Skip to content

What’s myelin and why is it important?

For this we need some background.

When we think of the nervous system, we generally think of two parts, first there’s the brain, called the Central Nervous System, CNS. Then there is the part that passes information to and from the brain. We call this the Peripheral Nervous System, PNS.

Nerve impulses from the body are passed along nerves by shifting chemicals. It is a slow process. Some nerves are fine with slow impulses, the nerves that cause your intestines to move food along, for instance. Then there are the nerves that must pass information very quickly.

clip_image002Imagine placing a hand on a hot stove. It wouldn’t do for the information to take a long time to get to the brain then a long time for the brain to communicate to the muscles to move the hand. The quicker the better. To do that, the fast nerves have a method to move the impulses quickly down a nerve. What happens is that the nerve is insulated with a sheath, this allows the impulse to rapidly skip down the nerve jumping long distances across the insulated portions. This insulation is called a myelin sheath.

If the myelin sheath doesn’t work properly, the nerve impulses don’t go quickly. This makes the myelin sheath extremely important. To coordinate complicated actions such as walking, running, and chewing, for examples, muscle groups need to work in complex coordinated patterns. Each muscle or set of muscles needs to contract in the proper sequence and exactly on cue. Any interruption or delay has severe consequences.

Animals and people have these important rapid transit nerves. Unfortunately, this myelin sheath can be damaged. Generally, it is the body’s own defense system that attacks this myelin sheath. It’s the same defense system that helps you conquer disease, and ward off infections. The body has a way of defining what is part of the body, named “self”, and what doesn’t belong, “non-self” which includes invading bacteria, virus, or protozoa. The body routinely attacks any “non-self” invaders and destroys them.

This “self” identification system is usually perfect. Not always, though. If the body misidentifies something that should be “self” as “non-self”, the body attacks the “non-self” with all the resources it has available. In general, it’s the immune system that is called into action. There’s also the inflammatory system which works hand in hand with the immune system to destroy invaders.

So how can this happen?

The body breaks down the invaders into small pieces. The body identifies each of these pieces, classifies them as “non-self” and produces antibodies against these pieces. This way the body can wipe out the invaders by attaching antibodies at many places. Think of an antibody like a hook. Each antibody is very specific and only attaches to the piece that it is meant to attack. The body produces a sea of these antibody hooks. If the target piece exists, the antibody hooks automatically attach and the rest of the immune system uses these hooks to help destroy the invaders.

Now suppose the system that determines “self” and “non-self” gets mixed up- or even duped. Suppose an invader doesn’t get classified as “non-self”. The body will not recognize it as an invader and will not attack it. Some bacteria will take advantage of this, they’ll coat themselves with materials that the body doesn’t recognize as foreign. Parasites disguise themselves by changing the way they present themselves, varying the expression of genes. Sometimes parasites are masters of disguise and hijack “self”-proteins in order to manipulate the immune system. The result is that if the body misinterprets what should be “self” as “non-self”, those antibody hooks will attach to normal tissue and the immune system will attack it.

This can happen with the myelin. There are several ways it can happen. Once it does happen, the immune system will break down the myelin sheaths. When that happens, myelin fragments are released into the blood stream. We test the blood for antibodies against myelin to see if those fragments are present. If they are present, we know that there is a problem.

Suppose one has a horse and that horse develops a coordination problem. Suppose it doesn’t walk well, it staggers and falls. If we test the blood and find the myelin fragments, that goes a very long way toward telling us why the horse has a problem and what to do about it.

If myelin is attacked by the immune system, all the myelin is attacked. We won’t generally see a single problem, we’ll see an array of signs-diffuse over the body. We call this array of signs “polyneuritis”. “Poly” means many, neuritis means the nerves are affected. If we’re talking about a horse, we tack on the word “equi” so we know we’re talking about the horse.

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.

tangle-of-nervesThe disease progression of polyneuritis equi (PE) includes an immunological response to an infection or allergic neuritis (in response to proteins released by trauma or infection).  The initial infection stimulates harmful responses that persist after the infection resolves and is no longer detected.  Damage is to the myelin covering nerves, specifically the P2 protein. A similar disease in people is Guillain-Barre syndrome.

A French physician described a variant of Guillain-Barre called Landry’s paralysis in 1859.  Landry described a wider group of peripheral neuropathies.  Polyneuritis equi may be similar to Landry’s paralysis. Most of the research in human neurological disease that depended on spinal tissue began to get material from horses when Mad Cow disease hit Europe.  The scientists didn’t want to continue to use nerve tissue from European cows.

We define polyneuritis equi by the presence of anti-myelin protein antibodies in serum of horses showing neurological disease.  Six published references link serum antibodies to anti-P2 protein with clinical signs in horses. There is also useful unpublished data. One researcher at CA Davis attempted to develop a P2 ELISA but failed to get a relationship between several cases and a positive ELISA test.  Another clinician at OSU tried to produce experimental polyneuritis equi by injecting P2 into a few horses, but his model failed. Why can we detect antibodies in serum when others didn’t make the connection? The negative data from these scientists are explained by the processes that produce disease. This is a boon for our work.

An antecedent infection sets off a harmful immune reaction.  The nerves are repaired by remyelination, but sometimes the process begins a damage/repair cycle. The repair process deposits microscopic calcium on the damaged nerve, calcification is a common result of chronic inflammation.  At this point the disease is terminal in horses. The disease is called cauda equina neuropathy (CEN) and is characterized by recognizable histological lesions that are a progressive granulomatous inflammation of peripheral nerves. CEN is chronic and has an apparent predisposition for involving the extradural nerve roots of the cauda equina.

There is an experimental model that was developed in rats. Rats are given P2 protein injections that results in EAN (experimental allergic neuritis). EAN can be induced in other animals. Rat-EAN can be induced by peripheral nerve myelin, myelin basic proteins, P2 protein, or small pieces of P2 protein, Neuritogenic Peptides. There is a positive correlation between the severity of the clinical signs and the dose of Neuritogenic Peptides from P2.  The disease in rats is characterized by demyelination of the roots of sacral and sciatic nerves given “high” doses of P2.

There is mild disease accompanied by mild signs in 40% of a low dose, P2-immunized group.  Neither group showed signs attributed to the central nervous system indicating the disease involves the peripheral nerves.  And ponder this, repeated stimulation using the P2 antigen resulted in refractory disease, the rats stopped getting sick! Compare that with results when giving repeated doses of the Neuritogenic Peptide—rats continued to suffer disease.

In a field case antibody is made anywhere on myelin protein.  If there is continued damage to one area of a nerve and on a smaller scale, the myelin P2 protein, then anti-P2 antibodies are produced.  These antibodies are measured by ELISA.  After several rounds of the inflammatory cycle it is probable that the nerves calcify.  Its possible that is the refractory stage of disease and no antibody is made, the damage is now due to the calcified nerves.  However, in disease many areas of P2 elicit antibody production and that includes the Neuritogenic Peptide.  The rat studies indicate there will be no refractory period and antibodies will continue to be measureable against the this peptide.

Based on these data we developed our ELISA to measure both P2 and the Neuritogenic Peptide, hopefully to gain enough data to stage the disease process.  The CA Davis team didn’t look at the neuritogenic peptide in their assay and, in late disease, it is probable P2 antibody wasn’t present.  In the OSU experimental model it would be expected that 40% of the horses would show mild disease; it would take at least 20 animals to come up with definitive disease using whole P2 protein.  However, if the Neuritogenic Peptide was employed, all the animals could be expected to show signs and measurable antibodies.

Why do horses get this disease?  You have to look at the structure of myelin P2 protein to understand and treat polyneuritis equi.

Todays challenge is showing that the uncommon disease, polyneuritis equi, PE, is a recognizable condition that veterinarians should consider as a diagnosis in horses with neuromuscular disease.  There are only a few published papers and manuscripts report the cause is unknown.  The cause is probably due to an infection that stimulates immunity.  Once turned on the horses immune reaction attacks the insulation on nerves, myelin proteins, to cause disease. There are two presentations of PE, classical and atypical.  The atypical presentation involves the (cranial) nerves, these are nerves that exit the skull above the cervical vertebrae. The classical presentation involves the sacral and coccygeal nerves leading to paralysis of the tail. rectum, and bladder with loss of sensation in the area controlled by these nerves.

A horse can have both classical signs with atypical components that include behavior changes, ataxia, proprioceptive deficits and hemi-paresis (sidewinder gait). Horses of any age, breed, or sex can be affected, ages of reported cases range from 1 to 35 years old. The amazing thing is that there is a specific marker,  antibody, anti myelin P2  antibodies, that are found in the serum of affected horses.  Identification of the marker was first published in 1981.  The ELISA test for detecting antibodies was published in 1987. We published our test in 2015 after looking a  statistically significant number of horses that presented with unusual, unresponsive disease.  These horses were “diagnosed” as equine protozoal myeloencephalitis.  These were chronic, relapsing cases often receiving multiple treatments for EPM.

Signs of polyneuritis equi are diffuse because the inflammation affects multiple nerves in the body.  A similar rare condition is cauda equina neuritis, this is a chronic untreatable disease that has an apparent predisposition to involve the extradural nerve roots of the “cauda equina”. The cauda equina nerves exit the spine after the terminal part of the spinal cord (see picture). Cauda equina neuritis (CEN) has a specific microscopic lesion, granulomatous inflammation of the peripheral nerves.  It is most likely that polyneuritis equi is a spectrum of disease that terminates in CEN.

Polyneuritis equi may be the result of the bodies response to several different organisms, perhaps virus, parasites, or even some bacteria.  Most veterinarians at referral clinics that suspect CEN look for the classic histopathology or perhaps ultrasound/radiographic evidence to the classic lesions. I spoke to 7 veterinarians at 5 university clinics and one veterinarian from Kentucky.   They don’t see or look for early PE. They are biased to look for chronic disease because end stage cases are referred to them, not the early ones.  It is logical they wouldn’t look for a rare disease, especially early in the course of the process. They overlook these cases.  It is probable that the peripheral neuropathy is reversible in polyneuritis equi, if it is detected and controlled early in the disease process.

If you think your horse has signs of polyneuritis equi discuss it with your veterinarian.  Have your veterinarian read our paper on the proposed mechanism of disease, especially the part on why the disease is overlooked.  Send a serum sample using the ELISA submission form, mark the Sidewinder MP2/MPP and CRP box.  We can discuss the most appropriate plan for the horse.

cauda equina anatomy

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.