A Promising Novel Treatment for Equine Herpesvirus Myeloencephalopathy

Equine herpesvirus type 1 (EHV-1) infection has become a concern for many horse owners, especially those whose horses are stabled in large barns with numerous other horses. Living in close quarters can cause outbreaks of not only respiratory disease and abortion but also acute and life-threatening neurologic disease.

EHV outbreaks are on the rise, and the associated morbidity and mortality can be quite profound, yet current vaccines formulated against EHV-1 are “not specifically preventive against the infection.”¹ A US Department of Agriculture analysis of data from 6 neurologic EHV-1 outbreaks between 2001 and 2005 revealed a mean attack rate of 33% and a mean case fatality rate of 40%.²

Clinical signs due to EHV-1 often occur about 6 to 10 days after infection and include weakness, fever, and urinary bladder atony. Acute, symmetric hind limb ataxia can occur as well as tetraparesis leading to recumbency in severe cases. Coughing and abortion may occur 2 weeks prior to the onset of neurologic deficits. Treatment is often limited to symptomatic therapy because the infection is viral; however, antiviral medications (eg, acyclovir, valacyclovir, ganciclovir) may also be used, even though “their... efficacy has not been proven under clinical conditions.”¹

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During a neuropathogenic EHV-1 outbreak, infected horses may develop equine herpesvirus myeloencephalopathy (EHM), a severe manifestation of the infection.¹ The neurologic deficits are due to gray and white matter injury of the spinal cord. The central nervous system can also be affected, with seizures and blindness reported occasionally. Affected horses that become recumbent often die or are euthanized.

Case Report

In a recent case study, investigators in southern Germany used heparin as a novel treatment approach during an acute EHV-1 outbreak with the neuropathogenic G2254 /D752 Pol variant.¹ Based on its ability to prevent EHV-1 entry into cells as well as its anticoagulation properties, the investigators hypothesized that heparin may reduce the incidence and severity of EHM during an outbreak of EHV-1. According to the investigators, “the pathogenesis of EHM is associated with vasculitis of small blood vessels within the central nervous system and subsequent thromboischemic damage to the surrounding neural tissue.” Thrombotic complications from EHV infection are also due to the virus “activating platelets through virus-associated tissue factor—initiated thrombin generation,” as demonstrated in a previous study.³ Heparin has multiple actions, including acting on antithrombin to prevent clot formation and inhibiting leukocytes from adhering to the endothelial cells lining the inner surface of blood vessels, potentially limiting endothelial cell damage.

The outbreak started with an abortion in the broodmare barn, then spread to barns housing sport horses. Eventually, 79 horses in 7 barns were affected; 61 exhibited at least 1 clinical sign of EHV-1 infection (fever in 55 horses, EHM in 8, and abortion in 6). Starting on the 10th day of the outbreak, subcutaneous heparin (25,000 IU twice daily) was administered for 3 days to 31 horses with fever. The first 30 horses that initially demonstrated only 1 clinical sign (fever) comprised the untreated control group.¹

The outcome for this EHV-1 outbreak was 8 cases of EHM, the majority of which were in the control group. Heparin-treated horses showed a “lower EHM incidence (1/31; 3.2%) than untreated horses (7/30; 23.3%; P = .03).” Horses that developed EHM also received a nonsteroidal anti-inflammatory drug (flunixin meglumine) daily.¹

Study Limitations

The results from this preliminary case report using a novel treatment during a natural EHV-1 outbreak are promising, despite the investigators’ acknowledgment of some limitations. This was not a prospective randomized controlled study but rather a retrospective analysis, and treatment was determined during a clinical situation in the field setting. Nevertheless, it is a strong initial investigation to determine a useful modality for treating horses suffering from EHV-1 infection and avoiding potentially severe complications such as EHM.

Unfractionated heparin was used in this study to treat affected horses. While unfractionated heparin can have untoward adverse effects, such as erythrocyte agglutination, thrombocytopenia, and a propensity for the patient to experience bleeding, the results in this study were positive. In future studies, however, it may be ideal to investigate treatment of horses affected by an EHV-1 outbreak using low-molecular-weight heparin to assess prevention of EHM. Low-molecular-weight heparin has been administered to horses in various other studies with reportedly fewer adverse effects.

Conclusion

The results from this study are also interesting in light of another recent report that demonstrated heparin inhibition of ex vivo EHV-1 platelet activation.⁴ “Our results indicate that heparin anticoagulants and strong nonselective (3-isobutyl-1methylxanthine; IBMX) or isoenzyme-3 selective (cilostazol) [phosphodiesterase] antagonists inhibit ex vivo EHV-1-induced platelet activation,” the study authors said. “These drugs have potential as adjunc- tive therapy to reduce the serious complications associated with EHV-1-induced thrombosis.”⁴

Dr. Bentz is a 1997 graduate of the University of Pennsylvania School of Veterinary Medicine. She is co-founder of Academic Veterinary Solutions, serves as equine chair for the Pennsylvania Veterinary Medical Association's Scientific Program Committee, teaches at University of Pennsylvania and Manor College, and is a consultant for Veterinary Information Network.

References:

• Walter J, Seeh C, Fey K, Bleul U, Osterrieder N. Prevention of equine herpesvirus myeloencephalopathy — is heparin a novel option? A case report. Tierärztl Prax Ausg G Grosstiere Nutztiere. 2016;44(G):313-317. doi: 10.15653/TPG-150451.
• Equine herpesvirus myeloencephalopathy: a potentially emerging disease. US Department of Agriculture Animal and Plant Health Inspection Service website. aphis.usda.gov/animal_health/emergingissues/downloads/ehv1final.pdf. Published January 2007. Accessed March 1, 2018.
• Stokol T, Yeo WM, Burnett D, et al. Equid herpesvirus type 1 activates platelets. PLoS ONE. 2015;10(4):e0122640. doi: 10.1371/journal.pone.0122640.
• Stokol T, Serpa PBS, Zahid MN, Brooks MB. Unfractionated and low-molecular-weight heparin and the phosphodiesterase inhibitors, IBMX and cilostazol, block ex vivo equid herpesvirus type-1-induced platelet activation. Front Vet Sci. 2016;3:99. doi: 10.3389/fvets.2016.00099.