Long-term Outcomes of Periurethral Sphincter Botulinum Toxin in Female Chronic Urinary Retention
Article information
Abstract
Purpose
Nonneurogenic chronic urinary retention is an uncommon problem in young female individuals, and a well characterised causes is Fowler syndrome (primary disorder of urethral sphincter relaxation). Intermittent catheterisation is often challenging, and gold standard treatment sacral neuromodulation is not widely available. Urethral sphincter botulinum toxin injection has been shown to be effective cross-sectionally, however little is known about long-term outcomes.
Methods
Female individuals presenting with urinary retention due to Fowler syndrome were reviewed retrospectively from a single tertiary referral centre over an 11-year period (2010–2021). One hundred units of onabotulinum toxin A (BoTX-A) was injected into the striated urethral sphincter in a divided dose by the periurethral approach. Efficacy and side effects were assessed 4 weeks after injection.
Results
Thirty-three female individuals with a mean age of 40.1±14.1 years received 165 unique urethral sphincter BoTX-A injections over 11 years. Nineteen individuals (57.6%) presented in acute urinary retention, and 28 (84.8%) were reliant on catheterisation. Twenty-one individuals (64%) responded to BoTX-A injections and had a significantly raised baseline maximum urethral closure pressure (MUCP), compared to nonresponders (114.6 cm H2O, P=0.012). Side effects were reported following 19 injections (11.5%) however, were mild and transient. Fifteen individuals received more than 1 botulinum toxin injection (median, 3 injections), with a median interval of 112 days (interquartile range) and efficacy persisted following repeat injections and no safety concerns were seen.
Conclusions
Sphincter botulinum toxin through the periurethral approach is safe and effective following repeat injections, and offers a low-cost, minimally invasive alternative to managing female chronic urinary retention due to Fowler syndrome, particularly when there was a high baseline MUCP.
INTRODUCTION
Nonneurogenic chronic urinary retention is an uncommon problem in young female individuals, and one of the well characterised causes is Fowler syndrome (a primary disorder of urethral sphincter relaxation) [1]. Individuals typically retain large volumes of urine (>1 L) with impaired sensations of bladder fullness, which may be associated with polycystic ovarian syndrome [1]. Intermittent self-catheterisation can be painful, and a ‘gripping’ sensation on catheter removal may be reported, which poses a challenge to catheterisation and increases the risk for developing complications of chronic urinary retention such as urinary tract infections.
Sacral neuromodulation (SNM) is a highly effective treatment, which restores voiding in nearly 70% of cases [2], however is associated with complications and a revision rate of up to 53% [3]. Access to SNM can be limited due to its’ expense and the specialised nature of the technique and, furthermore, SNM may not be suitable for all individuals with Fowler syndrome. Other surgical treatments such as urinary diversion are highly invasive and not suitable for all individuals. Botulinum toxin injections into the urethral sphincter is an alternative for treating urinary retention. Botulinum toxin injected into the external urethral sphincter was first investigated for Fowler syndrome in 1992, after promising results in detrusor sphincter dyssynergia (DSD) [4] however was found to be ineffective [5]. Although an open label study of periurethral botulinum toxin in Fowler syndrome demonstrated improvement in urine flowrate, postvoid residual and urethral pressure profile measurements, as well as individual reported satisfaction after 10 weeks [6], the sole randomised control trial in neurogenic and nonneurogenic individuals investigating urethral sphincter botulinum toxin reported a negative outcome [7]. Little is known about the long-term outcomes of periurethral sphincter botulinum toxin injection in a cohort of female individuals with urinary retention due Fowler syndrome, which is highly relevant as National Institute for Health and Care Excellence (NICE) has recently published a favourable guidance for urethral sphincter botulinum toxin injections for chronic nonobstructive urinary retention [8].
We report the long-term outcomes of periurethral sphincter botulinum toxin injection in a cohort of female individuals with urinary retention due Fowler syndrome.
MATERIALS AND METHODS
We reviewed the records of all individuals with Fowler syndrome who received urethral sphincter botulinum toxin between 1st March 2010 and 31st December 2021 in a tertiary hospital with local approval to provide off-label botulinum toxin injections as part of an institutionally approved audit with all assessments part of standard clinical care. Female individuals referred for urinary retention underwent a standard diagnostic evaluation which has already been outlined [9] and underwent specific investigations for Fowler syndrome including urethral sphincter electromyography (EMG), urodynamics and/or urethral pressure profilometry (UPP) to measure the maximum urethral closure pressure (MUCP). Urodynamics were performed in line with the International Continence Society published recommendations and standard urodynamic parameters were noted [10]. UPP control values have been shown to depend upon age and a normal control range was previously established giving the expected value according to the formula: 92-patient’s age in years, cm H2O [11,12]. Urethral sphincter botulinum toxin was offered to individuals meeting the diagnostic criteria for a primary disorder of urethral sphincter relaxation (Fowler syndrome) (abnormal concentric needle EMG of the striated urethral sphincter and/or abnormally elevated urethral pressure profile) and deemed suitable for this treatment following a multidisciplinary team discussion, as previously described [6]. Exclusion criteria were a history of urethral surgery, stress urinary incontinence, a neurological cause of abnormal sphincter function, pregnancy, current urinary tract infection, or prescribed anticoagulants. All individuals were counselled of the possible adverse events related to botulinum toxin injection (transient stress urinary incontinence, pain, and bleeding), and provided informed consent.
Onabotulinum toxin A (BoTX-A, BotoxTM; Abvie, Irvine, CA, USA), was injected into the external urethral sphincter as an outpatient procedure by the periurethral approach as previously described [6], though EMG guidance was avoided as this increased discomfort. Local anaesthetic cream (5% lidocaine and prilocaine) was applied around the external urethral meatus 30–45 minutes prior to the procedure, and in the supine position, 1 mL of 2% lidocaine was injected on either side of the external urethral meatus, followed by 100 units of BoTX-A, dissolved in saline (2 mL initially, reduced to 1 mL) injected periurethrally at the level of the striated urethral sphincter divided on either side at the 3 and 9 o’clock position. Once the local anaesthetic took effect, the duration of the procedure was approximately 10 minutes and individuals could leave the department immediately afterwards. Treatment outcomes were systematically assessed telephonically 4 weeks post-procedure using a proforma, and the treatment was considered successful (‘responders’) if there was reported improvement in one of the following voiding functions: reduction in catheter use, catheter freedom, increased ease of urinary flow, or ease of catheterisation, reduction in residual volume. Individuals were systematically asked about adverse effects at the 4 weeks call that included questions about stress urinary incontinence, pain, local site infection and bleeding.
Individuals contacted the department for repeat injections when the effects began to diminish, after a minimum of 12 weeks. Individuals who did not report improvement in voiding function were labelled as ‘nonresponders.’
Statistical analyses were performed using IBM SPSS Statistics ver. 28.0 (IBM Co., Armonk, NY, USA). Continuous variables were expressed as the mean±standard deviation. Between group analyses utilised chi-square test for categorical variables, and the independent t-test for continuous variables. All statistical analyses were 2-sided and considered significant at P<0.05.
RESULTS
Demographics and Baseline Voiding Dysfunction
A total of 165 urethral sphincter BoTX-A injections were administered across 33 unique individuals (mean, 5 injections per individual; median [range], 2 [1–25] injections per individual). The mean age at the time of receiving first BoTX-A injection was 40.1±14.1 years (Table 1). Baseline voiding function and investigations are shown in Table 1. Twenty-three individuals (69.7%) had one or more medical comorbidity. Twenty-six individuals (78.8%) were performing clean intermittent self-catheterisation (CISC). The frequency of baseline CISC was variable, from alternate days (n=2) to 8 times per day (n=1). The mean MUCP at baseline was raised at 105.5±25.9 cm H2O, compared with the mean expected MUCP of 59.4±11.2 cm H2O (Table 1).
BoTX-A Responders Versus Nonresponders
Among the 33 females receiving BoTX-A injections, twentyone (64%) were classed as a ‘responder’ (Table 2). The reported improvements were a reduction in CISC (n=11, 52.4%), catheter freedom (n=5, 23.8%), improved urinary flow (n=4, 19%), reduced straining (n=3, 14.3%), and improved bladder sensation (n=2, 9.5%). There were no significant differences in baseline demographics. A greater proportion of individuals in the nonresponder group performed CISC compared to the nonresponder group (83% vs. 76%, P=0.041) and were more likely to be in complete urinary retention (P=0.052). All individuals in the nonresponder group required catheterisation, either ISC (n=10) or suprapubic catherisation (n=2), compared with the responder group who ISC (n=16) or did not require regular catherisation (n=5). Baseline mean MUCP was significantly higher in the responder group compared to the nonresponder group (114.6±20 cm H2O vs. 88.6±26.4 cm H2O respectively, P=0.004).
Fifteen individuals (71.4%) who responded to the treatment underwent repeat BoTX-A injection (Table 3), at a median interval of 112 days (interquartile range, 70). 13 individuals received more than 3 BoTX-A injections, and 6 individuals received more than 10 injections each, comprising 107 of total injections.
Ten individuals discontinued treatment either after the first injection (n=6), or subsequent injections (n=4). They were followed up and the reasons for discontinuation were individual choice (n=2), overactive bladder symptoms (n=1), subsequently undergoing SNM (n=1) or moving elsewhere or lost to follow-up (n=6).
The following side effects (n=19, 11.5% of injections) were reported: mild degree of stress incontinence that was transient and fully resolved (n=11 injections; 6 were reported in the same individual), short-lasting pain and bleeding (n=6 injections) and transient urge incontinence (n=2 injections). One individual experienced mild stress incontinence after the first injection continued to report only mild and transient incontinence with repeat injections which did not progress and was closely monitored.
DISCUSSION
Our study is the longest observational review of urethral sphincter BoTX-A injections in female individuals with nonneurogenic chronic urinary that spanned an 11-year period. We showed that the minimally invasive periurethral approach of administering BoTX-A into the urethral sphincter was both safe and effective with a 64% response rate in female individuals with Fowler’s syndrome. Individuals who had a higher MUCP at baseline were significantly more likely to respond to BoTX-A injection. Furthermore, women who were performing intermittent catheterisation and presenting with a clinical picture of incomplete bladder emptying were more likely to be responders. Seventy-one point four percent of responders continued to report efficacy with repeat injections and no safety concerns were identified.
Both the bladder neck and the striated urethral sphincter should relax for successful voiding, and impaired relaxation of the urethral sphincter due to abnormal urethral sphincter activity can result in voiding dysfunction. Inhibitory signals from the striated urethral sphincter maintains continence, and this is exaggerated with a primary disorder of urethral sphincter relaxation as seen in Fowler syndrome. Brainstem activity is reduced when the bladder is filling in Fowler syndrome, as demonstrated by functional magnetic resonance imaging (fMRI) [13]. The mechanism is likely a strong inhibitory afferent signal generated by the urethra, which inhibits bladder afferent signals to higher centres such as the periaqueductal grey matter in the brainstem [13,14]. This is best evidenced by SNM restoring voiding in Fowler syndrome by modulating the urethral afferent signals, rather than a direct action upon the urethra [13,14].
Botulinum is a potent neurotoxin and its presynaptic action at the neuromuscular junction in striated muscle is widely used to treat spasticity and dystonia. The exact mechanism by which injection of botulinum toxin into the urethral sphincter improves voiding is unclear. At the urethral sphincter, botulinum toxin is proposed to block the presynaptic acetylcholine release at the neuromuscular junction and this ameliorates the abnormal urethral sphincter function [15,16]. It has been recognised that botulinum toxin can regulate sensory nerve function by blocking other neurotransmitters such as adenosine triphosphate, calcitonin gene-related peptide and substance P, and by blocking peripheral sensitisation can indirectly reduce central sensitisation as seen in migraine [17], and bladder pain syndrome [16]. Results from our study demonstrate that those with a higher MUCP at baseline respond better to urethral sphincter botulinum toxin injection. It is likely that striated muscle relaxation is the mechanism leading to improved voiding function, however a reduction in central sensitisation may also play a role. It has been shown previously that the MUCP reduces after botulinum toxin when repeated 4-week postinjection [6].
In the 1980’s, efficacy of urethral sphincter botulinum toxin for DSD was successfully established [4]. The therapeutic effect reduced urethral pressure and post void residual volumes [4]. Previous studies of urethral sphincter botulinum toxin injection efficacy in nonneurogenic individuals were thought to be unsuccessful, though the interpretation of these results have been limited by heterogeneous patient selection that included both neurogenic and nonneurogenic individuals, different methods of injection (transurethral or periurethral) and differing outcome measures of success [7,18-23]. The sole prospective randomised control trial comparing urethral sphincter botulinum toxin injection with a normal saline placebo injection in nonneurogenic individuals was reported a negative trial, with a success rate of only 43.5% [7]. However, this study evaluated a heterogenous group of nonneurogenic male and female individuals with voiding dysfunction, and was limited by a high withdrawal rate and short interval follow-up of one month [7]. Jiang et al. [7] did report significant improvement in detrusor pressure, maximum urinary flow rate and voided volume only in the botulinum toxin group, and repeat injections did result in subjective symptomatic improvement and an objective reduction in detrusor pressure.
There is a paucity of long-term data to determine the efficacy of this treatment in Fowler syndrome and to our knowledge, this is the first study that has evaluated the long-term outcome of urethral sphincter botulinum toxin injection in individuals with Fowler syndrome (primary disorder of urethral sphincter relaxation, high tone nonrelaxing sphincter). A successful response was seen in 64% (n=21), and 45% (n=15) received more than one repeat injection. The discontinuation rate due to personal choice, alternative treatment or overactive bladder symptoms was 19% in the responder group. Repeat botulinum toxin injections continued to have a therapeutic effect over time, with 6 individuals receiving more than 10 injections at a median interval of more than 3.5 months. There have been no safety concerns in individuals receiving multiple injections (n=2 had 25 injections), as seen in the extensive use of regular botulinum toxin injections for dystonia and spasticity.
The measurements of a successful outcomes are typically urodynamic (reduced detrusor pressure, earlier sensation bladder fullness), urinary flow rate and reduction in post void residual volume [18,20,22,24,25], and questionnaire-based quality of life and symptom assessment [24,26]. Specific success is seen in nonneurogenic individuals at rates of 58.5%–88.5% [6,18-20,22-25,27]. Nadeem et al. [27] demonstrated the durability of response in nonneurogenic females with voiding dysfunction sustained over 20 months in 60% with cystoscopic guided botulinum toxin injections with improved maximum flow rate and reduced postvoid residual. In our study, reported reduction in intermittent catheter use was an important indicator of success, and a willingness to undergo repeat injections. The interval between injections and duration of efficacy (median, 112 days) was similar to earlier reports when used for DSD secondary to a spinal cord injury [26,28]. Previous reports of residual volume significantly decreased at day 14 postinjection, but were not sustained at day 45 [29], with the treatment effect lasting less than 3 months [23].
We found responders had a raised MUCP, and it has been shown previously that in both neurogenic and nonneurogenic individuals with low bladder contractility, urethral sphincter botulinum toxin does reduce urethral pressure and the residual volume [21]. Failure of treatment is important to identify, and the significant baseline differences between treatment responders and nonresponders in our study was a raised MUCP and performing CISC. A mixed aetiology cohort with reduced detrusor contractility is more likely to fail treatment, with the inability to mount an effective detrusor contraction not mitigated by relaxation of the urethral sphincter [19]. The heterogeneity of individual groups in retrospective studies, does make it difficult to identify predictive factors of treatment success, for example an open bladder neck was identified to be a predictor of successful outcome [18].
Two routes of urethral sphincter botulinum toxin injection— cystoscopic guided injection or periurethral—have both been shown to be robust and durable in spinal cord injury [30]. Transrectal ultrasound guided transperineal botulinum toxin injection has been used in DSD [28], and combined fluoroscopic and EMG-guided transperineal injection has been used for DSD in a neurogenic population [26,31]. We initially performed periurethral BoTX-A injections using EMG guidance, as EMG-guided transperineal technique has been validated by MRI confirming the location of botulinum toxin injection [31]. We moved away from EMG-guided injections because of patient discomfort with similar outcomes and our experience in performing diagnostic periurethral sphincter EMG.
The recognised complications of urethral sphincter botulinum toxin injections are uncommon, as demonstrated in our cohort with a rate of 11.5% for stress incontinence [18], haematuria [24], and urinary incontinence (urgency or unspecified) [7,18,20,21,23]. There were no concerns in responders developing stress incontinence with repeat injections, and one individual was closely monitored without progression of stress incontinence with repeat injections. The periurethral procedure requires fewer health resources as it is outpatient based, utilising local anaesthesia and the entire appointment time is less than 1 hour, and was able to be successfully maintained during the coronavirus disease 2019 pandemic [32]. Psychological comorbidities did not predict outcomes in this study, consistent with SNM in Fowlers syndrome [33] and other urological indications for SNM as shown by a systematic review [34].
The study was limited by the small number of individuals, however nonneurogenic chronic urinary retention in females is uncommon and SNM will continue to remain a first line treatment. Furthermore, validated questionnaires were not used to capture efficacy in view of the paucity of questionnaires specifically designed to capture patient reported outcomes and symptoms in urinary retention who are using catheters when the service was started in 2010. Repeat urodynamic studies including uroflowmetry were not included as earlier studies have demonstrated improvements in objective voiding parameters. Patient attrition was high and could reflect the tertiary nature of the centre catering to a geographically spread-out population. The short duration of mean repeat injections and sustainability over longer periods needs to be evaluated.
In conclusion, periurethral botulinum toxin injection is an effective and safe treatment for treating nonneurogenic female chronic urinary retention long-term. It is a well-tolerated procedure, with a 64% response rate, few (11.5%) transient adverse events and after 11 years no safety concerns. Individual selection is important as this treatment was most effective in those responders with a significantly higher MUCP. Whereas SNM will always be first line treatment for managing chronic urinary retention in females, periurethral botulinum toxin injections are a tenable choice, particularly when SNM is not suitable and with recent favourable NICE guidance [8], more centres may take on this option.
Notes
Grant/Fund Support
JNP is supported in part by funding from the United Kingdom’s Department of Health NIHR Biomedical Research Centres funding scheme.
Research Ethics
This study was approved by institutional clinical audit committee Queen Square Quality and Safety team (approval no. 25-202223-CA).
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTION STATEMENT
· Conceptualization: SS, PM, MP, JNP
· Data curation: SLW, PA, JNP
· Formal analysis: SLW, PA, JNP
· Funding acquisition: JNP
· Methodology: SS, PM, MP, JNP
· Project administration: SLW, JNP
· Visualization: SLW, JNP
· Writing - original draft: SLW
· Writing - review & editing: SLW, SS, PM, MP, JNP