Eastern equine encephalitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Anthony Gallo, B.S. [2]

Synonyms and keywords: EEE; EEEV; East equine encephalitis; Triple E

Overview

Eastern equine encephalitis is a moderate to severe infection of the central nervous system. Eastern equine encephalitis belongs to the Group IV positive-sense ssRNA family of viruses. Eastern equine encephalitis is closely related to western equine encephalitis and Venezuelan equine encephalitis. Eastern equine encephalitis virus is usually transmitted via mosquitos to the human host. Eastern equine encephalitis is contracted by the bite of an infected mosquito, primarily Culiseta melanura. Eastern equine encephalitis virus must be differentiated from other diseases that cause fever, headache, seizures, and altered mental status. There are approximately 8 human cases of eastern equine encephalitis annually in the United States, most commonly affecting children under the age of 15 and adults over the age of 50. Prognosis for eastern equine encephalitis is generally poor. Approximately 33% of patients progress to mortality, and approximately 50% of surviving patients have mild to severe neurodegenerative losses and seizures. The diagnostic method of choice for eastern equine encephalitis virus is laboratory testing. There is no treatment for eastern equine encephalitis virus; the mainstay of therapy is supportive care. There are currently no human vaccines available for eastern equine encephalitis.

Historical Perspective

In 1831, eastern equine encephalitis virus was first reported in Massachusetts, USA following the sudden death of 75 horses, which died mysteriously of viral encephalitis. In 1938, the earliest evidence of eastern equine encephalitis virus activity in Canada was reported in the Ontario cities of St. George and St. Catharines.

Classification

Eastern equine encephalitis may be classified according to location of the disease into 2 subtypes: systemic or encephalitic. Eastern equine encephalitis may also be classified according to neuroinvasiveness of the disease into 2 subtypes: neuroinvasive and non-neuroinvasive. Eastern equine encephalitis belongs to the Group IV positive-sense ssRNA virus within the Togaviridae family of viruses, and the genus Alphavirus. Eastern equine encephalitis is closely related to western equine encephalitis virus and Venezuelan equine encephalitis virus. Eastern equine encephalitis is known as an arbovirus, or an arthropod-borne virus.

Pathophysiology

Eastern equine encephalitis virus is usually transmitted via mosquitos to the human host. Eastern equine encephalitis virus contains positive-sense viral RNA; this RNA has its genome directly utilized as if it were mRNA, producing a single protein which is modified by host and viral proteins to form the various proteins needed for replication. The following table is a summary of the eastern equine encephalitis virus:

Characteristic	Data
Nucleic acid	RNA
Sense	ssRNA(+)
Virion	Enveloped
Capsid	Spherical
Symmetry	Yes; T=4 icosahedral
Capsid monomers	240
Monomer length (diameter)	65-70 nm
Additional envelope information	80 spikes; each spike is a trimer of E1/E2 proteins
Genome shape	Linear
Genome length	11-12 kb
Nucleotide cap	Yes
Polyadenylated tail	Yes
Incubation period	4-10 days

Eastern equine encephalitis is contracted by the bite of an infected mosquito, primarily Culiseta melanura. The virus is maintained in a cycle between Culiseta melanura mosquitos and avian hosts in freshwater hardwood swamps. Culiseta melanura is not an important vector of eastern equine virus to humans because it feeds almost exclusively on birds. Transmission to humans requires mosquito species capable of creating a "bridge" between infected birds and uninfected mammals, such as some Aedes, Coquillettidia, and Culex species. The incubation period is 4-10 days. Humans and horses are dead-end hosts for the virus, meaning there is an insufficient amount of eastern equine encephalitis virus in the blood stream to infect a mosquito. Many cases in horses are fatal. There is no known transmission between horses and humans. Recent studies have demonstrated other equine, such as mules and donkeys, and other animals, such as pigs, reptiles, amphibians, and rodents, can be infected.

Eastern equine encephalitis virus is transmitted in the following pattern:

1. Attachment of the viral E glycoprotein to host receptors mediates clathrin-mediated endocytosis of virus into the host cell.
2. Fusion of virus membrane with the host cell membrane. RNA genome is released into the cytoplasm.
3. The positive-sense ssRNA virus is translated into a polyprotein, which is cleaved into non-structural proteins necessary for RNA synthesis (replication and transcription).
4. Replication takes place in cytoplasmic viral factories at the surface of endosomes. A dsRNA genome is synthesized from the genomic ssRNA(+).
5. The dsRNA genome is transcribed thereby providing viral mRNAs (new ssRNA(+) genomes).
6. Expression of the subgenomic RNA (sgRNA) gives rise to the structural proteins.
7. Virus assembly occurs at the endoplasmic reticulum.
8. Virions bud at the endoplasmic reticulum, are transported to the Golgi apparatus, and then exit the cell via the secretory pathway.

Causes

Eastern equine encephalitis may be caused by eastern equine encephalitis virus.

Differentiating Eastern equine encephalitis from Other Diseases

Eastern equine encephalitis virus must be differentiated from other diseases that cause fever, headache, seizures, and altered mental status, such as:

Disease	Findings
Western equine encephalitis	Western equine encephalitis presents with acute inflammation of the brain, caused by an arboviral infection; it is less severe than Eastern equine encephalitis. Other findings include fever, nausea, headache, vomiting, photophobia, seizures, and coma.
Venezuelan equine encephalitis	Venezuelan equine encephalitis presents with acute inflammation of the brain, caused by an arboviral infection; complications include severe brain damage. Other findings include fever, nausea, headache, photophobia, seizures, and coma.
Vector-borne encephalitis	Vector-borne encephalitis presents with acute inflammation of the brain, caused by a bacterial infection; complications include severe brain damage as the inflamed brain pushes against the skull, potentially leading to mortality. See also: Tick-borne encephalitis, California encephalitis virus, La Crosse encephalitis, Japanese encephalitis, and West Nile encephalitis
Viral encephalitis	Viral encephalitis presents with acute inflammation of the brain, caused by a viral infection; complications include severe brain damage as the inflamed brain pushes against the skull, potentially leading to mortality. See also: Herpes simplex encephalitis and VZV encephalitis
Encephalopathy	Encephalopathy presents with steady depression, generalized seizures. Generally absent are fever, headache, leukocytosis, and pleocytosis; MRI often appears normal.
Meningitis	Meningitis presents with headache, altered mental status, and inflammation of the meninges, which may develop in the setting of an infection, physical injury, cancer, or certain drugs; it may have an indolent evolution, resolving on its own, or may present as an rapidly evolving inflammation, causing neurologic damage and possible mortality. See also: Bacterial meningitis, Viral meningitis, and Fungal meningitis
Brain abscess	Brain abscess presents with an abscess in the brain caused by the inflammation and accumulation of infected material from local or remote infectious areas of the body; the infectious agent may also be introduced as a result of head trauma or neurological procedures.
Acute disseminated encephalomyelitis (ADEM)	Acute disseminated encephalomyelitis presents with scattered foci of demyelination and perivenular inflammation; it can cause focal neurological signs and decreased ability to focus.

Epidemiology and Demographics

Incidence

There are approximately 8 human cases of eastern equine encephalitis annually in the United States.

Age

Eastern equine encephalitis commonly affects individuals younger than 15 and older than 50 years of age.

Seasonal

Eastern equine encephalitis outbreaks have occurred when there is relatively higher rainfall in the late summer and early fall of the previous year and during the current summer of an outbreak. Specifically, the risk of contracting eastern equine encephalitis is highest from late July through September, when more mosquitos are present and active.

Geographic Location

The majority of eastern equine encephalitis cases are reported on the East Coast of the United States, specifically in Massachusetts, Florida, and New Jersey. Eastern equine encephalitis virus transmission is most common in and around freshwater hardwood swamps in the Atlantic and Gulf Coast states and the Great Lakes region.

Maps regarding geographic distribution of eastern equine encephalitis cases can be found here.

Risk Factors

Common risk factors in the development of eastern equine encephalitis include:

• Age (<15 years; >50 years)
• Immunosuppression
• Residing or visiting woodland areas
• Mosquito contact
• Bird contact
• Horse contact
• Summer season
• Outdoor recreational activities

Natural History, Complications, and Prognosis

Natural History

If left untreated, eastern equine encephalitis may cause uncontrolled fever, increased intracranial pressure, and seizures. Eastern equine encephalitis usually clears within 1-2 weeks and rarely recurs; the recovery period is significantly longer.

Complications

Common complications of eastern equine encephalitis include:

• Recurring seizures
• Coma
• Loss of basic motor skills
• Loss of coordination
• Meningitis
• Increased intracranial pressure
• Shock
• Respiratory failure

Prognosis

Prognosis for eastern equine encephalitis is generally poor. Approximately 33% of patients progress to mortality. Approximately 50% of surviving patients have mild to severe neurodegenerative losses and seizures.

Diagnosis

Diagnostic criteria

Neuroinvasive vs non-neuroinvasive eastern equine encephalitis can be differentiated based on both clinical and laboratory findings. These include:

Eastern Equine Encephalitis Subtype	Clinical Presentation	Laboratory Findings
Neuroinvasive	Template:Unicode Meningitis, encephalitis, acute flaccid paralysis, or other acute signs of central or peripheral neurologic dysfunction, as documented by a physician AND Template:Unicode Absence of a more likely clinical explanation	Template:Unicode Isolation of virus from, or demonstration of specific viral antigen or nucleic acid in, tissue, blood, cerebrospinal fluid (CSF) OR Template:Unicode Four-fold or greater change in virus-specific quantitative antibody titers in paired sera OR Template:Unicode Virus-specific IgM antibodies in serum with confirmatory virus-specific neutralizing antibodies in the same or a later specimen OR Template:Unicode Virus-specific IgM antibodies in cerebrospinal fluid, with or without a reported pleocytosis, and a negative result for other IgM antibodies in cerebrospinal fluid for arboviruses endemic to the region where exposure occurred
Non-neuroinvasive	Template:Unicode Fever and chills as reported by the patient or a health care provider AND Template:Unicode Absence of neuroinvasive disease AND Template:Unicode Absence of a more likely clinical explanation	Template:Unicode Isolation of virus from, or demonstration of specific viral antigen or nucleic acid in, tissue, blood, or other body fluid, excluding cerebrospinal fluid OR Template:Unicode Four-fold or greater change in virus-specific quantitative antibody titers in paired sera OR Template:Unicode Virus-specific IgM antibodies in serum with confirmatory virus-specific neutralizing antibodies in the same or a later specimen

History and Symptoms

If possible, a detailed and thorough history from the patient is necessary. Common symptoms of eastern equine encephalitis include:

• Fever
• Chills
• Headache
• Fatigue
• Muscle pain
• Dizziness
• Altered mental status

Physical Examination

Common physical examination findings of eastern equine encephalitis include:

• Fever
• Ataxia
• Seizures
• Obtundation
• Myalgia
• Acute flaccid myelitis
• Lethargy
• Meningism
• Photophobia

Laboratory Findings

The diagnostic method of choice for eastern equine encephalitis is laboratory testing. Laboratory findings consistent with the diagnosis of eastern equine encephalitis include:

• Serologic cross-reactivity
• Presence of IgM antibodies
• Persistence of IgG and neutralizing antibodies
• Confirmation of arboviral-specific neutralizing antibodies in enzyme linked immunosorbent assay (ELISA)
• Leukocytosis with a neutrophil predominance
• Normal glucose levels
• Hyponatremia
• In cerebrospinal fluid:
  • Significant pleocytosis
  • Increased protein levels
  • Slightly lower glucose levels

CT

On CT scan, eastern equine encephalitis is characterized by diffuse cerebral edema in 40% of patients.

MRI

On MRI, eastern equine encephalitis is characterized by abnormalities in the thalamus, basal ganglia, and brainstem.

EEG

On EEG, eastern equine encephalitis is typically diffusely slow with some patients having burst suppression, or diffuse high-voltage delta wave slowing.

Treatment

Medical Therapy

There is no treatment for eastern equine encephalitis; the mainstay of therapy is supportive care. Because supportive care is the only treatment for eastern equine encephalitis, physicians often do not request the tests required to specifically identify the eastern equine encephalitis virus.

Surgery

Surgical intervention is not recommended for the management of eastern equine encephalitis.

Prevention

There is no human vaccine for eastern equine encephalitis. There is an eastern equine encephalitis vaccine available for horses. In consultation with a veterinarian, vaccinate your horse(s) against the virus. Primary prevention strategies for eastern equine encephalitis include:

• Removal of standing water
• Screens on doors and windows
• When outdoors, wearing:
  • Insect repellent containing DEET
  • Long sleeves, pants; tucking in pants into high socks