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c23aa0c5320c9acbda08ddf7ab6dd4e0EPM is an overwhelming topic because the literature isn’t often clear and easy to find.  New information is especially important. We provide consulting as an adjunct to the veterinarian helping bring a horse back to use.

Our consulting is data driven.  Serum, and sometimes CSF, testing  forms the basis for our analysis. Infection with and exposure to S. neurona organisms are detected by serum tests. Sarcocystis neurona is the organism that can sometimes get into the brain of horses.  We developed tests identifying toxin-producing muscle cysts caused by Sarcocystis fayeri .   Fayeri causes signs that make horses look like they have EPM.  Most important, we developed serum tests that detect inflammation.  Inflammation is part of immune the response to parasitic infections in horses.  Inflammation can become unregulated .  Unregulated inflammation can lead to life-ending disease.  It is critical to treat uncontrolled inflammation  with drugs that target the disease process and that is why testing is important.  Identify and teat for the treatable.

EPM is a disease of inflammation and infection.  By definition, EPM requires that S. neurona is in the brain of horses. All serum and CSF tests for  “EPM”  detect antibody against S. neurona.  Non-specific tests pick up other protozoa as well, these organisms do not have EPM.  Importantly, NO TEST WILL TELL YOU THAT THERE ARE S NEURONA ORGANISMS IN THE BRAIN! Some tests give you a “percent chance” that the horse looks like “x-number” of horses that did have EPM isolated from brain tissue.  This is not the same thing as a diagnosis of EPM!  The “x”, the number of horses used to evaluate tests, is published. It can be as few as 9.  Bottom line here is that there are no EPM tests. Useful tests do exist and can take the mystery out of treating the horse with EPM.

Sarcocystis neurona  tests measure antibodies that identify this organism (or in non-specific tests, some other protozoa are identified as well). A horse that is exposed to S. neurona  produces antibodies. Controlled, blinded, challenge studies showed  that antibody levels were unrelated to the presence of  organisms in the brain.  In one study it was statistically significant that antibodies increases with duration of infection.  Important measures of antibody levels change with the history of the horse, that is the  immune background.  It a horse has had an infection before it is experienced.  No prior exposure means the horse is naive. It takes up to 7 months for antibodies to decrease in an “experienced” horse.  With each exposure the antibody level will go higher, and last longer. 

Seventy eight percent of normal horses have antibodies against S. neurona!  Twenty four percent of clinically normal horses have antibody against a toxin from muscle cysts due to S. fayeri-sarcocystosis! When the organism is in the environment antibodies will be produced and hang around a long time. Antibodies can cross the blood brain barrier for both S. neurona and S. fayeri.  Finding S. neurona antibodies in the CSF doesn’t guarantee the organism is in the brain tissues. The serum/CSF ratio is a calculation used by some laboratories to adjust for high serum antibody levels.  It is also suggested that this ratio changes with the population being tested.  Call us to review the literature on this topic.

Inflammation has been a back burner issue in EPM research for 30 years.  We propose that inflammation an important consideration to diagnose disease.  Treating inflammation is critical for management of horses with neuromuscular disease. Do you know why? Call and find out why horses have a high prevalence of neuroinflammation.

Our consult provides guidance for veterinarians faced with horses suffering from ataxia.  We concentrate on the diseases  “EPM”,  equine muscular sarcocystosis (EMS), sub-clinical inflammation after EPM treatment, and polyneuritis equi.  Horses with a presumptive EPM diagnosis benefit from testing.  Consulting will tell you when to test and which tests are most appropriate during and after treatment. We guide the veterinarian to treatment protocols that are, and are not, yet published.

Call us for a consult today!  Not sure if a consult is necessary?  We are happy to let you know what services are appropriate to each horse. We can increase your EPM IQ!

Equine Protozoal Myeloencephalitis is a very rare brain disease that is associated with protozoa that causes neurological disease.  Historically, horses with this disease had a poor prognosis.  It was unexpected that horses could resolve the clinical signs of EPM because it was thought that parasites caused physical damage in the brain or spinal cord. It turns out that there are three diseases masquerading as EPM, the good news is that these diseases are common and can be identified and treated.

Our view is different because we identify the cause and consequences of infection.  Infection causes inflammation of the nerves in the body and central nervous system.   Protozoal-induced inflammation can be effectively managed and treated. In some cases protozoal disease can be prevented.

Causes and risk factors of EPM   Sarcocystis neurona is a parasitic protozoa that was isolated from horses with EPM. Another organism, Neospora hughesii  is a very rare cause of EPM. Studies using postmortem data show most EPM horses were young Thoroughbreds, Standardbreds, and Quarter Horses.

Causes and risk factors of Sarcocystosis  If you look at seroprevalence data (a measure of antibodies in horses) almost all horses are positive for S. neurona because they had exposure to the organism and quickly resolved this very common infection.  Most horses do not get EPM and most horses resolved sarcocystosis.  Horses can get clinical signs associated with inflammation from diseases that look like EPM.

Causes and risk factors of polyneuritis  Polyneuritis is a generalized neuromuscular disease that can be caused by S neurona, S fayeri, or other factors (vaccination reaction, bacterial infections, viral infections, Lyme disease). Almost 1/3 of horses in this country have muscle cysts that are the end stage infection of Sarcocystis fayeri.  Usually this infection is benign, unless the horse is debilitated.  However, as the cysts breakdown they can release substances that induces an inflammatory response.  These horses have “sub-clinical” disease and become clinically ill as the inflammatory cycle isn't turned off. The cycle of inflammation produces signals that keep the inflammation going, in turn producing more pro-inflammatory signals.

Diagnostic testing There are no EPM tests!  There are antibody tests to detect S neurona and other organisms associated with EPM, such as S. fayeri.  All  “EPM” tests in the live animal are different methods of detecting antibody against S. neurona.   Antibody tests based on S. neurona have been used to predict how likely it is that a horse may have EPM.  The problem is that antibody lingers after S. neurona is gone.  And the level of antibody reached during and after infection is not statistically related to infection. S neurona tests are useful to rule in or rule out S. neurona as the cause of disease, but is not useful to detect current infection. Tests for S. neurona are specific (SAG 1, 5, 6) or non-specific (SAG 2, 4/3). Non-specific tests use carefully diluted serum to remove cross-reactive antibodies such as those that detect S. fayeriSarcocystis fayeri  tests detect antibodies directed against disease causing proteins and are associated with disease.

Inflammation causes clinical signs during infection.  The inflammatory component of disease causes inflammation of the nerves, called neuritis.  Inflammation can become the issue (polyneuritis equi) and the inflammatory cycles causes chronic disease.  Uncontrolled chronic inflammation can be life-threatening and is recognized as cauda equina syndrome.

A panel of tests that include the likely causes of  neuromuscular diseases are SAG 1, 5, 6, S fayeri, MP2/MPP, Lyme, and CRP levels.

Treatment  There are several approaches to treatment. Each animal is different and responds differently to treatment, however if clinical signs aren’t improving after initiation of treatment a review of the test results, further testing, and a change in treatment are indicated.  Double dosing an ineffective treatment is not a good treatment plan. If the disease process is inflammation, it is important to monitor the inflammation using CRP testing, treat until the inflammatory process has resolved (often weeks after the resolution of clinical signs), and then prevent relapses by monitoring the level of inflammation.

Prevention  If it is determined that a horse is continually exposed to S neurona or S fayeri  preventing infection is possible.  Preventing the production of antibody to S neurona with some drugs has been proven ineffective for preventing disease.  It is important to test and determine if there is continued exposure to the parasite because overuse of antimicrobials is unwise. Preventing pathologic inflammation is best accomplished by monitoring the CRP levels.blogger-image-702499765

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We are conducting an EPM-treatment effectiveness study that will compare the treatment response between two drugs. The new drug is compared to a drug selected from those that are available commercially. The commercially available drug is called the Active, we will compare our treatment to an Active. The FDA’s Freedom of Information (FOI) Summary reports important information that was used to license a drug, this information is publicly available. The FOI’s found for EPM treatments show between 15 and 59% effectiveness. Studies were done in less than fifty evaluable horses. It is important to replicate the parameters used to determine effectiveness in the Active in order to compare the results between the studies.

The effectiveness of two products (ReBalance® and Protazil®) defined a successful treatment when the Western Blot test on CSF, compared before and after treatment, were negative. That means if a horse did not improve clinically, but antibodies weren’t detected by CSF-immunoblot after treatment, the horse was considered successfully treated. The ReBalance study used a total of 26 horses to determine effectiveness. Rebalance® was successful in 15% of the horses, that means 4.2 horses showed an improvement in clinical exam after 90 days. A few more ReBalance-treated horses, 42%, improved after 210 days. And, if clinical exam was evaluated with western blot conversion to negative as the criteria for success…at 210 days, a few more horses were considered successes. One interpretation is that if no antibodies were detected then the parasites are gone; the horse didn’t improve because there was irreversible neurological damage. Although commonly believed, that is not our working model of EPM. We believe that neuroinflammation can be reversed, if diagnosed and treated properly.

The Protazil® FOI shows 59% of horses are better at 48 days, unless a negative western blot test is included in the effectiveness analysis. In that case, effectiveness is 67%. An advantage to comparing our drug to Protazil® is the duration to an expected response. The FOI reports an improvement 20 days after the end of treatment, day 48. That is a darn site better than 90-210 days.

The folks testing Marquis® reported in their FOI that “Western Blot of the CSF did not appear to be a major factor in determining treatment success nor a reliable measure of treatment success”. They used gait exam as their assessment parameter and showed 59% improvement based on that exam.

Remember it was shown (Furr et. al. 2006) that prophylactic treatment with anti-protozoals delay antibody production in horses given oocysts as challenge, the challenge is similar to how horses are naturally infected. It was Dr. Furr and his co-workers that showed a delay in antibody production did not indicate that clinical signs would be prevented when horses were given ponazuril as a preventive treatment. The down side to Marquis® is 110 days to show an improvement, 82 days after the end of treatment, and that is a bit too long for our ideal comparison.

There is one notable reference in the new Marquis® flyer we just received and worth a digression from our current topic. The flier cites a paper published years before S. neurona was isolated from an EPM horse! This paper is offered as evidence that ponazuril “kills the parasite that causes EPM to stop it from inflicting further damage to the central nervous system (CNS)”! The paper really reports the effects of trianzinones on developmental stages of Eimeria in chickens, no mention of S. neurona, EPM or CNS stages of sarcocystis that cause EPM. Eimeria are coccidian parasites, don’t develop muscle cysts, and does not cause EPM. Eimeria is found and stays in the gut of a chicken. The flyer also cites coccidia in calves, lambs, and pigs as references. We side with Dr. Dirikolu (JAVMA, Vol 242, 2013) that reviews in vitro and in vivo studies to “clearly indicate the removal of triazines after appropriate treatment time results in regrowth of parasites…suggesting that stages are inhibited and retain the ability to begin development again once the drug is removed”. That means the action of the drug, in horses with S. neurona infections, is static, it doesn’t kill (cidal) all the stages. That is one explanation why horses relapse on this treatment. That is why it is important to test the drug against the species of organism in the animal species for which it was intended.

We are conducting the study, in horses, to show the field effectiveness against suspected S. neurona in horses. From the forgoing information our logical selection is Protazil® as our active placebo for our study. We will evaluate the clinical response to the treatment, not an antibody difference measured on a test before and after treatment.

We proposed a study using two treatments. Veterinarians call this kind of study an active control effectiveness study design, there is no placebo because the active control serves as the placebo. The advantage with this type of study is that a client feels more secure that a horse with EPM is getting a treatment and not a “sugar pill”. A veterinarian can enroll a horse and we have to have some assurance that there will be 4 cases/site over a couple of years. The site is the veterinarians practice.

Orogin® is a drug that is designed to treat Equine Protozoal Myeloencephalitis (EPM) due to S. neurona in horses. The Orogin® effectiveness study uses an active controlled parallel arm effectiveness design with animals randomly assigned to treatment groups and receive either the investigational drug (Orogin®) or the active control (Protazil®). The study for Orogin® is limited to 70 horses. This is a study that will be part of our Freedom of Information Summary and, because it is an FDA study, it has a few strings attached.

This is not a placebo controlled study, the horse will get a drug to treat EPM. The signed Owner Consent form, is required. The owner consent form informs the horse owner that this is an investigational drug. Your horse will not be considered for entry into the study without this form in place. If you haven't signed this form, you are not in this study. Horses can receive an alternate treatment at day 10, if there is no improvement. Any horse that is removed from the study drug before the end of the study will be called a treatment failure. The horses are examined again at 48 days, the expected time for Protazil® to exert an effect.

What does it take for a horse to qualify for enrollment? The documentation for qualification is called the Qualification Record. There are three conditions that must be met to qualify 1) the horse must have a provisional diagnosis of EPM due to Sarcocystis neurona. 2) The animal must exhibit a minimum of a Grade 2 deficit, and the easy one 3) the animal is 9.6 months to 30 years. A Grade 2 deficit is defined as “neurological deficit obvious at normal gaits or posture; signs are exacerbated with manipulative procedures.”

There is a second part for the qualification into the study and that is disqualification because there are situations that will disqualify a horse. The horse can't be in another study or be unsuitable for this study. The horse can't enroll if it has another disease. If the horse can't get up, grade 5, or the owner can't get medication into the horse (or multiple folks will treat the horse) it won't meet the study qualification standards.

There are some other forms (all one page with check boxes) for the veterinarian to fill out, the Physical Exam form at day 0 and 48, the Data Collection forms at day 0, 10, 27, and 48 and a Supplemental History form (these document the criteria used to support the diagnosis of EPM). There is a blood draw before treatment and day 10, the blood is collected in a couple of red top and lavender top tubes, accompanied by a Sample Collection form. Owners participate in the observations by completing check boxes on the Client Observation form that note behavior, appetite, respiration, and occurrence of diarrhea for 28 days, the end of the Protazil® therapy. Additional space is provided for owner comments.

So far, so good. But the first inclusion criteria, a provisional diagnosis of EPM, may be the most difficult requirement for this study. The diagnosis of EPM must be supported by testing, along with any other diagnostic testing used generally by the veterinarian for the horse. This ensures the diagnosis is correct. The FDA set the standard as CSF analysis by Western Blot to support the diagnosis.

We recognize that CSF taps are not generally obtained in the field and most veterinarians test serum, or don't test at all. We strongly hold that serum testing guides the correct treatment and that is so important. Hopefully data from this study will support that rationale, just like the Marquis® study, that CSF testing isn’t the best criteria to determine a horse that will respond to treatment. What we know now, that was not known a few years ago, is that diseases (like S. fayeri or autoimmune polyneuritis) look like EPM but will not respond to ReBalance®, Marquis®, or Protazil®. That is why treatinginflammation that is common to S. neurona, S. fayeri, or autoimmune polyneuritis is important. We want to use the serum analysis to make these points in our FOI.

However, until there is a paradigm shift at FDA the horse must have a CSF tap to participate. We provide a CE course (3 credits) and teach a technique to obtain a CSF tap, in the field, in a standing horse. Field sedation techniques, using drugs most veterinarians have on hand, allow a veterinarian to get a CSF sample from the side of the neck. With a bit of practice, the tap can be obtained in a couple of minutes. You can email us for the link or go to the Learn More tab and copy the link from the slide presentation that describes Pathogenes CE program. We will run the CSF testing at no cost.

We are far from finished in our quest to make EPM treatable and affordable and need your help with these studies. If you desire new equine treatments in the pipeline veterinarians and owners will need to be proactive. From idea, to models, to field testing and ultimate use, it's expensive and time consuming. It's also highly rewarding. This is our commitment to the horse community and any part you can play is appreciated. A veterinarian can call and discuss the protocol and time commitments.

Between the dark and the daylight,

When the sun is ascending to power,

Comes a pause in the day's occupation

That is known as the Scientist's Hour.

It is dawn in tiny Fairfield, Florida, but Pathogenes is not sleeping in. Before daybreak, we begin to answer the emails which slithered in overnight when nobody was looking. It's also time to send out the documents which had gone directly to spam and to watch videos of ataxic horses from every state but Hawaii and Alaska, not to mention a few from our friends up North. We make early phone calls to our team of advisors across the country, wishing we had been more alert in Geography so that we'd recall that it is two hours earlier in the Mountain Time Zone. We are repaid for this failing later in the day when other poor Geography students telephone us at Pathogenes from Sacramento at ten p. m.

Our drop box at the end of the gated driveway oftentimes offers up samples from local vets and these are carried back to the lab. FedEx runs an early delivery route before the regular noon call so the gates must be opened well before eight a. m. The team arrives beginning at nine, a courier is dispatched to the small Farifield Post Office forthwith and the delivery trucks begin rolling in, culminating with UPS, the final visitor of the day, at seven p.m.

Our interpretations of the results from samples sent to us are the culmination of more than forty years of lab and field experience and fourteen years dedicated to EPM. And now we have yet another addition to the team. We call him Hal 9000P and he is tasked with test result interpretations and reporting.

 

Hal 9000’s people skills are renowned-- earning a top 100 award in his previous career, see his resume on Wikipedia. Hal 9000-P is a Cracker Jack at numbers, especially the numbers -1, 0 and 1. True/false and “not null” are Hal’s forte…beyond that Hal 9000 doesn’t read or speak. Austin trained Hal 9000-P to use our algorithm.

Submission Forms The submission form accompanies serum samples and gives us all the data we need to help you with your case of EPM. Our interpretation, coupled with a veterinarian’s neurological exam and field experience, simplifies treating equine protozoal myeloencephalitis. Sometimes, we find no submission form in the box, just a blood sample. Careful sleuthing by the lab crew can often reveal the source from the return address sticker. Failing that, we wait. Eventually, someone will call for the results.

Gait Assessment Score The veterinary exams are critical to a meaningful interpretation of our test. A trigger for “no interpretation” is absence of information on the submission form. A horse name and reporting email won’t give us anything to interpret—it may even trigger an email from Hal 9000.

It is well known that most horses in the United States are exposed to S. neurona resulting in serum antibodies, but yet there is no disease. This conundrum plagued EPM diagnosis for 25 years. We rely heavily on the gait assessment score (GAS), our hands are tied if there is no GAS on the form. A behavior problem should be scored as a “1”, issues such as head shaking and Horner’s (syndrome) make sense to us but Hal 9000 doesn’t interpret comments. He can evaluate a “1” listed as “Normal-deficit”, just check the box. We also need the submission form signed in order to use it for our FDA endeavors. You will get an interpretation without a signed submission, but the data is lost to our research. Be sure and download our newest, easy to fill out form on the services tab.

Send pre- and post treatment samples The follow-up sample is also critical to our analysis. If the second submission isn’t available, we won’t know how drugs. We hear that the once Grade 4 ataxic horse is now happily galloping in the meadow and can’t be caught…to us that is a treatment failure. We need that second signed submission form and blood sample.

Treatment response Initially our logic is based on the horse’s treatment history. If the horse has not been treated with an anti-protozoal AND there are antibodies to S. neurona then we want how the animal did clinically after treatment. Send us a quick email and let us know the response! Alternately, if there are no antibodies to S. neurona we still want your veterinarian to understand the disease process, this will lead to treatment options.

No S. neurona antibodies, GAS >0 We base our recommendations on statistics. We have tested and evaluated thousands of horses. We realize that some horses have no antibody; there are several situations could exist. No antibodies to S. neurona can indicate early infection (less than 17 days) or the horse has been exposed to anti-protozoals. Less likely reasons for lack of specific antibodies are that the animal has no ability to respond due to a defective immune system. This is a long held myth that there is a genetic predisposition to develop EPM—we don’t believe that. There is another theory…there are many unrecognized to S. neurona strains, thus all Sarcocystis may cause EPM—this is the Great Divide between our testing (specific) and the others (non-specific tests).

And, here is the most logical reason: it isn’t EPM. Yes, the horse can have neuroinflammation but not have active infection. In these cases we believe that a past infection with S. neurona, treatment of protozoa and not inflammation, is the problem. Our statistics show that in 80% of the cases without specific antibodies there is no infection. These cases can be treated. The numbers also indicate that 20% of the time we would miss early infections. When there is an early infection a post treatment test can determine active infection. A fourfold rise in titer (antibodies in the serum) indicates that there was active infection. The treatment decision is based on the veterinarian’s experience and risk assessment.

If a veterinarian is risk-averse, we offer C-reactive protein (CRP) testing. If the inflammation is due to ongoing S. neurona, Lyme, enteritis, gastritis, colitis, respiratory disease, tumor or other cause of inflammation the CRP will be high.

Treated The best time to retest is 8 weeks following treatment. We want to see that the antibodies are down to the undetected range. However, it the GAS is > 0 after treatment, we suggest determining the CRP and further treatment.

Relapse A relapse of EPM defined by us as insufficient treatment of IL6 mediated inflammation. Bute and banamine don’t work to treat this inflammatory path. A relapse can be due to incomplete removal of S. neurona, re-infection with S. neurona, or a reaction to another cause of IL6 mediated inflammation. We are documenting other reasons for IL6 inflammation, we recognize vaccination can induced ataxia in 0.3% of disease reported on our submission forms.

It’s the end of the day…we’ve used our lifetime of acquired knowledge to help you with your horse. We encourage you to forward your questions to Hal 9000…he’s waiting…