Ohio State University

College of Veterinary Medicine 

Treatment

Several regimens have been described previously for the treatment of EPM and >60% of horses respond to treament, and that clinical signs completely regress in 55-60% of the cases. The treatment most commonly used employs a combination of potentiated sulphonamides (Trimethoprim/Sulfas) and pyrimethamine. This combination causes a sequential blockade of folate metabolism in apicomplexan protozoa. Based on a recent pharmacokinetic study of pyrimethamine in horses, the dose required to reach the minimum inhibitory concentration (MIC) for Toxoplasma gondii in CSF is 1.0 mg/kg. The recommended dose of pyrimethamine is 1 mg/kg once a day for 60 to 90 days. However, it has been suggested that high dose pyramethamine therapy over this extended time period can result in anemia. Previous work using the 1 mg/kg dose of pyrimethamine once daily did not result in anemia, but the drug was only administered for 10 days to these normal horses. The trimethoprim/sulfa combinations have been recommended at a dose of 15 to 20 mg/kg bid per os for the full treatment period. If sulfonamides are used without the trimethoprim, the dose recommended is 20 mg/kg per os once or twice per day. Most of the treatments are administered for at least 12 weeks, but must sometimes be extended to 16 weeks or more. After initial therapy has been completed, some clinicians recommend periodically placing horses back on treatment if animals undergo some unusual stress. Other intermittent treatment therapies have also been used, such as treatment once every two to four weeks, or daily during the first week of every month. Intermittent treatment may increase the risk that parasites infecting a horse develop drug resistance. Therefore, we do not recommend intermittent or periodic treatments. Recent problems with the response to current therapy has led to increasing the dose of the sulfa/pyrimethamine mixture. Earlier, the only product applied at an increased dosage was the pyrimethamine; it was administered at 1.5 mg/kg, and sometimes even 2.0 mg/kg once a day. These increased dosages were used in cases that appeared to not respond within the first 30 to 60 days. A practice currently used by some clinicians for horses that do not respond to 30 days of treatment is to increase medication dosages. For example, if using the mixture from Mortar & Pestle, the dose for a 1,000 lb. horse is 30cc. Some clinicians are increasing it to 45cc. If no response is seen after 30 days of this dosage, the amount given is further increased to 60cc per day. This should only be done in consultation with your regular veterinarian. This also increases the importance of monitoring for signs of folic acid deficiency by evaluating CBC’s at least every two weeks. Recent discussions concerning EPM have led to reports of using tetracyclines in some cases that continue to be CSF+ even after many months (six months or longer) with the sulfa/pyrimethamine combination. This use is based upon tetracycline’s inhibitory effect on protein synthesis, however, no controlled trials have been performed at this time. The only reported antiprotozoal use of tetracycline was documented in sheep which received 30 mg/kg to treat a differentSarcocystis spp. infection. This an extremely high dosage, and is not recommended for use in horses. Some clinicians have experimented with administration of 6.6 mg/kg once or twice daily for one week. It is not clear why using tetracycline, a bacteriostatic agent, for one week would be curative. We would recommend that this therapy not be used or used with extreme caution until controlled clinical trials have been completed. Additional therapies are also being used by some clinicians. These therapies include the use of immune stimulants such as Eqstim, Equimune, alpha-interferon, or levamisole. These compounds may boost non-specific cell-mediated immunity. Cell-mediated immunity is necessary to rid the body of these parasites. The efficacy of these compounds has been established in humans with leishmaniasis. A new therapy (Diclazuril) has been receiving a lot of press recently and has been under study by the University of Kentucky. This new compound is a triazine derivative that has been used as a coccidiostat in other countries for a number of years. The site at which these compounds exert their effect is called a chloroplast which do not exist in mammals. For this reason, the compound should not be toxic to mammals, however, the toxicity studies have not been completed to date. The efficacy of this compound is very similar to the standard therapy discussed above, however, the treatment period is much shorter (four weeks) and therefore less costly. This compound has been used primarily in horses that have relapsed after the standard therapy with reasonably good success. This compound is available through the AAEP and the FDA by special permit. An additional triazine derivative (Toltrazuril) is available through the same sources as the Diclazuril. Current clinical trials are being performed at several sites throughout the US to establish efficacy against Sarcocystis neurona. A new therapy called Nitazoxanide (NTZ) is being investigated by Blue Ridge Pharmaceuticals. NTZ is a thiazolide derivative that demonstrates a wide spectrum of activity against bacteria, protozoa, and intestinal helminths. The drug is in development for humans to treat parasitic infections that are common in developing countries and to treat immunocompromised patients afflicted with cryptosporidiosis. Veterinarians may obtain more details on NTZ. The area is password protected. Please call 800-870-4264 to obtain the password to enter this area. We will need your name, your clinic address, your state veterinary license number, and your DEA number. When the horse has an acute onset of EPM which results in dramatic and progressive clinical signs, the use of antiinflammatory medications has been recommended. Use of antiinflammatory medications such as banamine phenylbutazone may be helpful. Intravenous administration of medical grade dimethyl sulfoxide (DMSO) at a dose of 1.0 ml/kg (approximately 1 gm/kg) in a 10% solution once daily for three days in a row. Some clinicians use dexamethasone parenterally in severely affected horses at a dose rate of 0.05 mg/kg bid or sometimes empirically at 50 mg. bid. However, we believe corticosteroids should be used judiciously. The exacerbation of signs in stressed patients and reports of horses with EPM showing a worsening of signs following the use of these medications suggest immunosuppression should be avoided. Ancillary treatments may include padded helmets, slings, good supportive care and a deeply bedded stall.Many horses appear to relapse days, weeks or months after treatment has stopped. Some apicomplexans have latent stages, however, Sarcocystis spp. are not known for this phenomenon. Sarcocystis faculata encephalitis in birds may persist for several months without reinfection, but this phenomenon may simply represent a low level infection and not the development of a true latent parasitic stage. A great deal concerning the life cycle of coccidia remains unknown. Now with the ability to produce experimental infections, we may be able to determine if S. neurona forms a latent stage or maintains a persistent, low level foci of infection. Re-infection may also be responsible in some cases. Reports at the EPM workshop in March of 1996 indicate that relapses occur approximately 10% of the time. More recently, it has been suggested that the relapse rate may be as high as 28%. However, this may be compounded by the premature withdrawal of medication or irregularities during medication administration. The efficacy of preventive therapies is open to debate.Because of the suspicion that protozoal infections occur more commonly in immunocompromised patients, immunomodulators or other therapies which may have a non-specific enhancement of the immune system may be helpful. The use of these products may have merit but further investigation is necessary. It is possible that these drugs may also enhance the immunopathologic effects associated with CNS infection.Prolonged therapy with antifolate medications should be monitored for signs of bone marrow suppression with resultant anemia, thrombocytopenia and/or neutropenia. Frequent blood samples for CBC’s is suggested on a biweekly basis. All horses that are receiving antifolate medications should have their blood tested for folate levels on a monthly basis. Antifolate medications may also cause reduced spermatogenesis in stallions and may be teratogenic to the fetus in mares. There is evidence to suggest that combinations of pyrimethamine and folic acid in the pregnant animal may lead to congenital defects in the fetus. This has been demonstrated in humans, rats, mice, hampsters, and pigs. There is also some evidence to suggest that this also happens in horses, therefore, we do not recommend the use of folic acid supplementation in horses, particularly in pregnant mares. The authors also recommend supplementation with vitamin E at the rate of 8,000 to 9,000 IU per day. Due to the role of vitamin E as an antioxidant, we feel that adding this to the treatment may aid in the healing of the nervous tissue. Acute colitis has also been associated with use of trimethoprim/sulfa combinations.It appears with the increased dosage of pyrimethamine that is being utilized for today’s treatment of EPM as well as the experimental medication usage, there is an increased incidence of what some people term a “treatment crisis”. This is a real problem that is a concern for many clinicians. It would appear this is related to a large dose of medication and subsequent development of an inflammatory response to the killing of large numbers of parasite at one time. The spinal canal is a very narrow space with limited room for expansion due to inflammation. Therefore it would seem prudent to start horses on EPM treatment with NSAID therapy at the same time to reduce inflammation and perhaps prevent this so-called crisis.

Merck Manual
Treatment
The FDA-approved treatments for EPM are ponazuril (5 mg/kg/day, PO, for 28 days), diclazuril (1 mg/kg/day, PO, for 28 days), and a combination of sulfadiazine and pyrimethamine (20 mg/kg and 1 mg/kg, respectively, for at least 90 days). The bioavailabilities of ponazuril and diclazuril are improved by concurrent PO administration of corn oil or DMSO. A loading dose of ponazuril (15 mg/kg, PO) may be given on the first day of treatment to rapidly attain therapeutic blood levels. The sulfadiazine/pyrimethamine product must be given at least 1 hr before or after hay is fed. Anemia may develop after prolonged treatment with sulfadiazine/pyrimethamine and is best prevented by providing folate-rich green forage such as alfalfa hay or green pasture. Approximately 60% of horses improve wit
each type of treatment, but <25% recover completely. Relapses occur commonly up to 2 yr after discontinuation of antiprotozoal therapy. Because immunosuppression/immunodeficiency may be a risk factor for EPM, immunomodulators (eg, mycobacterial cell-wall derivative, levamisole, killed parapox ovis, or transfer factor) are sometimes given as ancillary therapy.