Botulinum toxin A for the Treatment of Overactive Bladder

The standard treatment for overactive bladder starts with patient education and behavior therapies, followed by antimuscarinic agents. For patients with urgency urinary incontinence refractory to antimuscarinic therapy, currently both American Urological Association (AUA) and European Association of Urology (EAU) guidelines suggested that intravesical injection of botulinum toxin A should be offered. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as well as attenuation of central sensitization. Multiple randomized, placebo-controlled trials demonstrated that botulinum toxin A to be an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity. The urinary incontinence episodes, maximum cystometric capacity, and maximum detrusor pressure were improved greater by botulinum toxin A compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Therefore, botulinum toxin A offers an effective treatment option for patients with refractory overactive bladder.     

Botulinum toxin for the management of bladder dysfunction

This review highlights a recent innovation in the medical treatment of detrusor overactivity (DO). Anticholinergics are usually the gold standard to treat bladder overactivity. Adverse effects and lack of efficacy are the two main causes for considering alternative treatments. Until recently, invasive surgery (mainly bladder augmentation) was the only available treatment option for patients with intractable DO. This article considers botulinum toxin type A (BTX-A) injection as an alternative treatment to surgery in patients with DO who do not respond to anticholinergic therapy. To identify papers for inclusion in this review, we searched PubMed with the keywords 'botulinum toxin', 'overactive bladder', 'urinary incontinence' and 'neurogenic bladder' for the years 2000-5. Review articles were not included. Abstracts were cited only if they contained important new information. Experimental animal studies and articles or book chapters related to the use of botulinum toxin for other indications (such as achalasia and cervical dystonia) were analysed with regard to the mechanisms of action of botulinum toxin.From this review, it appears that BTX-A injection into the detrusor muscle is a very effective method for treating urinary incontinence secondary to neurogenic detrusor overactivity (NDO), as well as urinary incontinence due to idiopathic overactive bladder (IDO). In both conditions, the duration of effect seems to be at least 6 months. Overall success rates seem to be similar in both patient populations. For NDO, only one evidence-based medicine level 1 study is available, whereas for IDO, only evidence-based medicine level 3 or 4 studies have been published. Particularly in this latter indication, injection technique and outcome parameters vary from study to study and need to be standardised. Without randomised controlled studies aimed at comparing different techniques and dosages, it remains difficult to decide what technique is optimal for treating patients with IDO who are not willing to perform clean intermittent self-catheterisation (CISC). Therefore, studies that compare different dosages and techniques with the risk of needing CISC in regard to the duration of the effect are mandatory. As more studies of repeated injections have been published, it appears that, at least at medium follow-up, the toxin remains as effective as after the first injection, and there is no evidence of change in bladder compliance or detrusor fibrosis. However, long-term observational studies are necessary to assess these last points. Finally, the commonly reported dose appears to be well tolerated, since few adverse effects have been reported.     

The overactive bladder: review of current pharmacotherapy in adults. Part 2: treatment options in cases refractory to anticholinergics

In the first part of this review the potential pathophysiological factors involved in the overactive bladder were outlined, and the wide range of first-line anticholinergic pharmacotherapies available for such patients were reviewed. The second part will focus on the intravesical instillation of resiniferatoxin and injections of botulinum toxin into the bladder to treat overactive bladder and detrusor overactivity. Resiniferatoxin has been shown to increase bladder capacity and improve incontinence in patients with neurogenic and non-neurogenic detrusor overactivity. Botulinum toxin has successfully been used to treat neurogenic and idiopathic detrusor overactivity, with improvements observed in bladder capacity, decreases in detrusor pressures on filling and voiding, and increased volumes at first contraction. Further validation is required for both treatments, in the form of large randomised controlled trials, before their use can be considered routine, with particular focus on dosing required.     

Alternative use of botulinum toxin in urology

Botulinum toxin A is used in the treatment of lower urinary tract symptoms due to detrusor sphincter dysynergia and detrusor hyper-reflexia (neurogenic detrusor deficiency). The toxin acts by producing paralysis of muscle tissue and has been shown to be safe and effective in the treatment of conditions caused by increased muscle tonicity and spasticity. Here the literature is reviewed chronologically, the established and emerging indications for the urological use of botulinum toxin evaluated and future applications are also considered.     

Alternative use of botulinum toxin in urology

Botulinum toxin A is used in the treatment of lower urinary tract symptoms due to detrusor sphincter dysynergia and detrusor hyper-reflexia (neurogenic detrusor deficiency). The toxin acts by producing paralysis of muscle tissue and has been shown to be safe and effective in the treatment of conditions caused by increased muscle tonicity and spasticity. Here the literature is reviewed chronologically, the established and emerging indications for the urological use of botulinum toxin evaluated and future applications are also considered.     

经尿道前列腺电切治疗前列腺增生伴逼尿肌乏力的疗效分析

目的探讨经尿道前列腺电切（TURF）治疗前列腺增生（BPH）伴逼尿肌乏力的疗效。方法对确诊为前列腺增生并发逼尿肌乏力的患者行经尿道前列腺电切,手术前后分别记录国际前列腺症状评分（IPSS）、生活质量评估（QOL）、自由尿流率（Qmax）、残余尿量（PVR）、斥力流率测定,并进行治疗前后比较,分析手术疗效。结果入选32例确诊前列腺增生合并逼尿肌乏力患者,治疗前后IPSS评分、QOL评分自由尿流率、残余尿量、最大逼尿肌压力差异有显著性、结论BPH合并逼尿肌乏力患者可行TURP手术提高生活质量。     

BoNT/A1 Secondary Failure for the Treatment of Neurogenic Detrusor Overactivity: An Ex Vivo Functional Study

Management of neurogenic detrusor overactivity (NDO) remains a clinical priority to improve patients’ quality of life and prevent dramatic urological complications. Intradetrusor injection of onabotulinumtoxinA (BoNT/A1, botulinum neurotoxin A1) is approved as second therapeutic line in these patients, demonstrating a good efficacy. However, a loss of its efficacy over time has been described, with no clear understanding of the underlying mechanisms. This paper aims at shedding new light on BoNT/A1 secondary failure in NDO through functional and structural analysis. Three groups of patients (either non-NDO, NDO with no toxin history or toxin secondary failure) were investigated using an ex vivo bladder strip assay. Detrusor strips were tensed in organ baths and submitted to electrical field stimulation to generate contractions. Recombinant BoNT/A1 was then added at various concentrations and contractions recorded for 4 h. Histology exploring BoNT/A1 targets, fibrosis and neuronal markers was also used. Detrusor strips from patients with BoNT/A1 secondary failure displayed a smaller sensitivity to toxin ex vivo at 3 nM compared to the other groups. Histological evaluation demonstrated the presence of cleaved Synaptosomal-Associated Protein, 25 kDa (c-SNAP25) in the detrusor from the toxin-secondary failure population, indicating some remaining in vivo sensitivity to BoNT/A1 despite the therapeutic escape. Moreover, residual c-SNAP25 did not affect parasympathetic-driven contractions observed ex vivo. This study confirms the slightly lower efficacy of BoNT/A1 in the BoNT/A1 secondary failure NDO group, suggesting that the escape from BoNT/A1 efficacy in NDO occurs at least at the parasympathetic level and could imply compensatory mechanisms for detrusor contraction.     

Therapeutic Efficacy of Urethral Sphincteric Botulinum Toxin Injections for Female Sphincter Dysfunctions and a Search for Predictive Factors

External urethral sphincter (EUS) dysfunction is a common, bothersome female voiding dysfunction. This study aims to analyze the characteristics of different types of female EUS dysfunction, as well as to determine the outcome predictors of sphincteric botulinum toxin A (BoNT-A) injection. Women receiving sphincteric BoNT-A injections for refractory EUS dysfunction were retrospectively reviewed. A comparison of the baseline clinical, urodynamic parameters and the treatment responses were made for patients with different EUS dysfunctions. A total of 106 females were included. Significantly increased detrusor overactivity, detrusor contracting pressure and the bladder outlet obstruction index with decreased urge sensation were noted in patients diagnosed with dysfunctional voiding or detrusor sphincter dyssynergia comparing to those diagnosed with poor relaxation of the external urethral sphincter. The average subjective improvement rate was 67% for the injection. The therapeutic effect was not affected by the type of EUS dysfunction. The multivariate analysis revealed that bladder neck narrowing and catheterization history were predictive of negative outcomes. There is a distinct urodynamic presentation for each type of female EUS dysfunction. Sphincteric BoNT-A injection provides a good therapeutic outcome for refractory EUS dysfunction. A narrowing bladder neck and a history of catheterization suggest poor therapeutic outcomes.     

Botulinum toxin A treatment of adult upper and lower limb spasticity

This article discusses the treatment of spasticity with botulinum toxin A as a new approach in the neurological rehabilitation of patients after stroke. Clinical studies have been reviewed to provide information about target groups, technical aspects and the advantages and disadvantages of treating spasticity with botulinum toxin A. Open and controlled studies showed that the intramuscular injection of Dysport 500 to 1,500U or Botox 100 to 300U could reversibly relieve upper limb flexor and lower limb extensor spasticity. A reduced muscle tone, pain relief, better hand hygiene and improved walking function were the main benefits. Patients tolerated the treatment well. Activity or, if not possible, electrical stimulation of the injected muscles may enhance the effectiveness of the costly toxin. Serial casting is another option. With respect to the action of botulinum toxin A, it is suggested that the effect of the toxin could be mediated by paresis of both the extrafusal and intrafusal muscle fibres, thereby altering the afferent discharge in the muscle.     

Botulinum toxin type B: a new injectable treatment for cervical dystonia

Cervical dystonia (CD) causes involuntary muscle spasms and is often associated with pain. Recently, botulinum toxin type B (BTX-B) (Myobloc?, Elan South San Francisco, CA, USA) was approved for general use in the treatment of CD in the USA. In two large pivotal trials, BTX-B was found to be safe and effective in decreasing the movements, pain and disability associated with CD. Benefits were noted both in patients who no longer respond and in those who continue to respond to botulinum toxin type A (BTX-A). BTX-B offers an additional therapeutic option for patients with CD.     

Purinergic P2X3 heteroreceptors enhance parasympathetic motor drive in isolated porcine detrusor, a reliable model for development of P2X selective blockers for detrusor hyperactivity

Various forms of low urinary tract symptoms (LUTS) seem dependant upon dysregulation of the purinergic pathway which produces sensory- or motor-activated incontinence. A body of evidence in human urinary bladders supports a link between up-regulation of purinergic activity and the pathogenesis of detrusor instability. This study investigated the potential role of adenosine 5'-triphosphate (ATP) in the control of detrusor motor drive in a model of porcine urinary bladder. The involvement of ATP on excitatory activity was assessed by measuring neurally-evoked [(3)H]-acetylcholine (ACh) release and smooth muscle contraction in detrusor strips. Epithelium-deprived preparations were used to minimize the influence of non-neural sources of ACh and ATP on parasympathetic neurotransmission. ACh release and smooth muscle contractility were not significantly affected by neural ATP in normal detrusor, but markedly enhanced when ATP hydrolysis was reduced by ectoATPase inhibitors, as well as by α,β-methylene-ATP (ABMA), agonist resistant to ecto-enzymes degradation. Prejunctional P2X receptors located on cholinergic nerves are involved in such potentiating effect. These purinergic heteroreceptors were characterized as P2X(3) subunits by means of the putative antagonists: NF449 (P2X(1,3) selective), NF023 (P2X(1,3) selective), PPNDS (P2X(1) selective) and A-317491 (P2X(3) selective). In porcine detrusor, P2X(3) receptors are functionally expressed at neural site facilitating neurogenic ACh release. When purine breakdown is experimentally down-regulated to mimicking the impaired purinergic pathway observed in pathological human bladders, endogenous ATP can markedly enhance detrusor contractility through activation of these receptors. Since P2X(3) blockade represents a potential therapeutic approach for diseases of the urinary tract, isolated porcine detrusor represents a reliable model for development of novel selective P2X(3) antagonists beneficial in the treatment of detrusor hyperactivity.     

Afferent mechanism in the urinary tract

Much of the current research on lower urinary tract dysfunction is focused on afferent mechanisms. The main goals are to define and modulate the signaling pathways by which afferent information is generated and conveyed to the central nervous system. Alterations in bladder afferent mechanisms are a potential source of voiding dysfunction and an emerging source of drug targets. Even some established drug therapies such as muscarinic receptor antagonists, as well as emerging therapies such as botulinum toxin type-A, may act partly through afferent mechanisms. This review presents up-to-date findings on the localization of afferent fiber types within the bladder wall, afferent receptors and transmitters, and how these may communicate with the urothelium, interstitial cells, and detrusor smooth muscle to regulate micturition in normal and pathological bladders. Peripheral and central mechanisms of afferent sensitization and myogenic mechanisms that lead to detrusor overactivity, overactive bladder symptoms, and urgency sensations are also covered as well as new therapeutic approaches and new and established methods of measuring afferent activity.     

针灸治疗BPH致膀胱逼尿肌收缩无力TURP术后的临床观察

目的观察针灸治疗良性前列腺增生致膀胱逼尿肌无力患者经尿道前列腺电切术后效果。方法选择因良性前列腺增生、膀胱过度充盈致逼尿肌损伤,引起膀胱逼尿肌收缩无力并行经尿道前列腺电切术38例患者,术后采用电针刺激关元、中极、肾俞、次髎、三阴交、足三里穴,观察疗效。结果治疗4个疗程后,35例TURP术后留置膀胱造瘘管（1～8）周后全部拔除,排尿通畅。3例膀胱逼尿肌收缩功能几乎无任何改善。长期留置膀胱造瘘治疗。结论针灸治疗良性前列腺增生致膀胱逼尿肌无力经尿道前列腺电切术后疗效明确,可以减少膀胱造瘘率,提高患者的生活质量。     

经超声测定逼尿肌厚度在诊断老年女性膀胱出口梗阻中的应用

目的探讨研究经超声测量膀胱逼尿肌厚度在诊断老年女性膀胱出口梗阻中的应用价值。方法收集本院2009年9月至2012年9月伴有下尿路症状的102例60岁以上老年女性患者作为研究对象,将所有患者按压力流速测定结果分为梗阻组与非梗阻组,梗阻组Qmax≤12mL/s,最大尿流率时逼尿肌压力≥25cmH2O,非梗阻组Qmax>12mL/s,最大尿流率时逼尿肌压力<25cmH2O,分析并比较两组之间的年龄、尿动力学参数、膀胱逼尿肌厚度的差异,并计算膀胱逼尿肌厚度≥1.9mm时在无创诊断老年女性膀胱出口梗阻的特异性及敏感性。结果两组患者之间的年龄比较差异无统计学意义(P>0.05);两组最大逼尿肌压力、最大尿流率时逼尿肌压力、Qmax、排尿量、残余尿量及逼尿肌厚度比较差异有统计学意义(P<0.05),当膀胱前壁逼尿肌厚度≥1.9mm时,诊断膀胱出口梗阻的敏感性为39%,特异性为100%。结论经超声测定膀胱前壁逼尿肌厚度在诊断老年女性膀胱出口梗阻具有无创伤,简单、方便的特点,值得在临床推广。     

Botulinum toxin B: a review of its therapeutic potential in the management of cervical dystonia

Botulinum toxins are well known as the causative agents of human botulism food poisoning. However, in the past two decades they have become an important therapeutic mainstay in the treatment of dystonias including cervical dystonia, a neurological disorder characterised by involuntary contractions of the cervical and/or shoulder muscles. The toxins inhibit acetylcholine release from neuromuscular junctions, producing muscle weakness when injected into dystonic muscles. Data from three double-blind, randomised, placebo-controlled trials demonstrate that botulinum toxin B effectively reduces the severity, disability and pain of cervical dystonia. In two of the trials, mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 (primary efficacy measure) after botulinum toxin B 10 000U was reduced by 11.7 (25%) or 11 (21%) compared with baseline. These changes were significantly greater than those obtained with placebo [4.3 (10%) or 2 (4%)] and were generally similar in patients who were responsive or resistant to botulinum toxin A. Statistically significant benefits compared with placebo were also evident for a range of other efficacy parameters including TWSTRS-Severity, -Pain and -Disability subscales, patient- assessed pain and patient-/physician-assessed global improvement ratings. In another trial, the percentage of patients with botulinum toxin A-resistant or -responsive cervical dystonia who had a > or =20% improvement in the TWSTRS-Total score between baseline and week 4 was significantly higher with botulinum toxin B 2500 to 10 000U (58 to 77%) than with placebo (27%). Overall, botulinum toxin B was generally well tolerated. The most frequently reported treatment-related adverse events were dry mouth and dysphagia. Most adverse events in patients receiving botulinum toxin B were mild or moderate; no serious adverse events or laboratory abnormalities were associated with the use of botulinum toxin B and, where reported, no patients discontinued from any of the clinical trials as a result of adverse events. CONCLUSIONS: Botulinum toxin B has shown clinical efficacy in patients with cervical dystonia at doses up to 10 000U and is generally well tolerated. Its efficacy extends to patients who are resistant to botulinum toxin A. Although the potential for secondary resistance to botulinum toxin B remains unclear, it may occur less than with botulinum toxin A because methods for manufacturing commercially available botulinum toxin B do not include lyophilisation and the product does not require reconstitution before use. As injection with botulinum toxin is generally considered the treatment of choice for patients with cervical dystonia, botulinum toxin B should be considered a potential treatment option in this setting.     

Satisfaction with Detrusor OnabotulinumtoxinA Injections and Conversion to Other Bladder Management in Patients with Chronic Spinal Cord Injury

This study investigated the satisfaction with continued detrusor Botox injections for urinary incontinence and conversion to other surgical procedures and bladder management procedures for neurogenic detrusor overactivity (NDO) in patients with chronic spinal cord injury (SCI). A total of 223 patients with chronic SCI underwent detrusor Botox 200U for urodynamically confirmed NDO and urinary incontinence. After initial detrusor Botox injections, patients opted to either continue detrusor Botox injections every six to nine months and on clean intermittent catheterization (CIC), switch to other bladder management procedures, or receive surgical procedures to improve their urinary incontinence, correct emergent complications, or have better voiding conditions without CIC. Urinary incontinence improvement rates and satisfaction with bladder management were assessed and compared between different subgroups, urodynamic parameters, and bladder management procedures. Finally, a total of 154 male and 69 female patients were included, among whom 56 (25.1%), 81 (36.3%), 51 (22.9%), and 35 (15.7%) showed a marked, moderate, mild, and no reduction in urinary incontinence, respectively. However, only 48.4% of the patients continued detrusor Botox injections over the mean follow-up period of seven years. Patients with cervical or thoracic SCI had fair incontinence improvement rates. The presence of high detrusor pressure and higher-grade bladder outlet resistance also predicted a decrease in incontinence. Although more than 50% of the patients switched to other bladder management procedures or received surgical treatment, 69.1% expressed satisfaction with their current status. This large cohort of patients with chronic SCI who received initial detrusor Botox injections revealed that only 48.4% continued with Botox injections. Those who received surgical procedures due to urological complications or demanded change in bladder management could achieve high satisfaction rates.     

Botulinum Toxin in the Treatment of Headache

Botulinum toxin type A has been used in the treatment of chronic migraine for over a decade and has become established as a well-tolerated option for the preventive therapy of chronic migraine. Ongoing research is gradually shedding light on its mechanism of action in migraine prevention. Given that its mechanism of action is quite different from that of the new monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) or its receptor, it is unlikely to be displaced to any major extent by them. Both will likely remain as important tools for patients with chronic migraine and the clinicians assisting them. New types of botulinum toxin selective for sensory pain neurons may well be discovered or produced by recombinant DNA techniques in the coming decade, and this may greatly enhance its therapeutic usefulness. This review summarizes the evolution of botulinum toxin use in headache management over the past several decades and its role in the preventive treatment of chronic migraine and other headache disorders.     

Modulation of urinary bladder innervation: TRPV1 and botulinum toxin A

The persisting interest around neurotoxins such as vanilloids and botulinum toxin (BoNT) derives from their marked effect on detrusor overactivity refractory to conventional antimuscarinic treatments. In addition, both are administered by intravesical route. This offers three potential advantages. First, intravesical therapy is an easy way to provide high concentrations of pharmacological agents in the bladder tissue without causing unsuitable levels in other organs. Second, drugs effective on the bladder, but inappropriate for systemic administration, can be safely used as it is the case of vanilloids and BoNT. Third, the effects of one single treatment might be extremely longlasting, contributing to render these therapies highly attractive to patients despite the fact that the reasons to the prolonged effect are still incompletely understood. Attractive as it may be, intravesical pharmacological therapy should still be considered as a second-line treatment in patients refractory to conventional oral antimuscarinic therapy or who do not tolerate its systemic side effects. However, the increasing off-label use of these neurotoxins justifies a reappraisal of their pharmacological properties.     

Efficacy and Safety of Intravesical OnabotulinumtoxinA Injection in Patients with Detrusor Hyperactivity and Impaired Contractility

We investigated the efficacy and safety of intravesical onabotulinumtoxinA injection in patients with detrusor hyperactivity and impaired contractility (DHIC). Twenty-one patients with urodynamically proven DHIC and 21 age-matched patients with overactive bladder (OAB) with urodynamic detrusor overactivity were treated with intravesical injections of 100 U of onabotulinumtoxinA. The overactive bladder symptom score, urgency severity score, patient perception of bladder condition, global response assessment, voiding diary, and procedure-related adverse events (AE) at baseline, two weeks, one, three, and six months after treatment were assessed. The results showed that the subjective symptom scores improved significantly in both groups, and the scores did not differ between the groups. The decrease in urgency episodes and urgency urinary incontinence were noted in OAB patients but not in DHIC patients. Although the incidence of AEs was comparable between the groups, the therapeutic efficacy lasted for a mean of 4.9 ± 4.8 months in DHIC patients and 7.2 ± 3.3 months in OAB patients (p = 0.03). We concluded that the efficacy of intravesical onabotulinumtoxinA injection for DHIC patients was limited and short-term. Nevertheless, AEs did not increase in DHIC. Intravesical onabotulinumtoxinA might not be a good indication in patients with DHIC and high post-voiding residual urine. Physicians should inform patients of the potential benefits and risks of onabotulinumtoxinA injection for treatment of DHIC.     

Real-World Data Regarding Satisfaction to Botulinum Toxin A Injection into the Urethral Sphincter and Further Bladder Management for Voiding Dysfunction among Patients with Spinal Cord Injury and Voiding Dysfunction

Purpose: This study aimed to investigate improvement in voiding condition after the initial botulinum toxin A (BoNT-A) injection into the urethral sphincter among patients with chronic spinal cord injury (SCI) and voiding dysfunction. Moreover, subsequent surgical procedures and bladder management were evaluated. Materials and Methods: From 2011 to 2020, 118 patients with SCI and dysuria who wanted to void spontaneously received their first BoNT-A injection at a dose of 100 U into the urethral sphincter. Improvement in voiding and bladder conditions after BoNT-A treatment were assessed. Next, patients were encouraged to continually receive BoNT-A injections into the urethral sphincter, convert to other bladder managements, or undergo surgery. After undergoing bladder management and surgical procedures, the patients were requested to report improvement in voiding condition and overall satisfaction to bladder conditions. Then, data were compared. Results: In total, 94 male and 24 female participants were included in this analysis. Among them, 51 presented with cervical, 43 with thoracic, and 24 with lumbosacral SCI. After BoNT-A injections into the urethral sphincter, 71 (60.2%) patients, including 18 (15.3%) with excellent, and 53 (44.9%) with moderate improvement, had significant improvement in voiding condition. Patients with cervical SCI (66.6%), detrusor overactivity and detrusor sphincter dyssynergia (72.0%), partial hand function (80.0%), and incomplete SCI (68.4%) had a better improvement rate than the other subgroups. Only 42 (35.6%) patients continually received treatment with BoNT-A injections into the urethral sphincter. Meanwhile, more than 60% of patients who converted their treatment to augmentation enterocystoplasty (n = 5), bladder outlet surgery (n = 25), BoNT-A injections into the detrusor muscle (n = 20), and medical treatment (n = 55) had moderate and marked improvement in voiding dysfunction and overall satisfaction. Discussion: Although BoNT-A injections into the urethral sphincter could improve voiding condition, only patients with SCI who presented with voiding dysfunction were commonly satisfied. Those whose treatments were converted to other bladder managements, which can promote urinary continence, or to surgical procedures, which can facilitate spontaneous voiding, had favorable treatment outcomes.