Equine protozoal myeloencephalitis (EPM) is caused by CNS infection of equids with either of the apicomplexan protozoa Sarcocystis neurona or Neospora hughesi. Clinical signs can mimic other common neurological diseases and can be highly variable, with the most common being asymmetric ataxia and weakness of limbs and regional neurogenic muscle atrophy. Additional clinical signs include obtundation, seizures, facial paralysis, head tilt, and other signs of cranial nerve dysfunction. Support for the diagnosis is obtained using serum:CSF titer ratios from ELISA or indirect fluorescent antibody test results. EPM is treated with antiprotozoal drugs and sometimes ancillary treatments, such as immunomodulators.
Equine protozoal myeloencephalitis (EPM) is a common infectious neurological disease of horses in the Americas; it has been reported in most of the contiguous 48 states of the US, southern Canada, Mexico, and several countries in Central and South America. In countries outside of these areas, EPM occurs sporadically in horses that have previously spent time in the Americas.
Etiology and Epidemiology of Equine Protozoal Myeloencephalitis
Most cases of equine protozoal myeloencephalitis are caused by the apicomplexan protozoon Sarcocystis neurona. Horses are infected by ingestion of S neurona sporocysts in contaminated feed or water. The organism undergoes early asexual multiplication (schizogony) in extraneural tissues before parasitizing the CNS.
Like other Sarcocystis spp, S neurona has an obligate predator-prey life cycle.
The definitive (predator) host for S neurona in the US is the opossum (Didelphis virginiana). Opossums are infected by eating sarcocyst-containing muscle tissue from an infected intermediate (prey) host; after a brief prepatent period (probably 2–4 weeks), infectious sporocysts are passed in the possum's feces. Nine-banded armadillos, striped skunks, raccoons, sea otters, Pacific harbor seals, and domestic cats have all been implicated as intermediate hosts; however, the importance in nature of each of these species is unknown.
Dead-end hosts do not form infectious sarcocysts in their muscles, while intermediate hosts do. Because infectious sarcocysts are only rarely formed in equine muscle tissue, the horse is considered an aberrant, dead-end host for S neurona. When clinical disease occurs in the horse, schizonts and merozoites may be identified within equine nervous system tissues at postmortem, rather than sarcocysts in muscle.
Sporadic cases of EPM are associated with Neospora hughesi, an organism closely related to S neurona. The natural hosts of this organism have not yet been identified. Transplacental protozoal transmission, resulting in infected foals, has been documented for N hughesi but not for S neurona.
Clinical Findings of Equine Protozoal Myeloencephalitis
Because these protozoa can infect any part of the CNS, almost any neurological sign is possible with equine protozoal myeloencephalitis. Infected horses are not typically painful or febrile, which may help prioritize differential diagnoses. The disease usually begins insidiously but can present acutely and be severe at onset.
Pearls & Pitfalls
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Clinical signs of spinal cord involvement are more common than signs of brain disease with EPM. Horses with EPM involving the spinal cord can have asymmetric or symmetric weakness and ataxia in any number of limbs, sometimes with obvious muscle atrophy that may be most easily noted in the epaxial or gluteal regions. When the sacrocaudal spinal cord is involved, there can be clinical signs of cauda equina syndrome. EPM lesions in the spinal cord also can result in demarcated areas of spontaneous sweating or loss of reflexes and cutaneous sensation.
The following are some of the most common clinical signs of brain disease in horses with EPM:
dullness/listlessness
dysphagia
head tilt and leaning (vestibular signs)
facial nerve abnormalities, including ptosis, ear droop, and muzzle deviation
Any cranial nerve nucleus can be involved. There may be seizures, visual deficits including abnormal menace response, and behavioral abnormalities. EPM can progress to cause recumbency and death. Progression to recumbency can occur over hours or years and may happen steadily or in a stop-start fashion.
Lesions
With EPM, there can be focal discoloration, hemorrhage, or malacia of CNS tissue. Histologically, protozoa may be found in association with a mixed inflammatory cellular response and neuronal destruction.
Schizonts, in various stages of maturation, or free merozoites commonly are present in the cytoplasm of neurons or mononuclear phagocytes. Also parasitized are intravascular and tissue neutrophils and eosinophils and, more rarely, capillary endothelial cells and myelinated axons. Merozoites may be found extracellularly, especially in areas of necrosis. In at least 75% of clinical cases, protozoa are not observed on H&E-stained sections.
Diagnosis of Equine Protozoal Myeloencephalitis
Exclusion of differential diagnoses
Demonstration of threshold concentrations of antibodies in CSF and blood
Postmortem diagnosis of equine protozoal myeloencephalitis is confirmed by demonstration of protozoa in CNS lesions on the basis of distinctive morphology or by immunohistochemical staining, though presumptive histological diagnosis can be made based on characteristic inflammatory changes in tissue without identifying protozoa.
Testing for S neurona– or N hughesi–specific antibody is the basis for presumptive antemortem diagnosis of EPM, most accurately when intrathecal antibody production is demonstrated following CSF tap by determining a ratio between antibody titers in cerebrospinal fluid and serum in a paired sample. Serological tests for specific antibodies in blood against whole S neurona or N hughesi (eg, indirect fluorescent antibody test [IFAT]) or protozoal surface antigens (SAG 2,3,4) provide evidence of current or previous exposure to the organism. Thus, low or negative serum titers tend to exclude the diagnosis of EPM, particularly in regions where rates of exposure are high.
Conversely (and importantly), positive or high S neurona titers in serum have limited diagnostic utility in that such titers do not clearly distinguish horses with exposure from those with active, clinical EPM. The use of serology alone to determine if a horse has an active EPM infection without calculating serum:CSF antibody titer ratios can therefore yield false-positive results.
In horses with neurological signs, commercially available serum:CSF SAG 2,4,3 antibody titer ratios of < 1:100 are indicative of production of S neurona antibody in the CNS and are highly supportive of the diagnosis of EPM. Using a commercially available IFAT, a serum:CSF ratio ≤ 64 is suggestive of intrathecal antibody production. Testing and calculating a serum:CSF antibody titer ratio is also recommended in order to diagnose N hughesi; choice of test is based on clinician preference and location.
In a few horses with EPM, CSF analysis reveals abnormalities such as mononuclear pleocytosis and high protein concentration; however, in many cases these values are within normal limits. CSF cytology may be more likely to reveal evidence of or refute differential diagnoses.
Diagnostic procedures that can aid the veterinarian in ruling out some of the more common differential diagnoses include CSF cytological evaluation; imaging, such as radiography, CT, and myelography; additional infectious disease testing; and clinicopathological investigation.
Depending on the clinical signs, differential diagnoses may include the following:
cervical vertebral stenotic myelopathy
equine degenerative myeloencephalopathy/equine neuroaxonal dystrophy
traumatic brain or spinal cord injury
temporohyoid osteoarthropathy
equine herpesvirus 1 myeloencephalopathy
equine motor neuron disease
arboviral encephalomyelitis (eastern or western equine encephalitis, West Nile virus)
bacterial meningitis (Lyme neuroborreliosis vs other)
metabolic derangements
neoplasia
hepatoencephalopathy
leukoencephalomalacia
aberrant parasite migration
Treatment of Equine Protozoal Myeloencephalitis
Antiprotozoal drugs
Anti-inflammatories, vitamin E, and immunomodulators
The FDA-approved treatments for equine protozoal myeloencephalitis are ponazuril (paste, 5 mg/kg, PO, every 24 hours for 28 days), diclazuril (pellet, 1 mg/kg, PO, every 24 hours for 28 days), and a combination of sulfadiazine and pyrimethamine (liquid, 20 mg/kg and 1 mg/kg PO, respectively, every 24 hours for at least 90 days), each with apparently similar rates of efficacy.
The bioavailabilities of ponazuril and diclazuril may be improved by concurrent PO administration of corn oil or dimethyl sulfoxide (DMSO). A loading dose of ponazuril (15 mg/kg, PO) may be administered on the first day of treatment to rapidly attain therapeutic blood levels. The sulfadiazine/pyrimethamine product must be administered at least 1 hour before or after hay is fed to avoid dietary folate inhibition of pyrimethamine. Anemia can develop after prolonged treatment with sulfadiazine/pyrimethamine and is best prevented by providing folate-rich green forage such as alfalfa hay or green pasture.
Some clinicians will use combinatorial treatment (more than 1 of the aforementioned 3 antiprotozoal medications), particularly if no improvement is noted after the first month or two of treatment with 1 medication.
Approximately 60% of horses improve with each of the aforementioned treatments; however, < 25% recover completely. Relapses can occur up to 2 years after discontinuation of treatment with antiprotozoals. Of note, repeated immunodiagnostic testing is not recommended as a means for guiding duration of antiprotozoal treatment; rather, these decisions are typically made based on response to treatment.
Because immunosuppression/immunodeficiency can be a risk factor for EPM, immunomodulators (eg, mycobacterial cell-wall derivative, levamisole [1 mg/kg, PO, every 12 hours, for the first 2 weeks of antiprotozoal treatment and for the first week of each month thereafter], killed parapoxvirus ovis, or transfer factor) are sometimes administered as ancillary treatment, although no studies have been conducted to evaluate their efficacy in horses with EPM.
Nonsteroidal anti-inflammatory drugs (flunixin meglumine [1.1 mg/kg, IV, every 12–24 hours] and phenylbutazone [2–4.4 mg/kg, PO/IV, every 12 to 24 hours]) are often used during the first few days of antiprotozoal treatment.
In horses with severe ataxia or apparent brain involvement, corticosteroids such as dexamethasone (0.1 mg/kg, IM, every 24 hours for 4 days) may improve clinical signs. Vitamin E (20 IU/kg, PO, every 24 hours), an antioxidant, is also used adjunctively with antiprotozoal treatment.
Prevention and Control of Equine Protozoal Myeloencephalitis
No proven preventive is available for equine protozoal myeloencephalitis. A conditionally approved vaccine was marketed, but the license lapsed in 2008, and the vaccine is no longer offered. There is interest in using antiprotozoal drugs for prevention, and it has been shown that diclazuril every 24 hours prevents foals from seroconverting against S neurona and N hughesi.
Administration of biweekly diclazuril at half the label dose (0.5 mg/kg/day, PO, every 3–4 days) has been considered to reach therapeutic concentrations and may have a role in prevention; however, evidence-based protocols for preventive use of antiprotozoal drugs are not yet available (1).
The source of infective sporocysts is opossum feces, so it is prudent to prevent opossums' access to horse-feeding areas. Horse and pet feed should not be left out; open feed bags and garbage should be kept in closed galvanized metal containers, bird feeders should be eliminated, and fallen fruit should be removed. Opossums can be trapped and relocated. Because putative intermediate hosts cannot be directly infective for horses, it is unlikely that control of these populations will be useful in EPM prevention.
Key Points
Equine protozoal myeloencephalitis (EPM) is a common cause of infectious neurological disease of horses in the Americas.
Diagnosis is based on neurological signs, exclusion of differential diagnoses, and demonstration of intrathecal antibody production.
Antiprotozoal drugs improve clinical signs in most horses; however, complete recovery may not occur, and relapses are common.
There is no vaccine for EPM.
For More Information
Reed SM, Furr M, Howe DK, et al. Equine protozoal myeloencephalitis: an updated consensus statement with a focus on parasite biology, diagnosis, treatment, and prevention. 206;30(2):491-502.
Also see pet health content regarding equine protozoal myeloencephalitis.
References
Pusterla N, James K, Bain F, et al. Investigation of the bi-weekly administration of diclazuril on the antibody kinetics to Sarcocystis neurona in healthy horses. J Equine Vet Sci. 2021;104:103713. doi:10.1016/j.jevs.2021.103713
