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Venezuelan Encephalitis
Article Last Updated: Oct 10, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Iris Reyes, MD, Advisory Dean; Director of Quality Improvement, Associate Professor, Department of Emergency Medicine, University of Pennsylvania
Iris Reyes is a member of the following medical societies: American College of Emergency Physicians
Coauthor(s):
Sarah M Perman, MD, Resident, Department of Emergency Medicine, University of Pennsylvania Health Systems;
William H Shoff, MD, DTM&H, Director, PENN Travel Medicine, Associate Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania;
Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM, Associate Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania; Director of Education and Research, PENN Travel Medicine
Editors: Martin J Wood, MD †, Former Consulting Staff, Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, UK; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance; Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital; Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Author and Editor Disclosure
Synonyms and related keywords:
Venezuelan equine encephalitis, Venezuelan encephalitis, VEE, Venezuelan equine encephalitis virus, encephalomyelitis, peste loca
Background
Venezuelan equine encephalitis (VEE) is an acute viral disease characterized by fever, chills, headache, nausea, vomiting, lumbosacral pain, and myalgia, which may progress to encephalitis. It is caused by the Venezuelan equine encephalitis virus and is a significant disease in the 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 spread to the United States. Venezuelan equine encephalitis was first recognized 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. Researchers determined that these infections were acquired from aerosolized virus. In 1952, the first naturally acquired human case of Venezuelan equine encephalitis was reported from Colombia, while 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. Recent 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.1
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 both equines and humans, the enzootic Venezuelan equine encephalitis virus serotypes ID, IE, and IIIA can cause illness in humans, but not equines. Mosquitos typically transmit the enzootic strains designated ID through F and II through VI among small mammals. The mammals, usually rodents, show few adverse effects from the viral infection. Venezuelan equine encephalitis virus is highly infectious by the aerosol route, and numerous laboratory infections have occurred.
Pathophysiology
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 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. Although Venezuelan equine encephalitis virus can be demonstrated in human throat swabs, human-to-human transmission never has been demonstrated. For approximately one 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 CNS via the blood stream 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.2
Frequency
United States
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.
International
In 1938, Venezuelan equine encephalitis virus was first isolated from brains of infected horses during an epidemic in Venezuela. Venezuelan equine encephalitis continues to occur most commonly in Central and South America. 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.
Mortality/Morbidity
Non-neurologic 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), with a case fatality rate of 20%.
Race
Venezuelan equine encephalitis has no racial predilection.
Sex
Venezuelan equine encephalitis has no sexual predilection.
Age
Venezuelan equine encephalitis occurs in all age groups, but children are more likely to develop fatal encephalitis.
History
Inapparent Venezuelan equine encephalitis (VEE) viral infections are rare. Venezuelan equine encephalitis virus infection manifests as influenzalike symptoms approximately 1-6 days after infection.
- Typical initial symptoms of infection include the acute onset of a severe headache with or without associated photophobia, chills, malaise, fever, myalgia, lumbosacral pain, nausea, vomiting, and prostration. 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.
- The duration of illness is usually 2-3 days, with a prolonged 1- to 2-week convalescence characterized by weakness and lethargy.
- Maternal infection may result in fetal demise or abortion. Congenital infection with CNS malformations has been reported.
Physical
- In humans, fever is the most common physical finding of Venezuelan equine encephalitis virus infection.
- Pharyngitis, conjunctival congestion, facial flushing, and, rarely, lymphadenopathy are among the sparse 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 one week after infection.
- The development of encephalitis in equines is related to the magnitude of viremia.
Causes
- Venezuelan equine encephalitis virus is a positive-strand, unsegmented 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.
- Venezuelan equine encephalitis virus is a member of the genus Alphavirus of the family Togaviridae. These viruses were known formally as group A arboviruses. Epizootic viral strains IAB and IC are virulent in both 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 one week after the mosquito bites an infected equine or rodent host. The virus is then transmitted when the mosquito feeds on an uninfected host.
Arenaviruses
Coxsackieviruses
Cytomegalovirus
Dengue Fever
Echoviruses
Hepatitis, Viral
Herpes Simplex
Infectious Mononucleosis
Influenza
Leptospirosis
Listeria Monocytogenes
Lyme Disease
Malaria
Meningitis
Meningococcal Infections
Meningococcemia
Naegleria Infection
Norwalk Virus
Picornavirus-Overview
Q Fever
St. Louis Encephalitis
West Nile Encephalitis
Yellow Fever
Other Problems to be Considered
Any of the arthropod-borne viral diseases in their various forms not listed above might be mistaken for Venezuelan equine encephalitis (VEE). Acute HIV infection
Poliomyelitis
Colorado tick fever
Measles (rubeola)
Lab Studies
- 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.
- Levels of transaminases, particularly serum aspartate transaminase and lactate dehydrogenase, may be elevated in Venezuelan equine encephalitis (VEE).
- In patients who are severely ill with Venezuelan equine encephalitis, hepatic compromise may produce abnormalities in liver synthetic function testing.
- 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.
- Both eosinopenia and vacuolated monocytes have been described.
- Thrombocytopenia may also be observed.
- Urinalysis as part of the evaluation of other sources of infection is common. Urine culture and blood culture studies are case dependent.
- 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.
- 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 immunoglobulin G (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.
Imaging Studies
- Chest radiography and head 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.
Procedures
Lumbar puncture (LP) 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.
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.
Medical Care
Patients with non-neurologic Venezuelan equine encephalitis (VEE) virus infection generally require only supportive care, including fluid management for dehydration and electrolyte derangement caused by fever and vomiting. - 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.
- When possible, neurosurgical evaluation and treatment of secondary bacterial infection significantly improve the prognosis. Monitoring for increased intracranial pressure is beneficial.
- Prevention and treatment of secondary bacterial infection significantly improve the patient's prognosis.
- Trials are currently underway to develop a vaccine for Venezuelan equine encephalitis. V3526, a compound currently under investigation, is similar to TC-83, a previously studied compound. However, V3526 has improved immunogenicity. 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.3
Consultations
Neurosurgical evaluation and monitoring for increased intracranial pressure, when possible, is beneficial.
No specific treatment for Venezuelan equine encephalitis (VEE) infections exists.
Drug Category: Anticonvulsants
These agents are used to prevent seizure recurrence and to terminate clinical and electrical seizure activity.
| Drug Name | Phenytoin (Dilantin) |
|---|
| Description | Used for seizures. May act in motor cortex, where it may inhibit spread of seizure activity. Activity of brainstem centers responsible for tonic phase of grand mal seizures may also be inhibited. Dose should be individualized. Administer larger dose before retiring if dose cannot be divided equally. |
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| Adult Dose | Loading: 15-20 mg/kg PO/IV once or divided doses, followed by 100-150 mg per dose at 30-min intervals
Initial: 100 mg (125 mg susp) IV/PO tid
Maintenance: 300-400 mg/d PO/IV divided tid or qd/bid if using ER; increase to 600 mg/d (625 mg/d susp) may be necessary; not to exceed 1500 mg/d
Rate of infusion must not exceed 50 mg/min to avoid hypotension and arrhythmia |
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| Pediatric Dose | Loading: 15-20 mg/kg PO/IV once or divided doses
Initial: 5 mg/kg/d PO/IV divided bid/tid
Maintenance: 4-8 mg/kg PO/IV divided bid/tid
<6 years: Not established
>6 years: May require minimum adult dose (300 mg/d); not to exceed 300 mg/d |
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| Contraindications | Documented hypersensitivity; hypotension; second- and third-degree AV block |
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| Interactions | Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase phenytoin toxicity; phenytoin effects may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate; phenytoin may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, and valproic acid |
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| Pregnancy | D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
|
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| Precautions | Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if a skin rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in acute intermittent porphyria and diabetes (may elevate blood sugars); discontinue use if hepatic dysfunction occurs |
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| Drug Name | Carbamazepine (Tegretol) |
|---|
| Description | Used for seizures. Indicated for complex partial seizures and trigeminal neuralgia. May block posttetanic potentiation by reducing summation of temporal stimulation. Following a therapeutic response, may reduce dose to minimum effective level or discontinue treatment at least once q3mo. |
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| Adult Dose | 200 mg PO bid (100 mg PO qid susp); increase at weekly intervals by no more than 200 mg/d tid/qid (bid with ER) until best response obtained; not to exceed 1600 mg/d |
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| Pediatric Dose | <6 years: 10-20 mg/kg/d PO bid/tid (qid susp), increase weekly to achieve optimal clinical response tid/qid; not to exceed 100 mg/d
6-12 years: 100 mg PO bid (50 mg qid susp), increase gradually every wk by adding 100 mg/d PO divided tid/qid (bid with ER) until best response is obtained; not to exceed 1000 mg/d
>12 years: Administer as in adults; not to exceed 1000 mg/d in children aged 12-15 y or 1200 mg/d if >15 y |
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| Contraindications | Documented hypersensitivity; history of bone marrow depression; administration of MAOIs within last 14 d |
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| Interactions | Serum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; carbamazepine may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels) |
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| Pregnancy | D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
|
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| Precautions | Do not use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBCs and serum iron baseline levels prior to treatment, during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness |
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Transfer
- Patients with neurologic manifestations of Venezuelan equine encephalitis (VEE) should be transferred to a facility that can provide intensive care treatment, if necessary.
Deterrence/Prevention
- Mass vaccinations of equines can prevent Venezuelan equine encephalitis outbreaks in equines and humans. Once an outbreak has been identified, equines in threatened areas should be vaccinated.
- Large-scale aerial insecticide applications may decrease the number of disease-carrying mosquitoes.
- Immunization of laboratory workers exposed to Venezuelan equine encephalitis with live attenuated (TC-83) and formalin-inactivated (C-84) vaccines is recommended. However, these are not licensed for general public use.
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.
Prognosis
- Complete recovery is expected within several weeks of infection in non-neurologic cases of Venezuelan equine encephalitis virus infection.
- 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.
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 excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Encephalitis.
Medical/Legal Pitfalls
- Failure to obtain a travel history in patients who have ventured into endemic areas during an outbreak of Venezuelan equine encephalitis, limiting the ability to obtain an appropriate diagnosis
- Figueiredo LT. Emergent arboviruses in Brazil. Rev Soc Bras Med Trop. Mar-Apr 2007;40(2):224-9. [Medline].
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- Fine DL, Roberts BA, Teehee ML, et al. Venezuelan equine encephalitis virus vaccine candidate (V3526) safety, immunogenicity and efficacy in horses. Vaccine. Feb 26 2007;25(10):1868-76. [Medline].
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- Phillpotts RJ, O'brien L, Appleton RE, et al. Intranasal immunisation with defective adenovirus serotype 5 expressing the Venezuelan equine encephalitis virus E2 glycoprotein protects against airborne challenge with virulent virus. Vaccine. Feb 18 2005;23(13):1615-23. [Medline].
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Venezuelan Encephalitis excerpt Article Last Updated: Oct 10, 2008
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