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Botulinum Toxin Therapy for Neurogenic Detrusor Overactivity

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Botulinum Toxin Therapy for Neurogenic Detrusor Overactivity Botulinum Toxin Therapy for Neurogenic Detrusor Overactivity Marc C. Smaldone, MD, Benjamin T. Ristau, MD, Wendy W. Leng, MD* KEYWORDS Botulinum toxin Bladder dysfunction Neurogenic Detrusor overactivity Overactive bladder The overactive bladder (OAB) condition is even more disadvantaged by virtue of their neuro- a symptom complex characterized by urinary logic deficits. urgency with or without urge urinary incontinence Moreover, neurogenic bladder dysfunction has (UUI), and is often associated with frequency and the distinct potential to cause long-term renal nocturia. Overall, OAB prevalence in the United failure. The neural and/or myogenic deficits may States and European adult population is estimated gradually compromise the bladder’s storage func- to be 11.8%.1 OAB is not specific to any one tion, otherwise known as bladder compliance. condition. However, based on clinical convention; Such insidious, asymptomatic deterioration of OAB may then be further classified as neurogenic the neurogenic bladder’s compliance reflects or idiopathic. When OAB occurs in association a gradual loss of the lower urinary tract’s ability with a known underlying neurologic pathology to store increasing volume at the same low such as spinal cord injury (SCI) or multiple scle- ambient pressure. With the ensuing increase in in- rosis (MS), it is classified as neurogenic OAB. travesical storage pressure, the lower urinary tract When there is no evidence of any identifiable often responds by provoking random urethral neurologic disorder, it is classified as idiopathic leakage as a means to vent a high-pressure OAB. chamber.5 However, in some instances where OAB is a clinical diagnosis. By contrast, detru- the system fails to satisfactorily vent the high- sor overactivity (DO) describes the common uro- pressure chamber, the sustained high pressures dynamic testing observation in this population, transmit upstream to the renal pelvis. Over time, whereby involuntary detrusor contractions this sustained high-pressure transmission to the become evident during the bladder-filling phase.2 renal pelvis causes deterioration of glomerular For the purposes of this discussion of neurogenic filtration and eventual renal failure. This well- bladder dysfunction, the authors use the term characterized pathophysiologic process poses neurogenic detrusor overactivity (NDO). a dangerously asymptomatic phenomenon for Research demonstrates the significant impair- the NDO population.6 ment to quality of life (QOL)3 by OAB as well as Typically, first-line therapy for idiopathic OAB is its added burden of increasing health care costs.4 conservative in nature, encompassing behavioral While the OAB condition clearly affects QOL for all techniques, pelvic physiotherapy, and anti- sufferers, the subset of patients with NDO can be muscarinic pharmacotherapy. While conservative Department of Urology, University of Pittsburgh School of Medicine, Suite 700, Kaufmann Building, 3471 5th Avenue, Pittsburgh, PA 15213, USA * Corresponding author. E-mail address: [email protected] Urol Clin N Am 37 (2010) 567–580 doi:10.1016/j.ucl.2010.06.001 0094-0143/10/$ e see front matter Ó 2010 Elsevier Inc. All rights reserved. urologic.theclinics.com 568 Smaldone et al therapies are likewise reasonable for first-line intrinsic bladder reflexes, resulting in central management of NDO, the chances of successful desensitization and a decrease in urgency incontinence control are greatly hindered by (Fig. 1).15 Duration of effect is likely multifactorial patient disabilities and the underlying neurologic as well; mechanisms including chemical denerva- defects within the complex micturition circuit. In tion followed by axonal regeneration16 as well as other words, a significant fraction of NDO patients functional motor suppression through neurotrans- derive insufficient bladder control with conserva- mitter inhibitory effects14 have been proposed. tive treatment strategies. Moreover, this patient population disproportionately suffers more overall SEROTYPES, TOXICITIES, AND COMMERCIAL QOL impairment with their lower urinary tract PREPARATIONS dysfunction.7 A growing body of evidence suggests that intra- Seven BTX serotypes have been isolated, 2 of vesical injection of botulinum neurotoxin (BTX) is which (BTX-A and BTX-B) have been investigated an efficacious, minimally invasive alternative to in treating bladder dysfunction. The most more traditional surgical therapies (such as commonly investigated serotype worldwide, bladder augmentation or urinary diversion) in BTX-A received Food and Drug Administration patients with NDO who are intolerant or refractory (FDA) approval for therapeutic treatment of stra- to pharmacotherapy. Alternative intravesical bismus and blepharospasm in 1989, cervical dys- agents currently being evaluated include antimus- tonia in 2000, and cosmetic treatment of glabellar carinic agents (oxybutynin, atropine), local anes- wrinkles in 2002. In a recent review of all adverse thetics (lidocaine, bupivacaine), and vanilloids events (AE) reported to the FDA since BTX-A (capsaicin, resiniferatoxin), but randomized, was licensed in 1989, Cote and colleagues17 placebo-controlled evidence demonstrating safety described 217 serious AE, including 28 deaths. and efficacy is currently lacking.8 The objective of All occurred during therapeutic administration this review is to provide a focused summary of the but the investigators concluded that it was impos- current body of literature investigating the safety sible to determine a causal relationship between and efficacy of bladder BTX injection in patients the reported mortalities and BTX administration. with NDO. Additional AE included dysphagia (12%), muscle weakness (6%), allergic reaction (5%), and flu- MECHANISM OF ACTION like syndrome (5%). During cosmetic use, the investigators reported primarily nonserious AE Botulinum toxin, produced by the gram-positive and no deaths, most commonly lack of effect anaerobic bacterium Clostridium botulinum and (63%), injection site reaction (19%), and ptosis first isolated by van Ermengem in 1897,9 is among (11%). Although the FDA has not yet approved the most potent biologic neurotoxins known to BTX for urologic use in the United States, BTX is man. Structurally composed of a 150-kDa amino currently being investigated for urologic indica- acid di-chain molecule consisting of a light tions in clinical trials worldwide. At present, BTX (50 kDa) and heavy (100 kDa) chain linked by a di- is available as 3 major commercial preparations: sulfide bond, BTX’s primary mechanism of action Botox (BTX-A; Allergan, Irvine, CA, USA), Dysport is inhibition of acetylcholine release at the presyn- (BTX-A; Ipsen, Slough, UK), and Myobloc (BTX-B; aptic cholinergic junction.10 BTX’s high selectivity Solstice Neurosciences, San Diego, CA, USA).18 for cholinergic synapses results in targeted Each of these preparations has different dosages, blockade of cholinergic transmission, which safety profiles, and efficacy profiles, and cannot when targeted to striated muscle induces muscle be used interchangeably. In the only head to paresis.11 More specifically, BTX reduces type head comparison to date, Grosse and Ia/II intrafusal muscle fiber afferent conduction, colleagues18 performed an open-label, observa- affecting the spinal stretch reflex and decreasing tional case-control study comparing a single treat- muscle tone and contractility without affecting ment session of Dysport (500 U, 750 U, 1000 U) muscle strength.12,13 Investigators have postu- and Botox (300 U), finding no differences in thera- lated recently that, in addition a direct effect on de- peutic parameters between groups. trusor motor innervation, BTX may also affect afferent nervous transmission via the inhibition of RATIONALE FOR TREATMENT acetylcholine, adenosine triphosphate (ATP), glutamate, nerve growth factor, and substance Since the 1980s, clinicians have been using BTX to P, and a reduction in the axonal expression of treat neurologic disorders, such as blepharo- nerve capsaicin and purinergic (P2X) receptors.14 spasm, strabismus, focal dystonias, muscle Thus, it seems likely that BTX also modulates spasms and spasticity, axillary hyperhidrosis, Botulinum Toxin Therapy Fig. 1. 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 sub- urothelial 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
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