Search

This review summarizes the status of nocturia research, highlighting the condition's distinct nature, as well as areas where further studies are needed. Unlike other LUTS, nocturia has a specific and detrimental effect on the sleep period, and when >or=2 voids per night are experienced it is associated with various sequelae including reduced QoL and productivity, and increased morbidity and perhaps mortality. Many sources suggest that nocturia is associated with chronic medical illness, but little evidence demonstrates that successful treatment of these conditions results in normalization of nocturia, or that improvement in nocturia improves QoL and overall health. To date, management algorithms for LUTS have been based upon reasonable supposition and limited evidence, rather than controlled trials. Whilst a working clinical model is useful until conclusive research is available, a healthy scepticism should be maintained. It is likely that more than one contributory factor is responsible for nocturia, and management ought to better reflect this multifactorial pathophysiology. Indeed, traditional perspectives assuming nocturia to be part of the OAB or BPE symptom complex may have helped to propagate the misconception that therapy for these conditions is sufficient to improve nocturia. In reality, improvements in nocturia with anticholinergics, alpha-blockers and/or 5-alpha reductase inhibitors have been consistently disappointing. Antidiuretic therapy may represent a more tailored approach to management for many nocturia patients, given the high rates of nocturnal polyuria reported. Combination therapy may be required. Further high quality research on pathophysiology, management and patient-reported outcomes with treatment is needed to augment existing limited data., ((c) 2010 Wiley-Liss, Inc.)

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., (2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

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., (Copyright 2010 S. Karger AG, Basel.)

Introduction: Traditionally, urinary frequency and/or urgency incontinence have been the primary outcome measurements for the symptom complex of overactive bladder (OAB). However, urgency, by definition, precedes urgency incontinence, and drives frequency and nocturia in OAB and should be considered in this pivotal role., Materials and Methods: Review of published literature on this topic., Results: The management of urgency is evolving as of major clinical importance to patients. Recent use of diary-based urgency metrics has advanced our knowledge of the presence and nature of urgency symptoms, the impact on QoL and the response to treatment options., Conclusion: It is logical that the management of the number of urgency episodes and the degree of urgency, as well as the impact and bother associated with this core symptom are all taken into consideration along with patient interpretation to facilitate an effective outcome.

Localized phasic contractions in the bladder wall (autonomous activity) have been hypothesized to be an integral part of a motor/sensory system contributing to bladder sensation. The sites responsible for generating this activity, the mechanisms involved in its propagation and modulation remain unknown. This phasic motor activity is modulated by exogenous prostaglandins. Therefore, analysis of the sites of prostaglandin production and action within the bladder wall may shed light on the mechanisms of generation and modulation of this phasic activity. In this paper we report the localization of immuno-reactivity indicative of the expression of cyclo-oxygenase enzyme type I (COX I-IR) within the bladder wall. Basically, three types of COX I-IR cell were identified: epithelial cells in the basal and intermediate layers of the urothelium, complex vimentin-positive and COX I-IR cells in the lamina propria and vimentin-negative COX I-IR cells in the lamina propria and on the surface of the inner muscle bundles. These vimentin-negative/COX I-IR cells appear to be in close apposition to a continuous network of vimentin-positive cells, which extends from the lamina propria into the inner muscle layers and subsequently into the outer muscle layers. However, the interstitial cells in this region might form a distinctly different sub-type. First, the interstitial cells in this region differ from those in the inner layer by their responsiveness to NO with a rise in cGMP. Two subtypes have been identified: cells on the surface of the muscle bundles and within the muscle bundles. Second, COX I-IR cells are not associated with the interstitial cells in the outer layers. The physiological significance for these apparent differences in the interstitial cell network is not clear. However, such differences are likely to reflect differences in the processes involved in their activation, modulation and control.

Background: Previous studies demonstrate that tolterodine extended release (ER) significantly improves urgency urinary incontinence (UUI) episodes. Instruments that measure patient-reported outcomes (PROs) provide additional information that is valuable for assessing whether clinical improvements are meaningful to the patient. This study determined the correlation of changes in bladder diary variables and other PROs in subjects with overactive bladder (OAB)., Methods: Subjects with OAB, urinary frequency, and UUI were treated with 4 mg once-daily tolterodine ER or placebo for 12 weeks. Subjects completed 7-day bladder diaries, the Patient Perception of Bladder Condition (PPBC), and the King's Health Questionnaire (KHQ) at baseline and week 12. Only subjects who reported at least some minor bladder-related problems at baseline (PPBC score > or = 3) were included in this analysis., Results: Reductions in UUI episodes per week were significantly greater in the tolterodine ER group (n = 500) compared with the placebo group (n = 487) at week 12 (-71% vs -33%, P < 0.0001). A significantly greater percentage of subjects in the tolterodine ER group reported improvement on the PPBC versus placebo (58% vs 45%, P < 0.0001), and 7 of 10 KHQ domains were significantly improved versus placebo (all P < 0.05). Significant correlations were found for median percentage changes in UUI episodes with changes in PPBC scores (r = 0.35,P < 0.0001) and the 7 improved KHQ domains (r = 0.16-0.32, P < or = 0.0011). Changes in PPBC scores and all KHQ domains were significantly correlated (r = 0.13-0.38, P < or = 0.009) in the tolterodine ER group. Correlations among endpoints in the placebo group were similar to those observed in the tolterodine ER group., Conclusion: Improvement in UUI episodes after 12 weeks of treatment with tolterodine ER or placebo was correlated with improvements in patients' perception of their bladder-related problems and health-related quality of life. Correlations were moderate in magnitude but statistically significant, suggesting that PROs are important and relevant measures for evaluating OAB treatment.

A study was carried out to evaluate efficacy of Macroplastique(R) (MPQ) Implantation System (MIS) in women with urodynamic stress urinary incontinence (SUI) and urethral hypermobility after an unsuccessful conservative treatment. This is a prospective randomized controlled trial in women without previous incontinence surgery. Twenty-four women received MPQ. Twenty-one controls underwent a pelvic floor muscle exercises home program. Follow-up was at 3 months and the MPQ group also at 12 months. At 3 months, pad usage decreased significantly more in the MPQ group than in the control group (p = 0.015). According to physician and patient self-assessment, respectively, 71% and 63% women in the MPQ group were considered cured or markedly improved. This was significantly higher compared to controls. There was a significant higher increase of Incontinence Quality-of-Life questionnaire score in the MPQ group compared to controls (p = 0.017). Improvements in MPQ group at 3 months are sustained to 12 months. Adverse events were mild and transient. MIS is an acceptable option for women with SUI and urethral hypermobility.

Aims: Reactive nitrogen and oxygen species (RNOS) likely play a role in the development of bladder dysfunction related to bladder outlet obstruction. Antioxidants protect against these free radicals. The aim of our study was to investigate the effect of bladder outlet obstruction on the endogenous antioxidant status of the bladder and to correlate this to bladder structure and function., Methods: In 16 guinea pigs either a partial outlet obstruction or a sham operation was induced. The contractile responses of detrusor strips to electrical field stimulation (EFS), acetylcholine, potassium, and ATP were monitored 4 weeks after the operation. The nerve density in bladder tissue was determined by using the non-specific nerve marker PGP 9.5. Separate antioxidants and the total antioxidant status were assessed using the trolox equivalent antioxidant capacity (TEAC) test., Results: Contractile responses of detrusor strips to EFS were for the greater part based on neurogenic stimulation. The nerve-mediated responses in strips from obstructed bladders were lower compared to the sham group. Obstructed bladders showed a patchy denervation and the nerve density was significantly lower compared to the sham group. The total antioxidant capacity, the glutathione and the glutathione reductase (GR) levels significantly decreased in obstructed bladders compared to the sham group., Conclusion: This study demonstrates that the antioxidant status of guinea pig bladders exposed to outlet obstruction decreased which might be associated with the observed reduction in nerve density. The results strengthen the hypothesis that oxidative stress is involved in the pathophysiology of bladder dysfunction related to obstructed bladders. Neurourol. Urodynam. 28:461-467, 2009. (c) 2008 Wiley-Liss, Inc.

Objective: To compare, in a post hoc analysis of a phase III trial, the maximum recommended doses of fesoterodine (8 mg) and tolterodine (4 mg) for improving overactive bladder (OAB) symptoms and health-related quality of life (HRQoL), as fesoterodine effectively reduces OAB symptoms vs placebo., Patients and Methods: Eligible patients with frequency (> or =eight voids/24 h) and either urgency (> or =six episodes over 3 days) or urgency urinary incontinence (UUI; > or =three episodes over 3 days) were randomized to placebo, fesoterodine 4 or 8 mg, or tolterodine extended-release (ER) 4 mg for 12 weeks; fesoterodine 4 mg data were published elsewhere. Patients completed a 3-day bladder diary in which they recorded the time of each void, voided volume (VV), and the severity of urgency. A post hoc inferential analysis was conducted on the primary endpoint (voids/24 h), the two co-primary endpoints (UUI episodes/24 h and treatment response), several secondary endpoints (severe urgency plus UUI per 24 h, mean VV (MVV)/void, and continent days/week), HRQoL, using the King's Health Questionnaire (KHQ) and the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), and self-reported bladder-related problems. A subanalysis also assessed all endpoints for patients who were incontinent at baseline. Tolerability and safety were assessed by evaluating adverse events, residual urine volume, laboratory variables and treatment withdrawals., Results: By week 12, patients with OAB in both active-treatment groups showed significant improvements in most bladder diary variables and treatment response rates compared with placebo. Fesoterodine 8 mg was statistically significantly better than tolterodine ER 4 mg for improving UUI episodes, severe urgency plus UUI, mean VV, and number of continent days/week. In addition, the fesoterodine and tolterodine ER groups showed significantly greater improvements in HRQoL than the placebo group, with positive changes in most domains of the KHQ and an improvement in ICIQ-SF score. The fesoterodine 8-mg group had statistically significant improvements over placebo in eight of nine KHQ domains. A major improvement in the severity of bladder-related problems was reported by 39% of the fesoterodine 8 mg and 34% of the tolterodine ER groups vs 25% of those on placebo (P < or = 0.01). Results for the subgroup of incontinent patients at baseline were similar to the overall results. Adverse events reported most commonly with active treatment included dry mouth, constipation, dry eye, dry throat, and nausea., Conclusions: Both fesoterodine and tolterodine ER significantly improved OAB symptoms and HRQoL, with statistically significant advantages for fesoterodine 8 mg compared with tolterodine ER on several important endpoints.

Objective: To identify and characterize possible structural specialisations in the wall of the lower urinary tract (LUT) in the region of the bladder urethral junction (BUJ), with the specific objective of identifying regional variations in sensory nerve fibres and interstitial cells (ICs)., Materials and Methods: The bladder base and urethra was removed from five male guinea pigs killed by cervical dislocation. Tissue pieces were incubated in Krebs' solution at 36 degrees C, gassed with 95% O(2) and 5% CO(2), fixed in 4% paraformaldehyde and processed for immunohistochemistry. The nonspecific marker vimentin and the general neuronal marker protein gene product (PGP) 9.5 were used to identify ICs and nerve fibres, respectively. Specific antibody binding was visualized using the appropriate secondary antibodies., Results: The wall of the LUT in the region immediately between the bladder base and the urethra, the BUJ, differed in its cellular composition relative to the adjacent areas. PGP-positive (PGP(+)) nerve fibres, presumptive afferent fibres, lay within the urothelium running between the epithelial cells. There were two general nerve patterns: branching fibres with no varicosities, and complex fibres with varicosities. Fibre collaterals with varicosities exited the urothelium and occupied the space under the urothelium adjacent to the layer of suburothelial ICs. The latter, lamina propria and around the muscle bundles were identified using vimentin (vim(+)). In the base a few vim(+) cells were also PGP(+). In the region of the BUJ there was a decrease in the amount of smooth muscle. In this region, below the lamina propria, there was an area densely populated with vim(+)/PGP(+) ICs. Nerve fibres ran between the cells in this region., Conclusion: These structural specialisations within the urothelium and deeper layers of the BUJ suggest that they might be associated with specific functions. The localized highly branched network of the putative afferent nerves suggests the presence of a local axonal reflexes involving possible cross-talk between the urothelium and suburothelial layer. The function of the specialized region of ICs is not known and must await further information on the functional properties of this novel cell type. These observations show further the cellular heterogeneity of the cells in the LUT and the complexity of the structures. One of the major current challenges in functional urology is to understand the relationships between these novel structures and overall bladder and urethral function.

Objectives: Bladder outlet obstruction is correlated with an increased peroxidation of lipids. The aldehyde 4-hydroxynonenal (HNE) is produced in relative large amounts during lipid peroxidation. The aim of this study was to investigate the effect of HNE on excitation-contraction coupling of detrusor smooth muscle., Methods: We used smooth muscle strips from pig urinary bladder. Contractile responses to electrical field stimulation (EFS) (4 to 32 Hz), carbachol (10(-8) to 3.10(-5) M), and potassium (65.3 mM) were monitored before and after the addition of HNE. We investigated the effect of the synthetic thiol inactivator N-ethylmaleimide (NEM) on the stimulation pathways and compared it with the HNE-mediated effect., Results: Responses of detrusor strips to EFS were for the greater part based on neurogenic stimulation and the release of acetylcholine. HNE (100 microM) diminished contractile responses to EFS and carbachol to the same extent. The pD(2) value of the carbachol concentration response curve did not decrease after exposure to HNE. The maximal effect obtained with carbachol was significantly reduced after 100 microM HNE treatment. Contractions induced by potassium were affected in a similar degree by HNE compared with EFS- and carbachol-induced responses of comparable amplitude. Incubation of bladder strips with NEM had similar effects on pharmacological responses compared with HNE exposure., Conclusions: 4-Hydroxynonenal affects pig bladder contractility. L-type calcium channels and or the contractile system of the bladder muscle are susceptible to HNE-mediated damage. The cholinergic nerves and the muscarinic receptor signaling system remain largely unaffected. The effects of HNE are most likely mediated via alkylation of sulfhydryl groups.

Objective: To evaluate the urodynamic data before and 6 months after implantation of sacral neuromodulation (SNM, an established treatment for voiding dysfunction, including refractory urge urinary incontinence, UI) and to assess the correlation between the urodynamic data and clinical efficacy in patients with UI., Patients and Methods: In all, 111 patients with a >50% reduction in UI symptoms during a percutaneous nerve evaluation test qualified for surgical implantation of SNM. Patients were categorized in two subgroups, i.e. those with UI with or without confirmed detrusor overactivity (DO) at baseline. At the 6-month follow-up all patients had a second urodynamic investigation, with the stimulator switched on., Results: At baseline, there was urodynamically confirmed DO in 67 patients, while 44 showed no DO. A review of filling cystometry variables showed a statistically significant improvement in bladder volumes at first sensation of filling (FSF) and at maximum fill volume (MFV) before voiding for both UI subgroups, compared with baseline. In 51% of the patients with UI and DO at baseline, the DO resolved during the follow-up. However, those patients were no more clinically successful than those who still had DO (P = 0.73). At the 6-month follow-up, 55 of 84 implanted patients showed clinical benefit, having a >or=50% improvement in primary voiding diary variables. Patients with UI but no DO had a higher rate of clinical success (73%) than patients with UI and DO (61%), but the difference was not statistically significant., Conclusion: These urodynamic results show a statistically significant improvement in FSF and MFV in patients with UI with or with no DO after SNM. Although there was a urodynamic and clinical improvement in both groups, patients with UI but no DO are at least as successful as patients with UI and DO. Therefore in patients with UI, DO should not be a prerequisite selection criterion for using SNM.

Patients with symptoms of overactive bladder syndrome or non-obstructive urinary retention, refractory to conservative therapy, can nowadays be treated minimally invasively with sacral nerve stimulation (SNS). The use of electric currents to treat urological pathology has a long history but SNS therapy only received FDA approval in 1997. The mechanisms of action are still not known so there are different theories explaining the modulation effect. Recent studies have shown a central modulation effect. Predictive factors which can help to identify the perfect candidates are not known. Over the years the technique of SNS has become less invasive and because of two stage implantation test results have proven to be more reliable. The clinical results for this therapy have proven to be safe and effective and with the technical improvements over the years the re-operation and complication rates have decreased significantly. The clinical results have led to expanding indications because of positive effects in other symptoms. In the field of urology this has resulted in the use of SNS therapy for interstitial cystitis, neurogenic lower urinary dysfunction, and pediatric voiding dysfunction. In the field of gastro-intestinal pathology, SNS therapy is used to treat faecal incontinence and constipation., (Copyright 2007 Wiley-Liss, Inc.)

Purpose: This 5-year, prospective, multicenter trial evaluated the long-term safety and efficacy of sacral neuromodulation in patients with refractory urge incontinence, urgency frequency and retention., Materials and Methods: A total of 17 centers worldwide enrolled 163 patients (87% female). Following test stimulation 11 patients declined implantation and 152 underwent implantation using InterStim. Of those treated with implantation 96 (63.2%) had urge incontinence, 25 (16.4%) had urgency frequency and 31 (20.4%) had retention. Voiding diaries were collected annually for 5 years. Clinical success was defined as 50% or greater improvement from baseline in primary voiding diary variable(s)., Results: Data for all implanted cases were reported. For patients with urge incontinence mean leaking episodes per day decreased from 9.6 +/- 6.0 to 3.9 +/- 4.0 at 5 years. For patients with urgency frequency mean voids per day decreased from 19.3 +/- 7.0 to 14.8 +/- 7.6, and mean volume voided per void increased from 92.3 +/- 52.8 to 165.2 +/- 147.7 ml. For patients with retention the mean volume per catheterization decreased from 379.9 +/- 183.8 to 109.2 +/- 184.3 ml, and the mean number of catheterizations decreased from 5.3 +/- 2.8 to 1.9 +/- 2.8. All changes were statistically significant (p <0.001). No life threatening or irreversible adverse events occurred. In 102 patients 279 device or therapy related adverse events were observed. At 5 years after implantation 68% of patients with urge incontinence, 56% with urgency frequency and 71% with retention had successful outcomes., Conclusions: This long-term study demonstrates that InterStim therapy is safe and effective for restoring voiding in appropriately selected cases refractory to other forms of treatment.

Objective: To identify and describe changes to the motor component of the motor/sensory system, which contributes to sensation during the filling phase of the micturition cycle, as a result of surgically induced bladder pathology, i.e. damage to the bladder neck and outlet obstruction., Materials and Methods: Adult male guinea pigs (294-454 g) were assigned initially into three groups: (i) normal guinea pigs with no surgical intervention (control, seven); (ii) guinea pigs which, with full surgical anaesthesia, had a silver ring implanted around the bladder neck (obstructed, 13); and (iii) guinea pigs operated to expose the bladder neck but with no implantation of a ring (sham, six). At 2-4 weeks after surgery the bladders were isolated, weighed and the pressure recordings used to identify autonomous activity., Results: The bladder weights in all operated groups, including the sham, were greater than controls. Bladder weights in the obstructed guinea pigs varied considerably, reflecting the degree of pathological change. Consequently, bladders from this group were divided into those with high (OBH) and those with low bladder weight (OBL). The mean (sd) amplitudes of the autonomous contractions were 1.1 (0.1), 10.8 (1.8), 11.4 (2.5) and 17.1 (4.0) cmH(2)O in control, sham, OBL and OBH bladders, respectively, indicating a progressive alteration in function with the pathology. The changes in the sham group suggested that the pathological changes were not the result of obstruction but damage to the bladder neck, the implantation of the silver rings exacerbating the damage. There were episodes of rapid phasic activity (bursts) in 10 of 13 of the ring-implanted bladders, and in two of six in the sham group, but never in controls. Neither the autonomous activity nor the bursts were affected by tetrodotoxin (1 microm) or atropine (3 microm) but they were abolished by noradrenaline (3 microm). In control bladders, adding the muscarinic agonist arecaidine produced a transient acceleration of phasic activity and increased the amplitude of the contractions. There was a similar acceleration of activity in all the operated groups but the concentrations needed to achieve an increase in frequency were significantly lower, the relative sensitivity to arecaidine being OBH >/= OBL > sham > control., Conclusion: The mechanism involved in controlling the frequency of the motor component of the motor/sensory system, the 'pacemaker', appears to become progressively 'supersensitive' to cholinergic stimulation with the development of pathology. These observations are discussed in relation to the motor/sensory system and the origins of sensation in the bladder. The argument is proposed that damage to the bladder neck, not obstruction per se, results in altered nonmicturition activity which contributes to increased afferent output. In turn this contributes to the increased sensations of urge associated with bladder dysfunction. The cholinergic regulation of this altered 'pacemaker' might be the target for one of the therapeutic actions of anticholinergic drugs.

Interstitial cells (ICs) play a role in regulating normal bladder activity. This study explores the possibility that the sub-urothelial and muscle networks of NO/cGMP-responsive ICs are altered in animals with surgically induced outflow obstruction. In sham-operated animals, the urothelium comprised NO-stimulated cGMP-positive (cGMP(+)) umbrella cells, an intermediate layer and a basal layer that stained for nNOS. cGMP(+) sub-urothelial interstitial cells (su-ICs) were found below the urothelium. cGMP(+) cells were also associated with the outer muscle layers: on the serosal surface, on the surface of the muscle bundles and within the muscle bundles. Several differences were noted in tissues from obstructed animals: (1) the number of cGMP(+) umbrella cells and intensity of staining was reduced; (2) the intermediate layer of the urothelium consisted of multiple cell layers; (3) the su-IC layer was increased, with cells dispersed being throughout the lamina propria; (4) cGMP(+) cells were found within the inner muscle layer forming nodes between the muscle bundles; (5) the number of cells forming the muscle coat (serosa) was increased; (6) an extensive network of cGMP(+) cells penetrated the muscle bundles; (7) cGMP(+) cells surrounded the muscle bundles and nodes of ICs were apparent, these nodes being associated with nerve fibres; (8) nerves were found in the lamina propria but rarely associated with the urothelium. Thus, changes occur in the networks of ICs following bladder outflow obstruction. These changes must have functional consequences, some of which are discussed.

Objectives: To establish the functional consequences of exposing the isolated whole bladder preparation to exogenous prostaglandins (PGE(1), PGE(2), PGF(2alpha)) and to determine which cells express cyclooxygenase (COX) types I and II, to generate PG to effect these changes in vivo., Materials and Methods: Fifteen female guinea pigs (270-350 g) were used, i.e. seven for structural studies and eight for physiological measurement. For the structural study pieces of the lateral wall were incubated separately in Krebs' solution at 36 degrees C, gassed with 95% O(2) and 5% CO(2) with 1 mm isobutyl-methyl-xanthene. Individual pieces were then exposed to 100 microm of the nitric oxide (NO) donor NONOate for 10 min; control tissues remained in Krebs' solution. Tissues were then fixed in 4% paraformaldehyde. For the physiological experiments bladders were isolated and a cannula inserted into the urethra to monitor intravesical pressure. The bladders were suspended in a chamber containing carboxygenated physiological solution at 33-36 degrees C. All drugs were added to the abluminal bladder surface., Results: In the resting bladder there were small spontaneous transient rises in pressure, i.e. autonomous activity. Exposure to PGE(2) (3-300 nM) resulted in an increase in basal pressure on which were superimposed autonomous activity, which was increased both in amplitude and frequency. The changes in the amplitude and frequency depended on the concentration of PGE(2). After a brief exposure (240 s) to PGE(2) the augmentation of the autonomous activity continued for >60 min despite regular washing. The responses were similar with PGE(1) but the responses to PGF(2alpha) and arachidonic acid were reduced. The augmented activity was reduced by the EP1/EP2 receptor blocking agent AH6809 (10 microm). Using an antibody to the 70 kDa constitutive form (COX I), COX I immunoreactivity (COX I-IR) was located in cells in the basal urothelium, in lamina propria and cells on the surface of the inner muscle bundles. There were few COX I-IR cells associated with the outer muscle bundles. The COX I-IR cells lying within the lamina propria were distinct from the suburothelial cells which respond to NO with an increase in cGMP. The lamina propria COX I-IR cells appeared to form a network surrounding muscle trabeculae within the inner muscle layer. COX II-IR was associated with the nuclei of cells in the urothelium, lamina propria and muscle., Conclusions: These data show that PGs regulate autonomous activity. Potential sources of endogenous PG were identified. It is unclear how the PGs produced by these cells alter autonomous activity. There might be a direct activation of the muscle by PGs released by the network of superficial muscle interstitial cells, or PG released from the urothelium might influence phasic contractile activity via networks of COX I-IR interstitial cells. The possible roles and importance of this mechanism for bladder physiology and pathology are discussed.

Objective: To describe patient selection for sacral neuromodulation, also known as Interstim therapy, and the results of tined-lead implantation in the medium term., Patients and Methods: In all, 49 patients, 39 with refractory overactive bladder symptoms and 10 with urinary retention, were implanted with the tined lead under local anaesthesia. The mean (sd) test period was 12.4 (5.8) days. Patients were implanted when they had a > or = 50% improvement in voiding diary variables during the test period. The mean follow-up for implanted patients was 15.5 (7.9) months. Changes in voiding variables were compared using a t-test., Results: Ten patients had a one-stage and 39 a two-stage implant; of the latter group, 31 (80%) had a positive response and eight (21%) did not. In all, 31 patients were included in the follow-up. At the last follow-up, 28 (90%) patients had a >50% improvement in diary variables and three (10%) did not. In 21 patients with urgency symptoms the mean (sd) number of voids decreased from 11.7 (8.9)/day at baseline to 7.3 (3.4)/day (P = 0.1); the voided volume increased from 160.2 (70.7) mL to 231.1 (119.5) mL (P = 0.001); and the number of leakages decreased from 9.5 (8.7) to 3.3 (2.2)/day (P = 0.17). In the 10 patients with retention, the number of catheterizations decreased from 5.44 (1.6)/day with a volume of 297.6 (76.8) mL, to 1.2 (1.7)/day and 111.6 (158.1) mL; the mean number of voids increased from 3.7 (3.8)/day with a volume of 123.3 (141.7) mL, to 4.2 (2.4)/day and 248.3 (146.0)mL. There were no significant differences in the variables in the patients with retention. Seven patients had an adverse event. There was one incomplete electrode migration that was treated conservatively., Conclusion: This new minimally invasive approach gives positive results in the medium term. Two-stage testing with the tined lead seems more reliable than the classic percutaneous nerve evaluation. The lead anchoring method seems sufficient for fixing the electrode in the medium term.

Aims: Several pathophysiological conditions in the urinary bladder, for example, ischemia/reperfusion and inflammation are characterized by the formation of reactive oxygen species (ROS). The ROS are highly toxic because they can destroy proteins, DNA, and lipids. The aim of this study was to investigate the effect of oxidative stress on excitation-contraction coupling of detrusor smooth muscle., Materials and Methods: Smooth muscle strips were dissected from pig urinary bladder and mounted in organ baths. Oxidative stress was mimicked by the addition of Cumene hydroperoxide (CHP), a lipophilic hydroperoxide, to the organ baths. Contractile responses to electrical field stimulation (EFS: 4-32 Hz), carbachol (10(-8)-3 x 10(-5) M), potassium (65.3 mM), and ATP (1 mM) were monitored before and after the addition of CHP., Results: Responses of detrusor strips to EFS were for the greater part based on neurogenic stimulation and the release of acetylcholine. CHP diminished contractile responses to EFS and carbachol to the same extent. The pD(2) value of the carbachol concentration-response curve decreased significantly after exposure to 0.1 mM, 0.4 mM, 0.8 mM CHP. Furthermore the maximal effect obtained with carbachol was significantly reduced after 0.1 mM, 0.4 mM, and 0.8 mM CHP treatment. Contractions induced by potassium and ATP were significantly less affected by oxidative stress compared to EFS- and carbachol-induced responses of comparable amplitude., Conclusions: The results of our study demonstrate that oxidative stress induced by CHP affects pig bladder contractility. The muscarinic receptor signaling system is severely damaged. L-type calcium channels and the contractile system are less affected and cholinergic nerves remain largely unaffected., ((c) 2006 Wiley-Liss, Inc.)

Objective: To measure the prevalence of nocturia in general practice and to determine which factors are associated with nocturia., Subjects and Methods: Data were collected from 3048 elderly men, who completed a questionnaire that was sent to every man aged 55-75 years in 21 general practices in Maastricht (the Netherlands). The symptom of nocturia was defined as two or more nocturnal voids. We investigated the prevalence of nocturia and the predictive relationships with the following factors: cerebrovascular disease, diabetes mellitus/insipidus (DMI), Parkinson's diseases, cardiovascular disease, hypertension, bladder/prostate cancer, kidney diseases, urinary bladder inflammation, congenital diseases (kidneys or prostate), using medical treatment for lower urinary tract symptoms, other treatment, psychological depression, symptoms suggestive of benign prostatic hyperplasia (BPH), and alcohol intake., Results: Data from 2934 respondents were analysed; the prevalence of nocturia (two or more nocturnal voids) was 32.9% (965 men). The frequency of the number of nocturnal voids was: zero in 588 (20.0%), one in 1344 (45.8%), two in 611 (20.8%), three in 208 (7.1%), four in 70 (2.4%), and five or more in 76 (2.6%), with 37 values missing. A multivariate logistic regression analysis showed that nocturia in elderly men was significantly related to bladder/prostate cancer, cerebrovascular disease, treatment of voiding disorders, and moderate alcohol consumption. Next to these, BPH had a significant relationship with nocturia, especially in respondents with DMI and hypertension. Cardiovascular disease or hypertension was significantly related to nocturia, mutually replacing each other as a risk factor., Conclusion: Nocturia in elderly men is be related to many sources of potential risk factors: earlier urological diseases, cardiovascular and cerebrovascular diseases, BPH, DMI and behavioural habits. Some of these sources may interact and generate especially high risk in some groups for nocturia.

Objective: To analyse the influence of technical improvements of Sacral Nerve Stimulation (SNS) on the incidence of surgical interventions and subjective long-term results of SNS., Methods: Retrospective, transversal study analyzing records of implanted patients at our department of Urology., Results: Of 149 patients analyzed, 107 had overactive bladder symptoms and 42 had urinary retention. Mean follow-up was 64,2 (sd = 38,5) months. In the whole group 194 adverse events occurred. 6 Patients had infection in their implanted system, one was explanted for infection. Most events could be solved by giving advice or by reprogramming the stimulator. 129 reoperations have been performed and 21 patients had their system explanted. Analysis of the data shows a striking difference in the incidence of reoperations, but small differences in subjective results in the groups of patients implanted before or after 1996, suggesting that a proactive approach towards adverse events is worthwhile., Conclusions: SNS gives lasting benefit in patients with refractory symptoms of overactive bladder and non-obstructive urinary retention. The differences in outcomes and incidence of reoperation can be attributed to the learning curve and technical and surgical improvements in the application of SNS.

Objectives: To test the capability of the flavonoid galangin to protect pig urinary bladder from damage due to a period of repetitive field stimulation as well as a period of anoxia/glucopenia and reperfusion., Methods: Smooth muscle strips of the pig bladder were mounted for tension recording in small organ baths and the strips underwent either 1.5 hours of repetitive field stimulation at 32 Hz for 15 seconds every 5 minutes or under anoxia/glucopenia and reperfusion conditions. Galangin, at different concentrations, was added to the reperfusion Krebs solution to check the effect of this flavonoid compared with untreated strips under the same conditions. A group of experiments was performed to examine its possible underlying mechanisms., Results: Repetitive field stimulation for 1.5 hours caused a progressive decrease in the maximal contractile response to electrical field stimulation (34% decrease). Galangin (10(-7) M) partially prevented the progressive decrease in the contractile response. This effect was significantly reduced when verapamil was added to the solution. Galangin significantly improved the response of strips to electrical field stimulation under anoxia/glucopenia and reperfusion conditions compared with untreated tissues., Conclusions: Galangin has a protective effect on bladder contractility by an action that at least, in part, depends on l-type calcium channels. Furthermore, galangin protects detrusor nerves against the anoxia/glucopenic and reperfusion damage.

There is increasing evidence that the generation of free radicals plays a role in the development of bladder dysfunction. Flavonoids are a group of polyphenolic compounds with broad pharmacological activity. In the present study, the protective effects of the flavonoid galangin on the progressive decrease of bladder smooth muscle contractile responses during repetitive field stimulation (RFS; a model for muscular fatigue) were demonstrated. Pig detrusor strips were mounted for tension recording in organ baths aand were subjected to RFS for 90 min at 32 Hz for 15 s every 5 min. The strips were then washed four times with fresh buffer and allowed a period of recovery for 90 min. The 90 min of RFS caused a progressive decrease in maximal contractile response to electrical field stimulation and to muscarinic agonist-induced contractions (34% and 46% decrease, respectively). Galangin (10(-7) M) prevented the decrease in contractile smooth muscle response of strips to electrical field stimulation during RFS compared with untreated tissues. The antioxidant activity of galangin was assessed by measuring its ability to inhibit the lipid peroxidation induced by iron and ascorbate in rat liver microsomes (IC50 1.7+0.12x10(-6) M). If the data are confirmed in-vivo, exogenously administered galangin may be a new approach in the prevention and/or treatment of bladder dysfunction.

Aims: Flavonoids comprise a large group of natural polyphenolic compounds, which possess a wide spectrum of physiological and pharmacological effects. Recently, the flavonoid galangin was found to modulate smooth muscle contractility. The aim of the present study was to investigate the mechanism of actions of galangin on pig bladder smooth muscle and to characterize its potential as an alternative inhibitor of bladder smooth muscle contraction., Materials and Methods: Strips of pig detrusor muscle were mounted in separate 6-ml organ baths containing Krebs solution. The contractile response to carbachol (10(-8)-10(-4)M), potassium (2x10(-2)-10(-1)M), and electrical field stimulation-EFS (2-32 Hz) were determined before and after the addition of galangin (3x10(-5)M). The contractile responses to carbachol in calcium-free Krebs' solution plus EGTA and L-type channel blocker were determined in the absence and presence of the flavonoid. Furthermore, the effect of galangin was also evaluated after the administration in the bath of a number of antagonists/inhibitors including a combination of propranolol, phentolamine, capsazepine, and verapamil. Student's t-test and one factor ANOVA were used to determine the statistical significance of the effects., Results: Galangin inhibited the maximal contractile response to carbachol and potassium by 57.41% (P<0.01) and 33.52% (P<0.05), respectively. The maximum force of the carbachol-evoked contractions in calcium-free solution after incubation with galangin was 32% of the maximum initial force (Emax.initial: 5.8387+/-0.72 mN, Emax.Galangin: 1.9157+/-0.30 mN, P<0.01). The maximal contractile responses to EFS at 2, 4, 8, 16, and 32 Hz were reduced, compared to control, by 91.61% (P<0.01), 79.46% (P<0.01), 70.54% (P<0.01), 61.10% (P<0.01), and 9.8% (P>0.05), respectively. The inhibitory effect of galangin was unaffected by a combination of propranolol, phentolamine, and capsazepine (P>0.05). However, when verapamil was added to the medium, the inhibitory effects of galangin were partially blocked., Conclusions: Galangin, at high concentrations, exerts an inhibitory effect on pig bladder smooth muscle contractility through the inhibition of calcium influx and the modulation of intracellular calcium movement. Furthermore, we have demonstrated that the inhibitory effect of galangin involves, at least in part, L-type calcium channels pathways., (Copyright (c) 2005 Wiley-Liss, Inc.)

The precise effect of low estrogen levels on urinary bladder contractility remains controversial. The present study was designed to analyze the effect of 17beta-estradiol in bladder smooth muscle contractility and the involvement of specific estrogen receptor stimulation in this effect. Castrated male and female pig detrusor strips were mounted for tension recording in an organ bath, superfused with Krebs solution at 37 degrees C and stimulated electrically and pharmacologically. In order to verify the acute effect of 17beta-estradiol on muscle contractility, the strips were incubated with different concentrations of the hormone. Muscle contractions were induced by potassium chloride, acetylcholine chloride and electrical field stimulation. The involvement of the estrogen receptor in the effects of 17beta-estradiol was assessed by incubation of some strips with the selective estrogen receptor antagonist ICI 182.780 before estradiol was applied. Estradiol at a dose of 30 micromol/l elicited a lower amplitude of contractions induced by EFS, Ach and KCl in female as well as in castrated male pig bladder smooth muscle strips. The effects of 17beta-estradiol were stronger in contractions induced by potassium chloride than those induced by other forms of stimulation. Pre-treatment with the pure estrogen receptor antagonist had no effect on 17beta-estradiol-induced inhibition of muscle contractility. These observations suggest that 17beta-estradiol induces lower amplitude of contraction of female as well as castrated male pig detrusor which is not mediated by the classic estrogen receptor. Furthermore, we can conclude that estradiol has a stronger inhibitory effect on the depolarization of muscle cell membrane compared to a muscarinic receptor-induced contraction.

Objectives: To determine whether the human bladder can also adapt to an increased physiologic load, because bladder dysfunction is considered to be an important factor in the development of lower urinary tract symptoms. Animal studies have shown that bladder function can be improved by increasing the urine output., Methods: A total of 44 men between 55 and 75 years of age were asked to increase their daily fluid intake by 2 L for a 2-month period. The objective outcome measures were maximal urinary flow rate (Da Capo home uroflowmeter), maximal voided volume (frequency-volume chart), and average voided volume (frequency-volume chart). The International Prostate Symptom Score and global perceived benefit of the intervention were recorded to assess the subjective effects of the intervention., Results: The maximal flow rate increased by 13% (2.3 mL/s), the maximal voided volume increased by 23% (93.8 mL), and average voided volume increased by 25% (60.1 mL). Of the 44 participants, 56% reported an improvement in their lower urinary tract function, but the International Prostate Symptom Score increase was statistically significant at 1.2 point., Conclusions: The human bladder seems able to adapt to an increased load. Future randomized effectiveness studies with longer follow-up should be done to determine the upper limit of objective bladder adaptation. In addition, future studies should address the long-term efficacy in the prevention of symptoms.

Objective: The presence of an overactive detrusor (OD) is becoming more prevalent in the elderly and may severely influence the social life and activities of daily living in the senior, otherwise healthy, person. There is a marked age-dependent increase in OD above the age of 65 years, which is mainly attributed to dysfunction, with loss of voluntary control, of the micturition reflex and decreased perception of bladder fullness., Material and Methods: Herein, we evaluate the outcome of sacral nerve stimulation in five patients aged >65 years derived from a large, multinational, randomized, prospective study., Results: The effect on symptoms was excellent in two subjects. There was a moderate improvement in another subject and a variable but eventually small effect in the remaining two patients. The results appeared to be more favourable in younger patients., Conclusion: Our findings suggest that the outcome of sacral nerve stimulation is more unpredictable in the elderly, a fact that should be considered when counselling the patient. However, it should be remembered that, even for the older, active person, urge incontinence may have a severe impact on quality of life and that the majority of patients treated with an implant will benefit from this treatment.

This article reviews the literature on the pathophysiology of male lower urinary tract symptoms (LUTS) with the intention of developing a new preventive intervention for this bothersome disease. Traditionally, male voiding dysfunction has been thought to arise from bladder outlet obstruction (BOO) caused by prostatic enlargement. Many years of research, however, have shown that a clear relationship between the size of the prostate and the occurrence or severity of symptoms is doubtful. Because of its crucial role in urination, it is increasingly being accepted that the clinical manifestation of voiding dysfunction relies on the functional behaviour of the bladder. Several animal studies have shown that bladder performance can be improved by increasing urine output. Contrary to alterations observed in pathologic situations, an increased urine output provides a physiologic stimulus for animal bladder function improvement. We hypothesise that a trained bladder should be less susceptible to the harmful effects of ageing and obstruction. Future symptoms may thus be prevented. In humans an increased urine output can be achieved by drinking additional water, which could be an adequate preventive intervention.

Objective: To assess the efficacy of silicone microimplants (Macroplastique; polydimethylsiloxane) therapy for stress urinary incontinence in adult women, using a systematic review of identified studies., Materials and Methods: A computer-aided and manual search for published studies investigating silicone microimplants therapy for stress urinary incontinence in adult women. The methodological quality of the included studies was assessed using criteria based on generally accepted principles of interventional research., Results: Only two RCTs, only published as an abstract, were found. Eleven pre-experimental or observational studies were identified. Overall, the methodological quality was low. The main methodological shortcomings of the studies were: no random allocation procedure, lack of prestratification on prognostic determinants, no blinding, small sample sizes, and lack of proper analysis and presentation of results. There was variability in the indication for implantation, implantation procedure, rate and volume of silicone microimplants. The use of different outcome measures in most of the trials made comparison between studies difficult., Conclusions: Because of the low methodological quality of included studies, results should be interpreted with caution and no firm conclusions about the efficacy of silicone microimplants were possible. Randomized clinical trials, using valid and reliable subjective and objective measurements, are necessary to establish the efficacy of silicone microimplants therapy in treating stress urinary incontinence in adult women.

Objectives: Standard urodynamic investigations showed no correlation between the efficacy of sacral neuromodulation (SNS) and urodynamic data. Ambulant urodynamic investigations (ACM) are presented as more sensitive and reliable in detecting and quantifying bladder overactivity. In this study we looked at the correlation and results of ambulant urodynamic data and the clinical effects of SNS., Methods: Data of patients with bladder overactivity, who underwent an ACM before and during SNS were investigated. Blind analyses of the ACM were performed and the detrusor activity index (DAI) was calculated as the degree of bladder overactivity of the detrusor. The ACM parameters, before and during SNS, were analyzed and correlated to the clinical effect of SNS., Results: In 22 of the 34 patients a DAI before and during stimulation could be calculated because of quality aspects. In all other patients, the other ambulatory urodynamic parameters could be analyzed and a significant reduction was found in bladder overactivity. A significant correlation (p = 0.03) was found in DAI reduction of the ACM before and during SNS as compared to the clinical improvement in overactive bladder symptoms., Conclusions: The objective and subjective results show a decrease in bladder overactivity during SNS. During SNS bladder instabilities are still present, which is in accordance with the published literature. The reduction of the DAI during SNS as compared to before SNS correlates significantly to the clinical effect of SNS., (Copyright 2003 Elsevier Science B.V.)

Objective: To evaluate the quality of life, functional outcome and durability of the AMS 800 artificial urinary sphincter (AUS) in patients with urinary incontinence due to intrinsic sphincter deficiency of mixed origin., Patients and Methods: Between 1991 and 2000, 34 AUS were implanted in 31 patients (24 males/7 females) with mean age of 59 (range 15-75) years. Using a questionnaire, patients' urinary function and quality of life were assessed in 22 patients with an AUS in situ. To evaluate efficacy and durability of the device, the primary adequate function (P-AF) and additional procedure-assisted adequate function (APA-AF) rates were determined on the basis of a Kaplan-Meier survival analysis., Results: The social continence rate (0-1 pads/24 h) was 55% with a mean follow-up of 46 months. The revision rate was 26% and the explantation rate 35%. The 5-year P-AF and APA-AF rates were 41 and 44%, respectively. The pad score decreased from 2.95 to 1.23 after AUS implantation (p < 0.0001) leading to a high mean patient satisfaction (rated as 4.0 on a visual analog scale of 0-5). Twenty-one patients (95%) would undergo the procedure again under the same circumstances. Patients with previous anti-incontinence procedures showed a significantly higher explantation rate (p = 0.004)., Conclusion: In spite of a relatively high re-operation rate and moderate social continence state, patient satisfaction was found to be great mainly due to the relative improvement in incontinence. The AMS 800 AUS is a reliable device with few mechanical complications. Extensive preoperative counseling is mandatory., (Copyright 2003 S. Karger AG, Basel)

Objective: To assess the long-term efficacy and safety of two-stage sacral neuromodulation with an implantable pulse generator (IPG) in patients treated for urinary urge incontinence (UI) and/or urinary retention (UR)., Patients and Methods: The two-stage technique is used if patients have a good response during the acute phase of the percutaneous nerve evaluation (PNE) test, but have a poor response during the following 4-7 days (subchronic phase). In the first stage only the permanent electrode was implanted and connected to a temporary external stimulator, allowing patients to be assessed for longer. If the main symptoms improved by more than half the patient proceeded to the second stage, the insertion of the IPG. We reviewed all patients who underwent two-stage implantation; all had signed an informed consent and were asked to complete voiding diaries and a questionnaire to assess the subjective effects of the therapy. Safety was assessed from relevant medical events, management, and relative to the thera-py and resolution. Residual urine was assessed by self-catheterization. The long-term voiding diary results were compared with baseline estimates and analysed statistically using the two-sided Student's t-test., Results: Between 1991 and 1998, 15 patients (13 women and two men, mean age 53 years, range 44-66) underwent the two-stage technique; the mean (median, range) follow-up was 4.9 (5.2, 2.5-7.5) years. Seven patients had UI and seven had UR, with one having both. The mean (range) number of PNEs undertaken in each patient was 2.1 (1-4) and these all failed in the subchronic phase. All patients underwent a first- and second-stage implant after a mean (range) screening period of 12.2 (2-29) days. One patient was explanted after implantation of only the first stage, and two others explanted in a later phase because the IPG was ineffective during the follow-up. The voiding diary results of the remaining 12 patients showed improvement in all the main variables, and in the subjective assessment 11 reported an improvement and were satisfied with the therapy. There were 17 adverse events, 14 of which were resolved and seven of which required surgical intervention., Conclusion: The long-term results of the two-stage implantation show clinically and statistically significant improvements, probably because the implantation of the lead (first stage) more closely resembles the final therapy. If a temporary PNE test is not optimal (lead migration, longer testing needed), the two-stage technique can offer a good and safe alternative of comparable efficacy in the long-term. If the two-stage technique had not been available to these 12 patients they would not have been offered neuromodulation.

Purpose: Bilateral sacral nerve neuromodulation has been proposed as a more effective treatment for chronic voiding dysfunction. However no comparison with the unilateral approach has been performed. We investigated the possible advantage of bilateral sacral neuromodulation., Materials and Methods: In a prospective randomized crossover trial we investigated 33 patients who underwent bilateral implantation of a temporary test lead. Unilateral and bilateral test stimulation was continued for 4 to 6 days in all patients. Patients were randomly assigned to start with bilateral or unilateral stimulation. Between the stimulation episodes a 2-day washout interval was scheduled. Voiding diaries were completed at baseline and during the entire stimulation period. Sacral x-rays were taken to confirm lead positioning or possible migration after implantation and at the end of the test stimulation period. After 10 days the temporary leads were removed and voiding diaries were analyzed., Results: After stimulation sacral x-ray revealed test lead migration in 8 patients, leaving 12 patients with urge incontinence and 13 with voiding difficulty and urinary retention available for review. A statistically significant improvement in voiding parameters was seen during the test stimulation period. However no statistically significant improvement was seen due to bilateral stimulation compared to unilateral stimulation. Two patients with urinary retention only started voiding to completion during bilateral stimulation., Conclusions: Bilateral is in general not superior to unilateral sacral neuromodulation. However, in some individuals bilateral stimulation may be more effective in relieving symptoms. Therefore, if unilateral percutaneous nerve evaluation fails, a bilateral test should be considered.

Objectives: To investigate data from 211 patients who underwent a trial stimulation (percutaneous nerve evaluation [PNE]) to determine the clinical parameters that can enhance the prediction of PNE success. The advantageous effect of sacral neuromodulation depends on the accurate identification of suitable candidates during the preimplantation PNE., Methods: A total of 211 patients (161 women and 50 men), with refractory urge incontinence, urgency-frequency syndrome, and urinary retention, underwent a PNE. Patient data (demographics, medical history, urologic investigations, and diagnosis) were collected. The PNE results were evaluated from a voiding diary and patient history. More than 50% improvement of voiding parameters was considered a successful PNE, and those patients were selected for implantation. Logistic regression analysis was performed. The factors tested for predicting the test result were sex, patient age, diagnosis, previous surgery, neurogenic bladder dysfunction, duration of complaints, and previous treatments., Results: The PNEs were positive in 85 patients (40.3%) and negative in 105 patients (49.8%). In 18 patients (8.5%), the test electrode had migrated; 3 more patients were not assessable and were also excluded. Missing data on the variable "duration of complaints" reduced the number of patients in the analyses from 190 to 174 patients., Conclusions: Intervertebral disk prolapse, duration of complaints, neurogenic bladder dysfunction, and urge incontinence were found to be significant predictive factors. However, a PNE remains necessary to evaluate a patient's chance of implant success objectively.

Objective: In the standard operation procedure for sacral neuromodulation, the implantable pulse generator (IPG) is implanted in a subcutaneous pocket at the lower part of the anterior abdominal wall. This procedure requires a long operation time and three incisions. With the IPG in the abdominal wall, some patients complain of displacement or pain at the IPG site postoperatively. By modifying the technique of placement of the IPG, these disadvantages are overcome., Methods: Between August 1999 and July 2000, 39 patients underwent a buttock implant of the IPG. In 2 of these patients the position of the IPG was changed from abdominal region to the buttock. During follow-up, complications concerning the operation and location of the IPG were compared to the published literature., Results: Operation time is reduced in all patients by approximately 1 h. No repositioning of the patient is required during surgery. Only a short subcutaneous tunnel is required to connect the lead to the IPG. Pain at the level of the IPG was noted in 10% of the patients, which needed no further treatment. No infections were seen and the IPG did not displace postoperatively., Conclusion: Buttock placement of the IPG in sacral nerve stimulation leads to shorter operation time; only two incisions are needed instead of three and a shorter subcutaneous tunnel is needed. Using this technique there are less complications and a lower re-operation rate.

Functional voiding disorders, such as urge incontinence and urine retention, have a high prevalence and often lead to stigmatisation and a diminished quality of life. Patients with idiopathic voiding dysfunctions, for whom conservative treatments are insufficient, can currently be treated with sacral neuromodulation. In sacral neuromodulation a pulse generator is implanted; it is a reversible treatment that can be tested beforehand to evaluate if the patient is eligible for it. After implantation a good result is obtained, on average, in 73% of patients. Patients with spinal cord injury may currently be treated with electrical neurostimulation of the anterior sacral roots, which results in the ability to void without a residue, evacuate stools and obtain an erection or vaginal lubrication. Over 80% of the implanted patients with a spinal cord injury void without residual urine. Furthermore, continence is restored and the bladder capacity increases. In patients with therapy-resistant functional micturition disorders and in patients with spinal cord injury, neuromodulation and neurostimulation must be considered before invasive surgery is carried out.

Previously available antimuscarinic therapies for overactive bladder are poorly tolerated due to a high incidence of adverse events, notably dry mouth. Tolterodine is a bladder-selective, antimuscarinic agent for the treatment of frequency, urgency, and urge incontinence that characterize overactive bladder. In a 9-month open-label study, the safety, tolerability, and clinical efficacy of tolterodine 2 mg twice daily was evaluated in 854 patients with overactive bladder symptoms who had completed one of four 12 week randomized, controlled trials of tolterodine. Safety and tolerability were assessed in terms of adverse events and clinical/laboratory variables. Efficacy was assessed using micturition diaries and patient perception of their bladder condition. In all, 70% of patients remained on treatment for 9 months. Dry mouth was the most frequently reported adverse event, occurring in 28% of patients (intensity: 19% mild, 7% moderate, 2% severe). A total of 9% of patients withdrew due to adverse events. Dosage reduction occurred in 13% of patients. Significant improvements (P < 0.0001) in micturitions per 24 h (-22%), urge incontinence episodes per 24 h (-76%) and volume voided per micturition (+22%) were observed after 9 months of treatment, with 65% of patients reporting an improvement in perception of their bladder problems. The incidence of adverse events and improvements in micturition diary variables during open-label treatment were comparable with those observed during a 12 week randomized treatment. It was concluded that tolterodine is well tolerated and maintains its clinical efficacy during 9 months of treatment. The high proportion of patients remaining on treatment indicates that tolterodine is an effective long-term treatment for overactive bladder.

Objectives: To assess the long-term efficacy and safety of alfuzosin 10 mg OD in patients with symptomatic BPH., Methods: Patients (>50 years) were randomised to alfuzosin 10 mg OD, alfuzosin 2.5. mg t.i.d. or placebo for 3 months. Open-label alfuzosin 10 mg OD was continued for up to 1 year. Efficacy assessments included the International Prostate Symptom Score (I-PSS) and quality of life index and uroflowmetry., Results: At 3 months, there was a significant reduction in I-PSS and a significant improvement in peak flow rate for both alfuzosin groups compared with placebo (p < 0.05). Vasodilatory adverse experiences were more common in the alfuzosin 2.5 mg group than the 10 mg OD group. Improvements in symptoms and flow rate with alfuzosin 10 mg OD were maintained for up to 12 months., Conclusion: Alfuzosin 10 mg OD is an effective treatment for symptomatic BPH for at least 12 months, with a better cardiovascular safety profile than the immediate release formulation.

Purpose: We investigate the efficacy of sacral neurostimulation in patients with idiopathic urinary retention in a prospective, randomized multicenter trial., Materials and Methods: A total of 177 patients with urinary retention refractory to standard therapy were enrolled in the study. Greater than 50% improvement in baseline voiding symptoms during a 3 to 7-day percutaneous test stimulation qualified a patient for surgical implantation of an InterStim parallel system. Of the patients who qualified for implantation 37 were randomly assigned to a treatment and 31 to a control group. Patients in the treatment group underwent early surgical implantation of the sacral nerve stimulation system, while implantation was delayed in the control group for 6 months. Followup evaluations, including voiding diary analysis and temporary deactivation of the stimulator at 6 months, were conducted at 1, 3, 6, 12 and 18 months after implantation in the treatment group, and after 3 and 6 months in the control group., Results: Compared to the control group, patients implanted with the InterStim system had statistically and clinically significant reductions in the catheter volume per catheterization (p <0.0001). Of the patients treated with implants 69% eliminated catheterization at 6 months and an additional 14% had a 50% or greater reduction in catheter volume per catheterization. Therefore, successful results were achieved in 83% of the implant group with retention compared to 9% of the control group at 6 months. Temporary inactivation of sacral nerve stimulation therapy resulted in a significant increase in residual volumes (p <0.0001) but effectiveness of sacral nerve stimulation was sustained through 18 months after implant., Conclusions: Results of this prospective, randomized clinical study demonstrate that sacral nerve stimulation is effective for restoring voiding in patients with retention who are refractory to other forms of treatment.

Objectives: To evaluate the long-term efficacy of sacral nerve stimulation for refractory urinary urge incontinence., Study Design and Methods: Urge incontinent patients qualified for surgical implantation of a neurostimulator system after trial screening with percutaneous test stimulation. Surgical implantation of the InterStim System (Medtronic Inc., Minneapolis, Minn., USA) was performed in cases where a >50% reduction in incontinence symptoms was documented during the 3- to 7-day test stimulation period. The InterStim System consists of an implantable pulse generator, a transforamenally placed quadripolar lead, and an extension that connects these two devices for unilateral stimulation of the S3 or S4 sacral nerve. Efficacy for 96 implanted patients was based on urinary symptom changes as quantified in voiding diaries collected at baseline and annually after surgical implantation., Results: As compared to baseline, the group of 96 implanted patients demonstrated significant reductions in urge incontinent symptoms at an average of 30.8+/-14.8 (range 12-60) months with respect to the number of urge incontinent episodes per day, severity of leaking, and the number of absorbent pads/diapers replaced per day due to incontinence (all p<0.0001, respectively). Gender, pretreatment variables, and age were not found to be relevant factors that affected these results. 11 of the 96 patients underwent device explant due to lack of efficacy, pain or bowel dysfunction. These data were conservatively included in the efficacy results. No permanent injuries associated with the devices or therapy were reported., Conclusion: Sacral nerve stimulation is an effective treatment for refractory urge incontinence with sustained long-term benefit through an average of 30.8 months.

Many patients have chronic, debilitating symptoms of voiding dysfunction that are refractory to conventional medical or surgical therapies. This multicenter, prospective study evaluated the long-term effectiveness of sacral nerve stimulation using the implantable Medtronic InterStim therapy for urinary control in patients with otherwise intractable complaints of urinary urge incontinence, urgency-frequency, or retention. Each patient first underwent temporary, percutaneous sacral nerve test stimulation. If at least a 50% reduction in target symptoms was documented for at least 3 days, patients received a permanent Medtronic InterStim sacral nerve stimulation system that includes a surgically implanted lead and neurostimulator. Regular follow-up was conducted with outcome data. We report here on patients who have been observed from 1.5 to 3 years postimplantation. The results demonstrate that after 3 years, 59% of 41 urinary urge incontinent patients showed greater than 50% reduction in leaking episodes per day with 46% of patients being completely dry. After 2 years, 56% of the urgency-frequency patients showed greater than 50% reduction in voids per day. After 1. 5 years, 70% of 42 retention patients showed greater than 50% reduction in catheter volume per catheterization. We conclude that the Medtronic InterStim therapy for urinary control system is an effective therapy with sustained clinical benefit for patients with intractable symptoms of urinary urge incontinence, urgency-frequency, or retention.

Purpose: To evaluate the ability of two novel coiled test stimulation lead designs to reduce or eliminate undesired migration and concomitant loss or attenuation of responsiveness to sacral nerve stimulation (SNS) associated with standard percutaneous nerve evaluation (PNE) leads., Materials and Methods: The two novel leads (Coiled Leads 1 and 2) and a standard PNE lead were inserted bilaterally in sacral foramina of female goats. At various times thereafter threshold voltage responses were measured. Prior to lead removal, distance of lead migration was evaluated by x-ray imaging and the force necessary to displace the leads measured. Thereafter, as the leads were being removed, the force necessary for removal was also measured., Results: Migration was consistently either nil or minimal for both coiled leads. In contrast, migration of the standard lead occurred in all cases and was substantial in magnitude. A significant linear association was evident between the migration distance of the standard lead and the corresponding voltages needed to evoke a response. The forces necessary to displace Coiled Lead 1 and Coiled Lead 2 were both significantly higher (p <0.01) than those for the standard lead. In some cases comparatively high forces were needed for removal of Coiled Lead 1 but not Coiled Lead 2., Conclusions: Coiled lead designs appear to offer a potentially promising alternative to standard leads for PNE, allowing a wider range of patients to be correctly identified as candidates for sacral root neuromodulation. Coiled Lead 2 merits further investigation in human subjects.

Purpose: Neuromodulation of sacral nerves has shown promising results in correcting voiding dysfunction. We report the results of a multicenter trial designed to assess the efficacy of sacral nerve neuromodulation in patients presenting with refractory urinary urgency-frequency., Materials and Methods: A total of 51 patients from 12 centers underwent baseline assessment, including a detailed voiding diary, urodynamic evaluation and percutaneous test stimulation of the sacral nerves at S3 and/or S4. All patients enrolled in the study had undergone prior conventional treatment, such as pharmacotherapy, hydrodistention and surgical intervention, which failed. All patients demonstrated a satisfactory response to trial stimulation and were randomly divided into a stimulation group (25 patients) and a control group (26). A sacral nerve stimulation device was implanted after 6 months in the control group. Patients were followed at 1, 3 and 6 months, and at 6-month intervals for up to 2 years after implantation of a neuroprosthetic InterStim* system. dagger The study variables included the number of voids daily, volume voided per void and degree of urgency before void., Results: Compared to the control group, 6-month voiding diary results demonstrated statistically significant improvements (p <0.0001) in the stimulation group with respect to the number voids daily (16.9 +/- 9.7 to 9.3 +/- 5.1), volume per void (118 +/- 74 to 226 +/- 124 ml.) and degree of urgency (rank 2.2 +/- 0.6 to 1.6 +/- 0.9). Patients in the control group showed no significant changes in voiding parameters at 6 months. Significant improvements in favor of the stimulation group were noted in various parameters with respect to water cystometry and quality of life (SF-36). At 6 months after implant, neurostimulators were turned off in the stimulation group and urinary symptoms returned to baseline values. After reactivation of stimulation sustained efficacy was documented at 12 and 24 months., Conclusions: Neuromodulation of the sacral nerves is an effective, safe therapy that successfully treats significant symptoms of refractory urgency-frequency.

Objective: To assess the efficacy of physical therapies for first-line use in the treatment of urge urinary incontinence (UUI) in women, using a systematic review of randomized clinical trials (RCTs)., Materials and Methods: A computer-aided and manual search was carried out for RCTs published between 1980 and 1999 investigating the treatment of UUI defined by the keywords 'physical therapies', e.g. bladder (re)training (including 'behavioural' treatment), pelvic floor muscle (PFM) exercises, with or without biofeedback and/or electrical stimulation. The methodological quality of the included trials was assessed using methodological criteria, based on generally accepted principles of interventional research., Results: Fifteen RCTs were identified; the methodological quality of the studies was moderate, with a median (range) score of 6 (3-8.5) (maximum possible 10). Eight RCTs were considered of sufficient quality, i.e. an internal validity score of >/= 5.5 points on a scale of 0-10, and were included in a further analysis. Based on levels-of-evidence criteria, there is weak evidence to suggest that bladder (re)training is more effective than no treatment (controls), and that bladder (re)training is better than drug therapy. Stimulation types and parameters in the studies of electrical stimulation were heterogeneous. There is insufficient evidence that electrical stimulation is more effective than sham electrical simulation. To date there are too few studies to evaluate effects of PFM exercise with or without biofeedback, and of toilet training for women with UUI., Conclusion: Although almost all studies included reported positive results in favour of physical therapies for the treatment of UUI, more research of high methodological quality is required to evaluate the effects of each method in the range of physical therapies.

Objectives: To compare the effectiveness of sacral root neuromodulation with that of conservative management in ameliorating symptoms of refractory urinary urge incontinence and enhancing quality of life, to assess the objective response to neuromodulation as revealed by urodynamic testing, and to delineate the long-term outcomes of neuromodulation., Methods: Forty-four patients with refractory urge incontinence were randomized to undergo neuromodulation with an implantable impulse generator (n = 21) or to continue their prior conservative management (n = 23). At 6 months the control group was eligible for crossover to implant. Patient evaluation included voiding diaries, quality of life questionnaires, urodynamic testing, and documentation of adverse events. Long-term follow-up evaluations were conducted at 6-month intervals up to 36 months., Results: At 6 months mean leakage episodes, leakage severity and pad usage in the implant group were significantly lower by 88% (p < 0.0005), 24% (p = 0.047) and 90% (p < 0.0005), respectively, than the corresponding control group mean values. Improvements in leakage episodes and pad usage of >/=90% were attained by 75 and 85% of the implant group, respectively, but none of the control group. One third of implant patients, but none of the control patients, achieved >/=50% improvement in leakage severity. Over half of the implant patients (56%) were completely dry compared with 1 control patient (4%). Implant patients, but not control patients, exhibited significant improvement with respect to two quality of life measures. Neuromodulation resulted in increases of 220% (p < 0.0005) and 39% (p = 0.013), respectively, in urodynamically assessed bladder volume at first contraction and maximum fill. At 36 months the actuarial rate of treatment failure was 32.4% (95% CI, 17.0-56.0%). Adverse events most frequently involved pain at the implant site, and the incidence of serious complications was low., Conclusions: Neuromodulation is markedly more effective than conservative management in alleviating symptoms of refractory urge incontinence. Quality of life and urodynamic function are also improved by neuromodulation. The effects of neuromodulation are long-lasting, and associated morbidity is low.

Purpose: A prospective, randomized study was performed to evaluate sacral nerve stimulation for the treatment of refractory urinary urge incontinence., Materials and Methods: Primary outcome variables were obtained from voiding diaries. After baseline evaluation candidates who satisfied inclusion criteria were enrolled into the study. Test stimulation results determined eligibility for randomization into a stimulation (treatment) or delay (control) group. The stimulation group included 34 patients who underwent implantation and were followed for 6 months. The delay group comprised 42 patients who received standard medical therapy for 6 months and then were offered implantation. The stimulation group completed a therapy evaluation test (on versus off) after 6 months., Results: At 6 months the number of daily incontinence episodes, severity of episodes and absorbent pads or diapers replaced daily due to incontinence were significantly reduced in the stimulation compared to the delay group (all p<0.0001). Of the 34 stimulation group patients 16 (47%) were completely dry and an additional 10 (29%) demonstrated a greater than 50% reduction in incontinence episodes 6 months after implantation. Efficacy appeared to be sustained for 18 months. During the therapy evaluation test the group returned to baseline levels of incontinence when stimulation was inactivated. Urodynamic testing confirmed that sacral nerve stimulation did not adversely affect voiding function. Complications included implantable pulse generator site pain in 15.9% of the patients, implant site pain in 19.1% and lead migration in 7.0%. Surgical revision was required in 32.5% of patients with implants to resolve a complication. There were no reports of permanent injury or nerve damage., Conclusions: Sacral nerve stimulation is safe and effective in treating refractory urinary urge incontinence.

Different forms of dysfunction of the lower urinary tract can be treated with electrical stimulation. Currently, two operative treatment modalities are available. In patients with spinal cord injury the combination of posterior sacral root rhizotomies with implantation of electrodes on the anterior roots produces excellent results in terms of restoration of continence and bladder evacuation. In patients with chronic problems of urge incontinence, urgency/frequency and voiding dysfunction, neuromodulation of a sacral nerve with an implantable system can reduce the symptomatology significantly. Both these treatments are a valuable addition to the modern neuro-urological practice.