Friday, December 9, 2011

Equine Protozoal Myeloencephalitis (EPM): Update on treatment

Twenty years ago when I first ventured into EPM research, the standard course of treatment was pyrimethamine (Daraprim®), a common anti-malarial drug, in combination with trimethoprim/sulfadiazine. We used a fairly low dose, and treated for only a few months. However, upon following up with some of those early cases, we discovered that this treatment was not sufficient. Researchers in Oklahoma (Clarke, 1992) found that a much higher dose of pyrimethamine is required to achieve drug levels in the cerebrospinal fluid sufficient to kill the protozoa. After these findings, we adjusted our recommendations to a combination therapy of pyrimethamine (1.0 mg/kg daily), in combination with sulfadiazine (20 mg/kg daily). It turns out that trimethoprim is not recommended, and probably should be avoided, if possible, because it is likely to add to the toxicity of the pyrimethamine, without adding to the efficacy. It's been a long time since I patented that discovery, and there are many other options available now. This disease is absolutely curable, and if you stick to a program of appropriate treatment, you will be rewarded with a healthy horse.

Treatment for EPM has since taken many turns, and hopefully, new products will continue to be added to our arsenal for this disease.

  • Pyrimethamine/sulfadiazine is still the most common treatment, because compounding pharmacies have made it very affordable. This is a product which interferes with nucleotide synthesis and therefore the production of DNA. Horses require treatment for 6 to 8 months on this drug combination, and sometimes much longer. The biggest problem with this medication is that the long duration of treatment makes compliance difficult. Many horses are taken off the medication too soon, resulting in relapse of clinical signs.

Side effects are most commonly bone marrow suppression which is manifested as anemia and leukopenia (low white blood cell count). This product is not safe in the third trimester of pregnancy, resulting in foals with profound bone marrow suppression and kidney damage. A less common side effect of this product is a neurologic syndrome of ataxia and facial nerve paralysis, which is usually reversible when the drug is discontinued.

  • Ponazuril (Marquis®) is marketed as a paste formulation and has been available for over ten years. The label dose is 5 mg/kg for 28 days, but the relapse rate is high (35%) with this dose. Some studies have shown a higher efficacy with 10 mg/kg (or a double dose).

Minimal side effects are seen with ponazuril, although the safety studies indicated that with extremely high doses uterine edema is seen.

  • Diclazuril (Protozil®) is marketed as a daily pellet feed top dress at 1 mg/kg for 28 days. This is a difficult product to recommend, since the company's own research had only a 42% efficacy rate. We had reasonable efficacy in the 1990's when we studied a dose of 5 mg/kg, but the Protozil is very expensive at that dosing rate.
  • Nitazoxanide (NTZ) was approved right after Marquis in the early 2000's, but was taken off the market when Idexx dropped their pharmaceutical line. NTZ is very effective for EPM at 25 mg/kg for the first four days and then 50 mg/kg daily for 24 days. This product is highly soluble in fat, so added fat in the form of corn or other oil improves the absorption of the product. This product is only available as the human label tablets (Alinia®).

NTZ, while highly effective, has a number of serious side effects. Much of the product is not absorbed in the small intestines, and passes to the large colon, where it can alter the normal colonic flora. The end result can be absorption of endotoxins and in some cases diarrhea. Among the effects of the endotoxemia can be laminitis or founder. While uncommon, this possible sequela should be carefully watched for in the NTZ treated horse. In most horses, the concomitant administration of oil results in improved bioavailability, which results in less drug passing to the large colon, and a lower rate of side effects.

  • Decoquinate has recently been suggested as an EPM treatment in combination with levamisole as an immunomodulator (Oroquin-10®) for a 10 day course of treatment. Decoquinate is extremely inexpensive in the form of Deccox premix, a poultry coccidiostat which is added to poultry feeds to prevent coccidia. At the recommended dose of 0.5 mg decoquinate/kg, 4 g of Deccox premix is sufficient for each daily treatment. In cell cultures, decoquinate is highly effective against the rapidly dividing merozoite stage of the EPM organism. The question remains as to whether the decoquinate actually crosses the blood-brain barrier to get to the parasite. Hopefully, further investigation will add this inexpensive treatment to our arsenal.

    Oroquin-10 is a new treatment and as such there is no safety data available. The primary anti-protozoal ingredient, decoquinate, is very safe at high doses in horses. Levamisole has many potential side effects in humans, and has not been studied in horses.
  • Oxytetracycline is effective against many protozoa in this class. The problem with this drug is that protozoa become rapidly resistant, so it may work for a short period, but treatment doesn't result in a cure. The advantage of this drug is that it can be used intravenously, and in the case of a horse that cannot swallow oxytetracycline provides a way to get treatment into the animal.

In general, oxytetracycline is a commonly used antibiotic in horses for a myriad of conditions, and is relatively safe. In rare cases, oxytetracycline can cause diarrhea.

In addition to the anti-protozoal treatment, immunomodulators like levamisole are warranted. In addition to levamisole, there are several approved immunomodulators, including EqStim ®, Equimune ® and Zylexis ®. I investigated EqStim in the 1990s as an adjunctive treatment for EPM with pyrimethamine/sulfadiazine and found that horses on average required two months less treatment before clearing the EPM antibodies from the cerebrospinal fluid (negative CSF test). Any immunomodulator may be effective, but less is known about levamisole, so my preference is to stick with the approved products like EqStim.

Anti-inflammatory treatments are an essential adjunctive treatment for EPM. More damage is caused by the inflammation surrounding the protozoa than the protozoa themselves. This may include treatment with phenylbutazone or banamine (1.1 mg/kg 1-2 times daily for 3-7 days), as well as the addition of DMSO (1 g/kg in a 10% solution) administered either intravenously or by nasogastric tube. Corticosteroids may be used if necessary. Antiinflammatory drugs are occasionally necessary at other times during the first six weeks of treatment. Some horses actually get worse during treatment, presumably because of a reaction to the dying parasites, a condition which I termed a “treatment crisis” twenty years ago.

Important supplemental therapies are the addition of neuroprotective supplements, such as vitamin E, folic acid and thiamine.

Now that I've explained the different options, I'll tell you my personal recommendations for the treatment of an acute EPM case. I'm not interested in messing around with unproven treatments, unless I have a chronic, relapsing horse with EPM. My standard recommendation is double Marquis (10 mg/kg) for 28 days, followed by pyrimethamine/sulfadiazine for four months. Unfortunately, even with the higher dose of Marquis, some horses will relapse, making the four months of pyrimethamine/sulfa necessary.

Many of the clinical signs associated with EPM are caused by inflammation rather than the parasites themselves. Therefore, almost all of my EPM patients receive DMSO and a short course of flunixin (Banamine ®) to reduce inflammation. I also recommend daily Vitamin E and folic acid. My preference for immunostimulation is EqStim, which I use at the label recommendation of days 0, 3 and 7 and then twice monthly after the initial series.

2 comments:

  1. Keeping a horse is quite costly especially when it has illness. We might know how the horsemanship works but treating some diseases is not that easy. We still need the knowledge of veterinarian.

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  2. What is your recommended daily dosage for Vitamin E and Folic acid during treatment?

    ReplyDelete