Current and future international patterns of care of neurogenic bladder after spinal cord injury.

PURPOSE: We aim to summarize the literature on international patterns of care for patients with neurogenic bladder (NGB) from spinal cord injury (SCI). METHODS: We performed a PubMed database search, hand review of references, communication with professional societies, and registry evaluations for pertinent data. RESULTS: Established patterns of care, including SCI registries and specialty centers, are available in high-resource countries such as the US and UK. As such, mortality rates from complications of NGB/SCI are lower. Access to intermittent catheterization supplies, among other resources, may be inadequate in many low-income regions. Cultural and religious beliefs may also hinder integration of proper bladder management in SCI patients. While guidelines exist in many parts of the world, it is unclear how rigorously they are disseminated or followed. CONCLUSIONS: While there is a paucity of high-level evidence, the differences in patterns of care are closely related to socioeconomic status and resources of the geographic area. Future research efforts should focus on improving access to diagnostic modalities, supplies, and specialists in these areas.

Urinary incontinence in women: a comprehensive review of the pathophysiology, diagnosis and treatment.

Urinary incontinence (UI) or involuntary leakage of urine is a distressing and serious health problem. It has a significant psychosocial and economic burden leading to significant quality of life issues. UI is more prevalent than most chronic diseases yet largely underreported. Aging and age-related changes in the bladder play a significant role in the development of UI. This in combination with cognitive dysfunction, functional impairment, pharmacotherapy, smoking, childbearing, obesity and coexisiting comorbidities worsen the condition. Due to the burden UI places on the individual, their family and society, it is important for providers to diagnose and have ready treatment options available. The three most common types of UI are stress urinary incontinence (SUI), urge urinary incontinence (UUI), or a combination of both, mixed urinary incontinence (MUI). This review describes the pathophysiology of incontinence; and diagnosis and treatment (conservative, pharmacological, and surgical therapies) of incontinence in women.

Urinary incontinence in women: non-pharmacologic approaches and newer pharmacotherapies.

Stress urinary incontinence (SUI) is a common and bothersome problem for women. Sling surgery is the mainstay of surgical treatment of SUI. A review of PubMed literature using the following keywords was performed: stress urinary incontinence, women, sling, midurethral sling, mini-sling, outcomes, and complications. Literature within the last 10 years, systematic reviews, and meta-analyses were given preference. Slings placed at the bladder neck and the midurethra each corrects a particular anatomic weakness, as described in the "hammock hypothesis" and the "integral theory," respectively. At present, the literature suggests that the autologous bladder neck sling (BNS) and retropubic midurethral sling (MUS) have similar success rates, while the retropubic MUS appears to be more successful than the transobturator approach. The literature supporting single-incision mini-sling (SIMS) is still in the early stages and data to support its use over another MUS is absent. Each approach is associated with unique complications and adverse outcomes. While both BNS and MUS are effective in improving SUI in women, the ultimate choice of material and approach should be based both on surgeon experience and patient preference. Detailed informed consent discussion prior to any sling surgery cannot be overemphasized.

Clinical safety, tolerability and efficacy of combination tolterodine/pilocarpine in patients with overactive bladder.

AIMS: The purpose of this study was to assess the safety, tolerability and impact on overactive bladder (OAB) symptoms of a novel combination of tolterodine immediate-release (IR) 2 mg and delayed-release pilocarpine 9 mg in patients with OAB. METHODS: Eligible patients with OAB were randomised to each of three treatments [tolterodine/pilocarpine (2/9 mg), tolterodine IR 2 mg or placebo] twice daily for 4 weeks in a double-blind, crossover fashion. At the end of the 12-week, double-blind treatment period, patients could enter an open-label extension during which they were re-randomised to either tolterodine/pilocarpine (3/13.5 mg) twice daily or tolterodine extended-release 4 mg once daily for 12 weeks. RESULTS: A total of 138 patients were randomised to double-blind medication. Both tolterodine/pilocarpine (2/9) and tolterodine IR 2 mg significantly reduced incontinence episodes and daily micturitions (p < 0.001 vs. placebo), with similar reductions in symptoms observed between active treatment groups. Tolterodine/pilocarpine (2/9) was associated with consistently lower Visual Analogue Scale (VAS) scores for all dry mouth parameters compared with tolterodine alone. Salivary flow over a 3 h period remained fairly constant after tolterodine/pilocarpine (2/9) administration, similar to placebo, but decreased markedly after administration of tolterodine alone. In the extension study, patients receiving tolterodine/pilocarpine (3/13.5) reported comparable dry mouth VAS scores to tolterodine extended-release alone without additional side effects or loss of efficacy. The combination was well tolerated, and the adverse effects observed were consistent with the known safety profiles of tolterodine and pilocarpine. CONCLUSIONS: A combination of tolterodine/pilocarpine (2/9) effectively reduced the incidence of dry mouth compared with tolterodine IR alone while maintaining treatment efficacy in OAB.

Technical aspects of botulinum toxin type A injection in the bladder to treat urinary incontinence: reviewing the procedure.

AIMS: Standardise the injection technique with botulinum toxin type A (BoNT A) in the bladder of patients with overactive bladder (OAB) [idiopathic overactive bladder (iOAB) or neurogenic overactive bladder (nOAB) with urinary incontinence], using a literature review and a survey of an International expert panel. METHODS: PubMed literature searches of BoNT A in adults with iOAB/nOAB together with a survey of 13 experts from 10 countries. RESULTS: Data from 21 articles and completed questionnaires were collated. The procedure can be carried out in an out-/inpatient setting. Dose used in clinical studies vs. clinical practice was 300 and 200 U for nOAB and 200 and 100 U for iOAB. Recent studies have also demonstrated that there are no clinically relevant benefits between 100 and 150 U in iOAB or between 300 and 200 U in nOAB, though adverse effects are increased with higher doses. Usually, 30 sites for nOAB (range: 6.7-10 U/ml) and 20-30 sites for iOAB (range: 5-10 U/ml) are injected in clinical studies vs. 20-30 sites of 1 ml/injection for 200 U in nOAB and 10-20 sites of 0.5-1 ml/injection for 100 U in iOAB in clinical practice. BoNT A is usually injected directly into the detrusor, sparing the trigone. Flexible or rigid cystoscopes are used. The needle should be typically 22-27 gauge and 4 mm in length and should have a stopper to avoid any leakage or perforation of the bladder wall while ensuring a targeted injection. CONCLUSION: Based on the literature and survey analysis, recommendations are proposed for the standardisation of the injection procedure.

Systematic review of the relationship between bladder and bowel function: implications for patient management.

BACKGROUND: The complex relationship between bladder and bowel function has implications for treating pelvic disorders. In this systematic review, we discuss the relationship between bladder and bowel function and its implications for managing coexisting constipation and overactive bladder (OAB) symptoms. METHODS: Multiple PubMed searches of articles published in English from January 1990 through March 2011 were conducted using combinations of terms including bladder, bowel, crosstalk, lower urinary tract symptoms, OAB, incontinence, constipation, hypermotility, pathophysiology, prevalence, management and quality of life. Articles were selected for inclusion in the review based on their relevance to the topic. RESULTS: Animal studies and clinical data support bladder-bowel cross-sensitization, or crosstalk. In the rat, convergent neurons in the bladder and bowel as well as some superficial and deeper lumbosacral spinal neurons receive afferent signals from both bladder and bowel. On a functional level, in animals and humans, bowel distention affects bladder activity and vice versa. Clinically, the bladder-bowel relationship is evident through the presence of urinary symptoms in patients with irritable bowel syndrome and bowel symptoms in patients with acute cystitis. Functional gastrointestinal disorders, such as constipation, can contribute to the development of lower urinary tract symptoms, including OAB symptoms, and treatment of OAB with antimuscarinics can worsen constipation, a common antimuscarinic adverse effect. The initial approach to treating coexisting constipation and OAB should be to relieve constipation, which may resolve urinary symptoms. CONCLUSIONS: The relationship between bladder and bowel function should be considered when treating patients with urinary symptoms, bowel symptoms, or both.

Persistence and adherence in the treatment of overactive bladder syndrome with anticholinergic therapy: a systematic review of the literature.

Overactive bladder syndrome (OAB) is a chronic condition that has an impact on patients' daily activities and health-related quality of life (HRQL). Anticholinergic therapy is often prescribed following insufficient results with behaviour modification alone; however, rates of treatment discontinuation are consistently high. This study systematically reviewed persistence and adherence data in patients with OAB treated with anticholinergic therapy. A search focused on the intersection of OAB, persistence/adherence, and anticholinergic therapy was conducted in MEDLINE and EMBASE. Articles published after 1998 were reviewed and selected for inclusion based on prespecified criteria. A total of 147 articles and two abstracts were included in the review. Results from 12-week clinical trials showed high rates of discontinuation, ranging from 4% to 31% and 5% to 20% in treatment and placebo groups, respectively. Unsurprisingly, rates of discontinuation found in medical claims studies were substantially higher, with 43% to 83% of patients discontinuing medication within the first 30 days and rates continuing to rise over time. Findings from medical claims studies also suggest that over half of patients never refill their initial prescription and that adherence levels tend to be low, with mean/median medication possession ratio (MPR) values ranging from 0.30 to 0.83. The low levels of persistence and adherence documented in this review reveal cause for concern about the balance between the efficacy and tolerability of anticholinergic agents. Strategies should be identified to increase persistence and adherence. New agents and non-pharmacologic alternatives with good efficacy and minimal side effects should be explored.

Urinary urgency - translating the evidence base into daily clinical practice.

AIM: To consider the currently available knowledge and understanding of the symptom of urgency. MATERIALS & METHODS: Each faculty member reviewed the literature base of a different aspect of urgency and along with their personal clinical experience provided a base of evidence for discussion. RESULTS: This overview summarises relevant published literature and the current clinical experience of the authors. DISCUSSION: Whilst the mechanisms producing the sensation of urgency are still not fully understood and we are working within a definition that may complicate measurement and treatment, our pressing need is to effectively manage our patients for whom the practical nature of urgency can be all too apparent. CONCLUSION: Health care professionals have an important role to play today in helping to alleviate the widespread problem of urgency and its consequences.

Trospium chloride once-daily extended release is effective and well tolerated for the treatment of overactive bladder syndrome: an integrated analysis of two randomised, phase III trials.

BACKGROUND: Trospium chloride is an antimuscarinic agent with a hydrophilic polar quaternary amine structure that is minimally metabolised by hepatic cytochrome P450 and is actively excreted in the urine, each of which confers a potential benefit with regard to efficacy and tolerability. PURPOSE: We analysed pooled data from two identically designed phase III trials of a once-daily, extended-release (XR) formulation of trospium chloride (trospium XR 60-mg capsules) in subjects with overactive bladder syndrome (OAB). METHODS: Adults with OAB of > or = 6 months' duration with urinary urgency, frequency and > or = 1 urge urinary incontinence (UUI) episode/day were enrolled in these multicentre, parallel-group, double-blind trials. Participants were randomised (1 : 1) to receive trospium XR 60 mg or placebo for 12 weeks. Primary efficacy variables were changes in urinary frequency and the number of UUI episodes/day. Adverse events (AEs) were recorded throughout. RESULTS: In total, 1165 subjects were randomised (trospium XR, 578; placebo, 587). At baseline, subjects averaged 12.8 toilet voids/day and 4.1 UUI episodes/day. Compared with placebo, subjects treated with trospium XR had significantly greater reductions from baseline in the mean number of toilet voids/day (-1.9 vs. -2.7; p < 0.001) and UUI episodes/day (-1.8 vs. -2.4; p < 0.001) at week 12. The most frequent AEs considered possibly related to study treatment were dry mouth (trospium XR, 10.7%; placebo, 3.7%) and constipation (trospium XR, 8.5%; placebo, 1.5%). Notably, rates of central nervous system (CNS) AEs were lower with trospium XR vs. placebo (dizziness: 0.2% vs. 1.0%; headache: 1.4% vs. 2.4%). CONCLUSIONS: Treatment with trospium XR resulted in statistically significant improvements in both of the dual primary and all of the secondary outcome variables. Trospium XR demonstrated favourable rates of AEs, particularly CNS AEs (numerically lower than with placebo) and dry mouth (lower than previously reported with trospium immediate-release, although not compared in a head-to-head study).

[Botulinum toxin for the treatment of overactive bladder--an overview]. / Botulinumtoxin in der Therapie der überaktiven Blase--ein Uberblick.

This article shall give a state-of-the-art review about the treatment of neurogenic and idiopathic detrusor overactivity with botulinum toxin injections into the detrusor muscle. We searched PubMed for original articles up to December 2006. Abstracts published at international congresses were also considered if they provided substantial new information. Based on this review it appears that a majority of patients with spinal cord injury regains continence after botulinum toxin A injection and that in children with myelomeningocele a significant improvement in continence can also be achieved. A concomitant reduction of intravesical pressure protects the upper urinary tract in these patients. In idiopathic detrusor overactivity, injection of botulinum toxin A also resulted in improvement of continence and reduction of daily micturition frequency. For both indications a high success rate could be achieved with an average duration of the effect of 6 months. Repeated injections into the detrusor seem to have no adverse effects in terms of duration or strength of the effect. Side effects were marginal and systemic side effects were experienced only in individual cases; in some patients with idiopathic detrusor overactivity intermittent self-catheterization was required. Overall intradetrusor injections of botulinum toxin seem to be a new, highly effective, and safe alternative in the treatment of neurogenic and idiopathic detrusor overactivity.

Multicenter prospective randomized 52-week trial of calcium hydroxylapatite versus bovine dermal collagen for treatment of stress urinary incontinence.

OBJECTIVES: To evaluate the safety and effectiveness of soft-tissue augmentation of the urethral sphincter with calcium hydroxylapatite (CaHA; Coaptite) compared with glutaraldehyde cross-linked bovine collagen (Contigen) in female patients with stress urinary incontinence due to intrinsic sphincter deficiency and without associated urethral hypermobility. METHODS: This 12-month prospective, randomized, comparative, multicenter, single-blind, parallel, clinical trial of CaHA and collagen for soft-tissue augmentation of the urethral sphincter in the treatment of stress urinary incontinence enrolled 296 women. Up to five injections were performed in the first 6 months of the trial. Twelve-month postinjection efficacy data were available for 231 patients. RESULTS: The results indicated that CaHA and collagen were both well tolerated in this study. No systemic adverse events were observed with either product. We used the Stamey Urinary Incontinence Scale to grade the improvement, which was the primary endpoint of the study. At 12 months, 83 (63.4%) of 131 CaHA patients compared with 57 (57.0%) of 100 collagen patients showed improvement of one Stamey grade or more (P = 0.34). More CaHA patients required only one injection (n = 60; 38.0%) during the study compared with the Contigen patients (n = 36; 26.1%; P = 0.034). Also, the average total volume of material injected during the course of the study was less for CaHA than for collagen (4.0 mL versus 6.6 mL, respectively; P <0.0001). CONCLUSIONS: The results of the study have demonstrated that Coaptite is an appropriate and well-tolerated treatment for patients with incontinence due to intrinsic sphincter deficiency. This new soft-tissue augmentation material has a good safety profile and appears to provide durable improvement.

The standardization of terminology for researchers in female pelvic floor disorders.

The lack of standardized terminology in pelvic floor disorders (pelvic organ prolapse, urinary incontinence, and fecal incontinence) is a major obstacle to performing and interpreting research. The National Institutes of Health convened the Terminology Workshop for Researchers in Female Pelvic Floor Disorders to: (1) agree on standard terms for defining conditions and outcomes; (2) make recommendations for minimum data collection for research; and (3) identify high priority issues for future research. Pelvic organ prolapse was defined by physical examination staging using the International Continence Society system. Stress urinary incontinence was defined by symptoms and testing; 'cure' was defined as no stress incontinence symptoms, negative testing, and no new problems due to intervention. Overactive bladder was defined as urinary frequency and urgency, with and without urge incontinence. Detrusor instability was defined by cystometry. For all urinary symptoms, defining 'improvement' after intervention was identified as a high priority. For fecal incontinence, more research is needed before recommendations can be made. A standard terminology for research on pelvic floor disorders is presented and areas of high priority for future research are identified.

Delivery of injectable agents for treatment of stress urinary incontinence in women: evolving techniques.

PURPOSE: Periurethral bulking agents continue to be used as a minimally invasive alternative for management of stress urinary incontinence in men and women. Agents and delivery techniques will be evaluated and compared. MATERIALS AND METHODS: The only agents currently approved by the United States Food and Drug Administration (FDA) include glutaraldehyde cross-linked collagen, autologous fat, and carbon bead/carrier gel technology. Several other agents are undergoing FDA trial evaluation. These agents differ in material characteristics (particle size, viscosity) that, in some cases, produce different immediate and delayed tissue responses or reactions. RESULTS: Initial subjective cure rates with collagen are acceptable, but the majority of women require reinjection. The risk of allergic phenomena complicates collagen use. Carbon-based material appears to parallel collagen in durability, with the significant advantage of a nonimmunogenic response within host tissues. Autologous fat injection achieves early results similar to those with collagen, but is limited by resorption and fibrous replacement as well as local discomfort associated with harvesting procedures. Experience with newer agents is limited. Patient characteristics also influence response to injectable agents. CONCLUSIONS: Injectable agent materials and delivery techniques continue to evolve. The optimal material is yet to be defined.

Inducible nitric oxide synthase in the bladder of spinal cord injured patients with a chronic indwelling urinary catheter.

PURPOSE: Spinal cord injured patients are at increased risk for bladder carcinoma. Nitric oxide production in areas of chronic inflammation may provide a stimulus for carcinogenesis by serving as a source of nitrosating agents that generate potentially carcinogenic nitrosamines from secondary amines normally present in urine. MATERIALS AND METHODS: To determine whether inducible nitric oxide synthase is expressed as a catalyst for sustained nitric oxide production by cellular elements in chronically inflamed bladder mucosa immunohistochemical studies were performed on mucosal biopsies obtained from 37 adults with spinal cord injury. All participants had required a chronic indwelling urethral or suprapubic catheter for greater than 8 years. RESULTS: Histopathological studies revealed active inflammatory infiltrates in all 37 biopsy specimens, squamous metaplasia in 20, epithelial dysplasia in 3 and carcinoma in 1. Inducible nitric oxide synthase was detected in inflammatory cells localized to the lamina propria. Inducible nitric oxide synthase positive cells were identified as macrophages using monoclonal antibodies to macrophage antigen. There was no inducible nitric oxide synthase expression in the urothelial cell layers. Immunostaining for inducible nitric oxide synthase was not detected in bladder mucosal biopsy specimens obtained from cadaveric organ donors. CONCLUSIONS: Inducible nitric oxide synthase is expressed in inflammatory macrophages in areas of chronic inflammation in the bladder mucosa of spinal cord injured patients with a chronic indwelling bladder catheter. The expression of inducible nitric oxide synthase may potentially lead to the sustained production of nitric oxide and its oxidative products, the nitrosation of urinary amines and the formation of potentially carcinogenic nitrosamines in the bladder.

Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study.

OBJECTIVE: To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder. SUBJECTS AND METHODS: The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallel-group study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline. RESULTS: A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups. CONCLUSIONS: Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events.

Neuroanatomy of the female continence complex: clinical implications.

OBJECTIVES: Improved understanding of pelvic neuroanatomy in women has led to modified surgical approaches and additional considerations in pelvic surgery. The innervation of the external urinary sphincter and urethra is not well defined in women, and, as such, the continence complex is not well understood. METHODS: Fourteen pelvic sections from seven fresh female cadavers were dissected to investigate the neuroanatomy of the female continence complex. RESULTS: Neuroanatomic dissections of the continence mechanism revealed that branches of the pelvic nerve travel beneath the fascia of the levator ani muscle and approach the urinary sphincter in near midline position, posterolateral to the rectum. This pelvic nerve branch passes laterally around the vagina and rectum to enter the sphincter musculature at the 5-o'clock and 7-o'clock positions. The pudendal nerve, traveling in the pudendal canal, gives an intrapelvic branch that courses to the urinary sphincter. At the level of the proximal urinary sphincter, it joins the pelvic nerve branch to the urinary sphincter. CONCLUSIONS: These neuroanatomic dissections provide a basis for surgical modifications that may address a variety of concerns regarding urinary continence in female surgical patients. With improved understanding of the female continence complex, we may now have a more precise anatomic explanation for the high failure rates associated with transvaginal urethral suspension procedures. Additionally, awareness and preservation of the continence nerves during cystectomy may allow for greater use of orthotopic bladder replacement in women.

Evaluating the effectiveness of therapies for urinary incontinence.

Subjective criteria, behavioral/emotional factors, and quality-of-life assessments are necessary components in evaluating incontinence therapies. Behavioral regimens often yield a response that lasts beyond the end of therapy and, when combined with pharmacologic therapy, are likely to extend duration of response. In addition to objective efficacy criteria, a number of instruments evaluate quality-of-life issues. Shortened forms of these will likely overcome limitations on patient compliance and completion. New instruments continue to be developed, but until one or more are universally accepted, variations in reported outcomes can be expected.