Japanese Encephalitis 

Updated: Oct 05, 2018
Author: Antonette B Climaco, MD; Chief Editor: Burke A Cunha, MD 

Overview

Practice Essentials

Japanese encephalitis is a neurologic infection with a broad range of manifestations. It can range from subtle changes in behavior to serious problems, including blindness, ataxia, weakness, and movement disorders. Japanese encephalitis is caused by the Japanese encephalitis virus (JEV), a flavivirus, and is closely related to St. Louis encephalitis and West Nile encephalitis. It occurs primarily in rural areas of Asia (see the image below). Japanese encephalitis is spread through these regions by bites of culicine mosquitoes, most often Culex tritaeniorhynchus.

Japanese Encephalitis Virus Geographic Distributio Japanese Encephalitis Virus Geographic Distribution. Photo Courtesy of CDC.

Epidemiology

In the United States, Japanese encephalitis mostly develops among travelers returning from endemic countries. Countries with endemic Japanese encephalitis virus include Malaysia, Philippines, China, Taiwan, Bangladesh, Thailand, India, Japan, Pakistan, and several other countries in the neighboring regions. See the Epidemiology section for more details.

Signs and Symptoms

Individuals infected with Japanese encephalitis virus have a history of mosquito exposure in an endemic area. Such individuals may present with fever, headache, nausea, diarrhea, vomiting, and/or myalgia, followed by altered mental status, seizures, flaccid paralysis, hyperpneic breathing, extrapyramidal signs, and cranial nerve findings.

See Clinical Presentation for more detail.

Diagnosis

Japanese encephalitis virus–specific immunoglobulin M (IgM) capture enzyme-linked immunoassay (ELISA) on serum or cerebrospinal fluid (CSF) is the standard diagnostic test for Japanese encephalitis. Virus isolation from clinical specimens is difficult because viremia in humans is transient and low level. Lumbar puncture is performed to obtain CSF and to rule out other potential etiologies of encephalitis. The opening pressure may be high, CSF protein level may be high, and CSF glucose level is often normal. Potential bloodwork findings may include mild leukocytosis and hyponatremia. MRI and CT scanning of the brain may show bilateral thalamic lesions with hemorrhage. Electroencephalography (EEG) may show diffuse slowing.

See Workup for more detail.

Differential Diagnoses

Differential diagnoses include West Nile virus encephalitis, St. Louis encephalitis, Murray Valley encephalitis, herpes simplex virus encephalitis, dengue fever, Nipah virus infection, California encephalitis, pyogenic focal brain abscess, tuberculous meningitis, Rocky Mountain spotted fever, fungal infections, central nervous system (CNS) lupus, CNS tumors, and cerebrovascular accident (CVA).

Management

No antiviral agent is effective against Japanese encephalitis virus. Care is supportive, including management of intracranial pressure, if needed, airway protection, and seizure control.

See Treatment and Medication for more detail.

Prevention

Japanese encephalitis vaccine is available. Measures to prevent mosquito bites and to decrease the mosquito population and viral spread should be implemented.

See Treatment and Medication for more detail.

Prognosis

Mortality rates associated with Japanese encephalitis may exceed 35% in less-developed countries. The prognosis varies depending on several factors. Most cases improve between 6 months and 12 months. Approximately 33%-50% of survivors have major neurologic sequelae. Good prognostic factors include high CSF concentration of neutralizing antibodies. Poor prognostic factors include low Glasgow coma scale (GCS), hyponatremia, and age younger than 10 years.

See Prognosis for more detail.

Etiology

Japanese encephalitis virus, a flavivirus (single-stranded ribonucleic acid [RNA]), represents the most significant etiology of arboviral encephalitis worldwide. Japanese encephalitis virus belongs to the Japanese encephalitis serocomplex, which is composed of 9 genetically and antigenically related viruses of the Flaviviridae family. JE serocomplex flaviviruses include Alfuy virus, Cacipacore virus, Japanese encephalitis virus, Koutango virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, Usutu virus, West Nile virus including Kunjin virus, and Yaounde virus.[1]

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.

Japanese encephalitis virus is transmitted to humans via the bite of infected Culex mosquitoes, especially C tritaeniorhynchus. Other Culex vectors include Culexvishnui (India), Culexgelidus, and Culexfuscocephala (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 in Japanese encephalitis virus infection.

Humans are incidental and dead-end hosts, producing a low-grade, short-term viremia. Therefore, mosquitoes are unable to transmit the virus from one person to another.

Pigs and aquatic birds (eg, egrets, herons) serve as amplifying hosts. They develop persistent, high-grade viremia and represent the main vertebrate hosts and 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).

The main genotypic variants of Japanese encephalitis virus include the following:[2]

  • Japanese encephalitis virus genotype I isolates have been identified in northern Thailand, Cambodia, and Korea.
  • Japanese encephalitis virus genotype II isolates have been identified in southern Thailand, Malaysia, Indonesia and Northern Australia.
  • Japanese encephalitis virus genotype III isolates have been identified in Japan, China, Taiwan, Philippines, and the Asian subcontinent, including India and Nepal.
  • Japanese encephalitis virus genotype IV isolates have been identified in Indonesia.
  • Japanese encephalitis virus genotype V isolate have been identified in 1952 from a patient who originated in Muar, Malaysia (Muar strain). There is a report of its possible reemergence in the Republic of Korea. [3]

Pathophysiology

After attachment of the Japanese encephalitis virus to a host cell membrane, local membrane disruption may lead to entry of the virus into the cell itself. 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. The Japanese encephalitis virus replication cycle includes initial host cell receptor interaction of the virus followed by receptor-mediated endocytosis, fusion of the viral and host cell membranes, subsequent cytoplasmic release of viral genome, and several other transcription and pretranslation steps. Maturation of virus particles occurs in the Golgi complex, followed by ultimate release of the virus.[4]

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 Japanese encephalitis virus, 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, Japanese encephalitis virus 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). Japanese encephalitis virus 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.

Studies have found, in addition to neurons, other CNS cells such as astrocytes and microglial cells may also serve as reservoirs for viral replication, resulting in potential damage to the blood-brain barrier.[5]

Recent research indicates that matrix metalloproteinases and inhibitors of metalloproteinases likely play a role in pathogenesis during viral encephalitis by modulating the blood-brain barrier and affecting the entry of immune cells into the CNS. A 2016 study found that matrix metalloproteinases were up-regulated in mice infected with Japanese encephalitis virus, and inhibitors of metalloproteinases were down-regulated in the infected mice.[6]

Epidemiology

Serologic evidence of Japanese encephalitis virus 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 years) and elderly people. In nonendemic areas, Japanese encephalitis virus infection has no age predilection.

Occurrence in the United States

In the United States, Japanese encephalitis develops mostly among military personnel, expatriates, and, rarely, returning travelers. Before 1973, more than 300 cases of Japanese encephalitis were reported among US military personnel or their family members. From 1973-2013, 68 cases were reported to the Center for Disease Control and Prevention (CDC) among travelers and expatriates from nonendemic countries, 19 cases of which of which were from the United States; 8 cases occurred after 1992, when the Japanese encephalitis vaccine was made available in the United States.[7] The approximate risk estimate is less than 0.2 cases per 1 million US travelers.[8] Outbreaks are rare in the US territories of Guam and Saipan.

International occurrence

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 a seasonal disease, with most cases occurring in temperate areas from June to September. Further south, in subtropical areas, Japanese encephalitis virus transmission begins as early as March and extends until October. Transmission may occur all year in some tropical areas (eg, Indonesia). The annual incidence of Japanese encephalitis differs among affected countries. In endemic countries, the annual incidence is estimated at 5.4/100,000 in children aged 0-14 years and 0.6/100,000 in individuals older than 15 years.[9]

Areas of seasonal and year-round transmission of Japanese encephalitis virus are shown in the map below.

Japanese encephalitis, 2006. Courtesy of the WHO. Japanese encephalitis, 2006. Courtesy of the WHO.

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 Strait [10] )
  • Brunei
  • Pakistan
  • Papua New Guinea
  • Pacific Islands (rare outbreaks in Guam and Saipan)
  • Himalayas (under investigation as new emergence or improved detection) [11]

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.[12]

Two outbreaks of Japanese encephalitis have occurred in Australia, the first in 1995 on islands in the Torres Strait[10] and the second in 1998 on the Cape York Peninsula. In addition, in 2004, one Japanese encephalitis virus isolate was detected from a pool of Culex mosquitoes trapped on the Cape York Peninsula.

The incidence of Japanese encephalitis in China has decreased since the introduction of vaccination in 1980. While the incidence is decreasing in children, there is a higher incidence in adults, which is emerging as a public health problem. Epidemiological research into the spatial and temporal distribution of Japanese encephalitis virus revealed that children aged 0-15 years tend to become infected more commonly south of the Yangtze River and adults older than 40 years tend to become infected more commonly north of the Yangtze River.[13]

Overall, as with 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 Japanese encephalitis virus. 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.

Prognosis

The prognosis of symptomatic Japanese encephalitis virus infection varies. Two factors that portend a good prognosis include high concentrations of neutralizing antibodies in the cerebrospinal fluid (CSF) and high levels of Japanese encephalitis virus immunoglobulin G (IgG) in the CSF.

Overall, poor prognostic factors include the following:

  • Age younger than 10 years
  • Low Glasgow coma scale
  • Hyponatremia
  • Shock
  • Presence of immune complexes in CSF
  • Presence of increased amounts of antineurofilament antibodies
  • Increased levels of tumor necrosis factor
  • Coexisting neurocysticercosis

Proven risk factors for mortality include demonstration of virus in the CSF, low levels of IgG/IgM in the CSF or serum, and a decreased sensorium.

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. The main causes of Japanese encephalitis–related mortality include aspiration, seizures, increased intracranial pressure, and hypoglycemia.[14]

Most cases improve between 6 months (55%) and 12 months (78%).[15]

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.

Japanese encephalitis virus infection in the first or second trimester of pregnancy may lead to fetal death. Infection in the third trimester, although not systematically evaluated, appears to be associated with a normal fetal outcome.

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

Patient Education

For patient education information, see the Brain and Nervous System Center, as well as Encephalitis.

 

Presentation

History

Individuals with Japanese encephalitis virus (JEV) infection have a history of mosquito exposure in an endemic area. Most infections in humans are asymptomatic. Less than 1% of people infected with Japanese encephalitis virus develop symptomatic disease. Severe disease is estimated to occur at 1 per 250 Japanese encephalitis virus infections. Symptomatic Japanese encephalitis virus infection can present as a nonspecific febrile illness, aseptic meningitis, or encephalitis. 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 may rapidly follow and can range from mild confusion to agitation to overt coma. Seizures develop more often in children, while headache and meningismus are more common in adults. Acute encephalitis is the most common neurologic manifestation.

Mutism has been reported as a presenting symptom. Acute flaccid paralysis has also been described, attributed to the involvement of anterior horn cells resulting in a poliomyelitis-like presentation. Fevers disappear by the second week, and parkinsonian features (choreoathetoid movement, tremor, dystonia) develop as the other neurologic symptoms disappear.

Physical Examination

Neurologic signs of Japanese encephalitis vary.

Generalized weakness, hypertonia, and hyperreflexia (including the 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).

Parkinson-like 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).[16]

Patients may present with acute-onset symmetric paralysis, which may be concerning for Guillain-Barré syndrome.[17]

Complications

Coinfection of Japanese encephalitis virus and neurocysticercosis may result from the role of pigs in the life cycle of both viruses.[18, 19]

An unusual association between Japanese encephalitis virus and acute obstructive hydrocephalus has been described.[20]

A possible case of acute disseminated encephalomyelitis[21] and a case of acute transverse myelitis[22] have been described.

Bacterial infections (eg, pneumonia, urinary tract infection) related to the supportive care of patients with Japanese encephalitis virus are the most common complications.

Individuals from tropical areas where Japanese encephalitis virus is endemic also are at risk for infection with other tropical diseases (eg, malaria, typhoid fever, other parasitic infections).

 

DDx

Diagnostic Considerations

Viral infections to consider in the differential diagnoses of Japanese encephalitis include the following:

Bacterial infections to consider in the differential diagnoses of Japanese encephalitis include the following:

  • Pyogenic focal brain abscess
  • Tuberculous meningitis
  • Mycoplasma meningitis
  • Ehrlichiosis
  • Typhoid fever
  • Tuberculosis
  • Rocky Mountain spotted fever

Fungal infections, toxoplasmosis, and malaria should also be considered in the differential diagnoses.

Noninfectious conditions to consider in the differential diagnoses of Japanese encephalitis include the following:

  • CNS lupus erythematosus
  • CNS tumors (nonmetastatic)
  • Cerebrovascular diseases

See the following for more information:

Differential Diagnoses

 

Workup

Approach Considerations

Japanese encephalitis virus (JEV) infection should be suspected in a patient with symptoms and signs of neurologic infection who has recently traveled in an endemic country.

CBC count

A complete blood cell (CBC) count often shows nonspecific modest leukocytosis in the first week of illness. This may be followed by a relative leukopenia. A mild anemia may also be present. In one study, 15% of children with Japanese encephalitis had thrombocytopenia.

Serum sodium levels

Serum sodium levels may be depressed owing to inappropriate antidiuretic hormone secretion.

Liver function tests

A study of Indian children during the Uttar Pradesh Japanese encephalitis outbreak in 2005 noted elevated liver function test results in a large number of patients (all had elevated aspartate aminotransferase [AST] levels; 47.2% had elevated alanine aminotransferase levels).[12]

Serology

IgM antibody can be detected in CSF by 4 days after the onset of symptoms and in the serum by 7 days after symptom onset. See Immunoassays for more details.

Viral isolation

Isolation of Japanese encephalitis virus from clinical specimens or even the identification of positive genetic viral sequences in tissue, blood, or CSF is diagnostic. However, virus isolation is reported to be difficult in humans because of transient and low-level viremia.

For laboratory worker safety, a biosafety level 3 is required for working with Japanese encephalitis virus.

MRI and CT scanning

Magnetic resonance imaging (MRI) and computed tomography (CT) scans often show bilateral thalamic lesions with hemorrhage, with MRI being more sensitive. The basal ganglia, putamen, pons, spinal cord, and cerebellum may also show abnormalities. Hyperintense lesions may be observed in the areas of the thalamus, cerebrum, and cerebellum on T2-weighted MRIs.

Electroencephalography

Electroencephalography (EEG) often reveals diffuse continuous delta slowing, a diffuse delta pattern with spikes, theta waves, and burst suppression.

EEG changes do not correlate with the severity of Japanese encephalitis or its outcome.

Histologic findings

Changes are found in the thalamus, substantia nigra, brain stem, hippocampus, cerebellum, and spinal cord and include focal neuronal degeneration with diffuse and focal microglial proliferation and lymphocytic perivascular cuffing.

Lumbar Puncture

Lumbar puncture is performed to obtain CSF samples for diagnosis and for ruling out other causes of encephalitis.

The opening pressure is usually normal but may be raised.

CSF protein levels are mildly elevated, often less than 900 mg/dL. CSF glucose levels are often normal.

CSF cell count will show between 10 and several hundred white blood cells with lymphocytic predominance.

Japanese encephalitis virus may be isolated from the blood during the first week of illness. The CSF rarely yields virus, except in severe or fatal cases.

Immunoassays

The diagnosis of Japanese encephalitis is supported by a capture immunoassay methodology demonstrating IgM antibody in the CSF or the serum. Alternatively, 4-fold increase between the acute-phase and convalescent-phase serum may be used to establish a diagnosis of recent infection.

Japanese encephalitis virus–specific IgM capture-enzyme-linked immunoassay (ELISA) on serum or CSF is the standard diagnostic test for Japanese encephalitis. Sensitivity is nearly 100% when both serum and CSF are tested. False-negative results may occur if the samples are tested too early (eg, within the first week of illness). IgM antibody can be detected in CSF by 4 days after the onset of symptoms and in the serum by 7 days after symptom onset. Of note, IgM may be found in the serum but not in the CSF in vaccinated persons or in those with asymptomatic infections.

Some cross-reactivity may arise from other flaviviruses (eg, dengue and West Nile virus) and from Japanese encephalitis and yellow fever vaccinations. This phenomenon may contribute to misdiagnosis; parallel testing for Japanese encephalitis virus and other flaviviruses (eg, dengue) may be necessary.

IgM dot enzyme immunoassays for CSF and serum are simple, portable tests that compare favorably with capture ELISA for field diagnosis (sensitivity of 98.3% and specificity of 99.2% when compared with capture ELISA as the standard).[23]

 

Treatment

Approach Considerations

The most important factor in the appropriate management of intracranial pressure is to identify and initiate appropriate therapeutic interventions.

Patients with Japanese encephalitis should be monitored closely for complications, including bacterial infections (eg, pneumonia, urinary tract infections), decubitus ulcers, Guillain-Barré syndrome, and acute obstructive hydrocephalus.

Be cautious of coinfection with other tropical diseases (eg, tuberculosis, malaria, neurocysticercosis).

Supportive care

No clearly effective antiviral agent exists. Therapy for symptomatic Japanese encephalitis virus (JEV) infection is supportive. Patients often require feeding, airway management, and anticonvulsants for seizure control.

Management of intracranial pressure

Mannitol is used to decrease intracranial pressure, when needed. In the intensive care unit (ICU) setting, cerebral perfusion pressure (ie, mean arterial pressure minus intracranial pressure) must be maintained through appropriate modulation of systemic blood pressure.

Steroid therapy

Steroids (eg, dexamethasone) have not been shown to offer benefit.[24]

Experimental therapies

One small study demonstrated some benefit from interferon alfa.[25] However, a randomized trial of interferon alfa-2a in children demonstrated no benefit in overall outcome at discharge or at 3 months after discharge.[26]

One preliminary randomized trial of intravenous immunoglobulin (IVIG) in children showed no difference in outcome in those who received IVIG or placebo.[27]

Suramin,[28] a drug used to treat trypanosomal disease, and diethyldithiocarbamate[29] have shown reasonably good antiviral efficacy against Japanese encephalitis virus in vitro.

A novel intervention using a plant lignan called arctigenin has been shown to yield complete protection against experimental Japanese encephalitis in a mouse model. It appears to provide a newer mechanism of action by decreasing CNS viral replication, decreasing neuronal death, and reducing inflammation and oxidative stress.[30]

Minocycline was investigated for its role in protecting against encephalitis and neurodegeneration. Proposed protective effects may result from direct inhibition of viral replication and its anti-inflammatory and immunomodulatory properties.[31] It conferred complete protection in an experimental mouse model following Japanese encephalitis virus infection.[32] A 2016 study in Uttar Pradesh, India, where Japanese encephalitis virus is an important cause of encephalitis, found a trend toward a better outcome among patients presenting with acute encephalitis who received minocycline.[33]

Several studies have shown that tetracyclines and aminoglycoside-derivative compounds have been beneficial against reovirus, West Nile virus, and dengue virus. An in vitro study showed that doxycycline and kanamycin administered a dose-dependent manner decreased Japanese encephalitis viral RNA replication.[34]

Invasive monitoring

Patients with evidence of elevated intracranial pressure may require invasive monitoring.

Further care

In rare cases, relapses of Japanese encephalitis have been reported several months after recovery.

Patients may require long-term care and rehabilitation for residual neurologic deficits, including seizures and movement disorders.

Prevention: Vaccination

Vaccines

Japanese encephalitis vaccines used worldwide fall into 4 classes. They are based on Japanese encephalitis virus genotype III but are cross-protective against the other genotypes. The 4 vaccine classes include inactivated mouse brain vaccines, inactivated Vero cell-derived vaccines, live attenuated vaccines, and live recombinant (chimeric) vaccine, which is derived from yellow fever virus strain.

In the United States, 2 vaccines have been available for use: an inactivated mouse brain–derived vaccine (JE-VAX) and an inactivated Vero cell culture–derived vaccine (JE-VC; Ixiaro). JE-VAX is derived from the Nakayama Japanese encephalitis virus strain. It was licensed for use in the United States in 1992 but discontinued in 2006 because of safety issues. It has not been used since 2011. The only available Japanese encephalitis vaccine for use in the United States is Ixiaro, an inactivated vaccine prepared by propagating Japanese encephalitis virus strain SA14-14-2 in Vero cells. Ixiaro is indicated for adults and children aged 2 months or older. Primary immunization consists of a 2-dose series administered IM 28 days apart. Adults aged 18-65 years may receive an accelerated regimen 7 days apart. A single booster dose (third dose) may be given at least 11 months after completing the primary immunization series if ongoing exposure or reexposure to JEV is expected.[35]

Several other vaccines are available in Asian countries but are not available in the United States.

High seroprotection rates have been found in patients receiving the inactivated Vero cell–derived vaccines, ranging from 93%-99%.[14]

Novel nonparenteral vaccination approaches such as intranasal inoculation using mouse brain–derived inactivated Japanese encephalitis virus appear to have some potential for inducing immunogenicity but will likely require more effective adjuvant products.[36]

Vaccination Candidates

Currently, vaccination is recommended for travelers who plan to spend a month or longer in endemic areas during the Japanese encephalitis virus season, especially those who will visit rural and agricultural areas. Vaccination should be considered for short-term (< 1 month) travelers to endemic areas during the Japanese encephalitis virus season if they expect unprotected nighttime outdoor exposure. Persons visiting areas with active epidemic Japanese encephalitis should also be considered for vaccination even if their projected stay is less than 30 days. The vaccine is not recommended for short-term travelers who visit only urban areas.

Worldwide, Japanese encephalitis vaccine is recommended for persons living in endemic and epidemic areas.

Laboratory workers who could have potential exposure to Japanese encephalitis virus would likely benefit from vaccination.

Vaccination Dosing and Administration

The primary immunization schedule for the currently available Japanese encephalitis vaccine in the United States, Ixiaro, is 2 doses administered intramuscularly 28 days apart. For children aged 2 months to 2 years, each dose is 0.25 mL. For children older than 3 years and adults, each dose is 0.5 mL. The last dose should be given at least one week before travel or expected exposure.[35]

A booster dose is recommended for adults or children whose primary series of Ixiaro was given more than 1 year previously prior to reexposure or if there is continued risk for Japanese encephalitis virus infection. For those who have received the JE-VAX vaccine, booster with Ixiaro is not recommended, but they should receive the 2-dose series of Ixiaro before potential exposure.[35]

Dosing schedule for other vaccines vary by country.

Vaccination adverse effects

Mild adverse reactions are reported in as many as 20% of vaccine recipients; adverse reactions include local pain and redness, fever, gastrointestinal symptoms, headache, and myalgia. The incidence of reactions usually decreases with each subsequent dose. Hypersensitivity, including angioedema or urticaria, occurs in 0.6% of patients, with 2.6 per 100,000 vaccinees requiring hospitalization, and represents the main contraindication to the use of the vaccine. The hypersensitivity reaction may occur as late as 10-14 days after the last dose. To prepare for a possible delayed hypersensitivity reaction, patients should have access to medical care for 10 days after the last dose. Patients with a history of allergies or urticaria may be at higher risk for adverse reactions. Use caution when vaccinating patients with a history of multiple allergies, urticaria, or angioedema, because they may be at higher risk for adverse reactions.

Pregnant women should be vaccinated only if they are at high risk of exposure to Japanese encephalitis virus and must travel to areas during active viral transmission.

Cases of encephalitis and other potentially vaccine-related neurologic symptoms have been reported. A study in Japan in the 1960s and 1970s found a rate of severe neurologic reactions to be 1-2.3 cases per million persons vaccinated. This association has not yet been definitively established. Passive surveillance in the United States in the 1990s of more than 800,000 doses revealed no reported neurologic sequelae.

Other Modes of Prevention

The most important deterrent for people visiting endemic areas is avoidance of mosquito exposure, particularly at night. Persons living in or traveling to endemic areas should strongly consider the use of bed nets while sleeping and mosquito repellents with diethyltoluamide (DEET) during times when risk of contact with infected mosquitos exists. Use of long-sleeved shirts and pants in endemic areas is also important to prevent mosquito bites.

Measures to decrease mosquito populations and control viral spread, including the use of insecticides and larva-killing agents, juxtapositioning of larvivorous fish in rice paddies, and draining rice paddies, may be used.

Although used in the past, vaccination of swine has not demonstrated consistent effectiveness in reducing mosquito and/or human infections. Pigs can be relocated away from humans to potentially decrease viral spread.

Veterinary surveillance efforts could also be expanded to include epidemiologic monitoring of potentially infected goats as sentinel animals.[37]

Consultations

Consider consultation with an infectious disease specialist trained in tropical and travel medicine for all returning travelers with encephalitis.

Consultation with a neurologist may be required for assistance with management of neurologic sequelae.

Critical care specialists may be required for help with managing severely symptomatic patients in an intensive care setting.

Consultation with a neurosurgeon may be required to assist in managing elevated intracranial pressure.

 

Medication

Medication Summary

No effective antiviral exists.

As stated above, mannitol is used to decrease intracranial pressure, when needed.

There are 4 classes of Japanese encephalitis vaccines. Ixiaro is the Japanese encephalitis vaccine available in the United States.

Osmotic Diuretics

Class Summary

Mannitol is recommended by some experts to help reduce intracranial pressure. Mannitol induces diuresis, which increases serum osmotic concentration. In the brain, this causes water to flow from brain cells into vascular space, thereby decreasing intracranial pressure.

Mannitol (Osmitrol)

Mannitol may be used to decrease intracranial pressure. It may reduce subarachnoid space pressure by creating an osmotic gradient between CSF in the arachnoid space and plasma. This agent is not for long-term use.

Vaccine

Class Summary

Induction of the antibody response to vaccine provides the capability to neutralize live Japanese encephalitis virus (JEV).[38]

Japanese encephalitis virus vaccine (Ixiaro)

Ixiaro is an inactivated vaccine prepared by propagating Japanese encephalitis virus strain SA14-14-2 in Vero cells. It is available in prefilled, single-dose syringes without preservatives or thimerosal. Antibody response is measured with a 50% plaque-reduction neutralization antibody test; a threshold of 1:10 or higher is considered protective immunity.

It is the only currently available Japanese encephalitis vaccine in the United States.