Sacral neuromodulation in patients with refractory overactive bladder symptoms after failed Botulinum toxin therapy: Results in a large cohort of patients.

AIMS: Sacral neuromodulation (SNM) and Botulinum toxin A (BoNT-A) injections are well-known third-line treatment options in patients with refractory overactive bladder (OAB). Our aim is to evaluate the success rate of SNM in patients who received prior therapy with BoNT-A injections. METHODS: All patients with OAB symptoms referred for SNM between 2006 and 2019 were included. History taking and 3-day voiding diaries assessed the complaints and suitability for SNM. The success rate of SNM in patients who received prior BoNT-A was compared with BoNT-A naive patients. Success was defined as an improvement of 50% or greater in voiding diary parameters. Satisfaction was registered at their most recent visit. RESULTS: A total of 263 patients underwent SNM test stimulation, of which 75 (16 male/57 female) received prior BoNT-A and 188 (46 male/142 female) were BoNT-A naive. Success rate for SNM in BoNT-A naive patients was 72.9% and in BoNT-A patients 66.7% (p = 0.316). Success rate after ≤2 BoNT-A injections was 68.5%, compared to 61.1% after ≥3 injections (p > 0.05). Success rate in patients perceiving lack of efficacy of BoNT-A was 67.4% (p > 0.05), subjected to temporary CISC was 73.7% (p > 0.05) and with temporary effect of BoNT-A was 50% (p > 0.05). In 86% of BoNT-A patients the system was still activated and used to their satisfaction at their last follow-up visit (mean FU, 40.70 months). CONCLUSION: SNM in patients with refractory OAB who failed prior BoNT-A is an excellent approach. The number of injections nor reason of BoNT-A discontinuation have predictive value for success with SNM.

First-in-human implantation of a mid-field powered neurostimulator at the sacral nerve: Results from an acute study.

INTRODUCTION: Commercially approved implantable systems for sacral neuromodulation require the implantation of a multipolar lead subcutaneously connected to an implantable pulse generator (IPG). Eliminating the need for an IPG would eliminate the need for tunneling of the lead, reduce procedure time, infection risk, and the need for IPG replacement. The objective was to demonstrate the feasibility of implanting the AHLeveeS System in the S3 Foramen to stimulate the S3 sacral nerve. MATERIALS AND METHODS: A first-in-human, prospective, single center, nonrandomized, acute feasibility clinical investigation at the Maastricht University Medical Center+. Patients with refractory overactive bladder underwent acute implantation of the AHLeveeS neurostimulator before the InterStim procedure. Outcome measurements included motor responses, procedural time and a scoring of the difficulty of the implant and explant procedure. Retrospectively, qualitative responses to the stimulation protocol were assessed by video motion analyses. Only descriptive statistics were used. RESULTS: During the stimulation a motor response to stimulation was seen in four of the five subjects. In all implantations the AHLeveeS was correctly placed. The median time for complete procedure was 24 minutes. The implant and explant procedures were successfully performed and no device or procedure related adverse events occurred. CONCLUSIONS: The results from this acute first-in-human study demonstrate the feasibility of implantation and acute stimulation of the sacral nerve with this mid-field powered system. Future clinical studies will focus on safety and efficacy of a chronically implanted device.

A populational-based survey on the prevalence, incidence, and risk factors of urinary incontinence in older adults-results from the "SABE STUDY".

AIMS: To estimate the prevalence and incidence of urinary incontinence (UI) and identify the associated risk factors in a cohort of elderly individuals in Brazil. METHODS: In 2006, individuals aged ≥60 years were selected from the SABE Study (Health, Well-being, and Aging). The dependent variable was reported UI in 2009. UI was assessed using the International Consultation on Incontinence Questionnaire Urinary Incontinence-Short Form (ICIQ-UI SF). Incidence was measured in units of 1000 person-years, and Cox regression was applied for data analysis. Multivariate analysis was used to assess risk factors for UI. Incidence risk ratio (IRR) was used for comparison. RESULTS: This is the first study to examine the incidence of UI in Brazilian elderly individuals. In total, 1413 individuals were included; the mean age was 74.5 years, and 864 (61.8%) participants were female. The risk of UI was greater among women with cancer (other than skin) and among those with diabetes. In men, the risk of UI was greater for those in Instrumental Activities of Daily Living (IADL) category "5-8" and those who self-reported a "fair" health status. The prevalence of UI was 14.2% and 28.2% for men and women, respectively. The incidence rate of UI was 25.6 and 39.3 (×1000 person-years) for men and women, respectively. CONCLUSIONS: The incidence rate of UI among older adults in the Brazilian community was high for elderly individuals. The identified risk factors were diabetes and IADL category 5-8 (women) as well as cancer (other than skin) and self-reported health status (male).

"Focused introspection" during naturally increased diuresis: description and repeatability of a method to study bladder sensation non-invasively.

OBJECTIVE: To present and describe a non-invasive method to study the origin and development of bladder filling sensation and to evaluate the repeatability of the method. METHOD: Eighteen volunteers participated in the study and were given a water loading protocol consisting of 1,000 ml water intake 1 hr before the session and 200 ml every 10 min during the session. Protocol 1: To evaluate diuresis rate, seven participants were asked to void every 15 min and the voided volume was measured. Protocol 2: Eleven volunteers graded bladder sensation on regular time points, on an empty graph with time on the X-axis and intensity of sensation on the Y-axis. The protocol ended at absolute need to void (maximal intensity) and voided volumes were measured. This protocol was conducted three times with a 10 days interval. RESULTS: Protocol 1: The diuresis rate was not different during the sessions and showed no variation over the studied time period (P = 0.2). Protocol 2: For an individual, the diuresis rate was not different between the sessions. The curves in all patients showed a continuously increasing bladder intensity. In seven participants the curve was convex, in the other four, the curve was sigmoidal. For each individual the pattern was constant during the three sessions. CONCLUSION: A strict water loading protocol induces a constant diuresis. This allows individuals to draw an introspection bladder sensation curve with a specific shape, which can be used as a method to study the development of bladder sensation non-invasively.

Nocturia and obstructive sleep apnoea.

Nocturia, the need to urinate at night, is a common symptom in patients with obstructive sleep apnoea (OSA). Continuous positive airway pressure treatment can reduce nocturia in some patients, but the underlying mechanisms are complex and not fully understood. OSA affects the autonomic nervous system, oxidative stress and endothelial damage. Furthermore, the commonly held theory attributing polyuria to a false signal of cardiac overload and response natriuresis has limitations. A comprehensive approach to the management of nocturia in OSA, considering factors such as comorbidities, medication use, alcohol consumption and lifestyle, is needed. Effective management of nocturia in OSA requires a multidisciplinary approach, and urologists should be aware of the potential effect of OSA on physiology and refer patients for further testing at a sleep centre. In addition to continuous positive airway pressure, other interventions such as oral appliances and surgical obstruction treatment could be beneficial for some patients. Overall, understanding the complex interplay between OSA and nocturia is crucial for optimizing patient outcomes.

Sacral neuromodulation in patients with idiopathic overactive bladder after initial botulinum toxin therapy.

PURPOSE: We evaluated whether patients with overactive bladder and incontinence who discontinued intravesical botulinum toxin therapy can be successfully treated with sacral neuromodulation. MATERIALS AND METHODS: All patients who were referred to our center after discontinuation of botulinum toxin-A between 2005 and 2010 were included in this observational study. All patients underwent test stimulation with sacral neuromodulation and were evaluated with voiding diaries. Success was defined as more than 50% improvement in leakage episodes. Successful test stimulation was subsequently followed by a definitive implant. Patient satisfaction with sacral neuromodulation therapy was evaluated 1 year after the definitive implant. RESULTS: A total of 20 patients were included in the study. Of these patients 17 (85%) had discontinued botulinum toxin-A because of lack of efficacy and 3 had been treated successfully with botulinum toxin-A but requested a more permanent solution. The mean interval between the botulinum toxin-A and the sacral neuromodulation test stimulation was 23 months. In 14 patients (70%) the test stimulation was successful and they received a definitive implant. Of the 14 patients 5 even showed a decrease of greater than 90% in leakage episodes. One year after implantation 11 patients (79%) were satisfied with the sacral neuromodulation treatment. CONCLUSIONS: Despite the small sample size, this study indicates that patients who are dissatisfied with or in whom botulinum toxin-A treatment fails can respond successfully to sacral neuromodulation. The success rate of the test stimulation was comparable to that of patients who have never been treated with botulinum toxin-A. The 1-year satisfaction rate was comparable that of patients without a history of botulinum toxin-A treatment.

Distribution of phosphodiesterase type 5 (PDE5) in the lateral wall of the guinea pig urinary bladder.

OBJECTIVE: To study PDE5 localisation by visualising the product of phosphodiesterase type 5 (PDE5) inhibition, namely cGMP, to determine the site of action of inhibitors in the urinary bladder. MATERIALS AND METHODS: Bladders of nine male guinea pigs were dissected and treated in wells containing 2 mL Krebs' solution and 1 µM of the specific PDE5 inhibitor vardenafil at 36 °C for 30 min. After stimulating tissues with 100 µM of the nitric oxide (NO) donor diethylamine-NONOate for 10 min, the tissues were snap-frozen and 9-10 µm sections were cut. Sections were examined for cGMP immunoreactivity and also stained for vimentin, a marker for interstitial cells and the neuromarkers protein gene product 9.5 (PGP9.5), synaptic vesicle protein 2 (SV2), neurofilament (NF) and calcitonin gene-related peptide (CGRP), using the two-step indirect immunohistochemistry technique. RESULTS: After PDE5 inhibition, cGMP was found to be present in the urothelium, suburothelial interstitial cells and endothelium of blood vessels. cGMP was not expressed in nerves positive for CGRP, NF and SV2, and was expressed only in very few efferent nerves positive for PGP9.5. CONCLUSION: Our data show that the possible sites of action of PDE5 inhibition in the bladder are the urothelium, suburothelial interstitial cells and blood vessels, rather than the bladder nerve fibres.

The New England Research Institutes, Inc. (NERI) Nocturia Advisory Conference 2012: focus on outcomes of therapy.

A consensus statement published in 2011 summarised current research, clinical approaches, and treatment options for nocturia. Since that time, new research has refined our understanding of nocturia in clinically important ways and new evidence has been presented on the efficacy and outcomes of several treatment methods for this underreported, infrequently recognised, and undertreated problem in adults. This paper provides updated guidance to clinicians in light of recent advances in the field.

GAG layer replenishment therapy for chronic forms of cystitis with intravesical glycosaminoglycans--a review.

AIMS: Glycosaminoglycan (GAG) layer replenishment is a cornerstone in the therapy of interstitial cystitis (IC). During the last years intravesical GAG layer replenishment has proven to be an effective treatment for overactive bladder (OAB), radiation cystitis, and recurrent urinary tract infections (UTIs). METHODS: Examination of different substances available for intravesical GAG replenishment and evaluation of the evidence for the treatment of the above-mentioned conditions. RESULTS: We searched the Medical Literature Analysis and Retrieval System Online (MEDLINE) database for studies on intravesical GAG replenishment. A total of 27 clinical studies remain relevant to this topic, many of them with mixed patient selection and suboptimal definition of symptom improvement/success. Two placebo controlled studies with hyaluronic acid failed to show superiority and have not been published. One active controlled randomized study has been published showing that chondroitin sulphate 0.2% has a clear benefit for OAB patients. Another study with chondroitin sulphate 2.0% failed to show statistically significant evidence, but was underpowered. CONCLUSIONS: A short number of randomized controlled studies confirm efficacy of intravesical GAG layer replenishment therapy. Concluded from the study background (which comprises also uncontrolled studies), so far chondroitin sulphate 0.2% is in favor for intravesical GAG layer replenishment therapy. In general, large-scale trials are urgently needed to underline the benefit of this type of therapy.

The effect of indomethacin on the muscarinic induced contractions in the isolated normal guinea pig urinary bladder.

BACKGROUND: To investigate the effect of prostaglandin depletion by means of COX-inhibition on cholinergic enhanced spontaneous contractions. METHODS: The urethra and bladder of 9 male guinea pigs (weight 270-300 g) were removed and placed in an organ bath with Krebs' solution. A catheter was passed through the urethra through which the intravesical pressure was measured. The muscarinic agonist arecaidine, the non-selective COX inhibitor indomethacin, and PGE2 were subsequently added to the organ bath. The initial average frequency and amplitude of spontaneous contractions in the first 2 minutes after arecaidine application were labelled F(ini) and P(ini), respectively. The steady state frequency (F(steady)) and amplitude (P(steady)) were defined as the average frequency and amplitude during the 5 minutes before the next wash out. RESULTS: Application of 1 µM PGE2 increased the amplitude of spontaneous contractions without affecting frequency. 10 µM of indomethacin reduced amplitude but not frequency.The addition of indomethacin did not alter F(ini) after the first application (p = 0.7665). However, after the second wash, F(ini) was decreased (p = 0.0005). F(steady), P(steady) and P(ini) were not significantly different in any of the conditions. These effects of indomethacin were reversible by PGE2 addition.. CONCLUSIONS: Blocking PG synthesis decreased the cholinergically stimulated autonomous contractions in the isolated bladder. This suggests that PG could modify normal cholinergically evoked response. A combination of drugs inhibiting muscarinic receptors and PG function or production can then become an interesting focus of research on a treatment for overactive bladder syndrome.

Sacral neuromodulation for lower urinary tract dysfunction.

OBJECTIVES: To review the technique, indications, results and working mechanisms of sacral neuromodulation (SNM) for lower urinary tract dysfunction. METHODS: The available literature on SNM for lower urinary tract dysfunction was searched. Based on the information available in the literature and also based on personal experience, the urological indications, technique, mechanisms of action and results of SNM are presented and discussed. RESULTS: SNM for lower urinary tract dysfunction involves stimulation of the 3rd sacral nerve with an electrode implanted in the sacral foramen and connected to a pulse generator. The technique is accepted by the FDA since 1997. Currently, SNM for lower urinary tract dysfunction has been successfully used in about 26,000 patients with various forms of lower urinary tract dysfunction, including urgency, frequency and urgency incontinence as well as non-obstructive urinary retention. The actual procedure of SNM consists of a minimal invasive technique and is effective in about 70% of the patients who have been implanted with a permanent system. Also, in pelvic pain, interesting results have been described. SNM modulates the micturition reflexes at different levels in the central nervous system. CONCLUSIONS: Sacral neuromodulation is a safe and effective therapy for various forms of lower urinary tract dysfunction, including urgency, frequency and urgency incontinence as well as non-obstructive urinary retention. It should be the first choice after failure of maximal conservative therapy.

The distribution of the prostaglandin E receptor type 2 (EP2) in the detrusor of the guinea pig.

OBJECTIVE: To explore the distribution of prostaglandin E receptor type 2 (EP2) in the bladder muscle layers and its spatial relationship to cyclo-oxygenase type 1 (COX I). MATERIALS AND METHODS: Twelve male guinea pigs were killed by cervical dislocation, the bladders removed and fixed in 4% paraformaldehyde in PBS. Frozen sections of 10 µm were cut and stained with antibodies to EP2, COX I and vimentin. RESULTS: EP2 receptor immunoreactivity is located on the smooth muscle cells as well as on vimentin positive surface muscle and intramuscular interstitial cells. EP2 expression on interstitial cells is highly localized. Discrete regions of intense staining were observed on the interstitial cell processes. COX I is expressed in the muscle interstitial cells and was found to be located on discrete regions of the cell and cell processes. Double staining with EP2 and COX I suggests that the regions of a cell expressing EP2 are different from those expressing COX I. CONCLUSIONS: The presence of COX I, prostaglandin E receptor type 2 (EP2) immune-reactivity in the network of interstitial cells suggests a role of this network in the propagation of signals. Due to a cAMP coupling of the EP2 receptor in many other tissues and a lower dissociation constant of EP2, it is suggested that a rise in PG levels may gradually push the balance from a relaxant EP2 effect towards a contractile effect. Hence, PG could have a modulatory role on the non-voiding bladder contractions by changing the threshold level for excitability of the interstitial cell network.

Nocturia Think Tank: focus on nocturnal polyuria: ICI-RS 2011.

The following is a report of the proceedings of the Nocturia Think Tank sessions of the annual International Consultation on Incontinence-Research Society, which took place June 13-15, 2011 in Bristol, UK. The report is organized into sections pertaining to the main topics of discussions having occurred at that meeting, centering on the relationship of nocturnal polyuria (NP) and nocturia but also synthesizing more current evidence advancing our knowledge of the diagnosis and management of nocturia. This article is not meant to be a comprehensive review on the subject of nocturia, a number of which are available in the recent literature. All authors were physically present during, or in a preliminary session just prior to, the meeting in Bristol.

Does conservative management really benefit patients with OAB?

The benefit that patients with overactive bladder (OAB) experience with conservative management is an important aspect in the evaluation of this therapy. The first-line options include behavioral interventions, and several techniques are available. Clinical research indicates amelioration of individual symptoms with these techniques, but few studies have shown a positive effect on health-related quality-of-life parameters. After failure of behavioral therapy or in combination with a training program, pharmacological therapy with anticholinergics is the next step. Extensive clinical research into different pharmacological compounds has shown significant effects on the symptomatic elements of OAB. The clinical relevance and the effects on quality-of-life parameters with pharmacological therapy have also been evaluated and show a significant effect on specific aspects. Recently, clinical research in conservative management of patients with OAB has focused more on evaluating patients' perceptions of their condition and the effects of treatment with patient-reported outcome instruments. Future studies should include these tools in the evaluation of any therapy in OAB.

Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia.

PURPOSE: Nocturnal polyuria is a common but often overlooked cause of nocturia. We investigated the proportion of adults with 2 or greater voids nightly who had nocturnal polyuria in 2 cohorts from the United States and Europe. MATERIALS AND METHODS: Data on nocturnal polyuria were obtained from 3 or 7-day frequency-volume charts completed by patients as part of screening for inclusion in subsequent trials of nocturia therapy. Patients recorded the time and volume of each void. Nocturnal polyuria was defined as nocturnal urine volume greater than 33% of 24-hour volume, including the first morning void. RESULTS: In the first cohort 1,003 patients were screened, of whom 846 provided evaluable diary data, including 641 (76%) with nocturnal polyuria. Of the total screened population of 1,003 patients 641 (64%) had confirmed nocturnal polyuria. The prevalence of nocturnal polyuria increased with age but was high in all age groups. In the second cohort 1,412 patients were screened, of whom 917 provided evaluable diary data, including 806 (88%) with nocturnal polyuria. Of the total screened population of 1,412 patients 806 (57%) had confirmed nocturnal polyuria. The prevalence of nocturnal polyuria increased with age but was high in all age groups. Of 158 patients receiving benign prostatic hyperplasia and/or overactive bladder medication 141 (89%) had nocturnal polyuria. In each cohort the nocturnal polyuria prevalence was high in all ethnic groups (63% or greater). CONCLUSIONS: In this large study nocturnal polyuria was present in most patients with nocturia regardless of gender, age, ethnicity, country and concomitant benign prostatic hyperplasia/overactive bladder therapy.

The use of bilateral sacral nerve stimulation in patients with loss of unilateral treatment efficacy.

PURPOSE: We evaluated whether bilateral sacral nerve stimulation can be effective to restore treatment efficacy in patients in whom unilateral sacral neuromodulation fails. MATERIALS AND METHODS: Patients in whom unilateral sacral neuromodulation failed were included in analysis. The percutaneous nerve evaluation test was used to evaluate the effect of contralateral and bilateral stimulation. The stimulation electrode was placed in the contralateral S3 foramen and symptoms were self-recorded using a 3-day voiding diary. Clinical success was defined as more than 50% improvement in at least 1 relevant voiding diary parameter vs baseline. RESULTS: The 15 study patients underwent test stimulation with percutaneous nerve evaluation. In 3 patients lead migration was suspected and, thus, they were not included in analysis. Four of the remaining 12 patients had a successful response to percutaneous nerve evaluation, of whom 3 were eventually implanted with a contralateral lead. After 12 months of treatment 2 of the 3 patients had a successful outcome. CONCLUSIONS: In this pilot study only a select group of patients appeared to benefit from bilateral stimulation after unilateral therapy failure. Further investigation is needed to determine the predictive factors and cost-effectiveness of this treatment.

Degree of urge, perception of bladder fullness and bladder volume--how are they related?

PURPOSE: We evaluated the reliability of the degree of urge and perception of bladder fullness scales, the relationship between the scales and bladder volume, and possible differences between bladder sensations experienced in a controlled or an uncontrolled setting. MATERIALS AND METHODS: Volunteers and patients with overactive bladder symptoms participated in the protocols. They were asked to grade bladder sensation on a 4-point urge scale of no sensation to need to void now and assess the perception of fullness on a visual analog scale of empty to full bladder. This was assessed in a 3-day bladder diary and during controlled, noninvasive bladder filling. RESULTS: Each scale was reliable and significantly related to bladder volume (p <0.001). Agreement between the scales and voided volume was poor. Patients and volunteers grade bladder fullness and degree of urge higher in an uncontrolled than in a controlled setting. CONCLUSIONS: The perception of bladder fullness and the degree of urge have a significant relation to bladder volume in controlled and uncontrolled settings. Due to poor agreement between the scales and actual voided volume these scales cannot replace measuring voided volume. The perception of bladder sensation depends on the setting. Bladder sensation at the hospital might underestimate the bother of symptoms experienced by a patient in daily life.

The effect of pulse rate changes on the clinical outcome of sacral neuromodulation.

PURPOSE: We evaluated the effect of pulse rate changes on the clinical response to and stimulation related pain symptoms of sacral neuromodulation treatment. MATERIALS AND METHODS: In this pilot study we evaluated the effect of 4 pulse rates, including 5.2, 10, 21 and 40 Hz, in patients with a suboptimal response to sacral neuromodulation. The effect of each frequency was evaluated during a 6-day test period. To avoid the carryover effect stimulation was discontinued for 24 hours between consecutive test periods. On the last 3 days of each test period a voiding diary and questionnaire were completed. Changes in the clinical response and pain symptoms were compared between the 4 pulse rates using multivariate analysis. RESULTS: Of the 50 patients included in the study 40 (80%) were female. Mean ± SD age was 55.5 ± 12.3 years. Of the patients 41 (82%) had overactive bladder symptoms and 9 (18%) were in chronic nonobstructive urinary retention. No significant difference was found in clinical outcome on the voiding diary and questionnaire between the pulse rates and none of the 4 rates was significantly related to sacral neuromodulation associated pain. However, individuals appeared to benefit from changing the pulse rate in terms of treatment efficacy and stimulation related pain. CONCLUSIONS: On the group level none of the 4 pulse rates appeared to have a significantly different effect on clinical outcome or sacral neuromodulation related pain. However, an individualized approach to optimize treatment efficacy by changing the pulse rate appears to be useful.

Cost-effectiveness analysis of sacral neuromodulation and botulinum toxin A treatment for patients with idiopathic overactive bladder.

UNLABELLED: Study Type - Therapy (economic analysis). LEVEL OF EVIDENCE: 1b. OBJECTIVE: To assess and compare the costs and effects value of either starting with sacral neuromodulation (SNM) or botulinum toxin A (BTX) treatment in patients with refractory idiopathic overactive bladder from a societal perspective. MATERIALS AND METHODS: An economic model comparing SNM with BTX was developed. A clinical relevant effect (i.e. success) was defined as 50% or greater reduction in incontinence episodes or urgency frequency symptoms. Information on the clinical effectiveness of the two treatments and on the course of the disease with the two treatments were based primarily on published literature and, when required, on expert opinion. Both treatments were assumed to be performed under general anaesthesia and, for SNM treatment, first-stage tined lead test was used. All costs were based on national data from the year 2008. Analyses from the societal perspective were conducted for a 5-year duration. Costs were discounted at 4% and effects at 1.5%. In addition, different modelling scenarios were used to see determine any changes in the results obtained. RESULTS: Starting with SNM resulted in a higher quality adjusted life year (QALY) gain (difference of 0.23) and a higher cost (difference of €6428) compared to starting with BTX. The corresponding incremental cost-effectiveness ratio was €27,991/QALY. The probability of this ratio being cost effective (e.g. under €40,000/QALY) is 88%. SNM starts to be cost-effective after 4 years. SNM was not cost-effective in some other scenarios, such as when BTX was conducted under local anaesthesia or when peripheral nerve evaluation or bilateral testing was used for SNM. CONCLUSIONS: Starting with SNM, treatment is cost-effective after 5 years compared to BTX. However, in some scenarios, such as the use of local anaesthesia for BTX treatment and SNM peripheral nerve evaluation or bilateral test, SNM was not cost-effective.