West Nile Encephalomyelitis: Introduction - The Merck Veterinary Manual

West Nile Encephalomyelitis: Introduction

Etiology and Epidemiology

Clinical Findings

Lesions

Diagnosis

Treatment

Prevention and Control

Zoonotic Risk

See also west nile virus infection in poultry, West Nile Virus Infection in Poultry: Introduction.

West Nile virus (WNV) is a member of the Japanese encephalitis virus serocomplex in the genus Flavivirus. WNV was first identified in the blood of a woman in Uganda in 1937. By the 1950s, WNV was recognized as a virus that cycled between birds and ornithophilic mosquitos. WNV has the widest geographic distribution of all of the Flaviviruses. Prior to 1999, WNV was recognized in Africa, the Middle East, Asia, and occasionally in European countries. In 1999, WNV infection was first recognized in North America. Since then, the virus has spread throughout the USA and parts of Canada and Mexico. WNV isolated from the outbreak in New York in 1999 appears to be closely related to an isolate recovered from geese in Israel in 1998.

Etiology and Epidemiology:

WNV is maintained in an enzootic transmission cycle between wild birds and Culex mosquitos. WNV has been recovered from a wide range of North American mosquito species, with Culex spp thought to play the largest role in natural transmission. In the eastern and midwestern regions of the USA, C pipiens is one of the major vectors, while in the panhandle region and western regions of the USA, C tarsalis is thought to be one of the major vectors. WNV activity is based on the presence of competent vectors as well as bird hosts. Both wetland and terrestrial birds may be involved in the natural cycle of WNV. Migratory birds are thought to introduce the virus into a geographic region. A wide range of birds can be infected with WNV; many have high and sustained viremia but show little or no clinical disease. However, during the outbreak of WNV in the USA, fatal infections were common among corvids (eg, crows, blue jays, and magpies). The house finch may be one of the most efficient reservoirs of the virus due to the large numbers of this type of bird in the USA, the high viremia that these birds develop, and the fact that these birds have little or no disease associated with the infection. Ticks have been demonstrated to be infected with WNV, but their role in the natural transmission of WNV is unknown. Recently, other routes of exposure to WNV have been documented, including transplacental infection of one human infant. Experimentally, transmission has been documented between cohabitating birds and from oral exposure to WNV in drinking water in birds. Cats have become infected with WNV from consumption of infected mice.

Since the introduction of WNV into the USA, WNV antibodies have been detected in >150 species of birds, a large array of mammals, and in a few amphibians and reptiles. However, disease has been primarily observed in humans, equids, and corvids. Since 1999, illness due to WNV infection has been seen in a limited number of dogs, a cat, camelids, and a few sheep. Oral transmission is highly efficient in cats; therefore infected prey animals may serve as an important source of infection to carnivores. There have been clusters of WNV-induced illness and death in wild squirrels and farmed alligators. There has also been a report of WNV-induced disease in crocodiles. Whether or not this increased range of species susceptible to WNV-induced disease is due to increased scrutiny and monitoring, the level of viral challenge in the USA, or some other reason is unknown.

Encephalomyelitis due to WNV infection in horses has been called Near Eastern equine encephalitis or lordige in France. The frequency of inapparent infection in association with clinical disease is difficult to determine. Experimental induction of the disease in horses has been difficult; experimental challenges have not induced the severity of disease noted under field conditions with any of the models other than viral injection into the CSF. In the USA, ~10-39% of infected horses develop clinical disease. Once horses show clinical signs of WNV, the case fatality rate is ~30% in the USA. Recent outbreaks of WNV in horses in Italy and Morocco had case fatality rates of 43% and 45%, respectively. Outcome of disease could be based on multiple factors, such as host susceptibility, amount of the viral challenge, virulence of the virus, and treatment.

The spread of WNV across the USA since its introduction in 1999 has been remarkable. In 1999, there were 25 equine cases in a limited area around New York city. By 2002, there were >15,000 equine cases from 41 states. In late 2002, WNV was reclassified as an endemic disease agent in the USA. The number of equine WNV cases declined in 2003 for the first time since the virus was recognized in the USA. This decline could be due to several factors, including an increasing percentage of the equine population protected from disease due to vaccination or natural exposure to the virus, increased mosquito control efforts, lower viral challenge due to increasing immunity among bird populations, less frequent testing of suspect cases due to better recognition of the disease syndrome, and increased cost of testing for the disease. The virus appears to have found a niche wherever it has been introduced. It has been postulated that WNV has spread to new geographic regions through the migration of birds carrying the virus. The virus can be spread by multiple types of mosquitos, based on experimental studies. Horses and humans do not appear to develop adequate viral loads to act as a source of the virus for mosquitos. Cats appear to develop the highest viremia among domestic animals, but compared with birds the level of viremia in cats is relatively low. Thus, cats and dogs are unlikely to play an epidemiologic role as amplifying hosts.

Animals used as plasma or whole blood donors should be protected from WNV infection. Although horses do not develop adequate viremia to be a source of WNV for insect vectors, if several liters of infected blood or plasma were to be transfused into another horse, it could theoretically pose a risk to the recipient horse. No transfusion-induced WNV infection has been reported in horses, but it is recognized as a risk in human medicine.

Clinical Findings:

All equids appear equally susceptible to WNV encephalomyelitis (WNE), with biases in breed reflecting regional or hospital variations. Horses of all ages (range 4 mo to >30 yr) can be affected. Adult horses (12-14 yr) represent the mean age of most field populations of affected horses; however, in 2 referral hospital studies, 6-7 yr was the mean age.

The clinical signs and course of disease are highly variable in WNE. There are 2 lineage groups into which isolates of WNV can be placed, based on genetic sequencing. Horses are susceptible to lineage type I WNV, while demonstrating little disease to most African lineage type II WNV. Presenting complaints most often include neurologic abnormalities; other common initial complaints include colic, lameness, anorexia, and fever. Initial systemic signs include a mild low-grade fever, feed refusal, and depression. Neurologic signs are also 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 may occur independently in the front or hindlimbs, unilaterally, or in a single limb. In all clinical studies published to date, >90% of affected horses developed some type of spinal cord signs, while 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. Some horses have periods of cataplexy or narcolepsy that may render them temporarily or permanently recumbent. Coma, blindness, head pressing, and other signs of forebrain disease are seen, but are not as common as in alphavirus encephalitides. Fine and coarse tremors of the face and neck muscles are common and are described in 60-90% of horses. Cranial nerve deficits also are seen in 40-60% of clinically affected 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, urinary dysfunction ranging from mild straining to stranguria has been reported. After initial signs abate, severity of clinical signs increases within the first 7-10 days of onset in about one-third of cases. This resumption of clinical signs ranges from temporary and mild to progressive full paralysis.

The case fatality rate is generally 30-40%. In horses that progress to complete paralysis of one or more limbs, mortality rates are ~60-80%. Most of these horses are euthanized due to humane reasons, but spontaneous death does occur. Overt clinical signs in horses that recover can last from 1 day to several weeks, with improvement usually occurring within 7 days of the onset of clinical signs. While 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.

Many horses are euthanized due to sequelae. 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 intake, and renal damage due to concurrent NSAID use can occur. Skin and muscle necrosis are common in recumbent horses. Life-threatening trauma can also occur, including ruptured diaphragm, broken limbs, broken cervical vertebra, and skull fractures.

No consistent changes in clinical pathology have been found in WNE in horses, although peripheral lymphopenia is common. Hyponatremia is seen and is thought to be due to inappropriate antidiuretic hormone secretion. Horses are also frequently azotemic. While some reports demonstrate little value of CSF analysis, reports in larger groups of horses show abnormalities (primarily mononuclear pleocytosis and increased total protein) in up to 70% of horses tested. Lumbosacral samples have significantly higher proteins and cell counts.

Lesions:

Gross lesions in WNE are rare and are limited to small multifocal areas of discoloration and hemorrhage throughout the midbrain, brain stem and spinal cord. There may be congestion in the meninges of acutely affected animals. Microscopically, there is a non-necrotizing lymphohistiocytic poliomeningoencephalitis. Slight to severe inflammation, characterized by perivascular cuffing of lymphocytes and monocytes, is present. In the neuropil, dying neurons often are surrounded by microglial cells. Immunohistochemistry reveals positive staining for WNV in neural cytoplasm.

Diagnosis:

Serology is the key test for antemortem diagnosis of WNE in horses. IgM rises sharply and falls during the first 6-8 wk after exposure to WNV. Neutralizing antibody titers (primarily IgG) develop slowly during this time and stay elevated for several months. The IgM capture ELISA is the test of choice for detection of recent exposure to the virus. In most states, a veterinarian must submit the test, and any horse demonstrating clinical signs of encephalomyelitis must be reported to the state regulatory services.

Several postmortem diagnostic assays are available and, while specific, vary in sensitivity. Although WNV may cause severe clinical signs, viral levels in equine neural tissues are low. Immunohistochemistry provides confirmatory diagnosis; however, multiple sections of brain and spinal cord must be examined. This test is positive in 60-80% of horses that test positive for WNV by serology. Detection of viral nucleic acids also varies in sensitivity and depends on testing portions of the brain and spinal cord where higher titers of virus may be present. Either nested reverse transcriptase (rt)-PCR or real-time rt-PCR on the medulla oblongata and lumbar spinal cord is recommended. Viral culture of the brain is sensitive only in ~20-30% of clinical cases that test positively by serology.

Both infectious and noninfectious causes of brain and spinal cord diseases should be considered as differential diagnoses. Infectious causes include alphaviruses, rabies, equine protozoal myeloencephalitis (EPM), and equine herpesvirus 1; less likely causes are botulism and verminous meningoencephalomyelitis (eg, Halicephalobus gingivalis , Setaria , Strongylus vulgarus ). Noninfectious causes include hypocalcemia, tremorigenic toxicities, hepatoencephalopathy, and leukoencephalomalacia.

Treatment:

Treatment of WNE is supportive, as there is no specific antiviral therapy against flaviviruses. As with any of the viral encephalitides, management is focused on controlling pain and inflammation, preventing injuries associated with ataxia or recumbency, and providing supportive care. The treatment of horses with clinical signs has primarily focused on anti-inflammatory drug administration. 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. Steroids and NSAID have been given to many horses with WNV-induced disease. Some horses show immediate improvement with anti-inflammatory treatment (eg, a reduction in muscle fasciculations and a return to a more normal attitude), while others do not show any improvement. Recumbent horses are mentally alert and frequently thrash, causing self-inflicted wounds and posing a risk to personnel. Therapy of recumbent horses is generally more aggressive and includes dexamethasone (0.05-0.1 mg/kg, IV, sid) and mannitol (0.25-2.0 g/kg, IV). In a study of equine WNV cases in Colorado and Nebraska from 2002, the majority received some form of anti-inflammatory drug. Flunixin meglumine was the most common treatment, with ~50% receiving steroids and/or dimethyl sulfoxide. Steroid use was not found to be associated with the survival rate. Detomidine (0.02-0.04 mg/kg, IV or IM) is effective for prolonged tranquilization. Low dosages of acepromazine (0.02 mg/kg, IV, or 0.05 mg/kg, IM) provide excellent relief from anxiety in both recumbent and standing horses. Diazepam and butorphanol appear to increase anxiety and tremors and should be avoided. Phenobarbital to effect is appropriate for seizures. A sling and hoist may be used to assist horses that are recumbent and have difficulty rising. Some horses may require fluid and nutritional support. Treatment with antioxidants, such as vitamin E, may also be indicated.

Until EPM is ruled out, prophylactic antiprotozoal medications may be instituted. Other supportive measures (eg, oral and parental fluids and nutrition for dehydrated and dysphagic horses) are also important parts of therapy. Broad-spectrum antibiotics should be given for treatment of wounds, cellulitis, and pneumonia. Slinging of recumbent horses is essential to assess the degree of recumbency. Horses with intermittent or focal neuropathies have a better prognosis than those with complete flaccid paralysis. Slinging also maintains strength and decreases pulmonary and traumatic sequelae. Efficacy of specific antiviral agents for the treatment of naturally occurring WNV infection is unknown, even in humans. Interferon α-2b has been used in the treatment of WNV infection in horses, but the efficacy is unknown.

Equine serum and plasma antibody-containing products are available for treatment. Theoretically, these products may inactivate circulating WNV in horses showing signs of the disease and may protect horses exposed to the virus. One serum product was licensed by USDA in 2003 and another has a conditional license. Results of challenge studies or case-control field studies evaluating these products are not currently available.

Prevention and Control:

Options for prevention of WNV in equids include immunization, vector abatement, and optimization of overall health. Vaccines against alphaviruses that cause EEE, WEE, or Venezuelan equine encephalitis offer no cross-protection against WNV infection. A killed, adjuvanted, whole WNV vaccine was given limited approval in 2001 and was used in regions with WNV activity. The vaccine received full licensure in 2003 and has been used extensively to help prevent WNV infection in equids in the USA. The vaccine is approved for use in the prevention of viremia from WNV. A series of 2 vaccinations given 3-6 wk apart, prior to the period when vectors are active, is recommended in adult horses. In foals, an initial series of 3 immunizations is required and should follow a schedule of vaccination similar to that for EEE and WEE. Foals born to immunized mares or those that have had WNV infection should not be vaccinated until they are 6 mo of age. It appears that ~10% of properly immunized horses do not produce neutralizing antibodies to WNV and that 2.3-3% of equine WNV cases are seen in fully vaccinated horses. The duration of immunity from vaccination with the killed, adjuvanted WNV vaccine is unknown. It has been recommended that a booster be given every 3-4 mo in regions where the virus is active >3-4 mo/yr. A recombinant canarypox vaccine carrying protective prM/E genes of WNV was also licensed in 2003, but has not yet been scrutinized under field conditions. In initial experimental trials, all of the immunized horses (28) developed a detectable neutralizing antibody response. In a second study that involved a WNV-infected mosquito challenge of vaccinated and control horses, neither developed clinical signs of disease. All of the vaccinated horses were protected from viremia 2 wk after the primary vaccination and 1 vaccinated horse developed viremia when challenged 1 yr after the initial series, while 80% of the control horses developed a detectable viremia.

Protection of horses from WNV infection must also include efforts to minimize exposure to WNV-infected mosquitos. Briefly, mosquito mitigation includes applying an insect repellent that contains pyrethrin on the horse at least daily during vector season, especially at times of day when mosquitos may be most active. Fans that blow over horses housed in stalls can reduce mosquito feeding. 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 mosquitos. 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 mosquitos in the area.

Options for control of WNV infection in other animals emphasize reducing exposure. In dogs and cats, keeping them indoors or in a screened area, especially during the time when mosquitos are most active, reduces exposure. Disposal of dead birds or other small prey that might be eaten may reduce the chances of oral exposure. Because very few cases of WNV have been documented in dogs and cats, inconveniences associated with these prevention strategies should be weighed against the risk of WNV infection. The killed adjuvanted vaccine marketed for use in horses has been used in camelids without any reports of major adverse effects. Studies of the immunologic response in horses and camelids immunized with this vaccine are ongoing.

Zoonotic Risk:

Asymptomatic infection is the most common outcome of human exposure to WNV by a bite from an infected mosquito. The severe form of disease caused by infection occurs in ~1/150 persons exposed to the virus and is most common in the elderly. West Nile fever, a syndrome characterized by fever, headache, and malaise, is seen in ~20% of people infected with WNV.

Veterinarians should take biosecurity precautions when performing necropsies, especially on birds. Live birds infected with WNV may also pose a handling risk due to the very high viral load in cloacal fluid in some species. Appropriate barrier precautions are indicated.