Miscellaneous and Foreign Emerging Viruses Causing Neurologic Signs

Robert J. MacKay

Since the encroachment of West Nile virus (WNV) in 1999 into North America, the potential for emerging foreign disease with widespread effect has been realized.

Getah/Ross River Viruses

The Semliki Forest complex of the Togaviridae is widespread throughout its geographic range, either in the Orient (Getah virus) or South Pacific (Ross River virus). Although closely related, these viruses have little geographic overlap. Like the North American alphaviruses, these viruses are transmitted by mosquitoes. The reservoir for Getah virus is not known, although swine appear important in its transmission to mosquitoes.¹ Important reservoirs for Ross River virus are marsupials.² Getah virus infection may be transmitted by horses, but this is unlikely to occur with Ross River virus. Seroprevalence in horses varies from less than 10% to more than 90%.^3-5 Ross River virus infection is endemic in horses and widespread; seroprevalence among Australian horses ranges from 50% to 80%.^6,7

Clinical signs of Getah virus infection include fever, edema of the limbs, and urticaria over a course of 7 to 10 days.^3,5 Horses infected with Ross River virus may develop fever, lameness, swollen joints, inappetence, generalized stiffness, and even colic.⁸ Of the horses in which viral encephalitis cases were diagnosed during the 2011 Australian outbreak, more than 100 were seropositive for Ross River virus; however, detailed description of these cases has not yet been published.⁷ Getah virus and Ross River virus infections are diagnosed serologically or by reverse transcription polymerase chain reaction (RT-PCR) testing of blood samples.

Borna Disease

Classical Borna disease is a viral encephalitis principally of horses and sheep that was first recognized in southwestern Germany in the eighteenth century but is associated with the village of Borna in the Kingdom of Saxony, where the disease emerged in the late nineteenth century. It is estimated that approximately 16,000 horses in Saxony died of this disease annually from 1896 to 1940.¹⁰ These numbers declined rapidly in the 1960s in parallel with declining horse numbers, and only 1216 horses died of classical Borna disease in Saxony from 1958 to 1991.¹⁰ Outbreaks of classical Borna disease have been restricted to central Europe in the upper Rhine valley in Switzerland, Austria, and Liechtenstein. Borna disease virus-associated encephalitis has also been reported in humans, cattle, an alpaca, deer, zoo herbivores, cats, rabbits, and dogs.¹¹ Since the 1990s, evidence of Borna disease virus infection—including antibodies, antigen, RNA, or the virus itself—has been reported in many countries and in numerous mammalian species, including humans. There is serologic evidence of Borna disease virus infection in horses in the United States.^12,13 Some of these reports are questionable because of problems with contamination of samples by laboratory Borna disease virus strains and poorly validated immunoassays; however, there have been enough well-documented infections to confirm that Borna disease virus or Borna disease virus-like viruses are widespread.¹⁴ It is possible that Borna disease virus is involved in several human neuropsychiatric diseases, but evidence is lacking.

Borna disease virus 1 (BoDV-1), the etiologic agent of classical Borna disease, is a nonsegmented, negative-sense, single-stranded RNA virus of the order Mononegavirales, family Bornaviridae.

Most outbreaks in horses and sheep occur during the spring and early summer. Although horse-to-horse transmission is theoretically possible, it is unimportant in the evolution of an outbreak.¹⁴ The virus is probably maintained in small mammals with geographic ranges approximating the endemic Borna disease area. The bicolored white-toothed shrew is an important reservoir host in endemic areas.¹⁵ BoDV-1 is shed through nasal and lacrimal secretions and in the urine of infected animals.^14,16 BoDV-1 is resistant to drying and other adverse environmental conditions. It is assumed that BoDV-1 enters the horse though intranasal infection and migrates to the brain transaxonally.¹⁷ Direct replication occurs in neurons and glial cells, with centrifugal spread to peripheral nerves and retina. BoDV-1 infection of the retina may contribute to the blindness that characterizes acute Borna disease in horses.¹⁸ Subclinical BoDV-1 infection is common; in endemic areas, seroprevalence among horses ranges from 10% to 20%, and it is as high as 50% among stablemates of horses with Borna disease. In subclinically infected horses and in horses that recover from Borna disease, the virus becomes quiescent and largely unde­tected by the immune system.

The clinical signs of Borna disease in large animals are similar to those of the other equine encephalitides. The incuba­tion period is 4 weeks to 3 months. There is a predominance of forebrain signs initially, followed by signs of brainstem and spinal cord involvement. In moderate to severe cases, horse die 1 to 4 weeks after onset of signs. In mild cases, horses can recover, but abnormalities and exacerbations commonly persist.

For antemortem diagnosis, antibodies to the agent may be found in the serum and CSF of most infected animals by ELISA, indirect fluorescent antibody test (IFAT), and Western blot.¹⁵ CSF analysis often reveals mononuclear pleocytosis and high protein concentration. RT-PCR techniques have dem­onstrated virus in the CSF and peripheral mononuclear cells.¹⁹ The criteria for diagnosis in a horse with neurologic abnormali­ties include positivity for BoDV-1 antibodies in serum or CSF and characteristic histopathologic changes.

Pathologic abnormalities resemble those of a viral encepha­lomyelitis, and the diagnosis is confirmed by immunohisto­chemistry, virus isolation, and detection of viral nucleic acids.^14,15,20-24 The characteristic microscopic lesion of Borna disease is Joest-Degen inclusion bodies in the neuronal nucleus, but these are not always observed. Virus is detectable easily with monoclonal or polyclonal antibody tests. Histopathologic changes are those of a typical polioencephalomyelitis, with a particular loss of neurons in the hippocampus. The gray matter of the olfactory bulb, basal cortex, caudate nucleus, thalamus, hippocampus, and medulla oblongata is involved.

No antiviral agents are available for the treatment of BoDV-1 infection, and use of amantadine sulfate (developed for treatment of influenza infection) is controversial but common.^25,26 Likewise, vaccination as a protective strategy is controversial. It is widely assumed that a modified live vaccine would offer more protec­tion; however, the live vaccine available until the early 1990s in East Germany was removed from the market because of questionable efficacy.

Henipavirus

Hendra virus (HeV) is one of two Henipavirus species. HeV infec­tion of horses was first recognized in 1994 during simultaneous outbreaks of severe respiratory disease in Queensland, Australia: one in the Hendra suburb of Brisbane and the other near the town of Mackay. Of 22 affected horses, 14 died, and each outbreak was associated with transmission to humans, one of whom died.²⁷ As of 2015, there had been almost 50 outbreaks of HeV infection in horses, all but one in coastal Queensland and New South Wales. Five outbreaks also involved seven human cases, of which four were fatal. Although horses in the original outbreaks showed signs of fulminant febrile respiratory disease, neurologic signs dominated the clinical presentation in five horses in an unusual outbreak at an equine referral practice in the Redlands suburb of Brisbane in 2008. The illness was characterized by severe obtundation, dementia, head tilt, and progressive ataxia. More recently, the respiratory syndrome has been the typical presentation of horses with HeV infection; neurologic signs are observed only occasionally.

HeV replicates initially in the respiratory epithelium before spreading hematogenously to multiple organs, including the CNS, to cause widespread vasculitis, endothelial syncytia, vascular thrombosis and hemorrhage, and cellular necrosis.

Nipah virus (NiV), the other species of Henipavirus, emerged as the cause of porcine respiratory and encephalitis syndrome in Malaya in 19 98.^28-30 Signs were predominantly respiratory, and most affected pigs recovered.

HeV and NiV are closely related viruses; the genus, Henipavirus, belongs to the family Paramyxoviridae. They are enveloped, single-stranded, negative-sense RNA viruses. The henipaviruses are highly pathogenic for a wide range of mammals, including horses, pigs, and humans. The natural reservoirs throughout the geographic range (Northern Australia, Malaysia, and Bangladesh) are fruit bats from the genus Pteropus (also known as flying foxes).³² In each spillover event, the virus is probably transmitted to horses through contact with the urine or reproductive fluids of infected bats. During the incubation period in horses, HeV is infectious to other horses and to humans for at least 48 hours before the onset of clinical signs, and at least two outbreaks in stables were caused by introduction of horses that were incubating the virus before manifesting the disease. Virus is secreted in all body fluids and feces of infected horses, and appropriate precautions must be taken to prevent transmission to other horses and humans.

The disease is diagnosed both serologically by ELISA or neutralization test and by detection of RNA by RT-PCR in blood, other body fluids, or tissues taken at necropsy.^30,33

Infected horses are euthanized as a matter of public health. Ribavirin has been used with partial success to treat NiV and HeV infections of humans, and a monoclonal antibody (m102.4) has been shown to be protective in experimental animals if given before clinical signs are manifested and has been used in several exposed humans.³⁴ An HeV subunit vaccine (HeV-sG) has been tested successfully in multiple species, including horses, against both HeV and NiV challenge and was launched com­mercially in Australia in 2013 for vaccination of horses in endemic areas (EquiVac HeV, Pfizer Animal Health).³⁴

Bunyaviridae

The Bunyaviridae are mostly arboviruses and are found worldwide. These viruses are usually maintained in mosquito­vertebrate host-mosquito cycles, whereby midges act as the arthropod hosts for a few viruses.³⁵ Twelve serotypes, known collectively as the California serogroup, have been isolated in North America, South America, Africa, Europe, and Asia. In rare cases, these viruses can cause acute encephalitis in horses. Snowshoe hare, Main Drain, and Bunyamwera viruses have been associated with encephalitis in horses,^36-38 and serologic evidence of subclinical infections with Jamestown Canyon virus and Cache Valley virus have been found in horses in the United States.^39,40 Clinical signs in a horse from which Main Drain virus was isolated included ataxia, weakness, stiff neck, head pressing, dysphagia, tachycardia, and fever.³⁷

Equine Encephalosis

Equine encephalosis is an arthropod-borne viral infection, affecting all species of equids, and is characterized usually by mild or subclinical infection but occasionally by severe clinical disease.⁴¹ The causal agent, equine encephalosis virus (EEV), is transmitted through the bites of certain Culicoides spp. biting midges. EEV is an orbivirus, as are African horse sickness virus and bluetongue virus. All equids (horses, donkeys, zebras) are susceptible to EEV, although donkeys and zebras are thought to be resistant to the clinical disease. The infection is endemic in southern Africa, where seven EEV serotypes have been identified.⁴² An outbreak of febrile disease due to EEV in Israel in 2008 and 2009 involved 60 horses, and serologic evidence of the infection has since been found in several other areas outside southern Africa.^43,44

The virus was originally named for isolation from a horse with typical signs of encephalitis, including mild to severe ataxia, reluctance to walk, stiffness, dementia, and seizures.⁴¹ In its current forms, infections are either subclinical or associ­ated with an influenza-like syndrome of fever, edema, tachy­cardia, tachypnea, and congested mucosae. An African horse sickness-like syndrome of respiratory distress and cardiac failure has been described, and pregnant horses may abort. A competi­tive ELISA for detection of group-specific antibody to EEV has been described for use in diagnosis.⁴⁵ There is no recognized treatment for EEV infection or method of prevention.