Botulinum toxin therapy for neurogenic detrusor overactivity

Detrusor injection of botulinum toxin (BTX) has shown great promise in the treatment of neurogenic detrusor overactivity (NDO) refractory to conservative therapy. Despite a paucity of prospective evidence, there exists a growing consensus that BTX injection therapy is a well-tolerated, low-risk therapy. Injections result in substantial subjective improvement in continence and quality of life. Moreover, assessment of urodynamic parameters demonstrates objective changes: (1) an increase in maximum cystometric capacity; (2) when applicable, a reduction in maximal detrusor voiding pressures; and (3) an increase in bladder compliance in cases where baseline bladder compliance measures were abnormal. While BTX bladder injection offers both objective and subjective measures of incontinence control, treatment duration is limited by the gradual reinnervation of injected tissue over an approximately 6- to 9-month interval. However, repeat injection cycles do appear to achieve similar levels of efficacy. The objective of this review is to provide a focused summary of the current body of literature, investigating the safety and efficacy of bladder BTX injection in patients with NDO.     

Botulinum toxin treatment for overactive bladder and detrusor overactivity in adults

Objectives

To review the evidence in support of botulinum toxin (BoNT-A) for overactive bladder and detrusor overactivity in adults.

Methods

A search of Medline and Pubmed was undertaken using the search terms ‘botulinum toxin’ with ‘overactive bladder’, ‘detrusor overactivity’, ‘randomised trial’ and ‘trial’. A narrative review was undertaken based on the papers identified.

Results

Only four randomised trials reporting the effects of botulinum toxin in this group of patients exist, alongside three systematic reviews and numerous uncontrolled series. Overall, BoNT-A appears an effective treatment modality, with significant and clinically meaningful reductions in urinary symptoms. Urgency and urgency incontinence episodes appear more responsive than absolute frequency. The side effect profile can be predicted from the mode of action of BoNT-A and includes voiding difficulty and urinary tract infection. Few data exist comparing the efficacy and safety of different doses, nor directly comparing the two common preparations, onabotulintum toxin A with apobotulinum toxin A. The cost-effectiveness of BoNT-A remains to be fully evaluated.

Conclusions

BoNT-A is an emerging treatment for overactive bladder and detrusor overactivity. The data available to date are of moderate quality with few large randomised trials. However, the drug appears to be effective and safe, although further work is required to identify the most cost-effective dose and treatment interval for maximum benefit.     

Botulinum toxin A for treatment of neurogenic detrusor overactivity and incontinence in patients with spinal cord lesions

OBJECTIVE: To evaluate the efficacy of intravesical botulinum toxin A (BTA) in the treatment of severe neurogenic detrusor overactivity (NDO) with incontinence in patients with spinal cord lesions (SCLs). MATERIAL AND METHODS: Fifteen SCL patients suffering from NDO and incontinence were included in the study. The volume of urine leakage during episodes of incontinence was quantified, and filling cystometry was performed before and after BTA treatment. During BTA treatment, a total of 300 IU of BTA was injected cystoscopically into the detrusor muscle, excluding the trigone region. Antibiotic prophylaxis was given. RESULTS: Thirteen of 15 patients (87%) reported that they were fully continent after treatment and the volume of leakage in the two incontinent patients was significantly reduced. Anticholinergic medication was stopped in all patients after BTA treatment. Cystometry showed a marked reduction in pressures after treatment in all patients, with the maximum detrusor pressure during filling being significantly reduced (p < 0.0005) and the maximum volume at a detrusor pressure of <40 cmH2O being significantly increased (p < 0.0005) in all patients. The maximum bladder capacity was increased, although not significantly. The period during which the patients remained continent following treatment ranged from 4 to 12 months (median 7 months). With the exception of slight haematuria, which resolved spontaneously, no side-effects were observed, and no cases of autonomic hyperreflexia were seen during treatment. CONCLUSION: BTA proved to be a highly effective treatment modality for NDO and incontinence in SCL patients. Treatment was easy to perform and the duration of effect was acceptable. Furthermore, BTA treatment was associated with virtually no side-effects.     

European experience of 200 cases treated with botulinum-A toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity

OBJECTIVES: To present a comprehensive experience with botulinum-A toxin (BTA) injected into the detrusor muscle in patients with spinal cord injuries/diseases causing neurogenic incontinence. METHODS: Ten European medical centers provided the results of 231 patients with neurogenic detrusor overactivity who were treated with BTA. 300 units of Botox (Allergan Inc.) were injected cystoscopically into the detrusor muscle at 30 different locations, while sparing the trigonum. Urinary continence status, concomitant anticholinergic medication use and patient satisfaction were recorded. Key urodynamic parameters (reflex volume, maximum detrusor pressure during voiding, detrusor compliance and maximum cystometric bladder capacity) at baseline and at the first and second urodynamic follow-up examinations were analyzed. RESULTS: By the time of the initial (mean 12 weeks after injection) as well as at the second urodynamic follow-up examinations (mean 36 weeks after injection), the mean cystometric bladder capacity (p < 0.0001) and the mean reflex volume (p < 0.01) increased significantly, while the mean voiding pressure (p < 0.0001) decreased significantly. The mean bladder compliance had increased significantly (p < 0.0001) by the first follow-up examination and non-significantly by the time of the second follow-up. No injection related complications or toxin related side effects were reported. The patients considerably reduced or even stopped taking anticholinergic drugs without recurrence of reflex incontinence and were satisfied with the treatment. CONCLUSIONS: This retrospective European multicenter study presents the most extensive experience to date with BTA injections into the detrusor muscle to treat neurogenic incontinence due to detrusor overactivity and confirms that this new treatment is safe and valuable. Significant improvement of bladder function corresponds with continence and the subjective satisfaction indicated by the treated patients.     

Botulinum A toxin in the treatment of neurogenic detrusor overactivity: a consolidated field of application

Several studies show promising results in terms of both clinical and urodynamic improvements, supporting the efficacy, safety and tolerability of botulinum toxin serotype A (BoNT-A) for managing neurogenic detrusor overactivity (DO). DO due to spinal cord injuries represents the most frequently treated dysfunction, where the efficacy appears to be high, with beneficial effects on quality of life. Data on the management of DO in patients with multiple sclerosis, cerebrovascular accidents and Parkinson's disease are scarce or absent; thus, the suitability of BoNT-A in the treatment neurogenic DO of other diseases of central nervous origin requires further investigation. Indeed, good quality, randomized controlled trials are still needed to identify not only the most appropriate patients to treat, but also the appropriate dose, administration technique, frequency of treatment and any eventual long-term complications. Thus, the use of intravesical BoNT-A in the control of neurogenic DO appears to be promising, but the drug is still in phase 3 clinical development, and further high-quality research is essential.     

Botulinum toxin A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity/neurogenic overactive bladder: a systematic literature review

OBJECTIVES: This systematic literature review discusses the efficacy and safety of botulinum toxin type A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity (NDO) and urinary incontinence or overactive bladder symptoms of neurogenic origin (NOAB). METHODS: A MEDLINE and EMBASE search for clinical studies with botulinum toxin A injected into the detrusor of adults with NDO was performed. For several efficacy and safety variables data were extracted by one person and independently quality-controlled by another person. Extracted data were reviewed to propose recommendations for use in clinical practice based on level of evidence and expert opinion. RESULTS: A total of 18 articles evaluating the efficacy or safety of Botox in patients with NDO and incontinence/NOAB resistant to antimuscarinic therapy, with or without clean intermittent self-catheterisation (CIC), were selected. The amount of Botox injected was mostly 300 U, usually as 30 injections of 10 U/ml in the bladder (excluding the trigone) under cystoscopic guidance and with different types of anaesthesia. Most of the studies reported a significant improvement in clinical (approximately 40-80% of patients became completely dry between CICs) as well as urodynamic (in most studies mean maximum detrusor pressure was reduced to < or =40 cm H(2)O) variables and in the patients' quality of life, without major adverse events. CONCLUSIONS: Botox injections into the detrusor provide a clinically significant improvement in adults with NDO and incontinence/NOAB refractory to antimuscarinics. It seems to be very well tolerated. However, more adequately powered, well-designed, randomised, controlled studies evaluating the optimal dose, number and location of injections, impact on antimuscarinic regimen and CIC use, duration of effect, and when to perform repeat injections are warranted.     

Botulinum toxin injections for neurogenic and idiopathic detrusor overactivity: A critical analysis of results

OBJECTIVE: In recent years there has been an increasing use of the botulinum neurotoxins for the management of conditions characterised by detrusor overactivity. Early studies showed promising results in an area where few options previously existed between pharmacotherapy and surgery. This has led to an urgent need to assess the wide range of techniques and therapies available, as well as the efficacy and tolerability of the treatment. We performed a critical analysis of the numerous clinical studies for this novel treatment option in the management of neurogenic and idiopathic detrusor overactivity, with a view to directing further research and assisting urologists in the management of these conditions. METHODS: A systematic review of the literature, as well as a search for abstracts presented to relevant peer-reviewed meetings, was performed. All articles from 1988 onwards were included, prior to which no articles describing urologic use of botulinum neurotoxins had been published, although the majority of the articles have been published since 2000. RESULTS AND CONCLUSIONS: Although many of the studies were small, overwhelming evidence supports the efficacy, safety, and tolerability of the botulinum toxins, specifically serotype A, for the management of these conditions. Before this is accepted as a widespread treatment modality, good-quality evidence from large-scale randomised controlled trials is needed. These studies should identify not only the most appropriate patients to treat but also the best dose, administration technique, and frequency for treatment.     

Botulinum toxin A detrusor injections in patients with neurogenic detrusor overactivity significantly decrease the incidence of symptomatic urinary tract infections

OBJECTIVES: To study the effect of botulinum toxin A (BoNTA) injections into the detrusor muscle on the incidence of symptomatic urinary infections in patients with neurogenic detrusor overactivity. METHODS: Between February 2004 and June 2005, 30 patients (18 men, 12 women), mean age 39.4+/-12.1 yr, with neurogenic detrusor overactivity received an injection of 300 U Botox (Allergan Inc., Irvine, CA, USA) into the detrusor. Fifteen patients had multiple sclerosis, 14 had spinal cord injury, and 1 had myelitis. Twenty-two patients had urinary incontinence. Patients were either resistant to anticholinergic medications, had discontinued treatment because of adverse effects, or had contraindications to anticholinergic drugs. Before and 6 wk after injection, each patient kept a bladder diary and underwent urodynamic investigation, retrograde and voiding cystourethrography, and urine culture. All symptomatic urinary infections (pyelonephritis, orchitis, prostatitis) occurring in the 6 mo before and the 6 mo after injection were recorded. RESULTS: Before injection, the mean number of symptomatic urinary infections over 6 mo was 1.75+/-1.87. After injection, the mean was 0.2+/-0.41 (p=0.003), and only 3 patients presented symptomatic urinary infections. These patients were those who showed less improvement in their urodynamic parameters after injection (volume of the first uninhibited contraction, maximum bladder pressure, and maximum cystometric capacity, respectively; p=0.0037, p=0.0002, p=0.0027, ANOVA). CONCLUSIONS: BoNTA injections into the detrusor muscle significantly decreased the incidence of symptomatic urinary infections. This effect seems to be related to improvement in urodynamic parameters, reflecting improved reservoir capacity at low pressure.     

Neurotoxin treatments for urinary incontinence in subjects with spinal cord injury or multiple sclerosis: a systematic review of effectiveness and adverse effects

BACKGROUND/OBJECTIVE: The objective was to evaluate the effectiveness of neurotoxin treatments of urinary incontinence (UI) in individuals with spinal cord injury (SCI) or multiple sclerosis (MS). METHODS: Studies were included if published in English, presented randomized adults with SCI or MS, and reported UI outcomes. RESULTS: Ten trials randomizing 288 subjects with SCI (43%), MS (52%), or other spinal conditions (5%) and UI refractory to oral antimuscarinics were included. The overall mean age was 41 years, and 46% were women. Study durations ranged from 1 to 18 months. Treatments included botulinum toxin-A (BTX-A, 2 trials) and 2 vanilloid compounds, capsaicin (6 trials) and resiniferatoxin (4 trials). BTX-A was superior to placebo and resiniferatoxin in reducing daily UI episodes, mainly in individuals with SCI, although significant reductions vs placebo were not evident throughout the study duration. There were 1.1 fewer daily UI episodes in the BTX-A 200 unit group vs 0.1 fewer for the placebo group at the final week 24 assessment. Capsaicin was generally superior to placebo. The weighted difference between capsaicin and placebo in a pooled analysis of 2 trials enrolling subjects with either paraplegia or tetraplegia (n = 32) was -3.8 daily UI episodes [95% Cl -4.7 to -2.9] after 30 days. Capsaicin was comparable to resiniferatoxin. Pelvic pain and facial flushing were associated with capsaicin. CONCLUSION: Neurotoxins may improve refractive UI in adults with SCI or MS, although trial results were inconsistent. Trials were small in size and relatively short in duration. Further studies are needed to determine the efficacy and tolerability of long-term application.     

Botulinum toxin for the treatment of lower urinary tract symptoms: a review

AIMS: To review the available literature on the application of botulinum toxin in the urinary tract, with particular reference to its use in treating detrusor overactivity (DO). METHODS: Botulinum toxin, overactive bladder (OAB), detrusor instability, DO, detrusor sphincter dyssynergia (DSD), and lower urinary tract dysfunction were used on Medline Services as a source of articles for the review process. RESULTS: DO poses a significant burden on patients and their quality of life. Traditionally patients have been treated with anti-cholinergic drugs if symptomatic, however, a significant number find this treatment either ineffective or intolerable due to side effects. Recent developments in this field have instigated new treatment options, including botulinum toxin, for patients' refractory to first line medication. Botulinum toxin, one of the most poisonous substances known to man, is a neurotoxin produced by the bacterium Clostridium botulinum. Botulinum toxin injections into the external urethral sphincter to treat detrusor sphincter dyssynergia has been successfully used for some years but recently its use has expanded to include voiding dysfunction. Intradetrusal injections of botulinum toxin into patients with detrusor overactivity and symptoms of the overactive bladder have resulted in significant increases in mean maximum cystometric capacity and detrusor compliance with a reduction in mean maximum detrusor pressures. Subjective and objective assessments in these patients has shown significant improvements that last for 9-12 months. Repeated injections have had the same sustained benefits. CONCLUSIONS: Application of botulinum toxin in the lower urinary tract has produced promising results in treating lower urinary tract dysfunction, which needs further evaluation with randomised, placebo-controlled trials.     

Success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence

OBJECTIVES: Detrusor injections with botulinum toxin type A are an effective treatment for neurogenic detrusor overactivity, lasting for 9-12 months. When the patients develop botulinum resistance, subsequent injections might be less effective. Repeat injections in patients with severe neurogenic detrusor overactivity and incontinence were studied. METHODS: Patients received Botox (300 UI) or Dysport (750 UI) injections. Clinical variables: satisfaction, anticholinergics use, mean and maximum bladder capacity, continence volume. Cystometric parameters: compliance, cystometric capacity, reflex volume. Statistics: Anova, chi2-tests; t-tests and paired t-tests (p=0.05). RESULTS: Forty-three men and 23 women (mean age 38.3 years; mean duration of lesion 9.2 years) were included. The interval between subsequent injections (on average 9-11 months) did not change significantly (p=0.5594). The satisfaction was high and anticholinergics use decreased substantially (p=0.0000). Significant improvements were found in clinical parameters and in cystometric capacity, for compliance only at the second treatment. The incidence of reflex contractions was significantly reduced. Four patients had transient adverse events after Dysport. CONCLUSIONS: Repeat injections with botulinum toxin type A are as effective as the first one. The cause for repeat treatment is relapse of overactive bladder symptoms.