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“A lie told often enough becomes the truth”. --Vladimir Lenin

If you’re not talking about inflammation, then-- by exclusion-- you’re lying about equine protozoal myeloencephalitis.  Reviewing only the causative agents (protozoa), life-cycle of the parasite, antibody testing, and treatment perpetuates misunderstanding.  Old ideas (EPM is enzootic and effectively untreatable, most horses are doomed to relapse) repeated often enough become a self-fulfilling prophesy.

Instead of viewing EPM as a population of horses infected with S. neurona containing a sub-group of untreatable, relapsing horses, chew on this.  View the population of ataxic horses as the whole pie (data set).  Ataxia is ubiquitous in horses and ataxia has several etiologies.  Sometimes ataxia in horses is caused by S. neurona.  Our data associates ataxia and S. neurona  in 54% of ataxic horses.

The ideas are very similar, however the practical difference between the views is that we can treat the latter group successfully—we are all too familiar with the treatment success of the former group.  Treating inflammation appropriately is key.  Understanding and managing the two components of EPM, inflammation and infection, are important to long term success.  The successful management of a horse with EPM will not be achieved by treatment alone, management takes an understanding the disease process.  It takes some work and it isn’t hard.

We make the association based on a gait assessment score, GAS, and the presence of specific serum antibody to the predominant surface antigens of S. neurona-SAG 1, 5, or 6.  A GAS of >1 and an ELISA SAG 1, 5, or 6 titer >8 attributes the ataxia to S. neurona.  A response to treatment supports the diagnosis.

Horses that do not have antibodies to S. neurona, with a positive GAS, are considered the rest of the pie, 46%. Just for arguments sake, call this group of animals IE-- disease due to inflammatory encephalitis.

If licensed anti-protozoal drugs are used for treatment the treatment efficacy is (published) 58%.  The difference in treating inflammation along with an anti-protozoal in suspect cases of EPM is 35%.  Are we just treating IE horses with an effective immune modulator or is there reason to think S. neurona played a role in disease? That is an experimental question for scientists, horse owners and veterinarians want results.

When horses show signs after "EPM" treatment they are called “relapses”.  Relapses are attributed to ineffective killing of anti-protozoals or re-infection.  The relapse rate with conventional antiprotozoal drugs are reported as 25% (ReBalance) and 20% (Triazines)—all of these drugs decrease the detectable antibodies in serum leaving, on average, 17% of horses in the IE category—ataxic with no antibodies--these are post-treatment IE cases but are attributable to S. neurona.  The rate of relapse (inflammation post-treatment) is three times higher in horses in which the inflammation was not addressed at the time of protozoal killing. Seventy one percent of ataxic horses with a presumptive diagnosis of EPM (no alternate diagnosis) had a root cause of inflammation that was most likely due to S. neurona infections.  This should be the topic of conversation about EPM.

The math leaves us to believe that 22% of horses with IE are horses with inflammation with an undetermined cause.  In some cases, we detect the effectiveness treatment for IE by serum CRP.  The anticipated treatment failure rate of treating inflammation and ignoring the inciting infectious cause, including S. neurona, would be high.  Our data indicates that S. neurona is a significant cause of IE in horses and should be a top consideration in treatment options.  Our research indicates that inflammation is the larger issue.  When treatment fails other obvious causes of IE should be investigated.

Posted on June 15, 2011 by Administrator

How many horses have EPM?

One thing we’d like to know: how many horses in the United States have EPM? Most authors start out telling us how important and serious EPM is and then they tell us the seroprevalence, how many horses have antibodies to S. neurona. And then they say that EPM occurs in less than 1% of horses. That’s rare.

Published studies determine the prevalence of EPM on seroprevalence, the presence of antibody determined by Western blot. That number is between 30% to (more than) 60% and is regional. Seroprevalence has little to do with actual cases of EPM. Horses with antibodies to S. neurona are horses that can succumb to EPM. An infection is a prerequisite for disease and antibodies result from infections. Seroprevalence can tell us how many horses are at risk to get protozoal myeloencephalitis due to S. neurona. The number of horses with EPM, based on antibody (tested by Western blot) is high.

Even if we knew how many horses had a definitive diagnosis of EPM, that won’t help get us to the true incidence of disease. A definitive diagnosis is defined as an animal from which the organism was cultured from the central nervous system. The number of horses seen at referral clinics can give us an idea of true disease. If our defined population is the group of horses diagnosed at a referral clinic for their ataxia (or suspect EPM)– we’d expect the number of horses that have EPM to predominate and therefore skew the data to an increase in the number of horses with the disease. Other lesser causes of neurological disease (viral infections, trauma, wobbler syndrome) are included. It is difficult to isolate the organism, thus some of these horses are diagnosed with EPM based on histological lesions that consist of inflammation.

The comprehensive NAHMS study conducted in 1998 and published in 2001–the only government document, tells us that this serious disease is rare. For this study the authors surveyed veterinarians and horse facilities.

An estimate of the EPM horses in the United States

We expect to approximate the number of horses that contract EPM annually and guess it will be between “less than 1%” and the number predicted by Western blot seroprevalence. This is the morbidity. The current United States horse population is considered to be 7, 200,000. That means that the number of horses with EPM is less than 72,000 if we believe that disease is less than 1%.

The NAHMS reports that a veterinary diagnosis (with or without the support of diagnostics) was made in 14 cases out of 10,000 horses in 1998. That is a rate of 0.0014 or 0.14%. This rate means that only 10,080 horses have EPM. Intuitively, that is low. The NAHMS number is less than 72,000 and is the low estimate of 10,080.

I spoke with Frank Andrews, past president of the EPM Society. Dr. Andrews thought 50,000 would be a high number. He presented the Proportional Morbidity Data at the EPM meeting recently. The rate “which is PMR, proportional morbidity rate, is 0.88% and roughly correlates to incidence (the number of new cases presented to Universities over 17 years).” He agrees that the actual incidence of disease is low, but exposure is high in some areas. He also says that the PMR has not changed in the 17 years included in the study but pointed out that there was a spike in cases from 1995-1998. The reasons for the spike seen in morbidity data for EPM were the development and use of the Western Blot and an increase in cases sent to universities due to drug efficacy trials, not an outbreak of disease. That means there are potentially 63,360 cases.

Narrowing it down

The increase due to drug study trials and hopes of a diagnostic test gave a falsely elevated rate for the years 1995-1998. We removed these years from the data set– 14 years for analysis. Andrews says the rate was unchanged over all the years and removing the spike should render the data to more accurately reflect the true rate over time. The adjusted rate is more realistic and is 0.65%. That would still yield the high value for morbidity because these cases are from referral centers. It’s high because this is the rate determined from cases of ataxic horses that were seen at referral university clinics, other causes of ataxia are not sent for a diagnosis. But are there any other factors we should consider?

Our data from the Peptide ELISA shows that only the animals with a titer against SnSAG 1 and SnSAG 5 should be considered for animals that are susceptible to EPM. Data based on the Ohio State model that showed that SnSAG 5 can’t experimentally induce disease (disease is defined as parasites isolated from the CNS of a horse).

The number of isolates from horses with SnSAG 5 strains and seroprevalence of SnSAG 5 antibodies in pure and mixed infections will yield how many animals can get EPM from this strain. Our phenotype data shows that 6.6% of the animals with a presumptive diagnosis of EPM by clinical examination are infected with the SAG 5 phenotype. The Ohio studies indicate this strain will produce signs in response to inflammation.

Observations in the field support our findings. In the published field EPM cases for which the organism was isolated, only 7% displayed the SAG 5 phenotype, and there was evidence of mixed infections based on some of the published reports. The SnSAG 5 infections often resolve without treatment, based on the OSU studies.

Potentially all the SnSAG 1 infected animals are at risk for EPM.

The PRM report, adjusted for the spike, estimates the rate of EPM at 43, 992. That is 61 horses in 10,000. We averaged the high and the low estimates numbers to approximate the number of horses that have EPM and it is 27,003.

Equine protozoal myeloencephalitis (EPM) is a parasitic infection of horses caused by Sarcocystis neurona that can result in devastating neurologic disease. Infection with S. neurona can also cause a neuromuscular disease that doesn't result in destruction of neurological tissues, and this is treatable.  Diagnosis and treatment of EPM require a distinction between EPM and non-brain associated S. neurona infections, sarcocystosis.

EPM has a poor prognosis for getting a horse back to use if parasites occupy the brain and spinal cord (CNS).  The damage isn't reversible.  However, we realized that neuroinflammation can result in clinical signs that look like EPM. The parasite didn't ever get into the central nervous system.  Signs were caused by the inflammation from the parasite infection. When we treated the inflammation and the parasitic infection, the horses got better. We found that sarcocystosis is a highly treatable disease.

Equine protozoal myeloencephalitis is a clinical diagnosis made by a veterinarian.   The disease EPM means that parasites are in the brain tissues.  Detection of antibodies against Sarcocystis neurona enhance the probability that the infection is due to neurona. Lameness and other causes of neurological disease should be excluded, for the most part these are treatable diseases. EPM is rare in horses. However, Sarcocystis infections that result in antibody but not parasite entry into the CNS are common.

Sarcocystis neurona causes infections in horses. The horse is an unnatural host for the parasite. An infection results in immune responses. Infections are usually resolved without clinical signs!

Some horses do get clinical signs associated with S. neurona infections. Three clinically relevant EPM issues are the pathogenesis of disease in the horse (does the parasite get into the central nervous system), diagnosis (what do the diagnostic tests indicate), and treatment of the inflammatory component of disease.

Sensitive molecular based studies showed that the opossum was the definitive host of S. neurona. These same techniques later confounded diagnostic tests, the methods were just too sensitive! It is generally accepted that horses are dead end or aberrant hosts because sarcocysts (cysts in muscles are the end result of infections) from S. neurona have not been identified in horse muscle tissue. The horse is an natural host for Sarcocystis fayeri, this organism completes it's life cycle forming cysts in horses muscles.  Both organisms can make horses ataxic or wobbly, but these infections are treatable.

None of the experiments using challenge models (from infectious material derived from opossum feces) result in merozoites in the CNS. The entire set of S. neurona horse-challenge experiments did prove inflammation was the cause of clinical signs.  We showed that a (autologous leukocyte-merozoite challenge model) parasite can result in brain infections. A likely method of travel from the gut to the brain is by hitching a ride in a leukocyte, the gist of our model. The effects of inflammation in the merozoite model are clinically relevant because inflammation is a treatable part of the disease syndrome.

The presumptive diagnosis of EPM is based on detection of antibody to certain antigens of S. neurona in a horse with clinical signs of neuromuscular disease. Major surface antigens (SAG’s) have taken a central role in commercially available tests. It is important to understand the differences in SAG’s and the information they provide. The horse responds to infection using both immunity (antibody) and inflammation (innate immunity mediated through cytokines). Inflammation is a key issue in the disease process but had played no role in disease management until the use of CRP testing.

Normal anti-inflammatory agents, NSAID's, don't treat the right inflammatory pathway stimulated by Sarcocystis. The inflammation is treatable with the right drugs.  Successful outcome in horses with  "EPM" is correctly diagnosing the disease and treating for the treatable.

 

THE STORY OF THE RIVER

Once upon a time there was a small village on the edge of a river. The people there were good and life in the village was good. One day a villager noticed a baby floating down the river. The villager quickly swam out to save the baby from drowning. The next day this same villager noticed two babies in the river. He called for help, and both babies were rescued from the swift waters. And the following day four babies were seen caught in the turbulent current. And then eight, then more, and still more!

The villagers organized themselves quickly, setting up watchtowers and training teams of swimmers who could resist the swift waters and rescue babies. Rescue squads were soon working 24 hours a day. And each day the number of helpless babies floating down the river increased. The villagers organized themselves efficiently. The rescue squads were now snatching many children each day. While not all the babies, now very numerous, could be saved, the villagers felt they were doing well to save as many as they could each day. Indeed, the village priest blessed them in their good work. And life in the village continued on that basis.

One day, however, someone raised the question, “But where are all these babies coming from? Let’s organize a team to head upstream to find out who’s throwing all of these babies into the river in the first place!”

We’ve heard this story many times so the source is lost, but the message is true.  The presence of inflammation and it’s association with EPM is as old as the discovery of the disease itself.  Neuroinflammation associated with EPM is minimally responsive to steroid and non-steroidal anti-inflammatory drugs, NSAID's target prostaglandin mediated inflammation.  We have had success treating EPM-associated neuroinflammation by modulating the immune system directed by non-prostaglandin pathways.

We clearly showed that serum amyloid A (SAA) was elevated in horses with EPM, however this inflammatory marker was elevated very late in the course of disease. This makes SAA unattractive to help us identify a horse with EPM. We are closer to understanding what happens in S. neurona infections in horses when we concentrate on innate immune pathways.

Because C-reactive protein (CRP) is closely associated with IL6, a molecule found on nervous tissue linings, we measure CRP in suspect cases of EPM. Eighty percent of horses with an incomplete response or relapse case of EPM have highly elevated CRP values, the average value in this group of horses is more than 39 micrograms/ml of serum!  When the CRP was elevated prior to treatment in a horse with sarcocystosis, the value dropped post treatment.

A poor predictor of survival is no response to treatment and a CRP value that remains elevated.  Clinical signs remain the most important parameter for evaluating EPM cases, however CRP is useful to determine response to inflammation in the cases we are monitoring.

Why does cytokine-targeted treatment relieve the signs of EPM?  We turned to the human literature where IL6 receptor signaling is an active area of research.  What we found is that there are soluble cytokines (IL6 has a soluble receptor that can cross the blood brain barrier in many species)—why not in horses?

While there aren’t cells that are actively making IL6 in the central nervous system in EPM horses, the soluble IL6 receptor can bind cells that lack this receptor.  Once the IL6 receptor attaches to the cell, the cell binds molecules that ultimately turn on inflammation.  That may be how there are clinical signs without parasites in many cases of EPM. It was shown that there aren’t any detectable IL6 cytokine gene expression in the brain tissues of horses with EPM.  The only way our theory makes sense with this cytokine is via a circulating receptor that can bind receptor-less cells, as shown in humans.  There could be another cytokine, and even if we are are on the right track with IL6, it isn’t a solo act.  We can measure IL6 so it is our first target, IL6 stimulates C-reactive protein and that is easy to measure.

Our goal is a treatment that goes to the head of the inflammatory stream to turn off the pro-inflammatory cells off by preventing the synthesis of IL6 receptors. Once the signal pathway is blocked the signs of inflammation recede.