An Update on EPM: The Latest in Diagnostics and Treatment

Jean-Yin Tan, DVM, DACVIM Large Animal Internal Medicine

Diagnostics

“My horse has been just a little off, Doc. I don’t really want to pay for a full-blown lameness or neuro exam or anything. Would you mind just taking a blood test for EPM while you’re here?”

If you’re a general equine practitioner, you’ve likely been asked a question like this in the middle of a routine vaccine visit, by a horse owner who’s been dabbling in reading a few of the latest horse publications and learning some catch phrases from her friends. Since you were hoping to just quickly knock off a few vaccines while on your way to 5 more lengthy calls that you have to cram into your afternoon, chances are you’ve been tempted to just pull the blood sample. After all, a full neurologic exam would take a lot of time and money, and that’s not what the owner wants to do, right?

It might be time to educate your client. The first rule of interpreting any diagnostic tests for EPM is that a clinical diagnosis of EPM must be made. In the absence of detectable neurologic deficits and elimination of other differential diagnoses, confirmation of exposure to Sarcocystis neurona via any number of diagnostic tests can mean very little.

Western Blot. Sensitivity is 80% and specificity 38% for testing of the serum of neurologic horses. That means it can be used to rule out EPM, but the low specificity means a large number of false positives, making the test inappropriate for diagnosing EPM. Cross-reaction may also occur with nonpathogenic Sarcocystis fayeri, which uses the horse as a natural intermediate host.

IFAT. The indirect immunofluorescent antibody test is a quantitative serologic test for EPM which provides actual titers and a likelihood ratio of the disease. Although sensitivity (83% for serum) is similar to that of the Western blot, specificity (97% for serum) is higher using the IFAT. Serum and CSF results have a moderately strong correlation. Furthermore, blood contamination of up to 104 RBCs/l does not affect CSF test results. The IFAT can also be used to detect EPM attributed to Neospora hughesii. There is however, cross-reaction with S. fayeri.

SAG-1 ELISA. The latest test is an ELISA that detects a specific surface antigen SAG-1 found on S. neurona merozoites. Although the low sensitivity and specificity (68% and 71% respectively) and geographical variation in presence of the surface antigen inhibits the commercially available SAG-1 ELISA from being a reliable diagnostic test, there is some potential for a more reliable SAG-2 ELISA in the future, especially given the lack of cross-reactivity with S. fayeri and N. hughesi.

So, what should I do? The Western Blot, IFAT, and SAG-1 ELISA are all different ways of detecting anti-S. neurona antibodies in serum or CSF. Currently, the IFAT offers the highest sensitivity and specificity. It is important, however, to take into consideration that cross-reaction with S. fayeri and vaccination can affect results.

CLICK TO SEE THE FULL CHART


Treatment
“Doc, I read in a horse magazine about a medication called toltrazuril? Do you think we should try that on my horse? I think it’s supposed to work real well on EPM.”

It’s busy season and you haven’t had much of a chance to sit down, let alone read the latest in journals on equine neurologic disease. If you’ve never heard of toltrazuril, don’t panic. I’ve put together a brief synopsis of drugs used for EPM below.

Antiprotozoals. FDA approved options are: sulfadiazine/pyrimethamine, ponazuril, nitazoxanide, and diclazuril. In the studies cited, successful treatment is defined as improvement in neurological grade by at least 1 level or CSF testing becoming negative on Western blot.

Sulfadiazine/pyrimethamine (ReBalance). At 20mg/kg sulfadiazine and 1mg/kg pyrimethamine orally daily for 90 days, 62% of affected horses have successful outcomes. However, adverse effects from folic acid deficiency include bone marrow suppression (12%), GI disturbance, decreased spermatogenesis in stallions, and congenital defects in foals when used in pregnant mares.


Ponazuril (Marquis). At 5mg/kg orally daily for 28 days, this antiprotozoal drug is responsible for the successful treatment of 60% of horses and at double-dose, 65% of affected horses. There were no adverse effects in a study of 101 horses. However, possible side effects listed by the manufacturer include blisters, hives, diarrhea, colic, and a seizure.

Nitazoxanide (Navigator). Although no longer commercially available, this antiparasitic drug used at 50mg/kg orally daily for 28 days has been found to successfully treat 57% of horses. However, fatal enterocolitis, fever, anorexia, lethargy are noted side effects and affect up to 31% of horses.

Diclazuril. This FDA-approved but unmarketed antiprotozoal drug has been used as pellets at 1mg/kg orally daily for 28 days with a 67% success rate. Adverse reactions that may not necessarily be correlated with the drug include laminitis or decline in neurologic status.

Toltrazuril (Baycox 5%). An anti-coccidial drug used in other species, this drug is being reviewed by the FDA for use in horses for EPM. At 5mg/kg orally daily for 10 days, it has been found in limited studies to achieve excellent absorption into CSF with no adverse effects.

Antiinflammatories. Nonsteroidal antiinflammatory drugs can help decrease initial worsening of signs during treatment associated with inflammatory response to the parasite. Corticosteroids are not recommended but single doses may help curb inflammation and allow antiprotozoal drugs to work. Many veterinarians use DMSO as well. There have been no clinical trials to support or refute the use of Vitamin E and thiamine supplementation.

Immunostimulants. Some veterinarians have advocated the use of immunomodulation with drugs such as Prioponibacterium acnes, mycobacterial cell wall extracts, levamisole, and alpha-interferon. These could potentially affect T cell-mediated immunity and stimulate macrophages. However, without further investigation, theoretical immunopathologic effects on the CNS should also be considered.

What do I do if the horse relapses? It is theorized that 10% of horses relapse within 3 years of discontinuation of therapy. Treatment options include longer duration of therapy (off-label doubling of the standard period of treatment), using higher doses of ponazuril, combining ponazuril with sulfadiazine/pyrimethamine, using twice-weekly continuous therapy with sulfadiazine/pyrimethamine, and possibly using anthelmintic levamisole as an immunostimulant.

So…What should I treat with? Currently the only commercially available antiprotozoal with the least reported adverse effects is ponazuril. However, look for other options such as diclazuril or toltrazuril appearing on the market in the future. Although conservative use of antiinflammatories is widely accepted, the efficacy of treatments such as DMSO, thiamine, Vitamin E, and immunostimulants has not been specifically investigated but can be used at your discretion.

UPDATE
The new SAG-2 and SAG-4,3 assays for EPM which are now available. These have possible advantages over the previous available assays because:

-These surface antigens are those most commonly expressed by S. neurona strains
-Quantitative test

-Provide serum/CSF ratios

The disadvantage is that both CSF and blood samples need to be submitted to provide accurate information.

References
1. Daft B, Barr, BC, Gardner, IA, et al. Sensitivity and specificity of western blot testing of cerebrospinal fluid and serum for diagnosis of equine protozoal myeloencephalitis in horses with and without neurologic abnormalities. J Am Vet Med Assoc 2002;221:1007-1013.

2. Duarte P, Daft, BM, Conrad, PA, Packham, AE, Gardner, AE. Comparison of a serum indirect fluorescent antibody test with two Western blot tests for the diagnosis of equine protozoal myeloencephalitis. J Vet Diagn Invest 2003;15:8-13.

3. Duarte P, Daft, BM, Conrad, PA, et al. Evaluation and comparison of an indirect fluorescent antibody test for detection of antibodies to Sarcocystis neurona, using serum and cerebrospinal fluid of naturally and experimentally infected, and vaccinated horses. J Parasitol 2004;90:379-386.

4. Dubey J, Lindsay, DS, Saville, WJA, et al. A review of Sarcocystis neurona and equine protozoal myeloencephalitis (EPM). Vet Parasit 2001;95:89-131.

5. Furr M, McKenzie, H, Saville, WJA, et al. Prophylactic administration of ponazuril reduces clinical signs and delays seroconversion in horses challenged with Sarcocystis neurona. J Paristol 2006;92:637-643.

6. Granstrom D, Howe, D, Bentz, B, et al. Current treatments for equine protozoal myeloencephalitis. Equine Disease Quarterly 2007;16.

7. Hoane J, Morrow, JK, Saville WJ, et al. Enzyme-linked immunosorbent assays for detection of equine antibodies specific to Sarcocystis neurona surface antigens. Clin Diagn Lab Immunol 2005;12:1050-1056.

8. Johnson A. Evidence-based review of diagnosis and treatment of Sarcocystis neurona infection (Equine Protozoal Myeloencephalitis). AAEP 2009.

9. MacKay R. Equine essentials - equine protozoal myeloencephalitis: Managing relapses. Veterinary Technician 2008;29.

10. Reed S, Saville, WJ, Schneider, RK. Neurologic disease: Current topics in-depth. AAEP 2003.

11. Saville W, Dubey, JP, Oglesbee, MJ, et al. Experimental infection of ponies with Sarcocystis fayeri and differentiation from Sarcocystis neurona infections in horses. J Parasitol 2004;90:1487-1491.