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Keywords:

  • botulinum toxin A;
  • non-neurogenic overactive bladder;
  • short-term outcome

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

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.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

With aging, the proportion of people with overactive bladder (OAB) is increasing.1 It is reported that urgency urinary incontinence (UUI) severely impairs quality of life (QoL).2 Although anticholinergic agents are effective for most patients with OAB, some patients are refractory or cannot continue them because of adverse reactions, such as dry mouth, constipation and blurred vision.3,4 Deterioration of cognitive function can also be problematic among the elderly.5

Since Schurch et al. reported the effectiveness of botulinum toxin A (BTX-A) for neurogenic detrusor overactivity (DO), BTX-A injection into the bladder wall is also being considered as a promising treatment for non-neurogenic OAB.6–12 Although the use of BTX-A has not yet been approved for urinary tracts in Japan, Watanabe et al. reported the initial experience with intradetrusor BTX-A injection for Japanese patients with OAB.13,14 In the present report, we describe the short-term efficacy of BTX-A for Japanese individuals with non-neurogenic OAB.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Study design

The patients who met the following inclusion criteria were recruited into this prospective multicenter study: (i) subjects aged ≥20 years with non-neurogenic OAB; and (ii) complaining of UUI ≥ once a week despite taking anticholinergic agents, or incapable of continuing the agents because of adverse effects. Exclusion criteria were: (i) postvoid residual (PVR) ≥ 100 mL; (ii) apparent lower urinary tract obstruction or detrusor underactivity by urodynamic study (UDS); (iii) average voided volume on a 3-day frequency-volume chart (FVC) ≥ 200 mL; (iv) coexistence of stress or functional urinary incontinence; (v) urinary tract infection, bladder stone or malignancy of urinary tract; (vi) disorders of the neuromuscular junction, such as Lambert–Eaton myasthenic syndrome and amyotrophic lateral sclerosis; and (vii) swallowing problems. The patients were enrolled between June 2008 and February 2010. The study received ethical approval from the National Center for Geriatrics and Gerontology and each study site.

Pretreatment assessment

After a written informed consent was obtained, the anticholinergic agents, if taken, were withdrawn for 14 days or longer. Symptoms were assessed by the Overactive Bladder Symptom Score (OABSS), International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) and International Prostate Symptom Score (I-PSS).15–17 A 3-day FVC was also carried out. Subjects were instructed to record the time and volume of voided urine, and the experience of urgency and UUI. Uroflowmetry (UFM) and subsequent PVR measurement were examined. Cystometry with a filling rate of 50 mL normal saline per minute was also carried out as a UDS.

Injection technique

A total of 100 U of BTX-A (Botox; Allergan, Irvine, CA, USA) was reconstituted in 15 mL normal saline and then 0.5 mL (3.3 U) of the solution was injected at 30 submucosal sites of the posterior, lateral and anterior bladder wall, sparing the trigone (Fig. 1).

image

Figure 1. Injection methods of botulinum toxin A into the vesical submucosal layer. (a) Inserting the needle into the vesical wall and placing the needle tip in the submucosal layer. (b) Injecting 0.5 mL (3.3 U) of botulinum toxin A solution, making a bulge.

Download figure to PowerPoint

Follow-up assessment

The questionnaires, a 3-day FVC, UDS, UFM and PVR measurement were repeated after 4 weeks. Adverse effects (gross hematuria, micturition pain, difficulty on micturition/sensation of incomplete emptying, aspiration, weak muscle strength, headache, dizziness, numbness, tinnitus, sweating) were assessed at 2 and 4 weeks. The patients graded the adverse effects using the scale: “none”, “mild”, “moderate” and “severe”. Symptoms only graded “moderate” or “severe” were counted as adverse events.

Statistical analyses

Using the Wilcoxon signed-rank test in spss version 16, we analyzed the significance of differences in the parameters between the pre- and postinjection. A P-value <0.05 was considered significant. The primary end-point was a reduction of the number of UUI episodes postinjection.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The present study included nine men and eight women. The average patient age was 67 ± 12 years. Of these, eight men (89%) and three women (38%) were aged ≥65 years. Pre-injection UDS showed DO in 16 subjects (94%). The injection was carried out using a 23-G Williams cystoscopic injection needle for a rigid cystoscope in 16 patients or a 27-G Olympus needle (EndoTherapy, Tokyo, Japan) for a flexible scope in one. The anesthesia included local lidocaine anesthesia in two patients, caudal block in one patient, spinal anesthesia in 13 patients and general anesthesia in one patient.

Regarding the primary end-point, the frequency of pre-injection UUI in the daytime and night-time on FVC significantly decreased after injection (Table 1). In six of 15 subjects, daytime UUI completely disappeared. Daytime urinary frequency also decreased; however, the frequency of urgency did not decrease significantly in either the daytime or night-time. Maximum voided volume did not change significantly.

Table 1.  Changes in frequency-volume chart parameters
 Pre-injection (n)Postinjection (n)P-value
  1. Two patients did not record frequency-volume chart.

Daytime frequency11.3 ± 9.6 (15)9.6 ± 3.7 (15)0.018
Daytime maximum voided volume (mL)182.1 ± 57.0 (15)219.8 ± 87.8 (15)0.191
Daytime urgency3.3 ± 4.9 (15)2.7 ± 5.1 (15)0.114
Daytime urinary incontinence5.5 ± 5.6 (15)2.0 ± 5.1 (15)0.001
Night-time frequency2.3 ± 1.4 (15)2.1 ± 1.3 (15)0.531
Night-time maximum voided volume (mL)169.2 ± 97.2 (15)160.9 ± 89.5 (15)0.820
Night-time urgency1.3 ± 2.6 (15)1.1 ± 2.6 (15)0.395
Night-time urinary incontinence0.5 ± 0.8 (15)0.3 ± 0.9 (15)0.007

Changes in the cystometry and uroflowmetry parameters are shown in Table 2. DO disappeared in eight patients and the average decreased after injection. Bladder capacity at the first desire to urinate and maximum capacity were both significantly increased. The average flow rate significantly decreased and PVR significantly increased from the pre-injection to postinjection, whereas the maximum flow rate and voided volume did not change significantly. A total of 15 subjects had <100 mL of preoperative PVR; however, seven had more than 100 mL and one had more than 200 mL after injection.

Table 2.  Changes in the cystometry and uroflowmetry parameters
 Pre-injection (n)Postinjection (n)P-value
  1. Uroflowmetry and postvoid residual were not measured in two patients preoperatively. Uroflowmetry was not measured in one patient postoperatively.

Cystometry   
 Detrusor overactivity (cmH2O)58.6 ± 37.2 (17)27.3 ± 38.5 (17)0.002
present 16, absent 1present 8, absent 9
 Capacity at first desire to void (mL)96.9 ± 66.7 (17)152.3 ± 95.8 (17)0.003
 Maximum capacity (mL)179.9 ± 105.1 (17)267.4 ± 142.6 (17)0.002
Uroflowmetry   
 Voided volume (mL)139.5 ± 86.8 (15)151.5 ± 88.0 (16)0.975
 Maximum flow rate (mL/s)17.5 ± 13.9 (15)13.5 ± 9.3 (16)0.177
 Average flow rate (mL/s)7.7 ± 4.7 (15)5.4 ± 3.1 (16)0.019
 Postvoid residual (mL)21.5 ± 29.5 (15)71.9 ± 82.4 (17)0.005

Changes in symptom scores are shown in Table 3. The scores of daytime frequency, urgency and UUI in OABSS, and those of frequency, volume and interference with everyday life in ICIQ-SF significantly decreased after treatment. In I-PSS, the scores of daytime frequency and urgency, and the storage subscore also significantly decreased, and the scores regarding voiding symptoms did not worsen significantly.

Table 3.  Changes in symptom scores
 Pre-injection (n)Postinjection (n)P-value
  1. ICIQ-SF, International Consultation on Incontinence Questionnaire Short Form; I-PSS, International Prostate Symptom score; OABSS, Overactive Bladder Symptom Score.

OABSS   
   #1. Daytime frequency1.4 ± 0.5 (17)1.1 ± 0.7 (17)0.034
   #2. Night-time frequency2.4 ± 0.7 (17)2.0 ± 0.8 (17)0.083
   #3. Urgency3.8 ± 1.4 (17)2.6 ± 1.5 (17)0.017
   #4. Urge urinary incontinence3.9 ± 0.8 (16)1.5 ± 1.6 (17)0.001
  Total score11.2 ± 2.7 (15)7.1 ± 3.3 (17)0.001
ICIQ-SF   
   #1. Frequency3.8 ± 0.8 (16)1.7 ± 1.8 (15)0.003
   #2. Amount3.7 ± 1.5 (17)1.8 ± 1.6 (17)0.003
   #3. Interference with everyday life6.2 ± 2.9 (17)3.3 ± 3.1 (16)0.001
  Total score13.3 ± 4.4 (16)6.6 ± 5.7 (15)0.001
I-PSS   
   #1. Feeling of incomplete emptying1.8 ± 1.6 (17)2.3 ± 2.0 (16)0.512
   #2. Daytime frequency3.9 ± 1.3 (17)2.7 ± 1.8 (17)0.025
   #3. Intermittent stream1.5 ± 1.4 (17)2.4 ± 2.1 (17)0.248
   #4. Urgency4.1 ± 1.2 (17)1.5 ± 1.6 (17)0.001
   #5. Slow stream2.7 ± 1.8 (17)3.1 ± 1.7 (17)0.429
   #6. Straining1.9 ± 2.0 (17)2.5 ± 2.2 (17)0.258
   #7. Night-time frequency2.7 ± 1.3 (17)2.3 ± 1.3 (17)0.071
  Storage subscore (#2 + #4 + #7)10.7 ± 2.8 (17)6.5 ± 3.9 (17)0.001
  Voiding subscore (#1 + #3 + #5 + #6)8.0 ± 4.9 (17)9.8 ± 6.7 (16)0.31
  Total score18.7 ± 6.0 (17)16.5 ± 9.6 (16)0.46
 QoL index5.5 ± 1.03.5 ± 1.90.001

Regarding adverse effects, three of 17 patients (23.5%) and seven of 16 patients (43.8%) complained of moderate difficulty on micturition/sensation of incomplete emptying 2 and 4 weeks after treatment, respectively. However, none of the patients required clean intermittent catheterization (CIC). Micturition pain was reported by three patients at 2 weeks and two patients at 4 weeks. None complained of gross hematuria. Headache, tinnitus or sweating was recorded in one patient after 2 and 4 weeks; however, these were not considered as systemic adverse effects by the attending doctors.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Although there have been relatively few reports on BTX-A efficacy for refractory non-neurogenic OAB, it is becoming apparent that intravesical injection of BTX-A can improve the symptoms.6–14,18,19 In the present study, we showed the excellent short-term effects of submucosal BTX-A injection for Japanese patients with refractory OAB.

The number of UUI, the primary outcome measure, was significantly decreased on FVC as well as on questionnaires. Although urgency did not improve on FVC, the questionnaires showed significant improvement. However, voiding symptoms were not worsened. DO was eliminated in eight (50%) of 16 patients 4 weeks after injection, which is compatible with known rates ranging from 33% to 74%.8,9 Increase of cystometric capacity was also shown as other reports have pointed out.7–14,18–20

Regarding the adverse effects, a significant increase of PVR was shown, as was also in the previous reports.7,9–12,18–20 In the present study, 43.8% experienced difficulty on micturition/feeling of incomplete emptying 4 weeks after injection, and eight of 15 patients whose pre-injection PVR was <100 mL had more than 100 mL 4 weeks after injection. None of the patients required CIC, despite the high proportion of older men, with the rates of CIC reportedly ranging from 0% to 41%.20 The relatively low dose that is 100 U could account for there being no need to undergo CIC. Although Dmochowski et al. recently reported that a dose of 100 U is appropriate for non-neurogenic OAB, we used 100 U, referring to the reports of Sahari et al. and Brubaker et al.10,11 They reported the higher rates of CIC on intradetrusor injection of 200 U BTX-A. Regarding other complications, we did not encounter serious adverse effects in this series.

In summary, the efficacy of BTX-A submucosal injection for non-neurogenic OAB was promising. An extended follow-up study is needed to elucidate the long-term outcome.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This work was supported by Health and Labour Sciences Research Grants (Comprehensive Research on Aging and Health; H19-CHOJU-001) in Japan.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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