2011 ANNUAL MEETING HIGHLIGHTS Female Urology & Voiding Dysfunction Course #21IC
Female Urology: Controversies and Consensus: A Case-Based Approach
Incontinence in Women: An Objective Look at the Options
Complications of Incontinence and Prolapse Surgery: Evaluation, Intervention and Resolution – A Review from Both Specialties
Panel Discussion: Office Based Management of SUI in 2011 What is on the Horizon in Drug Therapy for OAB? How Do I Manage a Failed Mid Urethral Sling? Take Home Message: Female Urology/Incontinence
Robert C. Flanigan, M.D.
AUA 2011 ANNUAL MEETING HIGHLIGHTS
Female Urology & Voiding Dysfunction
American Urological Association 1000 Corporate Boulevard Linthicum, MD 21090 Copyright © 2011 by American Urological Association None of the contents may be reproduced in any form without prior written permission of the publisher. The opinions expressed in this publication are those of the speakers and do not necessarily reflect the opinions or recommendations of their affiliated institutions, the publisher, the American Urological Association or any other persons. Some articles in this publication may discuss unapproved or “off-label” uses of products. Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients’ conditions and of possible contraindications or dangers in use, review of any applicable manufacturers’ product information and comparison with the recommendations of the authorities.
This publication is supported by educational grants from American Medical Systems, Astellas Pharma Global Development, Boston Scientific and Ethicon, Inc.
AUA 2011 WASHINGTON, DC ANNUAL MEETING HIGHLIGHTS
Highlights on Female Urology & Voiding Dysfunction (from courses #21IC, #27IC and #42PG, 2011 AUA Annual Meeting)
Method of Participation To receive CME credit/hours of participation, participants must read the overview of the course, complete the online posttest, passing with a score of at least 80%, and submit the evaluation and the credit request form by visiting http:// www.AUANet.org/cme/FEUR11.
Media Used This CME enduring material activity consists of a printed overview of the content presented at a live course at the 2011 AUA Annual Meeting, and an online posttest and evaluation.
Hardware/Software Requirements A PC-compatible computer running Windows XP or later, a Macintosh computer running OS X 10.1 or later, or a Linux computer running Mozilla Firefox 3.0 or later. Processor speed of 800 MHz (1GHz preferred). A minimum of 128 MB of RAM (more preferred). A modem speed of at least 56k (broadband preferred). Internet browser should be one of the following: Internet Explorer 8.0 or later, Firefox 3.0 or later, Chrome 4.0 or later, or Safari 4.0 or later. Software requirement: Adobe Acrobat Reader 9 or newer. Estimated time to complete this CME enduring material activity: 1.5 hours Release Date: October 2011 Expiration Date: October 31, 2012
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content of an educational activity (ie activity planners and presenters) provided by the AUAER are required to disclose to the provider any relevant financial relationships they have with any commercial interest. The AUAER must determine if an individual’s commercial relationships may influence the educational content with regard to exposition or conclusion, and resolve any conflicts of interest prior to the commencement of the educational activity. The intent of this disclosure is not to prevent individuals with relevant financial relationships from serving as planners or presenters, but rather to provide the audience with information on which they can make informed judgments about the material presented.
Disclaimer The opinions and recommendations expressed by faculty, authors and other experts whose input is included in this program are their own and do not necessarily represent the viewpoint of the AUAER.
Course #21IC: Female Urology: Controversies and Consensus: A CaseBased Approach Faculty David R. Staskin, M.D. Course Director Associate Professor of Urology Director, Female Urology and Male Voiding Dysfunction St. Elizabeth’s Medical Center Tufts University School of Medicine Boston, MA Disclosures: Allergan, American Medical Systems, Astellas, Glaxo, Pfizer, Uroplasty: Consultant/Advisor David A. Ginsberg, M.D. Associate Professor of Clinical Urology University of Southern California Los Angeles, CA
Disclosures: Allergan: Meeting Participant/Lecturer; American Medical Systems: Meeting Participant/Lecturer, Consultant/Advisor; Boston Scientific: Consultant/Advisor; Medtronic, Tengion: Scientific Study/Trial Eric S. Rovner, M.D. Professor of Urology Attending Surgeon Medical University of South Carolina Charleston, SC Disclosures: Allergan: Consultant/Advisor, Meeting Participant/Lecturer, Scientific Study/Trial; Astellas: Meeting Participant/Lecturer, Consultant/Advisor; Contura, Johnson and Johnson, NIH/NIDDK: Scientific Study/Trial; Medtronics: Consultant/Advisor; NextMed: Investment Interest; Oceana Therapeutics: Consultant/Advisor; Pfizer: Consultant/Advisor, Meeting Participant/Lecturer; Solace: Scientific Study/Trial, Consultant/Advisor; Tengion: Consultant/Advisor
Learning Objectives At the conclusion of this CME enduring material activity, the participant should be able to: • demonstrate an appreciation for the complexities of the diagnosis and treatment of female patients with lower urinary tract symptoms and prolapse • apply evidence-based medical information into the algorithm for diagnosing and treating complex cases • identify controversial areas in the diagnosis and treatment of simple and complex cases, and apply a logic-based approach to identifying and categorizing clinical problems
Course #27IC: Incontinence in Women: An Objective Look at the Options
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tion—A Review from Both Specialties
Kristene E. Whitmore, M.D. Course Director Professor and Chair, Urology and Female Pelvic Medicine and Reconstructive Surgery Medical Director, Pelvic & Sexual Health Institute Drexel University College of Medicine Philadelphia, PA Disclosures: Ortho-McNeil: Consultant/ Advisor; Advanced Bionics: Scientific Study/Trial
At the conclusion of this CME enduring material activity, the participant should be able to: • summarize symptoms and presenting scenarios for common and uncommon complications of incontinence and prolapse surgery • distinguish appropriate work-up and evaluation of complications for incontinence and prolapse surgery • delineate and describe the appropriate choices for intervention for complications of lower urinary tract surgery • summarize the evidence supporting various evaluations and interventions for complications in this group of surgical procedures • apply appropriate patient counseling methods and facts for purposes of adequate patient education
Raymond A. Bologna, M.D. Associate Professor of Urology Chair, Department of Urology, Akron General Medical Center Northeast Ohio Universities Colleges of Medicine and Pharmacy Akron, OH Disclosures: American Medical Systems, Astellas, Medtronic, Pfizer: Meeting Participant/Lecturer; Novartis: Consultant/ Advisor Carole L. Gordon, M.D. Associate Professor Scott & White Waco, TX Disclosures: Nothing to disclose
Learning Objectives At the conclusion of this CME enduring material activity, the participant should be able to: • evaluate stress and urge incontinence as well as concomitant pelvic floor disorders in women • treat stress and urge incontinence with behavioral, pharmacological and surgical therapy • recognize and treat site specific defects of pelvic organ prolapse • appreciate the benefits of multimodal therapy for women with incontinence and other pelvic floor disorders
Course #42PG: Complications of Incontinence and Prolapse Surgery: Evaluation, Intervention and Resolu-
Roger R. Dmochowski, M.D. Course Director Professor, Department of Urologic Surgery Director of Patient Safety Vanderbilt University Medical Center Nashville, TN Disclosures: Allergan: Investigator; Antrares, Astellas, Medtronic, Merck, Pfizer, Serenity: Consultant/Advisor; Contura: Medical Monitor; Cook Medical: Investigator, Scientific Study/Trial Jerry G. Blaivas, M.D. Clinical Professor of Urology Weill-Cornell Medical Center New York, NY Disclosures: Allergan, Bayer, Endogun, Merck, Navasys Medical, Pfizer: Consultant/Advisor; HDH: Owner Mickey Karram, M.D. Volunteer Professor, Obstetrics and Gynecology University of Cincinnati Director, Urogynecology and Reconstructive Pelvic Surgery The Christ Hospital Cincinnati, OH Disclosures: American Medical Systems: Research Support; E-Medsco: Investment Interest; Ethicon Women’s Health & Urology: Research, Speaker’s Bureau, Consultant/Advisor; Astellas, Cooper Surgical: Speaker’s Bureau, Consultant/ Advisor Howard B. Goldman, M.D. Associate Professor and Fellowship Director Glickman Urologic and Kidney Institute Cleveland Clinic Cleveland, OH Disclosures: Allergan: Scientific Study/ Trial; American Medical Systems: Consultant/Advisor; Johnson and Johnson: Meeting Participant/Lecturer
Statement of Need Incontinence and pelvic organ prolapse in women are prevalent, have a great impact on their quality of life, and are managed with behavioral, pharmacological and/or surgical therapy. The evaluation includes identification of concomitant pelvic floor disorders. Evidencebased treatment mandates best clinical practice. A multimodal management model for stress and urge incontinence as well as pelvic floor disorders restores pelvic floor function. Successful surgical therapy for stress incontinence requires reconstruction of all site specific pelvic floor defects.
Target Audience Urologists, urologists in training and nonphysician providers involved in urology.
Accreditation The American Urological Association Education & Research Inc. is accredited by the Accreditation Council for Continuing Medical Education to pro▼ Continued on page 3
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vide continuing medical education for physicians.
las, Pharma Global Development, Boston Scientific and Ethicon, Inc.
Statement of Evidence-Based Content
The AUAER designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. The AUAER takes responsibility for the content, quality and scientific integrity of this CME activity.
Commercial Support This CME enduring material activity is supported through educational grants from American Medical Systems, Astel-
As a provider of continuing medical education accredited by the ACCME, it is the policy of the AUAER to review and certify that the content contained in this CME enduring material activity is valid, fair, balanced, scientifically rigorous and free of commercial bias.
content. The audience is advised that this CME enduring material activity may contain reference(s) to off-label or unapproved uses of drugs or devices. Please consult the prescribing information for full disclosure of approved uses. Copyright © 2011 by the American Urological Association
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AUA 2011 WASHINGTON, DC ANNUAL MEETING HIGHLIGHTS
Female Urology: Controversies and Consensus: A Case Based Approach David Staskin, M.D., Course Director; Eric S. Rovner, M.D. and David Ginsberg, M.D., Faculty
This course consisted of multiple case presentations. Audience response system feedback was solicited for evaluation and treatment, followed by a review of the available evidence-based medicine supplemented by panel opinion and audience participation. The 3 major topics were choice of stress incontinence surgery (SUI), surgical and nonsurgical management of mixed stress/urgency incontinence, and postoperative management of the obstructed patient.
Does One Surgery Fit All with SUI? The number of stress urinary incontinence operations performed in the United States has grown considerably during the last 10 to 15 years.1,2 During this time mid urethral polypropylene slings have become the surgical procedure of choice for many surgeons and patients with uncomplicated SUI. This preference is likely due to the low morbidity, technical ease and speed of the procedure, longterm durability, and rapid recovery and convalescence. These slings, of which there are many proprietary types, are similar in the completely tension-free, minimally invasive technique by which they are placed under the mid urethra. Depending on the choice of sling, they may be placed via a transvaginal, suprapubic or transobturator approach with no definite advantage in efficacy with any particular approach. The optimal approach when considering a mid urethral sling (transobturator vs retropubic vs mini-sling) or even the best alternative to a mid urethral sling (autologous fascial sling etc) is not well established. Individual patients with SUI have a variety of clinical variables at presentation including varying degrees of urethral function (Valsalva leak point pressure etc), urethral mobility, body habitus (obesity etc), history of failed SUI
surgery or other medical comorbidities. There are few, if any, prospective randomized controlled trials on any of these individual variables across different surgical procedures. The recently published update of the AUA guidelines on the surgical management of female SUI did not provide any guidance for selecting a surgical procedure for the index patient with SUI as they concluded that any of the 5 types of SUI surgeries examined was an option.Âł Therefore, the level of evidence supporting the universal use of any single SUI surgical procedure for the treatment of all patients with SUI is poor. In a recently completed National Institutes of Health trial comparing transobturator to retropubic mid urethral slings success rates were statistically equivalent and, depending on the definition, success rates were as high as 86% to 90% as defined by patient satisfaction but decreased to 56% to 62% when defined by a composite subjective score (absence of urinary incontinence in a 3-day diary, no re-treatment and absence of selfreported SUI on the MESA questionnaire).4 A post-hoc analysis showed no definite advantage to either approach with respect to urethral function but the study was not powered to show a difference. Overall, mid urethral sling is an effective although imperfect treatment for SUI. The optimal sling for all patients with SUI has not yet been identified.
Patient with Mixed Urinary Incontinence The identification and evaluation of a patient with mixed urinary incontinence (MUI) begin with a history suggesting the presence of SUI and urge urinary incontinence (UUI). When discussing symptoms with the patient it is important to ascertain which type of incontinence is more prevalent and bothersome as that
may help direct therapy. In addition to a history and physical examination, other helpful components of the evaluation include a voiding diary and urodynamic studies. It is important that urodynamics recreate patient symptoms, and this is when a voiding diary can be especially helpful as it should provide a good overview of the normal daily voiding routine. Initial treatment for patients with predominant stress or predominant urge incontinence is focused on the primary symptom. For patients with a true mix of SUI and UUI, a variety of options exist. Pelvic floor training is a possible first line therapy for patients with SUI or UUI and an option for MUI. For patients with an inadequate response to pelvic floor therapy or those interested in a more definitive repair, mid urethral sling is an option. So if the sling is performed for the SUI symptoms, the question is how do we counsel our patients on what to expect in regard to the UUI/overactive bladder (OAB) symptoms? Patients with MUI can expect approximately a 60% improvement in UUI and associated OAB symptoms.5 However, overall cure rates appear to be lower to the patient with UUI than SUI,6 and overall longterm cure rates may not be as durable for MUI compared to pure SUI.7 While urodynamics may help evaluate MUI preoperatively, it is not clear how they are able to predict post-sling clinical outcomes. Choe et al divided 132 patients with MUI undergoing a tensionfree vaginal tape (TVT) procedure into those with and without detrusor overactivity (DO).8 The SUI cure rate was not significantly different between the groups (although the trend was for less success if DO was present). However, there was a significantly greater OAB cure rate in patients with DO. The SISTEr (Stress Incontinence Surgical Treatment Efficacy randomized) trial compared Burch â–ź Continued on page 5
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vs pubovaginal sling in 635 patients, all of whom underwent preoperative urodynamics.9 There was no statistical difference between patients who did or did not have DO on urodynamics but this was a select group of patients with predominant symptoms of SUI. Other possible predictors of persistent UUI/ OAB symptoms after sling include age, nocturia, prior hysterectomy, concomitant prolapse repair and prior anticholinergic use. For patients with significant residual UUI/OAB symptoms in whom anticholinergics fail, options include neuromodulation and intra detrusor injections of botulinum toxin A (BTX-A). These therapies have no efficacy for SUI symptoms.
Patient with Obstruction Obstruction after a sling procedure can be identified by symptoms (history), signs (physical examination), urodynamic studies (post-void residual, flow, pressure flow) or radiographic studies (voiding cystourethrography or transvaginal ultrasound). However, the ability to diagnose obstruction with the classic symptoms of 1) the complete inability to void, 2) impaired emptying described by the patient as a poor flow, feeling of incomplete emptying and improvement with squatting or 3) more mild obstructive symptoms in a patient who voided without difficulty before surgery remains true in 2011 in the setting of the ability to perform complex testing. The literature suggests a 2% to 5% rate of obstruction for MUS (defined as symptoms of decreased emptying) treated with mid urethral sling. Most reports in the literature comprise case series or case reports, none of which is prospective to specifically evaluate obstructive symptoms, and there are no randomized studies prospectively pow-
ered to compare indications, time of intervention or treatment for obstruction. A review of the AUA guidelines3 and a recent meta-analysis were presented to examine the evidence for the incidence of obstruction with different mid urethral slings.9-11 In a case series from 2001, 17 of 600 (2.8%) patients with “obstruction” who responded to sling lysis (midline cutting of the sling) has stood the test of time.12 Of note, sling “loosening” was limited to 2 weeks following surgery after which “cutting” is recommended. A review of the MAUDE (Manufacturer and User Facility Device Experience) database (www.hhs.gov) reinforced the uselessness of a website devised for the reporting of “device malfunction” for analyzing surgical complications or adding to any scientific discussion or presentation. However, the recommendation to discuss/consent for the use of mesh products should become the standard of care. The consensus (panel and audience) for the treatment of obstruction after performance of an artificial graft mid urethral tension-free sling is as follows. Diagnosis: patient who voided before surgery now complains of difficulty emptying and has a clinically significant increase in urethral resistance/obstruction. The degree of bother in lieu of the preoperative symptoms and objective findings, and the postoperative symptoms of impaired flow and increased residual urine are paramount to the decision to intervene. Treatment: 1) wait and see – how long? Don’t wait (more than 1 to 2 weeks). 2) Dilate the urethra – folklore? Yes (you cannot move/loosen a sling by pulling down on the urethra, and don’t do it with the patient awake in the office!). 3) Alpha blockers – do they help mechanical obstruction? No. 4) Clean intermittent catheterization vs Foley catheter – how long? One to 2
weeks (better than a Foley). 5) Loosen the sling – when? Within 2 weeks. 6) Cut the sling vs urethrolysis – how? Excision/ deep dissection/removal is not necessary unless there is infected material (do not dissect deep in midline to avoid urethral damage). 7) Cut the sling and put in a new one – especially if the patient is still leaking at presentation? No, treat the obstruction first. ♦ 1. Waetjen LE, Subak LL, Shen H et al: Stress urinary incontinence surgery in the United States. Obstet Gynecol 2003; 101: 671. 2. Boyles SH, Weber AM and Meyn L: Procedures for urinary incontinence in the United States, 19791997. Am J Obst Gynecol 2003; 189: 70. 3. Dmochowski RR, Blaivas JM, Gormley EA et al: Update of AUA guideline on the surgical management of female stress urinary incontinence. J Urol 2010; 183: 1906. 4. Richter HE, Albo ME, Zyczynki HM et al: Retropubic versus transobturator midurethral slings for stress incontinence. N Engl J Med 2010; 362: 2066. 5. Segal JL, Vassallo B, Kleeman S et al: Prevalence of persistent and de novo overactive bladder symptoms after the tension-free vaginal tape. Obstet Gynecol 2004; 104: 1263. 6. Kulseng-Hanssen S, Husby H and Schiotz HA: The tension free vaginal tape operation for women with mixed incontinence: do preoperative variables predict the outcome? Neurourol Urodyn 2007; 26: 115. 7. Holmgren C, Nilsson S, Lanner L et al: Long-term results with tension-free vaginal tape on mixed and stress urinary incontinence. Obstet Gynecol 2005; 106: 38. 8. Choe JH, Choo MS and Lee KS: The impact of tension-free vaginal tape on overactive bladder symptoms in women with stress urinary incontinence: significance of detrusor overactivity. J Urol 2008; 179: 214. 9. Nager CW, FitzGerald MP, Kraus SR et al: Urodynamic measures do not predict continence outcomes after surgery for stress urinary incontinence in selected women. J Urol 2008; 179: 1470. 10. Novara G, Artibani W, Barber MD et al: Updated systematic review and meta-analysis of the comparative data on colposuspensions, pubovaginal slings, and midurethral tapes in the surgical treatment of female stress urinary incontinence. Eur Urol 2010; 58: 218. 11. Novara G, Galfano A, Boscolo-Berto R et al: Complication rates of tension-free midurethral slings in the treatment of female stress urinary incontinence: a systematic review and meta-analysis of randomized controlled trials comparing tension-free midurethral tapes to other surgical procedures and different devices. Eur Urol 2008; 53: 288. 12. Klutke C, Siegel S, Carlin B et al: Urinary retention after tension-free vaginal tape procedure: incidence and treatment. Urology 2001; 58: 697.
AUA 2011 WASHINGTON, DC ANNUAL MEETING HIGHLIGHTS
Incontinence in Women: An Objective Look at the Options Kristene E. Whitmore, M.D., Course Director; Raymond A. Bologna, M.D. and Carole L. Gordon, M.D., Faculty
Definitions Normal bladder function consists of a filling and storage phase with accommodation (increasing volume at low pressure), a closed bladder neck/outlet, and an emptying/voiding phase involving a coordinated detrusor contraction (magnitude/duration) and absence of anatomic obstruction. Overactive bladder is defined as frequency, urgency and/or urge urinary incontinence. Stress urinary incontinence is defined as involuntary leakage with effort, exertion, coughing or sneezing. Mixed urinary incontinence is defined as UUI and SUI. Voiding dysfunction involves detrusor overactivity, detrusor compliance, sphincter activity and sensation, and is neurogenic or nonneurogenic.1,2
Etiology The etiology of UUI peripherally involves damage to afferent terminals in the bladder or damage to central inhibiting pathways that can unmask primitive voiding reflexes.2 This damage results in leakage of acetylcholine (ACH) from parasympathetic nerve terminals during filling and storage with micromotion of detrusor bundles (neurogenic-myogenic theory).3 Changes in the properties, structure and innervation of the detrusor muscle can result in a change in afferent receptors and nerves in the urothelium and sub urothelium with increased sensory urothelial function and increased release of ACH, adenosine triphosphate, nitrous oxide, urothelial inhibitory factor and other factors that may activate afferent nerves. Changes in the detrusor muscle cells cause increased excitability, and impulse propagation and hypersensitivity to cholinergic stimulation leading to OAB.4 The etiology of SUI is predominately associated with vaginal childbirth
and is likely associated with deficient collagen properties in targeted populations.5
Causes Causes/risk factors related to UUI and SUI include bladder calculi, bladder cancer, increased post-void residual, interstitial cystitis/painful bladder syndrome (IC/PBS), urinary tract infection (UTI), urethral diverticulum, pelvic organ prolapse (POP), obesity, chronic cough, smoking, atrophic vaginitis, pelvic radiation, congestive heart failure, diabetes mellitus, upper motor lesions, impaired renal function, anxiety and habitual fluid intake. Another environmental risk factor is low socioeconomic status, and genetically a racial predisposition to SUI has been associated with varied pelvic anatomy.
Prevalence UUI and SUI are likely underreported secondary to the results of aging and childbirth, poor awareness of treatment options, low expectations of efficacy and treatment, embarrassment and lack of coping mechanisms. The prevalence of OAB among United States women is 16.9%, which increases with age (2% to 19%), and has been reported in up to 36% of survey responders.6 The prevalence of SUI is estimated at 29.5 million American women with SUI and MUI, which is present in 12% to 52% of nulliparous women. The EPINCONT (epidemiology of urinary incontinence) study revealed SUI in 50% of women, UUI in 11% and MUI in 36%. SUI was bothersome in 17% to 24% of incontinent women.7 In EPIQ (epidemiology of prolapse and incontinence) study 4, 103 women 25 to 84 years old were surveyed, and15% had SUI, 13% had OAB, 6% had POP, 25%
had fecal incontinence (FI) and 37% had more than 1 disorder.8 SUI is associated with straining to have a bowel movement and FI, and UUI is associated with FI.9,10
Quality of Life Impact OAB is 1 of the 4 leading health problems affecting the quality of life (QOL) of senior citizens. Urinary incontinence (UI) accounts for greater than 50% of nursing home admissions. Patients with UI complain of a significant decrease in sexual function, increase in sleep disturbances, decrease in participation of normal activities and increase in fear of stigmatization.11 UI is associated with an increased risk of falls (26%), fractures (34%), UTIs (21.7%) and skin infractions (7.57%). The SF-36â„˘ questionnaire indicated a significant decrease in all 4 physical and 4 emotional QOL domains. The Beck Depression Inventory indicated clinical depression in 60% of subjects with UUI, 42% with MUI and 14% with SUI.12
Economics The total estimated direct and indirect costs of UI is $12.6 and $19.5 billion, respectively, for OAB with institutional costs being the majority of the burden and, thus, Medicare mandates an incontinence evaluation for all institutionalized patients with incontinence.13,14 Brown et al estimated a potential swing of $3 million to treat UTIs and $300,000 for skin conditions if OAB was treated before patients entered a nursing home.1
Diagnostics Options An assessment of pelvic floor dysfunction is pivotal. Hypotonic disorders include SUI, POP and sphincteric incompetence. Hypertonic disorders include â–ź Continued on page 7
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OAB, IC/PBS, vulvodynia, chronic pelvic pain, overactive bowel syndrome and sexual dysfunction.15 Lower urinary tract nervous innervation is altered in patients with UUI in that unmyelinated c-fibers become the predominant sensory innervation which causes activation of a sustained guarding reflex.
Assessment History includes a medication list (prescriptions and over-the-counter drugs), duration of symptoms, type of symptoms (SUI vs UUI vs pain) and symptom bother. A validated questionnaire should be administered during initial and followup visits to monitor progress. The Incontinence Quality of Life Questionnaire is validated for males and females with UI. A voiding diary (validated) should also be administered.16 Sexual function can be determined using the FSFI (Female Sexual Function Index), and bowel function can be monitored using a bowel diary and the Cleveland Clinic bowel survey. Physical examination involves assessment of the external and internal pelvis as well as objective evidence of SUI. Digital pelvic floor muscle measurement and electromyography (EMG), manometry or perineometry can be performed to assess pelvic floor muscle function.17-22 The POPQ (pelvic organ prolapse quantification) examination assesses the stage (I to IV) of POP.23 Routine tests include urinalysis/culture. A 24-hour pad test should be considered for patients with SUI.24 Optional tests include urodynamics and cystoscopy. Urine cytology, renal ultrasound and cystoscopy should also be performed in patients with hematuria. Urodynamic testing should be considered before surgery, in patients refractory to therapy, and in those with SUI and detrusor overactivity, bladder outlet obstruction, neurogenic bladder and unclear symptoms.25 Pessary reduction to identify occult SUI has a 98% predictive value.26
Nonsurgical Treatment of SUI Lifestyle interventions for behavioral therapy include weight loss, smoking cessation, fluid management and cough prevention. An intensive weight loss program was associated with a 70% reduction in frequency of incontinence episodes in 226 patients compared to a structured education program.27 Mechanical devices include pessaries, the colpexin sphere and urethral occlusion devices. Pelvic floor muscle therapy (PFMT) is designed to increase strength, coordination, speed and endurance of the pelvic floor muscles in 6 weeks to 6 months based on digital assessment, EMG and/or perineometry to achieve a cure plus improvement rate of 41% to 100%.28 Adjunctive therapy with biofeedback and/or functional electrical stimulation or vaginal cones increased QOL and decreased 24-hour mean pad usage. Behavioral therapy did not significantly prevent surgical procedures.29-31 Transurethral radio frequency remodeling of the proximal urethra (Renessa® system) in 402 patients with SUI resulted in a 25% pad weight reduction and a 25% reduction in incontinence episodes at 18 months of followup.32
Nonsurgical Treatment of UUI Behavioral modification predominantly involves PFMT. The International Consultation on Incontinence Group recommends PFMT as first line therapy (grade A level of evidence) with a significant reduction in incontinence episodes and an increase in voiding intervals. Combining PFMT with pharmacological therapy has shown some benefit.33 Posterior tibial nerve stimulation in 220 adults with UUI resulted in a 54.5% vs 20.9% placebo moderate/marked improvement in symptoms.34
Medical Therapy for OAB Several head-to-head studies showed rapid results among the 8 popularly available agents. Treatment with 10 mg oxy-
butynin XL daily was superior to 4 mg tolterodine ER daily in mean change in incontinent episodes per 24 hours and the number of patients who became continent.35 Solifenacin resulted in fewer urgency episodes and fewer voids per day than 4 mg tolterodine ER daily.36 Antimuscarinic agents are chosen based on dosing options, efficacy, tolerability and safety. Adverse effects of antimuscarinic therapy most commonly include dry mouth, constipation and central nervous system events (somnolence, dizziness, headache and insomnia). Results of the Name-Face Association Test at 3 weeks showed no difference between darifenacin and placebo on delayed recall in 150 patients 60 years old or older. However, there were significantly lower scores in the oxybutynin ER group.37 In a crosssectional study of 3,000 elderly people with dementia half were taking anticholinergics which were associated with significantly worse cognitive function.38 Estrogen therapy for UI is not efficacious for SUI but may be useful for urgency and frequency.39
Surgical Treatment of SUI Periurethral bulking agents can be administered with the patient under local anesthesia and provide immediate relief. They are indicated for those desiring minimal invasiveness, the elderly and those at high anesthetic risk. The 2-year efficacy is 48%, de novo urge incontinence is 13% and complications are minimal.40 Needle suspension procedures for SUI are inferior to retropubic colposuspension and slings.41 The 2009 AUA guidelines for the surgical management of female stress incontinence are based on a meta-analysis of 436 suitable articles.40 The index patient is healthy and elects repair for SUI and/or prolapse. Surgical efficacy is defined as resolution and lack of recurrence of SUI, prolapse, and incidence and severity of adverse events. Objective demonstration of SUI precedes surgical treatment. Retropubic suspensions have ▼ Continued on page 8
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a 2-year efficacy rate of 74% to 76%, de novo urge incontinence rate is 7% and adverse events occurred in up to 13% of patients. Tension-free vaginal tape and tensionfree obturator synthetic mid urethral slings offer minimally invasive, low cost, effective and safe alternative techniques to traditional sling procedures with 88% improvement in subjective symptoms and an equal subjective cure rate.42 Mid urethral slings have a 2-year efficacy rate of 72% to 88% with or without concomitant prolapse surgery, 6% de novo urge incontinence rate and 3% retention rate. Mid urethral slings have a comparable efficacy to that of autologous slings. Intraoperative cystoscopy is recommended. Slings should be tensioned after prolapse surgery is completed.40,43 Repeat slings resulted in a lower success rate than the primary sling procedure, and the retropubic approach had a better outcome. Also there was a higher incidence of de novo urgency and urge icontinence.44 Persistent OAB symptoms after sling surgery have been reported in up to 30% of patients. Mesh erosion has occurred in more than 1,000 patients registered in the MAUDE database. Thus a warning has been issued to inform patients of this possibility.45 Site specific defect repair for concomitant POP needs to be considered to ensure successful pelvic floor reconstruction. The long-term outcome of POP surgery remains to be determined as does identification of the index patient for synthetic graft augmentation.
in 59 spinal cord injury patients.49 At 6-year followup 17 patients with neurogenic OAB had sustained improvement on QOL questionnaires and decreased incontinence episodes without adverse effects with a mean interval between 7.2 injections of 11 months.50 Analysis of 3 randomized controlled trials in a total of 99 patients receiving 300 units of BTX-A for idiopathic OAB revealed a significant decrease in incontinence episodes (3.88 per day) with a 26% retention rate.51,52 Of 21 patients 72 to 92 years old 76% had 75% improvement lasting 7.12 months with no side effects.53 BTX-A injections into high tone pelvic floor muscle trigger points have resulted in decreased pelvic pain and pelvic floor muscle pressure.54 Sacral nerve stimulation (SNS) at S3 with InterStim® has resulted in longterm (greater than 5 years) decreases in leakage episodes, voids per 24 hours and increased QOL.55-59 In 33 females with OAB significant improvement was noted in the FSFI and female sexual distress inventory 23 months after sacral nerve stimulation.60 A total of 34 patients who underwent SNS for UUI and FI with 23 to 29 months of followup had a significant reduction in FI episodes per week and a significant change in QOL surveys.61 Augmentation cystoplasty is effective in most patients with low bladder capacity but results in a 70% self-catheterization rate.60, 61 Multimodal therapy is key for treating UI, incorporating multiple forms of behavioral and pharmacological therapeutic interventions and/or surgery. ♦
Surgical Treatment of UUI
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 Urodyn 2002; 21: 167. 2. Abrams P, Kelleher C, Kerr LA et al: Overactive bladder significantly affects quality of life. Am J Manag Care 2000; 6: S580. 3. Brading AF: A myogenic basis for overactive bladder. Urology 1997; 50: 57. 4. Andersson KE: The importance of the cholinergic system in neurourology. Eur Urol 1998; 34: 6. 5. Bump RC and Norton PA: Epidemiology and natural history of pelvic floor dysfunction. Obstet Gynecol Clin North Am 1998; 25: 723. 6. Stewart WF, VanRooyen JB, Cundiff GW et al: Prevalence and burden of overactive bladder in the United States. World J Urol 2003; 20: 327. 7. Milsom I, Abrams P, Cardozo L et al: How wide-
Botulinum toxin is the most potent neurotoxin known. It binds ACH receptors, prevents exocytosis of cholinergic vesicles, decreases contractions and provides chemo-denervation for up to 6 months or more. Intravesical BTX-A injections have resulted in increased bladder capacity, decreased frequency, increased bladder compliance and increased QOL.46-48 A total of 150 units of intravesical BTX-A were as efficacious as 300 units with a significantly decreased retention rate
spread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001; 87: 760. 8. Lawrence J, Lukacz ES, Nager CW et al: Prevalence and co-occurrence of pelvic floor disorders in community dwelling women. Obstet Gynecol 2008; 111: 678. 9. Wyndaele M, De Winter BY, Pelckmans P et al: Lower bowel function in urinary incontinent, urinary continent women, and in controls. Neurourol and Urodyn 2011; 30: 138. 10. Uustal FE, Wingren G and Kjølhede P: Factors associated with pelvic floor dysfunction with emphasis on urinary and fecal incontinence and genital prolapse: an epidemiological study. Acta Obstet Gynecol Scand 2004; 83: 383. 11. Kobelt G, Kirchberger I and Malone-Lee J: Review. Quality of life aspects of the overactive bladder and the effect of treatment with tolterodine. BJU Int 1999; 83: 583. 12. Brown JS, McGhan WF and Chokroverty S: Comorbidities associated with overactive bladder. Am J Manag Care 2000; 6: S574. 13. Stewart K, McGhan WF, Offerdahl T et al: Overactive bladder patients and role of the pharmacist. J Am Pharm Assoc (Wash) 2002; 42: 469. 14. Hu TW, Wagner TH, Bentkover JD et al: Costs of urinary incontinence and overactive bladder in the United States: a comparative study. Urology 2004; 63: 461. 15. Messelink B, Benson T, Berghmans B et al: Standardization of terminology of pelvic floor muscle function and dysfunction: report from the pelvic floor clinical assessment group of the International Continence Society. Neurourol Urodyn 2005; 24: 374. 16. Handa VL and Masson RW: Measuring the severity of stress urinary incontinence using the Incontinence Impact Questionnaire. Neurourol Urodyn 2004; 23: 27. 17. FitzGerald MP and Kotarinos R: Rehabilitation of the short pelvic floor. I: Background and patient evaluation. Int Urogynecol J Pelvic Floor Dysfunct 2003; 14: 261. 18. Travell JG and Simons DG: Pelvic floor muscles. In: Myofascial Pain and Dysfunction: The Trigger Point Manual. Baltimore: Williams & Wilkins 1992; pp 110-131. 19. Bo K: Reproducibility of instruments designed to measure subjective evaluation of female stress urinary incontinence. Scand J Urol Nephrol 1994; 28: 97. 20. Lynch CM and Aronoff CK: Reproducibility of grading scales of pelvic muscle strength: standard versus tampon scale. Int Urogynecol J Pelvic Floor Dysfunct 2003; 14: 288. 21. Kearny R, Miller JM and Delancey JO: Interrater reliability and physical examination of the pubovisceral portion of the levator ani muscle, validity comparisons using MR imaging. Neurourol Urodyn 2006; 25: 50. 22. Frawley HC, Galea MP, Phillips BA et al: Reliability of pelvic floor muscle strength assessment using different test positions and tools. Neurourol Urodyn 2006; 25: 236. 23. Bump RC, Mattisson A, Bo K et al: The standardization of terminology of female pelvic organ prolapse and pelvic organ dysfunction. Am J Obstet Gynecol 1996; 175L: 10. 24. Morris AR, O’Sullivan R, Dunkley P et al: Extracorporeal magnetic stimulation is of limited clinical benefit to women with idiopathic detrusor overactivity: a randomized sham controlled trial. Eur Urol 2007; 52: 876. 25. Srikishna S, Robinson D and Cardozo L: Ringing the changes in evaluation of urogenital prolapse.
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Course #27IC ▼ Continued from page 8 Int Urogyn J, 2011; 22: 171. 26. Mourtzinos A, Maher MG, Raz S et al:: Spiral sling salvage anti-incontinence surgery for women with refractory stress urinary incontinence: surgical outcome and satisfaction determined by patient-driven questionnaires. Urology 2008; 72: 1044. 27. Subak LL, Wing R, West DS et al: Weight loss to treat urinary incontinence in overweight and obese women, N Engl J Med 2009; 360: 481. 28. Neumann PB, Grimmer KA and Deenadayalan Y: Pelvic floor muscle training and adjunctive therapies for the treatment of stress urinary incontinence in women: a systematic review. BMC Womens Health 2006; 6: 11. 29. Bo K, Talseth T and Holme I: Single blind, randomised controlled trial of pelvic floor exercises, electrical stimulation, vaginal cones, and no treatment in management of genuine stress incontinence in women. BMJ 1999; 318: 487. 30. Hay-Smith EJ, Bo K, Berghmans LC et al: Pelvic floor muscle training for urinary incontinence in women. In: Cochrane Library. Chichester, England: John Wiley & Sons; 2003, issue 1. 31. Arvonen T, Fianu-Jonasson A and Tyni-Lenné R: Effectiveness of two conservative modes of physical therapy in women with urinary stress incontinence. Neurourol Urodyn 2000, 20: 591. 32. Patrick DL, Martin ML, Bushnell DM et al: Quality of life of women with urinary incontinence: further development of the incontinence quality of life instrument (I-QOL). Urology 1999; 53: 71. 33. Burgio KL, Goode PS, Locher JL et al: Behavioral training with and without biofeedback in the treatment of urge incontinence in older women: a randomized controlled trial. JAMA 2002; 288: 2293. 34. Peters KM, Carrico DJ, Perez-Marrero RA et al: Randomized trial of percutaneous tibial nerve stimulation versus sham efficacy in the treatment of overactive bladder syndrome: results from the SUmiT trial. J Urol 2010; 183: 1438. 35. Diokno AC, Appell RA, Sand PK et al: Prospective, randomized double-blind study of the efficacy of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc 2003; 78: 687. 36. Chapple CR, Martinez-Garcia R, Selvaggi L et al: A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol 2005; 48: 464.
37. Lipton RB, Kolodner K and Wesnes K: Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol 2005; 173: 493. 38. Modi A, Weiner M, Craig BA et al: Concomitant use of anticholinergics with acetylcholinesterase inhibitors in Medicaid recipients with dementia and residing in nursing homes. J Am Geriatr Soc 2009; 57: 1238. 39. Sultana CJ and Walters MD: Estrogen and urinary incontinence in women. Maturitas 1994; 20: 129. 40. American Urological Association: The surgical management of female stress urinary incontinence. Clinical practice guideline. 2009. Available at http://www.auanet.org/products/guidelines/main_ reports/fsuimainrpt.pdf. 41. Lapitan MC, Cody DJ and Grant AM: Open retropubic colposuspension for urinary incontinence in women. Cochrane Database Syst Rev 2003; CD002912. 42. Mellier G, Benayed B, Bretones S et al: Suburethral tape via the obturator route: is the TOT a simplification of the TVT? Int Urogynecol J Pelvic Floor Dysfunct 2004; 15: 227. 43. Bombieri L, Freeman RM, Perkins EP et al: Why do women have voiding dysfunction and de novo detrusor instability after colposuspension? Br J Obstet Gynaecol 2002; 109: 402. 44. Stav K, Dwyer PL, Rosamilia A et al: Repeat synthetic mid urethral sling procedure for women with recurrent stress urinary incontinence. J Urol 2010; 183: 241. 45. Food and Drug Administration: Bowel and vascular injuries. (http://www.fda.gov/cdrh/safety/102008surgicalmesh.html). 46. Smith CP, Nishiguchi J, O’Leary M et al: Singleinstitution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology 2005; 65: 37. 47. Werner M, Schmid DM and Schussler B: Efficacy of botulinum-A toxin in the treatment of detrusor overactivity incontinence: a prospective nonrandomized study. Am J Obstet Gynecol 2005; 192: 1735. 48. Grosse J, Kramer G and Stohrer M: Success of repeat detrusor injections of botulinum A toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol 2005; 47: 653. 49. Schmid DM, Sauermann P, Werner M et al: Experience with 100 cases treated with botulinum-A toxin injections in the detrusor muscle for idio-
pathic overactive bladder syndrome refractory to anticholinergics. J Urol 2006; 176: 177. 50. Giannantoni A, Mearini E, Del Zingaro M et al: Six-year follow-up of botulinum toxin A intradetrusorial injections in patients with refractory neurogenic detrusor overactivity: clinical and urodynamic results. Eur Urol 2009: 55; 705. 51. Anger JT, Weinberg A, Suttorp MJ et al: Outcomes of intravesical botulinum toxin for idiopathic overactive bladder. J Urol 2010: 1830; 2258. 52. White WM, Pickens RB, Doggweiler R et al: Shortterm efficacy of botulinum toxin A for refractory overactive bladder in the elderly population. J Urol 2008; 180: 2522. 53. Thomson AJ, Jarvis SK, Lenart M et al: The use of botulinum toxin type A (BOTOX) as treatment for intractable chronic pelvic pain associated with spasm of the levator ani muscles. BJOG 2005; 112: 247. 54. Shaker HS and Hassouna M: Sacral nerve root neuromodulation: an effective treatment for refractory urge incontinence. J Urol 1998; 159: 1516. 55. Siegel SW, Catanzaro F, Dijkema HE et al: Longterm results of a multicenter study on sacral nerve stimulation for treatment of urinary urge incontinence, urgency-frequency, and retention. Urology 2000; 56: 87. 56. van Voskuilen AC, Oerlemans DJ, Weil EH et al: Long term results of neuromodulation by sacral nerve stimulation for lower urinary tract symptoms: a retrospective single center study. Eur Urol 2006; 49: 366. 57. Elhilali MM, Khaled SM, Kashiwabara T et al: Sacral neuromodulation: long-term experience of one center. Urology 2005; 65: 1114. 58. Lombardi G, Mondaini N, Macchiarella A et al: Clinical female sexual outcome after sacral neuromodulation implant for lower urinary tract symptoms (LUTS). J Sex Med 2008; 6: 1411. 59. Matzel KE, Kamm MA, Stösser M et al: Sacral spinal nerve stimulation for faecal incontinence: multicentre study. Lancet 2004; 363: 1270. 60. Yong SM, Dublin N, Pickard R et al: Urinary diversion and bladder reconstruction/replacement using intestinal segments for intractable incontinence or following cystectomy. Cochrane Database Syst Rev 2003; CD003306. 61. Chapple CR and Bryan NP: Surgery for detrusor overactivity. World J Urol 1998; 16: 268.
Complications of Incontinence and Prolapse Surgery: Evaluation, Intervention and Resolution: A Review from Both Specialties Roger R. Dmochowski, M.D., Course Director; Jerry Blaivas, M.D., Mickey Karram, M.D. and Howard Goldman, M.D., Faculty
The intent of the course was to review current evidence and experiential knowledge regarding the management of complications related to surgeries for the correction of pelvic organ prolapse and management of stress urinary incontinence. Unfortunately, a lack of experience generated from randomized controlled trials limits the amount of evi-
dence supporting remedial interventions for these complications and, therefore, most interventions are based on anecdotal and/or small cohort experiences. However, the numbers of patients experiencing these complications have been increasing recently as indicated in web databases, such as the MAUDE database, and in numerous clinical reports
summarizing experience with the use of mesh kits for pelvic organ prolapse and stress urinary incontinence. Also, recent clinical warnings have been advanced by the Food and Drug Administration regarding the use of mesh kits for prolapse repair. The foundation of the course was the avoidance of complications relat-
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ed to these interventions. A critical aspect of avoidance and management of these complications is initial patient awareness of the risks and benefits of interventions for prolapse and incontinence. The informed consent discussion should include the establishment of reasonable expectations as to success and also include a patient centric definition of what success is for that individual. Often, especially when dealing with pelvic organ prolapse, a constellation of symptoms occurs related to the urinary, bowel and genital tracts (alone or in combination). In addition, pelvic pain and defecatory dysfunction may also complicate the presentation of advanced pelvic organ prolapse. It is critical that patients be made aware of the constellation of these symptoms and are apprised regarding the possibility of improvement and/or resolution of these symptoms with the planned intervention. In a majority of cases improvement is the goal, not cure, and it is often a subjective phenomenon. Therefore, it is critical to identify the most bothersome symptoms and address interventions to alleviate those symptoms to the greatest possible extent. In addition to appropriate expectation setting regarding efficacy, a critical aspect of informed consent relates to discussion of common adverse events. A variety of medical complications are inherent to pelvic floor corrective surgery including cardiovascular, thrombotic, infectious, wound healing and hemorrhage related issues. Specific complications related to the use of interposition grafts should also be conveyed as part of the informed consent discussion (the potential of vaginal mesh exposure, urinary tract and bowel erosion, and other complications potentially resulting in symptoms affecting other aspects of function including sexual function). Appropriate postoperative activity and convalescence should be defined during the informed consent discussion. A successful surgical intervention is dependent on knowledge of the anatomy of the pelvic support structures used to correct prolapse and incon-
tinence. Finally, surgeon knowledge and familiarity with associated implantation equipment and technique are critical to avoid complications and ensure optimal outcomes. Specific surgical complications related to the urethra, bladder, ureter, bowel and vaginal injury were reviewed. Management of intraoperative injury is a key component of discussion. What is clear from the literature is that early recognition may prevent long-term complications and symptoms arising from those complications, although this is not absolute. Early recognition includes evaluation of the bladder with cystoscopy based on the AUA guideline recommendation. Cystoscopy should be performed during incontinence and prolapse procedures to ensure integrity of the bladder and urethral mucosa, and ureteral efflux indicating ureteral patency. Intraoperative recognition of injury allows immediate recognition and repair, appropriate drainage and the potential for avoidance of longterm symptomatic complaint. Similarly, meticulous evaluation of the posterior compartment and rectum during repair is critical to allow timely recognition and appropriate management of injury. Another significant aspect of the course was devoted to management of mesh related complications. The 2 most commonly encountered complications currently are vaginal mesh exposure and erosion into the urinary tract. Vaginal mesh exposure may be treated medically, although in most circumstances limited mesh excision is required with secondary closure of the vaginal mucosa and use of topical estrogens for resolution of exposure related phenomenon. Interestingly, vaginal mesh exposure may be absolutely asymptomatic or associated with dyspareunia, vaginal discharge and/or vaginal or pelvic pain. The decision for intervention may be based on concomitant symptom but the presence of exposure is critical to the discussion with the patient. Management of erosion into the urinary tract to the urethra or bladder involves delineation of the involved area,
careful controlled cystotomy or urethrotomy, removal of all mesh elements and sequential layered closure with interposition when possible. As recommended in the AUA guidelines, autologous slings should be considered as interposition material because of the incidence of concomitant recurrent urinary incontinence with urethral erosions. The majority of erosions may be managed vaginally but a laparoscopic or open approach may also be indicated in cases of complicated mesh erosion into the bladder. A particularly important aspect of the course involved discussion of the management of dyspareunia following pelvic organ prolapse correction. Understanding vaginal anatomy and surrounding structures for purposes of re-creating support is critical to avoid dyspareunia which often arises either solely or in combination with vaginal shortening, vaginal stenosis, vaginal synechiae and/or mesh/graft exposure. Although biological materials are less likely to cause exposure and erosion, they occasionally do cause chronic vaginal draining sites that require secondary treatment. Dyspareunia can be avoided by not over correcting and/or over placating vaginal tissues. Suture plication and/ or graft placement under tension often results in contraction and pain and/or dyspareunia. Therefore, repair should be performed with an attendant goal of allowing some laxity for associated postoperative fibrosis. It is critical to also remember the posterior orientation of the vagina for purposes of creating an anatomically correct outcome. Assessment of dyspareunia should include evaluation for the presence of fibrosis and/or stenosis which would require excision of scar and either inlay of graft material or loose re-correction. Additionally, vaginal shortening may require vaginal apical restoration with a biological graft. The use of additional topical emollients and topical estrogens is critical in the postoperative period to ensure optimization of outcome. Due to the subjective nature of this symptom, dyspareunia must be addressed â–ź Continued on page 11
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with the patient preoperatively to create reasonable outcome expectations. It is important to establish whether the patient already has this symptom and, therefore, the likelihood of its persistence postoperatively, and to educate the patient regarding the possibility of de novo development of this condition. Many individuals have dyspareunia as a
component of the preexistent prolapse and expect the prolapse correction to resolve it. Therefore, it is critical for the individual to have a reasonable understanding as to the potential that this condition may persist after surgery. The final summation of the course was that the best management of complications of lower urinary tract and pelvic
floor interventions is to avoid them. If encountered, however, early awareness and management of complications are critical to prevent the sequelae associated with chronic complications that may include symptoms not remediable by combined medical and surgical interventions at a later date. ♦
Panel Discussion: Office Based Management of SUI in 2011 Gary E. Lemack, M.D., Moderator; Richard D. Cespedes, Saad Juma and Deborah J. Lightner, Panelists
(Reprinted from AUA Daily News 2011; Monday, p 16) Four internationally recognized experts in the field of urinary incontinence will meet today to discuss several therapies that can be performed in the office to manage stress urinary incontinence (SUI). Beginning at 10:20 a.m. during the morning Plenary Session, the panel discussion Office Based Management of SUI in 2011 will be held in Hall D at the Walter E. Washington Convention Center. Gary Evan Lemack, M.D., Professor of Urology and Neurology, and Residency Program Director in Urology at the University of Texas Southwestern Medical Center in Dallas, will moderate the 25-minute discussion. Dr. Lemack currently serves on the AUA Guidelines Panel for Urodynamics and is the Resident Education Chairman on the Executive Committee of the Society of Urodynamics and Female Urology. “Each panelist will give a short review on the topic selected, followed by case presentations by myself during which I will ask the panelists to comment on the role of their selected method in that patient,” Dr. Lemack said. Panelist Saad Juma, M.D., Director of the Incontinence Research Institute in San Diego, will discuss the applica-
tion of controlled, low level radio frequency energy resulting in acute, focal collagen denaturation, with subsequent micro-remodeling of the affected collagen upon cooling and healing, without associated gross tissue necrosis or neurovascular injury. Transurethral radio frequency collagen remodeling of the bladder neck and proximal urethra is a Food and Drug Administration approved, office based, minimally invasive procedure for the management of urinary incontinence in women with SUI due to bladder neck hypermobility. “Women with anatomic stress urinary incontinence who have failed Kegel exercises, who are not good surgical candidates or who wish to avoid or postpone surgery are ideal candidates,” Dr. Juma said. “Additionally, patients who experience suboptimal primary surgical results may benefit from transurethral radio frequency collagen denaturation.” Dr. Juma has authored multiple articles, abstracts and textbook chapters, and presented at more than 100 national and international meetings on issues related to urinary incontinence, pelvic floor prolapse and neurogenic voiding dysfunction, including radio frequency collagen remodeling. Deborah J. Lightner, M.D., Professor of Urology at the Mayo Clinic, will also
sit on the panel. In addition to tremendous contributions to the literature on incontinence, Dr. Lightner served on the Practice Guidelines Committee of the AUA from 2001-2009 and is currently Chair of the Judicial and Ethics Committee of the AUA. “Dr. Lightner will discuss the current and historical role of vaginal wall support devices, as well as urethral plugs and barrier devices,” Dr. Lemack said. “While effective for mild to moderate leakage, historically their use has been limited by irritation related to the device and hematuria, particularly for urethral plugs. Nonetheless, the devices may have a role in patients at high risk for any invasive procedures, or in younger patients not ready for surgery with leakage related only to certain activities, such as athletics.” Finally, Richard Duane Cespedes, M.D., from the Comprehensive Continence and Pelvic Health Center at the Shore Health System in Easton, Maryland, will detail the use of injectables. Injection therapy for SUI is a minimally invasive, office based procedure that can be used as primary therapy or as adjunctive/salvage therapy for sling procedures. “As the population ages and more elderly patients seek treatment for SUI to maintain their active lifestyles, the demand for office based treatments will ▼ Continued on page 12
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increase, highlighting the importance of injection therapy in the urologist’s armamentarium,” Dr. Cespedes said. “When performing injection therapy, as with any procedure, proper patient selection is crucial for therapeutic success, patient satisfaction and minimizing costs.” Importantly, when performed in the clinic using local anesthesia, injectable agents give elderly patients who are poor surgical candidates or are on anticoagu-
lant therapy the opportunity to improve their quality of life with minimal morbidity and expense. The ideal female candidate for injection therapy is one with intrinsic sphincter deficiency, minimal urethral mobility and normal detrusor function. Clinically, these patients are often elderly and have some degree of detrusor instability. “Although equally effective, with few exceptions young healthy patients with
urethral hypermobility and SUI are not the best candidates for injection therapy because of the requirement for long-term re-injections,” Dr. Cespedes said. “Slings are clearly a better option in this group.” Dr. Cespedes has authored multiple articles and textbook chapters regarding injectable agents for the treatment of SUI. and is widely considered an expert in the field. ♦
State-of-the-Art Lecture: What is on the Horizon in Drug Therapy for Overactive Bladder? Dr. Karl-Erik Andersson, Department of Urology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
(Reprinted from AUANews 2011; Vol. 16, No. 4, pp 11-12) In women lower urinary tract symptoms (LUTS) have usually equated with the overactive bladder (OAB) syndrome and assumed to be caused by detrusor overactivity (DO). However, OAB is not solely a female disorder. Irwin et al reported that the prevalence in both sexes was around 12%, OAB increases with age and the prevalence of storage LUTS (suggestive of OAB) was twice as common as voiding LUTS in men.1 Concerning the pathophysiology of storage symptoms in men, focus has shifted from the prostate to the bladder as the main source and as a therapeutic target.2 This shift has created a renewed interest in drugs for the treatment of male LUTS/OAB, and opened the door for combinations of drugs. However, there is still a need for new alternatives.
Subtype Selective α1-Adrenoceptor Antagonists Currently used α1-adrenoceptor (AR) antagonists are effective for treating storage and voiding LUTS in men. However, in females with OAB α1-AR antagonists seem to be ineffective.3 In males the targets for the well documented effects
of α1-AR antagonists are the prostate (where there is a predominance of α1AARs) and the bladder (where α1D-ARs predominate) but it has not been established whether selectivity for α1A-, α1D- or α1A/D-ARs has any advantages. Commonly used drugs either have no subtype selectivity (doxazosin, terazosin, alfuzosin) or block α1A- and α1D ARs (tamsulosin, naftopidil). Silodosin, a new α1-AR antagonist with a high selectivity for α1A-ARs, was compared to tamsulosin and placebo in a multicenter, double-blind, placebo and active controlled parallel group study.4 There was no significant difference between the 2 α1-AR antagonists in terms of efficacy or quality of life parameters. The most frequent adverse event with silodosin was a reduced or absent ejaculation during orgasm (14%). Thus, it seems that selective blockade of α1A-ARs with silodosin is a clinically effective and well tolerated treatment of storage as well as voiding symptoms in men with LUTS/OAB. However, from an efficacy point of view, there seem to be no real advantages.
Antimuscarinic Agent/Combinations Current guidelines recommend the use of oral antimuscarinics as first line phar-
macologic therapy for the management of OAB in women. However, the drugs are now being recognized as safe and effective for male LUTS/OAB. Traditionally muscarinic receptor antagonists have been contraindicated in patients with benign prostatic hyperplasia due to fears of urinary retention. However, this dogma has been questioned and several studies have been performed in which α1-AR antagonists have been combined with muscarinic receptor antagonists with promising results.5
β3-Adrenoceptor Agonists The human detrusor muscle and urothelium contain β-adrenoceptors, and the β3-AR subtype has been identified as a therapeutic target.6 β3-AR selective agonists are being clinically evaluated for OAB but few studies have been published. Chapple et al reported the results of a controlled clinical trial with mirabegron in patients with OAB, and the primary efficacy analysis showed a statistically significant reduction in mean micturition frequency compared to placebo.7 Mirabegron was significantly superior to placebo with regard to mean volume voided per micturition, mean number of incontinence episodes, nocturia episodes, urgency incontinence episodes
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and urgency episodes per 24 hours. The drug was well tolerated, and the most commonly reported side effects were headache and gastrointestinal adverse effects. The results of this well conducted proof of concept study showed that the principle of β3-AR agonist may be useful to treat OAB with satisfactory safety. The effects of mirabegron are now well documented, and 17 trials with the drug are registered at ClinicalTrials.gov (data not yet published). The drug is expected to be introduced clinically in the near future.
Phosphodiesterase Inhibitors The observation that LUTS improved in patients treated for erectile dysfunction with phosphodiesterase type 5 (PDE5) inhibitors has sparked a new interest in using these drugs to treat male LUTS/OAB. The mechanism behind the beneficial effect of PDE5 inhibitors on LUTS/OAB and their site(s) of action largely remain to be elucidated. If the site of action were the smooth muscles of the outflow region and the effect was relaxation, an increase in flow rate should be expected. In none of the trials referred to was such an effect found. Whether PDE5 inhibitors are effective in females with LUTS/OAB has not yet been established.
Centrally Acting Drugs Reviewing some of the central mechanisms involved in micturition control, Holstege suggested that “the problem in OAB or urgency incontinence is at the level of the periaqueductal gray and the pontine micturition center, and their connections, and possible treatments for this condition should target the micturition pathways at that level.”8 Central nervous mechanisms have so far not been preferred targets for drugs aimed to treat OAB, since selective actions on
micturition may be difficult to obtain. However, there is some evidence that centrally acting drugs might work. Tramadol, a well-known analgesic drug, is a weak µ-receptor agonist metabolized to several different compounds. However, the drug (metabolites) also inhibits serotonin and noradrenaline reuptake. This profile is of particular interest since amine reuptake inhibition may be a useful principle for the treatment of LUTS/OAB, as shown in a placebo controlled study with duloxetine.9 A doubleblind, placebo controlled, randomized study of tramadol in patients with idiopathic DO documented that this drug provided beneficial clinical and urodynamic effects.10 Even if tramadol may not be suitable to treat LUTS/OAB (risk of dependency, constipation), the study proves the principle of modulating micturition via a central mechanism.
Other Potential Options For other classes of drugs, such as vitamin D analogues (elocalcitol), neurokinin-1 receptor antagonists (aprepitant, serlopitant), Ca2+ channel α2-delta ligands (gabapentin) and gonadotropin releasing hormone antagonists, results from positive proof of principle studies have been published. However, available information is not sufficient for proper assessment, and none of the drugs has so far been approved for LUTS/OAB treatment. Botulinum toxin A and the vanilloid receptor agonists, capsaicin and resiniferatoxin, are principles with good evidence of therapeutic neurogenic and idiopathic effect on DO. Botulinum toxin A, although not approved for use for OAB, has largely replaced the vanilloids as a therapeutic alternative in patients not responding to antimuscarinic treatment but it is still regarded as second line treatment.
Future Drugs Except for β3-AR agonists and PDE5 inhibitors, no “new” drugs for OAB treatment seem immediately ready for clinical introduction. There are many theoretically attractive new drug principles for future testing but only a few realistic alternatives are currently emerging on the horizon. ♦ 1. Irwin DE, Milsom I, Hunskaar S et al: Population based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006; 50: 1306. 2. Roosen A, Chapple CR, Dmochowski RR et al: A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature. Eur Urol 2009; 56: 810. 3. Robinson D, Cardozo L, Terpstra G et al: A randomized double-blind placebo-controlled multicentre study to explore the efficacy and safety of tamsulosin and tolterodine in women with overactive bladder syndrome. BJU Int 2007; 100: 840. 4. Chapple CR, Montorsi F, Tammela TLJ et al: Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, doubleblind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol 2010; Epub ahead of print. 5. Kaplan SA, Roehrborn CG, Abrams P et al: Antimuscarinics for treatment of storage lower urinary tract symptoms in men: a systematic review. Int J Clin Pract 2011; Epub ahead of print. 6. Tyagi P and Tyagi V: Mirabegron, a β3-adrenoceptor agonist for the potential treatment of urinary frequency, urinary incontinence or urgency associated with overactive bladder. IDrugs 2010; 13: 713. 7. Chapple CR, Yamaguchi O, Ridder A et al: Clinical proof of concept study (Blossom) shows novel B3 adrenoceptor agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder. Eur Urol Suppl 2008; 7: 239. 8. Holstege G: Micturition and the soul. J Comp Neurol 2005; 493: 15. 9. Steers WD, Herschorn S, Kreder KJ et al: Duloxetine compared with placebo for treating women with symptoms of overactive bladder. BJU Int 2007; 100: 337. 10. Safarinejad MR and Hosseini SY: Safety and efficacy of tramadol in the treatment of idiopathic detrusor overactivity: a double-blind, placebo-controlled, randomized study. Br J Clin Pharmacol 2006; 61: 456.
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State-of-the-Art Lecture: How Do I Manage a Failed Mid Urethral Sling? Dr. Eric S. Rovner, Department of Urology, Medical University of South Carolina, Charleston, South Carolina
(Reprinted from AUANews 2011; Vol. 16, No. 4, pp 13-14) The number of stress urinary incontinence (SUI) operations done in the United States has grown considerably during the last 10 to 15 years.1,2 During this time mid urethral polypropylene slings have gained considerable popularity, and are the surgical procedure of choice for many surgeons and patients with uncomplicated SUI. This is likely due to the low morbidity, technical ease and speed of the procedure, long-term durability, and rapid recovery and convalescence. These slings, of which there are many proprietary types, are similar in the completely tension-free, minimally invasive technique in which they are placed under the mid urethra. Depending on the choice of sling, these may be placed through a transvaginal, suprapubic or transobturator approach with no definite advantage in efficacy to any particular approach.3 Despite the rapid uptake of these procedures, failures do occur. Failure rates are variable and depend on several factors including the subpopulation studied (redo vs primary cases, intrinsic sphincter deficiency etc), the surgeon and, most importantly, the definition of failure. Defining failure in SUI surgery is difficult, and there is no universal agreement on how to do this accurately, simply and reproducibly. In general, as the definition of success becomes increasingly stringent, failure rates increase. Furthermore, when combining various parameters to create a composite success metric, failure rates can appear rather sobering as was evidenced in recent National Institutes of Health (NIH) sponsored trials.3, 4 For example, in a recently completed NIH trial, comparing transobturator to retropubic mid urethral slings, success rates were statistically equivalent between the 2 arms but depending on
the definition, success rates were 86% to 90% as defined by patient satisfaction but decreased to 56% to 62% when defined by a composite subjective score (absence of urinary incontinence in a 3-day diary, no re-treatment and absence of self-reported SUI on the Medical Epidemiology and Social Aspects of Aging questionnaire).3 Failure of mid urethral sling surgery may be due to several factors and certainly patient expectations of “cure” are important when considering failure. Without counseling, patient expectations of SUI surgery will often include complete absence of SUI permanently, no urgency or frequency ever, normal bladder emptying and complete absence of pain 100% of the time. Thus, managing patient expectations of success postoperatively begins with setting appropriate expectations going forward preoperatively. Understanding the reason for surgical failure is at least as important as treating it. SUI operations such as mid urethral slings are effective in properly selected patients. Indeed, the incidence of true, isolated recurrent SUI as a mechanism of failure should be low in these patients. The bladder is an “unreliable witness” and patient complaints of bothersome SUI following a presumably effective surgery should be thoroughly and completely investigated as they may have a more complex condition than just recurrent or persistent SUI. A complete history, voiding diary and physical examination are important. Observation and documentation of vaginal wall anatomy especially in regard to urethral mobility may be helpful in planning additional therapy. Many options exist for those individuals with true recurrent or persistent SUI after a thorough evaluation reveals no other complicating factors related to the primary surgery such as vaginal extrusion
of mesh or urethral obstruction. The optimal approach has not been defined. Data on nonsurgical therapies such as behavioral therapy and pharmacological therapy in this patient population are limited. Bulking agents are an option although long-term durability has not been documented. There are emerging data on redo surgery with another mid urethral sling or another anti-incontinence surgery but they are based largely on immature case series. Whether the initial sling should be removed partly or in its entirety is not well defined and, on a case-by-case basis, most often depends on findings on preoperative evaluation as well as intraoperative factors. Furthermore, the optimal approach when considering a redo mid urethral sling (transobturator vs retropubic) or even the best alternative to a mid urethral sling (autologous fascial sling etc) in this redo setting is not well established. Of course, mid urethral slings can fail for many other reasons including obstruction. These slings are designed to be tension-free and yet urinary incontinence following a mid urethral sling procedure may be due to de novo bladder outlet obstruction, which may be manifest as urgency/frequency, increased postvoid residual urine volume, positional voiding, recurrent urinary tract infections or other subtle symptoms. Treatment depends on the timing of the diagnosis relative to the procedure (days vs months postoperatively) as well as other factors. Overall, mid urethral sling is an effective yet imperfect treatment for SUI. As surgeons, we are sometimes not nearly as good as we think we are, or even as good as the literature would lead us to believe. Failures do exist. Nevertheless, after a thorough evaluation many of these cases can be salvaged, although the optimal evaluation and therapeutic intervention have not yet been defined. ♦ ▼ Continued on page 15
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Plenary Session ▼ Continued from page 14 1. Waetjen LE, Subak LL, Shen H et al: Stress urinary incontinence surgery in the United States. Obstet Gynecol 2003; 101: 671. 2. Boyles SH, Weber AM and Meyn L: Procedures for urinary incontinence in the United States, 19791997. Am J Obstet Gynecol 2003; 189: 70. 3. Richter HE, Albo ME, Zyczynski H et al: Retropubic versus transobturator midurethral slings
for stress incontinence. N Engl J Med 2010; 362: 2066. 4. Albo ME, Richter HE, Brubaker L et al: Burch colposuspension versus fascial sling to reduce urinary stress incontinence. N Engl J Med 2007; 356: 2143.
*Financial interest and/or other relationship with Pfizer, Allergan, Medtronic, Astellas, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Contura, Johnson and Johnson, Tengion, Solace and Oceana Therapeutics.
Take Home Message: Female Urology/Incontinence Dr. Paulo Palma, *São Paulo, Brazil, provided the audience with highlights of the AUA meeting on Female Urology and Incontinence. The abstract numbers are indicated in parentheses.
(Reprinted from AUANews 2011; Vol. 16, No. 7, pp 8-9) The winds of change brought more light than heat to this meeting.
Injectables and Adjustable Continence Therapy The good news is that nonabsorbable substances such as polydimethylsiloxane may produce long lasting, good results. An overall significant improvement rate of 84% (67% dry rate) was reported in patients with stress urinary incontinence (SUI) due to intrinsic sphincter deficiency after a 2-year followup (1337). A multicenter experience using autologous muscle derived cell therapy for the treatment of 64 patients with SUI was presented (1340). Different cell concentrations were injected and no adverse event was reported. Improvement was directly related to the cell concentration with best results using 200 million cells. These results may be the cornerstone for a new alternative in our armamentarium in the near future. After 4 years of followup of a Food and Drug Administration safety and efficacy study of adjustable continence therapy (ACT), optimal continence was achieved with a mean of 3 adjustments in 162 patients with recurrent SUI (1864). Mild balloon related problems were reported in 25% of the patients at the end of 12 months and permanent explants were performed in 29 patients. The dry rate was 51% at 12 months, 62% at 24 months, 74% at 36 months and
77% at 48 months. The conclusion was that ACT is a safe and effective treatment for complex SUI.
SUI and Slings Last year the TOMUS (transobturator mid urethral slings versus retropubic mid urethral slings) trial revealed similar results with both slings in a randomized equivalence trial after 1-year followup. This year after 24 months of followup the objective success rate was 77.3% for retropubic and 72.3% for transobturator slings (1164). No differences were noted regarding patient satisfaction with rates of 86.3% for retropubic and 88.1% for transobturator slings. Although objective outcomes of both slings were equivalent at 12 months, 24-month objective and subjective cure rates did not predefine criteria for equivalence.
Single Incision Mini Slings Since the first report comparing the single incision arc to arc mini sling in 1999, mini sling systems have evolved dramatically. Two presentations at this year’s meeting addressed 24-month results of the MiniArc® sling. In a 2-year prospective evaluation of 188 patients treated with the MiniArc sling the objective cure rate was 85.1% (cough stress test) and 80.7% (1-hour pad weight test) (1335). Complications were minimal, confirming the safety and efficacy of the technique. Long-term data on 120 patients indicated a 93% subjective cure (patients
denied symptoms of SUI) (1336), leading to the conclusion that mini sling results are durable and improve QOL with minimal effect on sexual function.
Tissue Engineering A phase 2 multicenter study on Tengion® Autologous Neo-Bladder Augment for augmentation cystoplasty was performed on 6 subjects with neurogenic bladder secondary to spinal cord injury (1512). Autologous material was obtained by open bladder biopsy and grown ex vivo. An autologous cell seeded biodegradable scaffold was implanted in 6 patients with the primary end point being a change from baseline in maximum detrusor pressure (Pdet). Responses were complete in 2 patients and partial in 2. The remaining 2 patients experienced no response. This study supports the feasibility of regenerative medicine in bladder augmentation.
Urinary Tract Infection The efficacy of intravesical hyaluronic acid (HA) instillations for the prevention of recurrent urinary tract infection (UTI) was reported (1871). This compound, which is found in bladder surface glycosaminoglycans, represents a barrier of the urothelium and may help prevent UTI. A total of 48 women with recurrent acute bacterial cystitis (Escherichia coli 76%) underwent 8 weekly instillations of 40 mg HA and were followed for 18 months. The mean frequency of UTI episodes before treatment was 1 episode ▼ Continued on page 16
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every 4 to 6 weeks. After treatment 36 (75%) patients were infection-free for the entire followup period, and 10 (20.8%) had recurrent UTI, but the mean interval between infections ranged from 39 days before to 190 days after treatment. Intravesical HA instillation appears to be a promising alternative for recurrent UTI, although randomized studies are needed.
Overactive Bladder Basic. Increased levels of urinary and serum nerve growth factor (NGF) were reported in patients refractory to antimuscarinic therapy compared to normal controls (1866). It was concluded that in this subset of patients bladder disorder may be related to inflammation and that increased circulating NGF levels might decrease the sensory threshold resulting in overactive bladder (OAB) symptoms. Urinary neurotrophins (NGF and brain derived neurotrophic factor) were evaluated as potential biomarkers of OAB in patients with OAB and in healthy
volunteers (1952). Both neurotrophins were increased in patients and decreased after 3 months of nonpharmacological intervention. This difference between patients and controls indicates that urinary neurotrophins can be potential biomarkers of OAB. New target. North American study on mirabegron, a selective β3 adrenoreceptor agonist, showed that it is effective and well tolerated in patients with OAB (1958). This multicenter, prospective, randomized, placebo controlled phase III trial addressed the efficacy and tolerability of once daily mirabegron. A total of 1,328 patients were randomized to receive placebo, or 50 or 100 mg mirabegron. Both doses of mirabegron caused statistically significant improvement compared to placebo. The incidence of adverse effects was similar in all groups, with hypertension and headache among the most frequent. It was concluded that this new agent was efficacious and well tolerated in this 12-week study. Percutaneous tibial nerve stimulation. Preliminary results of the STEP study were presented (1343). A total of 60
patients underwent weekly percutaneous tibial nerve stimulation (PTNS) therapy for 3 months and were selected for ongoing therapy up to 12 months. Voiding diary parameters at 6 and 12 months were significant for improvement compared to baseline for frequency, incontinence episodes, nighttime voids and moderate to severe urgency episodes. Sustained efficacy of PTNS was demonstrated for 12 months following initial success at 12 weeks. Prolapse. OAB symptoms and detrusor overactivity change for the better after surgical correction of vaginal vault prolapse repair (1872). A total of 43 patients underwent vaginal vault repair using different techniques. OAB symptoms were evaluated by urodynamics and questionnaires. Preoperatively 33 (76%) patients reported OAB symptoms, which subsided postoperatively in 25. No de novo urgency was reported in this study. *Financial interest and/or other relationship with Astellas, Promedon and EMS. ♦
Abstract 1154: Time-Course Changes In Urethral Function After Simulated Birth Trauma With or Without Ovariectomy in a Rat Model of Sneeze-Induced Stress Urinary Incontinence Takeya Kitta*, Hiroshi Tanaka, Takahiko Mitsui, Yukiko Kanno,Kimihiko Moriya, Katsuya Nonomura, Sapporo, Japan; Naoki Yoshimura, Pittsburgh, PA
(Reprinted from J Urol, suppl., 2011; 185: e463)
simulated birth trauma and/or ovariectomy (OVX) in rats.
INTRODUCTION AND OBJECTIVES: Pregnancy and vaginal child delivery are considered to be important causes of stress urinary incontinence (SUI) however the exact mechanisms by which urethral function is damaged is not well known. We performed a detailed time course evaluation of changes in the urethral continence reflex after
METHODS: Female Sprague-Dawley rats underwent bilateral OVX or sham operation. Simulated birth trauma was then induced by vaginal distension (VD) induced by balloon catheter inflation in the vagina, the timing of which was adjusted in order to perform the experiments 6 weeks after OVX. Four days, 1, 2 and 4 weeks after VD, sneeze induced
urethral responses and the incidence of SUI, which was identified by fluid leakage from the urethral orifice during sneezing. Urethral responses were measured using a microtransducer catheter inserted to the middle urethra from the urethral orifice to evaluate the amplitude of urethral responses during sneezing (A-URS) and urethral baseline pressure (UBP).
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RESULTS: Four days after VD, A-URS and UBP were significant decreased, and SUI during sneezing was seen in all rats with or without OVX (Fig. 1A & B). However, in rats without OVX, no leakage during sneezing was observed 2 weeks after VD (Fig. 1C) although A-URS was still significantly decreased up to 4 weeks after VD (Fig. 1A & B). In OVX rats, the reductions in A-URS and UBP were more pronounced in 2 and 4 weeks after VD compared to non-OVX rats (Fig. 1A & B), and sneeze-induced SUI was still seen in 5 of 8 rats (62.5%) 4 weeks after VD (Fig. 1C).
OVX. Thus, the history of vaginal birth trauma could be an important contributing factor to SUI, but additional factors such as estrogen deficiency are required to fully develop SUI conditions. ♦
Source of Funding: NIH DK067226, AR049398 andDK055387
CONCLUSIONS: Clinically, SUI after vaginal delivery usually disappears, but often reappears during peri or postmenopausal periods in women. The current results indicate that, although SUI disappears after simulated birth trauma (VD) the impairment of striated muscle urethral reflex activity (represented by A-URS) persists and that estrogen deficiency (OVX) aggravated the damage of urethral continence mechanisms induced by simulated birth trauma, resulting in overt SUI in VD rats with
Abstract 1338: A Nonhuman Primate Model of Urinary Sphincter Deficiency: Prelude To Testing Cell Therapies Sherif Badra*, Gordon McClorie, Winston-Salem, NC; Mohamed Sherif Mourad, Cairo, Egypt; J. Koudy Williams, Winston-Salem, NC
(Reprinted from J Urol, suppl., 2011; 185: e535) INTRODUCTION AND OBJECTIVES: Stress urinary incontinence (SUI) in women is a prevalent societal problem with significant impact on healthcare costs and quality of life. Results of recent clinical trials using autologous muscle-derived progenitor cells (MPCs) to treat SUI in women are promising. However, it remains unclear whether injected MPCs play a passive (bulking), or active (cell integration) role in sphincter regeneration. We plan to
address this gap in knowledge using a nonhuman primate animal model whose genetic, anatomic, physiologic, postural, intra-pelvic bladder location, age and hormone related changes in the genitourinary system, expose the urinary sphincter to structural and pharmacologic stressors common to middle-aged women. METHODS: 18 female cynomolgus monkeys 16-18 years of age (age equivalent of 45–55 year-old women) were used in this study. Biopsies were taken from the quadriceps muscle for isolation, expansion and lentiviral/GFP labeling
of MPCs. Monkeys were divided into two groups: control (n=4) and sphincter deficiency (n=14). The sphincter deficiency was produced by a combination of pudendal nerve denervation on both sides of the urethra and stripping of the outer muscle layer of the sphincter. In vivo urodynamic evaluations were done on all monkeys at baseline and then both 1 month and 3 months post-sphincter injury. RESULTS: Isolated cells expressed protein and message for the muscle precursor genes Myf5 and MyoD. They ▼ Continued on page 18
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were readily transduced with a lenti-GFP promoter and consistently expanded to 10–20 million cells within 4 passages. In vivo urodynamic evaluation of sphincter and bladder function indicated a marked decrease in urethral sphincteric pressure by 38–16% and an 18–10 mmHg increase in bladder pressure following
sphincter injury. These changes persist 3 months post-injury. CONCLUSIONS: MPCs from NHPs can be readily isolated, labeled and expanded to the numbers needed for sphincter injection. Sphincter deficiency can be produced in a consistent man-
ner and the deficiency is stable over a 3 month time period. This NHP model can now be used to determine the efficacy and role of injected MPCs in reducing urinary sphincter deficiency. ♦ Source of Funding: NIH RO1DK083688
Abstract 1506: Prevalence of Overactive Bladder (OAB) and Associated Risk Factors in 1,359 Patients With Type 2 Diabetes Yao-Chi Chuang*, Min-Shen Chung, Hsueh-Wen Chang, Wei-Chia Lee, Kaohsiung, Taiwan; Michael B. Chancellor, Royal Oak, MI; Rue- Tsuan Liu, Kaohsiung, Taiwan
(Reprinted from J Urol, suppl., 2011; 185: e604) INTRODUCTION AND OBJECTIVES: The aim of the study was to evaluate the prevalence of overactive bladder (OAB, dry and wet) and associated risk factors of OAB wet (with incontinence) in type 2 diabetes. METHODS: A self administered questionnaire containing overactive bladder symptom score (OABSS, 0–15, indicating increasing severity of symptoms) was obtained from subjects with type 2 diabetes at a dedicated diabetic center. The association of age, gender, duration of diabetes, body mass index (BMI), waist
circumference, glycated hemoglobin (Hb A1c) level, high sensitive CRP level, and diabetes associated complications to risk of OAB and OAB wet was evaluated.
OAB and OAB wet, respectively, after multivariate analysis. Hb A1c and CRP levels were similar between DM patients with and without OAB.
RESULTS: Of 1,359 consecutive subjects, 22.5% reported having OAB with 11.7% reporting OAB dry and 10.8% with OAB wet. There were statistically significant differences of symptom severity among no OAB, OAB dry, and OAB wet (OABSS 2.5/1.4, 5.9/1.6 and 8.9/2.6, respectively). The prevalence of OAB and OAB wet were 2.4 fold and 4.2 fold greater, respectively, in patients with DM duration >10 years and age >50 years. Age, male gender, and age, waist circumference were independent risk factors for
CONCLUSIONS: In a dedicated diabetic center where all patients were screened, 22.5% had OAB and 48.0 % of OAB patients had incontinence. These findings can help guide collaboration between urologists and diabetologists to work toward developing screening for and early treatment of urologic complications in higher risk patients. ♦ Source of Funding: Chang Gung Memorial Hospital CMRPG 860381
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Abstract 1958: The Selective Β3-Adrenoreceptor Agonist Mirabegron Is Effective and Well Tolerated in Patients With Overactive Bladder Syndrome Victor Nitti*, New York, NY; Sender Herschorn, Toronto, Canada; Stephen Auerbach, Newport Beach, CA; Maggie Ayers, Misun Lee, Nancy Martin, Deerfield, IL
(Reprinted from J Urol, suppl., 2011; 185: e783) INTRODUCTION AND OBJECTIVES: The efficacy and tolerability of mirabegron in a Phase III trial of patients with OAB in the United States and Canada are presented. METHODS: This 12-week, multicenter, randomized, doubleblind, parallelgroup, placebo-controlled trial enrolled patients ≥18 years with symptoms of OAB for ≥3 months. Patients who completed a 2-week, single-blind, placebo run-in, and experienced ≥8 micturitions/ 24 h and ≥3 urgency episodes (with or without incontinence) over a 3-day micturition diary period during screening, were randomized to receive placebo or mirabegron 50 or 100 mg once daily for 12 weeks. Co-primary endpoints were the changes from baseline to final visit in the mean number of incontinence episodes and micturitions/24 h. Efficacy was assessed according to patient micturition diaries and safety assessments included adverse event (AE) reporting.
incontinence episodes and micturitions. The incidence of treatment-emergent AEs was similar across the placebo and mirabegron 50 and 100 mg groups (50.1, 51.6 and 46.9%, respectively). The most commonly reported (≥3%) AEs in any treatment group were hypertension (6.6, 6.1 and 4.9%, respectively), urinary tract infection (1.8, 2.7 and 3.7%), headache (2.0, 3.2 and 3.0%) and nasopharyngitis (2.9, 3.4 and 2.5%). The incidence of serious AEs was 2.0, 2.5 and 3.2% in the
placebo and mirabegron 50 and 100 mg groups, respectively, and discontinuation rates due to AEs were 3.8, 4.1 and 4.4%. CONCLUSIONS: Mirabegron demonstrated statistically significant improvements in key OAB symptoms and was well tolerated in this 12-week, NorthAmerican study of patients with OAB.♦ Source of Funding: Sponsored by Astellas Pharma, Inc.
RESULTS: A total of 1328 patients were randomized and received study drug (placebo: n=453; mirabegron 50 mg: n=442; mirabegron 100 mg: n=433). Mean age was 60.1 years, 74.3% were female, 38.1% had mixed stress/urgency incontinence with urgency predominant, 32.2% had frequency without incontinence and 29.7% had urgency incontinence. Both mirabegron groups demonstrated statistically significant improvements compared with placebo in the coprimary and secondary efficacy endpoints (Table). Statistically significant improvements were evident at the first measured time point (Week 4) for ▼ Continued on page 20
Published on Oct 10, 2011