Success of Repeat Detrusor Injections of Botulinum A Toxin in Patients with Severe Neurogenic Detrusor Overactivity andincontinence

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1 European Urology European Urology 47 (2005) Success of Repeat Detrusor Injections of Botulinum A Toxin in Patients with Severe Neurogenic Detrusor Overactivity andincontinence Joachim Grosse*, Guus Kramer, Manfred Stöhrer Department of Urology, Berufsgenossenschaftliche Unfallklinik Murnau, Murnau, Germany Accepted 19 November 2004 Available online 10 December 2004 Abstract Objectives: Detrusor injections with botulinum toxin type A are an effective treatment for neurogenic detrusor overactivity, lasting for 9 12 months. When the patients develop botulinum resistance, subsequent injections might be less effective. Repeat injections in patients with severe neurogenic detrusor overactivity and incontinence were studied. Methods: Patients received Botox 1 (300 UI) or Dysport 1 (750 UI) injections. Clinical variables: satisfaction, anticholinergics use, mean and maximum bladder capacity, continence volume. Cystometric parameters: compliance, cystometric capacity, reflex volume. Statistics: Anova, x 2 -tests; t-tests and paired t-tests (p = 0.05). Results: Forty-three men and 23 women (mean age 38.3 years; mean duration of lesion 9.2 years) were included. The interval between subsequent injections (on average 9 11 months) did not change significantly (p = ). The satisfaction was high and anticholinergics use decreased substantially (p = ). Significant improvements were found in clinical parameters and in cystometric capacity, for compliance only at the second treatment. The incidence of reflex contractions was significantly reduced. Four patients had transient adverse events after Dysport 1. Conclusions: Repeat injections with botulinum toxin type A are as effective as the first one. The cause for repeat treatment is relapse of overactive bladder symptoms. # 2004 Elsevier B.V. All rights reserved. Keywords: Botulinum; Detrusor injections; Neurogenic detrusor overactivity; Neurogenic urinary incontinence; Spinal cord injury; Aseptic intermittent catheterisation; Botulinum resistance 1. Introduction The majority of patients with suprasacral spinal cord injury, multiple sclerosis, stroke, or myelomeningocele suffers from lower urinary tract dysfunction: detrusor overactivity and/or low compliance with or without urinary incontinence [1 4]. Anticholinergic treatment is the gold standard for this condition, but many patients with neurogenic detrusor overactivity [5] are refractory to treatment * Corresponding author. Present address: Department of Urology, University Clinic of the RWTH Aachen, Pauwelsstr. 30, Aachen, Germany. Tel ; Fax: address: jgrosse@ukaachen.de (J. Grosse). with anticholinergics, mainly because of adverse effects partly caused by the high dosage needed [6]. In these cases intravesical instillation of vanilloids (capsaicin or resiniferatoxin) can be offered. These drugs cause an irreversible damage of the afferent sensory unmyelinated C-fibres, but their effect is limited and is discussed controversially [7 9]. Alternatively, invasive (auto-)augmentation procedures can be used [10,11], but these have various adverse long term effects [12,13]. Sacral rhizotomy causes loss of reflex erections and thus the implantation of a sacral root neurostimulator thus is best restricted to patients with complete suprasacral cord lesions [14]. Single sessions of multifocal injections with botulinum A toxin (BTX-A) into the detrusor were reported /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.eururo

2 654 J. Grosse et al. / European Urology 47 (2005) to offer an effective and relatively non-invasive treatment for patients with refractory neurogenic detrusor overactivity [15,16]. The therapeutic effect lasted for about 11 months, after which the patients might elect a repeat injection. This ongoing prospective open label study examines the results of repeat detrusor injections in order to discover a possible increase of drug resistance. 2. Methods Patients with repeat BTX-A injections for neurogenic lower urinary tract dysfunction (detrusor overactivity, low compliance, reduced bladder capacity with or without incontinence) unmanageable by anticholinergic treatment and able to practice intermittent (self-)catheterisation were included in this study. Pregnant patients or patients with systemic or neuromuscular disease, coagulation disorders, or patients unable to practice intermittent catheterisation were excluded. Patients with congenital spinal cord conditions were not included in this study, as we have the impression that the results for this group are less positive. Two BTX-A complex preparations are commercially available (Botox 1, Allergan Inc; Dysport 1, Ipsen Pharma). The effective toxin equivalence ratio is given as 1:1 to 8:1 [17,18]; based on clinical experience in man an equal effect is accepted for 1 UI Botox 1 and UI Dysport 1 [19 23]. An initial titration phase (last half year of 1998) had learnt us that 200 UI or 250 UI Botox 1 (n = 5) and 500 UI Dysport 1 (n = 7) were less effective, later on 300 UI Botox 1 and 750 or 1000 UI Dysport 1 were used. The current clinical status and patient self-assessment (change in dosage of anticholinergics, subjective outcome, increase of mean and maximum bladder capacity, increase of continence volume defined as the patient s indication of the bladder volume at which incontinence starts) and the urodynamic status (compliance, cystometric capacity, reflex volume defined as the filling volume at the start of the first phasic detrusor contraction [5,24]) were used as outcome parameters. Video-urodynamics were performed at baseline, 3 months and 6 12 months after each treatment. Because of the induced detrusor paresis, it was decided not to use the maximum detrusor pressure during filling or during voiding as urodynamic variables. At the mentioned follow-up investigations the decision for necessary re-injection was made when objective data (urodynamic or more subjective clinical patterns, or radiological signs of trabeculation, cellules or reflux) deteriorated substantially. It was not possible to use only a single criterion to specify the need for re-injection. Methods, definitions and units conform to the standards recommended by the International Continence Society, except where specifically noted [5,24]. Statistical comparisons were made with Anova, x 2 -tests, and t-tests, all at a significance level p = The transurethral BTX-A injections were performed as an office procedure. General or spinal anaesthesia was applied for tetraplegic or incomplete paraplegic patients to prevent autonomous dysregulation. The bladder was pre-filled with ml saline. The BTX-A injections were mapped on the detrusor, sparing the trigone and the bladder neck. Botox UI was diluted in 15 ml 0.9% NaCl and ml (10 UI/injection) solution were performed, Dysport or 1000 UI was diluted in 10 ml 0.9% NaCl and ml (37.5 or 50 UI/injection) solution were performed. After 1 March 2002, 750 UI was used, diluted in 5 ml 0.9% NaCl and ml (30 UI/injection) solution were given to minimize the side effects. 3. Results Since 1 August 1998 BTX-A injections into the detrusor muscle were performed in 187 patients, of whom 66 (43 men and 23 women) had repeat injections (Table 1) and fulfilled our inclusion criteria for this study. The mean age at first BTX-A treatment was 38.5 (14 77) years. Traumatic spinal cord injury existed in 54 patients, multiple sclerosis in 4, myelitis and brain defects in 2, and aneurysm, dysmelia, hernia, iatrogenic, spinal cord tumor, and spinal cord ischemia in 1 each. The extent of the lesions is given in Table 2. The average duration of the condition at the first BTX-A injection was 9.2 ( ) years. Bladder emptying by aseptic intermittent self-catheterisation was practised by 53 patients, 24 of those also had spontaneous or triggered voiding. Eleven patients always voided spontaneously or by triggering, one was catheterised intermittently, and one had an indwelling catheter. Anticholinergic treatment was used by 53 patients at baseline. Medication was applied as either monotherapy or in combination with other anticholinergics. The daily dosages used were as followed: oxybutinin mg, propiverine mg, tolterodine 4 8 mg, trospium chloride mg. 13 patients did not use anticholinergics because of adverse effects or ineffectiveness. All patients complained of bladder overactivity and incontinence. The primary treatment indications were reduced bladder capacity in all patients combined with Table 1 Number and type of injections Injection sequence Number of patients Botox Dysport Table 2 Patient neuropathic characteristics Paraplegic Tetraplegic complete incomplete complete incomplete Male Female Total

3 J. Grosse et al. / European Urology 47 (2005) Table 3 Subjective satisfaction after botulinum toxin injections Injection #: Very satisfied (n) Satisfied (n) Minor improvement (n) Unchanged (n) Unknown a (n) Total (n) Total with satisfaction score (n) Major improvement (%) (Satisfied + Very satisfied) Fig. 1. Intervals between 1st, 2nd, 3rd and 4th botulinum A toxin injections. There is no significant difference between the intervals. acetylcholine adverse effects in 20 patients; low detrusor compliance in 12; incontinence in 34. Detrusor overactivity was confirmed by urodynamics in 55 patients. The remaining eleven patients complained of reflex incontinence but this was not objectified during baseline urodynamics Interval between injections The interval between the injections 1, 2, 3 and 4 is given in Fig. 1. From injection 4 to injection 5 the mean interval was (Botox , n = 3; Dysport , n = 2), from 5 to 6, months (Dysport 1, n = 3), and one patient had a seventh injection with Dysport 1 after 18.2 months. The difference between the intervals 1 2, 2 3 and 3 4 is not statistically significant (Anova, p = ), nor is the difference between Botox 1 and Dysport 1 for the intervals 1 2, 2 3, and 3 4 (t-tests, p = , p = , p = ). When eight patients with an interval of 3 months or less between the first and the second injections are considered as treatment failures and removed from the data base the statistical conclusions do not change Clinical data The effect of the BTX-A injections on the bladder function was observed by the patients within 1 3 weeks after the treatment. The great majority of the patients was satisfied by the treatment (Table 3). The changes in the clinical bladder condition after injections 1, 2 and 3 are given in Fig. 2. All three variables improved significantly after the treatment compared to the baseline values. For injections 1, 2 and 3 the Anova test values were p = for continence volume, functional capacity, and maximum capacity. a Unknown: Patients without follow-up or time interval since injection too short. These patients were not considered in the percentage calculation for satisfaction. After the first injection, anticholinergic treatment was still used by 37 patients (69%), but the dosage had been decreased in 15 of them. In 13 patients the dosage was unchanged, in six it was increased, and three patients started anticholinergics after the injection. The detailed breakdown is presented in Table 4. Fig. 3 depicts the frequency distribution and change in dosages of anticholinergic treatment after the BTX-A injections. From baseline up to injection 3, the changes of frequency distribution are significant (x 2 test, p = ) Urodynamic data The distributions of the cystometric capacity, the reflex volume, and the detrusor compliance are presented in Fig. 4. The changes from baseline up to injection 3 are significant, except for the compliance (Anova: capacity p = , reflex volume p = , compliance p = ). The incidence of this detrusor overactivity was markedly reduced after the BTX-A injections (Fig. 5). The difference between the baseline and after injections 1, 2, and 3 was significant (x 2 -test, p =0.0095). Fig. 2. Change in clinical variables after injections 1 3. Significant improvement of each parameter compared to baseline.

4 656 J. Grosse et al. / European Urology 47 (2005) Table 4 Change of different anticholinergics and dosages after first BTX-A injection compared to baseline Anticholinergic Baseline Changes in anticholinergics post treatment No medication Dose reduction Unchanged Increase 3/4 1/2 1/4 Oxybutinin Mono Combination Trospium chloride Mono Combination Tolterodine Mono Combination Propiverine Mono Combination None None X X X X 3 Total Dose reduction: 3/4: reduced by 67 99%; 1/2: reduced by 34 66%; 1/4: reduced by 10 33%; compared to baseline Time course of improvements Shortly after the treatment all variables improve considerable, as exemplified after injection 1 in Fig. 6. Over the course of time a reduction occurs, but at 9 months still an average improvement over baseline of 36% exists. Fig. 3. Significant decrease of anticholinergics use after injections Treatment failures Eight patients were injected for the second time within three months since the first injection (one Dysport 1, seven Botox 1 ). From the pre-operative data no indication could be derived for this lack of effect. Five of these patients received a third injection after an average of 10.0 months (5 19 months), two had their Fig. 4. Change in urodynamic variables after injections 1 3. Significant improvement of cystometric capacity and reflex volume compared to baseline. Fig. 5. Significant decrease of incidence of reflex contractions after injections 1 3.

5 J. Grosse et al. / European Urology 47 (2005) Fig. 6. Time course of variables after first botulinum A toxin injection. At 8.5 months for all variables still an improvement over baseline exists (overall average increase 35%). second injection recently, and one patient refused further botulinum treatment. Four more patients refused a second injection for a period of 2 4 years because of lack of effect of the first injection. Three of them had their second injection recently, one refused further botulinum treatment. The failing effect of the injections in all 12 patients was confirmed by the post-treatment urodynamical and clinical data Adverse effects Four patients observed transient muscular weakness in the trunk and/or extremities, all after Dysport 1 injections: one of them for two months after 1000 UI/10 ml, twoforfour weeks after 750 UI/10 ml one of those had two previous Botox 1 injections 300 UI/15 ml without problems. The fourth patient suffered for 2 months after Dysport UI/10 ml, for 6 weeks after Dysport UI/10 ml, and again for six weeks after Dysport UI/5 ml. As this patient was very satisfied with the treatment effects and had stated this condition only at the interview after the third injection, a possible change to Botox 1 was not yet performed. Most probably, this muscular weakness is caused by systemic dispersion of Dysport 1 in dosage and dilution volumes. No intervention was needed for this condition. 4. Discussion Purified BTX-A neurotoxin, injected intramuscularly, binds to the pre-synaptic terminal of motor neurons and selectively inhibits the calcium-mediated acetylcholine release at the pre-synaptic neuromuscular junction by blocking the activity of the synaptosomal protein SNAP-25 [25,26]. In this way it causes a decreased regional muscular contractility by chemical denervation [26,27] and induces reversible striated muscle weakness for several months. Botulinum toxin type A (BTX-A) is one of the seven toxin sub-types produced by the anaerobic bacterium Clostridium botulinum; purified BTX-A introduced 23 years ago for treatment of blepharospasms [28] is used since in a variety of disorders [29,30]. Safety and long lasting effect of BTX-A injections into smooth muscle for treatment of focal contractions or parasympathetic autonomic disorders like achalasia, focal hyperhydrosis, gustatoric sweating, or migraine are reported [31 33]. Chemical denervation is a reversible process: axons re-sprout within weeks to months in striated muscle [34,35]. Contrasting, Haferkamp et al. who studied detrusor biopsies from patients after botulinum toxin injections found no re-sprouting in 4/4 biopsies after 3 months, and observed re-sprouting in only 3/7 biopsies from a longer follow-up with a mean of 8.8 months after the treatment. The muscular structure of the detrusor was not compromized by the botulinum toxin or by the injection procedure [36]. In particular no fibrosis was observed. Axonal regeneration and the possible activation of antibodies, recruited by the amount of BTX-A protein injected, necessitate repeat injections or may cause treatment failures [37 39]. In the detrusor muscle however, axonal regeneration probably does not play a major role [36]. The mechanism by which the botulinum A toxin effect on the detrusor muscle fades out after about one year still needs to be disclosed. Botulinum toxin type A causes a fast paralysis of the detrusor muscle when injected directly into this muscle. The effect is noted within 4 days to 3 weeks by patients and was also documented by the urodynamic investigation. The efficacy of this treatment demonstrates a relatively long duration, up to nearly one year on average after a single session. The interval between the subsequent treatments in this study corroborates the findings in the literature [15,16,26,40]. In the present study, the botulinum toxin treatment was not conceived as a replacement for anticholinergics, but rather as an addition. Nevertheless a major proportion of patients was able to refrain from anticholinergics completely. From the average time course after treatment of the (semi-)objective variables studied no clear indication can be found for the timing of re-treatment after this period. The main symptom volunteered by the patients as the indication of a relapse is the return of detrusor overactivity. This was confirmed by urodynamics also: investigations performed shortly before the repeat injection showed a higher incidence of overactive

6 658 J. Grosse et al. / European Urology 47 (2005) contractions then earlier after treatment. It thus may be conjectured that the recurrence of overactive detrusor contractions is an early warning signal for the need of re-treatment. The parameters used for the description of the detrusor overactivity obviously do not deteriorate already at the same time. This condition appears to agree with the electronmicroscopical and histochemical finding of re-sprouting of the nerve endings after an interval of about 9 months [36]. Multiple drug treatments always carry the risk that the patient develops a drug resistance and that subsequent treatments are less effective than the earlier ones [41]. Although a reduced average interval was found between treatments 3 and 4 compared to the interval between treatments 1 2 and 2 3, this difference was not significant. It must be admitted however that the number of patients with 4 or more treatments is low and that a much longer follow up period will be necessary to reconcile this fear. Both brands of BTX-A, Botox 1 and Dysport 1 showed equal efficacy in the treatment with a toxin equivalence ration of 1 to 2.5. No predictive factors for treatment failures could be derived, but the failing efficacy could be objectively documented. Adverse events have been seldom and transient obviously the toxin diluted in small volumes is incorporated in the target organ and does not spread systemically in relevant volumes. However the risk of systemic dispersion appears to be higher for Dysport 1 [26]. In the present study only four patients receiving Dysport 1, mostly in relatively high boluses of saline (0.5 ml), observed transient muscular weakness. This was a major reason for the reduction of the Dysport 1 dilution and injection volumes (cf. Section 2). From the literature [42] and also from our own experience in patients not included in this study similar adverse events may also be observed in patients treated with Botox Conclusions Botulinum toxin type A detrusor injection is a safe, effective, fast-working and long-lasting treatment for neurogenic detrusor overactivity in about 90% of the patients elected. A single treatment session will effectively suppress the detrusor overactivity for a period of nearly one year. The optimal dose in adults is 300 UI for Botox 1 and 750 UI for Dysport 1. Repeat treatments are as effective as the first treatment. No indication for an increased drug resistance was found. The need for repetition of the injections is probably set by the recurrence of the detrusor overactivity, that is sensed by the patient and can be documented in the urodynamic investigation. References [1] Blaivas JG. Obstructive uropathy in the male. Urol Clin North Am 1996;23: [2] Hinson JL, Boone TB. 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