An Overview of Japanese Encephalitis

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus, closely related to West Nile virus and St. Louis encephalitis virus, that was first isolated in 1934 from the brain of a patient with fatal encephalitis in Tokyo, Japan.^1,2 JEV is primarily transmitted via Culex species of mosquitoes, particularly Culex tritaeniorhynchus, with wading birds and pigs acting as amplifying hosts.^1–3 Humans are incidental dead-end hosts as they do not develop sufficient viremia to infect mosquitos or other species. Most JEV transmission occurs in rural agricultural areas where rice production, irrigation, or pig farming occurs near human dwellings, increasing exposure to JEV-infected mosquitos.^1,3

JEV is currently endemic to parts of Asia and the Western Pacific (Figure 1), though can circulate outside its historic regions.^1–3 For instance, over 30 JEV disease cases were identified in an outbreak in southern and eastern Australia in early 2022, likely associated with local pig farms. ⁴ Peak JEV disease typically occurs summer through fall in temperate zones and year-round in tropical climates.^2,3 Incidence in endemic regions is estimated at approximately 70,000 cases/year (∼1.8 per 100,000 people), primarily in children aged 0-14 years, but cases are likely underreported and can significantly fluctuate during outbreaks.^1,5

Figure 1.

Geographic distribution of JEV courtesy of U.S. Centers for Disease Control and Prevention.

Less than 1% of human infections with JEV are symptomatic.^2,3 For those who develop disease, latency from infection to symptoms is typically 5-15 days. ³ Initial systemic symptoms are that of a non-specific febrile illness including fever, headache, and/or nausea and vomiting.^2,3 In a small portion, acute encephalitis can later develop with signs and symptoms including altered consciousness, seizures, and/or focal neurologic signs.^2,3,6 Some may develop other neuroinvasive syndromes such as meningitis, acute flaccid myelitis/poliomyelitis (which may mimic polio), or a para/post-infectious Guillain-Barré syndrome.^2,3,7,8 As with other flaviviruses, JEV has a predilection for subcortical deep brain nuclei, which can produce a Parkinsonian syndrome with masked facies, tremor, and/or rigidity.^2,3,6 Dystonia and other hyperkinetic movements may also occur, more commonly in children. ⁶ In neuroinvasive cases, cerebrospinal fluid (CSF) typically has a mild to moderate lymphocytic pleocytosis with mildly elevated protein and normal glucose. ³ Magnetic resonance imaging (MRI) of the brain most commonly shows thalamic, basal ganglia, or midbrain T2 hyperintense lesions, though lesions can occur in other areas.^2,3,6 In acute flaccid myelitis/poliomyelitis cases, MRI of the spinal cord may show a longitudinally extensive, gray matter predominant T2 hyperintense lesion. ⁸ The case fatality rate for those who develop neuroinvasive JEV disease is 20-30%. Of those that survive, up to 50% have significant neurologic or psychiatric sequelae.^3,6

Diagnosis of JEV infection is typically made by detecting JEV-specific immunoglobulin (Ig) M antibodies in the serum and/or CSF, which should be present in nearly all immunocompetent cases by 8 days after symptom onset.^2,3 Confirmatory JEV-specific neutralizing antibody testing can be done to rule out any potential test cross-reactivity with other related flaviviruses. ³ Detection of nucleic acid or live virus by culture does not usually occur in humans because of the low levels of viremia. However, in cases with biopsy tissue and in fatal cases, JEV nucleic acid, viral culture, or immunohistochemistry tests may play a role for diagnosis in immunocompromised hosts. ³

While small studies have been conducted examining various medications (eg, interferon, ribavirin, corticosteroids, intravenous immunoglobulin) in JEV and other flavivirus infections, there is still no proven specific treatment for JEV or other flavivirus diseases.^2,3,9 Care is largely supportive. Seizures, cerebral edema, coma, and/or acute flaccid paralysis may require intensive care management. ³

There is an inactivated Vero cell culture-derived JEV vaccine (IXIARO) licensed in the United States for those traveling to at risk areas. ³ An earlier mouse brain-derived vaccine (JE-VAX) was associated with acute disseminated encephalomyelitis and is no longer used. ² Other inactivated, live-attenuated, and live-recombinant JEV vaccines may be available in endemic countries.^1,2 In addition to vaccination, JEV infection risk can be reduced in endemic areas by preventing mosquito bites with insect repellent, wearing long pants and long-sleeved shirts, and/or using window screens or air conditioning to keep mosquitoes outside while indoors. ³ Clinicians can contact their local and/or state health departments for questions regarding Japanese encephalitis and for assistance with testing.

ORCID iD

Daniel M. Pastula https://orcid.org/0000-0001-9342-4459