We are not new to polyneuritis. The first experimentally induced cases we saw were in 2001 while testing a medication for Bayer Animal Health. It was surprising to all the veterinarians observing the horses the treated cohorts showed more severe clinical signs than the untreated, infected controls. It was confusing, especially to those wanting to prove effectiveness of a therapy.
To figure out what was going on, we conducted an extensive literature search. That led us to myelin basic protein, allergic encephalomyelitis, and encephalitogens. The literature introduced us to Dr. Kadlubowski and Ingram (1981) and later on Dr. Fordyce, an English researcher that used an enzyme linked immunosorbent assay (ELISA) to examine cauda equina neuritis (the early name for polyneuritis equi, PNE) and other equine neuropathies. His test detected 100% of the PNE cases he tested!
You might wonder why his ELISA didn’t rise to fame. Spoiler alert: it was technology. At the time, 1987, researchers used solubilized bovine or equine spinal tissues in the assay. That solubilized protein isn’t specific enough to get good results. Equine researchers tried the test, they also used myelin protein derived from spinal cord tissues and couldn’t diagnose PNE.
They injected horses with myelin protein in an effort to create disease, alas they didn’t see experimental PNE. Based on discussions at meetings these folks say the test has no value. I think they should qualify their comments and say “In our hands…”. The test works well in our hands, we used the newest molecular tools that were published. We ran the first polyneuritis test in our lab in 2014. We weren’t the first so we didn't invent it.
Refining the PNE diagnostic test
By the time we took an interest in using an ELISA to identify horses with signs of PNE, human research had advanced the tools we could use. Myelin protein 2 (MP2) was associated with some human neurological diseases, the protein was the same as that in horses, thus horse tissue became the gold standard used in the laboratories. Molecular biologists identified a small region on the MP2 protein that not only induced experimental allergic encephalitis, but the end of the molecule had an IL6 (inflammatory cytokine) receptor.
Homogenized spinal tissues gave way to MP2 recombinant proteins when the structure was published in 2005. The reactive part of the molecule, we call it MPP, was particularly interesting. We discovered a way to decrease expression of the IL6 receptor found on MP2. If we removed the receptor, we theorized, we may change the course of the disease. Unfortunately, the test described by Fordyce, that had piqued equine veterinarians interest, was left on the cutting room floor.
A left over part of the PNE research was the scoring system Fordyce used in his paper. He was looking at end-stage disease. And when we needed to identify horses with PNE before death, the Fordyce Score was considered the standard by The Agency (FDA) . Of course, we want to identify horses before they are in end-stage disease, and the ELISA may accomplish that. We are working to prove that. Another test we use is a neurofilament assay, it may do what we want and identify horses before they have immune mediated disease.
Clinical signs of PNE
Polyneuritis equi is a condition characterized by paresis of the tail, bladder, rectum, and the anal and urethral sphincters. Paresis or paralysis is accompanied by analgesia over the perineal region. Muscle wasting and an uneven gait can be seen. Cranial nerves can be involved. You will see a drooping lip or ears, inability to blink and wasting of chewing muscles. The experimental cases showed hypersensitivity in the skin over the neck and body, behavior changes, changes in vocalization, weakness, and chewing disorders.
The prognosis for PNE is poor for all animals and the current recommendations are to euthanize the horses. Post-mortem lesions in early cases show no macroscopic abnormalities. Histopathology will show demyelination and infiltration with lymphocytes, plasma cells and macrophages. Remyelination is observed. The early attempts at nerve regeneration suggest that if the inflammatory response is controlled early in the course of PNE, that treatment is possible.
In more advanced cases, the affected nerves are enlarged, firm, and nerve fibers degenerate. Both early and advanced lesions may be found in different parts of the same nerve, in different nerves of the same horse, and some peripheral nerves remain unaffected. Scaring, calcification, or fibrotic responses may hide the myelin proteins from the immune system, this is an important point when evaluating antibodies against MP2 or MPP. In late stage, untreatable disease the antibody test will be negative. It is useful to use serial testing and monitor the changes in antibodies. We can teach you how to do that and why.
There is an interesting and clinically relevant paper written by Conti et al (1992) and published in the Journal of Neuroimmunology. Briefly, they say Schwann cells make myelin. These cells express FcϒRIII and FcϒRIII-mediated immune responses play a role in the pathophysiology of experimental allergic neuritis (PNE for this discussion). The expression of this receptor is markedly induced in the nerves and nerve roots during the period of maximal clinical deficit. It wasn’t proven (that was 30 years ago) but proposed, that there was a correlation with the FcϒRIII receptor and increased immune complex binding capacity by endoneurial macrophages and NK (natural killer) cells. If true, and we think it is, there would be additional treatment decisions.
Often horses are misdiagnosed as having EPM and they are treated with anti-protozoal drugs. These drugs are ineffective and horses “relapse”. PNE is a chronic, relapsing condition that is rare. Unfortunately, most horses in the United States have antibodies against S. neurona and that leads to improper treatment as disease progresses.
Useful History in PNE
PNE is a rare and chronic, relapsing condition. It may be useful to use the Fordyce scale to evaluate a horse presented for chronic neuromuscular disease. Clinical signs used by Fordyce were paresis, weakness of the tail; perianal analgesia (loss of sensation around the anus); dribbles or retains urine; any cranial nerve neuropathy with hindquarter atrophy; rectal dysfunction (retains feces); inability to blink; muscle wasting; masseter muscle atrophy; ear droop; seropositive P2; histopathological lesions (cauda equina) consistent with PNE.
A diagnosis is most satisfactory when there is a response to treatment. Diagnosing PNE, like most neurological diseases, is an exclusionary diagnosis. That means the veterinarian rules out other causes of neuromuscular diseases as a cause of the clinical signs.
The cause of PNE is unknown. The prevailing theory is that PNE is immune mediated. Likely an allergic neuritis that is a response to an antigen released by trauma, infection, or a post-infectious allergic neuritis. A single infectious cause is not yet identified. Because an infectious etiology is unidentified it was proposed that disease is due to a “by-stander” mechanism. The infectious organism is no longer present, but the immune responses remain unresolved. This may be true if FcϒRIII-mediated immune responses are induced and not resolved.
PNE is comparable in its pathogenesis and lesions to the human Guillian-Barre syndrome and its laboratory model, experimental allergic (autoimmune) neuritis. Similar associations between anti-myelin proteins and disease are made in humans with multiple sclerosis (MS).
We are conducting a clinical field effectiveness trial to bring a treatment to horses suffering from PNE. If you have a suspect case please give us a call.