Overview: Japanese encephalitis

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Abstract

Japanese encephalitis (JE) is one of the most important endemic encephalitis in the world especially in Eastern and Southeastern Asia. JE affects over 50,000 patients and results in 15,000 deaths annually. JE virus is a single stranded positive sense RNA virus belonging to family flaviviridae. JE virus is transmitted through a zoonotic cycle between mosquitoes, pigs and water birds. Humans are accidentally infected and are a dead end host because of low level and transient viremia. In the northern region, large epidemics occur during summers whereas in the southern region JE tends to be endemic: cases occur throughout the year with a peak in the rainy season. Occurrence of JE is more closely related to temperature than to humidity. JE is regarded as a disease of children in the endemic areas but in the newly invaded areas, it affects both the adults and children because of the absence of protective antibodies. For every patient of JE, there are large numbers of subclinical cases (25–1000). Symptomatic JEV infection manifests with nonspecific febrile illness, aseptic meningitis or encephalitis. Encephalitis manifests with altered sensorium, seizures and focal neurological deficit. Acute flaccid paralysis may occur due to anterior horn cell involvement. A wide variety of movement disorders especially transient Parkinsonian features and dystonia (limb, axial, orofacial) are reported in 20–60% patients. JE mainly affects thalamus, corpus striatum, brainstem and spinal cord as revealed by MRI and on autopsy studies. Coinfection of JE and cysticercosis occurs because of the important role of pigs in the life cycle of both JEV and cysticercosis.

Laboratory diagnosis of JE is by IgM capture ELISA, which has high sensitivity and specificity. In the absence of specific antiviral therapy, JE is managed by symptomatic and supportive therapies and preventive measures. Purified formalin inactivated mouse brain derived vaccine and live attenuated vaccine (SA 14-14-2) are available; the latter is reported to be safe, effective and cheap. The role of Chimeric recombinant attenuated JE vaccine is under investigation. Control of JE is related to the wider issues of hygiene, environment, education and economy.

Introduction

Japanese encephalitis virus (JEV) belongs to the family flaviviridae and is transmitted between animals and human host by culex mosquitoes. Japanese encephalitis is prevalent throughout Eastern and Southern Asia and the Pacific Rim. The related neurotropic flaviviruses are found throughout the globe: Equine encephalitis virus and St. Louis encephalitis virus in North America, West Nile virus in Africa and the Middle East, Murray Valley encephalitis virus in Australia, Roccio virus in South America and Tick borne encephalitis virus in Russia. These viral encephalitides share many virological, epidemiological and clinical features (Solomon, 2004). Molecular studies have suggested that all the flaviviruses originated from a common ancestor about 10,000–20,000 years ago and are rapidly evolving to fill the ecological niches. Japanese encephalitis (JE) is the most important cause of viral encephalitis in Eastern and Southeast Asia. Up to 50,000 cases and 15,000 deaths annually are due to JE especially in the rural areas (Tsai, 1997, Solomon, 1997). The majority of JE victims are children and nearly half of the surviving patients have cognitive or motor sequelae. This review focuses on basic, clinical and preventive aspects of JE.

Section snippets

Historical aspects

Japanese encephalitis was recognized in horses and humans as early as 1871. In 1924 a severe epidemic was reported from Japan; a filterable agent was extracted from human brain and passed to rabbits, although the agent could not be characterized. Every 10 years, major epidemics were reported in Japan affecting over 6000 patients (Miyake, 1964). In 1934, Hyashi reproduced the disease in monkey by intra-cerebral inoculation. In 1935, JE virus was isolated from human brain in Tokyo, Japan, and its

Japanese encephalitis virus

Japanese encephalitis virus is a single stranded positive sense RNA virus wrapped in a nucleocapsid and is surrounded by a 50 nm glycoprotein containing envelope. The RNA comprises a 5′ untranslated region (UTR, a longer 3′ UTR and between them a single open reading frame (ORF) (Chambers et al., 1990). This encodes 3 structural proteins, capsid protein (C), precursor to the membrane protein (PrM), and envelope protein (E), and 7 nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). The

Age

JE is a disease of children in the endemic areas; however, it affects both adults and children in newly affected areas. In some areas of Northern India, Nepal and Sri Lanka, all age groups are affected by JE suggesting recent introduction of JEV into these countries. The travelers to endemic areas may have devastating illness due to lack of protective antibodies. The highest age specific attack rates are between 3 and 6 years of age. This has been attributed to high outside exposure especially

Pathogenesis and pathology

After the bite of an infected mosquito, the virus amplifies peripherally producing transient viremia before entering into the central nervous system. The sites of peripheral amplification are dermal tissue and then lymph nodes. The mechanism of entry of JEV across the blood brain barrier is not known. In experimental studies using Hamster model, St. Louis encephalitis has been shown to enter the central nervous system through the olfactory route (Monath et al., 1983). Intranasal spraying is

Immunology

Both humoral and cellular immune responses occur after JEV infection. Following the primary infection (first JEV infection), a rapid and potent IgM response occurs in serum and CSF within days. By the seventh day, all the patients have raised IgM titers (Burke et al., 1985). Usually the virus cannot be isolated from such patients; however, the failure to mount IgM response is associated with viral isolation and fatal outcome (Leake et al., 1986). Antibodies to JEV probably protect the host by

Investigations

In JE, there may be peripheral leucocytosis and hyponatremia. The typical CSF findings include moderate pleocytosis (10–100 mm−3), mild protein rise (50–200 mg/dl) and normal glucose. Usually there is lymphocytic pleocytosis but in the early stage polymorphs may predominate. Very rarely CSF may be acellular.

Prognosis and sequelae

Twenty to forty percent of patients with JE die during the acute stage (Misra and Kalita, 2002). About 50% of the survivors have severe neurological sequelae in the form of cognitive impairment, behavioral abnormality, focal weakness, seizures and a variety of movement disorders. About 20% of the patients may have seizures. Motor deficits have been reported in 30%. The poor prognostic predictors include extremes of age, high fever, deep coma, hypotonia, features of seizures, raised intracranial

Summary

JE continues to be an important health problem especially in the developing countries of South and Southeast Asia. In the absence of specific antiviral therapy, JE has to be managed by symptomatic and supportive measures and preventive strategies. Measures like vector control, environmental manipulation and change in agricultural practices are difficult to achieve. Control of JE in economically advanced countries suggests the important role of socioeconomic parameters such as education and

References (120)

  • U.K. Misra et al.

    Prognosis of Japanese encephalitis: a multivariate analysis

    J. Neurol. Sci.

    (1998)
  • U.K. Misra et al.

    Seizures in Japanese encephalitis

    J. Neurol. Sci.

    (2001)
  • S. Paranjpe et al.

    Phylogenetic analysis of the envelope gene of Japanese encephalitis virus

    Virus Res.

    (1996)
  • F.M. Rodrigues et al.

    Prevalence of antibodies to Japanese encephalitis and West Nile viruses among wild birds in the Krishna-Godavari Delta, Andhra Pradesh, India

    Trans. R. Soc. Trop. Med. Hyg.

    (1981)
  • H. Aihara et al.

    Establishment and characterization of Japanese encephalitis virus-specific, human CD4+ T-cell clones: flavivirus cross-reactivity, protein recognition, and cytotoxic activity

    J. Virol.

    (1998)
  • S. Asahina et al.

    Long distance flight of Culex tritaeniorynchus

    Jpn. J. Sanit. Zool.

    (1968)
  • G.N. Babu et al.

    Inflammatory markers in the patients of Japanese encephalitis

    Neurol. Res.

    (2006)
  • M.W. Benenson et al.

    The virulence to man of Japanese encephalitis virus in Thailand

    Am. J. Trop. Med. Hyg.

    (1975)
  • F. Billoir et al.

    Phylogeny of the genus flavivirus using complete coding sequences of arthropod-borne viruses and viruses with no known vector

    J. Gen. Virol.

    (2000)
  • E.L. Buescher et al.

    Ecological studies of Japanese encephaltiis in Japan. IX. Epidemiological correlations and conclusions

    Am. J. Trop. Med. Hyg.

    (1959)
  • E.L. Buescher et al.

    Immunologic studies of Japanese encephalitis virus in Japan. IV. Maternal antibody in birds

    J. Immunol.

    (1959)
  • E.L. Buescher

    Arthropod-borne encephalitides in Japan and Southeast Asia

    Am. J. Public Health

    (1956)
  • D.S. Burke et al.

    Japanese encephalitis

  • D.S. Burke et al.

    Levels of interferon in the plasma and cerebrospinal fluid of patients with acute Japanese encephalitis

    J. Infect. Dis.

    (1987)
  • D.S. Burke et al.

    Kinetics of IgM and IgG responses to Japanese encephalitis virus in human serum and cerebrospinal fluid

    J. Infect. Dis.

    (1985)
  • C.H. Calisher et al.

    Antigenic relationships between flaviviruses as determined by cross-neutralization tests with polyclonal antisera

    J. Gen. Virol.

    (1989)
  • D.L. Carmenaga et al.

    Cyclophosphamide: potentiated West Nile encephalitis: relative influence of cellular and humoral factors

    J. Infect. Dis.

    (1974)
  • M.S. Chakraborty et al.

    Inapparent infection by Japanese encephalitis (JE) virus in West Bengal

    Indian J. Public Health

    (1980)
  • T.J. Chambers et al.

    Flavivirus genome organization, expression, and replication

    Annu. Rev. Microbiol.

    (1990)
  • W.R. Chen et al.

    A new genotype of Japanese encephalitis virus from Indonesia

    Am. J. Trop. Med. Hyg.

    (1992)
  • W.R. Chen et al.

    Genetic variation of Japanese encephalitis virus in nature

    J. Gen. Virol.

    (1990)
  • Y. Chen et al.

    Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate

    Nat. Med.

    (1997)
  • A. Desai et al.

    Co-existence of cerebral cysticercosis with Japanese encephalitis: a prognostic modulator

    Epidemiol. Infect.

    (1997)
  • A. Desai et al.

    In vivo clearance of Japanese encephalitis virus by adoptively transferred virus specific cytotoxic T lymphocytes

    J. Biosci.

    (1997)
  • B. Dropulie et al.

    Entry of neurotropic arbovirusesnto the central nervous system: an in vitro study using mouse brain endothelium

    J. Infect. Dis.

    (1990)
  • M.W. Gaunt et al.

    Phylogenetic relationships of flaviviruses correlate with their epidemiology, disease association and biogeography

    J. Gen. Virol.

    (2001)
  • A. Ghoshal et al.

    Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis

    Glia

    (2007)
  • E.A. Gould et al.

    Evolution and dispersal of encephalitic flaviviruses

    Arch. Virol. Suppl.

    (2004)
  • M. Gourie Devi et al.

    Japanese encephalitis: an overview

  • D.E. Griffin

    Immune responses to RNA-virus infections of the CNS

    Nat. Rev. Immunol.

    (2003)
  • R.A. Grossman et al.

    Study of Japanese encephalitis virus in Chiangmai Valley, Thailand. 3. Human seroepidemiology and inapparent infections

    Am. J. Epidemiol.

    (1973)
  • D.J. Gubler

    Dengue and dengue haemorrhagic fever: its history and resurgence as a global public health problem

  • S.B. Halstead et al.

    Subclinical Japanese encephalitis. Infection of Americans with limited residence in Korea

    Am. J. Hyg.

    (1962)
  • W.M. Hammon et al.

    Passive immunity for arbovirus infection. I. Artificially induced prophylaxis in man and mouse for Japanese (B) encephalitis

    Am. J. Trop. Med. Hyg.

    (1973)
  • S.K. Handique et al.

    Temporal lobe involvement in Japanese encephalitis: problems in differential diagnosis

    Am. J. Neuroradiol.

    (2006)
  • J.N. Hanna et al.

    Japanese encephalitis in north Queensland, Australia, 1998

    Med. J. Aust.

    (1999)
  • J.N. Hanna et al.

    An outbreak of Japanese encephalitis in the Torres Strait, Australia, 1995

    Med. J. Aust.

    (1996)
  • T. Hase et al.

    Ultrastructural changes of mouse brain infected with Japanese encephalitis virus

    Int. J. Exp. Pathol.

    (1990)
  • W. Haymaker et al.

    Topogrpaphic distribution of lesions in central nervous system in Japanese B encepahalitis

    Arch. Neurol. Psychiatry

    (1947)
  • F.X. Heinz

    Family Flaviviridae, in virus Taxonomy

  • Cited by (0)

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