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Google is helping us with our work on equine protozoal myeloencephalitis (EPM) and polyneuritis equi (PNE), two important neurodegenerative diseases that affect horses. The Google questionnaire will help you, and us, with our ongoing work in this important field.

Does your horse have a neurodegenerative disease? These two forms are useful to tell us what is going on with the horse.

The  “Neurology Case Analysis for the Horse Owner” https://forms.gle/66qMFW8d2bCvxprq6 and “Neurology Case Analysis for the Veterinarian” https://forms.gle/LiVQR6zydeRTkVELA

If you have tested a horse by sending us a sample, we would like you to update our records.  To update the file please use this link to the form: https://forms.gle/HVzzLbezHDtjU1N18 Our records go back to 2001!  Your experiences are important to us, by updating our records you help us direct our attention to new research possibilities. Good communication led us to new diagnostics and novel treatment of PNE!

Any horse that was treated for EPM can give us valuable information.  If a sample was submitted to us and the horse was treated, please use this form to update us:https://forms.gle/CQcFqYsRjZbB8y196.  Remember, to have a horse in our records we must have a consult request from the veterinarian. The consult request was by the veterinarian.

Another form that is useful evaluates horses with a history of extended use of drugs.  This can be an important part of field safety evaluations.  To update us, please use this link: https://forms.gle/9dPR2nU5uoE7591i7

We have several ongoing studies that are useful for evaluating and licensing new therapies for horses.  To look at the inclusion criteria for a horse these links will take you to the proper form: If you treated with any product for EPM and the horse didn’t resolve the signs or has relapsed, use this link: https://forms.gle/rwUo6Tyfc7N9omTS6 and if your veterinarian suspects polyneuritis equi, use this study link https://forms.gle/fwDTrUfj25SK1aLe7

We hope you find these forms useful.

When does polyneuritis equi (PNE) begin in a horse? A polyneuropathy manifests in a horse that is susceptible to the disease.  Which horses are susceptible? Horses that are particularly “inflammatory” or a horse that is allergic to vaccines, even a horse with endocrine issues.  Some horses that contract a virus can succumb.  Once typical signs are present, the disease can be recognized.  But what about the pre-symptomatic phase, what does that look like in a horse with PNE? 

Biomarkers could identify the earliest stage of PNE, if one were looking. At this stage the horse doesn’t have any outward appearance that there is anything wrong, and if you could ask, the horse would agree, all is well.  At this phase it is entirely possible the horse clears the inflammatory issue, probably most of them do regain health and that is why this disease is so rare.

A few horses will start to show early signs of polyneuritis and these signs can be detected, although they are often attributed to other causes-like protozoal infections, EPM. The signs can be so subtle that an owner feels like there is something wrong but they can’t quite put a finger on it.  In human disease the period between possible symptoms/signs and definite symptoms/signs is called prodromal.  Once there is “phenoconversion” and the horse leaves the prodromal phase then enters the symptomatic phase, it isn’t hard to recognize the clinical presentation as PNE.

What is the duration of the sub-clinical phase of disease, the disease is present but there aren’t any outward signs? Polyneuritis equi is a rare neuromuscular disease that is difficult to recognize in the field even when clinical signs are present.  We think a field diagnosis is difficult because it isn’t a disease that is forefront on a clinicians differential diagnostic list.  As in other neurological disease syndromes, ones choice of descriptions has shaped concepts and paradigms in PNE-and that is that the disease is untreatable. Our work concentrates in early diagnosis and treatment options for horses with PNE because this is the meerkattime that damage isn’t permanent and the horse can be returned to normal. Veterinary training and the literature describe end-stage disease. Unfortunately, little can be done in the late stages, hence the grim prognosis and current recommendation of euthanasia.

It is our hope to change the way clinicians think about and diagnose PNE; that would change the paradigm.  It would change the outcome. Paradigm-changing is a step-wise process.  We spent years getting our ideas and research studies completed.  Now we will complete a clinical effectiveness trial on horses recognized with PNE, and many of these will be end-stage.  The study will allow us to collect effectiveness data and define biomarkers to detect treatable disease.  The goal is to use biomarkers in a second effectiveness study.  All the data will help us get answers to more questions. Can there be a genetic pre-disposition to disease?  Is disease caused by a specific virus or microbial agent?  Is it possible that environmental exposure to an “agent” is the inciting cause?  A useful strategy to study PNE is to define a population of horses that have a high likelihood of developing PNE.  can we define that population? You see, to change what’s ahead one has to continually look in a different direction. 

We will be sending out requests to veterinarians and owners that have cases suitable for our effectiveness field trial.  There are some criteria that make sure the horse can be included in the trial.  We can answer questions for you, if you think you have a horse with PNE. We will provide study medications at no cost and we will pay for some of the pre-entrance testing.  We need you to help us change the PNE paradigm.

 

blogger-image--213779556If you search the literature you will quickly realize that polyneuritis equi (PNE) has a grim prognosis. The prognosis is poor because there are no recognized treatments. Only palliative care and euthanasia are offered as the standard of care for the PNE horse.  It is our goal to change that with our Hope Initiative.

We began to recognize a pattern in horses with neuromuscular disease and a literature search led us to papers published in the 1980’s.   One paper authored by Fordyce gave specific signs used to evaluate horses with putative PNE and led to the Fordyce Score.  We found quite a bit of research done  in horses relating to PNE. The disease is rare and presents clinically with diffuse involvement of extradural nerve roots of multiple peripheral nerves. The pathology is a polyneuropathy characterized by  inflammation  and demyelination.  PNE has no known single cause.   The inflammatory process may initiate primary or secondary demyelination of nerves by a “bystander mechanism” where any antigen that reaches the peripheral nervous system attracts and activates lymphocytes and macrophages.  We’ve reviewed the topic for you in our eBook Polyneuritis explained, available on Amazon for $4.99. The disease may be reversed if it is caught early and remyelination of the nerves can restore function.

A spectrum of signs can be recognized in PNE-horses and careful case analysis gave us the heads-up that treatment may be initiated before chronic demyelination progressed to end-stage disease.  That’s when  we knew that a horse can recover from PNE.  We were surprised to find that the literature described a diagnostic test for myelin protein antibodies many years ago.  The presence of these antibodies were related to disease.  The molecular structure of myelin was determined and the immune-mediated process was determined experimentally in animals.  Some tweaks in the diagnostic protocol were needed, using a recombinant protein avoided non-specificity issues and folding  the protein into its native state was necessary to make the test useful.  Finally, epitope mapping was highly illuminating to understand the pathogenesis of disease.

We’re developing a  licensed treatment.  Our  next step  is a field effectiveness study.  A (any breed) horse that is between 2 and 30 years old , 605-2420 pounds and shows signs of PNE with a Fordyce score of 4 is considered eligible.  There are some other restrictions, and qualification to receive medication is made on a case-by-case basis. Some testing is required, horses need to be negative for sarcocystosis by serum analysis and the possibility of trauma is ruled out by examination, history, or radiography.  Your  veterinarian can use endoscopic exam or radiographs to rule out osteoarthropathy. Vaccinations must be current (within a year) and include rabies, EEE, WEE, and WNV. Of course, before starting any medications a serum chemistry and CBC should be done.

Some of the other qualifications are: the horse is expected to be manageable and cooperative with handling, examinations, and the owner is able to give medications daily.  The study involves a two week treatment and two clinical examinations made by your veterinarian.  The owner will need to fill out a  checklist each day the horse receives the medication and this checklist is how we evaluate the response to treatment.  If you are unsure that  your horse qualifies based on the clinical signs you are seeing, you can email us or use the following  links, answer some questions, and we’ll get back to you. https://forms.gle/cjTLUwMt4fqhovo77

You may already know, based on your experience, that your horse shows signs of PNE, or your veterinarian has made the diagnosis. This link is useful to determine the Fordyce score and eligibility for the study: https://forms.gle/jcuTjM4RoQUEip6q7

You or someone you know may love a horse suffering from PNE, tell them to contact us and join our Initiative to give hope to horses suffering with PNE.  blogger-image-702499765

We’ve been reading a lot about amyotrophic lateral sclerosis (ALS) lately.  One thing is abundantly clear and that is there will be no single treatment to cure this disease.  There are inherited forms of ALS, fALS, and then there are sporadic cases, sALS. Our take on the overall picture of ALS is that no matter the inciting event at some point there is a final common pathway…that is inflammation.

Dogs get late onset fALS.  We suspect horses get fALS as well.  Is someone looking for it?  It would be very rare and most likely, with no treatment options, the horse would be euthanized before a clinician would think of ALS. Horses get subclinical inflammation presenting as a peripheral neuropathy.  After some time passes the neuromuscular disease progresses to the lower motor neurons (polyneuritis equi) and then it affects the upper motor neurons if the horse lives long enough. Diagnosis is the big issue here, to recognize a case of equine ALS.

The sporadic form of ALS seems more insidious…the sub-clinical pathways probably take a long time to surface into clinical disease.  The dysregulated systems that are forefront in human fALS are being targeted with specific small molecules-it is unlikely they will target sALS patients.  Even after years of failed attempts to find the cure for ALS the approach is the same: one path-one drug. New molecules come along, and so far they failed, even if they showed promise in mice that develop ALS.

The newest platform is skipping the animal step and moving right into people with promising drugs or small molecules. The entry criteria for the studies using novel small molecules targeting fALS are not available to sALS.  The treatments are super expensive. These approaches will never translate into an equine therapy.

Back to our hypothesis that it will take multiple drugs to combat presumptive equine ALS (eALS).  And this is a huge problem.  If one decided on a cocktail that was effective, the licensing process for the therapy would be impossible to get through FDA.  The effectiveness trial is mind boggling…we are suggesting the cocktail may involve 5 drugs at a minimum. The safety trial alone would cost at least a million dollars, our one-drug safety trial was nearly a half-million alone.

How does one start to evaluate therapeutic cocktails for a rare disease such as ALS?   Initially an animal model of the disease is necessary.  And a non-subjective test to evaluate if the disease is present in the animal.  And then one needs to identify the drugs that could be beneficial based on a firm understanding of the disease process. After all this is complete, it would be possible to approach FDA.

After our experiences with a simple and direct treatment using two well known drugs with specific actions for a specific disease with a defined and useful animal model, we can absolutely say the task for licensing a putative five drug ALS cocktail is insurmountable.

Ah, but a man’s reach should exceed his grasp, Or what’s a heaven for? (Robert Browning)

We have an approach that just may be doable.  And that is finding single therapies that hit multiple targets.  Our idea will rest upon finding a useful diagnostic test to ascertain effectiveness.  We aren’t afraid to try our approach in ALS models and compare the results to multiple drugs that target dysfunctional ALS pathways. Of course, testing multiple drugs together is a huge step that is outside the box thinking.  Out of the box thinking is what it will take to tackle ALS.

Our reach is big.  We’ll let you know how it goes.

Scoring systems are useful to evaluate humans and animals.  The well known APGAR score is a test given to newborns soon after birth.  This test checks a baby’s heart rate, muscle tone, and other signs to see if extra medical care is needed.  The test is given at one minute after birth and again five minutes after birth. Another well known scoring system is the Mayhew Score, or more often the “Modified Mayhew Score”, that is intended to evaluate horses for equine protozoal myeloencephalitis.  The Mayhew Score differentiates upper motor neuron diseases from lower motor neuron diseases using an extensive neurological examination.  The scoring system allows the clinician to form a differential diagnosis list. Scoring systems are generally named for the author of the system.

The Fordyce Score is a system described by Fordyce, Edington, Bridges, Wright, and Edwards in 1987 that was designed to evaluate horses with cauda equina neuritis (polyneuritis equi, PNE) and differentiate PNE from other equine neuropathies by ELISA.

Polyneuritis equi is a condition with some specific characteristics that are paralysis of the tail, bladder, rectum and the anal and urethra sphincters, accompanied by an area of analgesia (loss of response to stimulus)  around the perineal region.  Muscle wasting is common over the hindquarters and the horse can have an uneven gait. Cranial nerves can be involved and characterized by a drooping lip and ears, inability to blink and atrophy of chewing muscles, although signs can involve other cranial nerves as well.

Because the pathology of PNE is inflammation of the nerve roots that form the cauda equina and any other peripheral nerves that are involved, it was common to examine affected nerves by histopathology.  Histopathology was used because horses were not diagnosed until late stage disease and euthanasia was the recommendation. The Fordyce team recognized that antibody against the animals own myelin protein could be measured pre-mortem using an ELISA test.  The first scientists to recognize that there were circulating antimyelin protein antibodies in experimental allergic neuritis in rats, was the Kadlubowski Group in 1980.  And in 1981, they recognized the same condition in horses with PNE.

Molecular techniques in the 1990’s allowed researchers to refine the antigens used to analyze serum samples.  This was important because laboratories that used a crude mix of myelin protein from horse spinal nerve tissues in their assays got varied results. The P2 myelin protein is the required  molecule and then it needs to be presented in its native form.  Rostami and Gregorian mapped the myelin P2 protein epitopes (short amino acid sequences that are reactive to the immune system) and showed that a small piece (peptide) of the protein caused an autoimmune reaction that appeared later in the course of disease.  The difference between the whole P2 protein antibody reaction and the peptide antibody reaction was that animals became refractory; they stopped responding to the epitopes on the whole P2 protein.  They stopped responding even when clinical disease was apparent.  Yet if the peptide was stimulating the animals’ immune system, they did not become refractory.

The animal isn’t a bystander in this disease.  The horse will heal the peripheral nerves because the cells that lay down more myelin (Schwann cells) are not compromised.  It is the degree of inflammation that can get out of control in late, irreversible disease.  In chronic disease the horse will heal (scar) the damaged nerves using fibrosis or calcium.  These healed nerves can’t conduct messages to the muscles that they innervate.  As the myelin is sequestered from the immune system the anti-myelin protein antibodies fade from disuse. This leaves the horse with end stage disease.  Thus there is a progression of anti P2 antibodies in the serum.  There will be no antibodies early in disease, as disease progresses antibodies are present, and finally, antibodies are absent in late disease due to the healing process.

Another IMG_0550reason for inconsistent assay results from some researchers was the selection of cases.  Because cases selected for study were end-stage it would not be expected that all horses would be seropositive on their ELISA assay.  A more uniform selection of cases can lend validity to the anti-myelin P2 serum assay and Fordyce was the first researcher to do this.  Fordyce clinically assessed animals for PNE giving one point to each of the following signs: tail paralysis, urine drippling, rectal dysfunction, perineal analgesia, muscle wastage over the hindquarters and any sign associated with a cranial nerve neuropathy, ear droop, inability to blink and masticatory muscle wastage (see picture). Fordyce considered a score of 4 or greater was consistent with PNE. Fordyce correlated 12 of 14 seropositive cases  (titer at 1 to 8) that were considered to have PNE based on clinical score and/or post mortem criteria .  These were gold standard cases. One horse had shivers and seroconverted to negative after 5 months. Thirteen horses with non-PNE neuropathies and 20 control negative sera were seronegative on the assay. Fordyce concluded that the presence of antibody to P2 in horses suffering from PNE is useful as a diagnostic for PNE.

We agree with Fordyce and have fine-tuned the anti-myelin protein P2 assay (MP2)  to include that small peptide (myelin protein 2 peptide, MPP) discovered a few years after his work was published. We believe that the value of a combined assay (MP2 and MPP) will allow us to measure the duration of the condition, if not the severity. The advantage to a diagnostic test is recognizing disease before it is late stage and irreversible. A diagnostic test will enable researchers to find effective treatments.  Let us know how you find the utility of the Fordyce Score system in your evaluation of equine neuropathies.  Call us to find out more about serum testing in these cases.