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 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.

New Technologies and Applications in Sacral Neuromodulation: An Update.

Recently rechargeable devices have been introduced for sacral neuromodulation (SNM) with conditional safety for full-body magnetic resonance imaging (MRI). Currently a recharge-free SNM device represents the standard implant; however, it is only approved for MRI head scans. As further new technologies with broader MRI capabilities are emerging, the advantages as well as disadvantages of both rechargeable versus recharge-free devices will be briefly discussed in this commentary from the perspective of patients, healthcare professionals, and providers.

Pathophysiological Mechanisms of Nocturia and Nocturnal Polyuria: The Contribution of Cellular Function, the Urinary Bladder Urothelium, and Circadian Rhythm.

Alterations to arginine vasopressin (AVP) secretion, the urinary bladder urothelium (UT) and other components of the bladder, and the water homeostasis biosystem may be relevant to the pathophysiology of nocturia and nocturnal polyuria (NP). AVP is the primary hormone involved in water homeostasis. Disruption to the physiological release of AVP or its target effects may relate to several urinary disturbances. Circadian dysregulation and the effects of aging, for example, the development of oxidative stress and mitochondrial dysfunction, may play a role in nocturia voiding symptoms. The urinary bladder UT not only acts as a highly efficient barrier that is maintained during the filling and voiding of the urinary bladder, but is also capable of sensory and transducer function through a network of functional receptors and ion channels that enable reciprocal communication between UT cells and neighboring elements of the bladder mucosa and wall. Functional components of the UT (eg, claudins and receptors or ion channels) play important roles in AVP-mediated water homeostasis. These components and functions involved in water homeostasis, as well as kidney function, may be affected by the aging process, including age-related mitochondrial dysfunction. The characteristics of NP are discussed and the association between NP and circadian rhythm is examined in light of reports that suggest that nocturia should be considered as a type of circadian dysfunction. Many possible pathologic mechanisms that underlie nocturia and NP have been identified. Future studies may provide further insight into pathophysiology with the hope of identifying new treatment modalities.

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).

Evidence for prostaglandin E2 receptor expression in the intramural ganglia of the guinea pig urinary bladder.

Intramural ganglia are present in the bladder wall of several species including human, pig, and guinea-pig. It has been suggested that there is a network of intramural ganglia in the bladder of these species that may be part of a motor-sensory system and receive afferent input. Prostaglandins (PG) have been suggested to play a role in this afferent signalling mechanism. To investigate the distribution of the prostaglandin E2 receptors EP1 and EP2 in and around intramural ganglia of the guinea pig, bladders of 6 guinea pigs were dissected, and processed for immunohistochemistry. Sections were examined for prostaglandin E2 receptor EP1- and EP2-immuno-reactivity and co-stained for vimentin, a marker for interstitial cells (IC) and cyclo-oxygenase 1 (COX I), the enzyme responsible for PG synthesis. Immunoreactivities for EP1 and EP2 were found in intramural ganglion cells. These cells were observed in between muscle bundles and on, or close to the serosal surface of the bladder. Furthermore, COX I was present in interstitial cells close to ganglion cells, indicating the possibility of a local synthesis of prostaglandins near the ganglia. The co-staining of EP1 or EP2 with vimentin showed that processes of interstitial cells run through the ganglia, often encircling or ensheathing cells. Therefore, it can be concluded that there is a close relationship between the intramural ganglia and the network of interstitial cells in the muscular layers of the bladder. EP1 and EP2 receptors are expressed on the ganglia and this arrangement suggests that intramural ganglia are involved in (pre)processing afferent information.

DOuble LOngitudinal Megapreputium Incision TEchnique: the DOLOMITE.

OBJECTIVE: To present a straightforward, reproducible technique with the basic principle of preserving all available outer penile shaft skin and using this to cover the dorsal side of the penis. The DOuble LOngitudinal Megapreputium Incision TEchnique is presented in a step-by-step fashion. MATERIALS AND METHODS: Six consecutive patients with a mean age of 13.3 months (range, 7-25) underwent this reconstruction between 2006 and 2011. The technique starts with 2 longitudinal incisions, the first on the ventral side, and the second on the dorsal side of the penis. After hinging the penile skin to the dorsal side, redundant inner preputial tissue is resected using diagonal incisions. Dartos is spared. A comparison with previously reported techniques and a concise review of existing literature are provided. RESULTS: The final cosmetic results, after an initial period of edematous swelling of the ventral aspect of the penis, were good in all patients. The bilateral diagonal scars on the penile shaft became inconspicuous over time. Voiding normalized. No complications occurred. CONCLUSION: The DOuble LOngitudinal Megapreputium Incision TEchnique provides a straightforward and reproducible surgical correction for congenital megaprepuce.

"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.

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 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.

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.

[A woman with urinary tract infections and flank pain]. / Een vrouw met urineweginfecties en flankpijn.

A 52-year-old woman presented with recurrent urinary tract infections and flank pain. Both an abdominal CT-scan and a plain abdominal X-ray showed bilateral nephrocalcinosis and a kidney stone in the left ureter. These findings are suggestive of medullary sponge kidneys.

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.

[Neuromodulation as a treatment for overactive bladder syndrome]. / Neuromodulatie voor overactieve-blaasklachten.

Neuromodulation is used as a treatment for overactive bladder syndrome, if conservative management is ineffective or only partially effective. Sacral neuromodulation is now a minimally invasive treatment as a result of improvements in surgical technique, and it has good long-term results. Nevertheless the risk of complications such as pain and decreasing effect is still present. Developments in alternative neuromodulation treatments, such as posterior tibial nerve stimulation, pudendal nerve stimulation and intravesical injection therapy with botulinum neurotoxin, have extended the role of neuromodulation. Intravesical injection therapy with botulinum toxin, along with sacral neuromodulation, has been included in the treatment algorithm of overactive bladder syndrome if this does not respond to conservative therapy. When choosing for a neuromodulation therapy, the side-effects and complications of the treatments should be considered alongside the specific patient situation and evidence for effectiveness and long-term effectiveness.

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.

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.