A) FOR THE TREATMENT OF BLADDER SYMPTOMS OF MULTIPLE SCLEROSIS (MS)

889

Intravesical administration of Botulinum A toxin in spinal cord injured patients: suburothelial versus intradetrusorial injections Santaniello F., Proietti S., Zucchi A., Costantini E., Vianello A., Porena M., Giannantoni A.

890

Botulinum toxin-A (BTA) in the treatment of neurogenic detrusor overactivity incontinence (NDOI) - A prospective randomized study to compare 30 vs. 10 injection sites

Karsenty G.1, Carsenac A.1, Boy S.2, Reitz A.2, Bardot P.1, Tournebise H.1, Bladou F.1, Serment G.1, Schurch B.2

University of Perugia, Department of Urology and Andrology, Perugia, Italy Introduction & Objectives: Botulinum A toxin (BoNT/A) injections into the detrusor muscle have been reported to provide satisfactory results in 60 to 100% of patients with neurogenic and non neurogenic detrusor overactivity. Recent experimental and clinical observations showed that BoNT/A can act at the level of the C fibers in the suburothelial space, thus modulating directly the afferent arc of the micturition reflex. We evaluated the efficacy and safety of BoNT/A suburothelial injections and intradetrusorial administration, comparing clinical and urodynamic effects over short-term follow up, in a group of spinal cord injured patients (SCI) with refractory NDO. Material & Methods: After a baseline evaluation including history, voiding diary and urodynamics, 25 patients were selected and randomized into two groups. Patients in group 1 (13) received suburothelial injections of BoNT/A 300 U diluted in 30 ml of normal saline, and patients in group 2 (12) received BoNT/A intradetrusorial injections, at the same dosage and dilution. BoNT/A was administered in 30 sites in the trigone, posterior and lateral walls of the bladder, and the procedure was performed in all cases under general anaesthesia. Clinical and urodynamic evaluations were repeated at 1 and 3 mos follow up. Results: Group 1. At 1 and 3 mos follow up, mean catheterizations and incontinence episodes were significantly reduced compared to baseline (p<0.05 and p<0.01, respectively). On urodynamics, we detected a significant increase in the first volume of uninhibited detrusor contractions (from 242.4 ± 98.7 to 354.6 ± 59.7 ml, p<0.001) and in maximum cystometric capacity (from 279. 8 ± 69 to 358.4 ± 45.1 ml, p<0.01). We observed a significant reduction in maximum pressure of uninhibited detrusor contractions. Group 2. A significant amelioration was observed in mean catheterizations and incontinent episodes, at the same time-points. The first volume of uninhibited detrusor contractions and maximum cystometric capacity significantly increased (from 214.6 ± 55 to 323.8 ± 49 ml, p<0.001, and from 290.4 ± 72 to 370.8 ± 50 ml, p<0.01, respectively). A significant reduction in maximum pressure of uninhibited detrusor contractions was detected. Suburothelial versus intradetrusorial injections: we could not detect any significant difference neither in clinical nor in urodynamics results between the two groups, at 1 and 3 mos follow up. No side effects were observed during or after both treatment modalities. Conclusions: In SCI patients affected by NDO, BoNT/A suburothelial injections are as effective and safe as intradetrusorial injections, in a short term follow up. This confirms the hypothesis that BoNT/A modulates the micturition reflex by acting at the level of the afferent C fibers into the bladder wall. Administering BoNT/A by suburothelial injections it is possible to avoid neuromuscolar junction blocking, and this may be crucial in patients with NNDO who want to void their bladder spontaneously.





891

Salvator Hospital, AP-HM, Medicine Faculty, University of Mediterranée, Urology, Marseille, France, 2Balgrist University Hospital - Paraplegic Research Center -Zurich University, Neuro-Urology, Zurich, Switzerland 1

Introduction & Objectives: Injection of 300 units of BTA into the bladder wall has been demonstrated to be a safe and effective treatment of NDOI. The initial injection technique consists of 3O injection spots disseminated over the detrusor muscle sparing the trigone. Spreading of biologic activity of BTA from a point injection has been shown to be dose dependent in the animal striated muscle but has never been studied in the smooth muscle. In this study the diffusion of the biologic effect of BTA into human bladder wall was estimated by decreasing the number of injection sites from 30 to 10. Material & Methods: A prospective, randomized, single blinded study was conducted in adult patients with chronic spinal cord lesion, suffering from refractory NDOI. Efficacy of two protocols injections of 300 units of BTA (Botox®) was compared. P1: 300 units over 30 points (10 units in1ml of saline/point) P2 same total dose over 10 points (30 units in 1ml of saline/point). Trigone was spared. Patients were evaluated before injection and 6, 12, 24, 36 weeks after. Hypothesis was equivalence between 30 and 10 injections in terms of improvement of cystomanometric bladder capacity (CBC). Decrease of incontinence episodes (NID), improvement of quality of life (Qualiveen™), and pain at the procedure were also evaluated. Equivalence in CBC, and QOL between P1 and P2 was tested using exact test of equivalence and Westlake’s interval. Needed sample size was 15 patient/group. Ethical committee approved the study. Results: Spinal cord lesion was traumatic (18), degenerative (8), infectious (3) or malformative (1) in 16 women and 14 men. Table summarizes changes after BTA injection. QOL was significantly improved in both groups until 24 weeks. There was no difference in sex ratio, age or baseline CBC between groups. Equivalence between P1 and P2 was demonstrated for both CBC and QOL during all the followup. There was no difference between P1 and P2 in term of NID at 12, 24 and 36 weeks (Mann-Withney). EVA among patients with preserved sensibility was significantly less with P2 (7.2+/-2.2 vs 3.4+/-4.4). No severe side effect was reported. CBC ml (sd) 30 inj. CBC ml (sd) 10 inj. NDI (sd) NDI (sd)

Baseline

6w

12w

24w

36w

259 (30)

441 (27)*

448 (27)*

438 (46)*

386 (63)

250 (30)

537 (30)*

431 (41)*

382 (38)*

341 (44)

4.7 (0.9) 3.5 (0.5)

1.0 (0.3)* 0.7 (0.3)*

1.1 (0.4)* 1.0 (0.4)*

2.6 (1.1)* 1.7 (0.5)*

2.9 (1.0) 2.3 (0.5)

Conclusions: Efficacy of bladder injections of 300 units of BTA to treat NDOI was not affected by a threefold increase in dose per injection point and subsequent threefold decrease in total number of injections. This observation provides an indirect evidence of a dose dependant diffusion of BTA biologic activity within bladder wall. Practically it allows us to shorten and simplify the procedure decreasing the pain as well as the risk of technical error or bleeding.



892

Detrusor injections of botulinum neurotoxin type A (BoNT/A) for the treatment of bladder symptoms of Multiple Sclerosis (MS)

The immediate effect intradetrusor injections of Botulinum neurotoxin A (BoNT/A) on the symptoms of the overactive bladder syndrome

Kalsi V.1, Gonzales G.1, Apostolidis A.1, Popat R.1, Elneil S.1, Dasgupta P.2, Fowler C.J.1

Kalsi V.1, Apostolidis A.1, Gonzales G.1, Elneil S.1, Dasgupta P.2, Fowler C.J.1

National Hospital for Neurology and Neurosurgery, Uro-Neurology, London, United Kingdom, Guy’s and St.Thomas’s Hospitals, Urology, London, United Kingdom 1

2

Introduction & Objectives: Bladder dysfunction as part of a symptom complex of spinal cord involvement is a common and disabling aspect of MS, the clinical picture being dominated by the symptoms of detrusor overactivity (DO), namely urinary urgency, frequency and urgency incontinence, leading to a diminished quality of life (QoL). The beneficial effects of detrusor BoNT/A have been well established in patients with DO due to spinal cord injury, however there is a paucity of experience with MS patients. We report for the first time the effect of only detrusor injections of BoNT/A on the symptoms, urodynamic changes and quality of life in a selected group of patients with an established diagnosis of MS. Material & Methods: Data were collected for 43 adults (4 men, 39 women, mean age 45.8 years, range 33 – 61) with urodynamically proven DO refractory to oral anticholinergics pre, 4 and 16 weeks post BoNT/A treatment. Pre-treatment 2 patients (4.7%) had an indwelling catheter and 28 (65.1%) were performing clean intermittent self catheterisation. The patients were treated with 300 units of BOTOX® using a minimally invasive local anaesthetic outpatient injection technique. Changes in the number of micturition episodes (“frequency”) and those associated with urgency (“urgency”), incontinence, and nocturia episodes over 24 hours were analysed from a 4-day voiding diary; urodynamic parameters were evaluated by standard voiding cystometry and QoL was assessed using the validated disease specific UDI-6 and IIQ-7 questionnaires, at all study time points. A positive clinical response was defined as more than a 25% improvement in at least 2 of the voiding diary and urodynamic parameters measured. The paired t test was used to compare data pre and post treatment. Results: All patients had a positive clinical response as per criteria stated above. The mean (± standard error) together with the pre-treatment comparison values are shown in the table below. Highly significant benefits (p<0.001) were recorded in all measured parameters and sustained at all follow-up time points. Parameter MCC (mls) Pdetmax (cmH2O) Frequency Nocturia Incontinence Urgency QoL score

Pre 235.6±22.1 51.3±4.1 12.5±0.7 1.4±0.2 3.9±0.5 7.7±0.7 21.9±1.9

4 weeks post 602.9±33.5 26.6±3.1 6.6±0.4 0.6±0.1 0.36±0.1 1.7±0.4 9.0±1.6

p Value (pre v 4 weeks) <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0002

All patients needed to do CISC post-treatment even the 13 (30.2%) who were not doing so pre-treatment. The mean duration of beneficial effects was 9.6 months (range 3–16). Conclusions: Intradetrusor BoNT/A is exceptionally efficacious in tackling bladder symptoms of MS patients who have reached a point where 1st line treatments are no longer effective thereby improving their QoL. A particularly important observation is the necessity for all MS patients to perform CISC post-treatment, and this has been shown not to adversely affect their QoL.

1 2

The National Hospital for Neurology and Neurosurgery, Uro-Neurology, London, United Kingdom, Guys and St. Thomas’ Hospitals, Urology, London, United Kingdom

Introduction & Objectives: Urgency and nocturia, whose pathophysiology is not fully understood, are now increasingly recognised as the most bothersome symptoms of the OABS. Intradetrusor BoNT/A injections is an effective treatment for intractable neurogenic or idiopathic detrusor overactivity (NDO/IDO). Previous studies have shown that at 1 month BoNT/A successfully suppresses urgency, urgency incontinence and frequency, but its immediate effect has not been studied. In addition, only one study to date has investigated the effect of BoNT/A on nocturia showing significant improvements at 1, 3, and 6 months. We examined the immediate effect of intradetrusor BoNT/A on the OABS symptoms by studying the daily changes during the week succeeding treatment of patients with NDO or IDO. Material & Methods: Twenty-five patients, 16 NDO (mean age 44.1 years) and 9 IDO (mean age 45.6 years, p=0.75), treated with 300U BOTOX® (NDO) or 200U BOTOX® (IDO) completed a 4-day voiding diary before and at 4 weeks post treatment and a 7-day diary starting the day immediately after injections. Patients were participants in a study approved by the local Ethics Committee. Data were analysed for intra-group daily changes during the 1st week and for further changes at 4 weeks. Parametric t-tests were used for statistical analysis (significance at p<0.05). Results: No differences were noted at baseline between the 2 groups in any of the studied variables: Urgency: NDO 8.1±0.8, IDO 9.3±1.7, p=0.46 – Incontinence: NDO 3.3±0.9, IDO 6.3±1.9, p=0.12 – 24-hour frequency: NDO 11.4±0.7, IDO 12.9±1.3, p=0.26 – nocturia: NDO 1.5±0.3, IDO 2.0±0.4, p=0.26). NDO: Significant improvements in urgency, 24-hour frequency and nocturia were seen as of Day 2 post-injection, in incontinence as of Day 3 post-injection, and were sustained at 4 weeks. IDO: The first significant change in urgency, frequency and incontinence was seen at Day 4 post-treatment. The decrease in urgency was sustained at all time points thereafter, whereas consistent statistical significance was not shown for incontinence and frequency despite persistent decreases in absolute values. No significant changes in nocturia were seen during the 1st week, despite a decrease in mean values as of day 5. All parameters significantly improved at 4 weeks. Conclusions: Intradetrusor BoNT/A ameliorates all OABS symptoms within the first week after treatment, but the pathological sensation of urgency is most rapidly and consistently affected in both NDO and IDO patients, suggesting an early, sustainable effect on bladder afferent pathways. Synchronous daily changes in frequency and nocturia suggest an element of nocturia is DO driven. An earlier trend for change is established in the NDO patients for all symptoms examined and it is not known if this is due to the toxin dose used or underlying pathophysiology.

Eur Urol Suppl 2007;6(2):245