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An encephalitogen is an agent that is capable of producing encephalitis. Encephalitis is caused by infections or allergic reactions. Cytokines, released by the host to fight pathologic agents, act as encephalitogens. The clinical presentation can be similar in central and peripheral events because cytokines act outside the brain on peripheral nerves using common mechanisms. The purpose of this discussion is to review some human research that can be applied to encephalitogens that we investigate and suggest how you can participate in our research.

Inflammation, when treated, can resolve or it can become chronic.  Chronic inflammation destroys tissue and can eventually remove insulating myelin protein from nerves.  Tissue damage isn’t necessarily permanent.  The body repairs the damaged protein along with or after the inflammatory cycle.  However, left long enough, the body will permanently bandage the area by laying down calcium.  Once calcium is deposited, the damage is permanent.

An antemortem biopsy sample from horses with disease can help us in several ways.  Skeletal muscle innervated by nerves arising from the cauda equina can show abnormalities that may help us further define polyneuritis equi. The types of cells present in disease can be characterized by special stains and molecular analysis. The long term goal of these types of analysis is to provide veterinarians with effective treatment protocols. Veterinarians can send a biopsy sample to us for a free analysis. We will analyze the tissues, archive the tissue samples, and publish the results. Please find the biopsy submission form on the testing page or follow this link: https://pathogenes.com/w/epm-testing/

New research shows the beneficial effects of non-toxic, non-steroidal treatments that could potentially improve neuroinflammation, protect from demyelination and axonal loss in people with multiple sclerosis (MS). We wonder if that is also true for horses with polyneuritis.  The advantage MS-researchers have in studying this complicated disease is a good animal model.  MS is hard to understand because small parts of protein molecules can trigger a cascade of common reactions and that makes it difficult to parse out cause and effect.

A disease that looks just like MS can be induced in laboratory animals: guinea pigs, mice and rats.  In some guinea pig and rat models, steroids make the signs worse.  Yet other studies report a decrease in pro-inflammatory cytokines suggesting a beneficial effect.

Once disease is induced in the mouse model, steroids reversed the pathology associated with the MS-like condition. Following oral steroid administration, mice lost the disease-associated clinical signs and regained normal motility.  In the mouse model, mice become ataxic with induced disease.  The mice relapsed following withdrawal of steroids, usually in less than two weeks. Polyneuritis equi is similar in pathology to MS in people (or another neurologic disease, Guillian Barre syndrome).

Horses with polyneuritis equi can show spontaneous remission early in the disease process.  [The MS mouse model is one in which spontaneous remission is not seen, leading to the conclusion remission in the signs was due to the steroid treatment.]  While steroids resolve disease signs, it is not long-term and the autoimmune process associated with the model disease is re-initiated with steroid withdrawal. An interesting finding is that the efficacy of the dose used in the studies was similar over a range of doses, although occasionally a mouse treated with the lowest dose did not respond to steroids.  The outcome of treatment of polyneuritis equi is generally poor and there are no published treatment protocols.

Scientists looked at the type of cells that responded to steroid treatment in the animals with induced MS.  A specific type of inflammation (infiltrate) was noted and it was accompanied by demyelination.  Following withdrawal of the steroid, there was a sharp rebound in the infiltrate that was initially observed. The researchers were left questioning the types of cells that were suppressed and what type of cells rebounded to cause the relapse. They focused on developing strategies for treating autoimmune disease by eliminating inflammatory cells produced in the initial response.  Their impression is that there are  pathogenic clones of cells responding from the host’s immune system and possibly target organs.  They also focus on inducing life-long antigen-specific immunological tolerance to prevent development or activation of new pathogenic clones, in other words, a vaccination. They concluded that steroids may provide a beneficial immunosuppressive effect.

So why are steroids not effective in horses with polyneuritis equi? In MS ,steroids are not curative because withdrawing steroids initiate clinical and pathological disease relapses that are accompanied by a return of the infiltrate reactive to the initial encephalitogen.  When they looked at all the data, they felt new autoantigen-specific clones (of cells) were prominent in the relapse, the term for this is epitope spread. The body was making new responses to the tissues.

If polyneuritis equi is stimulated by an organism, say Sarcocystis, then it becomes important to know if there is chronic exposure or if a one time infection caused disease.  These horses would react differently to treatment than for the antigen-associated autoimmunity.

Mouse-modelers also asked, What causes the clinical signs associated with the model? Is it the inflammation or the resultant pathology to the axons and myelin? Their data supported the concept that inflammatory cells, and the products they secrete, may be responsible for initiating and promoting the signs induced by the model. It is the immune response that caused disease. The mice completely recovered in the presence of existing lesions if that pathologic clone was absent. They suggest this is a direct influence of the lymphocytes, or their products, on the clinical signs of the disease.

Mice treated with steroids had less severe demyelination than untreated mice that already had disease or in mice with a relapse. There was less demyelination during remission suggesting that remyelination may have occurred in treated mice. The phenomenon of nerve regeneration or remyelination in a horse with polyneuritis equi was detected by histopathology and at the time, it was posed that enhanced regeneration could be possible if the inflammatory response was controlled early in the disease.

What does this mean to you and your horse?  Proteins that make up myelin are targets for immune responses in some diseases. The one we work with is MP2, myelin protein 2.  The pathogenicity of myelin proteins in human disease is envisioned because, in mice and rats and guinea pigs and horses, these proteins elicit an autoimmune response that leads to a disease that includes some degree of paralysis and motor impairment. The initial episode may become debilitating but most animals recover and are free of disease.  With time animals develop relapsing disease.

The widely held belief is that the basis for relapsing disease is a response to encephalitogens that are different that those there triggered the initial response, epitope spread, and was not detected in all studies. Researchers used mice to show that relapse was related only to the cells with the same specificity as the initial encephalitogen. They concluded with some encephalitogens epitopes don’t spread. Said another way, relapsing disease is due to the encephalitogen used to initiate the primary disease. Moreover, they could vaccinate and prevent relapses in mice. Because other researchers did demonstrate pathogenic epitope spread following encephalitogen-induced disease it is possible that outcome is dependent on the encephalitogen used to induce the primary disease episode.

The study to show this in horses is prohibitively expensive and there is no model to reliably create relapsing polyneuritis equi. Horses have different relapse rates, some months and some years. We can get meaningful data from natural cases.  If we analyzed biopsy samples from horses diagnosed with polyneuritis equi on a molecular level we could gather information on the types of lymphocytes present, the healing process, and document treatment protocols.  The biopsy can be done standing under local block by a field veterinarian.  Samples can be placed in the same fixative that is used for uterine biopsies.  Call to find out how you can help and if your horse would benefit from this study.

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.