Artificial urinary sphincter and female stress urinary incontinence over the past 50 years: a narrative review.

Background and Objective: The aim of the present report was to provide an overview of the use of the artificial urinary sphincter (AUS) in adult females with stress urinary incontinence (SUI) over the past 50 years. Methods: A literature search was conducted in December 2022 and January 2023 using the MEDLINE and Embase databases, screening for randomized controlled trials (RCTs), prospective and retrospective series and reviews on AUS. Only articles published in English or French were included. The search strategy involved a free text protocol and the narrative review reporting checklist was completed. Key Content and Findings: The AUS is a device used over the past 50 years for SUI caused by intrinsic sphincter deficiency (ISD). It has the theoretical ability to simulate the function of a biological urinary sphincter. Although the role of the AUS for females with ISD remains heterogeneous from one part of the world to the other, the existing literature demonstrates that AUS yields satisfactory functional outcomes in female SUI patients, comparable or better to what has been reported in male AUS series. Hence, the main barrier to its adoption has so far been the technical challenge of its implantation at the bladder neck. Regarding the results of AUS implantation in females, we included in this review 3 reviews, retrospective studies and 1 prospective study. In recent years, robotic techniques of female AUS implantation have spread significantly with promising outcomes including numerous reports suggesting that it may decrease its morbidity. In the near future, the development of electromechanical devices may further expand the role of AUS in the management of female SUI. Conclusions: While the use of AUS in female patients provides excellent functional outcomes, it has been limited to scarce centers. However, due to the rise of minimally invasive approaches, it has started spreading again over the past few years. The future of AUS is likely to be bright, fed by technological advances of the device and robotic surgical system, high level of evidence studies and joint efforts of the urological community to facilitate its diffusion across the world.

Burst Stimulation Evokes Increased Bladder and Urethral Pressure in Patients With Sacral Neuromodulation, Indicating Potential Activation of the Autonomic Nervous System: A Pilot Study.

OBJECTIVES: Currently, sacral neuromodulation (SNM) outcomes are often suboptimal, and changing stimulation parameters might improve SNM efficacy. Burst stimulation mimics physiological burst firing of the nervous system and might therefore benefit patients treated with SNM. The purpose of the present pilot study was to evaluate the effect of various Burst SNM paradigms on bladder and urethral pressure in patients with overactive bladder (OAB) or nonobstructive urinary retention (NOUR). MATERIALS AND METHODS: The bladder was filled to 50% of its capacity under general anesthesia in six patients with an implanted sacral lead for SNM purposes. Bladder pressure, and mid- and proximal urethral pressure were measured using conventional (Con-) SNM and various Burst SNM paradigms (10-20-40 Hz interburst frequency) with increasing amplitudes up to 5 mA for Con-SNM and 4 mA for Burst SNM. RESULTS: Burst SNM caused a substantial increase in both bladder and urethral pressure. In contrast, Con-SNM caused a milder increase in urethral pressure, and only one patient showed a modest increase in bladder pressure. Furthermore, the pressure increase was higher in the proximal urethra than in the midurethra using Burst-SNM, whereas Con-SNM caused comparable increases in proximal and midurethra pressure. CONCLUSIONS: Burst SNM induces bladder contraction compared with Con-SNM and induces higher pressure increases in bladder and proximal urethra than does Con-SNM in patients with OAB or NOUR, indicating a higher degree of autonomic nervous system stimulation. The observed responses could not be fully explained by the total charge of the Burst SNM paradigms, which suggests the importance of individual Burst SNM parameters, such as frequency and amplitude. Future studies should assess the feasibility and efficacy of Burst SNM in awake patients.

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.

The female urethral closure mechanism during physical stress.

The closure of the urethra under the condition of stress is the result of a reflex contraction of the urethral rhabdosphincter and pelvic floor muscles. This is likely induced by activity of the abdominal muscles due to a sudden increase in abdominal pressure. This reflex contraction with an increase of urethral pressure occurs a few milliseconds before an increase in intraabdominal pressure. The urethral pressure increase during stress is only possible with fixation of the urethra by the pubourethral ligaments (PUL), facilitating urethral kinking. The highest and most important increase in pressure and resistance occurs in the distal urethra due to this kinking of the urethra.

The association of fecal incontinence, constipation, and pelvic pain with the course of lower urinary tract symptoms in community-dwelling men and women.

BACKGROUND: Fecal incontinence, constipation, and pelvic pain are common pelvic floor symptoms (PFS), and frequently coexist with lower urinary tract symptoms (LUTS). However, their association with the longitudinal trajectory of LUTS have not been well described. Our objective was to investigate the association between PFS and the course of LUTS in community-dwelling men and women. METHODS: Men and women aged ≥16 years were invited to participate in a prospective observational cohort study. At baseline, and after 12 and 24 months, participants filled in the International Consultation on Incontinence Modular Questionnaire (ICIQ-MLUTS and ICIQ-FLUTS) for men and women respectively, the Wexner incontinence and constipation scale, and a questionnaire on pelvic pain. Generalized estimating equations were used to examine the association between change scores in defecation problems and pelvic pain, and LUTS change scores. RESULTS: A total of 694 men and 997 women gave informed consent, with 417 men and 566 women included in the analysis. The mean age was 63.2 ± 12.7 years for men and 58.6 ± 14.8 years for women. The study showed minor changes in LUTS scores over the 0-12 and 12-24-month periods. Generalized estimating equations revealed positive associations between changes in constipation and fecal incontinence and LUTS changes in both sexes. For instance, a one-point increase in Wexner constipation score was associated with 0.376 (0.165, 0.587) points higher LUTS change in men and 0.223 (0.109, 0.336) points in women during the 0-12-month follow-up. However, associations between changes in pain and LUTS scores varied across sexes and time periods. CONCLUSIONS: We observed minor changes in LUTS over time and weak associations between PFS and LUTS that sometimes differed between males and females, emphasizing the need for sex-specific considerations. These insights can provide valuable guidance for the development of targeted prevention trials, ultimately aiming to enhance overall pelvic health and patient well-being.

Quantification of Aging-Related Decreases in Sensory Innervation of the Bladder Trigone in Rats.

PURPOSE: The prevalence of lower urinary tract symptoms (LUTS), characterized by problems regarding storage and/or voiding of urine, is known to significantly increase with age. Effective communication between the lower urinary tract and the central nervous system (CNS) is essential for the optimal function of this system, and heavily relies on the efficient interaction between the bladder urothelium and the afferent nerve fibers situated in close proximity to the urothelium within the lamina propria. METHODS: We aimed to quantify aging-related differences in the expression of calcitonin gene-related peptide (CGRP, an established marker for sensory nerve fibers) in the trigonal mucosal layers of young (3-4 months) and aged (25-30 months) rats. We evaluated trigonal tissue from 3 animals per age group. Tissue was serially sectioned at 10 µm and stained for CGRP. Images were taken along the full length of the tissue. For each image we computed the total CGRP-positive area (µm2) and the median value for each animal was used for further analysis. RESULTS: Upon statistical analysis the aged rats show a significantly lower CGRP-positive area compared to young rats (P=0.0049). These results indicate that aging has a negative effect on the area of CGRP-positive signal in the trigone. CONCLUSION: The structural and functional integrity of the sensory web in the trigonum of rats is negatively affected by the aging process, potentially leading to impaired communication between the bladder urothelium the CNS. Consequently, these perturbations in the sensory system may contribute to the pathogenesis or exacerbation LUTS.

Depressive feelings as mediator in the relation between adverse childhood events and lower urinary tract symptoms in males and females.

BACKGROUND: Adverse childhood events (ACEs) are prevalent and lead to well-established adverse health sequelae in adulthood. Recent literature has claimed that exposure to trauma in early life may worsen lower urinary tract symptoms (LUTS) because emotion can alter the perception of bodily distress in the brain. Specifically, depressive symptoms might influence the association between ACEs and LUTS. We aimed to describe the associations between ACEs and LUTS among males and females and to determine whether depressive symptoms mediated these associations. METHODS: This study was a secondary analysis of the Coevorden observational cohort study (n = 1691, age ≥16 years). For this observational study participants filled in the male or female modules of the International Consultation on Incontinence Questionnaire for LUTS (ICIQ-MLUTS and ICIQ-FLUTS, respectively), the NEMESIS Childhood Trauma Questionnaire (emotional neglect, psychological abuse, physical abuse, and sexual abuse within the family), and the Patient Health Questionnaire (PHQ-9) for depression. RESULTS: Overall, 564 males and 811 females answered all required items related to LUTS and ACEs. A series of regression models were then estimated to test for mediation: LUTS on ACEs, depression on ACEs, and LUTS on both ACEs and depression. The models were also adjusted for the following covariates: age, body mass index, diabetes mellitus, current smokers, educational level, and vaginal delivery (if female). Depressive symptoms were shown to mediate the association between ACEs and LUTS in both males and females. CONCLUSION: Childhood adversity and depression are areas of interest during the clinical assessment of patients with LUTS. Early detection of these conditions might help to manage risk, aid in the prevention of LUTS, and facilitate trauma-informed care.

Functional neuroimaging related to lower urinary tract sensations: Future directions for study designs and selection of patient groups: ICI-RS 2023.

OBJECTIVES: Neuroimaging studies have advanced our understanding of the intricate central nervous system control network governing lower urinary tract (LUT) function, shedding light on mechanisms for urine storage and voiding. However, a lack of consensus in methodological approaches hinders the comparability of results among research groups and limits the translation of this knowledge to clinical applications, emphasizing the need for standardized methodologies and clinical utilization guidelines. METHODS: This paper reports the discussions of a workshop at the 2023 meeting of the International Consultation on Incontinence Research Society, which reviewed uncertainties and research priorities to progress the field of neuroimaging in LUT control and dysfunction. RESULTS: Neuroimaging holds great potential for improving our understanding of LUT control and pathophysiological conditions. To date, functional neuroimaging techniques have not yet achieved sufficient strength to make a direct clinical impact. Potential approaches that can improve the clinical utilization of neuroimaging were discussed and research questions proposed. CONCLUSIONS: Neuroimaging offers a valuable tool for investigating LUT control, but it's essential to acknowledge the potential for oversimplification when interpreting brain activity due to the complex neural processing and filtering of sensory information. Moreover, technical limitations pose challenges in assessing key brain stem and spinal cord centers, particularly in cases of neurological dysfunction, highlighting the need for more reliable imaging of these centers to advance our understanding of LUT function and dysfunction.

Effect of bladder outlet procedures on urodynamic assessments in men with an acontractile or underactive detrusor: A systematic review and meta-analysis.

OBJECTIVE: To review the effect of bladder outlet procedures on urodynamic outcomes and symptom scores in males with detrusor underactivity (DU) or acontractile detrusors (AD). MATERIALS AND METHODS: We performed a systematic review and meta-analysis of research publications derived from PubMed, Embase, Web of Science, and Ovid Medline to identify clinical studies of adult men with non-neurogenic DU or AD who underwent any bladder outlet procedure. Outcomes comprised the detrusor pressure at maximum flow (Pdet Qmax ), maximum flow rate (Qmax ), international prostate symptom score (IPSS), and quality of life (QoL). This study is registered under PROSPERO CRD42020215832. RESULTS: We included 13 studies of bladder outlet procedures, of which 6 reported decreased and 7 reported improved Pdet Qmax after the procedure. Meta-analysis revealed an increase in the pooled mean Pdet Qmax of 5.99 cmH2 0 after surgery (95% CI: 0.59-11.40; p = 0.03; I2 95%). Notably, the Pdet Qmax improved in all subgroups with a preoperative bladder contractility index (BCI) <50 and decreased in all subgroups with a BCI ≥50. All studies reported an improved Qmax after surgery, with a pooled mean difference of 5.87 mL/s (95% CI: 4.25-7.49; I2 93%). Only three studies reported QoL, but pooling suggested significant improvements after surgery (mean, -2.41 points; 95% CI: -2.81 to -2.01; p = 0.007). All seven studies reporting IPSS demonstrated improvement (mean, -12.82; 95% CI: -14.76 to -10.88; p < 0.001). CONCLUSIONS: This review shows that Pdet Qmax and Qmax increases after surgical bladder outlet procedures in men with DU and AD. Bladder outlet procedures should be discussed as part of the shared decision-making process for this group. The evidence was of low to very low certainty.

The Maximal Urethral Pressure at Rest and during Normal Bladder Filling Is Only Determined by the Activity of the Urethral Smooth Musculature in the Female.

The aim of this opinion paper is to determine the entities that define the maximal urethral pressure (MUP) during rest and during bladder filling that is needed to guarantee continence in females. For the development of this opinion, the literature was searched for via the Pubmed database and historic sources. Animal studies indicate that the maximal urethral pressure is determined by the smooth muscle activity in the mid-urethra. Additionally, during increased smooth muscle tone development, the largest sympathetic responses are found in the middle part of the urethra. This could be confirmed in human studies that are unable to find striated EMG activity in this area. Moreover, the external urethral striated sphincter is situated at the distal urethra, which is not the area with the highest pressure. The external urethral sphincter only provides additional urethral pressure in situations of exertion and physical activity. From a physics point of view, the phasic pressure of the external striated sphincter at the distal urethra cannot be added to the tonic pressure generated by the smooth muscle in the mid-urethra. The assertion that mid-urethral pressure is the result of different pressure forces around the urethra, including that of the external striated sphincter, is not supported by basic research evidence combined with physical calculation and should therefore be considered a misconception in the field of functional urology.

The test-retest reproducibility of the multiple array probe Leiden in men with lower urinary tract symptoms.

BACKGROUND: We aimed to study the test-retest reliability of the Multiple Array Probe Leiden (MAPLe), a multiple electrode probe designed to acquire and discriminate electromyography signals in the pelvic floor muscles, in men with lower urinary tract symptoms (LUTS). METHODS: Adult male patients with LUTS with sufficient knowledge of Dutch language, but without complications (e.g., urinary tract infection), or previous urologic cancer and/or urologic surgery were enrolled. In the initial study, next to physical examination and uroflowmetry, all men underwent MAPLe assessment at baseline and after 6 weeks. Second, participants were reinvited for a new assessment using a stricter protocol. A time interval of 2 h (M2) and 1 week (M3) after baseline (M1) allowed the calculation of the intraday agreement (M1 vs. M2), and the interday agreement (M1 vs. M3) for all 13 MAPLe variables. RESULTS: The outcomes of the initial study in 21 men suggested a poor test-retest reliability. The second study in 23 men showed a good test-retest reliability with intraclass correlations ranging from 0.61 (0.12-0.86) to 0.91 (0.81-0.96). The agreement was generally higher for the intraday determinations than for the interday determinations. CONCLUSIONS: This study revealed a good test-retest reliability of the MAPLe device in men with LUTS, when using a strict protocol. With a less strict protocol, the test-retest reliability of MAPLe was poor in this sample. To make valid interpretations of this device in a clinical or research setting, a strict protocol is needed.

Assessment of Brainstem Functional Organization in Healthy Adults and Overactive Bladder Patients Using Ultra-High Field fMRI.

The pathophysiological mechanisms of overactive bladder syndrome (OAB) remain largely unknown, with major involvement of the central nervous system (CNS). The periaqueductal gray (PAG) is a brainstem area which is indicated to play an essential role in bidirectional communication between the bladder and the CNS. We aimed to assess consistency of PAG functional organization across different bladder sensory states in OAB patients. We propose, that PAG functional organization patterns across sensory states will differ between controls and OAB patients. We analyzed fMRI scans at 7 Tesla from six controls and two OAB patients. The Louvain module detection algorithm was applied to parcellate the PAG in empty and full bladder states. We assessed within-subject consistency and investigated differences in this consistency between both groups. High within-subject agreement of PAG parcellations between empty and full bladder states was demonstrated in both groups. Additionally, we showed that the correlations between PAG clusters in both bladder states were significantly different in patients compared to controls (p = 0.039). The methods introduced here offer a promising tool to assess functional organization of the PAG and understand the underlying pathology and the role of this region in OAB syndrome.

Comparing male and female pelvic floor muscle function by the number and type of pelvic floor symptoms.

AIMS: Pelvic floor symptoms (PFS), including lower urinary tract symptoms, defecation problems, sexual dysfunction, and pelvic pain, are common in males and females. Comparing pelvic floor musculature (PFM) function between sexes may reveal important differences relevant to clinical care. This study aimed to compare male and female PFM function and to assess the function of both sexes with the number and type of PFS. METHODS: We purposively enrolled males and females aged ≥ 21 years with 0-4 PFS based on questionnaire responses in an observational cohort study. Participants then underwent PFM assessment, and muscle function in the external anal sphincter (EAS) and puborectal muscle (PRM) were compared between sexes. The relationships between muscle function and the number and type of PFS were explored. RESULTS: Of the invited 400 males and 608 females, 199 and 187 underwent PFM assessment, respectively. Compared with females, males more often showed increased EAS and PRM tone during assessments. Compared with males, females more often showed weaker maximum voluntary contraction (MVC) of the EAS and dysfunctional endurance of both muscles; additionally, those with zero or one PFS, sexual dysfunction, and pelvic pain more often showed a weak MVC of the PRM. CONCLUSIONS: Despite a few similarities between males and, females we found differences in muscle tone, MVC, and endurance between male and female PFM function. These findings provide useful insights into the differences in PFM function between males and females.

Replacement Adaptor 09106 for patients with a dynamic graciloplasty or patients with sacral neuromodulation and abdominal implantable pulse generators: a retrospective, single centre, Stage 2a/2b development IDEAL case series.

AIM: Due to the introduction of a new implantable pulse generator (IPG), the Interstim II, patients with either a dynamic graciloplasty or an abdominally placed IPG for sacral neuromodulation could not undergo surgery to replace their IPG in the case of end of battery life. For these patients, the Medtronic Replacement Adaptor 09106 was created. This retrospective case series aims to study safety and feasibility of the Medtronic Replacement Adaptor 09106 in patients with abdominally placed IPGs. METHODS: Seventeen patients (11 women, six men) received a replacement adaptor with a follow-up of 6 months. Outcome measures consisted of a bowel habit diary. Adverse events were classified using the Clavien-Dindo classification. RESULTS: Outcome measures in the bowel habit diaries after replacement (feasibility) did not differ significantly from outcome measures before replacement. Adverse events occurred in four out of 17 patients (24%): two patients initially showed pocket site pain (Clavien-Dindo Grade I), which resolved without intervention. One patient suffered from poor wound closure (Clavien-Dindo Grade II) and one patient had persisting pocket pain (Clavien-Dindo Grade IIIa) for which a pocket revision was performed. Statistical analyses were performed making paired comparisons using a Wilcoxon signed rank test. CONCLUSION: The Medtronic Replacement Adaptor 09106 is a valuable option for patients with dynamic graciloplasty or sacral neuromodulation and abdominal IPG and has complication rates similar to replacement of the Interstim without Replacement Adaptor 09106.

Between-subject similarity of functional connectivity-based organization of the human periaqueductal gray related to autonomic processing.

The periaqueductal gray (PAG) is a brain stem area designated to play an essential role in lower urinary tract (LUT) control. Post-mortem human and animal studies have indicated that the PAG is symmetrically organized in functionally and anatomically distinct columns which are involved in sympathetic or parasympathetic autonomic control of the LUT. The current study aims to find consistency across subjects and identify homologous clusters between subjects. Here, we evaluated data from 10 female participants. During a bladder filling protocol, we ran a resting-state functional magnetic resonance imaging (fMRI) scan while participants experienced a strong desire to void. A voxel-by-voxel correlation matrix of the PAG was created and parcellated using the Louvain module detection algorithm. Resulting in a map of the PAG in which each voxel is assigned to a cluster as determined by the Louvain module detection algorithm. The spatial similarity of resulting clusters between participants was assessed by computing the Dice similarity coefficient for all cluster comparisons. Next, we designed a permutation test to create randomized parcellation maps which enabled us to statistically test the similarity values observed across participants. We observed several significantly similar clusters between subjects compared to permutations (p ≤ 0.05). These results show that the PAG can be parcellated into distinct clusters which show a similar spatial distribution at the group level. This analysis is a crucial step to determine the agreement between in vivo PAG parcellations and the functional and anatomical columnar organization of the PAG which is known from previous research. These advancements may enable us to identify the relationship between LUT symptoms, such as urgency, and activity patterns in the PAG in normal and pathological states.

Exploring concomitant pelvic floor symptoms in community-dwelling females and males.

OBJECTIVES: Researchers and clinicians tend to focus on one pelvic floor symptom (PFS) at the time. However, the pelvic floor acts as one functional unit, increasing the likelihood of concurrent PFS in patients with pelvic floor dysfunction. There is also a paucity of literature on the prevalence of concomitant PFS, especially in males. Therefore, we explored the occurrence of concomitant PFS in community-dwelling males and females. MATERIALS AND METHODS: This prospective observational population-based cohort study included males and females aged ≥16 years from a single Dutch municipality. Participants completed validated questionnaires on lower urinary tract symptoms (LUTS), defecation problems, sexual dysfunction, pelvic pain, and pelvic organ prolapse. Medical general practitioner records were examined. Furthermore, a randomly selected group of non-responders aged <80 years received a short questionnaire, to study response bias. RESULTS: We invited 11 724 people, among which 839 females and 566 males completed the questionnaires. Of the female participants, 286 (34.1%) reported no PFS, and 251 (29.9%) reported two or more PFS. The most prevalent PFS clusters in females were sexual dysfunction and pelvic pain, sexual dysfunction and defecation problems, LUTS and defecation problems, and LUTS, defecation problems, and pelvic pain. Of the male participants, 212 (37.5%) reported no PFS, and 191 (33.7%) reported two or more PFS. The most prevalent clusters in males were sexual dysfunction and LUTS, defecation problems and LUTS, and sexual dysfunction, LUTS, and defecation problems. CONCLUSION: A considerable overlap existed between PFS, with differences in PFS clusters between females and males. Of note, females reported pelvic pain more than males. We conclude that healthcare providers should address all PFS in males and females.

Exploring pelvic floor muscle function in men with and without pelvic floor symptoms: A population-based study.

BACKGROUND: Pelvic floor symptoms (PFS), such as lower urinary tract symptoms, defecation disorders, sexual problems, and genital-pelvic pain, are prevalent in men. Thorough physical assessments of the external anal sphincter (EAS) and the puborectal muscle (PRM) are the keys to unraveling the role of muscle dysfunction. OBJECTIVES: To explore associations within and between the EAS and PRM and between muscle (dys-) function and the number of male PFS. METHODS: This cross-sectional study purposively enrolled men aged ≥21 years with 0-4 symptoms from a larger study. After extensive external and internal digital pelvic floor assessment, we explored (1) agreement between muscle function of the EAS versus PRM (using cross tabulation), (2) associations within and between the EAS and PRM (using heatmaps), and (3) associations between muscle function and number of PFS (using a visual presentation [heatmaps] and χ2  tests). RESULTS: Overall, 42 out of 199 men (21%) had completely normal muscle function. Sixty-six (33.2%) had no symptoms, of which 53 (80%) had some degree of muscle dysfunction. No clear dose-response relationship existed between muscle (dys-) function and the number of symptoms. The PRM showed both more dysfunction and severer dysfunction than the EAS. CONCLUSIONS: No clear association exists between muscle dysfunction and the number of symptoms, and the absence of PFS does not indicate normal muscle function for all men. Dysfunction levels are highest for the PRM. Further pelvic floor muscle research is warranted in men with PFS.

Muscarinic-3-receptor positive allosteric modulator ASP8302 in patients with underactive bladder. A randomized controlled trial.

AIM: The aim of this study is to evaluate safety and efficacy of ASP8302, a novel positive allosteric modulator for the muscarinic M3 receptor (M3-PAM), in patients with underactive bladder (UAB). METHODS: A randomized, double-blind, placebo-controlled multicenter study was performed in adult male/female subjects with UAB, defined as incomplete bladder emptying (postvoid residual volume [PVR] > 100 ml) without significant bladder outlet obstruction and/or overactive bladder. Subjects were randomized (1:1) to receive 4-week oral once-daily administration of 100 mg ASP8302 or matching placebo. Primary endpoint was a change from baseline in PVR measured by catheterization after standardized bladder filling (PVRC2 ). Other endpoints included PVR and bladder voiding efficiency (BVE) measured in various ways, uroflowmetry, bladder diary, and questionnaires. Pressure-flow studies were performed in a subgroup. RESULTS: One hundred and thirty-five patients were randomized (ASP8302 group: 65 patients, placebo group: 70 patients). The median change in PVRC2 was -40.0 ml (ASP8302) versus -35.0 ml (placebo) and the difference between groups was -5.0 ml (p = 0.960). In males, functional and symptomatic outcomes improved, for example, maximum urine flow rate (Qmax ) and detrusor pressure at Qmax (Pdet.Qmax ) increased (mean difference in change ASP8302 vs. placebo: 3.8 ml/s, p = 0.031 and 12.7 cm H2 O, p = 0.034, respectively). Urinary incontinence episodes/24 h decreased in males with preexisting incontinence (mean difference: -0.35; p = 0.028). The incidence of adverse events was similar between study groups (ASP8302: 33.3%, placebo: 31.4%). In the included subjects, both baseline urine flow and bladder voiding pressure was low. Compared with PVR, simultaneous BVE measurements were more consistent between various methods (spontaneous vs. standardized bladder filling, catheterization vs. ultrasound [US]). CONCLUSIONS: ASP8302 was safe and well tolerated in patients with UAB identified by nonurodynamic clinical criteria, but it did not show efficacy in the primary endpoint. However, in males it showed improvement of symptoms and functional parameters. BVE (using US) is a more optimal outcome measure than PVR in UAB.

Stress-Induced Changes in Trophic Factor Expression in the Rodent Urinary Bladder: Possible Links With Angiogenesis.

PURPOSE: Substantive evidence supports a role of chronic stress in the development, maintenance, and even enhancement of functional bladder disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS). Increased urinary frequency and bladder hyperalgesia have been reported in rodents exposed to a chronic stress paradigm. Here, we utilized a water avoidance stress (WAS) model in rodents to investigate the effect of chronic stress on vascular perfusion and angiogenesis. METHODS: Female Wistar-Kyoto rats were exposed to WAS for 10 consecutive days. Bladder neck tissues were analyzed by western immunoblot for vascular endothelial growth factor (VEGF) and nerve growth factor precursor (proNGF). Vascular perfusion was assessed by fluorescent microangiography followed by Hypoxyprobe testing to identify regions of tissue hypoxia. RESULTS: The expression of VEGF and proNGF in the bladder neck mucosa was significantly higher in the WAS rats than in the controls. There was a trend toward increased vascular perfusion, but without a statistically significant difference from the control group. The WAS rats displayed a 1.6-fold increase in perfusion. Additionally, a greater abundance of vessels was observed in the WAS rats, most notably in the microvasculature. CONCLUSION: These findings show that chronic psychological stress induces factors that can lead to increased microvasculature formation, especially around the bladder neck, the region that contains most nociceptive bladder afferents. These findings may indicate a link between angiogenesis and other inflammatory factors that contribute to structural changes and pain in IC/BPS.

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.