Botulinum-AToxin Detrusor and Sphincter Injection in Treatment of Overactive Bladder Syndrome: Objective Outcome and Patient Satisfaction

European Urology European Urology 48 (2005) 984 990 Botulinum-AToxin Detrusor and Sphincter Injection in Treatment of Overactive Bladder Syndrome: Objective Outcome and Patient Satisfaction Heinrich Schulte-Baukloh a, *, Catarina Weiß a, Thomas Stolze a, Jaqueline Herholz a, Burkard Stürzebecher a, Kurt Miller b, Helmut H. Knispel a a Department of Urology, St. Hedwig Hospital, Teaching Hospital of Charité University Hospital, Grosse Hamburger Str. 5-11, 10115, Berlin, Germany b Department of Urology, University Hospital Charité, Campus Benjamin Franklin, Berlin, Germany Accepted 30 June 2005 Available online 18 July 2005 Abstract Objective: We investigated the effect of botulinum-a toxin injections into the detrusor and external sphincter muscle in patients with overactive bladder (OAB) symptoms. Methods: We included 44 patients - 41 women and three men with a mean age of 66.1 years - who were suffering from OAB symptoms that were refractory to anticholinergic treatment. We injected 200 300 U of BTX-A (Botox 1 ) into the detrusor muscle; 22 patients also received external sphincter injections. For outcome analysis, we used a bladder diary, a urodynamic examination, and a questionnaire that consisted of 27 validated questions. Results: Changes in the bladder diary 4 weeks and 3, 6, and 9 months after BTX-A injection were as follows: Micturition frequency was reduced by 12%, 16%, 13% and 9%, respectively. Average pad use decreased from 4.2 pads per day to at most 2.4 pads per day after 6 months. Urodynamic changes were most distinct after 4 weeks: the volume when the first uninhibited detrusor contraction occurred increased from 149 18.2 ml to 263 24.2 ml, and maximum cystometric bladder capacity increased from 228 19.2 ml to 305 19.0 ml. Subjectively, 86% of the patients would choose this procedure for their bladder condition again. Residua 4 weeks after additional injection into the sphincter muscle were distinctly smaller than in the only detrusor group. Conclusions: BTX-A detrusor and sphincter injection is very effective in treating OAB symptoms. For patients who might be expected to have residual urine after injection only into the detrusor, additional injection of low doses of BTX-A into the external sphincter muscle could be one option to reduce that risk. # 2005 Elsevier B.V. All rights reserved. Keywords: Detrusor; Detrusor overactivity; Overactive bladder syndrome; OAB; Botulinum toxin; Botox The International Continence Society (ICS) defines overactive bladder (OAB) syndrome as a medical condition that consists of urinary frequency and urgency with or without urge incontinence in the absence of local pathologic factors [1]. OAB substantially affects quality of life [2]. Large survey studies found the prevalence of OAB in the United states and Europe to be 16 17% [3,4]. Although OAB can occur at any age, its prevalence * Corresponding author. Tel. +49 30 2311 2509; Fax: +49 30 2311 2434. E-mail address: hschultebaukloh@hotmail.com (H. Schulte-Baukloh). increases with age and is higher in women than men [4,5]. Various age-related changes in cell function, structural integrity, central nervous control, and hormone balance seem to be contributing factors [6,7]. Besides behavior therapy, biofeedback, and neuromodulation, especially anticholinergics are the mainstay of conservative treatment of OAB [8 12]. However, side effects or lack of effectiveness can lead to discontinuation of treatment in at least 25% of patients [13,14]. Botulinum toxin (BTX) is becoming more and more established in treatment of dysfunctional voiding of 0302-2838/$ see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2005.06.021

H. Schulte-Baukloh et al. / European Urology 48 (2005) 984 990 985 any origin. Reports of its use in urology date to 1988, when Dykstra et al. first reported the use of BTX-A in treatment of neurogenic detrusor sphincter dyssynergia (DSD) [15], but Schurch et al. [16] were the first to successfully treated neurogenic detrusor overactivity in spinal-cord-injured patients whose condition was refractory to anticholinergic drugs. There have also been reports of BTX detrusor injections in patients who have non-neurogenic OAB [17 22]. It is not uncommon for these patients to build up residual volume after exclusive detrusor injection, sometimes even requiring temporary catheterization [18 21]. Encouraged by our good experience with detrusor injections in children who had neuropathic bladder due to meningomyelocele [23], we conducted this study in adults who had non-neurogenic OAB. We were interested in an extended objective and subjective outcome analysis and an exploration of the benefits of additional external-sphincter injection in these patients. 1. Material and methods We included 41 women and three men in our 3-year prospective one-center study, which ran from January 2001 to December 2004. Their average age was 66.1 years (range, 30 91 years; median, 67 years). Inclusion criteria were OAB symptoms according to the ICS definition [1], such as increased daytime frequency, nocturia, and urgency with or without urge incontinence. Before inclusion, the symptoms had been shown to be refractory to several anticholinergic drugs and to such therapy as behavior, biofeedback, or neuromodulating therapy. Patients were asked to write in a standardized bladder diary. At the initial visit, we took a detailed history, conducted physical and neurourologic examinations, and performed laboratory studies of urine to exclude urinary infection. Vaginal examination was conducted to exclude anatomic abnormalities, such as pelvic-organ prolapse, and cystoscopy. Postvoiding residual volume was measured by catheterization within the context of the urodynamic examination. During that urodynamic examination, the reflex volume (the volume when the first uninhibited bladder contraction occurred), the volume when a strong desire to void was expressed, the maximum detrusor pressure, and the maximum cystometric bladder capacity were measured. We followed the recommendations of the ICS Standardization Committee [1] regarding urodynamic techniques strictly. Anticholinergic medication were stopped at least 14 days before enrollment except in four patients, in whom this medication had some benefit and who did not want to relinquish on it; the medication then had to be taken by those four patients in the same dosage over the entire study to ensure clear data. For our urodynamic studies, bladderfilling rate was 20 ml/min. We assessed subjective improvement in lower urinary tract symptoms after BTX-A therapy with three validated questionnaires that the patients were given at each visit. The Urogenital Distress Inventory (UDI-6) provides information on OAB symptoms, stress urinary incontinence, and symptoms of bladder outlet obstruction in women; the overall symptom score ranges from 0 (no symptoms) to 18 (very bothersome symptoms) [24]. The Symptom Severity Index (SSI) and the Symptom Impact Index (SII) [25] are valid and reliable instruments for assessing the severity of incontinence and its effect on patient s lives. The SSI investigates symptoms of incontinence itself (frequency, amount of urine leakage, activities that precipitate incontinence, and so on). The SII aims more at the daily activities and social activities that are restricted by incontinence. The SSI score ranges from 0 (no symptoms) to 20 (always symptoms), and the SII score from 0 to 13. To exclude possible influence by a doctor or a nurse, the questionnaires were filled out by the patients alone. For injection therapy, we used 200 300 U of Botox 1 (Allergan, Irvine, California). The BTX-A was diluted to 20 ml of normal saline. The toxin was injected transurethrally with a rigid cystoscope and a 6 Fr injection needle (Wolf 1 endoscopes, Germany) into 40 50 sites of the detrusor muscle. Before this study, we were used to sparing the trigone to avoid vesicoureteral reflux [23], assuggested by Schurch et al. [16]. Nowadays, we inject BTX-A into all sites of the detrusor muscle without excluding the trigone, because Chancellor et al. [17] could not find any iatrogenic reflux in OAB patients in whom he had injected BTX-A into the bladder base and the trigone. Patients who had even small amounts of residua (15 ml) (n = 22) also received a quadrant injection (50 100 U) in the external sphincter to circumvent postoperative urine retention and the need for self-catheterization; patients who we thought were at higher risk for urine retention, in particular because of distinct preoperative residua, received higher doses. Nevertheless, a total of 300 U of Botox 1 was never exceeded. The procedure was done under general, spinal, or local anesthesia in combination with light sedoanalgesia. The local anesthetic was 50 ml of Lidocain 1%, which was placed in the bladder via a transurethral catheter and stayed there for at least 20 min; under these conditions, the procedure was tolerated without discomfort, but it can be used only for detrusor injections. After injection therapy, a 16 Fr transurethral silicone balloon catheter was placed for at least 6 hours. Patients were discharged from the hospital on the same or the following day. Urodynamic-followup visits took place regularly: at 4 weeks and then 3, 6, and 9 months after BTX-A injection. For every followup visit, the bladder diary had to be used again for 3 days. At the 3-month followup visit, patients were asked to fill out, in addition, a postoperative satisfaction questionnaire as used by Choe et al. [26]. Values are given as means standard error of the means (SEM). For statistical analysis, we used the Wilcoxon pair-difference test, the Mann-Whitney test, and the Pearson chi-square test. We regarded p < 0.05 as statistically significant. The study protocol was approved by the local ethics committee of the Free University of Berlin. 2. Results Results are given as baseline values and the values after 1, 3, 6 and 9 months, respectively. 2.1. Bladder diary The daytime frequency (or nighttime frequency) changed from 9.67 0.60 (2.38 0.41) to 8.52 0.40 (2.00 0.24) (p < 0.05), 8.09 0.36 (1.57 0.18) (p < 0.05), 8.42 0.51 (1.82 0.35) (not significant), and 8.81 0.80 (1.75 0.35) (not significant). Maximum micturition volume increased from 227.03 25.46 ml to 258.98 24.22 ml (p < 0.05), 269.75

986 H. Schulte-Baukloh et al. / European Urology 48 (2005) 984 990 Fig. 1. Bladder diary before and relative changes 1, 3, 6 and 9 months after BTX-A injection therapy. Absolute values at baseline are given in bordeaux-colored columns; each was set at 100%. = p < 0.05; n.s. = not significant. 21.70 ml (p < 0.05), and 283.35 36.39 ml (not significant) and then decreased slightly to 220.56 35.15 ml (not significant). Pad use decreased from 4.22 0.53 pads per day to a minimum of 2.39 0.42 pads per day at 6 months (p < 0.05). For better visualization, the differences are shown in Fig. 1. 2.2. Urodynamics Urodynamic results - reflex volume, maximum detrusor pressure, and maximum cystometric bladder capacity (SEM) - are shown in Fig. 2. The volume when a strong desire to void was expressed by the patient increased from 194.42 19.10 ml to 302.57 19.66 ml, 266.59 25.75 ml, 301.50 26.01 ml, and 178.75 41.74 ml, respectively. 2.3. Validated incontinence questionnaires Assessment of subjective outcome indicated a clear reduction in the scores of the three evaluated instruments (UDI-6, SSI, and SII) at 4 weeks and 1, 3, and 6 months, namely, by 16.1% to 43%. The BTX-A effect had almost vanished at 9 months (Fig. 3). 2.4. Satisfaction questionnaire The overall rate of subjective response to the treatment was 86%. The scores on the satisfaction questionnaire (0 = completely dissatisfied to 10 = very satisfied) handed out at 3 months averaged 6.60 0.7. That is astonishing inasmuch as the question about urine control in comparison with the situation before injection therapy (1 = better, 2 = same, and 3 = worse) had an average answer of 1.30, and only 5.3% of the patients reported development of any complications after the procedure. Moreover, 86% of the patients would still choose the procedure for their bladder condition. No patient had to use a catheter to empty his or her bladder; but the question about the feeling of residual urine (0 = never to 3 = often) had an average answer of 1.16. 2.5. Comparison of outcome between detrusor injection alone and additional sphincter injection There were no significant differences between the two groups regarding micturition measures (daytime frequency and maximum voided volume), urodynamic measures (first uninhibited detrusor contraction, maximum detrusor pressure, and maximum cystometric capacity), or most of the evaluated questionnaires. However, the differences in detail were as follows: The increase in residua after BTX-A injection was indeed distinctly higher in the only detrusor group (D-only) than in the combined detrusor and sphincter (D + S) group at 4-weeks followup (Fig. 4). Regarding the development of de novo stress incontinence after additional injection into the sphincter muscle, the data are inconsistent. The reduction in pad use after injection therapy was significantly smaller in the D + S group ( 32%) than in the D-only group ( 44%) at four weeks followup (p = 0.023). Some questions were aimed at stress incontinence. There were no significant differences between the two groups in answers to question 3 of the UDI 6 ( urine leakage related to physical activity ) (p = 0.333) and question 5 of the SSI ( In the past week, how often have you

H. Schulte-Baukloh et al. / European Urology 48 (2005) 984 990 987 Fig. 3. Significant relative changes in Urogenital Distress Inventory (UDI- 6), Symptom Severity Index (SSI), and Symptom Impact Index (SII) 1, 3, and 6 months after BTX-A injection therapy (p < 0.05); 9-month changes compared with initial values were nonsignificant. Absolute score values at baseline are given in box; each was set at 100%. Fig. 4. Changes in residua before and after detrusor injection alone (D-only; n = 22) or combined with sphincter injection (D + S, n = 22). = p < 0.05; n.s. = not significant. Fig. 2. (a c) Urodynamic measures before and 1, 3, 6, and 9 months after BTX-A injection therapy. = p < 0.05; n.s. = not significant. leaked urine ) (p = 0.853). However, there was a slight difference in the answer to question 4 of the UDI-6 ( loss of small amounts of urine leakage (drops) ) at 3 months: a little bit was ticked slightly more often by the D + S group (n = 3) than by the D-only (n =0) group (p = 0.22). Question 1 of the SSI ( How often do you wet or leak urine ) also was answered in the same way and showed no significant difference (p = 0.356). All together, the answers lead to the assumption that a slightly higher incidence of stress incontinence after additional injection into the sphincter muscle cannot be excluded. Nevertheless, there was no difference in overall satisfaction between the two groups (p = 0.274), so the reduction in urgency and frequency seems to outweigh by far the mild symptoms of de novo stress incontinence. The effect of BTX-A injection lasted 6 months in all the measures evaluated. There were no toxin-related systemic side effects or injection-related local side effects (such as gross hematuria) at any time of followup. 3. Discussion Schurch et al. (2000) reported about their experience with BTX-A detrusor injections in 24 adult patients who had neurogenic detrusor overactivity due to spinal- cord injury [16]. After injection of 300 U of Botox 1, there was significant improvement in all urodynamic measures. At 6-week followup, mean reflex volume increased from a baseline 215.8 90.4 ml to 415.7 211.1 ml, and maximal cystometric bladder

988 H. Schulte-Baukloh et al. / European Urology 48 (2005) 984 990 capacity increased from 296.3 145.2 ml to 480.5 134.1 ml. Complete continence was restored in most patients. The report represented a milestone in the management of drug-resistant neurogenic bladder dysfunction. Several reports followed and showed the good results of this new therapy in children as well [23]. Recently, the largest study ever made in this relatively new field was published by Reitz et al. in this journal [27]: the results of a multicenter study of 200 patients strongly supported the overwhelming benefits of BTX- A detrusor injections in neurogenic patients. Meanwhile, there have also been reports of the use of BTX in non- neurogenic patients who had OAB symptoms. Chancellor et al. [17] reported on the AUA 2003 about their experience in 10 patients who had refractory idiopathic OAB. Initial urodynamic studies revealed involuntary detrusor contraction in all patients. The authors injected 100 300 U of BTX- A (brand not mentioned) cystoscopically into the bladder base and the trigone. Followup validation was done with bladder diaries only. None of the patients developed urinary retention, and 80% indicated decreases in voiding frequency and incontinence episodes. The effect lasted about 6 months. A year later, the same author reported similar results in a larger cohort of patients [28]; only one patient with multiple sclerosis built up some residuum but without requiring catheterization. In that series, the risk of stress incontinence after sphincter injection was stated to be small, which is consistent with our experience. Recently, Rapp et al. [18] reported on 35 OAB patients who were treated with 300 U of Botox 1 detrusor injections and were followed only with the Incontinence Impact Questionnaire (IIQ-7) and UDI- 6 as used by us. Unfortunately, there was no urodynamic followup and no measurement of residual volumes. Their findings regarding the subjective benefit of BTX-A injections were similar to ours. Followup was 6 months, and the effect of BTX-A seemed to vanish gradually after that time. Another report of 30 patients who had voiding dysfunction of different causes was presented by Kuo [19]. All patients had frequency, urgency, and urge incontinence that were refractory to anticholinergic treatment. Only 200 U of Botox 1 was administered into the detrusor muscle. Followup was short, up to 3 months. The overall success rate was 73.3%. BTX-A injection had a major side effect: six patients (20%) had increased postvoiding residual urine volume, and these patients required clean intermittent catheterization for a month. Urine retention was also reported in two of 50 patients who were treated for OABbySchmidetal.[20]. This side effect was found even when the dose of Botox 1 was only 100 200 U. Urine retention with the necessity of self-catheterization, even if only transient, is one of the most serious side effects for patients and often leads to rejection of this therapeutic option. That is of major interest as long as BTX is not an approved therapy but only an off-label use. It remains a challenge to detect reliably the patients who are at risk for distinct postinjection residua and thus to choose the right dose of BTX. Insufficient bladder emptying can result from detrusor contraction that is dysfunctional with respect to hypocontractility or from some dysfunctional voiding, for example, due to detrusor-sphincter dysfunction, which could have been demonstrated in patients with OAB [29]. When we detected some, even small amounts of preoperative residual urine, we supposed that the patients might be at risk for higher and eventually symptomatic residua after BTX-A detrusor injection alone; for the reasons mentioned above, such a patient received additional sphincter injections and we feel that the value of this strategy has been confirmed inasmuch as recent reports of BTX-A detrusor injections in idiopathic detrusor overactivity showed patients to be at risk for the necessity of de novo clean intermittent self-catheterization or suprapubic urine drainage of up to 45% [21]. In our series, residua were clearly smaller in patients who received additional sphincter injections of 50 100 U. The incidence of de novo stress incontinence in these patients is not clear, because patients answers to questions bearing on this problem have been inconsistent. Transient stress incontinence after sphincter injections reportedly occurs in about one-third of patients [30]. In the largest study of BTX sphincter injections for voiding dysfunction, Kuo found that 10 of 103 patients developed transient stress incontinence [31]. However, incontinence is usually much briefer than the beneficial effect of the treatment. In our series, no patient complained seriously about de novo stress incontinence, and the satisfaction and overall incontinence scores did not vary between the group who had only detrusor injections and the group that also had sphincter injections. On the contrary, the patients had smooth voiding after treatment, and the newly aquired freedom due to lower frequency and less urge incontinence by far outweighed some possible transient dribbling due to stress incontinence. However, the reduction of frequency was only moderate: our inclusion criteria might have led to a negatively selected and difficult-to-treat patient group - that is, patients who did not sufficiently react on several anticholinergic drugs before.

H. Schulte-Baukloh et al. / European Urology 48 (2005) 984 990 989 Regarding systemic side effects of BTX-A injections in urology, those were reported as isolated cases when general muscle weakness occurred after BTX-A sphincter [15] and detrusor [32] injections. We can strongly confirm the good experience of others who are working in this field and who found BTX-A injections to be safe [16,17,19,27,31]. The reports in this relatively new field vary considerably regarding doses, injection technique, followup assessment of various measures, and so on. In this study, we could not find the perfect relation of how much BTX-A should be injected into the detrusor muscle and the sphincter muscle to get the best results with regard to reduction of most worrisome urgency and frequency, on the one hand, and increase in potentially symptomatic residua vs de novo stress incontinence, on the other hand. To learn more about optimal dosage, further and preferably multicenter studies seem to be most promising. 4. Conclusion Botulinum-a toxin is very effective in the treatment of overactive bladder symptoms. That can be demonstrated not only with bladder diaries and urodynamic examinations but also with extensive subjective incontinence and satisfaction questionnaires. For patients who might be expected to have residual urine after injection only into the detrusor, additional injection of low doses of BTX-A into the external sphincter muscle could be one option to reduce that risk. Transient de novo stress incontinence is not a major risk in these cases. Acknowledgments We thank our study nurse C. Lange for valuable cooperation. References [1] Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. 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Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology 2004;63:868 72. [20] Schmid DM, Schurch B, John H, Hauri D. Botulinum toxin injections to treat overactive bladder. Eur Urol 2004;2(suppl. 3):131. [21] Kessler TM, Danuser H, Schumacher M, Studer UE, Burkhard FC. Botulinum A toxin injections into the detrusor: An effective treatment in idiopathic and neurogenic detrusor overactivity? Neurourol Urodyn Mar 3 [online], 2005. [22] Harper M, Popat RB, Dasgupta R, Fowler CJ, Dasgupta P. A minimally invasive technique for outpatient local anaesthetic administration of intradetrusor botulinum toxin in intractable detrusor overactivity. BJU Int 2003 Aug;92(3):325 6. [23] Schulte-Baukloh H, Michael T, Sturzebecher B, Knispel HH. Botulinum-a toxin detrusor injection as a novel approach in the treatment of bladder spasticity in children with neurogenic bladder. Eur Urol 2003;44:139 43.

990 H. Schulte-Baukloh et al. / European Urology 48 (2005) 984 990 [24] Uebersax JS, Wyman JF, Shumaker SA, McClish DK, Fantl JA. Short forms to assess life quality and symptom distress for urinary incontinence in women: the Incontinence Impact Questionnaire and the Urogenital Distress Inventory. Continence Program for Women Research Group. Neurourol Urodyn 1995;14:131 9. [25] Black N, Griffiths J, Pope C. Development of a Symptom Severity Index and a Symptom Impact Index for stress incontinence in women. Neurourol Urodyn 1996;15:630 40. [26] Choe JM, Ogan K, Bennett S. Antibacterial mesh sling: a prospective outcome analysis. Urology 2000;55:515 20. [27] Reitz A, Stohrer M, Kramer G, Del Popolo G, Chartier-Kastler E, Pannek J, et al. European experience of 200 cases treated with botulinum-a toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol 2004;45:510 5. [28] Chancellor MB, Smith CP. A single surgeon s six-year experience with botulinum toxin into the bladder and urethra. J Urol 2004;171(suppl.): 138. [29] Digesu GA, Hutchings A, Salvatore S, Selvaggi L, Milani R, Khullar V. Pressure flow study: a useful diagnostic test of female lower urinary tract symptoms. Neurourol Urodyn 2004;23:104 8. [30] Jost W. Pelvic floor and gastrointestinal uses. In: Moore P, Naumann M, editors. Handbook of Botulinum Toxin treatment. Blackwell Science; 2003. p. 360 7. [31] Kuo HC. Botulinum A toxin urethral injection for the treatment of lower urinary tract dysfunction. J Urol 2003;170:1908 12. [32] Wyndaele JJ, Van Dromme SA. Muscular weakness as side effect of botulinum toxin injection for neurogenic detrusor overactivity. Spinal Cord 2002;40:599 600. Editorial Comment Prokar Dasgupta, London, United Kingdom prokarurol@aol.com Botulinum toxin injections to treat detrusor overactivity refractory to first line therapies has generated considerable international interest despite the fact that this toxin is as yet unlicensed for this indication. The technique initially used rigid cystoscopy under anaesthetic or sedation but is now entirely minimally invasive using a flexible cystoscope and ultrafine injection needle under local anaesthetic as a daycase. It is regarded as less invasive than the alternatives of neuromodulation and augmentation cystoplasty. Efficacy in both idiopathic (IDO) and neurogenic detrusor overactivity (NDO) of over 90% has been reported and this is durable up to five years with repeat injections at roughly once a year. Longer term data and those from emerging randomised controlled trials are eagerly awaited. Not surprisingly, botulinum toxin seems to be filling the void between anticholinergics and major surgery as a promising second line treatment. One of the downsides of this modality is the need for clean intermittent self catheterisation (CISC) which can occur in between 10 20% of patients with IDO. This is particularly important in this patient group as they do not usually need other means of emptying their bladders. The majority of NDO patients already perform CISC even before receiving botulinum toxin. The authors describe and interesting concept of injecting both the bladder and external sphincter of IDO patients with botulinum toxin-a in varying doses, in the hope of reducing the need for CISC. Of note, the patients receiving bladder injections only, had higher residual volumes although this being an average of 110 ml indicates that they may not have needed CISC unless symptomatic. Moreover variable doses were employed and it is difficult to make a firm judgement of the dose needed in a particular clinical situation. This is not a dosing study. It is also well known that the effect of the toxin is about 9 12 months on smooth muscle such as the detrusor but about 3 months on the sphincter. Although not significant, one has to carefully counsel these patients about the possible risk of stress incontinence after combined injections as this is a symptom which they did not previously have. This is an interesting concept and it is good to see how urologists will continue to apply innovative minimally invasive techniques to help their patients. Who would have ever thought that one of the most toxic substances in the world would become so important urologically? We truly live in exciting times.