Use of botulinum toxin in individuals with neurogenic detrusor overactivity: State of the art review

Background

Botulinum neurotoxin (BoNT) injection into the bladder wall has been shown to be an effective alternative to anticholinergic (antimuscarinic) medications and more invasive surgery in those with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity (NDO) and urinary incontinence who are not tolerating anticholinergic medications. In August 2011, Botox^® (onabotulinumtoxinA) received Food and Drug Administration (FDA) approval for this use. Clinically, intradetrusor injection of BoNT has been found to decrease urinary incontinence and improve quality of life. Its impact on urodynamic parameters is an increase in the maximum cystometric (bladder) capacity and decrease in the maximum detrusor pressures. The most common side effects are urinary tract infections and urinary retention. There have been rare reports and a black box warning of distant spread of BoNT. BoNT has gained popularity because of its effectiveness and long duration of action, relative ease of administration, easy learning curve, reproducibility of results on repeated administration, and low incidence of complications.

Objective

To discuss the structure and function, mechanisms of action, clinical and urodynamic studies, injection technique, potential beneficial and adverse effects, and potential areas of research of BoNT.

Methods

Literature search focused on botulinum toxin in MEDLINE/PubMed. Search terms included botulinum toxin, neurogenic bladder, NDO, botox bladder, botox spinal cord injury, botox, FDA, botox side effects. All papers identified were English language, full-text papers. In addition, English abstracts of non-English papers were noted. The reference list of identified articles was also searched for further papers.

Conclusion

Botulinum toxin is an alternative treatment for individuals with NDO who fail to tolerate anticholinergic medications. Its popularity has increased because of the literature, which has supported its effectiveness, safety, easy use and learning curve, reproducibility of results on repeated use, and recent FDA approval of Botox^® (onabotulinumtoxinA).     

Efficacy, Tolerability and Safety of Propiverine Hydrochloride in Children and Adolescents with Congenital or Traumatic Neurogenic Detrusor Overactivity—A Retrospective Study

Objectives

Anticholinergic treatment combined with intermittent catheterisation is the cornerstone of the conservative treatment strategy in children with neurogenic detrusor overactivity, which in most cases is due to congenital causes. Efficacy, tolerability and safety of propiverine hydrochloride were evaluated retrospectively in these children.

Methods

At four specialized outpatient clinics, all children's records were scrutinized for first-line propiverine hydrochloride treatment, or second- or third-line treatment after failure of a non-selective alpha-blocker (phenoxybenzamine) and/or other anticholinergics (oxybutynin, trospium chloride). The primary efficacy outcomes were urodynamic parameters, with clinical symptoms as secondary outcomes. Statistical analysis was performed by paired t-tests (significance level p < 0.05).

Results

Altogether 74 children and adolescents (40 boys, 34 girls; age range 11 months–19 years) were treated with propiverine hydrochloride (average duration 2 years and approximately 4 months; individual dose range 5–75 mg). The primary efficacy outcome parameters improved significantly: maximum cystometric capacity 161.2 [standard deviation (SD) 97.3] to 252.2 ml (SD 117.2), p < 0.001; maximum detrusor pressure 43.8 (SD 39.2) to 27.1 cm H₂O (SD 26.4), p = 0.002; bladder compliance 7.6 (SD 6.4) to 17.0 ml/cm H₂O (SD 16.2), p < 0.001. Phasic detrusor overactivity was abolished by 63%; incontinence resolved by 54%. One patient spontaneously reported a typical anticholinergic adverse event, which resolved after dose reduction. No safety concerns were documented.

Conclusions

Propiverine hydrochloride is effective in neurogenic detrusor overactivity in children and adolescents, even in some of those cases unresponsive to other anticholinergics. The low incidence rate (<1.5%) of adverse events evidences a favourable risk-benefit profile of propiverine hydrochloride, considering in particular the total documented treatment and surveillance period of 171 patient years and nine months.     

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.     

Human urine with solifenacin intake but not tolterodine or darifenacin intake blocks detrusor overactivity

The objective of the study was to evaluate the local effects of three antimuscarinics excreted into human urine after oral ingestion. Two normal adult collected their voided urine after taking oral doses of tolterodine, darifenacin, and solifenacin for 7 days with a 14-day washout period. The urodynamic effect of intravesically administered human urine on carbachol-induced bladder overactivity was studied in female rats. Cystometric parameters were measured during continuous infusion of saline and human urine and then a mixture of carbachol (30 microM) and human urine. Carbachol significantly reduced the intercontraction interval and bladder capacity in the control (urine taken in the absence of oral antimuscarinics) and tolterodine- or darifenacin-administered groups. However, human urine obtained after taking solifenacin prevented the carbachol-induced detrusor overactivity. Urine excreted after oral ingestion of solifenacin provides a localized pharmacological advantage for the treatment of the overactive bladder syndrome.     

Electrical Stimulation of the Urethra Evokes Bladder Contractions in a Woman With Spinal Cord Injury

Objective:

Electrical stimulation of pudendal urethral afferents generates coordinated micturition in animals and bladder contractions in men after spinal cord injury (SCI), but there is no evidence of an analogous excitatory urethra-spinal-bladder reflex in women. The objective of this study was to determine whether electrical stimulation of the urethra could evoke bladder contractions in a woman with SCI.

Case Report:

A 38-year-old woman with a C6 ASIA A SCI who managed her bladder with clean intermittent catheterization and oxybutynin demonstrated neurogenic detrusor overactivity on urodynamics. Oxybutynin was discontinued 2 days prior to urodynamic testing with a custom 12F balloon catheter mounted with ring-shaped electrodes located in the bladder neck, mid urethra, and distal urethra. The inflated balloon was placed against the bladder neck to stabilize the catheter electrodes in place along the urethra. However, the balloon limited emptying during contractions. Urodynamics were performed at a filling rate of 25 mL/minute until a distention-evoked bladder contraction was observed. The urethra was stimulated over a range of bladder volumes and stimulus parameters to determine whether electrical stimulation could evoke a bladder contraction.

Findings:

Electrical stimulation via urethral electrodes evoked bladder contractions that were dependent on bladder volume (>70% capacity) and the intensity of stimulation.

Conclusions:

This is the first report of an excitatory urethra-spinal-bladder reflex in a woman with SCI. Future studies will determine whether this reflex can produce bladder emptying.     

电针调节骶3神经治疗神经源性逼尿肌过度活动的效果研究

目的 观察电针调节骶3神经治疗脊髓损伤患者逼尿肌过度活动及尿失禁的临床疗效. 方法 20例脊髓损伤后经影像尿动力学检查证明存在逼尿肌过度活动的患者纳人本研究.男18例,女2例.年龄17～58岁.取侧卧位,在尿动力学检查过程中逼尿肌刚开始收缩时对双侧骶3神经予电针治疗,改变电刺激的强度,选择出抑制逼尿肌收缩的最适合刺激强度.予适合强度的电刺激治疗同时行膀胱充盈测压,观察即时效应.有效者进行长期治疗,每日30 min,10 d为一疗程,3及9个疗程后复查尿动力学检查,观察长期效应.结果患者平均每天尿失禁次数、尿垫使用量分别从治疗前的8.93±3.27、3.93±1.54减至治疗后的7.00±2.51、3.21±0.89(P<0.05).出现首次逼尿肌收缩的膀胱容量明显增加,最大膀胱压力明显下降(P<0.05).2例完成3个疗程,1例完成9个疗程.此3例患者平均每天尿失禁次数、尿垫使用量分别从治疗前11.67±7.64、6.67±4.16减至4.00±1.73、2.33±0.58,首次逼尿肌收缩的膀胱容积均值从(73.9±10.3)ml增加至(111.6±17.6)ml.6例进行0.025 V和0.080 V的2个强度刺激,2组结果相比认为0.025 V更有效.结论电针调节双侧中髎穴骶3神经可显著增大出现首次逼尿肌收缩的容积,减少每周尿失禁的实际次数.以0.025 V进行电刺激,延长疗程,疗效可能更佳.     

Micturition reflex arc reconstruction including sensory and motor nerves after spinal cord injury: Urodynamic and electrophysiological responses

Abstract

Objective

To evaluate artificial reflex arcs for micturition using urodynamics and electrophysiological recordings.

Design

Sixteen beagles were equally and randomly divided into two groups.

Methods

In group A, anastomosis of the proximal end of the left L7 ventral root (VR) and distal end of the left S2 VR was performed, as well as anastomosis of the L7 dorsal root (DR) and S2 DR to reconstruct the sensory and the motor function of the bladder. In group B the proximal end of the left L7 VR and the distal end of the left S2 VR were anastomosed, while the left L7 DR was kept intact to reconstruct the motor function of the bladder. Outcome measures included electrophysiological testing and the urodynamic measures. In addition, we also monitored urinary infection rates.

Results

Stimulation to the left S2 DR in groups A and B both elevated the bladder pressure before and after the spinal lower motor neuron lesion. Single stimulation of the two groups both elicited evoked action potentials. Urinary infections occurred in group A (three occurrences) and in group B (eight occurrences) during the 3 months after the spinal lower motor neuron lesion.

Conclusion

Data showed that both reconstructive methods could induce bladder micturition and evoked action potentials. However, in group A the micturition response was better and the urinary infection rates were lower after the spinal lower motor neuron lesion. Thus, the artificial physiological reflex arc reconstruction method used in group A, with sensory input above the lesion, might provide a better alternative in clinical practice.     

Accuracy Of Bladder Stone Detection Using Abdominal X-Ray After Spinal Cord Injury

Abstract

Background: Bladder calculi are a common problern in those with spinal cord injury (SCI). Detection is important to prevent complications.

Objective: To determine the accuracy of bladder stone detection by abdominal x-rays.

Methods: X-ray reports from individuals with SCI with known bladder stones detected by cystoscopy were reviewed.

Main outcome measures: x-ray reports noted the presence or absence of bladder stones. The stone variables evaluated were stone composition (crystallographic analysis) , widest dimension of the largest stone (during cystoscopy) , and the total volume (cm3 ) of the stone mass removed.

Results: Sixty-two consecutive x-ray reports from individuals with bladder stones were reviewed. The majority of stones were calcium phosphate (46.8%) or struvite (26.7%). Regarding stone composition, the detection by x-ray was 28.6% for struvite stones and 41 .9% for calcium phosphate stones. Regarding diameter of largest stone, the detection by x-ray was 14% for stones < 0.5 cm, 0% for stones 0.5 cm to 0 .9 cm, 33% for stones 1.0 cm to 1.49 cm, 33% for stones 1.5 cm to 1.9 cm, and 54% for stones 2 2.0 cm. Regarding total volume of stones, the detection by x-ray was 0% forvolumes < 0.2 cm3 , 33% for volumes 0.2 cm3 to 0.39 cm3 , 60% for volumes 0.40 cm3 to 0.5 9 cm3 , 40% for volumes of 0.60 cm3 to 0.79 cm3 , 0% for stones from 0.8 cm3 to 0.99 cm3 , and 57% for volumes 2 1.0 cm3 . Overall, 13/ 62 (20.97%) of stones found during cystoscopy were detected by the x-ray.     

In the Human Urothelium and Suburothelium,Intradetrusor Botulinum Neurotoxin Type A Does Not Induce Apoptosis: Preliminary Results

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.     

Cost-consequence analysis evaluating the use of botulinum neurotoxin-A in patients with detrusor overactivity based on clinical outcomes observed at a single UK centre

OBJECTIVE(S): This study aimed to assess the resource utilisation, health benefits and cost-effectiveness of intra-detrusor injections of botulinum neurotoxin-A (BoNT/A) in patients with overactive bladder (OAB). METHODS: 101 patients with urodynamically-proven detrusor overactivity of either neurogenic (NDO; n = 63) or idiopathic (IDO; n = 38) origin received intra-detrusor injections of 200-300 units of BoNT/A in 20-30 ml saline as part of a research protocol. Twenty-nine patients received repeat injections after 7-26 months. Symptom severity and urodynamic parameters were assessed at 0, 4 and 16 weeks. The cost of therapy was quantified based on the NHS resources used by typical patients and was used to calculate the cost-effectiveness of BoNT/A compared with standard care from the perspective of the UK NHS. RESULTS: In an intent-to-treat analysis, 82% of patients showed a 25% or greater improvement in at least two out of five parameters (urinary frequency, urgency, urgency incontinence episodes, maximum cystometric capacity and maximum detrusor pressure) four weeks after treatment, reducing to 65% after 16 weeks. A 50% or greater improvement in the frequency of micturition, urgency or urgency incontinence was seen in 73% of patients at four weeks and 54% at 16 weeks. There were no significant differences between IDO and NDO patients in the proportion meeting these endpoints. Therapy cost pounds 826 per patient, with a cost-effectiveness ratio of pounds 617 per patient-year with > or = 25% clinical improvement. CONCLUSION(S): This study demonstrates that intra-detrusor BoNT/A is an effective treatment for OAB that is highly likely to be cost-effective in both idiopathic and neurogenic disease.     

Maximal bladder capacity is a positive predictor of response to desmopressin treatment in patients with MS and nocturia

Objective The aim of the study is to evaluate the efficacy of desmopressin therapy in the symptomatic treatment of nocturia in patients with multiple sclerosis (MS) and neurogenic detrusor overactivity, and to investigate the validity of maximal bladder capacity as a predictor of response to intranasal desmopressin inhalation. Material and methods A set of 20 women with MS and neurogenic detrusor overactivity enrolled in a prospective pilot study and were divided into two groups: Group A, the large bladder capacity group (maximal bladder capacity >250 ml, compliance >20 ml/cm H₂O, n = 10) and Group B, the small bladder capacity group (maximal bladder capacity <250 ml, compliance <20 ml/cm H₂O, n = 10). Maximal bladder capacities were measured by urodynamic evaluation. The dosage selected for the study was based on the established dose of commercially available desmopressin nasal spray (20 μg before bedtime) and on clinical trial experience. All patients were monitored for arterial blood pressure before and after treatment and for weight increase for the first 5 days of treatment. Night time voiding diaries were maintained for the 6 weeks of the trial; similarly, serum electrolyte levels and urine osmolality were measured twice weekly during the trial. Results The mean volume of nocturnal incontinence decreased significantly in both groups (P < 0.005). The average number of episodes of nocturia per night in Group A decreased from 2.35 to 0.89 and in Group B from 2.31 to 1.65. The maximum hours of sleep uninterrupted by nocturia increased from 2.54 to 4.62 in Group A and from 2.45 to 3.23 in Group B. Side effects were infrequent; only 2 patients complained of transient headaches. Neither hyponatremia nor serum electrolyte abnormalities occurred. Conclusions Our results suggest that desmopressin is effective in the symptomatic management of nocturia in patients with MS and neurogenic detrusor overactivity. Maximal bladder capacity is a valuable predictor of response to desmopressin.     

Electrical stimulation for the treatment of lower urinary tract dysfunction after spinal cord injury

Electrical stimulation for bladder control is an alternative to traditional methods of treating neurogenic lower urinary tract dysfunction (NLUTD) resulting from spinal cord injury (SCI). In this review, we systematically discuss the neurophysiology of bladder dysfunction following SCI and the applications of electrical stimulation for bladder control following SCI, spanning from historic clinical approaches to recent pre-clinical studies that offer promising new strategies that may improve the feasibility and success of electrical stimulation therapy in patients with SCI. Electrical stimulation provides a unique opportunity to control bladder function by exploiting neural control mechanisms. Our understanding of the applications and limitations of electrical stimulation for bladder control has improved due to many pre-clinical studies performed in animals and translational clinical studies. Techniques that have emerged as possible opportunities to control bladder function include pudendal nerve stimulation and novel methods of stimulation, such as high frequency nerve block. Further development of novel applications of electrical stimulation will drive progress towards effective therapy for SCI. The optimal solution for restoration of bladder control may encompass a combination of efficient, targeted electrical stimulation, possibly at multiple locations, and pharmacological treatment to enhance symptom control.     

Effective treatment of neurogenic detrusor dysfunction by combined high-dosed antimuscarinics without increased side-effects

OBJECTIVES: Patients with neurogenic bladder dysfunction demonstrate an insufficient treatment outcome under dosage-escalated monotherapy. With the objectives of continence and normalised bladder pressure, safe and tolerable non-invasive treatment alternatives were evaluated by using combined antimuscarinics. METHODS: Twenty-seven patients who were previously registered in a doubled antimuscarinics study were enrolled in this study. The patients demonstrated urodynamic-proven neurogenic bladder dysfunction with incontinence, reduced bladder capacity, and increased intravesical pressure, resulting from spinal cord injury (n=21); spinal cord dysplasia (myelomeningocele; n=3); multiple sclerosis (n=2), and viral encephalomyelitis (n=1). On the basis of the initial study treatment, they were allocated into three groups and treated with two antimuscarinics. Before enrollment, at 4 wk, and at 6 mo, patients underwent urodynamics and recorded bladder diaries, including side-effects. RESULTS: In all three groups, significant changes were noted at the 4-wk follow-up. Incontinence events decreased from an average of 7 to 1 event per day. The average median bladder capacity (180-393 ml) and reflex volume (125-335 ml) increased; detrusor compliance also improved (average, 15-33 ml/cm H2O). Seven patients reported side-effects; two discontinued the successful treatment. Two other patients did not reach satisfactory amelioration of the detrusor dysfunction. CONCLUSION: With combined high-dosage antimuscarinic medications, 85% of the patients who previously demonstrated unsatisfactory outcome with dosage-escalated monotherapy were treated successfully. The appearance of side-effects was comparable to that of normal-dosed antimuscarinics. Further studies are required to investigate the long-term pharmacological and physiological background of our findings.