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Small-vessel disease of the brain affecting the deep white matter characteristically manifests with neurological syndromes, such as vascular dementia and vascular parkinsonism. There is, however, compelling evidence to suggest that white matter disease can cause overactive bladder and incontinence, and in some patients these might be the initial manifestation. As white matter disease increases significantly with age, and preferentially affects the prefrontal deep white matter, white matter disease becomes an anatomical substrate in the brain etiology of overactive bladder. Treatment entails the management of small-vessel disease risk factors and anticholinergic drugs that do not easily penetrate the blood-brain barrier, to improve bladder control. In short, when caring for elderly overactive-bladder patients, we should look at both the brain and the bladder. [ABSTRACT FROM AUTHOR]

What's known on the subject? and What does the study add? The search for a biomarker in overactive bladder syndrome ( OAB) is an emerging field of interest, as bladder dysfunction is a common complaint that causes significant morbidity. A biomarker may give us insight as a diagnostic tool, and also inform us about how severe the condition is, how it may progress and how it may best be treated. The protein of interest here is nerve growth factor ( NGF) and it has been shown to be a dynamic molecule in the bladder of patients with OAB. Urinary levels have been seen to rise in patients with OAB and fall in those who respond to treatment. However, there have also been many studies that examine this trend in numerous other conditions, e.g. interstitial cystitis, bladder outflow obstruction, renal stone disease and patients with neurological impairment after stroke. As a result the specificity of this as a potential urinary biomarker for OAB is questioned. This is a review of published studies, which discusses the pros and cons of NGF as a potential urinary biomarker. The evidence is examined and the studies are summarised together in a Table. Questions remain about the reliability, practicality and specificity of NGF as a biomarker for OAB. These questions need to be addressed by further studies that could clarify the points raised. Objective To review the current literature on the use of urinary nerve growth factor ( NGF) as a potential biomarker for overactive bladder syndrome ( OAB)., Method A comprehensive electronic literature search was conducted using the PubMed database to identify publications relating to urinary NGF., Results There are a growing number of publications that have measured urinary NGF levels in different types of bladder dysfunction. These range from OAB, bladder pain syndrome, idiopathic and neurogenic detrusor overactivity, bladder oversensitivity and bladder outflow obstruction. Urinary NGF levels do appear to be raised in these pathological states when compared with healthy control samples., In patients with OAB, these raised urinary NGF levels appear to also reduce after successful treatment with antimuscarinics and botulinum toxin A, which indicates a potential use in monitoring responses to treatment., However, raised levels are not limited to OAB, which questions its specificity., Urinary NGF measurements are performed with an enzyme-linked immunosorbent assay using polyclonal antibodies to NGF. The technique requires standardisation, and the different antibodies to NGF require validating., Also a definition of what is the 'normal' range of NGF in urine is still required before it can be used as a diagnostic and prognostic tool., Conclusions Whilst the evidence for an increased urinary NGF in OAB appears convincing, many questions about its validity remain including: specificity, sensitivity, cost- and time-effectiveness., Many criteria for what constitutes a biomarker still need to be evaluated and met before this molecule can be considered for this role. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients with urgency urinary incontinence (UUI) due to overactive bladder (OAB) refractory to oral antimuscarinics have limited therapeutic options. OnabotulinumtoxinA appears to be an effective new treatment. Objective: Assess disease-specific quality-of-life outcomes and general health–related quality-of-life (HRQOL) outcomes following treatment with onabotulinumtoxinA in patients with idiopathic OAB and UUI inadequately managed with antimuscarinics. Design, setting, and participants: A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted at 40 sites from July 2005 to June 2008 with 313 patients (288 females) with idiopathic OAB experiencing eight or more UUI episodes per week and eight or more micturitions per day at baseline, with follow-up of 36 wk. Intervention: Intradetrusor onabotulinumtoxinA (50 U, 100 U, 150 U, 200 U, or 300 U) or placebo. Outcome measurements and statistical analysis: HRQOL was assessed using the urinary Incontinence-Specific Quality-of-Life Instrument (I-QOL), the King''s Health Questionnaire (KHQ) symptom component, and the Medical Outcomes Study 36-Item Short-Form Health Survey. Descriptive statistics were used for absolute scores/changes from baseline. Within-group changes from baseline were assessed using paired t tests. Change from baseline for each onabotulinumtoxinA group compared with placebo was analyzed using an analysis of covariance model. Results and limitations: OnabotulinumtoxinA treatment at doses ≥100 U produced significantly greater improvements than placebo in the I-QOL total and subscale scores at all follow-up visits from week 2 through week 24 (p <0.05). OnabotulinumtoxinA doses ≥100 U produced significantly greater improvements than placebo in the KHQ symptom score at a majority of follow-up visits. HRQOL instruments demonstrated low to moderate correlations (Spearman correlation range: 0.01–0.51) with the symptoms of UUI recorded using daily diary data, with I-QOL demonstrating the highest correlations. A study limitation was that certain quality-of-life measures were exploratory and not validated. Conclusions: A single onabotulinumtoxinA treatment with doses ≥100 U resulted in statistically significant and clinically meaningful improvement in HRQOL by week 2 compared with placebo, and this improvement was sustained for ≤36 wk in patients with idiopathic OAB and UUI who were inadequately managed by oral antimuscarinics. Trial registration: ClinicalTrials.gov identifier: NCT00168454. [Copyright &y& Elsevier]

This review article introduces the new concept of vascular incontinence, a disorder of bladder control resulting from cerebral white matter disease (WMD). The concept is based on the original observation in 1999 of a correlation between the severity of leukoareosis or WMD, urinary symptoms, gait disorder and cognitive impairment. Over the last 20 years, the realization that WMD is not a benign incidental finding in the elderly has become generally accepted and several studies have pointed to an association between geriatric syndromes and this type of pathology. The main brunt of WMD is in the frontal regions, a region recognized to be crucial for bladder control. Other disorders should be excluded, both neurological and urological, such as normal-pressure hydrocephalus, progressive supranuclear palsy, etc., and prostatic hyperplasia, physical stress incontinence, nocturnal polyuria, etc. Treatment involves management of small vessel disease risk factors and anticholinergic drugs that do not easily penetrate the blood brain barrier to improve bladder control. [ABSTRACT FROM AUTHOR]

Purpose: We studied the effect of repeat detrusor botulinum neurotoxin type A injections on urinary symptoms, health and quality of life in patients with refractory neurogenic detrusor overactivity secondary to multiple sclerosis. Materials and Methods: This was a prospective, open label, single center study in 137 patients with multiple sclerosis treated with detrusor injections of botulinum neurotoxin type A with observations made from 2002 to 2009. A minimally invasive outpatient technique was used for injection. Patients were asked to contact the department if and when they required repeat treatment. Recurrent detrusor overactivity was then identified on urodynamics. The primary outcomes measured were the change in symptoms and quality of life, as assessed by the Urogenital Distress Inventory, Incontinence Impact Questionnaire and EuroQol-5 Dimensions questionnaires (www.ion.ucl.ac.uk/departments/repair/themes/uroneurology) before and 4 weeks after botulinum treatment. Continence status, the need for clean intermittent self-catheterization before and after injections, and interinjection intervals were also analyzed. Results: Mean Urogenital Distress Inventory and Incontinence Impact Questionnaire 7 scores showed considerable improvement 4 weeks after each treatment even when repeated 6 times. Almost all patients relied on clean intermittent self-catheterization after treatment. Before the first treatment 83% of patients were incontinent but 4 weeks after the first treatment 76% (104 of 137) became completely dry. This efficacy was sustained with repeat injections. The median interval between re-treatments remained constant at 12 to 13 months. Conclusions: Repeated detrusor botulinum neurotoxin type A injections for refractory neurogenic detrusor overactivity in patients with multiple sclerosis have a consistent effect on bladder control, resulting in sustained improvement in quality of life. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the possible associations of urothelial and suburothelial muscarinic receptors with human bladder pathophysiology we examined the immunohistochemical expression of muscarinic receptors types 1, 2 and 3 in the bladder urothelium and suburothelium of patients with neurogenic or idiopathic detrusor overactivity compared with that in controls. We also examined associations with patient quantified symptoms and the effect of intradetrusor botulinum neurotoxin type A treatment. Materials and Methods: We obtained bladder biopsies from 36 patients with detrusor overactivity before, and 4 and 16 weeks after treatment with intradetrusor botulinum neurotoxin type A via flexible cystoscopy. Patients with neurogenic detrusor overactivity were injected with 300 U botulinum neurotoxin type A and those with idiopathic detrusor overactivity received 200 U. Control biopsies were taken from 7 patients during investigation for asymptomatic microscopic hematuria. We studied muscarinic receptor immunohistochemical expression using commercial antibodies to muscarinic receptors 1, 2 and 3 with results quantified by image analysis. Results: We noted decreased suburothelial muscarinic receptor immunoreactivity in detrusor overactivity biopsies vs controls, which were significant for muscarinic receptors 1 and 3. After successful botulinum neurotoxin treatment we noted only increased muscarinic receptor 1 and 2 immunoreactivity. Urothelial muscarinic receptor 1 and 3 immunoreactivity was increased after treatment. We identified no substantial urothelial muscarinic receptor 2 immunoreactivity. Receptor levels showed inverse correlations with patient urgency and frequency. Conclusions: Decreased muscarinic receptor levels in the urothelium and suburothelium of patients with detrusor overactivity were largely restored to control levels after successful treatment with botulinum neurotoxin type A. Correlations of receptor levels with patient symptoms further support a role for urothelial and suburothelial muscarinic receptors in detrusor overactivity in humans. [Copyright &y& Elsevier]

OBJECTIVE To assess whether incomplete bladder emptying and the need for clean intermittent self-catheterization (CISC) is predictable, by analysing urodynamic and detrusor contractility variables in patients treated with botulinum toxin-A (BTX-A) for refractory idiopathic detrusor overactivity (IDO). PATIENTS AND METHODS Sixty-seven patients (mean age 50.3) with IDO, from two centres, had bladder injections of 200 U BTX-A. Patients with difficulty in emptying their bladder and/or persistent overactive bladder symptoms, with postvoid residual volumes (PVR) of >150 mL after treatment were started on CISC. Urodynamics were conducted at baseline, 4 and 12–16 weeks after injection with BTX-A. Detrusor contractility was assessed using the projected isovolumetric pressure (PIP1) in women and bladder contractility index (BCI) in men. RESULTS There were improvements in the mean maximum cystometric capacity, bladder compliance and maximum detrusor pressures during filling cystometry after BTX-A injections. The PVR was significantly increased at 4 but not at 12 weeks. Nineteen patients required CISC and when compared with those not needing CISC their pretreatment maximum flow rate (15 vs 22 mL/s, P = 0.003), PIP1 (43 vs 58, P = 0.02) and BCI (113 vs 180, P = 0.001) were lower. Receiver operator characteristic curve analysis suggested that a PIP1 of ≤50 in women (sensitivity 0.83; specificity 0.70; area under the curve 0.822) and BCI ≤120 (sensitivity 0.7; specificity 0.79; area 0.879) might predict the need for CISC. CONCLUSION The maximum flow rate, PIP1 and BCI were significantly lower in patients who required CISC after BTX-A treatment than in those who did not. A PIP1 of ≤50 in women and a BCI of ≤120 might be predictive of a need for CISC in this setting, and might help when counselling patients. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which is concerned with research which investigated whether lesions or Alzheimer's disease contributes more to over active bladder and incontinence in elderly adults with dementia.

Abstract: Objectives: Intravesical resiniferatoxin (RTX) has been used with variable efficacy in the treatment of detrusor overactivity (DO). Patients with interstitial cystitis (IC) failed to benefit from this treatment, but a single placebo-controlled study in patients with non-IC painful bladders showed that RTX was effective in the short-term. We investigated the efficacy of intravesical RTX in patients with urgency and frequency due to increased bladder sensation. Methods: Patients with intractable urgency and frequency, with or without urgency incontinence or bladder pain/discomfort, and with no urodynamic evidence of DO were recruited. After a single intravesical instillation of 100ml 50nM RTX solution, patients were followed at 1, 3, and 6 mo for changes in urodynamics, bladder diary, the King''s Health Questionnaire (KHQ), and degree of bladder pain. Results: Fifteen patients (mean age, 52.5 yr) were treated. RTX significantly improved maximum cystometric capacity, volume at first desire to void, mean micturition volume, 24-h frequency, and daytime frequency for up to 6 mo after treatment. The overall KHQ score improved at all time points, with sustained improvements in the Symptom Severity, Incontinence Impact, and Personal Relationships domains. A >50% decrease in pain was reported by five of seven patients with painful bladders at 1 mo, but only one of seven at 6 mo. Conclusions: In our small open-label study, a single administration of intravesical RTX in patients with frequency and urgency due to increased bladder sensation significantly improved lower urinary tract symptoms, urodynamic parameters, and quality of life for up to 6 mo. [Copyright &y& Elsevier]

Abstract: Background: Treatment of human bladder overactivity with intradetrusor Botulinum-A neurotoxin (BoNT/A) injections temporarily blocks the presynaptic release of acetylcholine from the parasympathetic innervation and produces a paralysis of the detrusor smooth muscle. The efficacy of the treatment exceeds that expected from simple detrusor muscle paralysis, however, and its effect of reducing urgency is greatly welcomed by patients. Objectives: To examine whether BoNT/A has a complex effect on sensory mechanisms by inhibiting vesicular release of multiple excitatory neurotransmitters by urothelial and suburothelial nerves and reducing axonal expression of SNARE-complex dependant proteins. Methods: A literature review. Conclusions: We propose that a primary peripheral effect of BoNT/A is the inhibition of release of acetylcholine, ATP, substance P, and reduction in the axonal expression of the capsaicin and purinergic receptors. This may be followed by central desensitization through a decrease in central uptake of substance P and neurotrophic factors. The summation of these effects is a profound and long-lasting inhibition of those afferent and efferent mechanisms that are thought to be the pathophysiological basis for DO. [Copyright &y& Elsevier]

Abstract: Background: Objective improvement following intradetrusor injections of botulinum neurotoxin type A (BoNTA) is well documented. Although patient-related outcome measures are highly recommended for monitoring overactive bladder symptoms, no study before has dealt with the question of patient-reported complete continence after BoNTA treatment using validated questionnaires. Objective: To investigate the change in patient-reported continence rate after intradetrusor injections of BoNTA for treatment of refractory idiopathic detrusor overactivity (IDO) incontinence. Design, setting, and participants: Seventy-four patients (51 women, 23 men) with refractory IDO incontinence treated for the first time with intradetrusor injections of 200 U BoNTA were evaluated in this nonrandomised, open-label, cohort study. Measurements: Changes in patient-reported urinary frequency, urgency incontinence, and stress incontinence were assessed using the condition-specific validated short form of the Urogenital Distress Inventory (UDI 6) before and 4 wk after BoNTA treatment. Results and limitations: The patient-reported outcome of complete continence (defined as a score of 0 in both the urgency and stress incontinence subscales of the UDI 6) was 51% (38 of 74) 4 wk after intradetrusor injections of BoNTA. In patients who were not completely continent, median urgency incontinence scores reduced significantly from 100 to 0 (p <0.001), stress incontinence scores from 33 to 0 (p <0.001), and median urinary frequency scores from 100 to 33 (p <0.001), respectively. The inclusion of patients with mixed incontinence may have resulted in underestimation of the complete continence rate. Conclusions: An excellent response with >50% of patients reporting complete continence 4 wk after BoNTA treatment reveals the efficacy of this emerging treatment for patients with refractory IDO incontinence. Furthermore, in those in whom complete continence was not achieved, there was a notable and significant reduction in reported urgency incontinence, stress incontinence, and urinary frequency. [Copyright &y& Elsevier]

Abstract: Background: Intradetrusor injections of botulinum neurotoxin type A (BoNTA) are emerging as the preferred second-line treatment for neurogenic and idiopathic overactive bladder (OAB). In animal experiments, intradetrusor BoNTA injections have been shown to cause apoptosis in the bladder urothelium and suburothelium but not the detrusor. Objective: To investigate BoNTA-induced apoptosis in patients with refractory neurogenic OAB. Design, setting, and participants: Twelve refractory OAB patients with neurogenic detrusor overactivity resulting from multiple sclerosis (MS) and seven controls were included prospectively. Measurements: The number of apoptotic cells before and 4 wk after first intradetrusor BoNTA (300 U of BOTOX [Allergan, Irvine, CA, USA]) injections were estimated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) staining. Results and limitations: Comparison of TUNEL-positive cells (yes vs no) in the bladder urothelium and suburothelium revealed no significant differences in OAB patients before (4 of 12, 33%) versus after (3 of 12, 25%) BoNTA treatment (p =0.99). In addition, no significant differences (p =0.99) were found in OAB patients versus controls. Because our findings are based on first intradetrusor BoNTA injections only, it is unclear whether the results could be extrapolated to repeat injections. Conclusions: In contrast to preliminary animal experiments, first intradetrusor BoNTA injections for treating refractory neurogenic OAB—a highly effective treatment—did not induce apoptosis in the bladder urothelium and suburothelium. [Copyright &y& Elsevier]

Abstract: Context: The focus of clinical understanding and management of male storage lower urinary tract symptoms (LUTS) has shifted from the prostate to the bladder. This is mirrored by an increasing body of experimental evidence suggesting that the bladder is the central organ in the pathogenesis of LUTS. Objective: A systematic review of the literature available on pathophysiologic aspects of storage LUTS. Evidence acquisition: Medline was searched for the period ending December 2008 for studies on human and animal tissue exploring possible functional and structural alterations underlying bladder dysfunction. Further studies were chosen on the basis of manual searches of reference lists and review papers. Evidence synthesis: Numerous recent publications on LUTS pathophysiology were identified. They were grouped into studies exploring abnormalities on urothelial/suburothelial, muscular, or central levels. Conclusions: Studies revealed both structural and functional alterations in bladders from patients with LUTS symptoms or animals with experimentally induced bladder dysfunction. In particular, the urothelium and the suburothelial space, containing afferent nerve fibres and interstitial cells, have been found to form a functional unit that is essential in the process of bladder function. Various imbalances within this suburothelial complex have been identified as significant contributors to the generation of storage LUTS, along with potential abnormalities of central function. [Copyright &y& Elsevier]

Abstract: Objectives: Limited studies to date have reported on the onset of effect of intradetrusor botulinum neurotoxin type A (BoNTA) injections when used to treat the symptoms of the overactive bladder (OAB). Furthermore, few studies have examined the effect of BoNTA on urgency and nocturia, now recognised as the most bothersome symptoms of the OAB syndrome. We studied the immediate effect of BoNTA on the OAB symptoms by recording the daily changes during the week after treatment of patients with neurogenic or idiopathic detrusor overactivity (NDO/IDO). Methods: Twenty-four patients (16 NDO, 8 IDO) treated with 300mu BOTOX® (NDO) or 200mu (IDO) completed a 4-d voiding diary before and 4 wk after treatment and a 7-d diary starting the day immediately after injections. Data were analysed for intragroup daily changes during the first week and for further changes at 4 wk. Parametric t tests were used for statistical analysis (significance at p <0.05). Results: The two groups were comparable at baseline for all studied variables. In NDO, significant improvements in urgency, frequency, and nocturia were seen at day 2 post injection and in incontinence at day 3, and were sustained at 4 wk. In IDO, the first significant change in urgency, frequency, and incontinence was seen at day 4, with urgency showing the most consistent changes thereafter. All parameters significantly improved at 4 wk. Conclusions: Intradetrusor BoNTA ameliorates all OAB symptoms within the first week after treatment, but urgency is most rapidly and consistently affected, suggesting an early effect on bladder afferent pathways. Differences in the toxin dose or possibly underlying pathophysiology may account for an earlier trend for symptomatic improvement in the NDO patients. [Copyright &y& Elsevier]