GOVINDARAJ N. RAJKUMAR, DOUGLAS R. SMALL, ABDUL W. MUSTAFA and GRAEME CONN Department of Urology, Southern General Hospital, Glasgow, UK

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1 Original Article BTXA IN DETRUSOR FOR REFRACTORY IDIOPATHIC DOA RAJKUMAR et al. A prospective study to evaluate the safety, tolerability, efficacy and durability of response of intravesical injection of botulinum toxin type A into detrusor muscle in patients with refractory idiopathic detrusor overactivity GOVINDARAJ N. RAJKUMAR, DOUGLAS R. SMALL, ABDUL W. MUSTAFA and GRAEME CONN Department of Urology, Southern General Hospital, Glasgow, UK Accepted for publication 19 April 25 OBJECTIVES To assess, in a prospective study, whether botulinum toxin A (BTXA) injected into the detrusor muscle is safe and well tolerated, produces significant changes in urodynamic variables, if the effect is durable, as measured by the Bristol Female Lower Urinary Tract Symptom Questionnaire (BFLUTS), and to assess changes in quality of life, as measured by the Kings Health Questionnaire (KHQ), when it is used to manage idiopathic detrusor overactivity. PATIENTS AND METHODS This was a single-centre, prospective unrandomized study of 15 women to assess the efficacy of a single dose of 3 units of BTXA injected intravesically into the detrusor muscle, under cystoscopic control. Patient evaluation included a full history and examination, frequency/volume charts, BFLUTS and KHQ scores, and a conventional urodynamic study at baseline and at 6 weeks after treatment. Symptomatic improvement was assessed at 6 weeks and every 4 weeks thereafter until baseline values were reached. RESULTS All 15 patients completed the study; 14 noted an improvement in urgency and frequency immediately after treatment. There were no major adverse effects reported to date. The volume at first desire to void increased in 13 patients (P <.6), the maximum cystometric capacity increased in 1 (P <.11) and six of the 15 had no evidence of detrusor overactivity; in the remaining eight the volume at first overactive contraction increased in six (P <.23) and the volume at first overactivity incontinence increased in 11 (P <.5). The median modified projected isovolumetric pressure decreased significantly (P =.1), from 69 to 45. The improvement in frequency appeared to last up to 24 weeks, and that in urinary incontinence up to 2 weeks. The overall improvement in quality of life was maintained up to 24 weeks. CONCLUSION BTXA appears to be a safe treatment with good clinical efficacy in refractory idiopathic detrusor overactivity; the effects seem to last 2 24 weeks. KEYWORDS idiopathic detrusor overactivity, botulinum toxin type A, urodynamics INTRODUCTION Detrusor overactivity (DOA) has been defined [1] as the presence of involuntary detrusor contractions during the filling phase of cystometry, which may be spontaneous or provoked, and which the patient cannot completely suppress. Clinically, patients with DOA may present with symptoms of an overactive bladder, i.e. increased frequency and urgency with or without urinary incontinence. In the absence of local or metabolic factors explaining these symptoms, the condition is described as idiopathic DOA. Clinical symptoms of an overactive bladder are known to significantly compromise quality of life. It was estimated that ª17% of the adult population in Europe and the USA have some form of overactive bladder [2,3], and it is likely that a substantial proportion of them would have DOA, but the true prevalence has not been estimated. Currently, pharmacological treatment forms the cornerstone of managing DOA. Drug therapy augments behavioural therapy and includes anticholinergic agents, calcium-channel blockers and tricyclic antidepressants. However, a significant proportion of patients are unable to tolerate such medication or have severe symptoms that do not respond to conservative measures, and would benefit from more invasive therapeutic measures such as neuromodulation or surgery. The pathophysiology of DOA may include increased spontaneous myogenic activity and altered responsiveness to stimuli. Botulinum toxins produce their clinical effects of muscle relaxation by temporarily inhibiting the release of acetylcholine at the presynaptic cholinergic junction. In spinal cord-injured patients with neurogenic DOA, botulinum toxin A (BTXA) injections into the detrusor muscle improve lower urinary tract function by producing a temporary paralysis of muscle by inhibiting the release of acetylcholine from the presynaptic vesicles, resulting in increased bladder capacity and reduced urge incontinence [4]. Few studies have evaluated the use of BTXA in managing idiopathic DOA [5 7]. Thus we conducted a prospective study to evaluate the safety, tolerability, efficacy, and durability of the response to BTXA injected intravesically into the detrusor muscle, in patients with urodynamically confirmed DOA who had not responded satisfactorily to BJU INTERNATIONAL 96, doi:1.1111/j x x

2 BTXA IN DETRUSOR FOR REFRACTORY IDIOPATHIC DOA conservative measures and had symptoms severe enough to warrant further surgical options. The aims of the study were to assess whether BTXA injected into the detrusor muscle: (i) is safe and well tolerated; (ii) produces significant changes in urodynamic variables, e.g. first desire to void (FDV), volume at first overactive contraction (VFOAC), volume at first incontinence (VFOAI) and maximum cystometric capacity (MCC), Voiding detrusor contractility measured by the variable modified projected isovolumetric pressure (PIP 1 ) [8]; (iii) produces a significant change in symptoms and quality of life, as shown by changes in the frequency of voiding per 24 h, LUTS assessed by the Bristol Female LUTS Questionnaire (BFLUTS) [9], and quality of life by the King s Health Questionnaire (KHQ) [1]; and to assess the durability of the effect of BTXA. PATIENTS AND METHODS This was a single-centre, prospective unrandomized study of 15 women (mean age 44 years, range 2 61) to assess the efficacy of one dose of 3 units of BTXA, injected intravesically into the detrusor, for managing idiopathic detrusor instability. The patient evaluation included a full history and examination, frequency/volume charts, the BFLUTS and KHQ. None of the patients had had previous major urinary bladder surgery, and all had tried conservative treatment methods and found them unsatisfactory. At the time of the study none of the women was on any anticholinergic medication. They were also instructed not to start any new medication if possible during the follow-up. Patients with stress incontinence, or mixed incontinence where the predominant component was stress incontinence, were excluded. Approval from the Local Research Ethics Committee and a drug exemption certificate for the use of BTXA for DOA were obtained. Informed consent was obtained from all patients. Patients were assessed using conventional urodynamics unless this had been undertaken in the previous 6 months. Conventional filling and voiding urodynamics were conducted with standing provocative manoeuvres. Filling cystometry was measured with a 574 double-lumen urethral catheter (8 F) and abdominal pressure with a 5415 rectal balloon catheter (4.5 F, both Mediplus Ltd. High Wycombe, Bucks, UK). Over the course of the study two different urodynamic systems were used, i.e. the URO6 (Lectromed UK Ltd, Letchworth, Herts UK) and the Solar (Medical Measurement Systems, Enschede, the Netherlands). There were no changes in the catheters used. Patients were asked to void, were catheterized and the bladder drained. Adequate abdominal cancellation was checked via coughing before and during filling at 1 ml/min. Patients were asked to identify the FDV, any urgency and strong desire to void. With a full bladder the patient coughed while supine and any urodynamic stress incontinence was noted. Standing provocative manoeuvres were then used in an attempt to provoke both urodynamic stress incontinence and DOA. Finally, the patient voided with the urodynamic catheters in situ. Urodynamic variables measured were: on cystometry, the FDV, VFOAC, amplitude of first overactive contraction, strong desire to void and MCC, and on voiding, the voided volume, maximum urinary flow rate (Q max ) and pressure at this flow rate (P det Q max ). The urodynamic systems were maintained and calibrated according to the ICS Good Practice document [11]. BTXA, by its mode of action, might be expected to change the strength of the detrusor voiding contraction. Contractility was therefore assessed numerically in all patients both before and after BTXA if they had a complete voiding study. The modified PIP 1, as a measure of detrusor contractility, was calculated by adding Q max to P det Q max in the usual units [8]. Cystoscopy was performed under general anaesthesia and 3 units of BTXA in 3 ml normal saline injected intravesically into 3 sites in the detrusor muscle, avoiding the trigone (1 ml per site). The patients were evaluated after treatment by frequency/ volume charts, the BFLUTS and KHQ, and by a conventional urodynamic assessment at 6 weeks. All patients were assessed every 4 weeks thereafter with frequency/volume charts, BFLUTS and KHQ until they reached baseline values. This was a prospective open uncontrolled experimental trial; the outcome measures yielded matched-paired data, which were analysed using nonparametric statistics. We therefore quote the median (lower and upper quartiles) for the urodynamic variables. For hypothesis testing, the Wilcoxon matchedpairs signed-rank sum test was used, with 95% CI calculated using the Hodges- Lehmann Estimator (paired). RESULTS All 15 patients were injected with BTXA; all tolerated the procedure well and none reported any pain or discomfort. Fourteen of the 15 patients noticed an improvement in urgency and frequency immediately after treatment. There were no episodes of acute urinary retention and all patients voided spontaneously at the time of discharge. There were no major adverse effects reported. All patients were assessed urodynamically at 6 weeks; the results are summarized in Table 1. DOA was eliminated in six patients; the MCC increased in 1 (P <.15), the FDV increased in 12 (P <.7) and of the remaining nine patients with DOA the VFOAC increased in six (P <.27). In five patients DOA incontinence was detected and the associated volume increased in three (P <.29). Of the 15 women, all attempted pressure voiding at urodynamics before and after BTXA injection. Four had incomplete data at one of the studies; either they expelled the catheter or DOA caused them to flood to completion. There were thus 11 complete sets of voiding data. The contractility factor PIP 1 was calculated for each void and is shown in Table 1; the median decreased significantly (P =.1) from 69 to 45. It was possible to infer with reasonable clinical accuracy the completeness of the void, by comparing the instilled volume with the voided volume (all patients were emptied by catheter before starting to fill). Before BTXA all 15 patients either voided to completion or flooded to completion due to DOA. After injection, eight patients voided to probable completion, five had a residual on ultrasonography of 9, 13, 13, 18, 35 ml. The two others had inferred residuals of 23 and 25 ml. No patient was unable to void. The BFLUTS score improved in all patients (P <.1) and the KHQ showed improved scores in all at 6 weeks (P <.1). At 6 weeks the frequency of voiding had decreased in 14 patients and in the remaining woman was unchanged (P <.1). In 13 patients the symptoms returned to baseline levels at a mean (range) of 24 (1 52) weeks after 25 BJU INTERNATIONAL 849

3 RAJKUMAR ET AL. TABLE 1 A summary of the urodynamic results before and after BTXA treatment FDV, ml MCC, ml VFOAC, ml VFOAI, ml PIP 1 Patient before after before after before after before after before after N/A NI NI NOC 413 NI NOC 78 NI NOC NI NI NOC NI NI NOC 125 NI N/A N/A N/A NOC 44 NI N/A 49. Median Lower quartile Upper quartile P NOC, no overactive contraction; NI, no incontinence; N/A, not applicable. treatment. The remaining two patients were lost to follow-up after 14 and 2 weeks. Figure 1a d shows the temporal changes in the BFLUTS, KHQ, 24-h frequency and 24-h incontinence episodes. DISCUSSION In this study of 15 patients with idiopathic DOA, BTXA was safe and well tolerated, with the DOA eliminated in six. There was a statistically significant improvement in the FDV and in MCC at 6 weeks after treatment. The VFOAC also increased significantly, but the VFOAI was increased only in three patients; DOA incontinence persisted in five. BTXA appears to provide a therapeutic effect in idiopathic DOA by weakening the detrusor contraction. However, in patients with overactivity incontinence, the weakening may not be sufficient to prevent incontinence. Using a higher dose in these patients may prevent incontinence, but increases the risks of detrusor failure and consequent retention of urine. Detrusor contractility in the voiding phase has been assessed in several ways. Griffiths [8] recently reviewed several, including the Schäfer contractility nomogram [12], the Watts factor [13], and three types of stop test. Despite the complicated nature of some of these methods, Griffiths concluded that although a stop test is most responsive to changes in detrusor contractility, a simple index, PIP 1, was the next most useful variable. In the present study, detrusor contractility decreased significantly, but Griffiths [8] gives 49 as the mean value of PIP 1 in a sample of 1 elderly women (mean age 7 years) with urge incontinence. In the present patients (mean age 44 years) the mean PIP 1 after BTXA was 48, and so although contractility was reduced, the value is comparable with that from an older population who should not necessarily be skewed towards an underpowered voiding disorder. This is the first published quantitative assessment of voiding contractility after BTXA therapy. In the present study the therapeutic effects of BTXA lasted 2 24 weeks; there was some variability in response, with effects lasting only up to 1 weeks in one patient and in another the effect seemed to last for 52 weeks. Symptomatically, patients appeared to have an immediate improvement in the frequency of micturition and urgency. As noted, urinary incontinence persisted at 6 weeks in five of 11 patients who were incontinent before treatment. In addition, incontinence episodes appear to reach baseline levels much earlier than frequency. The results in other studies using BTXA for treating DOA [5 7] also confirmed an early and significant improvement in frequency and urgency. There was only slight or moderate improvement in incontinence. None of them reported residual urine volumes, but some studies had no urodynamic evaluation for an objective assessment of therapeutic effect, or a prolonged follow-up to evaluate the durability of the response. Schurch et al. [4] noted that in patients with neurogenic DOA the duration of action of BTXA appeared to be ª9 months, and that none of the patients followed up at 36 weeks required repeat BTXA injections for recurrent incontinence. Richter et al. [14], studying 7 patients with neurogenic DOA, reported continence in 65 patients after detrusor injections with BTXA, with a significant increase in bladder capacity and corresponding decrease in maximum detrusor pressure, with the therapeutic effect lasting 6 9 months. No adverse effects were noted in these studies BJU INTERNATIONAL

4 BTXA IN DETRUSOR FOR REFRACTORY IDIOPATHIC DOA FIG. 1. The percentage change in a, BFLUTS score; b, the KHQ; c, 24-h frequency; and d, 24-h incontinence episodes after BTXA treatment. 5 In the present study, the quality-of-life scores assessed by the KHQ showed a significant improvement at 6 weeks and at subsequent follow-up appeared to correlate well with the BFLUTS score. The variability of the CIs reflects the varying response to the follow-up questionnaires, which was not always complete. As long as the 95% CIs exclude zero, an effect can be postulated. In the case of BFLUTS and KHQ, the therapeutic response lasted for 24 weeks. The 24-h frequency was similar, although the trend of a complete return to baseline was not as clear. The change in the number of incontinence episodes in 24 h was statistically significant at a % score change b % score change c % change d 8 % change weeks (P <.26) but the trend is the least striking, with 95% CIs around zero for most of the follow-up. The main advantages of BTXA are its efficacy, safety, lack of adverse effects, and temporary action. Patients with resistance to one serotype may benefit from other serotypes and it is possible that some of these patients might respond better to another botulinum toxin (BTXB is currently available). Dykstra et al. [15] reported a pilot study on treating DOA with BTXB in 15 women, where the duration of the response appeared to be dosedependent, the longest being with 1 and 15 units, and which lasted for 3 months. There were no serious adverse effects reported. The temporary action of BTXA necessitates repeated injections and there were some concerns about the development of antibodies, and hence the long-term efficacy of treatment. The development of antibodies to BTX protein and clinical resistance to treatment with BTXA was reported with the original BTX (Lot 79 11) in patients undergoing repeated injections for torticollis [16]. However, the current BTX introduced in 1997 has a much lower antigenic potential and immunoresistance to treatment is rare, and has not been reported in any studies of treating lower urinary tract disorders. Grosse et al. [17] studied 11 patients with neurogenic lower urinary tract dysfunction who had repeated detrusor injections with BTXA, and suggested that there was no evidence of increased drug tolerance after multiple treatments. A continuing follow-up of this study should give a better estimate of the costeffectiveness of treatment. Larger scale studies, which would also investigate costeffectiveness and compare BTXA with other currently available treatments for refractory DOA, are required before there can be a decision about its place in treating DOA. Trials of BTXA should also be expanded to include treatment of other conditions which may benefit from this therapy, e.g. multiple sclerosis, interstitial cystitis and chronic pain syndromes. In conclusion, BTXA appears to be a safe treatment with good clinical efficacy in idiopathic DOA, and is a viable alternative when conventional therapies have failed to produce symptomatic improvement. BTXA (3 units) injected into the detrusor appears to produce significant changes in urodynamic values of FDV, MCC and VFOAI, which translates clinically into a symptomatic improvement. The effect lasts 2 24 weeks in patients with idiopathic DOA and no incontinence; its effects on incontinence are less durable. ACKNOWLEDGEMENTS Allergan Ltd, for kindly providing the Botox vials for the study, and the Bristol Urological Institute, for giving permission to use the BFLUTS questionnaire. 25 BJU INTERNATIONAL 851

5 RAJKUMAR ET AL. CONFLICT OF INTEREST None declared. REFERENCES 1 Abrams P, Cardozo L, Fall M et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodynam 22; 21: Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 21; 87: Stewart WF, Van Rooyen JB, Cundiff GW et al. Prevalence and burden of overactive bladder in the United States. World J Urol 23; 2: Schurch B, Stohrer M, Kramer G, Schmid DM, Gaul G, Hauri D. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 2; 164: Radzieszewski P, Dobronski P, Borkowski A. Treatment of the nonneurogenic storage and voiding disorders with the chemical denervation caused by botulinum toxin type A; a pilot study. Neurourol Urodynam 21; 2: Zarmann DH, Ishiogooka M, Schubert J, Schmidt RA. Trigonum and bladder base injection of severe urgency frequency syndrome refractory to conservative medical treatment and electrical stimulation. Neurourol Urodynam 21; 2: Rapp DE, Lucioni A, Katz EE et al. Use of botulinum-a toxin for the treatment of refractory overactive bladder symptoms: an initial experience. Urology 24; 63: Griffiths D. Detrusor contractility. Scand J Urol Nephrol Suppl 24; 215: Jackson S, Donovan J, Brookes S, Eckford S, Swithinbank L, Abrams P. The Bristol Female Lower Urinary Tract Symptoms questionnaire: development and psychometric testing. Br J Urol 1996; 77: Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A new questionnaire to assess the quality of life of urinary incontinent women. Br J Obstetrics Gynaecol 1997; 14: Schäfer W, Abrams P, Liao L et al. Good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies. Neurourol Urodynam 22; 21: Schäfer W. Analysis of bladder-outlet function with the linearized passive urethral resistance relation, linpurr, and a disease-specific approach for grading obstruction: from complex to simple. World J Urol 1995; 13: Griffiths DJ, Constantinou CE, van Mastrigt R. Urinary bladder function and its control in healthy females. Am J Physiol 1986; 251: R Richter R, Schaaf V. Botulinum-A-toxin for therapy of detrusor hyperreflexia in neurogenic bladders. Aktuelle Urologie 22; 33: Dykstra D, Enriquez A, Valley M. Treatment of overactive bladder with botulinum toxin type B. A pilot study. Int Urogynecol J 23; 14: Greene P, Fahn S, Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord 1994; 9: Grosse J, Kramer G, Schurch B, Stoher M. Repeat detrusor injections of botulinum A toxin in patients with neurogenic lower urinary tract dysfunction do not cause increased drug tolerance. Neurourol Urodynam 22; 21: Correspondence: Govindaraj N. Rajkumar, Department of Urology, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TF, UK. radhraj@btopenworld.com Abbreviations: DOA, detrusor overactivity; BTXA, botulinum toxin A; FDV, first desire to void; VFOAC, volume at first overactive contraction; VFOAI, volume at first incontinence; MCC, maximum cystometric capacity; PIP 1, modified projected isovolumetric pressure; BFLUTS, Bristol Female LUTS Questionnaire; KHQ, King s Health Questionnaire; Q max, maximum urinary flow rate; P det Q max, detrusor pressure at maximum flow BJU INTERNATIONAL