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The Future of Equine Protozoal Myeloencephalitis
Mary Kate Moran
Glen Allen High School
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Introduction
“Despite the progress made to date in our understanding of EPM, it has been and
continues to be one of the more challenging problems in modern veterinary medicine” (Gaining
Ground on EPM, 2009). The most prevalent equine neurologic disease in the United States, Equine
Protozoal Myeloencephalitis (EPM) has plagued thousands of horses across the country.
Originally called segmental myelitis, EPM is a neurologic disease passed from opossums to horses.
Since the beginning of the research in the 1970s, substantial ground has been made in
understanding the life of the protozoa that causes the debilitating disease. With that information,
researchers have developed methods to test for the presence of the protozoa as well as methods of
treatment to combat it. However, while these approaches have been developed with modern
research, their effectiveness continues to be questionable. As of now, there are multiple options
for both testing and treatment, each with positive and negative aspects. However, researchers still
face obstacles in developing improved options.
While significant progress has been made thus far, the lives of too many horses,
veterinarians, and owners are interrupted and altered by this neurologic disease. Currently, the
research regarding methods of diagnosis, treatment, and prevention is headed in the right direction;
however, there are still huge obstacles slowing the process that they will need to be overcome in
order to find successful methods of diagnosis, treatment, and prevention. It is necessary, though,
that researchers actively continue work towards the development of these methods, despite facing
challenges and slow progress, in order to eventually provide relief to all parties whose lives have
been affected.
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Life of the Parasite
Equine Protozoal Myeloencephalitis is caused by one of two protozoa. Most commonly,
the culprit is a single cell parasite known as Sarcocystis neurona. The life cycle begins in the
definitive host – the opossum – because sexual reproduction of the protozoa takes place in its
digestive system, excreting oocysts and sporocysts in the feces. The sporocysts are the infective
stage of the S. neurona live cycle. Asexual stages have been found in other animals, known as
intermediate hosts, including raccoons, armadillos, sea otters, skunks, and cats. Each of these
animals ingests the S. neurona sporocysts in the opossum feces, which leads to the formation of
sarcocysts in the animal’s muscles. When these animals die, the opossums consume the flesh of
the animal, including the sarcocysts in the muscles, returning to the beginning of the cycle. In
the intermediate hosts, the protozoa inhabits the animal’s skeletal muscles, rather than the
gastrointestinal tract, which means that the animals do not excrete sporocysts and that they
therefore cannot pass the organism to horses. When horses are infected through the consumption
of opossum feces, sporocysts travel from their gastrointestinal tract into the bloodstream and
across the blood-brain barrier. In horses, three weeks after infection, the protozoa is confined to
the central nervous system in the form of schizonts and merozoites. Horses are considered dead
end hosts, because they cannot pass the protozoa on to other animals and because they are the
animal affected by the disease (EPM/Sarcocystis neurona, 2013). The life cycle of S. neurona
presents challenges in studying EPM because it cannot be reproduced experimentally. This
problem has contributed greatly to the lack of progress in developing tests and treatments
(Gaining Ground on EPM, 2009).
There are three different genetic phenotypes of S. neurona, each able to cause the infection.
Current researchers theorize that the three different types each induce varying levels in the severity
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of the infection. They also believe that it is likely that some strains are resistant to certain types
of drugs, contributing the fact that some horses respond better to some treatment options than to
others (Ellison, 2011).
The other protozoa that causes EPM is Neospora hughesi. Far less information is known
about the life cycle of N. hughesi, and it is responsible for a much smaller percent of infected
horses than S. neurona. While both species occur throughout the country, N. hughesi is more
common in the western United States than in the east (Thomas, 2015). Because the protozoa live
anywhere that opossums live and because opossums can live practically anywhere in the United
States, almost all horses are at risk for EPM (EPM: Understanding this Debilitating Disease, 2005).
Initial Infection
While it is estimated that half of horses have been exposed to the S. neurona sporocysts,
only one percent of exposed horses actually become infected (EPM: Understanding this
Debilitating Disease, 2005). The fact that only certain horses contract the disease has interested
researchers greatly and has become a driving question for the future. There are many theories
regarding factors that can influence whether or not the horse becomes infected, including the
number of sporocysts ingested and the health of the immune system. Researchers have determined
that certain common drugs – like corticosteroids Dexamethasone and Prednisone – can hurt a
horse’s ability to fight off the sporocysts. Other factors that can influence whether or not the horse
becomes infected are related to stress that could make the horse’s immune system weaker and
therefore more susceptible. For example, a horse that is foaling, in pain, in surgery, or under
anesthesia is more at risk for EPM than a horse under normal conditions (Recognizing EPM in
Horses, n.d.). Many researchers also support the theory of different strains of each protozoa, with
varying degrees of pathogenicity. However, Dr. Stephen Reed, of Rood and Riddle Equine
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Hospital in Lexington, Kentucky, believes that, when it comes to likelihood of infection, “the
horse’s immune system is probably more important than the pathogenicity of organism.” Other
veterinarians, including Dr. Robert MacKay of the University of Florida, support the theory that
there is a genetic component within the equine genome that could explain some horses’
susceptibility (Kane, 2011).
Once the horse has been infected, these same factors – number of organisms, immune
system, and stress – can influence how the disease progresses. In addition the time between
ingestion and treatment as well as the location of damage can determine how quickly and how
completely the infection advances (EPM: Understanding this Debilitating Disease, 2005).
At the moment, the fact that some horses are more susceptible than others places an
important role in driving research programs. Some veterinarians and researchers are currently
tailoring their studies to answer this question, including examining the immune systems of infected
horses, the immune systems of healthy exposed horses, and the strains of the protozoa that could
perhaps be more virulent than others (Thomas, 2015).
Diagnosis
One substantial problem with EPM that researchers and veterinarians face currently is that
diagnosis can be extremely challenging. Contributing greatly to that is the fact that the clinical
signs vary significantly, as they are entirely dependent on the location of the damage to the horse’s
central nervous system. The most commonly reported early symptom is stumbling, which is often
confused with lameness, therefore muddling the diagnostics. Other symptoms include ataxia,
weight loss, depression, and gait abnormalities, which can very easily be missed or mistaken for
another condition. Classic tell-tale signs of EPM include asymmetries in weakness, stiffness, and
muscle atrophy, but by the time these symptoms present themselves, the damage may already be
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significant and widespread (EPM/Sarcocystis neurona, 2013). Other typical neurologic symptoms
are common, like attitude change, back soreness, circling, seizures, and collapse (Recognizing
EPM in Horses, n.d.). If the brain stem is damaged, the horse will usually develop additional
symptoms, such as head tilt, facial paralysis, or dysphagia (Equine Protozoal Myeloencephalitis).
Because of the wide variety of symptoms and the frequent overlap with other neurologic diseases,
it can be challenging for veterinarians to identify a case as EPM, leading to misdiagnoses.
Currently, the diagnostic tests for EPM are improving, but still lacking. The tests for EPM
detect antibodies to the protozoa in blood serum or cerebral spinal fluid. Some veterinarians
believe that cerebral spinal fluid will always be more accurate, but blood serum tests have been
improving. Many veterinarians support the blood serum tests because they are more easily
obtained when working in the field and therefore less stressful for the horse. The first relatively
effective test, which is still available, was the western immunoblot test. It has been used for years,
but it is extremely sensitive to blood contamination in the cerebral spinal fluid, leading to many
false-positives. Newer tests developed at UC Davis are SarcoFluor and NeoFluor, which are
immunofluorescent antibody tests (IFAT) for S. neurona and N. hughesi respectively. Each
determine quantitative values to reflect the titer levels and the likelihood of disease. Because they
are more specific and more sensitive than other blood tests, they have reduced the need to take
cerebral spinal fluid. However, while these tests are improvements on the western immunoblot
test, they too test for the antibodies. It is estimated that thirty to sixty percent of horses have the
antibodies, while less than one percent actually have EPM, meaning that a large percentage of
horses would test false-positive. These tests produce less false positives because they result in
quantitative titer values that correlate with the likelihood of disease (Gaining Ground on EPM,
2009).
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The enzyme linked immunosorbent assay (ELISA) tests are another type of quantitative
blood serum test that looks for “distinct surface antigens of S. neurona.” They, like the two IFAT
tests, can only show if the horse have been exposed to the protozoa at some point in its lifetime as
well as titers that correlate with likelihood of infection (Thomas, 2015). The main problem with
one of the ELISA tests is that many S. neurona lack the gene (SAG1) that it tests for, resulting in
false-negatives.
Currently, no ante-mortem test is considered definitive. Diagnosis must be made by
piecing together the results of a neurologic exam, serum tests, and cerebral spinal fluid evaluations,
while ruling out other neurologic disorders (Gaining Ground on EPM, 2009). The lack of
conclusiveness creates an element of uncertainty and therefore worry among veterinarians and
researchers, which has motivated them greatly in determining a definitive method of diagnosis,
which could in turn contribute greatly to developments in the areas of treatment and research.
Treatment
Currently, there are three FDA approved drugs to treat EPM, all considered to be about
equally effective. Each drug crosses the blood-brain barrier in order to stop the reproduction of
the protozoa or to kill them directly. The first drug is ponazuril, an oral paste that is administered
for twenty-eight days. The second is pyrimethemine and sulfadiazine, an oral suspension that is
administered for up to one hundred twenty days. The last and newest is diclazuril, an alfalfa
supplement that is administered for twenty eight days. Some veterinarians will choose to treat
severe cases with an initial loading dose – up to seven times the normal amount – in order to
achieve adequate levels in the cerebral spinal fluid quickly. In a recent Rood and Riddle study,
they demonstrated that a smaller initial dose can yield the same results. Other researchers recently
have been looking for supplements to enhance the treatment process. The University of Illinois
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studied the effect of pairing ponazuril with the organosulfur compound dimethyl sulfoxide
(DMSO), which allowed the drug to reach appropriate levels three times faster (Thomas, 2015).
Other supplements that may be effective in treating EPM include vitamin E, folic acid, and
thiamine (Recognizing EPM in Horses, n.d.).
In most cases, once the horse has been given an EPM diagnosis, the veterinarian will select
an anti-protozoal drug and begin the treatment process. The effectiveness of the drug is measured
by the elimination or reduction of the neurologic symptoms. However, the anti-protozoal drug
regimen is usually paired with periods of rest and anti-inflammatory drugs. The combination of
the two latter can often be enough to result in substantial improvement in the horse’s neurologic
functioning, which leads to the questioning of the efficacy of the anti-protozoal drugs themselves.
Dr. Siobhan Ellison of Pathogenes has been conducting research regarding the treatment
of EPM, challenging the assumption that it should be combated, like any other chronic, relapsing
disease, with progressively higher doses of drugs. Instead, she has hypothesized that perhaps the
disease should be broken into two separately-approached parts, as the “parasite infections are
responsive to antiprotozoal drugs but the consequences of the infections are not.” As the parasite
begins to die off in response to the typical anti-protozoal drugs, some horses develop a “treatment
crisis” – a severe immune reaction that causes spinal cord swelling and increased neurologic
symptoms. She has begun pairing the typical anti-protozoal drugs with an anti-inflammatory drug
in order to reduce the brain inflammation – the allergic encephalomyelitis of the “treatment crisis”
– and address both halves of the treatment process. Currently, her treatment options are available
experimentally, as they have not been tested extensively enough to be FDA approved, but the
concept has shown promising results in horses across the country (Ellison, 2011).
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Recovery & Relapse
A series of six clinical trials roughly estimated that less than ten percent of effected horses
completely recover from EPM during the period of evaluation. These studies have revealed the
limited effectiveness of current EPM treatment options, as well as the relative similarity in the
success of the drugs (MacKay, 2008). Sixty percent of horses begin to improve within the first
month of treatment. If they do not improve within two weeks of treatment, additional testing may
be necessary, simply because the symptoms are so ambiguous and so similar to other neurologic
diseases (Recognizing EPM in Horses, n.d.). Currently, veterinarians estimate that, with the drugs
available, the recovery rate is about sixty-five percent (Thomas, 2015). However, unfortunately,
about twenty-eight percent of horses relapse after their course of treatment, which is a reflection
on the ineffectiveness of the current treatment options in some horses (Recognizing EPM in
Horses, n.d.).
Relapse can be defined as the reappearance of clinical signs after the cessation of the
treatment process. It is very common for horses suffering from EPM to cycle through periods of
improvement and relapse throughout their lifetime, reflecting their inability to completely defeat
the disease. In a Ponazuril clinical trial, sixty-three out of 101 horses improved by day twentyeight and eight relapsed by day 118, which has led to the conclusion that approximately ten percent
of horses will relapse within mere months of treatment. While relapses usually occur because of
a reactivation of a previous infection, it is possible for a horse to develop a new infection. Relapse
should be treated exactly as the initial infection; however, it is important for veterinarians and
owners to remember to explore other options if the first proved unsuccessful (MacKay, 2008).
Researchers are trying to pinpoint methods to reduce the likelihood of relapse. Current
theories include extending the course of therapy, using higher drug doses, combining drugs,
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switching drugs, and giving an immunostimulant (MacKay, 2008). Relapse is a grueling struggle
for the horses, owners, and veterinarians, as it can become a life-long process. Determining a
method to effectively manage or reduce it would lift some of burden the disease places on the
parties involved.
Prevention
Presently, the only established methods to prevent EPM follow general rules of equine
care.
These include minimizing the horse’s contact with opossums, which can be nearly
impossible in certain areas of the United States, and limiting the factors that inhibit the animal’s
immune system, which too can be an unmanageable feat. In the past, researchers have looked to
develop a vaccine against the protozoa. However, while these products have been made available
in the past, they have not proven to be effective. Dr. Nicola Pusterla of University of California
at Davis explains that vaccines against protozoal diseases are challenging to effectively produce,
and because of this, “Not many vaccines have been developed for protozoal disease in humans or
animals” (Thomas, 2015).
Many research facilities are currently working to develop other methods of prevention.
One theory is that administering low doses of the anti-protozoal drugs to healthy horses could
prevent EPM. However, currently, this is still only a theory, as it has not been proven to be
effective. Research regarding methods of prevention has been challenging, due to the extreme
difficulty in creating EPM in laboratory conditions. Because no live model has been found, the
researchers must study infected horses, which requires keeping live colonies of both opossums and
raccoons as well as horses to reproduce the cycle of the disease. Dr. Steve Reed stated that one
desire for the future is to end the use of horses in the research process, because currently, additional
horses have to be infected in order for researchers to learn more about the disease. Because of
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this, the goal at clinics like Rood and Riddle is to find an appropriate model that can be used to
revisit the development of a vaccine (Thomas, 2015).
Also driving prevention research is the pursuit of the answer to the question of where horses
are most likely to contact the casual organisms. Some studies thus far have revealed that, while
the protozoa and the opossums live all across the country, there are specific hotspots with higher
than normal infection rates, including areas of Oklahoma, Ohio, Kentucky, and Texas. These
studies have also revealed parts of the nation with less than average rates, like areas of the northeast
and west coast. This information is helpful in developing methods of effective prevention, because
it gives a more accurate representation of the problem, and it will aid the general public in fighting
the progression of the disease, because the people with horses living in the hotspot regions can
take additional precautions with horses at higher risk like the young, the elderly, and those under
high stress (Thomas, 2015).
Conclusion
Since the 1970s, researchers have made substantial progress in understanding the life
cycles of the protozoan in order to develop effective methods to reduce – and ultimately eliminate
– the rates of the disease in horses across the country. Current methods of diagnosis have become
quantitative in nature and increasingly reliable, and treatment options are growing in accessibility
and effectiveness as researchers learn more about the complex disease the organisms that cause it.
However, they still need attention in order to eventually create the most successful and most
dependable tests and treatments available. The areas of research regarding prevention and relapse
are the most critical as far as the future of the disease, as success in these areas will prove to offer
the most substantial benefits to both effected and healthy horses. Despite the obstacles they face,
the researchers hold the ability to offer significant progress in the near future.
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Reference List
Ellison, S. P. (2011). Equine Protozoal Myeloencephalitis is a Paradox. Pathogenes. Retrieved
from www.pathogenes.com
EPM/Sarcocystis neurona. (2013, December 19). United States Department of Agriculture:
Agricultural Research Service. Retrieved from
http://www.ars.usda.gov/News/docs.htm?docid=11028
EPM: Understanding this Debilitating Disease. (2005, June 27). Bayer HealthCare Animal
Health Brochure. Retrieved from http://www.aaep.org/info/horse-health?publication=752
Equine Protozoal Myeloencephalitis. Ohio State University: Veterinary Preventative Medicine
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Gaining Ground on EPM. (July 2009). CEH Horse Report, 27 (2). Retrieved from
www.vetmed.ucdavis.edu/ceh
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Kane, E. (2011, October 1). Equine protozoal myeloencephalitis: Etiology, diagnosis, and
treatment. DVM 360. Retrieved from http://veterinarynews.dvm360.com/equineprotozoal-myeloencephalitis-etiology-diagnosis-and-treatment
MacKay, R. J. (January 2008). Equine Protozoal Myeoloencephalitis: Managing Relapses.
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es.pdf
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Thomas, H. S. (April 2015). On the Frontlines Against EPM. Equus, 451, 45-53.