Bladder Injections for Refractory Overactive Bladder: Intra‐ and Transvesical Procedures

154
Bladder Injections for Refractory Overactive Bladder: Intra‐ and Transvesical Procedures

Adam Althaus¹ & Anurag K. Das²

¹ Harvard Longwood Program in Urology, Boston, MA, USA

² Division of Urology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Introduction

Overactive bladder (OAB), as defined by the International Continence Society, is “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection (UTI) or other obvious pathology” [1]. OAB can be neurogenic (N‐OAB) or idiopathic (I‐OAB). N‐OAB results directly from neurologic disorders, such as multiple sclerosis, myelomeningocele, and spinal cord injury [2], while I‐OAB is a clinical diagnosis of exclusion after ruling out alternative sources of symptoms, such as benign prostatic hyperplasia (BPH), UTI, malignancy, or painful bladder syndrome [3, 4]. The worldwide incidence of OAB is estimated to be 11% [5], and the prevalence ranges from 7% to 27% in men and 9–43% in women [3, 5–12]. The primary concern for many OAB patients is reduced quality of life (QOL) [13–17]. I‐OAB leads to deterioration in QOL in about 50% of patients, with the proportion increasing to 80% in those with incontinence [17]. The impact on QOL can extend to sexual function, marital satisfaction, and psychosocial functioning with increased rates of depression associated with worsening incontinence symptoms [18–21].

First‐line treatment of OAB includes behavioral therapies combined with pharmacologic management when necessary [3, 4]. Behavioral modifications include bladder training, pelvic muscle training, fluid management, and bladder control strategies. Pharmacotherapy may be initiated simultaneously with behavioral therapy or when behavioral therapy is insufficient in managing symptoms. Pharmacologic options are considered second‐line interventions and include anticholinergic/antimuscarinic and beta‐adrenergic medications. Cholinergic receptors in the bladder, stimulated by acetylcholine released from parasympathetic neurons, are responsible for bladder contraction during voiding [22, 23]. However, such receptors exist elsewhere in the body, including the brain, salivary glands, heart, gastrointestinal tract, and eyes, resulting in side‐effects, such as cognitive problems, dry mouth, tachycardia, constipation, and blurred vision [3, 22, 23]. Such side‐effects, along with a relative lack of efficacy, have led to discontinuation of anticholinergic medication in >60% of patients at 12 months [24]. Almost half of patients discontinued medication because they felt it “did not work as expected,” and almost one‐fourth of patients cited the side‐effects as their reason [25]. Mirabegron, a beta‐adrenoceptor agonist, is an alternative to anticholinergic medications with similar efficacy for treatment of OAB [26] although currently there are relatively few studies. By targeting the sympathetic system, mirabegron can be used in patients with poor tolerance or contraindications to anticholinergic therapy. Mirabegron has been shown to have lower rates of dry mouth and constipation, which may contribute to higher rates of adherence and persistence at 12 months compared to anticholinergics [27].

Patients refractory to first‐ and second‐line treatments may be offered botulinum toxin A (BTX‐A) intravesical injections, peripheral tibial nerve stimulation, or sacral neuromodulation. In rare cases, the patient with refractory OAB may be offered indwelling catheterization or surgery, such as bladder augmentation or urinary diversion. This chapter discusses the mechanism, efficacy, technique, and side‐effects of endoscopic injections of BTX‐A into the detrusor wall of patients with refractory OAB.

Mechanism of action

Botulinum toxin is a potent neurotoxin produced by the anaerobic bacterium Clostridium botulinum, which can result in severe symptoms including mydriasis and progressive neuromuscular paralysis, producing muscle weakness, dyspnea, and possibly death. These symptoms were first described in the 1820s by the German physician Kerner who observed an outbreak among soldiers suffering “sausage poisoning” from having eaten infected sausages [28]. It was not until 1897 that the microbiologist van Ermengem discovered the culprit bacterium which he termed “bacillus botulinus” (from the Latin word botulus meaning sausage) after isolating it from the tissue of several people who died following a funeral dinner as well as from the smoked ham served that day [29]. Botulinum toxin was first used medically in 1977 by the opthalmologist Scott to treat patients with strabismus or blepharospasm, and US Food and Drug Administration (FDA) approval for this application was granted in 1989 [30]. In 1988, Dysktra et al. described the first urologic application of botulinum toxin – injection into the external urinary sphincter to treat detrusor sphincter dyssynergia in spinal cord injury patients [31]. Since that time, the urologic indications for therapy have expanded to include N‐OAB, I‐OAB, interstitial cystitis/bladder pain syndrome (IC/BPS), chronic pelvic pain syndrome, and detrusor sphincter dyssynergia (DSD).

The pathophysiology of OAB is not fully understood, but may involve lack of inhibition by upper motor neurons in patients with N‐OAB, and oversensitivity of sensory fibers and reflex pathways in patients with I‐OAB. Botulinum toxin has been shown to block both the afferent and efferent fibers, resulting in a decreased sensation of fullness, and reduced smooth muscle contractility, respectively [32–34]. Different strains of botulinum toxin (A to F) interact uniquely with different SNARE proteins, which are required for the release of acetylcholine from the presynaptic terminals. These interactions inhibit cholinergic neurotransmission at neuromuscular synapses and subsequently decrease or abolish muscle contractions [35]. BTX‐A has the longest duration of action and has become the focus of medical applications.

There are five different preparations of BTX‐A: onabotulinumtoxinA (Botox™), abobotulinumtoxinA (Dysport™), incobotulinumtoxinA (Xeomin™), Prosigne™, and Purtox™. Studies suggest that 1 unit of onabotulinumtoxinA is roughly equivalent to 3–5 units of abobotulinumtoxinA, 1 unit of Xeomin, and 1 unit of Prosigne, although no randomized control trials comparing dose, efficacy, and safety exist [36]. OnabotulinumtoxinA and abobotulinumtoxinA are the most commonly used preparations. Studies on abobotulinumtoxinA show similar treatment efficacy to onabotulinumtoxinA [36–39]. AbobotulinumtoxinA has been studied at doses of 500, 750, or 1000 U; 500 U resulted in too short a duration of action, while side‐effects with 1000 U were too great (reports of temporary generalized weakness) [40]. A study by Jeffery et al. demonstrated a clean intermittent catheterization (CIC) rate at six weeks of 35% for treatment of I‐OAB with Dysport 500 U [39]. Revindra et al. also showed abobotulinumtoxinA 500 U had a rate and duration of efficacy similar to that of onabotulinumtoxinA 200 U, but they demonstrated a higher rate of CIC in the abobotulinumtoxinA group (42% vs. 23%) [38]. The majority of evidence on BTX‐A therapy in OAB is with onabotulinumtoxinA use. Because of this, the remainder of the discussion will focus solely on onabotulinumtoxinA.

Results of onabotulinumtoxinA injection

The efficacy of injection of onabotulinumtoxinA into the detrusor smooth muscle of the bladder wall of patients with refractory N‐OAB was first demonstrated by Schurch et al. in 2000 [41]. In this study, 21 patients with spinal cord injury who experienced incontinence secondary to neurogenic detrusor overactivity, required CIC to empty, and had failed anticholinergics were treated with onabotulinumtoxinA. Following treatment they demonstrated a significant increase in mean maximum bladder capacity (from 296 to 480 ml, P < 0.016) and a significant decrease in mean maximum detrusor voiding pressure (from 65 to 35 cmH₂O, P < 0.016). Of the 21 patients, 17 were completely continent at six weeks follow‐up and were satisfied with the procedure; improvements in urodynamic parameters and incontinence persisted at 36 weeks in 11 patients [41]. Since that initial description, many studies have demonstrated the utility of onabotulinumtoxinA injection as an appropriate therapy for patients with I‐OAB and N‐OAB refractory to anticholinergics [3, 4, 36–71].

Neurogenic overactive bladder

Multiple placebo‐controlled studies have demonstrated the efficacy of onabotulinumtoxinA in patients with N‐OAB [45–51]. Two recent double‐blind, placebo‐controlled, Phase 3 studies demonstrating the efficacy of onabotulinumtoxinA in patients with N‐OAB provide the strongest evidence for its use [48, 49]. A total of 691 patients with N‐OAB secondary to multiple sclerosis (MS) or spinal cord injury (SCI) were included in a pooled analysis [48–50]. Patients were included if they had >14 episodes of urge incontinence per week and had failed a trial of appropriately dosed anticholinergic medication for >one month due to inefficacy or intolerance. Patients were then randomized to receive intradetrusor injections of 30 ml of onabotulinumtoxinA 200 U, 300 U, or placebo. The trigone was spared during injection. Six weeks following treatment statistically significant decreases in weekly urge incontinence episodes were seen in the 200 U (−22.6 MS, −19.6 SCI) and 300 U (−24.0 MS, −18.2 SCI) group compared to placebo (−14.0 MS, −6.4 SCI). In addition, rates of total continence at six weeks increased in both the 200 U (41.5% MS, 30.9% SCI) and 300 U groups (44.2% MS, 35.9% SCI) compared to placebo (10.7% MS, 7.3% SCI). Significant increases in I‐QOL scores were seen in both onabotulinumtoxinA groups compared to placebo. Urodynamic studies (UDS) performed at six weeks after injection demonstrated an increase in maximum cystometric capacity (MCC) compared to placebo (151–157 ml, 157.2–168 ml, and 6.5–18 ml). Mangera et al. performed a systematic review of available literature in 2014 supporting these findings. They reported statistically significant improvements in daily incontinence (−63%) as well as multiple UDS parameters, including MCC (+68%) [37].

The FDA‐approved starting dose for onabotulinumtoxinA in the treatment of N‐OAB is 200 U. Apostolidis et al. showed 200 U to be the most effective dose in a placebo‐controlled dose‐response study comparing 50, 100, and 200 U onabotulinumtoxinA [51]. In the previously discussed Phase 3 studies the 300 U dose did not add to the clinical efficacy in any subpopulation compared to 200 U [48–50].

Idiopathic overactive bladder

The American Urological Association (AUA) and Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU) released an amendment to the 2012 non‐neurogenic OAB guideline statement upgrading the use of onabotulinumtoxinA (100 U) as third‐line treatment from an option to standard [3, 4]. This was largely based on updated review of the literature with 27 new studies including five randomized trials with placebo control groups and 2 trials with active controls [4]. Several randomized, double‐blind trials were performed demonstrating the efficacy and tolerability of 100 U onabotulinumtoxinA [52–61]. The largest Phase 2 trial was performed by Dmochowski et al. who compared 50 U, 100 U, 150 U, 200 U, and 300 U onabotulinumtoxinA to placebo [52]. They found 100 U to be the optimal dose to improve UI episodes and other OAB symptoms, while doses of 150 U or greater led to a dose‐dependent increase in postvoid residual (PVR) without providing additional clinical benefit. Two Phase 3 double‐blind, placebo‐controlled trials performed by Chapple et al. and Nitti et al. provide the most robust evidence, showing a three‐ to fourfold decrease in frequency of UI episodes in 100 U onabotulinumtoxinA compared to placebo [62–64]. Pooled analysis of the data included 1097 patients with at least three UI episodes per three days and eight micturitions per day who had failed anticholinergic therapy due to inefficacy or intolerance. Subjects were then randomized to onabotulinumtoxinA 100 U or placebo divided in 20 detrusor injections. The trigone was spared during injection. The onabotulinumtoxinA group demonstrated a significant improvement in UI episodes per day compared to placebo (−2.8 vs. −0.95) at 12 weeks. The onabotulinumtoxinA arm also demonstrated 27.1% rate of total continence compared to 8.4% in the placebo arm. Furthermore, patients who received onabotulinumtoxinA were more likely to report improved frequency and urgency. A systematic review of available literature in 2014 reported statistically significant decrease in daily incontinence (−59%) as well as improvement in multiple UDS parameters including MCC (+58%) [37].

Rovner et al. demonstrated objective improvement in MCC on UDS in patients treated with onabotulinumtoxinA 100 U at 12 weeks compared to placebo (+71.0 ml vs. +49.5 ml), as well as improved compliance at MCC (+63.0 vs. 22.8 ml/cmH₂O) [65]. Of note, the presence of detrusor overactivity on baseline UDS did not impact the efficacy of onabotulinumtoxinA injection for patients with I‐OAB. Because of this, routine UDS testing is not required prior to treatment with onabotulinumtoxinA for I‐OAB [66].

Pediatric overactive bladder

Pediatric patients with myelomeningocele experience difficulty with bladder function, and many suffer from detrusor overactivity and incontinence. In addition, there is concern for deterioration of their upper tracts as they may have high bladder pressures due to poor or intermediate compliance and vesicoureteral reflux. OnabotulinumtoxinA is not currently approved for use in pediatric OAB, however multiple studies have demonstrated clinical benefit. Mangera et al. performed a systematic review of available literature on onabotulinumtoxinA use in pediatric N‐OAB refractory to medical management. OnabotulinumtoxinA treatment was found to improve MCC from 50% to 59% and maximum detrusor pressure decreased from 42% to 50% [37]. In addition, a reduction in the grade of vesicoureteral reflux was noted in one study, potentially as a result of decreasing bladder pressure [66]. Use of onabotulinumtoxinA in pediatric patients is being investigated for treatment of OAB in non‐neurogenic patients with positive preliminary data [67, 68]. Urethral external sphincteric injection of onabotulinumtoxinA in children with dysfunctional voiding has been shown to be beneficial as well [69–71].

Repeat injections

As the effects of onabotulinumtoxinA injection have been shown to last approximately 6–9 months, patients require repeat injections to continue to experience the therapeutic benefits. Initially there were concerns raised regarding the possibility that repeat injections would result in a blunted response over time due to antibody formation to the toxin. Several studies in N‐OAB patients have evaluated the efficacy of repeat injections of onabotulinumtoxinA with five to seven injections over a 6‐ to 8‐year period, and have demonstrated that urodynamic and clinical improvements in QOL and decreased medication requirements after the first injection were maintained for a duration of 6–9 months after each subsequent application [72–76]. In addition, it was postulated that repeat injections could result in fibrosis from repeated puncturing of the mucosa; however, several studies have investigated this and found no evidence of it [77–79].