Minimally Invasive Therapy for Urinary Incontinence and Pelvic Organ Prolapse (Current Clinical Urology) 2014th

12. Intravesical Therapy for Refractory Overactive Bladder and Detrusor Overactivity in Adults: Botulinum Toxin-A

Arun Sahai , Jai Seth2, Muhammed Shamim Khan1 and Prokar Dasgupta1

(1)

Department of Urology, Guy’s Hospital, MRC Center for Transplantation, King’s College London, King’s Health Partners, London, UK

(2)

Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, London, UK

Arun Sahai

Email: sonnyroth@yahoo.com

Abstract

It has been 11 years since the first publications on the use of intradetrusor botulinum toxin-A (BTX-A) injections to treat neurogenic detrusor overactivity (NDO) in patients with spinal cord injury (SCI) OnabotulinumtoxinA (Botox®; Allergan, Ltd., Irvine, USA) has recently been approved for use in the bladder of neurogenic patients with spinal cord injury or multiple sclerosis in various parts of the world including the USA and UK. In the near future, it is expected that the FDA in the USA and the MHRA in Europe will approve the use of this toxin in idiopathic detrusor overactivity (IDO). Over the last decade, there has been an explosion of publications on the use of this bladder therapy which is primarily used in patients with symptoms of overactive bladder (OAB) and/or detrusor overactivity (DO) who have failed conservative measures and oral medication with antimuscarinics. This is typically due to poor efficacy with antimuscarinics or poor tolerability due to side effects such as dry mouth, dry eyes, blurred vision and constipation. Initially proof of concept/open labelled studies were conducted, whilst later studies focussed on mechanisms of action. From these studies it became apparent that BTX was not simply working by efferent blockade at the neuromuscular junction, as in skeletal muscle, but was likely to have an effect on sensory nerves. Later publications emerged on technique of administration and evidence from level 1 small randomised blinded placebo-controlled trials in both NDO and IDO. Recently drug sponsored phase II and III double-blind randomised placebo-controlled trials have been conducted in both NDO and IDO. These trials are now published with the exception of the phase III data in IDO at the present time.

It has been 11 years since the first publications on the use of intradetrusor botulinum toxin-A (BTX-A) injections to treat neurogenic detrusor overactivity (NDO) in patients with spinal cord injury (SCI) [12]. OnabotulinumtoxinA (Botox®; Allergan, Ltd., Irvine, USA) has recently been approved for use in the bladder of neurogenic patients with SCI or multiple sclerosis in various parts of the world. In the near future, it is expected that the FDA in the USA and the MHRA in Europe will approve the use of this toxin in idiopathic overactive bladder. Over the last decade, there has been an explosion of publications on the use of this bladder therapy which is primarily used in patients with symptoms of overactive bladder (OAB) and/or detrusor overactivity (DO) who have failed conservative measures and oral medication with antimuscarinics. This is typically due to poor efficacy with antimuscarinics or poor tolerability due to side effects such as dry mouth, dry eyes, blurred vision and constipation. Initially proof of concept/open labelled studies were conducted, whilst later studies focussed on mechanisms of action. From these studies it became apparent that BTX was not simply working by efferent blockade at the neuromuscular junction, as in skeletal muscle, but was likely to have an effect on sensory nerves. Later publications emerged on technique of administration and evidence from level 1 small randomised blinded placebo-controlled trials in both NDO and IDO. Recently drug sponsored phase II and III double-blind randomised placebo-controlled trials have been conducted in both NDO and IDO. These trials are now published with the exception of the phase III data in IDO (at the time of writing this chapter).

OAB is a syndrome characterised by urgency with or without urgency incontinence but usually accompanied by frequency and nocturia [3]. The majority of patients have proven DO but treatment is often instigated without this knowledge by community practitioners based on symptoms alone. Therapeutic options are split into initial treatment and specialised therapy. Initial treatment encompasses lifestyle interventions, ‘bladder training’ and the use of oral antimuscarnics [4]. Pharmacotherapy in most individuals is still the first-line treatment. In the past, if this failed and symptoms were intractable and had a significant impact on quality of life (QoL) patients were managed with augmentation cystoplasty or urinary diversion. More recently other therapeutic options have been developed and include sacral neuromodulation and BTX injections into the bladder.

BTX is a neurotoxin produced by the gram-positive anaerobic spore-producing organism Clostridium botulinum (Fig. 12.1). It is one of the most poisonous naturally occurring toxins known to mankind [5]. Its effects range from food poisoning known as ‘botulism’ to an acute and symmetrical paralysis. The severity of its toxic effects ranges from mild weakness to respiratory failure, coma and death. Seven distinct botulinum neurotoxins isoforms (A-G) have been isolated [6]. Types A and B are presently used in clinical medicine today but some other types are the subject of ongoing research. BTX-A is made up of a heavy and light chain connected by a disulphide bond [7]. Currently several pharmaceutical companies produce and market BTX-A. The two commonest used preparations in the urinary tract are Botox®(Allergan Pharmaceuticals Ltd., USA) and Dysport® (Ipsen Biopharm Ltd., UK). However other preparations are available such as Xeomin® (Merz Pharmaceuticals UK Ltd., Herts, UK), Prosigne® (Lanzhou Biological Products, Lanzhou, China) and PurTox® (Mentor Corporation, Madison, WI, USA). Botulinum toxin type B (BTX-B) is commercially available as Myobloc® in the USA (Elan Pharmaceuticals, Inc.) and Neurobloc® in Europe (Elan Pharma International Ltd.). BTX-A toxicity is measured in mouse units (mU), which is ‘the amount fatal to 50 % of a batch of Swiss Webster mice’ [8]. One unit of BOTOX® (Allergan, Ltd., USA) is considered equivalent to 3–4 units of DYSPORT® (Ipsen, Ltd., UK). This is an important point to keep in mind when analysing different studies, so as not to inadvertently utilise incorrect doses. In an attempt to prevent dose errors and to recognise the different formulations the FDA has had new terminology recently approved. This is summarised in Table 12.1.

A321341_1_En_12_Fig1_HTML.jpg

Fig. 12.1

A photomicrograph of Clostridium botulinum type A viewed using a Gram stain technique

Table 12.1

FDA approved terminology for BTX products

Trade name

Old drug name

New drug name

Botox

Botulinum toxin-A

OnabotulinumtoxinA

Botox cosmetic

Botulinum toxin-A

OnabotulinumtoxinA

Dysport

Botulinum toxin-A

AbobotulinumtoxinA

Xeomin

Botulinum toxin-A

IncobotulinumtoxinA

Myobloc

Botulinum toxin-B

RimabotulinumtoxinB

The use of BTX-A to treat OAB and DO has been recognised by several bodies including the European Association of Urology (EAU) [4] and the National Institute of Clinical Excellence (NICE) [9], to name but a few, and is now featured in their guidelines. In addition the toxin has been given a grade A recommendation by an independent expert European body [10] and in a recent largest of its kind systematic review BTX-A has been recommended in many aspects of lower urinary tract dysfunction [11]. In this chapter we will focus on mechanisms of action of BTX-A in the bladder, its clinical efficacy and safety with emphasis on randomised placebo-controlled trials, review techniques of administration and lastly its cost-effectiveness.

Mechanism of Action

The initial work on mechanisms of action of BTX was studied in skeletal muscle which suggested that the toxin prevented presynaptic vesicular acetylcholine (ACh) release. Four steps are involved in this process: binding, translocation, cleavage and inhibition of transmitter release [7]. Once the neurotoxin is exogenously administered, it diffuses to cholinergic terminals where it binds to the SV2 receptor [12]. Once bound the toxin is internalised inside endocytic vesicles and binds to the lipid bilayer of the vesicle. The heavy chain is thought to play a key role in translocating the light chain into the cytosol, which occurs after the cleavage of the disulphide bond between them [1315]. The BTX light chain acting like an enzyme is able to cleave SNARE proteins within the nerve terminal [16]. Botulinum toxins B, D, F and G cleave VAMP/Synaptobrevin, A and E cleave SNAP-25 and C cleaves both SNAP-25 and syntaxin [17]. As the SNARE proteins are essential for normal vesicular transport and fusion, botulinum neurotoxins are able to prevent the release of ACh at the pre-synaptic membrane with resultant blockage of synaptic transmission and flaccid paralysis in the target muscle (see Fig. 12.2). This was the rationale for the introduction of this therapy to treat OAB and DO [2]. ATP, a purinergic neurotransmitter is believed to be co-released with ACh from parasympathetic cholinergic nerve terminals [1819]. It has been postulated that ATP via purinergic mechanisms contributes a significant amount to unstable contractions in IDO [2021]. Studies on guinea pig [1922] and rat [1922] bladder strips have shown that BTX is able to impair both ACh and ATP release, suggesting that its use in treating patients with DO and symptoms of OAB is well justified. However, it soon became evident that patients were also experiencing a welcome improvement in the sensation of urinary urgency, which is the hallmark of OAB. As a result, scientists and clinicians began investigating the possible effects of BTX on afferent nerves. In recent years there is evidence to suggest that BTX-A modulates sensory neurotransmission, although the exact mechanism remains unclear [23].

A321341_1_En_12_Fig2_HTML.gif

Fig. 12.2

Mechanism of action at the neuromuscular junction (a) normal and (b) after exogenous BTX-A administration. (From Seth JH, Dowson C, Khan MS, et al. Botulinum toxin-A for the treatment of overactive bladder: UK contributions. J Clin Urol 2013;6:77, copyright 2013 by SAGE. Reprinted by permission of SAGE.)

The sensation of ‘bladder fullness’ is provided by the urothelium, which has a strong role in mechanosensation. C-fibres comprise up to two thirds of bladder afferent nerves, and it is thought that these fibres are involved in the reorganisation of the reflex activity seen in OAB. The other predominant afferent fibre is the Aδ fibre. The myelinated Aδ fibres tend to be located within the detrusor muscle and respond to detrusor stretch. The unmyelinated C fibres tend to be dispersed more widely, in the detrusor, suburothelium and adjacent to urothelial cells, providing nociception and are sensitive to changes in temperature and pH. These nerves are thought to be important in the pathogenesis of urgency and OAB [2425]. Intrathecal BTX-A injection causes a significant reduction in recordings from c-fibre activity, with a less significant reduction in Aδ fibre activity [26].

Sensory signalling is aided by numerous receptors and sensory peptide substances. These include the capsaicin-sensitive ion channel receptor TRPV1, which has been shown in human and animal studies to have importance in the sensation of noxious stimuli in the bladder. It is thought that the stimulation of urothelium by stretch, inflammation, acidity and temperature causes local release of a variety of neuropeptides, including nerve growth factor (NGF), ATP, substance P (SP), neurokinin A (NKA) and calcitonin gene-related peptide (CGRP) [27]. In a study of dorsal root ganglion (DRG) cells, BTX-A has been shown to reduce the release of SP and disables SNARE-dependent exocytosis of TRPV1 to the plasma membrane [2829]. The density of substance P and CGRP immunoreactive nerves was increased by 82 % in patients with IDO, suggesting that there is an increase in these types of afferent neurons in patients with this condition [30]. In an isolated rat bladder model, Rapp et al., investigated the effect of BTX-A on CGRP release [31]. A mixture of capsaicin and ATP was used to evoke CGRP release from the bladder and BTX-A (100 U) was found to significantly reduce this evoked release compared with controls [31]. In a similar model the same group of authors investigated the effect of BTX-A in acute injury (HCL) and chronic inflammation (cyclophosphamide) [32]. They found that both HCL and cyclophosphamide increased substance P neurotransmitter release but only HCL increased CGRP release compared to controls. The administration of BTX-A (10 U) significantly reduced the levels of these neurotransmitters in this inflammatory model to levels consistent with controls [32].

There is growing evidence that the urothelium releases ATP in response to stretch, which in turn activates suburothelial purinergic neurons, which conveys information to the CNS to activate micturition [33]. Urothelial release of evoked ATP is increased in animal models of DO (SCI and cyclophosphamide-induced cystitis) and BTX-A significantly reduces this evoked release compared to controls [3435]. Application of ATP in rat bladders in vivo precipitates DO and this is also reduced by BTX-A [36]. By reducing urothelial ACh release, BTX-A may block both excitatory afferent signalling and detrusor parasympathetic transmission during urine storage, similar to oral antimuscarinic medications [23].

Bladder biopsies from patients with either NDO or IDO have shown an increased expression of the capsaicin receptor, TRPV1 and the purinergic receptor, P2X3 compared to controls [37]. BTX-A treatment has been demonstrated to significantly reduce these receptor levels at 4 and 16 weeks post- treatment. The fastest change was in the P2X3 immunoreactivity, which correlated with improvements in urinary urgency at both time points.

NGF is a signalling molecule produced in the urothelium. NGF is necessary for the survival of sympathetic fibres and receptor expression on small sensory fibres. It is thought that ultimately NGF, produced by the urothelium and smooth muscle, plays a role in triggering pathology-induced changes in C-fibre afferent nerve excitability after mechanical stretch, causing increased urinary frequency, reflex bladder activity and unstable bladder contractions [38]. Through immunohistochemistry techniques it has also been demonstrated that the quantities of NGF in human bladder tissue is raised in conditions such as painful inflammatory conditions, OAB, interstitial cystitis, bladder outflow obstruction and chronic prostatitis [38]. It has also been suggested that NGF production in the superficial layers of the bladder may leak into the urine with bladder stretching. Using an enzyme-linked immunosorbent assay (ELISA), the levels of NGF in the urine can be quantified. Significantly higher levels of urinary NGF have been found in OAB compared with healthy controls with no bladder symptoms. Bladder tissue and urinary levels of NGF have been demonstrated to be significantly reduced after BTX-A treatment, which may explain the reduction of nerve sprouting in the urothelium [3940].

As afferent mechanisms may be important in the pathophysiology of DO, the excellent therapeutic efficacy of BTX in the bladder may in part be explained by this proposed dual (efferent and afferent) mechanism of action.

Clinical Efficacy and Safety of BTX-A to Treat OAB/DO

Neurogenic Detrusor Overactivity

Level 1 Evidence

In 2005, Schurch et al., reported the first double-blind randomised placebo-controlled trial involving 59 NDO patients, predominantly with spinal cord injury (SCI), who were randomised to receive in a 1:1:1 ratio, 200, 300 U OnabotulinumtoxinA or placebo [41]. The primary end point of urinary incontinence (UI) episodes decreased significantly at all time points except at 12 and 18 weeks in the 200 U group. Interestingly, when compared with placebo, improvements only reached statistical significance in the 300 U group at 2 and 6 weeks and in the 200 U group at 24 weeks. Patients receiving BTX-A at either dose showed significant improvement in QoL as assessed by the incontinence quality of life (I-QOL) questionnaire administered at all follow-up time points. In a subsequent publication the I-QoL scores were broken down into their individual domains of avoidance limiting behaviour, psychosocial impact and social embarrassment and the same improvements were observed at all time points for 300 and 200 U except for psychosocial impact and social embarrassment at 24 weeks [42]. The commonest reported adverse event was UTI in 22 %. The authors concluded that 200 or 300 U was equally efficacious. Surprisingly antimuscarinic use remained similar in the study in contrast to the preliminary pilot study by Schurch et al., in 2000 [1]. The urinary incontinence, urodynamic and I-QOL results are summarised in Table 12.2.

Table 12.2

Summary of results from a phase II double-blind randomised placebo-controlled trial of OnabotulinumtoxinA in patients with NDO

Time point (weeks)

300 U (n = 19)

200 U (n = 19)

Placebo (n = 21)

Daily UI episodes

Baseline

 2.8 (1.86)

 1.9 (1.78)

 3.0 (3.29)

2

−1.3 (1.39)a

−1.0 (1.67)b

−0.2 (1.02)

6

−1.5 (2.33)a

−0.9 (1.84)b

−0.2 (1.45)

12

−1.2 (1.66)b

−0.9 (2.14)

−0.3 (1.46)

18

−1.2 (1.16)b

−0.8 (2.75)

−0.3 (1.59)

24

−0.9 (1.34)b

−1.1 (1.92)a

−0.1 (1.09)

MCC (mL)

Baseline

293.6

260.2

254.6

2

479.6 (186.1)a, b

482.5 (215.8)a, b

282.0 (27.4)

6

462.7 (169.1)a, b

448.8 (182.1)a

299.6 (45.0)

24

398.2 (92.9)b

440.9 (174.2)a, b

301.0 (41.6)

RDV (mL)

Baseline

254.8

169.1

202.4

2

198.1 (8.6)

306.9 (135.3)b

206.7 (4.3)

6

268.5 (96.0b)

234.2 (47.3)

244.6 (42.6)

24

305.4 (72.4)

327.4 (144.6)a, b

226.4 (23.5)

MDP (cmH2O)

Baseline

92.6

77.0

79.1

2

41.0 (−66.3)a, b

31.6 (−52.9)a, b

71.4 (−7.7)

6

45.9 (−62.2)

40.1 (−44.4)a, b

69.0 (−10.1)

24

55.2 (−35.5)a, b

48.8 (−38.7)a, b

80.6 (−1.4)

Median I-QOL score

Baseline

44.3

48.9

42.6

2

72.7b

79.5b

49.4

6

77.3b

84.1b

56.3

12

72.7b

84.1b

45.5

18

69.3b

85.2b

46.0

24

67.0b

86.4b

44.3

From Schurch B, de SM, Denys P et al. Botulinum toxin type is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomised, placebo-controlled 6-month study. J Urol2005;174(1):196-200; and Schurch B, Denys P, Kozma CM, Reese PR, Slaton T, Barron RL. Botulinum toxin A improves the quality of life of patients with neurogenic urinary incontinence. Eur Urol2007;52(3):850-858

Mean values (mean change from baseline) unless indicated

UI urinary incontinence, MCC maximum cystometric capacity, RDV reflex detrusor volume

aStatistically significant within-group changes from baseline and versus placebo

bStatistically significant changes versus placebo

The first double-blind randomised placebo-controlled trial with the use of AbobotulinumtoxinA 500 U in NDO was subsequently published [43]. In this small study 17 patients received AbobotulinumtoxinA and 10 patients placebo. Tolterodine was allowed 1-week post-injection for no or insufficient effect. Tolterodine usage was higher in the placebo group compared with BTX-A over the 26-week study period. UI episodes and MDP were significantly reduced following AbobotulinumtoxinA injections compared to placebo throughout the study and MCC increased significantly except for the end of study time point at 26 weeks. QoL was globally improved in the BTX-A group compared with placebo.

This year a randomised multi-centre double-blinded placebo-controlled study was reported from Canada assessing OnabotulinumtoxinA 300 U compared to placebo in 57 patients [44]. The study demonstrated significant improvements in UI episodes and QoL using the I-QOL questionnaire at 6, 24 and 36 weeks compared to placebo. Urodynamic parameters were generally improved for up to 24 weeks. Antimuscarinics usage at 6 weeks in those that were taking them previously was 67 % and 94 % for OnabotulinumtoxinA and placebo groups, respectively. The commonest adverse event was UTI [44].

Recently in a large phase III double-blind multi-centre placebo-controlled trial 275 patients were randomised to OnabotulinumtoxinA at 200, 300 U and placebo [45]. This is the largest study of its kind and included patients with both multiple sclerosis (MS) and SCI who had ≥14 UI episodes per week. The primary end point of UI episodes at 6 weeks was significantly reduced with OnabotulinumtoxinA at both doses compared with placebo. At this time point fully continent rates were 7.6 %, 38 % and 39.6 % for placebo, 200 U and 300 U, respectively. I-QOL scores were also significantly greater at 6 weeks suggesting improved QoL in those treated with OnabotulinumtoxinA compared with placebo. The urodynamic and UI data is summarised in Table 12.3. The median duration of effect of OnaboutlinumtoxinA was 42.1 weeks in contrast to placebo, which was 13.1 weeks. Seventy-four patients received a second injection with similar benefits. Approximately 50 % were not performing clean intermittent self-catheterisation (CISC) at baseline. The need to instigate CISC was 12 %, 30 % and 42 % in the placebo, 200 U and 300 U groups, respectively. This was at the clinicians’ discretion as opposed to a cut-off residual value. No neutralising antibodies were detected in the serum at the exit point of the study. The study concluded 200 U was equivalent to 300 U but with a better safety profile. Although typically open labelled studies utilised 300 U for treating NDO, on the basis of the phase II and III clinical trial data, it is likely the initial recommended dose for this patient population will be 200 U OnabotulinumtoxinA.

Table 12.3

Summary of results from a phase III double-blind randomised placebo-controlled trial of OnabotulinumtoxinA in patients with NDO

Time point (weeks)

300 U (n = 91)

200 U (n = 92)

Placebo (n = 92)

Weekly UI episodes

Baseline

 31.2 (18.1)

 32.5 (18.4)

 36.7 (30.7)

2

−15.8 (25.8)a

−18.8 (16.7)b

 −9.7 (17.9)

6

−19.4 (25.7)a

−21.8 (18.1)a

−13.2 (20.0)

12

−19.8 (18.6)b

−20.5 (18.9)a

−12.2 (22.2)

MCC (mL)

Baseline

246.8 (149.1)

247.3 (147.6)

249.4 (139.3)

6

157.2 (185.2)b

157.0 (164.8)b

  6.5 (144.8)

PdetmaxIDC (cmH2O)

Baseline

 42.1 (33.2)

 51.7 (41.0)

 41.5 (31.2)

6

−26.9 (33.2)b

−28.5 (47.8)b

  6.4 (41.1)

BC mL/cmH2O

Baseline

64.7 (87.6)

54.6 (63.5)

 58.1 (76.2)

6

60.9 (147.3)c

71.5 (157.1)c

  2.7 (97.8)

Patients with no IDC %

6

59.5

64.4

 17.4

I-QOL Score

6

24.3b

24.4b

 11.7

12

25.9b

25.1b

  8.6

From Cruz F, Herscorn S, Aliotta P et al. Efficacy and Safety of OnabotulinumtoxinA in Patients with Urinary Incontinence Due to Neurogenic Detrusor Overactivity: A Randomised, Double-Blind, Placebo-Controlled Trial. Eur Urol. 2011 Oct;60(4):742-50

Mean baseline and change from baseline scores and (standard deviation)

UI urinary incontinence, MCC maximum cystometric capacity, PdetmaxIDC maximum detrusor pressure during first involuntary detrusor contraction, BC bladder compliance

a p < 0.01

b p < 0.001

c p < 0.05 vs. placebo

Other Relevant Studies and Study Populations

Patient satisfaction is now regarded as an important parameter to assess following treatments especially newer therapies. Using a 5-point scale of very dissatisfied (1) to very satisfied (5) injections of 500 U AbobotulinumtoxinA was shown to improve the satisfaction score from a mean score of 1.6–3.8 in 16 NDO patients [46]. Hori et al., have also recently reported on patients satisfaction in a group of patients with SCI and NDO treated with AbobotulinumtoxinA [47]. Mean satisfaction scores were 6.2/10 and 90 % of patients were happy to have AbobotulinumtoxinA treatment as a long-term treatment strategy. Only 15 % would consider a permanent alternative solution such as clam ileocystoplasty.

The majority of studies show improvements in QoL with OnabotulinumtoxinA and AbobotulinumtoxinA injections, however, Kalsi et al., using the UDI-6 and IIQ-7 QoL questionnaires found a statistically significant correlation between improvements in QoL with improvements in frequency, urgency and urge urinary incontinence but not for urodynamic parameters in NDO patients [48].

How quickly do OnabotulinumtoxinA injections begin to change OAB symptoms? In our experience this has been quite variable ranging between 2 days and 2 weeks, although we have had 2 patients who have only experienced a change in symptoms after 4 weeks. Kalsi et al., recently addressed this with a 7-day voiding diary immediately after injection [49]. In the NDO group significant improvements compared to baseline were demonstrated as early as 2 days for urgency, frequency and nocturia with significant improvements with incontinence episodes by day 3.

Grosse et al., recently tried to establish whether any differences could be found when treating NDO with AbobotulinumtoxinA or OnabotulinumtoxinA and whether treatment with increasing doses of AbobotulinumtoxinA would correlate with a dose-dependent effect [50]. Limitations included its retrospective nature and that the OnabotulinumtoxinA group was a matched population of cases. Furthermore doses of AbobotulinumtoxinA varied between 500 and 1,000 U and of OnabotulinumtoxinA between 200 and 400 U. No significant differences were identified between the two formulations apart from continence volume being greater at 3 months in favour of AbobotulinumtoxinA. Furthermore no dose-dependent trend could be seen in clinical and urodynamic parameters at 3 and 9 months between the AbobotulinumtoxinA doses, however, at higher doses of toxin, time between repeat injections appeared longer although this was not statistically significant [50]. Recently a comprehensive systematic review has tried to address this question [11]. A full comprehensive review of the BTX-A literature was conducted and the authors concluded there was good evidence showing the benefits of both OnabotulinumtoxinA and AbobotulinumtoxinA in the treatment of NDO in adults; however, OnabotulinumtoxinA is better studied than abobotulinumtoxinA. Furthermore due to the heterogeneity of study protocols, direct comparisons were not possible. Both formulations improved symptoms, urodynamics and QoL and although interinjection interval and failure rates were quite wide ranging, they were similar between the two toxin formulations [11].

Kuo has also recently conducted a comparative study in patients with NDO with either cerebral vascular accident (CVA) or a suprasacral spinal cord lesion. Both groups were injected with 200 U OnabotulinumtoxinA [51]. Although reflex volume and MCC increased in those with CVA, large post-void residuals were noted with little change in incontinence. Overall, however a successful result (either continence or a subjective improvement in incontinence) was noted in only 50 % in those with CVA compared with 92 % in the SCI group. Further study in this area is required but certainly this study highlights that not all neurogenic bladder responds to BTX-A treatment equally and aetiology maybe significant with regard to outcomes.

Finally, Giannantoni et al., recently reported on 6 patients with NDO and severe Parkinson’s disease or Multiple System Atrophy successfully treated with OnabotulinumtoxinA 300 U [52]. Significant improvements in OAB symptoms, urodynamics and QoL as assessed by the I-QoL were observed following treatment at 1 and 3 months post-injection. These authors have also published results on 8 patients treated with OnabotulinumtoxinA 100 U in Parkinson’s disease patients alone with similar good results [53].

Repeated Injections

Several authors have published their results of repeated injections of BTX-A in NDO and this has recently been summarised [54]. Studies using OnabotulinumtoxinA [5560] and AbobotulinumtoxinA [6064] have both been published and overall the data suggests that repeated injections are equally efficacious as the first with continued benefit with regard to OAB symptoms, urodynamic parameters and QoL improvement [54]. However due to the reporting of these studies (some report on all injections, some report on a set number of patients who have had for example 5 injections), it is difficult to assess true efficacy as all patients who had BTX-A may not have been included. The largest study from Del Popolo et al., assessed Abobotulinum toxin at varying doses of 500–1,000 U in a cohort of 199 SCI patients with NDO [62]. In total 590 injections were performed in 199 patients with 49 patients having at least 5 injections. Statistical analysis was performed for up to 7 injections and significant improvements in maximum cystometric capacity, reflex detrusor volume and bladder compliance were observed. In addition UI rates were significantly reduced as was pad usage. Patient satisfaction improved after each injection compared with baseline and in only 10 % of patients did the effects of the toxin last <6 months [62]. Khan et al., reported on repeated injections in a cohort of 137 patients with multiple sclerosis and NDO treated with OnabotulinumtoxinA 300 U [59]. QoL as assessed by the UDI-6 and IIQ-7 showed considerable improvement 4 weeks after each treatment even when repeated six times. Four weeks after the first treatment, 76 % became completely dry. This efficacy was sustained with repeat injections. The median interval between re-treatments remained constant at 12–13 months. The vast majority were required to perform CISC post-treatment. Finally, Manfred Stoehrer’ group have published on their long-term experience using both OnabotulinumtoxinA (200–300 U) and AbobotulinumtoxinA (750–1,000 U) [6064]. No significant differences were found in the interval between injections 1–4. Duration of effect for injections 1–4 was approximately 10 months with no difference between the two formulations. Significant improvements in maximum cystometric capacity and reflex detrusor volume were observed. Although bladder compliance improved, this did not reach statistical significance for injections 1–3. Similar outcomes were shown with further follow-up with a mean duration of benefit of 8.7 months [60].

A concern from clinicians is the potential for fibrosis after repeated BTX-A injections, which may lead to reduced bladder compliance and worsening of OAB symptoms. In our repeat BTX-A study, bladder compliance is significantly improved following each repeated injection and no significant difference was demonstrated when comparing compliance following the first and fourth injection [65]. A recent histological study in NDO patients suggested OnabotulinumtoxinA-injected bladders (1–4 injections) had less fibrosis when compared to BTX-A naïve patients [66]. This was based on their own grading scale using a cut-off of 20 %, i.e. mild fibrosis if occupying <20 % of muscle fibres and/or submucosa and important fibrosis if >20 %. No differences in inflammation and oedema were observed in the two groups. Whether fibrosis occurs after 4 injections is yet to be determined but further study is required to assess this, especially as more patients may opt for repeated BTX-A injections over surgical treatment such as augmentation cystoplasty in managing their symptoms. Hafekamp et al., reported on a lack of structural changes before and after BTX injections in patients with NDO [67]. Contrary to reports with striated muscle very little axonal sprouting was observed following treatment. Apostolidis et al., assessed biopsies after one or a limited number of repeat BTX-A treatments and found no significant change in baseline inflammation [68]. Mild fibrosis was seen in 2.2 % of all biopsies which did not alter pre- or post-treatment. No evidence of dysplasia was seen.

Idiopathic Detrusor Overactivity and Bladder Oversensitivity

Level 1 Evidence

Our group reported on the first randomised, double-blind, placebo-controlled trial reporting the efficacy and safety of OnabotulinumtoxinA 200 U in treating patients with IDO [69]. The primary end point of the study, significantly increase in maximum cystometric capacity at 3 months, was achieved following OnabotulinumtoxinA compared with placebo. Overall significant improvements in OAB symptoms, urodynamic parameters and QoL as assessed by UDI-6, IIQ-7 and KHQ were observed in favour of OnabotulinumtoxinA in this small study [6970]. In the OnabotulinumtoxinA group, 50 % of patients were continent at follow-up, and the improvement lasted 24 weeks. Urinary frequency normalised in 57 % of patients in the OnabotulinumtoxinA group at 4 weeks and 36 % maintained this benefit at 24 weeks. Until this study the need to instigate CISC was reported typically between 0 and 15 %; however, the incidence in this study was 37.5 %. Since then other level 1 ongoing studies reporting experience with OnabotulinumtoxinA have confirmed that this figure is accurate for 200 U [6571]. The other common side effect was UTI, which occurred in 20.5 %, despite the use of prophylactic antibiotics. This is similar to the rate reported in the literature [4172].

Since this study was conducted and reported, three other randomised placebo-controlled trials have been published utilising BTX-A in patients with IDO [717374]. Brubaker et al., randomised female patients in a 2:1 fashion to OnabotulinumtoxinA 200 U or placebo [71]. An interval analysis suggested high rates of voiding dysfunction, necessitating CISC (43 %), and as a result the trial was halted. However, utilising the Patient Global Impression of Improvement Score (PGI-I), where patient perception is assessed on a 7-point scale, 60 % felt an improvement in the OnabotulinumtoxinA group with mean scores at 2 months better compared with placebo. Significant reduction in UI episodes were also observed in favour of OnabotulinumtoxinA at 1 and 2 months post-injection. Time to failure was longer in those treated with OnabotulinumtoxinA compared with placebo. Incidence of UTI was also high and was more prevalent in those who received OnabotulinumtoxinA and in particular in those performing CISC.

In another trial, OAB patients were recruited and randomised between OnabotulinumtoxinA 300 U, 200 U and placebo [73]. DO was not a prerequisite for inclusion into the study. Only the preliminary results, i.e. 6-week follow-up have been published so far and as the investigators were blinded to the doses, the two OnabotulinumtoxinA groups’ data were combined for the purpose of this analysis. Fifteen patients received either OnabotulinumtoxinA 200 or 300 U and 7 patient’s placebo. Significant reductions in UI episodes, 24-h pad weights and number of pads per day with improvements in QoL were observed for OnabotulinumtoxinA compared to placebo. However, no significant differences were observed between the two groups when assessing frequency, nocturia, maximum cystomteric capacity or reflex detrusor volume. Adverse events to note included 18 % with UTI and 27 % in the OnabotulinumtoxinA group had high PVR >200 mL. Despite the latter, only one patient was commenced on CISC.

A recent drug sponsored large phase II dose escalation randomised placebo-controlled study assessing OnabotulinumtoxinA in patients with refractory OAB was recently reported [74]. This multi-centre international study recruited 313 patients and randomised patients to 50, 100, 150, 200, 300 U and placebo. Approximately 75 % had IDO and the rest had bladder oversensitivity (BO), i.e. symptoms of OAB with no DO on urodynamics. At week 12, mean change from baseline in UUI episodes was –17.4, –20.7, –18.4, –23.0, –19.6 and –19.4 for the placebo and OnabotulinumtoxinA dose groups of 50 U, 100 U, 150 U, 200 U and 300 U, respectively. Dry rates were 15.9 %, 29.8 %, 37.0 %, 40.8 %, 30.9 % and 57.1 % in the placebo, and 50 U, 100 U, 150 U, 200 U and 300 U dose groups, respectively. Although a clear placebo effect is seen, there were statistically significant differences between active treatment and placebo at various time points. Using non-parametric analysis and a rank residual score, a dose-dependent effect was observed with minimal additional benefit for this parameter with doses >150 U. The lowest dose of 50 U did not appear to be as effective as doses 100–300 U. Those with IDO or BO had similar benefits. In a separate report assessing urodynamics, all doses were associated with significant increases in maximum cystometric capacity compared to baseline at 6 weeks; however, at 36 weeks this was only the case for 150, 200 and 300 U [75]. Reductions in UUI episodes appeared to be similar regardless of whether DO was present or not. Dose-dependent increases in PVR were observed up to 200 U. The maximal effect of increased PVR was at 2 weeks and thereafter values declined to 36 weeks. Adverse events reported significantly higher in the OnabotulinumtoxinA groups compared with placebo were high PVRs and UTI. The percentage of patients requiring an indwelling catheter or CISC were 0 %, 5.4 %, 10.9 %, 20.0 %, 21.2 % and 16.4 % for placebo, 50 U, 100 U, 150 U, 200 U and 300 U, respectively.

Three other small open labelled studies have also shown symptom benefit in the use of OnabotulinumtoxinA in treating BO [7678]. However in another randomised double-blind placebo-controlled study, the benefits were less evident [79]. The study utilised 100 U OnabotulinumtoxinA and although the primary end point of increase in maximum cystometric capacity was met in favour of OnabotulinumtoxinA this did not translate into OAB symptom or durable QoL benefit for patients with poor overall response rates.

Other Relevant Studies

Kalsi et al., using the UDI-6 and IIQ-7 questionnaires found a statistically significant correlation between improvements in QoL with improvements in urgency and urge urinary incontinence but not urodynamic parameters in IDO patients treated with OnabotulinumtoxinA 200 U [48]. The same group studied as to when OAB symptoms change following injection of the same dose [49]. The study showed frequency, urgency and UUI was significantly reduced by day 4 following treatment. Nocturia took longer to reduce significantly. Urgency remained significantly reduced after day 4 up until week 4 but frequency and UUI were a little more variable, although by week 4 all OAB symptoms including nocturia were significantly less compared to baseline.

In order to combat the risk of developing high PVR in patients with IDO an interesting and novel study compared bladder injections with bladder and urethral sphincter injections in combination in 44 predominantly female patients [80]. Sphincteric injections were given to those who had a PVR >15 mL at baseline. In total 200–300 U OnabotulinumtoxinA were administered with 50–100 U given in the external sphincter. Improvements in urinary frequency, pad usage and urodynamic parameters were observed. A significant PVR compared to baseline at 4 weeks was seen in those with bladder injection alone (78 mL) compared to combination treatment (28 mL). A potential concern with the technique was the development of de novo stress urinary incontinence in those who received sphincteric injections. Pad usage at 4 weeks was similar in both groups and when assessing questionnaires specific to this aspect, although more patients answered in favour of stress symptoms in the combination group (bladder + sphincter injection), this did not reach statistical significance.

White et al., have recently demonstrated that the use of OnabotulinumtoxinA 200 U appears to be equally efficacious in the elderly population (>75 years of age) [81]. In this study 2/3 of the patients had IDO and 1/3 NDO with 4 patients presenting with mixed incontinence. Approximately 75 % reported >50 % improvement in symptoms following OnabotulinumtoxinA injections at 1 month. Significant reductions were observed for frequency and pad usage per 24 h compared with baseline values. Five patients did not initially respond with two of these five responding after a further injection of OnabotulinumtoxinA. None of the patients interestingly developed high PVR or any other major complications. Mean duration of benefit was approximately 7 months.

In 2007, the first sets of studies using AbobotulinumtoxinA in the management of IDO were published. Ghalayini et al., published on their small series of both NDO and IDO patients treated with 500 U. In the IDO group consisting of 16 patients, significant improvements in OAB symptoms, urodynamic parameters and pad usage were seen at 6 weeks following treatment [46]. Median duration of action was 5 months. One patient developed retention of urine and 3 others required CISC for a short period of time. Another study from the UK utilised 500 U in treating refractory IDO also suggested significant benefit [82]. Sixty-three percent of patients were dry at 1 week and 32 % at 3 and 6 months. Significant reductions in frequency and urgency were seen up to 6 months compared to baseline. Pad usage was significantly less after 6 weeks of treatment. Although trends of improvement were seen in urodynamic parameters only first desire to void was significantly increased in BTX-A treated patients at 3 months. DO seen in 100 % pre-injection had resolved in 40 % by 3 months. Again high rates of voiding dysfunction were seen with 35 % requiring an SPC or CISC at 6 weeks follow-up.

Repeated Injections

We followed up our original cohort of 34 patients involved in the first randomised double-blind placebo-controlled trial in patients with IDO [65]. Twenty patients received a repeat injection and of these nine subsequently received a third and fourth injection. OnabotulinumtoxinA doses of 100–300 U were used. Significant improvements in OAB symptoms and QoL were observed after each injection as compared with baseline. Maximum cystometric capacity and bladder compliance increased with decrease in the maximum detrusor pressure during filling cystometry. When comparing OAB symptoms, QoL and urodynamic parameters 3 months after the first and last injections, no significant differences were found. Nine patients had their BTX-A dose altered, with better outcomes in five. The commonest reported problems were difficulty in emptying the bladder requiring CISC (25 % after the first repeated injection) and UTI. This study is the first to report on OAB symptom outcomes and a dose optimisation strategy following repeated BTX-A injections in an IDO population. This dose optimisation protocol (selected patients had a reduction in dose to try to avoid the need to perform CISC and poor responders to initial treatment had their doses increased) improved outcomes in 5/9 (56 %) patients. Clearly larger scale studies are required with more patients before one can say this is a reasonable and safe approach to employ. In this study 3/4 (75 %) patients who were classified as poor responders had significantly better outcomes with higher doses of the toxin. A subanalysis of our patients series has suggested a high mean MDP (>110 cm H2O) at baseline was a predictor for a poor response [83]. In these patients OnabotulinumtoxinA 200 U may not be sufficient to improve clinical outcomes and/or patient subjective assessment but with higher doses they are seen to improve both subjectively and objectively. We have also assessed the issue of difficulty emptying the bladder and the need for CISC following OnabotulinumtoxinA treatment with 200 U and have shown that preoperative detrusor contractility variables, calculated from urodynamics, maybe helpful in predicting CISC use.

Khan et al., recently have reported on QoL outcomes following up to six repeated BTX-A injections in IDO patients [84]. In total 129 injections were performed in 81 patients, but <5 patients were assessed after 4 injections. The median inter-interval injection was 14 months. Significant and sustained improvements in QoL were seen using validated questionnaires. The CISC rate was 43 % and UTIs were seen in 15 %.

Finally in our experience few studies report on discontinuation rates and the reasons why. In our recent publication on 207 injections in 100 patients, efficacy was maintained in patients who had 5 injections in terms of OAB symptoms and QoL improvements [85]. The data suggested drop out rates were approximately 25 % for injections 1–2 and then no other patient discontinued beyond the second injection. The commonest reason for discontinuing treatment was poor efficacy (13 %) or dislike of CISC (11 %).

Technique of Injection

The original description of BTX-A injections for the treatment of NDO was through a collagen flexible needle using a rigid cystoscope [1]. Since then the technique has evolved but the way in which the toxin is administered into the bladder has not been standardised and indeed practice varies around the world. In the initial experience with BTX-A and NDO, the trigone was avoided on the assumption that paralysing the trigonal muscle might induce VUR. Since then there has been mounting evidence that BTX may also affect sensory nerves and that afferent mechanisms have an important role in the pathophysiology of DO [27]. Investigators in the USA have advocated injecting the trigone [86], based on the fact that this area of the bladder contains the highest density of nerve fibres, including afferent population. Recently two studies have demonstrated that trigonal injections do not induce VUR, putting to rest the debate frequently contested at international meetings in those involved with injecting [8788]. In an OAB population (4 with IDO and 7 with sensory urgency) video urodynamics 6 weeks following BTX-A injections totalling 200 U into the bladder base and trigone suggested no new VUR and in the one patient who had VUR pretreatment this did not worsen [87]. In another study in NDO patients similar results were obtained in a population of 21 patients whose bladders were injected with a total of 300 U OnabotulinumtoxinA of which 50 U were injected in the trigonal area [88]. Again no new cases of VUR were seen.

The ‘Dasgupta technique’ is a minimally invasive, daycase, local anaesthetic procedure utilising a flexible cystoscope to perform BTX-A injections [8990]. Prophylactic antibiotics and 20 mL of 2 % lignocaine intraurethral gel are administered prior to the procedure. The injections are evenly distributed over the dome, posterior, right and left lateral walls of the bladder, avoiding the trigone. The technique has obvious benefits in terms of cost and ease of administration. In addition, the needle length (4 mm) is such that injection beyond the bladder is unlikely. Furthermore as an ultra-fine needle is used the chance of backflow of the toxin after removal of the needle is reduced. The ‘Dasgupta technique’ is quick; the procedure taking on average 15–20 min to perform and is also well tolerated with pain scores approximately 3–4 out of 10 on a visual analogue scale [91]. This minimally invasive technique has been adopted by some clinicians in the USA to treat patients with refractory OAB using 100 U of OnabotulinumtoxinA [92]. Ten injections are utilised and injected submucosally into the bladder base and trigone only. In their series of 10 patients similar efficacy was reproduced compared with their older rigid cystoscopic technique involving 30 injection sites. The added benefit appears to be that no patient developed urinary retention or an elevated post-void residual with the use of a reduced dose of BTX-A and this modified technique. Another group in the USA also using the ‘Dasgupta technique’ found the procedure was well tolerated and safe to use in the ‘office’ (outpatient) setting [93]. In this study mean pain scores in females and males were 3.1 and 1.6 out of 10, respectively. Only 1 patient out of 27 requested sedation if they were to have another BTX injection.

Mehnert et al., conducted a contrast MRI-based study in 6 patients following BTX-A injections + contrast to try and determine where the injection were likely to be placed [94]. As expected the majority of the injections were placed in the detrusor muscle (82 %) but some of the contrast material was seen to reach the perivesical fat tissue outside the detrusor. The technique employed utilised a rigid cystoscope and a 22G needle (0.7 cm) and had a needle length of 8 mm which was inserted into the bladder wall and withdrawn halfway prior to injection. Two injection techniques, 30 or 10 injections, were compared with similar outcomes clinically and in terms of contrast material present within and outside the detrusor.

In an attempt to improve the tolerability of the rigid cystoscopic technique similar to what was initially described by Schurch et al. [1], electromotive drug administration (EMDA) of lignocaine was assessed in a pilot study with good results [95]. Patients were compared with standard lignocaine instillation transurethrally (n = 10) to lignocaine instillation enhanced by EMDA (n = 28). The mean pain scores using a 10-point scale were 4 versus 0.5 in the lignocaine and lignocaine EMDA-enhanced groups, respectively. Despite the EMDA, the technique still was cost-effective when compared to spinal or general anaesthesia.

Another topic of debate amongst clinicians is the exact location and ideal depth of injections. As mentioned earlier some believe the bladder base and trigone should be targeted and others feel that a more global bladder approach would be better, particularly in NDO patients. As afferent nerve endings are in the suburothelium, some advocate injecting, ideally, in this layer. In practical terms, experts feel wherever the injection is located, whether the suburothelium or the detrusor, there is likely to be some diffusion of BTX in either direction. In cases of suburothelial injections a ‘bleb’ is raised and can be readily seen during cystoscopy (Fig. 12.3). Whether these are present or absent appears not to effect efficacy in our opinion and is also a shared view from other clinicians familiar with the technique, suggesting that the therapeutic effect is similar, as long as the bladder is successfully injected and there is no inadvertent injection into the bladder lumen or ‘backspill’ from the injection into the lumen.

A321341_1_En_12_Fig3_HTML.jpg

Fig. 12.3

Injection of BTX-A using the Dasgupta technique; Suburothelial bleb seen below sheath

In attempt to address some of these questions, Kuo et al., randomised 45 patients with refractory IDO to detrusor, suburothelial or bladder base injections [96]. Detrusor and suburothelial injections consisted of 40 injections distributed over the bladder avoiding the trigone and the bladder base injections involved only 10 injections into the trigone. In all cases a total of 100 U OnabotulinumtoxinA was administered using a rigid cystoscope. Satisfaction scores at 3 months were best in the suburothelial and detrusor groups with at least 50 % improvement seen in 80 % and 93 % of the groups, respectively, which compared favourably with the bladder base group which achieved the same outcomes in only 67 %. At 6 months this decreased to 47 %, 67 % and 13 % for suburothelial, detrusor and bladder base injections, respectively. Interestingly, no significant differences were observed in OAB symptoms or the urgency severity score at 3 months. Although not statistically significant, difficulty with urination and high post-void residuals were noted in 33 % (detrusor), 47 % (suburothelial) and 13 % in the bladder base. Furthermore acute urinary retention was seen in 13 % in the detrusor and suburothelial groups and in none in the bladder base group. When assessing urodynamics, maximum cystometric capacity and PVR were significantly higher in the detrusor and suburothelial groups compared to bladder base injections at 3 months but conversely functional bladder capacity was statistically higher in the bladder base group. Furthermore no evidence of VUR was seen in any group after BTX-A injections confirming that it is unlikely trigonal injections promote VUR. Lucioni et al., in their study comparing trigonal and non-trigonal injections were not able to show a difference in symptoms or QoL scores between the two groups at any follow-up time point [97]. However, a recent study from Ireland by Manecksha et al., looked at trigone inclusive (20 injections—5 in the trigone and 15 outside the trigone in the bladder) versus trigone sparing (20 injections throughout the bladder) AbobotulinumtoxinA (500 IU total) injections into the bladder to treat refractory OAB [98]. Utilising the overactive bladder symptom score (OABSS), significant reductions were seen in the in overall score and in the urgency subscale in favour of trigone inclusive technique.

Very recently the concept of BTX-A instillation has come to light. Chuang et al., have used liposomes, phospholipid-bilayered vesicles, to potentially facilitate the passage of BTX-A through the urothelium in a rat model [99]. In this unique study baseline cystometrograms were performed and a day later liposomes, BTX-A or lipotoxin (BTX-A + liposomes) were instilled into the bladder for 1 h. On day 8 bladder hyperactivity was induced by instilling acetic acid into the rat bladder and further cystometrograms were recorded. The inter-contraction interval was reduced by 57 %, 56 % and only 21 % following acetic acid administration in the liposome, BTX-A and lipotoxin groups, respectively. This suggests lipotoxin pretreatment suppresses acetic acid-induced bladder hyperactivity. Furthermore lipotoxin pretreated rats had significantly less inflammation in the bladder as assessed by standard immunohistochemistry. Reduced SNAP-25 expression and increased CGRP expression (indicating less release from the suburothelium in response to the acetic acid) was observed in the lipotoxin group when compared to the other groups. This rat-based model is the first to support the use of liposomes to transmit BTX-A to the suburothelium; however, the mechanism by which this is achieved is not yet been established. None the less this promising initial study will hopefully prompt further research into the possibility of BTX-A benefits without the need to perform injections which would most likely translate into better patient tolerability. Since then Khrut et al., have conducted a pilot study using an animal model of DO and compared bladder wall injections and instillations [100]. In the animal study, the average intermicturition and threshold pressures, as well as the number and amplitude of non-voiding bladder contractions decreased significantly in both instillation and injection groups. Micturition pressure decreased significantly only in the intramural injection group. The same authors on this basis decided to conduct a pilot study in 16 patients with refractory IDO. Although the treatment of instillation was well tolerated, 9/16 patients noted no change in symptoms and in those that did derive benefit, the mean duration of action was 6.8 weeks. No significant change in contractility variables were noted either in the human study. This study suggests intravesical instillation alone is not as efficacious as bladder injections, certainly in humans, and any benefit appears short-lived. Whether altered drug delivery with carrier molecules into the suburothelium and detrusor in humans can improve these results is still yet to be determined.

Health Economics and Cost Considerations

There is a limited amount of literature available on the cost-effectiveness of BTX in treating OAB. The current preferred method to assess cost-effectiveness of a new procedure is the cost per quality adjusted life years (QALY) gained [101]. The cost-effectiveness ratio is typically the cost of the new intervention minus the cost of current practice divided by the new intervention QALY minus the current practice QALY. A cost-effectiveness ratio of <£20,000–30,000/QALY is considered cost-effective by NICE [102]. In the UK a cost-effectiveness analysis was conducted. Although a cost per QALY gained calculation was not possible due to the lack of data linking bladder symptoms of DO to utility data needed to calculate QALYs gained, costing of the procedure were calculated based on NHS standard costs and NHS resources used by typical patients [101103]. The overall costs of one set of OnabotulinumtoxinA injections including clinic consultation, basic investigations such as urine dipstick and an urodynamic study, the injection procedure with consumables, clinic review in the outpatient clinic post-injection with a further urine dipstick and post-void residual, equated to £826 per patient.

In the USA, a cost-effectiveness model was utilised to assess BTX-A injections in comparison to antimuscarinics in treating urge urinary incontinence [104]. A 2-year time horizon was modelled and this allowed for a repeat injection of BTX-A if necessary. BTX-A treatment was costed at $4392 versus $2563 for anticholinergics but was more effective than anticholinergics. The cost-effectiveness ratio, i.e. the cost per QALY gained was $14,377 (approximately £8830) indicating that the BTX-A treatment was extremely cost-effective.

A more recent multi-centre study in Germany has recently reported outcomes of OnabotulinumtoxinA 300 U in treating NDO and its cost implications [105]. In 136 patients resource data was available 12 months pre- and post-BTX-A injection to make a cost analysis. Significant reductions were observed following treatment in UTIs (68 % to 28 %), incontinence episodes (63 % to 33 %) and incontinence aids (58 % to 28 %). As a result, significant cost savings were possible based on less antibiotic costs to treat UTIs (from approximately €160 to €80/year) and less equipment, e.g. pads, catheter costs used for incontinence (from approximately €2 to €1/day).

Watanabe et al., have assessed the 3-year costs comparing treatment options in patients refractory to anticholinergics, namely sacral neuromodulation, BTX-A injections and augmentation cystoplasty [106]. Their study based from a US tax payers perspective, assessed initial costs for the procedures and follow-up costs for 3 years. Their findings suggested BTX-A was the most cost-effective approach over the study period assessed with the sensitivity analysis suggesting over 3 years, costs included $25,384–$27,357, $4586–$11,476 and $12,315–$16,830, for sacral neuromodulation, BTX-A and augmentation cystoplasty, respectively. Further longer term analysis would be necessary however, as BTX-A injections are likely to be repeated where as neuromodulation and augmentation cystoplasty are more permanent interventions. Furthermore this study and many others do not factor in costs related to adverse events of BTX-A, namely increased UTI rate and the costs related to CISC.

Another study compared OnabotulinumtoxinA 300 U (10 injections over 5 years) and augmentation cystoplasty using a decision analysis model and demonstrated BTX-A treatment was less expensive over 5 years, costing $28,065 and was more cost-effective over 5 years if the effect lasted for >5.1 months. The model was based on a surgical complication rate of 40 % but if this rate fell to <14 %, augmentation cystoplasty was cheaper over the 5 years [107].

Using a Markov analytical model, sacral neuromodulation was compared to BTX-A over 5 years [108]. Success was defined as a 50 % reduction in UI episodes, daytime frequency or pad usage. The cost-effectiveness analysis after a 5-year period showed 4.95 QALYs for neuromodulation compared to 4.72 for BTX. The 5-year costs were €25,780 for SNM and €19,353 for BTX. Sacral neuromodulation only became cost-effective after 4 years. In this analysis it was presumed both procedures were performed under general anaesthesia and OnabotulinumtoxinA 200 U was injected yearly. If the analysis factored in the BTX-A injections under local anaesthesia or when peripheral nerve evaluation or bilateral testing was used for neuromodulation, BTX-A injections were more cost-effective.

Conclusions

Over the last decade, BTX-A has truly established itself as an effective, safe and repeatable option to treat refractory OAB and DO. Significant improvements in symptoms, urodynamic parameters and QoL are achievable. The commonest side effects reported are UTI and voiding dysfunction necessitating CISC. This is less of an issue in the neurogenic population where a considerable amount of patients already will be utilising CISC, however is more relevant to those with IDO and careful counselling with regard to this is essential. The mechanisms of action of the toxin are clearly complex within the bladder and there is significant evidence now which confirms both motor and sensory effects. It is likely following the large phase II and III trials recently published for OnabotulinumtoxinA that doses of 100 U and 200 U will be recommended for IDO and NDO, respectively. In our experience this is generally correct; however, there are some patients who will need dose optimisation and may even require higher doses in order to achieve the required goals (high voiding pressures, symptom control, prevention of voiding dysfunction). Techniques vary around the world and adaptations of the technique can be performed to suit the patient, e.g. trigonal injection may help reduce voiding dysfunction but possibly at the risk of less duration of action. It is expected that FDA and MHRA approval is on the horizon, which can only be a step forward in the right direction, so that the millions of people who suffer with OAB can have better access and be helped by this remarkable toxin.

Acknowledgments

A Sahai, MS Khan and P Dasgupta acknowledges financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. They also acknowledge the support of the MRC Centre for Transplantation. Christopher Dowson for his assistance with the figures in the chapter.

References

1.

Schurch B, Stohrer M, Kramer G, Schmid DM, Gaul G, 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(3 Pt 1):692–7.PubMed

2.

Schurch B, Schmid DM, Stohrer M. Treatment of neurogenic incontinence with botulinum toxin A. N Engl J Med. 2000;342(9):665.PubMed

3.

Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21(2):167–78.PubMed

4.

Thuroff JW, Abrams P, Andersson KE, et al. EAU guidelines on urinary incontinence. Eur Urol. 2011;59(3):387–400.PubMed

5.

Gill DM. Bacterial toxins: a table of lethal amounts. Microbiol Rev. 1982;46(1):86–94.PubMedCentralPubMed

6.

Simpson LL. Molecular pharmacology of botulinum toxin and tetanus toxin. Annu Rev Pharmacol Toxicol. 1986;26:427–53.PubMed

7.

Dolly JO, Aoki KR. The structure and mode of action of different botulinum toxins. Eur J Neurol. 2006;13 Suppl 4:1–9.PubMed

8.

Harper M, Fowler CJ, Dasgupta P. Botulinum toxin and its applications in the lower urinary tract. BJU Int. 2004;93(6):702–6.PubMed

9.

NICE. Urinary incontinence. The management of urinary incontinence in women. Report No.: NICE Clinical Guideline 40;2006.

10.

Apostolidis A, Dasgupta P, Denys P, 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. 2009;55(1):100–19.

11.

Mangera A, Andersson K-E, Apostolidis A, et al. Contemporary management of lower urinary tract disease with Botulinum toxin A: a systematic review of Botox (OnabotulinumtoxinA) and Dysport (AbobotulinumtoxinA). Eur Urol. 2011;60(4):784–95.PubMed

12.

Dong M, Yeh F, Tepp WH, et al. SV2 is the protein receptor for botulinum neurotoxin A. Science. 2006;312(5773):592–6.PubMed

13.

Black JD, Dolly JO. Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. I. Ultrastructural autoradiographic localization and quantitation of distinct membrane acceptors for types A and B on motor nerves. J Cell Biol. 1986;103(2):521–34.PubMed

14.

Black JD, Dolly JO. Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis. J Cell Biol. 1986;103(2):535–44.PubMed

15.

Dolly JO, Black J, Williams RS, Melling J. Acceptors for botulinum neurotoxin reside on motor nerve terminals and mediate its internalization. Nature. 1984;307(5950):457–60.PubMed

16.

Herreros J, Lalli G, Montecucco G, Schiavo G. Pathophysiological properties of clostridial neurotoxins in The comprehensive sourcebook of bacterial protein toxins. London: Academic; 2006.

17.

Schiavo G, Matteoli M, Montecucco C. Neurotoxins affecting neuroexocytosis. Physiol Rev. 2000;80(2):717–66.PubMed

18.

Burnstock G. Purinergic nerves. Pharmacol Rev. 1972;24(3):509–81.PubMed

19.

Mackenzie I, Burnstock G, Dolly JO. The effects of purified botulinum neurotoxin type A on cholinergic, adrenergic and non-adrenergic, atropine-resistant autonomic neuromuscular transmission. Neuroscience. 1982;7(4):997–1006.PubMed

20.

Bayliss M, Wu C, Newgreen D, Mundy AR, Fry CH. A quantitative study of atropine-resistant contractile responses in human detrusor smooth muscle, from stable, unstable and obstructed bladders. J Urol. 1999;162(5):1833–9.PubMed

21.

O’Reilly BA, Kosaka AH, Knight GF, et al. P2X receptors and their role in female idiopathic detrusor instability. J Urol. 2002;167(1):157–64.PubMed

22.

Smith CP, Franks ME, McNeil BK, et al. Effect of botulinum toxin A on the autonomic nervous system of the rat lower urinary tract. J Urol. 2003;169(5):1896–900.PubMed

23.

Kanai A, Wyndaele JJ, Andersson KE, et al. Researching bladder afferents-determining the effects of beta(3) -adrenergic receptor agonists and botulinum toxin type-A. Neurourol Urodyn. 2011;30(5):684–91.PubMed

24.

de Groat WC, Yoshimura N. Plasticity in reflex pathways to the lower urinary tract following spinal cord injury. Exp Neurol. 2012;235(1):123–32.PubMedCentralPubMed

25.

Michel MC, Chapple CR. Basic mechanisms of urgency: roles and benefits of pharmacotherapy. World J Urol. 2009;27(6):705–9.PubMedCentralPubMed

26.

Duggan MJ, Quinn CP, Chaddock JA, et al. Inhibition of release of neurotransmitters from rat dorsal root ganglia by a novel conjugate of a Clostridium botulinum toxin A endopeptidase fragment and Erythrina cristagalli lectin. J Biol Chem. 2002;277(38):34846–52.PubMed

27.

Apostolidis A, Dasgupta P, Fowler CJ. Proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity. Eur Urol. 2006;49(4):644–50.PubMed

28.

Morenilla-Palao C, Planells-Cases R, Garcia-Sanz N, Ferrer-Montiel A. Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity. J Biol Chem. 2004;279(24):25665–72.PubMed

29.

Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon. 2000;38(2):245–58.PubMed

30.

Smet PJ, Moore KH, Jonavicius J. Distribution and colocalization of calcitonin gene-related peptide, tachykinins, and vasoactive intestinal peptide in normal and idiopathic unstable human urinary bladder. Lab Invest. 1997;77(1):37–49.PubMed

31.

Rapp DE, Turk KW, Bales GT, Cook SP. Botulinum toxin type a inhibits calcitonin gene-related peptide release from isolated rat bladder. J Urol. 2006;175(3 Pt 1):1138–42.PubMed

32.

Lucioni A, Bales GT, Lotan TL, McGehee DS, Cook SP, Rapp DE. Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU Int. 2008;101(3):366–70.PubMed

33.

Burnstock G. Therapeutic potential of purinergic signalling for diseases of the urinary tract. BJU Int. 2011;107(2):192–204.PubMed

34.

Khera M, Somogyi GT, Kiss S, Boone TB, Smith CP. Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int. 2004;45(7):987–93.PubMed

35.

Smith CP, Vemulakonda VM, Kiss S, Boone TB, Somogyi GT. Enhanced ATP release from rat bladder urothelium during chronic bladder inflammation: effect of botulinum toxin A. Neurochem Int. 2005;47(4):291–7.PubMed

36.

Atiemo H, Wynes J, Chuo J, Nipkow L, Sklar GN, Chai TC. Effect of botulinum toxin on detrusor overactivity induced by intravesical adenosine triphosphate and capsaicin in a rat model. Urology. 2005;65(3):622–6.PubMed

37.

Apostolidis A, Popat R, Yiangou Y, et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol. 2005;174(3):977–82.PubMed

38.

Kuo HC, Liu HT, Chancellor MB. Can urinary nerve growth factor be a biomarker for overactive bladder? Rev Urol. 2010;12(2–3):e69–77.PubMedCentralPubMed

39.

Giannantoni A, Di Stasi SM, Nardicchi V, et al. Botulinum-A toxin injections into the detrusor muscle decrease nerve growth factor bladder tissue levels in patients with neurogenic detrusor overactivity. J Urol. 2006;175(6):2341–4.PubMed

40.

Liu HT, Chancellor MB, Kuo HC. Urinary nerve growth factor levels are elevated in patients with detrusor overactivity and decreased in responders to detrusor botulinum toxin-A injection. Eur Urol. 2009;56(4):700–6.PubMed

41.

Schurch B, de SM, Denys P, 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(1):196–200.PubMed

42.

Schurch B, Denys P, Kozma CM, Reese PR, Slaton T, Barron RL. Botulinum toxin A improves the quality of life of patients with neurogenic urinary incontinence. Eur Urol. 2007;52(3):850–8.PubMed

43.

Ehren I, Volz D, Farrelly E, 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(4):335–40.PubMed

44.

Herschorn S, Gajewski J, Ethans K, et al. Efficacy of botulinum toxin A injection for neurogenic detrusor overactivity and urinary incontinence: a randomized, double-blind trial. J Urol. 2011;185(6):2229–35.PubMed

45.

Cruz F, Herschorn S, Aliotta P, et al. Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial. Eur Urol. 2011;60(4):742–50.PubMed

46.

Ghalayini IF, Al-Ghazo MA. Intradetrusor injection of botulinum-A toxin in patients with idiopathic and neurogenic detrusor overactivity: urodynamic outcome and patient satisfaction. Neurourol Urodyn. 2007;26(4):531–6.PubMed

47.

Hori S, Patki P, Attar KH, Ismail S, Vasconcelos JC, Shah PJ. Patients’ perspective of botulinum toxin-A as a long-term treatment option for neurogenic detrusor overactivity secondary to spinal cord injury. BJU Int. 2009;104(2):216–20.PubMed

48.

Kalsi V, Apostolidis A, Popat R, Gonzales G, Fowler CJ, 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(3):528–35.PubMed

49.

Kalsi V, Apostolidis A, Gonzales G, Elneil S, Dasgupta P, Fowler CJ. Early effect on the overactive bladder symptoms following botulinum neurotoxin type A injections for detrusor overactivity. Eur Urol. 2008;54(1):181–7.PubMed

50.

Grosse J, Kramer G, Jakse G. Comparing two types of botulinum-A toxin detrusor injections in patients with severe neurogenic detrusor overactivity: a case-control study. BJU Int. 2009;104(5):651–6.PubMed

51.

Kuo HC. Therapeutic effects of suburothelial injection of botulinum a toxin for neurogenic detrusor overactivity due to chronic cerebrovascular accident and spinal cord lesions. Urology. 2006;67(2):232–6.PubMed

52.

Giannantoni A, Rossi A, Mearini E, Zingaro MD, Porena M, Berardelli A. Botulinum toxin A for overactive bladder and detrusor muscle overactivity in patients with Parkinson’s disease and multiple system atrophy. J Urol. 2009;182(4):1453–7.PubMed

53.

Giannantoni A, Conte A, Proietti S, et al. Botulinum toxin type A in patients with Parkinson’s disease and refractory overactive bladder. J Urol. 2011;186(3):960–4.PubMed

54.

Dowson C, Khan MS, Dasgupta P, Sahai A. Repeat botulinum toxin-A injections for treatment of adult detrusor overactivity. Nat Rev Urol. 2010;7(12):661–7.PubMed

55.

Giannantoni A, Mearini E, Del ZM, Porena M. Six-year follow-up of botulinum toxin A intradetrusorial injections in patients with refractory neurogenic detrusor overactivity: clinical and urodynamic results. Eur Urol. 2009;55(3):705–11.PubMed

56.

Kalsi V, Gonzales G, Popat R, et al. Botulinum injections for the treatment of bladder symptoms of multiple sclerosis. Ann Neurol. 2007;62(5):452–7.PubMed

57.

Karsenty G, Reitz A, Lindemann G, Boy S, 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(6):1193–7.PubMed

58.

Pannek J, Gocking K, Bersch U. Long-term effects of repeated intradetrusor botulinum neurotoxin A injections on detrusor function in patients with neurogenic bladder dysfunction. BJU Int. 2009;104(9):1246–50.PubMed

59.

Khan S, Game X, Kalsi V, et al. Long-term effect on quality of life of repeat detrusor injections of botulinum neurotoxin-A for detrusor overactivity in patients with multiple sclerosis. J Urol. 2011;185(4):1344–9.PubMed

60.

Stoehrer M, Wolff A, Kramer G, et al. Treatment of neurogenic detrusor overactivity with botulinum toxin A: the first seven years. Urol Int. 2009;83(4):379–85.PubMed

61.

Akbar M, Abel R, Seyler TM, et al. Repeated botulinum-A toxin injections in the treatment of myelodysplastic children and patients with spinal cord injuries with neurogenic bladder dysfunction. BJU Int. 2007;100(3):639–45.PubMed

62.

Del PG, Filocamo MT, Li Marzi V, et al. Neurogenic detrusor overactivity treated with english botulinum toxin a: 8-year experience of one single centre. Eur Urol. 2008;53(5):1013–20.

63.

Ghalayini IF, Al-Ghazo MA, Elnasser ZA. Is efficacy of repeated intradetrusor botulinum toxin type A (Dysport((R))) injections dose dependent? Clinical and urodynamic results after four injections in patients with drug-resistant neurogenic detrusor overactivity. Int Urol Nephrol. 2009;41(4):805–13.PubMed

64.

Grosse J, Kramer G, Stohrer M. Success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol. 2005;47(5):653–9.PubMed

65.

Sahai A, Dowson C, Khan MS, Dasgupta P. Repeated injections of botulinum toxin-A for idiopathic detrusor overactivity. Urology. 2010;75(3):552–8.PubMed

66.

Comperat E, Reitz A, Delcourt A, Capron F, Denys P, Chartier-Kastler E. 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. 2006;50(5):1058–64.PubMed

67.

Haferkamp A, Schurch B, Reitz A, et al. Lack of ultrastructural detrusor changes following endoscopic injection of botulinum toxin type a in overactive neurogenic bladder. Eur Urol. 2004;46(6):784–91.PubMed

68.

Apostolidis A, Jacques TS, Freeman A, et al. 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. 2008;53(6):1245–53.PubMed

69.

Sahai A, Khan MS, 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(6):2231–6.PubMed

70.

Sahai A, Dowson C, Khan MS, Dasgupta P. Improvement in quality of life after botulinum toxin-A injections for idiopathic detrusor overactivity: results from a randomized double-blind placebo-controlled trial. BJU Int. 2009;103(11):1509–15.PubMed

71.

Brubaker L, Richter HE, Visco A, et al. Refractory idiopathic urge urinary incontinence and botulinum A injection. J Urol. 2008;180(1):217–22.PubMedCentralPubMed

72.

Werner M, Schmid DM, Schussler B. Efficacy of botulinum-A toxin in the treatment of detrusor overactivity incontinence: a prospective nonrandomized study. Am J Obstet Gynecol. 2005;192(5):1735–40.PubMed

73.

Flynn MK, Amundsen CL, Perevich M, Liu F, Webster GD. Outcome of a randomized, double-blind, placebo controlled trial of botulinum A toxin for refractory overactive bladder. J Urol. 2009;181(6):2608–15.PubMedCentralPubMed

74.

Dmochowski R, Chapple C, Nitti VW, et al. Efficacy and safety of onabotulinumtoxinA for idiopathic overactive bladder: a double-blind, placebo controlled, randomized, dose ranging trial. J Urol. 2010;184(6):2416–22.PubMed

75.

Rovner E, Kennelly M, Schulte-Baukloh H, Zhou J, Haag-Molkenteller C, Dasgupta P. Urodynamic results and clinical outcomes with intradetrusor injections of onabotulinumtoxinA in a randomized, placebo-controlled dose-finding study in idiopathic overactive bladder. Neurourol Urodyn. 2011;30(4):556–62.PubMed

76.

Kanagarajah P, Ayyathurai R, Caruso DJ, Gomez C, Gousse AE. Role of botulinum toxin-A in refractory idiopathic overactive bladder patients without detrusor overactivity. Int Urol Nephrol. 2012;44(1):91–7.PubMed

77.

Schulte-Baukloh H, Weiss C, Stolze T, Sturzebecher B, Knispel HH. Botulinum-A toxin for treatment of overactive bladder without detrusor overactivity: urodynamic outcome and patient satisfaction. Urology. 2005;66(1):82–7.PubMed

78.

Schmid DM, Sauermann P, Werner 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(1):177–85.PubMed

79.

Dowson C, Sahai A, Watkins J, Dasgupta P, Khan MS. The safety and efficacy of botulinum toxin-A in the management of bladder oversensitivity: a randomised double-blind placebo-controlled trial. Int J Clin Pract. 2011;65(6):698–704.PubMed

80.

Schulte-Baukloh H, Weiss C, Stolze T, et al. Botulinum-A toxin detrusor and sphincter injection in treatment of overactive bladder syndrome: objective outcome and patient satisfaction. Eur Urol. 2005;48(6):984–90.PubMed

81.

White WM, Pickens RB, Doggweiler R, Klein FA. Short-term efficacy of botulinum toxin a for refractory overactive bladder in the elderly population. J Urol. 2008;180(6):2522–6.PubMed

82.

Jeffery S, Fynes M, Lee F, Wang K, Williams L, Morley R. Efficacy and complications of intradetrusor injection with botulinum toxin A in patients with refractory idiopathic detrusor overactivity. BJU Int. 2007;100(6):1302–6.PubMed

83.

Sahai A, Khan MS, Le GN, Dasgupta P. Urodynamic assessment of poor responders after botulinum toxin-A treatment for overactive bladder. Urology. 2008;71(3):455–9.PubMed

84.

Khan S, Kessler TM, Apostolidis A, et al. What a patient with refractory idiopathic detrusor overactivity should know about botulinum neurotoxin type a injection. J Urol. 2009;181(4):1773–8.PubMed

85.

Dowson C, Watkins J, Khan MS, Dasgupta P, Sahai A. Repeated botulinum toxin type A injections for refractory overactive bladder: medium-term outcomes, safety profile, and discontinuation rates. Eur Urol. 2012;61(4):834–9.PubMed

86.

Smith CP, Nishiguchi J, O’Leary M, Yoshimura N, Chancellor MB. Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology. 2005;65(1):37–41.PubMed

87.

Karsenty G, Elzayat E, Delapparent T, St-Denis B, Lemieux MC, Corcos J. Botulinum toxin type a injections into the trigone to treat idiopathic overactive bladder do not induce vesicoureteral reflux. J Urol. 2007;177(3):1011–4.PubMed

88.

Mascarenhas F, Cocuzza M, Gomes CM, Leao N. Trigonal injection of botulinum toxin-A does not cause vesicoureteral reflux in neurogenic patients. Neurourol Urodyn. 2008;27(4):311–4.PubMed

89.

Harper M, Popat RB, Dasgupta R, Fowler CJ, Dasgupta P. A minimally invasive technique for outpatient local anaesthetic administration of intradetrusor botulinum toxin in intractable detrusor overactivity. BJU Int. 2003;92(3):325–6.PubMed

90.

Sahai A, Kalsi V, Khan MS, Fowler CJ. Techniques for the intradetrusor administration of botulinum toxin. BJU Int. 2006;97(4):675–8.PubMed

91.

Popat R, Apostolidis A, Kalsi V, Gonzales G, Fowler CJ, Dasgupta P. A comparison between the response of patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity to the first intradetrusor injection of botulinum-A toxin. J Urol. 2005;174(3):984–9.PubMed

92.

Smith CP, Chancellor MB. Simplified bladder botulinum-toxin delivery technique using flexible cystoscope and 10 sites of injection. J Endourol. 2005;19(7):880–2.PubMed

93.

Cohen BL, Rivera R, Barboglio P, Gousse A. Safety and tolerability of sedation-free flexible cystoscopy for intradetrusor botulinum toxin-A injection. J Urol. 2007;177(3):1006–10.PubMed

94.

Mehnert U, Boy S, Schmid M, et al. A morphological evaluation of botulinum neurotoxin A injections into the detrusor muscle using magnetic resonance imaging. World J Urol. 2009;27(3):397–403.PubMed

95.

Schurch B, Reitz A, Tenti G. Electromotive drug administration of lidocaine to anesthetize the bladder before botulinum-A toxin injections into the detrusor. Spinal Cord. 2004;42(6):338–41.PubMed

96.

Kuo HC. Comparison of effectiveness of detrusor, suburothelial and bladder base injections of botulinum toxin a for idiopathic detrusor overactivity. J Urol. 2007;178(4 Pt 1):1359–63.PubMed

97.

Lucioni A, Rapp DE, Gong EM, Fedunok P, Bales GT. Intravesical botulinum type A toxin injection in patients with overactive bladder: Trigone versus trigone-sparing injection. Can J Urol. 2006;13(5):3291–5.PubMed

98.

Manecksha RP, Cullen IM, Ahmad S, et al. Prospective randomised controlled trial comparing trigone-sparing versus trigone-including intradetrusor injection of abobotulinumtoxinA for refractory idiopathic detrusor overactivity. Eur Urol. 2012;61(5):928–35.PubMed

99.

Chuang YC, Tyagi P, Huang CC, et al. Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using liposomes. J Urol. 2009;182(2):786–92.PubMed

100.

Krhut J, Zvara P. Intravesical instillation of botulinum toxin A: an in vivo murine study and pilot clinical trial. Int Urol Nephrol. 2011;43(2):337–43.PubMed

101.

Sangster P, Kalsi V. Health economics and intradetrusor injections of botulinum for the treatment of detrusor overactivity. BJU Int. 2008;102 Suppl 1:17–9.PubMed

102.

Devlin N, Parkin D. Does NICE have a cost-effectiveness threshold and what other factors influence its decisions? A binary choice analysis. Health Econ. 2004;13(5):437–52.PubMed

103.

Kalsi V, Popat RB, Apostolidis A, 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(3):519–27.PubMed

104.

Wu JM, Siddiqui NY, Amundsen CL, Myers ER, Havrilesky LJ, Visco AG. Cost-effectiveness of botulinum toxin a versus anticholinergic medications for idiopathic urge incontinence. J Urol. 2009;181(5):2181–6.PubMed

105.

Wefer B, Ehlken B, Bremer J, et al. Treatment outcomes and resource use of patients with neurogenic detrusor overactivity receiving botulinum toxin A (BOTOX((R))) therapy in Germany. World J Urol. 2010;28(3):385–90.PubMed

106.

Watanabe JH, Campbell JD, Ravelo A, Chancellor MB, Kowalski J, Sullivan SD. Cost analysis of interventions for antimuscarinic refractory patients with overactive bladder. Urology. 2010;76(4):835–40.PubMed

107.

Padmanabhan P, Scarpero HM, Milam DF, Dmochowski RR, Penson DF. Five-year cost analysis of intra-detrusor injection of botulinum toxin type A and augmentation cystoplasty for refractory neurogenic detrusor overactivity. World J Urol. 2011;29(1):51–7.PubMed

108.

Leong RK, de Wachter SG, Joore MA, van Kerrebroeck PE. Cost-effectiveness analysis of sacral neuromodulation and botulinum toxin A treatment for patients with idiopathic overactive bladder. BJU Int. 2011;108(4):558–64.PubMed


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