JAPANESE

ENCEPHALITIS
Dr.T.V.Rao MD

Dr.T.V.Rao MD

Japanese Encephalitis belongs to

Genus Flavivirus

Flaviviridae
Flavivirus

The name is derived

from
the Latin flavus
Flavus means yellow
Refers to yellow fever
virus

Enveloped
Single stranded RNA
virus
Morphology not well
defined
Center for Food Security and Public
Health Iowa State University - 2007

Genus - Flavivirus

Japanese B
encephalitis virus is
Spherical, 40 60 nm
in diameter
Contain a positive
sense Single stranded
RNA, 11 kb in size
RNA genome is
infectious
Several viruses in this
group are related.
Dr.T.V.Rao MD

A Flavivirus
Japanese

encephalitis ( previously
known as Japanese B encephalitis
is a disease caused by the mosquitoborne Japanese encephalitis virus. The
Japanese encephalitis virus is a virus
from the family Flaviviridae.
Domestic pigs and wild birds are
reservoirs of the virus; transmission to
humans may occur
Dr.T.V.Rao MD

Structure of Virus

The outer envelope is

formed by envelope
(E) protein and is the
protective antigen. It
aids in entry of the
virus to the inside of
the cell. The genome
also encodes several
non-structural
proteins also
(NS1,NS2a,NS2b,NS3,
N4a,NS4b,NS5). NS1
is produced as
secretary form also.
NS3 is a putative
helicase, and NS5 is

Dr.T.V.Rao MD

History
1870s:

Japan

Summer encephalitis epidemics

1924:

Great epidemic in Japan

6,125 human cases; 3,797 deaths

1935:

First isolated

From a fatal human encephalitis

case
1938:

Isolated from Culex

tritaeniorhynchus
Center for Food Security and Public
Health Iowa State University - 2007

History
1940-1978

Disease spread with epidemics in

China, Korea, and India
1983:

Immunization in South

Korea
Started as early as age 3
Endemic areas started earlier
1983-1987:

Vaccine available in
U.S. on investigational basis
Center for Food Security and Public
Health Iowa State University - 2007

What causes
encephalitis?

Viruses (most common)

More than 100 different viruses

can cause acute encephalitis
Seasonal and geographic
distribution can help narrow
differential diagnosis
Examples of common viruses:

Arbovirus
Enter viruses
Mumps, Varicella
Herpes simplex virus

Influenza
*Note: A large number of reported cases of encephalitis are due to an
cause
unspecified
Rabies

Japanese Encephalitis

First discovered and originally restricted to Japan. Now large scale

epidemics occur in China, India and other parts of Asia.

Flavivirus, transmitted by culex mosquitoes.

The virus is maintained in nature in a transmission cycle involving

mosquitoes, birds and pigs.

Most human infections are subclinical: the in apparent to clinical cases is

300:1

In clinical cases, a life-threatening encephalitis occurs.

The disease is usually diagnosed by serology. No specific therapy is

available.

Since Culex has a flight range of 20km, all local control measures will fail.
An effective vaccine is available.

Japanese B virus Infection

Infection is caused by a flavivirus, a single
stranded RNA virus. It is transmitted by
the bite of the Culex tritaeniorhynchus
mosquito. The virus multiplies at the site
of the bite and in regional lymph nodes
before viraemia develops. Viraemia can
lead to inflammatory changes in the heart,
lungs, liver, and reticuloendothelial
system.

Dr.T.V.Rao MD

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A leading cause of viral

Encephalitis

Japanese
encephalitis is the
leading cause of
viral encephalitis in
Asia, with 30,000
50,000 cases
reported annually.
Case-fatality rates
range from 0.3% to
60% and depends
on the population
and on age.

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Animal-Arthropod-Man
Cycle

Cycle of Infection in Japanese B

Viral Infection

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Transmission
Vector-borne disease
Enzootic cycle

Mosquitoes: Culex species

Culex tritaeniorhynchus

Reservoir/Amplifying hosts
Pigs, bats
Ardeid (wading) birds
Possibly reptiles and amphibians

Incidental hosts
Horses, humans, others
Center for Food Security and Public
Health Iowa State University - 2007

A Vector born- Arbovirus

Infection

Culex
tritaeniorhynchus a
rural Mosquito that
breeds in rice fields,
is the principle vector.
In India in 1955 the
virus were isolated
from Culex vishnui
mosquitoes in Vellore
region in Tamil Nadu
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Japanese Encephalitis
(JE)
Most important global
cause of arboviral
encephalitis with >
50,000 cases and 15,000
deaths reported each
year.
Only about 1 in 250 JE
infections result in
symptomatic illness.
Primarily affects children
If unrecognized, mortality is up to 30% with half of
1 to 15 years of age.
survivors sustain severe neurological sequelae.
Incubation period is 5
to 14 days.

INCIDENCE
Leading

cause of viral encephalitis

in Asia with 30-50,000 cases
reported annually
Fewer than 1 case/year in U.S.
civilians and military personnel
travelling to and living in Asia
Rare outbreaks in U.S. territories in
Western Pacific
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Dr.T.V.Rao MD

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Cycle of Events in Japanese

B Encephalitis

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Pass through two prominent

Hosts
Herons act as
reservoir hosts and
pigs as amplifier
hosts.
Human infection is a
tangential dead
end and infections
are spread when the
infected mosquitoes
reach high density.

Dr.T.V.Rao MD

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Pathogenesis of Flavivirus Infections

Subcutaneous injection

Extraneural Tissues
Connective tissue
Striated muscle
Pancreas
Adrenal
Smooth muscle

Regional lymph nodes

Efferent lymphatics
Thoracic duct

Reticuloendothelial
cell clearance

Plasma Viremia

Olfactory epithelium

Humoral antibody
Vascular endothelium

?
?

Neural Parenchyma
CNS antibody
Neurons, Glia(?)

Cellular dysfunction
Cellular lysis
Inflammation

lymphocytes, macrophage

Fields Virology, Vol 1, Fourth Edition.

Lippincott-Williams & Wilkins (Philadelphia), pp
1057, 2001

Clinical Manifestations
The incubation period is 6 to 16 days.
There is a prodrome of fever, headache,
nausea, diarrhoea, vomiting, and myalgia,
which may last for several days.
This may be followed by a spectrum of
neurological disease ranging from mild
confusion, to agitation, to overt coma.
Two thirds of patients have seizures. It is
more common in children, while headache
and meningism are more common in
adults.

Dr.T.V.Rao MD

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Common symptoms of encephalitis

Sudden fever
Headache

Lethargy
Change in
consciousness

Irritability or
restlessness
Tremors or
convulsions

Vomiting and
diarrhea

Can lead to Neurological

damage
Tremor

or other involuntary
movements are common.
Mutism has been described as a
presenting symptom. So has a
syndrome of acute flaccid
paralysis.
Fever resolves by the second
week, and choreoathetosis or
extra pyramidal symptoms
develop as the other
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Diagnosis of Japanese B
Encephalitis
The

isolation of virus from Blood,

CSF, or tissues.
Detection of Arbovirus specific
RNA in blood,CSF, or Tissue
However very few reference
laboratories can perform the
isolation in view of the biosafety
considerations
Dr.T.V.Rao MD

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Serology by ELISA
IgM capture enzyme-linked immunoassay
(ELISA) of serum or CSF is the standard
diagnostic test. Sensitivity is nearly 100%
when both serum and CSF are tested. Falsenegatives may result if the samples are tested
too early, as in the first week of illness.
New IgM dot enzyme immunoassays for CSF
and serum are portable and simple tests that
can be used in the field. Compared with ELISA
as the gold standard, the sensitivity and
specificity are around 98 and 99% respectively.

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Arbovirus Specific RNA

detection
Viral RNA is extracted from serum or from
suspected tissues of the patients or
mosquito homogenates.
The product is amplified by RTPCR and the
products analyzed by restriction digestion
and determined by nucleotide sequence of
PCR product.
The identified sequence is compared with
nucleotide sequence found in Gene bank or
other data bases

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False Positive Tests

There

is
some crossreactivity
with other
flavivirus and
from
Japanese
encephalitis
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Japanese Encephalitis B
Vaccine

Japanese Encephalitis B Vaccine has

been produced since 1992. The vaccine is
effective but not without risks and the
substantial risks of the disease and the risks
of the vaccine have to be balanced,
especially for stays of brief duration. These
are discussed more fully in the article on
that subject.
As with malaria, prophylaxis must be
supplemented by techniques to avoid being
bitten by mosquitoes.

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Preventive measures
Preventive measures include mosquito
control and locating piggeries away from
human dwellings
A formalin inactivated mouse brain
vaccine using the Nakayama strain has
been employed in human immunization in
Japan Two doses at two weeks interval
followed by a booster 6 12 months later
constitute a full course.
However the immunity was short lived

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Emerging Vaccines for JE virus

Two vaccines are manufactured and

distributed exclusively in Peoples Republic
of China
Inactivated vaccine grown in primary hamster
kidney cells
Live attenuated vaccine (SA14-14-2) grown in
hamster kidney cells

The third is manufactured in Japan and

distributed abroad by arrangement with
Sanofi-Pasteur
Licensed as JE-VAXR and is the only FDA
approved vaccine for use in the U.S.
Has been in wide use worldwide since the
1960s

Vaccination
Live

attenuated vaccine

Used in equine and swine

Successful for reducing incidence
Inactivated

vaccine (JE-VAX)

Used for humans

Japan, Korea, Taiwan, India, Thailand
Used for endemic or epidemic areas
Recommended for travelers
Visiting endemic areas for > 30 days
Center for Food Security and Public
Health Iowa State University - 2007

Later vaccines
A

live attenuated vaccine has been

developed in China from JE strain SA
14-14-2, passed through weanling
mice
The vaccine is produced in primary
bay hamster kidney cells.
Administered in two doses, one year
apart, the vaccine has been
reportedly effective in preventing
clinical disease
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Safety of Current JE
Vaccine

Side effects Generally inconsequential. Local

tenderness or mild systemic symptoms in 1030% - Fields virology
No neurologic events in Japanese surveillance
Infrequent allergic reactions in adult travelers
Urticaria, angioedema, bronchospasm, erythema
nodosum and e. multiforme

Incidence varies in different reports: 2/1000 to

1%
14,000 US Marines, 11 pruritus, 26 urticaria
History of urticaria after hymenoptera envenomation
or other provocations caused a relative risk increase
of 9.1
None of the reactions were severe or life threatening

Case control study in Australia identified

increased reaction risk if excessive alcohol

Prevention
Vector

control

Eliminate mosquito breeding areas

Adult and larvae control
Vaccination

Equine and swine

Humans
Personal

protective measures

Avoid prime mosquito hours

Use of repellants containing DEET
Center for Food Security and Public
Health Iowa State University - 2007

RESEARCH PRIORITIES
Facilitate

implementation of attenuated
vaccine in unvaccinated populations in
endemic areas
Develop improved vaccines
Identify risk factors for progression to
symptomatic encephalitis and viral
persistence
Describe clinical features of JE in AIDS and
determine its potential as an opportunistic
infection
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by Dr.T.V.Rao MD
for Medical and
Paramedical Professionals
in Developing World
Email
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