December 1999

Ask the Vet

EPM: Where do we go from here?

by Dr. Gregory L. Ferraro

While equine protozoal myeloencephalitis (EPM) was first described in the 1960's, the horse world generally views this condition as a disease of the 90's - it was in this decade that EPM first came to the attention of the horse world at large as a parasitic disease that affects the nervous system. Over the last 10 years, researchers 1) delineated the life cycle of a protozoal causal agent and named the parasite Sarcocystis neurona, 2) developed testing methods for both blood and cerebrospinal fluid to determine exposure to this parasite, 3) described the clinical symptoms of EPM, and 4) developed treatment regimens.

Considering that diseases caused by protozoal agents are among the most difficult for medical science to unravel, the veterinary community has made remarkable progress toward solving this problem in a relatively short period of time. As most in the horse industry are aware, however, the ultimate solution to this serious and debilitating problem of the horse is yet to be found.

Horse owners and their veterinarians commonly experience much confusion and frustration when dealing with the clinical syndrome of EPM. Many questions still exist regarding the infectious agent or agents, their distribution in nature and their modes of infection. Identifying EPM within the larger scope of all other equine neurologic diseases is a difficult challenge for veterinarians. Indeed, those laboratory tests that have been used to provide a positive diagnosis for EPM have now come under serious scrutiny by the medical community. Add to this the fact that treatment regimens previously thought to be curative for the disease now only seem to be providing temporary relief of its symptoms and one can readily understand the concerns being expressed within the horse industry.

Currently, we know that 1) EPM is a neurological disease of horses caused by protozoal parasites that infect and invade the central nervous system in a way yet to be described, 2) evidence of this infection can be determined during autopsy by the identifying characteristic lesions within the brain and spinal cord, 3) the presence of these lesions correlates well with the clinical symptoms generally attributed to EPM, 4) there are at least two protozoal parasites that cause these lesions and the resulting symptoms: Sarcocystis neurona and the newly identified, Neospora hughesi.

Researchers currently believe the life cycle of S. neurona includes the possum as the definitive host and birds as the intermediate hosts (although the range of birds involved is not yet defined). The horse is considered a dead end host for S. neurona, meaning that it cannot transmit the disease to other horses. The life cycle of the second protozoal cause of EPM (N. hughesi), most recently discovered by researchers at the Universities of Missouri and California at Davis, is yet to be delineated. The definitive and intermediate host or hosts have not been conclusively determined and the horse's position in the life cycle of the parasite has not been specified.

Dr. Barbara Daft of UC Davis is conducting studies utilizing postmortem tissues generated through cooperative efforts between the California Veterinary Diagnostic Laboratory System and the California horse racing industry. Her research has called into question the reliability of our current commercially available testing methods to identify EPM infection. Problems involving the development of host response antibodies, their cross-reactivity and sample contamination severely limit the usefulness of the Western blot test of serum and cerebrospinal fluid in the diagnosis of EPM. UC Davis researchers developed a different diagnostic test utilizing the positive identification of the parasite's DNA, however, they determined that it was not as useful as hoped and is not being recommended.

Finally, Dr. Antoinette Marsh at the University of Missouri, in collaboration with her former colleagues at UC Davis, has determined that the most commonly recommended treatment of pyri-methamine-sulfonamide combinations are not effective in killing the parasite. Instead, this treatment only serves to depress the parasite's viability such that the horse's immune system can control the infection during the treatment period. When treatment stops and the horse resumes athletic activities, the symptoms of the disease often recur. Several new therapeutic agents are being evaluated, but even if they prove effective in killing the parasite, clinically infected horses will still be left with a damaged central nervous system and, therefore, compromised performance.

Given this set of facts concerning EPM and the historical perspective of 10 years of diligent research by scientists at multiple institutions around the country; where do we go from here? What is the scientific approach and direction of effort that is most likely to solve this problem?

First and foremost, we must address exactly what we want to accomplish in our studies on EPM. Do we want to find an agent that kills the protozoal parasite or do we want to prevent the clinical entity of EPM. If killing the parasite is the only goal, then we can just continue to search our pharmacological armamentarium until we find an agent that kills the parasite, but not the horse. Unfortunately, that does nothing to solve the clinical syndrome of EPM. Once the animal shows evidence of the disease, its central nervous system is already damaged. Killing the infecting organism at this point does nothing more than save the life of the animal. It does not restore it to normal function and, therefore, usefulness. It is doubtful then, that the horse industry would be satisfied with such a solution.

The ultimate goal must be the prevention or elimination of the clinical entity known as EPM. If we are to do justice to the horse and its owner, the parasite must be prevented from invading the horse's brain and/or spinal cord. Given this requirement as the measure of success, the veterinary scientists of the UC Davis Center for Equine Health determined that they must find the point in parasite's life where it will be most easily destroyed. That key place and time must be found during the course of the parasite's development, during its passage through its definitive and intermediate hosts, or during its invasion of the horse's body where disease production can be optimally interdicted.

Consequently, the CEH consortium has designed a five year scientific plan of attack to find each parasite's point of vulnerability and determine the optimum method of disease prevention. The plan involves four distinct, yet interrelated areas of investigation.

1. Epidemiological study of EPM
   The CEH will conduct a comprehensive epidemiological investigation to determine the current parameters of EPM in California. Researchers will determine the percentage of equine neurological disease that can be attributed to EPM, the geographic distribution of the disease within the state and the characterization of risk factors or management practices associated with clinical infection. This information is necessary to narrow our field of investigation to allow for more rapid and efficient scientific investigation into the possible causes of the disease.

2. Ecological examination of the protozoal parasites
   The CEH will complete a thorough scientific analysis of the biological parameters of the protozoal parasites that cause EPM. All aspects of the parasites' life cycles, methods of reproduction, and modes of environmental distribution must be determined in detail if the optimum points of medical intercession are to be discovered. We must have a complete understanding of which animals, birds, etc. are involved in the natural life cycles of the parasites and how the parasites are transmitted from one host to the other. Some of this work has been done, but it is far from complete and as most people understand, in complex matters, a little bit of knowledge is dangerous. We simply cannot continue to make judgments regarding the control of EPM without uncovering all the details of this complex story.

3. Pathogenesis of the disease in the horse
   Currently, we simply do not know enough about what these protozoa do after they invade the horse's body. Once the parasite invades the body, how long does it take until the parasite enters the central nervous system? How long after that do clinical signs become apparent? In those horses that test positive for EPM yet have no clinical signs, where is the parasite? Has the animal's immune system eliminated it or is it encysted somewhere in the horse's body only to be reactivated at a later date? Can the parasite be transmitted across the placenta from an infected mare to her foal? These and many more questions regarding the process of infection and disease production within the horse's body have yet to be answered.

4. Development of accurate and reliable diagnostic testing
   The current commercially available testing methods for diagnosing EPM are simply not adequate. Neither the DNA analysis nor the Western blot based system for identifying the presence of the parasites is accurate enough to provide a basis for clinical judgment of infection in the horse. A new testing system must be developed that can reliably differentiate horses that are actively infected with either S. neurona or N. hughesi from those that have been exposed but are not infected.

The CEH, its UC Davis scientists and their collaborators feel strongly that the EPM problem can only be solved through this comprehensive and multifaceted approach. They have learned that the solutions to complex medical problems are best solved in the same way that NASA puts men into space: no one scientist or field of expertise is sufficient to accomplish such tasks. Rather, it takes a focused and sustained effort by many experts over time to fully achieve a successful outcome. The CEH scientists will be working diligently over the next several years to unravel this complex problem.