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Autoimmune Polyneuritis

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.