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Horses with polyneuritis equi (PE) can have muscle wasting and an abnormal gait, sidewinder is a good description. Polyneuritis equi is associated with paresis of the tail, bladder, rectum, and anal and urethral sphincters. Paralysis of certain cranial nerves may be present, a drooping lip and ears, inability to blink and wasting of the facial cheek muscles. The characteristic pathology is inflammation of the peripheral nerves and nerve roots. Microscopy of diseased areas reveal demyelination and remyelination that indicats a remitting/relapsing disease. In 1987 Dr. Fordyce used a serum assay to identify horses with polyneuritis equi because afflicted horses often have antibodies against myelin protein (P2). Pathogenes uses similar assays (P2, MPP) to detect antibodies against myelin proteins to suggest immune mediated disease in horses with clinical EPM.

The field diagnosis of polyneuritis equi can be facilitated by transrectal ultrasound of the extradural sacral nerve roots (as they exit the ventral sacral foramina). It may be useful to perform a biopsy of the sacrocaudalis dorsalis lateralis muscle in horses that show hyperesthesia, followed by hypoesthesia, because histopathology can be highly suggestive of polyneuritis equi.

knuckling horse

Acquired equine polyneuropathy (AEP) is the most common equine polyneuropathy seen in Norway, Sweden, and Finland. Scandinavian knuckling syndrome describes the clinical presentation. Mortality is between 29 to 53%, however horses that survive can recover and return to athletic use. AEP is seasonal, appears in clusters, and has a strong association to diet. This disease results in paresis. Microscopic examination reveals large fiber demyelinating polyneuropathy (inflammation) with conspicuous Schwann cell-associated features.

Siv Hanche-olsen et al (Equine Veterinary Journal, 2017) discussed long-term follow-up of Norwegian horses affected with AEP and we wondered if these horses, like polyneuritis horses in the US and similar neuromuscular diseases in people, had circulating anti-myelin protein antibodies. After a few emails and bureaucratic appeasement, the serum arrived.

We expected to detect antibodies against P2 in symptomatic horses because demyelination is a component of the disease process although it is known that AEP and PE are different diseases. Circulating P2 and MPP antibodies in horses are not known to be exclusive to polyneuritis equi. EPM is not found in Norway. Sarcocystis is present, but not S. neurona. We found S. fayeri antitoxin in most of the samples and, as expected, none of the horses had antibodies against S. neurona. Only of the sera from the horses had a normal CRP value, the others were elevated (36-65µg/ml)! None of the horses had P2 antibodies. Although we tested a small number of serum from horses our results indicate that PE and AEP are demyelinating diseases with a different pathogenesis.

There are neurologic diseases in people that may help guide our understanding of these two diseases. Experimental allergic encephalomyelitis, experimental allergic neuritis, and acute disseminated encephalomyelitis are also helpful models to define the disease processes. These disease models demonstrate immune attack on neural tissue caused by viral infections or in some cases, vaccination.

In the experimental allergic encephalomyelitis-model, a peripheral neuropathy, P2 protein antibodies are a component of disease. The P2 protein makes up a small part of the peripheral nervous system, most likely localized to the cytoplasmic face of the Schwann cell membrane. The function of the P2 protein on the Schwann cell is undefined but may be like similar proteins that bind lipophiles, suggesting a role in lipid transport and storage in these cells.

Myelin proteins are largely conserved across species and that is why equine myelin served in many experiments conducted by those that study human Multiple Sclerosis. Generally, there are differences between peripheral nerve myelin when compared to myelin found in the central nervous system (CNS). However, horses have an unusually high amount of P2 protein in the CNS-myelin when compared with other species. It is expected that a peripheral immune-mediated neuropathy would affect the central nervous system in some equine disease conditions.

Guillian-Barre (GB) syndrome is an immune mediated attack on peripheral nerve myelin. Pathology is found at the level of the proximal nerve roots and is due to local cytokine production (inflammation) rather than the development of circulating antibodies. Patients with GB have circulating myelin protein antibodies. In horses with PE there is inflammation and antibody associated with the pathology that is like GB syndrome in people.

Heavily myelinated sensory fibers (muscle stretch fibers) and motor axons are direct parts of the reflex arc. Deep tendon reflexes are almost always lost very early in the course of human disease. Numbness and tingling (sensory) usually precede flaccid weakness and ascending paralysis due to affected peripheral nerves. Inflammation can be associated with nerves supplying cranial muscles, disease may look CNS-mediated but it is peripheral neuroinflammation. The cause of disease could be molecular mimicry because specific infections have been associated with Guillian-Barre syndrome. Often there are relapses with spontaneous waxing and waning of symptoms.

Multiple Sclerosis (MS) is an immune disease mediated in the central nervous system. Because the optic nerve is an extension of the CNS the optic nerve can often show lesions. There are geographic areas with a very high incidence of disease (1 in 300 people) yet in nearby areas the disease is unknown. It is strongly thought that an environmental factor is associated with disease. An etiology is presently unknown although neuroborreliosis (Lyme disease) is a risk factor. Interestingly, moving from a high-risk to a low-risk area after the age of 15 does not appear to reduce one's chances of developing MS. It appears that whatever triggers the immune reaction that is active during MS does not appear to be present at the time of diagnosis. It is likely that both infectious and immune mechanisms contribute to the pathogenesis of MS. Antimyelin antibodies are present in patients with MS and may have predictive value for disease. A viral infection may trigger an inappropriate immune response with antibodies to a common virus-myelin antigen.

Some similarities of polyneuritis equi to Guillian-Barre syndrome and Multiple Sclerosis are circulating P2 antibodies, cytokine mediated inflammation, and remitting/relapsing disease. Polyneuritis equi and GB are peripheral diseases while MS is a central nervous system disease. Horses express more P2 in the CNS myelin than other species and may indicate why some horses exhibit CNS signs during disease. It was suggested by Allman (2009) that controlling inflammation in horses with polyneuritis equi may enhance the regeneration of nerves in horses with PE. Diagnosis and treatment of inflammation associated with polyneuritis equi is the subject of one of our clinical trials.

We did not find P2 antibodies nor MPP antibodies in five horses with acquired equine polyneuropathy suggesting a difference between PE and AEP. Acquired equine polyneuropathy is a peripheral inflammatory demyelinating polyneuropathy targeting large fibers associated with Schwann cells. A possible mechanism of disease in AEP is suggested by the experimental allergic neuritis model in rats. In the rat model a leukocyte receptor gene mediating activation of natural killer cells and macrophages by immune complexes was induced in cauda equina and sciatic nerves during the period of increasing weakness. The accumulation of the leukocyte receptor was attributed to macrophages and other cells of the immune system in the neural tissues rather than induction of the expression of the receptor by the Schwann cells. Examining the immune response by inflammatory cells after the inciting trigger for the inflammatory response during clinical disease may be interesting in AEP.

It is suggested by our work that equine polyneuropathies, like human neuromuscular disease, can look similar but have different cellular targets that require different treatments.

Equine Protozoal Myeloencephalitis has many presentations.  Horses can be ataxic, lame, or stumble.  Some horses have behavior changes.  And some horses may have trouble eating (dysphagia), show abnormal airway function, or even have seizures. Vital signs are usually normal and can have muscle atrophy.  A horse with suspect EPM may or may not have active protozoal infection.  It is likely the clinical signs are due to inflammation, a part of the disease syndrome.  Some horses may look like they get repeat infections, although this can be due to chronic inflammation.

The first “test” is done by a veterinarian, it is the neurologic examination.  Signs can include gait deficits, we call the exam a GAIT ASSESSMENT SCORE, GAS, the horse has a number value between 0 to 5.  Clinical signs can include behavior issues or cranial nerve deficits without an abnormal gait.  These horses receive a GAS of 1.

The next tests analyze for antibodies in serum and/or CSF. ELISA Submission Form EPM Chart

There are several antibody tests, pathogen specific tests are the SAG 1, 5, 6 ELISA.  These proteins define a serotype of the S. neurona that infected the horse. Horses can have multiple exposures.  A positive test is suggestive that the signs are due to S. neurona. The tests can be used to test antibodies present cerebrospinal fluid (CSF). We produced a video for a standing procedure for CSF collection, an experienced veterinarian can collect the fluid in a matter of minutes.

An important part of the analysis of serum is the level of C-reactive protein.  This is a measure of the inflammation, An elevated CRP that doesn’t decrease after treatment indicates a chronic condition.

A response to treatment is often used by a field veterinarian to help diagnose EPM.  If a horse has not been treated in the last 90 days it is considered untreated.  If there are protozoa present an antiprotozoal treatment is indicated. If there is no response to treatment in 14 days the treatment is considered a failure. A partial response to treatment may mean the horse has post-treatment EPM syndrome.

There are additional tests to run if a horse fails on treatment.  A serum test for S. fayeri is appropriate, especially if there is muscle wasting or loss.  A significantly elevated CRP value (>39) may indicate polyneuritis.  The MP2/MPP test can determine if there are antibodies against myelin protein.  This is an important distinction because treatment is different than those used for horses with EPM. If there is a partial response to treatment a change in CRP is a good indicator of treatment effect.

Lyme disease is also considered when horses are exposed to ticks that carry Borrelia.  Our screening test is used to determine if Lyme should be considered in horses entering the field trial. If the screen test is 40, positive, confirmatory testing or treatment is indicated.

A horse with a diagnosis of chronic EPM, also known as relapsing/remitting EPM, should be tested for MP2/MPP and CRP.  The CRP value is an indicator of sub-clinical disease and can be used in evaluating the end of treatment in autoimmune polyneuritis.

Here is a link to our testing options.  Pathogenes Testing Options

Occasionally horses that have been treated for EPM will relapse days or weeks later. Recurrence of signs of EPM can be due to S. neurona, S. fayeri, or polyneuritis equi. This blog introduces the experiment to investigate disease conditions in relapsing horses.

Clinical disease is associated with Sarcocystis fayeri and Sarcocystis neurona infections in horses. Both of these infections will produce inflammation that can produce a disease called polyneuritis equi.  Equine protozoal myeloencephalitis is a  tough disease to understand and the following question was posed by the EPM society as an area of high interest: a) can S. neurona establish a persistent but unapparent infection in the horse? We are investigating the seroprevalence of antibodies to S. neurona, S. fayeri, and polyneuritis equi in these relapsing horses in an effort to answer that question.

The Trojan horse model taught us that any horse can get disease, at least those we challenged showed signs. But some horses were more susceptible than others. We observed that organisms could more easily enter the cells of some horses.  Does that mean that genetics plays a part? We’re not sure yet.  The model taught us that antibodies horsegroupwere produced by day 17 of the infection, clinical signs could be as early as day 10, and in every case the signs were sequential.  That means each horse showed the same signs in a very predictable way.

In field cases of suspected EPM we start by measuring antibodies. In most of these cases, the disease is not acute, but has progressed to a chronic state.  A statistically significant finding in acute cases was that antibodies against S. neurona increased as the infection progressed, yet the clinical signs varied with the horse.  That means some horses which had experience with the organism would have more pronounced signs than those which were infected for the first time.  We learned about the immune response and protection against S. neurona by using our challenge model.  The immune responses were similar in the experimentally challenged horses and horses that were naturally infected.

What we couldn’t do with the model was create a chronic condition that mimicked what we see in field cases. Field cases offer various disease manifestations however we don’t know when the horse was infected or the immune background (experience) of the animal.  Sorting this out takes many observations over a long period.  Observations and measurements require objective tests, run many times, with the data evaluated statistically.

Our long term objective was to gather data from a lot of horses, over a year, and produce meaningful analysis.  We analyzed over 17,000 blood samples and saw a pattern in a hundred or so horses.  These horses were chronic and their signs reoccurred after treatment.  It could take a few weeks. or happen after years of being healthy.  Some horses responded to treatments we suggested but they would eventually show signs again.

After manikins-puzzle-four-orange-cartoon-characters-colored-pieces-white-background-34676756developing tools and identifying horses, we designed an experiment that could answer  the question posed by the EPM society.  The experiment is finishing up after 1 year.  Enrollment was staggered and new horses are enrolling, some horses are still completing 3, 6, 9 and 12 month evaluations.  The exciting, novel, and interesting findings are that we were able to define 3 disease conditions associated with EPM.  The data from the experiment is available from the International Journal of Applied Research in Veterinary Medicine, Vol 15, No 1, 2017.  The paper will show up on their web page. The next 3 blogs will define the three diseases and explain what it means to the horse and potential treatment.

For auld lang syne, my dear,
for auld lang syne,
we'll take a cup of kindness yet,
for auld lang syne.

As another year closes, Pathogenes gives a big THANK YOU to those who contributed to our research studies.  Each consult adds information to our system and renews our hope that we will find a cure for EPM.  In 2017, we are concentrating on FDA-approved studies which move our treatments closer to full licensing as well as publications that explain our work. We fondly remember those animals along the way that brought us here, like Lily a paint mare that was one our first cases in 2013.

We two have run about the slopes,
and picked the daisies fine;
But we've wandered many a weary foot,
since auld lang syne.

An autoimmune test was (developed in 2014) and  incorporated into our EPM panel in 2015.  The S. fayeri assay was added in 2015.  Results from these assays were published, hoping our information will make EPM a lot easier to understand.  Our work taught us how to better prevent disease. The road to prevention starts with a correct diagnosis.

Importantly, horses with a diagnosis of EPM may suffer from S. neurona or S. fayeri sarcocystosis.  Or they may have an autoimmune disease.  Autoimmune disease is present when the horse’s immune system attacks myelin protein, the covering found on nerve tissues.  Detecting antibodies against the horses own nervous tissues indicates the horse has polyneuritis.  We suggest that autoimmune polyneuritis may start with a protozoal infection which stimulates chronic inflammation in some animals.  Clinically, once the cause of the disease is identified, the horse can begin the recovery process. Antiprotozoal drugs aren’t the answer to autoimmune polyneuritis.

It is difficult to figure out what is going on in horses which “relapse” with supposed “EPM”.  That is because horses can have one or a combination of  three syndromes that we have identified as associated with S. neurona.  The three syndromes are: S. neurona sarcocystosis, S. fayeri sarcocystosis, or autoimmune polyneuritis.  Each of these diseases which looks like EPM has a different treatment protocol. Some “EPM” tests can’t distinguish S. neurona from S. fayeri. Our unique approach does just that.

The BIG question we wanted to answer was “Can we prevent EPM?”  The answer is suggested in data from a complicated study that started a year ago.  The study was non-blinded (everyone got the medication) and uncontrolled (no placebo was used).  Treatment was given to horses with known relapsing/remitting EPM.  To enter the study, the horses had to be successfully treated, they had a normal neurological gait score.  It was important that there was a history of at least one EPM relapse that followed successful EPM treatment.

Horses were categorized as EPM (antibody against S. neurona), SF (S fayeri antitoxin present in the serum), or MPP (antibody against myelin protein or the against the neuritogenic peptide contained on the myelin protein). 2016 S fayeri Ellison 2015 MPP MP2 Assay

It was interesting to see that there were more S. fayeri-infected horses than S. neurona-infected horses.  There were more autoimmune horses than expected; in fact the autoimmune group comprised the largest number of cases!  The smallest group were horses in the EPM category, meaning there were antibodies against S. neurona present but not S. fayeri or antimyelin protein antibodies.  It was obvious that horses with relapsing/remitting signs of EPM that have antimyelin protein antibodies needed an alternate diagnosis.

We interpreted a “treatment failure” as the horse getting signs consistent with EPM and the prophylaxis was not working.  These horses were removed from the study and received an alternate treatment.  Horses with a diagnosis of autoimmune polyneuritis received treatment according to protocols that have worked for the majority of cases.  Horses with evidence of autoimmune polyneuritis failed in the first 3 months of treatment.  Interestingly, the horses with a diagnosis of Sarcocystis infections did not fail.

We discovered some more interesting and surprising results.  For example, we have evidence that horses with recurring EPM are re-exposed continually from the environment. We found that treating horses in the SF category eliminated the S. fayeri toxin that may be responsible for neuromuscular disease.  And, it was possible to detect sub-clinical disease.  Right now, we are working on a lab value to predict when sub-clinical disease turns into apparent disease.

We discussed this study with veterinarians at the 2016 AAEP meeting in Orlando, Florida, a gathering of veterinarians interested in EPM treatment and prophylaxis. Again, thank you to those who took the time to stop by and discuss your cases! The EPM prophylaxis paper is available , however we will share our view of the data and how it affects treatment decisions concerning your case now.  Just give us a call. We need the consult form completed.  Find it on our web site:

Overall, in 2016 we learned more about chronic disease, how to prevent EPM and the incidences of autoimmune polyneuritis.  This year, we will add more information to the pathogenesis of disease and work out a method to stage polyneuritis in the diseased animal.  We will continue to  transfer our information to the EPM community and promote positive discussion among practitioners. And so we’ll take a cup o’ kindness yet, for auld lang syne.


Some horses with equine protozoal myeloencephalitis (EPM) resolve their issues with treatment, these cases are simple.  Some horses continue to have gait problems that span years, they “relapse” year after year.  These are complex cases.  One common strategy is to treat the EPM-suspect horse and see what happens.  If the horse fails on treatment or “relapses” some suggest that the relapses “must reflect either new infections or reactivation of latent  infections” (MacKay 2008).

The comments about treating relapses states: “there is no obvious rationale for using a different drug to treat recrudescent EPM than was used to treat the primary presentation.  In my (MacKay) experience, regardless of the drug used, the response to treatment of each successive relapse is incrementally less complete.”  This approach leads veterinarians to extend the course of therapy, use higher doses of the same therapy, combine antiprotozoal, switch from one approved drug to another, institute “maintenance” antiprotozoal drug therapy…

Complex neurologic cases may be difficult to treat, not due to a lack of treatment effectiveness, but rather a lack of understanding of the pathogenesis of disease and the the drugs that should be used for the disease process.  Treatment response is a part of elucidating the disease in horses.Testing is critical to understanding what the disease process is in the horse.

Diagnosis of EPM is difficult and it is common knowledge that there are no “EPM” tests.   EPM is a syndrome that involves protozoal infection and signs that result from Sarcocystis-associated  infection.  An antibody test that detects protozoa won’t diagnose the inflammatory component of disease.  The presence or absence of antibodies can rule in or rule out the involvement of Sarcocystis. The inflammatory processes can linger long after the horses immune system resolved the active infection.  Inflammation makes EPM complicated to detect and treat.  The inflammatory process is not detected by circulating or CSF antibodies.

We are piecing together puzzling aspects of neuromuscular disease in horses and can help you understand some of those difficult cases.  Important aspects to consider are the presence/absence of Sarcocystis neurona antibodies, the serotype of the S. neurona infection, the host’s inflammatory response to protozoal infections, the presence of Sarcocystis fayeri toxins in horses, autoimmune antibodies, and the pharmacodynamics of treatment on both the horse and the parasites.

Published data clearly showed the clinical difference between the S. neurona challenged immune-competent horse and the S. neurona challenged immune-deficient horse.  Immune-competent horses cleared parasites from the blood and suffered clinical signs of disease.  The immune-deficient horses were unable to clear the parasitemia and surprisingly, did not show any signs of disease (Sellon 2004)! One take home message was that immune cells were involved in parasite clearance as well and clinical signs.  Interestingly, the immuno-competent horses did not have parasites that could be recovered indicating the parasites were eliminated.  Parasites were recovered from the immune-deficient horses. Understanding disease involves animal models, these horse experiments show the immune system impacts the results of infection. We have a disease model that makes a normal horse act like an immune-deficient horse and that helps us understand the disease processes and the effects of some treatments.

Another telling experiment showed that anti-protozoal drugs can delay the production antibodies--but not prevent disease (Furr).  The message is that antibodies are not a measure of disease, but they are a method to associate disease to a particular organism.  Horses on “maintenance” doses of antiprotozoal drugs may test negative for antibodies yet have treatable disease.  One reason that antibodies are decreased (or delayed) is that some anti-protozoal drugs alter the protozoa’s expression of antigens that are used as markers in antibody tests. Using antiprotozoals to prevent antibody production is not a rational approach to preventing “EPM”.

A recent topic is the contribution of Sarcocystis fayeri to neuromuscular disease in horses.  Previously S. fayeri was considered a common and benign muscle infection in horses.  Researchers at UC Davis and Pathogenes believe that Fayeri may not be so benign. The UC Davis group associated a slight increase in muscle cysts in horses with neuromuscular disease (over the number of cysts found in clinically normal horses) while we associated neuromuscular disease with inflammation and S. fayeri antitoxin.

We have determined that autoimmune antibodies, not detected by S. neurona antibody assays, are present in some “relapse” horses.  These horses are not effectively treated with antiprotozoal drugs.  They respond to judicious use of steroids.  It is this disease process that showed us the obvious rationale for using a different drug to treat recrudescent EPM than was used to treat the primary presentation.  Of course, testing and defining the presence of autoimmune antibodies is as critical as the proper treatment.

No doubt these additional conditions found in the “EPM” horse are rare.  In our experience these diseases account for 50% of the horses that are diagnosed with the rare condition EPM.  We assayed sera from 7601 horses with neuromuscular disease and found only 3745 were “EPM” suspect.  The other 3856 were clinically ill due to undetermined causes that included autoimmune disease and S. fayeri toxins.

In the past two years we have identified 195 horses with autoimmune disease that have not, and would not, respond to any antiprotozoal treatment protocol.  We also identified 121 horses presumably suffering from S. fayeri toxins.  These horses become worse with some antiprotozoal treatment protocols.

It is important to understand the components of equine neuromuscular disease and focus less on branding these cases as EPM.  When EPM is the correct diagnosis understanding the inflammatory component of the disease process is important because pathological inflammation goes hand-in-hand with infection.

Call us with questions, we are happy to share our approach with you.