Mechanism of action

Botulinum toxin, produced by the gram-positive anaerobic bacterium Clostridium botulinum and first isolated by van Ermengem in 1897, is among the most potent biologic neurotoxins known to man. Structurally composed of a 150-kDa amino acid di-chain molecule consisting of a light (50 kDa) and heavy (100 kDa) chain linked by a disulfide bond, BTX’s primary mechanism of action is inhibition of acetylcholine release at the presynaptic cholinergic junction. BTX’s high selectivity for cholinergic synapses results in targeted blockade of cholinergic transmission, which when targeted to striated muscle induces muscle paresis. More specifically, BTX reduces type Ia/II intrafusal muscle fiber afferent conduction, affecting the spinal stretch reflex and decreasing muscle tone and contractility without affecting muscle strength. Investigators have postulated recently that, in addition a direct effect on detrusor motor innervation, BTX may also affect afferent nervous transmission via the inhibition of acetylcholine, adenosine triphosphate (ATP), glutamate, nerve growth factor, and substance P, and a reduction in the axonal expression of nerve capsaicin and purinergic (P2X) receptors. Thus, it seems likely that BTX also modulates intrinsic bladder reflexes, resulting in central desensitization and a decrease in urgency ( Fig. 1 ). Duration of effect is likely multifactorial as well; mechanisms including chemical denervation followed by axonal regeneration as well as functional motor suppression through neurotransmitter inhibitory effects have been proposed.

The structural components of the human bladder wall including the basal lamina (bl), myofibroblast layer (mf), and detrusor muscle (det). Superimposed are the known or proposed location of receptors and sites of neuropeptide/growth factor release involved in bladder mechanosensation. All connections identified by arrows are thought to be upregulated in detrusor overactivity and may be reduced with the peripheral afferent desensitization that follows injection of botulinum toxin. Thin solid arrows, a proposed pathway where urothelial vesicular ATP release activates P2X2-P2Y receptors or potentiates the response of TRPV1 receptors to irritative stimuli; thin dashed arrows, proposed pathways where vesicular acetylcholine (ACh) release from urothelial nerve terminals activates detrusor muscle muscarinic ACh receptors; thick dashed arrows, proposed pathways where substance P (SP) acts on NK1 receptors on the myofibroblast layer or potentiates the activation of TRPV1-P2X3 receptors in suburothelial afferents; thick solid arrows, nerve growth factor (NGF) is thought to affect the expression of TRPV1.

( Reprinted from 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]:647; Copyright [2006], with permission from Elsevier.)

Serotypes, toxicities, and commercial preparations

Seven BTX serotypes have been isolated, 2 of which (BTX-A and BTX-B) have been investigated in treating bladder dysfunction. The most commonly investigated serotype worldwide, BTX-A received Food and Drug Administration (FDA) approval for therapeutic treatment of strabismus and blepharospasm in 1989, cervical dystonia in 2000, and cosmetic treatment of glabellar wrinkles in 2002. In a recent review of all adverse events (AE) reported to the FDA since BTX-A was licensed in 1989, Cote and colleagues described 217 serious AE, including 28 deaths. All occurred during therapeutic administration but the investigators concluded that it was impossible to determine a causal relationship between the reported mortalities and BTX administration. Additional AE included dysphagia (12%), muscle weakness (6%), allergic reaction (5%), and flu-like syndrome (5%). During cosmetic use, the investigators reported primarily nonserious AE and no deaths, most commonly lack of effect (63%), injection site reaction (19%), and ptosis (11%). Although the FDA has not yet approved BTX for urologic use in the United States, BTX is currently being investigated for urologic indications in clinical trials worldwide. At present, BTX is available as 3 major commercial preparations: Botox (BTX-A; Allergan, Irvine, CA, USA), Dysport (BTX-A; Ipsen, Slough, UK), and Myobloc (BTX-B; Solstice Neurosciences, San Diego, CA, USA). Each of these preparations has different dosages, safety profiles, and efficacy profiles, and cannot be used interchangeably. In the only head to head comparison to date, Grosse and colleagues performed an open-label, observational case-control study comparing a single treatment session of Dysport (500 U, 750 U, 1000 U) and Botox (300 U), finding no differences in therapeutic parameters between groups.

Serotypes, toxicities, and commercial preparations

Seven BTX serotypes have been isolated, 2 of which (BTX-A and BTX-B) have been investigated in treating bladder dysfunction. The most commonly investigated serotype worldwide, BTX-A received Food and Drug Administration (FDA) approval for therapeutic treatment of strabismus and blepharospasm in 1989, cervical dystonia in 2000, and cosmetic treatment of glabellar wrinkles in 2002. In a recent review of all adverse events (AE) reported to the FDA since BTX-A was licensed in 1989, Cote and colleagues described 217 serious AE, including 28 deaths. All occurred during therapeutic administration but the investigators concluded that it was impossible to determine a causal relationship between the reported mortalities and BTX administration. Additional AE included dysphagia (12%), muscle weakness (6%), allergic reaction (5%), and flu-like syndrome (5%). During cosmetic use, the investigators reported primarily nonserious AE and no deaths, most commonly lack of effect (63%), injection site reaction (19%), and ptosis (11%). Although the FDA has not yet approved BTX for urologic use in the United States, BTX is currently being investigated for urologic indications in clinical trials worldwide. At present, BTX is available as 3 major commercial preparations: Botox (BTX-A; Allergan, Irvine, CA, USA), Dysport (BTX-A; Ipsen, Slough, UK), and Myobloc (BTX-B; Solstice Neurosciences, San Diego, CA, USA). Each of these preparations has different dosages, safety profiles, and efficacy profiles, and cannot be used interchangeably. In the only head to head comparison to date, Grosse and colleagues performed an open-label, observational case-control study comparing a single treatment session of Dysport (500 U, 750 U, 1000 U) and Botox (300 U), finding no differences in therapeutic parameters between groups.

Rationale for treatment

Since the 1980s, clinicians have been using BTX to treat neurologic disorders, such as blepharospasm, strabismus, focal dystonias, muscle spasms and spasticity, axillary hyperhidrosis, and achalasia. The initial application of BTX-A to the lower urinary tract targeted patients with detrusor external sphincter dyssynergia (DESD). BTX-A was injected into the urethral sphincter with the intention of weakening the urethral striated musculature enough to reduce urethral pressures, and in turn, to decrease bladder voiding pressures and post-void residual volumes (PVR). However, over the past decade the off-label use of BTX in treating detrusor overactivity (both neurogenic and idiopathic) has become a source of significant interest among urologists. Demonstrating posttreatment reduction in detrusor pressures during voiding and involuntary contractions has provided evidence of BTX’s effect on detrusor motor innervation, and patient-reported reduction in sensation of urgency lends support to a dual afferent mechanism of action as well.

With current investigations expanding the utility of BTX even further to include interstitial cystitis, pelvic floor dysfunction, and prostatic applications; there is currently a wide variation in reported dosages, injection techniques, and follow-up protocols being used. This pattern has led to current efforts to create evidence-based guidelines governing BTX use. However, it is clear that the dosage, number, and site of injection should be tailored to the individual needs of each patient based on etiology of bladder dysfunction. In patients with idiopathic DO or interstitial cystitis, the goals of treatment are to provide symptomatic relief, while avoiding negative side effects such as straining to void and urinary retention. However, in addition to improving QOL, the primary goals of BTX bladder injection in patients with neurogenic DO are to improve urodynamic storage parameters and minimize the risk of renal impairment. For these reasons, it is imperative that all NDO patients being evaluated for BTX injection undergo pretreatment urodynamics assessment. Because BTX chemical denervation is reversible over time, the main disadvantage of BTX injection is the need to undergo repeat injections. Fortunately, there is now evidence to suggest that repeat treatment is equally efficacious even after several injections.

Dosage, concentration, and injection technique

Published investigations to date have utilized varying doses, volumes, and injection target sites. These variations make systematic comparative assessment of the safety and efficacy of BTX difficult. A recent systematic literature review of BTX injection protocol characteristics reported that typically 300 U BTX-A (range 100–400 U) was injected in 30 sites (range 15–40) of 10 U/mL (range 6.7–25 U/mL) in the detrusor, with most investigators preferring to spare the trigone. Injection is typically performed under cystoscopic guidance (flexible or rigid), and can be performed under several types of anesthesia (none, local, spinal, or general).

Injection doses ranging from 100 to 400 U (Botox), and 500 to 1000 SU (Dysport) have been reported in published studies to date. The 300-U dose is the most consistently used across series, although isolated series have reported 100, 200, and 400 U. Although few studies have specifically investigated variable dosing, similar improvement has been reported regardless of total dose with respect to both subjective and objective outcomes. However, determining which dose offers maximum clinical effect with the least risk has not yet been determined. When an initial evaluation of BTX-A injection using 200 U and 300 U in 31 patients with NDO revealed that 2 patients receiving 200 U failed to show clinical improvement, Schurch and colleagues concluded that 300 U was the optimal treatment dose. However, prospective comparison of 200 U and 300 U in 59 patients with NDO showed significant subjective and objective improvement in all patients, with no differences between the 2 study arms. A recent meta-analysis of 8 randomized controlled OAB trials including BTX in at least one treatment arm reported that while low doses of BTX (100–150 U) appeared to have beneficial effects, higher doses (300 U) may be more effective. The investigators concluded that the optimal dose of BTX for efficacy and safety can not be determined until more definitive clinical trial data are available. A majority of investigations to date have utilized injection volumes ranging from 0.1 to 0.5 mL (6.7–25 U/mL)/injection site. Based on animal models, it has been proposed that larger dilution volumes will result in greater suburothelial diffusion with an increased treatment effect. However, this has not been demonstrated clinically, and there are concerns that larger volumes increase the potential for serosal extravasation and increased patient discomfort.

Although various techniques have been described, BTX injection is commonly performed under intravenous sedation or local anesthesia following administration of prophylactic antibiotics. In the operating room setting with the patient in the lithotomy position, a 21F rigid cystoscope and collagen injection needle are used to create a submucosal bleb under direct vision. If a flexible cystoscope is used, a longer needle and/or sheath for stabilization may be necessary. With increasing experience, the injection technique has been uneventfully performed in the office setting, using a flexible cystoscope under local anesthesia. This approach may facilitate cost reduction and avoidance of anesthetic risks.

With endoscopic guidance, toxin is injected via 15 to 40 evenly distributed intramural injection sites including the bladder base and posterolateral walls ( Fig. 2 ). As a general principle, the bladder dome is excluded because of concerns regarding intraperitoneal perforation and bowel injury, and the trigone is spared to avoid inducing vesicoureteral reflux. In cases of DO arising from nonneurogenic cause and/or in patients with isolated pain/sensory components, recent protocols have included trigonal injection, with good results.

Botulinum toxin injection technique. ( A ) Approximately 40 injections are injected within the bladder base, lateral walls, and/or the trigone, which is primarily used in the treatment of neurogenic detrusor overactivity. ( B ) A modified 10-point injection technique focusing on the bladder base and trigone, which can be performed as an outpatient treatment for idiopathic overactive bladder.

( Reprinted from Smith CP, Nishiguchi J, O’Leary M, et al. Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology 2005;65[1]:37–41; Copyright [2005], with permission from Elsevier.)

Treatment outcomes

A recent systematic literature review identified 18 studies investigating the use of BTX in patients with NDO. In this aggregate population of 698 patients, 83% had NDO with urinary incontinence refractory to high doses of anticholinergic therapy. Based on the aggregate outcomes, the investigators concluded that BTX detrusor injections provide a clinically significant benefit in adults with NDO and incontinence/OAB refractory to antimuscarinics. However, of the studies included in the systematic review, only 3 retrospective studies examined clinical series larger than 75 patients (all retrospective), and only 3 other studies were prospectively randomized with a control arm. The majority consisted of small open-labeled studies of less than 50 patients ( Table 1 ).

In a large multi-institutional retrospective series, Reitz and colleagues reported significant increases in mean cystometric bladder capacity ( P <.0001), mean reflex volume ( P <.01), and decreased mean voiding pressures ( P <.0001) in 231 patients with NDO. Patients were treated with 300 U BTX-A in 30 trigone-sparing injection sites; and with 36 week follow-up, patients reported considerably reduced anticholinergic drug dose requirements and high subjective satisfaction rates, with no injection related complications or side effects. Stoehrer and colleagues reported the results of BTX-A detrusor injections in 216 patients with NDO, comparing maximal detrusor pressure, detrusor compliance, reflex volume, cystometric capacity, as well as use of anticholinergic agents and patient satisfaction at 6 weeks and 6 months after treatment. Using either 300 U of Botox or 750 U of Dysport, the investigators reported a significant improvement in all urodynamic parameters as well as incontinence rates and decreased anticholinergic use, but no significant differences were noted when comparing the 2 BTX-A preparations. Recently, Del Popolo and colleagues reported their findings using 1000 U, 750 U, and 500 U of BTX-A (Dysport) in 199 patients with spinal cord lesions and refractory NDO. Following urodynamic evaluation at baseline, then 3, 6, and 12 months post injection; significant improvements were noted in maximum bladder capacity, reflex volume, bladder compliance, and pad usage ( P <.001). Of note, there were no significant differences in therapeutic effect or duration of effect when comparing the differing dosing regimens.

In a double-blinded, randomized, placebo-controlled, 3-arm study comparing 200 U BTX-A, 300 U BTX-A, and placebo in 59 patients with NDO (90% SCI, 10% MS) requiring clean intermittent catheterization (CIC), Schurch and colleagues investigated frequency of urinary incontinence, maximum cystometric capacity (MCC), reflex detrusor volume, and maximum detrusor pressure via patient voiding diary and urodynamic assessment at 24 weeks post injection. The investigators reported significant improvement in QOL (Incontinence Quality of Life questionnaire), posttreatment decreases in incontinence episodes (IE), and improvement in urodynamic bladder function in both BTX treatment groups ( P <.05) from the first evaluation at week 2 to the end of the 24-week study when compared with baseline. The reported side effects with BTX use were minimal and symptom improvement was similar in the 200 U and 300 U dosing regimen groups, with no significant improvement noted in the placebo arm. Giannantoni and colleagues randomized 75 patients with SCI and refractory NDO to a 2-arm controlled trial comparing intravesical instillation of resiniferatoxin (RTX) dissolved in normal saline (N = 40) and 30 trigone-sparing bladder injections of 300 U BTX-A diluted in 30 mL normal saline (N = 35). Clinical assessment and urodynamics were performed at baseline, then 6, 12, and 24 months post treatment. The investigators reported significant reductions in mean catheterization rate and IE, as well as significant increases in mean first involuntary detrusor contraction and mean maximum bladder capacity at all time points in both treatment groups. Although side effects were not reported with either treatment, the investigators did note a significant benefit with BTX compared with RTX regarding number of IE per 24 hours and maximum detrusor pressure. In the most recent prospective study to date, Ehren and colleagues randomized 31 patients with NDO to a single treatment of 500 U BTX-A (Dysport) versus placebo using urodynamic parameters (6, 12, and 26 weeks), QOL, IE, and intake of rescue tolterodine as outcome measures. A significantly lower intake of tolterodine ( P = .003), increased cystometric capacity at 6 ( P <.001) and 12 ( P = .026) weeks, decreased maximum detrusor pressure ( P <.01), and decreased IE ( P <.01) were found in the BTX treatment arm. The consensus from these reports suggests that BTX achieves measurable urodynamic and subjective improvement in NDO patients with minimal negative sequelae. However, repeat injections are necessary to achieve a sustained response. Although contemporary series differ with regard to study methodology and injection protocols, here the authors summarize and quantify the reported outcomes within the broad categories of subjective patient-reported outcome measures and objective urodynamic parameters.