Current Treatments for Equine Protozoal Myeloencephalitis

Equine Protozoal Myeloencephalitis (EPM) is one of the most common treatable neurological diseases of American horses and is caused by the apicomplexan protozoan Sarcocystis neurona. This protozoan penetrates the central nervous system, producing varying levels of neurological disease. In parts of the United States virtually all horses are exposed, with a small proportion (< 0.5%) exhibiting neurological symptoms. Because S. neurona can locate anywhere in the brain and spinal cord, the disease can mimic any neurological condition, and diagnosis can be challenging. EPM was first identified in the 1960s, with development of improved diagnostic tests in the 1990s. Since 2000, three Food and Drug Administration (FDA) approved treatments for EPM have been brought to market.

Treatment of EPM is challenging because S. neurona is an intracellular parasite and an expert in avoiding immune system attack. The three different anti-protozoal treatment modalities currently available work on entirely different pharmacological principles.

Traditionally, EPM was treated with combinations of pyrimethamine and a sulfonamide, one of the so-called “potentiated sulfonamides” used in classic anti-malarial therapy. These drugs act “in sequence” on nucleic acid synthesis. The sulfonamide directly inhibits the incorporation of para-amino benzoic acid (PABA) into folic acid, and pyrimethamine selectively inhibits dihydrofolate reductase. When present together in the brain at effective concentrations, these drugs produce a 1 to > 2 synergistic inhibition of nucleic acid metabolism. This combination was, for many years, the only known treatment for EPM, although the duration of treatment was often prolonged. Potentiated sulfonamide combinations have long been marketed by compounding pharmacies, and more recently, Phoenix Laboratories has brought to market an FDA-approved formulation of pyrimethamine and sulfadiazine, marketed as ReBalance™.

Side effects that may be associated with pyrimethamine-sulfonamide combinations are related to inhibition of host nucleic acid metabolism. Animals on potentiated sulfonamide treatments should optimally be monitored for inhibition of red cell formation, leukopenia, and thrombocytopenia. Some of the earlier potentiated sulfonamide preparations were associated with reports of reduced spermatogenesis in stallions.

Another treatment, Marquis™ (ponazuril), is adapted from a widely used poultry coccidiostat, toltrazuril. These drugs act by directly attacking the “apicoplast” organelle of S. neurona. Apicoplasts are chloroplast-related organelles that were acquired by S. neurona millions of years ago. They are highly susceptible to specific attack by herbicide-related drugs such as ponazuril. Working with these drugs, University of Kentucky researchers showed that they are highly specific and effective treatments for EPM. Ponazuril is well absorbed orally, has a 4.5 day plasma half-life, and is virtually non-toxic to equines at clinically effective doses. Single daily dosing is effective, and in an extensive field study, no adverse responses could be linked to treatment.

The manufacturer’s suggested treatment period is 28 days. Because of its unique mechanism of action, Marquist™ is essentially specific for apicomplexans, and a positive response to treatment offers strong support for an EPM diagnosis. Marketed in 2001, Marquist™ was the first FDA-approved treatment for EPM.

Nitazoxanide (Navigator™) is in a novel class of anti-infective drugs and is thought to act by inhibiting pyruvate-ferridoxin oxidoreductase in susceptible organisms. It has a broad spectrum of action, acting on enteric bacteria, protozoa, and viruses. In human medicine it has been approved as a broad spectrum anthelmintic and anti-viral drug.

The oral dose is carefully calculated, and treatment starts at a half daily dose for the first five days, increasing to the full dose of 22 mg/kg for the remaining 23 days. The principal adverse response in the horse relates to the drug’s broad enteric action, which can change equine intestinal flora and produce enteric problems. The addition of rice bran or corn oil to the diet helps to reduce the incidence of intestinal problems.

Horses on any long-term therapy for EPM should be monitored daily for adverse reactions and changes in clinical signs.

Numerous adjunctive therapies for EPM are also utilized. Anti-inflammatory therapy can help reduce inflammatory responses to the protozoan and may be useful in “treatment crisis” (transient worsening of clinical signs early in treatment) reported in some severe cases receiving an anti-protozoal medication. Use of corticosteroids in EPM cases is controversial among veterinarians.

Immune stimulants have also been recommended and include products such as Propionibacterium acnes administration, mycobacterial cell wall extracts, oral levamisole, and alpha-interferon. Additionally, a commercially available chemically inactivated vaccine of merozoites of S. neurona with an adjuvant has been suggested to further stimulate cell-mediated immunity.

Clinical experience suggests that rehabilitation is facilitated by mild to moderate unmounted, controlled exercise. The exercise level is dictated by the stability of the horse and the opinions of both the examining veterinarian and the owner. Complete recovery (to neurological normalcy) may not be possible, but rehabilitation and strengthening of affected horses can maximize the clinical outcome.

Based on contributions by David Granstrom, Dan Howe, Brad Bentz, Levent Dirikolu, and Thomas Tobin at the Maxwell H. Gluck Equine Research Center.