Equine Protozoal Myeloencephalitis

Equine Protozoal Myeloencephalitis

Philip J. Johnson Equine protozoal myeloencephalitis (EPM) is one of the more common infectious diseases affecting the CNS of (mostly) adult horses in the mid-west. Recognized in the USA in the 1960s, it was characterized based on its histopathological features as a ‘focal encephalitis-myelitis’. The presence of protozoa in these lesions was subsequently described in the 1970s, whereupon the condition has subsequently been known as EPM.

There are two apicomplexan protozoan parasites that have been implicated in EPM: Sarcocystis neurona and Neospora hughesi. There are still many knowledge gaps regarding the life cycle and pathophysiological significance of N. hughesi and its role as an etiological agent for EPM. The mode of transmission of N. hughesi to horses is not known, but it can be passed vertically (from mare to foal). Much more information is available regarding S. neurona, which is a much more commonly encountered etiological agent for EPM (EPM associated with N. hughesi infection is said to be rare). For its persistence in nature, S. neurona must cycle through two hosts. In the USA, the common opossum (Didelphis virginiana) is the ‘definitive horse’ for S. neurona (other marsupial species operate as definitive hosts in South and Central America). The protozoa exist in the intestinal tract of the opossum, where they undergo sexual reproduction leading to the genesis of sporozoite-containing sporocysts that are passed into the environment in feces. These sporocysts are infective for the ‘intermediate host’, which is infected by ingesting opossum feces or food/water that has been contaminated by opossum feces. Several mammalian species can play the role of intermediate host for S. neurona, including skunks, raccoons, armadillos, and cats. The protozoa migrate into striated muscles (myocardium, skeletal muscle) of intermediate hosts and develop into cysts (‘sarcocysts’). Continuance of the life cycle requires that the muscle cysts will be ingested by the definitive host, whereupon they will inhabit the opossum intestinal system. The horse is an inadvertent or ‘dead end’ host for S. neurona. In most cases, the horse’s immune system effectively controls the parasite and, albeit that there is an antibody response to the parasite (seroconversion), it is rare that the parasite enters the CNS and results in neurological disease (EPM). Susceptibility: Having a serum antibody titer against S. neurona indicates that the horse has encountered the parasite (and undergone seroconversion). Immunity against protozoan parasites is complicated and likely more centered on a robust cell-mediated immune response (needing a normal Th1 cell-mediated response, involving both interferon-gamma and interleukin-12). Therefore, demonstration of a positive serum antibody titer is reflective of exposure; positive seroprevalence for S. neurona varies between 1589% of horses with the highest seroprevalence rates being found in those geographical locations with greater opossum populations. Seroprevalence rates for N. hughesi have been reported between 3-34% (but some reporting has employed antibody detection assays that are not specific for this parasite, failing to satisfactorily differentiate it from N. caninum). A satisfactory explanation for the reason that only a small number of S. neurona exposures lead to neurological disease is still lacking. Putative explanations have included idiosyncratic immunosusceptibility of the host, size of infecting inoculum, differences regarding genetic and antigenic features of the parasite (‘virulence’). It has been suggested that exposed horses unable to respond with an adequate interferon-gamma response may be susceptible. Risk factors from the epidemiological perspective: Neurological disease is more commonly seen in young horses (<4 years of age) and older horses (>13 years). There is a seasonal variance with respect to new EPM encounters –disease is less common in the winter months and more common in spring (X3) and in the fall (X6). Other ‘positive’ risk factors include, as noted above, proximity to opossum populations (geographical variability), proximity to wooded areas, previous encounters with EPM, and various ‘stressful’ criteria (transport, injury, surgery, parturition, heavy exercise, change of management). EPM is more commonly seen in racehorses and show horses (competition stress) but less common in pleasure horses and horses used for breeding. Increased risk has also been reported when vermin (rats, mice) are plentiful and when horses are accommodated at premises in closer proximity to human population centers (wildlife encroachment). Advanced age and PPID are considered to be risk factors (reduced immune effectiveness). Risk of EPM is significantly less if wildlife is denied access to horse feed and if a river or creek runs through the nearby farm/woodland area (opossums less likely to move into closer proximity with horses).

Clinical presentation: Often is the case that, without a favorable response to treatment, EPM is characterized as a progressively debilitating disease of the CNS. The clinical chronology may arise as an acute syndrome or a chronic condition with worsening debility. Neuroanatomic localization may reveal focal or multifocal disease affecting either or both the brain and spinal cord. It has been stated that EPM should be (high) on the differential diagnosis list for most equine neurological syndromes. Of note, commonly encountered syndromes of EPM include unusual/atypical lameness (especially those that are difficult to localize), weakness/ataxia, dysphagia, abnormal upper airway function, and focal skeletal muscle atrophy. Other less commonly seen clinical manifestations of EPM include seizures, obtundation (brain involvement), head tilt (brainstem), facial nerve signs (brainstem), integumentary hypalgesia, hyporeflexia, sensory loss, dysuria, and collapse/inappropriate recumbency. Affected horses are often BAR with normal vital signs. It is common that the observed clinical picture is progressive and deteriorates over time. Affected horses are often presented for veterinary diagnosis of lameness. In those cases, lameness is not typically aggravated by limb flexion tests and lameness cannot be ‘blocked out’ with regional/joint anesthesia. Abnormal stances, stumbling, and interference may be noticed during the lameness examination and warrant closer scrutiny from the neurological perspective. Movement abnormalities resulting from neurological disease are not typically improved with NSAID treatment and tend to be variable/inconsistent (musculoskeletal lameness is usually consistent) during the examination protocol. In some cases, there may be both a neurological and a musculoskeletal component to observed movement abnormalities. There are three noteworthy clinical features of EPM that are helpful from the perspective of differentiating it from other neurological diseases with ataxia/weakness: EPM signs are often (but not always) asymmetrical; EPM is often (but not always) multifocal in its neuroanatomic diagnosis; there may be areas of focal skeletal muscle atrophy (asymmetrical or symmetrical). If these three neurological characteristics are identified in a patient with neurological disease, it is very likely explained by the EPM diagnosis. During movement evaluation, ataxia, weakness, and dysmetria may be observed in one or more limbs.

Differential diagnosis of EPM should include consideration of the following conditions: cervical vertebral stenotic myelopathy (‘wobbles syndrome’), CNS trauma, viral diseases (herpes myeloencephalopathy, West Nile viral myeloencephalopathy, rabies, etc), polyneuritis equi, motor neuron disease, degenerative myeloencephalopathy/neuroaxonal dystrophy (EDM/NAD), migrating helminth parasite (cerebrospinal nematodiasis), and others. Diagnosis of EPM: Although diagnosis of EPM may be suspected based on the clinical presentation and outcome of neurological examination, confirmation of diagnosis must be based on both the elimination of other reasonable and qualifying considerations and laboratory testing. For example, signs of symmetrical ataxia that are most evident in the pelvic limbs of a younger horse warrant consideration of cervical vertebral stenotic myelopathy and cervical vertebral radiography/myelography may be undertaken. It is important to emphasize that a diagnosis of EPM is not appropriate in the absence of bona fide neurological signs or in areas of the world (beyond the Americas) where S. neurona is not found. Although a positive serum antibody titer (against S. neurona) is ’supportive’ of an EPM diagnosis, it is not reliable for diagnostic confirmation (especially in Missouri where seroprevalence is quite high). A negative serum antibody titer suggests that EPM may not be present but should be re-tested after 2-3 weeks in acute cases. Diagnosis of EPM is most strongly corroborated by demonstrating an antibody titer in CSF that is higher than can be explained by diffusion of antibodies from the blood (which is based on the serum antibody titer). Having such a high CSF titer supports the fact that antibodies are being produced within the CSF (intrathecal production) in response to the presence of S. neurona in the CNS. In the past, veterinary diagnosis was established by demonstrating the presence of anti-S. neurona antibodies in the CSF using a Western immunoblot; this diagnostic test is no longer recommended. Presently, using an antibody detecting and quantification ELISA provided by a commercial laboratory (Equine Diagnostic Solutions, LLC, Kentucky, USA), the recommended test involves calculation of a ratio of serum:CSF titers (based on the SnSAG 2, 3, 4 antigens). Diagnosis of EPM resulting from S. neurona infection is supported when the ratio is less than 100. It is also recommended to test for N. hughesi (same laboratory).

Some other testing laboratories offer other/different methodological approaches for EPM diagnosis, but validation of those testing outcomes has not been as broadly accepted. Contact information for Equine Diagnostic Solutions, LLC, Kentucky, USA: https://edslabky.com Telephone: 859-288-5255 Treatment of EPM: Management of EPM entails the administration of an anti-protozoal treatment coupled with one or more adjunctive treatments. Presently, there are three principal anti-protozoal drug approaches: pyrimethamine with sulfadiazine (ReBalance™), diclazuril (Protazil™), and ponazuril (Marquis™). Although treatment of EPM with various other anti-protozoal drugs has also been advocated, published efficacy data are not available. Dietary folate can interfere with the oral bioavailability of administered pyrimethamine, so it is recommended that hay should not be fed 2 hours before or following treatment with ReBalance™. Co-administration of corn oil with the triazine agent ponazuril has been shown to result in higher serum and CSF levels. Other drugs that have been recommended alongside anti-protozoal treatments for EPM have included anti-inflammatory agents (such as flunixin meglumine or dexamethasone for a few days when commencing anti-protozoal treatments to lessen the risk of a ‘treatment crisis’). Several immunomodulator agents (including levamisole, EqStim™, and Equimmune™) have also been recommended upon consideration of the possibility that EPM is more likely in conditions associated with lowered immunity). Vitamin E and other antioxidant substances may be supplemented to ‘preserve’ damaged neurons. In older horses, PPID should be considered and, if present, treated with pergolide. Prevention of EPM: Although a vaccine that stimulated the systemic production of anti-S. neurona antibodies was briefly introduced some years ago, evidence that it prevented EPM was not forthcoming, and it is no longer available. Metaphylaxis is the term used to describe administration of anti-protozoal medication in the absence of disease intended to control S. neurona in at-risk individuals. To that end, daily treatment with either of the 2 recommended triazines (diclazuril or ponazuril) is sometimes recommended for a period of 7 days, once monthly. This metaphylactic approach is especially recommended for the long-term management of EPM-affected individuals that have responded well to treatment (under the assumption that there is an idiosyncratic susceptibility to EPM). References: Available upon request

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Equine

Kile S. Townsend, DVM, MS, DACVIM (LAIM)M

Assistant Teaching Professor of Equine Internal Medicine University of Missouri College of Veterinary Medicine Columbia, Mo.

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