Toby C. Chai

Retropubic versus Transobturator Midurethral Slings for Stress Incontinence

BACKGROUND Midurethral slings are increasingly used for the treatment of stress incontinence, but there are limited data comparing types of slings and associated complications. METHODS We performed a multicenter, randomized equivalence trial comparing outcomes with retropubic and transobturator midurethral slings in women with stress incontinence. The primary outcome was treatment success at 12 months according to both objective criteria (a negative stress test, a negative pad test, and no retreatment) and subjective criteria (self-reported absence of symptoms, no leakage episodes recorded, and no retreatment). The predetermined equivalence margin was +/-12 percentage points. RESULTS A total of 597 women were randomly assigned to a study group; 565 (94.6%) completed the 12-month assessment. The rates of objectively assessed treatment success were 80.8% in the retropubic-sling group and 77.7% in the transobturator-sling group (3.0 percentage-point difference; 95% confidence interval [CI], -3.6 to 9.6). The rates of subjectively assessed success were 62.2% and 55.8%, respectively (6.4 percentage-point difference; 95% CI, -1.6 to 14.3). The rates of voiding dysfunction requiring surgery were 2.7% in those who received retropubic slings and 0% in those who received transobturator slings (P=0.004), and the respective rates of neurologic symptoms were 4.0% and 9.4% (P=0.01). There were no significant differences between groups in postoperative urge incontinence, satisfaction with the results of the procedure, or quality of life. CONCLUSIONS The 12-month rates of objectively assessed success of treatment for stress incontinence with the retropubic and transobturator approaches met the prespecified criteria for equivalence; the rates of subjectively assessed success were similar between groups but did not meet the criteria for equivalence. Differences in the complications associated with the two procedures should be discussed with patients who are considering surgical treatment for incontinence. (ClinicalTrials.gov number, NCT00325039.)

AUGMENTED STRETCH ACTIVATED ADENOSINE TRIPHOSPHATE RELEASE FROM BLADDER UROEPITHELIAL CELLS IN PATIENTS WITH INTERSTITIAL CYSTITIS

PURPOSE Extracellular adenosine triphosphate (ATP) has been shown to mediate inflammation and nociception and, therefore, it may have a role in symptoms associated with interstitial cystitis. We theorized that the bladder uroepithelium releases ATP in response to stretch and, furthermore, this process is augmented in interstitial cystitis. MATERIALS AND METHODS We quantitated ATP using the luciferin-luciferase assay. Urinary ATP levels were compared in 35 patients with interstitial cystitis and in 33 normal controls after pH correction. Cultured interstitial cystitis and normal urothelial cells from the bladder biopsies of 5 patients each were stretched with the Flexcell 2000 machine (Flexcell International Corp., McKeesport, Pennsylvania) and supernatant ATP concentrations were measured. RESULTS Mean urinary ATP plus or minus standard error of mean was significantly higher in patients with interstitial cystitis than in controls (L value 985 +/- 161 versus 377 +/- 27, p = 0.0007). Supernatant ATP released by stretched interstitial cystitis cells was stretch intensity dependent when comparing 0%, 10% and 20% elongation, and was also significantly higher in stretched interstitial cystitis than in stretched normal cells. CONCLUSIONS Adenosine triphosphate was significantly elevated in the urine of individuals with interstitial cystitis and the stretch activated release of ATP was augmented in interstitial cystitis urothelium. Increased extracellular ATP may have a role in mechanosensory transduction and to our knowledge it represents a novel hypothesis.

Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor–like growth factor, and epidermal growth factor as urine markers for interstitial cystitis ☆

We previously determined that the urine of interstitial cystitis (IC) patients specifically contains a factor (antiproliferative factor [APF]) that inhibits primary bladder epithelial cell proliferation, and that it has significantly decreased levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and increased levels of epidermal growth factor (EGF) compared with urine from asymptomatic controls and patients with bacterial cystitis. We sought to confirm the specificity of these findings for IC using a larger patient population, including control patients with a variety of urogenital disorders. Clean catch urine specimens were collected from 219 symptomatic IC patients, 113 asymptomatic controls without bladder disease, and 211 patients with various urogenital diseases including acute bacterial cystitis, vulvovaginitis, chronic nonbacterial prostatitis, overactive bladder, hematuria, stress incontinence, neurogenic bladder, benign prostatic hyperplasia, bladder or pelvic pain without voiding symptoms, bladder cancer, prostate cancer, or miscellaneous diagnoses including anatomic disorders. APF activity was determined by (3)H-thymidine incorporation into primary normal adult human bladder epithelial cells. HB-EGF and EGF levels were determined by enzyme-linked immunosorbent assay. APF activity was present significantly more often in IC than control urine specimens (P <0.005 for IC vs any control group; sensitivity = 94%, specificity = 95%, P <10(-82) for IC vs all controls). HB-EGF levels were also significantly lower and EGF levels significantly higher in IC urine than in specimens from controls (P <10(-84) and P <10(-36), respectively). These findings confirm the utility of APF, HB-EGF, and EGF as markers for IC. Understanding the reasons for altered levels of these markers may lead to understanding the pathogenesis of this disorder.

Effect of amitriptyline on symptoms in treatment naive patients with interstitial cystitis/painful bladder syndrome.

PURPOSE Amitriptyline is frequently used to treat patients with interstitial cystitis/painful bladder syndrome. The evidence to support this practice is derived mainly from a small, single site clinical trial and case reports. MATERIALS AND METHODS We conducted a multicenter, randomized, double-blind, placebo controlled clinical trial of amitriptyline in subjects with interstitial cystitis/painful bladder syndrome who were naïve to therapy. Study participants in both treatment arms received a standardized education and behavioral modification program. The drug dose was increased during a 6-week period from 10 up to 75 mg once daily. The primary outcome was a patient reported global response assessment of symptom improvement evaluated after 12 weeks of treatment. RESULTS A total of 271 subjects were randomized and 231 (85%) provided a global response assessment at 12 weeks of followup. Study participants were primarily women (83%) and white (74%), with a median age of 38 years. In an intent to treat analysis (271) the rate of response of subjects reporting moderate or marked improvement from baseline in the amitriptyline and placebo groups was 55% and 45%, respectively (p = 0.12). Of the subgroup of subjects (207) who achieved a drug dose of at least 50 mg, a significantly higher response rate was observed in the amitriptyline group (66%) compared to placebo (47%) (p = 0.01). CONCLUSIONS When all randomized subjects were considered, amitriptyline plus an education and behavioral modification program did not significantly improve symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. However, amitriptyline may be beneficial in persons who can achieve a daily dose of 50 mg or greater, although this subgroup comparison was not specified in advance.

Percutaneous sacral third nerve root neurostimulation improves symptoms and normalizes urinary HB-EGF levels and antiproliferative activity in patients with interstitial cystitis

OBJECTIVES A highly effective treatment for interstitial cystitis (IC) remains elusive. We determined whether sacral third nerve root (S3) percutaneous neurostimulation (PNS) might be effective in relieving symptoms of IC, as well as in normalizing urinary factors that are specifically altered in IC. METHODS Six consecutive patients with symptoms and cystoscopic findings compatible with IC underwent 5 days of continuous S3 neurostimulation by way of leads placed percutaneously into the S3 foramen. Patients filled out voiding frequency diaries and pain and urgency questionnaires before PNS and at the end of PNS when the leads were removed. Urine specimens were collected at these two time points and measured for heparin-binding epidermal growth factor-like growth factor (HB-EGF) by enzyme-linked immunosorbent assay and for antiproliferative factor (APF) activity by (3)H-thymidine uptake by normal human bladder urothelial cells. RESULTS S3 PNS significantly improved all measured parameters toward normal values. Voiding frequency decreased twofold from 23.1 +/- 4.6 to 10.6 +/- 4.0 voids daily during PNS (P = 0.0001). Pelvic pain on a scale of 1 to 10 decreased from 7.0 +/- 1.6 to 2.3 +/- 3.2 (P = 0.05). Urinary urgency on a scale of 1 to 10 decreased from 6.0 +/- 2.2 to 1.8 +/- 1.7 (P = 0. 02). Urinary HB-EGF concentration increased sevenfold from 1.5 +/- 2. 1 to 11.0 +/- 1.7 ng/mL (P <0.0001), and urinary APF activity decreased from -76.1% +/- 31% to -4.5% +/- 8.8% (P = 0.005). CONCLUSIONS S3 PNS significantly decreased symptoms and normalized urinary HB-EGF and APF activity in patients with IC. These results suggest that permanent S3 PNS may be beneficial in treating IC.

Adverse events over two years after retropubic or transobturator midurethral sling surgery: findings from the Trial of Midurethral Slings (TOMUS) study.

OBJECTIVE To describe surgical complications in 597 women over a 24-month period after randomization to retropubic or transobturator midurethral slings. STUDY DESIGN During the Trial of Midurethral Slings study, the Data Safety Monitoring Board regularly reviewed summary reports of all adverse events using the Dindo Surgical Complication Scale. Logistic regression models were created to explore associations between clinicodemographic factors and surgical complications. RESULTS A total of 383 adverse events were observed among 253 of the 597 women (42%). Seventy-five adverse events (20%) were classified as serious (serious adverse events); occurring in 70 women. Intraoperative bladder perforation (15 events) occurred exclusively in the retropubic group. Neurologic adverse events were more common in the transobturator group than in retropubic (32 events vs 20 events, respectively). Twenty-three (4%) women experienced mesh complications, including delayed presentations, in both groups. CONCLUSION Adverse events vary by procedure, but are common after midurethral sling. Most events resolve without significant sequelae.

Urodynamic Measures Do Not Predict Stress Continence Outcomes After Surgery for Stress Urinary Incontinence in Selected Women

PURPOSE We determined the prognostic value of preoperative urodynamic results in patients with stress urinary incontinence. MATERIALS AND METHODS In a 9-center surgical trial, women with stress urinary incontinence were randomized to a Burch or pubovaginal sling procedure. Women were eligible for the study if they had predominant stress urinary incontinence symptoms, a positive cough stress test, a bladder capacity more than 200 ml and urethral hypermobility. Preoperative free uroflowmetry, filling cystometry and pressure flow studies were performed in all. Overall treatment success required a negative pad test, no urinary incontinence on a 3-day diary, a negative stress test, no self-reported stress urinary incontinence symptoms and no re-treatment for stress urinary incontinence. Stress specific success required all of the last 3 criteria. We examined urodynamic measures, and whether the presence of urodynamic stress incontinence, the presence of detrusor overactivity and Valsalva leak point pressure would predict surgical success. RESULTS Subjects with urodynamic stress incontinence had a 2-fold greater odds of overall success when compared with the No urodynamic stress incontinence group, but this trend did not quite reach statistical significance (OR 2.26; 95% C.I. 0.99, 5.17). Odds of stress specific success did not differ by urodynamic stress incontinence status. Subjects with detrusor overactivity did not have significantly worse success rates. Stratifying by treatment group, there was no difference in mean Valsalva leak point pressure values between surgical successes and failures. CONCLUSIONS We found a nearly statistically significant trend that women with urodynamic stress incontinence are twice as likely to have a successful overall outcome from surgical management of stress urinary incontinence as women without urodynamic stress incontinence. The level of Valsalva leak point pressure and the presence of detrusor overactivity do not predict the success outcomes after the Burch or autologous fascia sling procedures in women with pure or predominant stress urinary incontinence. The impact of urodynamic studies on surgical outcomes needs further investigation.

Behavioral Therapy to Enable Women with Urge Incontinence to Discontinue Drug Treatment: A Randomized Trial

BACKGROUND Women with urge urinary incontinence are commonly treated with antimuscarinic medications, but many discontinue therapy. OBJECTIVE To determine whether combining antimuscarinic drug therapy with supervised behavioral training, compared with drug therapy alone, improves the ability of women with urge incontinence to achieve clinically important reductions in incontinence episodes and to sustain these improvements after discontinuing drug therapy. DESIGN 2-stage, multicenter, randomized clinical trial conducted from July 2004 to January 2006. SETTING 9 university-affiliated outpatient clinics. PATIENTS 307 women with urge-predominant incontinence. INTERVENTION 10 weeks of open-label, extended-release tolterodine alone (n = 153) or combined with behavioral training (n = 154), followed by discontinuation of therapy and follow-up at 8 months. MEASUREMENTS The primary outcome, measured at 8 months, was no receipt of drugs or other therapy for urge incontinence and a 70% or greater reduction in frequency of incontinence episodes. Secondary outcomes were reduction in incontinence, self-reported satisfaction and improvement, and scores on validated questionnaires measuring symptom distress and bother and health-related quality of life. Study staff who performed outcome evaluations, but not participants and interventionists, were blinded to group assignment. RESULTS 237 participants completed the trial. According to life-table estimates, the rate of successful discontinuation of therapy at 8 months was the same in the combination therapy and drug therapy alone groups (41% in both groups; difference, 0 percentage points [95% CI, -12 to 12 percentage points]). A higher proportion of participants who received combination therapy than drug therapy alone achieved a 70% or greater reduction in incontinence at 10 weeks (69% vs. 58%; difference, 11 percentage points [CI, -0.3 to 22.1 percentage points]). Combination therapy yielded better outcomes over time on the Urogenital Distress Inventory and the Overactive Bladder Questionnaire (both P <0.001) at both time points for patient satisfaction and perceived improvement but not health-related quality of life. Adverse events were uncommon (12 events in 6 participants [3 in each group]). LIMITATIONS Behavioral therapy components (daily bladder diary and recommendations for fluid management) in the group receiving drug therapy alone may have attenuated between-group differences. Assigned treatment was completed by 68% of participants, whereas 8-month outcome status was assessed on 77%. CONCLUSION The addition of behavioral training to drug therapy may reduce incontinence frequency during active treatment but does not improve the ability to discontinue drug therapy and maintain improvement in urinary incontinence. Combination therapy has a beneficial effect on patient satisfaction, perceived improvement, and reduction of other bladder symptoms.

BLADDER STRETCH ALTERS URINARY HEPARIN-BINDING EPIDERMAL GROWTH FACTOR AND ANTIPROLIFERATIVE FACTOR IN PATIENTS WITH INTERSTITIAL CYSTITIS

PURPOSE The etiology of interstitial cystitis is unknown. Urine from patients with interstitial cystitis has been shown to inhibit urothelial proliferation through a putative antiproliferative factor and to contain decreased levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) compared to controls. Stretch of detrusor smooth muscle cells is known to stimulate HB-EGF production. Because bladder hydrodistention sometimes alleviates the symptoms of interstitial cystitis, we determined whether the stretch stimulus of hydrodistention alters antiproliferative factor activity and/or HB-EGF in interstitial cystitis urine specimens. MATERIALS AND METHODS Urine was collected immediately before, and 2 to 4 hours and 2 weeks after hydrodistention from 15 patients with symptoms and cystoscopic findings compatible with interstitial cystitis and 13 controls. Hydrodistention was performed with the subject under general or regional anesthesia and bladders were distended to 80 cm. water 3 times. Urinary HB-EGF was measured by enzyme-linked immunosorbent assay and urinary antiproliferative factor activity was determined by measuring 3H-thymidine uptake by normal human bladder urothelial cells. RESULTS Hydrodistention significantly increased urinary HB-EGF in patients with interstitial cystitis toward normal control values (before distention p = 0.003, 2 weeks after distention p = 0.67). Urine antiproliferative factor activity decreased significantly after hydrodistention in patients with interstitial cystitis. However, antiproliferative factor activity in interstitial cystitis and control specimens was still statistically different 2 weeks after distention (before distention p = 0.0000004, 2 weeks after distention p = 0.04). CONCLUSIONS Bladder stretch increased HB-EGF and conversely reduced antiproliferative factor activity in urine from patients with interstitial cystitis but not controls up to 2 weeks after distention. These results provide additional evidence for the possible role of antiproliferative factor and decreased HB-EGF in the pathophysiology of interstitial cystitis. To our knowledge this is also the first human study to show that in vivo bladder stretch can alter urinary factors that regulate cell growth.

NEUROPHYSIOLOGY OF MICTURITION AND CONTINENCE

This article reviews the neuroanatomy, neurophysiology, and neuropharmacology involved in micturition and continence. Knowledge of these topics helps the clinician diagnose and treat voiding disorders that are caused by disease, trauma, drugs, and aging.