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It is an ill wind that bloweth no man goodJohn Haywood 1562

Autoimmune polyneuritis is a disease that causes weakness and ataxia in horses.  It is related to horses diagnosed and treated for EPM. It is not a new disease but hasn't been in the EPM-discussion.  This post explains polyneuritis equi and using CRP levels to monitor the disease process.

A Little History The possibility of contracting variant Cruetzfeld-Jakob disease (the human form of bovine spongiform encephalopathy) was recognized when Mad Cow disease blew into Europe.  Risk spurred scientists to replace the well-characterized bovine neural tissues that were used in MS (multiple sclerosis) research with equine tissues. The flurry of equine experiments led to some very useful information.  In 1981, scientists raised the possibility that circulating antibodies to myelin protein played a role in neuritis of the cauda equina in horses.  An ELISA test was reported in 1987 for the differential diagnosis of cauda equina neuritis and other neuropathies in horses. Polyneuritis equi (PE) is the more correct term for neuritis of the cauda equina. Ellison 2015 MPP MP2 Assay ELISA Submission Form Pathogenes Testing Options

Several diseases are encompassed by the term polyneuritis equi. That complicates the understanding of this syndrome.  Suffice to say, much research is needed to determine cause and effect as well as the pathogenesis of polyneuritis equi in horses.

The pathology of polyneuritis equi is characterized by inflammation of the nerve roots that form the cauda equina (typical) and any other peripheral nerves (atypical) that are involved.  Histological examination of the affected nerves can show areas of demyelination and remyelination. These lesions are similar to experimental allergic neuritis.  Horses with clinically and pathologically diagnosed polyneuritis equi  had circulating antibodies against myelin protein that were similar to lesions in the experimental model. When it becomes necessary there is a procedure that may be used to confirm the diagnosis. Aleman 2009 PNE

The cause of polyneuritis equi is elusive.  A viral or an immune-mediate etiology are each possible.  These two theories may not be incompatible because an infectious agent may initiate an immune-mediated condition that stimulates a common pathologic pathway.

The distinction between chronic inflammatory demyelinating polyradiculoneuropathy and acute inflammatory demyelinating polyradiculoneuropathy and several disease-associated polyradiculoneuropathies (cancer, diabetes, liver disease) is important in human and equine medicine because the course of disease and prognosis are different.

Our approach to investigating polyneuritis in horses is by serum testing for MPP and MP2 antibodies followed by observing a response to treatment. We hypothesize that polyneuritis in horses is immune-mediated and it is not specific to cause.  For example, sarcocystosis due to S. neurona or S. fayeri can stimulate polyneuritis.  So can Borellia, the agent of Lyme disease. The pathway that results in clinical signs and pathology are the same, the stimuli are different.  Because the pathogenesis of disease is by a common pathway, the initial treatment of polyneuritis equi is the same, irrespective of the stimulus.  However, the identification of the etiology is important to treat the underlying cause of the proinflammatory-stimulating pathway.

The immune response is over reacting to an infection. Most of the time an immune response turns off once an infection resolves.  In some horses with polyneuritis, a chronic inflammatory condition results because the immune system is stuck in the “IL6 <-> CRP” cycle, each molecule stimulating the production of the other.  No “turn off” switch is initiated when the pathway is stuck.  Just the opposite happens.  The end result of molecular reactions turn on the reactions to stimulate the cycle again. Our approach is resetting this cycle using a protocol that prevents the short term production of IL6 receptors.

The proposed pathogenesis of polyneuritis equi. The immune response in polyneuritis equi is possibly via an IL6 (pro-inflammatory) pathway. Our reasoning is that:

  • innate immune responses stimulate IL6 production;
  • myelin protein displays IL6 receptors.

An experiment demonstrated horses with abnormal IL6 pathways do not get signs of polyneuritis equi, as opposed to horses with normal IL6 pathways, when given the same stimulus.

  • Horses treated for abnormal IL6 reactions resolve their clinical signs with treatment.
  • Untreated horses with chronic polyneuritis (atypical polyneuritis equi) get worse.
  • Untreated chronic polyneuritis progress to an immune mediated demyelinating neuropathy.

The waxing and waning of the immune mediated disease eventually results in microscopic calcium deposition on nerves. This terminal condition, classical polyneuritis equi, has no treatment in horses. The recommendation for classical cases of polyneuritis equi, once the diagnosis is confirmed, is euthanasia due to the poor prognosis and intensive nursing care required, even for symptomatic support. We do not recommend euthanasia until a response to treatment is investigated.

Many horses with neuropathy have increased CRP (stimulated by IL6).  That is why CRP is important to monitor the presence of disease.  Sub-clinical disease is diagnosed when CRP levels are elevated and there are no clinical signs.  The CRP levels are useful in monitoring these cases, treatment is needed until the CRP levels are normal.  Again, treatment to decrease inflammation is not useful in chronic cases unless the underlying condition is resolved.

You’re probably reading this because you have a horse that has relapsed multiple times or you are concerned about the CRP value.  Here is our quick reference:

CRP level is trending to a normal value (less than 16):  indicates the inflammatory process is resolved.  If clinical signs are still present they are probably due to a physical cause and more diagnostics are warranted.

CRP level is elevated or going up: indicates the inflammatory process is not resolved, subclinical disease is present.  If the horse is clinically normal, it may be useful to deworm with QUEST.  Quest is required to eliminate encysted small strongyles that may be associated with chronic inflammation.  It’s cheap, safe, and there is nothing to lose.  Have you considered hind gut ulcers?

CRP level is elevated or going up: if the horse is not clinically normal or relapses after treating the inflammatory pathway,  the underlying condition has not been resolved. A possibility is that S. neurona is causing continued exposure and disease; S. fayeri toxin is present and S. fayeri infection has not resolved or there is continued exposure in the environment.  Our ongoing study is designed to distinguish these conditions and is accepting cases.  The study is for 1 year.

CRP level is elevated and MP2/MPP antibodies are present: indicates that autoimmune polyneuritis is present.  This condition will not respond to antiprotozoal drugs.  This condition will require a different treatment protocol.  We are consulting with veterinarians/owners with sick horses about this disease and providing the most up to date protocols. Treatment may resolve clinical signs. CRP is used to detect subclinical disease that should be treated before clinical signs manifest.  If the CRP continues to go up, and clinical signs progress, further diagnostics are indicated.

Chronic relapsing disease with an elevated CRP that is unresponsive to treatment requires additional diagnostic workup. There are some diagnostics to assist in the ante-mortem diagnosis of classical polyneuritis equi. Aleman 2009 PNE The field procedure is a transrectal ultrasound of the extradural sacral nerves.  Also, biopsy of the sacrocaudorsalis dorsalis lateralis (the base of the tail) is useful.  There are  case reports describing the procedures and the results in two cases that may be useful.

We provide new and novel ideas for the treatment of conditions that are previously diagnosed as “EPM”.  Our work also makes sense of some of the most perplexing issues surrounding S. neurona sarcocystosis. Our papers are published and available to everyone.  You may give us a call for guidance with these cases, however to support our work and our time, we ask that you please submit samples for testing.  Our test results and responses to our protocols provides us with information that can lead to new treatments for these very complicated diseases.  There are few veterinarians working and publishing in this area. Supporting our work guarantees there will be more options in the pipeline.

blue day before oroquinInfection with Sarcocystis is called sarcocystosis. Equine sarcocystosis, or equine protozoal myeloencephalitis (EPM), is an infection by protozoa that results in inflammation of the nervous tissues.  These parasites can sometimes be found in the central nervous system (CNS) although inflammation can cause signs without the parasite entering the CNS.  Note that EPM is a syndrome, it is caused by infection and inflammation. Infection causes a variety of signs that include muscular disease and neurological dysfunction. Sarcocystosis can be chronic in horses, those that undergo treatment frequently relapse. Relapse is most likely due to re-exposure of the protozoa in the feed or environment.

There are two protozoa that infect horses, Sarcocystis neurona and Sarcocystis fayeri. The horse is a natural host for S fayeri and may be less inflammatory that S neurona.  The horse is not a natural host for S neurona, the infection is called aberrant. Both of these organisms can cause clinical signs that look like EPM. There are tests to detect infections and exposure to these organisms. 2016 S fayeri

Protozoal infection stimulates immunity in the horse.  Innate (cellular) responses that trigger specific defensive pathways are activated quickly. These pathways remain active as long as the infectious stimulus is present.  Sometimes, these pathways become chronic by creating a “feedback” loop.  The innate response stimulates the production of proinflammatory  molecules, these molecules feed a signal to initiate the inflammatory reaction again, hence the results of  starting inflammation can be a chronic cycle.  These pathways are not specific.  Any infection can stimulate the initial response. Normally, when the infection is treated effectively the protective responses turn off.  Chronic inflammation is a dysfunction of the immune system.

We test for the presence of proinflammatory molecules found in the blood stream.  This is useful and an adjunct to other tests that are specific.  In our laboratory we quantitate C-reactive protein (CRP) to identify the extent of the pro-inflammatory pathway.  Values are measured from 0-99.  An absolute value isn’t as valuable as evaluating a trend.  A value that is above 16 is abnormal.  Values that are above 39 are statistically significant and suggest the clinical signs are due to inflammation related to specific conditions that we can also detect.

Another type of immune response to protozoal infection is acquired immunity.  Acquired immune responses result in specific antibodies and memory cells that target the infection.  When the horse gets re-infected, memory cells are primed and ready to act faster that in the initial insult.  Re-infected horses are “experienced” with the infecting organism, whereas a horse with no experience is called “naïve”. Antibodies against S. neurona are used to link a causal agent with clinical signs seen in horses with EPM.  Similarly, S. fayeri  produces antibodies in horses.  We can use different tests to distinguish between S. neurona and S. fayeri  infections.

Opossum_03-HangingBranchThe horse acquires Sarcocystis neurona by eating hay or feed that is contaminated with neurona-infected opossum feces. Opossums are the definitive host.  Definitive hosts exclusively produce the infective stage of Sarcocystis.  The infectious “eggs” (sporocysts) hold sporozoites that are short-lived in the horses’ intestine. There are three serotypes of S. neurona that can cause sarcocystosis in horses.  Often, the opossum is infected with multiple serotypes!  Dogs are definitive hosts for S. fayeri . Horses are infected by eating hay or feed that is contaminated with fayeri-infected dog feces.  It was long thought that S. fayeri   infections in horses were benign, unless a horse was debilitated from starvation or another disease.  Up to one third of horses in the United States are infected with S. fayeri.

The horse is an unnatural host for S. neurona.  After the initial infection, the parasite goes through its life cycles: sporozoitesbovine produce 1st generation merozoites and this stage kills host cells. First generation merozoites mature and produce 2nd generation merozoites.  These second generation merozoites must enter muscle cells and turn into cysts.  The horse is an unfriendly host to neurona merozoites and S. neurona is unable to make cysts. The horse is very friendly to S. fayeri and the second generation fayeri merozoites encyst in muscles. The cysts eventually mature and die and this is when they release toxins that result in inflammatory reactions.

The horse responds to both Sarcocystis infections by innate immunity.  Elevated CRP levels are seen in both diseases. In fact, the horse can look normal and have an elevated CRP.  This is called sub-clinical inflammatory disease. Sporozoites of Sarcocystis don’t produce enough identifying molecules to simulate acquired immunity.  The acquired immune response to S. neurona is elicited by the merozoitesSometimes, as disease progresses or with some treatments, these organisms can hide the molecules that stimulate antibodies. However, if first generation merozoites are being produced from sporozoites, antibodies will be stimulated to the “new” infection, even if the infection doesn’t progress from the gut into the blood stream of the horse.

The foregoing is a description of the pathogenesis of sarcocystosis in horses and can be used to understand the results of testing.  The disease process, from infection to immunity, was used to form our three disease model of EPM which are: 1) S. neurona sarcocystosis, 2) S. fayeri sarcocystosis, and 3) post- treatment EPM inflammatory syndrome (PTEDS).  Pathologic PTEDS progresses into the treatable autoimmune polyneuritis or a condition known as polyneuritis equi.

An elevated CRP concentration indicates inflammation.  If there are no apparent clinical signs when the sample was taken, the horse has “sub-clinical” disease.  An elevated CRP value, found along with antibodies to a specific organism (S. neurona, S. fayeri, or Borrelia, Lyme)…indicates there is active disease.  We associate elevated CRP values in horses without Sarcocystis antibodies with pathologic, chronic inflammation that results in autoimmune polyneuritis.

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.

“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.

A long held belief is that a horse with EPM has antibodies to Sarcocystis neurona. Along with that idea is that spinal fluid (CSF) can improve the diagnosis of EPM--logic says if one detects antibody made in the CNS then organisms must be there. The antibodies are a response to local infection. The discussion quickly proceeds to the antigens used to detect antibodies--which are are most useful? Not up for debate is the question of active versus past infections. We already know that no antibody test can make that distinction. And that is because Equine Protozoal Myeloencephalitis is a disease, a syndrome, with infection and inflammation and both need to be recognized and treated.

We know, by experiment, that using CSF along with serum antibodies does not enhance the diagnosis of clinical EPM. In several randomized, controlled, masked studies (using horses) we determined that there was no statistical significance when CSF was used to diagnose disease. We used serial serum and CSF tested by SAG 1 ELISA (we used a SAG 1 challenge so that is our gold standard), and western blot (EBI, Lexington KY). Western blot was the test de jour and we added it to our testing to be complete.  We have discussed that topic in prior posts.

Another factor affecting antibody as a diagnostic aid is the horses’ prior history.  If a horse is naïve (the first infection) the antibody titer will be low and get higher as the infection continues.  An experienced horse, this is usually an older animal, develops a higher titer in a shorter period of time.  Antibody is detected by day 17 after infection.  These observations were statistically significant in randomized, controlled, masked studies (using horses).  We also know, and have discussed, that treatment (with triazine drugs) will delay an antibody response, again observed in randomized, controlled, masked studies. It takes very little drug to delay an antibody response, the serum levels are posted on our archived web page.  We suspect that other antiprotozoal drugs have the same quelling effect on antibody (but not clinical signs) but the data has not been published.  These confounding factors (an animals exposure and treatment history) change our diagnostic decision tree.

The first factor we look at is the exposure to antiprotozoal drugs.  Classically, the animal would not have a treatment history (and that would have to include no other animal served as an environmental contaminator).  When we look at submission forms a treatment history is included, but we are unsure of low level drug exposure.  The next most important factor is the presence of clinical signs.  If there are no antibodies (on our test a titer of <8) we look for a treatment response and recheck the horse at the end of treatment.  If there is a treatment response and no rise in titer we give a tentative diagnosis treatment-responsive inflammation.  Horses that respond to treatment a fourfold rise in titer increases the probability signs were due to active S. neurona.

Of course our diagnostic job is easier if the horse starts with an antibody titer (on our test >8).  If we see a response to treatment we just like to look for antibody again in 6-8 weeks to make sure the levels are <2 (on our test).  If we get a partial--or no response to treatment we look to inflammatory disease or seek other causes of the clinical signs.  A young horse (<2 would be a candidate for neck radiographs while an old horse would be a candidate for vitamin E treatment for equine motor neuron disease).  The expertise of the field veterinarian is important here.

The other half of our decision tree deals with inflammatory disease.  We use C-reactive protein, and in some instances serum IL6, to decide what the treatment steps are going forward.  A response to treatment indicates treatment-responsive inflammation--with or without S. neurona infection.  This is when an antibody response is useful developing a treatment plan.  When there is a treatment response and the CRP is falling to normal levels (we need serial testing to determine this) our follow up treatment if there are more issues.

The situation in which there is no response to treatment, the gait score is >2 and deteriorating, with a serum CRP concentration of >16 micrograms per ml further drastic measures are in order.  The first thing we try is using a treatment for encysted small strongyles that has good efficacy for this stage of parasite and rechecking the CRP in 7 days after de-worming.  In a few cases treating for Lyme, despite a negative test run at Cornell, has improved  horses clinical signs.  Sadly, in the other cases, we hit a dead end.  These cases are rare for us .03% of the submissions.  It may be useful to do a standing nerve biopsy.  A pre-mortem diagnosis can confirm untreatable disease in some of these horses.

What makes our approach to analysis of a case different is our first question—treatment--we don’t start our analysis with antibody—the confounding factors are too complex.  We start with treatment history and move to treatment response.  The serum testing is invaluable and is in our analysis so testing is critical and adds to our analysis.  The CRP is useful, it changes our treatment decisions in many cases.