BotulinumToxin as a NewTherapy Option for Voiding Disorders: Current State of the Art

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1 European Urology European Urology 44 (2003) Review BotulinumToxin as a NewTherapy Option for Voiding Disorders: Current State of the Art Thomas Leippold a, André Reitz b, Brigitte Schurch b,* a Department of Urology, University Hospital, Zurich, Switzerland b Neuro-Urology, Swiss Paraplegic Center, Balgrist University Hospital, Forchstrasse 340, 8008 Zurich, Switzerland Accepted 18 April 2003 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 have been neurogenic detrusor overactivity, detrusor-sphincter dyssynergia, motor and sensory urge and, more recently, chronic prostatic pain. The available literature was reviewed using Medline Services. The keywords botulinum-a toxin, detrusorsphincter dyssynergia, neurogenic bladder, spinal cord injury, denervation, chronic prostatic pain, chronic urinary retention were used to obtain references. A toxin injection is effective to treat detrusor-sphincter dyssynergia when injected either transurethrally or transperineally. After treatment, external urethral sphincter pressure, voiding pressure and post-void residual volume decreased. The effect lasts between 2 to 9 months depending on the number of injections. Best indications seem to be multiple sclerosis and incomplete spinal cord injury patients suffering from neurogenic detrusor overactivity and detrusor-sphincter dyssynergia. According to the previous results, the use of botulinum-a toxin injections into the external urethral sphincter has been extended to a variety of bladder obstructions and to decrease outlet resistance in patients with acontractile detrusor. In cases of successful treatment, spontaneous voiding re-occurs and catheterization can be resumed. Injections of the toxin into the external urethral sphincter also seem to have a beneficial effect on chronic prostatic pain, presumably by reducing hypertonicity and hyperactivity of the external urethral sphincter. Injections of botulinum-a toxin into the detrusor muscle has first been tested to treat neurogenic detrusor activity in spinal cord injured patients and in myelomeningocele children. Long lasting (mean 9 months) detrusor relaxation occurs after injection of usually 300 units of Botox 1. Continence is restored in about 95% of the patients and anticholinergic drugs can be markedly reduced or even stopped. Excellent results of botulinum-a toxin injections into the detrusor in neurogenic detrusor overactivity have lead to an expansion of this treatment to incontinence due to idiopathic detrusor overactivity. Although preliminary results are promising, adequate dosage of the toxin required for this indication is not yet known. In conclusion, it appears that botulinum toxin injection into either the external urethral sphincter or the detrusor offers new promising treatment options for many different urological dysfunctions. However, large controlled trials are absolutely required to establish the role of botulinum-a toxin injections in the fields of urology and neurourology on evidence based medicine. # 2003 Elsevier Science B.V. All rights reserved. Keywords: Botulinum toxin type A; Detrusor-sphincter dyssynergia; Neurogenic bladder; Spinal cord injury; Chronic prostatic pain; Chronic urinary retention * Corresponding author. Tel. þ ; Fax: þ address: schurchb@balgrist.unizh.ch (B. Schurch) /$ see front matter # 2003 Elsevier Science B.V. All rights reserved. doi: /s (03)

2 166 T. Leippold et al. / European Urology 44 (2003) Introduction Table 1 Intracellular substrates for different types of BTXs BTX serotype Substrate References BTX-A SNAP-25 [63] BTX-B VAMP/Synaptobrevin [64] BTX-C Syntaxin [65] BTX-D VAMP/Synaptobrevin Cellubrevin [63] BTX-E SNAP-25 [63] BTX-F VAMP/Synaptobrevin Cellubrevin [66] BTX-G Unknown SNAP-25: synaptosal associated protein 25, VAMP: vesicle associated membrane protein. According to references [63 66]. 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 chemodenervation and the 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, C1, D, E, F and G [1]. To date, botulinum toxin type A and B are in clinical use. However, 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]. The botulinum toxin molecule consists of a heavy chain (H chain, molecular weight 100 kd) and light chain (L chain, molecular weight 50 kd), which are bound together by heat labile disulfide bonds. The H chain with its carboxyl terminal is bound to the nerve terminals at the neuromuscular junction and the L chain is internalized by endocytosis. The L chain is the neurotoxic component. Neither the H nor the L chain can exert neurotoxicity independently. Botulinum-A toxin is bound to a hemaglutinin and forms a dimer reaching a molecular weight of 900 kd [6]. Botulinum-A toxin is a selective blocker of acetylcholine release from nerve endings and accordingly blocks neural transmission when injected into muscle [7]. After internalization, the L chain compromises the intracellular protein SNAP-25, effecting a lesion in the secretory pathway [8,9]. The synthesis and storage of neurotransmitters is not affected [10]. Different types of botulinum toxin cleave different parts of the protein complex necessary for docking acetycholine (Ach) vesicle (see Table 1). 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 [11,12]. Botulinum toxin inhibits prevalently the release of acetylcholine, but showed also in adequate quantities inhibition of noradrenaline, dopamine, serotonine, g-amino-butyrate, glycine and peptide methionine-enkephaline [13,14]. The botulinum toxin molecule cannot cross the blood brain barrier and therefore has no CNS effects [13]. The existence of botulinum toxin has been known for centuries; however, its positive effects have only been appreciated in recent decades. In 1895, the bacterium Bacillus Botulinus was identified by Professor Pierre Emile van Ermengem of Ellezelles, Belgium [6]. The agent, later renamed Clostridium Botulinum was the precursor to what is now known as botulinum toxin type A. It is believed that botulinum toxin type A was first isolated in purified form as a stable acid precipitate in the 1920s by Dr. Hermann Sommer at the University of California, San Francisco [6]. The resulting precipitate provides the basis of raw material for future studies [13,15]. In 1946, Edward J. Schantz, PhD., and colleagues succeeded in purifying botulinum toxin type A in crystalline form [16,17]. For the first time, researchers had the raw material they needed to study botulinum type A in greater detail. The first major result of these studies occurred in the 1950s. Dr. Vernon Brooks discovered that botulinum toxin type A, when injected into a hyperactive muscle, blocked the release of acetylcholine from motor nerve presynaptic endings, thus inducing a reversible paralysis of the injected muscle [6,15]. Dr. Brooks breakthrough sparked a new interest in botulinum neurotoxin as a potentially significant therapeutic agent [16,17]. In 1973, Dr. Alan Scott, an ophthalmologist, first published a study on the effect of botulinum toxin on the lateral rectus muscle of the monkey [18]. In 1981, he reported on the first application in humans, treating patients with strabismus [19]. Since United States FDA approval of botulinum-a toxin (Botox 1, Allergan) in 1989, the first therapeutic botulinum-neurotoxin based product for treatment of strabismus, benign essential blepharospasm and disorders of the VIIth nerve, worldwide experience has shown that this therapeutic agent is safe and effective for numerous indications. Subsequently, another botulinum toxin type A complex (Dysport 1, Ipsen) was approved in the United Kingdom

3 T. Leippold et al. / European Urology 44 (2003) Table 2 Characteristics of different commercially available botulinum toxins Toxin type Product Distributer Units per vial a Mean lethal intraperitoneal dose (LD50) Botulinum toxin type A Botox 1 Allergan 100 IU I U Botox 1 ¼ LD50 in mice Botulinum toxin type A Vistabel 1 Allergan 100 IU I U Vistabel 1 ¼ LD50 in mice Botulinum toxin type A Dysport 1 Ipsen Pharma 500 IU I U Dysport 1 ¼ LD50 in mice Botulinum toxin type B NeuroBloc 1 Elan Pharma 5000 IU 1 U NeuroBloc 1 ¼ LD50 in mice a The biological activity of one toxin type cannot be compared to or converted into units of another toxin type! in 1991, but this toxin is not currently available in 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 to single dose ratios (Table 2). In urology, indications for botulinum-a toxin have been neurogenic detrusor overactivity, detrusor-sphincter dyssynergia, motor and sensory urge and, more recently, chronic prostatic pain. The clinical experience over the last years with botulinum-a toxin in urological impaired patients will be illustrated in this review of literature. To perform this review we made use of Medline Services, looking at the references that matched keywords botulinum-a toxin, detrusorsphincter dyssynergia, neurogenic bladder, spinal cord injury, denervation, chronic prostatic pain, chronic urinary retention. 2. Botulinum toxin and detrusor-sphincter dyssynergia For overview of published results, see Table 3. Detrusor-sphincter dyssynergia is a major cause of morbidity in spinal cord injury patients. Spasmolytic agents (like baclofen or diazepam) or alpha-blockers reduce urethral obstruction but are often not effective [20,21]. Self-catheterization is a convenient therapy but not suitable for people with high tetraplegia because of the upper limb impairment. The possibility to induce a reversible chemical sphincterotomy with botulinum-a toxin injections and to lower detrusorsphincter dyssynergia in spinal cord injured patients have first been described by Dykstra et al. [22]. Thereafter, other authors reported on the technique and its results. The botulinum toxin has been either injected transurethrally via cystoscope or transperineally under electromyographic control. However, the dose, dilution volume and intervals between two injections vary from author to author. In their first report, Dykstra et al. proposed repeated transperineal or cystoscopic injections into two to three sites of the rhabdomyosphincter at weekly intervals. Main parameters to assess the effect of the toxin were the urethral pressure profile and the post-void residual volume. Three different protocols of weekly injections of increasing dose were developed. Best results were achieved in protocol 3. An initial dose of 140 units of toxin was injected transurethrally via cystoscope. All subsequent weekly doses were 240 units. Using this dose, an average of three injections was needed to produce Table 3 Botulinum toxin and detrusor-sphincter dyssynergia, overview and of published results Author and reference Dykstra et al. [22] Dykstra et al. [23] Petit et al. [24] Schurch et al. [25] Gallien et al. [28] 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 #: decrease; ": increase; : no measurement.

4 168 T. Leippold et al. / European Urology 44 (2003) maximum decrease in post-void residual volume. Unfortunately, the authors did not compare results from different protocols but reported on global results. Eight out of 11 patients improved. Urethral pressure profile decreased on an average by 27 cmh 2 O (from a mean of 78 cmh 2 O to 54 cmh 2 O), residual urine volume decreased by an average of 146 ml (from a mean of 217 ml to 110 ml). The duration of effect was about 50 days. No side effects were observed. In a second study, Dykstra and Sidi re-evaluated the ability of botulinum-a toxin to treat detrusor-sphincter dyssynergia in a double-blind study involving five spinal cord injured males [23]. An initial dose of 140 units of toxin or saline was injected into 3 to 4 sites on the external urethral sphincter through a cystoscope. The dose of toxin or saline in all subsequent weekly injections (maximum 3) was 240 units. Each dose of toxin or saline was diluted in 5.6 cc of normal saline. After treatment, the urethral pressure decreased by an average of 30 cmh 2 O, post-void residual volume of urine decreased by an average of 122 ml and bladder pressure during voiding decreased by an average of 30 cmh 2 Oin the three patients who received toxin injections. All these parameters remained unchanged from baseline value in the two patients who received normal saline. The duration of the toxin s effect averaged two months. Mild general weakness lasting 2 to 3 weeks was noted in all three patients treated with the toxin. Petit et al. performed one single injection of 150 units Dysport 1 diluted in 4 ml saline in 17 patients with spinal cord injury and detrusor-sphincter dyssynergia and reported on significant reductions in residual volume, detrusor voiding pressures and urethral pressures [24]. In a prospective study on 24 spinal cord injury patients, Schurch et al. compared the effect of one single injection (100 units of Botox 1 diluted in 1 ml) versus three repeated injections at monthly intervals [25]. In 21 out of the 24 patients, the maximum urethral pressure during detrusor-sphincter dyssynergia, duration of detrusorsphincter dyssynergia and basic urethral pressure significantly decreased by 48%, 47% and 20%, respectively. Nine out of 17 patients with increased post void residual volume had a mean decrease of 130 ml. Detrusor hypoactivity and bladder neck dyssynergia impaired full voiding in 8 cases. Improvement in autonomic dysreflexia was not noticed. The main point observed was a longer lasting effect of the repetitive injections on the voiding dysfunction (9 to 13 months), versus one single injection (2 3 months) [26]. This seems logical, as the effect of repetitive injections is cumulative. In patients with lesion above T6, transurethral injections of botulinum toxin into the urethral sphincter may require general anaesthesia because of the high risk of autonomic dysreflexia. Dykstra et al. first reported on the transperineal approach that aims at minimising the risk of autonomic dysreflexia [22]. The authors abandoned the technique very soon because of poor results of the treatment. However, the doses were much lower as those used by the transurethral approaches. Schurch et al. reported on the same results of both techniques (transurethral versus transperineal), when using the same amount of toxin [27]. Similarly, Gallien et al. reported on good results using the transperineal approaches [28]. Interestingly, these authors did not notice any significant decrease of the urethral pressure at rest after using the transperineal approach, as opposed to what was observed after the transurethral route of administration [23 25]. A possible explanation may be that the urethral pressure at rest is a static measurement while detrusor-sphincter dyssynergia is a dynamic phenomenon or because different components of the striated urethral sphincter are influenced by different routes of application. To clarify this point, it would be useful to analyze the effect of a combined approach. Recently, in a randomized double-blind study on 13 spinal cord injury patients with detrusor-sphincter dyssynergia, de Seze et al. compared the efficacy and tolerance of botulinum toxin (100 units of Botox 1 in 4 ml saline) versus lidocaine (4 ml at 0.5%) applied into the external urethral sphincter with a single transperineal injection [29]. The main criterion for the efficacy was the post-void residual volume assessed three times daily on day one (D1), D7 and D30 after each injection. Other criteria were micturition volume, maximal detrusor pressure, type of detrusor-sphincter dyssynergia and satisfaction score recorded on D0 and D30. They found a significant improvement in all parameters in the botulinum group but not in the lidocaine group and concluded on the superiority of botulinum toxin compared to lidocaine in improving clinical symptoms of urethral hypertonia associated with detrusor-sphincter dyssynergia in spinal cord injured patients. There is only one report of successful treatment of detrusor-sphincter dyssynergia with botulinum-a toxin injection in a 1-year old child with myelomeningocele. The dose applied was 40 units of Botox 1 [30] Conclusion According to all these reports, botulinum-a toxin injections into the external urethral sphincter appear to be efficient to treat detrusor-sphincter dyssynergia in spinal cord injured patients. However, large randomized studies comparing the effects of this treatment against placebo are still lacking. Conditions to achieve

5 T. Leippold et al. / European Urology 44 (2003) 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 [31]. Clinical effects begin within 5 to 7 days and last up to 6 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. 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 detrusor-sphincter 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. 3. Botulinum toxin and urinary retention Phelan et al. extended the role of botulinum-a toxin injections into the external urethral sphincter for a variety of bladder outlet obstructions and to decrease outlet resistance in patients with acontractile detrusor wishing to void by Valsalva manoeuvre [32]. Preoperatively, 19 of 21 patients were on indwelling catheter or intermittent catheterization. After injection of 100 units of Botox 1, all but 1 patient were able to void without catheterization. The authors concluded that botulinum-a toxin injections into the urethral sphincter is also an effective treatment for urinary retention. Because injections are localized only to the external sphincter, the risk of a new onset of incontinence is minimal. Kuo et al. repeated the experience in 20 patients with dysuria or urinary retention due to detrusor underactivity and non-relaxing urethral sphincter, who were refractory to conservative treatment [33]. After treatment, spontaneous voiding resumed in 11 patients and significantly improved in 5. This study clearly demonstrated that botulinum toxin might be effective in reducing urethral resistance and facilitate voiding efficiency in patients who had either cauda equina lesion or peripheral neuropathy, as well as in those with detrusor failure and poor relaxing urethral sphincter. As opposed to Kuo and Phelan reports [33,34], Fowler et al. found no significant improvement of micturition in six women who had difficulties in voiding or complete urinary retention due to abnormal myotonic-like electromyographic activity in the striated muscle of the urethral sphincter and who were treated with transperineal injection of botulinum toxin into the striated sphincter muscle [35] Conclusion Botulinum-A toxin injections might be an adequate option to treat urinary retention due to hypocontractile detrusor and non relaxing external urethral sphincter. However, actual controversial results strongly suggest that further studies are necessary to define the exact indication for the application of botulinum toxin injections in these cases. 4. Botulinum toxin and chronic prostatic pain 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. Zermann et al. injected botulinum-a toxin into the external urethral sphincter to find out whether chronic prostatic pain is driven by a spastic dysregulation of the somatic muscle [36]. In 11 patients with chronic prostatic pain, urodynamic investigation, pelvic floor function 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 and the urethral closure pressure, decrease of postvoidal residual volume and an increase of peak and average uroflow Conclusion Botulinum-A toxin injections into the external urethral sphincter seem to reduce the hypertonic and hyperactive sphincter activity and improve the lower urinary tract symptoms in patients with chronic prostatic pain. These results reinforce the hypothesis of a relationship between male genitourinary pain and motor dysregulation [37]. However, large controlled trials are needed to establish the role of botulinum-a toxin injections in male urology.

6 170 T. Leippold et al. / European Urology 44 (2003) Botulinum toxin and 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 [38]. 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 [39 42]. Furthermore, these drugs are often insufficiently effective [43]. 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 major benefits for urge incontinence [44,45]. However, sacral root rhizotomy is limited in male patients with suprasacral cord lesion, who want to preserve reflex erections [46]. Auto-augmentation, enterocystoplasty and ileal conduit are weighty surgical options which are to be considered as last alternative. The efficiency of intravesical application of vanilloid-antagonists (capsaicin and resiniferatoxin) is controversially discussed or has still to be evaluated [47,48]. 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 [49,50]. 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 [51]. Disorders of the parasympathetic autonomic nervous system such as achalasia and hyperhidrosis have been successfully treated with botulinum-a toxin injections [52 54]. 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 [55]. The patients with spinal cord injury selected for a preliminary study had severe neurogenic detrusor overactivity and suffered from incontinence resistant to anticholinergic drugs [49]. 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 (Fig. 1). A total of 19 patients were regularly observed over a period of 9 months by clinical and urodynamic checks. Six weeks Fig. 1. Mapping of the injection sites into the detrusor muscle. follow-up 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 (Table 4). 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 patients satisfaction was high. The actual experience of the European group increased to approximately 200 patients with the same results and profile [56]. 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 [57]. 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 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

7 T. Leippold et al. / European Urology 44 (2003) Table 4 Effect of botulinum-a toxin injections into the overactive detrusor muscle in spinal cord injured patients [49] Time after injection (weeks) Mean reflex volume (ml) Mean maximum bladder capacity (ml) Mean detrusor compliance (ml/cmh 2 O) Mean maximum voiding detrusor pressure a (cmh 2 O) No significant increase a The bladder filling was stopped as soon as the rise in detrusor pressure was constant and at maximum level. This value was then compared to the maximum detrusor voiding pressure prior to treatment. Table 5 Effect of botulinum-a toxin injections into the overactive detrusor muscle children with myelomeningocele [57] Time after injection (weeks) Mean reflex volume (ml) Mean maximum bladder capacity (ml) Mean detrusor compliance (ml/cmh 2 O) Mean maximum detrusor pressure (cmh 2 O) to mean detrusor compliance increased, mean maximal detrusor pressure decreased (Table 5). All results were significant and continence could be restored for at least the 4 weeks follow-up Conclusion The preliminary results of these two non-randomized prospective studies are overwhelming, especially considering the fact that in both 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 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 multicenter 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. 6. Botulinum toxin and idiopathic detrusor overactivity or sensory urge 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 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 patients with or without a neurological impairment suffering from incontinence with motor or sensory urge. The study included 16 patients, 9 with motor, and 7 with sensory urge. After injection of 200 units of Botox 1 into the detrusor muscle, 13 patients were dry and 3 patients with sensory incontinence remained incontinent. Nine of the treated patients were free of urge symptoms. One patient with motor and 6 patients with sensory urge noted no clinical improvement Conclusion 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. 7. General remarks 7.1. Contraindications of botulinum toxin injections General contraindications for botulinum-a toxin injections are myasthenia gravis, intake of aminoglucosides or of any drug that may interfere with

8 172 T. Leippold et al. / European Urology 44 (2003) neuromuscular transmission, Eaton-Lambert syndrome, breastfeeding, pregnancy, haemophilia, hereditary clotting factors deficiencies or other disorders that cause bleeding diathesis. Exclusion criteria were well respected in the studies mentioned above Side effects of botulinum-a toxin injections Possible side effects of botulinum-a toxin injections are general weakness, dysphagia, diplopia and blurred vision. Side effects related to botulinum-a toxin and the injection procedures were not described either by the European collective or by Schulte-Baukloh [56,57]. Surprisingly, Wyndaele and Van Dromme recently reported on severe generalized muscle weakness in two patients treated with botulinum toxin for neurogenic bladder overactivity [60]. In one case, the generalized weakness occurred after repeated injections of 300 and 1000 units Dysport 1 at 3 months interval, in the second one after injection of 300 units Botox 1. It is worthwhile mentioning that experience with Dysport 1 to treat neurogenic detrusor overactivity has not yet been published. The dosage conversion used by Wyndaele and Van Dromme is based on the published dose ratios Dysport 1 /Botox 1 (3 to 5). However, contrary to what has been published for the striated muscle, nothing is known about the diffusion of the botulinum toxin in the smooth muscle [61]. Higher diffusion ability of the English toxin (Dysport 1 ) might explain the observed generalized weakness. It is also surprising that in both cases bladder spasticity resumed already after 2 months. A false injection technique or too high a dilution volume might also explain systemic diffusion of the toxin with consecutive general side effects in both cases. An important point often discussed is the effect of repetitive injections on either the immunogenicity of the patients or the detrusor muscle. Recently, Gross et al. reported on the effect of repeated injections of botulinum-a toxin in 110 patients with neurogenic lower urinary tract dysfunction [62]. This study aimed at discovering a possible drug tolerance and comparing the two different commercialized toxins (Botox units and Dysport 1 500, 750, and 1000 units). Maximum injection number was 5. The authors concluded from their results that a second botulinum toxin injection appeared to last somewhat shorter than the first treatment, but later treatments seemed to have an efficacy interval similar to that after the first treatment. The explanation for this phenomenon remains unclear. The apparent better efficacy of Botox 1 compared to Dysport 1 was attributed to inadequate dosage of Dysport 1 in the first treatments with this compound. Transient side effects were reported in 4 patients after Dysport 1 (100 units); two reported constipation and the other two muscle weakness. No increase in drug tolerance after multiple treatment was observed. At least no change in the detrusor compliance was observed which clinically excluded any fibrosis of the detrusor muscle after repeated injections. However, further studies aiming at studying the histological aspects of the detrusor muscle before and after injections are necessary: (1) to understand the effect of the botulinum-a toxin injections on the smooth muscle and (2) to exclude any injections induced fibrosis. 8. Concluding remark Detrusor-sphincter dyssynergia, neurogenic detrusor overactivity, urinary incontinence, overactive bladder and chronic prostatic pain are important and common conditions that often fail to respond to current administered treatment. Many questions remain regarding the botulinum effect on neuronal pathways of the lower urinary tract. However, one cannot deny human ingenuity in transforming the lethal poison into a modern day therapeutic medicine. References [1] Simpson LL. 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