Urinary incontinence (UI), a prevalent condition affecting

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1 JOURNAL OF GYNECOLOGIC SURGERY Volume 29, Number 5, 2013 ª Mary Ann Liebert, Inc. DOI: /gyn Tension-Free Vaginal Tape Plus Intradetrusor BOTOX â Injection Versus Tension-Free Vaginal Tape Versus Intradetrusor BOTOX Injection in Equal-Weight Mixed Urinary Incontinence: A Prospective Randomized Study Maliheh Keshvari Shirvan, MD, 1 Seyed Ali Seyedi Noughabi, MD, 1 and Hamid Reza Rahimi, MD, PhD(cand) 1 Abstract Objective: The aim of this study was to determine the safety of the placement of tension-free vaginal tape (TVT) plus intradetrusor BOTOX Ò (onabotulinumtoxina; Allergan, Inc., headquartered in Irvine, CA) injection, and the outcome after 12 months. Design: An open, prospective study was conducted on 93 patients presenting with stress and urgency urinary incontinence of the same severity from the patients point of view. Materials and Methods: Subjects were divided into three groups: TVT + intradetrusor BOTOX injection (group 1); TVT only (group 2); or BOTOX injection only (group 3). At baseline, and at 1, 6, and 12 months, each patient was assessed by taking a medical history and performing a physical examination, including a cough test, a Q-Tip test, a 1-hour pad test, upper urinary tract sonography, postvoid residue, urinary analysis and culture, serum chemistry; and scores on the International Constellation on Incontinence Questionnaire (ICIQ) Urinary Incontinence (UI), the ICIQ Overactive Bladder (OAB), and the ICIQ Quality of Life (QOL) instruments. Urodynamic studies, including filling cystometry, uroflowmetry, and abdominal leak-point pressure at baseline were performed. At a 1-month follow-up, cystometry and uroflowmetry were performed. Data were then analyzed using SPSS, Pearson s v 2, and Mann Whitney U test. Results: The overall ICIQ-UI scores in group 1 declined from 15.4 to 2.5, 0, and 0, in 1, 6, and 12 months, respectively. In addition, ICIQ-OAB scores improved from an original mean baseline of 10.1 to 2.6, 0, and 1.1, in 1, 6, and 12 months, respectively. There was a significant improvement in urinary continence and, therefore, QOL for group 1 patients ( p < 0.05). ICIQ-UI and ICIQ-OAB scores showed remarkable improvement in patients who underwent the sling procedure (group 2) and the BOTOX injection (group 3), respectively ( p < 0.05). Nevertheless, the reverse did not occur. (There was insignificant change in ICIQ-OAB in group 2 and in ICIQ-UI in group 3). Retention occurred in 2, 0, and 2 patients in groups 1, 2, and 3, respectively, with no significant difference. Upper urinary-tract ultrasonography, urinary analysis and culture, and serum chemistry were normal in all patients. Conclusions: TVT plus intradetrusor BOTOX injection is a feasible and safe procedure. The results showed that there were subjects cured or with marked improvement at a 12-month followup. ( J GYNECOL SURG 29:235) Introduction Urinary incontinence (UI), a prevalent condition affecting almost 40% of women, is categorized into the three most common types: stress urinary incontinence (SUI), urge urinary incontinence (UUI), and mixed urinary incontinence (MUI). 1 3 The latter involves involuntary leakage in relation to urgency, exertion, sneezing, or coughing, 4 with a prevalence rate of 11% 61% (mean = 29%). 5,6 Management for these types of UI differ; MUI has both stress and urgency components, requiring that particular attention be given to the dominant component on presentation, 7 whereas SUI and UUI treatment primary includes behavioral modification as well as pelvic-floor training (PFMT). 8,9 1 Department of Urology, Imam Reza Academic Hospital, and 2 Student Research Committee, Modern Sciences & Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 235

2 236 SHIRVAN ET AL. Medical therapy has been shown to be of limited value in SUI. Some other treatments have been suggested, such as cell therapy, and injection of peripheral blood total nucleated cells (TNCs) and platelets is a safe and effective treatment for SUI. 10 Therefore, tension-free vaginal tape (TVT) would be the first choice for treating SUI Patients with UUI, however, do need anticholinergic drugs to regain bladder function control 7 ; nevertheless, adverse side-effects namely dry mouth, constipation, and nausea may restrict the drugs therapeutic value, ultimately leading to discontinuation. 14 The efficacy and safety of the TVT procedure in preventing postoperative SUI were studied by Groutz et al. in 2004, and the procedure showed good results. 15 Cheng and Liu found that a TVT-obturator, a novel midurethral sling, was a safe and effective procedure for treating female SUI after 5 years of follow-up in a series of patients. 16 In 2001, a case was reported of a patient with genuine SUI, who was treated successfully by TVT and had a term pregnancy and a successful vaginal delivery 17 ; TVT is considered worldwide to be an acceptable, simple, effective, and minimally invasive surgical procedure. BTXA Ô (botulinum toxin type A; Hugh Source International Ltd., Tsim Sha Tsui East, Kowloon, Hong Kong) has become popular for managing detrusor overactivity in individuals with spinal-cord injury. 6,18 Because of this product s lowering effect on detrusor-generated pressure, the product can also be used to treat idiopathic detrusor overactivity, thus reducing the need for anticholinergic medication, as well as improving continence. 19,20 Another assumption is that this product helps decrease the urgency via reducing the number of sensory receptors across the bladder epithelium. 21,22 Repeat injections with BTXA are effective, and have been shown to reduce overactive bladder symptoms in a study by Grosse et al. 23 Usually, treatment for MUI depends upon determining the dominant component, 7 but the current study was intended to investigate the efficacy of a new modality of treatment a combination of BotoxÒ (onabotulinumtoxina; Allergan, Inc., headquartered in Irvine, CA), a similar product to BTXA, and suburethral sling procedure, in MUI patients, with both urge and stress components of equal weight. Materials and Methods Patients were selected who had the diagnosis of MUI, with the two components of the condition perceived as being of equal severity from the patients point of view. These patients were recruited from female patients who were referred to the Imam-Reza and Om-Al-Banin clinics between 2009 and 2011, in blocks of 6 patients each. In addition to PFMT for SUI, these patients had been given oxybutynin (20 30 mg daily) and tolterodine (4 mg daily) for UUI before the study. Inclusion criteria were patients who had both SUI and UUI of the same severity that were resistant to conservative treatments, or who had SUI and UUI of the same severity and had side-effects from medications used as treatment. Exclusion criteria were patients with known vesicoureteral reflux, vaginal prolapse beyond the introitus, or other significant pelvic-floor abnormalities with high pressure instability; neuromuscular disorders (e.g., muscular dystrophy, multiple sclerosis); or uncontrolled diabetes; patients who were pregnant or lactating or who planned to become pregnant during course of the study; patients with morbid obesity (defined as a body mass index 40) who were, therefore, not expected to benefit from treatment; and patients with current or acute conditions involving cystitis or urethritis, a history of urogenital cancer, or a physical or mental disability. Ninety-three patients with MUI were selected for this prospective randomized study. The study was conducted in accordance with the 1996 version of principles of Declaration of Helsinki and with Good Clinical Practice standards. The study protocol, informed consent form, and the other study-related documents were reviewed and approved by the human research ethics committee of the Mashhad University of Medical Sciences. All patients were able to read and understand, and were willing to sign the informed consent form for the study. The severity of the kind of incontinence (UUI or SUI) from the patients point of view was equal in all patients. Ninety-three subjects were divided into three groups and randomization was performed on them; group 1 received TVT and BOTOX, Ò whereas the other two groups were given TVT or BOTOX (groups 2 and 3, respectively). For each patient, an upper urinary-tract scan, postvoid residue, and a 1-hour pad test were performed after taking a history and conducting a physical examination including a cough test and a Q-Tip test. Urine analysis, urine culturing, and serum chemistry were also performed. No residual volume was determined in all patients. Subjective symptoms and quality of life were evaluated using a validated disease-specific questionnaire the International Consultation on Incontinence Questionnaire Urinary Incontinence (ICIQ-UI) and quality of life (ICIQ-QOL), which were translated into the patients local language. The ICIQ-UI was calculated at baseline and repeated at 1, 6, and 12 months after treatment. A higher score on the ICIQ-UI and the ICIQ-QOL indicated an unfavorable and a favorable condition, respectively. In addition, a urodynamic study including filling cystometry in a prone position, uroflowmetry (UFL), and abdominal leak-point pressure (ALPP) were conducted. In patients with ALPP < 90 cm H 2 O, a urethral pressure profile (UPP) test was performed. Any urinary iodine concentration (UIC) or increase in intravesical pressure > 20 cm H 2 O was defined as detrusor overactivity. In group 1, the subjects were subsequently injected with BOTOX (DysportÒ [Medicis; Scottsdale, AZ] total dose 250 U), which was diluted in 30 cc of normal saline, under general anesthesia via cystoscope at 30 intradetrusor sites; 1 cc was injected into each site (as first delineated by Schurch et al. 24 ), avoiding the trigone. The TVT (Gynecare TVT, Ethicon Inc., Somerville, NJ) was placed by a well-trained surgeon, with the patient under general or spinal anaesthesia, after which a cystoscopic check was performed to ensure that no bladder trauma had occurred during the procedure, and also to inspect the new position of the proximal urethra. In group 2 the TVT was placed, and in group 3, and BOTOX injections were given to using the same method as was used for group 1. The following day, a urethral catheter that had been placed in each study patient was removed while the patients were still receiving first-generation cephalosporin, which was continued for 1 week postoperatively. Clean intermittent self-catheterization was taught to patients who had urinary retention. The patients in group 1 were not given any antimuscarinic drugs for the following year, during which they were followed (at months 1, 6, and 12); but, in groups 2 and 3, the medications and PFMT were continued, respectively.

3 Table 1. The Data of Group 1 (TVT + BOTOX Ò Injection), Group 2 (TVT), and Group 3 (BOTOX Injection) Variables Mean SD (or number and %) Group 1 (n = 31) Group 2 (n = 31) Group 3 (n = 31) Total (n = 93) p-value Age 58/4 9 61/4 8/5 61/5 9/2 60/4 8/9 0/302 4/6 2/00 3/8 2/2 3/6 2/2 4 2/2 0/164 Number of successful pregnancies Menopause 25 (80/6%) 29 (87/9%) 35 (86/2%) 79 (84/9%) 0/702 MDP 23/5 4/1 23/7 3/5 23/5 3/5 23/6 3/7 0/977 MDC 269/7 52/3 273/7 49/8 279/3 62/2 274/1 54/3 0/794 Pad Test Before operation (mean SD) 37/88 12/57 37/36 13/72 38/97 12/88 37/94 12/96 0/876* Number of pads user (%) 31 (100%) 31 (100%) 31 (100%) 93 (100%) 1st month F/U Number of pads user (%) 0 (0%) 9 (29%) 19 (61%) 28 (30/1%) < { 6th month F/U Number of pads user (%) 0 (0%) 9 (29%) 19 (61%) 28 (30/1%) < {{ 12th month F/U Number of pads user (%) 0 (0%) 9 (29%) 19 (61%) 28 (30/1%) < # ICIQ-UI Before operation 15/4 2 14/9 2/2 14/2 1/7 14/86 2/09 0/079* 1st month F/U 2/8 1/6 7/3 1/ /89 3/96 < 0.05 { 6th month F/U 0 6/6 1/4 10 1/1 5/49 4/2 < 0.05 {{ 12th month F/U 0 6/9 0/8 13/1 1/1 6/56 5/37 < 0.05 # ICIQ-QOL Before operation 34/8 4/6 34/9 4/2 34/9 4/2 68/27 10/00 0/577* 1st month F/U 79/4 10/8 47/9 4/4 40/7 2/7 43/35 12/86 < 0.05 { 6th month F/U 100/3 3/6 53/1 4/3 41/9 2/2 39/80 15/43 < 0.05 {{ 12th month F/U 102 3/2 53/2 4/3 37/3 3/1 43/27 15/68 < 0.05 # ICIQ-OAB Before operation 10/1 2/3 9/7 2/6 9/5 2/4 9/81 2/49 0/656* 1st month F/U 2/6 2 5/7 1/5 3/2 1/7 3/92 2/25 < 0.05 { 6th month F/U 0 7/1 1/5 0/5 0/7 2/7 3/4 < 0.05 {{ 12th month F/U 1/1 0/9 7/9 1/9 2/4 0/7 3/97 3/27 < 0.05 # PVR Less than 20 cc 26 (83/9%) 31 (100%) 24 (82/8%) 81 (87/09%) > 0.05 PVR 3 (9/7%) 0% 3 (10/3%) 6 (6/45%) Retention 2 (6/5%) 0% 2 (6/9%) 4 (4/30%) *Among groups before treatment; { among groups at 1st month of follow-up (F/U); {{ among groups 6th month of F/U; # among groups 12th month of F/U. Shaded areas indicate statistical significance. Botox Ò (onabotulinumtoxina; Allergan, Inc., headquartered in Irvine, CA): Brand used was Dysport Ò (Medicis; Scottsdale, AZ). TVT, tension-free vaginal tape; SD, standard deviation; MDP, mean detrusor pressure; MDC, mean detrusor capacity; ICIQ, International Constellation on Incontinence Questionnaire; UI, Urinary Incontinence; ICIQ-QOL, Quality of Life; ICIQ-OAB, Overactive Bladder; PVR, postvoiding residue. 237

4 238 SHIRVAN ET AL. Follow-up included taking a medical history, and conducting a physical examination, including a cough test, administering the ICIQ questionnaires, checking postvoid residual volume, and performing an upper urinary-tract scan. Cystometry and UFL were performed at the 3-month follow-up. The collated data were then statistically analyzed using Pearson s v 2 Student s t-test (paired) and a Mann Whitney U test to process categorical and continuous variables, respectively. Data analysis and storage were performed with SPSS 11.0, using a p-value of 0.05 to define significance. Results were presented as the mean unless otherwise indicated. The Kolmogorov-Smirnov test was used for quantitative analysis of variables, normal distribution, whereas analysis of variance (ANOVA) and Tukey post-hoc tests were used to measure changes in groups with respect to original baseline levels in months 1, 6, and 12. Comparative analysis was subsequently performed at 1, 6, and 12 months, using a repeatedmeasures ANOVA, whereas j 2 tests were the statistical means in qualitative measurements. Results There was no exclusion among the 93 subjects, whose demographic data and baseline measurements are summarized in Table 1. As shown in Table 1, there was no significant difference in terms of demographic characteristics or ICIQ scores and baseline urodynamic variables among the groups. ALPP in 2 patients in group 1 was < 60 cm H 2 O, and UPP in both of groups showed intrinsic sphincter deficiency (ISD); the algorithm of the treatment was the same. Figures 1 3 depict the ANOVA repeated measures for ICIQ scores obtained at follow-up visits. The overall ICIQ-UI (Fig.1) scores in group 1 declined from a baseline median of 15.4 to 2.5, 0, and 0, at 1, 6, and 12 month follow-ups, respectively. (No subject needed to wear a pad following treatment). In addition, the relevant detrusor overactivity component score (ICIQ-Overactive Bladder [OAB]) improved, from an original mean baseline of 10.1 to 2.6, 0, and 1.1 at 1, 6, and 12 months, FIG. 2. International Consultation on Incontinence Questionnaire Quality of Life (ICIQ-QOL) changes during study in each group. respectively (Fig. 3). As can be seen in Figure 2, there was a significant improvement in urinary continence and, therefore, QOL, for patients treated in group 1 ( p < 0.05). ICIQ-UI and ICIQ-OAB scores showed remarkable improvement in patients who underwent the sling procedure (group 2) or who had BOTOX injections (group 3), respectively ( p < 0.05). Nevertheless, the reverse did not occur (there was insignificant change in ICIQ-OAB in group 2 and in ICIQ-UI in group 3; Figs. 1 and 2). In the first month follow-up, retention occurred in 2, 0, and 2 patients in groups 1, 2, and 3, respectively, and there was no significant difference among the three groups according to v 2 ( p = 0102; j 2 = 6/589; seetable1). In addition, at the 6 and 12 month follow-ups, postvoiding residue (PVR) was < 20 cc in all patients. Upper urinary tract scan and UFL showed normal results in all patients. Abnormal cystometry (including any UIC or increase in intravesical pressure) was FIG. 1. International Consultation on Incontinence Questionnaire Urinary Incontinence (ICIQ-IU) changes during study in each group. FIG. 3. International Consultation on Incontinence Questionnaire Overactive Bladder (ICIQ-OAB) changes during study in each group.

5 TVT AND BTX-A IN SUI AND MUI 239 seen at at the 1-month follow-up in 6, 27, and 7 patients in groups 1, 2 and 3, respectively. No adverse operative and/or postoperative complications were reported. Thus, most of the subjects stopped taking anticholinergic medications throughout the entire follow-up time, except for patients in group 2; in that group, 27 patients needed anticholinergic medications after the procedure for some periods of time. Discussion MUI still remains an insurmountable clinical challenge under particular circumstances, requiring concurrent multimodal treatment. By and large, there is an inclination among clinicians to treat the SUI component, which is the most disturbing symptom, although it has the best response to treatment (surgery), whereas patients with predominant UUI receive medical treatment as well as PFMT. Nevertheless, there is still a lack of clarity regarding choice of treatment in patients with an equal proportion of, or at least nearly equally disturbing signs of, both stress and urge components of MUI. Conventionally, and despite the lack of clear guidance in this respect, the medical treatment for patients with MUI is still anticholinergics. 25 A recent Cochrane review of 13 trials of PFMT exercise found it of equal efficacy in both SUI and MUI patients. However, the multicenter Behavior Enhances Drug Reduction of Incontinence (BE-DRI) trial conducted by the Urinary Incontinence Treatment Network (UITN) confirmed the superiority of behavioral therapy, PFMT, and medication combined over unimodal medication therapy for reducing symptoms in patients with UUI. 26,27 Williams et al. failed to establish any link between floor therapies and UI reduction in patients with MUI, despite positive signs regarding pelvic-floor function. 28 BOTOX, first produced by Van Ermengem in 1897, 29 has been shown to inhibit the release of certain neurotransmitters, namely acetylcholine, adenosine triphosphate, and neuropeptides such as substance P, and also to downregulate the expression of purinergic and capsicin receptors on afferent neurons in the bladder. 30 This lends support to the assumption that BOTOX can ameliorate detrusor overactivity via both sensory and motor pathways, with the aim of reducing urinary symptoms as well as QOL. There are still doubts about whether or not BOTOX can have long-term adverse effects on detrusor activity; however, Haferkamp et al. observed no histopathologic changes 22 months following injection. 31 Another known restriction concerns the immune-mediated tolerance toward BTXA (as noted above, a similar product to BOTOX) following repeated application, which can be overcome by shifting to another product, BTXB, in case tolerance occurs. 32 The growing popularity of this mode of treatment, because of significant responses recorded, is still on the rise. Some studies have underlined the efficacy (up to 85%) of surgical treatment using a midurethral sling in patients with MUI. Interestingly, the subjective cure rates for patients with MUI tend to be lower than for patients with pure SUI, although this is not statistically significant. 33 In a study by Groutz et al. of 3 patients, short-term postoperative urinary retention and/or voiding difficulties occurred, and 1 patient underwent repeat surgery to adjust the sling. 34 In the current study, retention was seen in 4 patients (4.30% of total patients). The rate of onset of de novo irritative voiding after surgery ranges between 12% and 25.9%, for which a plausible explanation would be the use of PROLENE Ô tape use and local biologic alterations This problem is also often diagnosed late no sooner than 1 month postoperatively 35 and de novo urgency, seen in up to 26% of patients, is not as important when a combined regimen is used. Groutz et al. stated that the TVT operation is an invasive surgical procedure with excellent short- and medium-term objectivecurerates. 34 Failure of TVT occurs in > 10% of the operations; thus urogynecologists are faced with an unaddressed issue when performing or recommending such operations. 38 In the current study, ICIQ scores improved significantly at week 4 and afterward ( p > 0.001), indicating better continence. The drawback, however, was that it was impossible to blind the surgeons to the procedure. Conclusions Based on the short-term results in the current study, it is a safe assumption to claim that women with MUI have alternative treatment options. Given the high success rate of the combined procedure, as well as unreported morbidity and mortality, this procedure warrants further assessment, using larger samples studied for longer periods. Acknowledgments This research project was supported by the Mashhad University of Medical Science Research Council (project number: MUMS/89703). Disclosure Statement No competing financial interests exist. References 1. Chou EC, Blaivas JG, Chou LW, Flisser AJ, Panagopoulos G. Urodynamic characteristics of mixed urinary incontinence and idiopathic urge urinary incontinence. Neurourol Urodyn 2008;27: Hannestad YS, Rortveit G, Sandvik H, Hunskaar S. A community-based epidemiological survey of female urinary incontinence: The Norwegian EPINCONT study. Epidemiology of Incontinence in the County of Nord-Trondelag. J Clin Epidemiol 2000;53: Labrie J, van der Graaf Y, Buskens E, Tiersma SE, van der Vaart HC. Protocol for Physiotherapy Or TVT Randomised Efficacy Trial (PORTRET): A multicentre randomised controlled trial to assess the cost-effectiveness of the tension free vaginal tape versus pelvic floor muscle training in women with symptomatic moderate to severe stress urinary incontinence. 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Neurourol Urodyn 2004;23:282. Address correspondence to: Maliheh Keshvari Shirvan, MD Department of Urology Imam Reza Academic Hospital Faculty of Medicine Mashhad University of Medical Sciences Imam Reza Hospital Emam Reza Square Ebne Sina Avenue P.O. Box Mashhad Iran KeshvariM@mums.ac.ir