Eastern Equine Encephalitis

Overview

In the United States, equine encephalitides for which vaccines are available include eastern equine encephalomyelitis (EEE), western equine encephalomyelitis (WEE), Venezuelan equine encephalomyelitis (VEE) and West Nile Virus encephalomyelitis. Eastern Equine Encephalitis (EEE) is a viral disease of horses that can be transmitted to humans and results in symptoms that are flu like in its symptoms. In humans, EEE is uncommon but is likewise associated with a high rate of morbidity and mortality. Initial symptoms often progress rapidly to confusion, somnolence, or even coma. In North America, the enzootic vector for EEE is the mosquito Culiseta melanura, which is responsible for the spring-summer amplification of the virus in the mosquito-bird-mosquito cycle. Occasionally, other mosquito types (eg, Coquillettidia perturbans and the ubiquitous Aedes canadensis species) may act as bridges in the horse-to-human transmission. The viral reservoir varies depending on climate and habitat changes and often exhibits an annual fluctuation between avirulent and virulent strains. The degree of virulence is related to the host specifics of a given epizootic outbreak. Initial medical care focuses on making a prompt diagnosis that differentiates EEE from potentially treatable causes. Like all diseases caused by alphaviruses, EEE has no specific treatment. Management of this condition primarily rests on supportive and preventive measures.

Symptoms

EEE is characterized by diffuse central nervous system (CNS) involvement. A large number of immunologically active cells enter the brain parenchyma and perivascular areas and mediate much of the damage. Infiltrating neutrophils and macrophages cause neuronal destruction, neuronophagia, focal necrosis, and spotty demyelination. Vascular inflammation with endothelial proliferation, small vessel thrombosis, and perivascular cuffing may also develop.

Antigenic studies reveal that EEE primarily affects the perikaryon and dendrites of neurons, with minimal findings in glial cells. Occasionally, secondary glial proliferation and the formation of glial nodules occur. Cell death by apoptosis occurs primarily among the glial and inflammatory cells. Gross inspection on autopsy reveals edema, leptomeningeal vascular congestion, hemorrhage, and encephalomalacia. Patients who die late in the disease may exhibit diffuse cerebral atrophy, particularly of the cortex.

Causes

The mosquito injects the agent of EEE into the subcutaneous and cutaneous tissues of the host. EEE is not transmitted via the aerosol route. It may cross the placenta and infect the fetus. Because of low viral titers in the donor’s blood, EEE is unlikely to be transmitted via transfusion. The prodrome of fevers, chills, weakness, headache, and myalgias represents replication of the virus in nonneural tissues (tissue adjacent to the mosquito’s bite or the lymphatic system).

The virus then binds to specific tissue receptors, undergoes endocytosis, and initiates an RNA-dependent RNA and protein synthetic process. If the original inoculum is large enough, secondary viremia occurs, with eventual viral migration into the CNS via cerebral capillary endothelial cells. Poorly described features of the virus increase microvascular permeability of the brain. Cell-to-cell spread then occurs via dendrites and axons. 

EEE is caused by a virus from the Alphavirus genus, which is part of the antigenically similar family of viruses known as Togaviridae. (Alphaviruses are also responsible for WEE and VEE.) These alphaviruses are spherical and have a diameter of 60-65 nm. The outer layer consists of a glycoprotein shell with protruding glycoprotein spikes found beneath the lipid bilayer. The nucleocapsid core contains the single-stranded RNA genome.

The alphavirus that causes EEE is found mostly in the mosquito subtype C melanura; other infectious subtypes include the Aedes and Coquillettidia species.C melanura mosquitoes breed in freshwater swamps and feed on passerine birds. The infected birds subsequently exhibit high levels of viremia, which differs from human and equine cases, in which viremia is often low. 

Passerine birds serve as an effective reservoir for continued mosquito infection. Regardless of the extent of viremia in the birds, the outcome varies, ranging from asymptomatic states to death. With low viremia in horses and humans, neither of these species acts as a reservoir for further viral distribution.

The only individual risk factor for EEE is age; however, certain behaviors can also be risk factors (eg, outdoor activities during peak mosquito activity, most often in rural areas).

Prevention

Prevent mosquito bites. There is no vaccine or preventive drug

  • Use insect repellent containing DEET, picaridin, IR3535 or oil of lemon eucalyptus on exposed skin and/or clothing. The repellent/insecticide permethrin can be used on clothing to protect through several washes. Always follow label directions.
  • Wear long sleeves and pants when weather permits.
  • Have secure, intact screens on windows and doors to keep mosquitoes out.
  • Eliminate mosquito breeding sites by emptying standing water from flower pots, buckets, barrels, and other containers. Drill holes in tire swings so water drains out. Keep children's wading pools empty and on their sides when they are not being used.

Diagnosis

The current Centers for Disease Control and Prevention (CDC) guidelines for diagnosis of an arbovirus infection require the presence of an acute febrile illness with encephalitis during a time when viral transmission is likely and at least 1 of the following criteria is met:

  • Greater than 4-fold increase in the viral antibody titer between acute and convalescent sera (often 10 weeks apart)
  • Isolation of the virus from CSF, blood, or tissue
  • Immunoglobulin M (IgM) positive to the organism in the CSF; presumptive positives can be made from the remaining biochemical assays (eg, hemoagglutinin inhibition, immunofluorescence, neutralization, complement fixation)

Prognosis

EEE has an infection rate of 33%. The average duration of hospitalization is 16-20 days. The prognosis in infected patients is extremely poor; 50-70% of patients die. The morbidity rate is approximately 90%, representing a wide range of mild to severe impairment. Only 10% of patients fully recover.

Currently, no clinical or radiographic prognostic indicators are available for EEE. The location and the type of lesion on imaging do not correlate with long-term sequelae or mortality. Additionally, although younger patients with longer prodromes tend to have better outcomes, no study has proven any statistical significance. The initial history and physical examination often do not reveal any prognostic variables.

Changes in treatment regimens do not commonly affect outcome; in fact, one series revealed a poorer outcome with the use of steroids and anticonvulsants, but many confounding variables were involved in this determination.

Certain laboratory findings may have some significance. The expected outcome in a patient with an elevated white blood cell (WBC) count (>500/μL) in cerebrospinal fluid (CSF) is poorer than that in a patient with a lower CSF WBC count (ie, < 500 cells/μL). In addition, the prognosis in a hyponatremic patient with a sodium level lower than 130 mmol/L is poorer than that in a patient with a higher sodium level.

Treatment

Consultations are obtained primarily for supportive measures. The following consultations may be helpful:

Infectious disease specialist - Particularly relevant when the etiology of the encephalitis or meningoencephalitis is difficult to determine (his or her most important contribution will likely be the ability to rapidly determine a potentially reversible cause of the patient’s symptoms)

  • Neurologist - May provide early insightful information and aid with the diagnosis (via EEG) and treatment of complications
  • Critical care specialist - Valuable for coordinating ICU care if a general practitioner is treating the patient
  • Neurosurgeon - Needed only for treatment of neurologic complications or performance of brain biopsy

Long-Term Monitoring

Patients who survive infection usually need extensive rehabilitation. On the basis of the duration of symptoms and the extent of neurospasticity, schedule the patient for physical therapy upon recovery. In addition, depending on the specific defect, a patient may need consultations with speech and auditory therapists.

Because of the potential for high neurologic morbidity, arrange coordinated care and quality follow-up care. Patients often require close neurodiagnostic follow-up care. The primary care physician must also be aware of subtle changes in behavior, intelligence, and motor skills.

Approach Considerations

Like all disease caused by alphaviruses, eastern equine encephalitis (EEE) has no specific treatment.[6] Focus management primarily on supportive and preventive measures. Pharmacologic therapy consists primarily of antipyretics, analgesics, and anticonvulsants. If the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is present, treat accordingly. 

Carefully stabilize the patient before any other activity. Once the patient is comatose, undertake obvious measures (eg, respiratory maintenance with ventilator support in a critical care unit [CCU]). Additionally, as with all critically ill patients, carefully provide adequate nutritional support. No special dietary restrictions exist. Transfer an infected patient to the intensive care unit (ICU) when appropriate. 

Assess the many issues secondary to the high mortality of the disease. Ensure that a social worker and appropriate hospital services staff are available to the patient’s family.

No direct surgical treatments for this disease are available, except for the appropriate neurologic measures necessary to deal with significant central nervous system (CNS) bleeding or the consequences of markedly elevated CNS pressure.

Resources

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