The translational implications of the science behind the overactive bladder and the role of OnabotulinumtoxinA.

Urinary incontinence (UI) is a very common condition that can affect patients of all ages and the commonest cause is an overactive bladder (OAB). Most patients with OAB were treated with pharmacotherapy and major surgery. Over 25 years ago, Dasgupta, Fowler et al. studied the presence and role of C fibres in the human bladder which are highly sensitive to capsaicin, the active ingredient of chillies. When capsaicin was instilled into patients' bladders as a synthetic solution, it was found to be highly effective in some patients. Capsaicin was later replaced by Resiniferatoxin. Both toxins desensitised C-fibres through the capsaicin receptor, TRPV1, without any lasting damage to the bladder itself. The discovery of botulinum toxin and its use in the treatment of OAB represents a major breakthrough, in the treatment of OAB. Another key innovation was the development of technique to administer the drug under local anaesthesia which allowed numerous patients to benefit from treatment who would otherwise have been precluded because of the need for injection under general anaesthetic. After extensive trials over many years Botox (OnabotulinumtoxinA) is now licensed for use in OAB. Compared to other treatments for overactive bladder, OnabotulinumtoxinA is more cost-effective and less invasive. It is thought to have changed the quality of life of an estimated 5 million patients worldwide.

Sacral neuromodulation in the management of chronic pelvic pain: A systematic review and meta-analysis.

INTRODUCTION: Sacral neuromodulation (SNM) is a treatment approved for use in several conditions including refractory overactive bladder (OAB) and voiding dysfunction. Chronic pelvic pain (CPP) is a debilitating condition for which treatment is often challenging. SNM shows promising effect in patients with refractory CPP. However, there is a lack of clear evidence, especially in long-term outcomes. This systematic review will assess outcomes of SNM for treating CPP. METHODS: A systematic search of MEDLINE, Embase, Cochrane Central and clinical trial databases was completed from database inception until January 14, 2022. Studies using original data investigating SNM in an adult population with CPP which recorded pre and posttreatment pain scores were selected. Primary outcome was numerical change in pain score. Secondary outcomes were quality of life assessment and change in medication use and all-time complications of SNM. Risk of bias was assessed using the Newcastle Ottawa Tool for cohort studies. RESULTS: Twenty-six of 1026 identified articles were selected evaluating 853 patients with CPP. The implantation rate after test-phase success was 64.3%. Significant improvement of pain scores was reported in 13 studies; three studies reported no significant change. WMD in pain scores on a 10-point scale was -4.64 (95% confidence interval [CI] = -5.32 to -3.95, p < 0.00001) across 20 studies which were quantitatively synthesized: effects were maintained at long-term follow-up. Mean follow-up was 42.5 months (0-59). Quality of life was measured by RAND SF-36 and EQ-5D questionnaires and all studies reported improvement in quality of life. One hundred and eighty-nine complications were reported in 1555 patients (Clavien-Dindo Grade I-IIIb). Risk of bias ranged from low to high risk. Studies were case series and bias stemmed from selection bias and loss to follow-up. CONCLUSION: Sacral Neuromodulation is a reasonably effective treatment of Chronic Pelvic Pain and significantly reduces pain and increases patients' quality of life with immediate to long-term effects.

Does response to percutaneous tibial nerve stimulation predict similar outcome to sacral nerve stimulation?

AIMS: Percutaneous tibial nerve stimulation (PTNS) is a simple neuromodulation technique to treat an overactive bladder. It is unclear whether the response to PTNS would suggest a similar response to sacral nerve stimulation (SNS), and whether PTNS could be utilized as an alternative test phase for an SNS implant. This study assessed whether PTNS response was a reliable indicator for subsequent SNS trials. METHODS: We performed a retrospective review of the hospital databases to collect all patients who had PTNS and who subsequently had an SNS trial in two tertiary hospitals from 2014 to 2020. Response to both interventions was assessed. A 50% reduction in overactive symptoms (frequency-volume charts) was considered a positive response. McNemar's tests using exact binomial probability calculations were used. The statistical significance level was set to 0.05. RESULTS: Twenty-three patients who had PTNS subsequently went on to a trial of SNS. All patients except one had previously poor response to PTNS treatment. Eight of them also failed the SNS trial. However, 15 patients (including the PTNS responder) had a successful SNS trial and proceeded with the second-stage battery implantation. The difference in response rates between the PTNS and SNS trial was statistically significant (p < 0.001). CONCLUSIONS: Poor response to PTNS does not seem to predict the likelihood of patients responding to SNS. A negative PTNS trial should not preclude a trial of a sacral nerve implant. The predictive factors for good and poor responses will be the subject of a larger study.

Cost Effectiveness of Sacral Neuromodulation and OnabotulinumtoxinA in Managing Refractory Idiopathic Overactive Bladder.

Little information from clinical and modelled studies are available on cost effectiveness of OnabotulinumtoxinA and SNM for the treatment of idiopathic overactive bladder. We aimed to summarize the evidence in this regard from different healthcare systems. Seven studies from 5 countries were reviewed. Some modelled studies with a 10-year time frame showed that sacral neuromodulation became dominant long-term; others suggested OnabotulinumtoxinA was more cost effective at <5 years. There was considerable heterogeneity in the base case/sensitivity analysis and statistical modelling among the studies. Clinical studies with longer term follow-up will help determine cost effectiveness more accurately.

Shifting the treatment paradigm in idiopathic overactive bladder.

PURPOSE: Overactive Bladder (OAB) is a common condition that is known to have a significant impact on Health Related Quality of Life (HRQoL). Whilst all patients will initially benefit from lifestyle modifications and behavioural therapy in the first instance drug therapy remains integral in management pathways. The purpose of this review paper is to reappraise the evidence based approach to the management of OAB in addition to exploring a new treatment algorithm for the escalation of treatment in those patients with refractory symptoms. DESIGN: Literature Review RESULTS: Antimuscarinic drugs are currently the most commonly used medication although the introduction of mirabegron, a ß3 agonist, has provided an alternative and also allowed combination therapy in those patients who have failed to improve on primary therapy or who have troublesome side effects. For those patients with symptoms of refractory OAB more invasive therapies including OnabotulinumtoxinA, sacral neuromodulation and Percutaneous Tibial Nerve Stimulation (PTNS) may be indicated. CONCLUSION: We propose a new, evidence based, treatment algorithm for the management of OAB in patients who remain refractory to first line therapy.

How can we prevent postprostatectomy urinary incontinence by patient selection, and by preoperative, peroperative, and postoperative measures? International Consultation on Incontinence-Research Society 2018.

AIMS: To review current prevention strategies for urinary incontinence among patients undergoing radical prostatectomy (RP). METHODS: This is a consensus report of the proceedings of a research proposal from the annual International Consultation on Incontinence-Research Society (ICI-RS), 14 to 16 June 2018 (Bristol, UK): "How can we prevent postprostatectomy incontinence by patient selection, and by preoperative, peroperative, and postoperative measures?" RESULTS: Several baseline parameters were proposed as predicting factors for postprostatectomy urinary incontinence (PPUI), including age, tumor stage, prostate volume, preoperative lower urinary tract symptoms, maximum urethral closure pressure, and previous transurethral resection of the prostate. More recently, magnetic resonance imaging has been used to measure the membranous urethral length and sphincter volume. Peroperative techniques include preservative and reconstructive approaches. Bladder neck preservation improved early (6 months), as well as long-term (>12 months) continence rates. Several prospective studies have reported earlier return of continence following preservation of puboprostatic ligaments, although no long-term data are available. Preservation of the urethral length yielded controversial outcomes. Concerning postoperative strategies, it is probably optimal to remove the catheter in a window between 4 and 7 days if clinically appropriate; however, more research in this regard is still required. Postoperative PFME (preoperative pelvic floor muscle exercise) appears to speed up the recovery of continence after RP. CONCLUSIONS: Conservative strategies to prevent PPUI include proper patient selection and PFME. Peroperative techniques have largely shown benefit in the short term. Postoperative complications and timing of trial without catheter can influence continence status. Future research initiatives must assess peroperative and postoperative measures, with longer-term follow-up.

How can we better manage drug-resistant OAB/DO? ICI-RS 2018.

AIMS: Botulinum toxin A (BTX-A), sacral nerve stimulation (SNM), and posterior tibial nerve stimulation (PTNS) are established treatments for idiopathic overactive bladder (OAB) refractory to oral drug therapy. At the ICI-RS meeting in Bristol in 2018 a think tank was convened to address the question of how to better manage drug-resistant OAB/DO (detrusor overactivity). METHODS: The think tank conducted a literature review and an expert consensus meeting focusing on the evidence for predicting response and adverse events (AEs) with the current therapies for drug-resistant idiopathic OAB. RESULTS: Several factors have been associated with poor outcomes using BTX-A including increasing age, body mass index, male sex, and frailty. Voiding dysfunction with BTX-A also appears to be more prevalent in those with increasing age, male sex, higher baseline postvoid residual and with poorer contractility as assessed by urodynamic parameters. SNM full implantation appears to be higher with the first stage tined lead placement procedure compared to percutaneous nerve evaluation. Urodynamics do not appear to predict outcomes with SNM. Patients with psychiatric comorbidity are more likely to experience AEs with SNM. Outcomes related to lead positioning and the number of active electrodes are mixed in predicting long term success. Patients with increased daytime frequency and lower first sensation of bladder filling were independent factors associated with success with PTNS. CONCLUSIONS: Further research is required to optimize these procedures and to better understand which patients will benefit from the various options available in managing refractory OAB.

Nonantibiotic prevention and management of recurrent urinary tract infection.

Urinary tract infections (UTIs) are highly prevalent, lead to considerable patient morbidity, incur large financial costs to health-care systems and are one of the most common reasons for antibiotic use worldwide. The growing problem of antimicrobial resistance means that the search for nonantibiotic alternatives for the treatment and prevention of UTI is of critical importance. Potential nonantibiotic measures and treatments for UTIs include behavioural changes, dietary supplementation (such as Chinese herbal medicines and cranberry products), NSAIDs, probiotics, D-mannose, methenamine hippurate, estrogens, intravesical glycosaminoglycans, immunostimulants, vaccines and inoculation with less-pathogenic bacteria. Some of the results of trials of these approaches are promising; however, high-level evidence is required before firm recommendations for their use can be made. A combination of these agents might provide the optimal treatment to reduce recurrent UTI, and trials in specific population groups are required.

What is the exact working mechanism of botulinum toxin A and sacral nerve stimulation in the treatment of overactive bladder/detrusor overactivity? ICI-RS 2017.

AIMS: Botulinum toxin A (BTX-A) and sacral nerve stimulation (SNS) are established treatments for overactive bladder (OAB) and are standard of care in refractory cases in international guidelines. Despite long term use over decades their "exact" working mechanisms are not entirely clear. At the ICI-RS meeting in Bristol in 2017 a think tank was convened to address the question. METHODS: The think tank conducted a literature review and an expert consensus meeting focusing on current mechanisms and what could be learned from clinical experience and objective urodynamic data. RESULTS: BTX-A results suggests effects on both filling and voiding parts of the micturition cycle. The salient data in this regard is presented as well as additional studies related to the urothelium and evidence for central effects. Urodynamics have consistently shown increases in bladder capacity, compliance, and reductions in detrusor pressures during filling, however post void residuals also increase in a dose-dependent fashion. During SNS activation of somatic afferents inhibits bladder sensory pathways and reflex bladder hyperactivity. Evidence in cats suggest the inhibition of bladder activity occurs primarily in the CNS by inhibition of the ascending or descending pathways of the spinobulbospinal micturition reflex. Urodynamics have suggested improvement in bladder capacity and reduction in detrusor pressures during filling with little observed effects on voiding parameters. CONCLUSIONS: The working mechanism of BTX-A and SNS is complex. The exact mechanisms are still unknown, although considerable progress has been made in our understanding. Further research proposals are suggested to help further elucidate these mechanisms.

Long-term follow-up of sacral neuromodulation for lower urinary tract dysfunction.

OBJECTIVE: To report our long-term experience of sacral neuromodulation (SNM) for various lower urinary tract dysfunctions but with a focus on efficacy, safety, re-interventions and degree of success. PATIENTS AND METHODS: This is a single tertiary referral centre study that included 217 patients (86% female) who received an implantable pulse generator (IPG) (Interstim™, Medtronic, Minneapolis, USA) between 1996 and 2010. Success was considered if the initial ≥50% improvement in any of primary voiding diary variables persisted compared with baseline, but was further stratified. RESULTS: The mean duration of follow-up was 46.88 months. Success and cure rates were ≈70% and 20% for urgency incontinence, 68% and 33% for urgency frequency syndrome and 73% and 58% for idiopathic retention. In those patients with an unsuccessful therapy outcome, the mean time to failure was 24.6 months after implantation. There were 88 (41%) patients who had at least one device or treatment related surgical re-intervention. The re-intervention rate was 1.7 per patient with most of them (47%) occurring ≤2 years of follow-up. CONCLUSIONS: SNM appears effective in the long-term with a success rate after definitive IPG implant of ≈70% and complete cure rates ranging between 20% and 58% depending on indication. Patients with idiopathic retention appear to do best. The re-intervention rate is high with most occurring ≤2 years of implantation. It is likely that with the newer techniques used, efficacy and re-intervention rates will improve.