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Keywords:

  • botulinum toxin;
  • complications;
  • detrusor overactivity

Abstract

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

Objective

To report discontinuation rates, inter-injection interval and complication rates after repeated intravesical botulinum toxin type A for the treatment of detrusor overactivity.

Method

Patients with urodyamically proven detrusor overactivity who had two or more botulinum toxin type A injections in the period 2004–2011 at Freeman Hospital, Newcastle Upon Tyne, UK, were considered for the present study. Discontinuation rates, complication rates and interval between botulinum toxin type A treatments were retrospectively analyzed.

Results

Overall, 125 patients (median age 53 years, range 19–83 years) were included in the analysis. The female-to-male ratio was 2.4:1 and median follow up was 38 months. A total of 96 patients had idiopathic detrusor overactivity, whereas 29 had neurogenic detrusor overactivity. A total of 667 injections were carried out, with 125 patients receiving two injections, 60 receiving three injections, 28 receiving four injections, 14 receiving five injections, three receiving six injections, three receiving seven injections and two receiving eight injections. The mean interval (±standard deviation) between the first and second injection (n = 125) was 17.6 months (±10.4), between the second and third (n = 60) was 15.7 ± 7.4 months, between the third and fourth (n = 28) was 15.4 ± 8.6 months, and between the fourth and subsequent injections (n = 22) was 11.6 ± 4.5 months. A total of 26% required intermittent catheterization, and 18% developed recurrent urinary tract infections. There was a discontinuation rate of 25% at 60 months.

Conclusion

Repeated botulinum toxin type A injections represent a safe and effective method for managing patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity. We have shown that the inter-injection interval remains unchanged up to five injections.


Abbreviations & Acronyms
BoNTA

botulinum toxin type A

DO

detrusor overactivity

IDO

idiopathic detrusor overactivity

ISC

intermittent self catheterization

NDO

neurogenic detrusor overactivity

UTI

urinary tract infection

Introduction

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

Intravesical injections of BoNTA are increasingly being used in the management of patients with DO. Schurch et al.[1] initially described the use of local injections of BoNTA to treat NDO after earlier reports of its use for detrusor sphincter dyssynergia in spinal cord injury patients.[2] Since then, IDO that is refractory to treatment with anticholinergic medication has also been successfully managed by BoNTA.[3] The largest randomized controlled trial of BoNTA for refractory DO was reported by Tincello et al., which involved 240 women across eight urogynecology centers, and that study confirmed the efficacy and safety of the compound with one-third of women achieving continence, but the main complications were UTI and self-catheterization rates of 31% and 16%, respectively.[4]

It is well established that the effects of BoNTA are finite, and repeated injections are required to sustain the therapeutic effects.[5] Randomized controlled studies have confirmed the safety of intravesical BoNTA after a single treatment,[6-8] but few studies have investigated repeated injections.[9, 10]

The available data suggest an improvement in symptoms, as well as urodynamic parameters after repeated injections of BoNTA.[9-11] The reported incidence of adverse events is low, with urinary retention and infection being the most commonly observed.[9, 11] There is also a wide variation between the timing of repeat injections in the literature between 6 to 12 months.[5] There have also been reports of reduced efficacy after repeated injections.[5, 10]

In the present study, we describe the outcome of patients undergoing repeated intravesical BoNTA injections in a “real-life” mixed population of patients with IDO and NDO including response rates, treatment intervals and complications.

Methods

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

Inclusion criteria

Patients with overactive bladder and urodyamically proven DO (IDO and NDO) who were refractory to anticholinergic medications and who were treated with intravesical BoNTA at Freeman Hospital, Newcastle Upon Tyne, UK, in the period 2004–2011 were identified from a departmental database. After approval from the local audit and research department, a retrospective review of their records was then carried out to identify intervals between treatments, discontinuation and complication rates.

Assessment and follow up

Patients usually had a 4-day voiding diary completed at baseline, and urodynamics (filling and voiding cystometrogram) were carried out at baseline before the first BoNTA injection. Patients were initially assessed 2–3 months (6 monthly thereafter) after treatment, and any symptomatic benefit was noted. Improvement was assessed on patients' subjective improvement in OAB symptoms and documented on a voiding diary. Patients with recurrent symptoms and who showed a good initial response to BoNTA underwent repeat urodynamics, and if this confirmed DO they were offered a second injection. For subsequent injections, urodynamics were not routinely carried out preoperatively. The time interval between successive treatments was at least 3 months. Early in the series, anticholinergic medications were offered to patients as the effects of the BoNTA began to wear off in an attempt to increase the inter-injection interval. However, later in the series, with increased experience, repeat BoNTA injections were given as soon as symptoms were returning to baseline.

Injection technique

The injection was carried out under general anaesthetic. For patients with IDO, BoNTA (Allergan, Irvine, CA, USA) 200 U was reconstituted with 20 mL of 0.9% saline. Intradetrusor injections were given with a rigid 21-Fr rigid cystoscope, a flexible injector sheath and a disposable inner needle with a 27-G tip. Injections were at 10 U/mL/site throughout the bladder (posterior, anterior, right lateral and left lateral walls), but sparing the trigone area (“Dasgupta” technique).[8] Patients with NDO received 300 U.

Data analysis

Student's t-test was used to compare intervals between treatments. P < 0.05 was taken to be statistically significant. Kaplan–Meier plots were used to analyze discontinuation rates over the study period.

Results

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

In the study period, 125 patients with NDO or IDO received repeated BoNTA injections. For the 125 patients having repeat injections, the median age was 53 years (range 19–88 years), the female-to-male ratio was 2.4:1, and median follow up was 38 months. The majority of patients (91%) were treated as a day case or overnight stay. A total of 667 injections were carried out, with 125 patients receiving two injections, 60 receiving three injections, 28 receiving four injections, 14 receiving five injections, three receiving six injections, three receiving seven injections and two receiving eight injections. Kaplan–Meier plots showed that the discontinuation rate at 60 months was 25% for those on multiple treatments, indicating that patients were statistically less likely to discontinue once established on repeated BoNTA injections (Fig. 1).

figure

Figure 1. Kaplan–Meier plot showing discontinuation rates after single (image) and multiple (image) BoNTA injections (log–rank P = 0.0001).

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Inter-injection interval was unchanged with repeated BoNTA treatments

The median length of time of BoNTA effect for the 667 injections was 14.4 months. The mean interval (±standard deviation) between the first and second injection (n = 125) was 17.6 months (±10.4), between the second and third (n = 60) was 15.7 ± 7.4 months, between the third and fourth (n = 28) was 15.4 ± 8.6 months, and between the fourth and subsequent injections (n = 22) was 11.6 ± 4.5 months. There was no statistically significant difference between the time interval between the first four injections (P = 0.24). Statistical analyses were not carried out in patients receiving more than four injections because of the small numbers (n = 22). Although there appears to be a reduction in inter-interval injection between the fourth and subsequent injections, analysis of the data showed that the 22 patients who had four or more injections had among the lowest inter-interval injections between the first four injections (mean 12.3 ± 6.6), which could explain the apparent drop.

There was no difference in inter-interval injection time between IDO and NDO

We examined BoNTA efficacy in patients with NDO (n = 29) and IDO (n = 96) who had repeated injections. Patients with NDO with confirmed detrusor overactivity on urodynamics in our cohort included spina bifida (28%), multiple sclerosis (24%), Parkinson's disease (17%), stroke (14%), other neurodegenerative disease (10%) and others (7%). The mean interval between the first and second injection was 18.0 ± 11 months in IDO and 16.4 ± 8 months in NDO (P = 0.31). There were no statistical differences in time intervals between further injections.

After repeat BoNTA injections, there was 18% UTI rate and 26% ISC rate

Of the 125 patients, 17 (14%) did not respond to repeated BoNTA injections and opted for alternative treatments – long-term catheterization (n = 6), neuromodulation (n = 6), augmentation cystoplasty (n = 2) and ileal conduit diversion (n = 3). The two main complications noted after repeated BoNTA were inadequate bladder emptying (postvoid residual more than 150 mL) and UTI (grade II Clavien classification). In this cohort, 32 patients (26%) developed de novo inadequate bladder emptying requiring ISC. All episodes of inadequate bladder emptying occurred within the first three BoNTA injections, with 91% occurring within the first two. Patients with NDO were more likely to require ISC than those with IDO (P = 0.03). A total of 23 patients (18%) developed recurrent UTI defined as at least two episodes in 6 months. There was no difference in recurrent UTI rates between NDO and IDO patients.

Discussion

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

In the present study, we describe our clinical experience in 125 patients managed by repeated BoNTA treatments (total of 667 injections) with IDO and NDO with a median follow up of 38 months. This is one of the largest single-center patient cohorts managed by repeated BoNTA in the literature. Of patients receiving repeat BoNTA injections, 88% had three or more to manage their symptoms. For patients having repeated injections, the median length of time of BoNTA effect for the 235 injections was 14.4 months. We found that the efficacy of BoNTA, as measured by the mean inter-injection interval, was unchanged between the first four injections. This is in contrast to some studies that have shown a reduction in efficacy after repeated injections.[5, 10, 12]

In regard to the safety and efficacy of BoNTA, data from case series showed significant improvements in overactive bladder symptoms and quality of life, despite heterogeneity in the methodology and case mix.[13-15] More recently, a Cochrane systematic review and meta-analysis showed that in both patients with IDO and NDO, the effect of BoNTA might last for a 9–12 months, and that patients receiving repeated doses do not seem to become refractory.[16] In our cohort, we confirm that IDO and NDO patients did not experience a reduction in efficacy after repeated injections.

BoNTA has been used as repeated injections, and studies have shown a significant improvement in symptoms and quality of life.[9, 10, 17] In a cohort study of 81 patients with repeated BoNTA injections, Khan et al. showed a significant improvement in quality of life, which was sustained after repeated injections.[16] They reported a median inter-injection interval of 12–15 months at up to five injections, and an ISC rate of 43%. More recently, Dowson et al. recently reported medium-term outcomes of 100 patients undergoing repeated BoNTA injections.[10] They reported an ISC rate of 35% after the first injection, bacteriuria rate of 21% and mean inter-injection interval of 322 days.

Other studies have compared the efficacy of BoNTA in IDO versus NDO after repeated injections. A recent study by Game et al. looked at 151 patients and showed that although improvement in health-related quality of life was greater and the duration of efficacy shorter in NDO patients after the first injection, there was no significant difference after subsequent injections.[14] They also noted that the mean inter-injection interval in IDO and in NDO patients was similar from the second injection onwards. In the present study, we found no difference in inter-injection time between IDO and NDO.

The main adverse BoNTA effects we noted were UTI (18%) and the need for de novo ISC (26%). Previous studies looking at repeated BoNTA injections have shown ISC rates between 8% and 43%, and the present study compares well with the published literature.[7-9, 18] Kessler et al. have previously shown that in women treated with BoNTA, ISC did not appear to affect quality of life.[19] We recorded an 18% UTI rate, which is in keeping with previous reported rates of 13% and 43%.[6-8, 18] Previous studies have confirmed significantly higher UTI rates in patients receiving BoNTA compared with a placebo. Kuo et al. studied risk factors for adverse effects in 217 patients receiving BoNTA, and found that male sex, baseline post-micturation of ≥100 mL and BoNTA dose >100 U were significant.[20]

There were some limitations as a result of the retrospective nature of the present study. We did not routinely use a quality of life questionnaire to assess patient response to treatment. In addition, it was difficult to investigate the concurrent use of anticholinergic medication, which could have increased the inter-injection interval. Our first inter-injection interval was higher (17.6 months) than typically reported in the literature and could be as a result of anticholinergic medications being offered to patients as the effects of the BoNTA began to wear off in an attempt to increase the inter-injection interval. However, later in the series, with increased experience, repeat BoNTA injections were given as soon as symptoms were returning to baseline. We note that towards the end of the study (where repeat BoNTA injections were given as soon as symptoms were returning to baseline), the mean inter-injection interval between the fourth and subsequent injection was 11.6 months, which is more in line with intravesical botulinum toxin efficacy seen in clinical trials. Furthermore, initially in our series, patients were routinely having repeat urodynamics before having repeat injections, which could also have increased the observed inter-injection interval. These observations could account for the decrease in inter-injection interval seen with each subsequent injection. Furthermore, we only had a small number of patients who received five or more injections (n = 22), which makes meaningful statistical analysis of inter-injection intervals for those patients difficult. The present study nevertheless describes typical outcomes in a “real-life” mixed population of patients with IDO and NDO receiving repeated BoNTA including response rates, treatment intervals and complications.

The present study confirms the safety and efficacy of repeated intravesical BoNTA injections as a management strategy in IDO and NDO patients. We have shown that the inter-injection interval remained unchanged up to five injections. We report a UTI rate of 18%, an ISC rate of 26% and a discontinuation rate of 25% at 60 months after repeated BoNTA injections.

References

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