Equine protozoal myeloencephalitis (EPM) is a devastating disease that has confused researchers and veterinarians for over 20 years. Most importantly, EPM is a clinical diagnosis EPM Chart made by a veterinarian, there are no diagnostic tests to definitively diagnose disease. It's not just semantics, EPM means there are protozoa in the CNS while sarcocystosis means the horse has an infection but it is very treatable.
The most common diagnosis for neurologic disease in horses in the United States is EPM–it’s an epidemic! Less than 17,000 horses are cured and relapses are common. The disease costs many millions of dollars to the horse industry—and that was before the release of Marquis. The average cost of Marquis treatment is $3000.00, but many horse owners report the costs are far higher.
What makes us think that we have solved the EPM problem? Remember the scene in the movie City Slickers when Billy Crystal’s character, Mitch, is alone with Curly, played by Jack Palance? Curly is giving Mitch some life advice.
Curly: “Do you know what the secret of like is?” (holds up one finger) “This.”
Mitch: “Your finger?”
Curly: “One thing. Just one thing. You stick to that and the rest don’t mean s***.”
Mitch: “But, what is the ‘one thing’?”
Curly: “That’s what you have to find out.”
One thing about EPM
We set out to understand EPM. Once we defined three types of S. neurona antibodies in horses along with detecting inflammation (C-reactive protein), and detecting S. fayeri anti-toxin, we understood a great deal about EPM. Most importantly, we can be pretty sure inflammation is present and treating inflammation treats the clinical signs of sarcocystosis.
Clinical signs of EPM and sarcocystosis are indistinguishable, variable, and can be acute or chronic. There can be one sign, like lameness, or signs can be multifocal. Neurologic disease can involve the brain, brainstem, or spinal cord. Muscle disease and atrophy can be present. Signs can include difficulty eating, swallowing, or there can be evidence of abnormal upper airway function. Our work uses a scale of 0-5 for the evaluation of the gait (Gait Assessment Score or GAS). Issues with behavior or cranial nerves are scored as a GAS of 1.
Detecting S. neurona is accomplished by detecting antibodies produced during infection. Antibodies are made by the body in response to foreign substances. The merozoite stage (infective to horses) of S. neurona produces highly specific foreign-to-the-horse antigens, called SAG’s that are unique enough to be used like fingerprints. These fingerprint antigens are SAG 1, SAG 5, and SAG 6. Each merozoite only has one of the 3 SAG’s (they are mutually exclusive) but mixed infections are very common.
The presence and levels of antibodies induced by the SAG’s are detected by SAG 1, 5, 6 ELISA tests (Pathogenes Testing Options). A rise in a SAG titer, generally a 2 to 4 fold increase, indicates active infection. A decrease in an antibody titer indicates that the parasite is gone and this is measured 5 to 8 months after appropriate therapy. The SAG antibodies will be elevated and not decrease when there is continuous exposure in the environment.
Even an active S. neurona infection indicated by a positive SAG titer is not EPM because EPM is a clinical diagnosis. Signs must be associated with infection. Antibodies present in the blood doesn't indicate EPM (protozoa in the brain) just that the horse has or had an infection. An S. neurona infection can produce clinical signs of EPM if the inflammatory molecules inflame nervous tissues. It isn’t just semantics. In EPM the protozoa are in the brain and spinal cord, in sarcocystosis the parasite and/or inflammation are present.
The 2002 ACVIM consensus statement (J. Vet Intern Med 2002; 16:618-621) states that “a clinical diagnosis of EPM is currently best established in horses that have neurological abnormalities consistent with EPM and that have a positive immunoblot test on an uncontaminated CSF sample, in which lameness or other causes of neurological disease can be excluded…Finally, a favorable response to treatment, especially when subsequently followed by a relapse of similar clinical signs, is also supportive of a diagnosis of EPM in the living horse.”
They are saying to rule out everything else as a diagnosis for the horse with neurological signs, identify antibody to S. neurona (they indicated a CSF sample had to be used but they didn’t have the specific antigens SAG 1, 5, or 6 to evaluate back then—our tests don’t require CSF unless you are enrolling into our field trial). The ACVIM group says a response to treatment— with subsequent relapse supports the EPM diagnosis.
Our work has clarified that a relapse is perhaps a misinterpretation of the disease process. The inflammatory component to sarcocystosis needs to be treated and currently licensed antiprotozoal drugs don't treat inflammation. Horses with an inflammatory polyneuritis need longer treatment–4-8 weeks in some cases, but it is important to target the mechanism of disease.
Our one thing—we check the serum titers in horses suspected of having EPM. We recognize that the EPM horse has antibodies to SAG 1, 5, or 6 and the levels of antibody increase over time. That means the horse will change from negative to positive on the SAG 1, 5 or 6 ELISA. A horse with signs of EPM due to S. neurona will show a rise in titer—and we determine the titer. A higher titer indicates how long the horse has had disease, not the severity of the exposure.
If you want a more indepth understanding of our view please continue reading.
Five Myths that defined EPM
Veterinarians have been long told that EPM is a prevalent disease that is hard to diagnose. Some horses have a genetic predisposition to infection from one of many strains. The organism, S. neurona is neurotropic, that means it has a predilection for the central nervous system of the horse. These are five myths that have confounded the understanding of this disease.
The prevalence of EPM is unknown. The fact is that we don’t really know what the exposure, infection rate, or disease due to S. neurona is in the equine population. The answer to the question of prevalence of infection and determining active disease requires species specific antigens that discriminate between sarcocystis sp. that cause disease and those that don’t. Researchers have concentrated on S. neurona but S. fayeri is also associated with neuromuscular disease in horses.
All active S. neurona infections don’t result in EPM. The belief that EPM is prevalent came from Western Blot data and that test relies on interspecies antigens to detect antibodies. Also, confusion between EPM and active S. neurona infections adds to the myth. Recently it was shown that the morbidity of EPM is 0.88% of the equine population and that value hasn’t changed in many years (Frank Andrews, LSU). Horses have antibodies to S. neurona commonly, but don’t show clinical signs in every infection. Many horses resolve S. neurona infections without showing signs. Horses are re-exposed and each challenge increases the chances of clinical signs that are due to an inflammatory response. Infections don’t always progress to EPM (parasites in the CNS). Based on S. neurona specific SAG 1, 5, and 6, EPM is an uncommon disease and S. neurona infections that don’t progress to EPM can cause clinical signs.
A second myth is that EPM is hard to diagnose. Most veterinarians can identify a horse with clinical signs consistent with EPM. Most of these horses, as well as asymptomatic horses, have antibodies to S. neurona Horses with clinical signs of EPM, that have increasing antibodies to SAG 1, 5, or 6, and those that respond to effective treatment can help confirm the diagnosis of sarcocystosis due to S. neurona.
Some veterinarians believe that horses that get EPM are predisposed to get the infection. Any ages, breeds, or sex of horse can get EPM. If there is a heritable factor for a predisposition to EPM we bet that it will be found in the IL6 receptor genes.
Another myth is that there are many strains (phenotypes) of S. neurona. It’s true, but it’s not important that there are many strains of this organism. Identifying the strain isn’t what is essential to those of us treating EPM, it’s the serotype. There are only three serotypes of S. neurona (SAG 1, 5, 6) and they are important to a discussion of EPM. Antibody responses in horses can be distinguished by the serotype of the infection. This is very important because some phenotypes can resolve quickly or spontaneously, some are resistant to Marquis, diclazuril, or pyrimethamine-sulfa drugs, and not all of the phenotypes can cross into the CNS and cause EPM and multiply in the CNS. Strains are defined by many genotypes, the only level of distinction possible serologically is the serotype.
One thing leads to another
The confusion about this disease started when Western Blot was used to identify antibodies and not disease (but seropositive animals were identified as diseased). It made sense that if S. neurona invades the CNS, after all if it was uniquely neurotropic, infections would truly be difficult to treat. If the organism is in the CNS we expect drugs to take a long time to eliminate disease and we accept, and expect, poor efficacy based on this grim assumption. These assumptions were wrong. Antibody tests showed us which horses to treat. We also discovered that a second component of disease is found in the horse with EPM. This disorder is inflammatory encephalitis that is not responsive to anti-protozoal drugs. Inflammatory encephalitis responds to a course of immune modulating drugs. The basis we use to determine the presence of a lingering inflammatory encephalitis is the lack of antibody post-treatment and clinical signs remain or return. The C-reactive protein (CRP) is elevated in these horses, CRP is a measure of inflammation. And it is induced by the inflammatory pathways stimulated by protozoa.
In A nutshell
Equine protozoal myeloencephalitis is a commonly diagnosed, uncommon disease that is recognized by clinical exam and antibodies against S. neurona. Most horses are exposed to opossum feces and S. neurona infected horses produce antibodies identified by one or more of the three serotypes, SAG 1, 5, or 6. Sarcocystis neurona infected horses, and horses with EPM, respond to treatments that target protozoa and accompanying inflammation, called polyneuritis. Inflammatory encephalitis can be managed successfully. Clinical exam is crucial to recognizing and evaluating the horse with EPM. The clinical exam after treatment is just as important. Clinical management of EPM takes understanding the disease process and monitoring responses to drug therapy.