History and exam
Key diagnostic factors
common
presence of risk factors
Key risk factors include: age under 1 or over 65 years, immunodeficiency, viral infections, body fluid exposure, organ transplantation, animal or insect bites, location, and season.
fever
Frequently seen in infectious causes of encephalitis.[13] Important exceptions are immunocompromised patients (who may not be able to mount a fever response) as well as individuals with measles causing subacute sclerosing panencephalitis, varicella zoster virus infection, and hepatitis C.
rash
Vesicular eruption - enterovirus, herpes simplex virus (HSV), varicella zoster virus.
Maculopapular eruption - Epstein-Barr virus (after treatment with ampicillin), measles, human herpesvirus-6, Colorado tick fever, West Nile virus.
Malar rash - systemic lupus erythematosus.
Petechial rash - rickettsial fever.
Erythema migrans - Lyme disease.
Erythema nodosum - tuberculosis and histoplasmosis, sarcoidosis.
Erythema multiforme - HSV, Mycoplasma.
Mucous membrane lesions - herpes virus, Behcet's.
Pharyngitis - enterovirus, adenovirus.
Conjunctivitis - St. Louis encephalitis virus, adenovirus, leptospirosis (conjunctival suffusion).
Gumma - syphilis.
Kaposi's sarcoma - HIV/AIDS.
Non-healing skin lesions - Balamuthia mandrillaris, Acanthamoeba.
Genital lesions - HSV-2, Behcet's.
Lesions on the hands, feet and mouth - enteroviral infections (e.g., enterovirus 71).
altered mental state
A frequent component.[13] Alterations in higher mental function include lethargy, drowsiness, confusion, disorientation.[13]
Cognitive dysfunction with acute memory disturbances and psychiatric and behavioural manifestations (e.g., withdrawal, apathy, abulia, akinetic mutism, personality changes, psychotic behaviour, disorientation, and hallucinations) can be seen.
focal neurological deficit
These include aphasia, hemianopia, hemiparesis, ataxia, brisk tendon reflexes, Babinski's sign, cranial nerve deficits (seen in human herpesvirus-6, tuberculosis, syphilis, brucellosis, acute disseminated encephalomyelitis, West Nile virus, St. Louis encephalitis virus, varicella zoster virus, herpes B virus, rabies); tremors (arboviruses); myoclonus (subacute sclerosing panencephalitis); paraesthesias (Colorado tick fever, rabies); generalised weakness (West Nile virus, rabies).
meningismus
Some patients have evidence of meningeal inflammation with headache, photophobia, and neck stiffness.
uncommon
parotitis
Seen in mumps.
lymphadenopathy
Seen in Bartonella.
optic neuritis
Seen in acute disseminated encephalomyelitis.
acute flaccid paralysis
West Nile virus and other arboviruses, rabies.[13]
movement disorder
Creutzfeldt-Jakob disease (myoclonus), anti-N-methyl-D-aspartate receptor encephalitis (orofacial dyskinesias/myorhythmia), rabies, Whipple disease (oculomasticatory myorhythmia).
Other diagnostic factors
common
cough
Upper and lower respiratory tract symptoms and signs (e.g., cough) can occur in herpes simplex virus-1, influenza, parainfluenza, Mycoplasma pneumoniae, Q fever, Coccidioides, Histoplasma, blastomycosis, or rabies.
gastrointestinal infection
Enteroviruses, rotavirus, Whipple's disease.
seizures
Generalised tonic-clonic seizures and focal seizures (with or without secondary generalisation) are very frequently seen at some point in the clinical course. Most frequently seen in patients with measles causing subacute sclerosing panencephalitis, human herpesvirus-6 infection, and herpes simplex virus-1 infection. Status epilepticus that is particularly resistant to treatment is sometimes seen.[48] Faciobrachial dystonic seizures (e.g., rapid jerks of the face and/or ipsilateral arm and shoulder) are seen in limbic encephalitis associated with leucine-rich glioma-inactivated 1 antibodies.[49]
uncommon
biphasic illness
Enterovirus, Colorado tick fever.
autonomic and hypothalamic disturbances
Loss of temperature and vasomotor control (dysautonomia), diabetes insipidus, and syndrome of inappropriate secretion of antidiuretic hormone are sometimes part of the clinical picture in encephalitis and can contribute to morbidity and mortality.
Seen in anti-N-methyl-D-aspartate receptor encephalitis and anti-voltage gated potassium channel encephalitis.
myocarditis/pericarditis
Enterovirus, mumps, Chagas disease.
jaundice
May be seen in leptospirosis.
arthritis
Seen in Lyme disease, systemic lupus erythematosus.
retinitis
Cytomegalovirus, toxoplasmosis, West Nile virus, paraneoplastic syndrome.
parkinsonism
Arbovirus, toxoplasmosis.
Risk factors
strong
age <1 or >65 years
Increased risk of developing more extensive and prominent symptoms and signs of infective (viral) encephalitis.
Neonates are especially susceptible to infectious encephalitis.
Older individuals are at higher risk due to both weaker immune system as well as higher likelihood of malignancy.
immunodeficiency
Aetiological agent and clinical severity varies with host immune status.
Immunocompromised patients (e.g., patients with HIV infection and those receiving chemotherapy or immunosuppressive medications) tend to have more extensive and florid manifestations. They are susceptible to pathogens that usually do not cause encephalitis in immunocompetent hosts (e.g., cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, toxoplasmosis, JC virus, Candida, and Nocardia). Agammaglobulinaemic patients are particularly susceptible to enteroviral meningoencephalitis.[7]
vector exposure and/or animal bites
Mosquitoes can transmit West Nile virus, St. Louis encephalitis virus, Eastern equine, Western equine, Venezuelan equine, Japanese B, Murray Valley, Ilheus, and Rocio viruses.
Tick bites are associated with tick-borne encephalitis, Colorado tick fever, Powassan virus, Far Eastern, Central European, Kyasanur Forest disease virus, Louping Ill, Negishi, Russian spring-summer, Lyme disease, Rocky Mountain spotted fever, and Ehrlichia.
Animal bite/exposure is associated with rabies (bats), brucellosis, Bartonella (cats), Toxoplasma, Q fever, and herpes B (primates). It is important to note that lack of a known bite or other exposure history does not exclude the diagnosis of rabies.
location
Aetiological agents are endemic to certain locales.[33] Consider immigration and recent travel history.
Africa: malaria, trypanosomiasis, dengue, Ebola virus.
Asia: Japanese encephalitis virus, dengue, malaria, Nipah virus.
Australia: Murray Valley encephalitis, Kunjin virus, Australian bat lyssavirus.[34]
Europe: tick-borne encephalitis virus, West Nile virus, Toscana virus.
Central and South America: dengue, malaria, West Nile virus, Venezuelan equine encephalitis.
North America: West Nile virus and St. Louis encephalitis virus are common throughout the US. Coccidioides and blastomycosis are common in the southwestern and midwestern US, respectively. Lyme disease in northcentral and northeastern US.
post-infection
Bickerstaff's encephalitis, Rasmussen's encephalitis, anti-N-methyl-D-aspartate receptor encephalitis, and acute disseminated encephalomyelitis can be seen after the resolution of a viral illness (e.g., varicella, herpes virus, non-specific upper respiratory viral infections, mumps, rubella, enterovirus, Epstein-Barr virus, influenza viruses, adenovirus) and may be due to an autoimmune process.
blood/body fluid exposure
HIV and West Nile virus can be transmitted by contaminated blood products, needle sticks, and body fluid exposure.
organ transplantation
Rabies, West Nile virus, and cytomegalovirus infections have occurred in transplant patients who received organs from infected donors.[38]
season
Spring: Powassan virus, Colorado tick fever.
Summer: enterovirus, arboviruses, Colorado tick fever, Lyme disease (but may occur year-round).
Autumn: enterovirus, arboviruses, lymphocytic choriomeningitis virus (LCMV).
Winter: LCMV, influenza.
July-November: West Nile virus.
Rainy season: Venezuelan equine (May to December).
swimming or diving in warm freshwater or nasal/sinus irrigation
Associated with Naegleria.
weak
vaccination
Although most studies find no relation between vaccination and acute disseminated encephalomyelitis (ADEM), certain vaccines, including older vaccines containing neural tissues and those against COVID-19, may be associated with a rare risk of developing ADEM.[18][35][36]
Children not vaccinated against mumps and measles are at risk of developing measles or mumps encephalitis.
Rarely, unvaccinated children suffering from measles infection can develop subacute sclerosing panencephalitis, a progressive neurological deterioration typically leading to death within 4 years.[37]
occupation
Forestry worker: Lyme disease, Kyasanur Forest disease virus, rabies.
Farm workers: Nipah, avian influenza, brucellosis.
Abattoir workers: Q fever.
Laboratory workers: Ebola, Marburg, herpes B.
Healthcare workers and prison staff: Tuberculosis.
hunting/trekking in woods
Associated with Lyme disease (tick exposure) and rabies (through exposure to a rabid animal).
spelunking (cave-exploring)
Associated with rabies (through exposure to bats).
death in animals
Epidemic outbreaks of certain viral encephalitides in humans are frequently preceded by large-scale illnesses and death in animals (horses for equine encephalitides) and birds (West Nile virus).
cancer
Paraneoplastic encephalitis may be related to classical antibodies against intracellular onconeuronal antigens (e.g., anti-Hu, anti-Yo), or antibodies targeting neuronal surface or synaptic antigens (e.g., N-methyl-D-aspartate receptor-antibody and leucine-rich glioma inactivated-antibody).[39] Typically associated with cancer in the lung, breast, or reproductive organ.
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