Equine Encephalomyelitis: Introduction - The Merck Veterinary Manual

Equine Encephalomyelitis: Introduction
(Equine encephalitis)

Etiology and Epidemiology

Pathogenesis and Clinical Findings

The equine encephalitides are clinically similar and are characterized by signs of CNS dysfunction and moderate to high mortality. Arboviruses are the most common cause of equine encephalitis, but Sarcocystis neurona ( Sarcocystosis: Introduction) and Neospora sp ( Neosporosis: Introduction) may also cause encephalitis. Arboviruses are transmitted by mosquitos or other hematophagous insects and infect a variety of vertebrate hosts, sometimes including humans, and may cause serious disease. In the western hemisphere, most pathogenic arboviruses use a mosquito to bird or rodent cycle.

Etiology and Epidemiology:

The most pathogenic viruses for horses are alphaviruses of the family Togaviridae. These species include Eastern, Western, Highlands J, and Venezuelan viruses. Other alphaviruses associated occasionally with equine encephalitis are Semliki Forest, Ross River, and Una viruses. These viruses are not found in North America and only infrequently cause clinical disease. The Eastern equine encephalomyelitis (EEE) virus, although one virus, has 2 distinct antigenic variants that function as separate viruses. The North American variant is the most pathogenic and the most antigenically homogenous. It is found in eastern Canada; all states within the USA east of the Mississippi River and in Arkansas, Minnesota, South Dakota, and Texas; and in the Caribbean Islands. The South American virus is less pathogenic and more heterogeneous and is found in central and South America. Subtypes of the Western equine encephalomyelitis (WEE) group consist of WEE, Sindbis, Aura, Ft. Morgan, and Y 62-33. WEE is found in western Canada, states in the USA west of the Mississippi, and in Mexico and South America. The Highlands J (HJ) virus was originally classified as a subgroup of WEE but has subsequently been shown to be a distinct alphavirus. WEE previously isolated in the eastern USA has been shown to belong to the HJ virus serogroup. Venezuelan equine encephalomyelitis (VEE) has 6 antigenically related subtypes: subtype I (VEE), Everglades, Mucambo, Pixuna, Cabassou, and AG80-663. Within subtype I are 5 serovars. Until 1993, only subtype I, serovars A/B and C, caused sporadic epizootics in horses; other subtypes and variants cause enzootic or sylvatic cycles and appear to be nonpathogenic to equids. In 1993, however, an epizootic in Mexico was caused by subtype I, serovar E. Sylvatic or enzootic subtypes of VEE are found annually in tropical and subtropical areas of the USA, Mexico, and Central and South America. Sylvatic subtype II (Everglades) has been isolated from humans and mosquitos in Florida; subtype III has been isolated in the Rocky Mountains and northern plains states. Epizootic strains are not generally found in the USA, although there was an epizootic of VEE in 1971.

The principal means of transmission and amplification of EEE is a mosquito-vertebrate-mosquito cycle. EEE has been isolated from 27 different mosquitos in the USA. The primary mosquito vector for the enzootic or sylvatic cycle of EEE is Culiseta melanura . Population densities of C melanura are highest deep in the interior of swamp habitats, where most of the enzootic transmission of EEE occurs. During late summer and early fall, mosquitos leave the swamp breeding sites and move to drier, upland forested habitats. Epizootics in equids, epornitics in pheasant and quail, and human cases are seen when virus infection rates are high in birds. Aedes vexans and A canadensis mosquitos (which breed in containers) are believed to be responsible for bird to mammal transmission. The identification of vectors in epidemics is difficult because no single species is consistently associated with the transmission of the virus to horses and people.

Seasonal changes in C melanura biology and their relationship to EEE virus transmission vary with the geographic location and its associated climate. In subtropical areas (eg, Florida), transmission occurs throughout the year with a peak in summer. In more temperate regions, there is a distinct transmission season. The virus is not detected until midsummer and can remain active until the first heavy frost. Virus is isolated most often in late August through November. The mechanism of viral persistence during the winter in temperate areas, where transmission is not continuous, remains unknown. It is possible that sporadic epizootics result from adult mosquitos surviving periods of inactivity, long distance movement of infected vectors by wind currents occurs, or migration of infected hosts (birds), and subsequent climactic conditions favorable to mosquito proliferation. In South America, serologic studies suggest that forest-dwelling rodents and marsupials are the vertebrate hosts. EEE is readily recovered from sentinel mice and hamsters.

WEE is transmitted by mosquito vectors (primarily C tarsalis ) that breed in sunlit marshes and in pools of irrigation water in pastures and by the tick Dermacentor andersoni . Epizootics of WEE are associated with increased rainfall in early spring followed by warmer than normal temperatures.

Sylvatic VEE viruses are found throughout North, Central, and South America in jungle or swampy environments with persistent fresh or brackish water. The mosquitos that serve as the primary vectors for the bird- or rodent-mosquito life cycle are members of the subgenus Culex .

All subtypes of the VEE virus are serologically related and provide cross-protection against infection with epizootic VEE virus. The origin of epizootic strains is unknown and does not appear to have any relationship with the sylvatic subtypes. No single vector has been associated with transmission of the epizootic VEE virus—many mosquitos and other hematophagous insects have been incriminated. Epizootics of VEE appear sporadically in Central and South America. In 1993, an epizootic occurred in Chiapas, Mexico, caused by VEE subtype I, serovar E, which had not previously been associated with clinical disease outbreaks.

Viruses belonging to the family Flaviviridae and Bunyaviridae are less pathogenic than the Togaviridae. Flaviviruses present in the USA prior to 1999 that have been associated with encephalitis in horses are the St. Louis encephalitis virus and the Japanese B virus. The former is primarily a human pathogen found from central Canada to Argentina and is transmitted among birds by Culex mosquitos. Encephalitis can be produced experimentally in horses, but most naturally occurring infections in horses are asymptomatic. Japanese B virus is found throughout the Far East and is associated with clinical disease, although mortality is low.

In 1999, clinical disease caused by West Nile virus (WNV, West Nile Encephalomyelitis: Introduction), which is antigenically related to Japanese B virus, was seen in the USA in New York state in horses and humans as well as in birds, the primary vertebrate host. Since then, the virus has been found in 27 different species of mosquitos and >150 species of birds in the USA in 48 states and is now considered endemic. The viral strain of WNV in the USA is more pathogenic than the endemic strains found in Africa, Asia, and the Middle East, which is thought to result from a change in viral biology. WNV infection follows the pattern of EEE, occuring seasonally in temperate regions and throughout the year in subtropical areas.

Cache Valley virus (transmitted by mosquitos and Culicoides sp among rabbits), Maindrain virus (transmitted by Culicoides varipennis to hares and rodents in the western USA), and Snowshoe hare virus (transmitted by Culiseta and Aedes mosquitos among rabbits in southern Canada and northern USA) have all been identified, although infrequently, as the cause of encephalitis in horses.

Pathogenesis and Clinical Findings:

Head pressing, horse

The pathogenesis and clinical signs are similar for the alphaviruses. After inoculation by the vector, the virus travels via the lymphatics to lymph nodes and replicates in macrophages and neutrophils, resulting in lymphopenia, leukopenia, and fever. Subsequent replication occurs in other organs and is associated with viremia. Initially, horses are quiet and depressed with clinical neurologic signs generally occurring 5 days after infection. Any and all signs attributable to cortical and thalamic lesions may be seen, as well as brain-stem deficits as the neurologic signs progress. The lesions are not necessarily symmetrically distributed; therefore, neurologic deficits may be asymmetric. Clinical signs include altered mentation, impaired vision, aimless wandering, head pressing, circling, inability to swallow, irregular ataxic gait, paresis and paralysis, convulsions, and death. Most deaths occur within 2-3 days after onset of clinical signs.

In contrast, neurologic lesions in WNV are more prevalent in the brain stem than the cortical and thalamic regions, with lesions often increasing in number in the spinal cord. Thus, horses with WNV may present with signs of spinal cord ataxia, hyperesthesia, and muscle fasiculations without cortical signs. Fever occurs in <25% of horses with clinical disease from WNV.

Horses infected with the EEE virus have a transient but significant viremia and may, under circumstances of a large vector population and a large population of nearby horses, provide transient amplification of the virus. Horses infected with WEE and WNV do not have a significant viremia; therefore, they do not amplify the virus and are true dead-end hosts. Horses infected with the sylvatic subtypes of VEE are also dead-end hosts; however, horses infected with epizootic strains of VEE have a persistent and significant viremia that results in virus shedding in body fluids. Infection may pass from horse to horse via aerosolized respiratory secretions or direct contact. Horses infected with the epizootic strains of VEE are systemically ill, and many die without showing neurologic signs. Asymptomatic infections may occur with all viruses. Mortality of horses showing clinical signs from WEE is 20-50%, from EEE 50-90%, from VEE 50-75%, and from WNV 20-40%. Horses with clinical neurologic signs from alphavirus infection that recover have a high incidence of residual neurologic deficits, whereas many horses that recover from WNV have been reported to have no residual neurologic deficits.

Diagnosis:

A presumptive diagnosis may be made on the basis of clinical signs, the location of the affected horse(s), and season of the year. A specific diagnosis can be made only by virus isolation and identification or by detecting a specific increase in antibody titer between paired acute and convalescent sera. CSF from arbovirus-infected horses has an increased nucleated cell count (>50 cells/µL) that consists primarily of mononuclear cells and an increased protein concentration (>70 mg/dL). The virus may be isolated from the CSF of horses with acute infections. By the time neurologic signs are seen, viremia has ended; thus, virus isolation from blood is best attempted from febrile herdmates.

Serologic tests for acute and convalescent sera consist of hemagglutination inhibition, complement fixation, virus neutralization (PRNT), and antibody capture ELISA for IgM. Hemagglutination inhibition antibody cross-reacts among EEE, WEE, and VEE, but virus neutralizing antibody does not. By performing all 3 serologic tests, it is possible to differentiate between viruses. Antibody capture ELISA for IgM is specific for EEE and can be used to differentiate EEE from WEE; however, it will not distinguish between vaccinated and infected animals. WNV antibodies develop early after infection but not after vaccination; thus, IgM capture ELISA for these antibodies may be used to determine recent infection. Caution should be used in diagnosing VEE in regions where the sylvatic subtypes of the virus are found, as subtypes cross-react in serologic tests. Because virus neutralizing antibodies appear at the end of viremia and may precede the appearance of neurologic signs, paired samples may not show a 4-fold increase in horses with neurologic signs. Paired samples from febrile herdmates may be more diagnostic. Maternal antibodies may interfere with serodiagnosis in young foals.

In dead animals, the brain should be examined microscopically for the presence of nonsuppurative meningoencephalitis. Virus isolation should also be attempted from the brain (and from the spinal cord if WNV is suspected) of dead animals. Antigen capture ELISA for EEE and WNV may be used to help identify the virus in brain tissue. Immunohistochemistry and PCR may also be used to identify virus in neurologic tissue.

Differential diagnoses include rabies, hepatoencephalopathy, leukoencephalomalacia, protozoal encephalomyelitis, equine herpesvirus 1, verminous meningoencephalomyelitis, cranial trauma, botulism, and meningitis. Differential diagnoses for horses suspected to have WNV infection include hypocalcemia, tremorgenic toxicities, and compression of the spinal cord.

Treatment:

There is no specific therapy for viral encephalitis. Supportive care includes fluids if the horse is unable to drink, judicious use of anti-inflammatory agents, and anticonvulsants if necessary. Good nursing care is essential.

Prevention:

Susceptible horses should be vaccinated with formalin-inactivated viral vaccines for EEE, WEE, and VEE. Vaccines are commercially available in the mono-, bi-, or trivalent form. The viral strain of VEE in vaccines is TC-83, which was originally developed as a modified live inoculation to protect laboratory workers investigating VEE. The modified live vaccine was used in the 1971 outbreak of VEE in the USA and conferred immunity as soon as 3 days after inoculation. Horses vaccinated with this agent developed a transient viremia and often showed mild signs of illness. To address concerns that the virus would revert to the wild type, this strain is now inactivated in currently available vaccines. The initial vaccination protocol consists of 2 injections 30 days apart, followed by an annual or biannual booster depending on the geographic location of the horses.

Colostral antibodies at a titer >1:10 interfere with vaccination. Consequently, foals should be immunized at 3, 4, and 6 mo of age and then according to the protocol for adults. Mares should be vaccinated 3-4 wk before foaling.

An inactivated monovalent vaccine for WNV was licensed provisionally in 2001 and received full licensure in 2003. The vaccination protocol specifies 2 doses given IM, 3-6 wk apart, in adult horses. In foals, an initial series of 3 doses is required; the vaccination schedule should be similar to that for EEE and WEE. For the first million doses administered, adverse reactions to the virus were no different than those known to occur following alphavirus immunization. Efficacy studies are currently in progress. A recombinant canarypox vaccine was also licensed in 2003.

Vector suppression by elimination of breeding sites and control of mature insects, as well as protection of the hosts from insect predation, increase the success of preventive measures, particularly during epizootics. Horses may be partially protected from insect feeding by using repellents and by stabling with fans and screens to limit insect access.

Zoonotic Risk:

People may be infected by all 4 of the arboviruses that commonly cause viral encephalitis in horses. Clinical signs in humans vary from mild flu-like symptoms to death. Children, the elderly, and immunosupressed people are the most susceptible. People with neurologic disease due to arboviruses usually have permanent neurologic impairment on recovery. Human disease is reported infrequently and generally follows equine infections by ~2 wk. Veterinarians should be aware of the possibility of human infection and use repellents and other procedures to protect themselves from hematophagous insects when working in sylvatic virus habitats or handling viremic horses.