Six-Year Follow-Up of Botulinum Toxin A Intradetrusorial Injections in Patients with Refractory Neurogenic Detrusor Overactivity: Clinical and Urodynamic Results

Background

Most reports in the literature on botulinum toxin A (BoNTA) therapy for neurogenic detrusor overactivity (NDO) are based on the results of a single injection. Because most patients may require retreatment, the efficacy and safety of multiple injections must be addressed clearly.

Objective

To investigate the effectiveness and safety of BoNTA intradetrusorial injections in a group of spinal cord–injured (SCI) patients with refractory detrusor overactivity (DO).

Design, setting, and participants

Seventeen SCI patients were prospectively included in the study and followed up to 6 yr.

Intervention

All patients received repeat intradetrusorial injections of BoNTA 300 units (Botox, Allergan, Irvine, CA) under cystoscopic control on an inpatient basis.

Measurements

The preliminary assessment included voiding diary, urodynamics, kidney and bladder ultrasound, and cystourethrography. Patients also completed a standardised quality-of-life (QoL) questionnaire. Clinical evaluation, urodynamics, urinary tract imaging, and QoL assessment were repeated every year throughout the follow-up.

Results and limitations

Before treatment, all patients complained of urinary incontinence and had DO. Bilateral and monolateral renal pelvis dilatation were detected in six and five patients, respectively, and a monolateral and third-grade vesicoureteral reflux was observed in three. At 6-yr follow-up, a significant decrease in the frequency of daily incontinence episodes (p < 0.01), a significant increase in first uninhibited detrusor contraction and in maximum bladder capacity (p < 0.001 for both), and a significant decrease in maximum pressure of these contractions (p < 0.01) were observed. Fifteen patients (88.2%) were completely continent. Renal pelvis dilatation and vesicoureteral reflux resolved in all cases, and the QoL index significantly increased. Limitations of the study are related to the small number of included patients.

Conclusions

In SCI patients with refractory NDO who do not want or are unfit for invasive reconstructive surgery, BoNTA intravesical treatment represents a valid alternative to control DO and urinary incontinence and to preserve upper urinary tract function over a long-term follow-up.     

Suburothelial Myofibroblasts in the Human Overactive Bladder and the Effect of Botulinum Neurotoxin Type A Treatment

Background

An increasing body of evidence suggests a possible role of suburothelial myofibroblasts (MFs) in bladder mechanosensation and in the pathophysiology of detrusor overactivity (DO).

Objective

To determine whether markers of MFs, including gap junction protein connexin43 (Cx43) and c-kit have altered immunohistochemical expression in the suburothelium of patients with neurogenic DO (NDO) or idiopathic DO (IDO) and whether this is affected by successful treatment of DO with botulinum neurotoxin type A (BoNTA).

Design, setting, and participants

Patients with NDO (n = 10) or IDO (n = 11) were treated in a single-centre, open-label study of intradetrusor BoNTA injections. Control tissue was obtained from 10 patients undergoing pelvic-floor repair procedures who had no overactive bladder (OAB) symptoms. This study is registered with ClinicalTrials.gov, number NCT00662064.

Interventions

Bladder biopsies performed with flexible cystoscopes were obtained from control subjects and from NDO and IDO patients before BoNTA treatment and at 4 wk and 16 wk after treatment. They were studied with quantitative immunofluorescence using antibodies to connexin 43 (Cx43), vimentin, and c-kit.

Measurements

Differences in Cx43, vimentin, and c-kit immunoreactivity between control subjects and NDO or IDO patients (primary outcomes). Changes in NDO or IDO, Cx43 immunoreactivity, and c-kit immunoreactivity after BoNTA treatment (secondary outcomes).

Results and limitations

Cx43 immunoreactivity was increased in both IDO and NDO patients compared to controls, but remained unchanged after BoNTA treatment. C-kit immunoreactivity was similar in NDO/IDO patients and controls and remained unchanged after BoNTA treatment.

Conclusions

Increased gap junction formation in the suburothelium has been demonstrated in biopsies from humans with DO. It is hypothesised that this change could have a significant role in the pathogenesis of the detrusor abnormality. Successful treatment of NDO or IDO does not appear to be associated with changes in the expression of Cx43 or c-kit on suburothelial MFs.     

In the Human Urothelium and Suburothelium,Intradetrusor Botulinum Neurotoxin Type A Does Not Induce Apoptosis: Preliminary Results

Background

Intradetrusor injections of botulinum neurotoxin type A (BoNTA) are emerging as the preferred second-line treatment for neurogenic and idiopathic overactive bladder (OAB). In animal experiments, intradetrusor BoNTA injections have been shown to cause apoptosis in the bladder urothelium and suburothelium but not the detrusor.

Objective

To investigate BoNTA-induced apoptosis in patients with refractory neurogenic OAB.

Design, setting, and participants

Twelve refractory OAB patients with neurogenic detrusor overactivity resulting from multiple sclerosis (MS) and seven controls were included prospectively.

Measurements

The number of apoptotic cells before and 4 wk after first intradetrusor BoNTA (300 U of BOTOX [Allergan, Irvine, CA, USA]) injections were estimated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) staining.

Results and limitations

Comparison of TUNEL-positive cells (yes vs no) in the bladder urothelium and suburothelium revealed no significant differences in OAB patients before (4 of 12, 33%) versus after (3 of 12, 25%) BoNTA treatment (p = 0.99). In addition, no significant differences (p = 0.99) were found in OAB patients versus controls. Because our findings are based on first intradetrusor BoNTA injections only, it is unclear whether the results could be extrapolated to repeat injections.

Conclusions

In contrast to preliminary animal experiments, first intradetrusor BoNTA injections for treating refractory neurogenic OAB—a highly effective treatment—did not induce apoptosis in the bladder urothelium and suburothelium.     

Adverse Events of Intravesical Botulinum Toxin A Injections for Idiopathic Detrusor Overactivity: Risk Factors and Influence on Treatment Outcome

Background

Intravesical injection of botulinum toxin type A (BoNTA) provides effective treatment for detrusor overactivity and overactive bladder (OAB). However, the high rates of treatment-related adverse events (AEs) prevent its more widespread use.

Objective

To investigate the risk factors of increasing AEs after BoNTA injection for idiopathic detrusor overactivity (IDO).

Design, setting, and participants

This study included a total of 217 patients receiving their first intravesical BoNTA injection for refractory IDO in a tertiary university hospital from 2004 to 2009.

Measurements

AE incidence was analyzed according to gender, age, comorbidities, prostate condition in men, OAB subtype, BoNTA dose, injection site, and baseline urodynamic parameters. Successful outcome was determined based on patient perception of improvement of bladder condition at 3 mo.

Results and limitations

Successful outcomes were reported by 144 (66.3%) patients. By multivariable analysis, male gender (p = 0.013) and baseline postvoid residual (PVR) ≥100 ml (p = 0.003) were independent predictors of acute urinary retention (AUR). Baseline PVR ≥100 ml (p = 0.007) and receiving >100 U BoNTA (p = 0.029) were predictors of straining to void. The incidence of large PVR after treatment was associated with comorbidity (p = 0.011). Urinary tract infection occurred more frequently in women (p = 0.003) and in men with retaining prostate (p = 0.008). No AUR developed after bladder base/trigonal injection. Nevertheless, the occurrence of AUR or large PVR did not affect therapeutic outcome. This study is limited by nonconsecutive enrollment of patients.

Conclusions

Male gender, baseline PVR ≥100 ml, comorbidity, and BoNTA dose >100 U are risk factors for increasing incidence of AEs after intravesical BoNTA injection for IDO.     

Efficacy and Tolerability of Botulinum Toxin Type A in Patients with Neurogenic Detrusor Overactivity and Without Concomitant Anticholinergic Therapy: Comparison of Two Doses

Background

Botulinum toxin type A (BoNTA) has been reported to be effective for treatment of patients with neurogenic detrusor overactivity (NDO) refractory to anticholinergic agents. However, in most of the studies, the efficacy was associated with concomitant use of anticholinergics.

Objective

To evaluate the efficacy and tolerability of BoNTA and compare two different doses in patients with NDO without concomitant anticholinergics.

Design, setting, and participants

Between 2004 and 2006, adults with NDO refractory to anticholinergics or discontinued anticholinergics due to adverse events or contraindications from four different French clinical centres were included in a prospective, randomised, double-blind, comparative trial. Inclusion criteria were urinary incontinence (UI) resulting from NDO that could not be managed with anticholinergics. Patients with bladder cancer, lithiasis, or urinary infection were excluded.

Intervention

Patients were randomised to receive an intradetrusor injection of 500 U or 750 U of BoNTA.

Measurements

The initial evaluation (ie, clinical and urodynamic variables and quality of life [QoL]) was repeated at days 30, 90, 180, and 360. Primary outcome was complete continence rate at day 30. Secondary outcomes were cumulative incontinence rate, reappearance of leakages, pad usage, urodynamics, and QoL.

Results and limitations

Seventy-seven patients received 500 U (n = 39) or 750 U (n = 38) of BoNTA and were included in the full analysis set for efficacy analysis. Complete continence at day 30 was observed in 22 patients (56.4%) and 28 patients (73.7%) receiving 500 U or 750 U of BoNTA, respectively (p = 0.056; one-sided χ² test to compare to α = 0.025). The median delay in the reappearance of leakages was 168 d. Monotherapy of BoNTA significantly improved UI in patients with NDO. Although there was a trend towards a greater improvement with 750 U of BoNTA, no statistically significant differences in terms of clinical and urodynamic variables and QoL were found between the treatment groups. Tolerability was excellent and equivalent for both doses.

Conclusions

Monotherapy of BoNTA at Dysport (Ipsen, Brisbane, CA, USA) doses of 500 U or 750 U seems to be effective and well tolerated in patients with NDO.     

Complete Continence after Botulinum Neurotoxin Type A Injections for Refractory Idiopathic Detrusor Overactivity Incontinence: Patient-Reported Outcome at 4 Weeks

Background

Objective improvement following intradetrusor injections of botulinum neurotoxin type A (BoNTA) is well documented. Although patient-related outcome measures are highly recommended for monitoring overactive bladder symptoms, no study before has dealt with the question of patient-reported complete continence after BoNTA treatment using validated questionnaires.

Objective

To investigate the change in patient-reported continence rate after intradetrusor injections of BoNTA for treatment of refractory idiopathic detrusor overactivity (IDO) incontinence.

Design, setting, and participants

Seventy-four patients (51 women, 23 men) with refractory IDO incontinence treated for the first time with intradetrusor injections of 200 U BoNTA were evaluated in this nonrandomised, open-label, cohort study.

Measurements

Changes in patient-reported urinary frequency, urgency incontinence, and stress incontinence were assessed using the condition-specific validated short form of the Urogenital Distress Inventory (UDI 6) before and 4 wk after BoNTA treatment.

Results and limitations

The patient-reported outcome of complete continence (defined as a score of 0 in both the urgency and stress incontinence subscales of the UDI 6) was 51% (38 of 74) 4 wk after intradetrusor injections of BoNTA. In patients who were not completely continent, median urgency incontinence scores reduced significantly from 100 to 0 (p < 0.001), stress incontinence scores from 33 to 0 (p < 0.001), and median urinary frequency scores from 100 to 33 (p < 0.001), respectively. The inclusion of patients with mixed incontinence may have resulted in underestimation of the complete continence rate.

Conclusions

An excellent response with >50% of patients reporting complete continence 4 wk after BoNTA treatment reveals the efficacy of this emerging treatment for patients with refractory IDO incontinence. Furthermore, in those in whom complete continence was not achieved, there was a notable and significant reduction in reported urgency incontinence, stress incontinence, and urinary frequency.     

Contemporary management of lower urinary tract disease with botulinum toxin A: a systematic review of botox (onabotulinumtoxinA) and dysport (abobotulinumtoxinA)

Context

The use of botulinum toxin A (BoNTA) in the treatment of lower urinary tract dysfunction has expanded in recent years and the off-licence usage list includes neurogenic detrusor overactivity (NDO), idiopathic detrusor overactivity (IDO), painful bladder syndrome (PBS), and lower urinary tract symptoms resulting from bladder outflow obstruction (BOO) or detrusor sphincter dyssynergia (DSD). There are two commonly used preparations of BoNTA: Botox (onabotulinumtoxinA) and Dysport (abobotulinumtoxinA).

Objective

To compare the reported outcomes of onabotulinumtoxinA and abobotulinumtoxinA in the treatment of NDO, IDO, PBS, DSD, and BOO for adults and children.

Evidence acquisition

We performed a systematic review of the published literature on PubMed, Scopus, and Embase in the English language reporting on outcomes of both BoNTA preparations. Review articles and series with <10 cases were excluded. The articles were graded for level of evidence and conclusions drawn separately for data with higher-level evidence.

Evidence synthesis

There is high-level evidence for the use of onabotulinumtoxinA and abobotulinumtoxinA in adults with NDO but only for abobotulinumtoxinA in children with NDO. Only onabotulinumtoxinA has level 1 evidence supporting its use in IDO, BOO, DSD, and PBS/interstitial cystitis.

Conclusions

We identified good-quality studies that evaluated onabotulinumtoxinA for all the indications described above in adults; such was not the case with abobotulinumtoxinA. Although this does not imply that onabotulinumtoxinA is more effective than abobotulinumtoxinA, it should be a consideration when counselling patients on the use of botulinum toxin in urologic applications. The two preparations should not be used interchangeably, either in terms of predicting outcome or in determining doses to be used.     

Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial

Background

Neurogenic detrusor overactivity (NDO) frequently results in urinary incontinence (UI) which impairs quality of life (QOL) and puts the upper urinary tract at risk.

Objective

To assess the effects of onabotulinumtoxinA (BOTOX^®, Allergan, Inc.) on UI, urodynamic variables, and QOL in incontinent patients with NDO.

Design, setting, and participants

This multicentre, randomised, double-blind, placebo-controlled study enrolled patients with multiple sclerosis (MS; n = 154) or spinal cord injury (SCI; n = 121) with UI due to NDO (≥14 UI episodes per week).

Intervention

Patients received 30 intradetrusor injections of onabotulinumtoxinA 200 U (n = 92), 300 U (n = 91), or placebo (n = 92), avoiding the trigone.

Measurements

Primary end point was change from baseline in UI episodes per week (week 6). Secondary end points included urodynamics (maximum cystometric capacity [MCC], maximum detrusor pressure during first involuntary detrusor contraction [P_detmaxIDC]), and Incontinence Quality of Life (I-QOL) total score. Adverse events (AEs) were assessed.

Results and limitations

At baseline, mean UI episodes per week (33.5) were similar across groups. At week 6, onabotulinumtoxinA 200 U and 300 U significantly reduced UI episodes per week (−21.8 and −19.4, respectively) compared with placebo (−13.2; p < 0.01); onabotulinumtoxinA benefit was observed by the first posttreatment study visit at week 2. Improvements in MCC, P_detmaxIDC, and I-QOL at week 6 were significantly greater with both onabotulinumtoxinA doses than with placebo (p < 0.001). Benefits were observed in both the MS and SCI populations. The median time to patient request for retreatment was the same for both onabotulinumtoxinA doses (42.1 wk) and greater than placebo (13.1 wk; p < 0.001). Most frequent AEs were localised urologic events (urinary tract infections and urinary retention, which were dose related in patients not using clean intermittent catheterisation [CIC] at baseline). Significant increases in postvoid residual were observed in patients not using CIC prior to treatment, and 12%, 30%, and 42% of patients in the placebo, 200-U, and 300-U groups, respectively, initiated CIC posttreatment.

Conclusions

OnabotulinumtoxinA significantly reduced UI and improved urodynamics and QOL in MS and SCI patients with NDO. Both doses were well tolerated with no clinically relevant differences in efficacy or duration of effect between the two doses (http://www.clinicaltrials.gov; NCT00461292).     

A Longitudinal Population-based Survey of Urinary Incontinence,Overactive Bladder,and Other Lower Urinary Tract Symptoms in Women

Background

Female urinary incontinence (UI), overactive bladder (OAB), and other lower urinary tract symptoms (LUTS) are highly prevalent conditions with a profound influence on well-being and quality of life. There are a few studies describing progression as well as remission, in the short term, of UI in the general population as well as in selected groups; at present, there are very few population-based studies describing the natural course of other LUTS in the same women, and there are no long-term longitudinal studies.

Objective

To describe the prevalence of UI, OAB, and other LUTS in the same women studied prospectively over time and, thus, to assess possible progression or regression.

Design, setting, and participants

A longitudinal population-based study was performed in one primary health care district in the city of Gothenburg, Sweden. The participants were a sample of women aged ≥20 yr who were randomly selected from the Swedish National Population Register, assessed in 1991 (n = 2911), and available for reassessment in 2007 (n = 1408).

Methods

A self-administered postal questionnaire regarding UI, OAB, and other LUTS was returned by 77% of the contacted women in 1991. The same women who responded in 1991 and who were still alive and available in the Swedish National Population Register 16 yr later were reassessed using a similar self-administered postal questionnaire.

Results and limitations

In 2007, 1081 of the available 1408 women responded to the questionnaire (77%). The overall prevalence of UI, OAB, nocturia, and daytime micturition frequency of eight or more times per day increased by 13%, 9%, 20% (p < 0.001), and 3% (p < 0.05), respectively, from 1991 to 2007. The incidence of UI and OAB were 21% and 20%, respectively, and the corresponding remission rates were 34% and 43%, respectively. Women with OAB symptoms were classified as OAB dry or OAB wet, depending on the presence or absence of concomitant UI. The prevalence of OAB dry did not differ between the two assessment occasions (11% and 10%, respectively), but the prevalence of OAB wet increased from 6% to 16% (p < 0.001).

Conclusions

UI and other LUTS constitute dynamic conditions. In this study, there was a marked overall increase in the prevalence of UI, OAB, and nocturia in the same women from 1991 to 2007. Both incidence and remission of most symptoms were considerable.     

Urinary Incontinence,Overactive Bladder,and Other Lower Urinary Tract Symptoms: A Longitudinal Population-Based Survey in Men Aged 45–103 Years

Background

Lower urinary tract symptoms (LUTS) such as urinary incontinence (UI) and overactive bladder (OAB) are highly prevalent conditions, but there are few studies describing progression and remission of LUTS in men, especially over the long term.

Objective

To describe the prevalence of UI, OAB, and LUTS using current International Continence Society definitions in the same men studied longitudinally over time.

Design

Prospective, population-based, longitudinal study.

Setting and participants

In 1992, 10 458 men aged 45–99 yr, resident in the city of Gothenburg, were selected at random from the Population Register.

Measurements

The men received a postal questionnaire about the presence of LUTS, as well as questions on social, medical, health-related quality of life (HRQoL), and demographic data. Responders in 1992 were reassessed 11 yr later in 2003 using a similar questionnaire.

Results and limitations

In 2003, 4072 of the 7763 men who responded in 1992 were still available in the Population Register and 3257 men (80%) aged 56–103 yr, responded. Prevalence of UI and OAB had increased (p < 0.01) in the same men assessed in 1992 (4.5% and 15.6%, respectively) and 2003 (10.5% and 44.4%, respectively). The prevalence of nocturia, urgency, slow stream, hesitancy, incomplete emptying, postmicturition dribble, and the number of daytime micturitions had also increased (p < 0.01). Only a minority reported regression of symptoms. Men with UI or OAB reported a poorer (p < 0.001) HRQoL compared with men without UI or OAB.

Conclusions

There was a marked increase in the prevalence of UI, OAB, and other LUTS in the same men assessed longitudinally over this 11-yr period. UI and OAB had a negative influence on HRQoL, and men who developed UI or OAB had a greater deterioration in HRQoL than men who had no change in their UI/OAB status over time.     

Developing and Validating the International Consultation on Incontinence Questionnaire Bladder Diary

Background

Despite the common use of urinary diaries to assess lower urinary tract symptoms (LUTS), a standardised validated diary does not exist.

Objective

To develop a validated urinary diary, using the psychometric validation protocol used in previous International Consultation on Incontinence Questionnaire (ICIQ) modules.

Design, setting, and participants

We invited 400 consecutive patients attending the urology department for assessment of LUTS to complete a urinary diary (developed and validated for content in a previous study), and the ICIQ Male or Female LUTS questionnaire.

Outcome measurements and statistical analysis

To establish construct validity, the urinary diary was compared with known theories from published literature; to establish criterion validity, the diary was compared with questionnaire responses and/or urodynamic observations. Optimal diary duration was tested by comparing the 4-d diary against shorter durations. Patients completed a second diary after 2–3 wk for test-retest analysis, and a subset receiving sacral nerve stimulation completed the diary before and after treatment for analysis of responsiveness. A variety of statistical tests were used for different stages of the study.

Results and limitations

The urinary diaries and ICIQ LUTS questionnaires were completed by 264 patients. Construct validity was established for two of three tested hypotheses. Criterion testing showed good agreement between questionnaire and diary recordings of nocturia (κ = 0.653; p < 0.001; 92.2%) and incontinence (κ = 0.351; p < 0.001; 64.5%), whereas good agreement (κ = 0.378; p < 0.001; 69.2%) was observed between urodynamically proven incontinence and diary reports (n = 104). Diary recordings of urgency showed weak agreement with questionnaire responses (κ = −0.215; p < 0.001; 36%) and urodynamic observations (κ = −0.105; p = 0.256; 43.7%). The 3-d diary explained at least 94% of the total variance of the 4-d diary. A second diary for test-retest analysis was returned by 59 patients, demonstrating fair to excellent agreement (Spearman correlations: 0.49–0.88). Pre- and post-treatment analysis, on pilot testing, showed that the diary is responsive to change.

Conclusions

Using the ICIQ psychometric validation methodology, a bladder diary was developed for the assessment of LUTS and shown to be valid, reliable, and responsive to change. The 3-d diary has been accepted as the ICIQ bladder diary.

Patient summary

In this study, patients and clinicians developed and tested a diary in which patients can record their urinary symptoms. The resulting 3-d diary is called the ICIQ bladder diary and is available for adult men and women with urinary symptoms.     

Prevalence,Severity, and Symptom Bother of Lower Urinary Tract Symptoms among Men in the EPIC Study: Impact of Overactive Bladder

Background

Lower urinary tract symptoms (LUTS) are prevalent among men.

Objective

To describe the prevalence, severity, and symptom bother of LUTS in all men and men with overactive bladder (OAB) symptoms in the EPIC study.

Design, setting, and participants

A secondary analysis of data from EPIC, a multinational population-based survey of 19 165 adults, was performed. Current International Continence Society definitions were used for individual LUTS and OAB; OAB cases were defined as men reporting urgency.

Measurements

Participants were asked about the presence of individual LUTS and associated symptom bother. LUTS severity was measured using the International Prostate Symptom Score (IPSS).

Results and limitations

There was substantial overlap of storage, voiding, and postmicturition symptoms among all men (n = 7210) and in men with OAB symptoms (n = 502); men with OAB symptoms were more likely to experience multiple LUTS subtypes. Among both populations, nocturia was the most commonly reported symptom, except for urgency (the hallmark symptom) among men with OAB symptoms; terminal dribble and sensation of incomplete emptying were the most common voiding and postmicturition symptoms. The prevalence of all LUTS increased with age among the general population; only storage LUTS increased with age among men with OAB symptoms. Number of LUTS and mean IPSS increased with age in both populations but were higher among men with OAB symptoms at all ages; the proportion reporting moderate–severe LUTS was higher than the general population (30% vs 6%). The proportion of men with OAB symptoms reporting symptom bother increased with urgency severity and severity and number of LUTS. LUTS severity may have been underestimated by the IPSS, which does not assess incontinence.

Conclusions

Men with LUTS commonly experience coexisting storage, voiding, and postmicturition symptoms, emphasizing the need for comprehensive urologic assessments. Men with OAB symptoms reported more LUTS and greater severity than the general population. Symptom bother was related to number of LUTS and urgency severity.     

Tolterodine Treatment Improves Storage Symptoms Suggestive of Overactive Bladder in Men Treated With α-Blockers

Background

Some men receiving α-blocker therapy for lower urinary tract symptoms report persistent storage symptoms suggestive of overactive bladder (OAB).

Objective

To evaluate the efficacy of tolterodine extended release (ER) in men on α-blocker therapy.

Design, setting, and participants

This double-blind trial included men aged ≥40 yr with frequency, urgency, and at least moderate problems reported on the Patient Perception of Bladder Condition (PPBC), despite being on a stable dose of α-blocker for ≥1 mo.

Interventions

Subjects were randomized to tolterodine ER 4 mg per day or placebo for 12 wk while continuing their prescribed α-blocker therapy.

Measurements

At baseline and week 12, subjects completed the PPBC, International Prostate Symptom Score (IPSS), Overactive Bladder Questionnaire (OAB-q), and 5-d bladder diaries using the five-point Urinary Sensation Scale (USS). Frequency–urgency sum was defined as the sum of USS ratings for all micturitions.

Results and limitations

PPBC improvement from baseline to week 12 was reported by 63.6% and 61.6% of subjects receiving tolterodine ER plus α-blocker and placebo plus α-blocker, respectively; this treatment difference, which was the primary end point, was not statistically significant (p > 0.6699). At week 12, subjects receiving tolterodine ER plus α-blocker had significantly greater improvements versus placebo plus α-blocker in 24-h micturitions (−1.8 vs −1.2; p = 0.0079) and daytime micturitions (−1.3 vs −0.8; p = 0.0123); 24-h urgency episodes (−2.9 vs −1.8; p = 0.0010), daytime urgency episodes (−2.2 vs −1.4; p = 0.0017), and nocturnal urgency episodes (−0.5 vs −0.3; p = 0.0378); frequency–urgency sum (−7.8 vs −5.1; p = 0.0065); IPSS storage subscale (−2.6 vs −2.1; p = 0.0370); and OAB-q symptom bother scale (−17.9 vs −14.4; p = 0.0086) and coping domain (15.4 vs 12.4; p = 0.0491). Acute urinary retention requiring catheterization occurred in <1% of either group. There were no clinically meaningful changes in postvoid residual volume or maximum urinary flow rate.

Conclusions

Men with bothersome OAB symptoms despite continued α-blocker therapy showed significantly greater improvements in diary variables, IPSS Storage scores, and symptom bother when receiving additional tolterodine ER versus placebo plus α-blocker.     

Trigonal Injection of Botulinum Toxin A in Patients with Refractory Bladder Pain Syndrome/Interstitial Cystitis

Background

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic disease without an effective treatment, characterized by pain during bladder filling. Most nociceptive bladder afferents course in the trigone.

Objective

To evaluate efficacy and tolerability of trigonal injection of botulinum toxin A (BoNTA) in patients with BPS/IC. Urine concentration of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were also evaluated.

Design, setting, and participants

Women with refractory BPS/IC were included in an open, exploratory study.

Intervention

Under sedation, 100 U of BoNTA (Botox) were injected in 10 trigonal sites (10 U per 1 ml saline). Retreatment was allowed 3 mo after injection.

Measurements

Pain, urinary frequency, O’Leary-Sant score (OSS), quality of life, (QoL), and urodynamic testing at 1 and 3 mo and every 3 mo thereafter. Urine NGF and BDNF were assessed at the same points. Patients who were retreated were evaluated every 3 mo.

Results and limitations

All patients reported subjective improvement at 1- and 3-mo follow-up. Pain, daytime and nighttime voiding frequency, OSS, and QoL improved significantly. Bladder volume to first pain and maximal cystometric capacity more than doubled. Treatment remained effective in >50% of the patients for 9 mo. Retreatment was also effective in all cases, with similar duration. A significant, transient reduction in urinary NGF and BDNF was observed. No cases of voiding dysfunction occurred.The low number of patients and the lack of a placebo arm are obvious limitations of this study.

Conclusions

Trigonal injection of BoNTA is a safe and effective treatment for refractory BPS/IC.     

Gender and Age Differences in the Perception of Bother and Health Care Seeking for Lower Urinary Tract Symptoms: Results from the Hospitalised and Outpatients’ Profile and Expectations Study

Background

Few comparisons have been made of health care seeking behaviour for lower urinary tract symptoms (LUTS) between men and women, as well as trends across age groups.

Objective

To investigate the bother from LUTS and effect on health care seeking in both men and women of different age groups and in comparison between the two genders.

Design, setting, and participants

A representative cross section of each of 13 clinics of a general academic hospital, with equal numbers of subjects recruited in each of six design cells that were defined by age (18–40, 41–60, 61–80 yr) and gender.

Intervention

A 2-h in-person interview, conducted by a trained psychologist/interviewer in a clinic office.

Measurements

Severity of LUTS was measured by the International Prostate Symptom Score (IPSS). Treatment seeking was measured by a single item. A bother question was modified to assess overall bother. Impact on quality of life (QoL) was measured by the IPSS QoL question.

Results and limitations

The final study sample comprised 415 patients. More women than men reported the presence of LUTS (85.5% vs 75.2%; p = 0.01). LUTS were more bothersome in women (25.4% of women vs 17.6% of men with bother “some” or “a lot”; p = 0.02). Severity of LUTS increased with age in both genders (men: p < 0.001; women: p = 0.03). Bother from LUTS increased as severity of symptoms increased in both genders (p < 0.001) but was associated with age only in men (p < 0.001). QoL showed similar results as bother. Although men and women had equal prevalence of treatment seeking (27.9% vs 23.7%; p = 0.40), men, but not women, were more likely to seek treatment as age (p < 0.01) and severity of LUTS (p < 0.001) increased. In multivariate logistic regressions, only bother from LUTS was associated with treatment seeking in women, compared with bother, age, and the presence of voiding symptoms in men.

Conclusions

In our hospital-based sample, differences in LUTS frequency, bother, and health care seeking profiles between men and women suggest a different perception and response to LUTS between the two genders.     

Solifenacin Plus Tamsulosin Combination Treatment in Men With Lower Urinary Tract Symptoms and Bladder Outlet Obstruction: A Randomized Controlled Trial

Background

Alpha blockers are prescribed to manage lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Antimuscarinics are prescribed to treat overactive bladder (OAB).

Objective

To investigate the safety of a combination of solifenacin (SOLI) and tamsulosin oral controlled absorption system (TOCAS) in men with LUTS and bladder outlet obstruction (BOO).

Design, setting, and participants

Randomized, double-blind, parallel-group, placebo-controlled study in men aged >45 yr with LUTS and BOO for ≥3 mo, total International Prostate Symptom Score (IPSS) ≥8, BOO index ≥20, maximum urinary flow rate (Q_max) ≤12 ml/s, and voided volume ≥120 ml.

Interventions

Once-daily coadministration of TOCAS 0.4 mg plus SOLI 6 mg, TOCAS 0.4 mg plus SOLI 9 mg, or placebo for 12 wk.

Outcome measurements and statistical analysis

Primary (safety) measurements: Q_max and detrusor pressure at Q_max (P_detQ_max). Other safety assessments included postvoid residual (PVR) volume. Secondary end points included bladder contractile index (BCI) score and percent bladder voiding efficiency (BVE). An analysis of covariance model compared each TOCAS plus SOLI combination with placebo.

Results and limitations

Both active treatment groups were noninferior to placebo at end of treatment (EOT) for P_detQ_max and Q_max. Mean change from baseline PVR was significantly higher at all time points for TOCAS 0.4 mg plus SOLI 6 mg, and at weeks 2, 12, and EOT for TOCAS 0.4 mg plus SOLI 9 mg versus placebo. Both treatment groups were similar to placebo for BCI and BVE. Urinary retention was seen in only one patient receiving TOCAS 0.4 mg plus SOLI 6 mg. Limitations of the study were that prostate size and prostate-specific antigen level were not measured.

Conclusions

TOCAS 0.4 mg plus SOLI 6 mg or 9 mg was noninferior to placebo at EOT for P_detQ_max and Q_max in men with LUTS and BOO, and there was no clinical or statistical evidence of increased risk of urinary retention.     

Pilot Study of Liposome-encapsulated OnabotulinumtoxinA for Patients with Overactive Bladder: A Single-center Study

Background

Intradetrusor onabotulinumtoxinA (BoNT-A) injection benefits overactive bladder (OAB) patients, but increased postvoid residual (PVR) urine volume and urinary tract infection (UTI) remain risks. Intravesical instillation of liposomal BoNT-A instead of injection could prevent such adverse events.

Objective

To evaluate instillation of liquid liposomal BoNT-A (Lipotoxin) for the treatment of OAB and to determine its mechanism of action.

Design, setting, and participants

A double-blind randomized parallel controlled pilot trial in 24 OAB patients at a single tertiary center.

Intervention

Patients were randomly assigned to intravesical instillation of Lipotoxin containing 80 mg liposomes and 200 U BoNT-A or normal saline (N/S). Patients were retreated with Lipotoxin 1 mo later if they failed the first treatment.

Outcome measurement and statistical analysis

Voiding diaries, OAB symptom scores, urodynamic studies, and adverse events were monitored. The primary end point was change of total urinary frequency per 3 d at 1 mo after treatment. Immunohistochemistry and Western blotting for synaptic vesicle glycoprotein 2A (SV2A) and synaptosomal-associated protein, 25 kDa (SNAP25) were performed at baseline and 3 mo after treatment. The Wilcoxon rank sum test and Wilcoxon signed rank test were used for statistical analysis.

Results and limitations

At 1 mo after treatment, the change of urinary frequency per 3 d significantly improved in the Lipotoxin group (n = 12; median: −6.50; interquartile range [IQR]: −18.3 to −0.25; p = 0.008) but not in the N/S group. (n = 12.0; IQR: −7.75 to 8.0; p = 0.792). Urgency episodes also showed a significant decrease in the Lipotoxin group (−12.0; IQR: −20.3 to −2.75; p = 0.012) but not in the N/S group (−1.0; IQR: −11.0 to 2.5; p = 0.196). SV2A and SNAP25 were expressed in urothelial cells and suburothelial tissues. However, the protein expression did not significantly differ between responders and nonresponders at 3 mo after treatment.

Conclusions

Intravesical Lipotoxin instillation effectively reduced frequency episodes 1 mo after treatment in OAB patients without any increase in PVR or risk of UTI.

Patient summary

We demonstrated that intravesical Lipotoxin instillation reduced frequency episodes at 1 mo in overactive bladder patients. This procedure is safe, without an increase in postvoid residual or the risk of urinary tract infection.     

OnabotulinumtoxinA 100 U Significantly Improves All Idiopathic Overactive Bladder Symptoms and Quality of Life in Patients with Overactive Bladder and Urinary Incontinence: A Randomised,Double-Blind,Placebo-Controlled Trial

Background

Overactive bladder (OAB) syndrome with urinary incontinence (UI) is prevalent in the population and impairs health-related quality of life (HRQOL).

Objective

To assess the impact on efficacy, safety, and HRQOL of onabotulinumtoxinA (BOTOX^®, Allergan, Inc.) treatment in patients with OAB with UI.

Design, setting, and participants

This pivotal, multicentre, double-blind, randomised, placebo-controlled, phase 3 study enrolled patients with idiopathic OAB with ≥3 urgency UI episodes over 3 d and ≥8 micturitions per day who were inadequately managed by anticholinergics.

Intervention

OnabotulinumtoxinA at a 100 U dose (n = 277) or placebo (n = 271), administered as 20 intradetrusor injections of 0.5 ml.

Outcome measurements and statistical analysis

Co–primary end points were change from baseline in the number of UI episodes per day and proportion of patients reporting positive treatment response on the treatment benefit scale (TBS) at week 12. Additional end points included other OAB symptoms (episodes of urinary urgency incontinence, micturition, urgency, and nocturia) and HRQOL (Incontinence Quality of Life [I-QOL], King's Health Questionnaire [KHQ]). Safety assessments included adverse events (AEs), postvoid residual (PVR) urine volume, and initiation of clean intermittent catheterisation (CIC).

Results and limitations

OnabotulinumtoxinA significantly decreased UI episodes per day at week 12 (−2.95 for onabotulinumtoxinA versus −1.03 for placebo; p < 0.001). Reductions from baseline in all other OAB symptoms were also significantly greater following onabotulinumtoxinA compared with placebo (p ≤ 0.01). Patients perceived a significant improvement in their condition, as measured by patients with a positive treatment response on the TBS (62.8% for onabotulinumtoxinA versus 26.8% for placebo; p < 0.001). Clinically meaningful improvements from baseline in all I-QOL and KHQ multi-item domains (p < 0.001 versus placebo) indicated positive impact on HRQOL. AEs were mainly localised to the urinary tract. Mean PVR was higher in the onabotulinumtoxinA group (46.9 ml versus 10.1 ml at week 2; p < 0.001); 6.9% of onabotulinumtoxinA patients versus 0.7% of placebo patients initiated CIC.

Conclusions

OnabotulinumtoxinA 100 U was well tolerated and demonstrated significant and clinically relevant improvements in all OAB symptoms, patient-reported benefit, and HRQOL in patients inadequately managed by anticholinergics.

Trial registration

ClinicalTrials.gov: NCT00910520.     

Vardenafil decreases bladder afferent nerve activity in unanesthetized, decerebrate, spinal cord-injured rats

Background

Phosphodiesterase type 5 inhibitors (PDE5-Is) improve storage symptoms in benign prostatic hyperplasia patients, despite a lack of effect on peak urinary flow rate. Moreover, vardenafil improves urodynamic parameters in spinal cord-injured (SCI) patients with neurogenic detrusor overactivity (NDO). SCI rats also display NDO characterized by nonvoiding contractions (NVCs) during bladder filling, resulting in an increased bladder afferent nerve firing (BANF).

Objective

We postulated that vardenafil could improve urodynamic parameters by reducing BANF. The effect of vardenafil has been investigated on intravesical pressure by cystometry experiments while recording BANF in response to bladder filling.

Design, setting, and participants

Complete T7–T8 spinalization was performed in 15 female adult Sprague-Dawley rats (250–275 g).

Measurements

At 21–29 d postspinalization, fine filaments were dissected from the L6 dorsal roots and placed across a bipolar electrode. Bladder afferent nerve fibers were identified by electrical stimulation of the pelvic nerve and bladder distension. SCI rats were decerebrated before cystometry experiments. Bladders were filled to determine the maximal bladder filling volume (BFV) for each rat. Then, after bladder stabilization at 75% of maximal BFV, saline (n = 7) or vardenafil 1 mg/kg (n = 8) was delivered intravenously. NVCs and BANF were recorded for 45 min.

Results and limitations

In all SCI rats, BANF was already present and regular at resting conditions (26.2 ± 4.1 spikes per second). During bladder filling, intravesical pressure (IVP) slowly increased with transient NVCs superimposed. Concomitantly, BANF progressively increased up to 2.4-fold at maximal BFV (2.08 ± 0.24 ml). After stabilization at submaximal BFV, BANF was increased by 186 ± 37%. Vardenafil injection induced an immediate decrease in NVCs compared to saline (p < 0.001) and BANF (52% decrease vs 28% in saline after 45 min; p < 0.001).

Conclusions

Systemic vardenafil reduced both NVCs and BANF in unanesthetized, decerebrate, SCI rats. These findings provide new insights into the mechanism of action by which PDE5-Is improve storage symptoms in SCI patients.     

Repeated botulinum toxin type A injections for refractory overactive bladder: medium-term outcomes, safety profile, and discontinuation rates

Background

Efficacy and safety of botulinum toxin type A (BoNTA) injection is supported by level 1 evidence, but data regarding repeated injections are limited in patients with refractory overactive bladder (OAB) and idiopathic detrusor overactivity (IDO).

Objectives

Describe medium-term outcomes and discontinuation rates for patients adopting repeated BoNTA as a management strategy for IDO.

Design, setting, and participants

Prospective data from a single centre were collected from the first 100 patients.

Intervention

Bladder injection of BoNTA (predominantly 200 U onabotulinumtoxinA; Allergan Ltd., Marlow, Buckinghamshire, UK) in an outpatient setting.

Measurements

OAB symptoms, quality of life, discontinuation rates, interinjection interval, and adverse events were recorded. Data comparisons were performed using a generalised linear model or a chi-square test where appropriate.

Results and limitations

Two hundred seven injections were performed in 100 patients. All patients had 1 injection, 53 had a total of 2, 20 had 3, 13 had 4, 10 had 5, 5 had 6, 3 had 7, 1 had 8, 1 had 9, and 1 had 10 injections. Statistics were applied up to five repeated injections. A statistically significant reduction in frequency, urgency, and urge urinary incontinence were seen following the first BoNTA injection compared to baseline. This improvement was maintained after repeated injections and was not statistically different when comparing differences between injections. Thirty-seven patients stopped treatment after the first two injections; thereafter, dropouts were rare. The most common reasons for discontinuing treatment were poor efficacy (13%) and clean intermittent self-catheterisation (CISC)–related issues (11%). The incidence of CISC after the first injection was 35%. Bacteriuria was detected in 21% of patients. The mean interinjection interval was 322 d. Limitations included the concurrent use of antimuscarinic drugs in some patients.

Conclusions

BoNTA can provide a safe and effective medium-term management option for patients with refractory IDO. The most common reasons cited for stopping treatment were poor efficacy and CISC-related issues.