CHAPTER 39 Equine Herpesvirus Myeloencephalopathy
Equine herpesvirus myeloencephalopathy (EHM) is an infrequent but serious outcome of equine herpesvirus type 1 (EHV-1) infection. It is well established that EHV-1 infection is highly prevalent in horses throughout the world, and its most common clinical manifestations are pyrexia and respiratory tract disease, particularly in weanlings and young adults, and abortion in mares in late pregnancy. Subclinical spread of infection is also common, and the epidemiologic features of EHV-1 infection in horses are dependent on the ability of the virus to establish latent infection in the majority of exposed horses. Sporadically, and in the course of conventional outbreaks of EHV-1 infection, EHM can develop, typically affecting 10% to 50% of infected, viremic horses. This percentage can fluctuate substantially among horse operations, and it depends strongly on the demographics of a specific horse operation. It is widely believed that there has been an increase in EHM outbreaks in recent years in North America, and in 2007 EHM was declared to be a potentially emerging disease by the United States Department of Agriculture-Animal and Plant Health Inspection Service. Our understanding of what precipitates an EHM case or outbreak remains rudimentary, although key scientific advances have been made during the last decade (Box 39-1).
Primary EHV-1 infection occurs in the respiratory tract epithelium, resulting in erosion of the upper respiratory mucosal surface and viral shedding typically for 4 to 7 days after infection. Cell-to-cell spread results in arrival of virus in respiratory tract lymph nodes within 12 to 24 hours after infection. Leukocyte-associated viremia is established, which is directly responsible for the delivery of EHV-1 to other tissues; the specific leukocyte subset or subsets harboring EHV-1 remain poorly defined. Latency becomes established in the lymphoreticular system and trigeminal ganglion.
Viremia typically persists for 5 to 7 days, although reports of viremic periods lasting for 21 days exist. Viremia is a prerequisite for EHM, as it allows for transport of virus to the vasculature of the central nervous system (CNS), where endothelial infection occurs. This results in damage to the microvasculature of the CNS secondary to initiation of an inflammatory cascade, vasculitis, microthrombosis, and extravasation of mononuclear cells with perivascular cuffing and local hemorrhage. Although viremia is a common sequel to EHV-1 infection, transfer of virus to the CNS endothelium and development of EHM are not. The mechanism underlying CNS endothelial infection is unknown. The typical result is disseminated ischemic necrosis of the spinal cord. The gray matter and white matter of the spinal cord are most commonly affected, with the brainstem being infrequently affected. The forebrain is usually unaffected. This can result in a wide range of neurologic signs, but in many instances, EHM can lead to profound weakness, ataxia, and recumbency, which often makes euthanasia necessary.
Typically EHM develops 5 to 6 days after primary infection, although it can develop later. Clinical signs of EHM depend on the number, size, and locations of ischemic lesions in the spinal cord. Because of the virus’s preference for the spinal cord, a variable degree of asymmetric ataxia, dysmetria, and weakness in the forelimbs and hind limbs is observed. Horses with EHM frequently have difficulty urinating. A so-called upper motor neuron bladder is a common finding during the acute stages. Clinical disease has an acute onset and progresses rapidly for 24 to 48 hours. Gradual improvement with return to nearly full function over weeks to months may be seen in mildly affected horses that are ataxic but remain standing, whereas only limited improvement is seen in severely affected horses (those with profound weakness and inability to stand).
The understanding of how and when the cell-associated viremia of EHV-1 infection leads to EHM is poor. One or a combination of factors could contribute, including the level of viremia, the response of infected endothelial cells, and the inflammatory response to infection. Both viral and host factors could influence each of these outcomes. The level and duration of viremia has been considered a likely important determinant of EHM occurrence. This theory may have found support in the recent description of a genetic variant of EHV-1 (defined by a single nucleotide point mutation in the DNA polymerase gene) that is more commonly associated with neurologic disease. This mutation results in the presence of either aspartic acid (D) or an asparagine (N) residue at position 752. It is estimated that 80% to 90% of neurologic disease is caused by D752 isolates and 10% to 20% is caused by N752 isolates, whereas abortion outbreaks without EHM are almost always associated with N752 isolates. An important finding is that experimental equine infection with D752 isolates leads to higher levels of viremia compared with N752 isolates. In contrast, the D752 isolate does not cause higher levels of nasal viral shedding. Whether these high levels of viremia are causally related to occurrence of EHM or are an independent outcome is not known, but the D752 mutation may confer a replicative or infective advantage for the virus in leukocytes. Both types of isolates can establish latency, and the same isolate can be detected or can recrudesce in subsequent years.
It is important to note that the experimental infections with D752 isolates that led to high levels of viremia only infrequently led to cases of EHM, and then the prevalence was low and disease was mild. Clearly, other factors are important in development of EHM.