eMedicine Specialties > Infectious Diseases > CNS Infections

Japanese Encephalitis

Author: Asim A Jani, MD, MPH, FACP, Clinician-Educator and Epidemiologist, Consultant and Senior Physician, Florida Department of Health; Assistant Professor, University of Central Florida College of Medicine
Coauthor(s): Alexander J Kallen, MD, Instructor of Medicine, Department of Internal Medicine, Division of Outcomes Research, VA White River Junction, VT; Dartmouth Medical School
Contributor Information and Disclosures

Updated: May 6, 2009

Introduction

Background

Japanese encephalitis virus (JEV), a flavivirus (single-stranded RNA), represents the most significant etiology of arboviral encephalitis worldwide. Japanese encephalitis is a neurologic infection closely related to St. Louis encephalitis and West Nile encephalitis. JEV is spread throughout mostly rural areas of Asia by culicine mosquitoes, most often Culex tritaeniorhynchus. Approximately 3 billion people currently live in areas endemic for Japanese encephalitis; these areas extend from Pakistan to maritime Siberia and Japan.

Japanese encephalitis is relatively uncommon among travelers to endemic areas (<1 per 1 million short-term and urban travelers). At-risk individuals include long-term residents in endemic rural areas.

In 1934, a Japanese scientist, Hayashi, inoculated monkey brains with the virus, reproducing the disease. This virus was named Japanese B encephalitis virus after its association with the summer type (or type B) encephalitis.

JEV belongs to the Japanese encephalitis serocomplex, which is composed of 10 flaviviruses, including Alfuy, Koutango, Kokobera, Kunjin, Murray Valley encephalitis, Japanese encephalitis, Stratford, Usutu, West Nile, and St. Louis encephalitis. Usutu virus has emerged recently (as of 2002); it is an African mosquito-borne flavivirus.

Pathophysiology

JEV is transmitted to humans via the bite of infected mosquitoes. The virus initially propagates at the site of the bite and in regional lymph nodes. Two cellular characteristics are critical to the pathogenesis: (1) the M protein, which contains hydrophobic domains that help to anchor the virus onto the host cell, and (2) the E protein, which is the principal immunogenic feature and which is expressed on the membrane of infected cells. The E protein mediates membrane fusion of the viral envelope and the cellular membrane, promoting viral entry into the host cell. On a cellular level, after attachment of virus to host cell membrane, local membrane disruption may lead to entry of virus into the cell itself. Subsequently, viremia develops, leading to inflammatory changes in the heart, lungs, liver, and reticuloendothelial system. Most infections are cleared before the virus can invade the CNS, leading to subclinical disease.

Subclinical or mild forms of Japanese encephalitis resolve in a few days if the CNS is not involved. In such cases, the infection may not produce symptoms and therefore remains undetected. However, given the neurotropic character of JEV, neurologic invasion can develop, possibly by growth of the virus across vascular endothelial cells, leading to involvement of large areas of the brain, including the thalamus, basal ganglia, brain stem, cerebellum (especially the destruction of the cerebellar Purkinje cells), hippocampus, and cerebral cortex. Persistent infection and congenital transmission may occur. The levels of varying immune response (intrinsic, cellular, humoral) have been characterized. Higher levels of certain cytokines (interferon-alpha, interleukins 6 and 8) have been associated with an increased mortality risk. The types of response implicate impaired T-helper-cell immunity in patients with severe advanced disease.

Overall, JEV is believed to result in increased CNS pathology because of its direct neurotoxic effects in brain cells and its ability to prevent the development of new cells from neural stem/progenitor cells (NPCs). JEV likely represents the first mosquito-transmitted viral pathogen to affect neural stem cells. These cells can serve important roles in injury recovery; consequently, Japanese encephalitis–induced disruption of neural stem cell growth may be particularly important to further morbidity and mortality.

Frequency

United States

In the United States, Japanese encephalitis develops mostly among military personnel, expatriates, and, rarely, returning travelers. From 1978-1993, 12 cases occurred in the United States. The risk of symptomatic infection among travelers is estimated to be 1 case per 150,000 person-months in an endemic area. Outbreaks are rare in the US territories of Guam and Saipan.

International

Japanese encephalitis is a seasonal disease, with most cases occurring in temperate areas from June to September. Further south, in subtropical areas, JEV transmission begins as early as March and extends until October. Transmission may occur all year in some tropical areas (eg, Indonesia). Globally, more than 45,000 cases are reported each year, although this is likely an underestimation of the true incidence of the disease.

Local incidence rates range from 1-10 cases per 100,000 persons but can reach more than 100 cases per 100,000 persons during outbreaks. The travel-associated risk is overall relatively low (1 per 5,000–20,000 per week of travel), but the severity of natural infection and possible complications have been important factors that promote vaccination as a major preventive practice.

Countries with epidemic or endemic Japanese encephalitis include the following:

• Malaysia
• Burma
• Singapore (rare cases)
• Philippines
• Indonesia
• China
• Taiwan
• Russia (maritime Siberia)
• Bangladesh
• Laos
• Cambodia
• Thailand
• Vietnam
• India
• Nepal (especially the Terai region)
• Sri Lanka
• Korea
• Japan
• Australia (possibly in islands of Torres Strait¹ )
• Brunei
• Pakistan
• Papua New Guinea
• Pacific Islands (rare outbreaks in Guam and Saipan)

In 2005, a Japanese encephalitis epidemic occurred in the Indian states of Uttar Pradesh and Bihar and throughout Nepal, resulting in more than 5000 cases and approximately 1000 deaths.²

Two outbreaks of Japanese encephalitis have occurred in Australia, the first in 1995 on islands in the Torres Strait¹ and the second in 1998 on the Cape York Peninsula. In addition, in 2004, one JEV isolate was detected from a pool of Culex mosquitoes trapped on the Cape York Peninsula.

Overall, as in other emerging pathogens, many of which are zoonotic viruses, a very complicated interplay of ecologic, climatic, environmental, and human behavioral factors have resulted in widespread distribution of JEV. Even mosquitoes pushed along by wind currents have been considered contributory to viral spread, eg, from Papua New Guinea to the Torres Strait islands and the Australian mainland. However, no evidence shows that Japanese encephalitis epidemics are likely part of postflooding infectious disease outbreaks.

Mortality/Morbidity

Only 1 per 250 JEV infections results in symptomatic disease. Mortality rates in locales with intensive care capabilities are 5-10%. In less-developed areas, mortality rates may exceed 35%. Worldwide, more than 10,000 deaths attributable to Japanese encephalitis are reported per year.

Approximately 33-50% of survivors of symptomatic disease have major neurologic sequelae at 1 year, including seizure disorders, motor or cranial nerve paresis, or movement disorders. At 5 years, nearly 75% of such patients score lower on standardized tests than control subjects.

Previous dengue infection may be associated with decreased morbidity and mortality rates, possibly due to partial protection of cross-reacting antiflaviviral antibodies.

Proven risk factors for death include demonstration of virus in the cerebral spinal fluid (CSF), low levels of immunoglobulin G (IgG)/immunoglobulin M (IgM) in CSF or serum, and a decreased sensorium.

Sex

Symptomatic Japanese encephalitis has a male-to-female ratio of 1.5:1.

Age

Serologic evidence of JEV infection in endemic rural areas is found in nearly all inhabitants by early adulthood. Most symptomatic infections in endemic areas occur in young children (aged 2-10 y) and elderly people. In nonendemic areas, JEV infection has no age predilection.

Clinical

History

• The ratio of asymptomatic Japanese encephalitis virus (JEV) infection to symptomatic infection has been reported to range from 25-1000:1.
• Infected individuals have a history of mosquito exposure in an endemic area. The incubation period averages 6-8 days, with a range of 4-15 days. The prodromal period is characterized by fever, headache, nausea, diarrhea, vomiting, and myalgia, which may last for several days.
• Altered mental status follows, which can range from mild confusion to agitation to overt coma. Seizures develop in 66% of infected persons, most often in children, while headache and meningismus are more common in adults.
• Tremor or other involuntary movements are common, and mutism has been reported as a presenting symptom. A syndrome of acute flaccid paralysis has also been described, attributed to the involvement of spinal anterior cells resulting in a poliomyelitislike presentation. Fevers disappear by the second week, and choreoathetosis or extrapyramidal symptoms develop as the other neurologic symptoms disappear.
• JEV infection must be considered etiologic of Guillain-Barré syndrome in certain settings.³
• One study from Japan has suggested that JEV may also be a cause of aseptic meningitis.⁴

Physical

• Neurologic signs of Japanese encephalitis vary.
• Generalized weakness, hypertonia, and hyperreflexia (including presence of pathologic reflexes) are common.
• Papilledema develops in less than 10% of patients, and 33% have cranial nerve findings (eg, disconjugate gaze, cranial nerve palsies).
• Parkinsonianlike extrapyramidal signs are common, including masklike facies, tremor, rigidity, and choreoathetoid movements.
• In one study, central hyperpneic breathing and extrapyramidal signs were the best clinical predictors of infection (41% sensitive, 81% specific).⁵

Causes

• JEV is exemplary of its corresponding antigenic complex. It is one of 66 flaviviruses.
• Culex mosquitoes, especially C tritaeniorhynchus, transmit JEV. Other Culex vectors include Culex vishnui (India), Culex gelidus, and Culex fuscocephala (Thailand, India, Malaysia). They prefer to bite outdoors and are extremely active in the evening and night, when the risk of infection is greatest.
• Mosquitoes breed in collections of water (typically rice paddies), increasing the risk of infection in rural areas.
• Aedes mosquitoes have also been implicated.
• Humans and other mammals (eg, horses) are end hosts (low-grade, short-term viremia).
• Pigs and aquatic birds (eg, egrets, herons) serve as amplifying hosts. They develop persistent high-grade viremia and represent the main vertebrate hosts as the principal reservoir for the virus. Cattle develop only relatively low-grade viremia or none at all; these animals are not part of the natural transmission cycle of the virus.
• Horses and piglets (not adult pigs) may develop clinical illness with a symptom spectrum similar to that in humans (eg, fever, locomotion difficulty, confusion).
• There are 4 main genotypic variants of JEV, as follows:
  • JEV type I isolates have been identified in China, India, Japan, Nepal, Sri Lanka, Taiwan, and Vietnam.
  • JEV type II isolates have been identified in Cambodia and northern Thailand.
  • JEV type III isolates have been identified in Indonesia, Malaysia, and southern Thailand. This genotype appears to have had the greatest spread.
  • JEV type IV isolates were also identified in the Indonesian and Malaysian regions.

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