Eastern equine encephalitis

In most cases, infection with Eastern equine encephalitis virus (EEEV) is self-limiting with no symptoms. 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. A stiff neck is indicative of infection in the meninges and meningitis. Most seizures that occur are generalized, and most of these are tonic-clonic, followed by twitching. Focal seizures are less common, and complex seizures are the least common. In severe cases, status epilepticus may occur, in which there are prolonged seizures or multiple seizures consecutively without regaining consciousness between them. Elevated heart rate (tachycardia), elevated respiration rate (tachypnea), language difficulties (aphasia), and a strong desire to sleep (drowsiness or somnolence) may occur. Stupor or coma occur in most cases. Fluid may accumulate in the brain (cerebral edema), particularly in young children. Other possible symptoms include shock, which may be refractory, flaccid paralysis, difficulty speaking due to muscle weakness (dysarthria), discomfort to bright lights (photophobia), and diarrhea. ==Virology==

EEE is caused primarily by Eastern equine encephalitis virus (EEEV) and secondarily by Madariaga virus (MADV). EEEV and MADV belong to the genus Alphavirus in the family Togaviridae. which is the most severe alphavirus to affect humans. The non-structural proteins are nsP1, nsP2, nsP3, and nsP4. The structural proteins are the capsid protein (CP), E3, E2, 6K/TF, and E1. The functions of each protein are described hereafter. and Central America and is responsible for most human cases. The other types are found in Central America and South America, where they mainly cause disease in horses. Lineage I is Eastern equine encephalitis virus, while lineages II–IV are classified as a different species, Madariaga virus. Lineage II is distributed along the coasts of Central and South America, lineage III is found in the Amazon Basin, and lineage IV is in Brazil. North American strains are highly conserved genetically, as a single lineage has persisted as the dominant lineage since its isolation in 1933. ==Mechanism==

Transmission Transmission of EEEV is maintained in the wild in an enzootic cycle between passerine birds and mosquitos that feed on passerines. These birds are the natural reservoirs of the virus and serve as amplification hosts since the virus multiplies easily in their bodies, and marshlands, environments favorable for growth of mosquito larvae. Most transmission of EEEV occurs in these environments. While it is not known whether green herons are infected or develop viremia, there is some evidence that certain migratory ardeids are susceptible to EEEV in the southern United States. EEEV can infect osteoblasts, dendritic cells, fibroblasts, skin proximal keratinocytes, ventricular interstitial cells, and ovarian stromal cells. Other receptors that EEEV binds to include the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Immunology The host immune response is driven by stimulation of macrophages, dendritic cells, T lymphocytes, B lymphocytes, microglia, and astrocytes. The first cells targeted during infection are dendritic cells and fibroblasts, which causes activation of pattern recognition receptors (PRRs) that recognize viral double-stranded RNA. This initiates a series of signals through mitochondrial antiviral-signaling proteins (MAVS) that leads to type 1 interferon (IFN) production. Type 1 IFNs activate the JAK-STAT pathway, which leads to the expression of interferon-stimulated genes (ISGs) that restrict viral replication and spread. If early infection is not resolved, then EEEV can invade the CNS. EEEV can infect macrophages, which triggers production of cytokines. Infection increases the amount of chemokines in circulation, which alters the blood brain barrier and allows immune cells to infiltrate the CNS. CD4+ and CD8+ cells move to the brain and release pro-inflammatory cytokines, which worsens damage. EEEV can evade the immune response through various means. nsP2 suppresses the host interferon response, interferes with host nuclear import machinery, which degrades immune signaling molecules and represses transcription of ISGs, and it inhibits activation of transcription factors, such as STAT1, that are involved in the antiviral response. nsP2 causes downregulation of major histocompatibility complex (MHC) molecules, which hinders the ability of antigen-presenting cells to present viral antigens to T cells, which impairs activation of CD4+ and CD8+ T cells. Inhibition of nsP3 can interfere with the formation of stress granules, which prevents the host cell from effectively blocking viral replication. 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. ==Prevention==

Mosquito control methods such as insecticides, larvicides, elimination of mosquito breeding sites, and the use of insect repellents can reduce the spread of EEE and the likelihood of infection. Educating the public about how to avoid mosquito bites can also significantly reduce the risk of infection. Vaccination A vaccine is available for horses. This vaccine is an inactivated vaccine that uses the TC-83 strain of EEEV. It is usually given in combination with vaccines for Western equine encephalitis (WEE), Venezuelan equine encephalitis (VEE), and tetanus, and is also used by laboratory workers to protect from accidental exposure. The vaccine does not induce antibodies to South American forms of EEE. No vaccine specifically made for humans exists. Human vaccines that have been investigated for EEE include viral vector-based vaccines, plasmid DNA vaccines, and trivalent vaccines that protect against EEE, WEE, and VEE. ==Diagnosis==

Early diagnosis of EEE is difficult since symptoms overlap with other viral encephalitides. Detection of EEEV RNA in early infection can diagnose EEE, especially in the absence of IgM antibodies since the presence of EEEV RNA indicates recent infection. 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). Some other methods, usually used during autopsy, include isolation of EEEV in viral cultures, nucleic acid amplification assays, and immunohistochemical assays of infected CSF or brain tissue. Plaque reduction neutralization tests (PRNT) to detect EEEV-specific neutralizing antibodies can be performed for people who have elevated IgM titers to rule out false-positives. If samples are tested too soon, there may be false-negative results. Immunofluorescent assays may fail to diagnose EEE, in which case microparticle immunoassays can screen for EEEV IgM. Neuroimaging is helpful for identifying the severity of disease. Fluid-attenuated inversion recovery (FLAIR) scans, a type of magnetic resonance imaging (MRI), show significant involvement of the cortex, basal ganglia, thalami, and brainstem. Viral infiltration of deep gray matter structures such as the basal ganglia and thalami is visible. This occurs with other arthropod-borne viral infections as well as prion diseases, rabies, and autoimmune encephalitides. EEE can be distinguished from these diseases based on geography, how quickly symptoms develop, exposure to vectors, and family history. In rare cases, the middle cerebellar peduncle may be affected. A distinctive feature of EEE often visible in T2-weighted images is areas of increased signal in the basal ganglia and thalami. Electrical activity in the brain can be analyzed with electroencephalogram (EEG) tests. EEG findings range from mild diffuse encephalopathy to non-convulsive status epilepticus, which is reflective of the degree of brain dysfunction. In more severe cases, EEG shows extremely depressed brain activity. A lumbar puncture may be done to analyze CSF. EEEV infection has elevated opening pressure upon performing a lumbar puncture. Apart from antibody testing, analysis of CSF shows an increased prevalence of certain cells, particularly white blood cells (pleocytosis), in CSF. Initially, there is neutrophil-predominant pleocytosis, which shifts to lymphocyte-predominance. CSF contains elevated protein levels and normal glucose levels. Analysis of blood shows that in severe cases, there is too little sodium in the blood. Examination of central nervous system tissue shows infiltration of neutrophils and mononuclear cells, accumulation of inflammatory cells in perivascular space (perivascular cuffing), the presence of inclusion bodies, and necrosis of neurons. Autopsy results show severe loss of neurons and gliosis of the dorsal motor nucleus. ==Management==

There are no antiviral drugs currently in use to treat EEE. 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). Intravenous immunoglobulin (IVIg) has been tested as a potential treatment by silencing auto-reactive T cells and neutralizing pathogenic antibodies. IVIg treatment is safe, but results are mixed on whether it is an effective treatment. Physical therapy, occupational therapy, and speech therapy are often needed after EEE to deal with issues related to motor skills, daily life, and communication. ==Prognosis==

The case fatality rate of EEE in humans varies from 30% to 75% depending on age. Prognosis is worse in newborns under 1 year of age and in adults over 55, with death most likely in the elderly and least likely in middle-aged adults. Death is rapid and occurs 3–5 days after the start of infection. Very low levels of sodium in the blood and elevated white blood cell count in cerebrospinal fluid are associated with worse outcomes. A reduction in alertness and conscious upon hospital admission and seizures within 24 hours of symptoms appearing are associated with greater probability of death. Survival is more likely if bi-hemispheric or brainstem injury do not occur. The median duration of coma for those who recover from it is about 5 days. 50–90% of survivors experience long-term neurological damage or disability that ranges from minor to severe. Infants are the most likely to develop long-term neurological complications. Long-term complications include impaired language ability (aphasia), convulsions, seizures, paralysis, intellectual disability, personality and behavioral changes, emotional instability, memory loss, headaches, drowsiness, confusion, muscle twitching, photophobia, and sleep disorder. Coordination problems, abnormal muscle tightness (spasticity), and muscle weakness that can cause issues with balance and fine motor skills may also occur. Some survivors develop seizure disorders, which require continual treatment with anti-seizure medication. Post-traumatic stress disorder, depression, and anxiety are more common in EEE survivors than people who haven't had EEE. Chronic exhaustion is common after EEE, as are problems with the nervous system and joints that can cause persistent pain or discomfort. Long-term neurological complications are caused by damage to the brain during infection. For example, seizures following EEE are associated with damage to the temporal lobe. Other complications may be attributable to the death of neurons, inflammation of blood vessels (vasculitis), blood clots (thrombosis), and gliosis in motor neurons. ==Epidemiology==

EEE mainly occurs in the United States in states along the Atlantic Ocean, Gulf of Mexico, and in some areas near the Great Lakes. the United States, and Mexico. Cases have also been identified in Jamaica, but permanent enzootic circulation has not been verified there or in the Dominican Republic. In Central America, EEE cases have occurred in Panama. In South America, EEEV has been detected in Colombia, Ecuador, Venezuela, Guyana, Suriname, Brazil, and Argentina. ==In animals==

In horses, symptoms appear 1–3 weeks after being bitten by an infected mosquito. Symptoms begin with a fever that usually lasts 1 to 2 days. Horses develop anorexia, hyper-excitability, blindness, decreased muscle coordination, severe mental depression, convulsions, and they lie down horizontally (recumbency). They then develop paralysis that makes it difficult for them to raise their head. Complete paralysis and subsequently death usually occur 2–4 days after symptoms appear. The case fatality rate in horses is 70–90%, and those that survive have permanent brain damage. Juveniles are more vulnerable to severe disease. Outbreaks of EEE are most common in horses. Infection in birds is usually asymptomatic, but high mortality has been observed in chukar partridges, pheasants, egrets, glossy ibises, rock doves, house sparrows, psittacine birds, ratites, African penguins, chickens less than 14 days old, pigeons, Pekin ducks, and whooping cranes. Turkeys have high mortality and diseased egg production 2–3 days after infection, which lasts up to 15 days after the start of infection. Many domesticated birds develop encephalitis and disease in internal organs. Outbreaks sometimes occur in certain poultry such as pheasants, turkeys, ratites, and quails. Apart from birds, EEE has been observed in sheep, cattle, deer, llamas, alpacas, pigs, dogs, goats, bats, and small mammals such as rodents. Experimental studies in non-human primates show similar severe symptoms as those experienced by humans. ==History==

EEEV was first recorded during an outbreak in horses in Massachusetts, USA in 1831. During the outbreak, 75 horses died to neurological disease from midsummer to early autumn in eastern Massachusetts. Another equine epizootic occurred in Long Island, New York in 1845. 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. It was shown to be distinct from virus strains isolated from horses in California, now known as Western equine encephalitis virus. Madariaga virus was first identified in 1936 from a horse in Argentina. The first human cases were identified in 1938 in Massachusetts, during an outbreak with 38 human cases and 248 horse cases. 25 of the 38 human cases resulted in death. That same year, an epizootic occurred in Connecticut and Rhode Island and involved dozens of horses and multiple pheasant flocks. Southern New Jersey was historically an area greatly affected by EEE, with continual epizootics in the 1930s and epidemics in the following decades. The most severe was in 1959, in which 33 human cases of EEE occurred. Serological surveys of the population showed that only about 1 in 23 (4.3%) human infections resulted in encephalitis. EEEV was first isolated from a mosquito in 1949 in Cq. perturbans and in 1951 in Cs. melanura. Subsequent field studies showed that Cs. melanura was the primary enzootic reservoir of EEEV. Soon after EEV was discovered, birds were suspected as the primary amplification hosts of the virus. The virus was first isolated from domestic pheasants and pigeons in 1938 and then wild passerine birds in 1950. The first human case in New York was identified in 1971 and then discovered in upstate New York near Oneida Lake, far away from the coastal areas typically affected by EEE. The first human case in Michigan was in 1980. Sporadic disease outbreaks have occurred in eastern Connecticut and Rhode Island since 1938 and possibly before then. More recently, human cases have been expanding northward into New Hampshire for the first time in 2005, Vermont in 2012, and Maine in 2014. The first European case of EEE occurred in 2007 after a Scottish man became infected in New Hampshire. In 2010, lineages II, III, and IV were reclassified as a distinct species from EEEV, Madariaga virus. Canada reported its first human case of EEE in 2016 in southwestern Ontario. ==References==