Idiopathic Urgency Urinary Incontinence

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Idiopathic Urgency Urinary Incontinence Ingrid Nygaard, M.D. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations.

At least weekly, a 62-year-old kindergarten teacher has a strong sense of urgency to urinate that is followed by urinary leakage while she rushes to the bathroom during her lunch break. She also infrequently leaks drops of urine while exercising. Her medical history is notable for mild hypertension, for which she takes hydrochlorothia zide. On physical examination, she is found to be obese and not to have abdominal masses or clinically significant pelvic-organ prolapse. How should her case be evaluated and treated?

The Cl inic a l Probl em From the Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City. N Engl J Med 2010;363:1156-62. Copyright © 2010 Massachusetts Medical Society.

An audio version of this article is available at NEJM.org

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The term overactive bladder encompasses urgency urinary incontinence. The International Continence Society defines overactive bladder as “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology,” and urgency urinary incontinence as “involuntary loss of urine associated with urgency.”1 The vast majority of women with urgency urinary incontinence have no known neurologic deficit; such women are the focus of this review. Prevalence rates of urgency urinary incontinence and overactive bladder vary, depending on the definition and the population studied. A total of 5 to 10% of women have urgency urinary incontinence at least monthly. Overactive bladder is more common, affecting 10 to 15% of women.2 In many studies, urinating eight or more times in 24 hours has been used as the threshold for classifying abnormal urinary voiding as overactive bladder. However, in a racially diverse population of U.S. residents participating in a community study, the 95th percentile (i.e., the upper limit of the normal range) of the number of voidings per day was 13; the frequency of voiding was, not surprisingly, associated with fluid intake.3 Symptoms of overactive bladder wax and wane and resolve spontaneously over the period of a year in about one in four cases, but most women have symptoms for many years.2 Urgency urinary incontinence is usually associated with other symptoms. Many women also report stress incontinence, in which leakage occurs with physical exertion such as that involved in coughing, sneezing, or exercise.4 Treatment efforts should focus on the predominant symptom. Increasing age, female sex, obesity, impaired functional status, depression, recurrent urinary tract infection, diabetes, some neurologic disorders, and bladder symptoms in childhood are associated with overactive bladder, with or without urgency urinary incontinence.5,6 New-onset urgency urinary incontinence was reported in 3% of women in a large trial who underwent surgery for stress urinary incontinence.7

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Causes

Traditionally, urgency urinary incontinence is said to be due to uninhibited detrusor muscle contractions, or detrusor overactivity, during bladder filling. This overactivity may be caused by a neurologic disorder such as spinal cord injury, multiple sclerosis, or stroke (in the case of neurogenic detrusor overactivity) or by bladder abnormalities such as infection or lesions, but more commonly, no cause is identified (i.e., the disorder is classified as idiopathic detrusor overactivity). The association between urgency urinary incontinence and detrusor overactivity on urodynamic testing is weak,8 in part because of the high rate of false negative results of such brief, office-based testing. In addition, several factors, ranging from changes in the urothelium to diverse aspects of neural control, may cause symptoms of urgency incontinence without discernible detrusor contractions. Effect on the Quality of Life

Women with urgency urinary incontinence are generally more bothered by this symptom than are those with stress urinary incontinence because the leakage is unexpected, sudden, and often of large volume. They have worse scores on quality-of-life and depression scales, poorer quality of sleep, worse sexual function, and lower work productivity than matched controls.9,10

S t r ategie s a nd E v idence Evaluation

For women presenting with symptoms of urgency urinary incontinence, the history taking should focus on the symptoms of urinary urgency, urinary frequency, nocturia, and leakage and on precipitating factors, voiding habits, and bathroom accessibility. Neurologic symptoms such as dizziness, gait disturbance, visual changes, or memory deficits may suggest cerebrovascular insufficiency, multiple sclerosis, dementia, or other disorders and should prompt referral to a neurologist. Women should complete a voiding diary, in which they record the times of each voiding and each incontinence episode as well as the precipitating factors, the voided volumes, and the types and volumes of fluids ingested (for an example from the American Urogynecologic Society, see www.mypelvichealth .org/ToolsforPatients/BladderDiary/tabid/79/Default .aspx). Leakage that occurs on hearing the sound

of running water, washing hands, feeling the urge to urinate, or turning the front-door key in the lock suggests a diagnosis of urgency urinary incontinence. Completion of a voiding diary may provide objective evidence of overconsumption of caffeine or fluids. Validated brief questionnaires are also helpful in screening for urinary incontinence.11,12 Physical examination should be performed to rule out a pelvic mass and clinically significant pelvic-organ prolapse. The examination should include a gross assessment of neurologic function, with particular attention to the S2, S3, and S4 sacral nerves. It is helpful to observe women walk, since functional incontinence may occur when physical limitations impede their ability to reach the bathroom quickly. Measurement of residual urine after voiding is indicated in women reporting clinically significant symptoms of obstructive voiding or those in whom invasive therapies are planned. Residual volumes of less than 50 to 100 ml are considered to be normal.1 Bacteriuria can cause symptoms of overactive bladder, and the initial assessment should therefore include testing for bacteriuria, with treatment, if the results are positive. However, many older women have asymptomatic bacteriuria, and repeated treatment is unwarranted if initial treatment does not reduce symptoms. Hematuria in the absence of bacteriuria should prompt further evaluation. Overactive bladder and urgency urinary incontinence are clinical diagnoses and do not require specialized testing. Urodynamic testing is generally not necessary before the initiation of conservative treatment; it should be considered, however, in cases in which initial treatment fails, more complex pathophysiological factors may be involved, or surgery is planned. During urodynamic testing, pressure transducers placed in the bladder and in the vagina or rectum measure bladder and abdominal pressure, respectively, providing information about bladder pressures during filling and voiding, about urethral resistance, and about bladder sensation (Fig. 1). The results must be considered in the context of the patient’s history. Neither the cause nor the severity of detrusor overactivity can be judged on the basis of specific findings on urodynamic testing, and the results do not predict the success of treatment.8


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Cough but no leakage Slight urge to urinate

Strong urge to urinate Strong urge to urinate Leakage Detrusor overactivity

Bladder volume (ml)

Muscle Detrusor electrical pressure activity at body surface

Abdominal pressure

Vesical pressure

Figure 1. Example of Results of Urodynamic Testing in a Woman with Severe Urgency Urinary Incontinence. A filling cystometrogram (obtained as part of a urodynamic study) reveals uninhibited detrusor-muscle contraction (arrowheads). Values and curves reflecting bladder volume (in milliliters), muscle electrical activity (in motor units), and various pressures (in centimeters of water) are shown. Vesical pressure was measured with a pressure catheter in the bladder. Abdominal pressure was measured with a pressure catheter in the rectum. Detrusor pressure was calculated by subtracting the abdominal pressure from the vesical pressure. The muscle electrical activity at the body surface, as measured on electromyography, shows a slight increase as the patient tries to contract her muscles to prevent leakage.

Treatment

Lifestyle Changes

Obesity is a well-known risk factor for urinary incontinence. In the Program to Reduce Incontinence by Diet and Exercise (PRIDE) study (ClinicalTrials .gov number, NCT00091988), women with incontinence who were randomly assigned to undergo an intensive 6-month weight-loss intervention were significantly more likely than those randomly assigned to undergo usual care to have a reduction of 70% or more in the frequency of urgency incontinence episodes as recorded in a voiding diary (41% vs. 29%, P = 0.04).13 Other lifestyle factors may also contribute to incontinence. Smoking is variably associated with urinary incontinence, but data are lacking from trials assessing the effects of smoking cessation on this condition. Fluid intake has not been rigorously studied in this context but appears to have a minor role in provoking urinary incontinence. Given the potential adverse effects of severely restricting fluids, this should not be recommended unless a voiding diary clearly illustrates that uri1158

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nary output is high (e.g., more than 3000 ml per day). Although data are limited, higher caffeine intake has been associated with detrusor overactivity, and a small randomized trial showed that decreasing caffeine intake reduced the number of incontinence episodes.14,15 Behavioral Therapies

Bladder training is a behavioral technique in which patients learn to urinate according to a schedule, rather than in response to overly frequent urges. Patients record all episodes of voiding over a period of 6 to 8 weeks, learn methods of distraction and relaxation (e.g., performing mental mathematical calculations, deep breathing, or “freezing and squeezing” of the pelvic-floor muscles), and each week gradually increase the time between episodes of voiding, up to an interval of 2 to 3 hours while awake. In a Cochrane review, several outcomes appeared to be better in women who underwent bladder training than in women who did not undergo such training or those who received anticholinergic medications, but few of

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the differences were significant.16 The number of trials and the sample sizes were small, and the outcome measures differed among the studies. Exercises to strengthen pelvic-floor muscles (often called Kegel exercises) have long been used to treat stress urinary incontinence.17 A recent Cochrane review concluded that this therapy is more effective than no treatment, placebo, or inactive control treatments in women with a mix of stress and urgency urinary incontinence or with urgency incontinence alone.18 Because many women strain (perform the Valsalva maneuver) when asked to contract the pelvic-floor muscles, proper technique should be confirmed. By placing a finger in the woman’s vagina and observing the abdomen and perineum, the clinician can ensure that the woman is contracting the pelvic-floor muscles rather than the abdominal or gluteal muscles. As with any muscle-strengthening program, it is important that exercises be performed consistently, correctly, and over the long term. Many physical therapists recommend doing 3 sets of 15 contractions, held for 10 seconds each, per day.19 Electrical stimulation of the pelvic-floor muscles is a therapy in which electrical current is applied to the pelvic-floor muscles by means of a probe inserted into the vagina, with the aim of generating a passive contraction. The results of randomized trials comparing electrical stimulation and either no treatment or sham stimulation have been inconsistent, providing insufficient evidence at this point to recommend its use.20 Weighted cones may be worn vaginally to promote contraction of the pelvic-floor muscles. Small randomized trials have showed the use of cones to be superior to no treatment but not to pelvic-floor muscle exercises alone.21-23 There are scant data on the effect of extracorporeal magnetic stimulation, in which patients sit on a “magnet chair.” One sham-controlled trial showed that fewer episodes of urgency urinary incontinence occurred per day in the magnetic-stimulation group, but there were no significant differences between the two groups in any other outcomes, including the quality of life.20 Behavioral therapy may also be self-taught. In a randomized trial involving older women with urgency urinary incontinence, the percent reduction in incontinence episodes was similar after 8 weeks of behavioral therapy with biofeedback, after 8 weeks of behavioral therapy without biofeedback, and after self-administered behavioral treat-

ment according to a self-help booklet (63%, 69%, and 59% reduction, respectively).24 Pharmacologic Therapies

Various subtypes of muscarinic receptors are found in the bladder and elsewhere in the body. Pharmacologic treatments for urgency urinary incontinence are intended to block such receptors; some drugs (e.g., oxybutynin) are nonspecific blockers, whereas others (e.g., solifenacin and darifenacin) are specific to one or more receptor subtypes. Common side effects of all such agents include dry mouth, dry eyes, and constipation. A recent Agency for Healthcare Research and Quality (AHRQ) evidence report summarizes information from a review of the literature regarding outcomes of pharmacologic therapies for urgency urinary incontinence.2 In randomized trials comparing each of the six medications currently approved in the United States for urgency urinary incontinence (Table 1) with either another active medication or placebo — including comparisons of newer, selective agents with older, nonselective drugs — no one drug was definitively superior to another. On the basis of estimates from metaanalysis models, the use of placebo, immediaterelease medications, or extended-release medications (including patches) reduced the number of episodes of urgency urinary incontinence per day by 1.08, 1.46, and 1.78 episodes, respectively, and reduced the number of voiding episodes per day by 1.48, 2.17, and 2.24 episodes, respectively. In two trials, the decrease in the number of urgency incontinence episodes was significantly greater with extended-release forms of both oxybutynin and tolterodine than with immediate-release tolterodine. Across the studies summarized in the AHRQ report,2 the baseline numbers of episodes of urgency urinary incontinence ranged from 1.6 to 5.3 per day, and episodes of voiding from 7.2 to 13.7 per day — numbers high enough that the benefits of these therapies were considered by the authors to be modest. In most trials, however, pharmacologic treatments, as compared with placebo, have been shown to significantly improve the quality of life related to incontinence and to reduce the distress due to leakage. A total of 10 to 64% of women reported adverse events while receiving pharmacologic therapy, but symptoms were generally mild, and no more than 17% of women in any study withdrew because of side


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Table 1. Pharmacologic Therapies Indicated for Overactive Bladder with or without Urgency Incontinence. Compound

Usual Dose

Oxybutynin chloride (Ditropan, Ortho–McNeil–Janssen Pharmaceuticals and available as generic formulation)

5 mg by mouth 3–4 times daily

Oxybutynin chloride extended release (Ditropan XL, Ortho–McNeil–Janssen Pharmaceuticals and available as generic formulation)

5, 10, or 15 mg by mouth once daily

Oxybutynin transdermal patch (Oxytrol, Watson Pharmaceuticals)

One patch applied twice weekly

Oxybutynin gel 10% (Gelnique, Watson Pharmaceuticals)

One sachet applied daily

Tolterodine tartrate (Detrol, Pfizer)

2 mg by mouth twice daily

Tolterodine tartrate long-acting (Detrol LA, Pfizer)

4 mg by mouth once daily

Fesoterodine fumarate (Toviaz, Pfizer)*

4 or 8 mg by mouth once daily

Solifenacin succinate (Vesicare, Astellas Pharmaceuticals)

5 or 10 mg by mouth once daily

Trospium chloride (Sanctura, Allergan)

20 mg by mouth twice daily

Trospium chloride extended release (Sanctura XR, Allergan)

60 mg by mouth once daily

Darifenacin (Enablex, Novartis Pharmaceuticals)

7.5 or 15 mg by mouth once daily

* Tolterodine is the active metabolite of fesoterodine.

effects. Adverse events reported by women receiving active medication were often the same as those reported by women receiving placebo. Although some women report immediate worsening of symptoms after stopping anticholinergic therapy, others note sustained improvement for months or even longer after stopping. It has been suggested that combining behavioral therapy with medication might increase the likelihood of maintaining the improvement in symptoms once medication is stopped. In one randomized trial,25 women were treated for 10 weeks with tolterodine (extended-release formulation) given alone or in combination with behavioral therapy. The rate of successful drug discontinuation (defined as the use of no drug or other therapy for urgency urinary incontinence and a reduction by ≥70% in the frequency of urgency incontinence as compared with baseline) was the same (41%) in the two groups 6 months after the medication had been stopped. Most trials comparing pharmacologic and behavioral therapies have shown them to have similar efficacy, although in one study,26 the reduction in the frequency of episodes of urgency urinary incontinence was greater with multicomponent behavioral therapy (pelvic-muscle strengthening, distraction techniques, and bladder training) than with drug therapy. Previously, estrogen therapy was used as a treatment for urinary incontinence in postmenopausal women. However, this therapy is no longer recommended, in light of data from randomized trials 1160

showing that systemic estrogen therapy increases the incidence of urgency urinary incontinence and the severity of preexisting urgency incontinence.27,28 It is not known whether vaginal estrogen therapy affects urgency urinary incontinence. Procedural and Surgical Therapies

Procedural and surgical therapies for urgency urinary incontinence include sacral and peripheral neuromodulation, injection of drugs into the bladder muscle, and augmentation cystoplasty, which is a major surgical procedure. Conservative therapies should be tried before invasive procedures are recommended. Sacral-nerve stimulation is accomplished by placing an electrode along a sacral nerve (usually S3) and connecting it, under the skin, to an implanted programmable pulse generator. A Coch rane review concluded that two thirds of women undergoing sacral-nerve stimulation have at least a 50% reduction in bladder symptoms 6 months after pulse-generator implantation.29 S3 fibers may also be stimulated peripherally by means of the posterior tibial nerve. This treatment appears to provide a short-term benefit, with 55% of participants in one randomized trial reporting improvement after 12 weekly sessions, as compared with 21% of those receiving sham stimulation.30 Injection of botulinum toxin into the detrusor muscle is increasingly used to treat urgency urinary incontinence, though the toxin is not approved by the Food and Drug Administration for



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this indication. Botulinum-toxin injections have been reported to be superior to placebo injections in decreasing incontinence episodes, increasing maximum bladder capacity, and improving quality of life.31 In one randomized trial,32 the median duration of the response to botulinum-toxin injection among women who had a response was 373 days; however, urinary retention was common. Women considering this type of therapy need to understand that it is still experimental, that repeat injections will be needed, and that they must be willing to perform intermittent self-catheterization. The effectiveness and safety of repeated injections over a period of years are unknown. The capacity of the bladder may be surgically enlarged by implanting tissue, such as a segment of ileum, into the detrusor muscle, or by incising the muscle to form a bulge in the bladder mucosa. No randomized trials have been performed to assess such procedures, and cohort data are scant. With the advent of neuromodulation therapy, surgical enhancement of bladder capacity is rarely performed.

A r e a s of Uncer ta in t y Our understanding of the pathophysiology and natural history of urgency urinary incontinence remains incomplete and limits treatment efforts, since therapy is currently directed toward reducing symptoms rather than toward correcting an identified abnormality. The optimal use of various diagnostic tests in women with urgency urinary incontinence is uncertain. There are many questions about several commonly used treatments, including the role of local estrogen therapy, the effect of repeated injections of botulinum toxin, the effectiveness of combination therapies, and the comparative effectiveness and risks, particularly with long-term use, of the various treatment methods. Data on the efficacy of alternative therapies, such as acupuncture, are scant. One randomized trial comparing bladder-specific acupuncture with sham acupuncture showed similar reductions in the number of incontinence episodes in the two

groups, although there were greater improvements in the active-treatment group on some measures, such as the numbers of episodes of urinary urgency and urinary frequency.33

Guidel ine s The recommendations in this article are consistent with those provided by the National Institute for Health and Clinical Excellence in 200634 and by the American College of Obstetricians and Gynecologists (ACOG) in 2005.35

C onclusions a nd R ec om mendat ions The schoolteacher described in the vignette has symptoms of mixed urinary incontinence, but her most bothersome symptom is urgency urinary incontinence. As a first step, she should complete a 3-day voiding diary, and if present, infrequent voiding or excessive fluid or caffeine intake should be addressed. Weight loss should be recommended. Behavioral therapies, including pelvic-floor muscle training and bladder training, should be initiated. If symptoms do not improve, anticholinergic therapy can be started. Given the fact that the various anticholinergic medications have similar efficacies, I recommend beginning with the least expensive option. If no improvement is noted after 1 month, a higher dose or a different medication should be tried, since one medication may improve symptoms more than another in clinical practice, despite the similar efficacies in treatment trials. Urodynamic testing is not generally recommended before initiating noninvasive therapies. It is important to discuss reasonable expectations with the patient. Urgency urinary incontinence and overactive bladder are chronic conditions that wax and wane, may require more than one type of treatment, and are more likely to improve than to resolve completely. No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

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