results
Thirty-one of the patients with NDO received their first injection of BtA between April 2004 and December 2005:
20patients(64.5%)hadmedullarpathology,10(32.3%)had MSandone(3.2%)hadahistoryofspinabifida.
Themeanageofthecohortwas44.8yearsandthegender ratiowas15men/16women.
The mean period for medullar pathology was 8 years (S.D.:6.5;range:6months—24years)andthemeanperiod from MS diagnosis was 14.4 years (S.D.: 11.0; range:
2.5—39.7years).
Themeanperiodoffollow-upforthecohortwas5.6years (S.D.: 0.46;range:4.8—6.1years)andnopatientwaslost tofollow-up.
Beforethebeginningoftreatment,themeannumberof leaksper daywas4.75 (S.D.:2.87; range:0—14),3.5% of thepatientswerecontinentandthemeanQualiveenscore was2.469(S.D.:0.70;range:1.4—3.9).
On a urodynamic level, the mean MCC was 265.33mL (S.D.:118.2mL;range:90—500mL),theMDPwas65.29cm H2O (S.D.: 24.64cmH2O; range:23—130cmH2O)and the mean value of RV was 199.59mL (S.D.: 95.81mL; range:
57—408mL).
Twomonthsafterthefirst injection,themeannumber ofdailyleakswas0.75(S.D.:1.2;range:0—4;P<0.0005), 71.4% of the patients were continent and the Qualiveen scorewentfrom2.467to1.55(S.D.:0.86;range:0.1—3.9;
P<0.0005).
Onaurodynamiclevel,themeanMCCwas479.9mL(S.D.:
119.48;range:290—800mL;P<0.0005),theMDPwasinfe- riorto40cmH2Oin22outof31 patients(70.9%)andthe meanpostoperativevaluewas26.6cmH2O(S.D.:20.34cm H2O; range: 5—70cmH2O; P<0.0005). The mean RV was 468.5mL(S.D.:129.9mL;range:250—800mL;P<0.0005).
Accordingtotheabovedefinitions,28outof31patients (90.3%)wereconsideredasprimaryrespondersincluding27 goodrespondersandonepartialresponder.Threeoutof31 patients(9.7%)wereprimarynon-responders.
Fiveyearsafter the beginningof treatment, 17 out of 31patients(54.8%)wereregularlybeingreinjectedandstill consideredasresponders(60.7%oftheprimaryresponders) (17/28).Patientswerereinjectedwhentheypresentedclin- icalrecurrence(leakage betweenISC).Inallofthecases, recurrencewasconfirmedbyperformanceofaurodynamic work-up.AKaplan-Meyercurve(Fig.1)showstheevolution ofthe31patients.A‘‘disappearance’’onthecurvecorre- sponds toan abandonmentoftreatment. Fig.2shows the responsestotreatmentofourcohort.
The mean number of injections per patient was 6.06 (S.D.: 3.1;range:2—12).Themeanperiodbetweeninjec- tionswas8.3months(range:6—24months).
Figure1. Cohortesurveycurve.
For the 17 patients continuing injections, two months afterthe lasttreatment, themean numberof daily leaks was0.31(S.D.: 0.78; range:0—3;P<0.0005), 85.2%were continentand theQualiveen score was0.593 (S.D.: 0.33;
range0.2—1.2).
Onaurodynamiclevel,themeanMCCwas465mL(S.D.:
85.14mL; range:350—600mL; P<0.0005), mean MDP was 21.70cm H2O (S.D.: 17.33cm H2O; range: 3—60cm H2O:
P<0.0005)andthemeanRVwas475.4mL(S.D.:92.34mL;
range:350—600mL;P<0.0005).
Alloftheclinicalandmanometricresultsarecompara- tivelysummedupinFigs.3and4andFigs.S1—S3.
At5years,11outof28primaryresponders(39.3%)had abandonedBtA treatment. We identifiedthree causes for abandonment:
• secondaryfailureoftreatment orresistance(asdefined intheMethodssection)afteratleastoneeffectiveinjec- tion,accordingtothecriteriadefinedforgoodorpartial
31 patients First injection
28 primary responders 3 non responders
11 cessations of treatment
2 secondary failures 6 cessation self catheterisation 3 abandonments
17 still injected by BTA at 5 years
Figure2. Treatmentresponseofthecohort.
4.75
0.75 0.31
0.501 1.52 2.53 3.54 4.55
Before treatment aer first injecon aer the last injecon Figure3. Nombremoyendefuites.
responders. Two patients out of 11 (18.1%) had resis- tance after four effective injections for one and two effectiveinjectionsfortheother.This represented7.1%
of the primaryrespondersand 6.4%of the cohort. One patient had an enlargement enterocystoplasty and the otherstabilizedwithanticholinergictreatmentfollowing theplacementofaLioresalpumpforspasticity;
• discontinuingISCbecauseapatientwasunabletoperform themledtoastopinBtAtreatment.Sixoutof11patients (54.6%)couldnolonger ensuretheirISC, contraindicat- ing BtAtreatment. Two of thesepatients had medullar trauma: a C6—C7quadriplegic withincreasingISC diffi- culties(catherizationtimesuperiorto35minutes)anda D9paraplegicwithpelvictiltpreventingcatheterization.
Bothpatientshadcontinencecystotomyasanalternative.
The four other patients had MS, two with a modifica- tionintheircognitivefunctionsandthetwootherswith upper-limb motor difficulties.ISC becameimpossible in allfourofthesecases.ThreeofthemhadBrickerurinary diversions and one patient who refused this treatment currentlyhasanindwellingcatheter;
• threeoutof11patients(27.3%)stoppedtreatmentwith- out clinical or urodynamic failure. One patient whose anticholinergictreatment became sufficient againafter threeeffectiveinjectionsandtwopatientswhoserefusal toperformISCledtoabandonmentoftheirurinaryther- apeuticproject.
Wecouldnotidentifyanypredictivefactorsforprimary non-response,resistanceorabandonmentoftreatment.
Discussion
Afterthefirstintradetrusor injectionof BtAtotreatNDO, we observed a 90.3% rate of primary responders and an amplitude of effectcomparable to those reportedin the mainstreamliterature[1,5,8].Yet,at5years,only17out of the 28 primary responders (61%) were continuing BtA treatment for their vesico-sphincter dysfunction.In these 17 patients, the amplitude of effect (clinical and urody- namic) observed after the first injection was maintained during reinjections (six on average) as reported by Reitz et al.and Khan et al. in the twolargest studies devoted tothe effects of reinjections [9,10].In our cohort, resis- tance wasarare phenomenon (2/28 or 7%)and the least frequent causefor abandoningBtAtreatment. The causes forabandonmentoftreatmentweredominatedbythedif- ficultytoperformISCwhich progressivelyoccurredwithin theframeworkoftheevolutionofahandicap.
Threestudieshaveanalyzedprimaryandsecondaryfail- uresofBtAinjectionsforthetreatmentofNDO:Grosseetal.
[11],Chenetetal.[12],andDelPopoloetal.[13]reported 7 to10% primary failures and5 to 7%secondary failures, whichcorrespondstoourobservations.
The causes of primarytreatment failureof intradetru- sor injections of botulinum toxin are poorly understood.
The existence of vesicalcompliancedysfunction wascon- sidered following description of the technique by Brigitte Schurchasacauseofpoorresponseandhaslednumerous teamstoexcludepatientswithlowvesicalcompliancefrom theirstudies.Theresultsoftwoprincipalseriesdedicated
65.29
26.6 21.7
0 10 20 30 40 50 60 70
Before treatment aer first injecon aer the last injecon
cmH2O
Figure4. Maximaldetrusorpressure.
topatientswithlowcompliancedifferonthesubject:for Klaphajone, sevenpatients over10 withmedullarinjuries and low compliance improved with an injection of 300 units Botox [14] whereas for Horst, only onechild outof 11 had transitoryimprovement after toxin injection [15].
This difference could be due to variations in the defini- tionofcompliancedysfunctionorasChartierKastleretal.
suggested, to different forms of compliance dysfunction involvingornotirreversiblestructuralchangesinthevesical wall[16].Nopatientinourcohorthadcompliancedysfunc- tion(compliance<20cmH2O/mL).
Therearetwocausesofsecondaryfailureor resistance underdiscussion.Theappearanceofantitoxinneutralizing antibodiesormodificationsinducedbyrepeatedinjections in the wall leading to fibrosis and secondary compliance dysfunctionrenderingtoxintreatmentineffective.
The possibilityofthedevelopmentofanti-BtAantibod- ies(Ab-aBtA)hasbeen proposedfollowing observationsof secondaryresistanceafterrepeatedinjectionsin thestria muscle[17—20].
However, the cause-and-effect link between the pres- ence of Ab-aBtA and non-response is still being debated becauseseveralteams have notedadissociationbetween thepresenceofAb-aBtAin40%ofresponderpatientsandthe absenceof Ab-aBtAin 50%of thenon-responder patients.
Inameta-analysisof2240patientstreatedfromoneto15 timeswithBotox®BtAforfivedifferentindications,Nauman etal.[21]reported11cases(0.49%) withthe appearance of Ab-aBtA andonly threeout ofthe 11 patients became non-responders. Nocase involved vesical injectionswhich representedonly1%oftheindications(22/2240).
Itisdifficulttocomparetheseresultswiththoseobserved inurology.Indeed,theinjectedtissueisdifferent,injections invesicalsmoothmusclehave longeractionthan thosein striamuscle(6—9monthsversus2—4months[22])andthe exactmechanismsofthesedifferencesindurationofaction remain unknown. Seven studies have researched Ab-aBtA toexplain secondary treatment failureby BtA in urology.
Schulte-Bauklohetal.[23]studiedapopulationofpatients with NDO. Three treatment failures were noted and cor- responded tothree out of thefour patients withhigh Ab levels. On the other hand, one patient with a significant Ab level was totally satisfied with the treatment. In 17 childrenwithspinabifida,thesameteam(2011)observed thepresence ofantitoxin Abin 35%(6/17) leadingto12%
inefficacy (2/17) [24]. Kajbafzadeh et al. [25] studied a populationof44childrenwithNDO:43wereconsideredas improvedorcureddespitethepresenceofAb-aBtAin18%
ofthem.Finally,Hegeleetal.[26]onlynotedfiveoutof31 patients(16%)withantitoxinantibodies,twoofwhomhad an effective second injection. Therefore,these elements donotmake itpossible toconcludeona secondaryresis- tancetoBtAtreatment owingtothepresence ofAb-aBtA innon-responderswithNDO.Antitoxinantibodieswerenot researched inourcohort. Theother hypothesis toexplain resistancewastheappearanceofhistologicalmodification after repeated injections of BtA (parietal fibrosis). Three studieshavecometothesameconclusion:thereisnosig- nificant difference in inflammation, fibrosis or edema in patients withNDObeforeor afterone or severalintrade- trusorinjections of BtA[27—29]whether thepatients are respondersornot.
Ourstudy is the second after theMohee study tolook atabandonmentoftreatmentby intradetrusorBtAandits causes.At5years,wenotedahighrateofabandonmentof treatment(39%)althoughitwasinferiortothe45%reported byMoheeetal.[30].LiketheLeedsteam,weobservedthat themajorityofthecasesoftreatmentabandonmentwere linkedtoaproblemoftherapeutictolerance,inparticular, theproblemofperformingISC (6/11)or therefusal todo them(2/11)duringthecyclesofreinjection.
We noted that four out of the six cases of abandon- ment owing to ISC difficulties involved patients with MS ratherthan patientswithmedullarinjuries.However,this differencewasnotsignificant(P=0.15;Chi2testandYates correction). Thus, the MS etiology of NDO could be a medium-termriskfactorforabandonmentgiventheevolve- ment of the handicap in this pathology and despite a demonstratedefficacyinthispopulation[9].Largercohorts willbenecessarytoconfirmthis.
ContrarytoMoheeetal.,wedidnotobserveabandon- mentlinkedtorecurrenceofurinaryinfections(aposteriori analysisofthecausesofabandonment).However,ourstudy didnotinclude prospectivesystematic collectionof CBEU betweeninjections.Moreover,itshouldbenotedthatthe Britishstudyincludedalargeproportionofnon-neurologic patientswhoaredifficult tocompare withourpopulation vis-a-visurinarybacteriology.
Conclusion
RepeatedintradetrusorinjectionsofbotulinumtoxintypeA areeffectivein themedium term(5 years)for treatment of urinaryincontinence secondary toneurogenic detrusor overactivity. The principal cause of treatment abandon- ment is the increasing difficulty to perform intermittent self-catherizationsowingtotheevolutionofahandicappar- ticularlyinMSpatients.Primaryfailuresandresistanceare rareevents. A nationalmulticenter inventory (registry)is neededin ordertounderstand theirprecise characteriza- tion.
Disclosure of interest
Gilles Karsenty is or has been investigator consultant or speackerforAllergan,IPSEN,AstraTechandColoplast
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.purol.
2012.10.006.
References
[1] Karsenty G, et al. Botulinum toxin A (Botox) intradetrusor injections in adults with neurogenic detrusor overactiv- ity/neurogenic overactive bladder: a systematic literature review.EurUrol2008;53(2):275—87.
[2]Perrouin-Verbe B, et al. Criteria and best clinical practice guidelinesforfirstintradetrusorinjectionofbotulinumtoxin
type A to treat neurogenic detrusor overactivity. Prog Urol 2009;19(6):372—82.
[3]StohrerM,etal.EAUguidelinesonneurogeniclowerurinary tractdysfunction.EurUrol2009;56(1):81—8.
[4]WyndaeleJJ,etal.Neurologicurinaryincontinence.Neurourol Urodyn2010;29(1):159—64.
[5]ApostolidisA,etal.Recommendationsontheuseofbotulinum toxin inthe treatmentoflower urinary tract disordersand pelvic floordysfunctions: a European consensus report. Eur Urol2009;55(1):100—19.
[6] CostaP,etal.Qualityoflifeinspinalcordinjurypatientswith urinarydifficulties.Developmentandvalidationofqualiveen.
EurUrol2001;39(1):107—13.
[7] Bonniaud V, et al. Symptom and quality of life assess- mentinurinarydisorders.AnnReadaptMedPhys2005;48(6):
392—403.
[8]PatelAK,PattersonJM,ChappleCR.Botulinumtoxininjections for neurogenic and idiopathic detrusoroveractivity: A criti- calanalysisofresults.EurUrol2006;50(4):684—709[discussion 709—10].
[9]Khan S,et al.Long-term effectonqualityof lifeofrepeat detrusor injections of botulinum neurotoxin-A for detru- sor overactivity in patients with multiple sclerosis. J Urol 2011;185(4):1344—9.
[10]ReitzA,et al.Dorepeat intradetrusorbotulinumtoxintype a injections yield valuable results? Clinical and urodynamic resultsafterfiveinjectionsinpatientswithneurogenicdetru- soroveractivity.EurUrol2007;52(6):1729—35.
[11]Grosse J, Kramer G, Stohrer M. Success of repeat detru- sor injections of botulinum a toxin in patients withsevere neurogenic detrusoroveractivityand incontinence. EurUrol 2005;47(5):653—9.
[12]ChenetA,etal.EfficacyofrepeatinjectionsofbotulinumA toxintothedetrusorinneurogenicbladderoveractivity.Ann ReadaptMedPhys2007;50(8):651—60.
[13]DelPopoloG,etal.Neurogenicdetrusoroveractivitytreated withEnglishbotulinumtoxinA:8-yearexperienceofonesingle centre.EurUrol2008;53(5):1013—20.
[14]Klaphajone J, Kitisomprayoonkul W, Sriplakit S. Botulinum toxin type A injections for treating neurogenic detru- sor overactivity combined with low compliance bladder in patients with spinal cord lesions. Arch Phys Med Rehabil 2005;86(11):2114—48.
[15]Horst M,et al.Repeated Botulinum-Atoxininjectioninthe treatmentofneuropathicbladderdysfunctionandpoorblad- dercomplianceinchildrenwithmyelomeningocele.Neurourol Urodyn2011;30(8):1546—9.
[16]KarsentyG, et al.Pharmacological treatmentofneurogenic detrusorhyperactivity:intradetrusorbotulinumtoxinAinjec- tions.ProgUrol2007;17(3):568—75.
[17]AndersonTJ,etal.Botulinumtoxin treatmentofspasmodic torticollis.JRoyalSocMed1992;85(9):524—9.
[18]GreeneP,FahnS,DiamondB.developmentofresistance to botulinumtoxintype-ainpatientswithtorticollis.MovDisord 1994;9(2):213—7.
[19] Goschel H, et al. Botulinum a toxin therapy: Neutralizing andnonneutralizingantibodies-therapeuticconsequences.Exp Neurol1997;147(1):96—102.
[20]RollnikJD,etal.Neutralizingbotulinumtoxintypeaantibod- ies: clinicalobservations inpatients withcervical dystonia.
NeurClinNeurophysiol2001;2001(3):2—4.
[21]Naumann M, et al. Meta-analysis of neutralizing antibody conversionwithonabotulinumtoxinA(BOTOX®)acrossmultiple indications.MovDisord2010;25(13):2211—8.
[22]Holds JB,et al. Motor-nervesprouting inhuman orbicularis muscleafterbotulinum-ainjection.InvestOphthalmolVisSci 1990;31(5):964—7.
[23]Schulte-Baukloh H, et al. Botulinum neurotoxin type A in urology:antibodiesas acauseoftherapy failure.IntJUrol 2008;15(5):407—15.
[24]Schulte-BauklohH,etal.ResultsofaBoNT/Aantibodystudyin childrenandadolescentsafteronabotulinumtoxinA(Botox®) detrusorinjection.UrolInt2011;87(4):434—8.
[25] Kajbafzadeh A-M, et al. Antibody formation following botulinum toxin typeA (Dysport) injection in childrenwith intractablebladderhyper-reflexia.Urology2010;76(1):233—7.
[26]HegeleA,etal.AntibodiesafterbotulinumtoxinAinjection into musculusdetrusorvesicae: incidence and clinicalrele- vance.UrolInt2011;87(4):439—44.
[27]Apostolidis A, et al. Histological changes inthe urothelium and suburothelium of human overactive bladder following intradetrusorinjectionsofbotulinumneurotoxintypeAforthe treatmentofneurogenicor idiopathic detrusoroveractivity.
EurUrol2008;53(6):1245—53.
[28]ComperatE,etal.Histologic featuresintheurinarybladder wallaffectedfromneurogenicoveractivity—acomparisonof inflammation,oedemaandfibrosiswithandwithoutinjection ofbotulinumtoxintypeA.EurUrol2006;50(5):1058—64.
[29]HaferkampA,etal.Lackofultrastructuraldetrusorchanges followingendoscopic injection ofbotulinum toxin typea in overactiveneurogenicbladder.EurUrol2004;46(6):784—91.
[30]MoheeA,etal.Long-termoutcomeoftheuseofintravesical botulinumtoxinforthetreatmentofoveractivebladder(OAB).
BJUInt2012[Articlefirstpublishedonline:6Jun2012].
