The organisms that cause EPM can affect any tissue within the CNS including the brain, brainstem, and spinal cord. Consequently, any neurological abnormality exhibited by a horse could potentially be diagnosed as EPM. Clinical signs recognized in the earliest studies of this disease characterized horses with EPM as having non-symmetrical incoordination (ataxia) and associated muscle atrophy. Clinical signs in horses may occur suddenly or the disease may progress slowly over several months. Vague, intermittent lameness that is non-responsive to therapy and encephalitic signs may also be seen in affected horses. Gait abnormalities in EPM cases may include incoordination, muscular weakness in all four legs, knuckling, circling movements, and crossing over. Sometimes a horse may be down and unable to rise. Depending on the location of the lesion in the brainstem or spinal cord, clinical signs may or may not occur on both sides of the body simultaneously. Brainstem infections may result in head tilt, facial paralysis, circling, involuntary rapid eye movement, difficulty swallowing, facial paralysis, and apparent blindness with or without abnormal pupillary reflexes. Atrophy of the tongue and jaw muscles may occur. Regional sweating may also be observed. Although horses with EPM typically show asymmetrical, neurological abnormalities, some horses may exhibit symmetrical symptoms.

Cerebral signs are rarely seen in horses with EPM; however, three horses have displayed seizure activity. Visual problems and behavioral abnormalities have been reported in horses with EPM along with head shaking. After EPM treatment, head shaking ceased in the 3 horses reported.

Diagnosis may be difficult because a large number of horses have detectable quantities of antibody to S. neurona in the CSF for several months after EPM therapy, and horses that do not exhibit neurologic signs may also have S. neurona antibodies in CSF. Also, a false-positive test result may be caused by blood contamination during sampling. It has been recommended that the CSF indices (Albumin Quotient and IgG Index) may be used to aid in diagnosis and to monitor the response to therapy for EPM. Two studies suggest reliability of CSF indices may be questionable and one controlled investigation suggests CSF indices are inconsistent. Consequently, interpretation of CSF indices should be done with caution.

Polymerase chain reaction (PCR), which detects parasite DNA, is available to aid in diagnosing EPM; however, the sensitivity of PCR may be only approximately 40% or perhaps even lower. Analysis of CSF by PCR may be insensitive because the parasite is most frequently found in tissues and not floating freely in the CSF. Consequently, the parasite DNA may not be present, even when adjacent tissue is infected. Use of PCR is likely better utilized as a research tool at this time.

Cerebrospinal fluid analysis has been used to aid in determining the cause of neurologic diseases in the horse; however, recent studies suggest that neurologic disease of horses cannot be reliably differentiated based on CSF white blood cell counts, CK activity, AST activity, or protein concentration.

Several serologic tests have been developed for detection of N. caninum antibodies in animal species including ELISA, indirect fluorescent antibody test (IFAT), and the direct agglutination test. These antibody tests are only measures of exposure to the organism and do not indicate if there is an active infection.

Post-mortem examination was the first method used to diagnose EPM and is still considered to be the gold standard. Protozoan organisms can be seen in some of the lesions, but are often difficult to detect particularly if the animal has been treated with antiprotozoal medications. A more reliable diagnostic test for use in clinical cases is needed to better understand EPM and appropriately manage horses with this disease.

Little is known about the development of EPM. It is assumed the sporocysts of S. neurona are passed in the feces of the opossum and the infective oocysts are introduced into the feed and water supply of intermediate hosts, such as the horse. The sporocysts release sporozoites, which penetrate the gut and enter various organs via the blood stream, resulting in the formation of sarcocysts in the muscle. This infected muscle tissue is ingested by the predator or definitive host (opossum), completing the life cycle. Since sarcocysts of S. neurona have yet to be found in affected horses, the horse is likely a dead-end host.Little is known about the life cycle of N. caninum or N. hughesi in horses; however, the final host of N. caninum is likely the dog. These parasites have been found in horse tissues, as well as tissue cysts in two of the horses reported to have EPM caused by Neospora, unlike EPM caused by S. neurona. One case of neosporosis in a foal was determined to have been infected in utero, which has not been demonstrated in horses infected with S. neurona.

The EPM-causing organism S. neurona has been recovered from CNS lesions in several horses and subsequently propagated in culture in the laboratory. This stage of Sarcocystis spp. is not known to be transmissible to other horses or other animals. The mechanism by which this parasite stage enters the CNS is currently unknown, but likely enters the CNS via infected white blood cells or through the cells that form arterial walls.

Recent research has demonstrated that the opossum is likely the final host of S. neurona, although most of the specific details regarding the life cycle are currently unknown. Further evidence that the opossum is the final host for S. neurona was obtained by experimental induction of EPM using sporocysts from wild opossums and administering them to horses with subsequent development of neurologic disease. This study has been repeated by two other research groups, as well.

Although not normal, S. neurona may infect a large number of intermediate hosts. Several species of animals and birds have been reported to exhibit symptoms similar to those seen in horses with EPM. These reports indicate an S. neurona-like organism causes neurologic disease in dogs, sheep, cats, mink, raccoons, a striped skunk, a golden hawk, pacific harbor seals, sea otters, and chickens. In some of the intermediate hosts, such as harbor seals, sea otter, domestic cat, and now the striped skunk, there is evidence of sarcocysts in the muscle that were S. neurona-positive. In addition, recent evidence suggests the nine-banded armadillo and the raccoon develop sarcocysts in the muscle and may serve as natural intermediate hosts for S. neurona. This wide range of hosts is atypical for Sarcocystis spp. The life cycle for S. neurona has been completed experimentally in domestic cats, striped skunks, and naturally using the armadillo and raccoon. This suggests there may be many intermediate hosts which makes control of EPM very difficult.

Based on the estimated numbers of opossums in North America and their poor survival rate, it is speculated that EPM may be transmitted via methods other than direct contact with opossum feces. Research suggests sporocysts might be transmissible between intermediate hosts. Insects, such as flies and cockroaches, are thought to possibly carry S. neurona as transport hosts.

Stress is thought to play a role in the development of EPM. Other factors related to EPM development include size of the infective dose, immune status of the horse, and level of environmental stress. Protozoan parasites, such as N. caninum or T. gondii, can cause immune suppression, which increases the likelihood of succumbing to disease. Horses with compromised immune systems are more easily infected with S. neurona. Recent evidence demonstrated that health events prior to diagnosis of EPM were strongly associated with the disease.

While no formal studies of the incidence or prevalence of EPM in the U.S. have been conducted, an estimate of the incidence of EPM based on accessions to the University of Kentucky diagnostic laboratory was 1% of all horses or less each year. A recent USDA study demonstrated the average incidence of EPM was 14 ± 6 cases per 10,000 horses per year (0.14%). The incidence was lowest in farm/ranch horses (1±1 cases), 6±5 cases in pleasure horses, breeding horses (17±12 cases), racing horses not at racetracks (38±16 cases), and competition/show horses (51±39 cases).

Several authors have suggested prevalence of disease may be high among Standardbred horses and another case series reported that disease was most common in Thoroughbreds. A recent controlled investigation into risk factors for development of EPM did not find a breed preference, but occupations such as racing and showing had an increased risk for EPM compared to breeding and pleasure horses, similar to the recent NAHMS study.

Early reports on EPM suggested that young horses had an increased risk for disease and that at least 60% of the affected horses were four years old or younger. This finding of increased risk in young horses was also corroborated in a controlled study, but this controlled investigation also found an increased risk in horses >13 years of age.

EPM has been reported as a sporadic disease; however, there are reports of EPM cases from Panama in which all affected horses were stabled at the same location and also a report of an outbreak on a farm in Kentucky. A recent finding suggested there was an increased risk for EPM if the disease was previously diagnosed on the farm (>2.5 times higher), suggesting clusters of cases may occur.

Other risk factors for development of EPM that have been reported from Ohio include an increased risk if opossums were seen on the farm, presence of woods on the farm, seasonal effect, or occurrence of a health event prior to development of clinical signs of EPM. The seasonal effect increased the risk of EPM as the temperature increased, with the highest risk in the fall compared to the winter. There was a decreased risk for EPM if there was a creek or river present on the farm and if the feed was kept protected from wildlife access. The recent NAHMS study found an increase in risk if opossums were seen on the premises, and even higher risk if the opossums were seen frequently. The NAHMS study also found an increase in risk with increased numbers of horses, purchased versus home-grown grain, use of wood chips or shavings as bedding, presence of rats and mice on the premises, and increased human population density. A lower risk was seen in the NAHMS study where there were woods within five miles of the premises and where surface water was used as the primary drinking source. The NAHMS study corroborated the Ohio study in that the highest risk for disease was in the fall of the year. It is apparent that management and environment may play a role in development of clinical EPM.

The standard therapy originally used for horses with EPM was a combination of sulfadiazine and pyrimethamine (antifolate medications). Numerous changes have since been made with regard to dosage and duration of the therapy based on clinical impression rather than controlled clinical trials, but more recently, some therapeutic recommendations have been based on drug studies. Initially, the duration of therapy required to effectively treat horses with EPM were based on achieving a negative Western blot. However, many horses remain CSF positive for antibody to S. neurona for months following therapy. Many veterinarians recommend continuing medications for at least two weeks after disappearance of clinical signs or four weeks past a plateau of the clinical signs. Current drug recommendations are 20 mg/kg of sulfadiazine once or twice daily along with pyrimethamine at 1 mg/kg daily given orally for at least 150 to 180 days. Due to the long period of drug therapy, complete blood counts should be monitored for signs of folic acid deficiency, which may include bone marrow suppression, anemia, colitis, and birth defects. In most cases, anemias are mild and improve after withdrawal of the drug. One other side effect of this therapy is its negative effect on reproductive function in pony stallions. This suggests caution should be used when treating stallions for neurologic disease believed to be EPM.

New medications used recently to treat EPM include two triazine derivative drugs—diclazuril and toltrazuril. These drugs were originally designed for use as herbicides and have been used in other countries in the prophylaxis of coccidiosis in poultry and swine. Diclazuril is only available as a ration premix; therefore, large volumes have to be given daily and the poor palatability of diclazuril in its present form is a disadvantage. Diclazuril is administered at the rate of 5 mg/kg for a minimum of 28 days, but it may have to be administered by nasogastric tube daily. Toltrazuril is becoming very popular due to its ease of use and good absorption orally in horses, and toxicity studies in horses at 50 mg/kg for 10 days resulted in mild anorexia and depression. Currently, the recommended dose is 5-10 mg/kg for a minimum of 28 days.

Nitazoxanide (NTZ) is another novel treatment that has recently been used in the treatment of EPM with a broad spectrum of activity against bacterial, protozoal, and helminth parasites and has been shown to kill S. neurona in cell culture. Toxicity studies were performed in horses given 2X the recommended dose where they became lethargic after one week of daily dosing. At 4X the recommended dose, horses became significantly ill and one died. The suggested dose schedule is 25 mg/kg once daily for the first week and 50 mg/kg once daily for the next 23 days. All three of these new medications are being used in field trials to gain FDA approval.

Very recently a new treatment (ponazuril; Marquis^®*) was approved for the treatment of EPM by the FDA. Marquis^® is administered at 5 mg/kg orally once a day for 28 days. Toxicity testing at 2X and 6X the recommended dosage did not result in any serious side effects.

The prognosis for horses treated for EPM is suggested to result in an approximate improvement rate of 70% when using the standard therapy. Approximately 25% of affected horses may return to their original function. Diclazuril results in approximately 75% improvement in horses severely affected with EPM and approximately 30% of the horses (11/36) treated either returned to their original level of performance prior to EPM diagnosis or improved their level of performance. An efficacy study of 70 horses given NTZ found clinical signs improved in 63% of the horses. Some horses will relapse days, weeks, or even months after cessation of therapy, which may be due to a truly latent stage of the parasite, presence of a small persistent focus of infection, or perhaps re-exposure to the parasite. Estimates of the relapse rates range from 10% to 28% of treated horses using the standard therapy. For diclazuril, the relapse rate was less than 5%.

Before EPM, corticosteroids were widely recommended for treatment of neurologic diseases in horses; however, these drugs should be used with caution in suspected EPM cases due to the possibility of adversely affecting the host immune response to the organism. Nonsteroidal anti-inflammatory drugs, as well as dimethylsulfoxide, have also been routinely used since the mid 1980s.

Based on the persistence of the antibody to S. neurona for long periods in the CSF of some horses with EPM, some veterinarians recommend the use of immune stimulants based on the observation that some horses may not mount a sufficient immune response to eliminate the organism.

Historically, supplementation with folic acid, folinic acid, and/or brewer’s yeast has been recommended for treatment of presumed folic acid deficiency, particularly in pregnant mares. However, recently folic acid supplementation has been discouraged because of poor absorption and the potential for toxic effects on the bone marrow activity. Toxicity in newborn foals born to mares that were treated for EPM with antifolate medications and concurrently supplemented with folic acid has been reported. Although a cause and effect relationship between folic acid supplementation and developmental abnormalities has not been conclusively demonstrated, folic acid supplementation should not be used at the present time, particularly in pregnant mares, until controlled clinical trials can be performed to substantiate or refute these findings.

Additional supplements, such as vitamin E and thiamine, that may facilitate healing of nerve tissue have been recommended for treating horses with EPM; however, clinical trials have yet to be performed to establish the efficacy of this supplementation. Vitamin E, an antioxidant, is used because the neurologic tissue is susceptible to oxidant injury in horses with EPM.

Some cases of EPM may be prevented by denying access to feed and water by opossums and other pests, such as mice and rats. It would also be prudent to keep dogs away from a horse’s feed and water supply. Rodent-proof containers should be used for cereal grains. Additionally, the use of enclosed facilities to store forages will protect forages from wildlife access. Preventing bird access to facilities may help prevent some cases of EPM, although their role in the development of EPM is unknown. Transport vectors for S. neurona may also include insects such as flies and cockroaches; therefore, reducing the insect populations on farms may help reduce the incidence of EPM. Since succumbing to EPM often follows some other health event, careful monitoring of broodmares close to foaling and horses that develop a major illness or injury may help early diagnosis of EPM.

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