Botulinum Toxin: Poisoning the Spastic Bladder and Urethra

Treatment Update

TREATMENT UPDATE Botulinum Toxin: Poisoning the Spastic Bladder and Urethra Christopher P. Smith, MD,* George T. Somogyi, MD, PhD,† Michael B. Chancellor, MD* Departments of *Urology and †Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA Botulinum toxin has proven to be a safe and effective therapy for a variety of somatic and autonomic motor disorders. Urologists are now finding clinical success with urethral and bladder injection of this fascinating toxin for detrusor sphincter dyssynergia, conditions of pelvic floor spasticity, and overactive bladder. One cannot deny the ingenuity of man in transforming the lethal toxin of Clostridium botulinum into a modern day therapeutic medicine. [Rev Urol. 2002;4(2):61–68] © 2002 MedReviews, LLC Key words: Pathophysiology • Acetylcholine • Detrusor hyperreflexia • Detrusor external sphincter dyssynergia • Overactive bladder • Spinal cord injury B otulinum toxin, first isolated by van Ermengem in 1897, is the most potent biological toxin known to man.1 Through basic research, clinicians have been able to transform this lethal toxin into a health benefit. Clinicians have safely and successfully used this agent for the treatment of focal dystonias, muscle spasm, and spasticity.2,3 The toxin acts by inhibiting acetylcholine release at the presynaptic cholinergic junction. Clinically, the urologic community has utilized commercial preparations of botulinum toxin type A (BTX-A) to treat spinal cord injured (SCI) patients who suffer from detrusor external sphincter dyssynergia (DESD).4–6 More recently, Schurch and colleagues reported successful treatment of SCI patients with detrusor hyperreflexia using intravesical BTX-A injections at up to 30 sites.7 This article will review the mechanisms underlying the effects of BTX treatment, summarize the current usage of this exciting agent within the urologic community, and provide perspectives on future targets of this therapy. VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 61 Urologic Applications for Botulinum Toxin continued B OTULINUM T OXIN M OLECULE S S Zn Heavy chain Light chain Figure 1. Illustration of the active, dichain polypeptide form of botulinum toxin. The parent chain is cleaved into a heavy chain (~100 kDa) connected by a disulfide bond to a light chain (~50kDa) with an associated zinc (Zn) atom. Background and Pathophysiology Botulinum poisoning was first described in cases of sausage poisoning in the late 1700s in Germany. A local medical officer collected data on 230 cases of botulism, and the illness became known as “Kerner’s disease."8 It was not until 1897 that van Ermengem isolated the sporeforming obligate anaerobic bacteria, Clostridium botulinum.1 The pioneering work of Dickson and Shevky in 1923 lent first evidence that BTX impaired transmission at the muscle end organ.9 They demonstrated that BTX did not impair transmission in the nerve trunk nor responses to direct electrical stimulation of muscle preparations. However, it was not until Burgen’s work in 1949 that the foundation was laid for future clinical therapeutic applications.10 Burgen presented evidence that paralysis by BTX was due to the inhibition of the neurogenic release of acetylcholine. BTXs are synthesized as singlechain polypeptides with a molecular weight of around 150 kilodaltons (kDa).1111 Initially, the parent chain is 62 VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY cleaved into its active, dichain polypeptide form, consisting of a heavy chain (~100 kDa) connected by a disulfide bond to a light chain (~50 kDa) with an associated zinc atom (Figure 1).12 Three steps are required for toxin-induced paralysis: 1) binding and internalization of the toxin within the nerve terminal; 2) translocation of the light-chain into the cytosol; and 3) inhibition of neurotransmitter release. Binding of the toxin is a reversible, temperature-independent process and is mediated by the heavy chain.13 In contrast, internalization of both chains by an endocytotic/liposomal vesicle pathway is both a temperature-dependent and active process that is partly dependent on nerve stimulation and is independent of calcium concentration.14–17 Following internalization, the disulfide bond between the heavy and light chain is cleaved and the light chain is translocated into the cytosol. The light chain contains the zinc endopeptidase activity of BTX.16 The enzyme inhibits acetylcholine release by cleaving one or more proteins involved in the vesicle transport pathway. Acetylcholine release involves the Figure 2. Schematic diagram of a nerve terminal indicating the normal fusion of the synaptic vesicles with the plasma membrane. ACh, acetylcholine; VAMP, vesicle-associated membrane protein; SNAP-25, synaptosomeassociated protein 25 KDa. N ORMAL F USION AND R ELEASE OF AC H Nerve Terminal Axon ACh ACh Muscle Ca2+ Neurexin SNAP-25 VAMP/Synaptobrevin Syntaxin Synaptotagmin Urologic Applications for Botulinum Toxin adenosine-5'-triphosphate (ATP)-dependent transport of the vesicle from the cytosol to the plasma membrane.18 Vesicle docking requires the interaction of various cytoplasmic, vesicle, and target membrane proteins, some of which are specifically targeted with clostridial neurotoxins. BTX-A, for example, cleaves the cytosolic translocation protein SNAP-25, thus preventing vesicle fusion with the plasma membrane (Figures 2 and 3).19 B OTULINUM T OXIN B LOCKS R ELEASE OF AC H Nerve Terminal BDFG Axon ACh ACh ACE Atrophied Muscle C Ca2+ Clinical Applications Seven immunologically distinct neurotoxins are known: types A, B, C, D, E, F, and G. BTX-A (Botox®, Allergan, Irvine, CA) received U.S. Food and Drug Administration (FDA) approval in 1989 for the treatment of strabismus, benign essential blepharospasm, and disorders of the VIIth nerve. Since its introduction into clinical use in the 1980s, BTX-A has been successfully used to treat various conditions, including blepharospasm, strabismus, focal dystonias, muscle spasms and spasticity, axillary hyperhidrosis, and achalasia.2,3,20–22 More recently, the FDA approved a BTX-B complex preparation (Myobloc™, Elan Corporation, Dublin, Ireland) for clinical use in cervical dystonia patients. Neurexin SNAP-25 Synaptotagmin VAMP/Synaptobrevin Syntaxin Botulinum Toxin Figure 3. Schematic diagram of a nerve terminal indicating the blocking effect of botulinum toxin on normal fusion of the synaptic vesicles with the plasma membrane. Note after blocking of the vesicle transport by botulinum toxin, no acetylcholine (ACh) release occurs, leading to muscle atrophy. VAMP, vesicle-associated membrane protein; SNAP-25, synaptosome-associated protein 25 KDa. spasticity can be treated with BTX-A, although higher doses may be required. Unfortunately, the higher doses can lead to the development of antibodies that neutralize BTX-A effect.25,26 However, most of the literature regarding neutralizing antibody formation to BTX-A arose from a treatment paradigm whereby patients were being treated with “booster" injections. The restriction of treat- BTX-A represents a viable option in the treatment of detrusor external sphincter dyssynergia. Focal dystonia remains the primary indication for the neurological use of BTX-A. BTX-A is considered the first-choice treatment for blepharospasm, with response rates of 90% to 95%.23 It also remains the front-line treatment of adductor laryngeal dystonia, with patients regaining 90% of normal function lasting a mean of 15 weeks.24 Patients with cervical dystonia or ment to no more than every 3 months has resulted in a decreased incidence of neutralizing antibody formation in patients treated with BTX-A. Furthermore, current Botox has a much lower protein exposure, and immunoresistance to therapy in patients treated solely with current Botox has not been reported (R. Aoki, personal communication, August 2001). BTX-A has also been useful in disorders of autonomic motility and exocrine function, including achalasia, axillary hyperhidrosis, and vasomotor rhinitis.22,27,28 Urologic Applications Urethra Urologic applications of BTX-A have been primarily associated with cases of DESD. Management of SCI patients was revolutionized with the development of clean intermittent catheterization (CIC) by Lapides in 1971.29 However, not all patients are capable of performing CIC and require an alternative that decreases outlet resistance and allows continuous bladder decompression. Various alternatives have been described, including external sphincterotomy, radical transurethral resection of the prostate, and various denervation procedures (eg, dorsal rhizotomy).30 These procedures are unfortunately permanent and irreversible, and carry with them inherent risks (eg, bleeding, stricture formation, fistulas). BTX-A represents a viable option VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 63 Urologic Applications for Botulinum Toxin continued in the treatment of DESD. The toxin acts at the neuromuscular junction of the external sphincter to block vesicle transport of acetylcholine, in essence producing a chemical denervation. The clinical effects begin within 2 to 3 days and are reversible, as terminal nerve sprouting occurs within 3 to 6 months.31 Injection of BTX-A into the sternomastoid muscle of mice has been shown to induce the formation of terminal nerve sprouts from the parent terminal.32 The sprouts form functional synapses with the muscle but eventually regress at a time when the parent nerve terminal regains the ability to release neurotransmitters. It remains to be seen whether similar processes occur in autonomic nerves innervating the lower urinary tract. Dykstra investigated the effects of BTX-A injection in two studies of SCI patients with DESD. In the first study, published in 1988, all 10 patients that were evaluated by electromyography after injection showed signs of sphincter denervation.6 Urethral pressure profile decreased by an average of 27 cm H2O, and postvoid residuals decreased by an average of 146 mL after toxin injection. In 1990, Dykstra published the only double-blind, placebo controlled study of BTX-A decreased to an average of 30 cm H2O. Parameters were unchanged from baseline in the two patients who received normal saline injections. We performed a prospective study on 21 patients referred to our clinic with voiding dysfunction.33 All Following urethral injection of Botox, voiding pressures decreased an average of 38%. patients were evaluated with videourodynamics. Follow-up ranged from 3 to 16 months. Following urethral injection of Botox, voiding pressures decreased an average of 38%. Sixtyseven percent of patients reported improvement in voiding patterns. No complications or side effects were noted. Our results are consistent with the largest series to date treating DESD with BTX-A. In that study, Schurch treated 24 patients with SCI and DESD with BTX-A injection.34 Significant improvement in DESD was noted in 21/24 patients (88%), with decreased postvoid residuals in most patients. The effects lasted 3 to 9 months, with no adverse events reported. Thus, BTX-A toxin injections are a safe and efficacious treatment option for DESD. A case of functional urethral obstruction and detrusor acontractility following pubovaginal sling surgery was successfully treated by BTX-A urethral sphincter injection. injection into the external urethral sphincter of five men with SCI and DESD.5 Electromyography of the external urethral sphincter indicated denervation in the three patients who received toxin injections. The urethral pressure profile decreased an average of 25 cm H2O, postvoid residual decreased an average of 125 mL, and bladder pressure during voiding 64 VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY sympathetic transmission and smooth muscle dyssynergia. In addition to classic neuropathic DESD, we have expanded the indications for use of BTX-A to include patients with a variety of bladder outlet obstructions, excluding those The clinical success of BTX-A is supported by laboratory research demonstrating marked decreases in the release of labeled norepinephrine and acetylcholine in BTX-A-injected rat urethral sphincters.35 The therapeutic effect of inhibiting acetylcholine release is obvious; blockage of norepinephrine release may provide clinical benefit by inhibiting patients with obstruction secondary to fibrosis. We have successfully used BTX-A to treat voiding dysfunction in multiple sclerosis patients with DESD, patients with pelvic floor spasticity, and even in an acontractile multiple sclerosis patient who wished to void by valsalva.33 Recently, we reported a case of functional urethral obstruction and detrusor acontractility following pubovaginal sling surgery that was successfully treated by BTX-A urethral sphincter injection (Smith et al, unpublished data). Bladder Data has been accumulating on the clinical application of BTX-A to detrusor muscle in hyperreflexic bladders of SCI patients. A preliminary study by Schurch and colleagues in 31 patients with detrusor hyperreflexia demonstrated a significant increase in mean maximum bladder capacity (296 mL to 480 mL, P < .016) and a significant decrease in mean maximum detrusor voiding pressure (65 to 35 cm H2O, P < .016) in patients injected with BTX-A.7 A follow-up, long-term study completed by the same investigators in 87 patients with detrusor hyperreflexia corroborated the efficacy of intravesical BTX injection presented in their earlier work.36 In addition, they reported that clinical responses lasted 4 to 14 months and observed no Urologic Applications for Botulinum Toxin B OTULINUM T OXIN A PPLICATIONS Sensory Urgency IC DH Overactive Bladder DISD BNO BPH DESD 50, 100, or 200 U Botox. Four of seven patients responded to treatment with decreases in frequency and increased bladder capacity. No mention is made of vesicoureteral reflux as a complication of treatment. These latest clinical findings are supported by research of ours and others demonstrating the efficacy of BTX-A on autonomic nerves.40–43 Our studies found significant decreases in the release and uptake of labeled norepinephrine and acetylcholine in BTX-A-injected rat bladders.43 Future Perspectives Figure 4. Current and potential future targets for botulinum toxin within the lower urinary tract. IC, interstitial cystitis; DH, detrusor hyperreflexia; DISD, detrusor internal sphincter dyssynergia; BNO, bladder neck obstruction; BPH, benign prostatic hyperplasia; DESD, detrusor external sphincter dyssynergia. adverse effects with treatment. Detrusor muscle injections were performed in over 30 sites with either 300 U Botox or 500 to 750 U Dysport® (BTX-A; Ipsen Ltd, Berkshire, UK). The trigone was spared, presumably to avoid the potential complication of vesicoureteral reflux. In contrast, Del Popolo noted hyposthenia in 5/61 patients treated with high-dose intravesical BTX-A injections (300 U Botox or 1000 U Dysport).37 The supralesional weakness was transient in nature, disappearing 2 to 4 weeks after injection and was abolished with lower-dosage injections (500 U Dysport). Clearly, the dose and the volume injected appear to play a significant role in inducing systemic toxicity with BTXA. Multiple injections of lower doses would be expected to have a more localized and less systemic effect. However, the main disadvantage of intravesical BTX-A injections for many urologists is the repeated cystoscopies and toxin injections that are necessary to maintain clinical results. BTX-A injections have extended beyond the realm of neurogenic bladders to patients with non-neurogenic voiding and storage disorders. Radziszewski and associates reported favorably on the effects of intravesical BTX-A injections in a pilot study of patients with either idiopathic bladder overactivity or functional outlet obstruction.38 Following intravesical or sphincteric BTX-A injections, Selectivity of Toxin Isoforms An interesting side effect of patients with cervical dystonia injected with BTX-B (Myobloc) was the development of dry mouth.44 A rare occurrence following BTX-A treatment, dry mouth was unexpected, because the salivary glands were farther from the injection site than relatively unaffected lingual or lower facial muscles. This implies that BTX-B may have a greater affinity for cholinergic nerves innervating the salivary gland rather than lingual or lower facial muscles or, alternatively, that there are a higher number of Clearly, the dose and the volume injected appear to play a significant role in inducing systemic toxicity with BTX-A. patients demonstrated resolution of incontinence and improved voiding efficiency, respectively. Finally, Zermann and colleagues presented their experience with intravesical BTX-A injection in seven patients with severe urgency-frequency syndrome refractory to anticholinergic therapy or electrical stimulation.39 In contrast to other studies involving intravesical injections of BTX-A, the authors targeted the trigone and bladder base with 5 to 7 injections of BTX-B receptors in salivary gland compared to muscles of the lower face and tongue. Future studies should clarify whether similar effects are seen in parasympathetic cholinergic nerves innervating the lower urinary tract. In addition, evidence from Carpenter’s experiments in the late 1960s, as well as from our lab, suggest that the rat bladder is significantly more sensitive to the effects of BTX-D than BTX-A.40,45 In fact, VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 65 Urologic Applications for Botulinum Toxin continued Table 1 Current and Potential Applications of Botulinum Toxin Potential Urethra Applications • Detrusor external sphincter dyssynergia • Pelvic floor spasticity • Post-bladder neck suspension retention • Prostatitis • Benign prostatic hyperplasia • Bladder neck obstruction and dyssynergia Potential Bladder Applications • Detrusor hyperreflexia • Overactive bladder • Sensory urgency • Interstitial cystitis the rat bladder and urethra should prompt studies investigating the effects of BTX on disorders of increased sympathetic activity (eg, functional bladder neck obstruction, detrusor internal sphincter dyssynergia, and benign prostatic hyperplasia). Finally, if afferent nerve transmission is impaired by BTX, a significant patient population will be opened to this treatment (Figure 4, Table 1). Conclusions Carpenter found that parasympathetic blockade with BTX-D occurred before somatic neuromuscular blockade. It remains to be seen whether these effects are merely due to differing sensitivities of various cholinergic nerve endings to different toxins, or whether BTX-D’s greater efficacy in the bladder is due to an effect on noncholinergic transmission. Currently, no data exists on whether these same differences in rat bladder sensitivity to toxin isoforms exist in the human bladder. Afferent Effects Several investigators have demonstrated in vitro evidence of an afferent effect of BTX. Welch and colleagues reported that neuropeptide release from rat dorsal root ganglia was inhibited by BTX-A, B, C1, F treatment, and Purkiss and colleagues noted that incubation of rat dorsal root ganglia with BTX-A inhibited release of radioactively labeled glutamate.46,47 The inhibition of transmitter release from nociceptive neurons could impair mechanisms involved with central sensitization and position BTX as a therapeutic agent in conditions such as chronic pain. Current in vivo studies support a role for BTX-A in relieving nociceptive pain. In a model of pain associated with formalin-induced inflammation, rats were pretreated in the hind paw 66 VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY with BTX-A prior to injection with formalin.48 Formalin provokes pain via a direct stimulation of nociceptors (Phase 1) and, subsequently by inflammation (Phase II). Formalin was injected 5 and 12 days after BTX-A injection. Surrogate markers Botulinum toxin has proven to be a safe and effective therapy for a variety of somatic and autonomic motor disorders. Urologists are now finding clinical success with urethral and bladder BTX-A injections in the treatment of DESD, conditions of pelvic floor spasticity, and detrusor hyperreflexia. Research evidence should prompt studies investigating the effects of BTX on disorders of increased sympathetic activity (eg, functional bladder neck obstruction, detrusor internal sphincter dyssynergia, and benign prostatic hyperplasia). of pain included paw-licking and paw-lifting behavior. Pretreatment with BTX-A significantly reduced pain at 5 and 12 days post-injection. These results support clinical observations that BTX-A has an antinociceptive effect that is independent of its effects on the neuromuscular junction. Future studies will need to determine whether BTX-A has any effect on visceral afferent transmitter release. BTX-A has a potentially much wider spectrum of application within the urologic field than merely the treatment of detrusor hyperreflexia and DESD in SCI patients. Treatment should be extended to others, including the multiple sclerosis population and those with non-neurogenic voiding and storage disorders. Our basic research evidence that BTX-A inhibits norepinephrine release in Many questions remain regarding BTX’s effect on the neural pathways of the lower urinary tract. However, one cannot deny the ingenuity of man in transforming the lethal toxin of Clostridium botulinum into a modern day therapeutic medicine. References 1. 2. 3. 4. 5. van Ermengem E. Ueber einen neuen anaeroben Bacillus and seine Beziehungen zum Botulisms. Ztsch Hyg Infekt. 1987;26:1–56. Grazko MA, Polo KB, Jabbari B. Botulinum toxin A for spasticity, muscle spasms, and rigidity. Neurology. 1995;45:712–717. Jankovic J, Schwartz K, Donovan DT. Botulinum toxin in the treatment of cranial-cervical dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry. 1990;53:633–639. Petit H, Wiart E, Gaujard E, et al. Botulinum A toxin treatment for detrusor-sphincter dyssynergia in spinal cord disease. Spinal Cord. 1998;36:91–94. Dykstra DD, Sidi A. Treatment of detrusorsphincter dyssyngeria with botulinum A toxin: a double blind study. Arch Phys Med Rehabil. 1990;71:24–26. Urologic Applications for Botulinum Toxin 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Dykstra DD, Sidi AA, Scott AB, et al. Effects of botulinum A toxin on detrusor-sphincter dyssyngeria in spinal cord injury patients. J Urol. 1988;139:919–922. 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. Dickson EC. Botulism. A clinical and experimental study. In: Monographs of the Rockefeller Institute for Medical Research (No. 8). New York: Rockefeller Institute for Medical Research; 1918:1–117. Dickson EC, Shevky R. Botulism: studies on the manner in which the toxin of Clostridium botulinum acts upon the body. II. The effect on the voluntary nervous system. J Exp Med. 1923;38:327–346. Burgen ASV, Dickens F, Zatman LJ. The action of botulinum toxin on the neuromuscular junction. J Physiol (Lond). 1949;109:10–24. DasGupta BR. Structures of botulinum neurotoxin, its functional domains, and perspectives on the crystalline type A toxin. In: Jankovic J, Hallett M (eds). Therapy with Botulinum Toxin. New York: Marcel Dekker; 1994:15–39. Schiavo G, Rossetto O, Santucci A, et al. Botulinum neurotoxins are zinc proteins. J Biol Chem. 1992;267:23479–23483. Murayama S, Umezawa J, Terajima J, et al. Action of botulinum neurotoxin on acetycholine release from rat brain synaptosomes: putative internalization of the toxin into synaptosomes. J Biochem. 1987;102:1355–1364. Hughes R, Whaller BC. Influence of nerve ending activity and of drugs on the rate of paralysis of rat diaphragm preparations by Clostridium botulinum type A toxin. J Physiol. 1962 160:221–223. Nathan P, Dimitrijevic MR, Sherwood AM. Reflex path length and clonus frequency [letter]. J Neurol Neurosurg Psychiatry. 1985;48:725. Dolly JO. General properties and cellular mech- 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. anisms of neurotoxins. In: Jankovic J, Hallet M (eds). Therapy with Botulinum Toxin. New York: Marcel Dekker; 1994. Simpson LL. Peripheral actions of the botulinum toxins. In: Simpson LL (ed). Botulinum Neurotoxin and Tetanus Toxin. New York: Academic Press; 1989: 153–178. Barinaga M. Secrets of secretion revealed. Science. 1993;260:487–489. Schiavo G, Santucci A, DasGupta BR, et al. Botulinum neurotoxins serotypes A and E cleave Snap-25 at distinct COOH-terminal peptide bonds. FEBS Lett. 1993;335:99–103. Scott AB. Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol Soc. 1981;79:734–770. Kolbasnik J, Waterfall WE, Fachnie B, et al. Long-term efficacy of botulinum toxin in classical achalasia: a prospective study. Am J Gastroenterol. 1999;94:3434–3439. Schnider P, Binder M, Kittler H, et al. A randomized, double-blind, placebo-controlled trial of botulinum A toxin for severe axillary hyperhidrosis. Brit J Dermatol. 1999;140:677–680. Dutton JJ. Botulinum-A toxin in the treatment of craniocervical muscle spasms: short- and long-term, local and systemic effects. Surv Ophthalmol. 1996;41:51–65. Blitzer A, Brin MF, Stewart CF. Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients. Laryngoscope. 1998;108:1435–1441. Borodic G, Johnson E, Goodnough M, et al. Botulinum toxin therapy, immunologic resistance, and problems with available materials. Neurology. 1996;46:26–29. Jankovic J, Schwartz K. Responses and immunoresistance to botulinum toxin injections. Neurology. 1995;45:1743–1746. Pasricha PJ, Ravich WJ, Hendrix TR, et al. Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med. 1995;332:774–778. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. Kim KS, Kim SS, Yoon JH, et al. The effect of botulinum toxin type A injection for intrinsic rhinitis. J Laryngol Otol. 1998;112:248–251. Lapides J, Diokno AC, Silber SJ, Lowe BS. Clean, intermittent self-catheterization in the treatment of urinary tract disease. Trans Am Assoc Genitourin Surg. 1971;63:92–96. Koyanagi T, Morita H, Takamatsu T, et al. Radical transurethral resection of the prostate in male paraplegics revisited: further clinical experience and urodynamic considerations for its effectiveness. J Urol. 1987;137:72–76. Borodic GE, Joseph M, Fay L, et al. Botulinum A toxin for the treatment of spasmodic torticollis: dysphagia and regional toxin spread. Head Neck. 1990;12:392–399. de Paiva A, Meunier FA, Molgo J, et al. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci U S A. 1999;96:3200–3205. Phelan MW, Franks M, Somogyi GT, et al. Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction. J Urol. 2001;165:1107–1110. Schurch B, Hauri D, Rodic B, et al. Botulinum A toxin as a treatment of detrusor-sphincter dyssyngeria: a prospective study in 24 spinal cord injury patients. J Urol. 1996;155:1023–1029. McNeil BK, Smith CP, Franks ME, et al. Effect of botulinum toxin A on urethral neurotransmitter release: Implications on somatic/autonomic nerve transmission [abstract]. J Urol. 165:277. Schurch B, Stöhrer M, Kramer G, et al. Botulinum toxin-A to treat detrusor hyperreflexia in spinal cord injured patients [abstract]. Neurourol Urodyn. 2001;20:521–522. Del Popolo G. Botulinum-A toxin in the treatment of detrusor hyperreflexia [abstract]. Neurourol Urodyn. 2001;20:522–524. Radziszewski P, Dobronski P, Borkowski A. Main Points • Botulinum toxin (BTX), the most potent biological toxin known to man, acts by inhibiting acetylcholine release at the presynaptic cholinergic junction. • Since its introduction into clinical use in the 1980s, BTX type A (BTX-A) has been successfully used to treat various conditions, including blepharospasm, strabismus, focal dystonias, muscle spasms and spasticity, axillary hyperhidrosis, and achalasia. • BTX-A represents a viable option in the treatment of detrusor external sphincter dyssynergia (DESD), by acting at the neuromuscular junction of the external sphincter to block vesicle transport of acetylcholine, in essence producing a chemical denervation. • The authors have successfully used BTX-A to treat voiding dysfunction in multiple sclerosis patients with DESD, and patients with pelvic floor spasticity. • Data has been accumulating on the clinical application of BTX-A to detrusor muscle in hyperreflexic bladders of spinal cord injury patients; a preliminary study demonstrated a significant increase in mean maximum bladder capacity and a significant decrease in mean maximum detrusor voiding pressure. • BTX-A has a potentially much wider spectrum of application within the urologic field than merely the treatment of detrusor hyperreflexia and DESD in spinal cord injury patients. Treatment should be extended to others, including the multiple sclerosis population and those with non-neurogenic voiding and storage disorders. VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 67 Urologic Applications for Botulinum Toxin continued 39. 40. 41. 68 Treatment of the non-neurogenic storage and voiding disorders with the chemical denervation caused by botulinum toxin type A_a pilot study [abstract]. Neurourol Urodyn. 2001;20:410–412. Zermann DH, Ishigooka M, Schubert J, Schmidt RA. Trigonum and bladder base injection of botulinum toxin A (BTX) in patients with severe urgency-frequency-syndrome refractory to conservative medical treatment and electrical stimulation [abstract]. Neurourol Urodyn. 2001;20:412–413. Carpenter FG. Motor responses of the urinary bladder and skeletal muscle in botulinum intoxicated rates. J Physiol. 1967;188:1–11. Bigalke H, Habermann E. Blockade by tetanus and botulinum A toxin of postganglionic cholin- VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 42. 43. 44. ergic nerve endings in the myenteric plexus. Naunyn-Schmiedeberg’s Arch Pharmacol. 1980;312:255–263. 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. Franks ME, Somogyi GT, Phelan MW, et al. Botulinum toxin injection into the bladder wall decreases acetylcholine (ACh) and norepinephrine (NE) release: potential treatment for the overactive bladder [abstract]. J Urol. 2000;163:42. Aoki KR. Pharmacology and immunology of botulinum toxin serotypes. J Neurol. 2001;248(suppl 1):1/3–1/10. 45. 46. 47. 48. Smith CP, Fraser MO, Ghosh R, et al. Botulinum toxin D is more potent than botulinum toxin A in inhibiting bladder contractions. Paper presented at American Paraplegia Society 47th Annual Conference; Las Vegas, NV; September 4–6, 2001. Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon. 2000;38:245–258. Purkiss JR, Welch MJ, Doward S, et al. A method for the measurement of [3H]-glutamate release from cultured dorsal root ganglion neurons. Biochem Soc Trans. 1998;26:S108. Cui M, Aoki KR. Botulinum toxin type A (BTX-A) reduces inflammatory pain in the rat formalin model [abstract]. Cephalagia. 2000;20:414.