Japanese Encephalitis - Flowchart Note

1. AGENT & TRANSMISSION

Causative Agent
└── Japanese Encephalitis Virus (JEV)
    ├── Family: Flaviviridae, Genus: Flavivirus
    └── RNA virus (same family as Dengue, Zika, West Nile)

Vector
└── Culex tritaeniorhynchus mosquito
    ├── Ground-dwelling; breeds in flooded rice fields
    └── Peak biting: dusk to dawn (outdoors)

Transmission Cycle
Amplifying Hosts ──────────────────────────────────────────────┐
(Pigs + Wading Birds/Ducks)                                    │
        ↑          ↓                                            │
   Culex mosquito ← bites ← Pig/Bird (high viremia)            │
        │                                                       │
        ↓ bites human (DEAD-END HOST)                           │
       Human (low viremia - cannot amplify)

2. PATHOGENESIS

Infected Mosquito Bite
        │
        ▼
Virus replicates in SKIN
        │
        ▼
Spreads to Draining Lymph Nodes + Spleen
        │
        ▼
PRIMARY VIREMIA
(usually sub-clinical - most infections stop here → asymptomatic)
        │
        ▼ (in ~0.5% of infections)
SECONDARY VIREMIA
        │
        ▼
End-Organ Invasion
├── Brain (thalamus, basal ganglia, midbrain, cerebellum)
└── Spinal Cord
        │
        ▼
Apoptotic cell death + Inflammatory immune response
        │
        ▼
ENCEPHALITIS / MENINGOENCEPHALITIS

Only 1 in 200 infections results in severe disease. The majority are asymptomatic.

3. CLINICAL SPECTRUM

Incubation Period: 6-16 days
        │
        ▼
┌──────────────────────────────────────────────────────────────┐
│                     CLINICAL SPECTRUM                        │
├──────────────────────────────────────────────────────────────┤
│ ASYMPTOMATIC ──── Most common (>99% of infections)           │
│                                                              │
│ MILD FEBRILE ILLNESS                                         │
│  └── Fever, headache, nausea, vomiting, abdominal pain       │
│                                                              │
│ ASEPTIC MENINGITIS                                           │
│  └── Meningismus without brain parenchymal involvement       │
│                                                              │
│ ENCEPHALITIS (Severe, ~0.5%)                                 │
│  ├── Prodrome (2-4 days): Fever, headache, drowsiness        │
│  ├── Excitability / Delirium                                 │
│  ├── Seizures (common, especially in children)               │
│  ├── Hyperthermia                                            │
│  ├── Expressionless facies + Axial rigidity                  │
│  ├── Limb tremors + Myoclonus                                │
│  ├── Erratic eye movements + Cranial nerve palsies           │
│  ├── Ataxia (cerebellar)                                     │
│  ├── Limb paresis (LMN-type weakness)                        │
│  └── Coma → Death                                            │
└──────────────────────────────────────────────────────────────┘

4. DIAGNOSIS

Clinical Suspicion (endemic area + encephalitis)
        │
        ▼
┌─────────────────────────────────────────┐
│          INVESTIGATIONS                 │
├─────────────────────────────────────────┤
│ Blood:                                  │
│  └── JEV-specific IgM ELISA (serum)     │
│       Detectable by Day 7 of illness    │
│                                         │
│ Lumbar Puncture (CSF):                  │
│  ├── Pleocytosis: 10-500 WBC/μL         │
│  │    (early: PMN; late: lymphocytes)   │
│  ├── Protein: 50-100 mg/dL (elevated)   │
│  ├── Glucose: NORMAL                    │
│  └── JEV IgM ELISA in CSF              │
│       Sensitivity 65-70%, Spec 90-100%  │
│                                         │
│ MRI Brain:                              │
│  └── T2 hyperintensity in THALAMUS      │
│       (also: basal ganglia, midbrain,   │
│        cerebellum)                      │
│                                         │
│ Gold Standard:                          │
│  └── Plaque Reduction Neutralization   │
│       Test (PRNT)                       │
│  OR 4-fold rise in IgG titer            │
│                                         │
│ Early disease:                          │
│  └── RT-PCR (blood/CSF - detects        │
│       virus before antibody appears)    │
└─────────────────────────────────────────┘

5. TREATMENT

NO SPECIFIC ANTIVIRAL THERAPY AVAILABLE

(Interferon alfa-2a failed in RCT - no benefit on mortality or sequelae)

SUPPORTIVE CARE ONLY:
├── Control seizures (anticonvulsants)
├── Manage raised intracranial pressure
├── Airway and respiratory support (if comatose)
└── Prevention of secondary infections

6. PROGNOSIS

Case Fatality Rate: 20-30%
        │
        ├── Poor prognosis: prolonged fever, seizures, coma,
        │    high CNS viral load
        │
        └── Survivors (30-50% have long-term neurological sequelae):
             ├── Parkinsonism
             ├── Seizure disorders
             ├── Paresis / Paralysis
             ├── Cognitive impairment / Mental retardation
             └── Neuropsychiatric disorders

7. PREVENTION & CONTROL

PRIMARY PREVENTION
├── VACCINATION (most effective)
│    ├── Live-attenuated vaccine
│    ├── Recommended: Children 1-15 years (endemic areas)
│    ├── Travelers: 2 doses at Day 0 and Day 28
│    └── Highly efficacious even after first dose
│
├── VECTOR CONTROL
│    ├── Larvivorous fish in breeding sites
│    ├── Outdoor fogging with malathion (outbreaks)
│    └── NOT indoor residual spray (vectors are outdoor resters)
│
└── PERSONAL PROTECTION
     ├── Bed nets (dusk to dawn)
     ├── Protective clothing (full body cover)
     └── Keep pigs away from human dwellings

SECONDARY PREVENTION
├── Early diagnosis and case management
├── Sentinel surveillance at tertiary hospitals
└── Health education / community awareness

QUICK SUMMARY TABLE

RABIES - A Comprehensive Note

1. AGENT & EPIDEMIOLOGY

2. TRANSMISSION

ANIMAL (infected) ──bite──► HUMAN
                             OR
                  ──scratch──► HUMAN (if saliva contacts wound)
                             OR
           ──mucous membrane exposure──► HUMAN
                             OR
           ──organ/tissue transplant──► HUMAN (rare)
                             OR
           ──aerosol (lab/cave exposure)──► HUMAN (very rare)

❌ Human-to-human transmission is NOT documented (except organ transplant)
⚠️ Bat bites may be unrecognized (tiny puncture wounds)

3. PATHOGENESIS

① Virus inoculated at bite site (skin/subcutaneous tissue)
        │
        ▼
② Viral replication in MUSCLE (days to weeks, near the bite site)
        │
        ▼
③ Virus binds nicotinic acetylcholine receptors
   at neuromuscular junctions
        │
        ▼
④ Retrograde fast axonal transport along peripheral nerves
   (centripetal spread, ~250 mm/day; 12-hr delay at each synapse)
        │
        ▼
⑤ Replication in spinal cord motor neurons +
   Dorsal root ganglia → rapid ascent to brain
        │
        ▼
⑥ Brain infection → Neuronal dysfunction
   (brainstem, limbic system maximally affected)
        │
        ▼
⑦ Centrifugal spread along autonomic/sensory nerves
   → Salivary glands, skin, cornea, heart, adrenal glands
   → Virus shed in SALIVA (enables transmission)

Key concept: The long incubation period is because the virus stays near the bite site for most of the incubation period - this is the window for effective PEP.

• Negri bodies - eosinophilic cytoplasmic inclusions in neurons (especially Purkinje cells of cerebellum and pyramidal cells of hippocampus) - pathognomonic
• Babes nodules - microglial nodules in CNS parenchyma
• Surprisingly mild degenerative neuronal changes despite fatal outcome
• Neuronal dysfunction (not death) drives clinical disease

4. CLINICAL STAGES

┌────────────────────────────────────────────────────────────────┐
│ STAGE 1: INCUBATION PERIOD                                     │
│ Duration: Usually 20-90 days (range: days to >1 year)          │
│ Symptoms: NONE                                                  │
│ Shorter with: multiple bites, facial bites, deep wounds        │
└─────────────────────────┬──────────────────────────────────────┘
                          │
                          ▼
┌────────────────────────────────────────────────────────────────┐
│ STAGE 2: PRODROME                                              │
│ Duration: 2-10 days                                            │
│ ├── Fever, malaise, headache, anorexia, nausea, vomiting       │
│ ├── Anxiety / agitation                                        │
│ └── PATHOGNOMONIC: Paresthesias, pain, or PRURITUS             │
│      at/near the BITE SITE (50-80% of patients)                │
│      (due to infection of dorsal root/cranial sensory ganglia) │
└─────────────────────────┬──────────────────────────────────────┘
                          │
                          ▼
┌────────────────────────────────────────────────────────────────┐
│ STAGE 3: ACUTE NEUROLOGICAL PHASE                              │
│                                                                │
│ TWO FORMS:                                                     │
│                                                                │
│ A. ENCEPHALITIC / FURIOUS RABIES (~80%)                        │
│    ├── Agitation, hyperexcitability, combativeness             │
│    ├── Hallucinations, confusion, seizures                     │
│    ├── Fever (may reach 105-107°F)                             │
│    ├── HYDROPHOBIA - involuntary painful contraction of        │
│    │    pharynx/larynx/diaphragm on swallowing water           │
│    │    (due to brainstem dysfunction)                         │
│    ├── AEROPHOBIA - same spasms triggered by a draft of air    │
│    ├── "Foaming at the mouth" (hypersalivation + pharyngeal    │
│    │    dysfunction)                                           │
│    ├── Autonomic hyperactivity:                                │
│    │    ├── Hypersalivation, gooseflesh                        │
│    │    ├── Cardiac arrhythmias, priapism                      │
│    │    └── SIADH or Diabetes insipidus                        │
│    └── Episodes of lucidity between hyperexcitability          │
│         (become shorter as disease progresses)                 │
│                                                                │
│ B. PARALYTIC / DUMB RABIES (~20%)                              │
│    ├── Flaccid muscle weakness (LMN type)                      │
│    ├── Begins in bitten limb → spreads to quadriparesis        │
│    ├── Facial weakness common                                  │
│    ├── Sphincter involvement                                   │
│    ├── NO hydrophobia / aerophobia                             │
│    ├── Mimics Guillain-Barré syndrome                          │
│    └── Survives a few days longer than encephalitic form       │
└─────────────────────────┬──────────────────────────────────────┘
                          │
                          ▼
┌────────────────────────────────────────────────────────────────┐
│ STAGE 4: COMA                                                  │
│ ├── Cardiopulmonary failure                                    │
│ ├── Noncardiogenic pulmonary edema                             │
│ ├── GI hemorrhage                                              │
│ └── DEATH (virtually 100% fatal once symptoms appear)          │
└────────────────────────────────────────────────────────────────┘

5. DIAGNOSIS

CLINICAL SUSPICION
(encephalitis + animal bite history + hydrophobia/aerophobia)
        │
        ▼
┌────────────────────────────────────────────────────────────────┐
│                      INVESTIGATIONS                            │
├────────────────────────────────────────────────────────────────┤
│ CSF:                                                           │
│  ├── Mild mononuclear pleocytosis (<100 WBC/μL) in >50%       │
│  ├── Mildly elevated protein                                   │
│  └── Glucose: NORMAL                                           │
│      (Severe pleocytosis >1000 → look for alternate diagnosis) │
│                                                                │
│ Imaging (CT/MRI):                                              │
│  ├── CT head: Usually NORMAL                                   │
│  └── MRI: T2/FLAIR signal in brainstem, basal ganglia,        │
│       thalamus, midbrain (variable; nonspecific)               │
│                                                                │
│ Specific Tests:                                                │
│  ├── RT-PCR: saliva, CSF, skin biopsy, brain tissue           │
│  ├── Skin biopsy (nape of neck): Rabies antigen in            │
│  │    sensory nerve endings (immunofluorescence/               │
│  │    immunohistochemistry)                                    │
│  ├── Serum/CSF IgM/IgG antibodies                             │
│  │    (not detectable until 2nd week; patient may die first)   │
│  └── Brain biopsy/autopsy: Negri bodies (H&E stain);          │
│       immunofluorescence (more sensitive)                      │
└────────────────────────────────────────────────────────────────┘

6. POST-EXPOSURE PROPHYLAXIS (PEP)

PEP is effective when started promptly BEFORE symptoms develop.

EXPOSURE OCCURS
        │
        ▼
STEP 1: WOUND CARE (IMMEDIATE - most important first step)
        ├── Wash wound thoroughly with soap and water (≥15 min)
        ├── Apply povidone-iodine or alcohol
        └── Do NOT suture primarily (if possible)
        │
        ▼
STEP 2: ASSESS RISK (Was the animal rabid? Vaccine status?)
        │
        ▼
STEP 3: PASSIVE IMMUNIZATION
        └── Rabies Immunoglobulin (RIG)
             ├── Human RIG (HRIG): 20 IU/kg
             └── Equine RIG (ERIG): 40 IU/kg
             Inject as much as possible INTO and AROUND wound
             Remainder given IM at distant site
             Given ONLY on Day 0 (with 1st vaccine dose)
        │
        ▼
STEP 4: ACTIVE IMMUNIZATION (Rabies Vaccine)
        └── 4-dose regimen (post-2010):
             Day 0 → Day 3 → Day 7 → Day 14
             (Previously 5-dose; 4-dose is now standard)
             IM into deltoid (NOT gluteal region)

        ⚠️ Previously vaccinated individuals:
             → Give vaccine on Day 0 and Day 3 ONLY
             → NO RIG needed

7. PRE-EXPOSURE PROPHYLAXIS (PrEP)

3 doses: Day 0 → Day 7 → Day 21 or Day 28

Even after PrEP, if exposed: still need 2 booster doses (Day 0 + Day 3)
NO RIG required after pre-exposure vaccination

8. TREATMENT (Once Symptomatic)

NO PROVEN SPECIFIC TREATMENT

Antiviral attempts (ribavirin, interferon-alpha): FAILED
Milwaukee Protocol (therapeutic coma): 1 survivor reported;
    subsequent attempts → fatal outcome

Management = PALLIATIVE / SUPPORTIVE CARE only:
├── Seizure control
├── Sedation for agitation
├── Airway management
├── Cardiovascular support
└── Minimize patient suffering

9. PREVENTION (Public Health)

├── DOG VACCINATION (mass campaigns) - single most effective measure
├── Animal bite surveillance and stray dog control
├── Pre-exposure vaccination of high-risk groups
├── Post-exposure prophylaxis for ALL exposures
├── Public health education: seek care after animal bites
└── Avoid handling wild animals / bats

QUICK REFERENCE SUMMARY