Introduction
- Inflammation of brain parenchyma, invariably associated with meningeal inflammation (meningoencephalitis).
- May involve spinal cord (encephalomyelitis) or nerve roots (radiculitis).
- Acute Encephalitis Syndrome (AES) WHO clinical case definition: Acute onset fever, change in mental status (confusion, disorientation, coma, inability to talk), and/or new onset seizures (excluding simple febrile seizures).
Etiology
- Causative agent unidentified in >70% cases despite extensive laboratory workup.
- Categorized based on occurrence pattern.
| Category | Etiologic Agents | Remarks |
|---|---|---|
| Sporadic | Herpes Simplex Virus (HSV-1, HSV-2) | Most common sporadic cause in developed countries. HSV-1 accounts for 90% in older children; HSV-2 in neonates/immunocompromised. |
| Mumps, Measles, Varicella Zoster (VZV) | Vaccine-preventable. Rare in industrialized nations. VZV associated with vasculitis/cerebellitis. | |
| Enteroviruses (Coxsackie, ECHO, EV71) | Peak in summer/fall. High incidence in children. | |
| Rabies, HIV, Cytomegalovirus (CMV) | CMV/HIV common in immunocompromised hosts. | |
| Epidemic | Japanese Encephalitis Virus (JEV) | Most common vaccine-preventable epidemic cause in Asia. Mosquito-borne (Culex). Pigs/birds are reservoirs. |
| Dengue, West Nile Virus (WNV) | Mosquito-borne flaviviruses. | |
| Kyasanur Forest Disease (KFD) | Tick-borne. Endemic to Karnataka forests (India). | |
| Eastern/Western Equine Encephalitis | Mosquito-borne alphaviruses. | |
| Emerging | Nipah Virus | Paramyxovirus. Endemic in Southeast Asia. Fruit bats reservoir. High mortality (40-70%). |
Pathogenesis and Pathology
- Infection pathway dictates pathological manifestations.
Mechanisms of Injury
- Primary: Direct invasion and replication of infectious agent in tissue leading to necrosis.
- Parainfectious: Immune-mediated injury with marked demyelination and relative preservation of neurons/axons (e.g., Acute Disseminated Encephalomyelitis - ADEM).
Specific Pathologic Signatures
- Arboviruses: Lymphocytic meningoencephalitis. Perivascular inflammatory cell accumulation. Single-cell neuronal necrosis with phagocytosis (neuronophagia). Microglial nodule formation.
- Herpes Simplex Virus: Necrotizing and hemorrhagic infection. Severe predilection for inferior and medial regions of temporal lobes, orbital gyri of frontal lobes, and insula. Cowdry type A intranuclear viral inclusion bodies present in neurons and glia.
- Rabies: Predilection for basal structures.
Clinical Features
- Highly variable clinical profile ranging from mild to rapidly fatal. Acute onset.
- Prodrome: Fever, headache, nausea, vomiting, lethargy.
- Cerebral Dysfunction:
- Sensorial alterations: Irritability, mental dullness, stupor, deep coma.
- Generalized or focal seizures.
- Focal neurological deficits: Hemiparesis, cranial nerve palsies, speech disturbance.
- Specific Viral Syndromes:
- HSV Encephalitis (HSE): Focal seizures and deficits common. Neonatal HSE presents with disseminated infection and liver involvement.
- Japanese Encephalitis: High-grade fever, signs of meningeal irritation, cranial nerve palsies, prominent extrapyramidal symptoms, generalized/focal seizures.
- Nipah Virus: Severe encephalitis, reduced consciousness, prominent brainstem dysfunction.
- Enterovirus: Aseptic meningitis, acute flaccid paralysis, brainstem encephalitis (EV71).
Differential Diagnosis
| Feature | Viral Encephalitis | Encephalopathy (Metabolic/Toxic) |
|---|---|---|
| Pathology | Infectious inflammation of neurons. | Non-infectious generalized dysfunction. |
| Causes | Viral direct invasion. | Hypoglycemia, diabetic ketoacidosis, hepatic/renal failure, toxins, Reye's syndrome. |
| CSF | Pleocytosis present. | Normal. No pleocytosis. |
| Neuroimaging | Focal changes on MRI. | Non-focal, generalized changes. |
| EEG | Focal slowing or discharges (e.g., PLEDs). | Generalized slowing. No focal features. |
- Other Differentials: Acute Pyogenic Meningitis, Tuberculous Meningitis, Cerebral Malaria, ADEM, Mass lesions, CNS Vasculitis.
Diagnostic Evaluation
Baseline Investigations
- Peripheral Smear: Relative lymphocytosis common. Leukopenia and thrombocytopenia suggest rickettsial infection or viral hemorrhagic fever.
- Blood Chemistry: Liver enzymes elevated in EBV/CMV. Hyponatremia suggests Syndrome of Inappropriate Antidiuretic Hormone (SIADH).
- Blood Culture/Widal: Exclude bacterial meningitis, brain abscess, enteric encephalopathy.
Cerebrospinal Fluid (CSF) Analysis
- Lumbar Puncture (LP) mandatory unless contraindicated (raised Intracranial Pressure/papilledema).
| Parameter | Finding in Viral Encephalitis | Remarks |
|---|---|---|
| Gross Appearance | Clear to turbid. | Hemorrhagic/bloody in HSE or acute necrotizing hemorrhagic leukoencephalitis. |
| Pressure | Normal or slightly elevated. | |
| Cells | Mild-moderate pleocytosis (5-1,000 cells/mm3). | Initially polymorphonuclear, later lymphocytic. |
| Glucose | Normal ratio (>50% of blood sugar). | Hypoglycorrhachia (low glucose) seen in mumps, or HSE (5-25%). |
| Protein | Mildly elevated (0.5 - 1.0 g/L). |
- Correction for Bloody Tap: Subtract 1 WBC per 700 RBCs, and 0.1 g/dL protein per 1000 RBCs.
Specific Viral Diagnosis
- Polymerase Chain Reaction (PCR): Investigation of choice for DNA/RNA viruses in CSF. Specificity 94%, Sensitivity 98%. Replaces brain biopsy for HSE diagnosis. Rapid turnaround. Sensitive even after short antiviral course.
- Serology: Detection of IgM antibody in serum/CSF via ELISA. Mainstay for Japanese Encephalitis diagnosis. Useful for Dengue, Leptospira.
- Viral Culture: Rarely useful. Low diagnostic yield (<5%).
Neuroimaging (MRI & CT)
- MRI is imaging modality of choice. Fluid-attenuation inversion recovery (FLAIR) and diffusion-weighted sequences are extremely sensitive for early detection. More sensitive than CT.
| Virus | Characteristic MRI Findings |
|---|---|
| HSV | Bilateral/unilateral temporal lobes, inferior frontal cortex, insula. Hemorrhagic/necrotic lesions. |
| JEV / Arboviruses | Basal ganglia, thalamus (characteristic "Panda sign" in Midbrain). |
| VZV | Ischemic, hemorrhagic infarctions, small infarcts mixed with demyelinating lesions (vasculitis). |
| Nipah Virus | Discrete focal lesions in subcortical and deep white matter. |
| Enterovirus | Hyperintense signals in brainstem (rhombencephalitis). |
Electroencephalography (EEG)
- Generally shows nonspecific, diffuse, high-amplitude slow waves.
- Periodic Lateralized Epileptiform Discharges (PLEDs): Characteristic in temporal lobes for HSV encephalitis, though non-specific.
Management
General Supportive Care
- ICU Admission: Mandatory for severe VE. Modified Glasgow Coma Scale monitoring.
- Cardiorespiratory Support: Intubation and ventilation required for deep coma or refractory seizures.
- Fluid & Electrolytes: Maintain nutrition and hydration. Implement fluid restriction for SIADH.
Management of Immediate Complications
- Raised Intracranial Pressure (ICP):
- Nurse with head elevated to 30°.
- Administer IV Mannitol, oral glycerol, or Dexamethasone to reduce cerebral edema.
- Maintain ICP < 15 mm Hg.
- Seizure Control:
- Lorazepam is initial anticonvulsant of choice.
- IV Phenytoin or Fosphenytoin for maintenance.
- Refractory status epilepticus requires Midazolam infusion or Propofol.
Specific Antiviral Therapy
- Administer empiric parenteral antibiotics (cephalosporin) until bacterial meningitis/brain abscess excluded.
- Acyclovir (for HSE and VZV):
- Initiate immediately upon suspicion of VE before etiological diagnosis.
- Reduces mortality and morbidity in HSE.
- Dose (Neonates & <3 months): 20 mg/kg/dose 8-hourly IV infusion for 21 days.
- Dose (3 months - 12 years): 500 mg/m2 8-hourly IV for 14-21 days.
- Dose (12 - 18 years): 10 mg/kg/dose 8-hourly IV for 14-21 days.
- Monitor renal function. Ensure adequate hydration. Oral route ineffective.
- Ganciclovir/Foscarnet: Indicated for CMV encephalitis.
- Pleconaril: Used for enteroviral encephalitis.
Role of Corticosteroids
- Controversial in routine viral encephalitis.
- Efficacious in VZV encephalitis (reduces vasculitic component), ADEM, and in management of severe cerebral edema.
Prognosis and Rehabilitation
- Extent of permanent brain injury depends on age, immune status, and specific pathogen.
- HSE: Mortality in untreated cases ~70%. Two-thirds of survivors suffer significant neuropsychiatric sequelae (memory impairment, dysphasia, behavioral changes, epilepsy).
- JEV: Case-fatality ratio 20-30%. Significant neurological/cognitive sequelae in 30-50% survivors.
- Rehabilitation: Requires multidisciplinary approach involving pediatrician, pediatric neurologist, physiotherapist, speech therapist, and psychiatrist.
Prevention
- Vaccination:
- Universal immunization against Measles, Mumps, Rubella (MMR), Polio.
- Japanese Encephalitis: Inactivated mouse brain vaccine (Nakayama strain), Killed primary hamster kidney cell vaccine, Live SA-14-14-2 vaccine. Administer to populations in endemic/epidemic zones.
- Vector and Environmental Control (Arboviruses):
- Personal: Mosquito repellents, long-sleeved clothing, impregnated bednets.
- Environmental: Aerial/ground fogging with ultra-low volume insecticides (malathion/fenitrothion) in 2-3 km radius of infected area. Segregation of pigs from human dwellings.