JAPANESE ENCEPHALITIS

1. JAPANESE ENCEPHALITIS Lin Chaoshuang The Third Affiliated Hospital Sun-Yet sen University

2. Overview • Etiology • Epidemiology and history • Pathogenesis and Pathology • Clinical Manifestation • Diagnosis • Treatment • Prevention and Control

3. Etiology: The Organism • Arbovirus • Flavivirus • Enveloped • Single positive-stranded RNA virus 11kb • Morphology: sphere 40~50nm • The name is Latin for flavus • Flavus means “yellow” • Refers to yellow fever virus Flaviviridae

4. It has three proteins • Envelope protein • Core protein • Membrane protein Etiology: The Organism

5. Replication Flaviviruses replication process includes the entry by receptor-mediatedendocytosis, uncoating, protein synthesis, viral genome synthesis, assembly, and virus release by budding from plasma membrane or internal membrane.

6. History • 1870'’s: Japan • “Summer encephalitis” epidemics • 1924: Great epidemic in Japan • 6,125 human cases; 3,797 deaths (62% case-fatality rate) • 1935: First isolated in Japan • From a fatal human encephalitis case • 1938: Isolated from Culex tritaeniorhynchus

7. History • 1940-1978 • Disease spread with epidemics in China. Korea: 5,548 human cases in 1949 India: recognized in 1954, over 6,000 cases in 1978 • 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

8. Korea Japan China India Philipines Indonesia Epidemiology Geographic Distribution • Endemic in temperate and tropical regions of Asia • Reduced prevalence in Japan • 30,000-50,000 cases annually • Less than 1 case/year in U.S. www.cdc.gov/ncidod/dvbid/jencephalitis

9. JE Outbreaks in India • Outbreaks of JE occur in India for 27 years • Larger outbreak 1988: 1228 deaths • Total deaths in 27 years: 4000 deaths • Outbreak 2004: 50 deaths

10. Outbreak 2005 in India • Index case: Nepal, mid-June • First case India: July 20th • First outbreak alert: August 12th • Confirmation JE: August 21th • Total death: 1302 • Total cases: > 5000

11. JE in CHINA • Pandemic from 1960’s to early 1970’s. • Incident rate decreased since late 1970’s • Case reports were 5000～10000 cases /y these few years. • Outbreak in some areas. Prevalence in Shanxi Province Yuncheng: From 13 July to 14 Augest, 2006. 65 cases，19 deaths.

12. Transmission: Sourcesof Infection • Arthropod-borne viruses (Arboviruses, 虫媒病毒) • Enzootic or zoonosesdisease • Amplifying hosts • Pigs (the main reservoir) • Wading birds (egrets, herons), Bats • Incidental hosts • Horses, humans (dead-end hosts) • Others herons

13. Transmission: Routesof Transmission • Vectors: Mosquitoes • Culex species tritaeniorhynchus • The mosquitoes that transmit the virus breed in rice fields, and standing water. • In winter, virus persist in arthropod (节肢动物) eggs or migrate with birds. • Death of infected no-human vertebratesoccurs before human outbreak.

14. Transmission: Susceptible Population • Age: 2-10 years • Living in rural areas • People who live near stagnant water (mosquito breeding)

15. Epidemiologic Feature • The major outbreaks coincided with the heavy rainfall or floods. • Seasonal: more common in summer, July to October • Infection provides life long immunity.

16. DYNAMICS OF JE TRANSMISSION Vector Mosquito Environment Victim-Accidental Recovery with residual complications Full Recovery Death Host - Amplifying Host - Carrier

17. Pathogenesis The nature of flavivirus disease is determined primarily by • The specific tropisms of the individual virus type • The concentration of infecting virus • Individual host response to the infection

18. Pathogenesis JE Virus mononuclear phagocyte blood circulation viremia Adequate immunological Weak immunological response response subclinical or mild invades the CNS systemic diseaseinduce mortality

19. Pathogenesis • Initial viral replication may occur in local regional lymph nodes • Initially brain damage is due to viral infection and multiplication in neurons per se • Later immunopathological mechanisms may play a role.

20. Pathology • Degeneration and necrosis of neurocyte • Formation of malacoma focus (软化灶) • Blood vessel change and inflammatory reaction • Hyperplasy of colloid (胶质) cell

21. Manifestation • Most asymptomatic or mild signs • Ratio of subclinical to clinical ratio (250~300:1) • 50% develop permanent neurological damage • Incubation Period - 5 to 15 days

22. Clinical Manifestations Clinical manifestations depend upon: • Severity of infection • Susceptibility of the host • Location of the agent

23. Four stages • A Prodromal Stage • An Acute encephalitic Stage • The Convalescence Stage • A Sequela Stage

24. Prodromal Stage • The Prodromal stage usually lasts for 1 to 6 days. It can be as short as less than 24 hours or as long as 14 days • Acute • Fever with severe rigors, headache and malaise • Nausea, Vomiting, Abdominal pain • Drowsy • Neck rigidity • Convulsions, Seizures

25. The Acute Encephalitic Stage • Begins by the third to fifth day. • The symptoms include: • High fever: for about 7~10 days • Changes in consciousness: dullness, tremor, stupor, ataxia, focal or diffuse paralysis, coma • Convulsions: localized or generalized, Tremors in fingers, tongue, eyelids and eyes • Respiratory failure: maybe due to high intracranial pressure, edema of the brain, hernia of the brain. • Meningeal irritation sign:Stiff neck, positive Kernig’s sign and pathological reflexes.

26. The Convalescence Stage • Defervescence of fever • Defervescence of neurologic improvement • Usually lasts for at least two weeks.

27. A Sequela Stage • Neuropsychiatric sequelae • 30-50% of survivors • Characterised by • Persistance of signs of CNS injury • Mental impairment      • Increased deep Tendon reflexes      • Paresis either of the upper or lower motor neuron (下位运动神经元)      • Speech impairment      • Epilepsy, Abnormal movements, Behaviour abnormalities

28. Clinical spectrum of JE infection Die Severe Moderate Mild Asymptomatic • For every symptomatic JE case, there are likely to be about 300 – 1000 people infected with JE virus but without any clinical manifestation • People of any age can be infected. Adult infection most often occurs in areas where the disease is newly introduced.

29. Laboratory Investigation • Peripheral blood analysis: leucocytosis(10~20)X109/Lwithneutrophilic＞80% • Cerebrospinal fluid (CSF)analysis : Routine:clear, tension elevated, leucocytosis(50~500)X106/L Neutrophilsmay predominate in early CSF samples but alymphocytic pleocytosisis typical Biochemistry: proteinis moderately elevated glucose and chloride normal level

30. Laboratory Investigation • Serological tests: Specific IgM antibody A significant rise in IgG antibody titer should be seen with paired samples from the acute and convalescent stages. • The virus isolation: Isolated from CSF by inoculating into 2-4 day old mice and the virus is identified by haemagglutination inhibition. JE virus may also be identified by infection of cell cultures (chicken embryo or hamster kidney cells, or the mosquito cell line C3/36).

31. Diagnosis • Materials of epidemiology • Clinical • Laboratory Tests • Tentative diagnosis • Antibody titer: HI, IF, CF, ELISA • JE-specific IgM in serum or CSF • Definitive diagnosis • Virus isolation: Blood, CSF sample, brain

32. Differential Diagnosis • Toxic shigellosis and other Toxic Encephalopathy • Cerebral Malaria • Meningitis (other viral meningitis or encephalitis, partially treated bacterial meningitis, meningococcal meningitis, tuberculous or fungal meningitis) • Febrile Convulsions • Rey’s Syndrome • Rabies

33. Prognosis • Approximately 5-35% of cases are fatal, some with a fulminate course lasting a few days and others run a more protracted course in coma. • About 30-50% of those who survive may have serious neurologic sequelae.

34. Treatment • No specific therapy • Supportive care: intensive life support is indicated • Surveillance for cases of encephalitis

35. Treatment • Treatment of high fever Physical method: ice, alcohol, cool saline. Artificial hibernation • Seizure and convulsions management: Sedation, Corticosteroids may be used • For respiratory failure: Oxygen supply, artificial respiration • For raised intracranial pressure: Mannitol iv.drip 1mg/Kg every 6~8 hrs.

36. Prevention • Vector (Mosquito) control • Eliminate mosquito breeding areas: Chemical larvicides, Biolarvicides, Environmental management • Adult and larval control: Anti-larval treatment • Vaccination • Personal protective measures • Avoid prime mosquito hours: from dusk to dawn • Indoor spray and fogging: Use of Insecticide

37. Vaccination • Live attenuated vaccine • Successful for reducing incidence • SA 14-14-2 (Chinese live attenuated vaccine at affordable cost, safe, effective). • This vaccine was developed in China and has been used since 1988. • It has been licensed and used in South Korea.

38. Vaccination • Inactivated mouse brain vaccine(JE-VAX) • Comprising 3 doses: 0.5ml each time and the interval is 1~2 weeks in infancy, boosting 1.0ml in children. • Used for endemic or epidemic areas. • Recommended for travelers visiting • endemic areas for > 30 days.

39. THANKS