JAPANESE ENCEPHALITIS

S.K. Lam, Director, WHO Collaborating Centre for Arbovirus Reference and Research (DF/DHF), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.

Introduction

Japanese encephalitis (JE) is an acute viral infection of the central nervous system occurring in large numbers in many Asian countries, including Cambodia, China, India, Korea, Myanmar, Philippines, Nepal, Sri Lanka, Thailand and Vietnam. The annual incidence of clinical infection in endemic areas ranges from 10-100 per 100,000 population. Approximately 3 billion people and 60% of the world’s population live in endemic regions and about 50,000 JE cases are notified annually, with 10,000 deaths

Recurrent summer outbreaks of encephalitis, believed to be JE, were first reported in horses and humans in Japan since the last century. In 1924, the virus was isolated in rabbits from human brain tissue. It was initially called Japanese B encephalitis virus to distinguish it from the agent causing Von Economo’s type A encephalitis, which had different epidemiological characteristics. Japanese B encephalitis has fallen into disuse and the modifying B dropped.

JE is a mosquito-borne virus belonging to the family Flaviviridae. The virus is antigenically related to several other flaviviruses, including dengue viruses. Following an infectious mosquito bite, the initial viral replication occurs in local and regional lymph nodes. Viral invasion of the central nervous system probably occurs via the blood. Certain neurotransmitter receptors are believed to be involved in the binding of JE virions to cells in the CNS. The affinity of JE virus for neural tissue leads to propagation in the brain.

The known vectors of JE are Culicine mosquitoes, notably Culex (Cx) tritaeniorhynchus, Cx. vishnui,

Cx.gelidus and Cx. fuscocephala. These mosquitoes breed preferentially in irrigated rice fields, shallow ditches and water pools. They become infected from animals, in most cases viremic domestic pigs and water birds, and after 9-12 days of incubation, they can transmit the virus to other hosts. Humans are not considered a reservoir for viral transmission and man-to-man transmission has not been documented.

JE in Malaysia

The disease is endemic in Malaysia and the first report was published by Cruikshank in 1951, describing an outbreak among British prisoners during the Second World War. Paterson et al (1952) demonstrated neutralizing antibodies to JE virus in human and equine sera in Malaysia and Pond, McCrum and Simpson (1954) found that the virus also infected pigs, bovines, dogs, goats and sheep.

The number of cases from 1985-1993 totaled 273 but the actual number of cases could probably be more

(Tan Lian Haw, 1995). Three outbreaks have been reported, 1974 in Pulau Langkawi (10 cases, 2 deaths); 1988 in Pulau Pinang (9 cases and 4 deaths); and 1992 in Serian, Sarawak (9 cases, 4 deaths). Thirty-one percent of cases between 1989-1993 were in children 0-4 years, 52% in the 7-14 year age group, 9% in the 15-24 year age group and 8% in adults >25 years. Cases have occurred principally in children below 14 years accounting for 83% of all cases. More males (62%) are affected than females (38%).

The current outbreak in northern Perak has resulted in 9 deaths. The victims showed symptoms of high fever and headache for 5 to 7 days, followed by drowsiness and coma a day or two before their sudden deaths. Another outbreak has taken place in Negri Sembilan and to date, 4 deaths have been reported. The 14th death occurred in Malacca but the patient was from Negri Sembilan. Fogging to control the mosquito vectors as well as vaccination of pig farm workers and their families are being carried out to bring the situation under control.

Clinical Illness

The vast majority of JE infections are inapparent and only one in 25-1000 infections results in symptomatic illness. The principal clinical manifestation of illness is encephalitis; however, milder clinical presentations, such as aseptic meningitis or simple febrile illness with headache, are common. The incubation period is 5-15 days. Illness usually begins with an abrupt onset of high fever, change in mental status and headache, followed gradually by disturbances in speech, gait or other motor dysfunction. The initial presentation in children usually begins with gastrointestinal symptoms of anorexia, nausea, or abdominal pain. Irritability, vomiting and diarrhoea or an acute convulsion may be the earliest objective signs of illness in an infant or child. Seizures occur in over three-fourths of pediatric patients but are observed less frequently in adults. Conversely, headache and meningimus are more common in adults.

A progressive decline in alertness eventually leads to coma of varying degree. A majority of patients become totally unresponsive or responsive only to pain. Generalized hypertonia and hyperreflexia are the most common motor abnormalities, but focal motor deficits, including paresis and hemi- and tetraplegia, cranial nerve deficits and abnormal reflexes may also be present. Central hyperpnea, hypertension, pulmonary edema and urinary retention may also complicate the illness. Signs of extrapyramidal involvement, including tremor, mask-like facies, rigidity, and choreoathetoid movements are characteristics of JE, but these signs may be obscured by generalized weakness. Treatment is supportive.

Approximately 25-30% of cases are fatal, some occurring after a brief prodrome and fulminant course lasting a few days and others run a more protracted course in coma. Young children (under 10 years) are more likely to die, and if they survive, they are likely to have residual neurological deficits. Overall, approximately one third of surviving patients exhibit serious, residual neurological disability. Principal sequelae include memory loss, impaired cognition, behavioral disturbances, convulsions, motor weakness or paralysis, and abnormalities of tone and coordination. Persistent EEG abnormalities are common in children.

Clinical laboratory examination shows moderate peripheral leucocytosis with neurophilia and mild anemia. Neutrophils may predominate in early CSF samples but a lymphocytic pleocytosis is typical. CSF protein is moderately elevated in about 50% of cases. CT and MRI scans reveal low density areas and abnormal signal intensities in the thalamus, basal ganglia and putamen which correlate with clinical findings of tremor, rigidity and abnormal movements that are common in the acute phase of illness.

JE Vaccine

Currently, 3 types of JE vaccines are in large-scale use but the mouse brain-derived and inactivated vaccine based on the Nagayama strain (or Beijing-1 strain) is currently the only vaccine available on the international market. China produces two JE vaccines for domestic use, an inactivated JE vaccine as well as a live attenuated vaccine, both grown in primary hamster kidney cells. Controlled studies have shown that the commercially available mouse brain-derived vaccine is efficacious and without serious side effects for childhood vaccination. Local reactions such as tenderness, redness and swelling occur in 20% of vaccinees. A similar percentage may experience mild systemic symptoms, including headache, myalgia, gastro-intestinal symptoms and fever.

The mouse brain-derived vaccine is given subcutaneously in doses of 0.5 ml or 1 ml, the lower dose being for children aged 1-3. The manufacturers recommend that 2 injections be given at an interval of 1-2 weeks in primary immunization followed by a booster after 1 year, with subsequent boosters every 3-4 years to maintain immunity. In several Asian trials, primary immunization has a disease-preventing efficacy of >95%; 91% efficacy was achieved in a placebo-controlled trial.

A WHO position paper on JE vaccines has been published recently (WER, 1998).

Laboratory Diagnosis

Laboratory diagnosis of JE is mainly based on serological testing, using IgM-capture ELISA that detects specific IgM in the cerebrospinal fluid or in the blood of almost all patients within 4-7 days of onset of disease. Specific IgM can be detected in CSF and/or serum in approximately 75% of patients within the first 4 days after onset of illness and nearly all patients are positive 7 days after onset. Commercial kits are now available for detection of JE IgM using dot-blot or immunoprecipitation IgM assays. A new JE IgM capture ELISA test from Australia is also available.

Virus isolation can be performed using Vero, LLCMK2 and PS cells and the virus kills suckling mice inoculated intracerebrally. However, isolation is slow, technically difficult and not sensitive in patients presenting with encephalitis as they are no longer viremic. Polymerase chain reaction-based tests have been developed and have a role to play in JE diagnosis.

Although a history of exposure to an endemic area and certain clinical features may suggest JE, clinical diagnosis is unreliable and laboratory confirmation, principally by serology, is necessary. The WHO Collaborating Centre provides a comprehensive range of diagnostic tests for JE and is prepared to offer its assistance without charge during the on-going outbreak.

 

References

 

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