Japanese Encephalitis

1. Introduction

Japanese Encephalitis (JE) is a mosquito-borne viral disease causing acute inflammation of the brain. It is the leading cause of vaccine-preventable viral encephalitis in Asia. The disease is of significant public health importance in India, where it is a major contributor to Acute Encephalitis Syndrome (AES). While most infections are asymptomatic, clinical disease is characterized by high mortality and a high rate of permanent neurological sequelae in survivors.

2. Virology

Etiologic Agent

The Japanese Encephalitis Virus (JEV) belongs to the family Flaviviridae and the genus Flavivirus. It is part of the JE serocomplex, which also includes St. Louis encephalitis, West Nile, and Murray Valley encephalitis viruses.

Structure and Genome

JEV is a spherical, enveloped virus with a diameter of approximately 50 nm. It possesses a single-stranded, positive-sense RNA genome. The genome encodes three structural proteins: Capsid (C), Membrane (M), and Envelope (E), and seven non-structural proteins. The E glycoprotein is the major surface protein and plays a critical role in receptor binding, viral entry, and induction of neutralizing antibodies.

Genotypes

JEV is historically classified into five genotypes (I–V) based on the nucleotide sequence of the envelope gene.

• Genotype III was traditionally the most widely distributed strain in temperate Asia and was the strain used for original vaccine production.
• Genotype I has recently displaced Genotype III as the dominant circulating genotype in many parts of Asia.
• Genotype V is considered an emerging genotype. Despite these genotypic differences, JEV exists as a single serotype, meaning vaccines derived from one genotype (typically Genotype III) generally provide protection against others.

3. Epidemiology

Vector and Transmission

• Vector: JE is transmitted to humans through the bite of infected Culex mosquitoes. Culex tritaeniorhynchus is the primary vector across most of Asia. These mosquitoes breed prolifically in stagnant water bodies such as rice paddies, ground pools, and ditches. They are zoophilic (prefer animals) and are exophilic (rest outdoors).
• Transmission Cycle: The virus is maintained in an enzootic cycle involving mosquitoes and vertebrate hosts.
  • Reservoir Hosts: Ardeid birds (herons, egrets) act as natural reservoirs, maintaining the virus in the environment.
  • Amplifying Hosts: Pigs are the most important amplifying hosts. They develop high-titer viremia sufficient to infect feeding mosquitoes but usually remain asymptomatic. The intense breeding of mosquitoes in rice fields combined with pig rearing creates a high-risk environment for transmission ("pigs and paddy" ecology).
  • Dead-end Hosts: Humans and horses are incidental, dead-end hosts. They can develop clinical disease but do not develop viremia sufficient to infect mosquitoes, thus contributing little to the transmission cycle.

Geographic Distribution

JE is endemic throughout most of Asia and parts of the Western Pacific.

• Global: It affects countries including Japan, China, Korea, Taiwan, Thailand, Vietnam, Philippines, Indonesia, and India.
• India: JE is endemic in many states. Highly affected states include Uttar Pradesh (especially the Gorakhpur region), Bihar, Assam, West Bengal, Tamil Nadu, Andhra Pradesh, Karnataka, Goa, and Manipur.

Seasonality

Transmission patterns depend on climate and agricultural practices:

• Temperate Zones: Transmission is seasonal, peaking in summer and early autumn (June to September).
• Tropical/Subtropical Zones (e.g., Southern India): Transmission may be perennial (year-round) or have peaks associated with the monsoon rains and irrigation cycles. In India, outbreaks often follow the monsoon season.

Risk Factors

• Age: In endemic areas, JE is primarily a disease of children (typically <15 years), as most adults have acquired natural immunity through subclinical infection. In non-endemic areas or among travelers, all age groups are susceptible.
• Proximity to Reservoirs: Living near rice fields or pig sties significantly increases the risk of infection.
• Outdoor Activity: Exposure to mosquitoes during twilight and evening hours (when Culex vectors are most active) increases risk.

4. Pathogenesis

Following the bite of an infected mosquito, the virus replicates locally and in regional lymph nodes. This leads to a transient viremia, allowing the virus to spread to extraneural tissues like the spleen, liver, and kidneys.

• Neuroinvasion: In a minority of cases, the virus crosses the blood-brain barrier. The mechanisms may include passive transport across endothelial cells, infection of leukocytes (Trojan horse mechanism), or entry via olfactory neurons.
• Neuropathology: Once in the CNS, the virus causes direct neuronal destruction and induces an intense inflammatory response. Pathological changes include:
  • Anatomic Distribution: The thalamus, basal ganglia, and brainstem are characteristically involved. The hippocampus, temporal cortex, and spinal cord (anterior horn cells) may also be affected.
  • Microscopic Findings: Features include neuronal degeneration, neuronophagia, perivascular lymphocytic cuffing, and microglial nodules.

5. Clinical Manifestations

The vast majority (>99%) of JEV infections are asymptomatic or result in a mild, nonspecific febrile illness. Less than 1% of infected individuals develop clinical encephalitis.

Clinical Course

The incubation period ranges from 4 to 14 days. The illness typically progresses through three stages:

1. Prodromal Stage (2–3 days):

   • Abrupt onset of high-grade fever, headache, and chills.
   • Nonspecific symptoms: Anorexia, nausea, vomiting, and abdominal pain.
   • Respiratory symptoms may be present.

2. Acute Encephalitic Stage (3–4 days):

   • CNS Dysfunction: Progressive clouding of consciousness ranging from confusion and delirium to stupor and deep coma.
   • Seizures: Generalized tonic-clonic seizures are very common, especially in children (reported in 10–24% or more).
   • Movement Disorders: A distinctive feature of JE is the involvement of the extrapyramidal system. Signs include mask-like facies, tremors (non-intention), cogwheel rigidity, dystonia, and choreoathetoid movements.
   • Neurological Signs: Neck rigidity and Kernig’s sign may be present but are often less pronounced than in bacterial meningitis. Upper motor neuron signs (spasticity, hyperreflexia, Babinski sign) are common, but rapidly changing signs (e.g., hyperreflexia becoming hyporeflexia) are characteristic.
   • Other Features: Cranial nerve palsies and autonomic disturbances may occur. In severe cases, central neurogenic hyperventilation and posturing (decorticate or decerebrate) may develop.

3. Convalescent Stage (Weeks to Months):

   • Fever subsides, and neurologic deficits may stabilize or gradually improve.
   • Persistent sequelae such as motor weakness, paresis, seizures, and cognitive impairment are common.

Acute Encephalitis Syndrome (AES) Surveillance

In India, JE is reported under the broader umbrella of Acute Encephalitis Syndrome (AES) for surveillance purposes. The WHO clinical case definition for AES is:

• A person of any age, at any time of year, with the acute onset of fever and a change in mental status (confusion, disorientation, coma, or inability to talk) AND/OR new onset of seizures (excluding simple febrile seizures).

6. Diagnosis

Diagnosis is based on clinical suspicion, epidemiologic context, and laboratory confirmation.

Laboratory Investigations

• CSF Analysis:
  • Usually reveals a mild to moderate pleocytosis (10–1,000 cells/mm³).
  • Predominance of lymphocytes (though polymorphonuclear cells may predominate early).
  • Protein is mildly elevated (usually <100 mg/dL), and glucose is normal.
• Serology (Gold Standard):
  • IgM Capture ELISA: Detection of JEV-specific IgM antibodies in cerebrospinal fluid (CSF) or serum is the diagnostic method of choice. IgM can be detected in CSF/serum within 7 days of illness onset in nearly all cases.
  • CSF positivity is confirmatory for CNS infection.
  • Cross-reactivity with other flaviviruses (like Dengue or West Nile) can occur, requiring confirmatory neutralization tests if necessary.
• Molecular Testing: RT-PCR can detect viral RNA in blood or CSF, but the viremia is transient and often clears by the time neurological symptoms appear. Therefore, PCR has lower sensitivity than serology in the acute phase.

Neuroimaging

• MRI: Magnetic Resonance Imaging is more sensitive than CT.
  • Characteristic Finding: Bilateral hyperintensities on T2-weighted and FLAIR images involving the thalamus and basal ganglia (putamen, substantia nigra).
  • Midbrain, pons, and cerebellum may also show lesions.
  • Thalamic lesions are highly suggestive of JE in an endemic context but are not pathognomonic.

7. Differential Diagnosis

JE must be differentiated from other causes of acute febrile encephalopathy (AES):

1. Cerebral Malaria: Differentiated by peripheral smear/antigen testing, splenomegaly, and retinal changes.
2. Bacterial Meningitis: Differentiated by high CSF neutrophils, low glucose, and positive Gram stain/culture.
3. Other Viral Encephalitides:
   • Herpes Simplex Encephalitis (HSE): Typically affects the temporal lobes; presents with focal seizures. Treatable with Acyclovir.
   • Enteroviral Encephalitis: Often associated with hand-foot-mouth disease or herpangina.
   • Nipah Virus: Associated with respiratory distress and contact with bats/pigs.
   • West Nile Virus / Chandipura Virus: Other arboviral causes in India.
4. Tuberculous Meningitis: Subacute course, basal exudates on imaging, CSF lymphocytosis with low glucose.

8. Management

There is no specific antiviral therapy for Japanese Encephalitis. Management is primarily supportive and focused on preventing complications.

Supportive Care

• Airway and Breathing: Maintain airway patency; intubation and mechanical ventilation may be required for comatose patients or those with respiratory failure.
• Intracranial Pressure (ICP) Management:
  • Elevate head end to 30 degrees.
  • Use hyperosmolar therapy (Mannitol or hypertonic saline) for raised ICP.
  • Maintain normoglycemia and normothermia.
• Fluid and Electrolyte Balance: Monitor for Syndrome of Inappropriate Antidiuretic Hormone (SIADH), which causes hyponatremia and can worsen cerebral edema. Restrict fluids if SIADH is present.
• Seizure Control: Seizures must be treated aggressively as they increase ICP and metabolic demand. Benzodiazepines (Lorazepam/Diazepam) are first-line, followed by Phenytoin or Fosphenytoin.
• Nutrition: Nasogastric feeding should be initiated early in unconscious patients to prevent malnutrition.
• Prevention of Secondary Infections: Careful nursing to prevent bedsores and aspiration pneumonia.

Specific Therapies (Investigational)

• Corticosteroids: High-dose dexamethasone has been studied but was shown to have no clinical benefit in a randomized controlled trial.
• Antivirals/Immunomodulators: Interferon-alpha and Ribavirin have been tried but have not shown proven efficacy in human trials. IVIG has shown neutralizing antibody increase but no improvement in outcome.

9. Prognosis

JE carries a poor prognosis.

• Mortality: The case-fatality rate ranges from 20% to 30%. Death usually occurs during the acute phase due to raised intracranial pressure or respiratory failure.
• Sequelae: Among survivors, 30% to 50% suffer from significant long-term neurological or psychiatric sequelae.
  • Neurologic: Motor deficits (spasticity, paralysis), movement disorders (parkinsonism, dystonia), and seizures.
  • Cognitive/Psychiatric: Intellectual impairment, learning disabilities, behavioral abnormalities, and emotional instability.
  • Predictors of Poor Outcome: Prolonged fever, frequent seizures, deep coma, and respiratory failure are associated with worse outcomes.

10. Prevention

Prevention strategies rely on vaccination, vector control, and personal protection.

Vaccination

Vaccination is the single most effective preventive measure.

1. Live Attenuated Vaccine (SA 14-14-2):
   • This cell-culture-derived vaccine is the primary vaccine used in India's Universal Immunization Program (UIP) for endemic districts.
   • Schedule: Administered in two doses.
     • 1st Dose: At 9 months of age (along with measles vaccine).
     • 2nd Dose: At 16–24 months of age (along with DPT booster).
   • It is highly immunogenic and safe.
2. Inactivated Vero Cell Vaccine (e.g., JENVAC, IXIARO):
   • Available for travelers and adults.
   • Given as a two-dose primary series (Day 0 and Day 28).
3. Inactivated Mouse Brain Vaccine (Nakayama strain): Previously used in India but largely discontinued due to adverse events (allergic/neurologic) and need for multiple boosters.

Vector Control

• Larval Control: Use of larvicides (e.g., Abate) or biological control (larvivorous fish like Gambusia) in rice paddies.
• Adult Control: Indoor residual spraying or fogging (e.g., with Malathion) during outbreaks to reduce adult mosquito density.
• Environmental Management: Intermittent irrigation of rice fields (wet-dry irrigation) to disrupt mosquito breeding.

Personal Protection

• Use of insecticide-treated bed nets (ITNs).
• Wearing long-sleeved clothes and trousers.
• Use of mosquito repellents (DEET, Picaridin).
• Screening of houses to prevent mosquito entry.

Control of Amplifying Hosts

• Segregation of pigs from human habitats.
• Vaccination of pigs is possible but generally not practical or cost-effective for public health; preventing pig infection breaks the amplification cycle.