Japanese Encephalitis

Kaushik Bharati, PhD

What is Japanese encephalitis?

Japanese encephalitis (JE) is so called simply because of the fact that it was first reported from Japan, and the major complication is encephalitis (inflammation of the brain). JE is the most important form of viral encephalitis commonly known as “brain fever” that mostly affects children and young adolescents in Asia.

What causes Japanese encephalitis?

Japanese encephalitis is caused by a virus called Japanese encephalitis virus (JEV), which is a single-stranded RNA virus. JEV belongs to the family Flaviviridae and genus Flavivirus. The other Flaviviruses that cause human disease are Yellow Fever virus, dengue virus, West Nile virus and tick-borne encephalitis virus. Another flavivirus of importance in Karnataka (India) is the Kyasanur Forest disease virus, which causes a febrile illness, popularly called “monkey fever”.

How is Japanese encephalitis virus spread?

Japanese encephalitis virus is spread by the bite of infected Culex mosquitoes, predominantly Culex tritaeniorhynchus. In the JEV life-cycle, pigs act as the amplifying hosts, mosquitoes act as the vectors, and humans act as dead-end hosts. JEV replicates in pigs and the viral titers increase rapidly. Mosquitoes become infected by feeding on the viremic pigs. The virus infected mosquitoes then bite humans to spread the infection. Following the bite from an infected mosquito, the virus initially replicates locally, after which it spreads to the blood stream, and then enters the central nervous system (CNS), and eventually reaches the brain, causing a febrile illness, thereby giving rise to the name “brain fever”. Viral titers in humans are not high enough to cause further transmission, which is why humans are regarded as dead-end hosts.

Epidemiology of Japanese encephalitis

Japanese encephalitis virus is distributed throughout the temperate and tropical regions of southern and eastern Asia. Two major epidemiological patterns of disease are observed –epidemic or endemic. In the northern temperate areas, such as northern Vietnam, northern Thailand, Korea, Japan, Taiwan, China, Nepal, and northern India, JE occurs in the form of epidemics during the summer/monsoon months. In southern tropical areas, such as southern Vietnam, southern Thailand, Indonesia, Malaysia, Philippines, Sri Lanka and southern India, JE is endemic. The number of reported JE cases is 50,000 annually, which is probably a gross under-estimate as the disease is under-reported. Of the 50,000 JE cases reported annually, 10,000 prove to be fatal. Those who survive the disease are very often left with neurological and psychiatric problems, which can sometimes be life-long in the absence of proper medical care. JE, therefore, is a serious public health problem, even though its severity is often under-stated and under-appreciated. 

What are the signs and symptoms of Japanese encephalitis?

Japanese encephalitis infections are often asymptomatic, and might resemble a febrile illness. Approximately 1 in 300 cases of JE result in symptomatic disease. The first signs of infection appear after an incubation period of 1-6 days, but may take as long as 15 days to manifest. The onset of the disease may be acute or gradual. The initial prodromal stage is marked by fever above 38ËšC, chills, muscle and body pain, weakness, headache accompanied by nausea, vomiting and abdominal pain. CNS involvement (day 3-5) is marked by a progressive decline in alertness, often leading to coma. CNS infection can result in encephalitis, meningitis or myelitis, or a combination of all the three.

Various types of movement disorders are observed in JE patients, including a Parkinson’s like syndrome. Convulsions may be experienced in up to 87% of patients. The meningeal syndrome predominates with painful neck stiffness. Motor paralysis may also be present. A poliomyelitis-like acute flaccid paralysis can also occur, accompanied by other movement disorders

How is Japanese encephalitis diagnosed?

Diagnosis of JEV infection should be made within an epidemiological context. Because of clinical, biological and epidemiological similarities, three other viral diseases should be considered in the differential diagnosis. These are Herpes Simplex Virus (HSV) encephalitis, Dengue and West Nile encephalitis.

A thorough physical examination is crucial. The level of consciousness should be established with a quantitative scale such as the Glasgow Coma Scale (GCS).

Confirmation of a suspected case of JE requires laboratory diagnosis, which relies on virus isolation or demonstration of virus specific antigen or antibody in the cerebrospinal fluid (CSF) or serum. The humoral immune response to JEV infection involves early production of IgM antibodies in both serum and CSF, followed by IgG production. Hence, the IgM-capture ELISA (MAC ELISA), which detects specific IgM in CSF or serum of almost all patients within 7 days of onset of disease has become the practical standard for the diagnosis of JE. Three MAC ELISA kits are being manufactured commercially. These are:

• JE-Dengue IgM Combo ELISA Test (Panbio Limited)

• JE IgM ELISA (InBios International, Inc.)

• JEV CheX Kit (XCyton Diagnostics Ltd.)

These tests use cell culture-derived inactivated virus or recombinant E protein as the antigen.

Neuroimaging techniques such as Computed Tomography (CT Scan) and Magnetic Resonance Imaging (MRI) are carried out in JE patients. These techniques have revealed extensive bilateral damage to the thalamus, which is indicative of JE.

Molecular diagnostics using reverse transcription-polymerase chain reaction (RT-PCR) technique allows rapid detection of viral RNA in the CSF of JE patients. Another molecular technique, the reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay is a rapid real-time detection system for JEV, and the results can be obtained within 30 minutes under isothermal conditions at 63°C. This test could become useful in low resource settings as it does not require a thermocycler.

What is the treatment for Japanese encephalitis?

There is currently no specific treatment for JE. The aim of therapy is to manage the symptoms. Management is essentially symptomatic and supportive. This involves measures to control both the immediate complications of infection, including seizures and raised intracranial pressure, and the longer-term consequences of neurologic impairment, such as limb contractures and bed sores.

How can Japanese encephalitis be prevented?

Vaccination is the mainstay for prevention of JE. Currently, there are three JE vaccines. The first is licensed for use in China and four other Asian countries. The second is licensed in USA, Europe and Australia, while the third is in late stages of development. Two of the vaccines are cell culture-based, while the third is genetically-engineered.

SA14-14-2: This vaccine is based on the genetically stable, neuro-attenuated SA14-14-2 strain of JEV and has been developed by the Chengdu Institute of Biological Products, China. The vaccine is currently being manufactured as per WHO Guidelines for production of live JE vaccines for human use. This single-dose vaccine has been used in China since 1988, with over 200 million children successfully immunized with an excellent safety record. This Chinese vaccine is also used in India, Nepal, Sri Lanka and South Korea. A major advantage of this vaccine is that it is inexpensive and hence affordable by the economically weaker countries of Asia where JE is endemic.

IXIARO®: This is a purified, formalin-inactivated, whole-virus JE vaccine, manufactured by Intercell, an Austrian company. After extensive clinical trials of IXIARO®, using a two-dose regimen, the vaccine was approved by the US Food and Drug Administration (USFDA) in 2009. It has also been approved by the European Commission and the Australian Therapeutic Goods Administration (TGA). The vaccine is currently licensed for use in USA, Australia and Europe.  

IMOJEV®: Besides the above two JE vaccines that are commercially available, a very innovative genetically engineered third generation JE vaccine is in late stages of clinical development. This technology was initially developed at the St. Louis University Health Sciences Center and later by Acambis. Clinical trials using a single dose of IMOJEV® have shown the vaccine to be well tolerated as well as effective.  

Other preventive measures

These include:

• Changes in pig rearing practices

• Vector control

• Prophylactic vaccination of susceptible human populations

Moreover, avoiding mosquito bites by wearing full-sleeved shirts, restricting outdoor activities at dawn and dusk, and using mosquito repellents, could dramatically reduce the incidence of JE. Hence, what is truly required for JE control is the adoption of an integrated approach, including improved agricultural practices, improved living standards, greater health awareness, as well as a sustained mass childhood vaccination program. It should however be noted that unlike smallpox and polio, for which humans are the only host, JE is a zoonotic disease with large animal reservoirs and hence cannot be totally eradicated.

Conclusion

In the near future, greater challenges are likely to occur. These may stem from newer issues of this day and age. Climate change could well be one such issue. Changing weather patterns, especially rainfall patterns, could lead to altering agricultural practices, which would lead to unpredictable changes in mosquito breeding patterns. Moreover, changing bird migration patterns brought about by climate change, could lead to introduction of JE to new geographical locations. A sustained and integrated approach would definitely lead to proper management of JE in the near future, given the fact that good quality and effective vaccines are on the horizon.