Prognosis and treatment of dementia with Lewy bodies

INTRODUCTION — Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia after Alzheimer disease (AD). In addition to dementia, distinctive clinical features include cognitive fluctuations, visual hallucinations, parkinsonism, dysautonomia, sleep disorders, and antipsychotic sensitivity.

There is some clinical imperative to diagnose DLB, as increasing evidence suggests the prognosis is different from other degenerative dementias such as AD, and even Parkinson disease dementia (PDD). Although the treatment choices for DLB and PDD are similar, there are some special considerations for optimal treatment in DLB for best clinical efficacy and limitation of side effects.

While awareness of DLB among health care practitioners has increased, public awareness remains relatively low. Many patients diagnosed with DLB are challenged by being confronted with this unfamiliar diagnosis at a time when they are quite impaired; this contrasts with patients with mild cognitive impairment (MCI) or PDD who may have had some time to prepare. Thus, discussion of treatment and prognosis, as well as supportive care from a multidisciplinary team, are critical to patients and their caregivers.

This article will describe the prognosis and treatment of DLB; other aspects of DLB are discussed separately:

●(See "Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies".)

●(See "Clinical features and diagnosis of dementia with Lewy bodies".)

The treatment of other dementia syndromes and the treatment of dementia in general are discussed separately:

●(See "Treatment of Alzheimer disease".)

●(See "Cholinesterase inhibitors in the treatment of dementia".)

●(See "Management of neuropsychiatric symptoms of dementia".)

●(See "Cognitive impairment and dementia in Parkinson disease".)

●(See "Frontotemporal dementia: Treatment".)

●(See "Treatment of vascular cognitive impairment and dementia".)

PROGNOSIS

Life expectancy — Estimates of survival in patients with DLB range from 1.8 to 9.5 years, but studies have been limited by small sample size and lack of neuropathology. In a meta-analysis of 150 patients with neuropathologically confirmed DLB, mean survival was 6.1 years [1]. Several studies suggest that the survival for DLB is shorter compared with Alzheimer disease (AD), but is similar for DLB and Parkinson disease dementia (PDD) [2-5].

For individual patients, life expectancy can be hard to predict and is influenced by comorbidities. Many factors have been associated with poorer prognosis in DLB [3]. These factors include cognitive fluctuations, early hallucinations, and gait abnormalities. The degree of motor parkinsonism, presence of orthostatic hypotension, and prominent psychiatric symptoms, particularly those that require the use of antipsychotic drugs, contribute to shorter survival [6]. Evidence of comorbid AD such as apolipoprotein E epsilon 4 (APOE e4) genotype and increased hippocampal atrophy on magnetic resonance imaging (MRI) has also been associated with shorter survival time among patients with DLB [3,7].

Cognitive decline — Cognitive decline in DLB is progressive. In a five-year prospective cohort study of patients with mild dementia, the median time to reach severe dementia was approximately five years, with a mean annual decline in Mini-Mental State Examination (MMSE) score of 4.4 points/year [8]. These rates of decline were somewhat faster than those that were observed for patients with AD, a finding also observed in other studies [9,10].

Evidence suggests that comorbid AD pathology in DLB accelerates cognitive decline [11,12]. AD biomarkers measured in cerebrospinal fluid, such as low levels of amyloid beta 42 and elevated levels of total and phosphorylated tau, have been correlated with lower MMSE scores and with more rapid cognitive decline in patients with DLB [13]. Presence of an APOE e4 allele has also been associated with faster cognitive decline in DLB [14,15]. Although these biomarkers may be potentially useful for prognosis if confirmed in larger studies, they are not generally measured outside of research studies as they do not aid diagnosis.

Parkinsonism and nonmotor symptoms — Most patients with DLB have parkinsonism, which worsens over time, especially in patients for whom this is an early feature [16]. Nonmotor symptoms, including neuropsychiatric symptoms and autonomic dysfunction, also progress and are often distressing for both patients and caregivers. As an example, urinary symptoms are common in DLB, may lead to complications such as urinary infection or sepsis, and contribute to caregiver burden [17]. It is important to recognize and treat symptoms, as persistent autonomic dysfunction has been associated with reduced quality of life, autonomy, and survival [18,19].

Behavioral symptoms, particularly hallucinations and delusions but also anxiety and depression, are also associated with increased caregiver burden and subsequent residential/nursing care admission. These symptoms are described separately.

By contrast, sleep disturbances including rapid eye movement (REM) sleep behavior disorder may persist throughout the disease but often decrease in severity or "burn out" with time.

These clinical features along with their typical course are described in detail separately. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on 'Clinical features'.)

Nursing home admission — Nursing home admission is a major indicator of disease progression in dementia and often involves several factors such as old age, poor functional and cognitive status, neuropsychiatric or behavioral symptoms (ie, psychosis, aggression, wandering), isolation (ie, living alone), and increasing caregiver burden (or burnout). The degree of motor parkinsonism and psychiatric symptoms, particularly those that require antipsychotic medication, may contribute to earlier institutionalization compared with AD [20,21]; however, not all studies have confirmed a shorter time to nursing home placement in patients with DLB compared with other neurodegenerative dementias [2,22].

TREATMENT — Treatment of DLB is complex and ideally should involve a multidisciplinary team that includes the primary care provider, neurology and other specialists (psychiatry, neuropsychology, physiatry), as well as support from social work and palliative care in order to provide the patient and family the best possible treatment advice.

Patient and caregiver education regarding risks, benefits, and limitations of treatments is important. In many cases, treatment choices represent a trade-off between parkinsonism and psychosis, and the relative preferences of the patient and caregiver will be decisive.

There are currently no treatments with evidence of disease-modifying effects. Treatment is primarily symptomatic and targeted toward specific disease manifestations, although it is based upon somewhat limited evidence.

Cognition and neuropsychiatric symptoms

Nonpharmacologic management — Because medications may be poorly tolerated in DLB, nonpharmacologic behavioral strategies aimed at modifying stressors in the environment should be employed whenever possible. These are discussed in detail separately. (See "Management of neuropsychiatric symptoms of dementia", section on 'Nonpharmacologic therapies'.)

In addition, clinicians should first consider that some medications (eg, antiparkinson medications) and comorbid medical conditions may contribute to a decline in cognition or to behavioral manifestations (algorithm 1). Dose reduction or discontinuation of offending medications can sometimes be helpful but may come at a cost, such as worsening parkinsonism. Additionally, underlying medical conditions may complicate disease and contribute to cognitive and neuropsychiatric symptoms including delirium. (See "Management of neuropsychiatric symptoms of dementia", section on 'Evaluation for underlying cause'.)

Cholinesterase inhibitors — For most patients with DLB, we suggest a treatment trial with a cholinesterase inhibitor to ameliorate cognitive and behavioral symptoms. This approach is supported by data from trials and meta-analyses suggesting their effectiveness in DLB [23-25]. Such medications are widely used and considered the mainstay of treatment in DLB. Contraindications to these medications include cardiac conduction abnormalities and are discussed separately. (See "Cholinesterase inhibitors in the treatment of dementia", section on 'Contraindications and precautions'.)

Multiple anecdotal reports [26,27], open-label studies [28-32], and a limited number of randomized, controlled trials [33-35] suggest that cholinesterase inhibitors are efficacious in DLB, with reported benefit not only in cognition, but also for fluctuations, psychotic symptoms, activities of daily living, and reduced caregiver burden. In one observational study the use of these agents was associated with reduced risk of nursing home admission [21]. In some instances, the response is dramatic but temporary. The effect size has been reported to be larger than that in patients with Alzheimer disease (AD) [36].

●Specific agents – No head-to-head comparison trials of the cholinesterase inhibitors have been performed. Based upon placebo-controlled studies, it is likely that the cholinesterase inhibitors donepezil and rivastigmine appear similarly effective in DLB [25,37]. Both are recommended as first-line treatments for DLB by the United Kingdom National Institute for Health and Care Excellence. Donepezil is currently licensed for the treatment of DLB in Japan, and rivastigmine is licensed in the United States and United Kingdom for use in Parkinson disease dementia (PDD). Evidence for galantamine in DLB remains sparse. Dosing of individual cholinesterase inhibitors is provided in the table (table 1).

•Rivastigmine – A multicenter study randomly assigned 120 patients with DLB to rivastigmine (6 to 12 mg per day) or placebo for 20 weeks [33]. Patients on rivastigmine showed significantly reduced anxiety, delusions, and hallucinations (particularly visual) and had significantly better performance on a computerized battery of neuropsychologic tests, especially tasks requiring sustained attention. The differences between rivastigmine and placebo disappeared after drug discontinuation. The expected gastrointestinal side effects as well as hypersalivation, lacrimation, and urinary frequency were seen with a higher frequency in the rivastigmine group, but the drug was well tolerated overall.

Rivastigmine can also be administered by transdermal patch and may provide an option for patients with impaired swallowing and for those with gastrointestinal intolerance to oral medications. It can be titrated up to 9.5 mg per day with the option to advance to a 13.3 mg per day patch as the illness progresses.

•Donepezil – One randomized study of 140 patients with DLB found that 12 weeks of therapy with either 5 or 10 mg of donepezil was associated with significant improvements in both cognitive and behavioral measures, as well as caregiver burden when compared with placebo [34]. Results of a second randomized trial in 142 patients with DLB were more modest, however, and only the 10 mg dose was associated with an improvement in cognition compared with placebo [35]. Neither 5 nor 10 mg of donepezil led to significant improvements in neuropsychiatric symptoms in this study.

•Galantamine – Evidence for the efficacy of galantamine in DLB is limited to only open-label trials [29,32]. These reports indicate improvement in cognitive fluctuations, sleep disturbance, and neuropsychiatric symptoms, but inconsistent results for cognition in DLB.

●Adverse effects – While not reported in the randomized studies as significant risks, there have been case reports of worsening cognitive function, rapid eye movement (REM) sleep behavior disorder, or parkinsonism with cholinesterase inhibitors [38,39]; patients should be monitored carefully while using these drugs. Weight loss is a recognized side effect of cholinesterase inhibitors, but in most cases the degree of weight loss is modest [40]. Other aspects of treatment monitoring and the approach to common side effects are discussed separately. (See "Cholinesterase inhibitors in the treatment of dementia", section on 'Approach to common side effects'.)

●Duration of treatment – Though there are no clear guidelines for how long a treatment trial should be or how best to measure response to cholinesterase inhibitors, we generally recommend at least a six-month trial with focus on long-term maintenance of cognitive function and control of behavioral symptoms. While a small subset of patients have a fairly dramatic response, most patients and caregivers indicate a modest effect.

Lack of improvement alone is not a cause for discontinuation, as there is some evidence that cholinesterase inhibitors may slow overall deterioration in DLB [25]. In general, we endorse an individual approach, considering factors from both the patient and caregivers, that often involves trial and error and close monitoring of risks and benefits.

Memantine — Whether memantine should be used as monotherapy or together with cholinesterase inhibitors remains unclear and requires further study. In practice, memantine is sometimes used as a second-line therapy when patients indicate intolerance to cholinesterase inhibitors. Memantine is also occasionally used as an adjunct to cholinesterase inhibitors, although without supporting evidence in DLB.

Memantine has reported efficacy in moderate to severe AD and vascular dementia, but data in DLB are mixed. Beneficial effects of small magnitude have been demonstrated for global impression scores but not cognition or neuropsychiatric symptoms [24,25].

●A randomized controlled trial of 72 patients with either DLB or PDD found that patients treated with memantine for 24 weeks performed better on the AD cooperative study Clinical Global Impression of Change (ADCS-CGIC) scale, but not on most of the other secondary outcome measures [41].

●In a 24-week trial that compared memantine with placebo in 199 patients with either DLB or PDD, the subset of 75 patients with DLB (but not PDD or the group overall) demonstrated improvement in the ADCS-CGIC score, but not on most secondary outcome measures [42]. In a subset of patients followed for 36 months, a survival benefit for memantine was observed (13 of 18 versus 4 of 14), a finding that requires confirmation in a larger, independent sample [43].

●In a secondary analysis of a small randomized tolerability study, treating patients with memantine was associated with improved caregiver burden and individual goal attainment [44].

In most studies, memantine has been well tolerated [41,42]; however, some have noted that worsening of delusions and hallucinations with memantine may be particularly problematic in patients with DLB [45,46]. Caution should be exercised when using memantine in patients with impaired renal function or history of seizures. Memantine may also increase the risk toxicity if given with amantadine. Other side effects are discussed separately. (See "Treatment of Alzheimer disease", section on 'Memantine'.)

Antipsychotic drugs — Because of limited efficacy and significant safety concerns, antipsychotic medications are reserved for severe, refractory behavioral symptoms after other measures (including nonpharmacologic treatment and cholinesterase inhibitors) have been tried and other contributors have been excluded. (See "Management of neuropsychiatric symptoms of dementia", section on 'Evaluation for underlying cause' and "Management of neuropsychiatric symptoms of dementia", section on 'Initial management strategies'.)

In DLB, there is potential for severe sensitivity reactions, including exacerbation of parkinsonism, confusion, or autonomic dysfunction, which limits the usefulness of antipsychotic medications in these patients. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on 'Antipsychotic sensitivity'.)

When antipsychotic therapy is required, patients and caregivers should be warned about the possibility of severe side effects and caution should be exercised. In addition to the sensitivity reactions more specific to DLB, these drugs are associated with an increased risk of death when used in older adult patients with dementia. (See "Management of neuropsychiatric symptoms of dementia", section on 'Mortality risk' and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects", section on 'Adverse effects'.)

No clinical trials inform the use of antipsychotic agents in patients with DLB specifically. Randomized, placebo-controlled studies suggest that antipsychotic agents have limited efficacy in patients with dementia in general. (See "Management of neuropsychiatric symptoms of dementia".)

If antipsychotic therapy is required in patients with DLB, only atypical antipsychotic drugs, such as olanzapine, quetiapine, or clozapine, should be used in very small doses in order to reduce the risk of severe reaction [47-51]. The older, conventional antipsychotics such as haloperidol should be avoided unless urgently required [52].

●Quetiapine – Although quetiapine is often used in patients with Parkinson disease (PD) and is generally well tolerated, evidence supporting its use in DLB is restricted to case series [53]. A small clinical trial in a mixed dementia population (23 of 40 enrolled patients had DLB) did not reveal a benefit with quetiapine [25,54].

When prescribing quetiapine in patients with DLB, we typically start with a low dose (eg, 12.5 to 25 mg per day).

●Clozapine – Clozapine is supported by studies in PD psychosis; this provides indirect support for its use in DLB. These studies are discussed separately. (See "Management of nonmotor symptoms in Parkinson disease", section on 'Refractory psychotic symptoms'.)

Use of clozapine, however, requires specialized monitoring including frequent blood counts for agranulocytosis. More common side effects include sedation, drooling, dizziness, and orthostatic hypotension. (See "Schizophrenia in adults: Guidelines for prescribing clozapine".)

●Pimavanserin – Pimavanserin is approved by the US Food and Drug Administration (FDA) for use in patients with PD psychosis. However, the safety and efficacy of pimavanserin in Lewy body dementias has not been formally established, though a phase 3 clinical trial (NCT03325556) including patients with dementia is underway. Pimavanserin may also take up to four to six weeks to reach full efficacy and is thus not recommended for treatment of acute psychosis.

If the desired clinical response is not seen from one agent, it should be discontinued and another agent tried, rather than escalating the dose of the first agent. Management of severe agitation in the setting of dementia is discussed in detail separately. (See "Management of neuropsychiatric symptoms of dementia", section on 'Agitation or aggression'.)

Other psychotropic medications and treatment modalities — There have been no systematic studies of the use of antidepressants, anxiolytics, benzodiazepines, or anticonvulsants in the treatment of the behavioral and psychiatric symptoms in DLB [52]. The use of these agents in patients with dementia in general is discussed separately. (See "Management of neuropsychiatric symptoms of dementia", section on 'Antidepressant medication' and "Management of neuropsychiatric symptoms of dementia", section on 'Drugs with uncertain benefit'.)

●Selective serotonin reuptake inhibitors (and combined serotonin-norepinephrine reuptake inhibitors) are commonly used in the treatment of depression or anxiety. For some patients with DLB, these medications may affect sleep and potentially exacerbate REM sleep behavior disorder. In one report, 10 of 14 patients with DLB who were treated with citalopram withdrew because of adverse events [55].

●Benzodiazepines are generally avoided (except for REM sleep disorder), especially for long-term use, because of the potential for worsening confusion, gait disorder, and paradoxic agitation.

●Tricyclic agents are typically avoided because of their anticholinergic properties.

Nonpharmacologic treatment modalities have been evaluated in small case series:

●Electroconvulsive therapy was used successfully in two small case series of patients with depression and DLB [56,57]. Delirium is a potential side effect of concern in this patient population. (See "Overview of electroconvulsive therapy (ECT) for adults", section on 'Adverse cognitive effects'.)

●Repetitive transcranial magnetic stimulation (TMS) has been reported to be a safe therapeutic strategy successfully used in six patients with depression and DLB [57]. The safety and efficacy of TMS is discussed separately. (See "Unipolar depression in adults: Indications, efficacy, and safety of transcranial magnetic stimulation (TMS)".)

REM sleep behavior disorder — Treatment of REM sleep behavior disorder prioritizes establishing a safe sleeping environment. Pharmacotherapy with melatonin or clonazepam can be useful in ameliorating symptoms. The treatment of REM sleep behavior disorder is discussed in more detail separately. (See "Rapid eye movement sleep behavior disorder", section on 'Management'.)

Parkinsonian symptoms — Treatment of parkinsonian symptoms in DLB is similar to that for PD, if somewhat less successful [58-60]. Medication is typically required for symptoms that interfere with functioning or affect quality of life. Physical therapy and mobility aids may also help in the management of parkinsonism. The management of PD is discussed in detail separately. (See "Initial pharmacologic treatment of Parkinson disease" and "Nonpharmacologic management of Parkinson disease".)

There is concern that antiparkinson medications may exacerbate psychotic symptoms and orthostatic hypotension in DLB; however, clinical experience and small case series suggest that by using a conservative approach (small doses and slow upward titration), these agents are generally effective and well tolerated [39,61]. Worsening of psychotic symptoms may require the addition of a small dose of an atypical antipsychotic [61,62].

Levodopa seems to be more effective than dopamine agonists and produces fewer side effects [63]. A suggested initial dose is one-half tablet of carbidopa-levodopa (Sinemet) 25/100 mg three times daily, titrated upward over several weeks as tolerated and according to the clinical response. Anticholinergic agents are generally avoided in DLB because they may worsen cognitive function.

Orthostatic hypotension — Orthostatic hypotension is common in patients with DLB and can be disabling. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on 'Syncope or transient loss of consciousness'.)

A nonpharmacologic approach should be initiated first; this includes behavioral and lifestyle changes such as standing slowly, raising the head of the bed, increasing fluid and salt intake, and wearing compression stockings or an abdominal binder. Medications that may exacerbate hypotension should be discontinued where possible. (See "Treatment of orthostatic and postprandial hypotension", section on 'Nonpharmacologic measures'.)

Medical therapy is indicated when these measures fail and can improve symptoms in most patients with DLB [64,65]. While not specifically studied in these patients, fludrocortisone and the alpha-1 receptor agonist midodrine, or a combination of the two, are frequently used to treat symptomatic orthostatic hypotension in DLB. Droxidopa (a prodrug that is metabolized to norepinephrine) may be used as an alternative to midodrine. Patients treated with these medications should be monitored for potential supine hypertension; fludrocortisone additionally may cause fluid retention and electrolyte disturbances. The management of orthostatic hypotension is discussed in detail separately. (See "Treatment of orthostatic and postprandial hypotension", section on 'Pharmacotherapy'.)

Urinary symptoms — Urinary urgency, frequency, and incontinence are common in DLB. Treatment recommendations are largely based on symptomatic treatment in other settings. However, antimuscarinic agents (oxybutynin, solifenacin, and trospium) may worsen cognitive function and psychosis, and thus they are relatively contraindicated in DLB. Mirabegron, a beta-3 adrenoceptor agonist, is preferred as there is low risk for cognitive side effects. In one case series of patients with PD, mirabegron was well tolerated and moderately effective [66]. Dosing, administration, and side effects of mirabegron are discussed in detail separately. (See "Lower urinary tract symptoms in males" and "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment", section on 'Addition of medication'.)

Other aspects of the treatment of urgency incontinence are discussed in detail separately. (See "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment" and "Lower urinary tract symptoms in males".)

For patients with nocturnal polyuria and sleep fragmentation, desmopressin (oral or intranasal spray) at bedtime may be a viable option to reduce frequent nocturia and is generally well tolerated in patients with conditions related to DLB [67,68]. (See "Nocturia: Clinical presentation, evaluation, and management in adults", section on 'Refractory nocturia'.)

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: Cognitive impairment and dementia".)

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 5^th to 6^th 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 10^th to 12^th 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 topic (see "Patient education: Dementia with Lewy bodies (The Basics)")

●Beyond the Basics topic (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Prognosis – Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder in which cognition, behavioral symptoms, and parkinsonism worsen over time, shortening life expectancy and often requiring nursing home placement. (See 'Prognosis' above.)

●Treatment approach – There are currently no treatments with evidence of disease-modifying effects in DLB. Treatment is primarily symptomatic and targeted toward specific disease manifestations:

•Cognitive or behavioral symptoms – For patients with bothersome cognitive or behavioral symptoms, we suggest treatment with a cholinesterase inhibitor (Grade 2C). Such medications are widely used and considered the mainstay of treatment in DLB. (See 'Cholinesterase inhibitors' above.)

Memantine is a reasonable alternative when patients cannot tolerate cholinesterase inhibitors, but it may be more problematic in patients with DLB who have hallucinations or delusions. Memantine may be considered as an adjunct to cholinesterase inhibitors based on its use in Alzheimer disease (AD), but evidence in DLB is scant. (See 'Memantine' above.)

•Severe, refractory behavioral symptoms – Antipsychotic medications are reserved for severe, refractory behavioral symptoms after other measures (including nonpharmacologic treatment and cholinesterase inhibitors) have been tried and other contributors have been excluded. (See 'Nonpharmacologic management' above.)

For such patients, we suggest cautious addition of a low-dose atypical antipsychotic agent (eg, quetiapine 12.5 to 25 mg per day) (Grade 2C). Patients and caregivers must be informed of the risks, including increased mortality and the development of severe antipsychotic sensitivity reactions that are characteristic of DLB. (See 'Antipsychotic drugs' above.)

•Disabling parkinsonism – For patients with disabling parkinsonism, we suggest initiation of levodopa therapy (Grade 2B). Low doses and slow upward titration with monitoring for increased psychosis is advised (eg, one-half tablet of carbidopa-levodopa [Sinemet] 25/100 mg three times daily, titrated upward over several weeks as tolerated and according to the response). (See 'Parkinsonian symptoms' above.)

•REM sleep behavior disorder – Treatment of rapid eye movement (REM) sleep behavior disorder prioritizes establishing a safe sleeping environment; pharmacotherapy with melatonin or clonazepam can be useful in ameliorating symptoms. Recommendations are provided separately. (See "Rapid eye movement sleep behavior disorder", section on 'Management'.)

•Other symptoms – Treatment recommendations for orthostatic hypotension and urinary incontinence mirror those for other conditions, but with some modifications to limit adverse medication effects. (See 'Orthostatic hypotension' above and 'Urinary symptoms' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Ann Marie Hake, MD, and Martin R Farlow, MD, who contributed to earlier versions of this topic review.