Eastern equine encephalitis virus (EEEV) is one of the North American encephalitic arboviruses (Togaviridae family and genus Alphavirus) that is transmitted to humans by mosquito bites. EEE is the most clinically severe arboviral (ARthropod BOrne) encephalitis occurring in the United States. Among the four EEEV subtypes, subtype I causes the majority of symptomatic infections in humans and is commonly found in the United States and the Caribbean.

Birds serve as the primary reservoir hosts for EEEV. The mosquito Culiseta melanura is the primary vector of transmission for an enzootic cycle between birds and horses. Humans are incidentally infected by other mosquito vectors, such as Culex and Aedes species. An estimated 1 in 30 individuals exposed to EEEV develops clinical disease.

In the United States, most human cases occur along the Atlantic and Gulf coasts during summer and are typically found within 5 miles of swamplands or marshlands. Per the CDC, on average, only a few human cases of EEE are reported annually in the United States, with a peak in 2005 of 21 human cases of EEEV disease.

The clinical presentation of EEEV infection is nonspecific, with a prodrome of fever, headache, nausea, vomiting, and myalgia lasting about 1 week after the mosquito bite. These symptoms are usually self-limited and are followed by complete recovery in most patients. However, approximately 2% of infected adults and 6% of infected children develop encephalitis. Persons over age 60 and under age 15 seem to be at greatest risk for developing severe central nervous syndrome (CNS) disease when infected with EEEV. Common neurologic presentations include seizures, meningismus, cranial nerve palsies (especially the seventh cranial nerve), and focal weakness. Symptoms suggestive of brain stem involvement are gaze palsies, nystagmus, and pupillary abnormalities. Following the onset of neurologic symptoms, 90% of patients progress to coma and 50% of patients develop seizures or focal neurological signs. 

Common (in two-thirds of the patients) laboratory findings are peripheral blood leukocytosis with neutrophil predominance and serum hyponatremia (often attributable to syndrome of inappropriate antidiuretic hormone secretion [SIADH]). The median initial cerebrospinal fluid (CSF) white blood cell count (WBC) is 370 cells/mm³ with a median of 70% neutrophils. The CSF protein is elevated with a median of 97 mg/dL. Most patients demonstrate normal CSF glucose, although some cases of EEE with hypoglycorrhachia have been reported. Red blood cells (RBCs) in the CSF are common, reflecting the underlying necrotic and hemorrhagic nature of the encephalitis. EEE is associated with a high mortality rate of 30% and could be up to 75% in older patients over 60 years of age.

Poor prognostic predictors are noted to be high initial CSF WBC  >500 cells/mm³ (indicating severe cerebral inflammatory process) and serum hyponatremia <130 mEq/L. Severity of neuroradiographic lesions does not correlate with poor clinical outcome. 

Magnetic resonance imaging (MRI) is the most sensitive modality for radiographic evaluation of arboviral encephalitis. Common neuroradiographic abnormalities are increased signals observed in bilateral basal ganglia, thalami, and brain stem. These findings are also observed in other viral encephalitides such as West Nile virus encephalitis, Japanese B encephalitis, St. Louis encephalitis, measles, and mumps; they can also be seen in Creutzfeldt-Jakob disease.