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EPM due to Neospora

Equine protozoal myeloencephalitis caused by Sarcocystis neurona is rare, even more uncommon is EPM caused by Neospora hughesi.  Two organisms, N caninum and N hughesi are associated with disease in horses, N hughesi being identified as the cause of neurological disease in most cases. Healthy horses have Neospora antibodies in their serum (IFAT).  A recent survey reported 34% of over 5000 samples from horses in 18 states were positive.

Natural disease

Neospora hughesi, isolated from an infected horse, was proposed as a new species in 1998 and then it was reported in a Canadian horse in 2009. The protozoa  are associated with the viscera, the fetus, early abortions and a few cases of EPM.  The clinical signs are similar to those caused by S neurona.  EPM due to Neospora may be more of a concern in Canada than the US, that is because opossums aren't found in the western part of the country. Most clinical disease has been found  in animals suffering from another concurrent infection.  Disease is possibly related to horses with compromised immune systems. The definitive host and life-cycle for for N hughesi is unknown, the definitive host for N caninum include the dog and coyote. Isolation of the organisms from horses is rare.  Because there are only 3 characterized isolates of N hughesi a “gold standard” serum panel, needed to develop diagnostic tests, seems elusive.

Experimental disease

There is a report using experimentally infected horses to define immune parameters for diagnosis by IFAT.  The infected horses showed no clinical signs of disease, no gross or microscopic lesions, nor did they find the organisms in the horses.  Results for whole parasite ELISA and recombinant ELISA failed to discriminate between the noninfected and the experimentally infected animals. There was no correlation between antibody values and clinical progression, a similar result that they reported from samples obtained from the naturally infected Canadian horse. The IFAT validation paper also reported that sera from 2 of 3 naturally infected horses were comparable with values of noninfected (control) horses. Modified direct agglutination test (valuable in N caninum testing from numerous species) results are a bit hard to interpret because one infected horse was false negative at all time  points after challenge. And 3 of the 7 experimentally infected horses were false positive before infection.  Four of the 7 noninfected  horses were false-positive at multiple time intervals.

The IFAT using Neospora was negative for horses with proven S neurona. However, the IFAT detected a difference in serum antibody responses between N hughesi-infected and non infected horses. The CSF titers for the noninfected horses were negative, along with 2 of the 7 infected horses. Based on the IFAT titer results, 1:640 was selected as a cut-off value.  Puzzling and interesting, they reported that frozen-thawed samples had higher values than when tested prior to freezing. That's a tough one to figure out.

Also interesting, and puzzling, is 6 of 7  “infected” horses had low CSF titers (one was negative) and all were disease free.  That contrasts to a naturally diseased horse (gold standard positive) with a CSF titer considered “very high”, 5  to 10 serial dilutions higher than considered positive for the experimental infections. Whatever the source of the antibodies in the CSF in the experimentally infected horses, it wasn’t parasites in the CNS. The results of the IFAT infection study allows for detecting exposure and determining seroprevalence, but not disease in horses.

Cross-reactivity with other EPM organisms

The above IFAT study and a review of cross-reactivity studies indicates that testing format is important in distinguishing between Sarcocystis and Neospora. In 2005 a specific N hughesi ELISA test was developed.  ELISA was used for detecting N hughesi antibodies using recombinant antigens suggesting the potential for use of serodiagnosis of N hughesi infection in horses.  These tests do not unambiguously differentiate infections caused by N hughesi or N caninum but they do differentiate between Neospora and Sarcocystis.  Therefore, currently available Neospora ELISA  tests for serum are genus rather than species-specific for these protozoa.

What’s unknown

The important unknown is the relationship between N hughesi infected horses and clinical disease due to N hughesi.  How long are N hughesi antibodies detected after exposure?  That's not known. What is the life-cycle of the parasite? We don't know yet. What is the definitive host?  Probably a good guess is a dog or a coyote.  How about the relationship between S fayeri and Neospora? Is there a relationship between abortion or reproductive difficulty and Neospora in horses as in cattle? Yes, most likely yet unproven. It is suggested in the literature that horses have persistent infections, despite the inability to demonstrate parasites, is this true?  Does the parasite form cysts in horses? Horses are big, cysts are small.  Disease is rare.  It will be a long time to figure this one out.  There are no published effectiveness treatment studies. There are no licensed treatments for horses.

Why do you care?

A horse that is suspicious for EPM and with no antibodies against S neurona, perhaps testing for N hughesi is reasonable. It is more likely that S fayeri is the culprit. When using these tests, recognize the limits of testing and the validation that was used for tests. coyote-W.M.-Giuliano