Patrick J. Shenot

OnabotulinumtoxinA for the Treatment of Patients with Overactive Bladder and Urinary Incontinence: Results of a Phase 3, Randomized, Placebo Controlled Trial

Purpose: Overactive bladder affects 12% to 17% of the general population and almost a third experience urinary incontinence, which may severely impact health related quality of life. Oral anticholinergics are the mainstay of pharmacological treatment but they are limited by inadequate efficacy or side effects, leading to a high discontinuation rate. We report the results of the first large (557 patients), phase 3, placebo controlled trial of onabotulinumtoxinA in patients with overactive bladder and urinary incontinence inadequately managed with anticholinergics. Materials and Methods: Eligible patients with overactive bladder, 3 or more urgency urinary incontinence episodes in 3 days and 8 or more micturitions per day were randomized 1:1 to receive intradetrusor injection of onabotulinumtoxinA 100 U or placebo. Co‐primary end points were the change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a positive response on the treatment benefit scale at posttreatment week 12. Secondary end points included other overactive bladder symptoms and health related quality of life. Adverse events were assessed. Results: OnabotulinumtoxinA significantly decreased the daily frequency of urinary incontinence episodes vs placebo (−2.65 vs −0.87, p <0.001) and 22.9% vs 6.5% of patients became completely continent. A larger proportion of onabotulinumtoxinA than placebo treated patients reported a positive response on the treatment benefit scale (60.8% vs 29.2%, p <0.001). All other overactive bladder symptoms improved vs placebo (p ≤0.05). OnabotulinumtoxinA improved patient health related quality of life across multiple measures (p <0.001). Uncomplicated urinary tract infection was the most common adverse event. A 5.4% rate of urinary retention was observed. Conclusions: OnabotulinumtoxinA 100 U showed significant, clinically relevant improvement in all overactive bladder symptoms and health related quality of life in patients inadequately treated with anticholinergics and was well tolerated.

Intravesical Resiniferatoxin for Refractory Detrusor Hyperreflexia: A Multicenter, Blinded, Randomized, Placebo-Controlled Trial

Abstract Objective: Resiniferatoxin (RTX) is an analogue of capsaicin with more than 1,000 times its potency in desensitizing C-fiber bladder afferent neurons. This study investigated the safety and efficacy of intravesical RTX in patients with refractory detrusor hyperreflexia (DH). Methods: Thirty-six (22 males, 14 females) neurologically impaired patients (20 spinal cord injury, 7 multiple sclerosis, 9 other neurologic diseases) with urodynamically verified DH and intractable urinary symptoms despite previous anticholinergic drug use were treated prospectively with intravesical RTX using dose escalation in a double-blind fashion at 4 centers. Patients received a single instillation of 100 ml of placebo (n = 8 patients) or 0.005, 0.025, 0.05 , 0.10 , 0.2, 0.5, or 1.0 fLM of RTX (n = 4 each group). A visual analog pain scale (VAPS) (0-10; 10 = highest level of pain) was used to quantify discomfort of application. Treatment effect was monitored using a bladder diary and cystometric bladder capacity at weeks 1, 3, 6, and 1 2 posttreatment. Results: Mean VAPS scores revealed minimal to mild discomfort with values of 2.85 and 2.28 for the 0.5-j-LM and 1.0-j-LM RTX treatment groups, respectively. Due to the small sample size, there were no statistically significant changes in mean cystometric capacity (MCC) or incontinence episodes in each treatment dose group. However, at 3 weeks, MCC increased by 53% and 48% for the 0.5-j-μM and 1.0-j-μM RTX treatment groups, respectively. Patients in the 0.5-j-μM and 1.0-j-μM groups with MCC < 300 ml at baseline showed greater improvements in MCC at 120.5% and 48%, respectively. In some patients, MCC increased up to 500% over baseline, despite a low RTX dose. Incontinence episodes decreased by 51.9% and 52.7% for the 0.5-j-LM and 1.0-j-LM RTX treatment groups, respectively. There were no long-term complications. Conclusion: Intravesical RTX administration, in general, is a well-tolerated new therapy for DH. This patient group was refractory to all previous oral pharmacologic therapy, yet some patients responded with significant improvement in bladder capacity and continence function shortly after RTX administration. Patients at risk for autonomic dysreflexia require careful monitoring during RTX therapy.

LONG-TERM FOLLOWUP OF THE NORTH AMERICAN MULTICENTER UROLUME* TRIAL FOR THE TREATMENT OF EXTERNAL DETRUSOR-SPHINCTER DYSSYNERGIA

PURPOSE We determine the long-term efficacy and safety of the UroLume stent as minimally invasive treatment for external detrusor-sphincter dyssynergia in spinal cord injured men. MATERIALS AND METHODS A total of 160 spinal cord injured men with a mean age plus or minus standard deviation of 36.3 +/- 12.1 years (range 16 to 74) were prospectively treated with an endoprosthesis at 15 centers as part of the North American UroLume trial for external detrusor-sphincter dyssynergia. Urodynamic parameters, including voiding pressure, residual urine volume and bladder capacity, were compared before treatment and at 1, 2, 3, 4 and 5 years after treatment. RESULTS Mean voiding pressure was 75.1 +/- 28.2 cm. water before treatment in the 160 patients, and 37.4 +/- 23.9 at year 1 in 97, 39.5 +/- 22.2 at year 2 in 84, 42.6 +/- 27.3 at year 3 in 61, 46.3 +/- 33.2 at year 4 in 57 and 44.2 +/- 28.9 cm. at year 5 in 41 after stent insertion (p <0.001). Residual urine volume decreased after stent placement and was maintained throughout the 5-year followup (p <0.001). Mean cystometric capacity remained constant from 269 +/- 155 before insertion to 337 +/- 182 ml. 5 years later (p = 0.17). Hydronephrosis and autonomic dysreflexia improved or stabilized in most patients with functioning stents. Stent explant was necessary in 24 patients (15%), of whom 4 (16.7%) had another stent implanted. CONCLUSIONS The UroLume stent demonstrates long-term safety and efficacy for the treatment of external detrusor-sphincter dyssynergia. The outcome was similar in men with and without previous sphincterotomy.

REMOVAL OF UROLUME ENDOPROSTHESIS: EXPERIENCE OF THE NORTH AMERICAN STUDY GROUP FOR DETRUSOR-SPHINCTER DYSSYNERGIA APPLICATION

PURPOSE We present the experience of the North American UroLume Multicenter Study Group with removal of the UroLume endoprosthesis. MATERIALS AND METHODS A total of 160 neurologically impaired patients were enrolled in the North American UroLume Multicenter Study Group for detrusor external sphincter dyssynergia application. Analysis was performed in 2 groups of patients in which the device was removed during insertion and after implantation, respectively. RESULTS Device retrieval was required during insertion in 21 patients (13%) mainly due to misplacement or migration in 17. Extraction was done with minimal complications and in all but 2 cases subsequent UroLume implantation was successful. Of 158 men with the device in place 31 (19.6%) required removal. In 34 procedures 44 devices were removed, mainly due to migration. Time from implantation to removal ranged from 4 days to 66 months (mean 22 months). The UroLume was removed en bloc in 20 cases and in parts or wire by wire in 19. The majority of patients had no or minimal complications after extraction. Only 2 patients had serious temporary complications, including bleeding and urethral injury, with no lasting consequences. No malignancy developed as a result of UroLume insertion. CONCLUSIONS While there is a potential for urethral injury and bleeding, UroLume endoprosthesis removal is largely a simple procedure with minimal complications and consequences.

A Molecular Marker for the Development of Interstitial Cystitis in a Rat Model: Isoactin Gene Expression

PURPOSE To determine whether the differential expression of bladder smooth muscle isoactin can be used as a molecular marker for the development of interstitial cystitis (IC). METHODS Three groups of five female Sprague-Dawley rats each underwent urethral catheterization and intravesical instillation of 0.5 ml. of 0.4N HCl. One group was sacrificed one, two and four weeks after the application of HCl, and their bladders harvested for histologic examination and evaluation using Northern blot analysis of bladder smooth muscle isoactins. Five control animals were sacrificed and their bladders harvested to establish isoactin gene expression of bladder smooth muscle in the normal state. The bladders of the rats in each group were excised, immediately frozen in liquid nitrogen, pooled, then stored -70 degrees C until needed for RNA isolation. Isoactin cDNA probes have been developed, therefore isoactin specific cDNA insert fragments were isolated and insert DNA was purified by gel electrophoresis. Total cellular RNA was isolated from 1.0 gm. of bladder smooth muscle from each group. After spectrophotometric quantification, Northern Blot analysis was performed using 2% agarose-formaldehyde gels and Biotrans nylon membranes. Two complete Northern Blot series were run on a single gel and blotted to a single membrane to eliminate gel and blotting discrepancies. RESULTS Microscopic histologic analysis revealed detrusor mastocystosis and eosinophilia as has been noted in humans with chronic interstitial cystitis. Two weeks after the intravesical application of hydrochloric acid, the relative expression of gamma-smooth muscle isoactin was noted to increase by 1.7-fold, while alpha-smooth muscle isoactin expression increased by a factor of 9. These effects were seen to stabilize four weeks after acid application. CONCLUSIONS The intravesical application of dilute HCl in rats results in a histologic appearance which mimics that seen in humans with interstitial cystitis. The appearance of detrusor mastocytosis and eosinophilia was accompanied by a relative decrease in the expression of gamma- and a relative increase in alpha-smooth muscle isoactin gene expression. This pattern of smooth muscle isoactin expression is consistent with a more immature and possibly synthetic smooth muscle phenotype, which may be responsible for the clinical presentation of those with IC. Northern blot analysis of bladder smooth muscle cells may serve as an effective marker for the development of interstitial cystitis in humans.

OnabotulinumtoxinA improves quality of life in patients with neurogenic detrusor overactivity.

Objective: To evaluate the effects of onabotulinumtoxinA on patient-reported outcomes including health-related quality of life (HRQOL), treatment satisfaction, and treatment goal attainment in patients with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO). Methods: In this multicenter, double-blind, randomized, placebo-controlled, phase III, 52-week study (ClinicalTrials.gov NCT00311376), patients with UI due to NDO who were not adequately managed with anticholinergic therapy were treated with intradetrusor injections of onabotulinumtoxinA (200 or 300 U) or placebo (0.9% saline). HRQOL measures included the Incontinence Quality of Life (I-QOL) Questionnaire total score, and the 3 domain scores (avoidance and limiting behavior, psychosocial, and social embarrassment), the modified Overactive Bladder Patient Satisfaction with Treatment Questionnaire (OAB-PSTQ), and Patient Global Assessment. Assessments were made at baseline, posttreatment week 6 (primary time point), week 12, and at 12-week intervals. Results: Patients (mean age of 46 years with 30.5 weekly UI episodes at baseline) were randomized to receive placebo (n = 149) or onabotulinumtoxinA (200 U [n = 135] or 300 U [n = 132]). At week 6, improvements from baseline in I-QOL Questionnaire total score were greater (p < 0.001) in both onabotulinumtoxinA-treated groups vs placebo. Responses to the OAB-PSTQ also demonstrated greater mean improvements from baseline (p < 0.001) in both onabotulinumtoxinA-treated groups vs placebo at week 6. Patients who received onabotulinumtoxinA also reported greater improvement in the Patient Global Assessment than those in the placebo group (p ≤ 0.001 vs placebo). Conclusions: Patients with UI due to NDO reported greater improvement in HRQOL and treatment satisfaction with onabotulinumtoxinA than with placebo consistently across several patient-reported outcome instruments. Classification of evidence: This study provides Class I evidence that onabotulinumtoxinA intradetrusor injections (200 or 300 U) can improve quality of life measures in patients with NDO not adequately managed with anticholinergic therapy.

Early predictors of bladder recovery and urodynamics after spinal cord injury

Our purpose was to determine if intact perianal (S4–5) pin sensation (PPS) and bulbocavernosus (S2–4) reflex (BCR) shortly after spinal cord injury (SCI) are predictive of bladder function recovery. Twenty‐eight SCI patients (aged 18–68 years, Frankel Classification A–D, spinal injury level C4–T12), admitted within 72 hours of injury, underwent evaluation of initial PPS and BCR. The presence of intact PPS and BCR were correlated with the patients voiding function and urodynamic evaluation results 1 year postinjury. Of the 28 patients within 72 hours of SCI, PPS was intact in 17 (60%) and absent in 11 (40%), while 15 patients (54%) demonstrated a positive BCR and 13 (46%) did not. One year after SCI, no patient with absent PPS voided unassisted, while of the 17 patients with preserved PPS, 11 (65%) were voiding spontaneously. Of these 11 patients, urodynamic evaluation revealed detrusor areflexia in 1 (9%), normal detrusor function in 2 (18%), and detrusor hyperreflexia in 8 (73%), with 3 of these 8 patients (38%) also demonstrating detrusor‐sphincter dyssynergia. At 1 year postinjury, only 2 of 13 patients (15%) with an absent BCR voided spontaneously, while 9 of 15 patients (60%) with an intact BCR were able to void. Although PPS and BCR are moderately sensitive in predicting the return of spontaneous voiding, they cannot predict detrusor hyperreflexia and sphincter dyssynergia. Therefore, urodynamic study remains an essential component of initial urologic evaluation after SCI. Neurourol. Urodynam. 17:25–29, 1998.

Urinary dysfunction in lyme disease

Lyme disease, which is caused by the spirochete Borrelia burgdorferi, is associated with a variety of neurological sequelae. We describe 7 patients with neuro-borreliosis who also had lower urinary tract dysfunction. Urodynamic evaluation revealed detrusor hyperreflexia in 5 patients and detrusor areflexia in 2. Detrusor external sphincter dyssynergia was not noted on electromyography in any patient. We observed that the urinary tract may be involved in 2 respects in the course of Lyme disease: 1) voiding dysfunction may be part of neuro-borreliosis and 2) the spirochete may directly invade the urinary tract. In 1 patient bladder infection by the Lyme spirochete was documented on biopsy. Neurological and urological symptoms in all patients were slow to resolve and convalescence was protracted. Relapses of active Lyme disease and residual neurological deficits were common. Urologists practicing in areas endemic for Lyme disease need to be aware of B. burgdorferi infection in the differential diagnosis of neurogenic bladder dysfunction. Conservative bladder management including clean intermittent catheterization guided by urodynamic evaluation is recommended.

Latex allergy manifested in urological surgery and care of adult spinal cord injured patients

This report exemplifies the cases of two male and one female spinal cord injury (SCI) patients with latex allergy, two of whom had life threatening episodes of intraoperative cardiovascular collapse. The three patients were extensively exposed to latex products as a result of urinary management programs, and two developed marked hypotension immediately upon abdominal exploration during reconstructive urological surgery. The third case represents the development in a male of latex allergy to over 12 types of latex condoms manifest as penile dermatitis. In each of these cases, allergy and immunology consultation confirmed the latex allergy. The diagnosis of latex allergy was established using both Radioallergosorbert (RAST) testing and a skin test to the latex antigen. The two patients who experienced intraoperative cardiovascular collapse required resuscitation with intravenous fluids, epinephrine, and antihistamines. Because each episode of hypotension occurred during bowel manipulation with latex gloves, they were suspected of inducing anaphylaxis. In the third patient, latex allergy was suspected after the immediate resolution of allergic symptoms upon replacing latex condom catheters with those made of silicone. This is the first report of a life-threatening reaction to latex allergy in the SCI population. Measures instituted to prevent further latex-associated morbidity included the use of medical alert bracelets, self-administration epinephrine injection kits, and nonlatex appliances, including gloves, condoms, and urethral catheters. It is recommended that precautions against the development of anaphylaxis be undertaken in SCI patients with chronic exposure to latex-containing products.

Ureteroarterial fistula: A review of the literature.

Ureteroarterial fistulas are rare, erosive defects that occur between the distal segments of the ureter and the adjacent blood vessels in individuals with urologic and vascular comorbidities. Characterized by diffuse, pulsatile bleeding into the urinary tract, this condition carries a significant mortality rate in the absence of early recognition. Recent treatment efforts have focused on use of endovascular stenting techniques as an alternative to open surgical closure of the underlying defects in hemodynamically stable patients. We provide a literature review detailing the characteristics, mechanism, and management of ureteroarterial fistulas.