AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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

Pathophysiology

Japanese encephalitis 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. 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 central nervous system (CNS), leading to subclinical disease. However, 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, hippocampus, and cerebral cortex.

Frequency

United States

Japanese encephalitis mostly develops 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, transmission begins as early as March and extends until October. Transmission may occur all year in some tropical areas (eg, Indonesia). Worldwide, approximately 35,000-50,000 symptomatic cases are reported per 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.

Countries with epidemic or endemic JEV 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
• Brunei
• Pakistan
• Papua New Guinea
• Pacific Islands - rare outbreaks in Guam and Saipan

In 2005, epidemic JEV activity occurred in the Indian states of Uttar Pradesh and Bihar and throughout Nepal. This has resulted in over 5000 cases and approximately 1000 deaths.

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

Mortality/Morbidity

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

Approximately 33-50% of patients with symptomatic disease who survive have major neurologic sequelae at 1 year, including seizure disorders, motor or cranial nerve paresis, or movement disorders.

• Nearly 75% of symptomatic patients with JEV who are evaluated 5 years after the disease score lower than uninfected subjects on standardized tests.
• Previous dengue infection may be associated with decreased morbidity and mortality rates, possibly due to partial protection of cross-reacting antiflavivirus 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

The male-to-female ratio is 1.5:1 for symptomatic disease.

Age

Serologic evidence of 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 infections in nonendemic areas, disease occurs in all age groups.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Patients have a history of mosquito exposure in an endemic area. The incubation period ranges from 4-15 days, which is followed by a prodrome of 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 people, 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. Fevers disappear by the second week, and choreoathetosis or extrapyramidal symptoms develop as the other neurologic symptoms disappear.
• One study from Japan has suggested that Japanese encephalitis virus (JEV) may also be a cause of aseptic meningitis.

Physical

• Neurologic signs are varied.
• 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 frequently are observed, including masklike facies, tremor, rigidity, and choreoathetoid movements.
• In one study, central hyperpneic breathing and extrapyramidal signs were the best clinical predictors (41% sensitive, 81% specific) (Richman, 1997).

Causes

• Culex mosquitoes, especially C tritaeniorhynchus, transmit Japanese encephalitis. They prefer to bite outdoors and are extremely active in the evening and night, the time for the greatest risk for infection.
• Mosquitoes breed in collections of water (typically rice paddies), increasing the risk of infection in rural areas.
• Humans and other mammals (eg, horses) are dead-end hosts (low-grade, short-term viremia).
• Pigs and aquatic birds (eg, egrets, herons) serve as amplifying hosts because they have persistent high-grade viremia.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Nipah virus
Murray Valley encephalitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Complete blood cell count
• • A CBC count often shows nonspecific modest leukocytosis in the first week of illness. A mild anemia also may be present. In one study, 15% of children with Japanese encephalitis had thrombocytopenia.
  • Serum sodium levels may be depressed because of inappropriate antidiuretic hormone secretion.
• A study of Indian children during the Uttar Pradesh outbreak in 2005 noted elevated LFT results in a large number of patients with Japanese encephalitis (100% had elevated aspartate aminotransferase [AST] levels; 47.2% had elevated alanine aminotransferase levels).

Imaging Studies

• Findings on imaging studies may further support the diagnosis.
• MRI and a CT scan often show bilateral thalamic lesions with hemorrhage. The basal ganglia, putamen, pons, spinal cord, and cerebellum may also show abnormalities.

Other Tests

• EEG often reveals diffuse continuous delta slowing or diffuse delta pattern with spikes.
• EEG changes do not correlate with the severity of Japanese encephalitis or its outcome.

Procedures

• Lumbar puncture
• • A lumbar puncture is often performed to rule out other causes of encephalitis.
  • The opening pressure is usually normal.
  • CSF protein levels are mildly elevated in most cases. Between 10 and several hundred mononuclear white blood cells may be observed on cell count.
  • Virus can be isolated from the blood during the first week of illness. The CSF rarely yields virus, except in severe or fatal cases.
  • IgM capture enzyme-linked immunoassay (ELISA) of 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 first wk of illness).
  • Some cross-reactivity may arise from other flaviviruses (eg, dengue and West Nile virus) and from Japanese encephalitis and yellow fever vaccinations.
  • New IgM dot enzyme immunoassays for CSF and serum are portable, simple tests that compare favorably to the capture ELISA for field diagnosis (sensitivity 98.3%, specificity 99.2% when compared to capture ELISA as standard).

Histologic Findings

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

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Therapy for symptomatic Japanese encephalitis infection is supportive. Patients often require feeding, airway management, and seizure control. No clearly effective antiviral agents exist.
• Anticonvulsants to control seizures, ventilation support, and feeding are the standard treatments.
• Mannitol is used to decrease intracranial pressure when needed.
• Steroids (eg, dexamethasone) have not been shown to offer benefit, based on current studies.
• One small study demonstrated some benefit from interferon alfa (Harinatsu, 1985). However, a recent randomized trial of interferon alpha-2a in children demonstrated no benefit in overall outcome at discharge or at 3 months after discharge (Solomon, 2003).

Surgical Care

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

Consultations

• Consider consultation with an infectious disease physician 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 patients with elevated intracranial pressure.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Osmotic diuretics

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Follow patients' cases closely for complications, including bacterial infections (eg, pneumonia, urinary tract infections, decubitus ulcers).

Further Outpatient Care

• Relapses rarely have been reported several months after recovery.
• Patients may require long-term care and rehabilitation for residual neurologic deficits, including seizures and movement disorders.

Deterrence/Prevention

• The most important deterrent for people visiting endemic areas is avoiding mosquito exposure, particularly at night.
• Strongly consider the use of bed nets while sleeping and mosquito repellents with DEET (diethyltoluamide) during times when risk of contact with infected mosquitos exists.
• Vaccination
• • Japanese Encephalitis-VAX has been available in the United States since 1992. The vaccine is produced by BIKEN (Osaka, Japan) and is distributed by Aventis Pasteur. It is a formalin-inactivated, mouse brain–derived vaccine that is approximately 100% immunogenic after 3 doses (2 doses are used in native populations in endemic areas). Several other vaccines are available in Asian countries but are not available in the United States.
  • The current dosing schedule for patients aged 3 years or older is 1.0 mL subcutaneously on days 0, 7, and 30 (0.5 mL in patients aged 1-2 y).
  • A schedule of 0, 7, and 14 days may be used if time does not permit the longer dosing interval. Patients on the shorter schedule tend to have lower titers at 2 and 6 months after immunization than do patients on the longer schedule, although seroconversion rates appear similar.
  • The need for booster doses is not clear but could be considered 36 months or longer after the third dose. A second possible option is to follow antibody titers and revaccinate once titers fall to less than 1:10.
  • Administer the last dose of vaccine at least 10 days prior to travel in an endemic area.
  • Mild adverse reactions are reported in as many as 20% of people; 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. The hypersensitivity reaction may occur as late as 10-14 days after the last dose. Due to the 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.
  • 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. As yet, this association has not been definitively established. Passive surveillance in the United States in the 1990s of more than 800,000 doses revealed no reported neurologic sequelae
  • The vaccine is recommended for persons living in endemic and epidemic areas and for at-risk travelers planning extended trips to rural areas (arbitrarily defined as 30 d). Persons visiting areas with active epidemic Japanese encephalitis should be considered for vaccination even if their projected stay is less than 30 days. Vaccination for persons staying fewer than 30 days may be considered if they expect unprotected nighttime outdoor exposure in endemic areas.

Complications

• Bacterial infections (eg, pneumonia, urinary tract infection) related to the supportive care of these patients are the most common complication.
• Patients from tropical areas where Japanese encephalitis virus (JEV) is endemic also are at risk for infection from other tropical diseases (eg, malaria, typhoid fever, other parasitic infections).

Prognosis

• Prognosis in symptomatic infections varies. A significant number of patients who survive acute Japanese encephalitis develop residual neurologic deficits.
• Disabilities may range from subtle changes in behavior to serious problems, including blindness, ataxia, weakness, and movement disorders.
• Serious residual neurologic problems developed in as many as 50% of symptomatic patients at 1-year follow-up visits. Case-mortality rates may range from 20-50%.

Patient Education

• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Encephalitis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Be cautious of co-infection with other tropical disease (eg, tuberculosis, malaria).
• Because of the potential risk of angioedema, avoid the vaccine in pregnancy unless risk of infection is significant.
• Vaccinated patients should remain in an area where medical care is available for at least 10 days after receiving the vaccination because of the risk for respiratory compromise from angioedema.
• Use caution when vaccinating patients with a history of multiple allergies, urticaria, or angioedema because they may be at higher risk for adverse reactions.

Special Concerns

• 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.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Solomon T, Dung NM, Wills B, et al. Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebo-controlled trial. Lancet. Mar 8 2003;361(9360):821-6. [Medline].
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Article Last Updated: Jan 4, 2007