One treatment with onabotulinumtoxinA relieves symptoms of overactive bladder in patients refractory to one or more oral medications.

INTRODUCTION AND HYPOTHESIS: Patients with overactive bladder (OAB) often undergo prolonged treatment with one or more oral OAB medications. OnabotulinumtoxinA (onabotA), a type A botulinum toxin, may provide an appropriate alternative to oral treatments in patients intolerant of or refractory to one or more oral OAB medications. The GRACE study demonstrated real-world benefits of onabotA treatment for OAB in patients refractory to oral medications. This exploratory post hoc analysis of data from the GRACE study aims to determine if treatment history impacts benefit from treatment with onabotA. METHODS: This is a subanalysis of the GRACE study, a prospective observational study (NCT02161159) that enrolled patients with symptomatic OAB inadequately managed by at least one oral OAB medication. Patients had a treatment history of one or more anticholinergics (AC) and/or ß-3 adrenoreceptor agonists (ß-3) for relief of OAB; results were stratified according to treatment history. Patients in this analysis elected to discontinue oral medications upon treatment with onabotA. Safety was followed for 12 months in all patients that received at least 1 dose of onabotA; efficacy was determined over a 12-week period. RESULTS: Compared to baseline levels, significant reductions in urinary incontinence (UI), urgency, micturition, and nocturia were noted as early as 1 week and were sustained at 12 weeks, regardless of the type and number of oral medications taken before treatment with onabotA. At 12 weeks post-onabotA, the mean change from baseline UI episodes/day for those with a treatment history of only one AC was -2.4 (n = 43, p ≤ 0.001); more than one AC, -2.4 (n = 52, p ≤ 0.001); one ß-3, -3.3 (n = 12, p < 0.05); at least one AC and at least one ß-3, -3.2 (n = 56, p ≤ 0.001). Pad and liner use was significantly decreased at 12 weeks post-onabotA across all treatment history groups. Reductions in diaper pant use varied, with less of a reduction in patients with a treatment history of more than one AC compared to patients with a history of at least one AC and one ß-3 (p < 0.05) or those with a history of only one AC (p < 0.05). Overall, a total of 253/288 of patients (88%) reported improvements on the treatment benefit scale 12 weeks after treatment with onabotA, regardless of type and number of prior oral medications. In the population of patients that received at least one dose of onabotA (N = 504), 57 adverse events were reported in 38 patients (7.5%); 9 were serious (1.8%). Urinary retention was reported in 5 patients (1.0%); 1 was severe (0.2%). Symptomatic urinary tract infection was reported in 2 patients (0.4%). CONCLUSIONS: In this exploratory post hoc analysis of real-world data from the GRACE study, there were few significant differences in outcomes based on the type and number of prior oral medications. Thus, patients who are refractory to one or more oral OAB medications may benefit from earlier treatment with onabotA.

Subjective Outcome after Discontinuation of Botulinum Toxin-A Detrusor Injection for Lower Urinary Tract Disorders: The Majority Suffers!

INTRODUCTION: According to the EAU guidelines, botulinum toxin type A (BoNT-A) detrusor injections are one of the last options in the management of overactive bladder before opting for invasive surgery. So far, there have been no studies dedicated exclusively to such patients who have undergone this treatment and in whom this treatment has presumably failed. From the patient's point of view, there are questions regarding what reasons led to discontinuation, how patients perceive their BoNT-A treatment in hindsight, what further treatment do these patients receive, and how satisfied such patients are with their current situation. METHODS: A database of clinical and inpatient records was searched, and 695 records from 406 patients were identified in a 6-year period, who had received BoNT-A detrusor injections. There were 255 cases that were treated with BoNT-A injections into the detrusor muscle where the therapy was not repeated for at least 12 months (= suspected treatment failures). Interviews with these patients were conducted by mail and phone, and 115 questionnaires could be included in the analysis. RESULTS: From the subjective and prospective points of view of the patients, the most common reason for stopping the therapy was a lack of efficacy of BoNT-A injections (39.1%). For 26.1% of all patients, side effects were a reason for dissatisfaction but never a reason for discontinuation. For 10.4%, the reason for stopping the therapy was spontaneous improvement. 35.6% of the respondents had no follow-up therapy. Those with a follow-up therapy mostly returned to anticholinergic treatment (33%). Operations were carried out on 13%, of which about half were highly invasive. For 71.3% of those patients, who were under any current therapy, this therapy led to no improvement or only some improvement of the symptoms. Surprisingly, 50.4% of the respondents would choose to undergo BoNT-A injection therapy again. DISCUSSION/CONCLUSION: The majority of patients who did not continue BoNT-A therapy are still suffering from lower urinary tract symptoms. The lack of efficacy was the reason for stopping the BoNT-A injection therapy for less than half of the patients. From the patient's point of view, reasons other than the effectiveness also seem to be relevant in the choice of the treatment. When changing therapy, most returned to drug treatment. However, for the majority of patients with any follow-up therapy, this therapy could not improve the symptoms.

OnabotulinumtoxinA is a well tolerated and effective treatment for refractory overactive bladder in real-world practice.

INTRODUCTION AND HYPOTHESIS: In randomized clinical trials onabotulinumtoxinA was demonstrated to be an effective and well-tolerated treatment for overactive bladder (OAB) with urinary incontinence (UI). However, data reporting onabotulinumtoxinA use in everyday clinical practice are limited. Here, we present the results from a large, first-of-its-kind real-world study in patients with OAB. METHODS: This was a prospective, observational, multinational study (GRACE; ClinicalTrials.gov , NCT02161159) performed in four European countries. Patients (N = 504) aged ≥ 18 years with OAB inadequately managed with ≥ 1 anticholinergic received onabotulinumtoxinA per their physician's normal clinical practice. RESULTS: Physicians primarily used rigid cystoscopes for onabotulinumtoxinA injection; anesthesia/analgesia was utilized during most treatment procedures. Significant reductions in UI episodes/day from baseline to weeks 1 and 12 were observed as well as in micturition, urgency, and nocturia episodes/day. These improvements in urinary symptoms corresponded to higher scores on the treatment benefit scale at week 12. The use of other OAB medications dropped from baseline to weeks 1 and 12 and was sustained to week 52, which paralleled a reduction in the number of incontinence products used during that time frame. Adverse reactions were reported in 2.6% of patients throughout the study. CONCLUSIONS: In this real-world study, significant improvements in urinary symptoms were seen following onabotulinumtoxinA treatment as early as week 1 and sustained to at least week 12. This was accompanied by a reduced reliance upon incontinence products and reduction in concomitant OAB medication use. OnabotulinumtoxinA was well tolerated with no new safety signals.

Botulinumtoxin for bladder disorders.

An overactive neurogenic detrusor and an non-neurogenic overactive bladder both exhibit symptoms such as urgency and frequency, both with and without urinary incontinence, and are often accompanied by nocturia. OnabotulinumtoxinA-Detrusorinjection has become well established as a second line therapy in cases where anticholinergic medication has failed. The procedure can be performed under general or local anesthesia, in both in- and outpatient settings. The side effects of the procedure are primarily urinary tract infections and - especially in neurogenic bladder patients - urinary retention. This article focuses on the approved indications and summarizes the current scientific data.

Efficacy and safety of onabotulinumtoxinA therapy are sustained over 4 years of treatment in patients with neurogenic detrusor overactivity: Final results of a long-term extension study.

AIMS: To present final efficacy/safety results from a prospective, long-term extension trial of onabotulinumtoxinA for urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO); patients received treatment for up to 4 years. METHODS: Patients who completed a 52-week, phase III trial of onabotulinumtoxinA for NDO were eligible to enter a 3-year, multicenter, open-label extension study of intradetrusor onabotulinumtoxinA (200U or 300U). Patients were treated "as needed" based on their request and fulfillment of prespecified qualification criteria (≥12 weeks since previous treatment and a UI episode threshold). Assessments included change from study baseline in UI episodes/day (primary efficacy measure), volume/void, and Incontinence Quality of Life (I-QOL) total score (week 6); duration of effect; adverse events (AEs); and initiation of de novo clean intermittent catheterization (CIC). Data are presented for up to six treatments. RESULTS: OnabotulinumtoxinA 200U consistently reduced UI episodes/day; reductions from baseline ranged from -3.2 to -4.1 across six treatments. Volume/void consistently increased, nearly doubling after treatment. I-QOL improvements were consistently greater than twice the minimally important difference (+11 points). Overall median duration of effect was 9.0 months (200U). Results were similar for onabotulinumtoxinA 300U. Most common AEs were urinary tract infections and urinary retention. De novo CIC rates were 29.5, 3.4, and 6.0% (200U), and 43.0, 15.0, and 4.8% (300U) for treatments 1-3, respectively; de novo CIC rates were 0% for treatments 4-6. CONCLUSIONS: OnabotulinumtoxinA treatments consistently improve UI, volume/void, and QOL in patients with UI due to NDO in this 4-year study, with no new safety signals. Neurourol. Urodynam. 36:368-375, 2017. © 2015 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.

Impact of onabotulinumtoxinA on quality of life and practical aspects of daily living: A pooled analysis of two randomized controlled trials.

OBJECTIVE: To evaluate the impact of onabotulinumtoxinA on individual domains of the quality of life questionnaires in a pooled analysis of two phase 3 trials in overactive bladder patients with urinary incontinence who were inadequately managed by ≥1 anticholinergic. METHODS: Patients received intradetrusor injections of onabotulinumtoxinA 100U (n = 557) or placebo (n = 548). The proportions of patients with a positive response (condition "greatly improved" or "improved") on the Treatment Benefit Scale, and changes in Incontinence Quality of Life scores and King's Health Questionnaire domain scores were analyzed in the overall population and subgroups with clean intermittent catheterization use and urinary tract infection status during the first 12 weeks of treatment. Responses to individual King's Health Questionnaire items were also assessed. RESULTS: Significantly greater proportions of onabotulinumtoxinA-treated patients achieved positive Treatment Benefit Scale response versus placebo (61.8% vs. 28.0%; P < 0.001). OnabotulinumtoxinA showed significantly greater improvements versus placebo in Incontinence Quality of Life total (22.5 vs. 6.6), Incontinence Quality of Life subscale scores and all domains of the King's Health Questionnaire. Notably, a similar trend was observed regardless of clean intermittent catheterization/urinary tract infection status. Additionally, onabotulinumtoxinA resulted in significantly greater improvements than the placebo in practical aspects of patients daily lives, including pad use, need to change undergarments, sleep, relationship with partner and work life/daily activities. CONCLUSION: In overactive bladder patients with urinary incontinence, onabotulinu-mtoxinA 100U demonstrated significant improvements across the individual domains of the quality of life questionnaires, regardless of clean intermittent catheterization or urinary tract infection status, and provided a positive impact on practical aspects of patients' daily lives.

[Onabotulium toxin A detrusor injection: The "real world" of users, the "real world" of patients - Update BOTUROLOGY 2022]. / OnabotuliumtoxinA Detrusorinjektion: Die "Real World" der Anwender, die "Real World" der Patienten ­ Update BOTUROLOGY 2022.

BACKGROUND: OnabotulinumtoxinA (Botox) has been approved in Germany since 2013 for the second-line treatment of idiopathic overactive bladder in the form of a detrusor injection (OnabotA DI) after failure of anticholinergic therapy. Until 2018, however, its application lagged far behind the demand due to billing hurdles. Since the beginning of 2018, there has been an EBM (German Uniform Evaluation Standard) approval number in Germany for the transurethral application of Botox in urology. QUESTION: The aim of a survey performed in 2019 among course participants of regular injection workshops (WS-P) in our institution was to evaluate whether billability has changed user behaviour in Germany in line with the demand. A similar survey was carried out in 2021 to show the developments over the past two years. MATERIAL AND METHODS: In 2019, 88 consecutive participants in a user workshop that had been held regularly since 2013 were asked about their OnabotA DI practice anonymously via questionnaire. The survey was repeated in 2021 in an anonymous online survey of 55 course participants in order to evaluate changes in user behaviour over the past two years. RESULTS: Evaluation 2019: Response rate 35/88 of the questionnaires (39.8%); a large majority (82%) of the WS-P attended the workshop AFTER the establishment of the EBM code. Only 54.5% of the WS-P performed two or more (12% more than 10) OnabotA DIs per quarter after the workshop. Most users (85%) always or predominantly performed the procedure on an outpatient basis, 63% always or predominantly under local anesthesia. The majority (84%) administered no or only a perioperative antibiotic treatment, 13% for one week. 89% stated that at least 70% of their patients had no or only mild symptoms under the LA. In the 2021 evaluation, the users tended to perform the procedure more often on an outpatient basis and in LA, and more often without any antibiotics. CONCLUSIONS: The results of our user survey indicate that the implementation of the OnabotA DI has gained significant impetus since the EBM approval in Germany in January 2018. In most cases, the procedure can be performed easily on an outpatient basis under local anesthesia.

Individual receptor profiling as a novel tool to support diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC).

PURPOSE: Dysregulation of neurotransmitter receptors may contribute to bladder overactivity (OAB) symptoms. To address the question whether specific receptor expression patterns are associated with bladder pain syndrome/interstitial cystitis (BPS/IC), we examined the expression of muscarinic, purinergic and histamine receptors in the detrusor. METHODS: Detrusor receptor expression was investigated in bladder biopsies of female BPS/IC patients (n = 44; age 60.64 ± 13.78, mean ± SD) and carcinoma patients (n = 11; age 58.91 ± 12.72) undergoing cystectomy. Protein expression of muscarinic (M2, M3), purinergic (P2X1-3) and histamine receptors (H1, H2) was analysed by confocal immunofluorescence, and gene expression was quantified by real-time polymerase chain reaction (qPCR). RESULTS: M2, P2X1, P2X2 and H1 receptor immunoreactivity (-IR) was significantly enhanced in BPS/IC compared to the control group, while there was no difference for M3-, P2X3- and H2-IR. We calculated a score, which separated BPS/IC from control patients with an AUC of 89.46%, showing 84.09% sensitivity and 90.91% specificity. Patients had a 9.25 times enhanced calculated risk for BPS/IC. In addition, two patient subgroups (M2 > M3 and M3 > M2) were observed, which differed in associated purinergic and histamine receptor expression. CONCLUSIONS: M2, P2X1, P2X2 and H1 were significantly upregulated in BPS/IC patients, and H2 was occasionally highly overexpressed. There was no significant correlation between receptor protein and gene expression, implying posttranslational mechanisms being responsible for the altered receptor expressions. On the basis of individual receptor profiles, upregulated receptors could be targeted by monotherapy or combination therapy with already approved receptor inhibitors, thereby promoting tailored therapy for patients suffering from BPS/IC-like symptoms.

Real-Time Documentation of the Effect of Onabotulinumtoxin A Detrusor Injection in OAB Patients-Preliminary Results.

Introduction: Detrusor injection with onabotulinumtoxin A (OnabotA-DI) is an established therapy for overactive bladder (OAB). Little is known about the exact onset and course of the effect in the days after the injection therapy. By using a new type of app-controlled automated diary pod, for the first time, the precise onset of the effect of OnabotA-DI can be documented in real time. Materials and methods: Patients due for OnabotA-DI were asked to document voiding 3 days before and up to 3 weeks after therapy using the Diary Pod app. The detrusor injection was performed with onabotulinumtoxin A (Botox®), 100 units, at 20 sites of the detrusor muscle in a standardized manner. Voiding on the injection day itself was not documented. Results: A total of 17 patients (15 women, 2 men; aged 33−83 (mean 64.6; median 70) years) were included in the study. The handling of the Diary Pod app was user-friendly, and elderly patients did not encounter technical problems. The results of patients with reliably documented micturitions showed a continuous reduction in micturition frequency every day from the first day and significantly from day 5. For 24 h voiding, from 12.83 ± 5.54 in the 3 days before injection, the following mean values were found with significant (p < 0.05) changes after the intervention: 9.17 ± 3.19 on day 5, 8.75 ± 3.69 on day 10, 7.17 ± 2.04 on day 15, and 5.75 ± 0.5 on day 20. These changes were in similar proportions during the daytime and nighttime. Conclusions: Contrary to previous knowledge, the effect of the OnabotA-DI set in from the first postoperative days and was reflected a similar extent in day and night micturition. This study is the first to document the onset of action of OnabotA-DI in real time.

Urodynamic results and clinical outcomes with intradetrusor injections of onabotulinumtoxinA in a randomized, placebo-controlled dose-finding study in idiopathic overactive bladder.

AIMS: We assessed the effects of onabotulinumtoxinA (BOTOX®) on clinical and urodynamic variables in patients with idiopathic overactive bladder (OAB) and urinary urgency incontinence (UUI) with or without detrusor overactivity (DO), inadequately managed with anticholinergics. METHODS: Three hundred thirteen patients with OAB were randomized to double-blind intradetrusor injection with placebo (n = 44) or 1 of 5 onabotulinumtoxinA doses (50-300 U; n = 269). Primary efficacy variable was change from baseline in UUI episodes/week at week 12. Urodynamic assessments at baseline and weeks 12 and 36 included maximum cystometric capacity (MCC) and volume at first involuntary detrusor contraction (IDC). RESULTS: 76.0% of patients had baseline DO. Changes from baseline in MCC and volume at first IDC with onabotulinumtoxinA ≥100 U were superior to placebo at week 12, generally decreasing by week 36. Significant dose-dependent increases in MCC were observed for all onabotulinumtoxinA doses at week 12, and for 150, 200, and 300 U at week 36. Data suggested a dose-response relationship. At week 12 on diary, 15.9% of placebo and 29.8-57.1% of onabotulinumtoxinA 50-300 U recipients, respectively, did not demonstrate UUI. OnabotulinumtoxinA doses >150 U were more commonly associated with post-void residual urine volumes >200 ml. CONCLUSIONS: Improvements in urodynamic parameters and clinical outcomes generally trended together following onabotulinumtoxinA treatment. This therapy improved key urodynamic parameters in patients with idiopathic OAB and UUI, with no differences in outcomes between those with and those without baseline DO. Therefore, successful idiopathic OAB treatment with onabotulinumtoxinA does not appear to be related to pretreatment finding of DO.

Propiverine vs oxybutynin for treating neurogenic detrusor overactivity in children and adolescents: results of a multicentre observational cohort study.

OBJECTIVE: To compare, in a retrospective observational cohort study, the efficacy, tolerability, safety and clinical effectiveness of propiverine and oxybutynin in children and adolescents with neurogenic detrusor overactivity (NDO). PATIENTS AND METHODS: In all, 255 children and adolescents (aged 1-18 years) with NDO (199 myelomeningocele, 46 spinal cord injury, 10 other diagnoses) were enrolled at 14 study centres. To evaluate the efficacy of propiverine and oxybutynin, urodynamic and clinical variables were assessed before and after at least 12 month of the antimuscarinic agents administered at variable doses. RESULTS: In all, 127 patients given propiverine and 128 given oxybutynin were enrolled. The primary efficacy outcome, i.e. reductions in urodynamically assessed individual maximum detrusor pressure (P(detmax)), was assumed to indicate success in 74.2% of those on propiverine vs 49.6% on oxybutynin. The mean P(detmax) was significantly reduced during treatment, from 59.8 to 36.7 cmH(2)O in the propiverine and from 65.2 to 54.9 cmH(2)O in the oxybutynin groups. The mean maximum cystometric bladder capacity increased from 146 to 242 mL in the propiverine and from 222 to 310 mL in the oxybutynin group. Propiverine was better tolerated than oxybutynin, having fewer adverse drug reactions (9.4% vs 17.2%, odds ratio 2.04), and for its severity grades and premature treatment termination (none vs 11 cases). CONCLUSION: In this non-interventional study, reflecting 'real-life' clinical practice, comparing the efficacy, tolerability and safety of propiverine and oxybutynin in children and adolescents with NDO, propiverine was at least as effective as oxybutynin, but better tolerated, resulting in superior clinical effectiveness than for oxybutynin.

Botulinum neurotoxin type A in urology: antibodies as a cause of therapy failure.

OBJECTIVES: Botulinum toxin type A (BoNT/A) proved very effective in therapy for hyperactive detrusor or sphincter dysfunction of neurogenic and non-neurogenic origin. However, therapy may fail. In a search for possible reasons, we investigated the presence of BoNT/A antibodies (BoNT/A-AB) in patients who were treated more than once and correlated the presence of antibodies with clinical findings. METHODS: In 25 patients (aged 11-75 years; average, 48.3 years) who had experienced at least one previous BoNT/A detrusor and/or sphincter injection, BoNT/A-AB was detected with the mouse diaphragm assay before and within 3 months after the current injection. Clinically, subjective and objective outcomes of this injection session were determined on an efficacy scale. RESULTS: In eight patients, BoNT/A-AB was detected; titers were clearly positive in four patients and were borderline in four patients. The subjective and objective outcomes indicated complete therapy failure in three of four patients who were positive for BoNT/A-AB. In two patients, BoNT/A-AB developed after just one injection session. CONCLUSIONS: Botulinum toxin type A antibodies can develop after injection of BoNT/A for urologic disorders and the antibodies can lead to therapy failure. In patients with clinically complete therapy failure in whom no obvious other causes can be determined (such as a progressive disease in a patient with multiple sclerosis), screening for BoNT/A-AB should be carried out.

Improving the global management of the neurogenic bladder patient: part II. Future treatment strategies.

BACKGROUND: Patients with neurogenic bladder represent a small fraction of the total overactive bladder population. As a consequence, development of new therapies in this area has largely focused on idiopathic urinary incontinence. The absence of data for patients with neurological disease has far-reaching implications, affecting reimbursement and physicians' willingness to prescribe therapies, and limiting access of potential valuable treatments to patients whose lives are significantly impaired by inadequately managed bladder symptoms. SCOPE: The range of new therapies is increasing. Although many reviews of the overall safety, efficacy and mode of action of such treatments are available, there is limited information on how these treatments will best be used in clinical practice. We considered the current benefits and limitations of the various new licensed and unlicensed therapies and what role each would have in the future management of neurogenic urinary incontinence. CONCLUSIONS: A wide range of new treatments have been investigated for the management of overactive bladder; few, however, have been evaluated extensively in neurogenic urinary incontinence. Further studies are required to determine the optimal dosing regimes and formulations for individual sub-populations of neurogenic bladder patients and to determine the cost-effectiveness of these interventions. With the current experience available, two treatment algorithms for a subset of patients with neurological disease have also been proposed, which suggest at which stage of management and in which patients individual therapies for neurogenic urinary incontinence could be used.

Improving the global management of the neurogenic bladder patient: part I. The complexity of patients.

BACKGROUND: The management of urinary incontinence in patients with neurological disease is complex. Physicians face a multitude of challenges related to progression of the primary condition, the presence of a diversity of other related and unrelated symptoms, the safety, efficacy and tolerability issues associated with multiple therapies being required and the changing need for collaboration with other specialities. SCOPE: Current guidelines produced by the urological communities, as well as the disease-focused organizations, aim to standardize care in their specific group of patients. A passive approach to implementation, however, means that guidelines produced are all too frequently not readily available to, read by or followed by the wider audience. In addition, each speciality has its own guidelines and a different view of the primary focus of care in neurological patients, which may lead to variations in recommendations and, subsequently, in clinical practice. A review of current urological and disease specific guidelines was made to evaluate differences between the published guidance between the specialities and within urology itself. CONCLUSIONS: Although availability of effective therapies remains a cornerstone of neurogenic bladder treatment, consideration must also be given to the non-pharmacological and surgical issues related to the global management of this population. Improved cross-speciality interactions and development of patient-specific treatment and follow-up plans, which are in keeping with the current guidelines of each speciality involved, may serve to enhance physicians' understanding of the importance of effective urinary incontinence treatment as well as the overall management of the patient.

Botulinum toxin A detrusor injections reduce postsynaptic muscular M2, M3, P2X2, and P2X3 receptors in children and adolescents who have neurogenic detrusor overactivity: a single-blind study.

OBJECTIVE: To analyze the effect of OnabotulinumtoxinA detrusor injections on postsynaptic muscular receptors in children and adolescents with neurogenic detrusor overactivity. MATERIALS AND METHODS: A bladder augmentation became necessary in 10 children and adolescents (7 males, 3 females; median age, 12 years) who had neurogenic detrusor overactivity. Seven had previously received 1 to 8 (average 3.86) OnabotulinumtoxinA detrusor injections, but their detrusor pressure could not be maintained at tolerable levels because of low-compliance bladder. The last injection session had been completed an average of 3 months (range, 1.5-3.5 months) previously. Three patients had never received that therapy and were considered controls. On the bladder dome resections, a specific receptor analysis (muscarinic M2 and M3 and purinergic P2X1, P2X2, and P2X3) was performed with confocal immunofluorescence, and nerve fiber density was analyzed with light-microscopic 3,3'-diaminobenzidine-immunohistochemical staining. RESULTS: Receptor analysis showed a downregulation of all examined receptors after OnabotulinumtoxinA injections; the reductions in M2, M3, P2X2, and P2X3 receptors reached a significance level of P <.05 (Mann-Whitney test). The ratios of means (OnabotulinumtoxinA-to-control) were 0.26 for M2, 0.33 for M3, 0.35 for P2X1, 0.19 for P2X2, and 0.37 for P2X3. CONCLUSION: OnabotulinumtoxinA detrusor injections led to significant reductions in muscular M2, M3, P2X2, and P2X3 receptors. The reductions probably affect the generated force in the urinary bladder and could contribute to the clinically observed increase in residual urine.

Urodynamic effects of propiverine in children and adolescents with neurogenic bladder: results of a prospective long-term study.

OBJECTIVE: To evaluate prospectively the efficacy and tolerability of propiverine for long-term treatment of neurogenic detrusor overactivity (NDO) in children. MATERIALS AND METHODS: 17 children and adolescents with NDO (10 female, 7 male; average age at last consultation 13.0 years) were evaluated during long-term treatment with propiverine (0.8 mg/kg body weight/day). Outcome measurements included urodynamic parameters, continence, hydronephrosis and tolerability of propiverine. RESULTS: Average follow-up was 3.6 years (range 2.0-5.9). The average maximum detrusor pressure was 33.2 ± 4.8 cmH(2)O and bladder compliance was 20.0 ± 5.4 ml/cmH(2)O at the last follow-up visit. Maximum cystometric bladder capacity (MCBC) within the normal range was attained in 11 patients; it was still reduced (average of 61% of expected MCBC) in the remaining 6. Incontinence occurred on average once per day. Hydronephrosis was classified for each renal unit separately: grade 0 was measured in 26 and 22 cases, grade 1 or 2 in 6 and 8 cases, grade 3 or 4 in 2 and 4 cases pre and post treatment, respectively. In 6/17 patients adjuvant intravesical oxybutynin was applied, in 4 out of these 6 patients more invasive procedures, such as untethering, augmentation cystoplasty or botulinum toxin injections, were necessitated. Propiverine monotherapy was well tolerated in 11/17 patients. No serious adverse events were encountered during the study period. CONCLUSION: Long-term efficacy and tolerability of propiverine for NDO in children and adolescents is promising: clinically relevant improvements in key urodynamic outcomes were paralleled by improvements in incontinence score.

Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European consensus report.

CONTEXT: The increasing body of evidence and number of potential indications for the use of botulinum neurotoxins (BoNTs) in the lower urinary tract (LUT) underlines the pressing need for evidence-based guidelines. OBJECTIVE: A European expert panel consensus conference was convened with the main aim of evaluating the evidence and clinical considerations for the use of BoNTs in the treatment of urologic and pelvic-floor disorders and to propose relevant recommendations. EVIDENCE ACQUISITION: The quality of evidence from fully published English-language literature in the PubMed and EMBASE databases was assessed using the European Association of Urology (EAU) levels of evidence (LoE). Recommendations were graded and approved by a unanimous consensus of the panel. EVIDENCE SYNTHESIS: The use of botulinum neurotoxin type A (BoNTA) is recommended in the treatment of intractable symptoms of neurogenic detrusor overactivity (NDO) or idiopathic detrusor overactivity (IDO) in adults (grade A). Caution is recommended in IDO because the risk of voiding difficulty and duration of effect have not yet been accurately evaluated. Repeated treatment can be recommended in NDO (grade B). The depth and location for bladder injections should be within the detrusor muscle outside the trigone (grade C). Dosage in children should be determined by body weight, with caution regarding total dose if also being used for treatment of spasticity, and minimum age (grade B). Existing evidence is inconclusive for recommendations in neurogenic detrusor-sphincter dyssynergia, bladder pain syndrome, prostate diseases, and pelvic-floor disorders. The use of BoNTA in the LUT with the current dosages and techniques is considered to be safe overall (grade A). CONCLUSIONS: The consensus committee recommends larger placebo-controlled and comparative trials to evaluate the efficacy of single and repeat injections, the duration of effect, the optimal dosage and injection technique, the timing for repeat injection, and the short- and long-term safety of the treatment in LUT and pelvic-floor disorders.

Antibodies against botulinum neurotoxin type A as a cause of treatment failure after the first detrusor injection.

Botulinum neurotoxins are increasingly used in treatment for hyperactive detrusor and sphincter function. Although reported results are promising, conditions in some patients are refractory. We report what we believe to be the first urologic case of therapy failure possibly induced by botulinum toxin antibodies after just one injection and discuss treatment alternatives based on experience in other fields.

Persistence of the synaptosomal-associated protein-25 cleavage product after intradetrusor botulinum toxin A injections in patients with myelomeningocele showing an inadequate response to treatment.

OBJECTIVE To monitor the presence and cleavage of synaptosomal-associated protein of 25 kDa (SNAP-25) by botulinum toxin type A (botox-A), in human detrusor muscle, as the effects of botox-A in the urinary bladder last significantly longer than when applied for disorders of striated muscles. PATIENTS AND METHODS Tissue samples were obtained from eight patients with end-stage neurogenic bladder at different times after injection with botox-A. The resected bladder domes were examined using biochemical and immunohistological techniques. RESULTS The presence of intact SNAP-25 in human bladder was detected, for the first time, in all samples by both Western blotting and immunofluorescence. By contrast, detection of a band potentially representing toxin-cleaved SNAP-25(A) required its enrichment by precipitation with a specific antibody. This putative product was present in four of six patients treated with botox-A 5 weeks to 11 months previously, but could not be detected in one patient 30 months after botox injection, and in an untreated control. Fluorescence microscopy showed no obvious effects of the toxin treatment on the presence and pattern of SNAP-25-positive neurones. CONCLUSIONS A limited amount of SNAP-25 appears to be cleaved in nerves that innervate the smooth detrusor muscle in most patients who had been injected with botox-A; its absolute identification was precluded by the sensitivity of the detection. This protein was detectable much longer after toxin treatment than published for rodent striated muscle, and thus could contribute to the clinically reported longer duration of the effectiveness of botox-A.