Highlights From the Combined Society of Urodynamics and Female Urology, and International Society of Pelvic Neuromodulation Annual Meeting

Highlights From the Combined Society of Urodynamics and Female Urology, and International Society of Pelvic Neuromodulation Annual Meeting Gary E. Lemack,*,† Cindy Amundsen,‡ Gopal Badlani,§ Tomas Griebling,储 Kenneth Peters,¶ Larissa Rodriguez, Ajay Singla,** Christopher Smith,†† Maryrose Sullivan and Alexis Te‡‡ Key Words: congress, urodynamics, urinary incontinence, female, prostate year. These findings support the use of UDS in preoperative counseling before PVP. Data on a group of 265 patients (55 in AUR) who underwent PVP with 2-year followup were also reported. At treatment mean prostate volume was 90.9 ml with a patient age range of 44 to 103 years and a mean American Society of Anesthesiologists class of 2.2. No transfusions were required and 96% of patients were discharged home within 23 hours. Durable improvements in symptom scores (greater than 50%) and flow rates (greater than 100%) were reported, suggesting that PVP is a viable alternative for LUTS and/or AUR regardless of prostate size. Transurethral prostate resection was compared to 2 methods of transurethral ethanol ablation. Significant decreases in I-PSS were seen throughout followup with all 3 treatments. At 12 months of followup peak flow had increased by 35% following superficial ethanol injection, by 33% following deep injection and by 101% following transurethral prostate resection. In a separate study data were presented on 279 men with LUTS treated with a transurethral ethanol ablation procedure at 37 institutions worldwide. By 6 months I-PSS and quality of life scores demonstrated 52% to 55% improvement, while maximum urine flow improved by 45%, which was sustained at 2 years. The pathophysiology underlying LUTS following brachytherapy was also investigated. Of men referred for LUTS following brachytherapy 79% complained of OAB symptoms, 71% reported incontinence, 41% had obstructive symptoms and 30% had dysuria. The incidence of urethral obstruction was approximately 66% and DO was present in about 90% of cases. Low bladder compliance was present in 24% of cases. Of note, at cystoscopy 47% of the men had prostatic and/or urethral strictures, 19% had radiation prostatitis and 11% had stones adherent to the prostatic urethra. These findings suggest that the pathophysiology and severity of persistent LUTS in men who undergo brachytherapy differs from those in men with LUTS in the general population and cystoscopy has a significant diagnostic role.

he combined winter meeting of the Society for Urodynamics and Female Urology, and International Society of Pelvic Neuromodulation was held from February 22 to 25, 2006 on Grand Bahama Island, Freeport, Bahamas. Several sister societies with an interest in lower urinary tract health participated, including the Society for Genitourinary Reconstructive Surgery, Geriatric Urological Society and the International Continence Society. This review highlights new scientific presentations from the combined meeting.

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EVALUATION AND TREATMENT OF LUTS IN MEN The role of UDS before surgery was evaluated in men scheduled to undergo high power KTP PVP for benign prostatic hyperplasia. Of 40 men in AUR 20% had impaired detrusor contractility and 75% had DO preoperatively. Overall men in AUR benefited from PVP with an improvement in I-PSS, flow rate and post-void residual urine regardless of UDS. However, patients who were originally found to have DO had higher symptoms scores and they were also almost twice as likely to require anticholinergic therapy postoperatively. Men without impaired detrusor contractility had better symptom improvement, flow rates and post-void residual urine. Additionally, men with impaired detrusor contractility were more likely to undergo reoperation within the first

Submitted for publication April 6, 2006. * Correspondence: University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9110 (telephone: 214-648-7190; FAX: 214-648-8786). † Financial interest and/or other relationship with Pfizer, Astellas and Allergan. ‡ Financial interest and/or other relationship with NDI, Pfizer, Allergan, American Medical Systems and Life Tech. § Financial interest and/or other relationship with American Medical Systems, Johnson & Johnson, Pfizer, Novartis, and Yamanouchi. 储 Financial interest and/or other relationship with Medtronic and Pfizer. ¶ Financial interest and/or other relationship with Advanced Bionics, Medtronic, Indevus and Boston Scientific. ** Financial interest and/or other relationship with American Medical Systems and Astellas. † † Financial interest and/or other relationship with Allergan. ‡ ‡ Financial interest and/or other relationship with Laserscope, National Institutes of Health/National Institute for Diabetes and Digestive and Kidney Diseases, Glaxo, Sanofi Aventis and Astellas.

0022-5347/07/1772-0691/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION

GERIATRIC UROLOGY Recent census data revealed that 66.2% of older adults live with others in a community household setting, while approximately 1.45 million elderly individuals live in the almost

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Vol. 177, 691-695, February 2007 Printed in U.S.A. DOI:10.1016/j.juro.2006.09.054

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16,000 nursing homes in the United States. The prevalence of urinary incontinence in older adults is estimated to be 15% to 30% in community dwellers to greater than 50% in those in nursing homes. The economic impact is staggering with projected total costs of more than $8.3 billion annually. Interestingly the Centers for Medicare and Medicaid Services have targeted urinary incontinence as one of the key quality indicators for nursing homes. Fecal incontinence provides unique challenges in the geriatric population. Approximately 40% to 48% of nursing home residents experience combined urinary and fecal incontinence and another 2% to 12% have isolated fecal incontinence. Recent data suggest that implementing soluble fiber in the diets of older adults may improve fecal continence. Issues facing elderly patients contemplating pelvic surgery were also discussed. Recent data showed that older adults may have successful clinical outcomes, although postoperative complications are not well tolerated, which may lead to significant morbidity and mortality. Evaluation of functional capacity, including activities of daily living, instrumental activities of daily living, and baseline physical and cognitive function, can be quite valuable for predicting postoperative complications, such as delirium, falls, pneumonia, venous thromboembolism and wound complications. IC The Urothelium A small clinical trial investigating the permeability of IC bladders used quantitative fluorescein uptake to compare pathological (IC) bladders to controls. An unexpected finding was that, rather than demonstrating enhanced permeability, patients with IC had less permeability and less variability of quantitative fluorescein uptake than control patients, thereby questioning the role of urothelial permeability in IC. The role of the nuclear factor-␬B signaling pathway was studied in cell culture of IC urothelium compared to control. The investigators noted that an aberrant signaling pathway was present in IC cell culture compared to controls, leading to increased urothelial apoptosis. It was speculated that this abnormal signaling may lead to cytoprotective losses, which may have a role in the pathogenesis of IC. Epidemiology Results of a comprehensive symptom survey of 407 followed patients with IC and 5,000 age matched controls were reported. To estimate the true prevalence of IC various symptom combinations were examined. Using complaints of pelvic pain plus urinary urgency and/or frequency to define IC in the general population the prevalence was 4.4%, while the prevalence was 15.3% using pelvic pain only. Also, using the most conservative estimate of IC (self-reported IC and symptoms suggestive of IC) the prevalence was 1.3%. These findings highlight the variability in prevalence estimates of IC depending on the symptom criteria used. Neuromodulation Bilateral caudal epidural S2-S4 neuromodulation for the treatment of IC and OAB was reported. Overall 71% of patients had successful trial stimulation and underwent

permanent implantation. In the refractory IC population group IC symptoms and the problem index improved by 37%, and the female sexual function questionnaire improved by 56%. After implantation 13% of patients underwent device removal due to poor efficacy and 15% required revision. A report of 6-month followup with chronic PNS for IC demonstrated that 17 of 22 subjects with refractory IC tested with a sacral (SNS) and a pudendal lead had a positive clinical response and underwent placement of a permanent generator. Of those patients 13 of 17 found PNS to be superior. Daily voids decreased 33% with SNS and 41% with PNS. Mean voided volume increased 21% and 95%, and the IC symptom/problem index improved 38% and 44% with SNS and PNS, respectively. NEUROMODULATION Technique Neuromodulation continues to be an attractive therapy in patients with refractory urgency incontinence and voiding dysfunction. With the development of a tined lead adverse events and surgical revisions due to lead fracture and migration have decreased. Reports about difficult to treat subpopulations are optimistic. A randomized, prospective study of older urge incontinent women reported by Barawski et al was awarded the first prize in clinical research. They noted a higher likelihood of successful test stimulation with a 2-stage approach than with percutaneous needle electrode placement in this patient population (88% vs 46%, p ⫽ 0.02). Patient Selection Urodynamic parameters were found to be nonpredictive of the patient response to sacral neuromodulation. Interestingly OAB symptoms developing after incontinence/prolapse surgery were found to respond to sacral neuromodulation. After implantation neurophysiological testing may be able to monitor the effects of the therapy but more studies are needed. High long-term satisfaction (80% of patients satisfied at mean of 27 months) was reported, which correlated with improved quality of life in urge incontinent women. FEMALE SUI A number of studies were presented evaluating treatment for SUI in females. Most evaluated the outcome of mid urethral slings and focused on predictors of failure, such as preoperative symptoms of UI, particular preoperative urodynamic findings, race, age, body mass index and concomitant prolapse surgery, among others. The importance of patient driven subjective outcome determination and quality of life measures were also a focus of discussion. In the evaluation of SUI investigators noted poor reliability of self-reported daily pad use vs pad weights and they concluded that older women tend to report the use of more pads daily regardless of the actual volume of urine loss. Also, studying predictors of severity, investigators from a surgical trial in 650 women undergoing Burch colposuspension or pubovaginal sling for SUI noted that Valsalva leak point pressure correlated poorly with incontinence severity, determined by a validated questionnaire, and demonstrable

COMBINED ANNUAL MEETING HIGHLIGHTS stress incontinence, determined by an empty bladder stress test. Although the use of periurethral bulking agents remains somewhat limited, largely due to relatively low efficacy and the need for re-treatment, there remains enthusiasm for finding a more durable agent. A clinical trial evaluating the safety and efficacy of calcium hydroxylapatite was presented, in which 296 women were randomized to calcium hydroxylapatite or bovine collagen injections. The material was well tolerated but overall improvement at 12 months was not superior to that seen with collagen treatment. Several studies compared the outcomes of minimally invasive mid urethral slings. In a retrospective review of 750 patients who were treated with tension-free vaginal tape the overall resolution of UI in those with mixed incontinence was 70% with a de novo rate of 5%. In contrast, in patients undergoing concomitant prolapse surgery the cure rate of UI was only 55%. In a retrospective comparison of mid urethral retropubic slings (tension-free vaginal tape and SPARC™), transobturator slings and transvaginal bladder neck slings attached to Cooper’s ligament, bladder neck slings were more likely to result in persistent postoperative UI and DO. Transobturator slings appeared to be more likely than other surgeries to cure UI symptoms and DO in patients who underwent the procedure for symptoms of mixed incontinence, while they showed the lowest rate of de novo UI (less than 1%). Following the distal urethral polypropylene sling the resolution of UI appeared to be age dependent with younger patients more likely to experience UI. Complication rates of existing mid urethral slings were also discussed. When comparing the total number of major complications reported in the international literature to the number of these complications self-reported in the Manufacturer and User Facility Device Experience Food and Drug Administration database during a similar period, 1 group concluded that there appears to be significant underreporting of these complications in the academic literature. Similarly a study evaluating a 5% Medicare national sample of beneficiaries who underwent sling procedures also showed complication rates within the first postoperative year to be higher than those reported in the literature. Minor complications after mid urethral slings are more frequently reported, of which vaginal extrusion of mesh material is one of the most common. Investigators comparing rates of these complications among procedures found that the ObTape™ showed almost a 5 to 8-fold increase in vaginal erosion than SPARC or placement of a soft polypropylene sling with bone anchors, an erosion rate that is far greater than previously reported in multicenter studies. In addition, 63% of patients reported persistent significant voiding symptoms after explantation of mid urethral slings for erosion. Lastly, in women with refractory SUI use of a spiral (circumferential) polypropylene sling resulted in a completely dry rate of 52% with an 84% improvement rate. PELVIC ORGAN PROLAPSE Basic Science Two pilot studies investigated gene expression patterns in women with SUI. An evaluation of differential gene expres-

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sion patterns in postmenopausal women with and without SUI revealed that, compared to controls, 1,788 genes were over expressed, while 1,676 were under expressed in women with SUI. Certain proteins, such as collagens XXIV␣1 and XXV␣1, were under expressed in SUI females more than 3-fold compared to controls. In a separate study fibroblasts from vaginal tissue taken from continent and stress incontinent women were noted to be differentially responsive to estrogen. After exposure to 17-␤-estradiol there was a 5-fold increase in elastolytic activity in continent women, while a 5-fold decrease occurred in women with SUI, suggesting that differences in estrogen receptor expression and elastolytic activity may have a role in the etiology of SUI in some women. The effect of vaginal prolapse on smooth muscle contractility was studied using vaginal biopsies from patients undergoing repair for vault prolapse compared to controls. Essentially no smooth muscle contractility was noted in response to ␣ agonist or cholinergic stimulation in the prolapse group, while responses were noted in control tissue. No changes in myosin or ␣1 receptor protein concentrations were noted in either group, suggesting that changes in ␣-adrenergic isoform expression and/or receptor function may affect smooth muscle function, although it was unclear if this is a cause or an effect of prolapse. Evaluation Vaginal pack reduction during urodynamics for moderate to large cystocele was evaluated for predicting the stress incontinence outcome after anatomical repair. Of 53 women who did not leak during UDS only 4 (8%) required secondary anti-incontinence procedures following anterior vaginal wall suspension. Overall UDS findings with vaginal pack reduction correctly predicted the outcome in 82% of patients with positive and negative predictive values of 13% and 92%, respectively. Treatment The long-term outcomes of a technique using a single piece of monofilament polypropylene mesh to correct anterior compartment defects and provide mid urethral and vaginal vault support was also reported. Of 76 patients with a mean followup of 30.7 months recurrent prolapse was noted in 5.2%, while 86% reported being continent. Major complications such as vaginal erosion occurred in 2.1% of patients and urethrolysis for retention occurred in 1.1%. The outcome following Pelvicol™ mesh in 250 patients during a 5-year period was reported. Impaired vaginal healing and infection with Pelvicol in various pelvic floor reconstructions was noted in 8% of cases. Most patients experienced vaginal wound separation, while several had infection requiring excision or drainage. Histological analysis after excision revealed graft preservation without neovascularity or host fibroblast proliferation. To determine the impact of surgeon volume on sling procedures a review of a random 5% of Medicare beneficiaries from January 1999 to July 2000 who underwent sling procedures revealed statistically significant differences between high and low volume providers. High volume surgeons were more likely to perform concomitant prolapse surgery, while low volume surgeons had higher reoperation rates to correct prolapse during the first year. These results

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suggest that high volume surgeons are more likely to diagnose and treat prolapse at sling surgery or alternatively performing a sling alone may hasten the development of subsequent prolapse even if prolapse is not noted initially.

MALE INCONTINENCE In a study of men with post-prostatectomy incontinence researchers found that the likelihood of involuntary detrusor contraction was greater with a history of radiation therapy (10 times) or bladder neck contracture (5 times) and this urodynamic finding that could not be predicted by questionnaire. The same group evaluated the usefulness of 3 selfadministered questionnaires and found that improvements in 24-hour pad weight strongly correlated with changes using 2 validated incontinence questionnaires. The feasibility and efficacy of AUS placement following a male sling was evaluated. At a mean followup of 30 months sling surgery failed in 18 patients, of whom 11 underwent AUS implantation. No intraoperative complications were noted. Overall 81.8% of patients were cured/improved, suggesting that AUS as salvage is safe and efficacious. A retrospective study of 81 men who underwent a male sling (43) or AUS (38) was reported. The investigators subdivided these groups into mild to moderate and severe urinary incontinence groups. For mild to moderate incontinence 90% of patients were cured/improved with a male sling vs 80% of those with an AUS. Of patients with severe UI 72% were cured/improved with an AUS, while only 58% were improved after a sling. Somewhat different findings were noted in a similar comparative study of 56 men undergoing an AUS or male sling with a mean followup 25 to 30 months, in which similar outcomes were noted after the 2 procedures regardless of incontinence severity. A retrospective study of 271 men who received an AUS during 13 years was presented. Pad use significantly decreased from 5.3 to 1.1 at a followup of 36 months. The infection rate was 5.5%, while the cuff erosion rate was 6.4% and the device malfunction rate was 5.9%. The group also noted that radiation treatment did not impact overall the rate of infection, urethral atrophy or cuff erosion compared to nonradiotherapy patients. The overall revision rate was 26.9%.

BASIC RESEARCH: BLADDER AND PELVIC FLOOR Using an in vitro model to measure human bladder tissue contractility investigators discovered that ␳ kinase inhibition significantly attenuated the maximal contraction induced by carbachol and the remaining contraction appeared to be M2 mediated. Their finding suggests that ␳ kinase is activated by M3 muscarinic receptor stimulation. Phosphoinositide phospholipase or protein kinase C inhibition had no effect on carbachol contractions, implying that these pathways are not required for normal bladder contraction or parallel pathways exist. These signaling relationships were further explored in M2 and M3 receptor knockout mice. Inhibition of ␳ kinase completely inhibited contractions in M3 knockout bladders and inhibited maximal contraction by 40% in M2 receptor knockout mice, suggesting that ␳ kinase is required for M2 medi-

ated bladder contractions in mice and it participates in M3 mediated contractions. The relationship between mucosal muscarinic receptor density and the functionally predominate muscarinic subtype mediating bladder contraction was studied in organ transplant donor bladders. Investigators found that M2 and M3 receptor densities in the mucosa increased dramatically in bladders that generate predominantly M2 mediated contractions compared to those with primarily M3 mediated contractions, implying a possible role of urothelial muscarinic receptors in pathological bladder contractions. Several abstracts presented data on potential mechanisms underlying DO, possibilities for new approaches to treatment and alternative mechanisms of pharmacological action. For example, oxybutynin, which is known to have muscarinic and calcium channel blocking properties, was found to modulate C-fiber neuron excitability through the inhibition of voltage gated sodium channels, suggesting an additional mechanism by which oxybutynin exerts its effects in OAB. In a rat model of chronic bladder outlet obstruction dorsal root ganglion neurons were shown to be more sensitive to tetrodotoxin and have decreased action potential thresholds compared to normal values. The effect of combined 5-hydroxytryptamine type 3 receptor and noradrenaline reuptake inhibition using the drug DDP225 was studied in acetic acid irritated rat/cat bladders. DDP225 reversed the decreases in bladder capacity induced by acetic acid and increased functional bladder capacity without impairing bladder contractile function when given orally. Lastly, the prostacyclin receptor (subtype IP) antagonist RO3244019 was shown to increase intercontractile intervals and voided volumes in spinal cord injured rats, which suggests that neurogenic DO may in part be mediated by prostaglandins and the activation of prostacyclin receptors. Bladder dysfunction was characterized in a murine model of EAE. Mice with EAE showed urodynamic patterns, ranging from DO with detrusor-external sphincter dyssynergia to detrusor hypotonicity, suggesting that EAE could be used in future studies of multiple sclerosis induced bladder dysfunction. An update on the use of adipose stem cells for bladder augmentation was presented. Smooth muscle cells were differentiated from adipose stem cells and seeded in a 3-dimensional poly lactic-glycolic acid scaffold. Bladder augmentation using this construct following partial cystectomy in rats increased bladder capacity and compliance compared to unseeded grafts. Several research studies related to SUI were presented. In a model of SUI induced by urethrolysis adipose stem cells differentiated into smooth muscle cells were mixed with poly lactic-glycolic acid microspheres and injected into the urethra. After 2 weeks urethral resistance and function were restored relative to microsphere injection alone. Another group investigated the possible application of homing molecules that signal innate stem cell migration to ischemic injury sites. One such cytokine, monocyte chemotactic protein-3, was significantly over expressed in urethral and vaginal tissues of animals injured by vaginal distention, suggesting that specific stem cell homing molecules may initiate a repair mechanism that can be potentially exploited for SUI treatment. Using a similar distention model in which to compare diabetic and normal vaginal tissues more pronounced ischemic effects were noted in diabetes. Finally,

COMBINED ANNUAL MEETING HIGHLIGHTS angiotensin II was implicated in the maintenance of urethral tone and continence. Inhibition of angiotensin 1 receptors decreased urethral resistance in normal rats, while administration of angiotensin II increased resistance after pudendal nerve injury or urethrolysis. An important role for caveolae, which are flask-shaped invaginations of the plasma membrane, in modulating specific signal transduction pathways was demonstrated in bladder smooth muscle by Cristofaro et al in a study that was awarded first prize in the basic science essay contest. Caveolae were found to serve as a positive modulator of angiotensin and serotonin induced bladder contractions but also as a negative modulator of bradykinin or phenylephrine induced bladder contractions. In addition, caveolae gene expression increased with continuous electrical stimulation, suggesting that these organelles respond to changing bladder demands.

Abbreviations and Acronyms AUR AUS DO EAE IC I-PSS LUTS OAB PNS PVP

⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽

SNS SUI UDS UI

⫽ ⫽ ⫽ ⫽

acute urinary retention artificial urinary sphincter detrusor overactivity experimental autoimmune encephalitis interstitial cystitis International Prostate Symptom Score lower urinary tract symptoms overactive bladder pudendal nerve stimulation photoselective laser vaporization prostatectomy sacral nerve stimulation stress UI urodynamics urinary incontinence

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