Botox in Urology: A NewTreatment Modality without Limitations?

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1 EAU Update Series EAU Update Series 2 (2004) Botox in Urology: A NewTreatment Modality without Limitations? Brigitte Schurch*, André Reitz Neuro-Urology, Swiss Paraplegic Center, Balgrist University Hospital, Forchstrasse 340, CH-8008 Zurich, Switzerland Abstract Botulinum toxin is a presynaptic neuromuscular blocking agent inducing selective and reversible muscle weakness up to several months when injected intramuscularly in minute quantities. Different medical disciplines have discovered the toxin to treat mainly muscular hypercontraction. In urology, indications for botulinum-a toxin injections have been reported in detrusor-sphincter dyssynergia, chronic retention, chronic pelvic pain, begnin prostata hyperplasia, neurogenic detrusor overactivity and motor and sensory urinary urge incontinence. At this time, the use of botulinum-a toxin has still to be considered as an alternative treatment for it respective indications until large randomized controlled trials have proved their superiority to other therapies and long term benefit. # 2004 Elsevier B.V. All rights reserved. Keywords: Botulinum toxin; Detrusor-sphincter dyssynergia; Neurogenic bladder; Overactive bladder; Chronic prostatic pain; Benign prostatic hyperplasia; Chronic urinary retention 1. Introduction Clostridium botulinum, a gram-positive, rod-shaped anaerobic bacterium produces the botulinum toxin, a neurotoxin causing the food related poisoning called botulism. The therapeutic benefits derived from a local injection of a botulinum toxin preparation are based on site-specific delivery (e.g. intramuscular, subcutaneous) and the fact, that these components have a high affinity for uptake by cholinergic neurones. This results in a temporary loss or reduction of neuronal activity at the target organ (e.g. muscle, glands) with minimal risks of systemic adverse effects, when used in appropriate dose. Seven immunologically distinct antigenic subtypes of botulinum toxin have been identified: A, B, C, D, E, F and G [1]. To date, botulinum toxin types A and B are in clinical use, however the botulinum toxin type A is more potent [2 4] and has a longer duration of action than botulinum toxin type B, as indicated by electromyographic results [4]. The vast majority of commercial developments of botulinum toxin for clinical use have been based on botulinum toxin type A [5]. * Corresponding author. Tel ; Fax: address: schurchb@balgrist.unizh.ch (B. Schurch). Botulinum toxin type A is a selective blocker of acetylcholine release from nerve endings and accordingly blocks neural transmission when injected into muscle [6]. Botulinum toxin inhibits prevalently the release of acetylcholine at the presynaptic nerve endings, but showed also in adequate quantities inhibition of noradrenaline, dopamine, serotonine, g-amino-butyrate, glycine and peptide methionine-enkephalin [7,8]. Interestingly, according to in vitro and limited in vivo studies, it can be hypothesized that botulinum toxin treatment may reduce the local release of nociceptive neuropeptides from either cholinergic neurons or from C or A delta fibers in vivo [9 11]. Based on histological evidence, recovery of the chemodenervation after 3 to 6 months is thought to be due to a turnover of presynaptic molecules and nerve sprouting from the nerve terminal forming a new functional synapse [12,13]. Since United States FDA approval of botulinum-a toxin (Botox 1, Allergan) in 1989, the first therapeutic botulinum-neurotoxin based product for the treatment of strabismus, benign essential blepharospasm and disorders of the VIIth nerve, world-wide experience has shown that this therapeutic agent is safe and effective for numerous indications. Subsequently another botuli /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.euus

2 B. Schurch, A. Reitz / EAU Update Series 2 (2004) num toxin type A complex (Dysport 1, Ipsen) was approved in the United Kingdom in 1991, but this toxin is not currently available is the United States. Recently the US FDA approved a botulinum-b toxin complex preparation (Myobloc TM Elan; in Europe Neurobloc 1 ) for use in cervical dystonia patients. Although these three products are based on botulinum neurotoxins, they have sufficient different doses, efficacy and safety profiles, that these and other future botulinum toxin-based products should not be considered generic equivalents comparable by single dose ratios (Table 1). In urology, indications for botulinum-a toxin have been neurogenic detrusor overactivity, detrusorsphincter dyssynergia, motor and sensory urinary urge incontinence and more recently chronic prostatic pain and benign prostatic hyperplasia. 2. Detrusor-sphincter dyssynergia The possibility to induce a reversible chemical sphincterotomy with botulinum-a toxin injections and to lower detrusor-sphincter dyssynergia in spinal cord injured patients has first been described by Dykstra et al. [14,15]. Thereafter, other authors reported on the technique and its results. The botulinum toxin has been either injected transurethrally via a cystoscope or transperineally under electromyographic (EMG) control [16 19]. Both routes of injection had equivalent results and preferences depend on the ability of the therapist to perform EMG of the external urethral sphincter or cystoscopy [20]. Reduction of post-void residual volume, maximal urethral pressure, maximum detrusor pressure and severity of the detrusor-sphincter dyssynergia during voiding were considered as primary outcomes and could be shown to improve in most published studies (see Table 2). However, the dose, dilution volume and intervals between two injections vary from author to author. Based on the results of the literature it seems reasonable to use 100 units of Botox 1 or units of Dysport 1 and to diluted them in 4 ml of NaCl 0.9%. By endoscopic treatment the total units amount will be divided in 4 portions and injected at 4 injection sites into the external urethral sphincter (1, 5, 7 and 11 o clock). By the transperineal approach, the total amount will be injected either in 1 portion into the midline 2 cm above the external anal sphincter or in 2 portions 2 cm above and 1 cm laterally to the external anal sphincter into the left and right part of the external urethral sphincter. Unfortunately, there are only two randomized controlled studies, that prove the efficacy of botulinum-a toxin to treat detrusor sphincter dyssynergia [15,21]. Conditions to achieve good results on the voiding function after botulinum-a toxin injections into the external urethral sphincter are a sufficient voiding pressure and the correction of a concomitant bladder neck dyssynergia [16]. Clinical effects begin within 5 to 7 days and last up to 6 months (mean: 3 4 months). Thereafter, patients have to be re-injected to maintain efficacy of the treatment on the voiding dysfunction. The reversibility of the treatment might raise controversies, especially in high complete tetraplegic patients, where a surgical sphincterotomy might appear more secure and appropriate. For most authors botulinum toxin injections to treat detrusor-sphincter dyssynergia have to be considered in case of conservative treatment failures and before envisaging the implantation of an urethral stent or a surgical sphincterotomy [18,19,21]. Also, in our opinion, botulinum-a toxin injections into the external urethral sphincter should be regarded as a temporary solution for patients, who are candidates for a surgical sphincterotomy but cannot decide themselves for surgery. In these cases, the effect of the injections might simulate the effect of a surgical sphincterotomy and help the patients to opt for the surgical procedure. By contrast, botulinum-a toxin into the external urethral sphincter appears to be a worthwhile option in acute incomplete spinal cord injured patients with detrusorsphincter dyssynergia and high residual volume, where a recuperation of function might be expected. This indication can be extended to multiple sclerosis patients, where surgical procedures are always matter of discussion. However, dose finding and large randomized controlled studies comparing the effects of this treatment against placebo are necessary. Table 1 Characteristics of different commercially available botulinum toxin Toxin type Product Distributer Units per vial a Mean lethal intraperitoneal dose (LD50) Botulinum toxin type A Botox 1 Allergan 100 IU 1 U Botox 1 = LD50 in mice Botulinum toxin type A Vistabel 1 Allergan 100 IU 1 U Vistabel 1 = LD50 in mice Botulinum toxin type A Dysport 1 Ipsen Pharma 500 IU 1 U Dysport 1 = LD50 in mice Botulinum toxin type B NeuroBloc 1 Elan Pharma 5000 IU 1 U NeuroBloc 1 = LD50 in mice a The biological activity of one toxin type cannot be compared to or converted into units of another toxin type!

3 172 B. Schurch, A. Reitz / EAU Update Series 2 (2004) Table 2 Botulinum toxin and detrusor-sphincter dyssynergia overview of published results Author and reference Dykstra et al. [14] Dykstra et al. [15] Petit et al. [18] Schurch et al. [16] Gallien et al. [19] Urethral pressure # # # # Not significant Post-void residual volume # # # # Not significant Bladder pressure during voiding or # # # # uninhibited bladder contraction Mean maximum urethral pressure during DSD # Duration of DSD # Functional detrusor capacity " Autonomic dysreflexia # Not improved # Duration of effect 50 d 65 d 60 to 90 d 60 to 90 d 90 d 3. Chronic retention In patients with dysfunctional voiding due to urethral overactivity, non-bacterial prostatitis and detrusor underactivity, botulinum-a toxin has been shown to have a therapeutic effect on improving voiding efficiency and recovering detrusor contractility with few reported side effects. In Phelan s study 19 of 21 patients were on indwelling catheter or intermittent catheterization before injection of units of Botox 1. After treatment all but 1 were able to void without catheter [22]. Mean effect duration was usually 3 4 months. However, from this study it is not clear which type of lower urinary tract retention is most likely to benefit from botulinum-a toxin injections into the external urethral sphincter. In a prospective study on 103 patients with chronic retention of various aetiologies, Kuo found a therapeutic effect of the botulinum-a toxin treatment in decreasing urethral resistance and improving voiding efficiency through decreased voiding pressure, increased maximum flow rate and reduced post-void residual volume in 84.5% of the patients [23]. In patient with a successful result maximum flow rate increased by 49.3%, mean voiding pressure decreased by 31.8%, post-void residual volume decreased by 60.8% and maximal urethral closure pressure decreased by 28.1%. The therapeutic results among various diseases and types of lower urinary dysfunction and among patients who received 50 units and 100 units were analysed and compared. Favourable and unfavourable predictive factors were also looked for. From this study it appears that excellent results were more common in patient with cauda equina lesion (62.5%) and idiopathic detrusor underactivity (61.5%), possibly because all of these patients has a weak urethral sphincter and voided by abdominal straining. About 36% of the patients with urethral overactivity, (dysfunctional voiding and non-relaxing sphincter) had excellent result, whereas patients with detrusor-sphincter dyssynergia (DSD) ranked the last (27.6%). Moreover, 88% of patient with DSD or nonrelaxing urethral sphincter needed 100 units, while 72% with detrusor underactivity needed only 50 units to achieve good results. Patient age older than 50 years seems to be a favorable predictive factor for a successful result. Possible causes for treatment failure included psychological inhibition of voiding, low generation of abdominal pressure, non-relaxing urethral sphincter obstruction and bladder neck obstruction. Identifying these underlying cause may indicate appropriate therapy. Urethral overactivity can be managed by repeated urethral injections of high doses of botulinum toxin, whereas bladder neck obstruction has to be treated by transurethral incision of the bladder neck. 4. Chronicpelvicpain Chronic prostatic pain is a common situation confronting the practising urologist. Up to now, the different therapies of this syndrome and their longstanding results are mostly frustrating. The clinical observation that prostatic and pelvic pain is accompanied by motor and sensory disorders of the pelvic floor muscle led to the hypothesis that prostatic pain roots in a changed processing of afferent and efferent information with the central nervous system (CNS) [24]. Zermann et al. injected botulinum-a toxin into the external urethral sphincter to find out whether chronic prostatic pain is effectively driven by a spastic dysregulation of the somatic muscle [25]. In 11 male patients with chronic prostatic pain, urodynamic investigation, pelvic floor function examination and cystoscopy were conducted before and after a transurethral perisphincteric injection of 200 units of botulinum-a toxin (Botox 1 ). Nine of 11 patients reported subjective pain relief, the average pain level on a visual analogue scale 1 10 (1 no pain, 10 unbearable pain) decreasing from 7.2 to 1.6 after the injection. The pre-post-injection comparison of the urodynamic findings showed a decrease of the functional urethral length, urethral closure pressure and post-void residual volume and

4 B. Schurch, A. Reitz / EAU Update Series 2 (2004) an increase of peak and average uroflow. The injection of botulinum-a toxin was followed not only by functional but also by clinical weakening of the striated muscle, pain relief and significant improvement of urethral hyperalgesia. More recently Jarvis et al. investigated whether botulinum toxin type A injected into the levator ani muscles of women with objective pelvic floor muscle spasm decreases pain symptoms and improves quality of life [26]. In 12 women aged years with objective pelvic floor muscle hypertonicity and a minimum 2 years chronic pain history, they injected 40 units of Botox bilaterally into the puborectalis and pubococcygeus muscles under conscious sedation. After treatment, median visual analog scale scores were significantly improved for dyspareunia (80 vs. 28, p = 0.01) and dysmenorrhea (67 vs. 28, p = 0.03), with non-significant reduction in non-menstrual pelvic pain and dyschesia (64 vs. 37). Pelvic floor muscles manometry showed a 37% reduction in resting pressure at week 4, that maintained to 25% at week 12 (<0.0001). Quality of life scores (EQ-5D and SF-12) were improved at week 12, even not significantly. Sexual activity scores were markedly improved with a significant reduction in discomfort and improvement in habit. The conclusion from this pilot study was that there is evidence that women with pelvic floor muscles hypertonicity and pelvic pain may respond to botulinum type A injection into the pelvic floor muscle. To summarise, it appears that a barrage of nociceptive information from the dysfunctional pelvic floor overflows the CNS and therefore induce a change in CNS processing. Interrupting the afferent branch of the disturbed central circle is one opportunity to treat chronic pelvic pain [25]. 5. Begnin prostatic hyperplasia (BPH) Several treatment options are available for BPH patients including watchful waiting, medical therapy and surgical procedures [27 29]. Although transurethral resection is an effective treatment for symptomatic BPH, approximately 15 25% of patients who undergo surgery do not have satisfactory long-term outcome [30]. Mortality in the 30 days post-surgery was described to range from 0,4% for men aged 65 to 69 years to 1.9% for men aged 80 to 84 years and has fallen in recent years. Immediate surgical complications occurred in 12% of patients, including bleeding requiring intervention in 2%, erectile dysfunction in 14%, retrograde ejaculation in 74% and incontinence in about 5%. Finasteride and long-acting alpha1 adrenergic antagonists are effective drugs for BPH [31 33]. However, selective as well as less-selective alphablocker may be associated with dizziness, asthenia and postural hypotension limiting therapy. Furthermore, decrease in libido and impotence is more common in men taking finasteride. Botulinum-A toxin injection into the rat prostate has been demonstrated to induce selective denervation and subsequent atrophy of the gland [34]. Based on this report, Maria et al. conducted a prospective randomized controlled study in 30 men with BPH, who no longer responded favourably to medication and who refused to undergo surgery [35]. Patients in the verum group received 200 units of Botox 1 diluted in 4 ml saline versus 4 ml saline in the placebo group, The results were amazing. 13 out of the 15 patients in the treated group versus 3 out of the 15 patients in the control group had subjective symptomatic relief (p = ) at 1 and 2 month follow-up. In patients, who received botulinum-a toxin the AUA score was reduced by 52%, the prostate volume and post-void residual volume by 54% and 60%, respectively and the PSA concentration by 42% compared with baseline values at one month follow up and were even better at 2 months follow up. None of these parameters improved in the patients who receive saline. Follow-up average months. This study is of particular interest since it suggests that a botulinum-a toxin injection into the prostate will produce long-term effects more durable that a current medical or minimal invasive office based thermotherapy treatments. However, large controlled trials are still necessary to prove safety and efficacy of botulinum toxin injection to treat BPH. 6. Neurogenic detrusor overactivity Neurogenic detrusor overactivity is a condition that causes high intravesical pressure, reduced capacity, low compliance of the bladder and can lead to upper urinary tract damage. Current treatment options rely mainly on clean intermittent catheterization and anticholinergic medication to partially block the efferent parasympathetic innervation of the detrusor and inhibit involuntary bladder contractions [36]. The side effects of oral anticholinergic medication like dry mouth, constipation, dyspepsia, changes in visual accommodation, dizziness and somnolence are troublesome and reduce patient compliance [37 40]. Furthermore, these drugs are often insufficiently effective [41]. There are other treatment options in a selected group of spinal cord injured patients. Short-term maximum functional stimulation of the pudendal nerve afferents or implantation of a sacral root nerve stimulator may result in

5 174 B. Schurch, A. Reitz / EAU Update Series 2 (2004) major benefits for urinary urge incontinence [42]. However, sacral root rhizotomy is limited in male patients with suprasacral cord lesion, who want to preserve reflex erections [43,44]. Auto-augmentation, enterocystoplasty and ileal conduit are weighty surgical options which are to be considered as the last alternative. The efficiency of intravesical application of vanilloid-antagonists (capsaicin and resiniferatoxin) is controversially discussed or has still to be evaluated [45,46]. The effect of injecting botulinum-a toxin into the human detrusor muscle in spinal cord injured patients was first reported by Schurch et al. in a non-randomized prospective study [47,48]. The hypothesis of this trial was based on the study of Dickson and Shevky suggesting that parasympathetic action may be blocked by botulinum-a toxin [49]. Disorders of the parasympathetic autonomic nervous system such as achalasia and hyperhydrosis have been successfully treated with botulinum-a toxin injections [50 52]. A marked loss of contraction in a rat bladder after acute botulinum poisoning with decrease in acetylcholine release at motor nerve stimulation was observed by Carpenter [53]. The patients with spinal cord injury selected for a preliminary study had severe neurogenic detrusor overactivity and suffered from incontinence resistant to anticholinergic drugs [48]. They emptied their bladder by intermittent self-catheterization. Patients with low bladder compliance due to organic detrusor muscle changes or fibrosis were excluded units of botulinum-a toxin (Botox 1 ) were injected into the detrusor muscle sparing the trigone. The reason from sparing the trigone were: fear to induce a vesicorenal reflux and at the time of the conducted study, absent knowledge of the effect of botulinum A toxin on the adrenergic nerve and on the release of nociceptive neuropeptides. In total, 19 of the 21 treated patients could be regularly observed over a period of 9 months by clinical and urodynamic checks. Six weeks followup after injections showed a significant increase in the reflex volume and in the maximum cystometric bladder capacity. There was also a significant decrease in the maximum detrusor voiding pressure. At the 36 weeks follow-up, ongoing improvement occurred. The amount of anticholinergics could be reduced or even completely abolished. Continence was restored in all but 2 patients and patient s satisfaction was high. The actual experience of the European group increased to 200 patients with the same results and profile [54]. Two years later, Schulte-Baukloh et al. encouraged by the above described results, tested the efficacy of botulinum-a toxin in children with neurogenic detrusor overactivity due to myelomeningocele (MMC) [55]. The 17 children were using clean intermittent catheterization and anticholinergic drugs. Included were children aged 1 to 16 with either neurogenic detrusor overactivity or high intravesical pressure exceeding 40 cmh 2 O resistant to anticholinergic medication or unacceptable side effects. 85 to 300 units (12 U/kg) of botulinum-a toxin (Botox 1 ) were injected into the detrusor muscle and urodynamic checks were done 2 to 4 weeks after injection. Mean reflex volume, mean maximum bladder capacity and mean detrusor compliance increased, mean maximal detrusor pressure decreased. All results were significant and continence could be restored for at least the 4 weeks follow-up. These preliminary results were confirmed in a bigger patients collective and the effects of one botulinum-a toxin treatment in MMC children seems to last months, depending of the study [56,57]. The preliminary results of these non-randomized prospective studies are overwhelming, especially considering the fact that in all these studies the patients included were difficult cases for conservative treatment. In summary, botulinum-a toxin injections into the detrusor muscle seem to be indicated at present in spinal cord injured and MMC patients with incontinence due to neurogenic detrusor overactivity. This treatment option seems to establish its indication in cases where anticholinergic medication fails or is intolerable and appears to be a valuable alternative to surgery. However, despite all optimism, one has to be aware that the evaluation of botulinum-a toxin for neurogenic voiding dysfunction has been based on its clinical effect in open studies. A currently running multicentre double-blind, randomised, placebo-controlled study for botulinum-a toxin in spinal cord injured patients will be finished soon presenting results from the viewpoint of evidence-based medicine. 7. Idiopathic detrusor overactivity or sensory urinary urge incontinence Recently, Loch et al. reported on the effect of injections of 200 units of Botox 1 into the detrusor muscle in 30 patients with severe detrusor overactivity. Twenty of the 30 patients reported improved continence, the effect lasting 8 months. Therapy resistant patients were all the patients with interstitial cystitis. However, these authors deplored high residual volume and 1 acute retention, that might be explained by the high amount of toxin used for this indication [58]. As

6 B. Schurch, A. Reitz / EAU Update Series 2 (2004) opposed, Radzieszweski and Borkowski observed marked improvement of bladder overactivity in 12 patients at 1 month follow-up without change in the residual volume by using 300 units of Dysport 1 [59]. In another, not yet published prospective study by Schmid et al., botulinum-a toxin was tested on 50 patients with non-neurogenic detrusor overactivity suffering from incontinence despite administration of high anticholinergic doses [60]. 100 to 200 units of Botox were injected into the detrusor muscle at different sites under cystoscopic control. Micturition diary and urodynamic were used to assess efficacy of treatment. After botulinum-a toxin injection 40 patients (80%) showed significant improvement (p < 0.005) of their bladder function in regard to subjective symptoms as well as urodynamic parameters. Urgency and incontinence disappeared completely within 1 2 weeks after treatment. Frequency decreased from 11.5 to 4.5 micturitions/day and nocturia from 4.5 to 1, respectively. Maximum bladder capacity increased from mean 261 to 426 ml and pre-treatment detrusor instability (mean reflex volume: 189 ml) resolved. First urge volume increased from mean 152 to 256 ml. There were no severe side effects except 2 temporary urine retention. However in 10 patients clinical benefit was poor and analysis revealed preoperative very low detrusor compliance. Efficacy duration was mean 7 2 months. In summary, botulinum-a toxin injections into the detrusor muscle might represent an alternative treatment for severe detrusor overactivity resistant to conservative treatment. However, studies to ascertain the correct dose to achieve optimal symptomatic improvement for minimal residual volume and placebo-controlled trials are necessary. Patients with very low detrusor compliance seem not to benefit from the treatment. 8. Botulinum toxin type B in urology There are only two reports on the primary use of botulinum toxin type B (BTX-B) in urology. The first is a case report in a female patient with multiple sclerosis, detrusor hyperreflexia and reflex incontinence, who were injected with 5000, 7500 and diluted in 3 ml saline [61]. After each injection she was dry without having to catheterize herself. The effect lasts 4 months. In a open label dose escalation study the same authors aimed a testing the efficacy of botulinum type B in the treatments of 15 patients with non- neurogenic overactive bladder [62]. The BTX-B doses used in this study were 2500, 5000, 7500, and units. A paired t-test of the pre/post-frequency difference indicates that these 15 patients experienced an average of 5.27 fewer frequency episodes per day after treatment (p < 0.001). The longest duration effect was 3 months using to units of BTX-B (p < 0.001). In 2 case reports BTX-B injection (5000 to 7500 units) into the detrusor were used in patients with neurogenic incontinence showing resistance to the type A [63,64]. Resistance to type A was confirmed by measuring extensor digitorum brevis CMAPs amplitude elicited by electrical stimulation of the peroneal nerve [65]. Results on bladder dysfunction observed after BTX-B injections were comparable to those obtained after BTX-A. Accordingly to these 2 case reports, it appears that botulinum toxin type B may be an option for patients with neurogenic detrusor overactivity who became secondary resistant to the type A toxin after repeated injections. It must however be pointed out that in animal models such as in human experiments the injection of type B toxin in striated muscles has been shown to have a shorter duration of action than the type A toxin [66,67]. This was also observed in the few urological reports on injection of BTX-B into the detrusor. When using the type B toxin this needs to be considered, especially if the intention is to treat the patient primary with the type B. To our knowledge, almost nothing is known about the duration of action of a botulinum toxin type B injection in smooth muscles and therefore further research is required to clarify this point. It should be clear that antibody production against the type A toxin does not necessarily interfere with the type B toxin. Furthermore, antibody production probably depend on the individual immune responsiveness and is considered to have no direct effect on the patient s clinical response to the treatment [68]. Therefore, we think that in patients with a primary resistance to the type A toxin, which we define as the absence of a clinical and urodynamic effect after injection of an adequate dose of the type A toxin in the detrusor smooth muscle, an attempt with the type B toxin may be justified because both toxins interact with different target proteins and a primary non response to the type A toxin does not necessarily imply a non response to the type B toxin. 9. Conclusion Botulinum toxin type A injections have taken overtimes an increasing place in the urologic therapeutic arsenal. It should however been pointed out that most of the indications for using botulinum type A are

7 176 B. Schurch, A. Reitz / EAU Update Series 2 (2004) diseases refractory to usual conservative treatment and before irreversible surgery. Moreover large randomized controlled studies are still lacking, whatever the indication to inject the toxin, and are necessary to prove the efficacy of botulinum toxin injection on an evidence based medicine level. References [1] Simpson LL. Molecular pharmacology of botulinum toxin and tetanus toxin. Annu Rev Pharmacol Toxicol 1986;26: [2] Brashear A, Lew MF, Dykstra DD, Comella CL, Factor SA, Rodnitzky RL, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A- responsive cervical dystonia. Neurology 1999;53(7): [3] Brin MF, Blitzer A. Botulinum toxin: dangerous terminology errors. J R Soc Med 1993;86(8): [4] Sloop RR, Cole BA, Escutin RO. Human response to botulinum toxin injection: type B compared with type A. Neurology 1997; 49(1): [5] Aoki KR. Pharmacology and immunology of botulinum toxin serotypes. 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Which statement is correct? Botulinum-A toxin injections into the external urethral sphincter to treat urinary retention show the best results in A. cauda equina lesion, B. detrusor sphincter dyssynergia, C. idiopathic detrusor overactivity, D. non relaxing urethral sphincter, E. Fowler Syndrome.

9 178 B. Schurch, A. Reitz / EAU Update Series 2 (2004) Which statement is correct? The mechanism of action of botulinum A-toxin to treat chronic pelvic pain is supposed to be A. a diminution of the urethral closure pressure, B. a blockade of the cholinergic transmission, C. a barrage of nociceptive information of the dysfunctional pelvic floor to the brain, D. a pure antiinflammatory process. A. improve bladder function for an average of 3 months, B. is indicated by detrusor hyperreflexia and low compliance bladder, C. has been proved to be efficient on large randomized controlled studies, D. is indicated by reflex incontinence resistant to anticholinergic drugs. 4. Which statement is correct? Botulinum toxin injection to treat overactive bladder