Japanese Encephalitis

Definition and PathogenesisTop

1. Etiologic agent: Japanese encephalitis virus (JEV) belonging to the genus Flavivirus, family Flaviviridae. Five JEV genotypes have been identified to date, with genotype I currently being the dominant one in Asia.

2. Pathogenesis: Initially the virus replicates in cells at the site of the mosquito bite (ie, skin) and in local lymph nodes. This is followed by the viremic phase with transient inflammatory lesions in extraneural tissues such as the heart, lungs, liver, and reticuloendothelial system. Some patients have a neuroinfection; since JEV replicates in endothelial cells, a significant part of the central nervous system (CNS) may be involved, including the thalamus, basal ganglia, brainstem, cerebellum (with damage to Purkinje cells), hippocampus, and cerebral cortex. Apart from neurons the virus also attacks other cells in the CNS, including astrocytes and microglial cells, which may cause damage to the blood-brain barrier.

3. Reservoir and transmission: The reservoir of JEV is vertebrates, primarily pigs and wading birds. The vector is mosquitoes, mainly Culex spp, which are common in wet areas with rice fields and shallow freshwater reservoirs. The mosquitoes are typically active in the evenings and at night. Cases of JEV infection through transfusion of blood products from an infected donor have been reported.

4. Risk factors: Staying in countries with active JEV transmission, particularly in rural areas, in the period of intense transmission and outdoors at the time of the highest activity of Culex mosquitoes. Factors that increase the risk of JEV infection in travelers according to the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (CDC ACIP): Table 1.

5. Incubation and contagious period: The incubation period is 5 to 15 days. As the viral load is small, patients usually are not contagious for close contacts.

EpidemiologyTop

In Asia, Japanese encephalitis (JE) is the most common neuroinfection that can be prevented through vaccination. Each year ~68,000 cases are reported in East and South Asia and on some islands of Australia and Oceania. JEV transmission occurs mostly in rural areas, often in places with intense irrigation of rice fields. Cases have also been reported in some suburban and urban areas of Asia with favorable environmental conditions for transmission.

In temperate climate zones within Asia, infections in humans usually peak in the summer and autumn. In subtropics and tropics, transmission may occur year-round, with the majority of cases occurring during the wet season.

The risk of infection associated with travels to Asia is very low (<1/1,000,000 travelers) and depends on a number of factors that affect the exposure.

In endemic countries adults acquire immunity through vaccination or natural infection, and the disease is mainly seen in children. Travel-associated disease may occur at any age. Information for travelers on JEV transmission in individual countries is published by the CDC and can be found at cdc.gov (Table 5-14). It should be noted, however, that it is rather general and should be interpreted with caution, as JEV transmission may change within areas and from year to year.

Clinical Features and Natural HistoryTop

In most cases, JEV infection is asymptomatic or mild with fever, weakness, headache, or diarrhea.

In <1% of infected individuals nonspecific symptoms (above) are observed for a few days, followed by encephalitis with qualitative and quantitative disorders of consciousness (up to and including coma), aphasia, focal deficits, spastic paresis, and other movement disorders. Seizures are common (especially in children), usually in the form of generalized tonic-clonic attacks. Less frequent manifestations include flaccid paralysis, parkinsonism, and isolated aseptic meningitis (see Meningitis). In some patients JE initially presents as behavioral aberrations or acute psychosis.

Full-blown JE usually manifests as a severe neuroinfection and carries a high risk of death. Symptoms of increased intracranial pressure or brainstem involvement and status epilepticus are associated with poor prognosis.

DIAGNOSISTop

Diagnostic Tests

1. Identification of the etiologic agent:

1) Serologic studies: Detection of IgM antibodies in cerebrospinal fluid (CSF) or in serum (enzyme-linked immunosorbent assay [ELISA]). In most patients, JEV-specific IgM is detectable in CSF ≥4 days after symptom onset, and ≥7 days in serum (sensitivity >95% if ≥10 days after symptom onset). Because of the potential cross-reactions with antibodies against other flaviviruses (eg, dengue virus [DENV] or West Nile virus [WNV]), a plaque reduction neutralization test (PRNT) is performed: a ≥4-fold increase in the JEV-specific IgG titer detected through a PRNT in 2 serum samples collected ≥14 days apart (ie, acute and convalescent phases) confirms recent JEV infection. Past infection (ie, IgM may be persistently detectable for 30-90 days) or vaccination may also impact the interpretability of serologic studies.

2) Molecular studies (reverse transcriptase–polymerase chain reaction [RT-PCR], reverse transcription loop-mediated isothermal amplification [RT-LAMP]; material: CSF, blood, brain tissue) are not commonly used due to small viremic load in JE and sufficient diagnostic utility of serologic tests.

3) Detection of viral antigens in brain tissue (immunohistochemical or immunofluorescent method).

4) Virus isolation (by culture) from blood, CSF, or brain tissue (eg, in autopsy).

2. Other tests:

1) CSF examination: CSF opening pressure is increased in ~50% of patients. CSF analysis may show mild to moderate pleocytosis with lymphocytic predominance. CSF protein may be mildly elevated, with normal CSF-to-plasma glucose ratio.

2) Laboratory blood tests: Findings may include leukocytosis (in most patients), hyponatremia, thrombocytopenia, mild anemia, elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.

3) Imaging studies: Magnetic resonance imaging (MRI) of the brain frequently shows lesions in the thalamus, basal ganglia, midbrain, pons, and medulla oblongata.

4) Electroencephalography (EEG): Altered background activity in patients in coma (theta coma and delta coma patterns, focal paroxysmal discharges, burst-suppression pattern).

Diagnostic Criteria

Suspect JE in patients with signs and symptoms of neuroinfection who have recently traveled to or are staying in endemic regions. A definitive diagnosis can be made on the basis of infection confirmed in laboratory testing.

Case definitions according to the World Health Organization (WHO):

1) Suspected case: Any person with an acute onset of fever and ≥1 of the following:

a) Altered mental status (including confusion, disorientation, coma, inability to talk).

b) New-onset epileptic seizures (other than febrile seizures).

2) Laboratory-confirmed case: Any person who meets the criteria of a suspected case, with laboratory-confirmed JEV infection (see above).

3) Probable case: Any person with suspected JE who is in a close geographic and temporal relationship to a laboratory-confirmed case of JE in the context of a JEV outbreak.

Differential Diagnosis

Encephalitis caused by other microorganisms, parainfectious encephalitis, postinfectious encephalitis, other noninfectious diseases of the CNS.

TREATMENTTop

Antiviral Treatment

None available.

Symptomatic Treatment

Urgent initiation of intensive symptom management significantly reduces mortality. Maintaining normal intracranial pressure and cerebral perfusion pressure, seizure control, and preventing complications, including secondary bacterial infections (eg, aspiration pneumonia), are of particular importance.

PrognosisTop

In patients with mild symptoms, the prognosis is good. In patients with symptoms of neuroinfection secondary to JEV infection, the prognosis is poor. Mortality among hospitalized patients is between 20% and 30%; and 30% to 50% of JE survivors have chronic neurologic complications. Damage to the upper and lower motor neurons (paresis and paralysis) as well as cerebellar and extrapyramidal signs are the most common observations. Severe cognitive dysfunction, mental disorders, and epileptic seizures may develop. Approximately 50% of patients after full-blown JE have no manifest complications, only discreet cognitive dysfunction and behavioral disturbances.

PReventionTop

Specific Prevention

Vaccination: Immunization is usually recommended for long-term (≥1 month) and frequent travelers to JE-endemic areas, and should also be considered for travelers with an increased risk of infection based on travel duration, season, location, activities, and accommodations (Table 1). The inactivated Vero cell culture–derived vaccine (2 doses) is used for pretravel immunization in some European and North American countries. Different inactivated and live attenuated JE vaccines are used in other countries, but they are not licensed in Europe or North America.

Nonspecific Prevention

1. Mosquito protection and avoiding mosquito bites (see: Nonspecific Insect and Tick Bite Precautions). The effectiveness of environmental interventions to ensure vector control and reduce JE incidence has not been proven.

2. Patient isolation: Not required.

3. Personal protective equipment (PPE) for health care personnel: Standard.

TablesTop