The case for bladder botulinum toxin application

Botulinum toxin (BoNT) has been shown to be and effective agent in suppressing detrusor overactivity due to neurogenic causes. Recently, BoNT has been extended to patients who have idiopathic detrusor overactivity. This article reviews the use of BoNT to treat disorders of neurogenic detrusor overactivity and establishes BoNT as a therapeutic modality to treat idiopathic bladder overactivity. It is important to remember that the application of BoNT in the lower urinary tract is not approved by the regulatory agencies and caution should be applied until larger randomized clinical studies are completed.     

Intravesical botulinum toxin for overactive bladder syndrome without detrusor overactivity

ObjectiveTo report our experience of intravesical botulinum toxin for idiopathic overactive bladder syndrome (OAB) without detrusor overactivity (DOA) on urodynamic assessment.Patients and methodsData regarding presentation, diagnosis, urodynamic findings, date and dose of treatment, and outcomes were recorded prospectively for 94 patients undergoing intravesical botulinum toxin injection for idiopathic overactive bladder syndrome at our institution. The cohort included 19 patients without DOA on urodynamics. A positive response to treatment was defined as patient-reported improvement without the need for further treatment. ICIQ-OAB and UI scores, and bladder diary parameters were also recorded. Rates of urinary retention requiring intermittent or indwelling catheterisation were noted.ResultsThe overall response rate to treatment was 82% (n = 94). Patients without DOA (n = 19) had a response rate of 89%, which compared favourably with a response rate of 81% in patients with DOA (n = 75).Overall, 29% of patients who were voiding normally prior to treatment required intermittent self-catheterisation after the procedure. The requirement for self-catheterisation did not appear to be influenced by urodynamic findings.ConclusionThese preliminary, non-randomised data suggest that intravesical botulinum toxin injection may be efficacious in patients with OAB symptoms without DOA. Further evaluation by means of a randomised, controlled trial is suggested.     

Use and mechanism of botulinum toxin in overactive bladder treatment

Overactive bladder is very frequent in central neurogenic patients; it is a major cause of refractory incontinence despite anticholinergic treatment. In non-neurogenic patients it results in very distressing symptoms that associate urgency with or without incontinence and frequency. Botulinum toxin A is a well known agent used previously in the treatment of striated muscle spasmodism, which blocks the release of acetylcholine from nerve endings and neuro-muscular transmission. Its recent use in urology revealed a dramatic improvement in clinical and urodynamic parameters of the overactive bladder, associated with a long lasting effect over 6 to 9 months and an excellent tolerance. In neurogenic patients, the efficacy of botulinum injection was demonstrated over a placebo control group. Toxin was injected at 20 to 30 different sites in the detrusor muscle, with cystoscopy guidance. Recent studies showed a sub-epithelial mechanism of action on neuropeptides, which could explain an inhibitory effect of both efferent and afferent arms of the micturition reflex. Further studies remain necessary regarding the respective doses of Dysport and Botox toxin, selection of patients, combination with anticholinergic treatment, effects of repeated injections.     

Treatment of overactive bladder with botulinum toxin type B: a pilot study

The purpose of this study was to determine the efficacy and safety of botulinum toxin type B (BTX-B/Myobloc) in the treatment of patients with overactive bladder. This open-label dose-escalation study enrolled 15 female patients with urinary frequency with or without incontinence. The BTX-B doses used in this study were 2500, 3750, 5000, 10 000 and 15 000 units. Response was defined as a subjective improvement in frequency, urgency and incontinence symptoms. A paired t-test of the pre/post frequency difference indicates that these 15 patients experienced an average of 5.27 fewer frequency episodes per day after treatment with BTX-B. The p value for the paired t-test was <0.001. The longest duration effect was 3 months using 10 000–15 000 units of BTX-B. The correlation between dose and duration was very significant, with a correlation coefficient = 0.96, p<0.001. Based on these findings, we feel the use of botulinum toxin to treat patients with overactive bladder warrants further study.Abbreviations OAB Overactive bladder Editorial Comment: The authors discuss the short-term efficacy of botulinum toxin type B in patients with overactive bladder. An attempt is made to identify the highest safe dosage, but the data presented are limited and a final recommendation regarding this requires further study. The high correlation found between dosage and duration of efficacy is very interesting and clinically relevant. Such a relationship has not been previously described for botulinum toxin type A. The duration of response is concerning and does appear to be significantly lower than that previously published and what I have personally experienced with botulinum toxin type A. Although this may be due to variations in injection technique, it may also be a result of the type of toxin used. I agree that longer-term and comparative data are warranted.     

Lack of ultrastructural detrusor changes following endoscopic injection of botulinum toxin type a in overactive neurogenic bladder

INTRODUCTION: Endoscopical injections of Botulinum toxin type A into the detrusor muscle are gaining clinical acceptance in the treatment of neurogenic detrusor overactivity. Structural effects of Botulinum toxin type A are only known from studies on striated muscles, where a widespread nerve sprouting occurs temporarily. The aim of this study was to evaluate the ultrastructural effects of Botulinum toxin type A injections on the human detrusor. MATERIAL AND METHODS: 30 detrusor biopsies were obtained from 24 patients with neurogenic detrusor overactivity. Patients were divided into two groups: Group I included 13 biopsies from patients before the first Botulinum toxin type A injection. Group II included 6 biopsies from patients within 3 months after the first injection and 11 biopsies at the time of decreasing efficacy of Botulinum toxin type A. The biopsies were processed by standard procedure for detailed electron microscopic study and evaluated by 2 examiners without prior knowledge of clinical/urodynamic data. RESULTS: No statistically significant detrusor changes have been found concerning muscle cell fascicle structure (p = 0.445), width of intercellular space (p = 0.482) and number/kind of muscle cell junctions (p = 0.443). A median of 70% of intrinsic axon terminals presented with signs of degeneration in group I, a median of 66% in group II (p = 0.840). Out of 309 evaluated axon terminals in both groups, 1 sprouting axon was found in group I, 3 sprouting axons in group II (p = 0.864). Specimen from group I and group II showed only limited collagen deposits within the detrusor. No changes in the ultrastructure of the detrusor have been observed in those biopsies obtained before and after the Botulinum toxin type A injection of the same patient. CONCLUSION: This study verifies our earlier report of severe intrinsic axon degeneration in the detrusor of patients with neurogenic detrusor overactivity. It also shows nearly no structural differences of the detrusor before and after Botulinum toxin type A injections. Contrary to reports of striated muscle, axonal sprouting within the detrusor was very limited after Botulinum toxin type A injections indicating pathophysiologically different reactions to the toxin either between striated muscle and smooth muscle or between different treated diseases.     

Cost-effectiveness analysis of sacral neuromodulation and botulinum toxin A treatment for patients with idiopathic overactive bladder

Study Type – Therapy (economic analysis) Level of Evidence 1b

OBJECTIVE

To assess and compare the costs and effects value of either starting with sacral neuromodulation (SNM) or botulinum toxin A (BTX) treatment in patients with refractory idiopathic overactive bladder from a societal perspective.

MATERIALS AND METHODS

An economic model comparing SNM with BTX was developed. A clinical relevant effect (i.e. success) was defined as 50% or greater reduction in incontinence episodes or urgency frequency symptoms. Information on the clinical effectiveness of the two treatments and on the course of the disease with the two treatments were based primarily on published literature and, when required, on expert opinion. Both treatments were assumed to be performed under general anaesthesia and, for SNM treatment, first‐stage tined lead test was used. All costs were based on national data from the year 2008. Analyses from the societal perspective were conducted for a 5‐year duration. Costs were discounted at 4% and effects at 1.5%. In addition, different modelling scenarios were used to see determine any changes in the results obtained.

RESULTS

Starting with SNM resulted in a higher quality adjusted life year (QALY) gain (differenceof 0.23) and a higher cost (difference of €6428) compared to starting with BTX. The corresponding incremental cost‐effectiveness ratio was €27 991/QALY. The probability of this ratio being cost effective (e.g. under €40 000/QALY) is 88%. SNM starts to be cost‐effective after 4 years. SNM was not cost‐effective in some other scenarios, such as when BTX was conducted under local anaesthesia or when peripheral nerve evaluation or bilateral testing was used for SNM.

CONCLUSIONS

Starting with SNM, treatment is cost‐effective after 5 years compared to BTX. However, in some scenarios, such as the use of local anaesthesia for BTX treatment and SNM peripheral nerve evaluation or bilateral test, SNM was not cost‐effective.     

Botulinum toxin A submucosal injection for refractory non‐neurogenic overactive bladder: Early outcomes

The objective of the present study was to assess the short‐term effects of botulinum toxin A (BTX‐A) injection for refractory non‐neurogenic overactive bladder (OAB) in the setting of a prospective multicenter clinical trial. Refractory OAB was defined as persistent urgency urinary incontinence (UUI) ≥once a week despite taking anticholinergic agents, or the incapability to continue the agents because of the adverse effects. A total of 100 U of BTX‐A were reconstituted in 15 mL of normal saline and an aliquot of 0.5 mL was injected at 30 submucosal sites of the bladder wall. Nine men and eight women aged 67 ± 12 years were included. Subjective daytime frequency, urgency and UUI significantly decreased after treatment. On a 3‐day frequency‐volume chart, the daytime and night‐time frequency of UUI significantly decreased from 5.5 and 0.5 pre‐injection to 2.0 and 0.3 postinjection, respectively. Daytime urinary incontinence completely disappeared in six subjects. A urodynamic study showed the disappearance of detrusor overactivity in eight patients and a decrease in five patients. Maximum bladder capacity significantly increased from 179.9 to 267.3 mL. Difficulty on micturition or feeling of incomplete emptying was reported by 23.5% and 43.8% of patients at weeks 2 and 4, respectively. Postvoid residual urine increased to >100 mL in seven patients and >200 mL in one patient after injection; however, none of the patients required clean intermittent catheterization. These findings suggest promising efficacy of BTX‐A in Japanese OAB patients.     

Botulinum toxin treatment for overactive bladder: Risk of urinary retention

In recent years, botulinum-A neurotoxin has increasingly been used to manage lower urinary tract symptoms, including overactive bladder and detrusor overactivity (DO), either due to neurogenic or idiopathic etiology. Techniques, doses, and preparation vary. Although many studies have reported promising results regarding efficacy, potential adverse effects, particularly urinary retention, have been less comprehensively reported. We performed a critical review of published studies evaluating botulinum treatment for overactive bladder and its reported effects on voiding function. Acute urinary retention is recognized, though rare. Chronic urinary retention is inconsistently reported; it appears to be more common in neurogenic DO, but it can occur in idiopathic DO. Increased postvoid residuals have been reported by several studies, but the clinical significance that investigators attach to the observation varies. The detrimental effect of retention on quality of life can be considerable. Accordingly, patients should be fully counseled on the risks of urinary retention and trained in intermittent catheterization before the procedure. Postvoid residual assessment should be part of follow-up and patients should be warned of possible presentations.     

Early effect on the overactive bladder symptoms following botulinum neurotoxin type A injections for detrusor overactivity

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((R)) (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.     

Repeated botulinum toxin type A injections for refractory overactive bladder: medium-term outcomes, safety profile, and discontinuation rates

Background

Efficacy and safety of botulinum toxin type A (BoNTA) injection is supported by level 1 evidence, but data regarding repeated injections are limited in patients with refractory overactive bladder (OAB) and idiopathic detrusor overactivity (IDO).

Objectives

Describe medium-term outcomes and discontinuation rates for patients adopting repeated BoNTA as a management strategy for IDO.

Design, setting, and participants

Prospective data from a single centre were collected from the first 100 patients.

Intervention

Bladder injection of BoNTA (predominantly 200 U onabotulinumtoxinA; Allergan Ltd., Marlow, Buckinghamshire, UK) in an outpatient setting.

Measurements

OAB symptoms, quality of life, discontinuation rates, interinjection interval, and adverse events were recorded. Data comparisons were performed using a generalised linear model or a chi-square test where appropriate.

Results and limitations

Two hundred seven injections were performed in 100 patients. All patients had 1 injection, 53 had a total of 2, 20 had 3, 13 had 4, 10 had 5, 5 had 6, 3 had 7, 1 had 8, 1 had 9, and 1 had 10 injections. Statistics were applied up to five repeated injections. A statistically significant reduction in frequency, urgency, and urge urinary incontinence were seen following the first BoNTA injection compared to baseline. This improvement was maintained after repeated injections and was not statistically different when comparing differences between injections. Thirty-seven patients stopped treatment after the first two injections; thereafter, dropouts were rare. The most common reasons for discontinuing treatment were poor efficacy (13%) and clean intermittent self-catheterisation (CISC)–related issues (11%). The incidence of CISC after the first injection was 35%. Bacteriuria was detected in 21% of patients. The mean interinjection interval was 322 d. Limitations included the concurrent use of antimuscarinic drugs in some patients.

Conclusions

BoNTA can provide a safe and effective medium-term management option for patients with refractory IDO. The most common reasons cited for stopping treatment were poor efficacy and CISC-related issues.