Venezuelan Equine Encephalitis 

Updated: Jun 02, 2021
Author: Robert W Derlet, MD; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

Venezuelan equine encephalitis is an acute mosquito-transmitted disease characterized by fever, chills, headache, nausea, vomiting, lumbosacral pain, and myalgia.[1, 2, 3, 4]  Severe cases may  progress to encephalitis. It is caused by the Venezuelan equine encephalitis virus and has a significant presence in the tropical Americas. Epidemics of Venezuelan equine encephalitis involving tens of thousands of humans and hundreds of thousands of equines have been reported. Although predominantly a disease found in South and Central America, Venezuelan equine encephalitis has been reported in southern border areas of the United States.[5]

Venezuelan equine encephalitis may have been present for centuries as one of many undiagoised fevers common in the tropical Americas. The disease was first recognized as a unique mosquito borne virus in horses in Venezuela in 1938. In 1943, the first descriptions of Venezuelan equine encephalitis in humans were reported from laboratories where equine isolates were being characterized. In 1952, the first naturally acquired human case of Venezuelan equine encephalitis was reported from Colombia, whereas the first reported natural human infection in the United States was not documented until 1968.

A 1995 outbreak of Venezuelan equine encephalitis in Colombia and Venezuela affected an estimated 75,000 humans; 3000 people developed neurologic complications, and 300 fatalities occurred. Of the estimated 50,000 equines infected, 8% died of the disease. This was the first major epidemic of Venezuelan equine encephalitis in 22 years. The extensive transmission of the virus was probably due to a combination of unvaccinated horses and a record high level of rainfall leading to an increase in the mosquito population. 

Studies have begun to document a geographic spread of Venezuelan equine encephalitis. As new communications are created between countries, vector spread of the virus has been documented. Over the past few years, Venezuelan equine encephalitis has been found in Brazil and the northern countries of South America. This can be attributed to new trade routes being established and maintained.[6]

Major outbreaks involving humans have been associated with Venezuelan equine encephalitis subtype I, varieties AB and C. The IA and IB strains are considered genetically indistinguishable and are thus classified as IAB. While these epizootic strains are virulent in equines and humans, the enzootic Venezuelan equine encephalitis virus serotypes ID, IE, and IIIA can cause illness in humans but not in equines. All natural transmission of Venezuelan equine encephalitis is via mosquitoes.

Although a mosquito-transmitted disease, researchers determined that these infections can also be acquired from aerosolized virus. Venezuelan equine encephalitis virus is highly infectious by the aerosol route, and numerous laboratory infections have occurred, making it a possible biowarfare agent. For this reason the US Army has been active in vaccine development resaerch.

Go to Encephalitis and Viral Encephalitis for complete information on these topics.

Patient Education

Recognition of signs and symptoms of illness by those living and working in endemic areas is essential to limit the spread of Venezuelan equine encephalitis.

For patient education information, see the Brain and Nervous System Center, as well as Encephalitis.

Etiology

Venezuelan equine encephalitis virus is a positive-strand, unsegmented ribonucleic acid (RNA) virus. A lipid membrane encapsulates the icosahedral nucleocapsid. Two outwardly projecting glycoproteins, E1 and E2, are inserted in the lipid membrane surrounding the nucleocapsid. E2 appears to be primarily responsible for attachment of the viruses to cell surfaces. Antibodies to E2 can neutralize virus infectivity.[7]

Venezuelan equine encephalitis virus is a member of the genus Alphavirus of the family Togaviridae.[5] These viruses were known formally as group A arboviruses. Epizootic viral strains IAB and IC are virulent in humans and equines. Enzootic Venezuelan equine encephalitis serotypes ID, IE, and IIIA are avirulent in equines but can cause illness in humans.

Venezuelan equine encephalitis is an arthropod-borne virus, with the mosquito serving as the most common vector. The virus incubates in the mosquito for 1 week after the mosquito bites an infected equine or rodent host. The virus is then transmitted when the mosquito feeds on an uninfected host.

Venezuelan equine encephalitis has a zoonotic reservoir in bats, birds, rodents, equines (horses, donkeys, mules), and certain tropical jungle mammals. Rodents and other small animals are the most important amplifiers in endemic preservation of the virus in tropical forests, swamps, and marshlands. Horses are the most important amplifier hosts in large epidemic outbreaks.[8, 9]

Alphaviruses are limited in their geographic spread primarily by the presence of an appropriate competent arthropod vector. At least 10 mosquito species, including Aedes, Culex, Psorophora, Mansonia, and Deinocerites species, have been identified as probable epidemic vectors for the Venezuelan equine encephalitis virus, with different mosquito vectors possessing varying levels of efficiency. The principal vector for humans is A aegypti.

The mosquito vector becomes infected after biting a viremic equine host. Humans can develop a viremia significant enough to infect mosquitos, but humans never have been directly implicated in epidemic transmission.

For approximately 1 week, the virus replicates in the midgut epithelium of the mosquito. The virus then is disseminated to other organs, including the hemolymph and salivary glands. Spread to humans occurs when the infected mosquito deposits the virus in the skin of a naïve host while feeding. Viremia and a febrile response mark the initial phase of infection, during which the virus replicates in extraneural tissues. Sites of human replication remain unclear, but, in equines and laboratory rodents, the sites include skeletal muscle, lymphoid, and hematopoietic tissues. This may lead to relative lymphopenia, neutropenia, and thrombocytopenia.

Circulating virus gains access to the central nervous system (CNS) via the bloodstream or perhaps via the olfactory apparatus. Neuronal infection with Venezuelan equine encephalitis is associated with the onset of acute encephalitis and cell death by apoptosis.[10]

Although Venezuelan equine encephalitis virus can be demonstrated in human throat swabs, human-to-human transmission never has been conclusively demonstrated. However, the Centers for Disease Control and Prevention (CDC) extensively analyzed the 1995 Venezuelan equine encephalitis outbreak in northwest Colombia and reported a 5% secondary household attack rate.[11] Whether these secondary attacks were from bites by mosquitoes infected from animals or humans was unclear. At the present time, direct human-to-human transmission is not scientifically proven but is suspected.

Epidemiology

Outbreaks of Venezuelan equine encephalitis in the United States have been rare. From 1969-1972, a major outbreak of Venezuelan equine encephalitis involving much of Central America spread to Texas. Approximately 1500 horses died of Venezuelan equine encephalitis in Texas, and several hundred humans were infected.

Western equine encephalitis and eastern equine encephalitis alphaviruses are those most associated with a similar infection in the United States. Strains nonvirulent to equines (subtypes 1D and 1E) have caused sporadic infection in Central America and Florida. The mosquito vector and the rodents that live in tropical swamps and forests maintain these strains of Venezuelan equine encephalitis viruses.

Changing climatic patterns may favor establishment of the virus in wild rodents in warmer areas of the United States.

Venezuelan equine encephalitis continues to occur most commonly in Central and South America.[12] Tens of thousands of humans and hundreds of thousands of equine infections have resulted from periodic epidemics in these areas. Spread tends to occur to areas contiguous to the site of the outbreak.

Human seroprevelance in rural areas of Mexico has been reported to be more than 60% in older age groups. Thus, mild or asymptomic infections may be more common than previously believed.[13]

Data from epidemics demonstrate that children have the highest risk of acquiring moderate or severe forms of the infection.

Prognosis

Nonneurologic infections are self-limited, and complete recovery generally occurs within several weeks of onset. The overall fatality rate is less than 1%. Neurologic manifestations occur at a rate of 4-14% in infected children (< 1% in adults).

The fatality rate is approximately 20% in older children and young adults who develop acute encephalitis, but it is as high as 35% in persons aged 0-5 years.

Complications

Chronic neurologic deficits, such as dysarthria, motor disorders, abnormal reflexes, and affective disorders, may occur in patients who survive an episode of acute encephalitis. An increased risk for spontaneous abortions has been noted during Venezuelan equine encephalitis epidemics.

 

Presentation

History

Patients give a history of exposure to mosquitoes in an area endemic for Venezuelan equine encephalitis. Suspect Venezuelan equine encephalitis and dengue fever in anyone with a febrile illness who has recently traveled in rural areas of Central America or tropical South America.

 Venezuelan equine encephalitis virus infection manifests as influenzalike symptoms approximately 1-6 days after infection. Subclinical infections occur, but the incidence is unknown.

Typical initial symptoms of infection include  fatigue, weakness, malaise, fever, chills, myalgia, lumbosacral pain, nausea, vomiting, and prostration.  Severe headache with or without associated photophobia may also be reported. Fever may abate in a few days, followed by recrudescence the following day. These initial symptoms may be followed by diarrhea and a sore throat.

Most Venezuelan equine encephalitis virus infections in humans are relatively mild, with symptoms lasting 3-5 days.

Children are at particular risk to progress to clinical CNS involvement, especially encephalitis. Symptoms of CNS involvement include disorientation, somnolence, nuchal rigidity, convulsions, inappropriate antidiuretic hormone (ADH) secretion, paralysis, coma, and death.

Most persons have resolution of symptoms after 5 days; however, a subset of infected persons may remain symptomatic for as long as 2 weeks.

Maternal infection may result in fetal demise or abortion. Congenital infection with CNS malformations has been reported.

Physical Examination

In humans, fever is the most common physical finding of Venezuelan equine encephalitis virus infection. Tahcycardia, pharyngitis, conjunctival congestion, facial flushing, and, rarely, lymphadenopathy are among the  physical findings found in mild forms of Venezuelan equine encephalitis. Some patients may progress to exhibit somnolence, photophobia, and mild confusion.

The few patients with Venezuelan equine encephalitis who develop severe neurologic compromise develop significant physical findings, including nuchal rigidity, stupor, delirium, coma, nystagmus, cranial nerve palsies, pathologic reflexes, ataxia, and spastic paralysis. Tremors, abnormal movement disorders, and visual field defects are uncommon.

In equines, signs of infection, including fever, tachycardia, anorexia, and depression, usually appear approximately 2 days after infection. Encephalitis develops in some of these animals within 5-10 days of infection. The animals may show signs of circling, ataxia, and hyperexcitability. Death usually occurs approximately 1 week after infection. The development of encephalitis in equines is related to the magnitude of viremia.

 

DDx

Diagnostic Considerations

Any of the arthropod-borne viral diseases in their various forms not listed above might be mistaken for Venezuelan equine encephalitis.

Conditions to consider in the differential diagnosis of Venezuelan equine encephalitis, in addition to those in the next section, include the following:

  • Japanese encephalitis

  • Western equine encephalitis

  • Eastern equine encephalitis

  • Acute HIV infection

  • Poliomyelitis

  • Colorado tick fever

  • Measles (rubeola)

  • Listeria monocytogenes

  • Lyme disease

  • Malaria

  • Meningitis

  • Meningococcal infections

  • Meningococcemia

  • Naegleria infection

  • Norwalk virus

  • Picornavirus

  • Q fever

  • Echoviruses

  • Viral hepatitis

  • Herpes simplex

Differential Diagnoses

 

Workup

Approach Considerations

Encephalitis is clinically diagnosed in 2-4% of adults and in 3-5% of children infected with the virus.

In patients presenting to the emergency department (ED) with a febrile illness, perform standard laboratory tests, including a complete blood count (CBC), electrolyte assessment, liver function tests, urinalysis, and other tests as indicated by the history and physical examination. The results of most laboratory studies in patients infected with Venezuelan equine encephalitis are nonspecific for febrile illnesses.

Electrolytes, blood glucose, renal function

Routine laboratory studies for the evaluation of an acutely ill patient with fever and headache is likely to include evaluation of electrolytes, blood glucose, and renal function.

Transaminases

Levels of transaminases, particularly serum aspartate transaminase and lactate dehydrogenase, may be elevated in Venezuelan equine encephalitis.

Liver function testing

In patients who are severely ill with Venezuelan equine encephalitis, hepatic compromise may produce abnormalities in liver synthetic function testing.

Liver function testing may reveal elevated lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) levels.

CBC count

A CBC count for analysis of the white blood cell count, hemoglobin, and platelet count is usually included in the evaluation. A decreased lymphocyte or a lymphocyte and granulocyte count 1-3 days after onset of symptoms is common.

Eosinopenia and vacuolated monocytes have been described. Lymphopenia and thrombocytopenia may also be observed.

Urinalysis and cultures

Urinalysis as part of the evaluation of other sources of infection is common. Urine culture and blood culture studies are case dependent.

Viral isolation

A specific diagnosis of Venezuelan equine encephalitis may be made with isolation of virus in the blood or from a throat swab within 1-3 days after onset of symptoms.

Lumbar puncture

Lumbar puncture with analysis of the obtained cerebrospinal fluid (CSF) is essential in reaching a diagnosis and determining the severity of illness. In patients with Venezuelan equine encephalitis, CSF analysis typically reveals a mononuclear pleocytosis of several hundred cells with a glucose concentration within the reference range.

Serologic Studies

Sera from patients with full-blown Venezuelan equine encephalitis are usually negative for the virus, but the diagnosis can be made using serologic studies.

Enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and neutralization tests can be used to identify the virus. Immunoglobulin M (IgM) and IgG ELISA, using attenuated Venezuelan equine encephalitis as the antigen, are most sensitive but need to be followed by plaque reduction neutralization to provide diagnostic specificity. Demonstration of a 4-fold rise in serum antibody titer is also useful diagnostically.

Serum can also be sent to a laboratory with the ability to test for Venezuelan equine encephalitis and other, similar diseases using ultrasensitive qualitative detection by reverse transcription coupled real-time polymerase chain reaction (PCR) assay. Diagnostic methods also include microsphere-based immunoassay (MIA).

Imaging Studies

Chest radiography and head computed tomography (CT) scanning may be helpful adjuncts in assessing the complications of Venezuelan equine encephalitis or in helping to eliminate other diagnostic possibilities.

Interstitial infiltrates on chest radiography indicate acute pneumonitis, which is occasionally observed in patients with Venezuelan equine encephalitis. A CT scan of the head that reveals edema or hemorrhage necessitates emergency intervention. Magnetic resonance imaging (MRI) may also be useful in establishing the diagnosis of encephalitis.

Histologic Findings

Death due to Venezuelan equine encephalitis follows diffuse congestion and edema with hemorrhage in the brain, gastrointestinal tract, and lungs. Pathologic changes in the brain include congestion, perivascular cuffing and hemorrhage, glial nodule formation, and focal necrosis. The pathology is most prominent in the basal ganglia and substantia nigra but is also found in the cerebral cortices and deep white matter. Meningoencephalitis with necrotizing vasculitis and cerebritis has been observed in some patients. Hepatocellular degeneration and interstitial pneumonitis have been noted in fatal human infections.

Equine infections are characterized by a striking depletion of lymphocytes in the lymph nodes, spleen, and gastrointestinal tract.

 

Treatment

Approach Considerations

No specific treatment other than supportive care is available. Venezuelan equine encephalitis virus is an RNA virus; therefore, antivirals that have been successful against deoxyribonucleic acid (DNA) viruses are ineffective. Treatment of Venezuelan equine encephalitis is symptomatic and in the ED most likely involves correcting fluid deficiencies.

Patients with neurologic manifestations of Venezuelan equine encephalitis should be transferred to a facility that can provide intensive care treatment, if necessary.

Supportive care in nonneurologic Venezuelan equine encephalitis

Patients with nonneurologic Venezuelan equine encephalitis virus infection generally require only supportive care, including fluid management for dehydration and electrolyte derangement caused by fever and vomiting.

Supportive care in Venezuelan equine encephalitis with neurologic manifestations

Patients with neurologic manifestations of Venezuelan equine encephalitis require prompt supportive care to reduce the risk of mortality.

Appropriate measures include standard anticonvulsant therapy as treatment for seizures; fluid management for dehydration and electrolyte imbalance produced by fever, vomiting, decreased oral intake, and inappropriate ADH secretion; and proper airway and respiratory management in those progressing to coma.

Neurosurgical evaluation and monitoring for increased intracranial pressure are beneficial. Prevention and treatment of secondary bacterial infection significantly improve the patient's prognosis.

Consultations

Contact an infectious disease specialist if Venezuelan equine encephalitis is suspected. In addition, involve the county and/or state health department. Neurosurgical evaluation and monitoring for increased intracranial pressure, when possible, is beneficial.

Vaccine Development

Animal models used in vaccine development include hamsters, rabbits, mice, and guinea pigs. A vaccine has been developed for horses.[14, 15]  Cross reactivity and protection in horses has also been described with related alpha viruses including Eastern Equine Encephalitis, and Western Equine Encephilitis.

Human trials are currently underway to develop a vaccine for Venezuelan equine encephalitis. A phase 2 clinical trial sponsored by the US Army Research and Development Command is expected to be completed in 2023 using C-84 is a formalin-inactivated vaccine. Live attenuated vaccines, V3526, and TC-83 are also under investigation. Studies have shown that the V3526 vaccine has been safe and efficacious in the treatment of horses. Vaccination with V3526 results in a lack of detectable viremia; however, further research is needed to determine whether this vaccine will safely confer immunity in humans.[16, 17, 18]

Deterrence and Prevention

Protection from mosquito bites in endemic areas is important. Visitors to endemic areas should take appropriate precautions to avoid mosquito bites, including proper clothing, insect repellant, and mosquito nets. Large-scale aerial insecticide applications may decrease the number of disease-carrying mosquitoes.

 

Medication

Medication Summary

No specific medications are approved for treatment of Venezuelan equine encephalitis. In vitro laboratory studies suggest ribavirin and other nucleoside analogues may be appropriate, but these have not been used clinically in humans.

Anticonvulsants

Class Summary

These agents are used to prevent seizure recurrence and to terminate clinical and electrical seizure activity.

Phenytoin (Dilantin, Phenytek)

Phenytoin is used for seizures. It may act in the motor cortex, where it may inhibit the spread of seizure activity. The activity of brain stem centers responsible for the tonic phase of grand mal seizures may also be inhibited. The dose should be individualized. Administer a larger dose before retiring if the dose cannot be divided equally.

Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro)

This is used for seizures. It is indicated for complex partial seizures and trigeminal neuralgia. Carbamazepine may block posttetanic potentiation by reducing the summation of temporal stimulation. Following a therapeutic response, the drug dose may be reduced to its minimum effective level or treatment may be discontinued at least once every 3 months.

Antipyretics

Class Summary

These agents are helpful in relieving the associated lethargy, malaise, and fever associated with the disease.

Acetaminophen (Acephen, Feverall, Tylenol)

Acetaminophen inhibits the action of endogenous pyrogens on heat-regulating centers and reduces fever by a direct action on the hypothalamic heat-regulating centers, which, in turn, increases the dissipation of body heat via sweating and vasodilation.