Equine Herpesvirus Myeloencephalopathy (EHM)

Equine Herpesvirus Myeloencephalopathy (EHM) is a devastating neurological manifestation of infection with Equine Herpesvirus Type 1 (EHV-1), a ubiquitous alphaherpesvirus that causes respiratory disease, abortion, neonatal death, and, in a subset of infected horses, severe spinal cord and brainstem vasculitis leading to ataxia, paresis, urinary incontinence, and recumbency. EHM is characterized by a sudden onset of neurological deficits, often following a febrile respiratory episode or abortion storm, and can occur in horses of any age, breed, or discipline, though it is most commonly recognized in adult horses in group housing or training facilities. The disease is of significant concern to the equine industry due to its high morbidity, potential for mortality, and the need for strict biosecurity measures to control outbreaks. EHM is a non-suppurative, necrotizing vasculitis and thrombosis of the central nervous system (CNS), primarily affecting the spinal cord and brainstem, leading to ischemic and hemorrhagic lesions. The clinical presentation can range from mild hindlimb ataxia to severe tetraplegia and recumbency, with a mortality rate of 10-50% in affected horses. The disease is a major differential for any acute onset of neurological signs in horses, especially in the context of a recent febrile illness or exposure to new horses.

The primary causative agent of EHM is Equine Herpesvirus Type 1 (EHV-1), a double-stranded DNA virus belonging to the family Herpesviridae, subfamily Alphaherpesvirinae. EHV-1 is highly contagious and is transmitted primarily via respiratory secretions (aerosolized droplets) and direct contact with contaminated fomites, including feed, water, and equipment. The virus initially replicates in the upper respiratory tract epithelium, causing mild to moderate rhinitis and pharyngitis, often subclinical. Following primary replication, the virus enters the bloodstream via infected leukocytes (cell-associated viremia), leading to systemic dissemination. The neuropathogenic potential of EHV-1 is associated with a single nucleotide polymorphism (SNP) in the viral DNA polymerase gene (ORF30), specifically the substitution of aspartic acid (D) to asparagine (N) at position 752 (D752N). This mutation is strongly associated with the neuropathogenic phenotype, although non-neuropathogenic strains (N752) can also cause EHM in rare cases. The virus establishes lifelong latency in the trigeminal ganglia and lymphoreticular tissues, and reactivation can occur during periods of stress, immunosuppression, or concurrent disease, leading to viral shedding and potential spread. Other equine herpesviruses (EHV-4, EHV-3) are not typically associated with EHM, though EHV-4 has been rarely implicated. The pathogenesis of EHM involves viral infection of endothelial cells of the CNS vasculature, leading to vasculitis, thrombosis, and subsequent ischemic necrosis of the surrounding neural tissue. The resulting lesions are typically multifocal and bilaterally symmetrical, most commonly affecting the spinal cord (especially the lumbosacral and cervical regions) and brainstem.

EHM occurs worldwide and affects horses of all breeds, ages, and sexes, though it is most commonly reported in adult horses (2-15 years old) in group housing, boarding facilities, breeding farms, and show or racing stables. The disease is more prevalent in the winter and spring months, likely due to increased indoor housing and stress associated with transport and competition. Outbreaks are often associated with the introduction of a new horse into a population, particularly during periods of high stress such as weaning, sales, or training. The morbidity rate of EHV-1 infection can be as high as 90% in naive populations, but the incidence of EHM among infected horses is estimated at 1-10%, with higher rates in horses infected with the neuropathogenic strain (D752). The mortality rate for EHM ranges from 10% to 50%, with recumbent horses having a poorer prognosis. Certain breeds, such as Thoroughbreds, Standardbreds, and Warmbloods, may be overrepresented due to their high-density management and frequent movement, but no true breed predisposition exists. The disease has a significant economic impact due to quarantine costs, loss of performance, and mortality. In endemic areas, most adult horses are seropositive for EHV-1, indicating widespread exposure, but protective immunity is short-lived and does not prevent reinfection or reactivation. The case fatality rate is higher in horses that develop severe neurological signs, particularly those that become recumbent within 24 hours of onset.

The pathophysiology of EHM is a complex interplay of viral replication, immune-mediated responses, and vascular injury. After inhalation, EHV-1 infects the respiratory epithelium, where it replicates and causes cytolysis. The virus then infects circulating mononuclear cells (lymphocytes and monocytes), establishing a cell-associated viremia that allows systemic dissemination. The neuropathogenic strain (D752) exhibits enhanced replication in endothelial cells and a higher magnitude and duration of viremia, increasing the likelihood of CNS infection. The virus targets the endothelial cells of the CNS microvasculature, particularly in the spinal cord and brainstem, leading to direct viral-induced cytopathology and an inflammatory response. This results in vasculitis, characterized by infiltration of neutrophils and mononuclear cells into the vessel wall, endothelial swelling, and fibrinoid necrosis. Subsequent thrombosis and occlusion of the lumen cause ischemic infarction of the surrounding neural parenchyma, leading to axonal degeneration, demyelination, and necrosis. The lesions are typically multifocal and bilaterally symmetrical, with a predilection for the lumbosacral and cervical spinal cord enlargements. The resulting neurological deficits reflect the location and severity of the lesions, with hindlimb ataxia and paresis being the most common signs. The incubation period from exposure to clinical signs is typically 6-10 days, but can range from 3 to 14 days. The severity of EHM is influenced by viral strain, host immune status, and the presence of concurrent stressors. The immune response, particularly the cell-mediated immune response, is crucial for viral clearance, but excessive inflammation can exacerbate tissue damage. The virus can also establish latency in the trigeminal ganglia and lymphoreticular tissues, with reactivation leading to recrudescence and shedding.

Several intrinsic and extrinsic factors increase the risk of EHM development and severity. Intrinsic factors include age (adult horses > 3 years are more susceptible), breed (no true breed predisposition, but high-density management in Thoroughbreds and Warmbloods increases exposure), and immune status (horses with waning immunity or immunocompromised states are at higher risk). The presence of the neuropathogenic strain (D752) is a major risk factor for neurological disease. Extrinsic factors include high-density housing, recent introduction of new horses, transportation stress, weaning, intense training, and concurrent disease. Stress-induced immunosuppression can lead to viral reactivation and shedding in latently infected horses. Poor biosecurity practices, such as sharing equipment, water sources, and trailers, facilitate viral spread. Seasonal factors, such as winter confinement, increase the risk of aerosol transmission. Additionally, the use of immunosuppressive drugs, such as corticosteroids, can increase the risk of EHM in infected horses. Management practices that minimize stress and maintain good ventilation are critical in reducing the incidence of EHM.

The clinical signs of EHM typically appear 6-10 days after exposure, often following a mild febrile episode (rectal temperature > 101.5°F or 38.6°C) that may go unnoticed. The onset of neurological signs is often acute and may progress rapidly over 24-48 hours. The most common signs are symmetrical or asymmetrical ataxia and paresis, primarily affecting the hindlimbs, with a 'bunny-hopping' gait, pelvic sway, and difficulty backing or turning. Affected horses may show a low head carriage, base-wide stance, and knuckling of the hind fetlocks. Cranial nerve deficits can occur if the brainstem is involved, including facial nerve paralysis, dysphagia, and tongue weakness. Urinary incontinence is common due to bladder atony, leading to urine scalding and potential cystitis. In severe cases, horses may become recumbent and unable to rise, with a poor prognosis. Other systemic signs include fever, depression, anorexia, and mild respiratory signs such as nasal discharge and cough. Abortion in pregnant mares can occur concurrently or independently of neurological signs. The severity of clinical signs can be graded using a neurological scale (e.g., 0 = normal, 1 = mild ataxia, 2 = moderate ataxia, 3 = severe ataxia with paresis, 4 = recumbent but able to rise, 5 = recumbent and unable to rise). Physical examination may reveal tachycardia, tachypnea, and pyrexia. Bladder distension and urine dribbling are common findings. The neurological examination should include assessment of cranial nerves, gait, postural reactions, and spinal reflexes.

The differential diagnoses for EHM include other causes of acute neurological disease in horses. Key differentials include: 1) Equine Protozoal Myeloencephalitis (EPM) caused by Sarcocystis neurona, which typically presents with asymmetric ataxia and muscle atrophy, and can be differentiated by CSF Western blot or PCR. 2) West Nile Virus (WNV) encephalomyelitis, which causes fever, ataxia, and muscle fasciculations, and is diagnosed by serology (IgM capture ELISA) or PCR on CSF. 3) Rabies, which presents with progressive neurological signs, behavioral changes, and is invariably fatal; diagnosis is confirmed post-mortem by fluorescent antibody testing. 4) Cervical Vertebral Stenotic Myelopathy (CVSM or Wobbler syndrome), which is more common in young horses and presents with symmetric ataxia, but is often insidious in onset; diagnosis is based on cervical radiography and myelography. 5) Trauma to the spinal cord or head, which may have a history of injury and can be diagnosed by radiography or MRI. 6) Hepatic encephalopathy, which causes depression, head pressing, and ataxia, and is diagnosed by elevated liver enzymes and bile acids. 7) Botulism, which causes flaccid paralysis and dysphagia, and is diagnosed by toxin detection in serum or feces. 8) Equine Motor Neuron Disease (EMND), which causes muscle atrophy and weakness, but is chronic and progressive. 9) Lead poisoning, which can cause laryngeal paralysis and ataxia, and is diagnosed by blood lead levels. 10) Atypical myopathy, which causes muscle weakness and myoglobinuria, and is associated with sycamore tree exposure. Definitive diagnosis of EHM requires laboratory confirmation, but treatment should be initiated immediately if EHM is suspected.

The diagnostic algorithm for EHM begins with a thorough history and physical examination, including a complete neurological examination. If EHM is suspected, strict biosecurity measures should be implemented immediately, including isolation of the affected horse and quarantine of potentially exposed horses. The following steps are recommended: 1) Collect blood samples for hematology, serum biochemistry, and serology (paired acute and convalescent samples for EHV-1 antibody titers using complement fixation or ELISA). 2) Perform a nasopharyngeal swab and whole blood (EDTA) for viral detection by PCR (quantitative PCR for EHV-1, including genotyping for the D752/N752 polymorphism). 3) Collect cerebrospinal fluid (CSF) from the atlanto-occipital or lumbosacral site for analysis (CSF typically shows mild to moderate mononuclear pleocytosis and elevated protein) and EHV-1 PCR. 4) If the horse is febrile, perform a complete blood count and fibrinogen to assess inflammation. 5) Rule out other differentials through specific testing (e.g., EPM Western blot, WNV IgM, rabies direct fluorescent antibody test on brain tissue if the horse dies). 6) In cases of abortion, submit fetal tissues and placenta for EHV-1 PCR and histopathology. 7) Imaging (radiography, MRI) may be indicated to rule out trauma or CVSM, but is not essential for EHM diagnosis. 8) Post-mortem examination is crucial for confirmation, with histopathology of the CNS showing vasculitis and thrombosis. The diagnostic algorithm should be executed rapidly to initiate appropriate therapy and implement control measures.

Laboratory findings in EHM are non-specific but supportive. Hematology may reveal leukopenia (due to lymphopenia and neutropenia) during the viremic phase, followed by leukocytosis. Fibrinogen may be elevated due to inflammation. Serum biochemistry may show mild elevations in muscle enzymes (CK, AST) if the horse is recumbent or has muscle trauma. Blood gas and electrolyte analysis may reveal metabolic acidosis or electrolyte imbalances in recumbent horses. The most definitive laboratory finding is the detection of EHV-1 DNA by PCR in nasopharyngeal swabs, whole blood (buffy coat), or CSF. Quantitative PCR can differentiate neuropathogenic (D752) from non-neuropathogenic (N752) strains. Serology using paired serum samples (acute and convalescent, 2-3 weeks apart) can demonstrate a four-fold rise in antibody titers, but is retrospective. CSF analysis typically shows a mild to moderate mononuclear pleocytosis (10-100 cells/µL) and elevated protein (50-200 mg/dL), but these findings are not specific. In some cases, CSF may be normal. Viral isolation from nasopharyngeal swabs or blood is possible but less sensitive than PCR. Post-mortem, histopathology of the CNS reveals characteristic vasculitis, thrombosis, and ischemic necrosis, and EHV-1 antigen can be detected by immunohistochemistry.

Imaging modalities are not typically used for the diagnosis of EHM, but may be employed to rule out other causes of neurological signs. Radiography of the cervical spine can help diagnose CVSM or trauma. Myelography can be used to identify compressive lesions. MRI of the brain and spinal cord can reveal areas of ischemia, hemorrhage, or inflammation, but is rarely performed due to cost and availability. Ultrasonography is not useful for CNS evaluation. In cases of abortion, ultrasonography of the fetus may be performed, but is not diagnostic. The primary role of imaging in EHM is to exclude other differentials, as the diagnosis is primarily based on PCR and serology. Advanced imaging may be indicated in cases where trauma or compressive myelopathy is suspected, but the presence of fever and recent respiratory signs should raise suspicion for EHM.

Cytological analysis of CSF in EHM typically reveals a mild to moderate mononuclear pleocytosis, with lymphocytes and macrophages predominating. Neutrophils may be present in acute cases. Protein concentration is often elevated. These findings are non-specific and can be seen in other viral or immune-mediated diseases. Histopathological examination of the CNS at necropsy is the gold standard for diagnosis. Gross lesions may include multifocal areas of hemorrhage and malacia in the spinal cord and brainstem. Microscopic findings include necrotizing vasculitis with fibrinoid necrosis of vessel walls, thrombosis, perivascular cuffing with mononuclear cells, and areas of ischemic neuronal necrosis and axonal degeneration. The lesions are typically bilaterally symmetrical and most severe in the lumbosacral and cervical spinal cord. Immunohistochemistry can demonstrate EHV-1 antigen in endothelial cells and leukocytes within the lesions. In cases of abortion, histopathology of the fetus may show necrotizing hepatitis and intranuclear inclusion bodies in hepatocytes and adrenal glands.

Treatment of EHM is primarily supportive, as there is no specific antiviral therapy proven to be effective in horses. The goals are to reduce viral replication, manage inflammation, provide supportive care, and prevent complications. Antiviral drugs such as acyclovir, valacyclovir, and ganciclovir have been used, but their efficacy is questionable due to poor oral bioavailability and lack of clinical trials. Acyclovir (IV, 10-20 mg/kg q8h) or valacyclovir (PO, 20-40 mg/kg q8h) may be considered, but their use is controversial. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to reduce fever and inflammation, but should be used cautiously due to the risk of renal and gastrointestinal side effects. Flunixin meglumine (1.1 mg/kg IV q12-24h) or phenylbutazone (2.2-4.4 mg/kg IV or PO q12-24h) are commonly used. Corticosteroids such as dexamethasone (0.05-0.1 mg/kg IV q24h) may be used to reduce CNS inflammation, but their use is controversial due to potential immunosuppression and viral shedding. Supportive care is critical, including fluid therapy to maintain hydration, nutritional support, and bladder management. Recumbent horses require deep bedding, frequent turning, and slinging if possible. Urinary catheterization or manual bladder expression may be necessary. Antimicrobial therapy may be indicated for secondary infections, such as pneumonia or cystitis. The use of hyperimmune plasma or interferon has been suggested but lacks evidence. Strict biosecurity measures are essential to prevent spread to other horses. The prognosis for EHM is guarded, with a mortality rate of 10-50%. Horses that remain standing have a better prognosis, while those that become recumbent have a poor prognosis. Recovery can take weeks to months, and some horses may have residual neurological deficits.

The prognosis for EHM is guarded to poor, depending on the severity of clinical signs and the speed of intervention. The overall mortality rate is 10-50%, with recumbent horses having a mortality rate of up to 70%. Horses that remain ambulatory have a better chance of survival, with up to 80% recovering to some degree. However, recovery may be incomplete, and some horses may have permanent neurological deficits, such as ataxia or urinary incontinence. The prognosis is worse for horses that become recumbent within 24 hours of onset, those with severe brainstem involvement, and those that develop secondary complications such as pneumonia, cystitis, or decubital ulcers. Early recognition and aggressive supportive care can improve the outcome. The neuropathogenic strain (D752) is associated with a higher incidence of EHM and more severe disease. The prognosis for return to athletic function is variable; some horses may return to their previous level of performance, while others may be retired due to residual deficits. Serial neurological examinations can help assess progress. Negative prognostic indicators include recumbency, severe ataxia (grade 4-5), and lack of improvement within 48-72 hours.

Follow-up care for horses recovering from EHM is essential to monitor neurological status and prevent complications. Serial neurological examinations should be performed daily during the acute phase and then weekly or monthly during recovery. Horses should be monitored for urinary tract infections, as bladder dysfunction may persist. Regular assessment of body condition and nutritional status is important, as some horses may have difficulty eating or drinking. A gradual return to exercise is recommended, starting with hand-walking and progressing to under-saddle work as neurological function improves. The duration of recovery can be weeks to months. Pregnant mares should be monitored for abortion, and aborted fetuses should be tested for EHV-1. Biosecurity measures should be maintained for at least 4 weeks after the last clinical case, and potentially exposed horses should be quarantined for 28 days. Vaccination status should be reviewed, and vaccination may be considered for at-risk horses, though it does not prevent EHM. The horse's environment should be kept clean and stress-free to minimize the risk of reactivation. Long-term follow-up may include periodic neurological examinations and assessment of performance.

Clinical pearls: 1) EHM should be a top differential for any horse with acute onset of ataxia, especially if there is a history of fever or recent exposure to new horses. 2) Immediate isolation and biosecurity are critical to prevent outbreaks. 3) Nasopharyngeal swabs and whole blood for PCR should be collected early, as viral shedding may be transient. 4) The neuropathogenic strain (D752) is associated with a higher risk of EHM, but non-neuropathogenic strains can also cause disease. 5) Supportive care, including fluid therapy, bladder management, and nursing care, is the mainstay of treatment. 6) Corticosteroids may be beneficial in reducing CNS inflammation, but their use is controversial. 7) Prognosis is better for horses that remain standing. Pitfalls: 1) Failure to implement biosecurity measures early can lead to widespread outbreaks. 2) Over-reliance on antiviral drugs without evidence of efficacy. 3) Inadequate supportive care, especially in recumbent horses, leading to secondary complications. 4) Misdiagnosis as EPM or other neurological diseases, delaying appropriate treatment. 5) Failure to monitor for urinary tract infections in horses with bladder dysfunction. 6) Premature return to exercise, which can exacerbate neurological deficits. 7) Neglecting to test aborted fetuses for EHV-1, which can be a source of infection.

Current drug protocols for EHM are primarily supportive and based on expert opinion and limited evidence. Antiviral therapy: Acyclovir (IV, 10-20 mg/kg q8h) or valacyclovir (PO, 20-40 mg/kg q8h) may be used, but their efficacy is unproven. NSAIDs: Flunixin meglumine (1.1 mg/kg IV q12-24h) or phenylbutazone (2.2-4.4 mg/kg IV or PO q12-24h) for fever and inflammation. Corticosteroids: Dexamethasone (0.05-0.1 mg/kg IV q24h) may be used for severe CNS inflammation, but should be used with caution. Fluid therapy: Polyionic isotonic fluids (e.g., lactated Ringer's solution) at maintenance (50 ml/kg/day) or to correct dehydration. Hypertonic saline (7.5% NaCl, 2-4 ml/kg IV) may be used for shock. Nutritional support: If the horse cannot eat, enteral feeding via nasogastric tube or parenteral nutrition may be necessary. Bladder management: Urinary catheterization or manual expression, and antibiotics if infection develops. Antimicrobials: For secondary infections, penicillin G (22,000 IU/kg IV q6h) and gentamicin (6.6 mg/kg IV q24h) may be used. Gastrointestinal protectants: Omeprazole (1-2 mg/kg PO q24h) or sucralfate (20 mg/kg PO q6-8h) if NSAIDs are used. All dosages should be adjusted based on the horse's condition and renal function.

The evidence base for EHM is limited, with most recommendations based on expert opinion and extrapolation from other species. Key studies include: 1) A retrospective study by Henninger et al. (2007) described an outbreak of EHM caused by the neuropathogenic strain, highlighting the high morbidity and mortality. 2) A study by Pusterla et al. (2009) evaluated the use of quantitative PCR for detection of EHV-1 in blood and nasal secretions, demonstrating its utility in diagnosis. 3) A study by Goehring et al. (2010) investigated the efficacy of valacyclovir in experimentally infected horses, showing a reduction in viremia but no effect on clinical signs. 4) A consensus statement by the ACVIM (2012) provided guidelines for the prevention and control of EHV-1, emphasizing biosecurity and vaccination. 5) A study by Lunn et al. (2012) reviewed the pathogenesis of EHM and highlighted the role of the D752 mutation. 6) A study by Burgess et al. (2012) evaluated the use of corticosteroids in EHM, but found no clear benefit. 7) A meta-analysis by Kydd et al. (2012) assessed the efficacy of antiviral drugs, concluding that there is insufficient evidence to recommend their routine use. 8) A study by Walter et al. (2013) described the clinical features and outcomes of EHM in a large outbreak, reporting a mortality rate of 30%. 9) A study by Goodman et al. (2014) investigated the use of hyperimmune plasma, but found no significant benefit. 10) A study by Pusterla et al. (2016) evaluated the use of acyclovir in naturally infected horses, showing no improvement in outcome. Overall, the literature emphasizes the importance of early diagnosis, strict biosecurity, and supportive care, while the role of antiviral and anti-inflammatory drugs remains uncertain.