Hindsight, they say, is 20-20. Reviewing the EPM literature results in a paradigm shift that changes ones way of thinking about the disease. A shift in our opinions about EPM and its treatment resulted in realizing it is a treatable disease. Here we introduce some commonly held beliefs and illustrate an alternative interpretation. A cursory understanding of some molecular biology techniques and a willingness to review published data is all it takes to form your own opinions. Read on and unlock the mysteries of EPM!
There are five concepts that are readily accepted about EPM—so accepted that they are urban myths. The five myths that deserve scrutiny are: 1) The prevalence of S. neurona is high but disease is low; 2) Many strains of S. neurona cause disease; 3) Sarcocystis neurona is neurotropic; 4) Horses have a genetic predisposition for EPM and 5) Disease is due to parasites in the central nervous system.
Changing the perspective on these five issues makes EPM not only comprehensible, but highly treatable.
For example, most horses (when tested by Western blot tests) have antibodies detected in the serum (true) – remember, Western blots are interspecies tests. Sarcocystis neurona can be isolated from horses with EPM, with difficulty—post mortem—thus it is one etiologic agent of EPM. The majority of horses that have signs consistent with EPM have antibodies (when tested by Western blot tests) to S. neurona. Lesions most often associated with EPM are inflammatory–serum antibody tests don’t detect inflammation. We use C-reactive protein to detect treatable inflammation. Lots of horses have antibodies against S. neurona. Very few horses have parasites in the CNS so disease is low. However, many horses have signs of EPM. And more horses with neuromuscular disease have antibodies against S. neurona. It makes sense that the parasites are common, they stimulate an antibody reaction, and then they are removed. During infection inflammation is stimulated. Sometimes the inflammation isn't turned off.
The subjective Western blot test detects both non-specific and specific antigens to S. neurona. Most horses test positive for antibodies to S. neurona. Why do only a few of these horses succumb to EPM? Why don’t all horses with antibodies and clinical signs have lesions with parasites in the CNS? Why do some horses without antibodies respond to treatment?
The logical conclusion is while the set horses that have S. neurona antibodies detected by Western blot are numerous, this test doesn’t define the set of horses with EPM. The point isn’t that the Western blot is deficient as a diagnostic test for EPM but rather, why isn’t it a good test? A most obvious answer is that EPM is a syndrome that includes inflammation. That is why we spent years studying inflammation.
The name Sarcocystis neurona implies that it is neurotropic–meaning that the organism readily enters the CNS where it causes damage to these sensitive tissues. Does the rare occurrence of disease indicate that there are a few, particularly rare strains that are responsible for disease? Or is it the horse. Are some horses genetically predisposed to get EPM due to some idiosyncrasy of the immune system? And, once in the CNS, do the parasites cause career and sometimes life-threatening lesions that renders them useless? Is it possible that there are two diseases? Or, a syndrome, two aspects of one disease? If EPM is really inflammation initiated with parasites that induce an antibody reaction that in turn, removes them but leaves inflammation that is really the disease... Treatment is possible!
Sarcocystis neurona myeloencephalitis is rare. Protozoal myeloencephalitis by its name indicates inflammation is significant to the pathogenesis of disease. Why is the inflammatory component of the disease ignored in the treatment plan? Inflammation (a histological diagnosis) is always mentioned in papers that examine tissues from horses with EPM. In fact, EPM is so linked to inflammation, that a diagnosis “consistent with EPM” is based on histological evidence of inflammation in the absence of parasites. If one were to make a distinction between cases with parasites detected in the CNS (the definition of EPM) versus inflammatory encephalitis, then we propose subsets of horses would be identified that require different treatments. Two subsets of EPM suspect animals may be those with protozoal infections and those with inflammatory disease. (Update: this was posted in 2013, read our 2017 paper on the three diseases associated with EPM found on our home page!) Three diseases are sarcocystosis, S. fayeri, and polyneuritis equi.
An effort to identify S. neurona-induced inflammatory encephalitis versus other causes of inflammatory encephalitis requires that all disease causing S. neurona strains are identifiable and that strains or species of Sarcocystis that don’t cause disease are excluded from the analysis. This distinction can’t be made using inter-species antigens (antigens that are shared among Sarcocystis species). That is why we like specific tests.
The idea that S. neurona is neurotropic, that means it has a predilection to enter the CNS, has its roots in the name of the strain associated with EPM. And with that mind set, it makes sense to treat protozoa with drugs that enter the CNS. Sarcocystis reportedly can enter the CNS of their intermediate hosts. If there is nothing special about S. neurona’s proclivities, then what is the role of inflammation in EPM? Inflammatory lesions are far more common when compared to protozoa-associated lesions in the EPM literature. What if inflammation is the primary mediator of the signs of sarcocystosis?
The inflammatory response to pathogens elicit tissue injury. There are several interconnecting mechanisms of inflammation. The most familiar may be the potent mediators of inflammation that are derivatives of arachidonic acid. One familiar principal pathway of arachidonic acid metabolism is the cyclooxygenase (COX) pathway that responds well to steroids and NSAID’s. A lack of response by an EPM horse to steroids and NSAID’s indicates that an alternative inflammatory path may be involved in the pathogenesis of disease.
Acute inflammation and chronic inflammation may respond differently to treatment. Chronic inflammation can indicate the inflammatory response is out of regulatory control. The result can be more damage to the body than the agent itself would have produced. The clear research focus on the pathogen rather than treating acute and chronic inflammation present in cases of EPM has denied many horses useful life.
Treating inflammation without a clear understanding of the inflammatory mechanisms involved in the underlying pathology of disease is as unproductive as treating EPM with anti-protozoal drugs has been. Adding NSAID’s to FDA approved anti-protozoal drugs is not effective. Understanding the role of inflammation in EPM can not be under-emphasized.