Summary

Japanese Encephalitis (JE) is a vector-borne viral zoonosis that represents the leading cause of vaccine-preventable viral encephalitis in Asia. It is caused by the Japanese encephalitis virus (JEV), a single-stranded RNA flavivirus closely related to West Nile, St. Louis Encephalitis, and Dengue viruses.

The disease is endemic across 24 countries in Southeast Asia and the Western Pacific, putting over 3 billion people at risk. An estimated 68,000 clinical cases occur annually, though this is likely a gross underestimate due to poor surveillance. While less than 1% of infections result in symptomatic neuroinvasive disease, the consequences for those affected are devastating: High Case Fatality Rate (20-30%) and a high rate of permanent neurological sequelae (30-50%) in survivors.

Key Facts

Why This Matters Clinically

1. Diagnostic Challenge: JE mimics other causes of acute encephalitis (Herpes, Meningitis, Cerebral Malaria). Recognising the "Parkinsonian" features and travel history can save unnecessary treatments.
2. Vaccine Preventable: Almost all cases in travellers are preventable. Pre-travel counsel is critical.
3. Emerging Threat: Climate change and rice farming expansion are shifting the vector range. Cases have recently occurred in Australia (2022 outbreak), demonstrating its potential for spread.

Understanding the virus structure is key to understanding vaccine targets and serological cross-reactivity.

Classification

• Family: Flaviviridae (from Latin flavus = yellow, due to Yellow Fever).
• Genus: Flavivirus.
• Serogroup: Japanese Encephalitis Serocomplex.
  • Includes: West Nile Virus, St. Louis Encephalitis, Murray Valley Encephalitis, Usutu Virus.
  • Clinical Significance: This close relationship causes Serological Cross-Reactivity. An ELISA for JE might be false-positive if the patient had Dengue or West Nile. Confirmatory Plaque Reduction Neutralization Test (PRNT) is required.

Structure

JEV is a small (50nm) enveloped virus with a positive-sense single-stranded RNA genome (11kb).

1. Structural Proteins:
   • C (Capsid): Protects the RNA.
   • prM (Membrane): Important for maturation.
   • E (Envelope): The critical protein.
     • Contains the Receptor Binding Domain.
     • Target of Neutralising Antibodies.
     • Vaccines (Ixiaro, SA 14-14-2) target this protein.
2. Non-Structural Proteins (NS1-NS5):
   • NS1: Secreted antigen (used in diagnostics).
   • NS3: Protease/Helicase.
   • NS5: RNA-dependent RNA Polymerase (Replication).

Genotypes

There are 5 genotypes (GI - GV).

• Genotype III (G3): Historically the dominant strain in Asia. (The SA 14-14-2 vaccine is based on G3).
• Genotype I (G1): Has replaced G3 as the dominant strain in Asia over the last 20 years.
• Genotype V (G5): Originally from Malaysia. Re-emerged recently in Korea.
• Vaccine Implications: Fortunately, current G3-based vaccines (Ixiaro) provide protection against G1. However, protection against G5 is less certain and is an area of active research.

Vital Signs

• Temperature: Often > 40°C (Hyperpyrexia).
• Respiratory Pattern: Cheyne-Stokes or Central Neurogenic Hyperventilation (Midbrain compression).
• Cushing’s Reflex: Bradycardia + Hypertension (Sign of raised ICP).

Neurological Exam

• GCS: Documentation of baseline is critical.
• Meningism: Neck stiffness, Kernig’s, Brudzinski’s (Positive in 50%).
• Fundoscopy: Papilloedema (Blurring of disc margins).
• Tone:
  • Rigidity: "Lead-pipe" or "Cogwheel" (Extrapyramidal).
  • Spasticity: Clasp-knife (Pyramidal).
  • Flaccidity: Lower Motor Neuron (Anterior Horn Cell).
• Brainstem Reflexes: Pupillary light reflex, Oculocephalic (Doll's eye). Loss = Poor prognosis.

Differentiating JE from other causes of Acute Encephalitis Syndrome (AES) is difficult but critical.

Prevention relies on a two-pronged strategy: Mosquito Control and Vaccination.

1. Vector Control

• Personal Protection: DEET 50%, Long sleeves, Permethrin-treated clothing.
• Environmental:
  • Larvicides in rice paddies (difficult due to scale).
  • Pig Vaccination: Vaccinating pigs interrupts the amplification cycle. (Used in Japan/Korea but expensive).
  • Pig Segregation: Moving pig sties away from human habitation (e.g. >2km).
  • Alternate Wetting and Drying (AWD): An agricultural technique for rice that reduces mosquito breeding by periodically drying the fields (kills larvae) without harming the crop.

2. Vaccination Strategies

Two main types of vaccines are available globally.

Other Vaccines:

• IMOJEV (Sanofi): A Chimeric vaccine (Yellow Fever backbone with JE envelope). Used in Australia/Thailand. Single dose. High efficacy.
• Mouse Brain Vaccines (Nakayama strain): Older generation (JE-VAX). Discontinued due to risk of ADEM (Acute Disseminated Encephalomyelitis) and hypersensitivity.

3. Vaccination Guidelines (ACIP / WHO)

Who Should Be Vaccinated?

1. Residents of endemic areas (included in childhood EPI in many countries like Thailand, China, but not India universally).
2. Travellers:
   • Spending > 1 month in endemic areas.
   • Visiting rural areas (Rice paddies/Farms) regardless of duration.
   • During outbreaks.
   • Long-term expatriates.

Special Populations

• Pregnancy:
  • Inactivated (Ixiaro): Theoretical risk low, but lack data. Use only if risk of infection outweighs risk of vaccine (e.g., unavoidable outbreak exposure).
  • Live (SA 14-14-2): Contraindicated.
• HIV/Immunocompromised:
  • Avoid Live vaccines. Use Inactivated (Ixiaro).
• Children:
  • Ixiaro is approved from 2 months of age (Lower dose 0.25ml for <3 years).

5. Travel Risk Assessment Framework

Clinicians should use a systematic approach to advise travellers.

Step 1: Destination Risk

• High Risk: Rural areas of Hyper-endemic countries (India - UP/Bihar, Nepal - Terai, Vietnam - North, Thailand - North).
• Moderate Risk: Peri-urban areas or countries with good control (China, Japan, South Korea).
• Low Risk: Urban business travel (Tokya, Seoul, Bangkok, Singapore - eradicated).

Step 2: Seasonality

• Temperate Zones (China, Japan, Korea, Nepal, North India): Transmission is seasonal (May to October).
  • Action: Vaccine highly recommended if travelling during these months.
• Tropical Zones (Indonesia, Malaysia, Philippines, South Vietnam, South Thailand): Transmission is year-round.
  • Action: Risk is constant. Vaccine recommended for long stays at any time.

Step 3: Duration & Activity ("The Probability Equation")

• Risk = (Probability of Bite) x (Duration of Exposure).
• Short Duration (< 1 month):
  • Standard Tourist: (Hotel, Beach, City) -> Risk is negligible. Vaccine not routinely recommended.
  • Adventure Traveller: (Camping, Trekking, Cycling, Homestays) -> High exposure to evening mosquitoes. Vaccine recommended even for short trips (e.g., 2 weeks).
  • Expatriate: (Living in city but weekend trips to country) -> Vaccine recommended.

Step 4: Decision Matrix

6. Vaccine Administration Details

• Dosing:
  • Adults: 0.5ml IM (Deltoid).
  • Children (2m - 3y): 0.25ml IM (Anterolateral Thigh).
• Interactions: Can be given with Hep A, Typhoid, Rabies.
• Booster: A single booster dose at 12-24 months induces long-term immunity (likely > 10 years). JE cannot be eradicated from humans alone because of the animal reservoir.
• Surveillance: Monitoring seroconversion in Sentinel Pigs or Chickens. When pigs show IgM, human outbreaks follow in 2-3 weeks. (Early Warning System).
• Agricultural Reform: Promoting AWD irrigation (kills larvae).
• Pig Husbandry: Separating pigs from human dwellings.

7. Procedure Detail: JE Vaccination Administration

Correct administration ensures maximum immunogenicity and minimizes adverse events.

1. Preparation

• Cold Chain: Storage between 2°C and 8°C. Do NOT Freeze. Freezing destroys the potency (especially adjuvanted vaccines).
• Inspection:
  • Ixiaro: Should be a clear liquid with a white precipitate. Shake vigorously to obtain a uniform white suspension.
  • SA 14-14-2: Lyophilized powder. Reconstitute with supplied diluent only. Use within 1 hour.

2. Injection Technique

• Site:
  • Adults/Children > 1y: Deltoid muscle (Upper arm).
  • Infants (2m - 12m): Anterolateral aspect of the thigh (Vastus Lateralis).
  • Avoid: Gluteal region (Buttock) – decreased absorption into fat reduces efficacy.
• Method: Intramuscular (IM). Needle length 25mm (1 inch).

3. Post-Vaccination Care

• Observation: Monitor for 15 minutes for immediate anaphylaxis (rare but possible).
• Common Side Effects:
  • Pain/Redness at site (20-30%).
  • Headache/Myalgia (10-20%).
  • Fever (< 5%).
• Advice: Paracetamol is safe for symptomatic relief.

Mortality and morbidity are high. The "Rule of Thirds" applies:

• 1/3 Die: Usually in the acute phase from raised ICP or Status Epilepticus.
• 1/3 Survive with Severe Sequelae: Permanent brain damage.
• 1/3 Recover Fully: Though subtle cognitive deficits often persist.

Neurological Sequelae (The "Post-Encephalitic Syndrome")

1. Cognitive: Intellectual disability (IQ loss), learning difficulties, behavioural aggression (frontal lobe damage).
2. Motor:
   • Parkinsonism: Tremor, rigidity, bradykinesia (Thalamic/Basal Ganglia damage).
   • Paralysis: Hemiplegia or Monoplegia.
3. Seizures: Post-encephalitic epilepsy requires long-term anticonvulsants.

Rehabilitation Protocol (The Long Road)

Recovery is slow and often incomplete. A multidisciplinary approach is vital.

1. Physiotherapy (Motor)

• Tone Management:
  • Survivors often have dystonia and spasticity (mixed picture).
  • Interventions: Daily stretching, splinting (to prevent contractures), and Botulinum Toxin injections for focal spasticity.
• Mobility:
  • Early mobilization to prevent orthostatic pneumonia.
  • Gait re-training (often dealing with circumduction or scissoring gait).

2. Speech & Language Therapy (Bulbar)

• Dysphagia: Common due to brainstem involvement.
  • Assessment: Videofluoroscopy (Modified Barium Swallow).
  • Management: Thickeners, Texture modification, or PEG feeding if aspiration risk remains high.
• Dysarthria: "Scanning speech" or hypophonia (Parkinsonian) requires vocal exercises.

3. Occupational Therapy (Cognitive)

• Executive Function: Many children suffer from frontal lobe syndrome (Impulsivity, Poor planning).
• School Reintegration: Special educational needs (SEN) support is almost always required.
• ADLs: Adaptive equipment for feeding/dressing if fine motor skills (tremor) are affected.

4. Neuropsychiatry

• Behavioural Issues: Aggression and emotional lability are distressing for families.
• Management: Behavioural therapy + SSRIs or low-dose antipsychotics (Risperidone) for severe aggression.

Liverpool Outcome Score (for assessing disability)

Used to grade recovery at discharge and 6 months:

• Score 5: Full recovery.
• Score 4: Minor sequelae (independent).
• Score 3: Moderate sequelae (needs help with severe ADLs).
• Score 2: Severe sequelae (bedridden/dependent).
• Score 1: Death.

Public Health Burden

• Disability Adjusted Life Years (DALYs): In 2011, JE caused an estimated 709,000 DALYs globally.
• Economic Impact: Care for a survivor with severe sequelae costs >20x the GDP per capita in endemic countries.
• Cost-Effectiveness: Vaccination is highly cost-effective ($0.50/dose for SA 14-14-2) compared to acute care and lifelong disability support.

Key Guidelines

1. World Health Organization (WHO): Position Paper on JE Vaccines (Feb 2015). Recommends integration into national immunization programs in endemic areas.
2. CDC (USA): Yellow Book 2024 - Japanese Encephalitis Chapter.
3. ACIP (Advisory Committee on Immunization Practices): Recommendations for use of JE vaccines in travellers.

Landmark Studies

• Halstead et al. (1960s): Defined the transmission cycle involving birds and pigs.
• Hoke et al. (1988): The landmark efficacy trial of the inactivated vaccine (Biken) in Thailand. N=65,000. Efficacy 91%.
• Solomon et al. (2000s): Detailed the pathophysiology of neuroinvasion and the role of the thalamus.

Case 1: "The Rice Farmer's Child" (Classic Endemic)

History: A 5-year-old boy from rural Bihar (India) presents during monsoon season with 2 days of high fever and vomiting. This morning, he had a generalized tonic-clonic seizure. Exam: Comatose (GCS 7). Neck stiffness present. Generalized hypertonia (Rigidity). Investigations:

• CSF: Clear. WBC 80 (Lymphocytes). Protein 80. Glucose Normal.
• JE IgM in CSF: Positive. Outcome: Intubated for 5 days. Survived but developed severe dystonia and speech impairment. Learning Point: In endemic areas, Acute Encephalitis Syndrome (AES) in a child during monsoon is JE until proven otherwise.

Case 2: "The Backpacker" (Travel Medicine)

History: A 24-year-old British student returns from a 6-week volunteering trip in rural Vietnam. He did not get vaccinated "because it was too expensive". He presents with "flu" and confusion. Exam: Mask-like facies. Resting tremor in hands. Cogwheel rigidity in wrists. Diagnosis: Parkinsonian features in a febrile traveller = JE. MRI: Bilateral Thalamic hyperintensity. Outcome: Slow recovery over 6 months. Persistent emotional lability. Learning Point: Cost should not deter vaccination for high-risk itineraries.

Case 3: "The Misdiagnosis" (Rabies vs JE)

History: A 7yo girl presents with fever, agitation, and "strange behaviour". She is biting staff and is hydrophobic. Initial Thought: Rabies (Furious form). Prognosis fatal. Review: No history of dog bite. Parents mention pig farm nearby. Test: MRI shows Thalamic changes (JE) rather than Brainstem/Limbic changes (Rabies). JE IgM positive. Outcome: Supportive care. Survived. Learning Point: JE can present with severe agitation/psychosis mimicking rabies. Differentiation is vital as JE is survivable.

The "Iceberg" Analogy

Imagine Japanese Encephalitis like an iceberg.

• Underwater (The 99%): For every 250 people bitten by an infected mosquito, 249 will have NO symptoms or just a mild flu. They recover fully and don't even know they had it.
• The Tip (The 1%): 1 person will get the severe brain infection ("Encephalitis"). This is the dangerous part.

Why Pigs and Birds?

• The virus lives naturally in water birds (Herons).
• Mosquitoes bite the birds, then bite Pigs.
• Inside the pig, the virus multiplies into millions of copies. The pig is a "Virus Amplifier".
• If a mosquito bites that pig, it becomes a "Super-Spreader". If it then bites you, you get the virus.

FAQs

Q: Can I get it from another person? A: No. Humans are "dead-end hosts". The virus level in our blood is too low to infect a mosquito. You can touch, kiss, or care for a JE patient safely.

Q: Is there a cure? A: No. Antibiotics don't work (it's a virus). Antivirals don't work. We can only support the body (fluids, breathing machine) while the immune system fights it. This is why Vaccination is so important.

• 1871: "Summer Encephalitis" epidemics noted in Japan.
• 1924: The "Great Epidemic" in Japan (6,000 deaths).
• 1935: Virus isolated from the brain of a fatal case (Hayashi).
• 1938: Vaccine development began.
• 1950s: Discovery of the Pig-Mosquito cycle (Scherer et al).
• 2022: Virus spreads to Australia, declaring it a continent-wide threat.

High-Yield Board Exam Facts

1. Vector: Culex tritaeniorhynchus. (Remember: Culex = JE/West Nile. Aedes = Dengue/Zika. Anopheles = Malaria).
2. Reservoir: Ardeid Birds (Herons).
3. Amplifier: Pigs.
4. MRI Sign: Bilateral Thalamic Hyperintensity.
5. Clinical Sign: Parkinsonism (Cogwheel rigidity, Mask face).
6. Vaccine: IXIARO (Inactivated).

Clinical Signs to Look For

Common OSCE Stations

Station 1: Travel Medicine Counselling

• Scenario: 22yo student going to rural Thailand for 2 months. Asks if the £200 vaccine is worth it.
• Key Points:
  • Risk Assessment: Rural + Long Stay = High Risk.
  • Consequence: "If you get it, it's untreatable and often fatal."
  • Recommendation: Strongly advised.
  • Cost: "Is £200 worth protecting your brain?" (Sensitive but firm).

Station 2: Breaking Bad News

• Scenario: Parents of a 6yo boy with JE who is in a coma. MRI shows extensive thalamic damage.
• Key Points:
  • Prognosis: Be honest. "1/3 chance of death, 1/3 chance of survival with disability."
  • Sequelae: Prepare them for potential personality changes or learning difficulties if he wakes up.
  • Management: "We are doing everything to support him, but the virus has to run its course."

Viva Questions

Q: Why don't we cull the pigs to stop the spread? A: Pigs are a major economic source in Asia. Culling is not sustainable. Pig vaccination is a better strategy ("One Health" approach).

Q: Why is JE considered an "Iceberg" disease? A: Because <1% of infections are symptomatic. For every 1 encephalitis case, there are 250-500 asymptomatic seroconversions.

Q: Differentiate JE from Cerebral Malaria clinically. A: Malaria often presents with Splenomegaly, Retinopathy, and cyclical fever. JE presents with Parkinsonian signs (Rigidity, Tremor) which are absent in Malaria.