Acute viral encephalitis in children: Treatment and prevention

INTRODUCTION — Encephalitis is inflammation of the brain parenchyma, manifest by neurologic dysfunction (eg, altered mental status, behavior, or personality; motor or sensory deficits; speech or movement disorders; seizure) and evidence of central nervous system inflammation (eg, cerebrospinal fluid pleocytosis and/or findings consistent with encephalitis on neuroimaging or electroencephalogram).

The treatment and prevention of viral encephalitis in children will be discussed here. The pathogenesis, etiology, clinical manifestations, and diagnosis of viral encephalitis in children are discussed separately. (See "Acute viral encephalitis in children: Pathogenesis, epidemiology, and etiology" and "Acute viral encephalitis in children: Clinical manifestations and diagnosis".)

DEFINITIONS — Central nervous system (CNS) infections are described according to the site of infection:

●Encephalitis – Encephalitis is defined as inflammation of the brain parenchyma and is manifested by signs of neurologic dysfunction lasting at least 24 hours. Characteristic clinical features include altered mental status (decreased level of consciousness, lethargy, personality change, unusual behavior), seizures, and/or focal neurologic signs, often accompanied by fever, headache, nausea, and vomiting [1]. (See "Acute viral encephalitis in children: Clinical manifestations and diagnosis", section on 'Clinical features'.)

●Meningitis – Meningitis is inflammation of the meninges and is typically manifested by fever, headache, nausea, vomiting, photophobia, and stiff neck. (See "Viral meningitis in children: Clinical features and diagnosis", section on 'Clinical features'.)

●Rhombencephalitis – Rhombencephalitis, or brainstem encephalitis, is characterized by myoclonic jerks, tremor, ataxia, cranial nerve involvement, respiratory abnormalities, shock, and coma.

●Myelitis – Myelitis is inflammation of the spinal cord and is characterized by weakness, paralysis, bowel and/or bladder dysfunction, and changes in tone and reflexes. (See "Disorders affecting the spinal cord", section on 'Acute viral myelitis'.)

●Radiculitis – Radiculitis is inflammation of the nerve roots and is characterized by weakness, shooting pain, dysesthesia, and diminished reflexes.

Some viruses cause less discrete manifestations of CNS infection and are described with broader terms:

●Meningoencephalitis – Meningoencephalitis refers to CNS infection manifesting signs and symptoms consistent with inflammation of the meninges and brain parenchyma.

●Encephalomyelitis – Encephalomyelitis refers to CNS infection manifesting signs and symptoms consistent with inflammation of the brain parenchyma and spinal cord.

Abnormal brain function distinguishes encephalitis from meningitis. The distinction between these entities is frequently blurred as both may be present concurrently; however, it is important to try to determine the presence of encephalitis because the likely causes may differ somewhat (table 1).

●Encephalopathy – Encephalopathy is a disruption of brain function in the absence of a direct inflammatory process in brain parenchyma (eg, caused by metabolic disturbance, hypoxia, ischemia, drugs, intoxications, organ dysfunction, systemic infection). This is discussed separately. (See "Acute toxic-metabolic encephalopathy in children".)

SUPPORTIVE CARE — Encephalitis is an acute, life-threatening emergency, requiring prompt intervention. Assessment and management often are performed simultaneously (table 2). Supportive care is a critical aspect of the treatment of encephalitis. Initial supportive care measures may include stabilization of cardiorespiratory status and treatment of seizures. (See "Initial assessment and stabilization of children with respiratory or circulatory compromise" and "Management of convulsive status epilepticus in children".)

Monitoring — Patients with severe encephalitis (ie, those with seizures, cardiorespiratory compromise, coma, or severe neurologic compromise) should be cared for in an intensive care unit with close monitoring, including:

●Cardiorespiratory status.

●Neurologic status – The Glasgow coma scale (GCS) score (table 3), although not specifically validated in patients with encephalitis, can be helpful in quantifying the level of consciousness and monitoring neurologic progression. Acute deterioration in the neurologic status (eg, new focal findings, loss of pupillary reactivity, acute decline in GCS) should prompt repeat neuroimaging to evaluate for cerebral edema, hemorrhage, or other acute changes. Repeat neuroimaging may also be warranted in patients who do not improve as expected over the initial days to weeks. Computed tomography is typically performed to evaluate acute changes, and magnetic resonance imaging is performed when more detailed diagnostic and prognostic information is desired.

●Fluid balance and electrolytes – It is important to monitor fluid balance (eg, input, urine output, daily weight) and electrolyte status in patients with severe encephalitis, as is the case with all critically ill children. Hypovolemia (if present) should be addressed with appropriate volume expansion (eg, 20 mL/kg normal saline bolus). Subsequent fluid management generally consists of isotonic maintenance intravenous (IV) fluids to maintain euvolemia. Fluid restriction is not typically necessary. Patients who have depressed mental status and those in whom airway reflexes are not intact are kept nil per os. Enteral feeding tubes are used to provide adequate nutrition in patients who are not able to feed by mouth. Parenteral nutrition is generally reserved for patients who are unable to resume enteral feeding after one week. (See "Maintenance intravenous fluid therapy in children" and "Overview of enteral nutrition in infants and children" and "Parenteral nutrition in infants and children".)

Management of complications — Potential complications that must be anticipated include [2]:

●Seizures and status epilepticus, which should be treated aggressively. There is insufficient evidence to support or refute routine use of antiseizure medications for the primary or secondary prevention of seizures in patients with viral encephalitis [3]. We typically treat with antiseizure medications only if the child has clinical or electroencephalographic evidence of seizures. In most of these cases, ongoing treatment is necessary, at least through the acute phase of illness. (See "Management of convulsive status epilepticus in children", section on 'Emergency antiseizure treatment'.)

●Cerebral edema. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis" and "Elevated intracranial pressure (ICP) in children: Management".)

●Fluid and electrolyte disturbance (eg, the syndrome of inappropriate antidiuretic hormone secretion [SIADH]). (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)

●Abrupt cardiac and respiratory arrest of central origin. (See "Initial assessment and stabilization of children with respiratory or circulatory compromise".)

EMPIRIC ANTIMICROBIAL THERAPY — Empiric antimicrobial treatment is warranted in children who present with suspected encephalitis (eg, fever, seizures, decreased or altered mental status, cerebrospinal fluid [CSF] pleocytosis, neuroimaging and/or electroencephalogram findings not attributable to another identified cause). In most cases, initial empiric antimicrobial coverage includes intravenous (IV) acyclovir for potential herpes simplex virus (HSV) infection and empiric antibiotics (eg, vancomycin and a third-generation cephalosporin) for potential bacterial central nervous system (CNS) infection (table 2). Empiric coverage for other potential infectious causes (eg, influenza, Mycoplasma pneumonia, cat scratch disease, Rocky Mountain spotted fever [RMSF], ehrlichiosis, Q fever) is individualized based on the season, exposures, geographic region, and presenting symptoms. Antimicrobial therapy should be started as soon as possible, and, whenever possible, appropriate specimens should be collected prior to initiating antimicrobial therapy.

Empiric acyclovir — The indications for empiric acyclovir in neonates are reviewed separately. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Indications' and "The febrile infant (29 to 90 days of age): Management", section on 'Ill-appearing' and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Ill-appearing'.)

For infants and children beyond the neonatal period who present with suspected encephalitis, we recommend prompt initiation of IV acyclovir pending viral studies [4].

HSV encephalitis can be a devastating infection. The majority of survivors have neurologic deficits even when appropriately treated [5,6]. Several small randomized controlled trials in pediatric and adult patients found that antiviral therapy for HSV encephalitis reduces mortality [7-11]. Initial placebo-controlled trials found vidarabine reduced mortality from approximately 70 to 30 percent [7,8]. Subsequent trials found lower mortality with acyclovir compared with vidarabine [9-11]. (See "Herpes simplex virus type 1 encephalitis", section on 'Treatment'.)

Dose — The dose of acyclovir varies depending on age [12]:

●>28 days to <3 months – 20 mg/kg per dose IV every eight hours.

●≥3 months to <12 years – 10 to 15 mg/kg per dose IV every eight hours; an increased dose (20 mg/kg per dose every eight hours) is approved by the US Food and Drug Administration for the treatment of HSV encephalitis in this age group, but the risk of nephrotoxicity and encephalopathy may be increased; consultation with an infectious disease or pharmacology specialist may be warranted if administered with other nephrotoxic drugs or weight-based dosing exceeds 800 mg per dose [13].

●≥12 years – 10 mg/kg per dose IV every eight hours.

Shortages of IV acyclovir have occurred. If IV acyclovir is not available, alternative agents must be used. Specific recommendations are presented separately. (See "Acyclovir: An overview", section on 'If there is an acyclovir shortage'.)

Duration — The duration of empiric acyclovir therapy depends upon laboratory results:

●HSV confirmed or probable – If HSV polymerase chain reaction (PCR) from CSF or another site is positive, acyclovir should be continued for 21 days [14]. Lumbar puncture should be performed near the end of acyclovir treatment to ensure that HSV PCR is negative; acyclovir therapy should be continued if CSF HSV PCR remains positive. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Duration of therapy' and "Herpes simplex virus type 1 encephalitis", section on 'Discontinuation of therapy based on PCR results'.)

●HSV PCR is negative – For patients in whom HSV PCR is negative, the decision to continue acyclovir therapy must be individualized. If there are strong clinical indicators of HSV encephalitis (eg, temporal spikes on electroencephalogram or temporal lobe involvement on imaging), repeat lumbar puncture may be warranted to exclude the possibility of a false-negative result on initial testing [5,15,16]. Repeat lumbar puncture also may be warranted in patients with severe neurologic dysfunction even in the absence of clinical indicators of HSV, particularly if no specific alternative etiology has been identified. Additional factors to consider in the decision to continue or discontinue acyclovir therapy are discussed separately. (See "Herpes simplex virus type 1 encephalitis", section on 'Discontinuation of therapy based on PCR results'.)

Empiric antibiotics — The clinical manifestations and CSF indices of bacterial meningitis and viral encephalitis overlap (table 4). Given the serious consequences of delayed treatment for bacterial meningitis, the usual practice is to initiate empiric antibiotic therapy pending cultures in most patients who present with clinical findings suggestive of encephalitis (eg, fever, decreased or altered mental status, seizures, and CSF pleocytosis). Empiric treatment for bacterial meningitis usually consists of vancomycin plus a third-generation cephalosporin (ceftriaxone or cefotaxime). Antibiotics can be discontinued after 48 hours if cultures remain negative. Some experts advise discontinuing vancomycin sooner in cases with low suspicion for bacterial meningitis if Gram stain and molecular testing for Streptococcus pneumoniae (eg, on multiplex meningitis/encephalitis PCR panel) are negative [17,18]. (See "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Empiric therapy'.)

Other empiric therapy — Empiric therapy also may be indicated for other infectious causes of encephalitis that are suspected based on epidemiologic or clinical information (table 5 and table 6 and table 7) [15]. Examples include:

●Mycoplasma pneumoniae – A prodrome of fevers and respiratory symptoms prior to onset of neurologic symptoms may suggest M. pneumoniae; however, respiratory symptoms may be less prominent in some patients. The diagnosis is confirmed with PCR and/or serology. Empiric therapy typically consists of a macrolide antibiotic (eg, azithromycin). (See "Mycoplasma pneumoniae infection in children".)

●Influenza – Influenza infection may be suggested based upon the constellation of symptoms in the appropriate season. Patients with encephalitis due to suspected influenza should have appropriate testing performed. Treatment for seasonal influenza in children is summarized in the table (table 8) and discussed separately. (See "Seasonal influenza in children: Management".)

●Cat scratch disease (Bartonella henselae) – Cat scratch disease may be suspected based upon reported exposure to cats (particularly kittens) and other clinical findings (ie, lymphadenopathy). The diagnosis is confirmed with serology. Empiric therapy consists of doxycycline or azithromycin plus rifampin. (See "Treatment of cat scratch disease", section on 'Neurologic and ocular manifestations'.)

●RMSF (Rickettsia rickettsia) – RMSF may be suspected based upon suggestive clinical findings (maculopapular or petechial rash, particularly with centripetal spread (picture 1)) in the setting of exposure to ticks in an endemic region (North, Central, and South America as well as southeastern and south-central states in the United States) (figure 1). The diagnosis is confirmed with serology and/or PCR. Empiric therapy consists of doxycycline. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Treatment of Rocky Mountain spotted fever".)

●Ehrlichiosis – Clinical and epidemiologic clues to ehrlichial infections (human monocytotropic ehrlichiosis [Ehrlichia chaffeensis] and human granulocytotropic ehrlichiosis [Anaplasma phagocytophilum]) include exposure to ticks in endemic regions (figure 2A-B), headache, rash, leukopenia, thrombocytopenia, characteristic blood smear (picture 2A-B), and elevated transaminases. The diagnosis is confirmed with serology. Empiric therapy consists of doxycycline (same dosing as for RMSF). (See "Human ehrlichiosis and anaplasmosis".)

●Q fever – Exposure to farm animals (eg, sheep, goats, particularly placental tissue, parturient fluids, newborn animals) may suggest Q fever. The diagnosis is confirmed with serology and/or PCR. Empiric treatment consists of doxycycline.

THERAPY FOR SPECIFIC VIRUSES — Specific treatment options, when available, for the more common causes of viral encephalitis in children and adolescents are discussed separately:

●Enteroviruses and parechoviruses (see "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Treatment')

●Herpes simplex virus (HSV) (see "Herpes simplex virus type 1 encephalitis" and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Initial antiviral therapy')

●Influenza virus (see "Seasonal influenza in children: Management", section on 'Antiviral therapy')

●Arboviruses (see "Arthropod-borne encephalitides" and "Treatment and prevention of West Nile virus infection")

●Epstein-Barr virus (see "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Treatment')

●Cytomegalovirus (see "Overview of cytomegalovirus infections in children", section on 'Treatment')

●Human herpesvirus 6 (see "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment", section on 'Treatment')

●Varicella (see "Treatment of varicella (chickenpox) infection", section on 'Individuals with complications')

ADJUNCTIVE THERAPIES — Based on the available evidence, we suggest not routinely treating children with encephalitis with adjunctive therapies, including glucocorticoids, plasmapheresis, intravenous immune globulin (IVIG), interferon alfa, and therapeutic hypothermia [2,15,19-22]. Although observational reports have described beneficial effects of some of these adjunctive therapies in limited settings, the reports vary and a clear benefit has not been established [2,15].

An exception is the child with viral encephalitis who has an underlying humoral immunodeficiency (agammaglobulinemia, hypogammaglobulinemia), for whom replacement IVIG therapy is appropriate, as discussed separately. (See "Common variable immunodeficiency in children", section on 'Immune globulin'.)

In addition, immune-modifying therapies (eg, glucocorticoids, IVIG) are routinely used in the management of the following conditions, which can present with clinical, laboratory, and imaging findings similar to those of acute infectious encephalitis. These conditions are discussed separately:

●Acute disseminated encephalomyelitis (see "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis")

●Autoimmune encephalitis (see "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis")

●Coronavirus disease 2019 (COVID-19)-related multisystem inflammatory syndrome in children (MIS-C) (see "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Immunomodulatory therapy')

PROGNOSIS — The prognosis of viral encephalitis varies depending upon the age of the patient, neurologic findings at the time of presentation, and pathogen. Poor outcome is associated with the following factors [23-28]:

●Coma, convulsion, or focal neurologic findings in the acute phase

●Young age (<5 years)

●Need for intensive care

●Herpes simplex encephalitis

●Diffusion restriction on magnetic resonance imaging

Mortality — The overall risk of death in childhood encephalitis ranges from 0 to 7 percent [23,24,29,30]. However, mortality is increased with specific pathogens (eg, in herpes simplex encephalitis and eastern equine encephalitis). (See "Herpes simplex virus type 1 encephalitis", section on 'Outcomes' and "Arthropod-borne encephalitides", section on 'Eastern equine encephalitis virus'.)

Neurologic sequelae — In self-limited cases, lethargy and coma gradually improve over days to weeks [29]. Focal deficits resolve more slowly. In a series of 71 patients from a single institution, 24 children (34 percent) made a complete recovery within 6 to 12 months [25]. Persistent neurologic effects may include personality change, behavior disorder (including attention deficit disorder), movement disorder (including tic disorders), intellectual disability, learning disorders, blindness, paresis, ataxia, recurrent headaches, and sleeping problems [25-27].

In a study that evaluated neurologic outcomes in 99 children with encephalitis at a mean 35.6 months duration of follow-up, the following findings were noted [31]:

●No neurologic sequelae (51 percent)

●Learning problems (23 percent)

●Developmental delay (19 percent, including 7 percent with global developmental delay)

●Behavioral problems (10 percent)

●Motor deficit (2 percent)

●Visual defects (1 percent)

●Hearing impairment (1 percent)

●Bladder spasticity (1 percent)

Outcomes of specific viral pathogens

●Herpes simplex virus (HSV) encephalitis – At least two-thirds of children and adolescents surviving with HSV encephalitis have some form of neurologic debility (eg, seizure disorder, global developmental delay, residual hemiplegia) [5,6,9,25].

The outcome of neonatal HSV central nervous system (CNS) disease is discussed separately. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Outcome'.)

●Arboviruses – The outcome of arboviral encephalitis is discussed separately. (See "Arthropod-borne encephalitides".)

●Enteroviruses – Enteroviral encephalitis generally causes milder clinical disease than other viruses, except when it causes CNS infection in neonates with disseminated disease [25,32]. Enterovirus A71 (EV-A71), which causes epidemics worldwide, is associated with high morbidity and mortality [33-35]. In a retrospective review of 36 patients with EV-A71 CNS and cardiopulmonary failure, 15 died (12 during the acute phase and three during convalescence); 16 of the 21 survivors had severe sequelae (central hypoventilation, dysphagia, limb weakness) [33]. (See "Enterovirus and parechovirus infections: Epidemiology and pathogenesis" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)

LONG-TERM FOLLOW-UP — Supportive care, rehabilitation, and monitoring should continue for at least one year after discharge from the hospital [25]. Long-term sequelae of viral encephalitis may not manifest during the acute illness. These include motor incoordination, seizures, strabismus, amblyopia, hearing impairment, and behavioral disturbances [36].

Hearing evaluation should be performed at the time of or shortly after discharge from the hospital. Children and adolescents who survive encephalitis are at risk for developmental and/or intellectual disability. Developmental surveillance should continue throughout childhood. Neuropsychologic testing may be helpful in identifying neurologic deficits and formulating a treatment plan. (See "Hearing loss in children: Screening and evaluation" and "Developmental-behavioral surveillance and screening in primary care".)

PREVENTION AND CONTROL — Because treatment options for encephalitis are limited, prevention is paramount.

Primary prevention — Primary prevention measures include:

●Handwashing (see "Infection prevention: Precautions for preventing transmission of infection", section on 'Hand hygiene')

●Appropriate identification, monitoring, and treatment of genital herpes simplex virus (HSV) infection during pregnancy to prevent neonatal HSV (see "Genital herpes simplex virus infection and pregnancy")

●Routine immunization of infants, children, and adolescents (for measles, mumps, rubella, varicella, influenza) and appropriate immunization of travelers depending upon their destination(s) (eg, Japanese encephalitis vaccine, tick-borne encephalitis virus vaccine) (see "Immunizations for travel")

●Insect control and avoidance of mosquito and tick exposure (eg, draining stagnant water, appropriate dress, use of mosquito and tick repellants, mosquito netting, looking for ticks after hiking, etc) (see "Prevention of arthropod and insect bites: Repellents and other measures")

●Appropriate viral screening of blood products (eg, West Nile virus) (see "Blood donor screening: Laboratory testing", section on 'Viruses')

Infection control — Patients who are hospitalized with encephalitis are usually placed on droplet and contact precautions at the time of admission. Isolation precautions can be changed if and when a specific pathogen is identified. Consultation with the hospital infection control practitioner or local health department may be helpful in making decisions regarding isolation precautions and/or evaluation or treatment of contacts. (See "Infection prevention: Precautions for preventing transmission of infection".)

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: Infectious encephalitis".)

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 email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topics (see "Patient education: Encephalitis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview table – A quick summary of the management of suspected encephalitis in children is provided in the table (table 2).

●Supportive care – Potential complications include status epilepticus, cerebral edema, fluid and electrolyte disturbance, and cardiorespiratory failure. Patients with severe encephalitis (ie, those with seizures, cardiorespiratory compromise, coma, or severe neurologic compromise) should be cared for in an intensive care unit with close cardiorespiratory monitoring and careful attention to neurologic status, fluid balance, and electrolyte status. (See 'Supportive care' above.)

●Empiric antimicrobial therapy – All children who present with clinical findings that are consistent with encephalitis (ie, fever, seizures, decreased or altered mental status, cerebrospinal fluid [CSF] pleocytosis, abnormal neuroimaging and/or electroencephalogram findings not attributable to another identified cause) should receive prompt empiric antimicrobial treatment. Whenever possible, appropriate specimens should be collected prior to initiating antimicrobial therapy. (See 'Empiric antimicrobial therapy' above.)

•Acyclovir – For all children who present with suspected encephalitis, we recommend prompt initiation of acyclovir pending viral studies (Grade 1B). (See 'Empiric acyclovir' above and "Herpes simplex virus type 1 encephalitis" and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Initial antiviral therapy'.)

•Antibiotics – Empiric treatment for bacterial meningitis (vancomycin plus a third-generation cephalosporin [ceftriaxone or cefotaxime]) pending bacterial cultures is also usually warranted since, in most cases, bacterial meningitis cannot be excluded initially. (See 'Empiric antibiotics' above and "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Empiric therapy'.)

•Other empiric therapy – Empiric therapy also may be indicated for other infectious causes of encephalitis that are suspected based on epidemiologic or clinical information (table 5 and table 6 and table 7). (See 'Other empiric therapy' above.)

●Prognosis – The prognosis of viral encephalitis varies depending upon the age of the patient, neurologic findings at the time of presentation, and pathogen. The overall risk of death in childhood encephalitis ranges from 0 to 7 percent; however, the risk is increased with specific pathogens (eg, in herpes simplex encephalitis and eastern equine encephalitis). Long-term neurologic sequelae are common. (See 'Prognosis' above.)

●Long-term follow-up – Survivors of childhood encephalitis should be monitored for long-term sequelae, including motor incoordination, seizures, strabismus, amblyopia, hearing impairment, and behavioral disturbances. Hearing evaluation should be performed at the time of or shortly after discharge from the hospital. Developmental surveillance should continue throughout childhood. (See 'Long-term follow-up' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Krogstad, MD, who contributed to earlier versions of this topic review.