Do patients with OAB experience bladder sensations in the same way as healthy volunteers? A focus group investigation.

AIMS: To describe the terminology and pattern of bladder sensations experienced during non-invasive rapid bladder filling in a controlled setting in patients with OAB and to compare these results with a previous study conducted in healthy volunteers. METHODS: Three groups of patients with OAB, in total 10 patients, participated in three consecutive focus group sessions. Before each session a strict water loading protocol was given. During the first two sessions, participants described how they experienced their bladder sensations in daily life and during a non-invasive bladder filling with constant focus on their bladder. The third session focused on verifying the interpretation of the data gathered and describing the pattern of sensations. RESULTS: Patients describe their bladder sensations as a pressure or a tingling sensation and the pattern can be described by terms ranging from no sensation to an absolute need to void. The absolute need to void may develop suddenly or more slowly progressive. The mean development of bladder sensation is significantly different between patients and healthy volunteers as well as their average diuresis. CONCLUSIONS: Patients with OAB describe their bladder sensations as a pressure or a tingling sensation. There appear to be two types of urgency: a sudden absolute need to void and a slowly developing absolute need to void. Furthermore bladder sensation develops significantly different in volunteers than in OAB patients.

Robotic extravesical anti-reflux operations in complex cases: technical considerations and preliminary results.

OBJECTIVES: To evaluate technical aspects and outcome of robotic laparoscopic extravesical anti-reflux surgery in the treatment of high-grade vesicoureteral reflux (VUR) with associated complicating conditions. MATERIALS AND METHODS: Retrospective database and chart reviews were performed to identify a subgroup of patients with high-grade VUR who underwent robot-assisted anti-reflux surgery using the extravesical Lich-Gregoir repair and who additionally had preoperatively known complicating factors. Five such patients were operated on from 2005 to 2009. All had bilateral VUR, bladder dysfunction, breakthrough infections, renal scarring or at least one of the following complicating factors: posterior urethral valve bladders, duplex systems or para-ostial diverticula. Outcome and surgical aspects were assessed. RESULTS: At follow-up 9 of 10 ureters were free of reflux and diverticulae had disappeared completely. No lasting urinary retentions occurred but two boys needed reinsertion of a catheter for 24 h after surgery. No further complications were noted. There were no signs of obstruction, infections did not persist and there was no negative effect on bladder function. Dissection of para-ostial diverticula seemed the only additional technical challenge. CONCLUSIONS: Robot-assisted extravesical anti-reflux surgery seems a promising technique in the operative management of this unfavorable subset of patients. Reflux cure rate is higher than expected using injection therapy and at the same time morbidity seems lower than with open surgery. Further experience is needed to confirm these first impressions.

What treatment should we use if drugs fail for OAB; and, what really works after drugs?

AIMS: To determine (using structured brain storm sessions), which treatments should be used if drugs fail for OAB and to determine priority research questions in relation to this issue. METHODS: A frame work for discussion was prepared by the chairman of the session; this included a brief summary of the currently existing evidence. Several experts had been asked to prepare a presentation of their personal treatment algorithm and to identify the [lack of] evidence for such an algorithm. These presentations were summarized by the chairman. Next, this summary was discussed with a large group of experts and opinion leaders and audio-recorded. The proceedings of this process are the basis for this manuscript. RESULTS: The structured sessions resulted in detailed statements about: possible reasons for failure of conservative treatment, the evaluation of outcomes of RCT's, the use of botulinum toxin A in refractory OAB patients, the relative place of neuromodulation or sacral nerve stimulation and botulinum toxin A in the treatment of refractory OAB. CONCLUSIONS: A list of 10 unanswered questions and research topics was compiled. Additionally, 5 top priority research topics were identified.

Long-term safety, tolerability and efficacy of fesoterodine treatment in subjects with overactive bladder symptoms.

AIMS: The aim of this study was to assess the long-term safety, tolerability and efficacy of fesoterodine treatment in subjects with overactive bladder (OAB) symptoms. METHODS: This was an open-label extension study of a 12-week, double-blind fesoterodine study. During open-label treatment, all subjects received fesoterodine 8 mg for an initial 4 weeks, after which subjects could elect dose reduction to 4 mg or subsequent reescalation to 8 mg during clinic visits (dose reduction and reescalation each permitted once annually). The maximum allowable duration of open-label fesoterodine treatment ranged from 24 to 32 months across study sites. Safety and tolerability were evaluated via discontinuations, fesoterodine exposure, treatment-emergent adverse events (TEAEs) and subject-reported treatment tolerance. Three-day bladder diaries and other patient-reported outcomes (PROs) were assessed during the first 24 months of open-label treatment. PROs included evaluations of health-related quality of life [HRQL; King's Health Questionnaire (KHQ), and International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF)], severity of bladder-related problems and treatment satisfaction. Subjects completed 3-day diaries before open-label baseline and months 1, 4, 8, 12 and 24; the ICIQ-SF and measures of bladder-related problems and treatment satisfaction at open-label baseline and months 4, 12 and 24; and the KHQ at open-label baseline and months 12 and 24. RESULTS: Of the 417 eligible subjects who enrolled in the open-label extension, 61% continued fesoterodine treatment for > or = 24 months and 71% elected to maintain the fesoterodine 8-mg dose throughout treatment. No unexpected safety signals were observed. Most subjects rated treatment tolerance as at least 'good' throughout the study (> or = 88%). Dry mouth was the most commonly reported TEAE (34%) during open-label treatment, resulting in discontinuation in 2% of subjects (n = 8). Improvements from open-label baseline in OAB symptoms, HRQL and bladder-related problems were statistically significant at the earliest point measured and maintained through month 24. Treatment satisfaction rates were high throughout the study (> or = 84%). CONCLUSIONS: Long-term fesoterodine treatment was well tolerated and associated with sustained improvements in OAB symptoms and HRQL.

The localization of cyclo-oxygenase immuno-reactivity (COX I-IR) to the urothelium and to interstitial cells in the bladder wall.

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.

Selective stimulation of sacral nerve roots for bladder control: a study by computer modeling.

The aim of this study was to investigate theoretically the conditions for the activation of the detrusor muscle without activation of the urethral sphincter and afferent fibers, when stimulating the related sacral roots. Therefore, the sensitivity of excitation and blocking thresholds of nerve fibers within a sacral root to geometric and electrical parameters in tripolar stimulation using a cuff electrode, have been stimulated by a computer model. A 3-D rotationally symmetrical model, representing the geometry and electrical conductivity of a nerve root surrounded by cerebrospinal fluid and a cuff was used, in combination with a model representing the electrical properties of a myelinated nerve fiber. The electric behavior of nerve fibers having different diameters and positions in a sacral root was analyzed and the optimal geometric and electrical parameters to be used for sacral root stimulation were determined. The model predicts that an asymmetrical tripolar cuff can generate unidirectional action potentials in small nerve fibers while blocking the large fibers bidirectionally. This result shows that selective activation of the detrusor may be possible without activation of the urethral sphincter and the afferent fibers.

[Neuromodulation and neurostimulation in urology]. / Neuromodulatie en neurostimulatie in de urologie.

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.

Changes in bladder innervation in a mouse model of Alzheimer's disease.

AIM: The aims of this study were to compare the structure of bladders from a transgenic mouse model of Alzheimer's disease with age matched control animals and to explore the idea that any structural differences might be related to functional bladder changes associated with the condition. MATERIALS AND METHODS: Two groups of mice were used. Transgenic animals in which the murine Amyloid Precursor Protein (APP) gene has been partly replaced by the human APP including both the Swedish and London mutations and that overexpress a mutant of the human Presenilin 1 gene (PS1M146L) driven by the PDGF promoter. The transgenic mice (App(SL)/PS1(M146L)) aged 24+/-3 months were used. The second group was an age matched control group of C57 black mice. The bladders from each group were isolated, fixed in 4% paraformaldehyde and prepared for immunohistochemistry. Antibodies to the vesicular acetylcholine transporter (VAChT) and neuronal nitric oxide synthase (nNOS) were used to identify neural structures. RESULTS: Cholinergic nerves (VAChT(+)) were observed in the inner and outer muscle bundles of App(SL)/PS1(M146L) and control mice. No major differences were noted in the distribution of these fibres. In contrast, there was a distinct difference in the innervation of the sub-urothelial layer. In App1(SL)/PS1(M146L) mice there were numerous VAChT and nNOS positive fibres in sharp contrast to the paucity of similar nerves in control animals. VAChT and nNOS did not appear to co-localise in the same nerve fibres within the lamina propria. Pairs of nerve fibres, nNOS(+) and VAChT(+), were observed to be intertwined and run in close proximity. A particularly unusual feature of the App(SL)/PS1(M146L) mouse bladder was the presence of neurones within the bladder wall. These nerve cell bodies were seen in all App(SL)/PS1(M146L) mouse bladders. The neurones could be found singly or in small ganglion like groups of cells and were located in all layers of the bladder wall (sub-urothelium, in the lamina propria adjacent to the inner muscle and within the inner muscle and outer muscle layers). No nerve cells or small ganglia were noted in any of the control bladders studied. CONCLUSIONS: There are structural differences in the bladders of App(SL)/PS1(M146L) mice compared to control animals. These differences are associated with sub-urothelial nerves which, because of their location, are likely to be sensory fibres. This may lead to a changed sensory processing from the App(SL)/PS1(M146L) bladders. The physiological role of the intra-mural neurones and ganglia is not known. It is speculated that they may be associated with peripheral motor/sensory mechanisms linked to the generation and modulation of sensation.

Alterations to network of NO/cGMP-responsive interstitial cells induced by outlet obstruction in guinea-pig bladder.

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.

The role of electrical stimulation in voiding dysfunction.

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.

The efficacy and safety of a new once-a-day formulation of an alpha-blocker.

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.

Urethral sphincteric responses to sacral root stimulation.

Deafferentation and stimulation of sacral nerves in patients with complete spinal cord lesions is a good model to study the parasympathetic influence on urethral behavior. During intradural sacral deafferentation from S2 to S4/S5 in preparation for implantation of the Finetech-Brindley anterior sacral root stimulator, sacral roots were stimulated with 3 and 30 Hz and 3 and 10 V and the bladder and urethral responses noted. Stimulation of the posterior roots at 3 Hz gives a urethral relaxation without bladder contraction. At this frequency, anterior sacral root stimulation has no effect on bladder nor urethral pressure. Stimulation of the anterior roots at 30 Hz produces simultaneous bladder contraction and urethral relaxation. These findings support the presence of an afferent parasympathetic inhibitory mechanism in the spinal micturition center in the human.

The morbidity due to lower urinary tract function in spinal cord injury patients.

A review is given of 105 patients with a traumatic spinal cord injury. In 93 patients with a minimum follow up of one year the morbidity due to lower urinary tract function was evaluated, based on the situation at their last control visit. The relation was studied between bladder behaviour and the type of urine evacuation and their influence on upper urinary tract problems, urinary tract infections, stone formation and incontinence. Based on the results of this study the most appropriate method for control of bladder behaviour and urine evacuation in spinal cord injured patients is discussed in view of new treatment modalities such as dorsal rhizotomies and the implantation of an anterior sacral root stimulator.

Treatment of lower urinary tract dysfunction in patients with multiple sclerosis. Committee of the European Study Group of SUDIMS (Sexual and Urological Disorders in Multiple Sclerosis)

Bladder symptoms in patients with multiple sclerosis (MS) are common and usually arise as a result of spinal lesions which interrupt the neural pathways connecting the pontine micturition centre to the sacral spinal cord. Thus these symptoms are particularly likely to occur in those with lower limb neurological deficits. Fortunately bladder dysfunction in MS is rarely associated with serious upper tract disease so that the problem is usually one of symptomatic management. Lower urinary tract symptoms may be both "irritative" or "obstructive" in nature and can be explained in terms of underlying detrusor hyperreflexia and incomplete bladder emptying. Treatment is aimed at minimising both these effects. Oral anticholinergic medication can be effective in reducing detrusor hyperreflexia and intermittent catheterisation is used to reduce abnormally high post micturition residual volumes. With this simple treatment, often used in combination, many less severely affected patients with MS can gain considerable improvement in controlling urinary continence.

Sacral rhizotomies and electrical bladder stimulation in spinal cord injury. 2. Cost-effectiveness and quality of life analysis. Dutch Study Group on Sacral Anterior Root Stimulation.

OBJECTIVES: To present a cost-effectiveness analysis of sacral rhizotomies and electrical bladder stimulation compared with conventional care of neurogenic bladder dysfunction in patients with spinal cord injury. METHODS: During a 3-year inclusion period, data on costs and quality of life before the intervention were collected to describe conventional care. Data on the pre-implantation period, the implantation and a follow-up period of 2 years were collected following a strict protocol simultaneous with medical and urodynamic data and were used to calculate the costs and effects on quality of life of the implantation of the stimulator. RESULTS: Between June 1991 and June 1994, 52 patients with complete cervical or thoracic spinal cord lesions underwent sacral posterior rhizotomies and implantation of a Finetech-Brindley sacral anterior root stimulator. Although the initial costs of sacral anterior root stimulation are high, they are earned back in this series in about 8 years after the implantation. General indicators of the quality of life show no significant changes after the implantation. Factors related to psychological well-being and the patients' satisfaction with the emptying of the bladder increased significantly whereas the experienced problems of micturition and incontinence all decreased significantly. CONCLUSION: Sacral rhizotomies and electrical bladder stimulation make a cost-effective method of treatment of lower urinary tract dysfunction in patients with spinal cord injury. Considerable savings on health care costs are possible in the long run with simultaneous positive effects on aspects of health status.

Urinary bladder control by electrical stimulation: review of electrical stimulation techniques in spinal cord injury.

Evacuation of urine in paraplegics without the need for catheters would be possible when voiding could be induced by eliciting a bladder contraction. A challenging option to obtain detrusor contraction is electrical stimulation of the detrusor muscle or its motor nerves. This article reviews the 4 possible stimulation sites where stimulation would result in a detrusor contraction: the bladder wall, the pelvic nerves, the sacral roots, and the spinal cord. With respect to electrode application, sacral root stimulation is most attractive. However, in general, sacral root stimulation results in simultaneous activation of both the detrusor muscle and the urethral sphincter, leading to little or no voiding. Several methods are available to overcome the stimulation-induced detrusor-sphincter dyssynergia and allow urine evacuation. These methods, including poststimulus voiding, fatiguing of the sphincter, blocking pudendal nerve transmission, and selective stimulation techniques that allow selective detrusor activation by sacral root stimulation, are reviewed in this paper.

Selective detrusor activation by sacral ventral nerve-root stimulation: results of intraoperative testing in humans during implantation of a Finetech-Brindley system.

Electrical sacral nerve-root stimulation can be used to induce bladder contraction. However, bladder emptying is hampered by simultaneous contraction of the external urethral sphincter. Voiding may improve when using a stimulation method that allows selective detrusor activation. Both theoretical and animal studies have demonstrated that it is possible to obtain selective detrusor activation by sacral root stimulation using an selective anodal block. The objective of this paper is to demonstrate the feasibility of this stimulation method in humans. For investigation of the stimulation method, intraurethral and intravesical pressure responses to sacral root stimulation were measured in acute experiments on 12 patients. The results show that selective detrusor activation is possible in patients. Future perspectives are discussed.

Selective detrusor activation by electrical sacral nerve root stimulation in spinal cord injury.

Electrical sacral nerve root stimulation can be used in spinal cord injury patients to induce urinary bladder contraction. However, existing stimulation methods activate simultaneously both the detrusor muscle and the urethral sphincter. Urine evacuation is therefore only possible using poststimulus voiding. Micturition would improve if the detrusor muscle could selectively be activated. The purpose of this study was to demonstrate selective detrusor activation in patients by ventral sacral root stimulation. The stimulation method involves selective activation of the small diameter myelinated nerve fibers and consists of a combination of cathodal excitation and selective anodal blocking using a tripolar electrode. To investigate anodal blocking, the intraurethral pressure response to stimulation was measured in acute experiments performed on 12 patients. The influence of both pulse amplitude and pulse duration on the pressure response was analyzed. In 8 out of 12 patients anodal blocking of somatic motor fibers was possible. This study also indicates the feasibility of selective detrusor activation by sacral root stimulation.

Novel test lead designs for sacral nerve stimulation: improved passive fixation in an animal model.

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.