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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: www.pathogenes.com.

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.

S. neurona, electron micrograph

Apicomplexan parasites are intracellular protozoa that are responsible for a great range of diseases in man and animals. The family Sarcocystidae contain the cyst-forming coccidia, cysts form in muscle tissues of the prey-host. Carnivores (prey) eat the infected muscle tissue and that completes the parasites lifecycle. It is generally thought that muscle cysts (sarcocysts) cause no pathology in the prey-host, except perhaps in debilitated animals. A compromised host may lack a robust immune response that can limit the infection. Exposure to protozoa, and the resulting immunity, builds resistance to infections. It is well known that overuse of antimicrobials and antiparasitic agents was an unwise strategy, it is no different in the fight against Sarcocystis. An unintended consequence of chemical prophylaxis is an animal with no natural immunity.

Sarcocystis fayeri produces sarcocysts in horse muscles and like most Sarcocystis infections, this finding is considered incidental. Early research dismissed S. fayeri as a factor in equine protozoal myeloencephalitis (EPM). Experimentally infecting ponies with S. fayeri and evaluating the immune responses convinced the researchers that infections by two species neurona and fayeri, were indistinguishable using the IFAT test. Important molecular tests identifying S. neurona resulted in 22,076 nucleotide sequences. In contrast, S. fayeri has 15 reported sequences-all are the small subunit ribosomal RNA gene. Variability in the small subunit ribosomal gene is useful to identify Sarcocystis species. Incorrectly, S. neurona and S. falcatula were reported as the same organism based on synonymous regions of this gene.

Our investigations reveal the need for a reassessment of the pathogenesis of S. neurona infections in horses and a need evaluating the role of the immune responses in equine disease. There are reasons that S. fayeri should get a more serious look.

Sarcocystis neurona causes muscle weakness in horses but the parasite isn’t thought to develop cysts in horses. There are four horse-related species that develop cysts in horses: S. asinus, S. bertrami, S. equicanis, and S. fayeri. Canids, including dogs, are the reported definitive hosts for these organisms.

Generally sarcocysts are not associated with inflammation in horse muscles (examined by histopathology), although in some debilitated horses, muscle degeneration is reported. Equine sarcocystosis, considered a mild disease, but can cause fever, apathy, anorexia, myositis, difficulty chewing, muscle weakness, autoimmune disease and sometimes hair loss. Surprisingly the profound muscle weakness exhibited clinically doesn’t correlate with the mild lesions observed by histopathology. And this leads some to hypothesize that there is a toxin associated with muscle infections.

The toxin idea isn’t new. There were reports of Sarcocystis-cyst toxins, called sarcocystine, in 1899. A toxin was isolated from cattle muscle cysts and characterized one hundred years later. Yet the possibility of muscle toxins causing disease in horses hasn’t been evaluated. Sarcocystine causes disease in people. A toxin found in raw horsemeat was associated with human food poisoning. The toxin was isolated from S. fayeri sarcocysts and toxic effects were evaluated in rabbits. The protein toxin, histopathological lesions, animal feeding experiments, rabbit enterotoxin assays, enzymatic digestion experiments, and heat/acid lability assays are similar between S. cruzi and S. fayeri-cyst toxins.

So far, initial research on the enterotoxin from S. fayeri sarcocysts is in humans. It would be interesting to explore a relationship between a S. fayeri sarcocystine and myositis in horses.

There is enough molecular information to investigate sarcocystine as a cause of muscle weakness in horses. The proteomics suggest the S. fayeri sarcocystine is homologous to proteins of Eimeria tenella and Toxoplasma gondii. Protein similarity, if high enough, would indicate conservation of the protein and a role in parasite survival. Protein similarity between organisms would also sink the protein as a good diagnostic to implicate an organism. The best it could be is a diagnostic for protozoal myositis.

It is possible that detecting the sarcocystine would benefit the treatment of sarcocystosis in horses.

Coccidiosis in horses is complicated. It is important to examine many factors before initiating practices that have unintended consequences. It took many animal infection studies to correct the false claim that S. neurona and S. falcatula were synonymous. False assumptions have plagued EPM research for 25 years. This has cost many horses their lives. Studies that examine the effect of equine coccidial infections and the immune response to infection should dominate the conversation. Initially clarifying the definition of EPM and the pathogenesis of disease are important.

Recent attention to daily prophylaxis to reduce antibodies against S. neurona may have unintended consequences in the disease EPM. One must weigh the need for antibody prevention (the consequence of prophylaxis) against the risk of neurologic disease and the consequences to the reduction of natural protective immunity against coccidiosis in the horse. Natural immunity holds S. fayeri in check and probably minimizes the effect of cyst toxins on the infected horse.

Overuse of antimicrobials led to superbugs. The human pharmaceutical industry will spend the many millions of dollars to develop new antimicrobials—if they can. The animal pharmaceutical industry will not spend any dollars on developing new anti-protozoals for the treatment of EPM, especially if there is a resistant superbug. Unintended consequences of prophylaxis may be the release of toxins from S. fayeri cysts. A veterinarian may misdiagnose a toxic event for an active infection—how can one distinguish these cases?

Research developments newly reported for Sarcocystis neurona may impact horse owners their veterinarians.  A novel genotype XIII was reported by Barbosa et al in the International Journal for Parasitology (2015).  This novel genotype is a sea mammal-virulent SAG 1 strain supporting SAG 1 and 5 antigen types dominate animal disease. This strain is vertically transmitted, from the mother to the fetus indicating S. neurona is more like than unlike other pathogenic protozoa.  Our pending publications, reviewed in our last two blogs, report new tests for horses with recurrent or residual signs of EPM that seek to clarify the role of inflammation in suspect-EPM horses.  The bottom line is that the key to maintaining a healthy horse is management through testing and examinations and understanding the pathogenesis of disease.

Sarcocystis neurona possesses one of six major surface antigen genes, SAG’s 1-6, on its outer surface.  The horse makes antibodies to these SAG’s and the antibodies are detected in the serum by ELISA testing.  Minor differences within the SAG genes allows classification into genotypes, or antigen types.  For example a SAG 1 S. neurona may be antigen type II or XIII.  The horse can only distinguish between SAG’s 1, 5, or 6 (serotypes) not antigen types.  The SAG’s 2, 3, and 4 are genetically variable between serotypes, are present in all Sarcocystis, and allow molecular biologist to examine differences between SAG genes.  Geneticists look at allelic variation within the SAG genes and that allows them to sub-classify S. neurona into genotypes or antigen types.

We developed three SAG specific ELISA tests based on recombinant SAG 1, 5, and 6, the strains that infect horses .  The specificity of these tests allows us to distinguish between serotypes by the antibodies made in response to infection. The majority of all disease caused by S. neurona in animals is due to SAG 1 and SAG 5 serotypes.  There may be virulence differences between the S. neurona SAG 1: antigen type II or XIII (discussed in Barbosa’s paper).  What is clinically relevant in the sick horse is recognizing the  serotype.  Measuring specific antibodies allows the veterinarian to identify resistant infections, determine the response to treatment, and distinguish relapse versus re-infection.

Our newest work identifies horses that have chronic inflammation.  Inflammatory responses cause the clinical signs often associated with EPM.  Some horses won’t respond to antiprotozoal agents because the protozoa are gone.  A frustrating clinical presentation is identifiable with our new serum testing, MPP and IL6 ELISA’s.  Our approach to managing these horses has not changed, we still measure SAG antibodies pre- and post-treatment.  We assess the horses by gait score before and after treatment.  We monitor the CRP serum concentration.  What has changed is that we can identify horses that will relapse and give the veterinarian an explanation why and a management program.

It is well known that equine serum samples show variation in reactivity to different surface antigens of S. neurona.  The most useful clinical point: it is not the level of antibody (titer) present in a horse’s serum that is important, but noting that the levels rise with duration of infection.  Another general rule is that the first experience with infection (naïve horse) will induce antibody production. The levels are minimal and short lived (8 weeks or so).  A horse experienced with infections will get and maintain a higher antibody level up to 5 months in some animals.  Management of EPM cases requires multiple serum analysis.  A single point test can’t decipher a new infection or a relapse. Multiple tests can suggest it the animal has naive infection or chronic exposure.  The horse with chronic exposure is more likely to experience abnormal immune responses that may look like EPM but really suffer from chronic polyneuritis.  It is important to distinguish these infections because the clinical management differs.

There is a report for a new trivalent SAG chimera ELISA test for efficient detection of antibodies against S. neurona .  This is an ELISA test that seeks to reduce the time, materials, and cost associated with running multiple ELISA’s using SAG 2, 4/3.  The diagnostic protocol involves using the the SAG ELISA to determine a consensus serum-to-CSF ratio, ratios less than 100 suggest that antibodies against S. neurona are being produced in the CNS and therefore parasites are suspected in the CNS.  Diagnosis of EPM based on CSF results is still confounded by normal passive transfer of antibodies across the blood-brain barrier.  The changes to detection of SAG 2, 4/3 antibodies by the third generation test don’t identify the issues concerning non-specific testing, it can’t discern serotype, doesn’t indicate a treatment failure due to strain resistance, or point the clinician in the direction of inflammation when parasites aren’t there. It remains to be seen if the reduction in costs for time and materials will transfer to the client.

The most exciting new information is in the Barbosa paper.  They report vertical transmission in S. neurona in a sea lion, a harbor porpoise, five harbor seals, and a pygmy sperm whale. We suspected and reported S. neurona in the lung tissue of a fetus from a mare experimentally infected with S. neurona in 2004. We suggest that there is a unique window of opportunity for fetal infection, before the fetus gains cellular immunity.  The observations of Barbosa and sea mammal infections may change the opinion that S. neurona is not vertically transmitted in horses (Dubey).

The possibility that mares can transmit infections to the fetus may stimulate management changes on farms with a high incidence of EPM.  It would be a very rare condition and the veterinarian is the best source to analyze risks on a case-by-case basis.

Give us a call if you have questions or concerns about EPM .  We outline management protocols for horses as part of our consulting service.  We haven’t seen any new evidence that prods us to change our approach to the diagnosis of sarcocystosis or inflammatory mediated neuropathy.  We advise multiple exams, even in a recovered horse, once healthy let’s keep them that way!  We are committed to testing for SAG 1, 5, and 6 in independent ELISA tests, we won’t combine our three tests for convenience or price.  Confirming the presence of inflammation and distinguishing peripheral from central neuropathy are current goals.

We are committed to developing diagnostic tests and effective treatments for parasitic disease.

A Sidewinder is a term describing a neurologic older horse that has an unusual clinical presentation.  The horse has a lateral hemi-paresis that results in a gait that makes them list to one side or the other. Most Sidewinders are depressed.  The clinical presentation  (because they are depressed) classifies them having a multi-focal, diffuse neurologic disease (encephalomyelitis) of undetermined etiology.  In our consulting practice we saw a pattern to the clinical presentation of these idiopathic encephalopathies and wrote about them in a blog posted in February of 2012. Sidewinding horses have recently reached the level of recognition of clinicians at one university, we expect more discussion will be forthcoming.

To facilitate the veterinary interests and research community we are providing access to our database of the cases we have gathered data over several years.  This syndrome is recognized by clinical presentation and is a non-reportable disease.  The limits of our data are similar to all statistical databases, which includes under reporting and misclassification of disease.  Our data is captured by state of residence and not where the animal was exposed.  These cases are reported by veterinarians from field observations and are therefore termed anecdotal.

Three years ago our impression was that horses diagnosed with EPM were part of a larger group of ataxic horses and the weakness/hemi-paresis group were due to a subset of horses with an inflammatory syndrome.  Most of the horses are presumably diagnosed as suspect EPM, some of them have antibodies to S. neurona in the serum and some don’t.  There is usually a history of extensive clinical work up, referral to a university, CSF fluid analysis, and treatment for protozoa.  Generally these horses don’t respond to NSAID’s, steroids, or anti-protozoal drugs and show progressive disease.  The treatment protocol varies from the standard EPM treatment.

Clinically recognizable features are signalment (age is the only statistically related factor, 20-35 years old), depression, and a twisted gait.  Often the horse will use a stall wall for balance.  A complete blood count and clinical chemistry values are generally normal.   Antibody against S. neurona is not a significant factor.  There can be a varied and incomplete response to anti-protozoal drugs, anti-protozoal treatment does not maintain the horses and they are considered treatment failures.  An elevated C reactive protein is present in most, but not all of the animals and may be a significant factor.

We have not yet found the causal molecule in sidewinding horses. Histopathology was unremarkable in 4 cases (we concentrated on the choroid plexus), one case showed mild Wallerian degeneration.  A small percent of animals show signs related to vaccination and vaccination accompanied by specific treatment prevented recurrence of signs in these horses.  The resolution of signs with treatment can be directly associated with vaccination, there is no correlation with a specific adjuvant or manufacturer.  Note that vaccination is not the precipitating factor in most horses.

Some treated horses remained symptom free post-treatment and were had a good quality of life.  Due to the age of these animals most are trail riding, breeding stallions, and pasture pets.  Some animals show recurrence of signs after 12-15 months.

Our interpretation is that Sidewinders are a subset of neuromuscular diseases in horses, 20-35 years old with chronic inflammation due to unidentified causes.  Our differentials include infectious, metabolic, and immune mediated causes.  Infectious causes include chronic protozoa infection or chronic herpes viral infection.

Equine protozoal myeloencephalitis (EPM) is a syndrome that includes neuroinflammation. Recognizing the inflammatory component of the syndrome may make EPM a treatable disease, of course supporting a presumptive diagnosis requires a clinical examination and ruling out other causes of disease. Ruling out other diseases begins with a physical and neurological exam. Diagnostic tests can include radiographs and immunodiagnostics. Primary complaints that are related to an abnormal gait indicate a standard lameness exam (that includes nerve and joint blocks) should be performed. After routine diagnostic procedures, some veterinarians use a response to treatment to support a diagnosis.

When ataxia is apparent, ruling in/out the location of the problem is useful. Localizing the lesion is an achievable art. In early S. neurona infections vestibular disease is recognizable and can involve the peripheral or central vestibular system, brainstem, or cervical vertebrae. When localizing a lesion to the clinical signs an important consideration-- is it one lesion or a multifocal issue? The onset of signs can be sudden and indicate trauma, infections, inflammation, toxicity, or idiopathic causes. Chronic and non-progressive disease make trauma or infections more likely. A thorough examination and diagnostic testing can rule out or point to an etiology.

Induced EPM infections cause ataxia in horses. Prior to ataxia, central vestibular disease is apparent. Since publication of Early Signs of Equine Protozoal myeloencephalitis (Ellison, Kennedy, Brown, 2003. Journal of Applied Research in Veterinary Medicine p.272-278) the observations in 44 ataxic horses were documented. The determination of disease in horses in these blinded, placebo controlled studies was by a grade 2 ataxia. Observing the signs indicated in the chart below suggested central lesions quickly after S. neurona challenge.

The focus of EPM research is on the pathogenesis of protozoal encephalomyelitis. Vestibular disease is part of the disease process, as shown by documenting signs in challenged horses. In field cases, the most common causes of vestibular disease are trauma or infection. The clinical signs in horses are often acute. Management and treatment of these cases can be difficult. Central and peripheral lesions are treated differently with different prognosis and that makes differentiation between these two conditions important. Central vestibular disease (affecting the brainstem or ventral portion of the cerebellum) often results in severe signs including trouble eating, ataxia, and paresis in multiple limbs, or even recumbence. Central vestibular disease is often observed in cases of EPM. Early recognition of central vestibular disease associated with EPM combined with effective treatment can resolve clinical signs returning a horse to use.

The location of the protozoa in active EPM cases is currently under debate. Some practitioners argue that protozoa must be in the CNS to cause the observed inflammatory signs of disease. We argue that protozoa can occupy the CNS, breaching the blood brain barrier inside white blood cells (Trojan Horse model), but assert that this scenario is rare. Undoubtedly there are cases in which protozoa are found post mortem in horse with a diagnosis of EPM. The far more common condition is that protozoa are not found in histological samples. Histological specimens are rife with inflammatory lesions, considered evidence of protozoal infection. However, these lesions are not described as pathopneumonic. The term is idiopathic if a definitive diagnosis is not made.

The basis for our opinion is that protozoa are not found in the majority cases of suspect EPM that undergo post mortem examination. Even in the stress model used to induce EPM (Saville et al 2001. Veterinary Parasitology 211-222) the researchers were unable to demonstrate protozoa in the CNS of the challenged horses. Alleviation of signs can occur rapidly with treatment. Should necrotic lesions (due to parasites) be present in the CNS one would expect a long period for recovery including an aftermath of signs that could not be resolved.  A rapid response to treatment and return to use in suspect EPM cases is our goal.  Our goal is facilitated by an early recognition of central vestibular signs. No doubt EPM is a difficult disease to identify, treat, and manage. Our view is based on available literature, experiment, and clinical observations made by veterinarians. The optimistic view is that EPM is treatable because a large part of the disease syndrome is inflammation. Until scientific evidence shows us an alternative, defensible view, we will continue suggesting treating neuroinflammation as a practical approach to treating EPM.