The continuing threat of EPM

Progress has been made in the detection and treatment of this potentially debilitating neurological disease, but much remains to be done. Here’s where we stand.

Equine protozoal myeloencephalitis (EPM) doesn’t make headlines as often as it once did. But this potentially debilitating neurological disease remains a threat to horses all over the United States. If anything, its range is spreading.

Horses can develop EPM when they ingest feed and water contaminated with Sarcocystis neurona, one-celled organisms called protozoa, that are spread by opossums and carried by other wildlife. Less commonly, another protozoan, Neospora hughesi, causes the disease. Usually, when a horse ingests either protozoan his immune system eliminates the threat and he does not become ill. In some cases, however, the organisms cross the blood-brain barrier and attack the central nervous system (the brain and spinal cord), causing a range of neurological problems including muscle weakness and incoordination.

First identified in 1970, EPM remains difficult to diagnose and treat. Because not all horses exposed to the protozoa develop the disease, the presence of antibodies is not enough to diagnose EPM. Even with antiprotozoal drugs, the recovery rate is about 65 percent.

Clearly, more work is needed to combat EPM with a greater degree of success. Toward that end, a group called the EPM Society—a consortium of researchers and clinicians currently headed by Steve Reed, DVM, DACVIM, of Rood and Riddle Equine Hospital in Lexington, Kentucky—met last fall to share ideas on how to make more progress. “The goal of the meeting, which was attended by nearly 40 people from academia, equine practices and industry, was to brainstorm about what we know and what we don’t know about EPM,” says Nicola Pusterla, DVM, PhD, DACVIM, of the University of California–Davis, who adds that when certain dogmas have been established for a disease, they need to be revisited regularly to assess what works, what doesn’t, and what further research needs to be done: “There are still a lot of misconceptions about this disease and some areas that are not very clear. We reviewed some of the basic principles to see if they still apply and to determine the direction we need to go—where there is still a gap in our knowledge.”

Here’s what we know so far.

Detection and diagnosis

A number of tests are currently available that make use of the antibody-antigen bond to determine whether a horse has been exposed to S. neurona or N. hughesi, as well as how recently the infection occurred. All have advantages and drawbacks.

The Western blot is an older method that is still in use. A positive result on a Western blot indicates the presence of antibodies to S. neurona, but it cannot distinguish an older infection from a current, active one. The test may, however, be able to rule out EPM in a horse who has no antibodies. (Currently, there is no commercially available Western blot test to determine exposure to N. hughesi.)

Newer tests identify the quantity as well as the type of antibodies present in the horse’s blood. Higher titers of the antibodies may indicate a more recent infection that is causing active disease. “There are two main quanti-tative testing platforms currently used to determine antibody levels,” says Pusterla.

One is the indirect immunofluorescence antibody test (IFAT), which was developed at UC–Davis. Two IFAT tests are available, one for S. neurona and one for N. hughesi. These tests can also provide titers that can help distinguish whether the disease is active. “With a mathematical model the researchers have also determined probability of disease based on the titer,” says Pusterla. “If you have a neurological horse with clinical signs compatible with EPM, the higher the antibody titer is, the more likely you are dealing with EPM.”

The other platform relies on enzyme-linked immunosorbent assays (ELISA) to look for distinct surface antigens of S. neurona: surface antigen designated 1 (SAG1) 5 and 6; and SAG 2, 3 and 4. “These are quantitative assays,” says Pusterla. That is, they help to determine the total amount of antibodies in a horse’s blood.

“The overall consensus on these tests is that they perform very similarly,” says Pusterla; however, any serological test does not confirm but rather supports an EPM diagnosis.

All of these tests can be performed on either a blood sample or on a sample of cerebrospinal fluid (CSF), the clear fluid that surrounds and protects the brain and spinal cord inside the skull and vertebrae. A positive result on a blood test alone means only that the horse had at one point in his life been exposed to S. neurona. But exposure to S. neurona does not necessarily lead to EPM—the presence of antibodies in the blood doesn’t necessarily mean that neurological signs are caused by that organism.

Evidence that the organism has entered the cerebrospinal fluid is a clearer indication of EPM—and a positive result on both a blood test and a cerebrospinal fluid test taken from the same horse is currently the best method for a diagnosis of this disease.

“I feel most comfortable in calling it EPM if you have blood and spinal fluid samples and use the ELISA test,” says Amy Johnson, DVM, DACVIM, of the University of Pennsylvania. “It gives you a titer in both the blood and the spinal fluid, and by comparing these levels you have a pretty accurate indication whether or not the horse actually has nervous system infection. This is better than any of the other methods that use just spinal fluid or just blood. I am fairly confident in diagnosing EPM in the living horse using this test. There is no definitive diagnosis in the living horse, but this is the best way to test for EPM that we’ve ever had.”

However, extracting cerebrospinal fluid (a “spinal tap”) is a difficult and invasive procedure, and the risk of contamination of the sample with blood increases the possibility of false positives. For these reasons, it is used somewhat sparingly and many EPM diagnoses are made without it: Neurological signs coupled with the presence of antibodies to S. neurona in the horse’s blood are often considered adequate evidence of EPM.

“The debate remains on which tests are best,” says Reed. “I am still a firm believer in the notion that blood and cerebrospinal fluid tests are more accurate than blood alone, but there’s a large group of individuals who feel we need to continue to work on development of a blood test alone. This makes sense, because in many areas of the country the horse owner may not have access to veterinarians who feel comfortable doing a spinal tap in the field. Having a blood test that would be accurate enough would be very helpful.”

In the meantime, veterinarians sometimes rely on one other method when trying to determine whether a horse has EPM: Start him on anti-protozoal drugs and see how he responds—if he improves, EPM is likely. The diagnosis-through-treatment approach can work, says Pusterla, but requires caution: “A lot of horses who have EPM are also rested and given other types of medication such as anti-inflammatory drugs, and they get better,” he says. “But we don’t know whether clinical improvement was due to the antiprotozoal drugs or other drugs and rest.”

The bottom line is, despite advances in testing, veterinarians must still rely on traditional—even old-fashioned—methodology when diagnosing EPM, considering the big picture rather than relying mainly on lab results. “The serological tests help support a diagnosis, but we shouldn’t forget the horse’s history and clinical signs to conclude that a horse has EPM,” says Pusterla. “If a horse presents with asymmetrical and progressive clinical signs, this is worth looking into, versus a horse that presents with symmetrical neurological signs.”

Treatment options

Three FDA-approved anti-protozoal drugs are now available to treat EPM:

• Ponazuril (tradename Marquis; generic name toltrazuril sulfone), an oral paste administered once daily for 28 days.

• Pyrimethamine and sulfadiazine (tradename Rebalance), an oral suspension administered once daily for as long as 120 days.

• Diclazuril (tradename Protazil), a pelleted, alfalfa-based top-dressing fed for 28 days.

These medications cross the blood-brain barrier and enter the cerebrospinal fluid at levels high enough to either limit the reproduction of the protozoa or kill them outright. “All of the treatments have similar efficacy. Protazil [the newest of the three] has emerged as an alternative treatment but not necessarily a superior treatment,” says Johnson. “There is no one regimen or drug that is clearly superior to the others, but it is nice that owners and veterinarians have options. Part of the decision of which to use will depend on the owner and the horse, and the ease or reluctance of that horse taking oral medication.”

At the standard doses, it can take at least a few days for ponazuril to reach therapeutic levels in the CSF, but researchers are working to find ways to help the drug work faster. In 2009, a study from the University of Illinois showed that combining toltrazuril sulfone with DMSO (dimethylsulfoxide) helped the drug reach therapeutic levels three times faster than administering it without DMSO. “DMSO is very good at carrying many drugs through physiological barriers,” says Johnson. “Some practitioners do this and some don’t.”

In more severe cases, or if the disease is progressing rapidly, a veteri-narian may opt to start a course of ponazuril treatment with a “loading dose”—the administration of up to seven times the normal amount—before beginning the routine drug regimen. With this method, therapeutic levels of ponazuril in the CSF can be achieved much faster. “The initial loading dose that was published with the study in Illinois was seven times the label dosage,” says Johnson. “Thus, if you were using Marquis paste, you would give the whole tube—a week’sworth of the drug—at once.”

However, follow-up work done at Rood and Riddle showed that using a smaller loading dose of ponazuril would yield the same results. “That study showed that giving just three times the daily dose—about half the tube—was sufficient to raise spinal fluid levels quickly,” says Johnson. “Many practitioners today, but not all, are using a loading dose at the beginning of treatment. Even if you don’t use it, spinal fluid levels will eventually reach the point they need to be; it just takes longer. Whether or not your veterinarian will use DMSO depends on practitioner preference; at this point there is not a consensus regarding treatment protocols.”

Possibilities for prevention

For now, the most effective way to protect your horse from EPM is to limit his exposure to the causal protozoa, but that is easier said than done (see, “Managing to Prevent EPM,” page 50). Researchers are hard at work on other prevention measures.

For example, research is underway to determine whether therapeutic drugs, administered at a low dose, can be used to prevent EPM in healthy horses. Pusterla recently published a study in which diclazuril showed promise in protecting foals from S. neurona infection. (For a report on the study see “A Way to Prevent EPM?” Medical Front, page 14.)

No vaccine against EPM is currently available, and there probably won’t be one for some time. “It is very difficult to establish a vaccine for protozoa,” says Pusterla. “Not many vaccines have been developed for protozoal diseases in humans or animals. An EPM vaccine for horses with a conditional license [in 2001] was pulled off the market mainly because they were not able to establish a good animal model.”

Indeed, the lack of a good research model is one of the primary challenges EPM researchers must overcome—whether investigating treatments or potential vaccines: It is difficult to cause a horse to develop EPM in laboratory conditions.

“There are currently two models,” says Reed. “One is oral feeding of the protozoan sporocysts to the horses. That model requires maintaining a colony of raccoons, to be fed to the opossums. Then you sacrifice the opossums to get the sporocysts to feed to the horses. This model was a pretty good one for studying the disease, but it takes a lot of effort to maintain it. The other model involves collecting white blood cells from a horse and co-incubating them with the protozoa. Then horses are infected with intravenous injections, but this skips several stages of natural infection, which may mean that research findings might not apply in natural settings.”

Researchers have tried alternatives but, says Reed, “each model has its shortcomings. We looked at whether there are any small mammals, besides mice, that might serve as models, since the mouse model hasn’t been the best. Now we are talking about using [intermediate hosts, such as] raccoons, cats or armadillos. Our goal is to avoid using horses, if possible. We realize that at some point we may have to go back to the horse—since it is the host we are most concerned about—but we want to use as few horses as possible to infect with the disease.”

Reed adds, “If we can develop a good model, we may go back and start over again at looking at a vaccine. The early vaccine trials did not show good success. That doesn’t mean we should give up on creating a vaccine, but if we could do something like feed a low level of an antiprotozoal drug and keep the horses from becoming infected, it would be very helpful.”

Looking ahead

As with many diseases, the effort to combat EPM is complex and has many fronts. Nonetheless two basic questions remain to be answered: Where are horses most likely to encounter the causal organisms, and what can be done to prevent those who are infected from becoming ill?

Work is underway to better understand where exposure to the EPM parasites is greatest. “Unfortunately there is not a lot of recent data on prevalence,” says Pusterla. “Some states are ‘hot’ states, meaning higher infection rates in the horse population. There are more EPM cases in Oklahoma, Ohio, Kentucky and Texas, for instance, along with some of the Southern and Midwestern states. By contrast we see fewer cases in some of the Northern and Western states.

“To look at infection rates, we sample 100 healthy horses and see how many of them have evidence of past infection based on antibody titers,” Pusterla adds. “I have a graduate student looking at 5,200 serum samples collected from healthy horses during 2013 across the United States. The study represents 17 states in all the geographic areas, with approximately 300 animals per state. Her job is to determine sero-prevalence for both S. neurona and N. hughesi. This data will give us a better idea about where the hot spots are, and what the actual infection rate might be.”

Armed with that information, a person who lived in a hot spot might be able to take additional precautions with higher risk horses, such as younger ones entering stressful training. “You’d want to monitor these horses a bit more closely,” says Pusterla.

Likewise, researchers in the coming years also hope to answer another confounding question about EPM: Why do some horses develop the disease when others exposed to the same parasite do not?

“In some states 90 percent and in many states over 50 percent of the horses in a given area will have antibodies, indicating they have been infected,” says Reed. “Yet the incidence of severe disease is much lower than that. Is the reason for this difference something about the immune function? Are the horses who develop the disease immunocompromised? There may be something unique about the immune function of those horses who develop EPM, and particularly the horses who develop recurrent infections. Now and then we get a horse who responds to treatment but then has a substantial relapse or frequent relapses.”

Another possibility is that some strains of these parasites are more virulent than others. “Siobhan Ellison [DVM, PhD], in Florida, presented her hypothesis that certain protozoa have surface antigens that might be more likely to be infectious,” Reed says. “This is certainly a possibility.”

Advances in diagnostics and treatments have come a long way toward reducing the number of horses who succumb to EPM. Finding more effective ways to prevent and treat this disease is a challenging goal—but one that researchers have real hopes of achieving in the years to come.

This article first appeared in EQUUS issue #451, April 2015. 




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