Japanese Encephalitis

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

Essential update: CDC recommends Japanese encephalitis vaccination for young travelers
The CDC recently recommended that young travelers aged 2 months through 16 years be vaccinated against Japanese encephalitis if they are going to be visiting areas that are endemic for the disease, adding infants and children to existing recommendations for travelers aged 17 years or older.[1, 2] This recommendation followed approval by the FDA in May 2013 to extend use of the SA14 -14-2 strain Japanese encephalitis vaccine (Ixiaro), the only vaccine against the disease available in the United States, to children aged 2 months to 16 years.

Signs and symptoms

Patients with JEV infection have a history of mosquito exposure in an endemic area, with the subsequent occurrence of the following signs and symptoms: The prodromal period is characterized by fever, headache, nausea, diarrhea, vomiting, and myalgia, which may last for several days Altered mental status follows and can range from mild confusion to agitation to overt coma Seizures develop in 66% of infected persons, most often children Headache and meningismus occur, but are more common in adults Mutism has been reported as a presenting symptom A syndrome of acute flaccid paralysis has been described Generalized weakness, hypertonia, and hyperreflexia (including the presence of pathologic reflexes) are common Papilledema occurs, albeit in less than 10% of patients Cranial nerve findings (eg, disconjugate gaze, cranial nerve palsies) are found in 33% of patients Fevers disappear by the second week, and extrapyramidal symptoms develop as the other neurologic symptoms disappear; Parkinsonlike 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).[3] See Clinical Presentation for more detail.

Diagnosis
Laboratory studies Complete blood count (CBC) - Nonspecific, modest leukocytosis is often found in the first week of illness; in one study, 15% of children with Japanese encephalitis had thrombocytopenia Serum sodium levels - Sodium levels may be depressed secondary to inappropriate antidiuretic hormone
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secretion Liver function tests Viral isolation - Isolation of JEV from clinical specimens or even the identification of positive genetic viral sequences in tissue, blood, or cerebrospinal fluid (CSF) is diagnostic Immunoassays - Immunoglobulin M (IgM) ! capture enzyme-linked immunoassay (ELISA) of serum or CSF is the standard diagnostic test for Japanese encephalitis Imaging studies Magnetic resonance imaging (MRI) and computed tomography (CT) scanning 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 MRI scans. Electroencephalography Electroencephalography (EEG) often reveals diffuse, continuous delta slowing; a diffuse delta pattern with spikes; theta waves; and burst suppression. 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. See Workup for more detail.

Management
No clearly effective antiviral agents exist for Japanese encephalitis, with therapy instead being supportive. Patients often require the following: Feeding Airway management Anticonvulsants for seizure control Management of intracranial pressure The osmotic diuretic 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. Vaccination Japanese encephalitis vaccines that have been used worldwide include the following: Inactivated mouse brain vaccine (Nakayama and Beijing-1 strains)[4] Inactivated primary hamster kidney cell vaccine (P3 strains) Live attenuated primary hamster kidney cell vaccine (SA14 -14-2 strain) See Treatment and Medication for more detail.

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Geographic distribution of Japanese encephalitis. Courtesy of the CDC.

Background
Japanese encephalitis virus (JEV), a flavivirus (single-stranded ribonucleic acid [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. (Areas where the population is at risk for JEV infection are shown on the map below.) (See Etiology and Epidemiology.)

Geographic distribution of Japanese encephalitis. Courtesy of the CDC.

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. (See Epidemiology.) 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 is one of 66 flaviviruses. It belongs to the Japanese encephalitis serocomplex, which is composed of several flaviviruses, including Alfuy, Koutango, Kokobera, Kunjin, Murray Valley encephalitis, Japanese encephalitis, Stratford, Usutu, West Nile, and St. Louis encephalitis. Usutu virus, an African mosquito-borne flavivirus, emerged in 2002 and since then has appeared in many European countries, presenting even further surveillance and transmission challenges.[5] (See Etiology.) The ratio of asymptomatic JEV infection to symptomatic infection has been reported to range from 25-1000:1. (See History and Physical Examination.) JEV infection must be considered etiologic of Guillain-Barr syndrome in certain settings.[6] One study from Japan has suggested that JEV may also be a cause of aseptic meningitis.[7] See the following for more information: California Encephalitis CBRNE--Venezuelan Equine Encephalitis Eastern Equine Encephalitis Encephalitis Herpes Simplex Encephalitis HIV-Associated Cytomegalovirus Encephalitis St. Louis Encephalitis Venezuelan Equine Encephalitis
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Viral Encephalitis West Nile Encephalitis Western Equine Encephalitis

Complications
Neurologic manifestations of JEV infection range from subtle changes in behavior to serious problems, including blindness, ataxia, weakness, and movement disorders. (See History, Physical Examination.) Bacterial infections (eg, pneumonia, urinary tract infection) related to the supportive care of patients with JEV are the most common complications. Patients from tropical areas where JEV is endemic also are at risk for infection with other tropical diseases (eg, malaria, typhoid fever, other parasitic infections).

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

Pathophysiology
On a cellular level, after attachment of the Japanese encephalitis virus (JEV) to a host cell membrane, local membrane disruption may lead to entry of the 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 central nervous system (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 encephalitisinduced disruption of neural stem cell growth may be particularly important to further morbidity and mortality. Recent studies indicate that other CNS cells besides neurons, such as astrocytes and microglial cells, may have replicative viral infection due to JEV, resulting in potential damage to the blood-brain barrier as well.{{Rev18}

Etiology
Japanese encephalitis virus (JEV) is exemplary of its corresponding antigenic complex. JEV is transmitted to humans via the bite of infected Culex mosquitoes, especially C tritaeniorhynchus. Other Culex vectors include C vishnui (India), C gelidus, and C 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 in JEV infection. 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 lowgrade viremia or none at all; these animals are not part of the natural transmission cycle of the virus.
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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 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 JEV replication cycle includes initial host cell receptor interaction of JEV 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 JEV.[8]

Epidemiology
Symptomatic Japanese encephalitis has a male-to-female ratio of 1.5:1. Serologic evidence of Japanese encephalitis virus (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.

Occurrence in the 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 occurrence
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. (Areas of seasonal and year-round transmission of JEV are shown on the map below.)

Japanese encephalitis, 2006. Courtesy of the WHO.

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 5,00020,000 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:
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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[9] ) 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.[10] Two outbreaks of Japanese encephalitis have occurred in Australia, the first in 1995 on islands in the Torres Strait[9] 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 post flooding infectious disease outbreaks.

Prognosis
Only 1 per 250 Japanese encephalitis virus (JEV) infections results in symptomatic disease. The prognosis of symptomatic JEV infection varies. Two factors that portend a good prognosis include high concentrations of neutralizing antibodies in the cerebrospinal fluid (CSF) and high levels of JEV 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 death include demonstration of virus in the CSF, low levels of IgG/IgM in the CSF or serum, and a decreased sensorium. Japanese encephalitis virus (JEV) 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
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outcome. 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. 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. Previous dengue infection may be associated with decreased morbidity and mortality rates, possibly due to partial protection of cross-reacting antiflaviviral antibodies.

Contributor Information and Disclosures

Author Asim A Jani, MD, MPH, FACP Clinician-Educator and Epidemiologist, Consultant and Senior Physician, Florida Department of Health; Diplomate, Infectious Diseases, Internal Medicine and Preventive Medicine Asim A Jani, MD, MPH, FACP is a member of the following medical societies: American Association of Public Health Physicians, American College of Physicians, American College of Preventive Medicine, American Medical Association, American Public Health Association, and Infectious Diseases Society of America Disclosure: Nothing to disclose. Chief Editor Burke A Cunha, MD Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America Disclosure: Nothing to disclose. Additional Contributors Joseph F John Jr, MD, FACP, FIDSA, FSHEA Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina College of Medicine; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center Disclosure: Nothing to disclose. Alexander J Kallen, MD Instructor of Medicine, Department of Internal Medicine, Division of Outcomes Research, Dartmouth Medical School, Veterans Affairs Medical Center of White River Junction, VT Alexander J Kallen, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society for Microbiology, California Medical Association, and Infectious Diseases Society of America Disclosure: Nothing to disclose. Klaus-Dieter Lessnau, MD, FCCP Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital Klaus-Dieter Lessnau, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Thoracic Society, and Society of Critical Care Medicine Disclosure: Sepracor None None Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment

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References
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encephalitis virus in goats raised in Korea. J Vet Sci. Jun 2007;8(2):197-9. [Medline]. [Full Text]. 20. Solomon T, Thao TT, Lewthwaite P, Ooi MH, Kneen R, Dung NM, et al. A cohort study to assess the new WHO Japanese encephalitis surveillance standards. Bull World Health Organ. Mar 2008;86(3):178-86. [Medline]. [Full Text]. 21. Schiler KL, Samuel M, Wai KL. Vaccines for preventing Japanese encephalitis. Cochrane Database Syst Rev. Jul 18 2007;CD004263. [Medline]. Medscape Reference 2011 WebMD, LLC

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