Overview of Equine Arboviral Encephalomyelitis

The initial clinical signs are similar for the arboviruses; progression of clinical signs and severity of disease are the differentiating features. Initially, horses are quiet and depressed, with clinical neurologic signs generally occurring 9–11 days after infection. Compared with WEE and WNV disease, clinical signs of EEEV (and VEEV) encephalomyelitis more frequently include altered mentation, impaired vision, aimless wandering, head pressing, circling, inability to swallow, irregular ataxic gait, paresis and paralysis, seizures, and death. Spinal signs are often symmetric with ataxia in all limbs, rapidly progressing to quadriparesis, along with intensification of forebrain signs. Many horses progress to recumbence within 12–18 hr of onset of neurologic abnormalities. Most deaths occur within 2–3 days after the onset of signs.

The clinical signs and course of disease are highly variable in WNV disease and other flavivirus encephalomyelitis. Presenting complaints most often include neurologic abnormalities; other common initial complaints include colic, lameness, anorexia, and fever. Initial systemic signs include a mild fever, feed refusal, and depression. Neurologic signs are highly variable, but spinal cord disease and moderate mental aberrations are most consistent. Spinal cord disease manifests as asymmetric, multifocal or diffuse ataxia and paresis. Severe manifestations of WNV may occur independently in the fore- or hindlimbs, unilaterally, or in a single limb. In all clinical studies published to date, for WNV, >90% of affected horses developed some type of spinal cord signs, whereas 40%–60% developed behavioral changes characterized by periods of hyperesthesia, ranging from mild apprehension to overt hyperexcitability, with fractious reactions to aural, visual, and tactile stimuli. Fine and coarse tremors of the face and neck muscles are common, described in 60%–90% of horses. Some horses have periods of cataplexy or narcolepsy that may render them temporarily or permanently recumbent.

Cranial nerve deficits can be seen in all arbovirus infections of horses; these include most cranial nerves with cell bodies located in the mid- and hindbrains. Weakness and/or paralysis of the face and tongue are most frequent. Horses with facial and tongue paresis can be dysphagic, and overt signs of quidding or even esophageal choke can develop. Many horses with severe mental depression and facial paresis will keep their heads low, resulting in severe facial edema. Occasionally, head tilt may be seen. Infrequently in WNV disease, urinary dysfunction ranging from mild straining to stranguria has been reported, making differentiation from equine herpesvirus 1 (EHV-1) more challenging.

During the neurologic phase, horses frequently thrash and injure themselves. Sepsis from trauma in recumbent horses also occurs. Prolonged recumbency leads to pulmonary infections, especially in foals, in which a long duration of slinging and treatment may be pursued more frequently than in large, recumbent animals. Dysphagia leads to decreased water and food intake, with renal damage due to concurrent use of anti-inflammatory drugs. Skin and muscle necrosis are common in recumbent horses. Life-threatening trauma can also occur, including a ruptured diaphragm and fractures.

No consistent changes in clinical pathology have been found in equine viral encephalitis. With EEEV and WNV in horses, peripheral lymphopenia is common. Horses are frequently azotemic, likely from decreased food and water intake.

In general, no pathognomonic signs distinguish flavivirus infection in horses from other CNS diseases, and a full diagnostic evaluation should be performed. Confirmation of flavivirus infection with encephalitis in horses begins with assessment of 1) whether the horse meets the case definition based on clinical signs; (2) whether the horse resides in an area in which flavivirus has been confirmed in the current calendar year in mosquitoes, birds, people, or horses; and (3) lack of appropriate vaccination.

In terms of antemortem diagnostic testing, analysis of CSF can be a valuable adjunct to presumptive clinical assessment. CSF analyzed from horses with acute EEEV infection typically shows a neutrophilic pleocytosis with markedly increased total solids. Horses infected with EEEV that are partially immune may have predominantly mononuclear cells, but nondegenerate neutrophils are still present. Although WNV-infected horses can have normal CSF, if the CSF is abnormal, there is a mononuclear pleocytosis with moderately to markedly increased total solids. In a few horses with acute infections, virus may be isolated from the CSF. By the time neurologic signs are seen, viremia has ended and detection of virus in the plasma of clinically affected horses is of no value.

Serology is the key to antemortem diagnosis of recent alphavirus and flavivirus infection in horses showing clinical signs. IgM antibody rises sharply and is increased in 85%–90% of horses with clinical arboviral encephalitis. Thus, the IgM capture ELISA is the test of choice to detect recent exposure to these viruses. Neutralizing antibody titers (primarily IgG) develop slowly during this time and stay increased for several months. Although neutralizing antibody tests will differentiate between subtypes of these viruses, and are thus considered the gold standard for confirmatory serology, paired serum samples are essential to detect recent exposure and to differentiate antibody response due to field infection from vaccine responses for any of these viruses. Because virus-neutralizing antibodies appear at the end of viremia and may precede appearance of neurologic signs, paired samples may not show a 4-fold increase in horses while demonstrating neurologic signs. In horses that succumb without premortem and postmortem testing, paired samples from febrile herdmates may be necessary to confirm presence of arbovirus activity within a locale. Maternal antibodies may interfere with neutralizing responses in young foals. This response is confounded by recent vaccination. The most common neutralizing antibody test formats are the classic plaque reduction neutralization test (PRNT) and a microwell format test. Practical application of the microwell vs the PRNT indicates that the endpoint titer in the microwell test can be several logs higher than in the PRNT, so results cannot be compared between samples.

Several postmortem diagnostic assays are available and, although specific, they vary in sensitivity, depending on the virus. The midbrain and brain stem have the highest concentrations of encephalitic viruses, including rabies virus. Immunohistochemistry and PCR testing for EEEV and EHV-1 are relatively straightforward compared with that for WNV. Diagnostic testing continues to confirm the unreliability of detection of virus, even by PCR, because of the low viral load in WNV infection. Often, only a single neuron in one or two sections may yield positive virus staining in the horse by immunohistochemistry. When tested by PCR, the limited viral load dictates accurate testing of appropriate tissues consisting of several locations, including thalamus, hypothalamus, rostral colliculus, pons, medulla, and anatomically identified spinal cord. Viral isolation is still important for molecular epidemiology.

Infectious and noninfectious causes of brain and spinal cord diseases should be considered as differential diagnoses. Infectious causes include alphaviruses, rabies, equine protozoal myeloencephalitis (see Equine Protozoal Myeloencephalitis), and EHV-1; less likely causes are botulism and verminous meningoencephalomyelitis (eg, Halicephalobus gingivalis, Setaria spp, Strongylus vulgaris). Noninfectious causes include hypocalcemia, tremorigenic toxicities, hepatoencephalopathy, and leukoencephalomalacia.

Treatment of viral encephalitis is supportive, because there are no specific antiviral therapies. Management is focused on controlling pain and inflammation, preventing injuries associated with ataxia or recumbency, and providing supportive care. Intervention does not appear to significantly affect the outcome of most fulminate EEEV infections. For WNV, flunixin meglumine (1.1 mg/kg, IV, bid) early in the course of the disease decreases the severity of muscle tremors and fasciculations within a few hours of administration.

Recumbent horses that are mentally alert frequently thrash, causing self-inflicted wounds and posing a risk to personnel. Responses to tranquilizers and anticonvulsant medications are variable, depending on the virus and severity of disease. A sling and hoist may be used to assist horses that are recumbent and have difficulty rising; however, recumbent horses with EEEV generally are too comatose to sling. Dysphagic horses require fluid and nutritional support.

Until equine protozoal myeloencephalitis is excluded, prophylactic antiprotozoal medications may be instituted. Other supportive measures (eg, oral and parental fluids and nutrition for dehydrated and dysphagic horses) are also important. Broad-spectrum antibiotics should be given for treatment of wounds, cellulitis, and pneumonia. Horses with intermittent or focal neuropathies have a better prognosis than those with complete flaccid paralysis or that appear comatose. Efficacy of specific antiviral agents for treatment of naturally occurring WNV or EEEV infection is unknown, even in people. Recent work with passive immunotherapy indicates possible benefit after the onset of clinical signs in WNV models.

Mortality of horses showing clinical signs from EEEV is 50%–90%, from WEEV 20%–50%, from VEEV 50%–75%, and from flavivirus infections 35%-45%. 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 disease have been reported to have no residual neurologic deficits. In EEEV infection, death is frequently spontaneous. With WNV disease, horses are euthanized for humane reasons, but spontaneous death does occur. In EEEV, most surviving horses exhibit longterm neurologic signs. In WNV disease, overt clinical signs in horses that recover can last from 1 day to several weeks; improvement usually occurs within 7 days of onset of clinical signs. Although 80%–90% of owners report that the horse returns to normal function 1–6 mo after disease, at least 10% of owners report longterm deficits that limit athletic potential and resale value. Deficits include residual weakness or ataxia in one or more limbs, fatigue with exercise, focal or generalized muscle atrophy, and changes in personality and behavioral aberrations.

Vaccination against alphaviruses and flaviviruses as core annual vaccines are considered the standard of care for all horses in the USA as endorsed by the American Association of Equine Practitioners. Formalin-inactivated whole viral vaccines for EEEV, WEEV, and VEEV are commercially available in bi- and trivalent forms, usually formulated with tetanus toxoid; several now include WNV. Nonvaccinated adult horses require the label priming two injections. For adult horses in temperate climates, an annual vaccine within 1 mo before the start of the arbovirus season is recommended. However, for horses that travel between northern and southern areas affected by the virus, injections should be given two or even three times yearly in active arbovirus seasons. Mares should be vaccinated 1 mo before foaling to induce colostral antibody. If a pregnant mare is naive, the full priming series starting 2 mo before foaling is recommended. However, some mares do not produce colostral antibody if vaccinated for the first time during gestation.

In foals that have received adequate colostrum from vaccinated dams, vaccination should begin at 5–6 mo of age; foals should receive two additional vaccinations at 30 and 90 days after the first one. It is unclear whether maternal antibody interferes with vaccine responses in foals; however, epidemiologic evidence strongly indicates that horses between 4 mo and 4 yr old are highly susceptible to EEEV. If there is early spring (March) activity in the southeastern USA, horses may require three injections throughout the year, especially in horses <5 yr old and in horses that have recently arrived in the southeastern USA. In foals born to nonvaccinated or minimally vaccinated mares, maternal immunity may wane, and vaccination should be performed at 4, 5, and 6 mo of age. In Florida, where the highest numbers of EEEV cases occur, horses of all ages should be vaccinated in January and again in April before the peak of the season. A third vaccination should be administered late in the summer if the season is particularly active. The frequency of vaccination may be minimized to once or twice per year in climates that have short mosquito seasons and in which limited activity has historically been reported.

Currently, several whole inactivated virion vaccines, one recombinant inactivated vaccine, and a canarypox-vectored vaccine are licensed for prevention of WNV viremia in most of the Americas, including the USA and Canada, and Europe. An inactivated virus vaccine is readily available against Japanese encephalitis virus. There is experimental evidence that the canarypox WNV lineage 1 vaccine provides cross-protection against WNV lineage 2 infection. WNV challenge studies indicate that ~10% of properly immunized horses do not produce neutralizing antibodies to WNV and that 2.3%–3% of equine WNV cases seen in the field are in fully vaccinated horses. The duration of immunity from vaccination with the killed, adjuvanted WNV vaccine is unknown.

Protection of horses from arboviruses must also include efforts to minimize exposure to infected mosquitoes. Mosquito mitigation includes applying an insect repellent that contains permethrin on the horses at least daily during vector season, especially at times of day when mosquitoes may be most active. Environmental management is also essential and includes keeping the barn area, paddocks, and pastures cleared of weeds and organic material, such as feces, that might harbor adult mosquitoes. Cleaning water tanks and buckets at least weekly will reduce mosquito breeding areas. Removal of other containers such as flower pots and used tires that may hold stagnant water is essential for reducing the number of mosquitoes in the area.

Options for control of arbovirus infection in other animals emphasize reduction of exposure. Few arbovirus infections have been documented in dogs and cats; however, exposure to EEEV and WNV is detected in both species during arbovirus seasons. In active years, young dogs have been reported to be susceptible to EEEV infection.

Keeping dogs and cats indoors or in a screened area, especially during the time when mosquitoes are most active, reduces exposure. Disposal of dead birds or other small prey that might be eaten may reduce oral exposure.

Clinical cases of both of these diseases have also been recorded in other domestic and exotic animals during active seasons. Emus are exceptionally susceptible to EEEV. These animals are used for the commercial food industry, and infection results in high viremia and high amounts of virus shedding rectally, orally, and in regurgitated material. Vaccination will prevent viremia, shedding, and disease. Camelids are susceptible to WNV, and numerous reports of disease and pathology were recorded as the virus spread across North America. The killed, adjuvanted vaccine marketed for use in horses has been used in camelids without any reports of major adverse effects, and animals have demonstrated production of neutralizing antibody.

The reporting of these diseases (or suspicion of such) on an international and national basis is a basic duty of all veterinarians to ensure the health and safety of horses and people. As such, a thorough diagnostic investigation to confirm these infections is imperative, irrespective of state resources available for subsidized testing.

People may be infected by most of the arboviruses that commonly cause viral encephalitis in horses. Clinical signs in people vary from mild flu-like symptoms to death. Children, the elderly, and those who are immunosuppressed are the most susceptible. People with neurologic disease due to arboviruses usually have permanent neurologic impairment after 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. In addition, waterproof clothing (gown, boots, gloves), respirator (N-95 or N-99 mask), face shield, and hair covering are recommended during all necropsies performed on horses suspected of having encephalomyelitis.