Cotransplantation with specific populations of spina bifida bone marrow stem/progenitor cells enhances urinary bladder regeneration.

Spina bifida (SB) patients afflicted with myelomeningocele typically possess a neurogenic urinary bladder and exhibit varying degrees of bladder dysfunction. Although surgical intervention in the form of enterocystoplasty is the current standard of care in which to remedy the neurogenic bladder, it is still a stop-gap measure and is associated with many complications due to the use of bowel as a source of replacement tissue. Contemporary bladder tissue engineering strategies lack the ability to reform bladder smooth muscle, vasculature, and promote peripheral nerve tissue growth when using autologous populations of cells. Within the context of this study, we demonstrate the role of two specific populations of bone marrow (BM) stem/progenitor cells used in combination with a synthetic elastomeric scaffold that provides a unique and alternative means to current bladder regeneration approaches. In vitro differentiation, gene expression, and proliferation are similar among donor mesenchymal stem cells (MSCs), whereas poly(1,8-octanediol-cocitrate) scaffolds seeded with SB BM MSCs perform analogously to control counterparts with regard to bladder smooth muscle wall formation in vivo. SB CD34(+) hematopoietic stem/progenitor cells cotransplanted with donor-matched MSCs cause a dramatic increase in tissue vascularization as well as an induction of peripheral nerve growth in grafted areas compared with samples not seeded with hematopoietic stem/progenitor cells. Finally, MSC/CD34(+) grafts provided the impetus for rapid urothelium regeneration. Data suggest that autologous BM stem/progenitor cells may be used as alternate, nonpathogenic cell sources for SB patient-specific bladder tissue regeneration in lieu of current enterocystoplasty procedures and have implications for other bladder regenerative therapies.

Myogenic bladder defects in mouse models of human oculodentodigital dysplasia.

To date, over 65 mutations in the gene encoding Cx43 (connexin43) have been linked to the autosomal-dominant disease ODDD (oculodentodigital dysplasia). A subset of these patients experience bladder incontinence which could be due to underlying neurogenic deterioration or aberrant myogenic regulation. BSMCs (bladder smooth muscle cells) from wild-type and two Cx43 mutant lines (Cx43(G60S) and Cx43(I130T)) that mimic ODDD exhibit a significant reduction in total Cx43. Dye transfer studies revealed that the G60S mutant was a potent dominant-negative inhibitor of co-expressed Cx43, a property not equally shared by the I130T mutant. BSMCs from both mutant mouse strains were defective in their ability to contract, which is indicative of phenotype changes due to harbouring the Cx43 mutants. Upon stretching, Cx43 levels were significantly elevated in controls and mutants containing BSMCs, but the non-muscle myosin heavy chain A levels were only reduced in cells from control mice. Although the Cx43(G60S) mutant mice showed no difference in voided urine volume or frequency, the Cx43(I130T) mice voided less frequently. Thus, similar to the diversity of morbidities seen in ODDD patients, genetically modified mice also display mutation-specific changes in bladder function. Furthermore, although mutant mice have compromised smooth muscle contraction and response to stretch, overriding bladder defects in Cx43(I130T) mice are likely to be complemented by neurogenic changes.

Endoscopic treatment of vesicoureteral reflux with non-simultaneous involuntary detrusor contraction in chronic spinal cord injury patients with neurogenic detrusor overactivity.

OBJECTIVE: To analyze whether it is correct to use endoscopic treatment via bulking agents of vesicoureteral reflux (VUR) seen on video urodynamics with non-simultaneous involuntary detrusor contraction in chronic spinal cord injury (SCI) patients with neurogenic detrusor overactivity (NDO). METHODS: A retrospective study was performed with a cohort of 76 patients (age 48.9 ± 14.4 years) (mean ± standard deviation) of both sexes with chronic SCI who underwent endoscopic treatment of VUR during the years 2008 to 2011. Patients were subjected to clinical examinations and video urodynamic studies preoperatively and 22 ± 11.4 months after the intervention. RESULTS: Resolution of VUR was achieved in 46 cases (61%). Cured patients had a statistically significant younger age and showed stress urinary incontinence more frequently. On the contrary, a greater grade of VUR, presence of bilateral reflux and presence of NDO were positively associated with treatment failure. The variables that independently influenced the cure of the reflux were NDO and reflux grade. CONCLUSIONS: The failure rate was high in patients with NDO, even though the reflux was not synchronous with involuntary detrusor contraction, and therefore these patients should have NDO eradicated before doing any anti-reflux procedures.

A novel animal model of underactive bladder: analysis of lower urinary tract function in a rat lumbar canal stenosis model.

AIMS: An animal model of neurogenic underactive bladder (UAB) has not been established. It was reported that a rat lumbar spinal canal stenosis (LCS) model created by cauda equina compression manifested intermittent claudication and allodynia. In this study, we examined the lower urinary tract function of the rat LCS model. METHODS: One small hole was drilled at the fifth lumbar vertebral arch (sham), and a rectangular piece of silicone rubber was inserted into the L5-L6 epidural space (LCS). Before and after surgery, a metabolic cage study was performed. After surgery, awake cystometry (CMG) and an in vitro muscle strip study were performed. Bladder morphology was evaluated by hematoxylin and eosin staining. RESULTS: The LCS rats showed a significant decrease in voided volume and a significant increase in postvoid residual volume and residual urine rate compared with Sham rats. CMG showed that the postvoid residual urine volume and numbers of non-voiding contractions significantly increased, while the voided volume, threshold pressure, and maximum intravesical pressure during voiding significantly decreased. There were no significant differences between sham and LCS rats in response to carbachol. In contrast, there was a significant increase in response to field stimulation, especially at lower frequencies, in LCS rats. LCS rats showed no obvious difference in detrusor morphology. CONCLUSIONS: This rat model requires a relatively simple surgical procedure and has characteristics of neurogenic UAB. It seems to be useful in the pathophysiological elucidation of UAB and might have potential for assessment of pharmacotherapy of UAB.

Pharmacotherapy for overactive bladder: an evidence-based approach to selecting an antimuscarinic agent.

Multiple drugs are now available for the treatment of overactive bladder. Currently, the pharmacological approach is to deal with the problem at the neuromuscular junction by attempting to stop the activity of the neurotransmitter with antimuscarinic medications. This article reviews the positive and negative aspects of the agents that are currently available for use in the US. In randomised clinical trials, extended-release formulations of these agents appear as effective as the immediate-release formulations, but are associated with fewer adverse effects. Attempts to use entities that are muscarinic M(3) selective antimuscarinic agents have not significantly improved the efficacy, but have reduced the major adverse effect of excessively dry mouth. Dose escalation or titration is addressed to enhance efficacy further. None of these drugs appear to cause significant cardiac or CNS adverse events. This supports the continued use of these agents for overactive bladder symptomatology, as they appear to be effective in reducing symptoms and remain generally well tolerated.

[Use of oral anticholinergic therapy in children under 1 years of age with high risk bladder]. / Utilización de anticolinérgicos orales en menores de 1 año portadores de vejiga de alto riesgo.

THE AIM: To assess the effectiveness and safety of the treatment with oral anticholinergic agents (Oxybutin clorure) in patients under 1 year old, and who aree carriers of high risk bladder secondary to neurological illness as well as no neurological one. MATERIAL AND METHODS: Since 1989, we have indicated treatment with anticholinergic agents to 16 patients: 9 patients had neurogenic bladder secondary to: myelomeningocele (n=7) and sacrocoxigeal teratoma (n=2). Others 7 patients had non neurogenic bladder secondary to: posterior urethral valvulas (n=1), valvula-like syndrome (n=4), post-surgery of neonatal giant bladder diverticulum (n=1) and Prune-Belly syndrome (n=1). The urodinamic study was performed during the first six months of life, being "high risk bladder" defined according to the parameters of compliance vesical and pressure of leak at point (PER). Five of the patients showed neonatal cronic renal failure (CRF), who were treated by cutaneus temporary derivation. All patients at treatment with anticholinergic agents at a 0.2 mg/kg/day dose was established; other early adjunctive treatment prior to the closure of the urinary derivation in children with CRF(n=5); or as a part of the conservative treatment (n=3), alone or associate to intermittent bladder catheterization (IBC) (n=8). During the treatment with anticholinergic agents, the cardiac frequency was controlled by EKG registration in 6 patients, being the rest of the children clinicaly controled (skin colour, mouth dryness, cardiac frequency and intestinal function). RESULTS: In all the cases, the minimum duration of the treatment was one year, until the functional stabilization of the urinary tract. It is to underline the absence of secondary complications which would have caused the suspension or the reduction of the treatment at long term. Conventional studies of urologicals image and urodinamic studies, showed the stabilization of the urinary tract and also the preservation of kidney function and not only was demonstrated in those patients with oral anticholinergic agent as their unique treatment, but also in those patients who had previously been derivated. The previous vesical stabilization allowed the optimum result of subsequent corrective surgeries in five patients (ureteroneocystostomy and vesiscotomy clousure. In cases with previous derivation, the treatment with oral anticholinergic agents made easier vesicostomic clousure in the forth quarter of the first year old wih the maintenance of the vesical stability. CONCLUSIONS: The use of oral anticholinergic agents at a dose of 0.2 mg/kg/day, has resulted to be safe as well as effective in the treatment of high risk bladder in infancy those with less than one year of life. In those patients with serious dysplasia by reflux, it contributes to the preservation of kidney function, it makes easier the early desderivation and it also stabilizes in a functional way the bladder as a previous step to subsequent reconstructive surgeries.

Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis.

OBJECTIVES: To examine the safety, efficacy, and tolerability of tolterodine in four randomized, double-blind, parallel, multicenter, 12-week studies of patients with overactive bladder. METHODS: Two of the four studies compared tolterodine (2 mg twice daily) to oxybutynin (5 mg three times daily) and placebo, one study compared tolterodine (2 mg twice daily) to oxybutynin (5 mg three times daily), and one study compared two dosages of tolterodine (1 and 2 mg twice daily) to placebo. Efficacy was determined from micturition diaries and patient perception of their bladder condition. Safety and tolerability were assessed from adverse events and laboratory measures. RESULTS: A total of 1,120 patients were randomized and treated at 134 centers. For the primary efficacy variable, the number of micturitions/24 hours, pooled results showed a significant decrease from baseline for the 1 mg tolterodine (P < 0.001), 2 mg tolterodine (P < 0.001), and 5 mg oxybutynin (P < 0.01) groups, compared to placebo. Both tolterodine doses and oxybutynin significantly decreased incontinence episodes/24 hours and significantly increased volume voided/micturition, compared to placebo. Tolterodine at a dose of 2 mg twice daily and 5 mg oxybutynin twice daily were significantly more effective in improving patient perception of bladder condition than placebo. Tolterodine at a dose of 2 mg and 5 mg oxybutynin were equivalent in their effectiveness. Tolterodine at doses of 1 mg and 2 mg were tolerated significantly better than oxybutynin when adverse events, dry mouth (both frequency and intensity), dose reductions, and patient withdrawals were considered. CONCLUSIONS: Although oxybutynin is highly effective, its clinical utility is limited by systemic side effects that lead to frequent discontinuation of treatment or dose reductions. Patients receiving tolterodine should not experience these limitations and instead will get safe and long-term effective treatment for their condition.

Use of Memokath temporary urethral stent in treatment of detrusor-sphincter dyssynergia.

In spinal-injured patients, detrusor-sphincter dyssynergia (DSD) can lead to high intravesical pressures, upper tract dilation, and recurrent infections. The standard treatment for DSD is sphincterotomy and, more recently, permanent sphincter stenting. Many spinal-injury patients would prefer a reversible treatment because of concern about fertility or because they are awaiting a "miracle cure." There is also concern over the theoretical long-term risk of squamous carcinoma after permanent stenting. In view of this, the Memokath, a thermosensitive temporary stent, has been undergoing trials at our center to determine which patients could benefit. Fourteen Memokath stents have been inserted in spinal-injured patients with DSD at our center, and they have been followed up for as long as 2 years. Stents were placed under cystoscopic guidance as a day case procedure. The stents were inserted either through the sphincter alone (short [4-cm] stents; 3 patients) or through the sphincter and bladder neck (long [5-7-cm] stents; 11 patients). There were no complications during surgery in either placement or removal of these stents. There was a significant (p < 0.001) reduction in the residual urine volume after stenting. Preoperative hydronephrosis and attacks of autonomic dysreflexia noted in some patients also resolved after stenting. Short stents that bridge the external urethral sphincter were ineffective in emptying the neuropathic bladder. Therefore, we advise that only long stents that lie across both the bladder neck and the external sphincter be used. Because of its easily reversible nature, the Memokath should be adopted for use in patients who are unsure about their preferred option of bladder management and those involved in a fertility program.

[Clinical effects of oxybutynin hydrochloride in the treatment of unstable bladder and overactive neurogenic bladder: a long-term clinical trial].

Clinical effects and therapeutic usefulness of oxybutynin hydrochloride were evaluated in a long-term clinical trial on patients with unstable bladders and neurogenic bladders. Of the 46 patients entered into the trial, 37 were those diagnosed with an unstable bladder and 9 with a neurogenic bladder with overactive detrusor. In 37 of the cases (80%), the period of drug administration reached up to 12 weeks and in 16 cases (34%) the drugs were administered for more than 24 weeks. The average administration period was 165.9 days. The average total given dose was 1776.9 mg and average dose per day was 10.7 mg. Excellent and good responses were obtained in 76.3, 88.9 and 69.6% at 12 and 24 weeks after start of administration and at the time of discontinuing the drug, respectively. The cystometric changes at pre- and post-administration were evaluated on 23 cases and revealed a significant increase in volume at first sensation and maximum desire to void. Maximum resting intravesical pressure was significantly declined and uninhibited detrusor contractions were significantly suppressed. Side effects were noted in 11 of the 46 cases (23.9%), most of which were well tolerated by the patients. In 4 cases the drug had to be discontinued because of the side effects. Dry mouth was the most common side effect, occupying almost half of the incidents. No significant abnormality was noted on blood laboratory data, blood pressure or heart rate, following the drug administration. In one case slight increase in serum glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase was encountered, but its relationship with the drug was obscure. The clinical usefulness of this drug (excellent and good) was 78.9, 88.9 and 69.6% at 12 and 24 weeks after start of administration, and at the time of drug discontinuation, respectively. The present long-term trial proved that oxybutynin hydrochloride is an exceedingly effective and safe agent for clinical management of unstable bladder and overactive neurogenic bladder.

Propiverine: a review of its use in the treatment of adults and children with overactive bladder associated with idiopathic or neurogenic detrusor overactivity, and in men with lower urinary tract symptoms.

Propiverine is a well established antimuscarinic agent with a mixed mode of action in the treatment of symptoms associated with overactive bladder (OAB). As well as blocking muscarinic receptors in the detrusor muscle, the drug also inhibits cellular calcium influx, thereby diminishing muscle spasm. In patients with symptoms of OAB resulting from idiopathic detrusor overactivity (IDO) or neurogenic detrusor overactivity (NDO), propiverine demonstrated dose-dependent efficacy and tolerability, with adverse events consistent with those associated with all antimuscarinic agents. In adults with IDO, propiverine demonstrated similar efficacy to that of other antimuscarinic agents (including solifenacin, tolterodine, oxybutynin and imidafenacin) and, in adults with NDO, propiverine and oxybutynin demonstrated similar efficacy. Propiverine was generally well tolerated in these patient populations, with a lower incidence of dry mouth than that associated with oxybutynin. In men with lower urinary tract symptoms (LUTS), and in whom the presence of benign prostatic enlargement (BPE) was implicated, propiverine administered as add-on therapy to an α(1)-adrenoceptor antagonist demonstrated similar or superior efficacy to that achieved with an α(1)-adrenoceptor antagonist alone, and combination therapy was particularly effective in patients with urinary storage symptoms. Combination therapy was generally well tolerated, but was associated with a higher incidence of adverse events than an α(1)-adrenoceptor antagonist alone. In children and adolescents with IDO/OAB or NDO, propiverine was generally more effective and better tolerated than oxybutynin. In conclusion, propiverine provides a valuable option for the treatment of adults and children with OAB associated with IDO or NDO, and in men with storage LUTS.

Anticholinergic drugs for adult neurogenic detrusor overactivity: a systematic review and meta-analysis.

CONTEXT: There is a lack of evidence about the efficacy and safety of anticholinergic drugs and about the optimal anticholinergic drug, if any, for the treatment of adult neurogenic detrusor overactivity (NDO). OBJECTIVE: Review the current evidence on the efficacy, safety, and tolerability of anticholinergic drugs in the treatment of adult NDO. EVIDENCE ACQUISITION: A literature search was conducted from 1966 to May 2011. Meta-analysis of all published randomised controlled trials (RCTs) comparing anticholinergic drugs with placebo and comparing different types, doses, and routes of administration of anticholinergic drugs, in adults with NDO, was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. The primary outcome was patient-reported cure/improvement of overactive bladder symptoms. Secondary outcomes were quality of life (QoL) changes, bladder diary events, urodynamic outcomes, adverse events, and costs to health services. EVIDENCE SYNTHESIS: A total of 960 patients from 16 RCTs with mean follow-up of 3.8 wk were included. Anticholinergic drugs were associated with statistically significantly better patient-reported cure/improvement (risk ratio: 2.80; 95% confidence interval [CI], 1.64 to 4.77), higher maximum cystometric capacity (weighted mean difference [WMD]: 49.49; 95% CI, 15.38 to 84.20), higher volume at first contraction (WMD: 49.92; 95% CI, 20.06 to 79.78), and lower maximum detrusor pressure (WMD: -38.30; 95% CI, -53.17 to -23.43) when compared with placebo. The dry-mouth rates were statistically significantly higher with anticholinergics, with no difference in withdrawals because of adverse events. There was no statistically significant difference in any of the outcomes between oxybutynin and other anticholinergics or among different doses and preparations of anticholinergic drugs. No study reported QoL changes or costs to health services. CONCLUSIONS: Compared with placebo, anticholinergic treatment in patients with NDO is associated with better patient-reported cure/improvement and significant reduction of maximum detrusor pressure; however, there is a higher incidence of adverse events. None of the anticholinergic drugs or different dosages assessed in this review was superior to another.

Propiverine compared to oxybutynin in neurogenic detrusor overactivity--results of a randomized, double-blind, multicenter clinical study.

OBJECTIVES: To compare the efficacy and tolerability of propiverine and oxybutynin in patients with neurogenic detrusor overactivity. METHODS: Patients were eligible, if at least 18 years of age and suffering from neurogenic detrusor overactivity. Eligibility also required a maximum cystometric capacity less than 300 ml. After a one-week run-in period, propiverine 15 mg t.i.d. or oxybutynin 5mg t.i.d. were administered for 21 days. As primary efficacy outcomes urodynamic parameters were assessed. As tolerability outcome the percentage of patients with newly manifesting anticholinergic adverse events was taken. RESULTS: 131 patients were recruited at 20 study centers. The maximum cystometric capacity (ml) was increased significantly in the propiverine group from 198 (+/-110) to 309 (+/-166), and in the oxybutynin group from 164 (+/-64) to 298 (+/-125). Similarly, maximum detrusor pressure during the filling phase (cm H(2)O) was lowered significantly in the propiverine group from 56.8 (+/-36.2) to 37.8 (+/-31.6), and in the oxybutynin group from 68.6 (+/-34.5) to 43.1 (+/-29.2). No significant differences resulted between treatment groups. Anticholinergic adverse events were reported less frequently in the propiverine compared to the oxybutynin group (63.0% versus 77.8%). Dryness of the mouth, the most frequent adverse event, was reported significantly less (47.1% versus 67.2%; p=0.02) in the propiverine compared to the oxybutynin group. CONCLUSION: Propiverine and oxybutynin are equally effective in increasing bladder capacity and lowering bladder pressure in patients with neurogenic detrusor overactivity. The trend for better tolerability of propiverine compared to oxybutynin achieved significance for dryness of the mouth.

A urethral stent for the treatment of detrusor-striated sphincter dyssynergia.

OBJECTIVE: To assess the technique, efficacy and complications of the Ultraflex urethral stent (Boston Scientific Corp., Boston, MA) for the treatment of detrusor-striated sphincter dyssynergia (DSD). PATIENTS AND METHODS: Forty consecutive patients with DSD who had a Ultraflex stent placed in the membranous urethra were evaluated prospectively. DSD was caused by spinal cord injury in 30, multiple sclerosis in six and other neurological diseases in four. All patients were either tetraplegic or paraplegic and unable to use intermittent self-catheterization. Previous bladder management consisted of an indwelling catheter in 15 patients, chronic suprapubic catheters in two, intermittent catheterization in nine, and trigger reflex micturition in 14. The Ultraflex stent was placed under local anaesthesia. The stents were 50 mm long in 36 patients, 45 mm in two and 40 mm in two. The mean (SD) follow-up was 16.9 (13. 8) months. RESULTS: The mean (SD) residual urine decreased from 245. 9 (117) mL before stenting to 65.2 (19.3) mL at 12 months afterward (n = 19). One stent was removed at 13 months for chronic prostatic and urinary tract infection leading to autonomic dysreflexia. There was no stent stenosis and 17 of 18 stents had > 75% epithelial coverage at one year. None of the stents migrated. Seven patients underwent secondary bladder neck incision through the stent. The stent length was increased in four patients using a second overlapping distal stent, twice during the first procedure and twice within 6 months because the sphincter was inadequately covered. CONCLUSIONS: The Ultraflex stent achieved the expected results for a prosthetic sphincterotomy and appears to be an appropriate but less invasive treatment for DSD.

Solifenacin: treatment of overactive bladder.

An investigational muscarinic antagonist, solifenacin is indicated in the treatment of overactive bladder. Solifenacin works to decrease bladder activity by inhibiting contraction of the smooth muscle wall surrounding the bladder. Micturition normally occurs following stimulation of acetylcholine muscarinic M3 receptors within the detrusor muscle wall. As a potent and selective muscarinic receptor antagonist, solifenacin acts specifically at the M3 receptor site. Initial data have shown solifenacin to be more bladder-selective than its predecessors. It is this selective mode of action that gives solifenacin the potential to limit commonly experienced anticholinergic side effects. These developments could translate into higher patient compliance with the potential for better long-term results. Solifenacin has been shown to have a favorable risk/benefit ratio. At a once-daily oral dose of 5 mg/day, clinical data have shown solifenacin to be effective in reducing the symptoms of overactive bladder, with an incidence of dry mouth comparable to that associated with placebo. Results from phase I, II and III clinical trials have shown solifenacin to have a promising efficacy and safety profile for the treatment of overactive bladder. Comparative clinical trials are now needed to determine whether these initial results can prove solifenacin to be more beneficial than other commonly administered antimuscarinics.

Lowering of maximum urethral pressure by (D-Met2, Pro5)-enkephalinamide in patients with neurogenic vesicourethral dysfunction due to spinal cord injury.

The effect of (D-Met2, Pro5)-enkephalinamide upon urethra in patients with chronic neurogenic vesicourethral dysfunction due to spinal cord injury was investigated. Urethral pressure profile was recorded with Urolab 1154 and 1700A urethral pressure profile puller-pump. Ten mg of the drug was administered subcutaneously. Urethral pressure profile was again recorded at 10, 20, 30, 40, 50 and 60 min after drug administration. Heart rate was also noted at these time points. There was a significant decrease in maximum urethral pressure from 134 +/- 19 cm H2O in the basal study to 107 +/- 28 cm H2O at 10 min (p less than 0.01); 102 +/- 30 cm H2O at 20 min (p less than 0.001); 94 +/- 19 cm H2O at 30 min (p less than 0.001); 100 +/- 20 cm H2O at 40 min (p less than 0.001); 102 +/- 29 cm H2O at 50 min (p less than 0.001); and 109 +/- 36 cm H2O at 60 min (p less than 0.001) after subcutaneous administration of (D-Met2, Pro5)-enkephalinamide. There was a significant increase in heart rate from 81 +/- 5 to 95 +/- 9 at 10 min (p less than 0.01) and to 87 +/- 10 at 20 min (p less than 0.01) after the drug. Subsequenly, the heart rate returned to near-basal values. The side effects were: conjunctival injection in all the cases; dryness of mouth in two; itching over the body in one; sensation of insect crawling over the body in one; and feeling of oppression over the chest immediately after drug administration in one.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravesical therapy options for neurogenic detrusor overactivity.

STUDY DESIGN: Review article. SETTING: Neuro-Urology, Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland. OBJECTIVES: This review considers intravesical treatment options of neurogenic detrusor overactivity and discusses the underlying mechanism of action, clinical safety and efficacy, and the future trends. METHODS: The available literature was reviewed using medline services. RESULTS: Oral anticholinergic drugs are widely used to treat detrusor overactivity, but they are ineffective in some patients or cause systemic side effects such as blurred vision or dry mouth. As an alternative, topical therapy strategies have been suggested to achieve a profound inhibition of the overactive detrusor and to avoid high systemic drug levels. Currently available intravesical treatment options either act on the afferent arc of the reflex such as local anaesthetics or vanilloids or on the efferent cholinergic transmission to the detrusor muscle such as intravesical oxybutynin or botulinum toxin. Although an established and effective therapy, intravesical oxybutynin is not widely used. Evidence for clinical significance of intravesical atropine and local anaesthetic is missing. Intravesical capsaicin has been shown to improve clinical and urodynamic parameters, but cause pain in some patients. The intravesical instillation of resiniferatoxin and the injection of botulinum-A toxin into the detrusor muscle are promising new options; however, randomised placebo-controlled studies to prove their safety and efficacy are still missing. CONCLUSION: Intravesical treatment strategies in patients with neurogenic detrusor overactivity may provide alternatives to established therapies such as oral anticholinergics. The selectivity of the intravesical treatment and the reduction or even the absence of side effects are major advantages of this topical approach.

The spectrum of autoimmune autonomic neuropathies.

We analyzed the clinical characteristics of 18 patients (13 female, 5 male) who had autoimmune autonomic neuropathy (AAN) and ganglionic acetylcholine receptor (AChR) autoantibodies. Mean age was 61.4 years (standard deviation, 12.0 years). Ten patients had subacute symptom onset, six with an antecedent event. Eight patients had chronic AAN, characterized by insidious symptom onset, without antecedent event, and gradual progression. A majority of patients with high antibody values (>1.00 nmol/L) had a combination of sicca complex (marked dry eyes and dry mouth), abnormal pupillary light response, upper gastrointestinal symptoms, and neurogenic bladder. Chronic AAN segregated into two subgroups. One subgroup (N = 4) had low antibody titer (0.09 +/- 0.01 nmol/L) and a paucity of cholinergic symptoms. It was indistinguishable from pure autonomic failure. The other subgroup (N = 4) had high antibody titer (11.6 +/- 2.08 nmol/L), sicca complex, abnormal pupils, and neurogenic bladder; three had severe upper gastrointestinal dysfunction. Higher antibody titers correlated with greater autonomic dysfunction and more frequent cholinergic dysautonomia. These observations expand the clinical spectrum of AAN to include chronic cases, some being indistinguishable from pure autonomic failure, and support the concept that ganglionic AChR antibodies are important diagnostically and pathophysiologically in acquired dysautonomia.