Therapy for EPM includes several different approaches. The most important part of the therapy is antibiotics that inhibit replication of the protozoa. Anti-inflammatory medication that limits the swelling and inflammation in the nervous tissue is recommended in many cases of EPM. Additional therapy, such as supportive care, or treatment for any secondary problems may also be necessary.
There have been recent exciting developments in the arena of antibiotics for the treatment of EPM. While there are no currently FDA-approved drugs for this disease, there have been a number of products either available by personal use importation, or off-label for horses. Most of the newer drugs can be used for a much shorter duration of treatment than the old pyrimethamine-sulfa products, although much less is known about these other drugs.
Current dosage recommendations for this anti-protozoal therapy are 1.1 mg/kg of pyrimethamine in combination with 20 mg/kg of sulfadiazine once daily. This combination is available from compounding pharmacies that are licensed to use this product, such as Vet's Choice (888-809-3710). Alternatively, pyrimethamine is available as 25 mg tablets (Daraprim, Burroughs-Wellcome) (20 tablets for 450 kg horse) once daily, and 12-25 mg/kg of a sulfonamide once to twice daily (depending upon the sulfonamide). Often, trimethoprim-sulfamethoxazole is used, but trimethoprim is not necessary in the treatment of EPM, and actually contributes to some toxicity problems, and therefore should not be used. Horses should remain on both the pyrimethamine and sulfonamide for the duration of treatment, because closely related protozoa, including Falciparium spp. (malaria) and Toxoplasma gondii, have been shown to become resistant to pyrimethamine in the absence of sulfonamides.
The method of administration is extremely important. Many horses which have been treated by adding the drugs directly to the feed have failed to respond until the medication was administered by dose syringe into the mouth. Horses that do not eat their grain all at one time probably do not achieve drug levels which are high enough to kill the parasite. Additionally, the pyrimethamine should be administered once daily and not divided into two daily doses. Peak drug levels appear to be necessary to achieve minimal inhibitory concentrations.
Feed, especially that containing folic acid, such as hay and grain, interferes with the absorption of the pyrimethamine. It does not affect the sulfonamide absorption. Therefore, any pyrimethamine-containing drug should be administered on an empty stomach; either two hours after feeding or one hour before feeding. Grain probably interferes with absorption less than hay, so the drug may be administered with a small amount of grain if the horse will eat it all at one time.
Different horses may also absorb the drug differently, resulting in different results in each individual horse. Administering lower doses, or dividing the dose and administering twice daily for periods of time during the treatment is probably dangerous, because it could encourage selection for a resistant population of protozoa. A lower dose (0.5 mg/kg, once daily) should be reserved for horses which exhibit signs of toxicity at the higher dose.
Sufficient duration of treatment is equally important as sufficient dose. When horses are treated for four weeks after the resolution of clinical signs, the relapse rate is estimated to be between 10-30%. When horses are treated empirically without waiting for four weeks after the resolution of signs, horses will relapse at a rate of 40-50%. The best method to determine when a horse can safely be taken off medication without a relapse is to retest the spinal fluid of the horse for antibodies by Western blot. If the test is negative, the rate of relapse is less than 5%. If the test is positive, the rate of relapse is higher than 95%.
When relapses occur, the protozoa that have been selected may be resistant to medication, and therefore, the duration of treatment the second time should be at least twice as long. Some horses that have relapsed when the medication is discontinued ultimately relapse every time the medication is withdrawn, and therefore need to remain on treatment indefinitely. Extreme caution should be taken when recommending that medication be discontinued, because there is currently no alternative medication.
One outdated recommendation was to treat for 5 days out of every month. This ultimately results in the production of a highly resistant protozoal population. Since there is no alternative medication available at this time, once your horse has a resistant EPM infection, the prognosis is poor.
Folinic acid (Leucovorin) may be administered once side effects occur. Alternatively, folic acid is much less expensive and has some effect both treating and preventing signs of toxicity. There has been recent concern about folic acid potentiating the toxicity of the pyrimethamine. No concrete evidence has been produced in horses to support this viewpoint, but folic acid should probably not be used in pregnant animals until this controversy is solved by appropriate studies in horses. Folic acid is still recommended in performance horses to prevent the development of anemia in horses on treatment.
The drugs, pyrimethamine and trimethoprim, kill the parasite by competitively inhibiting the dihydrofolate reductase enzyme (DHFR), interfering with production of the active form of folic acid, tetrahydrofolate. These drugs can also interfere with folic acid metabolism by the horse, resulting in folic acid deficiency, and subsequent anemia. The protozoa cannot use folic acid, so the supplementation of horses with folic acid prevents some of the side effects of folic acid deficiency without interfering with anti-parasitic activity. Once anemia or leukopenia has occurred, folic acid (40 mg/day) may be effective for treatment without adversely affecting treatment of the parasitic infection, according to preliminary studies. In some cases, the dose of folic acid should be increased.
Pyrimethamine-sulfadiazine inhibits the bone marrow, which manifests itself as anemia and leukopenia. These side effects are rarely severe, and occur in as many as 25% of horses treated. Therefore, it is recommended that a complete blood count be taken at regular intervals during therapy. Folic acid supplementation during treatment will ameliorate these signs. Abortions in mares and the birth of abnormal foals that do not live may occur, and a temporary effect on fertility in stallions may be recognized. Finally, a syndrome of bone marrow suppression with worsening ataxia is rarely identified in horses on this combination.
Nitazoxanide (NTZ) is available from the company, Blue Ridge Pharmaceuticals, as part of a broad field trial which is part of an FDA submission for this drug. The company will provide the drug for an administrative fee, if the treating veterinarian agrees to adhere to an experimental protocol, and keep certain records.
The dose of NTZ is 25 mg/kg for five days and then 50 mg/kg for 23 more days. It is provided by the company as a box of 28 tubes of paste. This amount of drug for this time period has been associated with an 86% improvement (75% improved by >1 neurologic grade, 11% improved by less than one grade), with only 5% relapses within two months after treatment. There was also a 5% rate of CSF becoming negative after this time period.
NTZ comes in an oral paste form. Unlike pyrimethamine, which is better absorbed on an empty stomach, NTZ is an oil-soluble drug that is better absorbed on a full stomach. The drug should be given immediately after a grain meal, and corn oil may be added to enhance drug absorption. The addition of corn oil is not recommended as a routine measure, and you should consult your veterinarian regarding an individual case.
NTZ has some adverse effects on the gastrointestinal tract, and all of the potential side effects are related to this action. The most common adverse effect is fever, which is usually identified within six hours of the dose, and is usually below 102 F. Mild gas-type colic, slight loosening of the feces, and anorexia can also be observed with NTZ. Increased digital pulses in the front feet, accompanied by soreness in the feet can be rarely observed, but the significance of these signs is uncertain, since no radiographic changes or long term sequelae have been seen after one of these events. The majority of side effects are transient, but the company recommends discontinuing NTZ when an event occurs, and starting back on NTZ once the event has resolved. In my hands, only a small number of horses need to be taken off the NTZ for any adverse events. Probably the most attractive feature of NTZ is the lack of side effects in any treated pregnant mares (about 6 mares).
Toltrazuril (Baycox®, Bayer Corporation) is not available in the US for any use, although it can be legally imported under the personal use importation rule. This permits the importation of small quantities of drugs, enough to treat one or two horses, for the treatment of diseases for which there are no FDA approved treatments. Your veterinarian must write to the manufacturer, in this case, Bayer Canada, and copy the letter to the FDA. This allows the importation of unapproved drugs on a case by case basis.
The dose of toltrazuril is 5 to 10 mg/kg once daily. The duration may be anywhere from 28 to 90 days, depending upon the recommendations of different veterinarians. Most people using the drug recommend either 10 mg/kg daily for the 28 days, or 5 mg/kg for at least 45 days. There are some veterinarians that use large doses which are administered by nasogastric tube and given 10 days apart. Unfortunately, there is a high rate of relapses associated with this practice, and the principles associated with this drug, such as drug half-life in the body do not support this practice.
Baycox comes from the Canadian manufacturer as tablets. These are ground up and administered by mouth, or alternatively can be given by nasogastric tube.
There do not appear to be a lot of side effects of Baycox in horses, even at high doses. There are anecdotal reports of increased kidney enzymes in some horses, and the company reports uterine edema in mare treated with high doses of the related drug, ponazuril. Until more information is available from a large number of treated horses, caution should be exercised when this drug is used in horses, particularly in pregnant mares.
Diclazuril (Clinicox®, Janssen Pharmaceuticals) is also a Canadian drug which is not available in the United States, but may be obtained via personal use importation. There was an injectable product available from a compounding pharmacy, but it was extremely controversial, and associated with both miraculous cure testamonials and sudden death testamonials. The injectable product is no longer available. Horse owners and veterinarians should be extremely cautious about testamonials that do not stand the test of scientific evaluation.
Clinicox comes as a pre-mix product that is manufactured for mixing into poultry feed. It consists of Diclazuril in a pure soy protein base. The recommended dose is 5 to 10 mg/kg, which comes to about a pound of the pre-mix once or twice a day. In my experience, the relapse rate with this drug is extremely high, and most horses treated with Diclazuril end up treated with pyrimethamine-sulfadiazine.
Clinicox is usually mixed with feed. Many horses are reluctant to eat Clinicox, and it must be given by nasogastric tube in those horses.
Most of the side effects associated with Clinicox are related to the pure protein base. If this drug is used, protein should be decreased out of the rest of the horse's diet. For example, alfalfa and other legumes should be eliminated from the diet, and a low protein grain (8% protein), or plain oats should replace the grain in the diet. Side effects are uncommon and include colic, founder and diarrhea..
Oxytetracycline is available in the United States for use in cattle, and is commonly used off label in horses for Potomac Horse Fever, Ehrlichiosis and lung infections. The related drug, Doxycycline may also have some effect on EPM.
Oxytetracycline is given IV once daily at a dose of 10 mg/kg. I have given this drug for as long as six weeks, but this is not recommended. There is a temporary improvement with this drug in horses, but the protozoa becomes resistant very quickly, and the horses relapse. Oxytetracycline may have a role in the acute therapy of an EPM horse, but it does not provide any long term cure.
Used for five to seven days, oxytetracycline causes few adverse effects. Those rare cases reported are diarrhea, colic and founder.
All of the above treatments can be associated with about a 10% rate of horses experiencing a "treatment crisis," in which the neurologic signs actually worsen while on medication. This may be the result of an inflammatory response to the dying parasites, which are unable to evade the immune system as well as live parasites. This "crisis" usually responds to the same type of anti-inflammatory treatment as originally indicated in horses which exhibit acute EPM. The specific type of anti-inflammatory medication varies depending upon the specific case, and therefore, I will not discuss specifics here. The particular treatment regimen should be discussed with your veterinarian.
Supplementation with vitamin E (8000 IU per day) may be helpful adjunct to treatment in all neurologic disease. Vitamin E is an anti-oxidant that provides some anti-inflammatory properties in the central nervous system at high concentrations. Supplementation with vitamin E has been advocated in several different neurologic diseases. This supplement is helpful in many different neurologic diseases, and recommended at a level of 8000 to 9000 IU per day.
The short-term treatment regimens, including NTZ, Baycox and Clinicox, are very attractive, because they do not require months of long-term therapy. However, the allure of a short-term treatment should not overshadow the fact that pyrimethamine-sulfadiazine has a long term record of success. In addition, if the horse relapses after a short course of medication, the end result is still a failure. Therefore, for the average case of EPM, I still recommend pyrimethamine-sulfadiazine. However, for young performance horses that are not actively competing at the time of the diagnosis and breeding animals, my first choice is NTZ. NTZ is the only drug for which I have a high level of confidence and safety in pregnant mares. In performance horses that cannot have at least a month off and for most pleasure horses, I recommend pyrimethamine-sulfa. Both diclazuril and oxytetracycline do not appear to have long term success unless used in conjunction with pyrimethamine-sulfa. My experience with Baycox is minimal, but the few cases that I have followed have relapsed after the treatment, which has not given me great confidence in the drug at this time. Nonetheless, many good veterinarians do use Baycox.