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Review – Neuro-urology

Botulinum Toxin A (BotoxW) Intradetrusor Injections inAdults with Neurogenic Detrusor Overactivity/NeurogenicOveractive Bladder: A Systematic Literature Review

Gilles Karsenty a, Pierre Denys b, Gerard Amarenco c, Marianne De Seze d, Xavier Game e,Francois Haab f, Jacques Kerdraon g, Brigitte Perrouin-Verbe h, Alain Ruffion i,Christian Saussine j, Jean-Marc Soler k, Brigitte Schurch l, Emmanuel Chartier-Kastler m,*aHopital Sainte Marguerite, Marseille, FrancebHopital Raymond Poincare, Garches, FrancecHopital Rothschild, Paris, FrancedHopital Pellegrin, Bordeaux, FranceeHopital Rangueil, Toulouse, FrancefHopital Tenon, Paris, FrancegCentre Mutualiste de Reeducation et de Readaptation Fonctionnelles de Kerpape, Ploemeur, FrancehHopital St Jacques, Nantes, FranceiHopital Henry Gabrielle, Saint Genis Laval, FrancejHopital Civil, Strasbourg, FrancekCentre Bouffard Vercelli, Cerbere, FrancelHopital Universitaire Balgrist, Zurich, SwitzerlandmHopital Pitie-Salpetriere, Paris, France

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journa l homepage: www.europeanurology.com

Article info

Article history:Accepted October 5, 2007Published online ahead ofprint on October 16, 2007

Keywords:Botulinum toxin type ACholinergic antagonistOveractive bladderUrinary bladderNeurogenicUrinary incontinenceUrodynamics

Abstract

Objectives: This systematic literature review discusses the efficacy andsafety of botulinum toxin type A (Botox1) intradetrusor injections inadults with neurogenic detrusor overactivity (NDO) and urinary incon-tinence or overactive bladder symptoms of neurogenic origin (NOAB).Methods: A MEDLINE and EMBASE search for clinical studies with botu-linum toxin A injected into the detrusor of adults with NDO was per-formed. For several efficacy and safety variables data were extracted byone person and independently quality-controlled by another person.Extracted data were reviewed to propose recommendations for use inclinical practice based on level of evidence and expert opinion.Results: A total of 18 articles evaluating the efficacy or safety of Botox inpatients with NDO and incontinence/NOAB resistant to antimuscarinictherapy, with or without clean intermittent self-catheterisation (CIC),were selected. The amount of Botox injected was mostly 300 U, usually as

* Corresponding author. Department of Urology, Medical School Pierre et Marie Curie,University Paris VI, Hopital Pitie-Salpetriere, 83, Boulevard de L’Hopital, 75013 Paris, France.Tel. +33 1421 77 129; Fax: +33 1421 77 160.E-mail address: emmanuel.chartier-kastler@psl.aphp.fr (E. Chartier-Kastler).

0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.10.013

30 injections of 10 U/ml in the bladder (excluding the trigone) undercystoscopic guidance and with different types of anaesthesia. Most ofthe studies reported a significant improvement in clinical (approximately40–80% of patients became completely dry between CICs) as well asurodynamic (in most studies mean maximum detrusor pressure wasreduced to �40 cm H2O) variables and in the patients’ quality of life,without major adverse events.Conclusions: Botox injections into the detrusor provide a clinically sig-nificant improvement in adults with NDO and incontinence/NOABrefractory to antimuscarinics. It seems to be very well tolerated. How-ever, more adequately powered, well-designed, randomised, controlledstudies evaluating the optimal dose, number and location of injections,impact on antimuscarinic regimen and CIC use, duration of effect, andwhen to perform repeat injections are warranted.# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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1. Introduction

In patients with neurologic disorders, bladder dys-function associated with detrusor overactivity (DO)constantly impairs quality of life (QoL) and oftenposes a threat for the upper urinary tract (UUT).Therefore, it represents a major health problem inthis population. According to the standardisation ofterminology of lower urinary tract function publishedby the International Continence Society (ICS), DO is aurodynamic observation characterised by involun-tary detrusor contractions during the filling phasethat may be spontaneous or provoked. When there isa relevant underlying neurologic condition (eg, spinalcord injury [SCI] or multiple sclerosis [MS]), this isqualified as neurogenic DO (NDO) [1]. Overactivebladder (OAB) is a symptom complex described asurgency, with or without urge incontinence, usuallywith frequency and nocturia [1]. Although OAB is notspecific for any condition or urodynamic finding,patients with OAB are often found to have DO. Oralantimuscarinic agents have been widely used as first-line treatment for patients with NDO or neurogenicOAB (NOAB). However, they are ineffective in somepatients or can cause troublesome systemic side-effects such as dry mouth, constipation, and blurredvision. Intravesical treatment strategies may providealternatives to achieve a profound inhibition of NDOand to avoid high systemic drug levels.

Botulinum toxin (BTX), first isolated by vanErmengem [2] in 1897, is a potent neurotoxin pro-duced by the gram-positive anaerobic bacteriumClostridium botulinum. From a structural viewpoint,the toxin is a 150-kD amino acid di-chain moleculeconsisting of a light (50 kD) and a heavy chain(100 kD), which are linked by a disulfide bond. Therole of BTX at the neuromuscular junction has beenwell described and consists of inhibition of acetylcho-

line neurotransmitter release resulting in striatedmuscle relaxation [3]. However, increasing evidencesuggests a much greater range of neurologic effects ofBTX. BTX has been found to inhibit the release of anumber of neurotransmitters (including acetylcho-line, adenosine triphosphate, and neuropeptidessuch as substance P) and to down-regulate theexpression of purinergic and capsaicin receptors onafferent neurons within the bladder [4]. These datasupport the belief that BTX works to treat DO and OABby both sensory and motor pathways.

Of the seven distinct but structurally similarserotypes of BTX, types A and B have been used withclinically beneficial outcomes in various neurologicdisorders. The serotype A product, BTX-A, was firstinvestigated in 1990 for the treatment of detrusorexternal sphincter dyssynergia in patients with SCI[5]. Following its success for this indication, theeffect of injecting BTX-A into the detrusor muscle ofpatients with NDO was first presented at the ICSmeeting in 1999 by Stohrer and Schurch [6].Although BTX-A is not yet approved by the US Foodand Drug Administration (FDA) or the EuropeanMedicines Agency (EMEA) for the treatment ofpatients with NDO or NOAB, two toxins arecommercially available (Botox1, Allergan, Irving,CA, USA and Dysport1, Ipsen-Biotech, Paris, France).

The use of BTX-A in the treatment of patients withNDO aims to improve urinary symptoms, to reduceUUT risk and to improve QoL. It has been developedas a second-line treatment option (ie, intoleranceor failure after treatment and evaluation with anappropriate dose and for an appropriate period[minimal 2 mo] of antimuscarinics) for patientswith NDO with urinary incontinence or other NOABsymptoms able and willing to perform clean inter-mittent (self)-catheterisation (CIC). Patients withclear contraindications to BTX-A (eg, patients with

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myasthenia gravis) should be excluded from treat-ment. There is currently no clear consensus about theoptimal use of this innovative treatment in clinicalpractice. Issues of optimal dose, number and locationof injections, type of cystoscope and anaesthesiarequired depending on patient aetiology, timing ofrepeat injection, and safety could have an importantimpact on clinical outcomes and need furtherinvestigation.

Based on the results of a systematic literaturereview of clinical studies evaluating the efficacy orsafety (or both) of BTX-A in adults with NDO/NOABand subsequent clinical expert discussion of theoutcomes, this review paper will provide moreinsight into these topics on an evidence-basedmedicine level. We will only discuss the use ofBotox, because Botox and Dysport are biologicproducts that differ in terms of pharmacodynamicfeatures (due to variability in neurotoxin-derivedbacterial strain, excipients, and manufacturingprocess) and dose contained in each vial [7–9].Several studies have demonstrated that this leads tosignificant differences in the adverse events (AEs)profile between Botox and Dysport [9–12].

2. Methods

2.1. Search strategy

A literature search was performed in the MEDLINE (PubMed)

and EMBASE (from 1993 until March 2007) databases in

February and March 2007 to retrieve fully published English-

language clinical studies on BTX-A. In MEDLINE, the search for

retrieving the references was performed by exploding and

combining the followingmedicalsubject heading (MeSH) terms:

‘‘Urinary bladder, Neurogenic’’ and ‘‘Botulinum Toxin Type A.’’

The results were limited for ‘‘English language.’’ Thereafter, the

limitations ‘‘human,’’ ‘‘clinical trial,’’ and ‘‘adult, 19+ years’’

were used; recently published (2005–2007) review articles were

identified by limiting for ‘‘review.’’ In EMBASE, the search was

performed by exploding the EMTREE term ‘‘Neurogenic-

Bladder’’ and combining this with ‘‘Botulinum-Toxin-A.’’ The

results were limited to ‘‘English language.’’

2.2. Selection of studies for data extraction

The abstracts of the MEDLINE and EMBASE English-language

references were all read to select articles that concerned

clinical studies evaluating the efficacy or safety (or both) of

BTX-A intradetrusor injection in adults suffering from NDO/

NOAB. The records of the MEDLINE limitations search for

‘‘human,’’ ‘‘clinical trial,’’ and ‘‘adult, 19+ years’’ were also

used to identify these articles/studies. Reference lists of

review articles, identified by limiting the MEDLINE search

for ‘‘review,’’ were also checked to pick up any missed articles/

studies. Exclusion criteria included references that concerned

urethral sphincter injection, patients with detrusor sphincter

dyssynergia, or the BTX-A product of Dysport. Studies

involving both Botox and Dysport without separate analyses

were also excluded. When selected articles concerned the

same study, only the latest report with the highest number of

patients or longest follow-up was included.

2.3. Data extraction

Each of the studies/articles was reviewed for extracting (1)

study and patient characteristics, (2) injection protocol

characteristics, (3) impact on clinical variables (number of

micturition and incontinence episodes/24 h, number [%] of

patients becoming partially or fully continent, impact on use

of antimuscarinics), (4) impact on urodynamic variables

(maximum detrusor pressure [Pdetmax], maximum cysto-

metric capacity [MCC], reflex detrusor volume [RDV], ie,

bladder volume at first involuntary detrusor contraction,

and bladder compliance), and (5) percentage of patients with

AEs, in particular injection site pain, urinary tract infection

(UTI), haematuria, urinary retention (UR), de novo CIC, and

muscle weakness. The data were extracted by one person and

thereafter quality-controlled by a second person.

2.4. Data interpretation

The extracted data were reviewed, interpreted, and discussed

to propose recommendations for use in clinical practice based

on level of evidence and expert opinion. The outcome is

integrated in the Results and Discussion sections.

3. Results

3.1. MEDLINE and EMBASE search

The MEDLINE search identified 52 and the EMBASEsearch 58 English-language papers on the use ofBTX-A for NDO/NOAB. After applying the selectioncriteria and checking the reference list of severalreview articles [7,8,13–16] to pick up any missedarticles/studies, a total of 18 articles concerningclinical studies with Botox were selected (Table 1).

3.2. Study and patient characteristics

Of the 698 patients included in the 18 selectedstudies (Table 1), 83% had NDO with urinaryincontinence and/or NOAB (mainly due to SCI[57%] and MS [17%]) and refractory to usually highdoses of antimuscarinic agents. Only three studiesalso enrolled patients with idiopathic DO (IDO) orbladder outlet obstruction (BOO). In 13 of 18 articles,the initial bladder emptying modality was specified;it was CIC in 84% of these patients. Most studieswere small-scale studies enrolling fewer than50 patients. There were three larger-scale studies:Schurch et al [17] enrolled 59 patients in a double-blind, randomised, placebo-controlled, three-arm,

Table 1 – Study and patient characteristics of articles selected for systematic literature review on Botox in adults with NOAB

First author No. ofpatients

Neurogenicdisorder

Studydesign

Level ofevidence

No. onCIC

beforetreatment

Amount ofBotox, U

Activetreatment

meanfollow- up,

wk

(Mean)duration ofeffect, wk

Schurch [17] 59 SCI: n = 53 Randomised,

placebo-

controlled

1b 59 200a 24 At least 24

MS: n = 6 300

Giannantoni [18] 75 SCI Randomised,

active comparator-

controlled

1b 75 300b 112c 35 (per

injection)

Karsenty [20] 17 SCI: n = 16 Open-label 3 13 300 208 39

MS: n = 1

Schulte-Baukloh [21] 16 MS Open-label 3 0 300 12 and 24 At least 12

Kalsi [22] 32 MS: n = 24 Open-label 14 300 16 At least 16

SCI: n = 2

Other: n = 6

Giannantoni [23] 23 SCI Open-label 3 Unknown 300 12 At least 12

Kuo [24] 24 CVA: n = 12 Open-label 3 0 200 12 12

SCI: n = 7

MS: n = 4

Other: n = 1

Klaphajone [25] 10d SCI: n = 9 Open-label 3 10 300 16 and 36 At least 16

Other: n = 1

Popat [26] 44 MS: n = 29 Open-label 3 31 300 16 At least 16

SCI: n = 5

Other: n = 10

Kessler [27] 11 SCI: n = 2 Open-label 3 Unknown 300 1 22

MS: n = 3

Other: n = 6

Hajebrahimi [28] 10 SCI Open-label 3 10 400 12 At least 12

Smith [29] 42 SCI: n = 1 Open-label 3 Unknown 100–300 24 At least 24

MS: n = 16

CVA: n = 2

IOAB: n = 17

Other: n = 6

Bagi [30] 15 SCI Open-label 3 15 300 6 30

Kuo [31] 30 NOAB: n = 12 Open-label 3 Unknown 200 12 21

IOAB: n = 8

BOO: n = 10

Reitz [19] 200 SCI: n = 167 Open-label 3 188e 300 12 and 36 At least 36

MS: n = 11

Other: n = 22

Harper [32] 39 NOAB Open-label 3 Unknown 200 4 and 16

IOAB 300

Kennelly [33] 10 SCI: n = 6 Open-label 3 10 300 6, 12, and 24 12–24

MS: n = 4

Schurch [34] 21 SCI Open-label 3 21 200–300 6 and 36 At least 36

SCI = spinal cord injury; MS = multiple sclerosis; CVA = cerebrovascular accident; IOAB = idiopathic overactive bladder; NOAB = neurogenic

overactive bladder; BOO = bladder outlet obstruction; CIC = clean intermittent catheterisation.a Nineteen patients received 200 U or 300 U Botox, 21 patients received placebo.b Forty patients received 300 U Botox, 35 patients received resiniferatoxin.c A mean number of 3.4 injections with mean time interval between injections of 7.5 mo.d Nine of 10 patients had low bladder compliance.e Twelve remaining patients were on indwelling catheter before the treatment.

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Table 2 – Botox injection protocol characteristics

First author Dilution,U/ml

Type ofcystoscope

Injection sites No. ofinjections

Type of anaesthesia

Schurch [17] 6.7–10 Rigid Dome 30 None, local, spinal, or general

Giannantoni [18] 10 Rigid Dome 30 Sedation or spinal

Karsenty [20] 10 Rigid Dome and base 30 None or local

Schulte-Baukloh [21] 15 Rigid Dome, base, and trigone 40 Local, spinal, or general

Kalsi [22] 10 Flexible Dome and base 30 Local

Giannantoni [23] 10 Rigid Dome and base 30 Spinal or sedation

Kuo [24] 10 Rigid Basea 40 General

Klaphajone [25] 20 Flexible Dome and base 15–30 General

Popat [26] 10 Flexible Dome and base 30 Local

Kessler [27] 10 Rigid Dome and base 30 Unknown

Hajebrahimi [28] 10 Rigid Dome 40 None or general

Smith [29] 10 Rigid Base and trigone 30–40 Light sedation

Bagi [30] 10 Rigid Dome 30 General or local

Kuo [31] 25 Rigid Base 40 General

Reitz [19] 10 Rigid Dome and base 30 None, local, spinal or general

Harper [32] 10 Flexible Dome and base 20–30 Local

Kennelly [33] 10 Rigid Dome and base 30 Intravenous sedation

Schurch [34] 10 Rigid Dome 20–30 None or local

a Suburothelial injection.

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parallel group study; Giannantoni et al [18] enrolled75 patients in a randomised, resiniferatoxin-con-trolled, two-arm, parallel group study; and Reitz et al[19] reviewed retrospectively data from 200 patients.The majority of the studies were open-label studies[19–34], except for the placebo-controlled study bySchurch et al [17] and the study with resiniferatoxinas active comparator by Giannantoni et al [18].Follow-up ranged from 12 up to 36 wk, except for twostudies evaluating the impact of repeated injections,which lasted 2–4 yr [18,20].

Table 3 – Impact of Botox on the number of incontinence epis

First author No. of patients(on CIC)

Meanbaseline

Schurch [17]: 24 wk

Placebo 21 (21) 3.0

Botox1 200 U 19 (19) 1.9

Botox1 300 U 19 (19) 2.8

Giannantoni [18]: 26 wk

Resiniferatoxin 35 (35) 4.9

Botox1 300 U 40 (40) 5.2

Karsenty [20]

First injection 17 (13) 2.6

Last injectiona 17 (13) 2.6

Kalsi [22]: 16 wk 32 (14) 3.4

Giannantoni [23]: 12 wk 23 5.4

Popat [26]: 16 wk 44 (31) 3.9

CIC = clean intermittent catheterisation.a Mean number of 5.4 injections with mean time interval between injec* p < 0.05.*** p < 0.001.y Significant vs. placebo or resiniferatoxin.

3.3. Injection protocol

In most of the studies (11 of 18), the amount of Botoxinjected was 300 U (Table 1), usually as 30 injectionsites (range: 15–40) of 10 U/ml (range: 6.7–25 U/ml) inthe bladder (usually sparing the trigone) undercystoscopic guidance (flexible or rigid) and withdifferent types of anaesthesia (none, local, spinal, orgeneral; Table 2). A few trials used doses of 200 U(2 studies), 200–300 U (3 studies), 100–300 U (1 study),or 400 U (1 study).

odes/24 h

Mean endpoint

Mean changevs. baseline

Mean % changevs. baseline

2.9 �0.1 �3

0.8 �1.1* �58

1.9 �0.9*,y �32

2.1 �2.8*** �57

1.2 �4.0***,y �77

0 �2.6 �100

0 �2.6 �100

0.5 �2.9*** �85

2.0 �3.4*** �63

0.7 �3.2*** �68

tions 7.6–9.1 mo.

Fig. 1 – Percent of patients who became completely continent [17–19,23–28,30,31,33,34].

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3.4. Efficacy

3.4.1. Clinical variables: frequency, leakage, and QoL

In the studies reporting the impact of Botox on thedaily frequency of urinary incontinence episodes,the mean number of daily incontinence episodeswas between two and five with most patientsbeing on CIC (Table 3). The two controlled studiesdemonstrated that the efficacy of Botox is signifi-cantly superior to that of both placebo (level ofevidence 1b) and resiniferatoxin (level of evidence1b; Table 3) [17,18]. Open-label case series confirmedthis trend (level of evidence 3; Table 3) [20,22,23,26].Up to 26 wk after Botox injection, the percentagereduction in the mean number of daily urinaryincontinence episodes (between CICs) from baselinewas approximately 60–80%. Furthermore, between42% and 87% of patients became completely con-

Fig. 2 – Percent mean change in quality of life [17,21,22,31]. UDI

Index; SII = Symptom Impact Index; I-QOL = Incontinence Quali

Symptom Score.

tinent (between CICs) after Botox treatment (if theoutliers of 8% in the two studies by Kuo et al [24,31],which included a high percentage of patients with acerebrovascular accident [CVA] or IDO/BOO, aredisregarded; Fig. 1) [17–19,23,25–28,30,33,34]. Themean number of daily micturition (ie, frequency)episodes was also reduced from baseline by approxi-mately 40–60% (data not shown) [21–23,26,27,29].The decrease in frequency and leakage was asso-ciated with an improvement in the patients’ QoL by35–65% versus baseline (Fig. 2) [17,21,22,31], whichwas significantly superior to the effect of placebo[17]. In some studies, the impact of Botox on theuse of antimuscarinic agents was also documented[19,23,26,30,33,34]. In studies in which patientswere instructed to reduce the dose of or dis-continue antimuscarinic treatment, the antimus-carinic agents could be discontinued in 28–58% of

-6 = Urogenital Distress Inventory; SSI = Symptom Severity

ty of Life Questionnaire; I-PSS = International Prostate

Table 4 – Impact of Botox on Pdetmax (cm H2O)

First author No. ofpatients

Meanbaseline

Meanend point

Mean changevs. baseline

Mean % changevs. baseline

Schurch [17]: 24 wk

Placebo 21 79.1 80.6 1.4 2

Botox 200 U 19 77.0 48.8 �38.7*,y �50

Botox 300 U 19 92.6 55.2 �35.5*,y �38

Giannantoni [18]: 26 wk

Resiniferatoxin 35 83.0 74.4 �8.6 �10

Botox 300 U 40 74.9 42.0 �32.9** �44

Karsenty [20]

First injection 17 75.5 28.8 �46.7*** �62

Last injectiona 17 75.5 27.4 �48.1*** �65

Schulte-Baukloh [21]

12 wk 16b 57.1 44.4 �12.7** �22

24 wk 16b 57.1 24.4 �32.7* �57

Kalsi [22]: 16 wk 32 54.2 24.8 �29.4*** �54

Giannantoni [23]: 12 wk 23 62.3 24.6 �37.7*** �61

Kuo [24]: 12 wk

CVA 12 27.3 19.8 �7.5 �27

SCL 12 39.1 25.7 �13.4 �34

Klaphajone [25]

16 wk 10 60.4 �24.2 �36.2*** �60

36 wk 10 60.4 �46.0 �14.4* �24

Popat [26]: 16 wk 44c 60.8 26.9 �33.9*** �42

Kesslerd [27]: 1 wk 11 40.0 24.0 �16.0** �40

Hajebrahimi [28]: 12 wk 10 69.6 58.8 �10.8 �16

Smith [29]: 24 wk 22 58.0 52.0 �6.0 �10

Bagi [30]: 6 wk 14 86.0 35.0 �51.0*** �59

Reitz [19]

12 wk 200 61.0 30.0 �31.0*** �51

36 wk 99 61.0 44.0 �17.0*** �28

Kennelly [33]

6 wk 10 41.8 27.3 �14.5 �35

12 wk 10 41.8 24.2 �17.6 �42

24 wk 10 41.8 39.9 �1.9 �5

Schurch [34]

6 wk 19 65.6 35.0 �30.6* �47

36 wk 11 65.6e 36.5 �29.1* �44

Pdetmax = maximum detrusor pressure.a Mean number of 5.4 injections with mean time interval between injections 7.6–9.1 mo.b From 16 at baseline to 14 and 9 after 12 and 24 wk.c From 44 at baseline to 29 at end point.d Median instead of mean values.e Baseline of 19 patients.* p < 0.05.** p < 0.01.*** p < 0.001.y Significant versus placebo or resiniferatoxin.

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patients [19,26,33,34]. In most other patients, thedose could be reduced.

3.4.2. Urodynamic variables

A positive impact of Botox on urodynamic variableswas also demonstrated. Table 4 shows the impact onPdetmax. The mean Pdetmax at baseline was ingeneral between 60 and 80 cm H2O. The two

controlled studies showed that Botox was signifi-cantly superior in reducing Pdetmax compared toboth placebo and resiniferatoxin [17,18]. The otheropen-label studies confirmed the positive impactof Botox on Pdetmax [19–30,33,34]. The percentagemean reduction in Pdetmax from baseline wasapproximately 40–60%, if for each study the largestreduction over time was considered and some

Fig. 3 – Mean maximum detrusor pressure (Pdet.max) at end point (lowest value per study included) [17–30,33,34].

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outliers were disregarded (some of the outlierstudies again included a high percentage of patientswith a CVA or IDO [24,29]). Moreover, in most of thestudies mean Pdetmax was reduced with Botox to<40 cm H2O, which is generally regarded as thedesired Pdetmax for UUT protection [35] (Fig. 3).

The reduction in Pdetmax was accompanied by anincrease in MCC (Table 5), which was superior to thatof placebo [17] and resiniferatoxin [18]. The meanMCC at baseline was, in general, between 175 and300 ml. In most studies, the percentage increase inmean MCC from baseline ranged between 40% and60% with increases of 100–200% in studies ofpatients with a relatively low mean MCC at baseline[17–34].

Many studies also assessed the RDV, which wassignificantly increased from baseline with Botox[17–21,23–25,28,33,34]. Bladder compliance is aurodynamic variable useful to monitor long-termsafety of Botox as well as an outcome variable inpatients with NDO. Although the mean baselinevalue was normal in the majority of studies (in 4 ofthe 6 studies that reported bladder compliancethe mean baseline value was >20 ml/cm H2O), thebladder compliance also increased with treatmentcompared to baseline [19,20,25,27,33,34].

3.4.3. Onset, time to maximum, and duration of effect/timing

of repeat injections

The study by Schurch et al [17] noticed significantimprovements versus placebo in the number ofincontinence episodes, QoL, and urodynamic para-meters within 2 wk after Botox injection. Thesebenefits reached their maximum between 2 and6 wk and were maintained throughout the 24-wk

study period [17]. Several other open-label studiesconfirmed that these improvements were signifi-cant versus baseline at the first assessment after2 wk [31] or 4 wk [21,24,26] or even within the firstweek [27] with maximum effects obtained between1 and 4 wk [29].

A recent study by Karsenty et al [20] reported onthe persistence of effect after repeated injectionsin 17 patients who received at least two repeatinjections. The success of the first injection wasdefined as a decrease in the number of incontinenceepisodes per day and improvement in MCC, Pdetmax,and RDV. Repeated injections were usually donewhen the patient reported recurrent leakage and aconcomitant UTI had been excluded. The mean timeinterval between repeated Botox injections rangedbetween 7.6 and 9.1 mo (approximately 36 wk) withsustained efficacy both in terms of diary changesand urodynamic variables. In another longer termstudy by Giannantoni et al [18], the efficacy of Botoxwas also sustained for 36 wk (approximately 8–9 mo)after which repeat injection was needed. A few otherstudies indicated that the efficacy may decreasefaster (after 12–24 wk) [19,25,33]. This may, inparticular, apply to patients with low bladdercompliance [25]. In studies evaluating QoL signifi-cant improvements were noticed up to 12–24 wkafter treatment [17,21,22,31].

3.5. Safety

Botox was well tolerated in all 18 studies. Althoughthe occurrence of local or systemic AEs was not verywell reported in most of the studies, most frequentAEs appeared to be injection site pain [17], procedure-

Table 5 – Impact of Botox on MCC (ml)

First author No. ofpatients

Meanbaseline

Meanend point

Mean changevs. baseline

Mean % changevs. baseline

Schurch [17]: 24 wk

Placebo 21 254.6 301.0 41.6 16

Botox 200 U 19 260.2 440.9 174.2* 67

Botox 300 U 19 293.6 398.2 92.9y 32

Giannantoni [18]: 26 wk

Resiniferatoxin 35 235.6 329.0 93.4** 40

Botox1 300 U 40 249.8 384.4 134.6**,y 54

Karsenty [20]

First injection 17 348.8 499.1 150.3*** 43

Last injectiona 17 348.8 461.8 113.0*** 32

Schulte-Baukloh [21]

12 wk 16b 265.4 336.1 70.7* 27

24 wk 16b 265.4 360.8 95.4 36

Kalsi [22]: 16 wk 32 186.0 495.5 309.5*** 166

Giannantoni [23]: 12 wk 23 246.3 459.2 212.9*** 86

Kuo [24]: 12 wk

CVA 12 198.3 254.5 56.2 28

SCL 12 176.2 255.3 79.1 45

Klaphajone [25]

16 wk 10 175.0 �290.0 115.0** 66

36 wk 10 175.0 �215.0 40.0 23

Popat [26]: 16 wk 44c 229.1 427.0 197.9*** 181

Kesslerd [27]: 1 wk 11 190.0 410.0 220.0** 116

Hajebrahimi [28]: 12 wk 10 290.0 518.2 228.2* 74

Smith [29]: 24 wk 22 153.0 246.0 93.0* 61

Bagi [30]: 6 wk 14 350.0 457.0 107.0 31

Kuo [31]: 12 wk 30e 222.5 247.1 24.6 11

Reitz [19]

12 wk 200 272.0 420.0 148.0*** 54

36 wk 99 272.0 352.0 80.0*** 29

Harper [32]: 16 wk 39 174.0 580.0 406.0 233

Kennelly [33]

6 wk 10 270.0 418.0 148.0** 55

12 wk 10 270.0 428.0 158.0** 59

24 wk 10 270.0 333.0 63.0 23

Schurch [34]

6 wk 19 296.3 480.5 184.2* 62

36 wk 11 296.3f 457.5 161.2* 54

MCC = maximum cystometric capacity.a Mean number of 5.4 injections with mean time interval between injections 7.6–9.1 mo.b From 16 at baseline to 14 and 9 after 12 and 24 wks.c From 44 at baseline to 29 at end point.d Median instead of mean values.e Follow-up in 24 patients.f Baseline of 19 patients.* p < 0.05.** p < 0.01.*** p < 0.001.y Significant versus placebo or resiniferatoxin.

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 2 7 5 – 2 8 7 283

related UTI (in 2–32% of patients) [17,24,26,31],and mild haematuria (in 2–21% of patients) [17,24–26,31]. Sometimes an increase in postvoid residualpotentially resulting in UR (0–33% of patients)[17,24,26,29,31,33] or de novo CIC (6–88% of patients)[21,22,24,26,27,31] also occurred. Muscle weakness

was not reported to have occurred in any of thestudies. The only study in which AEs were reported ina structured way was the placebo-controlled study bySchurch et al [17], which confirmed injection site painand UTI as the most frequent AEs (Table 6). Allpatients were on CIC before treatment with Botox and

Table 6 – Treatment-emergent AEs reported in theplacebo-controlled study by Schurch et al [17]

AE Placebo(n = 21)

Botox 200 U(n = 19)

Botox 300 U(n = 19)

Injection site pain 1 (5%) 0 2 (11%)

UTI 3 (14%) 6 (32%) 4 (21%)

AE = adverse event; UTI = urinary tract infection.

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 2 7 5 – 2 8 7284

therefore de novo CIC did not occur. In two studies,Botox was injected in the trigone but the occurrenceof vesicoureteral reflux (VUR) was not reported[21,29].

4. Discussion

From this systematic literature review, we canconclude that injection of Botox into the detrusorof adults with NDO and urinary incontinence orother NOAB symptoms who have failed antimus-carinic therapy has beneficial effects both on clinicaland urodynamic variables. Complete continencewas achieved in approximately 40–80% of patientsand in most studies mean Pdetmax was reduced to or<40 cm H2O.

The most commonly used dose of Botox is 300 U.Schurch et al [17] found that both doses of 200 and300 U Botox induced significant decreases in incon-tinence episodes and improved urodynamics andQoL compared to placebo, suggesting that lowerdoses could be used. However, no conclusions couldbe reached regarding the optimal dose because thestudy was not powered to detect significant differ-ences between the doses. Kuo et al [24] also reportedbeneficial results with 200 U Botox in patients withSCI. Except for one study using 400 U Botox [28],higher doses have not been investigated. As aconsequence, it is still not fully clear whether thedose of 300 U Botox is the optimum dose.

Usually, 30 injections of 10 U/ml were performed.It may be that by reducing the number of injectionsto, for example, 10 at the same dose of 300 U, efficacyremains but with a less painful and faster injectionprocedure [36]. The long-term risk of fibrosis mayalso be reduced but the risk of a false puncturein terms of systemic AEs may be increased andshould therefore be assessed. It may be worthwhileto investigate these potential differences between10 and 30 injections of a dose of 300 U in futurestudies.

Botox has been injected directly into the detrusorin almost all studies. One study performed subur-othelial injections to take advantage of the pre-sumed effect on afferent sensory nerves [24]. Most

studies reported spared the trigone, whereas twostudies injected the trigone without reporting casesof VUR [21,29]. Based on this we believe thatcurrently intradetrusor injection sparing the trigoneis still the reference location.

Other variables of the technique are the type ofcystoscope and anaesthesia used. There is no studythat compares efficacy or tolerance of Botox injec-tions when using a rigid or a flexible cystoscope.Although both types of cystoscopes (flexible andrigid) have been used, rigid ones were the mostcommonly used. However, in our opinion a flexiblecystoscope may have an advantage in men withpreserved sensibility or, independent of gender, inpatients with SCI with a lesion above T6 becausereduction of pain or stimulation prevents autonomicdysreflexia [37]. All types of anaesthesia (none, local,spinal, or general) have been used for Botox injection.We believe that the type of anaesthesia is the choiceof the patient and the surgeon, depending mainly onbladder and urethral sensation. General anaesthesiamay be considered for extremely anxious or sensitivepatients and for neurogenic patients who are at riskfor autonomic dysreflexia.

In adults with NDO/NOAB, with or without CIC,Botox has a fast onset of action with significanteffects reached within 1–2 wk and maximum effectswithin 4–6 wk. The longer term repeat injectionstudies suggest that the effect of an intradetrusorinjection of Botox lasts for 36 wk or approximately8–9 mo [18,20]. Of the shorter term studies runningfor 24–36 wk some showed also sustained efficacyuntil 36 wk, whereas a few showed worsening inefficacy between 12 and 24 wk. The duration ofeffect should therefore be further clarified inspecifically designed studies.

In some studies, the dose of antimuscarinicscould be reduced or even discontinued. However, forthe vast majority of studies the antimuscarinicregimen used throughout the study was not clearlydescribed and therefore its potential impact on theefficacy of Botox cannot be assessed. Therefore,future studies should better describe the antimus-carinic regimen and the policy of dose reductionafter treatment to determine whether adjuvantantimuscarinic drugs have an impact on the efficacyor duration of effect of Botox.

An important question to be answered is howBotox should, based on the currently available dataand physician experience, best be applied in clinicalpractice?

In our opinion, patients with symptoms related toNDO who have failed antimuscarinic therapy andare on or willing and able to perform CIC seem to beeligible candidates for Botox treatment.

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 2 7 5 – 2 8 7 285

Before the injection, urologists should ade-quately inform the patient about the potential riskof Botox-related AEs. Although in most articlesreporting of AEs could have been more structured,the most frequent AEs of Botox seem to be injectionsite pain, procedure-related UTI, and (mild) hae-maturia. Sometimes an increase in postvoid resi-dual resulting in UR or de novo CIC also occurred.However, in this population with DO from neuro-genic origin the majority of patients have difficultyemptying their bladder. CIC is therefore requiredand we consider UR induced by Botox as less of aproblem. Among patients with preserved voiding, itwill be important to know the proportion of patientswith UR and need for CIC, which is not clearlydescribed in the literature. AEs such as muscleweakness and vision disturbances have beenreported to occur in a limited number of patientsin several studies [38], but muscle weakness wasnever reported in our selected articles. The articlesreporting muscle weakness were not included inour systematic literature review because theyconcerned studies with injection into the urethralsphincter [5,39], relating to both Botox and Dysport[40], or case reports [41]. Muscle weakness ispossibly a dose-related effect or related to repeatinjection intervals or injection techniques (eg, dueto perforation of the detrusor muscle duringinjection and local diffusion in the neighbouringstructures). If this systemic AE occurs, it is self-limiting and lasts for 3 mo. To adequately assess theincidence of specific AEs and prevent under-evaluation, future studies should put more effortinto adequate documenting and reporting of localand systemic AEs.

Lastly, the optimal policy for reinjections andwhen patients should return for repeat injectionare questions of utmost importance. Three mainoptions may be evaluated and compared: (1) rein-jection after a predefined time interval of 8–9 mobased on literature data on duration of effect, (2)reinjection after the same time as the first injectionwas active, which takes into account interindividualvariation, and (3) reinjection only based on symp-toms or urodynamic worsening. In our opinion, it isat least clear that patients suffering from NDO/NOAB should not receive repeated injections in caseof persistence of compliance problems, no or limitedurodynamic or symptomatic improvement after twoinjection sessions, or severe AEs whatever theinjection number was.

To further improve the future application ofBotox, we believe that research should focus onassessing the optimal dose (including dilutionvolume and number of injections) of Botox, also in

terms of onset and duration of effect/timing ofrepeated injections and in patients not on CIC. Thecurrent reporting of data does not allow us todiscriminate as to whether the effect on incon-tinence and duration of effect are only due to Botoxor are also due to adjuvant use of antimuscarinics. Itmay also be that combination therapy is morebeneficial or may allow the use of lower doses ofantimuscarinics or Botox (with a lower rate of AEs).All of these questions should be of help in preparingfurther adequately powered, well-designed, rando-mised, controlled trials.

5. Conclusions

We can conclude that treatment with Botox intra-detrusor injections provides a clinically significantbenefit to adults with NDO/NOAB resistant toantimuscarinics. The onset of effect is fast (within1–2 wk) and after reinjection (time interval betweeninjections approximately 8–9 mo), the effect on theclinical and urodynamic variables persists. More-over, treatment with Botox seems to be very welltolerated with minimal injection site and systemicside-effects. Therefore, this treatment exhibits avery promising risk-to-benefit ratio for chronictreatment of NDO/NOAB. However, adequatelypowered, well-designed, randomised, controlledtrials are still lacking and a number of questionsneed to be investigated further. The optimal dosewith the longest duration of efficacy and acceptablelevel of AEs, the timing and indications for repeatinjection, and the type of patients benefiting mostneed to be further clarified. Future studies shouldalso put more effort into adequate reporting anddocumenting of AEs.

Conflicts of interest

G. Karsenty is a consultant for Allergan andMedtronic. P. Denys is a consultant for Allergan,Medtronic, and Ono Pharma. F. Haab is a consultantfor Bayer, Astellas, Pfizer, and Allergan. E. Chartier-Kastler is a consultant for Allergan, Medtronic,Astellas, and Coloplast.

Acknowledgements

The authors are grateful to Ismar Healthcare NV,Belgium for conducting the systematic literaturesearch and for providing assistance with dataextraction and editing of the manuscript.

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 2 7 5 – 2 8 7286

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