Epidemiology and Pathogenesis: the Perfect Storm

Outbreaks of EHM are rare events, and the most common manifestation of an outbreak is a cluster of neurologically affected horses that is outnumbered by febrile horses. During an interview with The New York Times, Colorado State University faculty member Dr. Paul Morley compared the 2011 EHM outbreak in Ogden, Utah, with a “perfect storm” in the meteorologic sense. In epidemiology, risk factors are variables associated with increased or decreased risk for disease or infection. In a perfect storm, all facilitating risk factors are present at the same time and place, while factors decreasing risk are absent or negligible. The sum of risk factors will determine severity and the number of affected animals. Risk factors for an EHM outbreak are the presence of one or more virus-shedding horses and the proximity of susceptible horses in relation to the shedder or shedders. However, given that experimental intranasal and pharyngeal EHV-1 inoculation with large quantities of neuropathogenic strain does not consistently reproduce the syndrome of EHM in otherwise successfully infected animals, clearly other risk factors are necessary to progress from a primary respiratory tract infection to clinical EHM. Risk factors that may culminate into an EHM outbreak include transportation or attending an event (mingling); fall, winter, or spring season (possibly associated with indoor events and activities); crowding; and shared airspace. Age and breed are also risk factors for increased EHM incidence because adult horses of tall breeds (i.e., draft horses, warmbloods, western performance breeds of North America, Standardbreds, and Thoroughbreds) are at greater risk for developing EHM than adolescent horses or animals of pony breeds. Mitigation or intervention during an outbreak, isolation and institution of sick bays, and the taking of preventative measures such as biosecurity and vaccination all constitute negative risk factors.

Key to development of EHM is a cell-associated viremia, wherein virus-containing lymphocytes and monocytes, collectively called peripheral blood mononuclear cells (PBMCs), circulate. Infected PBMCs contact endothelial cells (ECs) in CNS vasculature, allowing virus to translocate from PBMCs into ECs. Because vascular pathologic changes are seen in close proximity to infected ECs, it is thought that this translocation of virus and infection of EC will lead to EHM secondary to local vasculitis, local thrombosis, and hemorrhage.

Clinical Signs

Fever is a typical sign of EHV infection. From study of experimental infections, it is known that fever during EHV infection is biphasic, with a primary fever developing during the first 48 hours after infection and a secondary fever developing during viremia. Clinical EHM typically develops during or upon cessation of viremia. Clinical signs of EHM depend on the number, size, and location of ischemic lesions in the spinal cord. Because disease is typically multifocal, any local neuronal reflex systems (gray matter disease) or long spinal cord tracts (white matter disease) can be affected. The same long tract system over its entire length can be affected at multiple sites. This pathology results in variable degrees and symmetry of ataxia, dysmetria, and weakness of forelimbs and hind limbs. Frequently, EHM-affected horses have difficulty urinating because of an upper motor neuron bladder. In this condition, while the detrusor muscle of the bladder is contracting, the urethral sphincter is tightly closed, and the horse is unable to urinate. Clinical disease has an acute onset and progresses rapidly over 24 to 48 hours, but then stabilizes. Gradual improvement with return to full or nearly full function can take weeks to months. The chances for full recovery are greater in mildly affected horses, usually in horses that do not become recumbent.

Diagnosis

Reaching a definitive diagnosis of EHM in an individual horse may only be possible after polymerase chain reaction (PCR) or immunohistologic examination of CNS tissue. Occasionally, a presumptive diagnosis can be made when EHV-1 is diagnosed in combination with appropriate clinical and clinicopathologic findings. In an acute case, when EHM is a differential diagnosis, the following samples should be collected and submitted to a suitable laboratory: a nasal swab (ideally sent in virus transport medium for virus isolation); a venous blood sample collected in EDTA; a cerebrospinal fluid sample if possible; and an acute serum sample.

Polymerase chain reaction analysis of nasal swabs and PBMCs (in venous blood) is the method of choice for rapid and sensitive diagnosis of EHV-1 infection. Positive results for herpesvirus in a nasal swab or in PBMCs are a strong indication of EHM in a horse with clinical neurologic signs. Nevertheless, it is important to recognize that EHM may develop just as nasal viral shedding has ended and even after viremia is detectable. Repeated testing is indicated if clinical signs of EHM are present, and the diagnosis cannot be ruled out solely on the basis of failure to detect EHV-1. Currently, conventional and quantitative PCR analysis is widely available and highly specific. However, sensitivity of conventional PCR is not as good as with real-time PCR. Tests targeting amplicons in the gB gene are currently the most useful and sensitive. Tests are also available, both conventional and real-time PCR, that can differentiate EHV-1 isolates carrying the D₇₅₂ and N₇₅₂ genetic markers. These tests are not believed to be as sensitive as the gB-based tests, and at present the implications of this finding for management of EHV-1 outbreaks, or individual horses actively or latently infected with these isolates, are uncertain. For these reasons, real-time PCR tests targeting the gB sequence are the preferred method of viral detection.

Cerebrospinal fluid analysis can be supportive of an EHM diagnosis and can be of value while PCR results are pending. Xanthochromia of CSF and a high protein concentration without cellular pleocytosis can be found in up to 50% of horses with EHM and neurologic signs. However, any type of multifocal or diffuse pathology of CNS vasculature pathology can manifest similarly. Therefore, it is important to regard any individual horses presumed to have EHM in combination with epidemiologic risk factors as described earlier.

Seroconversion is a reliable diagnostic test for EHV-1 infection. However, it requires a second serum sample collected 3 weeks after onset of clinical signs to demonstrate a fourfold titer increase.

Virus culture is time consuming (taking at least 3 to 5 days) and requires an experienced laboratory. However, the test is valuable for epidemiologic studies and research.