Viral Encephalitis

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.