European Urology 45 (2004)

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1 European Urology European Urology 45 (2004) European Experience of 200 CasesTreated with Botulinum-A Toxin Injections into the Detrusor Muscle for Urinary Incontinence due to Neurogenic Detrusor Overactivity André Reitz a,, Manfred Stöhrer b, Guus Kramer b, Giulio Del Popolo c, Emmanuel Chartier-Kastler d,jürgen Pannek e, Harald Burgdörfer f, Konrad Göcking g, Helmut Madersbacher h, Stefan Schumacher i, Rudolf Richter j, Jan von Tobel a, Brigitte Schurch a a Neuro-Urology, Swiss Paraplegic Center, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland b Department of Urology, Unfallklinik Murnau, Germany c Neuro-Urology, Spinal Unit of Florence, Italy d Department of Urology, Pitie-Salpetriere Hospital, Université Pierre et Marie Curie, Paris, France e Department of Urology, University of Bochum, Germany f Neuro-Urology, Spinal Cord Injury Center, Hamburg, Germany g Department of Urology, Swiss Paraplegic Center Nottwil, Switzerland h Neuro-Urology, University Hospital Innsbruck, Austria i Department of Urology, University of Bonn, Germany j Department of Urology, Klinik Bergmannstrost Halle, Germany Accepted 3 December 2003 Published online 20 December 2003 Abstract Objectives: To present a comprehensive experience with botulinum-a toxin (BTA) injected into the detrusor muscle in patients with spinal cord injuries/diseases causing neurogenic incontinence. Methods: Ten European medical centers provided the results of 231 patients with neurogenic detrusor overactivity who were treated with BTA. 300 units of Botox 1 (Allergan Inc.) were injected cystoscopically into the detrusor muscle at 30 different locations, while sparing the trigonum. Urinary continence status, concomitant anticholinergic medication use and patient satisfaction were recorded. Key urodynamic parameters (reflex volume, maximum detrusor pressure during voiding, detrusor compliance and maximum cystometric bladder capacity) at baseline and at the first and second urodynamic follow-up examinations were analyzed. Results: By the time of the initial (mean 12 weeks after injection) as well as at the second urodynamic follow-up examinations (mean 36 weeks after injection), the mean cystometric bladder capacity ( p < 0:0001) and the mean reflex volume ( p < 0:01) increased significantly, while the mean voiding pressure ( p < 0:0001) decreased significantly. The mean bladder compliance had increased significantly ( p < 0:0001) by the first follow-up examination and non-significantly by the time of the second follow-up. No injection related complications or toxin related side effects were reported. The patients considerably reduced or even stopped taking anticholinergic drugs without recurrence of reflex incontinence and were satisfied with the treatment. Conclusions: This retrospective European multicenter study presents the most extensive experience to date with BTA injections into the detrusor muscle to treat neurogenic incontinence due to detrusor overactivity and confirms that this new treatment is safe and valuable. Significant improvement of bladder function corresponds with continence and the subjective satisfaction indicated by the treated patients. # 2003 Elsevier B.V. All rights reserved. Keywords: Spinal cord disease; Neurogenic bladder; Urinary incontinence; Botulinum toxin type A Corresponding author. Tel. þ ; Fax: þ address: areitz@balgrist.unizh.ch (A. Reitz) /$ see front matter # 2003 Elsevier B.V. All rights reserved. doi: /j.eururo

2 A. Reitz et al. / European Urology 45 (2004) Introduction Botulinum neurotoxin type A (BTA) synthesized in Clostridium botulinum is the disease agent for botulism and most potent natural poison. From the structural point of view the toxin is a 150 kd amino acid di-chain molecule consisting of a light (50 kd) and a heavy chain (100 kd) which are linked by a disulfide bond [1]. The toxicity of the BTA is a result of a multi-step mechanism [2]. The neurotoxin binds to the pre-synaptic nerve endings of cholinergic neurons and enters the neuron by receptor mediated endocytosis. There the catalytic domain specifically cleaves the SNAP-25 protein essential for normal synaptic vesical fusion. This cleavage results in the inhibition of neuronal acetylcholine secretion, ultimately leading to a temporary chemodenervation and the loss or reduction of neuronal activity at the target organs [1,3]. In general, this chemodenervation is fully reversible. Regeneration process relies on the formation of functional neuronal sprouts that reconnect pre-synaptic nerve endings with their target organs (muscles or glands) [4]. The first therapeutic applications were reported in patients with strabismus and blepharospasmus [5,6]. Currently, the toxin is a safe and highly effective therapeutic agent for numerous indications including cervical dystonia [7], juvenile cerebral palsy [8], focal spasticity [9], hyperhidrosis [10] and detrusor-sphincter dyssynergia [11 14]. Also disorders of smooth muscle systems such as achalasia [15] and anal fissure [16] have been successfully treated with BTA. Recently, the efficiency of BTA injections into the detrusor smooth muscle to treat major detrusor overactivity and neurogenic incontinence has been proven [17 20]. This minimally invasive procedure offers a new therapeutic option between ineffective or incompatible anticholinergic drug therapy and surgery like enterocystoplasty. This study provides a comprehensive European experience with BTA injections into the detrusor muscle in patients with neurogenic incontinence due to detrusor overactivity. 2. Patients and methods According to a protocol first introduced in 1999 [17] in total 231 patients with neurogenic detrusor overactivity and incontinence due to spinal cord injuries, multiple sclerosis, spina bifida or myelomeningocele were treated with BTA injected into the detrusor muscle (for details see Fig. 1). This retrospective study involves the data provided by a total of ten European medical centers found in Germany, Italy, France, Austria, and Switzerland. A survey form was developed to collect all relevant data concerning medical and thoracolumbar lesions T10-L2: n = 24 cervical lesions C4-C7: n = 59 thoracic lesions T1-T9: n = 84 n = multiple sclerosis 22 myelomeningocele 167 spinal cord injury Fig. 1. Aethiology of the neurogenic detrusor overactivity in the studied population. urological histories, clinical and urodynamic baseline values, concomitant medications, BTA treatment details, clinical and urodynamic outcomes at first and second follow-up examinations and subjective satisfaction as indicated by the treated patients. This study analyzed the results recorded only after one BTA injection and all results associated with reinjections were excluded. Out of the 231 recorded treatment data 31 data sets were incomplete and therefore excluded. The results of 200 patients including 131 males and 69 females treated with BTA injections into the detrusor were finally included in the study. In 146 cases the indication for injecting the detrusor muscle with BTA was neurogenic incontinence. 20 patients were dry but suffered from severe side effects associated with their anticholinergic medication and were therefore treated with BTA. 34 patients presented with both incontinence and the severe side effects of their anticholinergic medication. In this group of patients the doses of the anticholinergic drugs could not increased as high as required to ensure continence because their side effects already appeared at low or normal doses. Clean intermittent self-catheterisation (CIC) was performed by 188 patients to empty their bladder, while 12 patients relied on indwelling catheters because of severe incontinence. The evaluations before injection with BTA included a clinical examination, urine analysis and complete urodynamic assessment. The number of voidings, used pads and episodes of incontinence per day were recorded, as well as the use of a urinary condom. Doses and methods of administration (oral or instillation) of anticholinergic drugs before and after treatment with BTA were recorded and analyzed. Complete urodynamic assessments were performed according to the Good Urodynamic Practice recommended by the International Continence Society [21]. Urodynamic parameter were defined as available following the standardisation reports of the International Continence Society [22,23]. During baseline urodynamics and follow-up examinations special attention was paid to the following key parameters: (1) the reflex volume (RV) defined as the infused volume at the start of the first reflex detrusor contraction during the filling phase, (2) the maximum detrusor pressure during voiding (MVP), (3) the bladder compliance described as the relationship between the change in bladder volume and the change in detrusor pressure and is calculated by dividing the volume change by the change in detrusor pressure during that change in bladder volume as well as (4) the maximum cystometric bladder capacity in patients with impaired sensation (MCBC) defined as the infused volume when involuntary voiding occurred or in the absence of involuntary voiding when the investigator decides to stop filling (usually at 500 ml).

3 512 A. Reitz et al. / European Urology 45 (2004) BTA injections were performed with a normal 22 FF rigid cystoscope and a flexible injection needle. In patients with preserved bladder sensibility a local or general anaesthesia was required. In patients with a complete spinal cord lesion and absent bladder sensibility usually no anaesthesia was necessary. In patients with high lesions (T6 and higher) a local anaesthesia with instillation of 50 ml lidocaine 2% into the bladder was done prior to the procedure to avoid autonomic dysreflexia. The risk of a possible autonomic dysregulation was the reason why cardiovascular monitoring was ensured during the cystoscopy and the subsequent injection of the toxin. 300 units of Botox 1 (Allergan Inc) were injected into the detrusor muscle at 30 different sites (10 units of the toxin per ml and per site) sparing the trigonum. After injections the patients were instructed to reduce anticholinergic drugs starting one week after treatment. Clinical and urodynamical data of the first and the second urodynamic follow-up examination were analyzed. From the clinical point of view, continence or the number of incontinence episodes per day, as well as patient satisfaction were recorded using analog scales. The urodynamic parameters RV, MVP, detrusor compliance and MCBC measured at the first and the second follow-ups were compared to baseline values. Data were statistically evaluated by analysis of variance for repeated measurements (level of significance p < 0:05). 3. Results All patients presented with neurogenic detrusor overactivity, and in 92 cases this was accompanied by detrusor sphincter dyssynergia. Before injection, 163 patients were on anticholinergic drugs. 86 took oxybutynin (80 orally and 6 using intravesical instillation), 33 took trospium chloride, 26 tolterodine, 6 propiverin and 12 took a combination of oxybutynin and trospium chloride (see Figs. 2 and 3). The injection appeared as an easy and minimally invasive procedure. For the injection procedure a general anesthesia was required in 109 patients and a spinal anesthesia was done in 45 patients. 46 patients underwent the procedure in local anesthesia. No injection related complications or toxin related side effects were reported in the studied population. mean doses of AC at baseline Propiverine Tolterodine Trospium chloride Oxybutynin instillation Oxybutynin oral mean doses of AC at 12 week follow-up mean dose (mg) Fig. 3. Mean dosages (standard deviation shown as bars) of anticholinergic drugs (AC) before and after BTA injection. By the time of the first urodynamic follow-up examination occurring mean 12 weeks after injection (mean 83.6 days, S.D. 29 days) we observed a significant increase in the mean MCBC from 272 ml to 420 ml ( p < 0:0001), a significant increase in the mean RV from 236 ml to 387 ml ( p < 0:0001) and a significant reduction of the mean MVP from 61 cmh 2 O to 30 cmh 2 O(p < 0:0001). The mean bladder compliance increased significantly ( p < 0:0001) from 32 ml/ cmh 2 O to 72 ml/cmh 2 O (see Figs. 4 and 5). From the clinical point of view, 132 out of 180 incontinent baseline 1st urodynamic follow-up (mean 12 weeks after injection) 2nd urodynamic follow-up (mean 36 weeks after injection) reflex volume (ml) bladder capacity (ml) n = 200 p<0.001 vs baseline Fig. 4. Urodynamic results: reflex volume and maximum cystometric bladder capacity at baseline, first and second follow-up examination. Number of patients on AC at baseline Oxybutynin/Trospium Propiverine Tolterodine Trospium chloride Oxybutynin instillation Oxybutynin oral Number of patients on AC at 12 week follow-up baseline 1st urodynamic follow-up (mean 12 weeks after injection) 2nd urodynamic follow-up (mean 36 weeks after injection) voiding pressure (cm water) compliance (ml/cm water) n = 200 p<0.001 vs baseline Fig. 2. Number of patients on anticholinergic drugs (AC) before and after BTA injection. Fig. 5. Urodynamic results: voiding pressure and bladder compliance at baseline, first and second follow-up examination.

4 A. Reitz et al. / European Urology 45 (2004) patients reported complete continence after treatment, while 48 patients reported improvement but some level of continuing incontinence. Concomitant anticholinergic medication could be discontinued in 45 patients and considerably reduced in 118 patients (see Figs. 2 and 3). For 99 of 200 patients a second clinical and urodynamical follow-up was analyzed which occurred mean 36 weeks (mean 256 days, S.D. 51 days) after injection with BTA. At this examination there was a significant increase in the mean MCBC from 272 ml to 352 ml ( p < 0:0001), a significant increase in the mean RV from 236 ml to 291 ml ( p < 0:01) and a significant reduction of the mean MVP from 61 cmh 2 O to 44 cmh 2 O(p < 0:0001). The mean bladder compliance increased non significantly from 32 ml/cmh 2 Oto 51 ml/cmh 2 O. By the time of this second follow-up 72 patients reported complete continence and 27 reported recurrent incontinence. 4. Discussion The physiologic alterations that accompany spinal cord injury (SCI), myelomeningocele (MMC) or multiple sclerosis (MS) can lead to significant bladder dysfunction. These disturbances are known to have a major impact on overall morbidity and patient s quality of life. In the majority of SCI, MMC and MS patients bladder dysfunction can be categorized as upper motor neuron (UMN) dysfunction. The UMN syndrome presents as a disruption of the descending pathways providing the inhibitory input to the sacral micturition center. The loss of supraspinal control leads to involuntary, reflexive bladder contraction and frequently to neurogenic incontinence. Additionally, in most cases an impaired coordination of the detrusor and sphincter system (detrusor sphincter dyssynergia) can results in elevated bladder pressures during micturition which leads to structural bladder damage, to vesicoureteral reflux and subsequent to renal insufficiency. Management strategies for UMN syndrome should meet three main objectives: low-pressure urine storage, low-pressure voiding and adequate urine drainage. However, from the patient s point of view the most important goals are continence and a good tolerability of the therapy. Treatment options to achieve low-pressure urine storage involve non-invasive therapy such as anticholinergic medication combined with CIC to ensure low-pressure voiding without leaving any residual urine in the bladder. However, in a considerable number of patients oral anticholinergic drugs are ineffective to achieve continence or cause serious side effects such as a dry mouth or constipation. Usually, in these cases the last alternative remained invasive surgery such as sacral root stimulation [24] or bladder augmentation [25,26]. As an alternative to oral anticholinergic medication the injection of BTA into the detrusor muscle has been suggested for patients with ineffective or incompatible anticholinergic drug therapy prior to surgery like enterocystoplasty. First trials with BTA indicated promising results concerning the clinical and urodynamic benefits of this new treatment option. The neurotoxin injected into the bladder wall blocked the neuromuscular junction and relaxed the detrusor muscle for a period up to at least 36 weeks [17 19]. This report presents the data of 200 patients treated with BTA and confirms the preliminary results reported in In patients presenting with severe neurogenic detrusor overactivity and incontinence who do not respond to oral anticholinergics, high bladder pressures frequently lead to a structural bladder damage with restricted capacity and compliance. In these difficult cases, the BTA was injected into the detrusor muscle. The injections appeared as a simple and safe procedure without any complications or adverse effects. A dose titration study of the population studied in 2000 revealed that 300 units of Botox 1 diluted in 30 ml saline and injected at 30 locations within the detrusor muscle are sufficient to treat even severe neurogenic detrusor overactivity [17,19]. It may be conjectured that highly efficient binding of the neurotoxin to the intramuscular nerve terminals prevents passage into the circulatory system and any subsequent systemic side effects. Basic research will be necessary to prove or disprove this assumption. The trigonum was not injected and no injections were made near the ostium to avoid any damage to the upper urinary tract. The decision not to inject the trigonum was based on certain major considerations. The submucosal nerve plexus, which is thought to be mainly sensory, is particularly prominent in the trigonum [27] and inserting a syringe needle into this area risks impairing sensory nerve endings. Also, trigonal innervation is more complex than bladder dome innervation. The superficial and deep trigonum appears to be innervated by adrenergic, cholinergic and nonadrenergic noncholinergic excitatory pathways [28]. Therefore, the effect of botulinum-a toxin, which selectively blocks the release of acetylcholine, would have been more difficult to analyze. In the studied population it needs to be considered, that most patients were prior to surgical intervention because of severe complications of the neurogenic detrusor overactivity. At the first follow-up examination after 12 weeks, 132 out 180 patients who were

5 514 A. Reitz et al. / European Urology 45 (2004) previously incontinent reported complete continence after BTA injection. In 48 patients the continence status improved, although they were not completely continent. 45 of 163 patients who were previously using oral anticholinergics could completely discontinue the medication after treatment with BTA. In the remaining 118 patients the intake of oral anticholinergics could be considerably reduced, which ended or alleviate the systemic side effects. However, it remains to be determined why these patients had to continue taking anticholinergic medication. From the urologist s point of view, the objective improvement of bladder function as indicated by the urodynamic data objectively supports patient s reports of improved or complete continence. For protection of bladder integrity and the upper urinary tract, low pressure storage and low pressure voiding is essential. The relaxation of the detrusor muscle induced by BTA injections increased reflex volume and bladder capacity significantly after 12 and 36 weeks. This enabled patients to reduce the number of catheterisations within 24 h and improved patient s quality of life. High voiding pressures, which are responsible for severe long-term complications were significantly reduced to normal values both after 12 and 36 weeks. Bladder compliance was normal before treatment, and increased significantly after 12 but not after 36 weeks. However, it is recognized that severe restriction in bladder compliance due to organic detrusor muscle changes or fibrosis does not respond to any conservative treatments. In this situation, surgical interventions such as autoaugmentation, enterocystoplasty or an ileal conduit should be considered. The duration of induced detrusor paralysis was 9 months or more versus 3 to 4 month after a injection into the external urethral sphincter muscle [12]. These results strongly suggest that smooth and striated muscles react differently to the toxin. Molgo [29] and Holds et al. [30] reported axonal sprouting into a striated muscle after botulinum-a toxin injections in animals and humans, which is consistent with local reinnervation after acute poisoning. To our knowledge no relevant studies have been done in smooth muscle. Consequently, it remains difficult to determine whether the long duration of paralysis in smooth muscle induced by the toxin is due to delayed axonal outgrowth. In the studied population 9 out of 200 patients were identified as non-responders who experienced neither clinical or urodynamic benefits. The reason why these patients did not respond could not be determined, however errors during toxin preparation, dilution or injection can not be excluded. The beneficial effects in the 191 responders concerned clinical as well as urodynamic parameters. From the patient s point of view the efficacy to ensure continence and a good tolerability of the BTA treatment are essential, because these points have a major impact on patient compliance and quality of life. Urodynamically most patients achieved a state of low pressure urine storage and in combination with CIC also low-pressure voiding and adequate urine drainage. Therefore, we are convinced that the injection of BTA into the detrusor muscle, combined with CIC, offers an adequate management option for patients with incontinence due to neurogenic detrusor overactivity. 5. Conclusion This retrospective European multicenter study presents the most extensive experience to date with BTA injected into the detrusor muscle to treat neurogenic incontinence due to detrusor overactivity and confirms that this new approach is a safe and valuable therapy. Significant improved bladder function corresponds with continence and subjective satisfaction as indicated by the treated patients. Acknowledgements The authors are grateful to Mr. Peter Knapp for the excellent technical and scientific support and thank Mr. Huub van Hedel for statistical assistance. This study was supported by the Swiss National Foundation (Grant No ). References [1] Montecucco C, Schiavo G. Structure and function of tetanus and botulinum neurotoxins. Q Rev Biophys 1995;28(4): [2] Simpson LL. Kinetic studies on the interaction between botulinum toxin type A and the cholinergic neuromuscular junction. J Pharmacol Exp Ther 1980;212(1): [3] Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol 1998;5(10): [4] de Paiva A, Meunier FA, Molgo J, Aoki KR, Dolly JO. 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 USA 1999;96(6): [5] Scott AB. 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