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Keywords:

  • lower urinary tract symptoms;
  • onabotulinumtoxina;
  • primary bladder-neck dysfunction;
  • urinary bladder-neck obstruction

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Objective

To determine efficacy and safety of OnabotulinumtoxinA (BoNT-A) injection therapy in medically refractory patients with lower urinary tract symptoms (LUTS) due to primary bladder-neck dysfunction (PBND).

Materials and Methods

Thirty-five consecutive ambulatory males diagnosed with PBND and refractory to medical therapy, with IPSS > 15, Qmax < 15 ml/sec, and total prostate volume < 30 cm3, were screened from January 2010 to December 2011. Eligible patients underwent transurethral bladder-neck injection of BoNT-A (200 U, 50 U/ml × 4 sites) and were assessed at baseline, 2-, 6-, 9-, and 12-month postprocedure and until duration of clinical response. The primary outcome was the change from baseline in total IPSS, and secondary outcome were storage- and voiding-IPSS, QoL score, Qmax, and postvoiding residual volume (PVR), patient-reported outcomes. Adverse effects were also recorded, including ejaculatory dysfunctions.

Results

Of 30 enrolled patients (mean age 33.8 years), 29 (96.7%) completed the study. A statistically significant improvement of total IPSS was observed from 21.9 at baseline, to 7.8, 10.3, and 16.6 at 2, 6, and 9 months, respectively (P < 0.000). Statistically significant improvements from baseline of storage- and voiding-IPSS, QoL score, Qmax, and PVR were also observed until 9-month postprocedure. The proportion of patients with overall satisfaction was favorable although decreasing from 80% at 2 months, to 44.8% at 12 months. No significant adverse effects or ejaculatory dysfunctions were noted.

Conclusions

BoNT-A injection therapy appears effective and safe in medically refractory men with PBND, although repeated procedures are required for long-term sustained benefit. Randomized controlled trials are warranted in order to corroborate these results. Neurourol. Urodynam. 33:142–146, 2014. © 2013 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Primary bladder-neck dysfunction (PBND) is characterized by a non-neurogenic failure of bladder neck to relax during voluntary voiding, causing lower urinary tract symptoms (LUTS), in the absence of other causes of anatomical obstruction, such as benign prostatic hyperplasia (BPH).[1]

Although the true prevalence of PBND is unknown, it accounts for 33–54% of diagnoses made on video-urodynamic studies (VUDS) in young men with LUTS.[1, 2] The aetiology is basically unclear, although a sympathetic hypertonicity leading to a lissosphincter dysfunction, thickening of the bladder neck and reflex inhibition of detrusor contractility has been suggested.[1-3] VUDS helps to show the incomplete or delayed opening of bladder neck during voluntary voiding, associated to low flow and high or normal detrusor voiding pressure.[1] Therapy relies mainly on α-blockers and transurethral incision of the bladder neck (TUIBN), but they do have relevant limitations such as adverse effects, significant failure rate and limited long-term adherence with α-blockers,[1, 2, 4-6] risk of retrograde ejaculation with TUIBN.[5-7]

Botulinum neurotoxin (BoNT) that block at the injection site the release of neurotransmitters, for example, acetylcholine and norepinephrine, from pre-synaptic nerves, has been demonstrated to affect sympathetic activity in urethral smooth muscle.[8] Injection of BoNT at the level of bladder neck, urethra, and prostate is a novel emerging treatment for LUTS caused by BPH[9] or by voiding dysfunctions characterized by non-relaxing proximal urethra/bladder neck,[10] however, only a pilot study including eight patients followed-up for 32 weeks has been published on its use to treat PBND.[11]

The aim of this study was to evaluate long-term efficacy and safety of bladder-neck injection of BoNT type A (BoNT-A) in young men with medically refractory LUTS due to PBND, assessing both objective and patient-reported outcomes (PROs).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Recruitment of Participants

From January 2010 to December 2011, men aged 18–50 years, diagnosed with PBND on VUDS, refractory to α-blockers with or without anticolinergics for at least 3 months as defined by persistent moderate to severe LUTS (International Prostate Symptom Score [IPSS] > 15) and maximum urinary flow rate (Qmax) < 15 ml/sec with a minimum voided volume > 125 ml, were eligible for inclusion in the study. Diagnosis of PBND on VUDS was based on the evidence of incomplete or delayed opening of bladder neck during voluntary detrusor contraction.[1] No voiding pressure criteria were used, although voiding parameters were recorded.

The main exclusion criteria were total prostate volume (TPV) > 30 cm3, detrusor overactivity, infravesical obstruction from any cause other than PBND, active urinary tract infections (UTIs), history of recurrent UTIs, prostate or bladder pathologies, previous lower urinary tract surgeries, neurological disorders.

Study Design, Ethics, and Reporting

A prospective, single-center, single-armed, cohort study was designed. After a wash-out phase from previous pharmacological therapies of 28 days, ambulatory, consecutive subjects fulfilling the selection criteria underwent the study therapy. A minimum of five visits was foreseen: at baseline, and at 2-, 6-, 9-, and 12-month post-therapy. Afterwards, patients continued to be reassessed every 2 months until duration of clinical response.

The study has been performed in accordance with last version of the Declaration of Helsinki, and our Institutional Review Board approved the protocol. Patients were asked to sign a written informed consent before study entry. Urodynamic methods, definitions, and units conformed to the standards recommended by the International Continence Society.[12] The study has been reported according to the STROBE checklist.

Baseline Evaluation

Enrolled subjects were assessed preoperatively by means of collection of medical history, comprehensive urological and physical evaluation including digital rectal examination, check of concomitant medications, urinalysis and urine culture, measurement of TPV by transrectal ultrasonography, uroflowmetry with postvoid residual urine (PVR) volume scan, VUDS (Urolab Opus 6; LifTech, Stafford, TX) and urethrocystoscopy. Finally, patients were administered the IPSS,[13] including seven symptomatic questions (“total IPSS,” response scale 0–35) and a question on LUTS-related quality-of-life (“QoL score,” response scale 0–6).

Intervention

Patients received 200 U of BoNT-A (Botox®, Allergan, Irvine, CA) diluted in 4 ml of saline (50 U/ml) and injected transurethrally at four sites (3-6-9-12 o'clock, 1 ml/site) into the bladder neck, at about 1 cm from bladder-neck rim, using a 23 gauge needle through a 22F rigid cystoscope, in lithotomy position and general anesthesia (propofol). One-shot dose of a quinolone was routinely administered before procedure in order to prevent UTIs. Mean duration of the procedures was 14 ± 3 min. A Foley catheter was inserted only in patients with postoperative complete urinary retention. All patients were discharged from the hospital the next day after spontaneous voiding without problems.

Outcomes Measures

The primary outcome was the change in total IPSS mean score. Secondary outcomes were storage- and voiding-IPSS subscores, QoL score, Qmax, and PVR. Patients were also administered a PROs questionnaire including three items from the Patient Perception of Study Medication questionnaire, an instrument developed by GlaxoSmithKline to measure patient satisfaction in the setting of BPH and LUTS pharmacotherapy.[14][15] At the end of the study or at withdrawal, patients were also asked to report their willingness to re-do the treatment under the same circumstances and to recommend the treatment to another person with the same problem (“yes” or “not”).

Safety of the treatment was assessed by recording both local and systemic complications, and adverse effects during procedure and follow-up, including ejaculatory dysfunctions.

Statistical Analyses

The variables considered in the study were described as mean and ±SE or range. Data were compared by using the Wilcoxon test or the Student t-test, as appropriate. Normality was checked by using the Kolmogorov–Smirnov test. Log-rank test and Cox proportional-hazards regression model were used for univariate and multivariate analyses, respectively, in order to study the association between time to failure (improvement from baseline of less than 50% in total IPSS) and meaningful baseline characteristics (age, duration of symptoms, IPSS score, and subscores, TPV, Qmax, PVR, maximum voiding pressure, PdetQmax, Abrams–Griffiths category).

Confidence intervals are 95% and two-sided P < 0.05 was deemed to indicate statistical significance. All calculations were carried out with MedCalc for Windows, version 12.3.0 (MedCalc Software, Mariakerke, Belgium).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Patients Disposition and Characteristics

Of 35 screened patients, 30 patients (mean age of 33.8 year, range 19–48) were recruited and assessed at 2 and 6 months, and 29 (96.7%) completed the study. The mean duration of LUTS was 4.6 year (range 1–7). Previuos α-blocker therapy included tamsulosin (24 patients) and alfuzosin (six patients), and three patients also took anticolinergics. Mean TPV was of 24.0 ± 0.8 cm3. At pressure-flow study, mean PdetQmax, mean maximum voiding pressure and mean maximum voiding volume were of 48.0 ± 2.9 cmH2O, 69.0 ± 10.3 cmH2O, and 358.0 ± 41.0 ml, respectively. Twenty-six (86.7%) patients were in the “equivocal” obstruction category of the Abrams–Griffiths nomogram, and the other four (13.3%) patients in the “obstructed” category. Mean follow-up period was of 11.4 ± 2.7 months. During the study period, no patient underwent additional interventions.

Efficacy Results

Changes from baseline in International Prostate Symptom Score

Mean IPSS values and mean rates of change from baseline are shown in Table I and Figure 1, respectively. A reduction in mean total IPSS from baseline was observed at all postoperative evaluations, but it failed to achieve statistical significance at 12 months. The rate of change from baseline in total IPSS values appeared to be very large in the early follow-up period, however, it showed a progressive downtrend later on.

Table I. Changes From Baseline in International Prostate Symptom Score (IPSS), Storage and Voiding Subscores, QoL, and Uroflow Parameters
ParametersBaseline2 months (n = 30)6 months (n = 30)9 months (n = 29)12 months (n = 29)
  1. Numbers indicate mean values ± SE.

  2. The P-values indicate statistical significance of difference with baseline.

Total IPSS21.9 ± 1.67.8 ± 1.1, P < 0.00010.3 ± 1.3, P < 0.00016.6 ± 1.5, P < 0.00019.9 ± 1.5, P = 0.059
Storage-IPSS8.3 ± 0.94.4 ± 0.9, P = 0.0004.3 ± 0.9, P = 0.0006.5 ± 1.0, P = 0.0177.3 ± 1.0, P = 0.146
Voiding-IPSS13.6 ± 1.13.4 ± 0.5, P < 0.0006.0 ± 0.7, P = 0.00010.1 ± 1.0, P = 0.00012.6 ± 1.0, P = 0.055
QoL (Q.8 of IPSS)5.0 ± 0.22.3 ± 0.3, P < 0.0002.6 ± 0.3, P < 0.0003.4 ± 0.2, P < 0.0004.9 ± 0.2, P = 0.365
Qmax (ml/sec)7.8 ± 0.616.9 ± 0.9, P < 0.00015.5 ± 0.8, P < 0.00012.7 ± 0.6, P = 0.0018.6 ± 0.6, P = 0.237
PVR (ml)55.4 ± 6.035.8 ± 6.2, P < 0.00036.5 ± 5.9, P < 0.00043.6 ± 5.8, P = 0.01751.2 ± 6.4, P = 0.208
image

Figure 1. Time course of changes from baseline (%, SEM) in International Prostate Symptom Score (total IPSS) and subscores (storage- and voiding-IPSS).

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Changes from baseline in International Prostate Symptom Subscores

A reduction from baseline in mean values of both storage-IPSS and voiding-IPSS was observed at all postoperative evaluations, but it failed to achieve statistical significance at 12 months (Table I and Fig. 1). The rate of change of voiding-IPSS was higher than those of storage-IPSS at 2-month evaluation only.

Changes from baseline in quality-of-life

An improvement in QoL score was reported at all scheduled follow-up evaluations (Table I). Once again, the changes from baseline were highly statistically significant at 2-, 6-, and 9-month evaluations, but not at 12 months.

Changes from baseline in uroflow parameters

The increase in mean Qmax values from baseline remained statistically significant until 9 months, although a continuous downtrend was observed after the early increase (Table I). Similarly, statistically significant reduction in mean PVR from baseline was observed at 2-, 6-, and 9-month evaluation, but not at 12 months (Table I).

Patient-reported outcomes

Table II displays mean postoperative PRO scores at each visit. An improvement of their LUTS was experienced by 86.7% and 73.3% of patients at 2 and 6 months, respectively, but only by 50.0% and 10.3% of patients at 9 and 12 months, respectively.

Table II. Patient-Reported Outcome (PRO) Measures
PRO measures2 months (n = 30)6 months (n = 30)9 months (n = 29)12 months (n = 29)
  1. Numbers indicate mean values ± SE.

  2. P-values indicate statistical significance of difference with previous assessment.

  3. For patient global impression of improvement (PGI-I), the subject was asked “since you underwent the study therapy, how has control of your urinary problems changed?”; the response scale (1–7, higher score indicating better outcome) was: much worse/much less control; worse; somewhat worse; no change; somewhat improved; improved; much improved. For patient satisfaction with efficacy (PSAT-E), the subject was asked “how satisfied are you with the effect of the study therapy on control of your urinary problems?”; and for patient overall satisfaction (PSAT-O), the subject was asked “overall, how satisfied are you with the study therapy and its effects on your urinary problems?”; the response scales (1–7, higher score indicating better outcome) were: very dissatisfied; dissatisfied; somewhat dissatisfied; neutral (neither satisfied nor dissatisfied); somewhat satisfied; satisfied; very satisfied.

PGI-I5.7 ± 0.25.0 ± 0.2, P = 0.0004.4 ± 0.2, P = 0.0003.5 ± 0.2, P < 0.000
PSAT-E5.5 ± 0.34.9 ± 0.3, P = 0.0004.4 ± 0.3, P = 0.0043.8 ± 0.3, P = 0.002
PSAT-O5.6 ± 0.35.2 ± 0.4, P = 0.0545.0 ± 0.3, P = 0.0314.1 ± 0.3, P = 0.000

Satisfaction with the efficacy of the treatment on LUTS control was reported by 80.0%, 70%, and 46.7% of patients at 2, 6, and 9 months, respectively, and 41.4% was still satisfied at 12 months. Likewise, 80.0%, 73.3%, and 60.0% of patients expressed overall satisfaction at 2, 6, and 9 months, respectively, and 44.8% still reported satisfaction at 12 months. In all, 23 (79.3%) patients would repeat the same treatment in the same circumstances and 25 (86.2%) patients would recommend the treatment to another person with the same problem.

Univariate and multivariate analyses

Among evaluated baseline variables, duration of symptoms > 5 years (P = 0.039) and storage-IPSS > 10 (P = 0.016) turned out to be the only predictors for failure at univariate analysis. However, no independent predictors were found at multivariate analysis.

Safety Results

During treatment and follow-up, no systemic adverse effects related to the treatment were reported. Postoperatively, 19 (63.3%) and 13 (43.3%) patients reported painful micturition and mild gross hematuria, respectively, but both problems resolved spontaneously in 24 hr. Four (13.3%) patients experienced postoperative complete urinary retention requiring overnight urethral catheterization. No patients reported long-term local side-effects or ejaculatory dysfunctions.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

The results of the present study showed that transurethral injection of BoNT-A into the bladder neck is an effective treatment in younger patients with medically refractory PBND. A very satisfactory symptomatic improvement was observed until 6 months that remained statistically significant until 9 months, although a continuous postoperative uptrend of total IPSS was observed. Changes from baseline of Qmax and PVR confirmed the efficacy of the study treatment and mirrored the time course observed with IPSS. The mean duration of action of 8–11 months reported by most studies on the treatment of various lower urinary tract dysfunctions with BoNT-A[9-11] is in agreement with our findings. The loss of efficacy overtime is not surprising when using BoNT and is expected for all clinical uses of this drug. Furthermore, the treatment was well tolerated, without serious adverse effects and ejaculatory dysfunctions.

In a previous pilot study by Lim et al.,[11] eight medically refractory men (mean age of 36.9 years), diagnosed with PBND on VUDS, received 100 U of BoNT-A injected into the bladder neck and proximal prostatic urethra (10 U/ml × 10 sites). The authors reported that seven (87.5%) patients had >50% reduction of IPSS at 6 weeks from baseline, and that the overall mean reduction was 50%. IPSS change from baseline continued to be statistically significant at 8 months and three (37.5%) patients had recurrence of LUTS at mean of 8-month posttherapy. In agreement with our findings, the observed decrease in IPSS was higher than that of about 17–36% achieved with placebo based on α-blockers trials. None reported any adverse effects or ejaculatory dysfunction. In disagreement with our results, Qmax also improved, but the difference versus baseline was statistically significant only until 6 weeks. However, based on the well-known dose-response effect of BoNT, we used a double dose of BoNT-A with the assumption that a higher dose would allow improving the clinical efficacy. The same dose has been largely used in BPH patients' series without increasing adverse effects.[9] On the other hand, we used a small dilution volume in order to avoid the need for routine catheterization and to limit the risk of postoperative urinary retention; this risk would be expected to be higher when injecting a greater dilution volume directly into the bladder neck of patients with bladder neck dysfunction, taking also into account the delayed therapeutic effect of the BoNT.

Noteworthy, an improvement of both storage and voiding LUTS was observed. This finding is in agreement with those of previous studies.[11, 16] Although the underlying mechanism remains to be clarified, the improvement of storage LUTS is of interest because urgency and frequency are the most frequent patient-reported most bothersome symptoms and are often maintained after medical treatment.[17]

Similarly to BPH, PBND might be defined by the LUTS whose severity is not strictly related to objectively measurable parameters and whose impact on patients is heterogeneous. As a result, the value of PROs, such as patient's perceptions and satisfaction with therapy has been increasingly acknowledged in clinical practice guidelines for LUTS management.[18-20] In the present study, we provided an insight into the effect of BoNT-A from the patient's perspective. The assessment of PROs showed very satisfactory results with nearly 80% willingness to re-do the procedure. These findings were comparable with those reported in other studies on treatment of LUTS with BoNT-A[3, 16] or conventional drug therapies.[15, 21-23]

Our results compare favorably also with those reported in studies on TUIBN.[5-7] The TUIBN has the advantage of sustained long-term benefit without the need of re-do procedures. However, the main concern with this invasive treatment is the development of retrograde ejaculation in 11–27% of patients,[5] although modifications of the technique have been reported to allow avoiding this troublesome dysfunction.[5, 7, 24] Significant risk of reduced sperm counts has been reported also after modified, unilateral TUIBN.[7]

Most patients in the present study were in the “equivocal” obstruction category of Abrams–Griffiths nomogram. This finding is in compliance with previous studies reporting that PBND on VUDS is not necessarily characterized by high voiding pressure, but patients can have low flow associated to slightly increased or normal voiding pressure.[1, 2, 6, 11]

We think that BoNT-A therapy could be of value in patients where conventional pharmacological therapies is limited by suboptimal efficacy, adverse effects or low compliance, or in those willing to avoid/delay the risk of retrograde ejaculation, although they must be aware of the need for repeated injections and that the use of BoNT in this setting is still off-label. In particular, BoNT-A therapy may have a still more significant role in the treatment of younger patients that do not tolerate the side effects, especially ejaculatory dysfunctions, associated to conventional treatment options.

The main strengths of this study are in the prospective design, the length of the follow-up allowing elucidation of the long-term efficacy and safety profile of BoNT-A in the treatment of PBND, the low rate of lost-to-follow-up, the assessment of both objective and subjective multiple outcome measures with the collection of useful information from the patient's perspective.

The generalizability of our findings is limited by the open-label, non-comparative design of the study, with lack of a placebo arm. Consequently, the results of this study, while encouraging, should not be embraced into regular practice as such. Multicenter, randomized placebo-controlled trials are needed, although the relatively low prevalence of the disorder and the invasiveness of the procedure make it difficult to embark such a studies. Other limitations are the relatively small sample size, the single-center nature, the selection and recall biases, and the use of diagnostic tools (IPSS and PROs questionnaire, Abrams–Griffiths nomogram) not validated in this specific setting.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Our results show that bladder neck injection of BoNT-A is safe and effective in improving LUTS and uroflow parameters in patients with medically refractory PBND. The clinical benefit is confirmed by satisfying patient-perceived outcomes. The treatment is safe and not associated to ejaculatory dysfunctions. Repeated treatments are required for long-term sustained effectiveness. These promising results warrant confirmation in randomized controlled trials with appropriate dose titration.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES