- Email: [email protected]
What a Patient With Refractory Idiopathic Detrusor Overactivity Should Know About Botulinum Neurotoxin Type A Injection
What a Patient With Refractory Idiopathic Detrusor Overactivity Should Know About Botulinum Neurotoxin Type A Injection Shahid Khan,* Thomas M. Kessler,*,† Apostolos Apostolidis,‡ Vinay Kalsi, Jalesh Panicker, Alexander Roosen, Gwen Gonzales, Collete Haslam, Sohier Elneil,† Clare J. Fowler§,储 and Prokar Dasgupta‡ From the Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, University College London Hospitals National Health Service Foundation Trust (SK, TMK, AA, VK, JP, AR, GG, CH, SE, CJF, PD) and Department of Urology, Guys‘ and St. Thomas‘ Hospitals National Health Service Foundation Trust (PD), London, United Kingdom, and Second Department of Urology, Aristotle University of Thessaloniki, Papageorgiou Hospital (AA), Thessaloniki, Greece
Purpose: We documented the effects of intradetrusor injections of botulinum neurotoxin type A (Botox®) for refractory idiopathic detrusor overactivity so that prospective patients maybe properly informed about possible improvement in quality of life, the duration of interinjection intervals and the risk of clean intermittent self-catheterization. Materials and Methods: A total of 81 consecutive patients with refractory idiopathic detrusor overactivity treated with intradetrusor injections of 200 U botulinum neurotoxin type A at 20 sites per injection course were evaluated in this prospective, nonrandomized, open label cohort study. The primary outcome was changes in quality of life, as assessed by the short form of the Urogenital Distress Inventory and the Incontinence Impact Questionnaire before and after treatment. Secondary outcomes were the interinjection interval and the need for clean intermittent self-catheterization. Results: After intradetrusor botulinum neurotoxin type A injections there was significant improvement in quality of life, which was sustained after repeat injections. Mean Urogenital Distress Inventory and Incontinence Impact Questionnaire scores decreased from 56 to 26 and 59 to 21 after injection 1 in 81 patients, from 52 to 30 and 51 to 24 after injection 2 in 24, from 40 to 19 and 43 to 17 after injection 3 in 13, from 44 to 17 and 61 to 15 after injection 4 in 6 and from 51 to 17 and 63 to 14 after injection 5 in 4, respectively. The median interinjection interval was 15, 12, 14 and 13 months between injections 1 and 2, 2 and 3, 3 and 4, and 4 and 5, respectively. Considering a post-void residual urine of greater than 100 ml with lower urinary tract symptoms as the indication for clean intermittent self-catheterization, the overall clean intermittent self-catheterization rate after treatment was 43%. Conclusions: Intradetrusor botulinum neurotoxin type A injections for refractory idiopathic detrusor overactivity significantly improved quality of life. This effect was sustained after repeat injection. More than 2 of 5 patients with refractory idiopathic detrusor overactivity required clean intermittent self-catheterization after botulinum neurotoxin type A injections and all prospective patients should be informed about this. Key Words: urinary bladder, overactive; botulinum toxin type A; recurrence; catheterization; quality of life
0022-5347/09/1814-1773/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 181, 1773-1778, April 2009 Printed in U.S.A. DOI:10.1016/j.juro.2008.11.110
Abbreviations and Acronyms BoNT/A ⫽ botulinum neurotoxin type A CISC ⫽ clean intermittent selfcatheterization DO ⫽ detrusor overactivity IDO ⫽ idiopathic DO IIQ-7 ⫽ Incontinence Impact Questionnaire NDO ⫽ neurogenic DO OAB ⫽ overactive bladder PVR ⫽ post-void residual QOL ⫽ quality of life UDI-6 ⫽ Urogenital Distress Inventory Submitted for publication August 21, 2008. Study received ethics committee approval. Supported by unrestricted educational grants from Allergan Ltd. (AA, CJF, PD), grants from the Swiss National Science Foundation (TMK) and the German Research Foundation (AR), and the Department of Health National Institute for Health Research Biomedical Research Centres funding scheme. * Equal study contribution. † Financial interest and/or other relationship with Medtronic. ‡ Financial interest and/or other relationship with Allergan. § Correspondence: Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, University College London Hospitals National Health Service Foundation Trust, Queen Sq., London WC1N 3BG, United Kingdom (e-mail: [email protected]. 储 Financial interest and/or other relationship with Allergan and Medtronic.
www.jurology.com
1773
1774
REFRACTORY IDIOPATHIC DETRUSOR OVERACTIVITY AND BOTULINUM INJECTION
FOLLOWING the introduction of BoNT/A to treat incontinence in patients with NDO1 it started to be used for refractory IDO. The efficacy of intradetrusor BoNT/A injections for NDO is now well established and it has been confirmed by 2 randomized, placebo controlled trials.2,3 Similar effects were recently demonstrated in patients with IDO in randomized, placebo controlled studies. 4,5 However, unlike for NDO,6 –10 to our knowledge the effects of repeat intradetrusor BoNT/A injections for IDO have not yet been reported. Clinical efficacy and potential adverse events are of particular importance when counseling patients before BoNT/A treatment. The duration of the beneficial effects of intradetrusor BoNT/A for nonneurogenic OAB has not been fully determined but several single injection studies have shown symptomatic and urodynamic improvements lasting at least 6 months.11,12 An increase in PVR and the potential need for CISC are the most common side effects but the reported rates vary considerably from 3% to 50%.4,5,11,13,14 Recommendations on the use of BoNT/A for lower urinary tract dysfunction, including IDO, were recently published in a European consensus report.15 We document the effects of repeat intradetrusor BoNT/A (200 U Botox) for refractory IDO so that prospective patients can be properly informed about a possible improvement in QOL, the duration of interinjection intervals and the risk of CISC.
PATIENTS AND METHODS Patients We report a prospective, nonrandomized, open label cohort study in patients with refractory IDO treated at a single center since 2002. Study inclusion criteria were urodynamically proven DO in patients with nonneurological OAB who had failed to respond to behavioral treatment and pharmacotherapy with more than 1 antimuscarinic for at least 3 months, no previous surgery for OAB and willingness to perform CISC after BoNT/A, if necessary. Urodynamic studies were performed according to Good Urodynamic Practices. Patients who had neurological disease, were younger than 18 years old, were receiving oral anticoagulants/antiplatelet agents, were pregnant and were lactating were excluded from analysis. Urinary tract infections were treated before BoNT/A injections according to the antibiotic sensitivity pattern. All patients provided written informed consent before treatment. This study had the approval of the local ethics committee. All methods, definitions and units conform to the standards recommended by the International Continence Society.
0427 sheath of the 2 mm diameter working channel of a flexible cystoscope (Olympus KeyMed, Southend-on-Sea, United Kingdom). BoNT/A (200 U Botox), diluted 1:10 with 0.9% saline, was injected at 20 sites in the detrusor, sparing the trigone. The bladder was emptied after the procedure. Patients were discharged home without an indwelling catheter on 100 mg trimethoprim twice daily for 3 days.
Followup Assessment Followup of bladder diary parameters and urodynamic investigations 4 and 16 weeks after BoNT/A injections were performed in the early study period until July 2005. They have been reported previously.12 QOL was assessed using the short forms of 2 validated condition specific QOL questionnaires, UDI-6 and IIQ-7,17 before and 4 weeks after BoNT/A injections. The mean value of all UDI-6 and IIQ-7 items completed (item range 0 to 3) was calculated and multiplied by 331⁄3 to achieve a range of 0 to 100 with higher scores indicating more bother and impact, respectively.17 An assessment of PVR and urinalysis was done 2 weeks after injections. Because there are no generally accepted criteria for initiating CISC, PVR greater than 100 ml with lower urinary tract symptoms was considered the indication for CISC based on our clinical experience. Urinary tract infections were treated according to antibiotic sensitivity but patients were not routinely prescribed prophylactic antibiotics if they were performing CISC. Patients were instructed to decrease or stop antimuscarinics after OAB symptoms improved and restart medicines when they experienced a decrease of the BoNT/A effect. Patients were given written advice to report back after OAB symptoms recurred. When they did not contact the department, every effort was made to communicate with them by telephone or mail. Patients with recurrent OAB symptoms were scheduled for followup urodynamic investigation and, if urodynamics demonstrated DO, repeat BoNT/A injections were arranged. Before repeat injection the QOL assessment was repeated. There was no minimum time point before repeat injection was considered.
Outcome Measures Primary outcome measures were changes in QOL, as assessed by UDI-6 and IIQ-7 before and 4 weeks after BoNT/A injection. Secondary outcomes were interinjection intervals and the need for CISC.
Statistical Analysis Normally distributed data are presented as the mean ⫾ SD and skewed data are presented as the median and IQR. To compare related samples the paired t test was used for normally distributed data and the Wilcoxon signed rank test was used for skewed data. BoNT/A interinjection intervals and CISC rates after different injection courses were compared by applying the Kruskal-Wallis 1-way ANOVA and Fisher exact test, respectively, with p ⬍0.05 considered significant. Statistical analysis was performed using SPSS® 16.0.
Injection Technique Intradetrusor BoNT/A injections were performed on an outpatient basis using the previously described minimally invasive technique.16 After intraurethral instillation of 20 ml 2% lidocaine gel and exposure for 2 to 5 minutes a 27 gauge 4 mm MAJ-656 needle was passed through the NM-101C-
RESULTS The study included 81 consecutive patients with refractory IDO in whom a total of 129 intradetrusor injections were performed. Mean ⫾ SD patient age
REFRACTORY IDIOPATHIC DETRUSOR OVERACTIVITY AND BOTULINUM INJECTION
was 51 ⫾ 16 years (range 18 to 80) and mean followup was 2.8 ⫾ 1.8 years (range 0.3 to 5.7). The table lists baseline patient characteristics before the first BoNT/A treatment. Of the 81 patients 56 (70%) were female. Statistically only end filling pressure was different between the genders, although there was a trend toward differences in other baseline characteristics (table 1). At the time of the first BoNT/A injection 77 of 81 patients (95%) were on antimuscarinics. The remaining 5% of patients found that side effects were intolerable. Of the 81 patients treated with BoNT/A 25 (31%) reported that they did not yet need re-treatment because OAB symptoms had not returned. However, 17 of these 25 patients (68%) had a followup of less than 14 months. In 46 of the 81 patients (57%) recurrent OAB symptoms was reported and DO was demonstrated urodynamically. Of these patients 40 of 81 (49%) needed re-injection, of whom 24 received re-injection, 14 were scheduled for re-injection and 2 received re-injection elsewhere. However, 6 of 81 patients (8%) refused repeat injection for personal reasons (4) and due to the need for CISC (2). Eight of the 81 patients (10%) failed to respond to all attempts to contact them and 2 (2%) died of causes unrelated to IDO. Of patients already re-injected 24, 13, 6, 4 and 1 returned for intradetrusor BoNT/A injections 2 to 6, respectively. The overall median interinjection interval was 14 months (IQR 11–17). The median interinjection interval between courses 1 and 2, 2 and 3, 3 and 4, and 4 and 5 was 15 (IQR 11–27), 12 (IQR 10 –15), 14 (IQR 7–19) and 13 months (IQR 9 –15), respectively. There was no statistically significant difference between the interinjection intervals of the consecutive injection courses (p ⫽ 0.4, fig. 1). After BoNT/A injection there was a significant improvement in QOL, which was sustained after repeat injections (fig. 2). Mean UDI-6 and IIQ-7 scores decreased from 56 to 26 and 59 to 21 after injection 1 in 81 patients (each p ⬍0.001), from 52 to 30 and 51 to 24 after injection 2 in 24 (each p ⬍0.001), from 40 to 19 and 43 to 17 after injection 3 in 13 (p ⬍0.001 and 0.02), from 44 to 17 and 61 to 15 after injection 4 (no p value available because there were 6 patients) and from 51 to 17 and 63 to 14 Baseline patient characteristics before first botulinum neurotoxin type A injection
No. pts Age Followup (yrs) Max cystometric capacity (ml) End filling pressure (cm H2O) UDI-6 IIQ-7
Mean ⫾ SD Women
Mean ⫾ SD Men
p Value
56 50 ⫾ 15 2.6 ⫾ 1.7 210 ⫾ 100 28 ⫾ 16 58 ⫾ 18 60 ⫾ 28
25 54 ⫾ 18 3.2 ⫾ 2 185 ⫾ 85 42 ⫾ 16 52 ⫾ 17 50 ⫾ 29
0.3 0.2 0.3 0.002 0.3 0.2
1775
Figure 1. Interinjection intervals of consecutive intradetrusor BoNT/A injection courses for refractory IDO were not significantly different.
after injection 5 (no p value available because there were 4 patients), respectively. Before BoNT/A injections all patients voided spontaneously. After BoNT/A treatment 31 of 81 (38%), 11 of 24 (46%), 5 of 13 (39%) and 3 of 6 (50%) patients required CISC after injections 1 to 4, respectively (fig. 3). CISC rates did not differ significantly between injection courses (p ⫽ 0.87). The overall CISC rate was 43% (35 of 81 patients). After a patient required CISC after BoNT/A injections, it was always needed after subsequent injections. CISC became necessary after injection 2 in 3 patients and after injection 4 in 1 but it was not required after the preceding injections. All patients who needed catheterization managed CISC and none required an indwelling catheter. After the first BoNT/A injection a comparison of QOL in 31 patients performing CISC and in 50 who did not revealed no significant difference on UDI-6 and IIQ-7 (p ⫽ 0.9 and 0.4, respectively). In addition, there were no significant differences between females and males regarding QOL on UDI-6 and IIQ-7 (p ⫽ 0.2 and 0.5, respectively), the CISC rate (p ⫽ 0.6) and urinary tract infection (p ⫽ 0.09). Antibiotic treatment for lower urinary tract infection was required in 19 patients (15%) after a total of 129 injection treatments. No other BoNT/A injection related adverse events were reported.
DISCUSSION To our knowledge this is the first study documenting the effects of repeat intradetrusor BoNT/A for refractory IDO. What we found is significant improvement in QOL after BoNT/A injection, which was sustained and reproducible after repeat injections.
1776
REFRACTORY IDIOPATHIC DETRUSOR OVERACTIVITY AND BOTULINUM INJECTION
UDI-6 Scores
A
80 60 40 20
Pr e B P o oN T/ st A B oN 1 Pr T/ e A B 1 o Po N T/ st A B oN 2 Pr T/ e A B 2 o Po N T/ st A B oN 3 Pr T/ e A B 3 Po oN T/ st A B oN 4 Pr T/ e A B 4 o Po N T/ st A B oN 5 T/ A 5
0
p<0.001
p<0.001
p<0.001
n=6, no p
n=4, no p
IIQ-7 Scores
B
80 60 40 20
Pr
e
B
Po oN T/ st A B oN 1 Pr T/ e A B 1 o Po N T/ st A B oN 2 Pr T/ e A B 2 Po oN T st /A B oN 3 Pr T/ e A B 3 Po oN T/ st A B oN 4 Pr T/ e A B 4 o Po N T/ st A B oN 5 T/ A 5
0
p<0.001
p<0.001
p=0.02
n=6, no p
n=4, no p
Figure 2. Sustained and significant improvement in QOL after repeat intradetrusor BoNT/A injections for refractory IDO, as assessed by UDI-6 (A) and IIQ-7 (B).
REFRACTORY IDIOPATHIC DETRUSOR OVERACTIVITY AND BOTULINUM INJECTION
Figure 3. Patients requiring CISC vs those voiding normally after intradetrusor BoNT/A injections for refractory IDO.
Few previous studies in patients with nonneurogenic OAB have shown significant amelioration in QOL after a single BoNT/A injection.4,5,18 Our findings in patients with IDO are also in line with the results of repeat injections in patients with NDO.9,10 Few other groups to date have examined the actual duration of effect and time of symptomatic recurrence in patients with IDO after BoNT/A treatment. In our study 57% of patients experienced recurrent OAB symptoms and 49% requested repeat BoNT/A injections. Of patients with a followup of more than 14 months 10% did not report recurrent OAB symptoms. This compares with the findings of Kuschel et al, who reported that 18% of patients with refractory IDO who received intradetrusor BoNT/A injections did not require further treatment.19 However, it is at variance with the findings of Schmid et al, who observed a recurrence rate of only 28% of patients at a mean of 12 months, implying that the remaining 72% were cured and did not need further treatment during a followup of 6.5 years.14 This may be due to the differing inclusion criteria of urodynamic evidence for DO in the series by Kuschel et al19 and our study. The interinjection interval in NDO studies is 9 to 13 months.6,7,10 Although a direct comparison cannot be made with NDO studies since a different dose of BoNT/A was used, our results are similar to those of Del Popolo et al, who used various doses of Dysport®.10 To our knowledge the explanation for why some patients seem to be cured after BoNT/A injections is unknown. It could be because they cope better when symptoms return, or because DO is permanently eliminated. Since to our knowledge the fundamental pathogenesis of IDO remains to be elucidated, hypotheses about the possible long-term BoNT/A effect are inevitably speculative but it is a fascinating observation that merits further investigation.
1777
There are no generally accepted predictive factors for the need for CISC after BoNT/A injection. However, reported CISC rates seem to depend on the etiology of DO, the injected dose and the definition of significant PVR. In patients with NDO secondary to multiple sclerosis we found that the CISC rate was almost 100% using 300 U Botox9 but it seems likely that the neural mechanism for voiding is affected in this group. When injecting the same dose in patients with IDO, Kessler et al found a de novo CISC rate of 50%.13 At a smaller dose of 200 U Botox the 2 placebo controlled trials in patients with IDO showed that CISC was needed in 38% and 43%, respectively.4,5 This is similar to our study, in which 38% of our patients were introduced to CISC after injection 1 and remained comparable after repeat injections. In contrast, a CISC rate of 3% to 4% was observed by Schmid et al using 100 U Botox in patients with refractory OAB.11,14 Different PVR cutoffs for initiating CISC add to the varying CISC rate among published series. In the current study a PVR of greater than 100 ml with lower urinary tract symptoms was considered an indication for CISC, whereas others have accepted a higher PVR of up to 150 to 200 ml before performing CISC.4,5,11,13 Although it remains to be established which dose has the best effect with the lowest CISC rate, depending on the severity of preexisting symptoms dose modulation may be appropriate. Since the ongoing randomized, placebo controlled, dose-response study NCT00168454 may answer these questions, we await the results to guide our decision on dose modulation. Remarkably the need to perform CISC had no effect on our patient QOL after BoNT/A injection. This could be because we did not use a CISC specific QOL questionnaire and/or the number of patients was too small. Alternatively the fact that we stipulated that willingness to perform CISC was an essential inclusion criterion meant that we properly managed patient expectations. This was certainly the case when a highly significant improvement in QOL was achieved despite an almost 100% CISC rate after intradetrusor BoNT/A injections for NDO in patients with multiple sclerosis.9 Moreover, most patients perceive CISC as an easy and painless procedure that does not interfere with daily activity.20 Although to our knowledge we document for the first time the effects of repeat intradetrusor BoNT/A for refractory IDO, we are aware of the limitations in our study. Results are based on a single center study with many patients treated for the first time and a decreased number returning for repeat injections. Our study was neither randomized nor placebo controlled, but rather prospective, open labeled and representative of daily clinical experience. In contrast to other studies, our patients did not return at fixed intervals, but reported back only when OAB symptoms recurred. QOL assessment was performed 4 weeks after treatment but not serially. The period during which patients performed CISC was not assessed in the current
1778
REFRACTORY IDIOPATHIC DETRUSOR OVERACTIVITY AND BOTULINUM INJECTION
study, although it is part of an ongoing evaluation. In addition, we advised patients to decrease or stop antimuscarinics after an improvement in OAB symptoms following BoNT/A injection and restart medication when symptoms recurred. This may have resulted in some delay in reevaluation and overestimation of the interinjection interval, and it may have had a confounding effect on the QOL outcome. However, it is not known whether concurrent use of antimuscarinics and BoNT/A treatment have a synergistic effect. This needs further investigation.
peared to be cured. After intradetrusor BoNT/A treatment more than 2 of 5 patients with refractory IDO may need to perform CISC. Importantly if CISC becomes necessary after BoNT/A injection, it seems to be needed after all subsequent treatments. Moreover, CISC may become necessary after later injections even if it was not initially required. The postinjection urinary tract infection rate was 15%. Therefore, all patients should be informed of the potential need to perform CISC after BoNT/A injection and the willingness to do so should be a prerequisite for this still unlicensed, off label treatment.
CONCLUSIONS Intradetrusor BoNT/A injections for refractory IDO improve QOL significantly and this effect is sustained after repeat injections. Of patients with a followup of greater than 14 months 10% did not experience recurrent OAB symptoms and they ap-
ACKNOWLEDGMENTS This study was performed at University College London Hospitals/University College of London. Allergan Ltd., United Kingdom provided Botox for the early period of this study.
REFERENCES 1. Schurch B, Stohrer M, Kramer G, Schmid DM, Gaul G and Hauri D: Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 2000; 164: 692. 2. Schurch B, de Seze M, Denys P, Chartier-Kastler E, Haab F, Everaert K et al: Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005; 174: 196. 3. Ehren I, Volz D, Farrelly E, Berglund L, Brundin L, Hultling C et al: Efficacy and impact of botulinum toxin A on quality of life in patients with neurogenic detrusor overactivity: a randomised, placebo-controlled, double-blind study. Scand J Urol Nephrol 2007; 41: 335. 4. Sahai A, Khan MS and Dasgupta P: Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial. J Urol 2007; 177: 2231. 5. Brubaker L, Richter HE, Visco A, Mahajan S, Nygaard I, Braun TM et al: Refractory idiopathic urge urinary incontinence and botulinum A injection. J Urol 2008; 180: 217. 6. Grosse J, Kramer G and Stohrer M: Success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol 2005; 47: 653. 7. Karsenty G, Reitz A, Lindemann G, Boy S and Schurch B: Persistence of therapeutic effect after repeated injections of botulinum toxin type A to treat incontinence due to neurogenic detrusor overactivity. Urology 2006; 68: 1193.
8. Reitz A, Denys P, Fermanian C, Schurch B, Comperat E and Chartier-Kastler E: Do repeat intradetrusor botulinum toxin type a injections yield valuable results? Clinical and urodynamic results after five injections in patients with neurogenic detrusor overactivity. Eur Urol 2007; 52: 1729.
into the detrusor muscle for overactive bladder refractory to anticholinergics. Eur Urol, suppl., 2008; 7: 212, abstract 568.
9. Kalsi V, Gonzales G, Popat R, Apostolidis A, Elneil S, Dasgupta P et al: Botulinum injections for the treatment of bladder symptoms of multiple sclerosis. Ann Neurol 2007; 62: 452.
15. Apostolidis A, Dasgupta P, Denys P, Elneil S, Fowler CJ, Giannantoni A et al: Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: A European consensus report. Eur Urol, Epub ahead of print September 17, 2008.
10. Del Popolo G, Filocamo MT, Li Marzi V, Macchiarella A, Cecconi F, Lombardi G et al: Neurogenic detrusor overactivity treated with English botulinum toxin a: 8-year experience of one single centre. Eur Urol 2008; 53: 1013.
16. Harper M, Popat RB, Dasgupta R, Fowler CJ and Dasgupta P: A minimally invasive technique for outpatient local anaesthetic administration of intradetrusor botulinum toxin in intractable detrusor overactivity. BJU Int 2003; 92: 325.
11. Schmid DM, Sauermann P, Werner M, Schuessler B, Blick N, Muentener M et al: Experience with 100 cases treated with botulinum-A toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome refractory to anticholinergics. J Urol 2006; 176: 177.
17. Uebersax JS, Wyman JF, Shumaker SA, McClish DK and Fantl JA: Short forms to assess life quality and symptom distress for urinary incontinence in women: the Incontinence Impact Questionnaire and the Urogenital Distress Inventory. Continence Program for Women Research Group. Neurourol Urodyn 1995; 14: 131.
12. Kalsi V, Popat RB, Apostolidis A, Kavia R, Odeyemi IA, Dakin HA et al: 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. Eur Urol 2006; 49: 519. 13. Kessler TM, Danuser H, Schumacher M, Studer UE and Burkhard FC: Botulinum A toxin injections into the detrusor: an effective treatment in idiopathic and neurogenic detrusor overactivity? Neurourol Urodyn 2005; 24: 231. 14. Schmid DM, Roy-Guggenbuehl SG, Werner MW, Perruchini DP, Sulser TS and Schurch B: The Zurich experiences including 6 year results of 200 cases treated with botulinum-A toxin injections
18. Kalsi V, Apostolidis A, Popat R, Gonzales G, Fowler CJ and Dasgupta P: Quality of life changes in patients with neurogenic versus idiopathic detrusor overactivity after intradetrusor injections of botulinum neurotoxin type A and correlations with lower urinary tract symptoms and urodynamic changes. Eur Urol 2006; 49: 528. 19. Kuschel S, Werner M, Schmid DM, Faust E and Schuessler B: Botulinum toxin-A for idiopathic overactivity of the vesical detrusor: a 2-year follow-up. Int Urogynecol J Pelvic Floor Dysfunct 2008; 19: 905. 20. Kessler TM, Ryu G and Burkhard FC: Clean intermittent self-catheterization: a burden for the patient? Neurourol Urodyn 2009; 28: 18.
Purpose: We documented the effects of intradetrusor injections of botulinum neurotoxin type A (Botox®) for refractory idiopathic detrusor overactivity so that prospective patients maybe properly informed about possible improvement in quality of life, the duration of interinjection intervals and the risk of clean intermittent self-catheterization. Materials and Methods: A total of 81 consecutive patients with refractory idiopathic detrusor overactivity treated with intradetrusor injections of 200 U botulinum neurotoxin type A at 20 sites per injection course were evaluated in this prospective, nonrandomized, open label cohort study. The primary outcome was changes in quality of life, as assessed by the short form of the Urogenital Distress Inventory and the Incontinence Impact Questionnaire before and after treatment. Secondary outcomes were the interinjection interval and the need for clean intermittent self-catheterization. Results: After intradetrusor botulinum neurotoxin type A injections there was significant improvement in quality of life, which was sustained after repeat injections. Mean Urogenital Distress Inventory and Incontinence Impact Questionnaire scores decreased from 56 to 26 and 59 to 21 after injection 1 in 81 patients, from 52 to 30 and 51 to 24 after injection 2 in 24, from 40 to 19 and 43 to 17 after injection 3 in 13, from 44 to 17 and 61 to 15 after injection 4 in 6 and from 51 to 17 and 63 to 14 after injection 5 in 4, respectively. The median interinjection interval was 15, 12, 14 and 13 months between injections 1 and 2, 2 and 3, 3 and 4, and 4 and 5, respectively. Considering a post-void residual urine of greater than 100 ml with lower urinary tract symptoms as the indication for clean intermittent self-catheterization, the overall clean intermittent self-catheterization rate after treatment was 43%. Conclusions: Intradetrusor botulinum neurotoxin type A injections for refractory idiopathic detrusor overactivity significantly improved quality of life. This effect was sustained after repeat injection. More than 2 of 5 patients with refractory idiopathic detrusor overactivity required clean intermittent self-catheterization after botulinum neurotoxin type A injections and all prospective patients should be informed about this. Key Words: urinary bladder, overactive; botulinum toxin type A; recurrence; catheterization; quality of life
0022-5347/09/1814-1773/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 181, 1773-1778, April 2009 Printed in U.S.A. DOI:10.1016/j.juro.2008.11.110
Abbreviations and Acronyms BoNT/A ⫽ botulinum neurotoxin type A CISC ⫽ clean intermittent selfcatheterization DO ⫽ detrusor overactivity IDO ⫽ idiopathic DO IIQ-7 ⫽ Incontinence Impact Questionnaire NDO ⫽ neurogenic DO OAB ⫽ overactive bladder PVR ⫽ post-void residual QOL ⫽ quality of life UDI-6 ⫽ Urogenital Distress Inventory Submitted for publication August 21, 2008. Study received ethics committee approval. Supported by unrestricted educational grants from Allergan Ltd. (AA, CJF, PD), grants from the Swiss National Science Foundation (TMK) and the German Research Foundation (AR), and the Department of Health National Institute for Health Research Biomedical Research Centres funding scheme. * Equal study contribution. † Financial interest and/or other relationship with Medtronic. ‡ Financial interest and/or other relationship with Allergan. § Correspondence: Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, University College London Hospitals National Health Service Foundation Trust, Queen Sq., London WC1N 3BG, United Kingdom (e-mail: [email protected]. 储 Financial interest and/or other relationship with Allergan and Medtronic.
www.jurology.com
1773
1774
REFRACTORY IDIOPATHIC DETRUSOR OVERACTIVITY AND BOTULINUM INJECTION
FOLLOWING the introduction of BoNT/A to treat incontinence in patients with NDO1 it started to be used for refractory IDO. The efficacy of intradetrusor BoNT/A injections for NDO is now well established and it has been confirmed by 2 randomized, placebo controlled trials.2,3 Similar effects were recently demonstrated in patients with IDO in randomized, placebo controlled studies. 4,5 However, unlike for NDO,6 –10 to our knowledge the effects of repeat intradetrusor BoNT/A injections for IDO have not yet been reported. Clinical efficacy and potential adverse events are of particular importance when counseling patients before BoNT/A treatment. The duration of the beneficial effects of intradetrusor BoNT/A for nonneurogenic OAB has not been fully determined but several single injection studies have shown symptomatic and urodynamic improvements lasting at least 6 months.11,12 An increase in PVR and the potential need for CISC are the most common side effects but the reported rates vary considerably from 3% to 50%.4,5,11,13,14 Recommendations on the use of BoNT/A for lower urinary tract dysfunction, including IDO, were recently published in a European consensus report.15 We document the effects of repeat intradetrusor BoNT/A (200 U Botox) for refractory IDO so that prospective patients can be properly informed about a possible improvement in QOL, the duration of interinjection intervals and the risk of CISC.
PATIENTS AND METHODS Patients We report a prospective, nonrandomized, open label cohort study in patients with refractory IDO treated at a single center since 2002. Study inclusion criteria were urodynamically proven DO in patients with nonneurological OAB who had failed to respond to behavioral treatment and pharmacotherapy with more than 1 antimuscarinic for at least 3 months, no previous surgery for OAB and willingness to perform CISC after BoNT/A, if necessary. Urodynamic studies were performed according to Good Urodynamic Practices. Patients who had neurological disease, were younger than 18 years old, were receiving oral anticoagulants/antiplatelet agents, were pregnant and were lactating were excluded from analysis. Urinary tract infections were treated before BoNT/A injections according to the antibiotic sensitivity pattern. All patients provided written informed consent before treatment. This study had the approval of the local ethics committee. All methods, definitions and units conform to the standards recommended by the International Continence Society.
0427 sheath of the 2 mm diameter working channel of a flexible cystoscope (Olympus KeyMed, Southend-on-Sea, United Kingdom). BoNT/A (200 U Botox), diluted 1:10 with 0.9% saline, was injected at 20 sites in the detrusor, sparing the trigone. The bladder was emptied after the procedure. Patients were discharged home without an indwelling catheter on 100 mg trimethoprim twice daily for 3 days.
Followup Assessment Followup of bladder diary parameters and urodynamic investigations 4 and 16 weeks after BoNT/A injections were performed in the early study period until July 2005. They have been reported previously.12 QOL was assessed using the short forms of 2 validated condition specific QOL questionnaires, UDI-6 and IIQ-7,17 before and 4 weeks after BoNT/A injections. The mean value of all UDI-6 and IIQ-7 items completed (item range 0 to 3) was calculated and multiplied by 331⁄3 to achieve a range of 0 to 100 with higher scores indicating more bother and impact, respectively.17 An assessment of PVR and urinalysis was done 2 weeks after injections. Because there are no generally accepted criteria for initiating CISC, PVR greater than 100 ml with lower urinary tract symptoms was considered the indication for CISC based on our clinical experience. Urinary tract infections were treated according to antibiotic sensitivity but patients were not routinely prescribed prophylactic antibiotics if they were performing CISC. Patients were instructed to decrease or stop antimuscarinics after OAB symptoms improved and restart medicines when they experienced a decrease of the BoNT/A effect. Patients were given written advice to report back after OAB symptoms recurred. When they did not contact the department, every effort was made to communicate with them by telephone or mail. Patients with recurrent OAB symptoms were scheduled for followup urodynamic investigation and, if urodynamics demonstrated DO, repeat BoNT/A injections were arranged. Before repeat injection the QOL assessment was repeated. There was no minimum time point before repeat injection was considered.
Outcome Measures Primary outcome measures were changes in QOL, as assessed by UDI-6 and IIQ-7 before and 4 weeks after BoNT/A injection. Secondary outcomes were interinjection intervals and the need for CISC.
Statistical Analysis Normally distributed data are presented as the mean ⫾ SD and skewed data are presented as the median and IQR. To compare related samples the paired t test was used for normally distributed data and the Wilcoxon signed rank test was used for skewed data. BoNT/A interinjection intervals and CISC rates after different injection courses were compared by applying the Kruskal-Wallis 1-way ANOVA and Fisher exact test, respectively, with p ⬍0.05 considered significant. Statistical analysis was performed using SPSS® 16.0.
Injection Technique Intradetrusor BoNT/A injections were performed on an outpatient basis using the previously described minimally invasive technique.16 After intraurethral instillation of 20 ml 2% lidocaine gel and exposure for 2 to 5 minutes a 27 gauge 4 mm MAJ-656 needle was passed through the NM-101C-
RESULTS The study included 81 consecutive patients with refractory IDO in whom a total of 129 intradetrusor injections were performed. Mean ⫾ SD patient age
REFRACTORY IDIOPATHIC DETRUSOR OVERACTIVITY AND BOTULINUM INJECTION
was 51 ⫾ 16 years (range 18 to 80) and mean followup was 2.8 ⫾ 1.8 years (range 0.3 to 5.7). The table lists baseline patient characteristics before the first BoNT/A treatment. Of the 81 patients 56 (70%) were female. Statistically only end filling pressure was different between the genders, although there was a trend toward differences in other baseline characteristics (table 1). At the time of the first BoNT/A injection 77 of 81 patients (95%) were on antimuscarinics. The remaining 5% of patients found that side effects were intolerable. Of the 81 patients treated with BoNT/A 25 (31%) reported that they did not yet need re-treatment because OAB symptoms had not returned. However, 17 of these 25 patients (68%) had a followup of less than 14 months. In 46 of the 81 patients (57%) recurrent OAB symptoms was reported and DO was demonstrated urodynamically. Of these patients 40 of 81 (49%) needed re-injection, of whom 24 received re-injection, 14 were scheduled for re-injection and 2 received re-injection elsewhere. However, 6 of 81 patients (8%) refused repeat injection for personal reasons (4) and due to the need for CISC (2). Eight of the 81 patients (10%) failed to respond to all attempts to contact them and 2 (2%) died of causes unrelated to IDO. Of patients already re-injected 24, 13, 6, 4 and 1 returned for intradetrusor BoNT/A injections 2 to 6, respectively. The overall median interinjection interval was 14 months (IQR 11–17). The median interinjection interval between courses 1 and 2, 2 and 3, 3 and 4, and 4 and 5 was 15 (IQR 11–27), 12 (IQR 10 –15), 14 (IQR 7–19) and 13 months (IQR 9 –15), respectively. There was no statistically significant difference between the interinjection intervals of the consecutive injection courses (p ⫽ 0.4, fig. 1). After BoNT/A injection there was a significant improvement in QOL, which was sustained after repeat injections (fig. 2). Mean UDI-6 and IIQ-7 scores decreased from 56 to 26 and 59 to 21 after injection 1 in 81 patients (each p ⬍0.001), from 52 to 30 and 51 to 24 after injection 2 in 24 (each p ⬍0.001), from 40 to 19 and 43 to 17 after injection 3 in 13 (p ⬍0.001 and 0.02), from 44 to 17 and 61 to 15 after injection 4 (no p value available because there were 6 patients) and from 51 to 17 and 63 to 14 Baseline patient characteristics before first botulinum neurotoxin type A injection
No. pts Age Followup (yrs) Max cystometric capacity (ml) End filling pressure (cm H2O) UDI-6 IIQ-7
Mean ⫾ SD Women
Mean ⫾ SD Men
p Value
56 50 ⫾ 15 2.6 ⫾ 1.7 210 ⫾ 100 28 ⫾ 16 58 ⫾ 18 60 ⫾ 28
25 54 ⫾ 18 3.2 ⫾ 2 185 ⫾ 85 42 ⫾ 16 52 ⫾ 17 50 ⫾ 29
0.3 0.2 0.3 0.002 0.3 0.2
1775
Figure 1. Interinjection intervals of consecutive intradetrusor BoNT/A injection courses for refractory IDO were not significantly different.
after injection 5 (no p value available because there were 4 patients), respectively. Before BoNT/A injections all patients voided spontaneously. After BoNT/A treatment 31 of 81 (38%), 11 of 24 (46%), 5 of 13 (39%) and 3 of 6 (50%) patients required CISC after injections 1 to 4, respectively (fig. 3). CISC rates did not differ significantly between injection courses (p ⫽ 0.87). The overall CISC rate was 43% (35 of 81 patients). After a patient required CISC after BoNT/A injections, it was always needed after subsequent injections. CISC became necessary after injection 2 in 3 patients and after injection 4 in 1 but it was not required after the preceding injections. All patients who needed catheterization managed CISC and none required an indwelling catheter. After the first BoNT/A injection a comparison of QOL in 31 patients performing CISC and in 50 who did not revealed no significant difference on UDI-6 and IIQ-7 (p ⫽ 0.9 and 0.4, respectively). In addition, there were no significant differences between females and males regarding QOL on UDI-6 and IIQ-7 (p ⫽ 0.2 and 0.5, respectively), the CISC rate (p ⫽ 0.6) and urinary tract infection (p ⫽ 0.09). Antibiotic treatment for lower urinary tract infection was required in 19 patients (15%) after a total of 129 injection treatments. No other BoNT/A injection related adverse events were reported.
DISCUSSION To our knowledge this is the first study documenting the effects of repeat intradetrusor BoNT/A for refractory IDO. What we found is significant improvement in QOL after BoNT/A injection, which was sustained and reproducible after repeat injections.
1776
REFRACTORY IDIOPATHIC DETRUSOR OVERACTIVITY AND BOTULINUM INJECTION
UDI-6 Scores
A
80 60 40 20
Pr e B P o oN T/ st A B oN 1 Pr T/ e A B 1 o Po N T/ st A B oN 2 Pr T/ e A B 2 o Po N T/ st A B oN 3 Pr T/ e A B 3 Po oN T/ st A B oN 4 Pr T/ e A B 4 o Po N T/ st A B oN 5 T/ A 5
0
p<0.001
p<0.001
p<0.001
n=6, no p
n=4, no p
IIQ-7 Scores
B
80 60 40 20
Pr
e
B
Po oN T/ st A B oN 1 Pr T/ e A B 1 o Po N T/ st A B oN 2 Pr T/ e A B 2 Po oN T st /A B oN 3 Pr T/ e A B 3 Po oN T/ st A B oN 4 Pr T/ e A B 4 o Po N T/ st A B oN 5 T/ A 5
0
p<0.001
p<0.001
p=0.02
n=6, no p
n=4, no p
Figure 2. Sustained and significant improvement in QOL after repeat intradetrusor BoNT/A injections for refractory IDO, as assessed by UDI-6 (A) and IIQ-7 (B).
REFRACTORY IDIOPATHIC DETRUSOR OVERACTIVITY AND BOTULINUM INJECTION
Figure 3. Patients requiring CISC vs those voiding normally after intradetrusor BoNT/A injections for refractory IDO.
Few previous studies in patients with nonneurogenic OAB have shown significant amelioration in QOL after a single BoNT/A injection.4,5,18 Our findings in patients with IDO are also in line with the results of repeat injections in patients with NDO.9,10 Few other groups to date have examined the actual duration of effect and time of symptomatic recurrence in patients with IDO after BoNT/A treatment. In our study 57% of patients experienced recurrent OAB symptoms and 49% requested repeat BoNT/A injections. Of patients with a followup of more than 14 months 10% did not report recurrent OAB symptoms. This compares with the findings of Kuschel et al, who reported that 18% of patients with refractory IDO who received intradetrusor BoNT/A injections did not require further treatment.19 However, it is at variance with the findings of Schmid et al, who observed a recurrence rate of only 28% of patients at a mean of 12 months, implying that the remaining 72% were cured and did not need further treatment during a followup of 6.5 years.14 This may be due to the differing inclusion criteria of urodynamic evidence for DO in the series by Kuschel et al19 and our study. The interinjection interval in NDO studies is 9 to 13 months.6,7,10 Although a direct comparison cannot be made with NDO studies since a different dose of BoNT/A was used, our results are similar to those of Del Popolo et al, who used various doses of Dysport®.10 To our knowledge the explanation for why some patients seem to be cured after BoNT/A injections is unknown. It could be because they cope better when symptoms return, or because DO is permanently eliminated. Since to our knowledge the fundamental pathogenesis of IDO remains to be elucidated, hypotheses about the possible long-term BoNT/A effect are inevitably speculative but it is a fascinating observation that merits further investigation.
1777
There are no generally accepted predictive factors for the need for CISC after BoNT/A injection. However, reported CISC rates seem to depend on the etiology of DO, the injected dose and the definition of significant PVR. In patients with NDO secondary to multiple sclerosis we found that the CISC rate was almost 100% using 300 U Botox9 but it seems likely that the neural mechanism for voiding is affected in this group. When injecting the same dose in patients with IDO, Kessler et al found a de novo CISC rate of 50%.13 At a smaller dose of 200 U Botox the 2 placebo controlled trials in patients with IDO showed that CISC was needed in 38% and 43%, respectively.4,5 This is similar to our study, in which 38% of our patients were introduced to CISC after injection 1 and remained comparable after repeat injections. In contrast, a CISC rate of 3% to 4% was observed by Schmid et al using 100 U Botox in patients with refractory OAB.11,14 Different PVR cutoffs for initiating CISC add to the varying CISC rate among published series. In the current study a PVR of greater than 100 ml with lower urinary tract symptoms was considered an indication for CISC, whereas others have accepted a higher PVR of up to 150 to 200 ml before performing CISC.4,5,11,13 Although it remains to be established which dose has the best effect with the lowest CISC rate, depending on the severity of preexisting symptoms dose modulation may be appropriate. Since the ongoing randomized, placebo controlled, dose-response study NCT00168454 may answer these questions, we await the results to guide our decision on dose modulation. Remarkably the need to perform CISC had no effect on our patient QOL after BoNT/A injection. This could be because we did not use a CISC specific QOL questionnaire and/or the number of patients was too small. Alternatively the fact that we stipulated that willingness to perform CISC was an essential inclusion criterion meant that we properly managed patient expectations. This was certainly the case when a highly significant improvement in QOL was achieved despite an almost 100% CISC rate after intradetrusor BoNT/A injections for NDO in patients with multiple sclerosis.9 Moreover, most patients perceive CISC as an easy and painless procedure that does not interfere with daily activity.20 Although to our knowledge we document for the first time the effects of repeat intradetrusor BoNT/A for refractory IDO, we are aware of the limitations in our study. Results are based on a single center study with many patients treated for the first time and a decreased number returning for repeat injections. Our study was neither randomized nor placebo controlled, but rather prospective, open labeled and representative of daily clinical experience. In contrast to other studies, our patients did not return at fixed intervals, but reported back only when OAB symptoms recurred. QOL assessment was performed 4 weeks after treatment but not serially. The period during which patients performed CISC was not assessed in the current
1778
REFRACTORY IDIOPATHIC DETRUSOR OVERACTIVITY AND BOTULINUM INJECTION
study, although it is part of an ongoing evaluation. In addition, we advised patients to decrease or stop antimuscarinics after an improvement in OAB symptoms following BoNT/A injection and restart medication when symptoms recurred. This may have resulted in some delay in reevaluation and overestimation of the interinjection interval, and it may have had a confounding effect on the QOL outcome. However, it is not known whether concurrent use of antimuscarinics and BoNT/A treatment have a synergistic effect. This needs further investigation.
peared to be cured. After intradetrusor BoNT/A treatment more than 2 of 5 patients with refractory IDO may need to perform CISC. Importantly if CISC becomes necessary after BoNT/A injection, it seems to be needed after all subsequent treatments. Moreover, CISC may become necessary after later injections even if it was not initially required. The postinjection urinary tract infection rate was 15%. Therefore, all patients should be informed of the potential need to perform CISC after BoNT/A injection and the willingness to do so should be a prerequisite for this still unlicensed, off label treatment.
CONCLUSIONS Intradetrusor BoNT/A injections for refractory IDO improve QOL significantly and this effect is sustained after repeat injections. Of patients with a followup of greater than 14 months 10% did not experience recurrent OAB symptoms and they ap-
ACKNOWLEDGMENTS This study was performed at University College London Hospitals/University College of London. Allergan Ltd., United Kingdom provided Botox for the early period of this study.
REFERENCES 1. Schurch B, Stohrer M, Kramer G, Schmid DM, Gaul G and Hauri D: Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 2000; 164: 692. 2. Schurch B, de Seze M, Denys P, Chartier-Kastler E, Haab F, Everaert K et al: Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005; 174: 196. 3. Ehren I, Volz D, Farrelly E, Berglund L, Brundin L, Hultling C et al: Efficacy and impact of botulinum toxin A on quality of life in patients with neurogenic detrusor overactivity: a randomised, placebo-controlled, double-blind study. Scand J Urol Nephrol 2007; 41: 335. 4. Sahai A, Khan MS and Dasgupta P: Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial. J Urol 2007; 177: 2231. 5. Brubaker L, Richter HE, Visco A, Mahajan S, Nygaard I, Braun TM et al: Refractory idiopathic urge urinary incontinence and botulinum A injection. J Urol 2008; 180: 217. 6. Grosse J, Kramer G and Stohrer M: Success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol 2005; 47: 653. 7. Karsenty G, Reitz A, Lindemann G, Boy S and Schurch B: Persistence of therapeutic effect after repeated injections of botulinum toxin type A to treat incontinence due to neurogenic detrusor overactivity. Urology 2006; 68: 1193.
8. Reitz A, Denys P, Fermanian C, Schurch B, Comperat E and Chartier-Kastler E: Do repeat intradetrusor botulinum toxin type a injections yield valuable results? Clinical and urodynamic results after five injections in patients with neurogenic detrusor overactivity. Eur Urol 2007; 52: 1729.
into the detrusor muscle for overactive bladder refractory to anticholinergics. Eur Urol, suppl., 2008; 7: 212, abstract 568.
9. Kalsi V, Gonzales G, Popat R, Apostolidis A, Elneil S, Dasgupta P et al: Botulinum injections for the treatment of bladder symptoms of multiple sclerosis. Ann Neurol 2007; 62: 452.
15. Apostolidis A, Dasgupta P, Denys P, Elneil S, Fowler CJ, Giannantoni A et al: Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: A European consensus report. Eur Urol, Epub ahead of print September 17, 2008.
10. Del Popolo G, Filocamo MT, Li Marzi V, Macchiarella A, Cecconi F, Lombardi G et al: Neurogenic detrusor overactivity treated with English botulinum toxin a: 8-year experience of one single centre. Eur Urol 2008; 53: 1013.
16. Harper M, Popat RB, Dasgupta R, Fowler CJ and Dasgupta P: A minimally invasive technique for outpatient local anaesthetic administration of intradetrusor botulinum toxin in intractable detrusor overactivity. BJU Int 2003; 92: 325.
11. Schmid DM, Sauermann P, Werner M, Schuessler B, Blick N, Muentener M et al: Experience with 100 cases treated with botulinum-A toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome refractory to anticholinergics. J Urol 2006; 176: 177.
17. Uebersax JS, Wyman JF, Shumaker SA, McClish DK and Fantl JA: Short forms to assess life quality and symptom distress for urinary incontinence in women: the Incontinence Impact Questionnaire and the Urogenital Distress Inventory. Continence Program for Women Research Group. Neurourol Urodyn 1995; 14: 131.
12. Kalsi V, Popat RB, Apostolidis A, Kavia R, Odeyemi IA, Dakin HA et al: 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. Eur Urol 2006; 49: 519. 13. Kessler TM, Danuser H, Schumacher M, Studer UE and Burkhard FC: Botulinum A toxin injections into the detrusor: an effective treatment in idiopathic and neurogenic detrusor overactivity? Neurourol Urodyn 2005; 24: 231. 14. Schmid DM, Roy-Guggenbuehl SG, Werner MW, Perruchini DP, Sulser TS and Schurch B: The Zurich experiences including 6 year results of 200 cases treated with botulinum-A toxin injections
18. Kalsi V, Apostolidis A, Popat R, Gonzales G, Fowler CJ and Dasgupta P: Quality of life changes in patients with neurogenic versus idiopathic detrusor overactivity after intradetrusor injections of botulinum neurotoxin type A and correlations with lower urinary tract symptoms and urodynamic changes. Eur Urol 2006; 49: 528. 19. Kuschel S, Werner M, Schmid DM, Faust E and Schuessler B: Botulinum toxin-A for idiopathic overactivity of the vesical detrusor: a 2-year follow-up. Int Urogynecol J Pelvic Floor Dysfunct 2008; 19: 905. 20. Kessler TM, Ryu G and Burkhard FC: Clean intermittent self-catheterization: a burden for the patient? Neurourol Urodyn 2009; 28: 18.