Medium- to long-term outcomes of botulinum toxin A for idiopathic overactive bladder

Abstract

Botulinum toxin A (BoNT-A) has become an important therapeutic tool in the management of refractory overactive bladder (OAB). Over the last decade, there have been growing numbers of patients receiving repeat injections and these outcomes have begun to be reported in large, high-quality cohorts. This article reviews the current evidence for the medium- to long-term use of BoNT-A in adults with idiopathic detrusor overactivity (IDO) receiving repeat injections. We find that medium-term outcomes are encouraging but long-term outcomes are not as extensively reported. There is high-quality evidence that efficacy following the first injection persists across multiple treatment cycles. There are no additional safety concerns from repeat injections up to six treatment cycles. However, there is a need for further data to confirm the efficacy and safety of BoNT-A beyond the follow-up period in the current literature.

Keywords

botulinum toxin overactive bladder detrusor overactivity botox onabotulinumtoxinA Dysport abobotulinumtoxinA

Introduction

Botulinum toxin A (BoNT-A) injections have become a well established therapy in the management of refractory overactive bladder (OAB). There are increasing numbers of patients receiving repeat injections on a regular basis. OnabotulinumtoxinA (BOTOX; Allergan, Inc., Irvine, USA) has been approved for the treatment of refractory OAB. It has been shown to be effective and well tolerated in phase III multicentre randomized, double-blind, placebo-controlled trials utilizing a 100 U dose [Chapple et al. 2013; Nitti et al. 2013].

This review discusses the current literature on BoNT-A as a medium- to long-term treatment for idiopathic OAB. This review covers the efficacy, quality of life, injection intervals, immunological aspects and longer term safety reported across the published literature in this group treated with BoNT-A.

Methods

A search of the PubMed database was performed using the MeSH terms ‘Botulinum A toxin’ or ‘overactive bladder’ and keywords ‘botulinum neurotoxin’, ‘idiopathic detrusor overactivity’. The inclusion criteria were papers reporting the medium- to long-term outcomes in adults with idiopathic OAB. These studies generally reported follow up in terms of number of treatment cycles. Therefore medium-term outcomes were defined as more than one treatment cycle and long-term outcomes as more than five treatment cycles. The term ‘refractory OAB’ includes patients who had an inadequate response or were unable to tolerate first-line medical and behavioural treatments. No language exclusions were applied. The bibliographies of the papers were examined for additional studies meeting the inclusion criteria. Overall 12 published papers were identified and underwent full review.

Efficacy

Levels of evidence

There have been two phase III placebo-controlled trials which have provided level 1 evidence for the short-term efficacy of a single injection of onabotulinumtoxinA 100 U in OAB [Chapple et al. 2013; Nitti et al. 2013]. The only longitudinal randomized controlled trial [Gousse et al. 2011] was a dose-ranging study comparing six injections of onabotulinumtoxinA 100 U and 150 U administered at 24-week intervals up to 3 years. Sixty patients were randomized but there was a significant dropout rate with only nine patients (15%) completing the study. This demonstrates the challenge of investigating medium- to long-term outcomes in a randomized controlled trial setting.

The remaining published studies comprised level 2 or 3 evidence divided into prospective longitudinal studies and retrospective case series (Table 1). The standard follow up across these studies is on average around 3 years, although the maximum for an individual patient is up to 7 years [Veeratterapillay et al. 2014]. The number of repeat injections ranges from 2 to 10 [Dowson et al. 2012], with the majority of studies providing data on approximately three to four repeat injections (Table 2). Given that patients have been receiving repeat BoNT-A injections for over a decade, longer-term data are still required to fully evaluate the outcomes of BoNT-A injections beyond 3–4 years.

Table 1.

Summary of studies.

Study	Design	Level of evidence*	Patients	Preparation and dose	Duration of follow up	Maximum injections	Injection interval	Outcome measures
Kuschel et al. [2008]	Prospective longitudinal study	2	26	BOTOX 100 U	2 years^{$ †}	3 injections	14 months^$ (range 5–26)	Discontinuation rates after 2 years of follow up
Khan et al. [2009]	Prospective longitudinal study	2	81	BOTOX 200 U	2.8 years^$ (range 0.3–5.7)	6 injections	14 months^† (IQR 11–17)	Quality of life scores (UDI-6 and IIQ-7) after first and subsequent injections
Sahai et al. [2010]	Prospective longitudinal study	2	34	BOTOX 100–300 U	Up to 4 years	4 injections	14 months^†	After first and subsequent injections: Urodynamics for maximum of 3 cycles Voiding diaries Quality of life scores (UDI-6 and IIQ-7)
Frohme et al. [2010] (in German)	Prospective case series	3	40	Dysport 500 U	9 months^† (range 1–45)	4 injections	6 months^$ (range 2–10)	Voiding diaries after first and subsequent injections
Game et al. [2011]	Retrospective case series	3	42	BOTOX 200 U	2.3 years^$	5 injections	17.1 months^$	Quality of life scores (UDI-6, IIQ-7 and EQ-5D) after first and subsequent injections
Gousse et al. [2011]	Randomized controlled trial	1	60	BOTOX 100–150 U	3 years^{$ †}	6 injections	2 months^{$ †} (set by protocol)	Quality of life (UDI-6) and Global Impression (VAS) scores after first and subsequent injections
Dowson et al. [2012]	Prospective longitudinal study	2	100	BOTOX 100–300 U	NR	10 injections	10.7 months^$	After first and subsequent injections: Voiding diaries Quality of life scores (UDI-6 and IIQ-7)
Granese et al. [2012]	Prospective cohort study	2	68	BOTOX 100 U	1.1 years^$	2 injections	12 months^$	After first and second injection: Urodynamics parameters Voiding diaries
Irwin et al. [2013]	Prospective case series	3	73	Dysport 250 U	NR	>4 injections	26.7 months^$	Duration of effect and reinjection interval
Mohee et al. [2013]	Retrospective case series	3	104	BOTOX 100–200 U	⩾3 years	4 injections	8 months^$	Discontinuation rates in patients with > 3 years of follow up
Abeywickrama et al. [2014]	Prospective case series	3	33	Dysport 500–750 U	Up to 7 years	>3 injections	17.2 months^$	After first and subsequent 3 injections Voiding diaries Quality of life scores (ICIQ-SF)
Veeratterapillay et al. [2014]	Retrospective case series	3	96	BOTOX 200 U	3.2 years^{† ‡}	8 injections‡	14.4 months^{† ‡}	Discontinuation rates in patients with ⩾1 injection
Nitti et al. [2016]	Prospective longitudinal study	2	829	BOTOX 100 U	3.2 years^†	6 injections	7.6 months^§	After first and subsequent 6 injections in patients with 3.5 years of follow up: Voiding diaries Quality of Life scores (I-QOL, KHQ and TBS)

Level of evidence was rated according to a modified Oxford system as used by the European Urology Association [Thuroff et al. 2011].

Mean.

†

Median.

‡

Includes IDO (96 patients) and NDO (29 patients).

Time to request for treatment.

EQ-5D, EuroQol five-dimensional; ICIQ-SF, International Consultation on Incontinence Questionnaire-Short Form; IDO, idiopathic detrusor overactivity; IIQ-7, Incontinence Impact Questionnaire 7; I-QOL, Incontinence Quality of Life Questionnaire; IQR, interquartile range; KHQ, King’s Health Questionnaire; NDO, neurogenic detrusor overactivity; NR, not reported; TBS, Treatment Benefit Scale; UDI-6, Urinary Distress Inventory 6; VAS, visual analogue scale.

Table 2.

Number of repeat injections.

Study	Number of injections
	1	2	3	4	5	6	7	8	9	10
Kuschel et al. [2008]	26	11	1	–	–	–	–	–	–	–
Khan et al. [2009]	81	24	13	6	4	1	–	–	–	–
Sahai et al. [2010]	34	20	9	9	–	–	–	–	–	–
Frohme et al. [2010] (in German)	40	15	4	1	–	–	–	–	–	–
Game et al. [2011]	42	42	16	12	10	–	–	–	–	–
Gousse et al. [2011]	60	36	23	16	12	9	–	–	–	–
Dowson et al. [2012]	100	53	20	13	10	5	3	1	1	1
Granese et al. [2012]	68	20	–	–	–	–	–	–	–	–
Veeratterapillay et al. [2014] * ^$	–	125	60	28	14	3	3	2	–	–
Nitti et al. [2016]	829	608	388	273	185	139	–	–	–	–

Includes patients with idiopathic detrusor overactivity and NDO.

All patients received repeat injections.

NDO, neurogenic detrusor overactivity; NR, not reported.

The largest cohort is from the phase III extension study in which patients from the pivotal randomized controlled trials (RCTs) were invited to participate in a 3.5-year follow-up period [Nitti et al. 2016]. The other studies are smaller cohorts and they have significant variability in methodology, follow up and outcome measures. Some studies report efficacy data for a set duration of follow up [Granese et al. 2012; Kuschel et al. 2008; Mohee et al. 2013], others compare efficacy across the first and subsequent injections [Dowson et al. 2012; Game et al. 2011; Gousse et al. 2011; Khan et al. 2009; Sahai et al. 2010] and others select patients who have undergone a set number of injections but do not comment on the size of the original cohort [Abeywickrama et al. 2014]. All these methods bias the outcome data and skew it towards a positive effect as patients discontinuing treatment are not included in the efficacy outcome measures.

A range of efficacy outcomes have been used, including urodynamic parameters, voiding diaries and quality of life scores. There are limited studies which evaluate the effect of repeat injections on urodynamic parameters [Granese et al. 2012; Sahai et al. 2010]. The majority of studies use quality of life scores as the primary outcome measure [Game et al. 2011; Gousse et al. 2011; Khan et al. 2009] and some combine these with voiding diaries to provide objective data on symptoms [Dowson et al. 2012; Nitti et al. 2016; Sahai et al. 2010; Veeratterapillay et al. 2014]. A few studies do not report any specific efficacy outcomes but it is inferred from discontinuation rates across treatment cycles [Frohme et al. 2010; Irwin et al. 2013; Kuschel et al. 2008; Mohee et al. 2013; Veeratterapillay et al. 2014].

Urodynamic outcomes

There are two studies which assess changes in urodynamic parameters after repeat injections. Sahai and colleagues showed a significant improvement in maximum cystometric capacity (MCC), a decrease in maximum detrusor pressure and no reduction in bladder compliance (BC) across three injections Sahai et al. [2010]. This was confirmed by Granese and colleagues who found a persistent improvement in MCC and BC after the second treatment cycle and an average duration of urodynamic efficacy of 9 months [Granese et al. 2012].

Voiding diaries

Voiding diaries following repeat injections have been analysed by four studies [Abeywickrama et al. 2014; Dowson et al. 2012; Nitti et al. 2016; Sahai et al. 2010]. These studies have demonstrated an improvement in frequency, urgency, and urgency incontinence (UI) compared with baseline. The phase III extension study showed an absolute reduction of UI episodes of around three per day which was sustained across six treatment cycles [Nitti et al. 2016]. This was combined with a consistent increase in volume voided, a reduction in urgency episodes and a decrease in frequency episodes. Abeywickrama and colleagues reported an improvement in nocturia which was constant across three injections [Abeywickrama et al. 2014].

Quality of life and patient satisfaction scores

The early studies evaluated quality of life using the Urinary Distress Inventory 6 (UDI-6) and Incontinence Impact Questionnaire (IIQ-7) [Dowson et al. 2012; Game et al. 2011; Sahai et al. 2010]. Dowson and colleagues and Game and colleagues have shown a consistent improvement in both scores following up to five injections [Dowson et al. 2012; Game et al. 2011].

Recent studies have included global satisfaction scores and alternative questionnaires such as the International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) [Abeywickrama et al. 2014], Incontinence Quality of Life questionnaire (I-QOL) and Treatment Benefit Scale (TBS) [Nitti et al. 2016]. These show that high quality of life scores and satisfaction rates, up to 90%, are consistent across treatment cycles.

Different preparations

AbobotulinumtoxinA (Dysport, Ipsen Biopharm Ltd, Slough, UK) and onabotulinumtoxinA are both type A serotypes but they are manufactured using different isolation, purification and extraction processes [Brin et al. 2014]. This results in different dosing units and they cannot be used interchangeably [Mangera et al. 2011]. The majority of published studies use onabotulinumtoxinA (BOTOX) as the only licensed preparation for refractory IDO [Dowson et al. 2012; Game et al. 2011; Gousse et al. 2011; Granese et al. 2012; Khan et al. 2009; Kuschel et al. 2008; Mohee et al. 2013; Nitti et al. 2016; Sahai et al. 2010; Veeratterapillay et al. 2014]. There are three studies which report the outcomes for abobotulinumtoxinA [Abeywickrama et al. 2014; Frohme et al. 2010; Irwin et al. 2013]. These are smaller cohorts with fewer repeat injections and shorter follow up. They are spread across a range of doses for abobotulinumtoxinA from 250 to 750 U. This wide range of doses makes comparisons between preparations challenging. The recommended dose conversion ratio is 3:1 (Dysport:BOTOX) [Irwin et al. 2013; Sampaio et al. 2004]; however, this ratio has been controversial, with some studies suggesting the true ratio lies between 2 and 2.5:1 [Ravindra et al. 2013].

The most extensive study is a prospective case series including 33 women who had more than three injections of Dysport 500 or 750 U [Abeywickrama et al. 2014]. This study found a significant and sustained improvement in urinary frequency and quality of life scores across three treatment cycles. Given the limited data and uncertainties around dosage of abobotulinumtoxinA, it appears that more studies are needed to confirm the long-term efficacy and safety profile of abobotulinumtoxinA.

Duration of effect

The duration of effect is an important factor for counselling patients and planning clinical services. High-volume centres have increasing numbers of patients undergoing multiple repeat injections and need to plan availability of reinjection resources. The majority of studies report the ‘reinjection interval’ and there is a wide range in the published data from 6 months to 26.7 months [Frohme et al. 2010; Irwin et al. 2013]. Two studies report a significant increasing interval with each injection [Abeywickrama et al. 2014; Irwin et al. 2013], two studies report a decreasing interval [Dowson et al. 2012; Sahai et al. 2010] and two did not find any change in interval across each injection [Khan et al. 2009; Veeratterapillay et al. 2014].

The variability of results is likely because the reinjection interval is not an accurate method of evaluating duration of effect as it can be confounded by multiple local factors such as waiting lists, minimum injection intervals [Sahai et al. 2010; Veeratterapillay et al. 2014] and concomitant use of antimuscarinics to delay retreatment [Dowson et al. 2012; Sahai et al. 2010; Veeratterapillay et al. 2014]. A more reliable definition is used by the phase III extension study that reports the reinjection request time [Nitti et al. 2016]. The mean time between requests for reinjection was 7.6 months but this was equally distributed between patients requesting retreatment before 6 months, from 6 to 12 months, and beyond 12 months. The longitudinal analysis showed that this request time either increased or remained stable across the six treatment cycles [De Ridder et al. 2015]. A mean duration of efficacy of approximately 7–8 months is consistent with reports in neurogenic overactive bladder [Apostolidis et al. 2009] and in urodynamic studies showing return of detrusor contractility after BoNT-A injection [Rovner et al. 2011].

Adverse events

Urinary tract infection

Urinary tract infections (UTIs) are common after any endoscopic procedure but are more common following BoTN-A injection. The combined safety data from the two pivotal RCTs reported a rate of 25.5% with onabotulinumtoxinA and 9.6% with placebo. The definition of UTI was a positive urine culture with bacteriuria count of more than 10⁵ colony-forming units/ml, together with leukocyturia of over five per high power field, even in the absence of symptoms [Sievert et al. 2014].

The long-term extension study for one to six injections reported UTI rates as 17.0%, 16.1%, 17.5%, 14.7%, 13.5% and 14.4%, respectively [Nitti et al. 2016]. Problems with recurrent UTIs post BoNT-A have been identified as the primary reason for cessation of treatment in 16.7% of patients undergoing repeat injection [Mohee et al. 2013].

Voiding dysfunction and clean intermittent self-catheterization use

The risk of clean intermittent self-catheterization (CISC) due to voiding dysfunction is particularly concerning for patients with OAB who are less likely to have prior experience with catheterization. Mohee and colleagues found that the need for CISC was the most common reason for cessation of treatment in a cohort in which two-thirds of patients had discontinued treatment at 3-year follow up [Mohee et al. 2013]. The rate of CISC is dose dependent. The phase III extension study has reported a CISC rate of 6.5% [Sievert et al. 2014] for 100 U. However, earlier studies have suggested higher rates and have had different criteria to instigate CISC [Brubaker et al. 2008; Sahai et al. 2007].

Following a repeat injection, the risk of CISC is highly dependent on whether CISC has been required in previous treatment cycles. Khan and colleagues showed that the need for CISC remained stable over multiple injections and patients who required CISC after the first injection generally needed it with repeat injections [Khan et al. 2009].

Other adverse events

Other side effects of botulinum toxin include haematuria, dysuria, complicated UTI and generalized muscle weakness. No study has reported worsening risk of haematuria or significant pain that persists after repeated injections. There are individual reports of patients with IDO experiencing general muscle weakness which is transient and resolves within a few weeks after the injection [Jeffery et al. 2007]. This rare side effect is more common in neurological patients but is seen in IDO at higher doses [Kuo et al. 2010]. No study has shown that this side effect occurs more frequently with repeat injections in IDO, although in patients with neurogenic overactive bladder there have been reports of cases of generalized muscle weakness which reoccurred with repeat injections [Pannek et al. 2009].

Histological and immunological effects

Histological effects

Although the action of single BoNT-A injections is reversible, there have been theoretical concerns that multiple injections could cause irreversible histological changes, such as bladder fibrosis leading to reduced BC. Early animal studies suggested BoNT-A injections led to apoptosis of the bladder urothelium and other studies have shown that it causes prostate atrophy by activating apoptotic pathways in rats [Watanabe et al. 2010].

The results from animal experiments have not been replicated in human subjects [Kessler et al. 2010]. Histological analysis of bladder biopsies from patients who received up to four injections has shown no significant evidence of fibrosis, hyperplasia or dysplasia [Apostolidis et al. 2008]. Other histological studies have shown a reduction in bladder fibrosis [Comperat et al. 2006] and improved BC after up to four injections [Sahai et al. 2010]. Although the medium-term histological results are positive, supplementary data are needed to confirm the long-term effects of exposure to BoNT-A injections.

Immunological effects

As BoNT-A injections are formed of nonhuman proteins, they have the potential to act as antigens, leading to the formation of neutralizing antibodies [Naumann et al. 2013]. If produced in sufficient concentrations, these antibodies can inhibit the activity of botulinum toxin, leading to treatment resistance. The antigenicity of BoNT-A preparations depends on the amount of nonhuman protein which is presented to the immune system. The current formulations, on the market since 2001, have a reduced protein content with the aim of reducing the immunogenic potential of the toxin [Yablon et al. 2007].

A phase II dose-ranging randomized controlled trial in patients with OAB found antibodies in two patients (6.6%) receiving 150 U but their presence had no significant impact on efficacy [Denys et al. 2012]. Antibody formation has been more extensively studied in patients with neurogenic detrusor overactivity (NDO) and these studies have produced equivocal results depending on the detection method used. One study used a mouse diaphragm assay to demonstrate the formation of antibodies in 8 out of 25 patients with NDO up to three months following a repeat injection [Schulte-Baukloh et al. 2008]. In contrast, a prospective study of children with NDO used an enzyme-linked immunosorbent assay technique and found that while antibody titres may temporarily increase, they returned to baseline after 3 months and the presence of antibodies did not correlate with treatment failure [Kajbafzadeh et al. 2010]. A meta-analysis of five studies investigating antibody conversion across multiple BoNT-A indications showed that the risk of developing antibodies was 0.49% (11 out of 2240 patients) and only three patients became clinically unresponsive to treatment [Naumann et al. 2010].

None of the studies evaluating medium- to long-term outcomes in patients with OAB have specifically tested for the development of antibodies (Table 1). There are a few reports of nonresponse to treatment but it is important to distinguish between immunogenicity and other factors causing a poor response. There are multiple reasons for treatment failure, including improper vial storage, incorrect toxin reconstitution or poor administration techniques. Therefore, the long-term potential for antibody formation is not fully established and to reduce the potential for antibody formation it is recommended that patients on long-term treatment continue to receive the lowest effective dose at the longest dose interval.

Conclusion

The current literature shows that repeated BoNT-A injections are safe and efficacious in patients with OAB. There is high-quality evidence that efficacy following the first injection persists across multiple treatment cycles. Repeat injections do not appear to cause bladder fibrosis, antibody formation or increasing incidence of adverse events. There are no additional safety concerns from repeat injections although urinary tract infection and risk of clean intermittent self-catheterization remain an issue and high discontinuation rates outside of clinical trials require further investigation. The long-term outcomes are not as extensively reported, although medium-term results are encouraging with reasonable data up to six injections. Supplementary data from larger cohorts are required to confirm significant and sustained long-term efficacy and safety.

Footnotes

Acknowledgements

The authors acknowledge the support of the MRC Centre for Transplantation. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.

Funding

The authors acknowledge financial support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre at Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust.

Conflict of interest statement

DE-E has no conflicts of interest to declare. AS has been a trial investigator and advisor for Allergan Ltd, has received honoraria for speaking on behalf of Allergan Ltd and has received an unrestricted educational grant for research purposes.

References

Abeywickrama

Arunkalaivanan

Quinlan

(2014) Repeated botulinum toxin type A (Dysport) injections for women with intractable detrusor overactivity: a prospective outcome study. Int Urogynecol J 25: 601–605.

Apostolidis

Dasgupta

Denys

Elneil

Fowler

Giannantoni

. (2009) 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 55: 100–120.

Apostolidis

Jacques

Freeman

Kalsi

Popat

Gonzales

. (2008) Histological changes in the urothelium and suburothelium of human overactive bladder following intradetrusor injections of botulinum neurotoxin type A for the treatment of neurogenic or idiopathic detrusor overactivity. Eur Urol 53: 1245–1253.

Brin

James

Maltman

(2014) Botulinum toxin type A products are not interchangeable: a review of the evidence. Biologics 8: 227–241.

Brubaker

Richter

Visco

Mahajan

Nygaard

Braun

. (2008) Refractory idiopathic urge urinary incontinence and botulinum a injection. J Urol 180: 217–222.

Chapple

Sievert

Macdiarmid

Khullar

Radziszewski

Nardo

. (2013) OnabotulinumtoxinA 100 U significantly improves all idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and urinary incontinence: a randomised, double-blind, placebo-controlled trial. Eur Urol 64: 249–256.

Comperat

Reitz

Delcourt

Capron

Denys

Chartier-Kastler

. (2006) Histologic features in the urinary bladder wall affected from neurogenic overactivity – a comparison of inflammation, oedema and fibrosis with and without injection of botulinum toxin type A. Eur Urol 50: 1058–1064.

Denys

Le Normand

Ghout

Costa

Chartier-Kastler

Grise

. (2012) Efficacy and safety of low doses of onabotulinumtoxinA for the treatment of refractory idiopathic overactive bladder: a multicentre, double-blind, randomised, placebo-controlled dose-ranging study. Eur Urol 61: 520–529.

De Ridder

Sussman

Sand

Sievert

Radomski

Jenkins

. (2015) Durable duration of effect and positive treatment response with long-term onabotulinumtoxinA treatment in patients with over-active bladder syndrome: final results of 3.5 years study. Eur Urol 14: 1–500.

10.

Dowson

Watkins

Khan

Dasgupta

Sahai

(2012) Repeated botulinum toxin type A injections for refractory overactive bladder: medium-term outcomes, safety profile, and discontinuation rates. Eur Urol 61: 834–839.

11.

Frohme

Varga

Olbert

Schrader

Hofmann

Hegele

(2010) Wirkung Von Botulinumtoxin a in Der Ein- Und Mehrmaligen Behandlung Der Uberaktiven Blase [Effects of botulinum toxin type A in the single and repeated treatment of overactive bladder. A prospective analysis.]. Urologe A 49: 639–644 (in German).

12.

Game

Khan

Panicker

Kalsi

Dalton

Elneil

. (2011) Comparison of the impact on health-related quality of life of repeated detrusor injections of botulinum toxin in patients with idiopathic or neurogenic detrusor overactivity. BJU Int 107: 1786–1792.

13.

Gousse

Kanagarajah

Ayyathurai

Handa

Dabas

Gomez

(2011) Repeat intradetrusor injections of onabotulinum toxin a for refractory idiopathic overactive bladder patients: a single-center experience. Female Pelvic Med Reconstr Surg 17: 253–257.

14.

Granese

Adile

Gugliotta

Cucinella

Saitta

Adile

(2012) Botox(®) for idiopathic overactive bladder: efficacy, duration and safety. Effectiveness of subsequent injection. Arch Gynecol Obstet 286: 923–929.

15.

Irwin

Somov

Ekwueme

(2013) Patient reported outcomes of abobotulinumtoxinA injection treatment for idiopathic detrusor overactivity: a pragmatic approach to management in secondary care. J Clin Urol 6: 59–63.

16.

Jeffery

Fynes

Lee

Wang

Williams

Morley

(2007) Efficacy and complications of intradetrusor injection with botulinum toxin A in patients with refractory idiopathic detrusor overactivity. BJU Int 100: 1302–1306.

17.

Kajbafzadeh

Nikfarjam

Mahboubi

Dianat

(2010) Antibody formation following botulinum toxin type A (Dysport) injection in children with intractable bladder hyper-reflexia. Urology 76: 233–237.

18.

Kessler

Khan

Panicker

Elneil

Brandner

Fowler

. (2010) In the human urothelium and suburothelium, intradetrusor botulinum neurotoxin type A does not induce apoptosis: preliminary results. Eur Urol 57: 879–883.

19.

Khan

Kessler

Apostolidis

Kalsi

Panicker

Roosen

. (2009) What a patient with refractory idiopathic detrusor overactivity should know about botulinum neurotoxin type A injection. J Urol 181: 1773–1778.

20.

Kuo

Liao

Chung

(2010) Adverse events of intravesical botulinum toxin a injections for idiopathic detrusor overactivity: risk factors and influence on treatment outcome. Eur Urol 58: 919–926.

21.

Kuschel

Werner

Schmid

Faust

Schuessler

(2008) Botulinum toxin-A for idiopathic overactivity of the vesical detrusor: a 2-year follow-up. Int Urogynecol J Pelvic Floor Dysfunct 19: 905–909.

22.

Mangera

Andersson

Apostolidis

Chapple

Dasgupta

Giannantoni

. (2011) Contemporary management of lower urinary tract disease with botulinum toxin A: a systematic review of BOTOX (onabotulinumtoxinA) and Dysport (abobotulinumtoxinA). Eur Urol 60: 784–795.

23.

Mohee

Khan

Harris

Eardley

(2013) Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder (OAB). BJU Int 111: 106–113.

24.

Naumann

Boo

Ackerman

Gallagher

(2013) Immunogenicity of botulinum toxins. J Neural Transm 120: 275–290.

25.

Naumann

Carruthers

Aurora

Zafonte

Abu-Shakra

. (2010) Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX^®)) across multiple indications. Mov Disord 25: 2211–2218.

26.

Nitti

Dmochowski

Herschorn

Sand

Thompson

Nardo

. (2013) OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J Urol 189: 2186–2193.

27.

Nitti

Ginsberg

Sievert

Sussman

Radomski

Sand

. (2016) Durable efficacy and safety of long-term onabotulinumtoxinA treatment in patients with overactive bladder syndrome: final results of a 3.5-year study. J Urol 196: 791–800.

28.

Pannek

Göcking

Bersch

(2009) Long-term effects of repeated intradetrusor botulinum neurotoxin A injections on detrusor function in patients with neurogenic bladder dysfunction. BJU Int 104: 1246–1250.

29.

Ravindra

Jackson

Parkinson

(2013) Botulinum toxin type A for the treatment of non-neurogenic overactive bladder: does using onabotulinumtoxinA (BOTOX^®) or abobotulinumtoxina (Dysport^®) make a difference? BJU Int 112: 94–99.

30.

Rovner

Kennelly

Schulte-Baukloh

Zhou

Haag-Molkenteller

Dasgupta

(2011) Urodynamic results and clinical outcomes with intradetrusor injections of onabotulinumtoxinA in a randomized, placebo-controlled dose-finding study in idiopathic overactive bladder. Neurourol Urodyn 30: 556–562.

31.

Sahai

Dowson

Khan

Dasgupta

(2010) Repeated injections of botulinum toxin-A for idiopathic detrusor overactivity. Urology 75: 552–558.

32.

Sahai

Khan

Dasgupta

(2007) Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial. J Urol 177: 2231–2236.

33.

Sampaio

Costa

Ferreira

(2004) Clinical comparability of marketed formulations of botulinum toxin. Mov Disord 19: S129–S136.

34.

Schulte-Baukloh

Bigalke

Miller

Heine

Pape

Lehmann

. (2008) Botulinum neurotoxin type A in urology: antibodies as a cause of therapy failure. Int J Urol 15: 407–415.

35.

Sievert

Chapple

Herschorn

Joshi

Zhou

Nardo

. (2014) OnabotulinumtoxinA 100U provides significant improvements in overactive bladder symptoms in patients with urinary incontinence regardless of the number of anticholinergic therapies used or reason for inadequate management of overactive bladder. Int J Clin Pract 68: 1246–1256.

36.

Thuroff

Abrams

Andersson

Artibani

Chapple

Drake

. (2011) EAU guidelines on urinary incontinence. Eur Urol 59: 387–400.

37.

Veeratterapillay

Harding

Teo

Vasdev

Abroaf

Dorkin

. (2014) Discontinuation rates and inter-injection interval for repeated intravesical botulinum toxin type A injections for detrusor overactivity. Int J Urol 21: 175–178.

38.

Watanabe

Masago

Miyagawa

(2010) Apoptotic action of botulinum toxin on detrusor muscle in rats. Urol Int 84: 341–346.

39.

Yablon

Brashear

Gordon

Elovic

Turkel

Daggett

. (2007) Formation of neutralizing antibodies in patients receiving botulinum toxin type A for treatment of poststroke spasticity: a pooled-data analysis of three clinical trials. Clin Ther 29: 683–690.