Etiology

An etiologic agent is only identified in around 50% of cases.[6][7][21][22][23][24][25]

Viruses are the main identified cause of encephalitis, with herpes simplex virus (HSV) being the most commonly identified globally.[26]​ Japanese encephalitis (JE) is an important viral cause in Asia, particularly in rural and suburban areas where pigs are thought to act as amplifier hosts.[27]​ The global incidence of JE is unknown.[28] In the US, West Nile virus is a consideration for patients with encephalitis; it is a leading cause of domestically acquired arboviral disease with over 60% of West Nile virus cases in the US reported as encephalitis in 2021.[29]​ Other arboviruses (ARthropod-BOrne viruses) with ticks and mosquitoes as vectors are a main contributor to encephalitic etiologies worldwide. CDC: Division of vector-borne diseases (DVBD) Opens in new window

The incidence of encephalitis in patients with HIV has improved since the advent of highly active antiretroviral therapy, mainly manifested by a decrease in incidence of toxoplasma encephalitis. Neisseria meningitides is the main bacterial cause of meningoencephalitis and disproportionately affects the young (<1 year old) and old (>65 years old).[7]

Immune-mediated or autoimmune encephalitis remains relatively rare, despite accounting for approximately one third of cases with identified etiology. Incidence is increasing, likely due to the widening availability of diagnostic testing, growing number of identified antibodies and more awareness among clinical practitioners.[6][30]​ It can be associated with a preceding infection or a presence of an underlying malignancy. In adults, anti-NMDAR antibodies are the most common cause of autoimmune encephalitis, and typically associated with the presence of ovarian teratoma.[31]​ Acute disseminated encephalomyelitis (ADEM) is thought to be a post-infectious response, and is a common cause of autoimmune encephalitis in children.

The following is a list of the main etiologic agents in encephalitis.

Viral infections:

  • Herpes viruses: herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus-6, herpes B virus

  • Picornaviridae/enteroviruses: enterovirus-71, coxsackievirus, poliovirus

  • Parechovirus

  • Flaviviruses: West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, Powassan virus, dengue virus

  • Bunyavirus: La Crosse virus, Jamestown Canyon virus, Toscana virus

  • Togavirus: chikungunya virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus, Eastern equine encephalitis virus

  • Paramyxovirus: Nipah virus, Hendra virus

  • Others: coronaviruses, snowshoe hare virus, lymphocytic choriomeningitis virus, mumps virus, HIV, rabies virus, measles virus, adenovirus, influenza virus, parainfluenza virus, hepatitis C virus, rotavirus, parvovirus B19, BK virus, JC virus, cycloviruses, and Zika.

Bacterial infections:

  • Neisseria meningitidis

  • Tuberculosis

  • Treponema pallidum (syphilis)

  • Listeria

  • Bartonella (cat-scratch disease)

  • Borrelia burgdorferi (Lyme disease)

  • Rickettsia and ehrlichiosis (Rocky Mountain spotted fever, Ehrlichia, Coxiella burnetii)

  • Mycoplasma

  • Typhoid fever

  • Brucellosis

  • Leptospirosis

  • Tropheryma whipplei (Whipple disease)

  • Actinomyces

  • Streptococcus agalactiae

  • Klebsiella

  • Streptococcus pneumoniae

  • Staphylococcus aureus

  • Streptococcus viridans

  • Group C beta-hemolytic streptococci

  • Nocardia.

Fungal infections:

  • Cryptococcus

  • Coccidioides

  • Histoplasma

  • Blastomycosis

  • Candida.

Parasitic infections:

  • Toxoplasma gondii

  • Cysticercosis

  • Naegleria fowleri

  • Entamoeba histolytica

  • Plasmodium falciparum

  • Balamuthia mandrillaris

  • Baylisascaris procyonis

  • Echinococcus granulosis

  • Human African trypanosomiasis

  • Schistosomiasis

  • Angiostrongylus cantonensis.

Parainfectious:

  • ADEM

  • Acute hemorrhagic leukoencephalitis

  • Bickerstaff encephalitis

  • Rasmussen encephalitis.

Prion diseases:

  • Creutzfeldt-Jakob disease.

Paraneoplastic syndromes:

  • "Classical" antibodies against intracellular onconeuronal antigens (e.g., anti-Hu, anti-Yo)

  • Surface antibodies targeting neuronal surface or synaptic antigens (e.g., N-methyl-D-aspartate receptor-antibody and leucine-rich glioma inactivated-antibody).

Pathophysiology

Encephalitis is an inflammatory process in the brain parenchyma. It is associated with clinical evidence of brain dysfunction due to infectious (usually viral) or noninfectious (usually autoimmune) processes. The pattern of brain involvement depends on the specific pathogen, the immunologic state of the host, and a range of environmental factors. In viral encephalitis, the virus initially gains entry and replicates in local or regional tissue, such as the gastrointestinal tract, skin, urogenital system, or respiratory system. Subsequent dissemination to the central nervous system occurs by hematogenous routes (including enterovirus, arboviruses, herpes simplex virus, HIV, mumps) or via retrograde axonal transport, as with the herpes virus, the rabies virus, or variant scrapie-isoform prion proteins.

Depending on the interactions between the neurotropic properties of the virus and the host immune response (mediated by humoral antibodies, cytotoxic T cells, cytokines, innate immunity of each neuronal subtype), infection and inflammation of brain parenchyma occur.[32] In these cases, neuronal involvement occurs along with evidence of a productive viral infection. In contrast, autoimmune etiologies are thought to result from antibodies or T-cells directed against normal brain antigens, which play a role in anti-N-methyl-D-aspartate (NMDA) receptor encephalitis and other paraneoplastic syndromes. Given the immune-mediated pathophysiology of autoimmune encephalitis, these conditions are typically amenable to immunosuppressive therapy.

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