Neurological symptoms usually appear a few days later and include altered mental state, encephalitis, photophobia, seizures, paralysis, and loss of consciousness and coma.

In South America, rodents and marsupials may be reservoirs of MADV, and Culex mosquitos of the subgenus Melanoconion are likely the main enzootic vectors.

These mosquitos feed on the blood of both avian and mammalian hosts and include Coquillettidia perturbans and various species of the Aedes, Anopheles, and Culex genera.

The disease occurs along the eastern side of the Americas, mainly in the USA in states bordering the Atlantic Ocean, Gulf of Mexico, and Great Lakes.

Fewer than ten human cases occur in a typical year, usually in close proximity to hardwood freshwater swamps and marshes where Cs.

[1][2] In about 5% of cases,[3] though, the virus invades the central nervous system, where it causes Eastern equine encephalitis (EEE), also called triple E or sleeping sickness.

[5][7][8] Usually within a few days, central nervous system involvement becomes apparent due to the emergence of neurological symptoms such as alterations in mental state, heightened irritability and agitation, personality changes, confusion, encephalitis, convulsions, seizures, paralysis, and loss of consciousness and coma.

[5] Other possible symptoms include shock, which may be refractory, flaccid paralysis, difficulty speaking due to muscle weakness (dysarthria),[9] discomfort to bright lights (photophobia),[4] and diarrhea.

melanura mainly inhabits low-lying freshwater hardwood swamps, sphagnum bogs,[16][17] and marshlands, environments favorable for growth of mosquito larvae.

The wood thrush (Hlocichia mustelina) and the American robin (Turdus migratorius) contribute disproportionately to virus transmission as these are the main bloodmeal sources for Cs.

[2][11] At the cellular level, infection results in the formation of fibers extending from the surface of the cell membrane, which can aid in transmitting the virus without it being as exposed to the extracellular environment.

[9] In South America, Madariaga virus is found mainly in Culex mosquitos,[1] particularly those of the Melanoconion subgenus, which may serve as enzootic vectors.

[8][14] Infection starts with replication in lymphoid tissues, then spreads through the bloodstream[5] and olfactory nerves[9] to the central nervous system, where EEEV causes encephalitis and other symptoms.

[5] Injury of neurons occurs directly from viral toxicity and secondarily through inflammation in the CNS, which affects the basal ganglia, thalami, and cortex.

[5] EEEV binds efficiently to haparan sulfate receptors, which blocks it from infecting peripheral lymphoid tissues or myeloid cells.

Type 1 IFNs activate the JAK-STAT pathway, which leads to the expression of interferon-stimulated genes (ISGs) that restrict viral replication and spread.

Infection increases the amount of chemokines in circulation, which alters the blood brain barrier and allows immune cells to infiltrate the CNS.

EEEV's interference with PRR and IFN signaling also creates an imbalance in the immune response—there is excessive production of pro-inflammatory cytokines, which contributes to disease severity.

[13] The primary means of diagnosis, however, is by testing for anti-EEEV-specific IgM in serum or cerebrospinal fluid (CSF) via enzyme-linked immunosorbent assay (ELISA).

Fluid-attenuated inversion recovery (FLAIR) scans, a type of magnetic resonance imaging (MRI), show significant involvement of the cortex, basal ganglia, thalami, and brainstem.

EEE can be distinguished from these diseases based on geography, how quickly symptoms develop, exposure to vectors, and family history.

EEG findings range from mild diffuse encephalopathy to non-convulsive status epilepticus, which is reflective of the degree of brain dysfunction.

[1] Treatment of severe illness is supportive and includes corticosteroids, anti-convulsants to manage seizures, intravenous fluids, tracheal intubation to aid with respiration, and fever-reducing drugs (anti-pyretics).

A reduction in alertness and conscious upon hospital admission and seizures within 24 hours of symptoms appearing are associated with greater probability of death.

[8] Long-term complications include impaired language ability (aphasia),[8] convulsions, seizures, paralysis, intellectual disability, personality and behavioral changes,[6][8] emotional instability, memory loss, headaches, drowsiness, confusion, muscle twitching, photophobia, and sleep disorder.

[16] The spread of EEE may be due to regeneration of local habitats, which are recovering from prolonged periods of environmental destruction for the agriculture and logging industries.

Horses develop anorexia, hyper-excitability, blindness, decreased muscle coordination, severe mental depression, convulsions, and they lie down horizontally (recumbency).

[1] Apart from birds, EEE has been observed in sheep, cattle, deer, llamas, alpacas, pigs, dogs, goats, bats, and small mammals such as rodents.

EEEV was first isolated from horse brains and linked to EEE during an epizootic in the coastal parts of Delaware, Maryland, New Jersey, and Virginia in 1933.

That same year, an epizootic occurred in Connecticut and Rhode Island and involved dozens of horses and multiple pheasant flocks.