Skip to content

Clinical signs of PNE are due to pathology

Some diseases are easy to spot. Unique clinical signs can be directly associated with disease, skin fungus for example. It’s hard to ignore your horse when he squints a tearing and swollen eye, those are hallmark signs of a painful corneal ulcer! Fortunately, some diseases have definitive tests.

There are also diseases that aren’t so easily recognize. The veterinarian makes a diagnosis by evaluating the clinical signs and narrowing down the possible disease list with an array of laboratory testing. Yet, some difficult-to-diagnose diseases don’t have definitive tests to get them onto or off the differential diagnosis list.

What can make the definitive diagnosis of some diseases elusive is a fundamental principle: the body reacts to multiple insults by using a few selective, well differentiated pathways. Innate immunity is a quick, generic response system and is a first line of defense against infections. A more refined, specific, and later developing response is called adaptive immunity. An adaptive response results in specific antibody molecules and sensitized T-cells that are “trained” to recognize a distinct infectious agent. Innate immune responses are non-specific and common to infections while adaptive immune responses are the bodies red flags that may used for a definitive diagnosis.

We are going to explain why polyneuritis equi, that is primarily a dysfunction of the inflammatory response system, can be difficult to recognize. To understand PNE, one must have a brief understanding of how inflammation causes clinical signs.

In polyneuritis the thing that is different is that the immune system is now attacking something it shouldn’t. The first step in the immune process is the inflammatory response. Inflammation is a very early response. Even though it is very early it is possible to pick up some nonspecific inflammatory elements in a blood sample. In the PNE disease process abnormal values are associated with subclinical signs. Subclinical means that the signs are generally too subtle to be picked up on a physical exam.

It is important for the body to react quickly to infections. Rapid reactions employed by the innate immune system require communication between several first responding cells to the infection. The blood stream serves as a rapid transit system for the First Responders that are white blood cells (WBC) in innate immunity. These circulating cells are trained in surveillance and at the first encounter with foreign entities they sound the alarm. The signals they use are cytokines. Cytokines are chemicals that exert an effect on individual cells and sometimes on tissues.

The immune system is very economical. Sometimes cytokines turn things off and sometimes cytokines turn things on. Cytokines can turn one pathway in a cell on and at the same time turn off a pathway in the same cell. Think of a switching station along a railroad, pulling one lever changes the destination of the train to a meeting in New York or a party in Florida. Knowing when to pull the lever is important and that is context. Cytokines receive context from other reactions and other cells that let the immune response know where the party is happening.

Innate immune (early and quick) reactions start with inflammation. The five hallmark signs of inflammation are heat, pain, redness, swelling, and loss of function. These signs occur on a large, gross, as well as a microscopic or cellular level. The current discussion focuses on cellular reactions responsible for the gross signs seen in the horse. Inflammation yields changes in measurable clinical laboratory values that may help with a diagnosis of inflammation. Remember that these early, acute reactions are not specific to a specific disease but the response to infection.

Initially, subtle microscopic changes set in motion by cytokines have no outward effect on the horse. The effect is sub-clinical. Yet the ability to measure very minute amounts (or in some cases changes in amounts) of cytokines are accomplished in the laboratory. As the effects of cytokine reactions progress to larger areas of tissues the clinical signs will be noticeable in the horse.

Horses with PNE usually have normal WBC counts. Testing for specific antibodies against bacteria and protozoa will often be negative. Antibody against myelin P2 protein can be absent (early) or present (during fulminant disease). The following discussion will explain why when you test and the context of testing are important for diagnosis and perhaps prognosis of PNE.

End-stage disease, when a horse is beyond help, is where the current recognition of PNE stands. We want to change that. Late in disease, a transrectal ultrasound scan may show swelling of the sacral nerves as they exit the ventral sacral foramina. A biopsy of the sacrocaudalis dorsalis lateralis muscle was useful in one published case. In this case, the horse had no feeling in the tail (clinical signs were paresis or paralysis of the tail and decreased sensitivity). A biopsy showed that WBC’s had infiltrated the tissues and obliterated the nerve structure, but not the muscle fibers. Even in this end-stage case an attempt at healing myelin was observed. In some areas that were examined under the microscope, there was new myelin but in other areas, damaged nerves were covered with fibrotic tissue, the process of fibrosis.

Fibrosis is interesting, it is the body’s attempt to cover nerves that have lost nerve-insulating myelin due to chronic inflammation. The body can remyelinate nerves if inflammation is turned off, but if the repair process is thwarted by chronic inflammation, fibrosis takes over. Myelin allows rapid conduction of messages through the nerve whereas fibrin does not. The clinical signs will not respond to any treatment in late-stage disease when nerves are fibrosed. The antibody response to myelin may be absent because the reactive areas of the nerve are covered by fibrosis. The net results is a horse may produce an overabundant amount of granulation tissue that potentiates instead of controls the inflammatory reaction.

Observing remyelination in the presence of inflammation is good news, if fibrosis hasn’t occurred. Depressing the initial inflammatory reaction may reverse the clinical signs of disease. The propensity of the horse to have inflammation may be an anatomical difference in this species because horses have significantly more myelin P2 than other species.

A more in-depth view of the process of disease rests in the type of cells that are responding. Inflammatory T-cells and antibody producing cells (CD20+) infiltrate the damaged neural tissues. The infiltrating cells are macrophages (CD11a+ and c+), immunoreactive CD8+, cytotoxic T-lymphocytes, and a few CD4+ helper T-lymphocytes and CD3+ T-cells.

The bottom line is histopathology supports an adaptive immune response to inflammation caused by virus, chronic protozoal exposure, rickettsial infections, and immune-mediated diseases. We’re not the first ones to ask if PNE is a result of multiple etiologies that set the immune system into motion via common pathways.

PNE was described in the literature (medical books and journals) a long time ago. There are other things that can look like PNE to the clinician examining a horse with neurologic deficits. Many of the published reports were written before the development of the sensitive molecular tools we have today. There were no diagnostic tools to differentiate PNE from some of the other causes of neuromuscular disease. This meant the reports sometimes muddled the various findings. This in no way means the reports weren’t good, they were. The books and the papers are not wrong, they’re just outdated or incomplete. They don’t include the precision with which we can define the disease today. Still, a lot of their findings are valuable. Remember that PNE had no cure and it was often diagnosed late in the disease process. The changes were end stage disease that were found by microscopic examination after an animal was destroyed.

Some published reports cite the involvement of tissues encasing the cerebellum and cerebral hemispheres, although most agree the disease involves the peripheral nervous system and not the central nervous system. In chronic PNE the branches of trigeminal nerves show lesions, again infiltration by inflammatory cells and perineural fibrosis. The spinal column can show reddening and swelling with peridural edema. Lymphocytic infiltrations can be present in various nerves, the femoral nerve or cranial nerves. Horses with long-term disease can also have calcification of spinal nerve roots and extensive perineural fat. The results of these lesions are paresis or paralysis, sensitivity, muscle wasting, gait anomalies, tripping, and dropping feed.

When researchers attempted to find the causes of PNE, it was difficult. It’s a rare disease. They looked for infections and signs of trauma. Recall that in the past, at the time of diagnosis, PNE was already advanced. If there was an infection that started the process, that infection was already cleared by the immune system, long before the late signs of PNE appeared. There are other causes of nerve demyelination. Since PNE is the result of the immune response, it doesn’t matter too much what sets innate immunity into motion. It matters that the immune system has “seen” the myelin and now sets out to destroy it.

Normally reactive myelin P2 exists inside the Schwann cells membrane. The macrophages (white blood cells) exist in the blood. The myelin P2 is not exposed to the blood stream, so the immune system doesn’t know it is there. That’s the way it is supposed to work. What can happen, though, is that there’s a disruption in the normal Schwann cells integrity and the myelin P2 is exposed to the bloodstream resulting in inflammation. Let me digress for a moment.

There are speculations as to the etiology of polyneuritis equi. The problem is that the disease isn’t reproduceable using organisms or trauma. By the time chronic inflammation sets in the body has exterminated the organisms sometimes leaving only the residual antibody responses.

Polyneuritis equi is a primary demyelination disease. Primary demyelination can occur without inflammation, this can occur in lead poisoning. Primary demyelination can occur with inflammation where the inflammatory cells are mainly lymphocytes and macrophages. Inflammatory demyelination is thought to have an autoimmune pathogenesis, but the reaction isn’t necessarily against “self”. We discussed the up-regulation of certain antibody binding areas on myelin P2 as a response to T-cell stimulation in another section.

It was proposed that antigens, or “self”-proteins that reach the peripheral nervous system attract and activate lymphocytes and macrophages. These cells become a nonspecific cause of a primary or even secondary demyelination. This is called a “bystander” mechanism. Finding an infectious cause of PNE is unexpected in this scenario.

It is apparent from the discussion that two processes may be at play. There is an innate immune response that is a quick inflammatory defense against infections. The infection can be a bacterium, a virus, or a protozoan. After the acute phase reaction, the body equilibrates, and the cytokines facilitate a robust adaptive immune response. Normally, acute inflammation switches off while an adaptive reaction is switched on, a cytokine success.

Occasionally the acute inflammatory reaction doesn’t turn off. It becomes dysregulated. The cytokines forget context and keep the acute reaction in play. The reaction becomes chronic. The cytokines and their end-products keep the reactions going in an endless cycle. As chronic inflammation (T-cells) continue to destroy myelin an adaptive reaction against “self”-myelin ensues. At this point anti-myelin P2 antibodies are measurable.

It is important to recognize where in the cycle the disease is manifesting. We do that by measuring an acute phase cytokine, C reactive protein (CRP), and adaptive reactions against two areas of myelin P2. The cytokine CRP is one “turn-on” signal for acute inflammation.

To recap here, a horse will have clinical signs and acute inflammation, elevated CRP and no measurable P2 antibody and it is treatable. As disease progresses a little more, we measure antibodies against whole myelin P2. Further along, with more progressive disease, the horse may become refractory to the whole P2 protein, those antibodies decline, and only the T-cell stimulating protein antibodies (neuritogenic peptide) linger, most horses are still treatable and need management. Once the body fibroses damaged nerves and myelin is no longer exposed, the the antimyelin P2 antibodies decline. Nerves can’t conduct signals yielding clinical signs that are progressively worse. And the horse is untreatable.