Special Report: EPM

The world of equine health will never be the same. That statement seems out of context when talking about one research project about one parasite that causes one disease. But, horse owners know that equine protozoal myeloencephalitis (EPM)–the

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The world of equine health will never be the same. That statement seems out of context when talking about one research project about one parasite that causes one disease. But, horse owners know that equine protozoal myeloencephalitis (EPM)–the multi-faceted neurologic disease caused by the single-celled protozoal parasite Sarcocystis neurona–is a tremendous problem in the horse industry. One research group estimated that just the diagnosis and treatment of horses with clinical signs of EPM costs over $1 million each year! And that does not take into account loss of performance time and earnings, nursing care, extra cost of ancillary management and upkeep, and the potential loss of the animal never returning to his original level of competitiveness!


The research project from the United States Department of Agriculture (USDA) and The Ohio State University that carved the path for huge strides to be made against EPM determined that the common domestic cat could be used to complete the life cycle of the parasite in the laboratory (see sidebar below). This knowledge will open doors to create a way to give the disease to horses in order to test vaccines and treatments.

The research project itself was a demonstration of how the world must face disease problems of the future. It was conducted by a group of researchers headed by J.P. Dubey, BVSc, MVSc, PhD (parasitology), a senior scientist with the USDA; and William (Bill) Saville, DVM, PhD, Dipl. ACVIM, of The Ohio State University. Other collaborators were D.S. Lindsay, PhD, of the Virginia-Maryland Regional College of Veterinary Medicine; R.W. (Bill) Stich, BS, MS, PhD (parasitology) of Ohio State; Jon F. Stanek (a student working on his masters who will enter vet school at Ohio State this fall); C.A. Speer, PhD, formerly of Montana State University now at the University of Tennessee; B.M. Rosenthal, PhD, USDA; Chinedu Njoku, DVM, PhD (veterinary pharmacology), a post-doctorate research associate at Ohio State; O.C.H. Kwok, PhD, of USDA; S.K. Shen, PhD, of USDA; and Steve Reed, DVM, Dipl. ACVIM, of Ohio State (clinician). Input also was received from David Granstrom, DVM, PhD, Dipl. ACVIM, a former full-time EPM researcher currently working with the American Veterinary Medical Association (AVMA), and Michael Oglesbee, DVM, PhD, a neuropathologist at Ohio State who assisted the team.

Why did it take so long–and take so many different talents–to solve the life cycle of a single-celled parasite? Because it is a member of a family of parasites that has proven over the decades to be difficult to understand, and control. That family includes malaria, which can be treated in humans, but not prevented or cured. However, that family also includes trichomoniasis in cattle and giardia in dogs and cats, and both of those parasites have a federally licensed vaccine on the market (created by Fort Dodge Animal Health, the makers of the current EPM vaccine released under conditional license; see page 14).

An EPM Society recently was formed to bring together researchers to share information and knowledge in order to encourage even quicker advances. The EPM Society is modeled after one created several years ago to solve the problem of heartworms in dogs. That project involved a wide range of researchers and institutions each contributing to the solution. And now, as pet owners, we know that with proper management and treatment, heartworm is a preventable disease.

Hopefully, horse owners will be able to look back in a few years and say the same thing about EPM.

The Mastermind

There are many areas of study when it comes to EPM. There is the life cycle and what that means to understanding the parasite and how to stop it. There is the way in which it infests and spreads in the horse. There are all the various treatments and preventives that could be used or currently are in use. There are various management techniques and risk factors to be considered and put into use at the farm level.

It should be noted that researchers in the past have fed horses S. neurona sporocysts, had the horses develop neurologic signs and antibodies, but could not recover the parasite in any tissue cultures. This suggests that most horses can eradicate S. neurona from their tissues, and highlights the need for developing a model whereby horses reliably can be given EPM in a laboratory setting.

A group of researchers headed by Dubey recently published a review article in Veterinary Parasitology of all the previously published and known scientific information concerning EPM. Dubey is with the USDA’s Agricultural Research Service, Animal and Natural Resources Institute, Parasite Biology, Epidemiology, and Systematics Laboratory at the Beltsville Agricultural Research Center in Maryland. The review paper was co-authored by Lyndsay, Saville, Reed, Granstrom, and Speer. However, it was Dubey who first came up with the idea of using the domestic cat as the laboratory model for the intermediate host in the S. neurona life cycle.

Dubey, a former professor at Ohio State, approached the research group at his former alma mater to assist him in conducting the experiments that completed the life cycle. Using the cat wasn’t a new idea to Dubey, who had seen a natural S. neurona infection in a cat in 1994. He had done work with the S. neurona parasite in laboratory mice, which was the only animal model available, but wanted to develop a model in a larger animal.

Besides the cat and the horse, an EPM-like disease also exists in raccoons, minks, skunks, a pony, a zebra, Southern sea otters, and Pacific harbor seals. Completing this first life cycle for use in the horse will also help in solving problems in these other animals.

But while this seems like a breakthrough of only a few short months of work, it actually was typical of research. It took years to come to the point of understanding the disease enough to develop the research, and two years to get to the published, peer-reviewed point we are at today.

“Ohio State played a vital role” in the research, said Dubey. “We’ve known this (cat model) for about two years, but it took all this time to prove it! We have no idea if the cat is the ‘natural’ host. We don’t know. Theoretically it is possible, but it is not an easy thing to find out.”

Ongoing research is looking at the role the cat might play in the farm environment. However, researchers warn that before horse owners start eliminating cats from the barn, they should consider the consequences. What if mice or other small mammals are part of the natural life cycle of S. neurona? If cats are eliminated, then it could make the problem worse! Enough is known at this point to say if you have a dead cat on your property, remove it so opossums can’t eat it.

Dubey stressed the most important thing now is understanding the conditions under which the disease is induced in the horse. As was said earlier, many horses are exposed to the parasite, but only a few get the disease. Dubey added the following two points.

“We need to understand the mechanisms of the disease because without that, there is no way to evaluate drugs. We also know that diagnosis is still a problem. We can look at drugs like Diclazuril in cell culture, and that’s a stepping stone (in understanding). But we still have to look at things in the whole animal.

“In knockout mice (genetically altered, immunocompromised mice), Diclazuril kills the invading stages, so perhaps it will be useful as a preventive in horses. But will it kill the parasite before it reaches the brain?

“Right now, it’s anybody’s guess on treatments because we aren’t 100% sure if the horse has EPM!” added Dubey. “So if you treated a horse and it got better, you can’t actually say the problems were caused by Sarcocystis neurona. Until the model (of creating disease in the horse) can be solved, treatments are guesswork. Only Diclazuril has been scientifically tested in an animal model (mice).”

Dubey reminded horse owners that even though the life cycle has been solved in the laboratory, researchers are far from being able to test drugs. “The disease must be reproduced in the horse reliably,” he said.

That means in an experimental setting, researchers can give a horse X amount of the parasite under X conditions and that horse will develop neurologic signs of EPM within X days.

“Horse owners must understand that this is a complicated disease, and there is a lot we don’t know,” added Dubey. “The new drugs coming out look more promising than the sulfas and pyrimethamines. And the very fact that a company is interested in developing a vaccine is great hope. The government is not interested because the horse is not a food animal. The only two parasitic vaccines marketed (for large animals) are against organisms we discovered (Neospora caninum and Toxoplasma gondii) in cattle.”

Dubey also stressed the need and hope for a simpler and more effective test.

EPM In Horses

In 1997, the federal government conducted its first survey of the equine industry to determine what was important, what the problems are, and trends in management practices, among other things. Of the specific infectious diseases listed in the National Animal Health Monitoring System (NAHMS) survey, equine infectious anemia (EIA) and equine protozoal myeloencephalitis (EPM) were the most common top priorities, irrespective of respondents’ region, horse use, or number of horses owned.

Horses are an aberrant or dead-end host for the parasite S. neurona. What this means is that the horse can pick up sporocysts (one stage of the parasite life cycle) from the environment, but the life cycle cannot be completed in the horse. However, the sporocysts picked up in the environment can multiply asexually in the horse, so the horse might pick up only a few from the environment, but there might be thousands or millions of merozoites in the infected horse. That initial infection or the multiplication of the parasite triggers the immune system to develop antibodies.

So far, those stages of the parasite have been reported only in the brain and spinal cord of the horse. Researchers have noted that while it is very unlikely that the horse advances the life cycle of S. neurona, sarcocysts (one stage of a parasite life cycle) have been found in the muscles of horses, but so far, not from the species of S. neurona. But, if S. neurona is found in the muscles, that means some other animal could eat that infected muscle and possibly complete the life cycle.

At the present time, it is known that horses do not shed the parasite in their feces, and that horses cannot give the parasite to other horses. It also is known that the parasite S. fayeri, which passes normally from the horse to the dog, does not present a health problem to the horse.

Researchers also note that while the opossum is a definitive host of the S. neurona life cycle, it would be premature to assume that it is the only definitive host. For example, Sarcocystis cruzi is a common parasite of cattle. The definitive hosts are the dog, fox, jackal, coyote, and raccoon.

Treatments

There are several different medications or combinations of medications currently being used to treat horses with neurologic signs of EPM. As of this writing, however, no medications have been licensed by the FDA for use in treating EPM in horses. Two companies, Bayer Animal Health and Blue Ridge Pharmaceuticals (a subsidiary of Idexx), have submitted paperwork to the FDA on two different treatment medications; Bayer on a Toltrazuril derivative called Ponazuril (toltrazuril sulfone), and Blue Ridge on nitazoxanide, or NTZ). There is no indication when or if either of the treatments will receive approval, or which will be approved first.

Currently, the most common treatment protocol for a horse with EPM is a combination of sulfadiazine and pyrimethamine (which interfere with folic acid necessary for the parasite). These might be followed by or used in conjunction with Toltrazuril. Any treatment involving sulfadiazine/ pyrimethamine will require monitoring of the horse’s bloodwork to detect anemia (reduction in red blood cells) or leukopenia (reduction in leukocytes in the blood).

Duration of treatment with sulfadiazine/ pyrimethamine usually is a minimum of five months, or until one month after the neurologic signs have either disappeared or remained the same (stabilized). There is the possibility of relapse after treatment with sulfadiazine/pyrimethamine in about 30% of horses.

(General immune system stimulants also have been tried in conjunction with different treatments, as have herbal supplements and acupuncture.)

A medication called Diclazuril currently is under development by Schering-Plough Animal Health for treating EPM in the horse. Early in the treatment protocols for horses, a related product called Clinicox (for chickens) was imported from Canada under a special license. Now, Clinicox is licensed for chickens in the United States by Schering-Plough Animal Health.

Dubey mentioned earlier that Diclazuril is the only treatment that has been tested in the mouse model. He also said that research has shown that Diclazuril is absorbed quickly after being fed to a horse. Dubey reported that Diclazuril can kill the early stages of S. neurona and “may be useful as a prophylactic against S. neurona infections in horses.”

Martin Furr, DVM, Dipl. ACVIM, of the Virginia-Maryland Regional College of Veterinary Medicine’s Marion du Pont Scott Equine Medical Center reported last year that Toltrazuril “has potential efficacy for the treatment of EPM.”

Ponazuril recently was tested in a treatment study at seven sites involving 100 horses and was reported to have very favorable clinical results.

NTZ also underwent a successful field trial, with previous studies indicating that it had the ability to be absorbed. However, previous studies indicated that NTZ at high doses could cause illness or death.

It has been reported that treating mares with sulfonamides, pyri-methamine, folic acid (as a supplement because of the disruption of folic acid production with sulfonamide and pyrimethamine treatment), and vit-amin E can cause congenital abnormalities in the fetuses of pregnant mares, and possibly affect the performance of breeding stallions.

Risk Factors

Dubey reported only one pony as having clinical signs of EPM. Epidemiologic studies have shown that while ponies, donkeys, and mules do develop antibodies against S. neurona, researchers feel that since there have been no other reported cases, non-horse equids have resistance to the disease. Similarly, seroprevalence for S. neurona was high in draft breeds in one study, but those horses had a lower incidence of disease.

Several case studies have been done on risk factors associated with development of EPM. Risk factors from an Ohio State study under controlled conditions include:


  • Young horses (one to five years) and old horses (greater than 13 years) have a higher risk of developing EPM. The highest risk was in 3-year-olds.
  • EPM risks are higher in spring, summer, and fall as compared to winter. The highest risk reported was in the fall.
  • Disease likely was due to management effects rather than genetics.
  • Stress (such as transportation) was questioned as a factor.
  • Racehorses and show horses had the highest risk for EPM (possibly related to stress). However, moderate exercise is known to strengthen the immune system.
  • Risk of EPM was 2.5 times higher if opossums were seen on the property.
  • Protection of feed from wildlife was associated with a one-third decrease in risk.
  • Presence of water (creek or river) on the property reduced the risk of EPM by 50%.
  • Presence of a wooded area on the property doubled the risk of EPM.
  • Treated horses had the greatest chance of improvement (10 times higher than non-treated horses).

Based on this information, horse owners and managers should reduce stress whenever possible, and should try to manipulate the horse’s environment to take advantage of the above known risk factors where possible.





EPM Life Cycle Solved In The Laboratory

The most recent Journal of Parasitology contained an article that opens the door for battling equine protozoal myeloencephalitis (EPM). Researchers J.P. Dubey, BVSc, PhD, senior scientist at the Parasite Biology and Epidemiology Laboratory of the U.S. Department of Agriculture, William J.A. Saville, DVM, Dipl. ACVIM, assistant professor of the Department of Veterinary Preventive Medicine at The Ohio State University, D.S. Lind-say, PhD, of the Virginia-Maryland Regional College of Veterinary Medicine, and others found they could use the common domestic cat as the experimental intermediate host for the life cycle of the causative protozoal parasite Sarcocystis neurona.


It already was known that the opossum is the definitive host, and the horse is an aberrant, intermediate host. The horse is considered to be a dead-end host (the parasite can’t complete its life cycle in the horse, and a positive horse can’t pass the parasite to another horse). This new breakthrough allowed researchers to complete the life cycle in the laboratory, thus allowing them to give EPM to horses in an experimental setting. This means that preventive vaccines and medical treatments for EPM can be challenged and proven effective or ineffective in the laboratory. Research needs to continue to determine if the cat is the natural intermediate host in the life cycle, or if there are others. Saville emphasized that: “At this point in time, cats should not be eliminated until the true natural intermediate host (or hosts) is determined

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Written by:

Kimberly S. Brown is the editor of EquiManagement/EquiManagement.com and the group publisher of the Equine Health Network at Equine Network LLC.

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