Encephalitis is the term used to describe an inflammatory process of the substance of the brain. This distinguishes it from meningitis which is an inflammatory process of the coverings of the brain. There are patients who have inflammation of both areas and this is described as meningo-encephalitis. Patients with encephalitis and those with meningitis present differently. The underlying causes of encephalitis are different from causes of meningitis. Encephalitis has many causes, as outlined below. The inflammatory process may be infectious in origin or non-infectious. Viral encephalitis is the commonest cause of infecious encephalitis. Non-infectious causes of encephalitis include autoimmune and paraneoplastic diseases.

Clinical features:

The cardinal symptom of encephalitis is confusion. In other words, encephalitis presents as a cause of encephalopathy. There is loss of attention, disorientation and in severe cases decreased level of consciousness. The encephalopathy is often accompanied by a fever, headache or a seizure. As a clinical pearl: the presence of fever in a patient with encephalopathy should always raise encephalitis in the differential diagnosis even though the eventual diagnosis may be a systemic infection.
When there is a high enough clinical suspicion of encephalitis, empiric therapy is often started with acyclovir for Herpes Simplex Virus (HSV) encephalitis while the investigations are being obtained for confirmation and for competing diseases. This is a clinical decision that is individualized based on potential benefits vs. risks.

Investigations to consider:


  • Patterns of disease on MRI may help narrow down the cause of encephalitis
  • To assess for competing causes (diseases other than encephalitis) in the differential diagnosis

CSF analysis:

  • Often abnormal, raised WCC, mildly elevated protein
  • Gram stain & culture
  • VDRL: syphilis
  • PCR: HSV, VZV, EBV, CMV, enterovirus, WNV, TB
  • Serology: WNV, VZV, measles
  • AFB & culture: TB
  • India ink: Cryptococcus
  • Cryptococcal antigen
  • CSF wet mount: Naegleria fowleri
  • IgG index

Electroencephalography, EEG:

  • May demonstrate slowing of background, dysregulation, Periodic Lateralized Epileptiform Discharges (PLEDs) or seizures

Blood tests:

  • LFTs: EBV, herpes viruses, Alpers syndrome
  • Amylase: mumps
  • Tests for infections:
    • Blood smear: atypical lymphocytes in EBV
    • Heterophil antibody: EBV
    • Cryptococcal antigen
    • Toxoplasma serology
  • Paraneoplastic antibodies/autoimmune antibodies: Anti-Hu (ANNA-1), CV2 (CRMP5), Ma2/Ta, amphiphysin, Yo, Ri, Zic4, voltage gated potassium channel (VGKC), anti-NMDA antibodies
  • Voltage-gated potassium channels (VGKC): autoimmune or paraneoplastic limbic encephalitis
  • POLG mutation analysis: mitochondrial disease

Brain biopsy in some cases
Muscle biopsy:

  • Mitochondrial DNA analysis for mitochondrial disease

Causes of encephalitis:

  • Viral encephalitis:
    • HSV1, HSV2, VZV, CMV, EBV
    • Measles, mumps
    • Polio, Rabies
    • Arboviruses: West nile virus, Japanese B encephalitis, St. Louis encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, and Venezuelan equine encephalitis virus, tick borne encephalitis viruses
    • Influenza A virus
  • Bacterial encephalitis:
    • Listeria monocytogenes (Listeria rhombencephalitis)
    • Mycobacterium tuberculosis
    • Other bacteria: Borrelia burgdorferi (Lyme disease), Mycoplasma pneumoniae, Leptospirosis, Brucellosis, Leptospirosis, Legionella, Tropheryma whippeli (Whipple’s disease), Nocardia actinomyces, Treponema pallidum, Salmonella typhi,
    • Rickettsial, Rickettsia rickettsia (Rocky Mountain spotted fever), Rickettsia typhi (endemic typhus), Rickettsia prowazeki (epidemic typhus), Coxiella burnetti (Q fever), Ehrlichiosis (Ehrlichia chaffeensis—human monocytic ehrlichiosis)
  • Fungal encephalitis:
    • Cryptococcus, Aspergillosis, Candidiasis
    • Coccidiomycosis, Histoplasmosis
    • North American blastomycosis
  • Parasitic:
    • Toxoplasma gondii
    • Cerebral malaria
    • Trypanosomiasis (sleeping sickness)
    • Echinococcus granulosus, Schistosomiasis
  • Non-infectious:

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