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Acquired equine polyneuropathy

Horses with polyneuritis equi (PE) can have muscle wasting and an abnormal gait, sidewinder is a good description. Polyneuritis equi is associated with paresis of the tail, bladder, rectum, and anal and urethral sphincters. Paralysis of certain cranial nerves may be present, a drooping lip and ears, inability to blink and wasting of the facial cheek muscles. The characteristic pathology is inflammation of the peripheral nerves and nerve roots. Microscopy of diseased areas reveal demyelination and remyelination that indicats a remitting/relapsing disease. In 1987 Dr. Fordyce used a serum assay to identify horses with polyneuritis equi because afflicted horses often have antibodies against myelin protein (P2). Pathogenes uses similar assays (P2, MPP) to detect antibodies against myelin proteins to suggest immune mediated disease in horses with clinical EPM.

The field diagnosis of polyneuritis equi can be facilitated by transrectal ultrasound of the extradural sacral nerve roots (as they exit the ventral sacral foramina). It may be useful to perform a biopsy of the sacrocaudalis dorsalis lateralis muscle in horses that show hyperesthesia, followed by hypoesthesia, because histopathology can be highly suggestive of polyneuritis equi.

knuckling horse

Acquired equine polyneuropathy (AEP) is the most common equine polyneuropathy seen in Norway, Sweden, and Finland. Scandinavian knuckling syndrome describes the clinical presentation. Mortality is between 29 to 53%, however horses that survive can recover and return to athletic use. AEP is seasonal, appears in clusters, and has a strong association to diet. This disease results in paresis. Microscopic examination reveals large fiber demyelinating polyneuropathy (inflammation) with conspicuous Schwann cell-associated features.

Siv Hanche-olsen et al (Equine Veterinary Journal, 2017) discussed long-term follow-up of Norwegian horses affected with AEP and we wondered if these horses, like polyneuritis horses in the US and similar neuromuscular diseases in people, had circulating anti-myelin protein antibodies. After a few emails and bureaucratic appeasement, the serum arrived.

We expected to detect antibodies against P2 in symptomatic horses because demyelination is a component of the disease process although it is known that AEP and PE are different diseases. Circulating P2 and MPP antibodies in horses are not known to be exclusive to polyneuritis equi. EPM is not found in Norway. Sarcocystis is present, but not S. neurona. We found S. fayeri antitoxin in most of the samples and, as expected, none of the horses had antibodies against S. neurona. Only of the sera from the horses had a normal CRP value, the others were elevated (36-65µg/ml)! None of the horses had P2 antibodies. Although we tested a small number of serum from horses our results indicate that PE and AEP are demyelinating diseases with a different pathogenesis.

There are neurologic diseases in people that may help guide our understanding of these two diseases. Experimental allergic encephalomyelitis, experimental allergic neuritis, and acute disseminated encephalomyelitis are also helpful models to define the disease processes. These disease models demonstrate immune attack on neural tissue caused by viral infections or in some cases, vaccination.

In the experimental allergic encephalomyelitis-model, a peripheral neuropathy, P2 protein antibodies are a component of disease. The P2 protein makes up a small part of the peripheral nervous system, most likely localized to the cytoplasmic face of the Schwann cell membrane. The function of the P2 protein on the Schwann cell is undefined but may be like similar proteins that bind lipophiles, suggesting a role in lipid transport and storage in these cells.

Myelin proteins are largely conserved across species and that is why equine myelin served in many experiments conducted by those that study human Multiple Sclerosis. Generally, there are differences between peripheral nerve myelin when compared to myelin found in the central nervous system (CNS). However, horses have an unusually high amount of P2 protein in the CNS-myelin when compared with other species. It is expected that a peripheral immune-mediated neuropathy would affect the central nervous system in some equine disease conditions.

Guillian-Barre (GB) syndrome is an immune mediated attack on peripheral nerve myelin. Pathology is found at the level of the proximal nerve roots and is due to local cytokine production (inflammation) rather than the development of circulating antibodies. Patients with GB have circulating myelin protein antibodies. In horses with PE there is inflammation and antibody associated with the pathology that is like GB syndrome in people.

Heavily myelinated sensory fibers (muscle stretch fibers) and motor axons are direct parts of the reflex arc. Deep tendon reflexes are almost always lost very early in the course of human disease. Numbness and tingling (sensory) usually precede flaccid weakness and ascending paralysis due to affected peripheral nerves. Inflammation can be associated with nerves supplying cranial muscles, disease may look CNS-mediated but it is peripheral neuroinflammation. The cause of disease could be molecular mimicry because specific infections have been associated with Guillian-Barre syndrome. Often there are relapses with spontaneous waxing and waning of symptoms.

Multiple Sclerosis (MS) is an immune disease mediated in the central nervous system. Because the optic nerve is an extension of the CNS the optic nerve can often show lesions. There are geographic areas with a very high incidence of disease (1 in 300 people) yet in nearby areas the disease is unknown. It is strongly thought that an environmental factor is associated with disease. An etiology is presently unknown although neuroborreliosis (Lyme disease) is a risk factor. Interestingly, moving from a high-risk to a low-risk area after the age of 15 does not appear to reduce one's chances of developing MS. It appears that whatever triggers the immune reaction that is active during MS does not appear to be present at the time of diagnosis. It is likely that both infectious and immune mechanisms contribute to the pathogenesis of MS. Antimyelin antibodies are present in patients with MS and may have predictive value for disease. A viral infection may trigger an inappropriate immune response with antibodies to a common virus-myelin antigen.

Some similarities of polyneuritis equi to Guillian-Barre syndrome and Multiple Sclerosis are circulating P2 antibodies, cytokine mediated inflammation, and remitting/relapsing disease. Polyneuritis equi and GB are peripheral diseases while MS is a central nervous system disease. Horses express more P2 in the CNS myelin than other species and may indicate why some horses exhibit CNS signs during disease. It was suggested by Allman (2009) that controlling inflammation in horses with polyneuritis equi may enhance the regeneration of nerves in horses with PE. Diagnosis and treatment of inflammation associated with polyneuritis equi is the subject of one of our clinical trials.

We did not find P2 antibodies nor MPP antibodies in five horses with acquired equine polyneuropathy suggesting a difference between PE and AEP. Acquired equine polyneuropathy is a peripheral inflammatory demyelinating polyneuropathy targeting large fibers associated with Schwann cells. A possible mechanism of disease in AEP is suggested by the experimental allergic neuritis model in rats. In the rat model a leukocyte receptor gene mediating activation of natural killer cells and macrophages by immune complexes was induced in cauda equina and sciatic nerves during the period of increasing weakness. The accumulation of the leukocyte receptor was attributed to macrophages and other cells of the immune system in the neural tissues rather than induction of the expression of the receptor by the Schwann cells. Examining the immune response by inflammatory cells after the inciting trigger for the inflammatory response during clinical disease may be interesting in AEP.

It is suggested by our work that equine polyneuropathies, like human neuromuscular disease, can look similar but have different cellular targets that require different treatments.