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Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment

Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment
Literature review current through: May 2024.
This topic last updated: Dec 01, 2023.

INTRODUCTION — Urgency urinary incontinence describes having the urge to void immediately preceding or accompanying involuntary urine leakage. Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without incontinence, nocturia, and urinary frequency. Treatments for both, which include behavior modification, pharmacotherapy, and procedures, are typically prescribed in a stepped approach.

This topic will discuss the treatment of both urgency urinary incontinence and OAB in females. The evaluation of urinary incontinence in females as well as treatment of other types of female urinary incontinence are presented in separate discussions. (See "Female urinary incontinence: Evaluation" and "Female urinary incontinence: Treatment".)

In this topic, when discussing study results, we will use the terms "women" or "patients" as they are used in the studies presented. However, we recognize that not all genetic females identify as women, and we encourage the reader to consider the specific counseling and treatment needs of transgender and gender nonbinary individuals.

INITIAL EVALUATION AND REFERRAL — Prior to treatment, patients who present with symptoms of urinary incontinence of any type undergo an initial evaluation to exclude urinary tract infection, characterize the type of incontinence, and identify individuals who may benefit from alternate treatment plans. During this process, patients are also counseled about lifestyle and behavioral changes (eg, smoking cessation, weight loss for individuals with obesity, appropriate fluid intake) as well as over-the-counter products (eg, pads, incontinence underwear, urine-wicking devices) to help them manage their incontinence symptoms.

Evaluation – Evaluation of female urinary incontinence is discussed in detail separately. (See "Female urinary incontinence: Evaluation".)

Indications for referral – Examples of indications for referral include lack of response to lifestyle and behavioral changes, neurologic disease (eg, multiple sclerosis, spinal cord injury, spina bifida), and evidence of other contributing pathology (eg, abdominal or pelvic masses, hematuria). (See "Female urinary incontinence: Treatment", section on 'Identify indications for referral' and "Female urinary incontinence: Treatment", section on 'Unique populations'.)

Protective garments – Patients often find guidance about choosing protective incontinence garments helpful as supportive therapy while they work through the approach below. Commercially available moisture wicking devices may provide additional skin protection for patients with severe incontinence that cannot be managed with medical, procedural, or surgical interventions [1]. (See "Female urinary incontinence: Treatment", section on 'Symptom management with pads and/or wicking catheters'.)

INITIAL APPROACH TO TREATMENT

Trial of pelvic floor exercises, lifestyle therapy, and behavioral changes — We begin treatment of urgency urinary incontinence, urgency-predominant mixed urinary incontinence, or overactive bladder (OAB) with the same conservative measures that are used for other types of urinary incontinence in females. If not already initiated, this approach includes education on pelvic floor muscle exercises to suppress urgency, modification of contributory medications/substances (table 1), and promotion of a healthy lifestyle and behaviors (eg, smoking cessation, weight loss for individuals with obesity). We also advise bladder training (table 2) and offer treatment of vulvovaginal atrophy (if present) with topical estrogen therapy [2-5]. While bladder training may be of limited benefit [5], it is a low-risk and low-resource intervention.

The emphasis of treatment is to improve quality of life aligned with patient goals and expectations. Risks and side effects of therapy should be carefully balanced with benefits of urinary incontinence treatments. As indirect evidence supporting the role of lifestyle and behavior modifications, the beneficial effect of placebo seen in trials of patients with OAB may be explained by calendaring effect (eg, keeping a diary) and a lower fluid intake among patients in the placebo-treated group compared with the active treatment group [6]. (See "Female urinary incontinence: Treatment", section on 'Initial treatment' and "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Vaginal estrogen therapy'.)

The role of complementary and alternative therapies in treating OAB is unclear as data from large trials are lacking. While observational studies have reported a benefit for hypnotherapy, one study comparing hypnotherapy with medication did not find hypnotherapy as helpful as the medication [7,8]. For acupuncture, two different meta-analyses reported conflicting results as to the efficacy of acupuncture compared with sham treatment and medication [9,10]. Although trial data are needed before adopting routine use of these treatments, they appear to be low-risk, and patients who desire a trial of these complementary therapies may reasonably do so.

Supervised or augmented pelvic floor muscle training — A variety of techniques are available for performing pelvic floor muscle exercises. Systematic reviews have determined that pelvic floor muscle training is superior to sham or no treatment, but that no one method of exercise is superior to another and all result in improved symptoms and quality of life [11,12].

For patients who are able to isolate their pelvic floor on physical examination and are motivated to perform these exercises on their own, we provide verbal and written instructions on how to perform the exercises. (See "Female urinary incontinence: Treatment", section on 'Initial instructions'.)

For those who have poor pelvic muscle coordination, significant weakness, or inability to isolate their pelvic floor muscles, we suggest supervised pelvic floor physical therapy by a physical therapist specifically trained in the modalities to improve pelvic floor muscle function [13]. Pelvic floor physical therapy requires subspecialty education [14]. (See "Female urinary incontinence: Treatment", section on 'Supplemental modalities'.)

Addition of medication — We offer adjunctive medication if initial treatments do not provide sufficient symptoms relief or if patients desire a trial of pharmacotherapy before completing a trial of exercises, lifestyle, and behavioral therapies. We counsel patients that it can take 6 to 12 weeks to see an effect from the initial interventions. However, in some cases, patients prefer to maximize their treatment approach and are willing to accept the side effects of additional medications. In these cases, we suggest that patients continue pelvic floor exercises and other behavioral therapies while initiating medical treatment because combination therapy appears more effective than either approach alone [15]. In one multicenter trial, combination therapy had a beneficial effect on patient satisfaction, self-reported improvement, and reduction of other bladder symptoms, although it was not shown to improve the ability to discontinue medications at 10 weeks [16]. We advise patients to continue medications as long as they see improvements in their symptoms and are not experiencing bothersome side effects. The onset of a beneficial medical effect can occur as early as the first week, although it can take up to three months to have maximum effect. Patients may stop therapy at any time and consider resuming as needed if bothersome symptoms recur.

Our approach — Beta-3 adrenergic agonist drugs and antimuscarinic agents are the main options for treatment of OAB symptoms (table 3) [4]. As efficacy is similar for the two groups, we and others suggest initial drug treatment with beta-3 adrenergic agonists because of the increased risk of side effects, including long-term risk of dementia, with anticholinergic drugs as reported in case-control and cohort studies [4,17-21]. However, from a practical perspective, choice of initial agent is often influenced by third-party payor coverage, availability and cost. The beta-3 adrenergic agonists are a newer drug class and therefore, in the United States, tend to be more expensive with less coverage across insurance providers than anticholinergics.

Initial improvement in symptoms may be noted within the first two weeks of treatment but optimization of effect can take up to 12 weeks. We educate patients about these time intervals to avoid early medication discontinuation.

Brief comparison of drug classes — Beta-3 adrenergic agonist drugs and antimuscarinic agents are the main options for treatment of OAB symptoms (table 3) [4]. Both classes can be used for single-agent treatment or used together for combination treatment. (See 'Medication prescribing details' below.)

Beta-3 adrenergic agonist drugs — The beta-3 adrenergic agonists mirabegron and vibegron work by stimulating the receptors in the bladder responsible for smooth muscle relaxation [22]. While trials that directly compare the two beta-3 agonists are lacking, two network meta-analyses suggest similar efficacy overall [23,24]. Vibegron may have slightly larger reductions in mean voided volume and fewer nasopharyngeal and cardiovascular side effects, but the clinical significance of this is unclear [23,24]. Compared with antimuscarinic medications, these drugs have similar efficacy with fewer adverse effects. (See 'Beta-3 adrenergic agonists' below.)

Treatment efficacy appears superior to placebo and similar to antimuscarinics. (See 'Efficacy' below.)

When adverse events occur, they typically include headache, gastrointestinal effects (nausea, diarrhea, constipation, etc), and rhinorrhea/nasopharyngitis. Hypertension is a noted concern with mirabegron but not seen in clinical trials of vibegron. (See 'Adverse effects' below.)

Antimuscarinic drugs — These agents are a subtype of anticholinergic agents; they block muscarinic receptor stimulation by acetylcholine and reduce smooth muscle contraction of the bladder [25]. Such blockade during bladder storage results in increased bladder capacity and decreased urgency [26]. Advantages include common availability, low-cost generic options, short- and long-acting formulations, and potential for combination therapy with beta-3 adrenergic agonists, but these medications also more frequently cause side effects as well as impact cognition. (See 'Antimuscarinics (anticholinergics)' below.)

Systematic reviews of randomized trials have reported benefit compared with placebo. Trials comparing the multiple antimuscarinic drug options are limited. (See 'Drugs, selection, and administration' below and 'Efficacy' below.)

Common adverse effects include dry mouth, dry eye, and constipation. Patients with cognitive impairment, and older adults in general, are at increased susceptibility to adverse drug reactions from anticholinergic medications, including possible increased risk of dementia, which are discussed below. (See 'Adverse drug effects' below.)

Assess treatment response and adjust medication — We assess symptom improvement and medication tolerance at follow-up visits scheduled four to six weeks from starting medication. We specifically discuss any ongoing urinary symptoms, new drug-related adverse effects, and medication compliance. Once appropriate use of the drug is confirmed, next steps vary based on the patient’s symptoms.

No or minimal improvement – For those with inadequate response, we confirm adherence to behavioral, dietary, lifestyle, and medication dosing. Next, these patients may benefit from drug adjustment (dose or class) or combination pharmacotherapy (antimuscarinic plus beta-3 adrenergic agonist) [27]. If the patient has some improvement and is willing to give the initial drug choice more time and is tolerating the medication, we titrate the drug up to maximum tolerated dose before switching to another agent. Discussions of drug dosing and adjustment are presented below:

Beta-3 adrenergic agonists (see 'Drugs and dosage' below)

Antimuscarinic drugs (see 'Drugs, selection, and administration' below)

Partial response – For patients whose symptoms improve and who are tolerating the medication, we increase the medication dose and reassess in four to six additional weeks. Dose increases can continue to the maximum (table 3). Patients with partial response on maximum drug dose may benefit from combination treatment with a drug from the other class (antimuscarinic or beta-3 adrenergic agonist). Adverse effects with combination therapy are not anticipated to be additive, but supporting data are limited. An antimuscarinic (solifenacin or trospium) and mirabegron are commonly used for combination therapy [28-32]. Dose increase and combination therapy are discussed in detail separately. (See 'Adjusting antimuscarinics' below and 'Combination pharmacotherapy' below.)

Intolerable side effects – Patients with intolerable side effects are advised to stop the medication. Those who have tried only one medication class are offered a trial of the alternate class. Individuals who have experienced intolerable side effects with both medication classes are offered advanced treatment including percutaneous tibial nerve stimulation (PTNS), botulinum toxin, or sacral nerve stimulation (SNS). (See 'Advanced therapies' below.)

If symptoms persist or side effects are intolerable despite trying at least two medications, progression to advanced therapy is offered [27]. (See 'Patients with continued symptoms' below.)

PATIENTS WITH CONTINUED SYMPTOMS — Patients who have persistent urgency urinary incontinence or other irritative symptoms despite an adequate trial of initial treatments and pharmacotherapies, or who are unable to tolerate pharmacologic therapy, can be referred to a specialist to discuss further options for treatment [27]. In general, we try at least two pharmacotherapies prior to advanced therapies.

Advanced therapies — Advanced therapies range from noninvasive office-based acupuncture-like nerve stimulation (PTNS) and office-based injections of botulinum toxin A to surgically implanted nerve stimulation devices (tibial nerve stimulation and SNM) [27]:

Selection of therapy — The selection of advanced therapy should be based on a detailed discussion with the patient regarding safety, efficacy, and time commitment as well as consideration of insurance coverage for the various approaches. In general, we promote the least invasive approaches to advanced therapy first unless patients have specific time or financial considerations. In the United States, this approach typically results in initial trial of PTNS or transcutaneous tibial nerve stimulation (TTNS), although European countries consider PTNS a first-line approach, on par with medication [33,34]. Individuals who are unsatisfied with the results of nerve stimulation or unable to undergo regular treatments are next offered either detrusor botulinum toxin injections or sacral nerve stimulation (SNS) [34]. Botulinum toxin injections are typically administered in the office with no surgical preparation or recovery time, last between 6 to 12 months, and have been shown to be more cost-effective than historic modes of SNS [35]. The advent of magnetic resonance imaging (MRI) compatible and rechargeable implanted programmable devices may result in improved cost-effectiveness of modern SNS implants; however, data are lacking.

Tibial nerve stimulation

Treatment options

Percutaneous stimulation of the tibial nerve – PTNS, one type of electrical stimulation therapy, benefits some patients with detrusor overactivity and may be more effective than antimuscarinic drugs at reducing the number of urgency incontinence episodes [33,36-38]. In an office setting, a clinician (nurse or physician) places an acupuncture-like needle medially behind the ankle and administers mild electrical stimulation for 30 minutes. These sessions occur once a week for 12 weeks followed by maintenance therapy of approximately once a month if the patient desires. Optimal duration of treatment and timing of maintenance therapy has not been established. An observational study of 470 women undergoing PTNS reported 71 percent of patients completed all 12 weeks of treatment; of those, 30 percent achieved success by eight weeks and 41 percent achieved success by 12 weeks based on global impression of improvement and 10 point or more improvement in OAB questionnaire short-form scores [39]. For individuals who receive peak effect prior to 12 weeks of completed PTNS sessions, it is not known if maintenance therapy started earlier than 12 weeks is as effective as if started after the anticipated 12 weeks.

Transcutaneous tibial nerve stimulation – TTNS, a variant of PTNS, may be offered to patients who are unable to attend in-office sessions [40,41]. We believe TTNS offers a low-cost, convenient option for patients who are unwilling or unable to attend frequent office visits. Comparative efficacy to sham or other tibial nerve stimulation procedures are limited; however, risks and costs are relatively low. Thus, we offer this therapy for patients particularly if they are unwilling or unable to attend in-person PTNS sessions.

Implantable tibial nerve stimulator – Implantable wireless neurostimulation devices (eCoin Valencia Technologies and Revi Blue Wind Medical) are currently available for treatment of urgency urinary incontinence, with or without urinary urgency symptoms [42-46]. The device is surgically implanted near the posterior tibial nerve as an office procedure and is stimulated intrinsically as a battery (eCoin) or externally (Revi). The eCoin device, once programmed does not require routine office visits or patient activation of the device to control the stimulation. The Revi implant device is smaller than the eCoin and has no battery. The wearable unit uses magnetic coupling to transmit energy to the implant, which generates electrical pulses to stimulate the tibial nerve, but requires the patient to initiate the therapy or attend office visits to activate the device. Open labeled, single-assignment, industry-sponsored trials demonstrate improvements in urgency urinary incontinence episodes, urgency urinary symptoms, and quality of life in both male and female patients [42,43,47]; however, device-related adverse events are common. . Cost-effectiveness of these devices compared to other advanced therapies will help inform the role of implanted tibial nerve stimulation. From a practical standpoint, patients with severe lower extremity edema, neuropathy, or peripheral vascular disorders may not be ideal.

Supporting data

A 2016 meta-analysis of multiple, nonimplanted types of electrical stimulation for OAB concluded that electrical stimulation appeared to be more effective than either no treatment or drug treatment for OAB [48]. There were insufficient data to determine if electrical stimulation was more effective than conservative treatment with pelvic floor muscle training or to determine which type of electrical stimulation was most effective.

Systematic reviews of studies specifically evaluating PTNS generally demonstrated a benefit, with an approximate efficacy of 60 percent, similar to that of anticholinergic medications [36,38,49,50]. Compared with anticholinergics, PTNS is more effective in reduction of UUI episodes, but similar in overall frequency, urgency, and symptom reduction [33]. Combined therapy with anticholinergics does not appear to add any benefit over PTNS alone.  

While a systematic review comparing PTNS with TTNS found insufficient evidence to rigorously compare these two approaches for neurogenic and non-neurogenic urgency urinary incontinence, a small trial of PTNS versus TTNS reported similar reductions in symptoms and improved quality of life for both therapies [51-53].

Long-term efficacy – Maintained efficacy has been reported at 30 months for daytime urinary frequency and 18 months for nighttime frequency [54]. Reported rates of side effects are low [38,49,50]. In one study, lack of efficacy was the most common reason for noncompliance [55].

Botulinum toxin — For patients with urgency or urgency-predominant mixed incontinence who do not respond to, or cannot tolerate pharmacotherapy, injection of botulinum toxin into the detrusor muscle is an option (figure 1 and movie 1) [56]. These injections are typically performed under local anesthesia in the office setting and do not require significant preparation or recovery. Onset of action occurs in approximately two weeks and duration of effect is reported between 3 and 12 months. In our practice, most patients require repeat injections every 9 to 12 months and patients can receive up to a total of 400 units in a year. Due to the known risk of transient urinary retention with botulinum toxin therapy, we generally avoid this therapy in patients with a history of urinary retention unless they are willing to learn self-catheterization. Botulinum toxin injection is also associated with increased rate of urinary tract infection and thus patients with recurrent urinary tract infections may not be optimal candidates.

Detailed discussions of botulinum toxin for OAB are presented separately. (See "Botulinum toxin for treatment of lower urinary tract conditions: Indications and clinical evaluation" and "Botulinum toxin for treatment of overactive bladder: Injection and complications".)

Sacral nerve stimulation — Sacral nerve stimulation (SNS), also known as sacral neuromodulation (SNM), is a minimally invasive surgical electrical stimulation option to treat OAB symptoms that is offered to patients whose symptoms do not respond to initial interventions and pharmacotherapy [27,34].

System types

Rechargeable – InterStim micro system, InterStim II, and Axonics, which include MRI-compatible options [57,58]. These devices require the patient to have the cognitive ability and desire to manage the technology; perform a testing procedure; monitor the impact of stimulation on urinary incontinence episodes, urgency, and pad usage for a week or two; and manage the recharging process should they select this option. InterStim micro and Axonics have rechargeable implanted programmable device options, which can increase battery life to 15 years or more and may be more cost-effective than the traditional nonrechargeable option [59-61]. Recharging frequency depends on a number of factors, including the amplitude of the stimulation and the product selected, but is generally required once a month. Younger and thinner patients often prefer the rechargeable battery size and are willing to manage the recharging in exchange for a smaller battery.

Extended nonrechargeable – Newer models of batteries include recharge-free options for both Medtronic and Axonics. These systems have extended battery functionality that lasts 15 years or more and are selectively MRI compatible [62,63]. The recharge-free batteries are two to three times the size of the rechargeable batteries but may be preferable in patients who dislike or have (or will have) difficulty with the technical aspects of recharging.

Insertion procedure – SNM involves placement of a wire lead into the S3 foramen that is connected to a stimulation device. The procedure includes a test phase and a second-stage implantation phase. The test phase can be done with temporary percutaneous nerve evaluation (PNE) leads, usually placed bilaterally in the outpatient clinic setting. Positive predictive values for PNE are high (99 percent); however, negative predictive values for PNE are lower than for the staged approach (82 versus 93 percent) [64]. Therefore, the author prefers a staged approach, performed in a surgical setting, in which a permanent lead wire is placed into one S3 foramen (or rarely, both) and tunneled under the skin to connect to a temporary external stimulation device. Some patients prefer a less invasive approach and/or may have different copays that make the PNE option preferable. In both settings, patients are asked to maintain voiding diaries to document their urinary urgency, frequency, and urinary urgency leakage severity at baseline for three days prior to the test phase and then daily during the one to two-week testing period. If greater than 50 percent improvement in any of these parameters is confirmed, the patient can elect permanent implantation with a pacemaker-like stimulator (implanted programmable device) placed under the skin of the upper buttock. If the test phase is unsuccessful, then the lead is removed.

Supporting data – A 2015 review of 16 studies concluded that there was evidence of benefit for SNM in some patients [36]. Some have reported improvement rates of 60 to 90 percent and cure rates of 30 to 50 percent [65,66].

InterStim device – In one randomized trial of 147 patients (93 percent female) with OAB, patients who had SNM were more likely to have improved or greatly improved urinary symptoms at six months than those who had standard medical therapy (86 versus 44 percent) [67].

Axonics device – An observational study that followed 129 individuals (98 percent female) with urgency urinary incontinence after implantation of the Axonics sacral nerve stimulation device reported response rates (> 50 percent reduction in urgency urinary incontinence) of 89 percent at one year and 93 percent at two years (121 participants) [68,69]. At two years of follow-up, of the 93 percent with response, 83 percent reported ≥75 percent reduction in urgency urinary incontinence episodes and 37 percent had no urgency urinary incontinence leakage on diary [68]. Daily urinary urgency incontinence episodes reduced from 5.6 ± 0.3 at baseline to 1.0 ± 0.2 at 2 years and no serious adverse events were noted. All patients were able to recharge the device and 94 percent reported no difficulties in doing so.

Comparison with botulinum toxin injections – A trial comparing onabotulinumtoxinA and SNM (InterStim) in female patients with refractory urge incontinence reported a statistically greater reduction in incontinence episodes for the onabotulinumtoxinA group (-3.9 versus -3.3 urgency urinary incontinence episodes per day, mean difference 0.63, 95% CI 0.13-1.14) [56]. The clinical significance of this change is unclear. A more detailed discussion of this trial can be found separately. (See "Botulinum toxin for treatment of lower urinary tract conditions: Indications and clinical evaluation".)

Risk of adverse events – Early placements of the initial device, InterStim, were associated with high five-year reintervention rates (up to 30 percent) for device malfunction or treatment failure [36,70]. A retrospective analysis of a statewide claims database reported that 14 percent of 4313 patients who had SNM placement had reintervention within one year, and 38 percent of 1514 patients who had the device underwent reintervention within five years [70]. Almost half of the reinterventions at one year were for device malfunction, whereas at five years almost two-thirds were for device malfunction, with one-third for treatment failure. A trial of the Axonics SNM system in 51 patients reported adverse event rates of up to 21 percent, with the majority of these being adverse stimulation sensation [65]. Revisions or removals within one year were 8 percent for infection, migration, or lack of efficacy. Long-term data on device malfunction and revisions for newer MRI-compatible and rechargeable devices are not yet available.

Laser therapy — Data from one small trial suggest vaginal laser therapy may have a role in the treatment of OAB [71]. However, treatment efficacy and safety need to be demonstrated in large trials with long-term follow-up before advising laser therapy for general use for OAB treatment [72]. Discussion of laser therapy for treatment of genitourinary syndrome of menopause is presented separately. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Laser or radiofrequency devices'.)

Surgery — Patients whose symptoms persist despite other therapies should be evaluated by a urologist to consider surgical options. These may include augmentation cystoplasty, urinary diversion, or placement of a suprapubic bladder catheter [34]. We do not recommend placement of indwelling urethral foley catheters for management of urinary incontinence. (See "Stress urinary incontinence in females: Persistent/recurrent symptoms after surgical treatment", section on 'Urinary diversion' and "Placement and management of urinary bladder catheters in adults".)

Wicking devices for symptom control — Commercially available moisture wicking devices may provide additional skin protection for patients with severe incontinence that cannot be managed with medical, procedural, or surgical interventions [1]. This is a comfort management approach only and not a treatment for the causes of incontinence.

SPECIAL POPULATIONS

Older age or cognitive impairment — As for other patients, nonpharmacologic approaches (eg, prompted voiding, scheduling toileting) are preferred first-line treatments OAB when feasible [4]. If a medication trial is elected, we and others avoid use of antimuscarinic medications for OAB in individuals >65 years or those with cognitive impairment of any age [4,73]. This approach is based on the body of evidence indicating increased risk of anticholinergic side effects from use of antimuscarinic medications in older adults. Whether or not antimuscarinic drugs increase the risk of dementia is under active investigation. The available body of evidence suggests an association between anticholinergic medications and increased risk of dementia, but causation has not been established [17-21]. (See 'Adverse drug effects' below.)

For those who desire a trial of medication after appropriate counseling, we start with the lowest dose of beta-3 adrenergic agonist and titrate increases based on clinical response and side effects for mirabegron (vibegron is available only in one dose).

If beta-3 adrenergic agonist medications are not available, darifenacin and trospium chloride may lessen impact on the central nervous system as these drugs are purported not to cross the blood brain barrier [74]. However, clinical trials of these drugs in this vulnerable population have not been performed to confirm safety.

Mixed urinary incontinence — In patients with both stress and urgency urinary incontinence (mixed incontinence), those with urgency-predominant symptoms are treated similarly as those with pure urgency incontinence or OAB, although there are few data evaluating antimuscarinics in this subgroup [75]. We follow the steps as outlined. For patients who do not respond to trial of medication, insertion of a mid-urethral sling intended to treat stress urinary incontinence may be beneficial [76]. Studies to evaluate the role of midurethral sling surgery compared with Botox treatments for mixed urinary incontinence are ongoing [77]. Treatment of mixed urinary incontinence is discussed separately. (See "Female urinary incontinence: Treatment", section on 'Mixed incontinence treatment'.)

MEDICATION PRESCRIBING DETAILS

Beta-3 adrenergic agonists — Mirabegron and vibegron are beta-3 adrenergic receptor agonists used to treat symptoms of overactive bladder (OAB) [28,78].

Drugs and dosage

Mirabegron – Mirabegron is available as extended-release daily oral tablets in doses of 25 and 50 mg [28]. The mirabegron tablet should be swallowed whole, in contrast to vibegron, which can be swallowed whole or crushed. Mirabegron is avoided in individuals with poorly controlled hypertension or who develop new hypertension while using the medication. After four to six weeks of treatment, we assess patient response and document blood pressure. Management of patients with established or new hypertension is discussed below. (See 'Adverse effects' below.)

MonotherapyMirabegron is available in 25 and 50 mg extended-release doses. Mirabegron monotherapy is started at 25 mg daily [28]. Although up to eight weeks may be required for full efficacy, the dose can be increased to 50 mg daily as quickly as four weeks from initiation if patients are tolerating the drug but have inadequate symptom control. In our practice, the typical time frame to assess medication impact is four to six weeks. Patients with severe renal or moderate hepatic impairment should not receive more than 25 mg daily.

Combination therapy – For individuals with refractory OAB, mirabegron can be used with the antimuscarinic solifenacin. (See 'Combination pharmacotherapy' below.)

Vibegron – Vibegron is given as a single 75 mg oral dose daily [78]. For individuals who are unable to swallow pills, vibegron tablets may be crushed and taken with food. In clinical trials, vibegron is not associated with hypertension and may be preferred in hypertensive patients with poorly controlled blood pressure. Although clinical experience is limited, strategies for follow-up and reassessment are similar to other OAB medications. (See 'Adverse effects' below.)

Efficacy — Beta-3 adrenergic agonists appear to be at least as effective as antimuscarinic agents and may be preferred in some clinical instances, including older adults [79]. Studies have reported both improvement in incontinence episodes and in quality of life measures [28,78,80].

Comparison with placebo – Both mirabegron and vibegron improve OAB symptoms compared with placebo [33]. Similar improvements for both drugs have been reported for mean number of incontinence episodes per 24 hours, mean number of micturition episodes per 24 hours, and mean number of urgency urinary incontinence episodes per 24 hours [81,82].

Comparison with anticholinergic medications – The clinical effectiveness of both mirabegron and vibegron appears to be similar to that of the antimuscarinics, although beta adrenergic medications may be more effective at reducing nocturia episodes [33,83,84]. Reduced discontinuation rates and fewer treatment-related adverse effects may favor the beta-3 adrenergic agonists [33,85,86].

Mirabegron – In a meta-analysis that included seven trials of mirabegron in females with OAB, significant reductions were reported in the number of episodes per 24 hours of urinary urgency (1.3 to 2.2 episodes), frequency (2.04 to 2.33 episodes), nocturia (0.42 to 0.5 episodes), and urgency urinary incontinence (0.9 to 1.04 episodes) after 12 weeks of mirabegron treatment compared with baseline values in all studies [87]. Efficacy was similar to that of antimuscarinic agents but with fewer adverse events. Hypertension occurred in 2 percent of individuals treated with mirabegron.

Vibegron – Vibegron appears to be at least as effective as antimuscarinic agents with similar rates of adverse effects.

-A meta-analysis of three trials including over 1700 patients that compared vibegron with antimuscarinic monotherapy reported similar outcomes on bladder symptoms with fewer treatment-related adverse effects for vibegron [86]. Specifically, the mean number of micturition episodes, mean number of urgency episodes, mean number of urgency incontinence episodes, mean number of incontinence episodes, and discontinuation rates due to an adverse event were not statistically different between the drugs.

-In the phase 3 trial comparing vibegron 75 mg with tolterodine 4 mg (extended release) in 505 individuals, improvement in OAB wet symptoms was greater for vibegron [88]. At week 52 of treatment, more patients receiving vibegron experienced ≥75 percent reduction in urge urinary incontinence episodes (61 versus 54 percent) and more reported a 100 percent reduction (40 versus 34 percent) compared with those receiving tolterodine. While patient discontinuation resulting from adverse effects was greater for tolterodine compared with vibegron (3.4 versus 1.5 percent, respectively), this difference was not statistically significant or clinically meaningful.

Adverse effects — The beta-3 adrenergic agonists mirabegron and vibegron have similar efficacy to antimuscarinics with lower rates of adverse events, including in patients age ≥65 years [86,88,89].

Both mirabegron and vibegron

Urinary retention – Urinary retention is a potential adverse effect of antimuscarinic and beta-3 adrenergic agonists. Although initial mirabegron trial data did not report urinary retention, new-onset urinary retention may be more likely in those receiving mirabegron combined with an anticholinergic [28]. Initial trial data for vibegron reported urinary retention in less than 2 percent of study participants [78]. A detailed discussion of voiding trials is presented in content on urinary retention following surgery. (See "Postoperative urinary retention in females", section on 'Voiding trials'.)

Other side effects – A systematic review noted lower rates of dry mouth and constipation with mirabegron than with antimuscarinics [83]. Common side effects of beta 3 agonists include headache, runny nose, and gastrointestinal upset, which are often mild and rarely lead to discontinuation.

Hypertension with mirabegronPatients with severe or uncontrolled hypertension should not take mirabegron [28]. While clinical trials have reported small increases in blood pressure compared with placebo (increases of systolic 3.5 and diastolic 1.5 mmHg compared with placebo), some patients develop hypertension [28,84].

Incidence In a pooled analysis of 668 persons aged 65 and older, treatment-emergent hypertension developed in 8 percent on placebo, 14 percent on mirabegron 25 mg, and 10 percent on mirabegron 50 mg [90]. By contrast, vibegron does not appear to cause hypertension [78].

Our approach

-Initial drug start – We document the patient’s blood pressure prior to starting mirabegron. For patients with blood pressure elevated above 140/90, we advise the patient to repeat blood pressure measurements at home within a week of starting therapy. For patients with blood pressure of 160/100 or above, we refer them to their primary care doctor to improve blood pressure control prior to starting medication for OAB. Vibegron is a reasonable alternative beta-3 adrenergic agonist for these patients if available. If vibegron is not an option, individuals with improved blood pressure control below 140/90 may then start mirabegron.

-Follow-up visit – At the follow-up visit after starting mirabegron, we again check and document the patient’s blood pressure. For patients with blood pressure elevated above 140/90 but below 160/100, we advise the patient to repeat blood pressure measurements at home and send us the results. Those with persistently elevated blood pressure may require an alternative therapy. If blood pressure is above 160/100, we discontinue mirabegron.

No impact on cognitive or cardiac function

Cognitive change – In a 12-week trial comparing mirabegron with placebo in patients aged ≥65 years, scores of mild cognitive impairment (Montreal Cognitive Assessment) were similar for the two groups [91]. Initial trial data of vibegron did not report cognitive change or impairment as an adverse effect [78].

Arrhythmia – Although initial trial data raised concern for an association between mirabegron and cardiac arrhythmias, a meta-analysis of four trials including over 1500 patients reported a nonsignificant trend (odds ratio [OR] 1.67, 95% CI 0.95-2.92), and a cohort study over of 16,000 patients reported no effect [81,92].

Drug discontinuation – For mirabegron, 2 to 10 percent of patients discontinue the medication because of adverse medication effects [28,85]. Mirabegron is more likely to be continued compared with antimuscarinic drugs [93]. Initial trial data did not report vibegron discontinuation from adverse effects [78].

Antimuscarinics (anticholinergics)

Drugs, selection, and administration — There are seven antimuscarinic agents available in different doses and formulations: darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, trospium, and propiverine (primarily used in Asia). We attempt to tailor therapy based on the risks and side effect profiles of each medication (table 3) [94]. As efficacy across the various formulations is similar, selection of the appropriate drug for an individual patient is primarily dictated by side effect profile, tolerability, medical comorbidities, or insurance coverage [95].

From a practical clinical perspective:

Initial drug choice – When antimuscarinic therapy is selected, we prefer trospium or darifenacin rather than other antimuscarinic agents to potentially minimize risk of cognitive impact [74]. A systemic review reported no new cognitive decline with use of trospium (six studies) or darifenacin (three studies) among individuals both with and without baseline cognitive decline [96]. We start with the lowest drug dose. Trospium needs to be taken on an empty stomach; extended-release trospium formulations may be preferred to minimize the difficulties in taking a twice-daily medication on an empty stomach. After two to six weeks of treatment, we reassess patient response and increase the dose if the patient has insufficient response but is otherwise tolerating the medication. (See 'Adverse drug effects' below.)

Role of generic medications – Lower-cost generic formulations are typically preferred because they are more widely covered by insurers. Specific drug selection is based on patient comorbidities and insurer coverage [97].

Use of oxybutynin – Oxybutynin, in either immediate- or extended- release formulations, is commonly available and generally available on insurance formularies. While immediate-release oxybutynin is often the first medication prescribed by clinicians because it is the least costly and most widely covered option, it is often not well tolerated because of dry mouth, dry eye, and constipation. If a trial of oxybutynin is required for insurance purposes, transdermal preparations are available over the counter and can decrease side effects. However, manufacturing shortages can limit availability.

Immediate versus extended-release formulations – We prefer extended- over immediate-release formulations to minimize side effects, improve adherence, and minimize drug discontinuation [36,98,99]. Except for solifenacin, extended-release formulations cannot be cut or crushed. Immediate-release antimuscarinic preparations can be useful when a patient desires improved continence at specific times (eg, going to an event).

Contraindications – Antimuscarinics are contraindicated in patients with uncontrolled tachyarrhythmias, myasthenia gravis, gastric retention and narrow angle-closure glaucoma (see "Angle-closure glaucoma"). They are used with caution in older adults or in those with cognitive impairment, urinary retention, and gastric retention [4].

Efficacy — Systematic reviews of randomized trials have found that antimuscarinics have a modest benefit over placebo in reducing urgency urinary incontinence [99-102]. Efficacy of all the antimuscarinic agents is thought to be similar, although definitive conclusions are precluded by the paucity of head-to-head trial data [103].

Comparison with placebo – Two different systematic reviews (n = 72 and 71 trials) found that antimuscarinic medications were more effective than placebo at improving urgency urinary incontinence, but with low magnitude of effect (table 4) [99,102].

Benefits – Compared with placebo, antimuscarinic drugs therapy resulted in [102]:

-Small improvement in mean condition-specific quality of life (mean difference [MD] 4.41 lower, 95% CI 5.28 to 3.54 lower, scale range -100 to 0)

-Small reductions in mean number of urgency episodes per 24 hours (MD 0.85 lower, 95% CI 1.03 lower to 0.76 lower) and mean number of micturitions per 24 hours (MD 0.85 lower, 95% CI 0.98 lower to 0.73 lower).

Adverse effects – Use of antimuscarinic drugs was also associated with greater likelihood of dry mouth (relative risk 3.50, 95% CI 3.26-3.75), urinary retention (RR 3.52, 59% CI 2.04-6.08), and study withdrawal (RR 1.37, 95% CI 1.21-1.56) [102].

Comparison with nondrug therapies – A meta-analysis of 23 trials including over 3600 adult participants reported that symptomatic improvement was more common for those treated with antimuscarinic drugs compared with bladder training (42 versus 57 percent of patients were not improved, seven trials, 346 participants) [95]. Combined antimuscarinic drug treatment and bladder training was associated with greater improvement compared with bladder training alone (27 versus 47 percent of patients not improved, three trials, 164 participants). Definitive conclusions are limited by the use of multiple medications and doses, small number of trial participants, and wide range of follow-up duration (2 to 52 weeks).

Comparison with beta-3 adrenergic agonists – The efficacy of antimuscarinic medications is similarly to that of the beta-3 adrenergic agonists mirabegron and vibegron [83,84]. (See 'Efficacy' above.)

Cure rate – In a systematic review of patients (mostly female) treated with antimuscarinic drugs for urgency urinary incontinence, the median cure rate was 49 percent with an interquartile range [IQR] of 35.6 to 58 percent [104].

Adverse drug effects

Common side effects – All antimuscarinics exert peripheral anticholinergic effects that may limit drug tolerability and dose escalation [99,105]. In addition to the potential for urinary retention, common anticholinergic effects include dry mouth, constipation, blurred vision for near objects, tachycardia, drowsiness, and decreased cognitive function.

Urinary retention – Antimuscarinics may cause urinary retention. A postvoid residual (PVR) should be checked in patients at higher risk for retention, including those who develop difficulty urinating or worsening incontinence on an OAB medication, those taking other medications with anticholinergic effects, and those with pelvic organ prolapse beyond the hymen. In our practice, we consider a PVR >1/3 of the total voided volume to be abnormal (eg, >100 mL residual after a void of 300 mL); however, it is reasonable to continue therapy unless voiding difficulty, urinary infection, or worsening OAB occurs. However, if any of these do occur, the medication should be stopped and this class of drug avoided unless the patient can perform self-catheterization if needed. (See "Female urinary incontinence: Evaluation", section on 'Clinical tests'.)

Risk of dementia – An increased risk of dementia with use of anticholinergic drugs has been reported in case-control and cohort studies [4,17-21]. In the largest study comparing over 58,000 patients with dementia with over 225,000 control individuals, exposure to antimuscarinic bladder agents over the prior 1 to 11 years was associated with an approximately 65 percent increased dementia risk (adjusted OR 1.65, 95% CI 1.56-1.75) [17]. However, while these studies suggest an association between antimuscarinic medications and dementia, causality cannot be determined. For example, patients at increased risk for brain disease may also be at increased risk for other neurologic dysfunction, including OAB. Randomly assigned controlled trials are not feasible to evaluate this outcome. (See "Risk factors for cognitive decline and dementia" and "Epidemiology, pathology, and pathogenesis of Alzheimer disease" and "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Medications'.)

Drug discontinuation from adverse effects – In clinical trials of patients with incontinence, discontinuation of all antimuscarinics due to adverse effects was higher compared with placebo [99,100]. A systematic review including 72 randomized trials reported medication discontinuation rates of 1 to 6 percent [99]. By six months and one year, less than 50 and 36 percent of patients continue medication, respectively [106]. In a study of over 29,000 females, dry mouth was the most common reason for discontinuation [107]. Constipation and compensatory fluid intake for dry mouth may exacerbate urinary incontinence.

Adjusting antimuscarinics

Assess medication adherence – For patients who do not experience sufficient improvement in symptoms after an adequate trial with a specific antimuscarinic, we assess adherence to medication. If the patient is tolerating the antimuscarinic medication without side effects but with limited adherence, we encourage regular usage of the medication and reassess in follow-up.

Dose modification – Many of the anticholinergic medications have various dose options (table 3). It is our standard practice to begin with the lowest available dose with an option to increase to a higher dose after two weeks as needed if side effects are tolerable. Tolterodine 2 mg extended release, oxybutynin 5 mg extended release, darifenacin 7.5 mg, and fesoterodine 4 mg can be doubled in dose and a new prescription for higher dose provided as needed if effective. Solifenacin can be prescribed at 10 mg initially and cut in half to start and increased to a whole tablet as needed (solifenacin is the only extended-release antimuscarinic that can be cut or crushed).

Trial of different antimuscarinic – For patients experiencing side effects or with inadequate response at maximum dose, changing to a different antimuscarinic may be beneficial. Side effect profiles differ among antimuscarinics and patients may respond to one antimuscarinic and not another (table 3). As efficacy across the various formulations is similar, selection of the appropriate drug for an individual patient is primarily dictated by side effect profile, tolerability, medical comorbidities, or insurance coverage.

Combination pharmacotherapy – Patients with partial but inadequate response to antimuscarinic therapy may benefit from combined treatment with an antimuscarinic drug and a beta-3 adrenergic agonist. (See 'Combination pharmacotherapy' below.)

Combination pharmacotherapy — Options for combination therapy include use of a beta-3 adrenergic agonist plus an antimuscarinic drug or two antimuscarinic drugs together. While both approaches have demonstrated efficacy, we prefer to initiate and maximize beta-3 agonist therapy, if the patient’s insurance and other circumstances allow, and then add an anticholinergic (preferably trospium due to purported limited CNS impact [74]). We consider this change if the patient is not satisfied with results after four to six weeks of maximized single-agent treatment. We do not routinely use two antimuscarinic agents together due to concerns over increased side effects and long-term cumulative anticholinergic burden which has been associated with increased risk of dementia.

Combined antimuscarinic and beta-3 adrenergic agonist – Combination antimuscarinic and beta-3 agonist treatment is helpful for patients with persistent symptoms who are unable to increase the dose of the initial medication dose secondary to side effects or dose limits. Adverse effect profiles are the same as for each medication used alone.

Drug dosing – For combination therapy, oral mirabegron 25 mg is typically used with oral solifenacin 5 mg; both drugs are taken once daily [28]. For those with inadequate response, the mirabegron dose can be increased to mirabegron 50 mg after four to eight weeks. In randomly assigned trials, mirabegron plus solifenacin (5 mg oral tablet daily) had superior efficacy over either agent alone [28,29]. Combination therapy may be more likely to cause dry mouth, constipation, and cognitive side effects because of the addition of the antimuscarinic agent.

Efficacy – In two trials comparing mirabegron plus solifenacin in various dosage combinations (mirabegron 25 or 50 mg plus solifenacin 5 or 10 mg) with solifenacin alone (5 or 10 mg), combination therapy resulted in improved OAB symptoms compared with either monotherapy dose [30-32]. Urinary retention has been reported when mirabegron is used with an antimuscarinic agent [28]. (See 'Drugs and dosage' above.)

Dual antimuscarinic – Dual antimuscarinic therapy may be helpful in those patients with OAB who have a partial but inadequate response to single-agent treatment and are unable to access beta-3 adrenergic agonist medications. Patients considering dual antimuscarinic therapy should be counseled regarding increased risk of anticholinergic side effects and need for followup monitoring, particularly for urinary retention. In three studies of patients age ≥65 years with moderate to severe OAB, treatment with trospium plus solifenacin, in various dose combinations and durations as compared with placebo, was associated with reductions in number episodes of incontinence, frequency of urination, and episodes of urinary urgency as well as improvements in health care-related quality of life [108-110]. Short-term cognitive function parameters did not change with use of higher (daily treatment with solifenacin 20 mg and trospium 60 mg) or lower dose regimens (daily treatment with solifenacin 10 mg and trospium 30 mg) compared with placebo [110]. Long-term data on potential cognitive impact from this drug combination are lacking.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urinary incontinence in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Urinary incontinence in females (The Basics)" and "Patient education: Pelvic floor muscle exercises (The Basics)" and "Patient education: Neurogenic bladder in adults (The Basics)" and "Patient education: Deciding about surgery for stress urinary incontinence in females (The Basics)" and "Patient education: Treatments for urgency incontinence in females (The Basics)")  

Beyond the Basics topics (see "Patient education: Urinary incontinence in women (Beyond the Basics)" and "Patient education: Urinary incontinence treatments for women (Beyond the Basics)" and "Patient education: Pelvic floor muscle exercises (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Pretreatment evaluation – Prior to initiating therapy for urgency urinary incontinence in female patients, patients with concerning symptoms should be evaluated for urinary tract infection, advanced pelvic organ prolapse beyond the hymen, reversible underlying conditions (eg, obesity, smoking, excessive fluid intake), and medications that may contribute to incontinence. (See 'Initial evaluation and referral' above.)

Trial of pelvic floor physical therapy and behavioral changes

Initial treatment for all patients with urinary incontinence (stress, urgency, or mixed) includes initiating pelvic floor exercises, modifying contributory medical (table 1) and lifestyle (eg, obesity) factors, advising bladder training (table 2), and treating vulvovaginal atrophy (if present) with topical estrogen therapy. Pelvic floor muscle exercises may be initiated with verbal or written instructions. (See 'Supervised or augmented pelvic floor muscle training' above and 'Trial of pelvic floor exercises, lifestyle therapy, and behavioral changes' above.)

For those who have difficulty or no improvement with unsupervised physical therapy, we suggest supervised pelvic floor physical therapy by a physical therapist specifically trained in the modalities (Grade 2C). (See 'Supervised or augmented pelvic floor muscle training' above and "Female urinary incontinence: Treatment", section on 'Supplemental modalities'.)

Addition of pharmacotherapy – For patients in whom the initial treatments are ineffective, we suggest adding a trial of medication (Grade 2C). Combination therapy appears more effective than either approach alone.

Selection of medication

-For patients who elect a trial of pharmacotherapy, we suggest initial treatment with a beta-3 adrenergic agonist rather than an antimuscarinic agent (table 3) (Grade 2B). Efficacy is similar for the two drug classes but antimuscarinic agents have more adverse effects. In addition, case-control and cohort studies have raised concerns for an increased risk of dementia with anticholinergic drugs. Efficacy data appear to be similar for the beta-3 adrenergic drugs mirabegron and vibegron. (See 'Our approach' above.)

-For patients who cannot access beta-3 adrenergic agonist medications for reasons of availability or cost, antimuscarinic agents are a reasonable alternative as initial therapy. Of the available antimuscarinics, trospium and darifenacin are preferred over other antimuscarinic agents based on limited data from animal and in vitro studies that found poor central nervous system penetration by trospium and darifenacin compared with the other antimuscarinic drugs. However, studies assessing cognitive effects in humans are lacking and the other antimuscarinic drugs are reasonable alternative choices. With any antimuscarinic drug, we start with the lowest drug dose and reassess patient response in two to six weeks. Dose increases are titrated to patient response and development of side effects.

Contraindications

-Beta-3 adrenergic agonists – Individuals with poorly controlled hypertension should avoid mirabegron but not vibegron. (See 'Adverse effects' above.)

-Antimuscarinics – These medications are contraindicated in patients with uncontrolled tachyarrhythmias, myasthenia gravis, gastric retention, and narrow angle-closure glaucoma. Patients should be counseled on the risks of long-term exposure of high-dose anticholinergics as well as possible increased risk of dementia. (See 'Drugs, selection, and administration' above.)

Assessment of response – At follow-up visits, we assess symptom improvement and medication tolerance at four to six weeks. We specifically discuss any ongoing urinary symptoms, new drug-related adverse effects, and medication compliance. Once appropriate use of the drug is confirmed, next steps vary based on the presence of no versus partial response and presence of adverse drug-related effects.

-For patients with an insufficient response to beta-3 adrenergic agonist drugs or antimuscarinic medication, we maximize dosing and allow up to 12 weeks to achieve maximum response. For those who cannot tolerate therapy with one agent, we switch pharmacotherapy to the other class (ie, antimuscarinic or beta-3 adrenergic agonist). (See 'Assess treatment response and adjust medication' above.)

-A trial of combination drug therapy can be used for patients with persistent symptoms on maximum dosing or who are unable to increase the dose secondary to side effects. (See 'Combination pharmacotherapy' above.)

Special populations – Patients age ≥65 years, with cognitive change or dementia, and with mixed urinary incontinence require additional consideration. For those with dementia or cognitive impairment, nonpharmacologic approaches or beta-adrenergic pharmacotherapy are preferred because these individuals are particularly vulnerable to adverse effects of antimuscarinic agents. (See 'Special populations' above.)

Persistent symptoms – Individuals with persistent symptoms despite exercise and lifestyle therapies followed by a trial of at least two pharmacologic therapies (or inability to tolerate them) warrant referral to a specialist to consider advanced treatment options or surgery. (See 'Patients with continued symptoms' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Catherine E DuBeau, MD, who contributed to an earlier version of this topic review.

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Topic 114501 Version 34.0

References

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