Botulinum Toxin for the Treatment of Idiopathic and Neurogenic Overactive Bladder: State of the Art

Treatment Update

RIU0320_11-20.qxd 11/20/06 3:01 PM Page 198 TREATMENT UPDATE Botulinum Toxin for the Treatment of Idiopathic and Neurogenic Overactive Bladder: State of the Art Victor W. Nitti, MD Department of Urology, New York University School of Medicine, New York, NY The pharmacologic treatment of overactive bladder and detrusor overactivity, whether idiopathic or neurogenic, has centered around blocking muscarinic receptors on the detrusor muscle. Although newer agents have been developed with better tolerability and safety, the basic mechanism by which the “irritable” detrusor is treated has not changed in decades. Although effective in many cases of idiopathic and neurogenic detrusor overactivity and overactive bladder, antimuscarinic agents fall short in many other cases because of lack of efficacy and/or tolerability. For the past several years, there has been increasing evidence to support the use of botulinum toxin for the treatment of detrusor overactivity and overactive bladder syndrome not effectively treated by anticholinergics. From early open-label studies to the more recent randomized, controlled trials, efficacy and tolerability data have been very encouraging. Botulinum toxin is not yet approved by the US Food and Drug Administration for the treatment of detrusor overactivity and overactive bladder, but the positive results seen thus far cannot be ignored. [Rev Urol. 2006;8(4):198-208] © 2006 MedReviews, LLC Key words: Antimuscarinic agents • Botulinum toxin • Detrusor overactivity • Overactive bladder harmacologic treatment of overactive bladder syndrome (OAB) and detrusor overactivity (DO) has centered around blocking post-synaptic muscarinic receptors on the detrusor muscle, thus preventing or decreasing involuntary detrusor contractions. Antimuscarinic agents are effective in this regard; however, approximately 25% to 40% of patients fail to get adequate symptom relief when incontinence is the primary outcome variable.1 In addition, because these P 198 VOL. 8 NO. 4 2006 REVIEWS IN UROLOGY RIU0320_11-20.qxd 11/20/06 3:01 PM Page 199 Botulinum Toxin for OAB medications are not uroselective, antimuscarinic side effects, especially dry mouth and constipation, limit their usefulness2 and result in relatively high discontinuation rates outside large-scale clinical trials. Thus, there is a need for treatments other than systemic antimuscarinic agents and behavioral modification to treat this highly prevalent condition. Botulinum toxin has been used to treat detrusor overactivity for the past several years. Since the initial report of botulinum toxin type A (BoNTA) in 19 spinal cord–injured patients,3 there has been an explosion of reports on the use of botulinum toxin in various conditions with associated bladder overactivity. Although the use of botulinum toxin for the treatment of OAB and DO is currently not approved by the US Food and Drug Administration (FDA) or by the European regulatory agencies, its use in investigational protocols and “off label” continues to grow. Current information on the mechanism of action of botulinum toxin in the bladder and the results of clinical trials using botulinum toxin for the treatment of OAB, neurogenic DO, and nonneurogenic DO are reviewed in this article. On the basis of the available information, we will suggest where BoNTA fits into the current treatment algorithm. Because almost all of the literature pertains to type A, and more specifically to BOTOX® (Allergan, Irvine, CA), and because these complex biologicals are not interchangeable (discussed later), discussion of preclinical and clinical data will relate only to BOTOX unless otherwise specified. Overactive Bladder: What Are We Treating? The International Continence Society (ICS) defines OAB as a symptom complex consisting of urgency with or without urge incontinence, usually with frequency and nocturia, in the absence of local pathologic or hormonal factors.4 Thus it is a symptom complex defined by symptoms and not any specific condition or urodynamic finding causing the symptoms. DO, on the other hand, is a urodynamic observation characterized by involuntary detrusor contractions during the filling phase that may be spontaneous or provoked.4 DO is described as neurogenic DO when associated with a relevant neurologic condition and as idiopathic DO when there is no such association. Patients with OAB are often found to have DO when studied, but this is not a requirement for diagnosis. Thus OAB is a condition and DO is a urodynamic finding. In most cases of OAB in the nonneurogenic patient, treatment is driven by the symptoms and the degree of bother to the patient. However, the treatment of bladder dysfunction and symptoms in the neurogenic patient is often driven by urodynamic findings, especially when those findings pose a threat to the kidneys (eg, high bladder storage pressures caused by impaired compliance and/or high-pressure DO). Thus, as we review the mechanism of action of botulinum toxin and the results of clinical trials, it is important to remember that in some cases the primary endpoint is a urodynamic effect and in some cases it is an effect of symptoms. Botulinum Toxin: Structure, Types, and Mechanism of Action Botulinum toxin is the most potent naturally occurring neurotoxin known. It causes flaccid paralysis of skeletal muscle by blocking presynaptic-release acetylcholine (Ach) from the nerve terminal. Derived from the grampositive coccus Clostridium botulinum, it was first approved by the FDA in 1989 to treat strabismus, benign essential blepharospasm, and disorders of cranial nerve VII. Over the next 17 years, its medicinal use has expanded to treat various disorders of muscle spasticity and dystonia. The first reported use of BoNTA in the lower urinary tract was in 1987, when it was injected into the external sphincter muscle to treat detrusor– external sphincter dyssynergia.5 Seven distinct structural serotypes of botulinum toxin have been identified (A, B, C, D, E, F, and G).6 Types A and B have been most widely used for medicinal purposes.7-9 All serotypes have a common basic structure with some variations in amino acid sequences. The functional core of the botulinum toxin molecule is a dichain complex composed of a light chain of 50 kd and a heavy chain of 100 kd. The light chain is the truly active moiety of the molecule. It is a metalloenzyme (zinc) endopeptidase that cleaves certain intracellular target proteins, giving the drug its effect. It is connected to the heavy chain by a disulfide bond. The heavy chain is the attachment site recognition portion of the molecule. It binds to the presynaptic nerve terminal and enters the cell by endocytosis. Once the botulinum toxin is intracellar, the disulfide bond is broken and the light chain is translocated out of the endocytotic vesical into the cysoplasm. Here the light chain can disrupt the exocytosis of neurotransmitters such as Ach. The process of neurotransmitter exocytosis is complex and requires binding of the synaptic vesical (which contains the neurotransmitter) membrane proteins to plasma membrane proteins, which then trigger the exocytotic process after membrane depolarization and calcium influx. Three proteins are critical for this process to occur. Synaptobrevin (vesicle-associated membrane protein [VAMP]) is located on the synaptic vesical membrane; synaptosome- VOL. 8 NO. 4 2006 REVIEWS IN UROLOGY 199 RIU0320_11-20.qxd 11/20/06 3:01 PM Page 200 Botulinum Toxin for OAB continued B-D-F-G VAMP (Synaptobrevin) Syntaxin Synaptic Vesicle A-C-E SNAP-25 HighAffinity Acceptor Ca2
Plas m e aM mb r an e Calcium Channel Figure 1. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex at the nerve terminal. There are 3 intracellular proteins that make up the SNARE complex and act as target sites for botulinum toxin: SNAP-25 (synaptosome-associated protein 25 kd), VAMP (vesicle-associated membrane protein, also called synaptobrevin), and syntaxin. These docking proteins are required for the docking and release of acetylcholine and other neurotransmitters from vesicles near the neuromuscular junction. Image courtesy of Allergan Inc. associated protein 25 kd (SNAP-25) and syntaxin are located on the plasma membrane of the presynaptic nerve terminal. Together these make up the soluble N-ethylmaleimidesensitive factor attachment protein receptor (SNARE) complex (Figure 1). Disrupting the formation of this complex will prevent exocytosis of the neurotransmitter, and stimulation of postsynaptic receptors (such as those on muscle) is prevented. Different botulinum toxin serotypes disrupt the SNARE complex at different points. Botulinum toxin types A, C, and E cleave the SNAP-25 protein on the plasma membrane. Botulinum toxin types B, D, F, and G cleave the VAMP protein on the synaptic vesical membrane. When this occurs, the SNARE complex cannot form, vesicals containing Ach and other transmitters 200 VOL. 8 NO. 4 2006 cannot dock to and fuse with the neuronal membrane, and neurotransmitters are not released. Most of the effects of botulinum toxin are thought to result from the inhibition of Ach release from the presynaptic nerve terminal. When this occurs, Ach receptors in the muscle are not stimulated. Specifically with intradetrusor injections, affected muscarinic receptors in the detrusor muscle cannot be stimulated and detrusor voluntary contractions are suppressed. Review of the clinical data shows a profound effect of botulinum toxin on involuntary detrusor contractions and elevated detrusor pressures (see below). It is clear that neurotransmitters other than Ach are also affected by botulinum toxin, including sensory/ afferent neurotransmitters. It is likely REVIEWS IN UROLOGY these also play a role in the therapeutic effects of BoNTA in OAB. BoNTA has been found to inhibit Ach and adenosine triphosphate release from urothelium in rats and guinea pigs.10,11 BoNTA has been shown to inhibit the stimulated (but not basal) release of calcitonin gene–related peptide (CGRP) from trigeminal ganglia neurons12 and sensory neurons in the isolated rat bladder.13 BoNTA has also been shown to inhibit the release of glutamate14 and substance P15 from sensory neurons. Apostolidis and colleagues16 studied human bladder biopsy specimens from patients with neurogenic and idiopathic DO. They found that BoNTA-treated bladders had decreased levels of TRPV1 and P2X3, 2 sensory receptors found in the suburothelium. Finally, 2 recent publications addressed the effects of BoNTA on detrusor composition. Comperat and associates17 studied cystectomy specimens from patients with neurogenic DO who received or did not receive BoNTA injections as prior treatment for DO. The investigators found no difference in inflammation or edema, but there was significantly less fibrosis in the BoNTA-treated bladders. Giannantoni and co-workers18 found that BoNTA decreased bladder tissue content of nerve growth factor (NGF) at 1 and 3 months after treatment. They theorized that this occurred either as a result of decreased Ach or other neurotransmitter release at the presynaptic level. NGF has a key role in the survival of sensory neurons, maintaining the normal properties of C afferent fibers. All these data help support the belief that botulinum toxin works to treat DO and OAB by both sensory and motor pathways and may have a positive effect on bladder wall structure and fibrosis. Confirmatory studies regarding the latter are necessary to make definitive conclusions. RIU0320_11-20.qxd 11/20/06 3:01 PM Page 201 Botulinum Toxin for OAB Although almost all urological literature involves BoNTA, there are a few reports involving type B. BoNTA disrupts the SNARE complex by cleaving SNAP-25, whereas BoNTB targets VAMP (Figure 1). There are biochemical differences between the different botulinum toxin types and even between formulations of the same serotype. These distinctions are probably what has led to differences in the therapeutic profile (dose, efficacy, duration, safety) of various toxins; therefore, clinical comparisons between toxins with respect to these parameters should be made with caution. Two different BoNTA formulations have been used in the bladder: BOTOX and Dysport® (Ipsen, Boston, MA). Although both are type A toxins, they are derived from different bacterial strains, have different molecular weights, and are manufactured differently. BOTOX is vacuum dried, whereas Dysport is freeze dried (a more toxin-disruptive process). BOTOX comes in 100-U vials and Dysport in 500-U vials, but that does not imply that there is an equivalence or formula to convert one type to another. The reader should carefully examine clinical trials using each of the agents to determine the appropriate dosage. Botulinum Toxin: Intradetrusor Injection Technique A number of variables are involved in botulinum toxin administration, including type and amount of toxin, dilution volume, location, number, and depth of injections, instrumentation, and anesthesia technique. A number of protocols have been proven to work well; however, the optimal amount and dilution of toxin and injection site protocol have not been established. Table 1 summarizes these variables for the major trials discussed in this review. As one can imagine, with so many variables, establishing an “optimal protocol” for a given patient type is very challenging. Most of the work on DO and OAB has been done with BoNTA, with a few studies on botulinum toxin type B. The BOTOX formulation of BoNTA has been studied the most; however, there are a number of studies on Dysport as well. At the time of this writing, BOTOX is the only formulation of BoNTA available in the United States. Botulinum toxin has been injected directly into the detrusor in almost all studies. One investigator has reported on submucosal injections, perhaps to take advantage of the presumed effect on afferent sensory nerves.18 The initial studies injected toxin into the lateral and posterior bladder wall, sparing the dome (to avoid intraperitoneal injection) and the trigone. The trigone was avoided because of the fear of reflux, but this has not been found to be a problem in series in which the trigone was injected. Nevertheless, because initial protocols spared the trigone, many subsequent studies did as well (Table 1). Some investigators have proposed injecting the bladder base and trigone only,19 but the usefulness of this technique needs to be confirmed. The dilution of toxin and the amount of liquid injected into the bladder have also varied. Initial studies diluted 100 U of BOTOX in 10 mL of preservative-free normal saline (NS).3 Although more concentrated dilutions have been used, most experts agree that a higher volume (eg, at least 5 mL per 100 U BOTOX) provides better coverage of the bladder. Thus, based on the current literature, 10 to 30 mL of total volume injected (the same would apply for BOTOX, Dysport, or type B toxin) seems to be reasonable, with higher doses typically using the higher end of this range. The number of injection sites has varied from about 10 to 50, with most studies doing 20 to 30 injections (Table 1). To see how much of the bladder was covered by injections, Boy and colleagues20 injected 6 patients who had neurogenic DO with BoNTA (BOTOX) plus a magnetic tracer and then studied the patients with magnetic resonance imaging to determine the dispersion of the injected liquid. Two common volumes were used: 3 patients received 300 U in 30 mL NS at 30 sites (10 U/site), and 3 patients received 300 U in 10 mL at 10 sites (30 U/site). Both protocols achieved good coverage, with the larger volume covering 33% of bladder versus 25% for the smaller volume. Overall, 12.9% of the liquid was found in the perivesical fat. An example of a commonly used injection template is shown in Figure 2. Botulinum toxin can be delivered with a rigid or flexible scope, depending on patient or surgeon preference. Rigid systems allow for quicker, more controllable injections, whereas flexible scopes are generally more comfortable for patients, especially males. Both local and general anesthesia has been used for botulinum toxin injection. We have found local anesthesia to work well, with excellent patient tolerability, and to be ideal for the office setting. Our local anesthesia protocol is shown in Table 2. Conscious sedation may also be used for more anxious or sensitive patients, although we rarely find it necessary. General anesthesia may be considered for extremely anxious or sensitive patients and for neurogenic patients who are at high risk for autonomic dysreflexia. General anesthesia is required for most pediatric applications. Studies in Neurogenic Detrusor Overactivity The initial studies on the use of botulinum toxin for DO were done in patients with neurogenic DO who were refractory to antimuscarinic therapy (ie, had inadequate response or lack of tolerability). For this difficult group VOL. 8 NO. 4 2006 REVIEWS IN UROLOGY 201 202 VOL. 8 NO. 4 2006 REVIEWS IN UROLOGY 2000 2004 2005 2006 2004 2005 2004 2005 2005 2005 2005 2006 2004 2005 2003 2004 2006 Schurch B et al3 Reitz A et al21 Grosse J et al25 Patki P et al26 Giannantoni A et al29 Schurch B et al30 Kuo HC31 Popat R et al32 Kessler TM et al33 Kuo HC35 Werner M et al34 Schmid DM et al36 Rapp DE et al37 Ghei M et al39 Schulte-Baukloh H et al40 Riccabona M et al41 Hoebeke P et al42 21 15 20 20 35 100 26 20 22 75 30 59 12 37 66 200 19 Patients (No.) Pediatric IDO Pediatric NDO IDO (17) NDO (3) Pediatric NDO IDO Women OAB IDO or “hypersensitive bladder” OAB IDO (18) NDO (12) IDO (31) NDO (44) IDO (11) NDO (11) IDO NDO NDO NDO NDO Impaired compliance NDO NDO Population BoNTA (BOTOX) BoNTA (BOTOX) BoNTA (BOTOX) BoNTA (BOTOX) BoNTB BoNTA (BOTOX) BoNTA (BOTOX) BoNTA (BOTOX) BoNTA (BOTOX) BoNTA (BOTOX) BoNTA (BOTOX) BoNTA (BOTOX) BoNTA (BOTOX) BoNTA (Dysport) BoNTA (BOTOX®) BoNTA (BOTOX) BoNTA (BOTOX) (Dysport®) Toxin 100 U 10 U/kg 12 U/kg 5000 U 300 U 100 U 100 U 200 U 200 U IDO 300 U NDO 300 U 200 U 200-300 U 300 U 1000 U 300 U 750 U 300 U 200-300 U Amount of Toxin 100 U/15 mL 10 U/1 mL 15-20 U/mL 5000 U/20 mL 100 U/10 mL 100 U/10 mL 100 U/30 mL 100 U/10 mL 100 U/10 mL 100 U/10 mL 100 U/4 mL 200-300 U/30 mL 100 U/10 mL 1000 U/30 mL 300 U/15 mL 750 U/5 mL 100 U/10 mL 100 U/10 mL Dilution* 15 25-40 30-50 10 30 30 30 40 20 (IDO) 30 (NDO) 30 40 30 30 30 30 25 30 20-30 Injections (No.) Detrusor including the trigone Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Suburothelial posterior and lateral walls Trigone sparing Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Detrusor sparing the trigone Injection Sites General General General IV sedation General Spinal Spinal General Local
sedation IV sedation General NA Local None or local or general General or spinal for tetraplegics or paraplegics Local with sedation or general Sedation or spinal None Local Spinal General General None or local Type of Anesthesia Rigid Rigid Rigid NA Rigid Rigid Rigid Rigid NA Flexible Rigid NA NA Rigid NA Rigid Rigid Type of Scope *All dilutions done with normal saline. BoNTA, botulinum toxin type A; BoNTB, botulinum toxin type B; IDO, idiopathic detrusor overactivity; IV, intravenous; NA, not applicable; NDO, neurogenic detrusor overactivity. Year Study Table 1 Summary of Major Botulinum Toxin Studies for the Treatment of Detrusor Overactivity and Overactive Bladder (OAB) RIU0320_11-20.qxd 11/20/06 3:01 PM Page 202 RIU0320_11-20.qxd 11/20/06 3:01 PM Page 203 Botulinum Toxin for OAB Dome Injection sites Opening of left ureter Base Trigone Figure 2. Example of an injection template showing 20 injections throughout the posterior and lateral walls of the bladder sparing the trigone and dome. The inset shows an injection into the detrusor. Image courtesy of Allergan Inc. of patients, augmentation cystoplasty is the traditional next step in management when storage pressures are elevated. The first published study was by Schurch and associates3 in 2000. They studied a group of 19 spinal cord–injured patients with DO who managed bladder emptying by clean intermittent self-catheterization (CISC). Thus, in the initial studies, Table 2 Local Anesthesia Protocol for Botulinum Toxin Injection Table 3 Urodynamic Results in 19 Patients in the Initial Study on Botulinum Toxin Type A in Neurogenic Detrusor Overactivity 1. Catheterize the patient and empty the bladder. 2. Instill 40 mL 1%-2% lidocaine liquid. 3. Remove the catheter and inject 10 mL 2% viscous lidocaine into the urethra. 4. Wait 15-20 minutes. 5. Insert the cystoscope and empty the bladder. 6. Refill the bladder with approximately 100 mL normal saline and begin injections. there was no fear of urinary retention as emptying by CISC was the goal. In this study, as in most studies on neurogenic DO, the primary outcome measures were related to urodynamic criteria: volume at first involuntary contraction (reflex volume), maximum detrusor pressure (pdet max), maximum cystometric capacity (MCC), and compliance. Using a rigid cystoscope, 200 to 300 U of BoNTA (BOTOX) diluted 100 U/10 mL in NS was injected into the detrusor (posterior and lateral walls) sparing the trigone. The trigone was initially spared because of the theoretical effects on vesicoureteral reflux. The investigators showed significant improvement in reflux volume, MCC, compliance, and pdet max at 6 and 12 weeks (Table 3) with continued improvement at 36 weeks, with some regression. In addition, at 6 weeks, 17 of 19 patients became totally continent. These very favorable results in an open-label study inspired others to continue research in neurogenic DO. In 2004, Reitz and co-workers21 reported on a 200-patient multicenter, open-label study on BoNTA in neurogenic DO (eg, due to spinal cord injury, Reflex Volume (mL) PVR (mL) MCC (mL) Compliance (mL/cm H2O) pdet max (mL/cm H2O) Baseline (n = 19) 216 261 296 32.6 65.6 6 wk (n = 19) 416 491 481 62.1 35.0 12 wk (n = 11) 320 413 458 50.2 37.0 Time All values are mean. MCC, maximum cystometric capacity; pdet max, maximum detrusor pressure; PVR, postvoid residual. Data from Schurch B et al.3 VOL. 8 NO. 4 2006 REVIEWS IN UROLOGY 203 RIU0320_11-20.qxd 11/20/06 3:01 PM Page 204 Botulinum Toxin for OAB continued multiple sclerosis, or myelomeningocele). The investigators injected 300 U of BoNTA (BOTOX) at 30 sites excluding the trigone at a dilution of 100 U/10 mL. Thus the protocol was similar to the Schurch study. They allowed patients on antimuscarinic agents to continue them, even though the response was less than adequate. These investigators, too, showed significant improvements in all urodynamic parameters; in addition, 73% of incontinent patients became continent at 12 weeks and in 72% of these, complete continence persisted at 36 weeks. Also of interest was the fact that at 12 weeks, antimuscarinic agents were discontinued in 28% and reduced in 72% of patients. Two other smaller studies both had similar results, urodynamic parameters. Maximum cystometric capacity increased from 259 to 522 mL, and pdet max decreased from 54 to 24 cm H2O. DO was abolished in 76% of patients, and 69% of incontinent patients became continent. Of the patients who were on antimuscarinic agents, 52% stopped and 32% reduced usage. The mean duration of symptomatic improvement was 9 months (2-21), and 32% of patients had a duration of response of 12 months or longer. Two case reports described the successful use of botulinum toxin type B in patients who became resistant to BoNTA.27,28 The first controlled study of BoNTA in neurogenic DO was reported by Giannantoni and associates in 2004.29 They randomized patients with neu- BoNTA (BOTOX) and intravesical resiniferotoxin both resulted in improvement in continence and urodynamic parameters at 6, 12, and 18 months; however, the improvements were significantly better with BoNTA for all variables at all time points. with major improvements in urodynamic parameters and continence and reduction in antimuscarinic use.22,23 In all 4 studies, there were no drug- or injection-related adverse events reported. One other study suggested that BoNTA was not as effective in DO caused by cerebrovascular accident as it was in DO caused by spinal cord lesions.24 Two peer-reviewed studies investigated BoNTA (Dysport) for neurogenic DO. Grosse and colleagues25 showed significant symptomatic and urodynamic improvement with repeat injections of BoNTA in patients who received either 300 U of BOTOX or 750 U of Dysport. More recently, Patki and colleagues26 reported on 37 spinal cord–injured patients. The researchers injected 1000 U of Dysport diluted in 30 mL NS at 30 sites sparing the trigone. At 3 months there were significant improvements in all 204 VOL. 8 NO. 4 2006 rogenic DO to receive either 300 U BoNTA (BOTOX) or 0.6 mol/L of intravesical resiniferotoxin (RTX) in 50 mL NS. Repeat injections or instillations were allowed. Both treatments resulted in improvement in continence and urodynamic parameters at 6, 12, and 18 months; however, the improvements were significantly better with BoNTA for all variables at all time points. In addition, RTX patients was reported in 2005. Schurch and associates30 randomized 59 patients with neurogenic DO to receive either 200 U of BoNTA, 300 U of BoNTA, or placebo. In this 24-week study, significant improvements in key urodynamic parameters were seen at all time points in the BoNTA–treated patients but not in the placebo-treated patients (P  .05). After treatment, there were significant decreases in incontinence episodes at most time points in the 2 BoNTA groups. The mean reduction in incontinence episodes for the 2 BoNTA groups at all time points was approximately 50% compared with zero for the placebo group (P  .05). There were significant improvements in incontinence quality-of-life scores for both BoNTA groups versus baseline at all time points (P  .0002) but not for placebo. In addition, quality-of-life scores were significantly better for BoNTA- versus placebo-treated patients at all time points (P  .05). The 200-U dose seemed to be equally as effective as the 300-U dose; however, no conclusions could be reached regarding optimal dose as the study was not powered to compare different doses. All published series support the use of botulinum toxin for the treatment of neurogenic DO. Several open-label studies, 1 randomized controlled study, and 1 randomized placebocontrolled study all have shown good All published series support the use of botulinum toxin for the treatment of neurogenic DO. Several open-label studies, 1 randomized controlled study, and 1 randomized placebo-controlled study all have shown good efficacy with respect to symptoms and urodynamic findings. received a mean of 8.6 instillations whereas BoNTA patients received a mean of 2.1 injections over an 18month period. The first randomized, placebocontrolled study of BoNTA (BOTOX) REVIEWS IN UROLOGY efficacy with respect to symptoms and urodynamic findings. There have been no negative open-label or randomized controlled studies. Future studies will help determine the optimal dose and injection protocol. RIU0320_11-20.qxd 11/20/06 3:01 PM Page 205 Botulinum Toxin for OAB Studies in Idiopathic DO and OAB The use of botulinum toxin in patients with OAB and idiopathic DO has been increasing. To date, all the published studies have been open label. The first published studies on idiopathic DO contained mixed series of patients with neurogenic and idiopathic DO that used 200 to 300 U of BoNTA (BOTOX) in the idiopathic patients.31-33 Initial results were encouraging, showing similar efficacy in the idiopathic patients. However, transient retention was seen in sev- crease in postvoid residual (PVR) at 4 weeks (from 18 to 63 mL), and 2 women experienced temporary urinary retention requiring CISC. Kuo35 showed an 85% response rate (45% continent, 40% improved) in 20 patients with nonneurogenic DO and incontinence with suburothelial injection of 200 U of BoNTA (BOTOX). Interestingly, PVR volume was increased by 7 times the baseline value at 2 weeks and remained at 3 times the baseline at 6 months. The higher PVRs reported in this study may be related to the submucosal injection Most studies of botulinum toxin in idiopathic DO and OAB have shown good efficacy and no significant side effects other than urinary retention, which occurs infrequently. eral idiopathic patients in 2 of the studies.31,33 Popat and co-workers32 compared the response to the first injection of BoNTA (BOTOX) in neurogenic DO patients with that in idiopathic DO patients. The former group received 300 U, whereas the latter group got 200 U. There was no difference in urodynamic or symptomatic responses except for the symptom of urgency, for which the neurogenic population had a better response. Werner and colleagues34 reported on 26 women with urge incontinence and documented DO treated with BoNTA (BOTOX). The investigators used 100 U injected at 20 sites in the bladder and evaluated urodynamic and symptomatic response. At 4 and 20 weeks, they found significant improvements in MCC, volume at first desire, and volume at strong desire. In addition, DO was abolished in 54% and 65% of women at the same 2 time points. At 20 weeks, 80% of women were dry and daytime frequency decreased from 11.7 to 6.2 whereas nighttime frequency decreased from 2.6 to 1.2. There was a modest in- technique, which may have more effect on afferent reflexes. The largest study on idiopathic DO was reported by Schmid and associates.36 They injected 100 men and women with OAB (idiopathic DO with or without incontinence, or “hypersensitive bladder” without DO) with 100 U of BoNTA (BOTOX) at 30 sites sparing the trigone. With respect to symptoms, urgency disappeared in 72% and 66% of patients at 4 and 12 weeks, respectively. Of the 84 incontinent patients, 74% and 80% reported complete continence at 4 and 12 weeks, respectively; frequency of micturition was also significantly reduced. Improvements were also seen in urodynamic parameters, with DO resolving in 74% of patients who had it initially. Only 8 patients had a poor response, all of whom had decreased bladder compliance. Temporary urinary retention was seen in 4 patients. The mean duration of effect was at least 6  2 months. Finally, repeat injections were successfully preformed in 8 patients 9 months after initial injection. Rapp and co-workers37 studied the effects of BoNTA on an OAB population that was not characterized urodynamically. These patients had refractory frequency, urgency, and/or urge incontinence and were treated with 300 U of BoNTA (BOTOX). Response rates in this series were lower than those in patients with proven DO, with only 34% having “symptom resolution” and 26% having “slight improvement.” Another small study of 7 women with OAB and no DO showed symptomatic improvement in 5.38 Botulinum toxin type B has been used to treat idiopathic DO.39 In a double-blind, placebo-controlled crossover study of 20 women with DO, 17 had a nonneurogenic cause. Although the study periods were short—6 weeks for each arm—there were statistically significant differences in the change in average voided volume, urinary frequency, and episodes of incontinence between active treatment (5000 U BoNTB) and placebo. There were similarly significant paired differences in the change in quality of life, affecting 5 domains of the King’s Health Questionnaire. Most studies of botulinum toxin in idiopathic DO and OAB have shown good efficacy and no significant side effects other than urinary retention, which occurs infrequently but nevertheless is a risk. With the exception of 1 small study on BoNTB, all published data have been from openlabel trials. These studies suggest that lower doses of BoNTA (at least for BOTOX) may be effective compared with the doses used for neurogenic DO. Much less data are available on treating OAB without a urodynamic diagnosis of DO. As is the case for neurogenic DO, the optimal dosage and injection technique have not been determined. Randomized, controlled trials will help in that regard. VOL. 8 NO. 4 2006 REVIEWS IN UROLOGY 205 RIU0320_11-20.qxd 11/20/06 3:01 PM Page 206 Botulinum Toxin for OAB continued Studies in Pediatric Detrusor Overactivity Botulinum toxin type A has been successfully used to treat DO in the pediatric population. In most cases, however, general anesthesia is required for injection. In 2003, Schulte-Baukloh and colleagues40 treated 20 children, mean age 12.2 years, with neurogenic DO (16 myelomeningoceles, 2 spinal cord tumors, 1 trauma, and 1 unknown cause) refractory or intolerant to antimuscarinic therapy. All had intravesical pressures greater than 40 cm H2O. The children were treated with BoNTA (BOTOX) at a dose of 12 U/kg (max. 300 U) diluted in 15 to 20 mL NS and injected at 30 to 50 sites. Urodynamic and symptomatic improvements were seen at 2 to 4 weeks and 3 months and then diminished at 6 months. No significant side effects were reported. These investigators further reported a retrospective follow-up of 10 children who received multiple injections (3-5) under the same protocol.41 Children were injected on average every 7.8 months (range, 4-18 months). Children showed continued urodynamic improvements after each injection, with no evidence of tolerance and no side effects. Riccabona and associates40 treated a similar group of 15 children with 10 U/kg (up to 360 U) of BoNTA (BOTOX) and found significant symptomatic (13 of 15 became continent) and urodynamic improvements. Mean duration of effect was 10.5 months. Recently the first series on nonneurogenic DO in the pediatric population was published.42 Twenty-one refractory incontinent children (10 girls and 11 boys) were treated with 100 U of BoNTA (BOTOX). Fifteen patients were followed at least 6 months, and of these, 9 had a complete response (no urgency and dry during the day), 3 had a partial response (decreased urgency and incontinence), and 3 had no response. Eight 206 VOL. 8 NO. 4 2006 of the 9 complete responders kept that response for 12 months, whereas 1 relapsed at 8 months and was successfully re-treated. One child had transient urinary retention (10 days), and 1 had transient vesicoureteral reflux. The published data support the efficacy of BoNTA for refractory DO in the pediatric population, whether it is of neurogenic or nonneurogenic origin. Although caution must be taken in interpreting these results as all the studies were open label, these studies a critical PVR volume (also not consistently defined) and does not necessarily reflect a complete inability to void. CISC is initiated on the basis of clinical parameters and is also not reflective of a specific PVR volume. Systemic adverse events occur when the toxin migrates away from the detrusor. Generalized muscle weakness or hyposthenia has been reported in several studies using Dysport. Grosse and colleagues25 reported that 4 of 66 patients (6%) The published data support the efficacy of BoNTA for refractory DO in the pediatric population, whether it is of neurogenic or nonneurogenic origin. have consistently shown acceptable efficacy without major side effects. Repeat injections have been successfully performed. Consideration must be given to the fact that general anesthesia is required for administration in this population. Botulinum Toxin Adverse Events Adverse events related to intradetrusor botulinum toxin injection can be divided into local and systemic events. Local events include pain, infection, and hematuria. These are due to the procedure and not the toxin. In addition, intradetrusor injections can be associated with excessive detrusor relaxation, resulting in detrusor underactivity and subsequent transient elevation of PVR volume or urinary retention. Studies in neurogenic and idiopathic subjects have consistently shown that treatments, particularly BoNTA, are well tolerated. A summary of the idiopathic trials (Table 1) shows that with respect to elevated PVR volume, “urinary retention” occurs in approximately 5% and the need for CISC in up to 16% of patients. It must be emphasized that “urinary retention” is not consistently defined and is usually a reflection of REVIEWS IN UROLOGY developed transient muscle weakness in the trunk and/or extremities lasting for up to 2 months. Del Popola and colleagues43 reported a 5% incidence of hyposthenia in 53 patients with neurogenic DO. This seems to be a dose-related effect, because muscle weakness was not observed in studies using a lower dose. The occurrence of muscle weakness with Dysport may also be related to injection volume, dilution volume, or site of injection. Other than 1 case of arm muscle weakness in 1 BOTOX-treated subject,44 focal limb or generalized muscle weakness has not been reported with BOTOX. Summary Botulinum toxin treats DO and OAB by a unique mechanism of action. The clinical data available support its use in neurogenic and nonneurogenic DO and OAB in adults and neurogenic and nonneurogenic DO in children. Thus far, very good efficacy has been seen in a mostly refractory, difficultto-treat population. Adverse events have been minimal, and the ones of major significance have been related to incomplete bladder emptying in the idiopathic population. Further studies RIU0320_11-20.qxd 11/20/06 3:01 PM Page 207 Botulinum Toxin for OAB are necessary to define optimal dosing and injection protocols for specific patient populations. Dr. Nitti acts as a consultant for Allergan Inc. References 1. 2. 3. 4. 5. 6. Weain AJ. Diagnosis and treatment of overactive bladder. Urology. 2003;62(suppl 5B):20-27. Andersson KE, Appell R, Cardozo L, et al. Pharmacological treatment of urinary incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence (Edition 2005) 3rd International Consultation on Incontinence. Plymouth, UK: Health Publications Ltd; 2005:809-854. Schurch B, Stohrer M, Kramer G, et al. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol. 2000;164:692-697. Abrams P, Cardoza L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation subcommittee of the International Continence Society. Urology. 2003;61:37-49. Sidi AA, Dykstra DD. Botulinum A toxin selective paralysis of the urethral rhabdosphincter: Pilot study of a new treatment for detrusor sphincter dyssynergia [abstract]. J Urol. 1987; 137(4 pt 2):249A. Simpson LL. Molecular pharmacology of botulinum toxin and tetanus toxoid. Annu Rev 7. 8. 9. 10. 11. 12. 13. 14. 15. Pharmacol Toxicol. 1986;26:427-453. Brashear A, Lwe MF, Dykstra DD, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type-A responsive cervical dystonia. Neurology. 1999;53:1439-1446. Brin MF, Lew MF, Lew CH, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type-A resistant cervical dystonia. Neurology. 1999;53:1431-1448. Sloop RR, Cole BA, Escutin RO. Human response to botulinum toxin injection: type B compared with type A. Neurology. 1997;49:189-194. Smoth 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;169:1896-1900. 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;7:997-1006. Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache. 2004;44:35-42. Rapp DE, Turk KW, Bales GT, Cook SP. Botulinum toxin type A inhibits calcitonin generelated peptide release from isolated rat bladder. J Urol. 2006;175:1138-1142. Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain. 2004;107:125-133. Botulinum toxin inhibits substance P release in inflammatory rat bladder model. J Urol. 2006: 175(4 suppl):92-93. 16. 17. 18. 19. 20. 21. 22. 23. Apostolidis A, Popat R, Yiangou Y, et al. Decrease sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol. 2005;174:977-983. Comperat E, Reitz A, Delcourt A, et al. 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;50:1058-1064. Giannantoni A, DiStasi 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;175:2341-2344. Smith CB, Nishiguchi J, Oleary M, et al. Singleinstitution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology. 2005;65:37-41. Boy S, Schmid M, Reitz A, et al. Botulinum toxin injections into the bladder wall—a morphological evaluation of the injection technique using magnetic resonance imaging. J Urol. 2006;174 (4 suppl):415. Reitz A, Stohrer M, Kramer G, et al. European experience of 200 cases treated with botulinumA toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol. 2004;45:510-515. Bagi P, Beiring-Sorensen F. Botulinum toxin A for treatment of neurogenic detrusor overactivity and incontinence in patients with spinal cord lesions. Scand J Urol Nephrol. 2004;38:495-498. Hajebrahimi S, Altaweel W, Cadoret J, et al. Efficacy of botulinum-A toxin in adults with Main Points • Although the use of botulinum toxin for the treatment of overactive bladder (OAB) and detrusor overactivity (DO) is currently not approved by the US Food and Drug Administration or by the European regulatory agencies, its use in investigational protocols and “off label” continues to grow. • Two different botulinum toxin type A (BoNTA) formulations have been used in the bladder: BOTOX® (Allergan, Irvine, CA) and Dysport® (Ipsen, Boston, MA). Although both are type A toxins, they are derived from different bacterial strains, have different molecular weights, and are manufactured differently. Most studies on DO and OAB have used BOTOX, and it must be emphasized that this formulation is not interchangeable with other botulinum toxin products and should not be converted using a dose ratio. • A number of variables are involved in botulinum toxin administration, including type and amount of toxin, dilution volume, location, number, and depth of injections, instrumentation, and anesthesia technique. A number of protocols have been proven to work well; however, the optimal amount and dilution of toxin and injection site protocol have not been established. • All published series support the use of botulinum toxin for the treatment of neurogenic DO. Several open-label studies, 1 randomized controlled study, and 1 randomized placebo-controlled study all have shown good efficacy with respect to symptoms and urodynamic findings. • Most studies of botulinum toxin in idiopathic DO have shown good efficacy and no significant side effects other than urinary retention, which occurs infrequently. These studies suggest that lower doses of BoNTA (at least for BOTOX) may be effective compared with the doses used for neurogenic DO. Much less data are available on treating OAB without a urodynamic diagnosis of DO. • The published data support the efficacy of BoNTA for refractory DO in the pediatric population, whether it is of neurogenic or nonneurogenic origin. Consideration must be given to the fact that general anesthesia is required for administration in this population. VOL. 8 NO. 4 2006 REVIEWS IN UROLOGY 207 RIU0320_11-20.qxd 11/20/06 3:01 PM Page 208 Botulinum Toxin for OAB continued 24. 25. 26. 27. 28. 29. 30. 208 neurogenic overactive bladder: initial results. Can J Urol. 2005;12:2543-2546. 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;67:232-236. 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;47:653-659. Patki P, Hamid R, Arumugam K, et al. Botulinum toxin-type A in the treatment of drug-resistant neurogenic detrusor overactivity secondary to traumatic spinal cord injury. BJU Int. 2006;98:77-82. Pistolesi D, Selli C, Rossi B, Stampaccia G. Botulinum toxin type B for type A resistant blader spasticity. J Urol. 2004;171:802-803. Reitz A, Schurch B. Botulinum toxin type B injection for management of type A resistant neurogenic detrusor overactivity. J Urol. 2004:171: 804-806. Giannantoni A, Di Stasi SM, Stephen RL, et al. Intravesical resiniferatoxin versus botulinum-A toxin injections for neurogenic detrusor overactivity: a prospective randomized study. J Urol. 2004;172:240-243. Schurch B, De Seze M, 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;174:196-200. VOL. 8 NO. 4 2006 31. 32. 33. 34. 35. 36. 37. REVIEWS IN UROLOGY Kuo HC. Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology. 2004;63:868-872. Popat R, Apostolidis A, Kalsi V, et al. 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;174:984-989. Kessler TM, Danuser H, Schumacher M, et al. Botulinum A toxin injections into the detrusor: an effective treatment in idiopathic and neurogenic detrusor overactivity. Neurourol Urodyn. 2005;24:231-236. 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: 1735-1740. Kuo HC. Clinical effects of suburothelial injection of botulinum A toxin on patients with nonneurogenic detrusor overactivity refractory to anticholinergics. Urology. 2005;66:94-97. Schmid DM, Sauermann P, Werner M, et al. Experience with 100 cases treated with botulinumA toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome refractory to anticholinergics. J Urol. 2006;176:177-185. Rapp DE, Lucioni A, Katz EE, et al. Use of botulinum-A toxin for the treatment of refractory overactive bladder symptoms: an initial experience. Urology. 2004;63:1071-1075. 38. 39. 40. 41. 42. 43. 44. Schulte-Baukloh H, Weiss C, Stolze T, et al. Botulinum-A toxin for treatment of overactive bladder without detrusor overactivity: urodynamic outcome and patient satisfaction. Urology. 2005;66:82-87. Ghei M, Maraj BH, Miller R, et al. Effects of botulinum toxin B on refractory detrusor overactivity: a randomized, double-blind, placebo controlled, crossover trial. J Urol. 2005;174: 1873-1877. Schulte-Baukloh H, Michael T, Sturzebecher B, Knispel HH. Botulinum-A toxin detrusor injection as a novel approach in the treatment of bladder spasticity in children with neurogenic bladder. Eur Urol. 2003;44:139-143. Riccabona M, Koen M, Schindler M, et al. Botulinum-A toxin injection into the detrusor: a safe alternative in the treatment of children with myelomeningocele with detrusor hyperreflexia. J Urol. 2004;171:845-848. Hoebeke P, De Caestecker K, Vande walle J, et al. The effect of botulinum-A toxin in incontinent children with therapy resistant overactive detrusor. J Urol. 2006;176:328-331. Del Popolo G, Li Marzi V, Lombardi G. Efficacy, safety, and dosage of English botulinum toxin-A in neurogenic detrusor overactivity [abstract]. Eur Urol Suppl. 2004;3:168. Wynhdaele JJ, Van Dromme SA. Muscular weakness as a side effect of botulinum toxin injection for neurogenic detrusor overactivity. Spinal Cord. 2002;40:599-600.