european urology 53 (2008)

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1 european urology 53 (2008) available at journal homepage: Review Neuro-urology Botulinum Toxin A (Botox W ) Intradetrusor Injections in Adults with Neurogenic Detrusor Overactivity/Neurogenic Overactive Bladder: A Systematic Literature Review Gilles Karsenty a, Pierre Denys b,gérard Amarenco c, Marianne De Seze d, Xavier Gamé e, François 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, * a Hôpital Sainte Marguerite, Marseille, France b Hôpital Raymond Poincaré, Garches, France c Hôpital Rothschild, Paris, France d Hôpital Pellegrin, Bordeaux, France e Hôpital Rangueil, Toulouse, France f Hôpital Tenon, Paris, France g Centre Mutualiste de Rééducation et de Réadaptation Fonctionnelles de Kerpape, Ploemeur, France h Hôpital St Jacques, Nantes, France i Hôpital Henry Gabrielle, Saint Genis Laval, France j Hôpital Civil, Strasbourg, France k Centre Bouffard Vercelli, Cerbère, France l Hôpital Universitaire Balgrist, Zurich, Switzerland m Hôpital Pitié-Salpêtrière, Paris, France Article info Article history: Accepted October 5, 2007 Published online ahead of print on October 16, 2007 Keywords: Botulinum toxin type A Cholinergic antagonist Overactive bladder Urinary bladder Neurogenic Urinary incontinence Urodynamics Abstract Objectives: This systematic literature review discusses the efficacy and safety of botulinum toxin type A (Botox 1 ) intradetrusor injections in adults with neurogenic detrusor overactivity (NDO) and urinary incontinence or overactive bladder symptoms of neurogenic origin (NOAB). Methods: A MEDLINE and EMBASE search for clinical studies with botulinum toxin A injected into the detrusor of adults with NDO was performed. For several efficacy and safety variables data were extracted by one person and independently quality-controlled by another person. Extracted data were reviewed to propose recommendations for use in clinical practice based on level of evidence and expert opinion. Results: A total of 18 articles evaluating the efficacy or safety of Botox in patients with NDO and incontinence/noab resistant to antimuscarinic therapy, 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, Hôpital Pitié-Salpêtrière, 83, Boulevard de L Hôpital, Paris, France. Tel ; Fax: address: emmanuel.chartier-kastler@psl.aphp.fr (E. Chartier-Kastler) /$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 276 european urology 53 (2008) injections of 10 U/ml in the bladder (excluding the trigone) under cystoscopic guidance and with different types of anaesthesia. Most of the studies reported a significant improvement in clinical (approximately 40 80% of patients became completely dry between CICs) as well as urodynamic (in most studies mean maximum detrusor pressure was reduced to 40 cm H 2 O) variables and in the patients quality of life, without major adverse events. Conclusions: Botox injections into the detrusor provide a clinically significant improvement in adults with NDO and incontinence/noab refractory to antimuscarinics. It seems to be very well tolerated. However, more adequately powered, well-designed, randomised, controlled studies evaluating the optimal dose, number and location of injections, impact on antimuscarinic regimen and CIC use, duration of effect, and when to perform repeat injections are warranted. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. 1. Introduction In patients with neurologic disorders, bladder dysfunction associated with detrusor overactivity (DO) constantly impairs quality of life (QoL) and often poses a threat for the upper urinary tract (UUT). Therefore, it represents a major health problem in this population. According to the standardisation of terminology of lower urinary tract function published by the International Continence Society (ICS), DO is a urodynamic observation characterised by involuntary detrusor contractions during the filling phase that may be spontaneous or provoked. When there is a relevant underlying neurologic condition (eg, spinal cord injury [SCI] or multiple sclerosis [MS]), this is qualified as neurogenic DO (NDO) [1]. Overactive bladder (OAB) is a symptom complex described as urgency, with or without urge incontinence, usually with frequency and nocturia [1]. Although OAB is not specific for any condition or urodynamic finding, patients with OAB are often found to have DO. Oral antimuscarinic agents have been widely used as firstline treatment for patients with NDO or neurogenic OAB (NOAB). However, they are ineffective in some patients or can cause troublesome systemic sideeffects such as dry mouth, constipation, and blurred vision. Intravesical treatment strategies may provide alternatives to achieve a profound inhibition of NDO and to avoid high systemic drug levels. Botulinum toxin (BTX), first isolated by van Ermengem [2] in 1897, is a potent neurotoxin produced by the gram-positive anaerobic bacterium Clostridium botulinum. From a structural viewpoint, the toxin is a 150-kD amino acid di-chain molecule consisting of a light (50 kd) and a heavy chain (100 kd), which are linked by a disulfide bond. The role of BTX at the neuromuscular junction has been well described and consists of inhibition of acetylcholine neurotransmitter release resulting in striated muscle relaxation [3]. However, increasing evidence suggests a much greater range of neurologic effects of BTX. BTX has been found to inhibit the release of a number of neurotransmitters (including acetylcholine, adenosine triphosphate, and neuropeptides such as substance P) and to down-regulate the expression of purinergic and capsaicin receptors on afferent neurons within the bladder [4]. These data support the belief that BTX works to treat DO and OAB by both sensory and motor pathways. Of the seven distinct but structurally similar serotypes of BTX, types A and B have been used with clinically beneficial outcomes in various neurologic disorders. The serotype A product, BTX-A, was first investigated in 1990 for the treatment of detrusor external sphincter dyssynergia in patients with SCI [5]. Following its success for this indication, the effect of injecting BTX-A into the detrusor muscle of patients with NDO was first presented at the ICS meeting in 1999 by Stöhrer and Schurch [6]. Although BTX-A is not yet approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMEA) for the treatment of patients with NDO or NOAB, two toxins are commercially available (Botox 1, Allergan, Irving, CA, USA and Dysport 1, Ipsen-Biotech, Paris, France). The use of BTX-A in the treatment of patients with NDO aims to improve urinary symptoms, to reduce UUT risk and to improve QoL. It has been developed as a second-line treatment option (ie, intolerance or failure after treatment and evaluation with an appropriate dose and for an appropriate period [minimal 2 mo] of antimuscarinics) for patients with NDO with urinary incontinence or other NOAB symptoms able and willing to perform clean intermittent (self)-catheterisation (CIC). Patients with clear contraindications to BTX-A (eg, patients with

3 european urology 53 (2008) myasthenia gravis) should be excluded from treatment. There is currently no clear consensus about the optimal use of this innovative treatment in clinical practice. Issues of optimal dose, number and location of injections, type of cystoscope and anaesthesia required depending on patient aetiology, timing of repeat injection, and safety could have an important impact on clinical outcomes and need further investigation. Based on the results of a systematic literature review of clinical studies evaluating the efficacy or safety (or both) of BTX-A in adults with NDO/NOAB and subsequent clinical expert discussion of the outcomes, this review paper will provide more insight into these topics on an evidence-based medicine level. We will only discuss the use of Botox, because Botox and Dysport are biologic products that differ in terms of pharmacodynamic features (due to variability in neurotoxin-derived bacterial strain, excipients, and manufacturing process) and dose contained in each vial [7 9]. Several studies have demonstrated that this leads to significant 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 Englishlanguage clinical studies on BTX-A. In MEDLINE, the search for retrieving the references was performed by exploding and combining the following medical subject 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 ( ) 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 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 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 [Pdet max ], maximum cystometric 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 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 EMBASE search 58 English-language papers on the use of BTX-A for NDO/NOAB. After applying the selection criteria and checking the reference list of several review articles [7,8,13 16] to pick up any missed articles/studies, a total of 18 articles concerning clinical studies with Botox were selected (Table 1) Study and patient characteristics Of the 698 patients included in the 18 selected studies (Table 1), 83% had NDO with urinary incontinence and/or NOAB (mainly due to SCI [57%] and MS [17%]) and refractory to usually high doses of antimuscarinic agents. Only three studies also enrolled patients with idiopathic DO (IDO) or bladder outlet obstruction (BOO). In 13 of 18 articles, the initial bladder emptying modality was specified; it was CIC in 84% of these patients. Most studies were small-scale studies enrolling fewer than 50 patients. There were three larger-scale studies: Schurch et al [17] enrolled 59 patients in a doubleblind, randomised, placebo-controlled, three-arm,

4 278 european urology 53 (2008) Table 1 Study and patient characteristics of articles selected for systematic literature review on Botox in adults with NOAB First author No. of patients Neurogenic disorder Study design Level of evidence No. on CIC before treatment Amount of Botox, U Active treatment mean follow- up, wk (Mean) duration of effect, wk Schurch [17] 59 SCI: n = 53 Randomised, 1b a 24 At least 24 MS: n = 6 placebocontrolled 300 Giannantoni [18] 75 SCI Randomised, active comparatorcontrolled 1b b 112 c 35 (per injection) Karsenty [20] 17 SCI: n = 16 Open-label MS: n =1 Schulte-Baukloh [21] 16 MS Open-label and 24 At least 12 Kalsi [22] 32 MS: n = 24 Open-label At least 16 SCI: n =2 Other: n =6 Giannantoni [23] 23 SCI Open-label 3 Unknown At least 12 Kuo [24] 24 CVA: n = 12 Open-label SCI: n =7 MS: n =4 Other: n =1 Klaphajone [25] 10 d SCI: n = 9 Open-label and 36 At least 16 Other: n =1 Popat [26] 44 MS: n = 29 Open-label At least 16 SCI: n =5 Other: n =10 Kessler [27] 11 SCI: n = 2 Open-label 3 Unknown MS: n =3 Other: n =6 Hajebrahimi [28] 10 SCI Open-label At least 12 Smith [29] 42 SCI: n = 1 Open-label 3 Unknown At least 24 MS: n =16 CVA: n =2 IOAB: n =17 Other: n =6 Bagi [30] 15 SCI Open-label Kuo [31] 30 NOAB: n = 12 Open-label 3 Unknown IOAB: n =8 BOO: n =10 Reitz [19] 200 SCI: n = 167 Open-label e and 36 At least 36 MS: n =11 Other: n =22 Harper [32] 39 NOAB Open-label 3 Unknown and 16 IOAB 300 Kennelly [33] 10 SCI: n = 6 Open-label , 12, and MS: n =4 Schurch [34] 21 SCI Open-label 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.

5 european urology 53 (2008) Table 2 Botox injection protocol characteristics First author Dilution, U/ml Type of cystoscope Injection sites No. of injections Type of anaesthesia Schurch [17] 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 Base a 40 General Klaphajone [25] 20 Flexible Dome and base 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 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 Local Kennelly [33] 10 Rigid Dome and base 30 Intravenous sedation Schurch [34] 10 Rigid Dome None or local a Suburothelial injection. parallel group study; Giannantoni et al [18] enrolled 75 patients in a randomised, resiniferatoxin-controlled, 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 by Schurch et al [17] and the study with resiniferatoxin as active comparator by Giannantoni et al [18]. Follow-up ranged from 12 up to 36 wk, except for two studies evaluating the impact of repeated injections, which lasted 2 4 yr [18,20] Injection protocol In most of the studies (11 of 18), the amount of Botox injected was 300 U (Table 1), usually as 30 injection sites (range: 15 40) of 10 U/ml (range: U/ml) in the bladder (usually sparing the trigone) under cystoscopic guidance (flexible or rigid) and with different types of anaesthesia (none, local, spinal, or general; Table 2). A few trials used doses of 200 U (2 studies), U (3 studies), U (1 study), or 400 U (1 study). Table 3 Impact of Botox on the number of incontinence episodes/24 h First author No. of patients (on CIC) Mean baseline Mean end point Mean change vs. baseline Mean % change vs. baseline Schurch [17]: 24wk Placebo 21 (21) Botox U 19 (19) * 58 Botox U 19 (19) *,y 32 Giannantoni [18]: 26wk Resiniferatoxin 35 (35) *** 57 Botox U 40 (40) ***,y 77 Karsenty [20] First injection 17 (13) Last injection a 17 (13) Kalsi [22]: 16 wk 32 (14) *** 85 Giannantoni [23]: 12 wk *** 63 Popat [26]: 16 wk 44 (31) *** 68 CIC = clean intermittent catheterisation. a Mean number of 5.4 injections with mean time interval between injections mo. * p < *** p < y Significant vs. placebo or resiniferatoxin.

6 280 european urology 53 (2008) Fig. 1 Percent of patients who became completely continent [17 19,23 28,30,31,33,34] Efficacy Clinical variables: frequency, leakage, and QoL In the studies reporting the impact of Botox on the daily frequency of urinary incontinence episodes, the mean number of daily incontinence episodes was between two and five with most patients being on CIC (Table 3). The two controlled studies demonstrated that the efficacy of Botox is significantly superior to that of both placebo (level of evidence 1b) and resiniferatoxin (level of evidence 1b; Table 3) [17,18]. Open-label case series confirmed this trend (level of evidence 3; Table 3) [20,22,23,26]. Up to 26 wk after Botox injection, the percentage reduction in the mean number of daily urinary incontinence episodes (between CICs) from baseline was approximately 60 80%. Furthermore, between 42% and 87% of patients became completely continent (between CICs) after Botox treatment (if the outliers of 8% in the two studies by Kuo et al [24,31], which included a high percentage of patients with a cerebrovascular accident [CVA] or IDO/BOO, are disregarded; Fig. 1) [17 19,23,25 28,30,33,34]. The mean number of daily micturition (ie, frequency) episodes was also reduced from baseline by approximately 40 60% (data not shown) [21 23,26,27,29]. The decrease in frequency and leakage was associated with an improvement in the patients QoL by 35 65% versus baseline (Fig. 2) [17,21,22,31], which was significantly superior to the effect of placebo [17]. In some studies, the impact of Botox on the use of antimuscarinic agents was also documented [19,23,26,30,33,34]. In studies in which patients were instructed to reduce the dose of or discontinue antimuscarinic treatment, the antimuscarinic agents could be discontinued in 28 58% of Fig. 2 Percent mean change in quality of life [17,21,22,31]. UDI-6 = Urogenital Distress Inventory; SSI = Symptom Severity Index; SII = Symptom Impact Index; I-QOL = Incontinence Quality of Life Questionnaire; I-PSS = International Prostate Symptom Score.

7 european urology 53 (2008) Table 4 Impact of Botox on Pdet max (cm H 2 O) First author No. of patients Mean baseline Mean end point Mean change vs. baseline Mean % change vs. baseline Schurch [17]: 24wk Placebo Botox 200 U *,y 50 Botox 300 U *,y 38 Giannantoni [18]: 26wk Resiniferatoxin Botox 300 U ** 44 Karsenty [20] First injection *** 62 Last injection a *** 65 Schulte-Baukloh [21] 12 wk 16 b ** wk 16 b * 57 Kalsi [22]: 16 wk *** 54 Giannantoni [23]: 12 wk *** 61 Kuo [24]: 12wk CVA SCL Klaphajone [25] 16 wk *** wk * 24 Popat [26]: 16wk 44 c *** 42 Kessler d [27]: 1 wk ** 40 Hajebrahimi [28]: 12 wk Smith [29]: 24 wk Bagi [30]: 6 wk *** 59 Reitz [19] 12 wk *** wk *** 28 Kennelly [33] 6 wk wk wk Schurch [34] 6 wk * wk e * 44 Pdet max = maximum detrusor pressure. a Mean number of 5.4 injections with mean time interval between injections 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 < ** p < *** p < y Significant versus placebo or resiniferatoxin. patients [19,26,33,34]. In most other patients, the dose could be reduced Urodynamic variables A positive impact of Botox on urodynamic variables was also demonstrated. Table 4 shows the impact on Pdet max. The mean Pdet max at baseline was in general between 60 and 80 cm H 2 O. The two controlled studies showed that Botox was significantly superior in reducing Pdet max compared to both placebo and resiniferatoxin [17,18]. The other open-label studies confirmed the positive impact of Botox on Pdet max [19 30,33,34]. The percentage mean reduction in Pdet max from baseline was approximately 40 60%, if for each study the largest reduction over time was considered and some

8 282 european urology 53 (2008) Fig. 3 Mean maximum detrusor pressure (Pdet.max ) at end point (lowest value per study included) [17 30,33,34]. outliers were disregarded (some of the outlier studies again included a high percentage of patients with a CVA or IDO [24,29]). Moreover, in most of the studies mean Pdet max was reduced with Botox to <40 cm H 2 O, which is generally regarded as the desired Pdet max for UUT protection [35] (Fig. 3). The reduction in Pdet max was accompanied by an increase in MCC (Table 5), which was superior to that of placebo [17] and resiniferatoxin [18]. The mean MCC at baseline was, in general, between 175 and 300 ml. In most studies, the percentage increase in mean MCC from baseline ranged between 40% and 60% with increases of % in studies of patients with a relatively low mean MCC at baseline [17 34]. Many studies also assessed the RDV, which was significantly increased from baseline with Botox [17 21,23 25,28,33,34]. Bladder compliance is a urodynamic variable useful to monitor long-term safety of Botox as well as an outcome variable in patients with NDO. Although the mean baseline value was normal in the majority of studies (in 4 of the 6 studies that reported bladder compliance the mean baseline value was >20 ml/cm H 2 O), the bladder compliance also increased with treatment compared to baseline [19,20,25,27,33,34] Onset, time to maximum, and duration of effect/timing of repeat injections The study by Schurch et al [17] noticed significant improvements versus placebo in the number of incontinence episodes, QoL, and urodynamic parameters within 2 wk after Botox injection. These benefits reached their maximum between 2 and 6 wk and were maintained throughout the 24-wk study period [17]. Several other open-label studies confirmed that these improvements were significant versus baseline at the first assessment after 2wk[31] or 4 wk [21,24,26] or even within the first week [27] with maximum effects obtained between 1 and 4 wk [29]. A recent study by Karsenty et al [20] reported on the persistence of effect after repeated injections in 17 patients who received at least two repeat injections. The success of the first injection was defined as a decrease in the number of incontinence episodes per day and improvement in MCC, Pdet max, and RDV. Repeated injections were usually done when the patient reported recurrent leakage and a concomitant UTI had been excluded. The mean time interval between repeated Botox injections ranged between 7.6 and 9.1 mo (approximately 36 wk) with sustained efficacy both in terms of diary changes and urodynamic variables. In another longer term study by Giannantoni et al [18], the efficacy of Botox was also sustained for 36 wk (approximately 8 9 mo) after which repeat injection was needed. A few other studies indicated that the efficacy may decrease faster (after wk) [19,25,33]. This may, in particular, apply to patients with low bladder compliance [25]. In studies evaluating QoL significant improvements were noticed up to wk after treatment [17,21,22,31] Safety Botox was well tolerated in all 18 studies. Although the occurrence of local or systemic AEs was not very well reported in most of the studies, most frequent AEs appeared to be injection site pain [17],procedure-

9 european urology 53 (2008) Table 5 Impact of Botox on MCC (ml) First author No. of patients Mean baseline Mean end point Mean change vs. baseline Mean % change vs. baseline Schurch [17]: 24wk Placebo Botox 200 U * 67 Botox 300 U y 32 Giannantoni [18]: 26wk Resiniferatoxin ** 40 Botox U **,y 54 Karsenty [20] First injection *** 43 Last injection a *** 32 Schulte-Baukloh [21] 12 wk 16 b * wk 16 b Kalsi [22]: 16 wk *** 166 Giannantoni [23]: 12 wk *** 86 Kuo [24]: 12wk CVA SCL Klaphajone [25] 16 wk ** wk Popat [26]: 16wk 44 c *** 181 Kessler d [27]: 1 wk ** 116 Hajebrahimi [28]: 12 wk * 74 Smith [29]: 24 wk * 61 Bagi [30]: 6 wk Kuo [31]: 12wk 30 e Reitz [19] 12 wk *** wk *** 29 Harper [32]: 16 wk Kennelly [33] 6 wk ** wk ** wk Schurch [34] 6 wk * wk f * 54 MCC = maximum cystometric capacity. a Mean number of 5.4 injections with mean time interval between injections 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 < ** p < *** p < y Significant versus placebo or resiniferatoxin. 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 residual potentially 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 the studies. The only study in which AEs were reported in a structured way was the placebo-controlled study by Schurch et al [17], which confirmed injection site pain and UTI as the most frequent AEs (Table 6). All patients were on CIC before treatment with Botox and

10 284 european urology 53 (2008) Table 6 Treatment-emergent AEs reported in the placebo-controlled study by Schurch et al [17] AE therefore de novo CIC did not occur. In two studies, Botox was injected in the trigone but the occurrence of vesicoureteral reflux (VUR) was not reported [21,29]. 4. Discussion 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. From this systematic literature review, we can conclude that injection of Botox into the detrusor of adults with NDO and urinary incontinence or other NOAB symptoms who have failed antimuscarinic therapy has beneficial effects both on clinical and urodynamic variables. Complete continence was achieved in approximately 40 80% of patients and in most studies mean Pdet max was reduced to or <40 cm H 2 O. The most commonly used dose of Botox is 300 U. Schurch et al [17] found that both doses of 200 and 300 U Botox induced significant decreases in incontinence episodes and improved urodynamics and QoL compared to placebo, suggesting that lower doses could be used. However, no conclusions could be reached regarding the optimal dose because the study was not powered to detect significant differences between the doses. Kuo et al [24] also reported beneficial results with 200 U Botox in patients with SCI. Except for one study using 400 U Botox [28], higher doses have not been investigated. As a consequence, it is still not fully clear whether the dose 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 injections to, for example, 10 at the same dose of 300 U, efficacy remains but with a less painful and faster injection procedure [36]. The long-term risk of fibrosis may also be reduced but the risk of a false puncture in terms of systemic AEs may be increased and should therefore be assessed. It may be worthwhile to investigate these potential differences between 10 and 30 injections of a dose of 300 U in future studies. Botox has been injected directly into the detrusor in almost all studies. One study performed suburothelial injections to take advantage of the presumed effect on afferent sensory nerves [24]. Most studies reported spared the trigone, whereas two studies injected the trigone without reporting cases of VUR [21,29]. Based on this we believe that currently intradetrusor injection sparing the trigone is still the reference location. Other variables of the technique are the type of cystoscope and anaesthesia used. There is no study that compares efficacy or tolerance of Botox injections when using a rigid or a flexible cystoscope. Although both types of cystoscopes (flexible and rigid) have been used, rigid ones were the most commonly used. However, in our opinion a flexible cystoscope may have an advantage in men with preserved sensibility or, independent of gender, in patients with SCI with a lesion above T6 because reduction of pain or stimulation prevents autonomic dysreflexia [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 choice of the patient and the surgeon, depending mainly on bladder and urethral sensation. General anaesthesia may be considered for extremely anxious or sensitive patients and for neurogenic patients who are at risk for autonomic dysreflexia. In adults with NDO/NOAB, with or without CIC, Botox has a fast onset of action with significant effects reached within 1 2 wk and maximum effects within 4 6 wk. The longer term repeat injection studies suggest that the effect of an intradetrusor injection of Botox lasts for 36 wk or approximately 8 9 mo [18,20]. Of the shorter term studies running for wk some showed also sustained efficacy until 36 wk, whereas a few showed worsening in efficacy between 12 and 24 wk. The duration of effect should therefore be further clarified in specifically designed studies. In some studies, the dose of antimuscarinics could be reduced or even discontinued. However, for the vast majority of studies the antimuscarinic regimen used throughout the study was not clearly described and therefore its potential impact on the efficacy of Botox cannot be assessed. Therefore, future studies should better describe the antimuscarinic regimen and the policy of dose reduction after treatment to determine whether adjuvant antimuscarinic drugs have an impact on the efficacy or duration of effect of Botox. An important question to be answered is how Botox should, based on the currently available data and physician experience, best be applied in clinical practice? In our opinion, patients with symptoms related to NDO who have failed antimuscarinic therapy and are on or willing and able to perform CIC seem to be eligible candidates for Botox treatment.

11 european urology 53 (2008) Before the injection, urologists should adequately inform the patient about the potential risk of Botox-related AEs. Although in most articles reporting of AEs could have been more structured, the most frequent AEs of Botox seem to be injection site pain, procedure-related UTI, and (mild) haematuria. Sometimes an increase in postvoid residual resulting in UR or de novo CIC also occurred. However, in this population with DO from neurogenic origin the majority of patients have difficulty emptying their bladder. CIC is therefore required and we consider UR induced by Botox as less of a problem. Among patients with preserved voiding, it will be important to know the proportion of patients with UR and need for CIC, which is not clearly described in the literature. AEs such as muscle weakness and vision disturbances have been reported to occur in a limited number of patients in several studies [38], but muscle weakness was never reported in our selected articles. The articles reporting muscle weakness were not included in our systematic literature review because they concerned studies with injection into the urethral sphincter [5,39], relating to both Botox and Dysport [40], or case reports [41]. Muscle weakness is possibly a dose-related effect or related to repeat injection intervals or injection techniques (eg, due to perforation of the detrusor muscle during injection and local diffusion in the neighbouring structures). If this systemic AE occurs, it is selflimiting and lasts for 3 mo. To adequately assess the incidence of specific AEs and prevent underevaluation, future studies should put more effort into adequate documenting and reporting of local and systemic AEs. Lastly, the optimal policy for reinjections and when patients should return for repeat injection are questions of utmost importance. Three main options may be evaluated and compared: (1) reinjection after a predefined time interval of 8 9 mo based on literature data on duration of effect, (2) reinjection after the same time as the first injection was active, which takes into account interindividual variation, and (3) reinjection only based on symptoms or urodynamic worsening. In our opinion, it is at least clear that patients suffering from NDO/ NOAB should not receive repeated injections in case of persistence of compliance problems, no or limited urodynamic or symptomatic improvement after two injection sessions, or severe AEs whatever the injection number was. To further improve the future application of Botox, we believe that research should focus on assessing the optimal dose (including dilution volume and number of injections) of Botox, also in terms of onset and duration of effect/timing of repeated injections and in patients not on CIC. The current reporting of data does not allow us to discriminate as to whether the effect on incontinence and duration of effect are only due to Botox or are also due to adjuvant use of antimuscarinics. It may also be that combination therapy is more beneficial or may allow the use of lower doses of antimuscarinics or Botox (with a lower rate of AEs). All of these questions should be of help in preparing further adequately powered, well-designed, randomised, controlled trials. 5. Conclusions We can conclude that treatment with Botox intradetrusor injections provides a clinically significant benefit to adults with NDO/NOAB resistant to antimuscarinics. The onset of effect is fast (within 1 2 wk) and after reinjection (time interval between injections approximately 8 9 mo), the effect on the clinical and urodynamic variables persists. Moreover, treatment with Botox seems to be very well tolerated with minimal injection site and systemic side-effects. Therefore, this treatment exhibits a very promising risk-to-benefit ratio for chronic treatment of NDO/NOAB. However, adequately powered, well-designed, randomised, controlled trials are still lacking and a number of questions need to be investigated further. The optimal dose with the longest duration of efficacy and acceptable level of AEs, the timing and indications for repeat injection, and the type of patients benefiting most need to be further clarified. Future studies should also put more effort into adequate reporting and documenting of AEs. Conflicts of interest G. Karsenty is a consultant for Allergan and Medtronic. P. Denys is a consultant for Allergan, Medtronic, and Ono Pharma. F. Haab is a consultant for 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 literature search and for providing assistance with data extraction and editing of the manuscript.

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