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sidewinder3 (2)Horses with neuromuscular disease that are unresponsive to the usual treatments can be frustrating for veterinarians and horse owners. This post encourages you to get in touch with us if you have a horse with "EPM" and is not responding to treatment. ELISA Submission Form

 

We are following 38 horses that have clinical signs consistent with polyneuritis equi or cauda equina neuritis, an often overlooked syndrome associated with EPM. Our goal is to develop a treatment protocol for veterinarians dealing with these cases. Sometimes these horses are weak on one side, they have hemiparesis, and that prevents them from tracking normally.  The weak rear end falls to the weak side.  A commonly used descriptive term is "sidewinder". Ellison 2015 MPP MP2 Assay

There are other clinical signs of this disease.  Dragging limbs, tripping, or even drooling and dropping feed (cranial nerve dysfunction) are observed. The tongue can be atonic.  Another sign in these horses can be dripping urine or an inability to empty the bladder.  The most common comment in the history is multiple EPM treatments. We developed tests that can lead to a diagnosis of polyneuritis equi. Pathogenes Testing Options

Historically, the distinction between polyneuritis equi and cauda equina neuritis was the presence of cranial nerve involvement.  Discerning the disease by cranial nerve signs may not be accurate because horses with cauda equina may also have cranial nerve deficits.  In terminal cauda equina, horses are unable to urinate and often colic.  We don’t distinguish the two diseases by cranial nerve function because the owners and veterinarians involved with the horses we track often report difficulties with chewing, droopy lips, or facial muscle atrophy. These signs are often responsive to specific treatment.

Two serum tests, MPP and MP2,  measure anti-myelin protein antibodies.  Horses with polyneuritis equi often have circulating antibodies that are reactive against myelin protein and/or a reactive site on myelin.  The presence of antibodies are evidence that an autoimmune reaction is involved in the disease process.  A positive test can assist in diagnosis and potentially life-saving treatment.  2015 EPM and MPP

Eventually we think we will be able to stage to degree of damage using these tests. The C-reactive protein assay (CRP) may be the most useful test for case monitoring after a diagnosis is made.  The CRP assay is useful because response to treatment precedes a reduction in the pathologic inflammatory cycle. It may be that polyneuritis is the early stages of disease that ends in cauda equina syndrome.  That is to say, chronic idiopathic polyneuritis left untreated will eventually develop into clinical cauda equina.

If we understand the disease process correctly, it may be possible to prevent the progression of disease.  We are following the clinical course of 38 horses, their therapy, and the outcome of treatment.  We are assembling the data for a statistical analysis of the diagnostic and treatment options.  This data-based approach will be very useful to veterinarians trying to manage these horses.  The long game is devising a standard treatment protocol for afflicted horses to keep them healthy,  but we are not there yet.

Recently Dr. H. wrote a quick email asking if it was concerning that the CRP (C-reactive protein) level remained elevated in his patient, a 7 year old mare with a 3-year history of relapsing disease.  The good news is that she is currently clinically great while receiving treatment.  He wanted to know what is next.  What can be expected?  Unfortunately for Dr. H.,  we don’t have all the answers.  We sent back all the variables, the possibilities, and the literature he could review to make his clinical decisions.

Dr. Laura Benedetti is busy contacting veterinarians, asking for gait scores to update our records and requesting blood samples on the horses we’ve identified that could have this condition.  She answers emails about polyneuritis equi.  What is missing from the process is a forum for owners to discuss their horses with other owners similarly diagnosed horses.  While there are numerous forums and posts about individual horses with suspected EPM, these sites aren’t that useful for those facing a polyneuritis equi diagnosis for their horse.

We were pleased with the support offered to Taylor Lin (Blaze was posted on January 22 at Pathogenes Inc. Facebook), who initially felt alone before finding others who had been there before and kindly posted comments.

Horses with polyneuritis equi and cauda equina should receive a potential diagnosis and an individualized treatment protocol based on data that includes clinical examination by a veterinarian and laboratory testing.  Sub-clinical disease is an important aspect of chronic idiopathic polyneuritis. Dr. H’s mare  looks great and is performing well.  However, serum testing indicates she still has disease that needs to be treated.  Often the CRP can be used determine an endpoint to treatment.

We welcome you to post your questions and observations on Pathogenes Inc. Facebook page.  The information will be useful for others facing this disease in their horse.  Pictures and short videos are also welcome.  Individual treatment options are discussed privately with veterinarians because these need to be tailored to the specific 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 horse is evaluated for muscle wasting, an abnormal gait, and paralysis/paresis of limbs and or cranial nerves and given a presumptive diagnosis of equine protozoal myeloencephalitis.  This horse may or may not be positive on tests that measure antibodies to S. neurona, most commonly it will test positive.  What can be confusing is that the horse can improve with treatment.  And sometimes the horse will improve without treatment.  Often horses with this clinical presentation relapse.

We may have found a link between these chronic-relapsing EPM-suspect horses and polyneuritis equi.  The etiology of polyneuritis equi is unknown but is generally considered an immune-mediated peripheral polyneuritis.  Serum antibodies against equine myelin proteins are found in horses with polyneuritis equi, the test was developed in England decades ago. The relapsing signs are related to demyelination followed by re-myelination of the nerves.  Eventually the auto-immune polyneuritis horses succumb to the disease because the inability to urinate or control bowel function are untreatable.

The link between EPM and immune-mediated clinical signs were discussed more than 14 years ago.  In 2002 researchers at Ohio State (Soflay, Reed, and others) considered cytokine mediated neuropathy in explaining their clinical observations in S. neurona challenged horses that did not have parasites in the CNS.  Inflammatory lesions in the CNS were the criteria for validation sample selection for “EPM” tests.  And that is the issue with “EPM” tests.  We stand our ground that antibody tests detect Sarcocysis antibodies and some antibodies are specific for S. neurona.  EPM is related to S. neurona antibodies but the inflammatory component of disease is not, and by definition a horse with EPM has clinical signs-and by all indications the clinical signs are due to inflammation.  And some of these horses may have polyneuritis equi.  And perhaps S. neurona is one etiology of polyneuritis equi.

What did we show in our more recent studies?  First, we determined that serum antibodies against a reactive site of equine myelin protein 2 that is linked to polyneuritis equi are found in horses with a diagnosis of EPM.  Possibly there is an IL6 reactive site on the disease producing region of equine myelin 2.  Drugs that decrease the synthesis of IL6 can reduce or eliminate clinical signs of disease due to inflammation.

Proteomics is the study of genes (sequences) and how they function.  The tests that we used in our proteomic studies are useful in clinical cases. The clinical cases we examined take us back to the CRP levels in horses. We found the higher the CRP value the more likely the horse has anti-equine myelin proteins.  Now we want to relate our observations to IL6 mediated polyneuropathy.  That would allow us to associate the IL6 pro-inflammatory pathway to disease in horses.  It may take a few more months of experiment to predict outcome of cases with our new tests.  What we can do now is more completely evaluate inflammation by a serum test and discuss our work and how it may affect your case.

Diagnosing an autoimmune reaction in a sidewinding horse can lead to effective treatment!  Pathogenes Testing Options

Sidewinder is a term that describes the clinical presentation of a horse with a unilateral weakness/hemiparesis causing the hind quarter to track either side of the front quarter. Cauda equina neuritis (CEN) is an uncommon condition in the horse clinically characterized by paresis/paralysis of the tail, rectum, and bladder and a loss of sensation in the sacral dermatome with a surrounding zone of hyperesthesia and can be seen in sidewinding horses. Frequently, CEN is associated with cranial nerve paralysis, hindquarter muscle wasting, and an abnormal gait.

The disease in sidewinders describes a syndrome with characteristic clinical signs, predictable outcomes, and no recognized necropsy findings.  It is termed idiopathic. Often clinical signs are due to peripheral and central nervous system (CNS) inflammation, central lesions may indicate the presence of encephalomyelitis. The inflammatory pathological lesions of CEN is similar to those described in allergic neuritis. Experimental allergic encephalitis (EAE) is an induced autoimmune disease of the CNS that is readily induced in many mammalian species by immunization with CNS tissues.

Horses with serum antibody to specific proteins correlate well with clinical and pathologically diagnosed disease and indicate the pathogenesis of disease is immune mediated. The purpose of our current investigation is to determine the presence of antibodies against specific proteins in serum of horses with a diagnosis of idiopathic encephalomyelitis that present with a sidewinding gait. Give us a call to see if your case qualifies for free testing.  We may have your sample on file if it was submitted within the last 6 months, if we tested your horse for S. neurona antibody, that was clinically a sidewinder, we will go back and run our new test on the saved serum.

Several things are important to us.  The degree of disease based on the modified Rostami scale (a number between 0 and 3).  The score is 0 = a normal animal; 1 = is mild (more than 5% weight loss and a flaccid tail; 2 = moderate; and 3= severe with paraplegia or tetraplegia; a typical sidewinding gait.  The distinction between a central and peripheral lesion that is causing the signs is an important factor in diagnosis and treatment expectations.  While there can be both central and peripheral lesions, we want to discriminate between the two populations of horses if a distinction exists.

Email us the answer to the following questions (give a numerical score for the first assessment; circle the presence of any other signs) :

  • Clinical assessment (numerical score)
  • Ataxic, gait anomaly, sidewinder
  • Weight loss
  • Signs attributable to central lesion
  • Behavior change
  • Muscle wasting: back muscles
  • Muscle wasting: gluteal
  • Muscle wasting: masseter muscles
  • Tail paresis
  • Urinary incontinence
  • Rectal dysfunction
  • Perianal analgesia
  • Cranial nerve neuropathy
  • Muzzle twist
  • Eye lid paresis
  • Facial paresis

Update: 2018 ELISA Submission Form

Determining the cause of polyneuritis equi and autoimmune polyneuritis may be possible.  There are no published protocols for polyneuritis equi, our treatment protocol is available to veterinarians when they are faced with a horse with antibodies against myelin protein.  Our next step is in staging disease.  Our autoimmune tests, MPP/MP2 can help us do that.  Call for details.

 

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.