"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 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.

Psychological and psychiatric factors as predictors for success in sacral neuromodulation treatment.

UNLABELLED: What's known on the subject? and What does the study add? Sacral neuromodulation (SNM) is a well-established treatment for patients with chronic LUTS. The selection of eligible candidates could be improved by identifying factors that can predict a successful response. In the present study, we evaluated the role of various psychological and psychiatric factors in relation to SNM treatment. OBJECTIVE: • To evaluate if psychological and psychiatric factors can predict the outcome of test stimulation or permanent treatment with sacral neuromodulation (SNM). PATIENTS AND METHODS: • Between 2006 and 2009, patients with overactive bladder syndrome or non-obstructive urinary retention who were eligible for test stimulation were included. • All patients completed the Amsterdam Biographic Questionnaire (ABQ), which measures the personality traits of the patient, and the Symptom Check-List-90-Revised (SCL-90-R), which is a screening instrument for neuroticism, and for current level of complaints. • The results of the questionnaires were compared with the outcomes of test stimulation and permanent treatment. • In addition to the questionnaires, we also included the psychiatric history as a potential predictive factor. RESULTS: • On univariate analysis there was no relationship between the psychological characteristics and the outcome of test stimulation or the occurrence of adverse events (AEs) with permanent treatment. • A history of psychiatric disease was not related to the outcome of test stimulation, but was shown to be a positive predictor for the occurrence of AEs with permanent SNM treatment. CONCLUSIONS: • In the present study there was no evidence that psychological screening with the ABQ or SCL-90-R can predict the outcome of SNM treatment. • Patients with a medical history of psychiatric disease appear to be more likely to encounter AEs with permanent SNM 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.

Normal bladder sensations in healthy volunteers: a focus group investigation.

AIMS: To describe the bladder sensations experienced during non-invasive rapid bladder filling in a controlled setting in healthy volunteers. METHODS: Three groups of healthy volunteers, total 11 subjects (4 men, 7 women), participated in three consecutive focus group sessions. Before each session a strict water loading protocol was given. The first two sessions focused on how participants described and experienced bladder sensations in daily life and during a physiological bladder filling with constant focus on their bladder. The third session focused on verifying the interpretation of the data gathered so far and describing the pattern of sensations. RESULTS: During the focus group sessions with constant focus on their bladder, all participants experienced their bladder sensation as a continuous progression. Healthy subjects describe their bladder sensation(s) as a "pressure" and a "tingling" sensation, but a terminology ranging from no sensations to an absolute need to void is used by all participants and better describes the pattern in which the need to void develops in healthy volunteers. CONCLUSIONS: By means of focus group research it is possible to describe the development of normal bladder sensation and to refine terminology used by healthy participants. The findings show that two types of bladder sensations are reported spontaneously by healthy uninitiated volunteers, pressure and a tingling sensation, of which the first develops in a continuous manner. The pattern in which the absolute need develops is described by the terms: no sensation, weak awareness, stronger awareness, weak need, stronger need and absolute need to void.

PNE versus 1st stage tined lead procedure: a direct comparison to select the most sensitive test method to identify patients suitable for sacral neuromodulation therapy.

AIMS: To compare the patient's response rate to the Percutaneous Nerve Evaluation test (PNE) and the 1st stage tined-lead placement test (FSTLP) for sacral neuromodulation therapy (SNM). METHODS: Single center study on patients with refractory idiopathic overactive bladder syndrome (OAB) or non-obstructive urinary retention, screened with both PNE and FSTLP. Patients were followed prospectively and their response rate based on bladder diary after PNE was compared to that after FSTLP. More than 50% improvement in at least two relevant urinary symptoms was considered a positive response. A Wilcoxon paired test was done to compare the rates of the two screening options and logistic regression to determine possible associations. A follow-up was conducted to determine the long-term failure rate. RESULTS: One hundred patients were included (82 female, 69 OAB). The mean age was 55 years (SD 13). The positive response rate on PNE was 47%. FSTLP showed a 69% positive response rate, which was negatively related to age. The 22% gain in positive response was statistically significant (P < 0.001) and positively associated with female gender and younger age. All 69 patients with a positive response to FSTLP received SNM treatment. Failure rate after an average of 2 years was 2.9%. CONCLUSIONS: This study suggests that FSTLP may be a more sensitive screening method than PNE to identify patients eligible for SNM therapy, warranting randomized trials.

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.

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.

Long-term results of sacral neuromodulation with the tined lead procedure.

PURPOSE: We present long-term followup data on the outcome of sacral neuromodulation using the tined lead procedure. MATERIALS AND METHODS: We conducted a single center study including all patients who received an implantable neurostimulator between 2002 and 2005 using the tined lead technique. Treatment efficacy was evaluated by comparing the data of a 3-day voiding diary filled out in May 2009 to the data before the onset of sacral neuromodulation treatment (baseline). Clinical success was defined as more than 50% improvement in at least 1 of the relevant voiding diary parameters. RESULTS: A total of 64 patients underwent implantation with an implantable neurostimulator using the tined lead procedure. Mean followup was 53 months (range 35 to 77). Five patients died of causes unrelated to sacral neuromodulation and they were not included in analysis. The implantable neurostimulator was removed from 7 patients and 3 stopped using the neurostimulator. Voiding diary analysis showed that 38 of 59 patients (64%) were successfully treated. There were 21 patients (33%) who underwent a surgical revision due to an adverse event and 1 (1.6%) who underwent lead revision because of suspected lead migration. CONCLUSIONS: Sacral neuromodulation with the tined lead procedure is a safe and effective treatment for patients with overactive bladder symptoms or urinary retention.

Current information on sacral neuromodulation and botulinum toxin treatment for refractory idiopathic overactive bladder syndrome: a review.

The overactive bladder syndrome (OAB) negatively affects the daily life of many people. Conservative treatments, such as antimuscarinics, do not always lead to sufficient improvement of the complaints and/or are often associated with considerable side effects resulting in treatment failure. In the case of failure or intolerable side effects, sacral neuromodulation (SNM) and botulinum toxin are minimally invasive and reversible alternatives. Currently, of these alternatives only SNM with InterStimTM therapy has FDA approval for use in OAB patients. This review attempts to provide an update on the current position of SNM and botulinum toxin in the second-line management of adults with idiopathic OAB, based on the available clinical evidence concerning the efficacy and safety.

Prostaglandin receptor EP1 and EP2 site in guinea pig bladder urothelium and lamina propria.

PURPOSE: Urothelium has 2 main functions. It is a barrier to urine and has a sensory role. In response to stretch urothelium releases various substances that modulate afferent nerve activity. Recent data on the localization of cyclooxygenase type 1, the enzyme responsible for prostaglandin production, suggests that prostaglandin may have complex local action. MATERIALS AND METHODS: The bladders of 7 guinea pigs were stained for prostaglandin receptors type 1 and 2, and costained for vimentin and cyclooxygenase I. RESULTS: Prostaglandin receptor type 1 staining was seen in urothelial cells and in the suburothelium. Urothelial staining, which was often punctuate and weak, was detected in all urothelial cell layers, including suburothelial cells. In contrast, strong prostaglandin receptor type 2 staining was seen in the urothelium and in suburothelial cells. Cyclooxygenase I was absent in interstitial cells and umbrella cells with the highest concentration in the basal cell layer. CONCLUSIONS: Interstitial cells express prostaglandin receptor types 1 and 2, indicating that they can respond to prostaglandin. Umbrella cells do not express cyclooxygenase I. Cyclooxygenase I was present in basal urothelial cells, making them a possible site of prostaglandin synthesis. Thus, prostaglandin produced by urothelium may target prostaglandin receptor types 1 and 2 in the urothelium and suburothelium. Therefore prostaglandin is hypothesized to have a role in signal regulation in the bladder wall.