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Many researchers are to be commended for their important studies on this disease, and we can’t hope to do justice to everyone in this foreword. However, from the initial work of Dr. David Granstrom to the present, many groups of researchers are now forging ahead unraveling this enigmatic disease. Dr. J. P. Dubey, a renowned protozoologist, has been instrumental in solving the biology of the organism and in collaboration with Dr. Steve Reed and myself in the equine model work in Ohio. That work is being complemented by Drs. John Dame and Rob McKay in Florida, Drs. Pat Conrad and David Wilson in California, Dr. Antoinette Marsh in Missouri, Dr. Debra Sellon in Washington, Drs. Hal Schott and Linda Mansfield in Michigan, and Dr. Dan Howe in Kentucky. Through the work of these and other investigators, we are well on the way to understanding this devastating disease of the horse. I commend Dr. Granstrom for his work and for the knowledge he is providing through this important text. William J.A. Saville, DVM, Diplomate ACVIM, PhD Associate Professor Department of Veterinary Preventive Medicine College of Veterinary Medicine The Ohio State University

History of the Disease

quine protozoal myeloencephalitis (EPM) is the most commonly diagnosed equine neurological disease in North America. Unfortunately, it presents a number of perplexing problems for owners and veterinarians that also make it one of the most difficult diseases to understand. Although a great deal has been learned about EPM since it first was described in the early 1960s, we are still far from fully understanding it today. Isolation of Sarcocystis neurona, the parasite that causes EPM, and the subsequent development of a laboratory diagnostic test in 1991 touched off an explosion of interest in EPM. It soon was learned that EPM was the real culprit in many clinical problems that had been incorrectly diagnosed or had not been diagnosed at all. The EPM test was used to determine exposure rates that approached 50% among the general horse population in several states. Seemingly overnight, EPM became the diagnosis du jour. EPM has been found only in horses that originated in the Western Hemisphere. Although cases have been reported from Europe, Australia, and Africa, the affected horses were imported from the West. The first cases of EPM recognizedin North America were from the Northeast. The disease now is recognized throughout the United States and southern Canada, as well as Central and South America. It is uncommon in the arid western United States, but the transient nature of the horse population has resulted in many confirmed cases, even from the desert Southwest. EPM affects all breeds at almost any age, but it seems concentrated in Thoroughbreds and Standardbreds under age four. One of the foremost problems associated with EPM simply has been arriving at an accurate diagnosis. Clinical signs of the disease are so varied that it easily can be confused with almost any equine neurological disease, and many non-neurological diseases as well. Horses might be affected so mildly that it is difficult to detect a problem, or so severely that they are unable to stand. The disease can strike rapidly or insidiously but most commonly produces gradually progressive incoordination and/or weakness of one or both rear limbs. Laboratory diagnosis has been a tremendous help, although some confusion and controversy regarding appropriate interpretation of test results have persisted. Another problem area has involved effective treatment. Although some diversity of opinion still exists, it has taken years for a relatively standard treatment regimen to evolve. Some horses have made dramatic recoveries following treatment, while others have completely failed to respond. Nonetheless, the majority (55%–65%) of horses respond favorably to treatment. Unfortunately only a fairly small percentage, possibly as high as 10%, recover completely. It is most common for horses to make significant improvement over two to four months, then gradually plateau with some slight residual weakness or incoordination. The need for persistent treatment of some horses to avoid relapse following complete or partial recovery has presented a challenge. In a significant development, Bayer has released Marquis, the first FDA-approved drug for the treatment of EPM. Marquis or ponazuril sulfone is a metabolite of toltrazuril, which has been shown to kill S. neurona in laboratory tests. Earlier drugs used to treat EPM interfere with parasite multiplication, thus relying on the horse’s immune system to kill the parasite. Interestingly, the relapse rate associated with toltrazuril therapy appears to be much lower. Identification of the opossum as the definitive host has provided an unprecedented opportunity to study S. neurona. The infective form of the parasite (sporocyst) was isolated from the opossum and used for direct study in the laboratory and in the field. The disease was reproduced experimentally, making it possible to conduct controlled trials to evaluate the efficacy of potential vaccines and treatments. In the last few years, several species have been identified as intermediate hosts. These include the cat, skunk, armadillo, raccoon, and sea otter. Undoubtedly, other species will be added to the growing list of animals capable of transmitting the parasite to the opossum. These findings should expedite development of effective methods of prevention and control of EPM.

Searching for the cauSe Rest assured, EPM has been with us for as long as opossums and horses have covered the same ground. However, few causes of equine neurological disease were well differentiated prior to 1960. The terms “wobbler” and “spinal ataxia” (incoordination) were used as descriptive diagnoses that simply characterized the typical movement displayed by affected horses. In the early 1960s two veterinary pathologists, Dr. John McGrath of the University of Pennsylvania and Dr. James Rooney of the University of Kentucky, independently described focal areas of hemorrhage in the central nervous system (CNS) of horses that had died due to neurological disease. These areas had unique microscopic changes that distinguished them from CNS damage caused by other known equine neurological diseases. AT A GLANCE The initial EPM case in • Veterinary pathologists in the Ke n t u c k y w a s f o u n d i n a 1960s first recognized the disease that became known as Standardbred returning from ePM. tracks in the northeastern United • In 1976 Dr. J.P. Dubey identified States. Once the disease was recthe parasite as a species of ognized, it was found in many Sarcosystis. horses, including those that had • During the late 1970s, researchnot left Kentucky. Workers at the ers described many of the clinical signs of EPM to help distinUniversity of Kentucky reported guish it from other equine neuro44 cases from late 1964 to 1968. logical diseases; blood tests were EPM initially was given descripdeveloped to detect antibodies to Sarcocystis. tive names because protozoan parasites had not been observed • The parasite was cultured by Dr. Dubey at the USDA-ARS, and a in damaged areas of the CNS. It parasite-specific EPM diagnostic was first called “segmental mytest was developed at the University of Kentucky in 1991. elitis” and later changed to “focal myelitis-encephalitis” to reflect • A DNA test for S. neurona was developed in 1994. focal or small scattered areas of damage in both the spinal cord • In early 1995, the opossum was identified as the definitive host of (myelitis) and brain (encephalithe parasite. tis). • The FDA approved the drug Researchers speculated that Marquis to treat EPM in 2001. the disease was caused by moldy feed. However, the microscopic damage was different from that found in moldy corn poisoning. Experiments conducted using various moldy feeds failed to reproduce EPM. The microscopic damage caused by EPM was similar to that caused by equine viral encephalomyelitis (Eastern, Western, and Venezuelan). However, consistent, recognizable differences were apparent. Interestingly, in 1974 three different groups, led by Dr. John Cusick of the University of Illinois, Dr. J. P. Dubey of Ohio State University, and Dr. Jill Beech of the University of Pennsylvania, independently reported the presence of protozoan parasites in characteristic areas of CNS damage. Following some initial confusion regarding the identity of the parasite, it was shown that it was similar to, but definitely not, Toxoplasma gondii, a known pathogenic (harmful) protozoan of humans and many animals. Although the exact type of parasite was not known, Beech suggested that the drugs used to treat a similar protozoan affecting humans — toxoplasmosis — might be effective against the new EPM organism. Recognition of the parasite and the availability of treatment were the first major breakthroughs in EPM research since the disease had been described 12 years earlier. In 1976 Dubey first suggested that the parasite was a species of Sarcocystis. He conducted numerous experiments to identify the parasite and its life cycle. After moving to the U.S. Department of Agriculture’s Agricultural Research Service, he and his co-workers, Dr. Stan Davis of the USDA-ARS and Dr. Dwight Bowman of Cornell University, cultured the parasite from an affected horse in 1990 and named it S. neurona. It had been 16 years since the last major breakthrough. Although this isolate soon died out, the experimental method had been established. A second isolate quickly was cultured from an equine spinal cord. This was followed by many isolations at the University of Kentucky and, subsequently, the University of California at Davis, Michigan State University, the University of Florida, and other locations. During the late 1970s, Dr. Joe Mayhew and others at Cornell University carefully described many of the clinical aspects of the disease to help veterinarians differentiate EPM from other equine neurological diseases.

Unfortunately, no consistently reliable indicators of EPM could be found. During this period, Dr. Ron Fayer of the USDA-ARS and Dr. J. Carl Fox of Oklahoma State University each developed blood tests to detect antibodies to Sarcocystis in animals. Although quite different methods were used for each test, both immunoassays were based on Sarcocystis parasites isolated from cattle muscle. This meant that the tests were not specific for immunity to S. neurona. That would not have been a problem if S. neurona had been the only Sarcocystis found in the horse. However, Dubey had estimated that 30% of horses in the United States also are infected with Sarcocystis fayeri, a relatively non-pathogenic parasite of the horse. Dubey discovered S. fayeri and named it in honor of Fayer, the first person to culture any Sarcocystis. The culturing of Sarcocystis was a very significant event because it proved that Sarcocystis were protozoans, not fungi as previously believed.

DIAgNoSTIc TEST DEVEloPED Cultured S. neurona merozoites were used to develop the parasite-specific EPM diagnostic test at the University of Kentucky in 1991. The Western blot, or EPM test for blood or spinal fluid, was designed to differentiate exposure to S. neurona and S. fayeri. Initially, it was believed that the presence of S. neurona-specific antibodies in equine serum indicated the horse had active EPM. This error was quickly recognized as exposure data were collected, showing an average of 20% of normal horses on five farms tested positive. Although these data turned out to be well below those of larger surveys, they served to demonstrate that exposure to the parasite without clinical disease was common. Ultimately, cerebrospinal fluid (CSF) was found to provide valuable diagnostic information to differentiate exposure from active disease. Less than six months after the initial laboratory cultivation of S. neurona, the EPM test was fully operational, signaling the next major breakthrough. Both the initial culture and development of the EPM test were presented at a 1991 meeting of the American Association of Veterinary Parasitologists and the American Veterinary Medical Association. Collaborations with Dr. Steve Reed of Ohio State University and Dr. Alvin Gajadhar of Agriculture Canada were formed, which had a profound impact on EPM research at the University of Kentucky. Reed and Lexington, Kentucky, veterinary internists Dr. Doug Byars and Dr. Bill Bernard contributed their time and case material to the project in which University of Kentucky pathologists also played an essential role. Soon, case material was arriving from many Central Kentucky veterinarians and eventually from throughout the Western Hemisphere. Gajadhar and University of Kentucky graduate students Dr. Clara Fenger and John Langemeier collaborated in the development of S. neurona DNA tests in 1994. These results, in conjunction with field wildlife work done in collaboration with Dr. Judy Marteniuk and Dr. Jon Patterson of Michigan State University, resulted in identification of the opossum as the definitive host of S. neurona in early 1995. This work also led directly to the comparison of S. falcatula from birds and S. neurona ribosomal genes by Dr. John Dame and Dr. Rob MacKay of the University of Florida in late 1995. Subsequent work by the Florida group and Dr. Antoinette Marsh at the University of Missouri demonstrated that these parasites were distinct. Recently, Dr. Dubey and the Ohio State University group identified the cat (2000) and raccoon (2001) as two of the intermediate hosts of S. neurona. The University of Florida group also added the skunk and armadillo to the growing list of intermediate hosts.

Work at the University of Kentucky culminated in another asignificant breakthrough — experimental reproduction of EPM in several horses in late 1995. Drs. Bill Saville and Steve Reed at Ohio State University have continued to refine the infection model, which is being used to study new treatments, vaccines, and host-parasite interactions that are critical for understanding and ultimately defeating the disease. Strong public interest and general recognition of the scope of the problem have compelled granting agencies and corporate interests to fund more EPM research. Although intense public pressure for answers has made progress seem slow, a series of research breakthroughs actually have occurred in rapid succession. In fact, more has been learned about EPM in the past 10 years than the previous 30. In the six years since the first edition of Understanding EPM was published in 1997, a major controlled study has defined many of the risk factors for the disease, the infection model has been improved, five intermediate hosts have been identified, much of the parasite’s DNA has been sequenced, an FDA-approved drug is available with more on the way, and an experimental vaccine is under evaluation. Although much work remains before the threat of EPM is eliminated, clearly, the research community has been gaining ground.

EPM is caused by the parasite Sarcocystis neurona. All species of Sarcocystis are members of a vast group of single-celled animals known as protozoa. Most protozoans are microscopic, free-living organisms that do little harm. However, the genus Sarcocystis is made up of more than 100 individual species that are members of a large group (phylum) of parasitic protozoa known as apicomplexa. They depend on the cells of an animal host to survive and are unable to live indefinitely outside that host. Apicomplexans exist in many forms during the course of their reproductive cycle, but commonly exist in various merozoite stages — motile, banana-shaped bodies a few microns lonpg (1 micron = 1/1,000,000 meters). The pointed end or apex of each merozoite is equipped with an elegantly formed system of fine tubules that allow it to penetrate host cell membranes. This is known as the apical complex and is the basis for membership in the phylum apicomplexa. Members of the genus Sarcocystis have developed an incredibly ingenious scheme for survival. Each species has adapted to a predator-prey or scavenger-carrion relationship found among animals in nature. Individual

Sarcocystis species usually remain limited to a specific predator-prey or scavenger-carrion relationship and fail to AT A GLANCE infect unrelated hosts. By con• Equine protozoal myeloencephavention, parasitologists refer to litis (EPM) is caused by the parasite Sarcocystis neurona. the host that harbors sexually reproducing forms of a parasite • The opossum is the definitive host of S. neurona; horses become inas the definitive host of that fected by ingesting water or food parasite. Sexual reproduction contaminated by opossum dropoccurs in cells lining the small pings. intestine of the definitive host • The horse is a dead-end host for after the host has eaten infectthe parasite, meaning it cannot spread S. neurona to other horses ed prey or carrion. This form or other animals. of reproduction is considered • The length of time between ingessexual because two gametes tion of the parasite and the onset (similar to a sperm and an egg) of clinical signs can vary from less than 30 days to several produced from separate meroyears. Some horses can harbor zoites join to form a “fertilized the parasite without ever developing clinical signs. e g g ” k n ow n a s a n o o c y s t . Sarcocystis oocysts are rounded • The parasite can travel to any point in the central nervous microscopic bodies that consist system, including the brain and of two oval sporocysts, each the spinal cord. containing four banana-shaped sporozoites. Once fully formed, oocysts break free of intestinal lining cells and mix into the intestinal contents. Sarcocystis oocysts are unusually fragile and commonly rupture during the journey through the intestinal tract. Individual sporocysts are found free in the feces of the definitive host, ultimately contaminating the environment and gaining access to the food and water of the prey animal or intermediate host. Sporocysts can survive for up to one year or more under temperate conditions and are resistant to common disinfectants such as chlorine bleach. Dry conditions and prolonged freezing eventually kill them. Once eaten by an appropriate intermediate host, sporocysts “hatch” or excyst in the small intestine. Motile sporozoites are released that quickly penetrate the intestine and enter specialized endothelial cells that line the interior surface of nearby blood vessels. Once inside the blood vessel wall, the parasites begin rapid asexual division. More than 100 individual merozoites (tachyzoites) can bud from the nucleus of an original sporozoite to form a Sarcocystis falcatula sarcocyst in bird muscle. teaming mass of merozoites known as a meront (or schizont). The endothelial cell eventually bursts, showering the bloodstream with new merozoites. Each merozoite is carried to another endothelial cell and the process is repeated at least once more. Thus, the parasite has managed to amplify dramatically the initial infection and enhance its chances for survival. However, some infections can become rapidly fatal if a large dose of sporocysts has been ingested by the intermediate host. After the last round of rapid asexual division, merozoites typically enter individual muscle cells and begin to divide very slowly. A cyst wall forms around the developing parasites to create a sarcocyst in the muscle of the intermediate host. Mature or infective sarcocysts generally are present in the muscle two months following sporocyst ingestion. Sarcocysts grow slowly and can remain in the muscle of the intermediate host for extended periods, up to several years, without causing any disturbance. Sarcocysts of some species grow so large that they become visible to the naked eye. Perhaps, you have seen S. rileyi in the muscles of ducks or geese. They look like grains of rice embedded in the muscle fibers. Although rare, mild to severe myositis A schizont (flower-shaped body) in a cell (muscle inflammaculture. The S. neurona organism is dividing tion) can develop asexually. early in the course of heavy infections with various species. Sarcocysts of individual species of Sarcocystis are infective for a narrow range of definitive hosts. The relationship is somewhat less restrictive than the sporocyst-intermediate host interaction, but it still is quite limited. For example, Sarcocystis cruzi sporocysts infect cattle but not other ruminants (sheep, deer, elk), while S. cruzi sarcocysts infect all canids (dog, wolf, coyote, fox), as well as the raccoon. Sarcocystis muris sporocysts infect mice, but not other rodents, while S. muris sarcocysts infect all felids. Sarcocystis falcatula sporocysts are quite unusual because they infect a wide variety of birds. Once infected muscle has been eaten and digested, individual merozoites (bradyzoites) are released into the small intestine of the definitive host. They quickly enter

The life cycle of the EPM parasite
Intermediate hosts

Definitive host

Aberrant host

Raccoons and other “intermediate hosts” carry the parasite in their muscles; opossums eat “intermediate hosts” and pass the parasite in their feces, where it is picked up when horses eat or drink.

intestinal lining cells and form “male” and “female” gametes as the process of sexual reproduction begins once again. Sporocysts can appear in the feces of the definitive host a little more than a week following the ingestion of infected meat. Sarcocystis fayeri and two other species of Sarcocystis use this life cycle to alternate between horses and canids. Infection rarely results in clinical signs, but a few cases of severe myositis have been reported in the veterinary literature. Unlike S. fayeri, merozoites of S. neurona enter the central nervous system (CNS), not muscle. The mode of entry into the CNS is not known. It is assumed that they directly penetrate the blood-brain barrier, a layer of tightly joined endothelial cells lining CNS blood vessels. It also is possible that merozoites enter the CNS hidden within white blood cells that routinely pass through the bloodbrain barrier. Some have suggested that merozoites leave blood vessels in other parts of the body, enter adjacent peripheral nerves, and migrate up the nerves to reach the CNS. This seems highly unlikely. Intracellular merozoites of this stage divide rapidly; meronts developing at distant sites should produce local inflammation in peripheral nerves. The pain associated with the inflammation could be blocked with local anesthetic. Certainly, horses often have multiple problems, but one of the hallmarks of EPM diagnosis is apparent lameness that cannot be blocked locally. Once inside the CNS, sarcocysts fail to form and merozoites continue rapidly dividing into large meronts inside nerve cells and other cell types in the horse’s brain and spinal cord. Merozoites are not infective for definitive hosts, so the infection does not spread if the horse dies and is eaten. Horses are accidental or aberrant dead-end hosts of S. neurona. Once sporocysts have excysted in the

horse’s small intestine, the parasite cannot be passed to another host. There has been some speculation that pregnant mares might pass S. neurona to their unborn foals, but that has never been confirmed. It is worth considering because prenatal transmission of Sarcocystis is known to occur in many appropriate intermediate hosts. For example, S. cruzi has caused a number of abortion “storms” in cattle. Neospora caninum, another apicomplexan protozoa that cycles between cattle and canids, is a major cause of abortion in dairy cattle around the world. A closely related species, Neospora hughesi, was cultured from the CNS of a horse in California with protozoal encephalitis. The distribution of N. hughesi is not known. Although both species have been reported in the horse, equine neosporosis appears to play a minor role in EPM. Only a limited number of general infections have been reported, including an aborted equine fetus. We now know that the opossum is the definitive host of S. neurona and that horses become infected by ingesting food or water contaminated by infected opossum droppings. Sporocysts can be disseminated in a variety of ways. Birds attracted to seeds or bugs feeding on opossum feces have been shown to pass sporocysts in their feces. Sporocysts can be transported to intermediate hosts in or on various bugs and insects attracted to opossum feces. One study demonstrated that sporocysts stick to the feet and legs of flies that land on the feces of an infected definitive host. An unexplored method of dissemination involves a type of grain or harvest mite. These microscopic insects feed on a wide variety of organic matter in soil and are an essential part of the life cycle of equine tapeworms. They ingest tapeworm eggs from horse feces that subsequently hatch and develop into an infective intermediate stage called a cysticercoid.

Horses become infected as they graze on pasture or eat mites with hay. Mites feed in the top layer of soil, but migrate up blades of grass during the day. Tapeworms mostly are viewed as nuisance parasites, and their control in equine deworming programs often is overlooked. Consequently, a high percentage of horses are infected. Perhaps a similar scenario partially is responsible for the high exposure rate of S. neurona among horses. The length of time between sporocyst ingestion and the onset of clinical signs, called the incubation period, is highly variable. Experimental studies at the University of Kentucky, the University of Florida, and Ohio State University demonstrated that clinical signs of EPM can develop less than 30 days after sporocyst ingestion. It also is known that horses shipped to countries without EPM can harbor S. neurona for months or even years prior to the onset of clinical signs. The parasite’s location during this period is not known, but it seems likely that it persists in low numbers in the CNS. Infection has not been found anywhere else in the horse’s body. The other half of the S. neurona life cycle was discovered over the last few years. Initial molecular and immunologic comparisons suggested that S. neurona was actually S. falcatula. It has been known since 1978 that S. falcatula cycles between opossums and various birds. The parasite originally was named when small, but visible, sarcocysts were observed in the muscles of a rose-breasted grosbeak more than 100 years ago. However, additional molecular evidence and transmission studies demonstrated that S. falcatula is distinct from S. neurona. Dubey and collaborators at Ohio State University identified the cat as the first recognized intermediate host of S. neurona. Because the discovery was made in the laboratory, some questioned its significance in nature. Subsequent work has demonstrated sarcocysts in the muscles of feral cats. However, the exposure rate among cats appears to be low, suggesting that they play a limited role in spreading the infection among opossums. Researchers at the University of Florida next identified the armadillo, followed quickly by the skunk. Dubey’s group then identified the raccoon as still another intermediate host. Interestingly, these species represent a large percentage of the animals killed on American roadways, which fits quite well with the opportunistic feeding habits of the opossum. It may be possible to reduce the amount of exposure in your area by encouraging rapid removal of road-killed animals. Recently, S. neurona sarcocysts were found in sea otters, presumably due to surface run-off and contamination of coastal waters. Given the broad array of intermediate hosts identified to date, it seems likely that more will be added to the list in the years to come.

EPidEMiology And RiSk FAcToRS Epidemiology refers to the study of the health and disease of a population rather than an individual. Epidemiologic studies gather information about a population to discover factors that increase the risk of spreading and maintaining a particular disease among the individuals of the population. Ultimately, understanding the risk factors for the population directly benefits the individual as well. Several epidemiologic studies have been done to evaluate EPM over the years. A major limiting factor associated with earlier studies was the reliance on post-mortem examination to confirm the diagnosis of EPM. The only horses evaluated were those so severely affected that they failed to survive. Therefore, only a small proportion of the horses with EPM were included in the studies. In addition, regional bias was introduced due to the variable cost of post-mortem examination and the extent of the CNS evaluation performed at each facility. Some state diagnostic laboratories provide free services, while others charge hundreds of dollars for an examination that includes the entire CNS. Removal of the brain and spinal cord of an adult horse is very labor-intensive. Partial removal is much easier to perform, but several feet of valuable tissue are lost. It also is very difficult for veterinarians in the field to submit more than the brain and the first few inches of spinal cord for examination. Despite these shortcomings, retrospective studies of post-mortem data have provided a great deal of useful information. The type of information usually gathered includes age, breed, and sex of horse; location; number of horses affected; number dead; and a brief clinical history. Clinical histories include duration of illness, clinical signs, treatment, and response to treatment.

EPM cAn STRikE AlMoST Any hoRSE The American College of Veterinary Internal Medicine (ACVIM) sponsored an EPM workshop at its 1988 annual meeting. Veterinary pathologists, parasitologists, and clinicians gathered from across North America. The workshop was based on 364 post-mortem confirmed cases of EPM from veterinary diagnostic laboratories in California, Florida, Illinois, Kentucky, New York, Ohio, Oklahoma, Pennsylvania, Texas, and Ontario, Canada. Representatives from each institution presented a review of cases accumulated over an average of six years (range of four to 12 years). Affected horses ranged in age from two months to 19 years. The majority of the affected horses were young; more than 60% were four years old or less. The most commonly affected breeds in rank order were Thoroughbreds, Standardbreds, and Quarter Horses, but most other breeds and ponies were affected. No preference was found based on sex, geographic location, or time of year. Post-mortem studies at Cornell University and the University of Kentucky reported 25% and 9%, respectively, of neurological disease submissions were due to EPM. A clinical retrospective (with or without postmortem) done at Ohio State University from 1991 to 1994 found that 25% of all spinal ataxia was due to EPM. Although many other neurological diseases are present, EPM is without doubt the most common neurological disease among horses in North America today. Results from the 1988 workshop generally agreed with those of a four-year retrospective study done at the University of Kentucky’s Livestock Disease Diagnostic Center from 1988 to 1991. At Kentucky, 60% of affected horses were three years old or less. In addition, a seasonal trend was noted as more cases were diagnosed in the spring and summer. Other regional studies done at Cornell University and the University of Pennsylvania found that Standardbreds were more frequently affected than Thoroughbreds even though fewer Standardbreds were received for examination. The Pennsylvania study also found that young male horses were most often affected, but this was attributed to the over-representation of this group among the racehorse population that dominated its clinical practice. One final difference from the ACVIM study should be noted. While that study was national in scope, a number of arid western states were not in attendance. That was because very little EPM occurs in these states. Therefore, the fact that no geographic predilection was found is not too surprising. Researchers at Ohio State University in 2000 published a more sophisticated analysis of the risk factors for EPM. All information collected from horses with EPM was compared with the same information gathered from non-infected horses during the same time period. This was done to eliminate any risk factors that were not specific for EPM. This is called a “case-controlled” study. Increased risk for EPM was associated with age (one to five years old), season (spring, summer, fall), other EPM cases on the premises, opossums on the premises, certain health events prior to admission (lameness, foaling, accidental injury), and racing or showing as a primary use. Reduced risk was associated with protection of feed from wildlife and a the presence of a nearby creek or river. The USDA National Animal Health Monitoring System (NAHMS) completed an extensive study of U.S. horses in 1998. Included in this survey of equine owners were questions about EPM. Three of every 100 farms reported cases of veterinary-diagnosed EPM on the premises. Risk factors identified by the NAHMS survey included season (summer, fall), region (central and northeast), opossums on premises, operation size (20 or more horses), and primary use (showing/competition, racing). Although age and breed certainly seem to be factors, all horses are susceptible to S. neurona. Management factors associated with racing must be considered. Young horses are placed into rigorous training and competition schedules that often require thousands of miles of travel during the season. Although racehorses generally receive excellent care, physical and environmental stresses are known to affect the immune system negatively. EPM frequently has been associated with known causes of stress such as shipping and pregnancy. Initial disease and clinical relapse also have been associated with heavy work and steroid administration. Steroids are excellent anti-inflammatory drugs that also result in some suppression of the immune response. Low levels are produced naturally in the body and are essential for life. Increased release of steroids during periods of physical or environmental stress is partly to blame for immune suppression. Many veterinary clinicians and researchers believe that stress is a major risk factor for the development of clinical signs of EPM. Researchers at Ohio State University recently demonstrated the validity of this concept. They greatly improved the reliability of EPM infection trials by shipping horses from Canada to Ohio prior to sporocyst administration to induce mild stress. An issue related to immune status is genetic predisposition to susceptibility. This topic has received only anecdotal consideration at best. Certainly, some individuals in any population will be more susceptible to a particular infectious agent than others. Internal factors that control the immune response are passed genetically from parents to their offspring. However, there is no hard evidence to suggest that affected stallions or mares pass any increased susceptibility to EPM to their foals. While this may occur, the lack of obvious evidence suggests that other risk factors are more important.

dEvEloPing EPM REquiRES ExPoSuRE FiRST Before stress can influence the clinical onset of EPM, horses must first be exposed to S. neurona. The number of parasites ingested is a known risk factor for the development of clinical sarcocystosis in many intermediate hosts. Sarcocystis cruzi in cattle provide an excellent example. It has been demonstrated experimentally that small numbers of sporocysts produce no obvious signs of infection in cattle. In fact, it has been estimated that all cattle in the United States eventually become exposed to at least one species of Sarcocystis. Like EPM, relatively few exposures result in clinical disease. Larger numbers of S. cruzi sporocysts produce myositis, chronic wasting, and abortion, while even larger doses result in widespread areas of inflammation, anemia, and death. By comparison, initial EPM infection trials required extremely large numbers of sporocysts to produce neurological disease AT A GLANCE experimentally. Although none • EPM can affect any breed, but one of the horses were severely afmajor study found that the most commonly affected breeds were fected, low doses were not efT h o ro u g h b re d s, S ta n d a rd fective. These early experibreds, and quarter horses in that order. ments were conducted using sporocysts collected from feral • young horses are affected more often than older horses, but older opossums. It has since been h o r s e s a re ex p o s e d m o re discovered that the opossum frequently. harbors several species of • Stress is thought to trigger Sarcocystis. Undoubtedly, the clinical onset in some horses. actual number of S. neurona • horses must be exposed to the sporocysts administered was parasite before they can develop EPM. much lower than first believed. Current infection trials use • Blood tests can confirm exposure to EPM, but a positive blood test sporocysts collected from labodoes not mean that a horse has ratory opossums. In addition, the disease. special tests are used to verify the identity of sporocysts before administration. More recent trials have demonstrated that it is possible to produce EPM with low numbers of sporocysts; however, high doses produce clinical signs more reliably in less time. The EPM blood test has been used to estimate the prevalence of S. neurona antibodies in serum (seroprevalence) among horses in several states. The first large study included 40 randomly selected farms from the Bluegrass region of Central Kentucky. Blood samples from more than 500 horses were tested, which resulted in an exposure rate of more than 45%. A similar exposure rate was found in a study of 117 horses randomly selected from all Thoroughbred farms in Chester County, Pennsylvania.

A somewhat different experimental approach was used to estimate seroprevalence in Oregon. Twenty-one veterinarians, distributed evenly across the state, randomly collected 334 blood samples from client horses. An average exposure rate of 45% was found. However, when sample results were evaluated based on geographic location, a fascinating discovery was made. (The state was divided longitudinally into four equal sections from east to west.) Seroprevalence dramatically increased from a low of 22% in the arid eastern region to a high of 65% in the humid west. Interestingly, these results mirror the location of the opossum population in Oregon. Another study of 300 horses was done using blood samples from wild horses caught in Utah. Seroprevalence was less than 1%. Apparently, opossums and sporocysts both do poorly in hot, dry climates. Two seroprevalence studies have been done using blood randomly selected from samples submitted for Coggins testing. A current Coggins test is required for most equine events and interstate travel. Some argue that this mobility introduces too much error for accurate analysis of exposure rate based on Coggins samples. Undoubtedly, travel does affect the results. However, samples submitted for Coggins testing provide a readily available resource that is very well defined. Totally random sampling of all horses in a large area is labor intensive and cost prohibitive. The largest EPM study using Coggins blood samples was done in Ohio, where more than 1,000 samples were selected. The excellent information included with the samples revealed that submissions were present from 81 of 88 Ohio counties and virtually all breeds found in the state. The average exposure rate was almost 54%. However, a significant difference in exposure rate was found between the northeast (45%) and the southwest regions (62%) of the state. This was found to be associated with the number of days below freezing in each region. As the number of days below freezing increased, the seroprevalence decreased. Just as the Oregon study confirmed the effect of arid conditions on sporocyst survival, the Ohio study provided practical confirmation that sporocysts are susceptible to prolonged freezing. This result also helps validate the use of Coggins blood samples for seroprevalence studies. A similar study was done at Colorado State University using more than 600 Coggins samples. Seroprevalence was 34%. This result coincides with the lower exposure rate found in the arid regions of eastern Oregon. A seroprevalence study of Michigan horses was completed by researchers at Michigan State University. However, a modified version of the standard EPM test was used to conduct the study, making it difficult to compare the results (60%). Limited information on Neospora seroprevalence is available. Twenty-three percent of the serum samples collected (296) from two equine slaughterhouses in the United States were positive. A large study (536 serum samples) done in Alabama found a 12% exposure rate, but a different type of test was used.

oldER hoRSES ExPoSEd MoRE oFTEn A direct correlation between age and seroprevalence was a recurrent theme among the seroprevalence studies. The exposure rate consistently increased with age. This is not too surprising, given that older horses have had more time to become exposed. However, the degree of increase is both startling and informative. In Pennsylvania (state average 45%), horses less than one year old had an exposure rate of 15% and horses older than 14 were exposed 61% of the time. Similarly, in Oregon (state average 45%), horses less than one year old had an exposure rate of 15%, while horses older than 15 were positive 64% of the time. Aged horses in the Ohio study (state average 54%) reached the highest exposure rate. Horses less than six years old had an exposure rate of 46%, while 82% of horses older than 16 tested positive. The Colorado study reported 27% exposure among horse less than five years of age, increasing to 37% for horses more than 10 years of age. Undoubtedly, horses are exposed to S. neurona repeatedly. If the interval between significant exposures is not prolonged, antibody production is boosted and the horse could remain positive for an indefinite period. We already know that horses can remain seropositive for years without developing clinical signs. It is also readily apparent that the parasite can be harbored in the horse for months, or even years, before causing clinical disease. This has been demonstrated by the two-year delay in development of clinical disease in horses shipped to countries where EPM is not known to occur. Unfortunately, these cases were reported before the advent of the EPM test, so information regarding the presence of antibody in serum or spinal fluid is not available.

RESEARch in PRogRESS Several research groups continue to work on developing a more reliable infection model in the horse. An ideal model would produce a predictable level of clinical disease in each horse that received a standard oral dose of sporocysts. In addition, it would be possible to find parasites in damaged areas of the CNS at the end of the experiment. The availability of a reliable model would permit researchers to unlock many of the secrets of the disease: how merozoites enter the CNS; how the parasite remains undetectable for months or years in the horse’s body; how horses fight off infection; what the basis is for breed predilection; investigating an underlying genetic predisposition to clinical disease. Normal horses appear to have the ability to eliminate the parasite rapidly, making it extremely difficult to study the infection. The Ohio State model appears to be the most consistent model to date, although parasites have not been found following infection. The model uses travel stress to uniformly enhance the susceptibility of experimental animals. The model appears to have sufficient reliability to test the efficacy of new drugs and vaccines. A number of equine infection models have been Sporozoites cultured from the opossum. developed that rely on alternate routes of parasite administration or genetic immunodeficiency. These are useful to study some aspects of the disease; however, they fail to emulate natural infection. Therefore, it remains necessary to develop an ideal infection model, as defined, to provide definitive answers to many of the questions surrounding EPM.

brief review of the horse’s nervous system will help provide a more complete understanding of the clinical signs of EPM. The basic subunit of the nervous system is the nerve cell or neuron. Neurons conduct nerve impulses, which form the communication network for the entire body. Neurons are “terminally differentiated” cells. In other words, they are so advanced that they can no longer divide. Once damaged beyond repair, individual neurons are lost forever. However, there are more than enough neurons built into the nervous system. They operate in interconnected groups so that if one neuron dies, the function it performed is not necessarily lost. Neurons extend a few short processes and one long process called an axon, or nerve fiber, to communicate. Information is transmitted to and from the central nervous system through a continuous succession of neurons and axons, which form nerves. There are three types of neurons: sensory, interneuron, and motor. Sensory neurons are located outside the CNS and gather information about the body and environment. The CNS is bombarded constantly by incoming signals from the axons of sensory nerves. Some neurons actually provide inhibitory input. Without these inhibitory signals to regulate incoming information, the brain would be unable to function. For example, strychnine poisoning depresses inhibitory neurons and results in widespread muscular contraction due to the loss of down regulation. Interneurons are located within the CNS. Their function is to relay information from the sensory neurons and other interneurons back to motor neurons. Motor neurons are located in the CNS and send signals via axons to all the muscles and glands throughout the body. Motor nerve signals initiate action in muscles and glands and provide constant low-level stimulation, which maintains muscle tone.

EPM develops in the horse’s central nervous system.

What are the clinical signs of EPM?

The brain processes the sensory information received from the rest of the body and transmits signals that reflect decisions to initiate action. The brain, essentially a large mass of interconnected neurons and axons, must respond properly to all stimuli for the body to function normally. Specific groups of neurons Cranial nerves and FunCtions in well-defined areas of no. name Function the brain cooperate to I. Olfactory Sense of smell perform the specific funcII. Optic Sight tions necessary for life. III. Occulomotor Iris (pupil constriction), Twelve cranial nerves origeye muscles, upper eyelid inate from discrete neuron IV. Trochlear Eye muscles groupings or nuclei in the V. Trigeminal Jaw muscles; Sensory to face, mouth, brainstem, which control and teeth most functions of the head VI. Abducens Eye muscles and neck. Ever y body VII. Facial Facial muscles; function is controlled by Sensory to first 2/3 of tongue the CNS: heartbeat, temVIII. Vestibulocochlear Hearing and equilibrium perature regulation, intesIX. Glossopharyngeal Tongue, throat, and palate muscles; Sensory to throat tinal motility, breathing, and last 1/3 of tongue body movement, emotion, X. Vagus Organ muscles etc. Damage to specific (lungs, heart, intestines), palate muscle; Sensory to areas results in very prethroat and lungs dictable clinical signs. XI. Spinal Accessory Throat and shoulder muscles The horse’s spinal cord XII. Hypoglossal Tongue is a soft, white, cylindrical structure that runs from the base of the skull to the small of the back. Its diameter varies from one-half inch to more than an inch as it travels inside the vertebral column toward the tail. Location along the vertebral column is designated by region: cervical (neck), thoracic (chest), lumbar (mid-back), sacral (lower back), coccygeal (tail), and vertebral number within the region (C1-7, T1-18, L1-6, S1-5, Cy1-21). When cut in crosssection, the spinal cord is oval and reveals a butterfly shaped gray area (gray matter) surrounded by white matter. Gray matter is made up of neurons (interneurons and motor neurons), while white matter consists of axons from sensory (ascending) and motor (descending) neurons. Spinal nerves exit the spinal cord at each vertebral joint. Spinal nerves are formed by thousands of sensory and motor axons. Except for the cranial nerves, all the nerves supplying the periphery (rest of the body) ultimately branch from spinal nerves. Damage to the root or starting point of a particular spinal nerve within the spinal cord results in very specific loss of function(s) controlled by that nerve and its branches. This often includes the loss or enhancement of specific reflexes, which can be useful for diagnosis.

at a GlanCe InFEcTIOn, InFlAMMATIOn, And clInIcAl dISEASE • Inflammation of the central nervous system results when the Sarcocystis neurona can strike horse’s immune system fights the the CNS anywhere along the invading parasites. brain or spinal cord. It attacks • Inflammation and swelling gray and white matter with caused by S. neurona infection similar frequency. It most often sometimes can lead to a lifethreatening situation. infects several specific areas at once (multifocal) and rarely • Clinical signs of EPM are directly related to the site of specific produces diffuse or widespread lesions in the brain or spinal damage. EPM is a highly varicord. able clinical disease. Depending • Clinical signs can range from seion the location and number of zures and depression to loss of sight, hearing, taste, touch, and parasites present, individual incoordination. fections might manifest insidiously, producing very subtle signs, or might strike with incredible speed, resulting in very dramatic loss of function. Although unusual, the inflammation and swelling caused by S. neurona infection can become rapidly life-threatening. Since the CNS is encased in bone, there is very little room to accommodate swelling. The resultant pressure compromises the blood supply to the CNS, which is critical for the survival of nervous tissue. Neurons are so specialized that they have very little energy reser ve. Consequently, they have a very high oxygen requirement and die within seconds if this demand is not met. This helps explain how a horse can appear normal loading onto a trailer in the morning and be unable to walk down the ramp that afternoon. When merozoites penetrate the CNS, a battle ensues. The horse’s immune S. neurona merozoites in a cell from system initiates a cascade tissue culture. of events resulting in inflammation and cell death. It is ironic that the battle itself can become life-threatening. One aspect of this battle is a dramatic increase in the porosity of the horse’s blood-brain barrier. A rapid influx of fluid, serum components, and white blood cells occurs, which is required to repel the invaders. However, there is no corresponding increase in outflow. The resultant disruption of normal CNS architecture and increased pressure restrict normal blood flow to the immediate area. Interference with oxygen availability results in rapid neuronal death. In addition, toxic products released to kill parasites and substances inadvertently released from dead and dying cells further contribute to the damage. At post-mortem, the damaged areas, called lesions, typically appear as focal areas of hemorrhage and swelling on the cut surface of the spinal cord. The elimination of parasites removes the stimulus for these events, and damaged areas eventually are cleaned up by specialized cells, which multiply for this purpose. Lost neurons cannot be replaced, but gradually damaged areas heal, leaving characteristic scars. Clinical signs caused by pressure, without widespread neuronal death, should subside. Neurological deficits due to the death of neurons or axons can return only if a sufficient number of appropriate neurons remain to compensate for their loss. The repair and recovery process can take months, particularly when some parasites persist. At present, we do not know if this battle in the CNS is waged routinely following ingestion of sporocysts, or if many merozoites are eliminated before crossing the blood-brain barrier. It seems likely that both scenarios occur on a fairly routine basis. The emergence of clinical signs on any given day would simply depend on which direction the dynamic balance between the parasite

Some clinical signs, such as back soreness, are not always associated with neurological disease.

burden and host response is tipped.

SIGnS OF EPM cAn VAry wIdEly It now should be evident that the clinical signs of EPM are directly related to the location of specific lesions in the brain or spinal cord. Because the disease is multifocal, affecting more than one area at the same time, a wide range of neurological deficits may occur in various combinations within any individual. Damage to the brain might result in behavioral or cognitive deficits unique to the cerebral cortex (seizures, depression, memory loss) or might produce signs attributable to brainstem damage (loss of sight, hearing, balance, smell, taste, touch, coordination; difficulty eating; personality change). Due to the integration or processing of all information in the brain, brain damage might mimic direct sensory Some horses with EPM develop a drooping lip (coordination) and/or motor or other signs of facial paralysis. (muscle wasting, weakness, paralysis) pathway damage to the spinal cord or peripheral nerves. Many authors have commented in the veterinary and lay literature about the vast array of common to bizarre clinical signs associated with EPM. I think most would agree that ataxia (incoordination) of one or both rear limbs is recognized more frequently than any other clinical sign of EPM.

If both back legs are affected, one is usually more severely affected than the other because separate areas of infection are responsible for impairing the function of each limb. at a GlanCe Clinicians often refer to this as • Ataxia, or incoordination of one or “asymmetric posterior ataxia,” both rear limbs, is recognized more frequently than any other which may “lateralize” to the clinical sign of EPM. left or right side of the horse • Horses with EPM sometimes have dependent on which is more a proprioceptive deficit, meaning severely affected. Typically, the their awareness of limb placement is compromised. underlying cause of this problem is a discrete lesion(s) • Muscle atrophy sometimes accompanies ataxia and cominvolving sensory axons in the monly occurs over the hips or spinal cord past the second thoshoulders. racic vertebra (T2). However, • When EPM strikes the brain, inlesions of the brain, brainstem, fection can lead to behavioral or inner ear also may cause changes. a t a x i a . S e n s o r y p a t h way • Subtle neurological signs can damage to the spinal cord up to signal EPM. They might include bucking, high head carriage, back and including T2 involves the soreness, inappropriate lead front legs, but often includes changes, and unequal stride length. one or both back legs due to lesions affecting sensory axons • Each case of EPM is different and unpredictable, adding to the supplying the rear limbs. Nerves confusion and debate over the serving the front limbs branch disease. from the spinal cord before T2, and those serving the rear limbs branch after T2. Damage to the motor pathways of the spinal cord might result in weakness (truncal sway, toe dragging), paralysis, and atrophy (wasting) of the muscle(s) served by the affected nerves. Muscle atrophy most commonly occurs over the hips or shoulders, and only rarely becomes widespread. Many of these clinical signs often accompany ataxia. It becomes easy to appreciate why a horse with multiple lesions in gray and white matter of the spinal cord becomes ataxic. Loss of sensory and motor nerve input diminishes proprioception (sense of limb position) and the horse’s ability to initiate movement. Lesions occurring at the sacral end of the spinal cord (L6-S2) frequently result in the loss of muscle tone in the anus and tail, as well as loss of skin sensation in the area. Affected horses might dribble urine due to partial or complete bladder paralysis. Rectal paralysis also occurs, which can lead to colic due to impaction. Subtle signs associated with mild CNS lesions apparently are more common than generally appreciated (or accepted). It seems reasonable to assume that a gradual (or occasionally rapid) progression of clinical signs results as lesions become worse and infection spreads. At some point, the effects of infection become recognizable. Part of the controversy surrounding EPM is due to the difficulty in detecting subtle signs, then attributing them to EPM. For example, many diseases result in training problems and/or poor athletic performance. While it is clear that EPM is certainly one of these, the real question becomes “how often?” It is not always readily apparent that some clinical signs are associated with neurological disease at all. Many are more often associated with various causes of lameness, muscle soreness, and behavioral problems. Those described include frequent bucking, head tossing, high head carriage, back soreness, inappropriate lead changes, unequal stride length, and other subtle gait abnormalities. The most compelling reason to consider EPM when these clinical signs are observed is the growing body of evidence provided by affected horses that progressed from subtle to obvious neurological signs followed by response to treatment or post-mortem confirmation. At the same time, many horses exhibit these signs and do not appear to progress. Did they have EPM and fight it off without treatment? Did they ever have EPM at all? It is very difficult to determine. In addition, it is important to realize that neurological disease can cause secondary musculoskeletal injuries and true lameness. All of these factors add to the confusion and debate over EPM and create quite a dilemma for veterinary practitioners. It becomes that much more difficult to decide when to place EPM on the list of possible causes of various clinical problems. One of the most important points to remember is that EPM produces highly variable clinical disease. Each individual case is unique and unpredictable. Many of the questions regarding the how, when, why, and where of EPM do not have good answers. It is unrealistic to expect the attending veterinarian to provide definitive answers. Ultimately, the knowledge and experience of the attending veterinarian provide the best hope for a rapid, accurate diagnosis. Various diagnostic aids often prove helpful and will be discussed in the subsequent chapter.

veterinarian’s ability to make the correct diagnosis is always enhanced by a thorough, accurate clinical history of the affected horse and others at the same location. Important clues about the cause of the disorder might be revealed. In addition to age, breed, and sex, the veterinarian will need to know the vaccination and deworming schedule, feeding history, changes in appetite, any behavioral changes, the rate of onset and duration of any clinical signs, and all recent changes in the horse’s environment or management. A thorough neurological examination is the single most important part of an effective diagnostic plan for EPM. Musculoskeletal injuries (muscle, tendon, ligament, or bone) occur much more commonly than EPM. Therefore, the importance of differentiating lameness from neurological deficits is critical. Musculoskeletal injuries might result from underlying neurological disorders, making the recognition of concurrent neurological deficits more difficult. In many cases, this differentiation can be made easily, but unusual or mildly affected horses can be very difficult to assess. The use of local anesthetics to perform nerve blocks is often helpful. Horses return to normal following a nerve block only when the problem is local. Clinical signs due to AT A GLANCE central nervous system involve• A thorough neurological exam is ment are unaffected by local or crucial in effectively diagnosing EPM. regional nerve blocks. The horse will continue to appear • All other disorders should be ruled out first. “lame.” The multifocal nature of CNS damage due to EPM is • Other equine diseases can affect the horse’s neurological system. often useful for differentiation from lameness, as well as other • Laboratory tests can help differentiate EPM from other diseases. neurological disorders. Clinical evidence of neurological • Development of accurate diagnostic tests for EPM is continuing. damage at multiple sites within the CNS is highly suggestive of EPM. This evidence is especially helpful when improvement or complete function has returned to an individual limb following a nerve block but other limbs fail to respond. After recognizing that a neurological disease is at work, the veterinarian must differentiate the particular disorder(s) responsible. Again, a thorough neurological exam is of the utmost importance. Careful consideration of exam results and history should suggest a short list of differential diagnoses that might require additional diagnostic testing. The chart that appears at the end of this chapter is an example of an excellent neurological examination form developed at Ohio State University. Hopefully, a thorough discussion of this form and the underlying reasons for its configuration will help illustrate the complexity of neurological diseases in general and provide a greater understanding of EPM. The basis of the neurological exam form can be found in the neuroanatomical discussion in the previous chapter. A methodical, systematic analysis of neural pathways, starting with the head and ending at the tail, has been outlined. Behavioral abnormalities (depression, belligerence, loss of appetite), seizures, or blindness might indicate brain lesions. Reflexes involving the cranial and other peripheral nerves are evaluated on both sides of the body. Loss of skin sensation is evaluated and mapped if present. Differentiation between the loss of skin sensation and the ability to feel pain is useful to help determine the extent of damage. Many muscles and muscle groups are assessed for tone and strength and compared from side to side. Movement is evaluated in all directions and under different circumstances to evaluate sensory and motor innervation. Standing limb position or placement is tested to further assess proprioception and to help localize CNS damage.

DiffErEntiAL DiAgnOsis Although EPM is the most commonly diagnosed equine neurological disease in the Western Hemisphere, many other neurological disorders affect horses as well. Accurate interpretation of neurological exam findings and clinical history requires a thorough understanding of these disorders. A discussion of the most common of these follows in approximate order of occurrence in North America. Regional differences in frequency are common. Consult your veterinarian to learn which disorders are most common in your area.
Cervical Vertebral Myelopathy

For many years incoordinated horses were simply known as “wobblers.” Today, the term refers primarily to horses with a developmental disorder of the cervical spine known as cervical vertebral myelopathy (CVM) or cervical stenotic myelopathy (CSM). The disease is common among young (one to three years old), rapidly growing male horses of various breeds (Thoroughbreds, Standardbreds, large draft breeds). Narrowing of the spinal canal due to malformation of growing vertebrae and overriding adjacent vertebrae compresses the spinal cord. The cause of these developmental abnormalities appears to be related to genetic predisposition (conformation and growth potential) and diet (high carbohydrate, high zinc, low copper). Proprioceptive tracts in the white matter are the most consistently and severely damaged, but motor pathways also can be affected. Although cord compression might occur in one or more sites, damage to the axons extends well above and below the local area of injury. The consistent nature of the damage is due to the relatively uniform nature of cord compression from the bottom and sides of the vertebral canal. Affected horses exhibit characteristic clinical signs that primarily vary in degree of severity. These include symmetric ataxia and weakness (toe dragging, stumbling), which are usually worse in the rear legs. Clinical signs can become exaggerated by extending the neck up or bending it down. Infrequently, asymmetric ataxia can occur if degenerative vertebral joint disease (arthritis) becomes more severe on one side of the neck and compresses the spinal cord unilaterally. Neck pain is not usually associated with CVM; however, severe arthritic changes can result in bone growth that impinges on spinal nerves as they branch from the spinal cord and exit the spinal canal at vertebral joints. This results in neck pain, local muscle atrophy, and loss of cervical reflexes and skin sensation. The diagnosis of CVM is greatly enhanced by the use of radiography (X-ray). Cervical radiographs taken with careful attention to detail provide a great deal of information regarding the likelihood of CVM. Unfortunately, many clinically normal horses have radiographic evidence of cervical vertebral joint disease. A more definitive diagnosis

requires a myelogram. This is a series of special radiographs of the neck prepared by the addition of an X-rayabsorbing dye into the horse’s spinal fluid. The dye is visible on radiographs of the spinal canal. Severe cord compression prevents the passage of dye through affected vertebral joint(s). Nutritional and surgical therapies for CVM are available and have proven effective for many horses. However, improvement generally depends on the length of time clinical signs have been present prior to the initiation of treatment. This is simply a reflection of the poor regenerative ability of the CNS.
Trauma

Trauma is another common cause of neurological deficits in the horse. Falls, collisions, kicks, and physical abuse can result in direct injury to nervous tissue with or without skull or vertebral fracture. Peripheral nerve damage is frequently associated with trauma and must be considered as well. Horses of all ages and breeds can be injured, but young, excitable horses and performance horses are more prone to accidental injury. The sudden onset of neurological signs always suggests trauma, but it is important to remember that EPM can strike quickly and that horses with neurological deficits are often predisposed to mishap. Fortunately, several factors help differentiate neurological deficits due to traumatic injury from those associated with EPM. Clinical signs depend on the location and severity of CNS injury. Horses might be down and comatose or simply appear stiff. Careful neurological examination should localize damage to a single area of the CNS. Injuries to the brainstem and cervical spinal cord occur most frequently. Pain and external evidence of injury, such as swelling and skin damage, frequently are present at the site of impact. Radiographs often are helpful.

E P M

Inflammation and muscle degeneration caused by the S. fayeri sarcocyst, a species of Sarcocystis; Inset: S. fayeri sarcocyst in the muscle.

A section of spinal cord damaged by the EPM parasite.

Spinal cord from an affected horse, showing hemorrhage and swelling.

A thorough neurological exam is crucial in diagnosing EPM. In photos 1-3, the veterinarian assesses whether a horse knows where his rear limbs are placed. Many horses suffering from EPM experience a proprioceptive deficit, meaning their awareness of limb placement is compromised.

In photo 4, the veterinarian tests for weakness in the rear legs. In photo 5, the vet checks for asymmetry in the muscles that are required for swallowing and the muscles that move the larynx. Below, the veterinarian draws cerebrospinal fluid for the EPM diagnostic test. The fluid can be drawn from the croup area or from behind the poll.

Lumbosacral CSF tap.

Atlanto-occipital CSF tap.

Rear limb incoordination, or ataxia, is perhaps the most common clinical sign of EPM. This horse is exhibiting abnormal body posture and placement of the rear legs.

The horse in photos 1-2 has difficulty backing and knowing where his rear limbs are, both of which are signs associated with EPM.

When turning, a horse with EPM frequently swings his outside rear leg out farther than normal, as does the horse in photo 3. The horse in photo 4 shows atrophy, or loss of muscle mass, another common sign of EPM.

This Quarter Horse, donated to the University of Kentucky, shows muscle atrophy in the hindquarters, difficutly turning, and weakness in the rear legs.

The clinical signs of EPM can vary from very abnormal body posture (top left) to mild ataxia (top right and bottom).

These photos were taken from a video of a mare with EPM before she began the experimental drug treatment program at the University of Kentucky. She now can walk straight and can fend for herself.

In the absence of displaced skull or vertebral fractures, initial trauma might result in minimal disruption of normal CNS architecture. However, hemorrhage and swelling within the bony confines of the CNS rapidly compromise the delivery of oxygen to neurons and other cells. Without rapid medical intervention, peak damage is usually reached within 24 hours. The clinical condition should then stabilize or begin to improve without further progression, unless re-injury occurs. Depending on the severity of the injury, response to therapy can be rapid, very gradual over an extended period, or negligible. Residual neurological deficits are common.
Equine Degenerative Myeloencephalopathy

Equine degenerative myeloencephalopathy (EDM) is a very common neurological disease of horses in the northeastern United States. It also occurs with somewhat less frequency in the rest of North America and Europe. The disease was first described in 1976 and, like EPM, it causes progressive ataxia and weakness in young horses of many breeds. Symmetric ataxia is common and generally most severe in the back legs. Clinical signs most often begin in weanlings and plateau by two years of age. Onset is usually insidious, although acute cases have been reported. EDM has been linked to areas with limited pasture availability and reliance on pelleted feeds and hay. A great deal of evidence suggests that vitamin E deficiency and genetic predisposition are significant risk factors for EDM. Exposure to creosote wood preservatives and possibly pyrethrin insecticides might increase the risk of horses developing EDM. The disease produces diffuse, bilaterally symmetrical degeneration of proprioceptive tracts in white matter of the spinal cord. Although lesions can develop in the brainstem, cranial nerve deficits do not occur. In addition, muscle atrophy and loss of skin sensation are not associated with EDM. If any of these signs develop, EDM can be dropped from the list of differential diagnoses. EDM is frequently diagnosed by a process of elimination as other neurological diseases are removed from consideration by the results of diagnostic testing. Affected horses are treated using daily, high-dose vitamin E supplementation for several years. Although some horses improve, EDM appears to be more effectively prevented than treated. Prevention also relies on daily vitamin E supplementation, but at a much lower dose.
Equine herpesvirus-1

Equine herpesvirus-1 (EHV-1) is a contagious virus that causes abortion and upper respiratory and neurological disease among horses worldwide. The virus has produced outbreaks at breeding farms, training facilities, and racetracks. It has an affinity for vascular endothelial cells of the CNS, infecting them preferentially. Subsequent viral multiplication results in damage to the blood vessels (vasculitis), which interferes with oxygen delivery to the CNS. Gray and white matter of the spinal cord most often are affected, resulting in symmetric ataxia and weakness of the rear legs, bladder paralysis, and loss of tail and anal tone. Treatment often is successful if affected horses retain the ability to stand. Some recover rapidly while others improve gradually for many months. Residual neurological deficits may remain. EHV-1 vaccines are available but have been unable to prevent neurological disease.
West Nile Virus

West Nile Virus (WNV) is a recent addition (1999) to the list of equine (and human) neurological diseases in North America. The disease started in New York and has quickly spread to most parts of the United States in a few short

years. Birds serve as the primary reservoir for the virus, which is spread by mosquitoes. Common clinical signs include asymmetric neurological deficits, weakness, and ataxia, making it very difficult to differentiate from EPM. A reliable blood test is available to confirm the diagnosis.

OthEr nEurOLOgicAL DisEAsEs EPM, trauma, CVM, EDM, EHV, and WNV account for the vast majority of equine neurological diseases in North America. However, a number of other neurological diseases that are easily confused with EPM occur sporadically.
Otitis Media/Interna

Middle and inner ear infection (otitis media/interna) and temporohyoid osteoarthropathy involve progressive inflammation of the middle ear and the associated joint between the temporal and stylohyoid bones. The underlying cause of middle ear disease is believed to be chronic middle ear infection that spreads to the bone. Chronic arthritis of the temporohyoid joint results in fusion of the joint and loss of normal mobility. Pressure develops from movement of the tongue and larynx, resulting in fracture of the skull and occasionally the stylohyoid bone. Initially, horses exhibit signs of ear pain, such as ear rubbing, head tossing, and sensitivity to touch. Continued arthritic changes damage cranial nerve VII (facial) and VIII (vestibulocochlear), resulting in facial paralysis, head tilt, and ataxia. Occasionally, cranial nerves IX (glossopharyngeal) and X (vagus) are injured as well, resulting in difficulty eating and swallowing (dysphagia). Blindfolding horses with ataxia due to vestibulocochlear nerve or associated brainstem damage will make them unable to compensate visually for the loss of balance and make the ataxia much worse. Radiographs and video endo59

scope examination of the guttural pouches are also helpful. Antibacterial and anti-inflammatory therapy, as well as surgical intervention, frequently return horses to normal function.
Verminous Encephalomyelitis

Various parasites (worms and fly larvae) inadvertently migrate into the CNS during part of their developmental cycle. Several are primary equine parasites, some are misplaced from other animals, and still others are free-living opportunists. Most worms gain entry through ingestion and penetration of the gut to reach the bloodstream. One type enters the bloodstream through mosquito bites, while the most common type (Halicephalobus deletrix) enters the nose while horses are drinking. Heel fly larvae penetrate the skin and migrate directly to the CNS. Fortunately, parasite migration in the CNS is rare. Clinical signs are variable and depend on the route of migration. Asymmetric, multifocal signs are most common. The brain is affected more frequently than the spinal cord. Onset is typically sudden, and the course of infection is usually rapid. However, chronic infections have been reported. Differential diagnosis is difficult. Occasionally, microscopic evaluation of CSF reveals a white blood cell type (eosinophil) that is associated with the presence of worms. Treatment includes anti-inflammatory drugs, antiparasitic drugs, and good nursing care. Although residual neurological deficits are common, many horses respond favorably to treatment.
Cauda Equina Syndrome

Cauda equina syndrome refers to a set of neurological deficits that result from damage to the sacral spinal cord and its spinal nerves. Cauda equina means “horse tail” in Latin and refers to the physical resemblance of the many

branching spinal nerves to a horse’s tail. The clinical signs of cauda equina syndrome are identical to those described for EHV-1. In fact, EHV-1, as well as EPM, trauma, tumors, abscesses, migrating parasites (worms), and ingestion of sorghum-sudan grass are all considered causes of cauda equina syndrome. Polyneuritis equi is a very similar syndrome that affects older horses and is believed to be caused by a misdirected immune response against the horse’s own CNS. Progressive inflammation of the sacral spinal cord and brainstem can occur. Cranial nerve signs include facial paralysis, jaw muscle atrophy, head tilt, and loss of equilibrium with ataxia. Successful treatment of cauda equina syndrome is dependent on the underlying cause. Polyneuritis equi seldom responds to treatment.
Rabies

Although rabies virus infection is relatively uncommon in the horse, it should always be considered when neurological deficits have been present for less than 10 days. Rabies usually results in death in three to 10 days unless anti-inflammatory drugs prolong the course inadvertently. Clinical signs of rabies are highly variable and can include ataxia, rear limb weakness, extremely sensitive skin, and atypical or aggressive behavior. The disease inevitably progresses to coma and death unless it is recognized quickly and the horse euthanized. The disease can be effectively prevented with the use of available vaccines.
Neoplasia

Many neurological disorders that have not been discussed occur in horses. Hopefully, most will agree that those left out are either easily differentiated from EPM or occur too infrequently in most of North America for consideration here. These disorders include other viral, bacte61

rial, and fungal CNS infections; bacterial vertebral infection; epidural abscesses; tetanus; botulism; mycotoxins (moldy corn poisoning); Lyme disease; toxic plants or chemicals; metabolic disorders (liver disease, hypoglycemia); congenital abnormalities; motor neuron disease; postanesthetic hemorrhagic myelopathy; epilepsy; and narcolepsy. Consult your veterinarian if you need additional information regarding any of these disorders.

AnciLLAry DiAgnOstic AiDs The usefulness of nerve blocks, radiographs, myelograms, and video endoscopy has been discussed. Other useful diagnostic aids include nuclear scintigraphy, electromyograms (EMG), electroencephalograms (EEG), ultrasound, thermography, computed tomography (CT scan), and magnetic resonance imaging (MRI). Many of these techniques are available only at large referral centers and veterinary teaching hospitals. Although few veterinarians have access to CT and MRI, these technologies have proven to be extremely helpful for the diagnosis of equine neurological diseases. Hopefully, they will become more widely available in the future. LAbOrAtOry tEsting Laboratory diagnostic tests provide a useful adjunct to clinical examination for the differentiation of EPM from other neurological diseases. A number of laboratory tests are available. Complete (CBC) and differential blood counts help differentiate various types of infectious and non-infectious diseases by evaluation of the number, type, and characteristics of red and white blood cells present in a blood sample. Veterinarians often evaluate multiple blood samples over a period of days or weeks to monitor changes that might suggest a diagnosis or indicate a change in the condition. Unfortunately, EPM rarely causes any detectable changes in the CBC or differential cell count. Serum chemistry profiles include a broad array of tests to evaluate electrolyte balance, hydration, liver and kidney funcAT A GLANCE tion, muscle damage, inflamma• Various laboratory tests can help tory activity, and antibody prodistinguish EPM from other neurological diseases. duction. Although these tests can help diagnose other diseas• the presence of antibodies to the EPM parasite in blood and es, EPM does not produce any cerebrospinal fluid is the basis consistent changes. of the EPM diagnostic test. Muscle samples can be collect• One study found that testing ceed and processed to differentirebrospinal fluid would detect S. neurona antibodies in nine out ate primary muscle disorders of 10 horses showing neurologifrom loss of innervation. EMGs cal signs of EPM. also are used to evaluate muscle • immunoblot and DnA testing innervation. can help determine exposure to Cerebrospinal fluid (CSF) S. neurona. samples can be collected and analyzed for a number of factors that often are useful for differentiation between infectious and non-infectious neurological diseases. These include color, clarity, cell counts, and concentration of protein, enzymes, glucose, electrolytes, and antibody. Blood contamination of CSF during the spinal tap and sample collection is common and, unfortunately, precludes useful analysis of the sample. When this occurs, the horse should be re-tapped in a few days. This does not appear to jeopardize the reliability of test results. It should be remembered that traumatic injury and verminous encephalomyelitis also can cause hemorrhage into the CSF. Nonetheless, EPM rarely produces consistent changes in these parameters. The ratio of CSF protein (albumin) concentration to serum albumin concentration provides an index called the albumin quotient (AQ). Albumin is the major protein of serum and is not produced in CSF. It must enter the CSF from serum. Therefore, comparing AQ from abnormal horses to the range of values for AQ established from normal horses helps veterinarians determine the integrity of the blood-brain barrier. If the CSF albumin concentration is significantly elevated, accidental blood contamination of the sample must be considered. Immunoglobulin type G (IgG) is the most abundant class of antibody produced in the horse. Total IgG concentration is determined in CSF and serum, and the ratio is used in conjunction with the AQ to evaluate local IgG production in the CNS. EPM, as well as some other CNS diseases, routinely causes elevated IgG production in the CNS. The presence of S. neurona-specific antibody in serum and CSF is the basis of the EPM diagnostic test. The EPM test was developed in 1991 using cultured S. neurona merozoites and antiserum from horses with EPM or S. fayeri exposure. Rabbit antisera against S. neurona, S. cruzi, and S. muris also were used for comparison. Cultured merozoites were dissolved and individual proteins in the mixture were electrically separated in a thin sheet of clear gel (electrophoresis). A piece of paper was placed over the gel, and an electric current was used to transfer (blot) the separated proteins onto the paper. This made it possible to compare the reactivity of antibodies produced against several Sarcocystis to S. neurona proteins (immunoblot analysis). Eight unique proteins that reacted only with antibodies produced against S. neurona were identified. Several of these proteins became the basis of the EPM test developed at the University of Kentucky, then transferred to the university-owned Equine Biodiagnostics in 1995. Immunoblot testing of equine serum and CSF provides veterinarians with valuable information regarding exposure to S. neurona. Antibodies directed against proteins shared by S. fayeri and similar organisms are differentiated. Although we have continued to make improvements in the EPM test over the years, it still is based on the original immunoblot technique. Every aspect of the test has been optimized and standardized for maximum sensitivity and specificity, as well as minimal test-to-test variation. Extensive internal and external control samples are run on every blot to ensure the accuracy and reliability of each result. A purported improvement in the standard EPM test was introduced by other investigators in 2000. The modified test relies on pre-treatment of blotted parasite proteins with anti-S. cruzi serum collected from cattle. This change was made in an attempt to block access to antibodies in test serum that may inadvertently cross-react with proteins considered specific for S. neurona, thus reducing the possibility of a false positive test result. Since target proteins for the standard test were selected based, in part, on the lack of cross-reactivity with S. cruzi antiserum, the opportunity for test improvement is limited. Following statistical analysis of their results, the investigators also selected a different set of target proteins to indicate a positive test. At least one of the proteins selected appears to cross-react with S. fayeri, among other protozoan parasites. A recent comparison of the tests was published by a third group that indicated the modified test was not performing up to expectations. A fluorescent immunoassay (FIAX) based on S. cruzi bradyzoites isolated from cattle muscle has been available to test horses for Sarcocystis exposure since the mid-1980s. The test relies on antibodies in equine serum that cross-react with S. cruzi proteins. This means that many non-specific antibodies to S. fayeri and S. neurona present in a horse’s serum will react in the test. Since approximately 30% of horses are believed to be exposed to S. fayeri, the usefulness of this test is questionable. Shared serum samples have demonstrated that those with positive FIAX values might test negative by immunoblot analysis. Similarly, sera with negative FIAX values have tested positive on immunoblot. The FIAX test is attractive to veterinarians because it provides an approximate numerical measure of the amount of antibody present. Veterinarians like to know if serum antibody concentration is increasing or decreasing over time to determine if an infection is recent or on its way out. However, EPM confounds the use of antibody concentration whether FIAX values are accurate or not. Horses with active EPM might have extremely low amounts of serum (or CSF) antibody. Occasionally, affected horses have even tested negative. If any specific antibody is detected in the serum (or CSF), exposure has occurred. The parasite has proven its ability to cause disease months after initial exposure. Presumably, serum antibodies rise following each exposure and begin to fall shortly after the parasite crosses the blood-brain barrier and enters the CNS. An exposure rate of 45% indicates that horses probably ingest sporocysts on a fairly routine basis. Therefore, it makes little difference if serum (or CSF) antibody concentration is high or low; it is most important to know whether antibodies are present or not, that is, if the sample tests positive or negative. An increasing concentration of specific antibody indicates recent exposure, which may or may not be relevant to the current disease problem. Recently, two additional tests were introduced that produce approximate estimates of the amount of anti-S. neurona antibody present in equine serum samples. Both assays rely on whole parasites to detect the presence of anti-S. neurona antibodies. In the S. neurona direct agglutination test (SAT), serum samples are mixed with killed S. neurona merozites. A positive SAT result depends on the ability of antibodies present in the serum sample to crosslink with merozites forming a distinct pattern on the bottom of the test tube. The developers have claimed approximately 90% agreement with the standard EPM test, but the work has not been published for peer review. The second test uses an older methodology to detect anti-S. neurona antibodies. The indirect fluorescent antibody test (IFAT) uses fluorescence to detect antibodies similar to the FIAX mentioned previously. Killed S. neurona merozoites are fixed on microscope slides and incubated with equine serum samples. Initial results published using this technique compared favorably with the standard EPM test. However, the number of horses tested was limited. Since S. neurona and S. fayeri share many proteins, it is seems unlikely that this assay will perform as well as the standard EPM test under the rigors of routine clinical testing. Time will tell. A 1967 report based on data from a horse that had died due to Neospora caninum encephalitis suggested that antibodies produced against N. caninum cross-react with some S. neurona- specific proteins. However, careful evaluation of the material presented indicates that the information was confounded. The horse clearly was exposed to S. neurona, as well as N. caninum. Presumably, anti-S. neurona antibodies from serum were present in CSF. Alternatively, S. neurona merozoites also were present in the CNS. A related study, using rabbit antiserum prepared against S. neurona and N. caninum, failed to demonstrate any cross-reactivity with the specific proteins. It is now generally recognized that the standard EPM test does not cross-react with N. caninum or N. hughesi, as the agent isolated from horses was recently named. The results of EPM tests on CSF samples from 295 horses euthanized due to neurological disease were compared with post-mortem diagnoses. Many equine neurological diseases were represented in the study. Approximately 40% of the horses had post-mortem diagnoses of EPM. The sensitivity and specificity of CSF test results were both approximately 90%. Sensitivity reflects the number of horses that tested CSF positive out of all horses diagnosed with EPM at post-mortem. Specificity reflects the number of horses that tested CSF negative from all the horses that did not have EPM at post-mortem. These results indicate that the EPM test would detect S. neurona antibodies in the CSF of nine out of 10 horses showing neurological signs. Several of the horses that tested false negative had been ill for less than three weeks. Although the incubation period of EPM appears to be sufficient to permit production of detectable amounts of specific antibody in most cases, false negative CSF test results do occur. It is advisable to retest horses with acute neurological disease that initially test negative. Nonetheless, some horses remain negative and simply fail to produce a detectable antibody response to the specific proteins used for analysis. Specificity of 90% suggests that one in 10 horses with neurological signs would test positive for S. neurona antibodies in CSF even though they have another neurological disease. Whenever the integrity of the blood-brain barrier is compromised, antibodies from the blood stream can leak into the CSF and produce a false positive test result. False positive CSF test results were noted from cases of CVM, viral encephalitis, trauma, EDM, moldy corn poisoning, and CNS abscess. However, the most common cause of false positive test results for CSF is blood contamination at the time of collection. The AQ, total albumin, and red blood cell count should help determine if CSF has been blood contaminated or the blood-brain barrier has been damaged. However, CSF contamination with a small amount of serum with a very high concentration of specific antibody may not be detected using these methods. It is very important to note that sensitivity and specificity were calculated using CSF from horses that had obvious neurological disease. Sensitivity and specificity should not be extrapolated to interpret CSF test results for horses without neurological signs. As discussed previously, not enough is known about the activity of S. neurona in the horse for adequate interpretation of CSF test results from normal horses. Understandably, it is disconcerting to realize that parasites are likely to be present in the CNS whenever antibodies are detected in CSF; nonetheless, the likelihood of clinical disease is unknown. The horse might become ill tomorrow, two years from now, or not at all. Opinions on how to handle this situation differ widely. It seems reasonable to assume that the horse is handling the parasite adequately for the moment, but how will the battle go tomorrow? Since we do not know the likelihood of complete parasite elimination without treatment but can easily appreciate how quickly the disease can cause permanent damage, a single round of therapy seems reasonable. Many excellent veterinarians disagree with this approach. Their concern might be justified. Treatment is expensive and not without some risk. It is entirely possible that we eventually will discover that the vast majority of these horses actually eliminate the parasite without treatment. It should be clear that, for the moment, CSF test results from normal horses cannot be adequately interpreted to justify consideration during the sale of a horse. Seroprevalence studies of normal horse populations have shown that a positive EPM blood test result indicates exposure only. The relatively few number of EPM cases compared with the large number of exposed horses suggests that many are exposed, but few become ill. The sensitivity and specificity of EPM blood test results from the 295 horse post-mortem study reinforce these findings. Sensitivity was approximately 90%, but specificity was only 70%. Most of the horses with EPM tested positive, but 30% of those with other neurological disease did as well. The real value of EPM blood testing among normal horses appears to be a negative test. A 2001 paper also compared standard EPM test results for serum and CSF with post-mortem results. Sixty-five horses with neurological disease and 169 horses without non-neurological diseases were studied. Although test sensitivity was similar to that reported above, specificity was lower. A number of reasons may explain the divergent results. However, it is important to remember that even though post-mortem examination is considered the current gold standard for this type of comparison, the technique is far from perfect. It is impossible to adequately examine the entire equine CNS under the microscope in order to declare an individual animal EPM-free. A reliable infection trial conducted with negative horses held in complete isolation is required to provide more definitive results. Although still limited in number, serum and CSF samples from the Ohio State infection model should help resolve this issue. Unfortunately, EPM tests may perform somewhat differently when subjected to the demands of routine clinical testing. The varied background, health status, and myriad exposures possible among horses from the general population cannot be adequately modeled. Parasite DNA-specific polymerase chain reaction (PCR) testing of CSF also provides information regarding the presence of S. neurona in the CNS. Although the sensitivity of PCR testing is apparently much lower than initially estimated, the demonstrated ability to detect parasite DNA in false negative CSF samples makes it a useful adjunct for the diagnosis of EPM in selected cases. Parasite DNA can be rapidly destroyed by enzymatic action in the CSF and

appears to find its way into the CSF rarely during the course of infection.

rEsEArch in PrOgrEss: nEw AnD iMPrOVED tEsts Further enhancement of EPM testing methods are still needed. Various laboratories around the United States are working on improved diagnostic tests using a variety of formats. An enzyme linked immunosorbant assay (ELISA) using a variety of specific recombinant target proteins is likely to provide the best possible test. The S. neurona DNA sequencing project being conducted at the University of Kentucky provides an excellent opportunity for advancement in this area. Parasite DNA sequencing, in conjunction with a reliable infection model, will make it possible to compare multiple strains of S. neurona for the identification of highly specific target proteins and improved diagnostic testing. The infection model also will provide valuable information regarding the spread of S. neurona in the horse’s body, and help explain how some parasites escape elimination. Better understanding of the host-parasite relationship will allow more accurate interpretation of test results and the development of optimal treatment guidelines. The continued development of accurate diagnostic tests for other equine neurological diseases will help veterinarians differentiate these diseases from EPM more efficiently.

Case Review I
(The following case review illustrates many of the points discussed and provides a typical example of the case histories used to develop the recommendations found in this text.) A 7-year-old Thoroughbred mare began dragging her right rear toe and seemed slightly lame. The mare was bright and alert but had difficulty eating and dropped a large amount of sweet feed each day. Her condition gradually worsened over the next two weeks, and she began to stumble when ridden. The mare was a lightly used pleasure horse. The owner consulted a veterinarian Vaccinations and deworming had been done on a regular schedule and were up to date. The mare had not been ill or injured in the last year. The owner had taken her on a trail ride in a neighboring county four weeks earlier. Temperature, pulse, and respiratory rate were normal. A neurological exam revealed abnormal tongue strength and loss of tail tone as well as delayed placing reactions and ataxia involving the rear limbs. This condition was more pronounced on the left. Based on the presence of progressive multifocal neurological signs and the age of

the horse, the veterinarian discounted the possibility of cervical vertebral myeloencephalopathy, trauma, or equine degenerative myeloencephalopathy. The clinical signs and history suggested EPM, but equine herpesvirus-1 and cauda equina/polyneuritis equi remained possibilities. An inspection of the barn revealed a family of opossums living in the hay loft. The veterinarian decided to place the mare on treatment for EPM and attempted to confirm the diagnosis by testing serum and cerebrospinal fluid for the presence of S. neurona-specific antibodies. Routine blood work, including CBC, differential cell count, and serum chemistries, was normal. Serum and CSF both tested positive in the EPM test. CSF was clear and colorless. CSF albumin, AQ, IgG index, and cell counts were within normal limits. In addition, the mare was responding to treatment. She appeared to recover fully after three months and treatment was discontinued. Relapse, then progress Six weeks later she began dragging her right rear toe and dropping grain. The owner immediately called the veterinarian, and the mare was re-started on pyrimethamine/ sulfa therapy. Her condition failed to improve. After three months, the mare was still dragging her toe. Blood and spinal fluid samples were taken, and both tested positive in the EPM test. The mare was placed on a double dose of both drugs. Clinical signs slowly improved and appeared to stabilize after three months. Although the blood test was still positive, CSF tested negative. Treatment was discontinued, and the mare did not relapse in subsequent months. Now it would be possible for the veterinarian to prescribe ponazuril therapy to avoid using high-dose pyrimethamine/sulfa treatment.

Case Review II
A two-year-old Thoroughbred gelding began training poorly. Neurological examination revealed mild asymmetric ataxia of the rear limbs. A presumptive diagnosis of EPM was made, and the horse was placed on pyrimethamine/sulfa therapy. An EPM blood test was positive. Gradual improvement was noted, and training was resumed. Treatment was discontinued after three months, but clinical signs returned this former racehorse responded well to a within four weeks. third round of treatment. The horse was placed on treatment again and responded gradually. Training was resumed, and the horse was raced several months later while still on treatment. The horse performed poorly, and mild ataxia was still present. The horse was removed from training and rested for several weeks without treatment. Clinical signs became progressively worse. EPM tests on both blood and spinal fluid

were positive. Deterioration, then improvement Treatment was started, and the horse dramatically worsened and was unable to stand. The condition did not respond rapidly to anti-inflammatory drugs, and the horse was placed in a sling. Gradual improvement was noted, and the sling was removed after eight weeks. Treatment was discontinued, and the horse was turned out daily into increasingly larger paddocks to exercise until he was able to return to pasture. The horse had slight residual neurological deficits but did not relapse. Once again, the use of ponazuril may have enhanced the effectiveness of treatment for this horse.

Each veterinarian develops therapeutic preferences based on personal experience. However, only one drug has been approved by the FDA for EPM treatment. Bayer released ponazuril sulfone (Marquis) for the treatment of EPM in 2001. Ponazuril sulfone is a metabolite of toltrazuril, a member of the triazine family of antiprotozoal drugs. Initial work on the use of toltrazuril and the related drug, diclazuril, for EPM treatment was done at the University of Kentucky. Triazines are attractive because the group is generally safe for use in mammals and appears to kill many protozoa in laboratory tests instead of simply preventing multiplication. Earlier drugs used to treat EPM interfere with parasite multiplication, thus relying on the horse’s immune system to kill the parasite. Ponazuril is administered orally, once daily at 5 mg/kg for 28 days. Interestingly, the response to therapy (70%–75%) is similar to the earlier non-approved combination therapy, but the relapse rate associated with ponazuril appears to be much lower. Some practitioners believe the relapse rate is best reduced by initiating ponazuril therapy at 10 mg/kg for 28 days or extending therapy at the recommended dose to 56 days.

Previously, standard therapy for EPM was based on the use of pyrimethamine (Daraprim) and a sulfa drug. AT A GLANCE These drugs act in sequence to • The FDA has approved ponazuril interfere with the parasite’s sulfone (Marquis) for the treatability to produce an essential ment of EPM. requirement for DNA replica• The use of pyrimethamine tion. In sufficient amounts, the (Daraprim) and a sulfa drug had been standard therapy before combination acts synergistically Marquis. to slow parasite multiplication. • Most horses respond to both therAlthough the drugs are unable apies but fewer relapses are reto kill parasites directly, multiported with Marquis. plication is slowed enough to • Horses must receive adequate help the horse’s immune reamounts of drug therapy to improve. sponse gain control. For many years veterinary • Horses attempting to recover from EPM should not be placed in texts recommended the use of a stressful situations. sulfa drug — trimethoprim combination (sulfadiazine in Tribrissen or sulfamethoxazole in SMZ-TMP) with pyrimethamine. The need for trimethoprim was questioned when it was realized that the dose used to treat EPM (15–30 mg/kg as a combined dose twice daily) would result in cerebrospinal fluid (CSF) concentrations below the amount necessary to inhibit similar protozoa in laboratory tests. Since the inclusion of trimethoprim also increased the likelihood of anemia and diarrhea, many veterinarians dropped it from their recommendations. However, some veterinarians believe that horses respond faster and have fewer relapses when trimethoprim is included. Early pyrimethamine recommendations (0.25 mg/kg once daily for 30 days) appear to have been inadequate. Experience and a 1992 study demonstrating pyrimethamine’s relatively poor ability to cross the blood-brain barrier prompted a dramatic increase in the amount of pyrimethamine recommended (0.5–1.0 mg/kg once daily) for treatment. In addition, the frequent lack of rapid improvement and post-treatment relapse led to an increase in the length of treatment (eight weeks). Veterinarians quickly recognized that the variability of response to treatment was too great to rely on a set length of treatment. If used, treatment should continue for a least one month after the horse stops showing further improvement. Using this rule of thumb, the average length of treatment approaches four months. The most common form of the pyrimethamine/sulfa combination is a commercially prepared liquid formulation of pyrimethamine/sulfadiazine, which delivers 20 mg/kg sulfadiazine and 1.0 mg/kg pyrimethamine at the recommended dose once daily. This appears to work reasonably well, but initial treatment failure or relapse still occurs. Veterinary referral centers using this protocol have reported up to a 75% initial response rate, although less than 25% of these made a full recovery. Mildly affected horses treated early in the course of infection have a much greater opportunity for complete recovery no matter what drug(s) are used. Chronic signs of CNS damage such as muscle atrophy rarely improve. It has been estimated that neurological signs return within a few weeks or months of therapy in up to 25% of horses treated with pyrimethamine/sulfa and only 5% with ponazuril. Many veterinarians have attempted to reduce the number of relapses by continuing treatment until the EPM test on CSF is negative. In theory, parasite-specific antibodies should clear the CSF within a few weeks of parasite elimination. Experience suggests that an extremely low number of horses relapse when CSF is negative at the time treatment is discontinued. The majority of horses should test CSF negative by the time the rule of thumb for treatment length has been fully applied. However, some horses remain CSF positive for an extended period after full recovery or stabilization without further improvement. The most likely explanation for this is the continued presence of parasites in the CNS. Some veterinarians theorize that the parasites have been eliminated and that the test remains positive due to antibody leakage from the bloodstream and/or an unknown mechanism that causes continued antibody production in the CNS without the presence of parasites. Not all horses taken off treatment with positive CSF relapse. Some could have eliminated the parasite recently, and some will eliminate the parasite on their own. Certainly, it is very cumbersome, expensive, and usually impractical to treat horses indefinitely. Increasing the dosage of ponazuril or pyrimethamine/ sulfa may reduce the number of horses that persistently test positive in CSF. The margin of safety for ponazuril is very high. However, increasing the dose of pyrimethamine/sulfa combination increases the potential for more severe side effects. These include anemia, low white blood cell counts, and short-term depression. Some researchers also have suggested that abortion may occur; however, definitive studies to prove these theories have not been done in the horse. It seems most reasonable to increase the dose within safe limits and to maintain the rule of thumb regarding the length of treatment. Many veterinarians recommend 1.5 to two times the dose of pyrimethamine for initial treatment or after 30 days if there is not satisfactory progress. A monthly complete blood count is recommended to monitor anemia when using standard therapy and would be even more important at the higher dose. Some veterinarians also monitor serum folate concentration at monthly intervals. It is advisable to avoid higher doses in pregnant mares until more is known about the effects of therapy. When relapse does occur, it is important to increase the dose or change the type of drug(s) used. Some veterinarians advocate combining both therapies to help eliminate the infection. Obviously, the combination ponazuril and pyrimethamine/sulfa has not been approved by the FDA and would be relatively expensive. Unless the horse has become re-infected (which may be extremely unusual), the population of parasites causing the problem descend directly from those most resistant to the first round of therapy. It is unreasonable to assume that use of the same therapy would accomplish much more than another relapse. Medication or supplements to stimulate the immune system may help, but no reports of improved treatment response have been published. It also is possible that immune stimulants could exacerbate the problem by increasing the amount of CNS inflammation. EPM medication is given orally.

GivE MEDicATion ProPErly Ponazuril is distributed as a paste for oral administration according to the manufacturer’s recommendations, which results in uniform drug delivery. More careful administration of pyrimethamine/sulfa therapy is required to ensure consistent treatment. The liquid combination should be given on an empty stomach to prevent interference with absorption from the gut. Grass and hay have been shown to decrease the uptake of these drugs. Feed should be withheld for at least two hours before and one hour after administration. Although grain causes much less interference than grass and hay, it is still far better to place the medication directly in the horse’s mouth than on the feed. Horses that do not receive an adequate amount of the drugs will not improve. In fact, erratic blood concentrations that dip below the amount required to impair parasite division will encourage the development of drug-resistant strains. Your time, effort, and money will be wasted. Anti-inflammatory drugs during the first one to two weeks of treatment and any time the condition appears to worsen during treatment should help minimize further damage due to parasite death and the host response. Dimethyl sulfoxide (DMSO) and flunixin meglumine (Banamine) or phenylbutazone are used most frequently. Horses that are severely affected often receive moderate doses of dexamethasone for one to three days. Longer use might cause suppression of the immune response. Oral vitamin E supplementation (10–20 international units/kg daily) also is recommended to help prevent injury during the inflammatory process and promote healing of the CNS. Due to poor absorption in the horse, folic acid supplementation for the prevention or treatment of anemia and prevention of potential pregnancy problems during pyrimethamine/sulfa therapy is not likely to be effective. Folinic acid (a variant of folic acid) is well absorbed and highly effective in other species, but the cost of supplemental administration in the horse is prohibitive. F o r t u n a t e l y, good quality pasture and Horses can work lightly as their condition improves. alfalfa hay are

excellent sources of folinic acid and are highly recommended during pyrimethamine/sulfa treatment. If life-threatening anemia develops, your veterinarian may elect to try folinic acid supplementation or discontinue treatment for two to three weeks to allow recovery. Changing medication would alleviate the problem without a gap in therapy.

AvoiD STrESS DurinG rEcovEry It is important not to stress horses attempting to recover from EPM. The amount of activity appropriate for each case is highly variable and dependent on the circumstances surrounding the individual. Horses that are severely affected should be confined in a heavily bedded box stall until they are able to move easily. Try to avoid making any dramatic changes in the horse’s environment to avoid stress. Prolonged inactivity is not beneficial. Light exercise is appropriate as improvement of the condition permits. Work can be increased gradually as the horse improves

Alternative therapies can help reduce the soreness sometimes associated with EPM.

and drug therapy nears completion. It is better to be patient and to avoid overworking a horse on treatment. At best, too much work too soon prolongs the length of time to full recovery and the return to normal activity. At worst, there will be an opportunity for a post-mortem diagnosis.

AlTErnATivE THErAPy Chiropractic, massage therapy, and acupuncture all seem to help sore horses feel better. Because asymmetric ataxia can produce soreness and injury, these therapies should be helpful. None of these methods eliminate parasites by themselves, but they may serve as a useful adjunct to standard therapy. This is not an endorsement for the diagnosis of EPM using acupuncture. The accuracy of this technique has not been substantiated experimentally. rESEArcH in ProGrESS: nEw DruGS Schering is pursuing FDA approval of diclazuril, and Blue Ridge Pharmaceuticals is working on the approval of nitazoxanide (NTZ) for the treatment of EPM. NTZ is a nitrothiazole derivative with broad spectrum activity against many organisms, including bacteria, intestinal worms, and protozoa. The effectiveness of these drugs appears to be similar to ponazuril or pyrimethamine/sulfa. The initial dosage and administration schedule for nitazoxanide required modification due to safety concerns. Research has been published suggesting that pyrantel (Strongid, Pfizer), a commonly used equine dewormer, can inhibit the growth of S. neurona in tissue culture. However, the drug failed to protect immune compromised mice from S. neurona infection in controlled feeding trials.

Horse owners and managers can take a number of steps to help reduce the risk of EPM for the horses in their care. Prevention can be broken down into three basic areas: health and condition, facility maintenance, and travel planning.

HealtH & Condition A healthy, fit horse is the best protection against many equine diseases, and EPM is no exception. As we have discussed, the horse’s immune system is the key to overcoming EPM. The development of clinical signs appears to be related to the number of sporocysts ingested, but the ability of an individual to resist infection will affect the actual number of sporocysts required. Therefore, all of the routine preventive health care recommendations apply to EPM as well. These include routine vaccination for other diseases, regular deworming, proper nutrition, plenty of exercise, routine foot care, preventive dental care, and routine examination by your veterinarian. Performance horses should be properly conditioned to avoid injury and overwork. Small health problems can lead quickly to large ones when ignored. The stress associated with other diseases might provide an ideal opportunity for S. neurona to emerge from hiding. Horses experience mental as well as physical stress. Careful attention to the personality and individual needs of each horse will reduce stress. Whenever possible, avoid unnecessary management decisions that introduce significant changes in the horse’s physical and social environment. This is especially important when other stressful events are scheduled. It is very important to seek prompt veterinary assistance whenever any sign(s) associated with EPM is noticed. Horses that receive prompt, aggressive treatment early in the course of the disease have the best chance for complete recovery.

Facility MaintenanCe The condition and layout of physical facilities can help avoid injuries and reduce exposure to EPM. Horse-friendly design and construction and routine maintenance will help prevent physical stress due to injury and bacterial infection that can predispose horses to EPM. It is important to limit the access of opossums in the horse’s environment as much as possible. Individual opossums cover a fairly small territory during their lives (approximately one square mile). They are prolific and have an average lifespan of three years. They live much longer in captivity because it is much easier to avoid their No. 1 predator: the automobile. Because a single female can produce up to 30 offspring a year, local populations can become quite dense. Many assume that a local opossum problem does not exist because opossums are rarely seen on the property. However, opossums are nocturnal and live ones are rarely seen during the day. Opossums have a ravenous appetite and will eat virtually anything. It is important to keep the area clean. Pet food,garbage, and anything edible should be kept inaccessible. This is especially true of dead cats, raccoons, skunks, and armadillos, all of which are now considered intermediate hosts. Dead birds and rodents also should be removed quickly. Livestock feeds, including hay and grain, should be stored away from opossums. Sarcocystis sporocysts are very resistant to the action of disinfectant solutions. Chlorine is completely ineffective. A recent article demonstrated that the only effective method to kill sporocysts in the environment is steam cleaning. Unattractive wire fencing designed to prevent opossums from entering pastures is available. Live trapping and relocation of opossums should be attempted to reduce sporocyst contamination of the area. Horse feed should be kept clean and as free of bugs as possible. Extrusion and some pelleting processes produce sufficient heat to kill sporocysts present in the ingredients. It is not known if feed represents a significant source of sporocyst exposure. Fly control might be helpful. Covering barn openings with hardware cloth, which is easier to maintain than screens, will prevent the entry of opossums and birds. Methods to limit fecal contamination of outdoor water sources from opossums and birds should be considered.

travel Planning Long trailer rides are extremely stressful and are commonly mentioned in the clinical history of horses that develop EPM. Plans should be made to avoid travel stress. Adequate hydration is essential. Routine vaccinations should be up to date to avoid stress associated with various contagious diseases. It also is important to minimize corticosteroid use to avoid immune suppression. Many horses travel extensively and are dependent on the feed and water supplies at various local facilities. It is important to consider the potential for exposure under these circumstances and to plan to avoid exposure at your destination.

researCH in Progress
Vaccine development

The development of vaccines to protect against protozoal parasites in horses is extremely difficult. However, progress has been made toward effective vaccine development against protozoal diseases of other animals. Recent advancements in our ability to test potential vaccines in the horse make it possible to be optimistic for progress in this area. Fort Dodge Animal Health, a pharmaceutical company, was granted provisional approval for an experimental killed S. neurona merozoite vaccine. The vaccine has not been tested using the EPM infection model. It is not known whether the vaccine prevents clinical disease. A large multicenter study has been organized through Texas A&M University’s College of Veterinary Medicine to assess vaccine efficacy. The vaccination history of horses diagnosed with EPM will be evaluated. Several university research groups are searching actively for protective components of S. neurona. This work may lead to effective immune therapy, whether or not an effective vaccine becomes a reality.

Therapy

A number of research groups are attempting to develop preventative formulations of drugs used to treat EPM. This work holds great promise for those attempting to maintain horses in areas with chronic EPM problems.

FREQUENTLY ASKED QUESTIONS
What is EPM? Equine protozoal myeloencephalitis is the most commonly diagnosed neurological disease of horses in North America. Clinical signs are caused by infection of the brain and spinal cord with the protozoal parasite Sarcocystis neurona. How do horses get EPM? Opossums shed infective S. neurona sporocysts in their feces. Horses become infected by ingesting sporocysts in contaminated food or water. Is EPM contagious? Sarcocystis infections are not contagious. Parasite survival requires alternating infection of a meat eater and its prey or carrion. The infective stage for the predator or scavenger only develops in the tissues of the appropriate prey or carrion. The life cycle of S. neurona cannot be completed in the horse, which is considered a dead-end host. Thus, the infectious stage for the opossum does not develop. The raccoon, cat, skunk, armadillo, and sea otter have been identified as intermediate hosts.

Why are only some horses affected? A number of factors are believed to contribute to the development of clinical disease. These include the number of parasites ingested, the horse’s immune status, and stress. Immunity can be compromised by some medications, various diseases, and stress. Stress can result from heavy exercise, injury, long distance travel, pregnancy, or mental distress. How can I tell if my horse has EPM? The clinical signs of EPM are quite variable. However, the most common clinical signs include progressive incoordination of the rear limbs and weakness. A complete neurological examination and laboratory testing are the most effective means of diagnosis. What does a positive EPM test mean? The EPM test detects antibodies that are specific for S. neurona in the blood or spinal fluid of horses. The presence of specific antibodies in blood indicates that the horse has been exposed to the parasite. However, exposure is quite common. The horse might never develop EPM. Horses with other neurological diseases frequently test positive for exposure to S. neurona. A positive spinal fluid sample indicates that the parasite has entered the CNS unless the sample is blood contaminated. This is a strong indication that clinical signs are due to EPM. Should EPM testing be done pre-purchase? Not in my opinion. Exposure is too common. A positive blood test is of little concern. Spinal fluid testing is not recommended for normal horses. Test results cannot be interpreted reliably.

Can EPM be treated? Ponazuril (Marquis), an FDA-approved treatment, is available. The earlier, non-approved combination therapy also remains effective. Therapy should be started quickly to provide maximum benefit. Is treatment expensive? Optimal treatment is relatively expensive. Cost includes diagnosis and management, as well as appropriate medication. Medication and supplements alone can cost $250– $1,000 a month, depending on the treatment regimen prescribed. Can I continue to work my horse during treatment? Every situation is unique. Severely affected horses should be confined to help prevent further injury. Horses with adequate mobility appear to benefit from light exercise. However, stress reduces the horse’s ability to fight infection. In my opinion, heavy work or full training should be avoided while horses are on medication and continuing to show improvement. Will my horse eventually recover? It is impossible to predict on an individual basis. Mildly affected horses that are diagnosed quickly and receive prompt treatment have the best chance to make a full recovery. Severely affected horses and those that have had clinical signs for many weeks often show significant improvement, but are more likely to have some residual neurological deficits. It has been estimated that up to 75% of treated horses show improvement and that less than 25% recover completely.

What can I do to prevent EPM? The parasite is spread by opossums. Relocation of opossums away from horses and protection of feed and water from fecal contamination should help reduce the risk of exposure. Should I treat my horse periodically to prevent disease? It is not advisable. Short-term (less than 90 days) periodic treatment might result in the development of drugresistant parasite strains in your horse. If clinical disease does develop, it will be more difficult to treat. Are researchers working on a cure or a vaccine for EPM? Yes. Several groups are working on improved treatments and vaccine development. EPM can cause permanent CNS damage prior to diagnosis. Therefore, a cure is not really possible, only more effective medications. Vaccine development will be difficult. Sarcocystis neurona is much more complex genetically than a virus or bacteria. Although it is unlikely that a vaccine will ever be able to prevent infection completely, it might be possible to improve a horse’s ability to eliminate the parasite before it causes clinical disease. Fort Dodge Animal Health has a provisionally approved experimental vaccine available that is under ongoing evaluation for efficacy.

GLOSSARY
Antibody/Immunoglobulin — specialized proteins that are custom-made by white blood cells to help fight specific infectious agents Apicomplexa — a large grouping (Phylum) of intracellular protozoal parasites that each contains an apical complex for penetration into host cells Ataxia — incoordinated movement Atrophy — loss of muscle mass Axon — a long, narrow process that extends from a neuron and transmits nerve impulses Blood-brain barrier — tightly joined layer of cells lining central nervous system blood vessels that prevents blood components from entering the cerebrospinal fluid Bradyzoite — slowly dividing asexual stage of Sarcocystis found in sarcocysts; infectious stage for the definitive host Central nervous system (CNS) — brain, brainstem, and spinal cord Cerebrospinal fluid (CSF) — colorless fluid which acts like a “shock-absorber” to protect the central nervous system from injury

Cervical spine — that part of the spinal column from the base of the skull to the shoulders Cranial nerves — set of 12 peripheral nerves originating from the brainstem that control sight, smell, taste, hearing, balance, chewing, swallowing, and muscles of the face, eyes, and shoulders Definitive host — the animal host that harbors the sexual stages of parasite reproduction Differential diagnoses — a list of diseases most likely to be responsible for the clinical signs observed Epidemiology — the study of disease in a population rather than an individual Encephalitis — infection of the brain Gray matter — concentrated area of neurons in the central nervous system that appear gray Immune system — body defense network made up of several specialized white blood cell types that are spread throughout the body to recognize foreign invaders and attack them directly or by releasing specific antibodies Immunoblot analysis — method used for the current EPM test that detects antibodies directed against parasite-specific proteins in the serum or CSF of infected horses Incubation period — the length of time between parasite (sporocyst) ingestion and the onset of clinical signs Inflammation — a non-specific process activated in response to infectious agents or injuries in an effort to eliminate the invader or repair of the injured area; characterized by swelling, redness, and pain outside the central nervous system Intermediate host — animal host that harbors the asexually dividing forms of Sarcocystis or other parasites (raccoon, skunk, cat, armadillo, sea otter)

Motor neuron — nerve cell located in the central nervous system that sends nerve impulses that initiate muscle activity Lumbar spine — portion of the spinal column in the small of the back Merozoite — generic term referring to individual parasites produced by asexual multiplication (bradyzoites and tachyzoites are both merozoites) Myelitis — infection of the spinal cord Myeloencephalitis — infection of the spinal cord and brain Myeloencephalopathy — non-infectious disease process of the spinal cord and brain Myelopathy — non-infectious disease process of the brain Neospora hughesi (formerly caninum) — Apicomplexan protozoa that causes equine abortion and may infect the central nervous system Neurological examination — a thorough, systematic physical evaluation of the nervous system PCR — polymerase chain reaction, a diagnostic and research technique designed to amplify very small amounts of DNA into easily detectable amounts Peripheral nerve — all nerves outside the central nervous system Proprioception — ability to sense limb position Protozoa — very small, single-celled animals which can be parasitic Risk factor — a circumstance that predisposes animals to exposure or the actual development of a disease Sacrum — a single bone formed by the fusion of five to six vertebrae that attaches the end of the spinal column to the pelvis

Sarcocyst — a large grouping (cyst) of bradyzoites located in the muscles of the intermediate host Sarcocystis fayeri — species of Sarcocystis which cycles between horses and canines and may cause muscle soreness in horses Sarcocystis neurona — the causative agent of EPM; the opossum is the definitive host; the intermediate host includes the raccoon, skunk, cat, armadillo, and sea otter Sarcocystis falcatula — species of Sarcocystis that cycles between opossums and various birds Sensory neuron — neurons located outside the central nervous system which send signals from the periphery back to the central nervous system Seroprevalence — the percent of a population with antibodies to a particular infectious agent Spinal nerve — nerves branching directly from the spinal cord to the rest of the body Tachyzoite — rapidly dividing stage of Sarcocystis that often develops in the walls of blood vessels of the intermediate host; stage of S. neurona responsible for causing EPM Sporocyst — the stage of Sarcocystis produced in opossum intestines and shed into the environment to infect the intermediate host Thoracic spine — that part of the spine from the shoulders to the small of the back Vascular endothelium — a layer of cells lining blood vessels throughout the body White matter — central nervous system tissue made up almost entirely of axons

EPM sites on the Internet
• Bayer, Your Horse’s Health — EPM Information
www.yourhorseshealth.com/epm/

• The Horse: Your Guide to Equine Health Care
www.thehorse.com

• EPM Society
www.epmsociety.org

• National Animal Health Monitoring System Equine Reports
www.aphis.usda.gov/vs/ceah/cahm/Equine/equin.htm

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Oxidation is the biochemical process by which energy is created for cells to maintain both integrity and function. When not all of the oxygen is consumed during oxidation, damaging reactive oxygen species (ROS) are produced.

“These ROS damage DNA, lipids, and contribute to degenerative changes such as aging and cancer,” said Williams. “Antioxidants may prevent damage by scavenging ROS, decreasing the conversion of less reactive ROS to more reactive ROS, assisting the repair of damage caused by ROS, and providing a favorable environment for other antioxidants.”

The positive effects of both vitamin E and vitamin C in exercising horses have been reported in athletic horses.

“For example, horses supplemented with vitamin E had a more moderate degree of programmed cell death (apoptosis) in white blood cells, higher levels of other antioxidants in their systems like glutathione, and lower levels of the muscle enzyme creatine kinase, which can leak out of potentially damaged cells and into the blood if not protected,” summarized Williams.

Williams’ review of the literature on antioxidants also found that older horses also appear to have higher degrees of apoptosis in their white blood cells and may be able to reap the protective rewards of antioxidant supplementation, especially while exercising.

Williams did note, however, that caution should be taken when supplementing with high levels of vitamin E.

“Research studies conducted in my laboratory indicated that high levels of vitamin E (10 times the recommended 1000 UI/day) may be detrimental to the metabolism of beta-carotene, a precursor of vitamin A,” Williams explained. “High levels of vitamin E should be avoided.”

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Earlier thought held that A. perfoliata did not actually cause disease in horses, but that the parasites were simply an incidental finding in horses’ guts.

According to the researchers, “since the 1980s, an increasing prevalence of case reports describing a close association between specific causes of equine colic, such as impaction, intestinal rupture, intussusception, volvulus, and large intestine obstructions and severe A. perfoliata infestations has increased the interest in the pathological effects of this parasite.”

The researchers therefore sought to investigate changes in the equine gut associated with tapeworms at the junction between the last part of the small intestine (ileum) and the first part of the large intestine (cecum), referred to as the ileocecal junction. The team randomly selected 31 horses (11 parasite-free and 20 horses with spontaneous A. perfoliata infections) and evaluated the ileocecal junctions.

A significant relationship between parasitic burden and microscopic grade of damage to multiple layers of the intestine (mucosa and submucosa) was noted. In addition, hypertrophy (abnormal enlargement) of circular muscular layer of the intestine was obvious. Finally, injury to intestinal nervous elements, referred to as the enteric nervous system, was noted in horses with moderate to high parasitism.

According to the study authors, “our results might support a close correlation between colic and A. perfoliata infestation in the horse.”

They also noted that the enteric nervous system lesions suggest that the use of “well-timed diagnostic tests and orderly preventative deworming programs” are indicated in horses with moderate infestations to “prevent or minimize the risk of colic caused by A. perfoliata.”

The study, “Pathological changes caused by Anoplocephala perfoliata in the equine ileocecal junction,” was published in the journal Veterinary Research Communications in May 2010.

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According to the researchers, back pain is a major cause of altered gait and performance in horses; however, only a few studies assessing the equine back using radiographs (X rays) have been performed, particularly in Standardbreds.

To investigate the frequency and location of the most common lesions from the 14th thoracic vertebrae (T14) to the third lumbar vertebrae (L3), veterinarians reviewed radiographs from 102 French trotters with back pain and 16 without. The two main anatomic structures of interest were the dorsal spinal processes (DSP, the bony part of the vertebrae extending up from the spinal column) and the synovial intervertebral articulations (SIA, the joints between each of the individual vertebrae along the spinal column).

Key findings reported by the veterinarians were:

• 10/16 (62%) of the horses in the control group had lesions noted on X ray;
• 98/102 (96%) horses with back pain had radiological lesions;
• The number of lesions per horse and the number of affected intervertebral spaces was higher in the horses with back pain;
• For the different types of DSP lesions, the grade (severity) of the lesions was higher in the horses with back pain compared to the control group;
• Impingement of the spinous processes was most commonly noted between the fifteenth and eighteenth thoracic vertebrae whereas DSP lesions were more commonly encountered between the seventeenth lumbar vertebrae and the lumbar vertebrae.

The veterinarians noted that there was no significant difference in age, sex, activity, and mean number of race starts or mean earnings at the time of examination between the two groups of horses.

Based on this study, radiographic lesions of the back were less severe and more localized in the painful group than horses without back pain. According to the authors of the report, this survey might “improve the diagnosis and management of racing Standardbreds presented for investigation of back pain.”

The study, “Location of radiological lesions of the thoracolumbar column in French trotters with and without signs of back pain,” was published in the Jan. 9, 2010, edition of the Veterinary Record.

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