To understand the best approach to treating equine protozoal myeloencephalitis (EPM), it is helpful to have a brief look at how the protozoa (single-celled parasites) that cause EPM--Sarcocystis neurona--enter the central nervous system.

David Granstrom, DVM, PhD, one of the pioneer researchers into EPM when he worked at the University of Kentucky's Gluck Equine Research Center, describes how the protozoa, as intracellular parasites, are able to evade a horse's immune response: "The immune system is constantly on the alert for anything penetrating the body that it does not recognize as 'self.' It accomplishes this task using a wide array of receptors on the surface of cells throughout the body. Intracellular parasites, like S. neurona, are able to penetrate specific host cells and multiply, essentially hidden from immune receptors at the cell surface. This strategy is most effective when the parasite is largely dormant, dividing very slowly without producing byproducts that could escape to the cell surface, thus, alerting the immune system. Interestingly, S. neurona multiplies rapidly in the horse, but in some cases manages to persist for several years without causing clinical signs. The mechanism for this remains unknown, although there is limited experimental evidence that the parasite produces a factor or factors that suppress a specific immune pathway responsible for killing intracellular parasites."

Sharon Witonsky, DVM, PhD, Dipl. ACVIM, an associate professor of large animal clinical sciences at the Virginia-Maryland Regional College of Veterinary Medicine, has been looking into a mechanism by which the protozoa enter the central nervous system. Witonsky remarks, "We hypothesize that with normal leukocyte (white blood cell) circulation throughout the body, once S. neurona infects leukocytes, they can penetrate the central nervous system. It is not clear how S. neurona migrates from the GI (gastrointestinal) tract into the leukocytes. Nor is it known exactly how or why S. neurona-infected leukocytes enter the central nervous system and then establish disease in the central nervous system."

"The stage of the parasite that causes clinical EPM divides rapidly and eventually ruptures whatever cell it has invaded, releasing dozens of parasites looking for a new home." --Dr. David Granstrom
Granstrom reports, "The stage of the parasite that causes clinical EPM divides rapidly and eventually ruptures whatever cell it has invaded, releasing dozens of parasites looking for a new home."

Witonsky continues, "It is evident that S. neurona egresses from the leukocytes and then infects cells which are permissive."

Once in the central nervous system, the protozoa invade nerve cells and other cell types, continue their life cycle, and cause damage.

While many horses might be exposed, less than 1% develop neurologic disease. Granstrom says, "Some horses are able to control the multiplication process once exposed, and thereby avoid clinical disease, while others aren't so lucky."

Debra Sellon, DVM, PhD, Dipl. ACVIM, a professor of equine medicine at Washington State University's veterinary school, describes work in progress to identify possible risk factors in developing EPM. She explains, "At WSU we have infected mice with S. neurona in an attempt to compare the outcome of infection in different genetic strains of mice. We found that one strain (BALB/c) of mice is relatively resistant to disease following infection with S. neurona. Even when these mice lack all B and T cells, some of the most important cells of the immune system, they do not develop any recognizable evidence of disease after infection. In contrast, a different (C57Bl/6) strain of mice with similar immune deficiencies develops quite severe disease after infection. We don't know how this information might apply to horses. However, it clearly indicates the possibility that genetic differences might impact disease outcome."

Granstrom notes that Thoroughbreds and Standardbreds were found to be over-represented in some EPM studies, so there could be some breed predilection. However, Sellon stresses that results from her study in mice must be interpreted with caution.

EPM Treatment

Optimal goals in managing EPM are to cure the horse with treatment and to return him to normal neurologic function. Objectives for successful treatment must consider that the organism is proficient in hiding from the host's immune system because it invades the cells of the nerves and spinal cord, as described above. Witonsky remarks, "The brain is more of an immune-privileged site, so S. neurona may be better able to establish infection there with more limited detection by the immune system."

Similarly, any medication must be able to pass through the blood-brain barrier to achieve an effective concentration in the central nervous tissues.

Currently, three treatment options are available to help kill the intracellular protozoa:

Potentiated sulfonamide medications in combination with pyrimethamine used to be the sole and primary means of treatment, requiring prolonged administration for many months. This strategy is still an option, with a commercial formulation (ReBalance) available that combines pyrimethamine and sulfadiazine for ease of administration. Adverse side effects can occur specific to the mode of action: Potentiated sulfonamides inhibit not only the parasite's synthesis of nucleic acids, particularly para-amino benzoic acid (PABA) that is critical for producing folic acid, but they also limit the host's ability to do the same. Folic acid is necessary for building mammalian blood cells, so long-term treatment with sulfonamide-pyrimethamine can cause anemia. Because of the drug's folate-inhibiting effects on growing fetuses, caution should be taken in treating pregnant mares.

Ponazuril (Marquis, manufactured by Bayer Animal Health) is another treatment option, one that is prepared from herbicidal chemicals. This drug is useful since S. neurona is a protozoon that contains plantlike (chloroplast) components. Ponazuril directly attacks the protozoa without exerting effects on mammalian tissue, making it a safe option for EPM treatment. It need only be given once a day and has good absorption when administered orally. A usual course of treatment is 28 days.

Nitazoxanide (Navigator, manufactured by IDEXX) inhibits specific enzymes required for protozoan survival. As opposed to the previous two medications that inhibit replication of the protozoa, this drug directly kills the organisms. However, this medication also interferes with enzyme production in some bacteria and viruses, including bacterial flora within a horse's gastrointestinal tract. It is important when using nitazoxanide to dose the horse at an accurate body weight and to monitor for colic, diarrhea, or intestinal abnormalities. The 28-day treatment begins with a half dose (25 mg/kg), then after five days the dose is increased (50 mg/kg) for the remaining treatment course.

Because of the significance of adverse side effects, nitazoxanide has often been reserved for use in horses that have either not responded to other treatments or have relapsed following treatment with the other two options. Rob Keene, DVM, a field veterinarian for IDEXX Laboratories, notes, "Treatment-related adverse events are minimized by stopping treatment if a horse stops eating or if the fever exceeds 103°F, and also by administration of a high-fat diet (rice bran or corn oil) during the course of treatment."

Granstrom reports, "Although far less common, Neospora hughesi infection produces essentially the same clinical disease as EPM. Laboratory testing has shown that N. hughesi is susceptible to many of the same drugs used to treat S. neurona infection. I am unaware of any work done to establish a unique treatment regimen for equine neosporosis."

Granstrom remarks, "Each of the FDA-approved drugs has been shown to be effective against S. neurona, although there are differences. Clinicians initiate therapy with the drug or combination of drugs that works best in their hands. If that fails, they may try a higher dose of the same drug or select another drug or drug combination."

"The inflammation associated with rapid destruction of parasites as treatment begins can cause transient worsening of clinical signs." --Dr. David Granstrom
He also considers secondary effects of treatment, noting, "The inflammation associated with rapid destruction of parasites as treatment begins can cause transient worsening of clinical signs."

In most cases, anti-inflammatory medications will help to reduce inflammation within the central nervous system and limit worsening of clinical signs that can occur early in the course of treatment.

Immune Stimulants

Immune stimulants (or vaccination) in the face of infection have been reported to exert favorable effects on stimulating the horse's immune system. (Vaccination is no longer an option as the previously available vaccine has been taken off the market.) Regarding immune stimulants, Granstrom says, "Many clinicians believe that immune stimulants help affected horses overcome S. neurona infection. I am unaware of any controlled clinical trials performed to confirm this clinical impression, but there is strong evidence that stress and possibly immune suppression play a role in the development of clinical disease. The use of immune stimulants is a reasonable approach, although it is important to remember that the immune response also plays a role in damaging the infected area. Targeted immune stimulation has the potential to be highly beneficial for the treatment of EPM, as well as prevention."

Resolution of Neurologic Signs

Even with the implementation of timely treatment, not all horses with EPM will recover completely. Granstrom describes what happens to the central nervous tissue: "Clinical signs of EPM are caused by direct infection and loss of nervous tissue, as well as inflammation and swelling in the local area. As the infection subsides, function may return if sufficient nervous tissue remains to transmit nervous impulses through the affected area. If the damage is too severe, loss of function may be permanent. With prompt diagnosis and appropriate treatment, approximately 10-20% of infected horses may recover fully, as based on the clinical impression of veterinary specialists with extensive experience."

Take-Home Message

The protozoa that cause EPM evade a horse's immune system, invade the central nervous system, and damage nerve tissues. Effective treatment relies on drugs that can cross the blood-brain barrier to inhibit multiplication of the protozoa so the horse's immune system can eliminate the parasite, or drugs that directly kill the organisms. Ideally, EPM medications should exert minimal adverse effects on the horse. A timely diagnosis limits the extent of nerve damage and improves the chances for a more complete resolution of neurologic signs.

About the Author

Nancy S. Loving, DVM

Nancy S. Loving, DVM, owns Loving Equine Clinic in Boulder, Colorado, and has a special interest in managing the care of sport horses. Her book, All Horse Systems Go, is a comprehensive veterinary care and conditioning resource in full color that covers all facets of horse care. She has also authored the books Go the Distance as a resource for endurance horse owners, Conformation and Performance, and First Aid for Horse and Rider in addition to many veterinary articles for both horse owner and professional audiences.

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