European Urology

1. Introduction

Bladder-neck dyssynergia (BND) is characterized as an inadequate opening of the bladder neck during micturition, resulting in obstruction to urinary flow in the absence of other anatomical obstruction [1]. BND has also been termed Marion's disease, dysfunctional bladder neck, and primary bladder-neck obstruction. It commonly occurs in men younger than 50 yr and accounts for 33–54% of diagnoses made on videourodynamics studies (VUDS) in young men with lower urinary tract symptoms (LUTS) [2], and [3].

Exact etiology of BND is unclear. Studies thus far suggest abnormal morphological arrangement of the detrusor or trigonal musculature [4]; a higher density of neuropeptide Y immunoreactive nerves, which increase the sympathetic tone of the bladder neck and cause a functional obstruction [5]; or an extension of functional striated sphincter to the bladder neck, causing an ineffective voiding pattern [6].

Treatment options include pharmacotherapy with α-blockers and transurethral incision of the bladder neck. α-Blockers have a success rate of only 54–70% [2], [3], and [7] and has poor long-term compliance rates of 13–30% [2], [3], [7], and [8]. In fact some studies reported no significant benefits with α-blockers [4], and [8].

TUIBN is curative in 82–100% [4], [7], [8], [9], and [10] but causes retrograde ejaculation in 11–27% [7], [9], and [11]. Some have advocated that a single incision will suffice and result in a lower retrograde ejaculation rate of 0–16% [4], [8], and [11]. However Kochakarn et al. [10] found a 70% decrease in sperm counts without a decrease in ejaculatory volume pre- and post-unilateral incision of the bladder neck. In this study, two patients became azoospermic.

BoNTA has established applications in treating skeletal muscle spasms and off-label use in neurogenic detrusor overactivity and nonneurogenic voiding dysfunction [1], [12], [13], [14], and [15]. BoNTA inhibits acetylcholine release into the neuromuscular junction of both presynaptic motor and autonomic neurons [16] including efferent neurons innervating exocrine glands and smooth muscles, such as gastrointestinal and urogenital sphincters. Thus BoNTA has been used for focal hyperhidrosis, hypersalivation, hyperlacrimation, achalasia, and sphincter of Oddi dysfunction [17].

In studies employing the same principle of a presynaptic neuromuscular blockade, reports of BoNTA's use in treating detrusor external sphincter dyssynergia in spinal cord–injured patients, detrusor overactivity, and benign prostatic obstruction have largely been positive [12], [13], [14], [15], [18], [19], [20], [21], and [22].

Given that the main theories of BND revolve around increased smooth muscle tone, this prospective study aims to investigate the effect of BoNTA when injected into the bladder neck and prostate of males with BND.

2. Methods

From July 2005 to November 2006, males diagnosed with BND on VUDS who had failed a trial of bladder training and α-blockers with or without anticholingerics for a minimum period of 3 mo were recruited in this nonblinded, uncontrolled prospective study. All patients were older than 18 yr, had moderate to severe LUTS (IPSS > 15) and maximum urinary flow rate < 15 ml/s. Diagnosis of BND was made on VUDS when narrowing at the vesicle neck was noted during voluntary micturition. This diagnosis was confirmed by Whiteside “trapping of contrast” when patients were asked to momentarily stop micturition during voluntary voiding. Care was taken to exclude bladder outlet obstruction due to a narrowed prostatic channel, which has a very different appearance. No voiding pressure criteria were used; however, the opening pressure, voiding pressure at peak flow, and obstruction status on Abrams-Griffiths curve were noted. Approval by the institutional review board and ethics committee, and informed consent from patients were obtained.

Patients with previous pelvic, urethral, prostate, bladder or bladder-neck surgeries or pathologies, or central or peripheral neurological disorders or neuromuscular conditions were excluded. Patients with benign prostatic enlargement (BPE) on subsequent flexible cystoscopy were also excluded. Finally patients unable or unwilling to complete a 3-d frequency-volume chart, IPSS-QoL questionnaire, or repeat VUDS at 6 wk postprocedure, or to comply with the study protocol were excluded.

Those who agreed to participate were reevaluated with a history, physical examination, and a screening protocol, which included a urinalysis and urine culture, a kidney-ureters-bladder (KUB) X-ray, uroflowmetry, and postvoid residual (PVR) volume scan, a 3-d frequency–volume chart, a preprocedure IPSS-QoL questionnaire, a flexible cystoscopy, and a VUDS.

A 22F rigid cystoscope was inserted under general anesthesia and the bladder was surveyed; prostatic lobe enlargement was again excluded. BOTOX^® (Allergan) diluted at 10 U/ml with preservative-free saline was injected transurethrally at 10 sites into the patients’ bladder necks and lateral lobes of their prostates. All patients were discharged the same day after voiding without problems.

Patients were reviewed at 1, 6, and 12 wk and at 4-wk intervals thereafter by means of a 3-d frequency–volume chart, free uroflometry, PVR volume scan, and IPSS-QoL questionnaire. Pressure flow studies were repeated at 6 wk postprocedure. Adverse events if any were also documented at each visit. Patients whose symptoms recurred were offered a repeat injection.

Successful outcome was defined as a reduction of IPSS score of > 50% from baseline and improvement of peak urinary flow rate of ≥ 3 ml/s.

The nonparametric Wilcoxon signed rank test with multiple comparison corrections by the Bonferroni adjustment method was used for statistical analysis. Statistical significance was considered at p < 0.05 after adjustment.

3. Results

Thirteen patients met our study criteria and 8 patients consented for the study. Mean age was 36.9 yr (range, 20–52). Mean duration of symptoms was 6.5 yr (range, 1–25) before diagnosis. Mean follow-up period was 10.4 mo (range, 5–19); 6 of 8 patients have exceeded 32 wk of follow-up.

Overall, a 55% reduction in mean IPSS was observed at week 1. All 8 patients had > 7 points reduction in IPSS with 7 of 8 (87.5%) achieving > 50% reduction of IPSS from baseline. These improvements were maintained at 4 mo but showed a slight uptrend at 8 mo, although these levels did not reach pretreatment levels. QoL scores improved by > 40% (Table 1).

Six of 8 (75.0%) patients had > 3 ml/s increase in maximum urinary flow rate with overall mean maximum urinary flow rates improving from 11.6 to 17.2 (p = 0.048) at 6 wk. These results were maintained beyond 32 wk in terms of absolute values despite their failing to achieve statistical significance after 16 wk.

Daytime frequency and mean voiding interval were significantly reduced at 6 wk but failed to maintain statistical significance at 16 wk after adjustment. These symptoms appeared to recur at 8 mo. No significant changes were noted in the mean voided volume and largest voided volume (Table 1).

Individual urodynamics results are shown in Table 2.

Opening pressures decreased by 23% and mean maximum voiding pressure decreased by 41% on repeat urodynamics. A 14% reduction was observed in voiding pressure at maximum flow rate (PdetQ_max) although this value did not achieve statistical significance (Table 1). Five of 8 patients shifted from the equivocal to the unobstructed region on the Abrams-Griffiths nomogram (Table 2).

Three of 8 (37.5%) patients had recurrence of symptoms at a mean of 8 mo (range, 6–10) posttherapy. All of them had further relief of symptoms after a second BoNTA injection (mean IPSS improved by 40.6%). Five patients had no recurrence of symptoms until a mean of 10.8 mo. Two of 8 patients actually remained symptom-free despite being 1 yr posttherapy.

All patients tolerated treatment well. No patient withdrew from the study. Potential side effects like urinary retention, urinary incontinence, gross hematuria, urinary tract infection, or systemic weakness were not reported. In addition, no patient reported any decrease in ejaculatory volume or ejaculatory dysfunction.

4. Discussion

BND is an underdiagnosed condition in younger men presenting with LUTS. Diagnosis is made on VUDS when delayed and incomplete bladder-neck opening is seen during voluntary voiding. The opening pressures and PdetQ_max in our cohort are only minimally raised by established criteria for bladder outlet obstruction, implying that high obstructive voiding pressures are not mandatory for diagnosis. In fact all our patients were in the equivocal rather than the obstructed region of the Abrams-Griffiths nomogram. Indeed, Nitti [1] has commented that voiding pressures may range from 20 to 200 cm H₂O. Furthermore, Nitti [2] classified BND into three distinct types: classic high pressure low flow, normal pressure low flow with bladder-neck narrowing, and delayed opening of the bladder neck. Although cystoscopic appearance of a high bladder neck is not a stated requirement, it was observed in all our patients.

Case series of BoNTA use in BPE reported variable success with reduction in prostate volumes ranging from 13–55% [18], [19], [20], [21], and [22]. The exact mechanism for volume reduction is unclear but is likely related to a reduced neurotropic influence on the prostate. One postulation suggests that denervation alters growth factor expression in the prostate, causing programmed cell death and glandular atrophy [20], and [23].

Because the two main theories of BND revolve around an extension of the external sphincter and increased sympathetic tone at the bladder neck, we postulated that BoNTA might result in a similar relaxation or even atrophy of the bladder neck, reducing the delay in bladder-neck opening and improving flow.

The mechanism behind the concomitant reduction of storage symptoms can only be speculated. The action of BoNTA does not seem to be restricted to efferent autonomic neurons but may also affect afferent autonomic neurons and ganglionic neurons [24]. A recent review of the use of BoNTA in overactive bladder by Apostolidis [15] proposed that BoNTA inhibits the release of excitatory neurotransmitters such as acetylcholine, adenosine triphosphate, and substance P, and reduces axonal expression of capsaicin and purinergic receptors, resulting in central desensitisation, thus improving storage symptoms.

Our dosing aliquots and method of injection were extrapolated from case series of BoNTA in treatment of BPE, overactive bladder, and idiopathic detrusor overactivity [13], [14], and [19] because there were no reports of BoNTA use in BND from our literature review. Chuang et al. [19] and Park et al. [22] injected 100 U of BoNTA into smaller prostates (<30 g) of Asian men, and Kuo [20] injected BoNTA into 10 sites in separate Asian studies. All studies showed good results without any reported adverse effects. Hence we chose to inject our cohort of young Asian men with small prostates with 100 U of BoNTA into 10 sites.

Our definitions of success were based on use of α-blockers for BPE in placebo-controlled trials because this is a pilot study with no precedent in our literature reviews. Success is defined by > 50% drop in IPSS and > 3 ml/s increase in maximum flow. In placebo-controlled α-blockers trials [25], and [26], use of placebos resulted in a 0.7–1.4 ml/s increase in mean maximum flow and 17–33% decrease in IPSS, whereas use of α-blockers resulted in a 2.2–3.6 ml/s increase in mean maximum flow and 39–49% decrease in IPSS. In another placebo-controlled BoNTA trial [18], use of BoNTA in BPE patients resulted in an increase of mean maximum flow of 6.8 ml/s and a 54% decrease in IPSS, whereas use of placebo resulted in minimal changes in mean maximum flow and IPSS. Our results of a 5.6 ml/s increase in mean maximum flow and 55% decrease in IPSS are greater than those achieved with placebos and comparable with those achieved with α-blockers and BoNTA in these trials.

Opening pressures and mean maximum voiding pressures were significantly improved on urodynamics. If delayed bladder-neck opening resulted in true BND, improved bladder-neck relaxation may explain this finding. Most patients reported subjective improvements in their symptoms. Although other urodynamics parameters showed some improvements, they failed to reach statistical significance, probably because of our small sample size.

BND is not characterized by high voiding pressures and patients can have slightly increased or even normal voiding pressures [2], [3], and [8]. It is therefore unclear if a significant reduction in voiding pressures should be expected although there was a clear trend of improvement noted in our patients.

Many studies involving BoNTA for various voiding dysfunction conditions showed that the mean duration of action of BoNTA is about 8–11 mo [12], [14], and [15], which largely concurred with our finding. Maria et al. [18] reported improvement of maximum flow rates that were maintained beyond 12 mo after injection of 200 U of BoNTA diluted in 4 ml and injected into each lobe of the prostate. This prolonged effect might be due to glandular atrophy. Skeletal muscle atrophy from BoNTA is well described and has even been exploited for cosmetic purposes [27], and [28]. It can only be speculated that the prolonged effect in two of our patients is due to bladder-neck atrophy.

Our mean duration of effect implies that repeat injections can be performed about three times in 2 yr. Our three patients with recurrence of symptoms showed resolution of symptoms following a second BoNTA injection.

In our nonblinded, uncontrolled study with a small sample size, many parameters showed improvements but failed to achieve statistical significance. Although it might not be possible for this pilot study to prove the efficacy or evaluation of the safety of BoNTA in treatment of patients with BND, nevertheless it shows promising results.

5. Conclusion

Placebo-controlled trials and larger studies exploring higher doses and differing dilutions of BoNTA are required. It is possible that early repeat injections in partial responders or an increase in the dose may prove more effective.

Conflicts of interest

The authors have nothing to disclose.