Tag Archives: treatment crisis

EPM Tilter. What Do The Numbers Mean?

During my horse’s recent Lymphingitis flare-up, the vet advised that we run labs to test for Lyme and EPM due to his presenting symptoms (hind weakness, twisting his back leg at the walk/walking sideways I refer to it as- “Chance’s swagger”).  As I noted previously, Chance’s Lyme test revealed that he was at the beginning stages of an acute infection…yay for the labs at Cornell University for their amazing ability to give you more than a positive or negative!

A little history before getting to the EPM Tilter results.

About 2ish years ago, Chance was diagnosed with EPM (and one of the reasons opossums and I are not friends since they host the disease as do a few other culprits).  Chance immediately began EPM treatment- he received Protazil in his feed for one month. After hours of research I chose Protazil, although extremely expensive (if you order from http://www.drfosterandsmith.com they sometimes have promotions where you receive store credit for every $100.00 you spend…they did when I ordered and I got a “free” dog bed that my dogs adore), due to the decreased likelihood of Chance experiencing a “Treatment Crisis” (worsening of symptoms) and the ease of administration (other brands require the drug being administered 1 hour before eating or an hour after and so on).  Typically, EPM treatment is done for 30 days and, depending on the residual symptoms, some may require subsequent treatments.  While Chance’s symptoms improved, I wanted to ensure that we annihilated the disease and did another round of treatment but this time with Marquis.  At the end of two months, Chance’s ataxia was gone!

Fast forward to September 2016…Chance, just having a Lymphingitis flare-up, has been tested for Lyme and EPM. Lyme came back positive.  And….so did the EPM test..well, kind of.  Wonderful.  (See why I loathe opossums?)

Chance’s EPM test #2 on 8/30/16 (the 1st one was 2ish years ago) showed the following:

“Combined SAG 2,3,4 Tilter on serum= 1:2000”

So, what does this mean?

The test revealed that Chance had “positive, specific antibodies” detected in the blood work.  This means that he had EXPOSURE to S. Neurona, a causative agent of EPM.   Serum tilters range from <1:250 (negative) to >1:4000 (high positive).  S. Neurona (SarcoFluor) is one of two protozoa found in EPM infected horses, the other protazoa is N. Hughesil (NeoFluor). S. Neurona is most frequently seen, whereas N. Hughesil is not as common.

The vet ran another EPM test to confirm the findings in the 8/30/16 test.  The results showed that Chance had “Combined SAG 2,3,4 Tilter on serum= 1:1000.  Again, Chance showed EPM protozoa in the positive-ish range.

I initially had not seen the results but was told by the vet that he was EPM negative.  So when I asked for the test results to be emailed to me and saw the numbers I sort of freaked out…I emailed the vet to ask for clarification.  She explained,

“The EPM test shows that he was exposed to the organism in the first test we did which is why we did a follow-up test. Since his exposure level dropped from 1:2000 to 1:1000 this shows that he does not have the disease. There is no good one time test for EPM once they are exposed which is why we had to do the repeat to compare the two.”

While this explanation offered me comfort, I was confused…why does he have any protozoa in his blood if he doesn’t have EPM?

I spoke to another vet and she explained it in a bit more detail…I am hoping I am summarizing what she said correctly..

When a horse tests positive for EPM they either have an active disease or they may not.  However, when the test does from 1:2000 down to 1:1000 this typically means that the horse’s immune system is working correctly to fight the disease off- active or not.  EPM testing typically provides you with a % of the chance your horse has an active EPM infection, or at least if you send it to Cornell University.  For instance, lets say a horse gets the results back and it shows that they are “positive” or have been exposed to S. Neurona (one of the two EPM protozoa)…their results are  1:647.  This means that, after doing a bunch of adding and multiplying that this vet kindly did for me, the horse has a 60-70% chance of having ACTIVE EPM.  Meaning, he most likely would be symptomatic (ie: behavioral changes, ataxia, weight loss, difficulty eating, changes in soundness, and a bunch of other neurological symptoms).

My hunch is that Chance’s immune system was boosted because I started him on Transfer Factor (amazing stuff… more information can be found in some of my older posts) again as soon as his results came back positive for Lyme.

Here are the 3 EPM tilters that were run on Chance (oldest to most recent) along with his Lyme test results:

epm-2014

epm-test-results-8-31-16

EPM results 9-8-16 copy.jpg

lyme-titer-8-30-16

EPM Treatment Research

Ohio State University

College of Veterinary Medicine 

Treatment

Several regimens have been described previously for the treatment of EPM and >60% of horses respond to treament, and that clinical signs completely regress in 55-60% of the cases. The treatment most commonly used employs a combination of potentiated sulphonamides (Trimethoprim/Sulfas) and pyrimethamine. This combination causes a sequential blockade of folate metabolism in apicomplexan protozoa. Based on a recent pharmacokinetic study of pyrimethamine in horses, the dose required to reach the minimum inhibitory concentration (MIC) for Toxoplasma gondii in CSF is 1.0 mg/kg. The recommended dose of pyrimethamine is 1 mg/kg once a day for 60 to 90 days. However, it has been suggested that high dose pyramethamine therapy over this extended time period can result in anemia. Previous work using the 1 mg/kg dose of pyrimethamine once daily did not result in anemia, but the drug was only administered for 10 days to these normal horses. The trimethoprim/sulfa combinations have been recommended at a dose of 15 to 20 mg/kg bid per os for the full treatment period. If sulfonamides are used without the trimethoprim, the dose recommended is 20 mg/kg per os once or twice per day. Most of the treatments are administered for at least 12 weeks, but must sometimes be extended to 16 weeks or more. After initial therapy has been completed, some clinicians recommend periodically placing horses back on treatment if animals undergo some unusual stress. Other intermittent treatment therapies have also been used, such as treatment once every two to four weeks, or daily during the first week of every month. Intermittent treatment may increase the risk that parasites infecting a horse develop drug resistance. Therefore, we do not recommend intermittent or periodic treatments. Recent problems with the response to current therapy has led to increasing the dose of the sulfa/pyrimethamine mixture. Earlier, the only product applied at an increased dosage was the pyrimethamine; it was administered at 1.5 mg/kg, and sometimes even 2.0 mg/kg once a day. These increased dosages were used in cases that appeared to not respond within the first 30 to 60 days. A practice currently used by some clinicians for horses that do not respond to 30 days of treatment is to increase medication dosages. For example, if using the mixture from Mortar & Pestle, the dose for a 1,000 lb. horse is 30cc. Some clinicians are increasing it to 45cc. If no response is seen after 30 days of this dosage, the amount given is further increased to 60cc per day. This should only be done in consultation with your regular veterinarian. This also increases the importance of monitoring for signs of folic acid deficiency by evaluating CBC’s at least every two weeks. Recent discussions concerning EPM have led to reports of using tetracyclines in some cases that continue to be CSF+ even after many months (six months or longer) with the sulfa/pyrimethamine combination. This use is based upon tetracycline’s inhibitory effect on protein synthesis, however, no controlled trials have been performed at this time. The only reported antiprotozoal use of tetracycline was documented in sheep which received 30 mg/kg to treat a differentSarcocystis spp. infection. This an extremely high dosage, and is not recommended for use in horses. Some clinicians have experimented with administration of 6.6 mg/kg once or twice daily for one week. It is not clear why using tetracycline, a bacteriostatic agent, for one week would be curative. We would recommend that this therapy not be used or used with extreme caution until controlled clinical trials have been completed. Additional therapies are also being used by some clinicians. These therapies include the use of immune stimulants such as Eqstim, Equimune, alpha-interferon, or levamisole. These compounds may boost non-specific cell-mediated immunity. Cell-mediated immunity is necessary to rid the body of these parasites. The efficacy of these compounds has been established in humans with leishmaniasis. A new therapy (Diclazuril) has been receiving a lot of press recently and has been under study by the University of Kentucky. This new compound is a triazine derivative that has been used as a coccidiostat in other countries for a number of years. The site at which these compounds exert their effect is called a chloroplast which do not exist in mammals. For this reason, the compound should not be toxic to mammals, however, the toxicity studies have not been completed to date. The efficacy of this compound is very similar to the standard therapy discussed above, however, the treatment period is much shorter (four weeks) and therefore less costly. This compound has been used primarily in horses that have relapsed after the standard therapy with reasonably good success. This compound is available through the AAEP and the FDA by special permit. An additional triazine derivative (Toltrazuril) is available through the same sources as the Diclazuril. Current clinical trials are being performed at several sites throughout the US to establish efficacy against Sarcocystis neurona. A new therapy called Nitazoxanide (NTZ) is being investigated by Blue Ridge Pharmaceuticals. NTZ is a thiazolide derivative that demonstrates a wide spectrum of activity against bacteria, protozoa, and intestinal helminths. The drug is in development for humans to treat parasitic infections that are common in developing countries and to treat immunocompromised patients afflicted with cryptosporidiosis. Veterinarians may obtain more details on NTZ. The area is password protected. Please call 800-870-4264 to obtain the password to enter this area. We will need your name, your clinic address, your state veterinary license number, and your DEA number. When the horse has an acute onset of EPM which results in dramatic and progressive clinical signs, the use of antiinflammatory medications has been recommended. Use of antiinflammatory medications such as banamine phenylbutazone may be helpful. Intravenous administration of medical grade dimethyl sulfoxide (DMSO) at a dose of 1.0 ml/kg (approximately 1 gm/kg) in a 10% solution once daily for three days in a row. Some clinicians use dexamethasone parenterally in severely affected horses at a dose rate of 0.05 mg/kg bid or sometimes empirically at 50 mg. bid. However, we believe corticosteroids should be used judiciously. The exacerbation of signs in stressed patients and reports of horses with EPM showing a worsening of signs following the use of these medications suggest immunosuppression should be avoided. Ancillary treatments may include padded helmets, slings, good supportive care and a deeply bedded stall.Many horses appear to relapse days, weeks or months after treatment has stopped. Some apicomplexans have latent stages, however, Sarcocystis spp. are not known for this phenomenon. Sarcocystis faculata encephalitis in birds may persist for several months without reinfection, but this phenomenon may simply represent a low level infection and not the development of a true latent parasitic stage. A great deal concerning the life cycle of coccidia remains unknown. Now with the ability to produce experimental infections, we may be able to determine if S. neurona forms a latent stage or maintains a persistent, low level foci of infection. Re-infection may also be responsible in some cases. Reports at the EPM workshop in March of 1996 indicate that relapses occur approximately 10% of the time. More recently, it has been suggested that the relapse rate may be as high as 28%. However, this may be compounded by the premature withdrawal of medication or irregularities during medication administration. The efficacy of preventive therapies is open to debate.Because of the suspicion that protozoal infections occur more commonly in immunocompromised patients, immunomodulators or other therapies which may have a non-specific enhancement of the immune system may be helpful. The use of these products may have merit but further investigation is necessary. It is possible that these drugs may also enhance the immunopathologic effects associated with CNS infection.Prolonged therapy with antifolate medications should be monitored for signs of bone marrow suppression with resultant anemia, thrombocytopenia and/or neutropenia. Frequent blood samples for CBC’s is suggested on a biweekly basis. All horses that are receiving antifolate medications should have their blood tested for folate levels on a monthly basis. Antifolate medications may also cause reduced spermatogenesis in stallions and may be teratogenic to the fetus in mares. There is evidence to suggest that combinations of pyrimethamine and folic acid in the pregnant animal may lead to congenital defects in the fetus. This has been demonstrated in humans, rats, mice, hampsters, and pigs. There is also some evidence to suggest that this also happens in horses, therefore, we do not recommend the use of folic acid supplementation in horses, particularly in pregnant mares. The authors also recommend supplementation with vitamin E at the rate of 8,000 to 9,000 IU per day. Due to the role of vitamin E as an antioxidant, we feel that adding this to the treatment may aid in the healing of the nervous tissue. Acute colitis has also been associated with use of trimethoprim/sulfa combinations.It appears with the increased dosage of pyrimethamine that is being utilized for today’s treatment of EPM as well as the experimental medication usage, there is an increased incidence of what some people term a “treatment crisis”. This is a real problem that is a concern for many clinicians. It would appear this is related to a large dose of medication and subsequent development of an inflammatory response to the killing of large numbers of parasite at one time. The spinal canal is a very narrow space with limited room for expansion due to inflammation. Therefore it would seem prudent to start horses on EPM treatment with NSAID therapy at the same time to reduce inflammation and perhaps prevent this so-called crisis.

Treatment Crisis (WARNING: DISTURBING)

Sure enough Chance experienced his very own treatment crisis about a week into treatment.  The twisting of his back right hind was the worse it has ever been!

We gave him a dose of the Equinox (pain medication that is easier on his stomach) and the Ulcer Guard and wrapped his hind legs.  He was on stall rest for about a week and was hand walked twice daily.

Below is Chance during his treatment crisis.

An All Natural Option?

While doing research on EPM, and ways to prevent a treatment crisis, I came across something called MicroLactin. Below are two of the many studies I found regarding the use of MicroLactin and its use for EPM.

STUDY 1: Journal of Equine Veterinary Science (Impact Factor: 0.89). 09/2005; 25(9):380-382. DOI: 10.1016/j.jevs.2005.08.004
ABSTRACT Fifty-eight horses with inflammation from lameness/foot trauma, muscle and skin trauma, and respiratory, gastrointestinal, and soft tissue toxins were fed MicroLactin (Duralactin Equine, Veterinary Products Laboratories, Phoenix, AZ) as an aid to therapy to inhibit neutrophil participation in the inflammatory response. Based on clinical signs of observed improvement and owner's observations, there was 86% positive effect, 14% no effect. Owner's satisfaction of results was seen by continued use of MicroLactin instead of nonsteroidal anti-inflammatory drugs and steroids in respiratory inflammation and in chronic lameness, myositis, and skin inflammation.
STUDY 2:  Sandhill Equine Center, Southern Pines, NC Journal of Equine Veterinary Science (Impact Factor: 0.89). 06/2009; 29(6):547-550. DOI: 10.1016/j.jevs.2009.05.004
ABSTRACT MicroLactin is a patented milk protein concentrate whose mode of action is proposed to inhibit neutrophil activation in inflammation and to bolster the immune response in musculoskeletal diseases. MicroLactin was empirically used in the treatment of a series of equine clinical cases. MicroLactin was given in two trials to 166 horses in which neutrophils were associated with an inflammatory response. The primary clinical groups having the greatest positive responders to the use of MicroLactin were: respiratory (92%), joint lameness/foot trauma (90%), muscle injury/myositis (92%), equine protozoal myeloencephalitis (EPM) (81%), skin trauma/hypersensitivity (89%), and toxic enteritis (89%). Positive clinical results were seen within 10 to 14 days when MicroLactin was used as a daily treatment either alone or in combination with other anti-inflammatory agents or as an adjunct to the primary treatment.

Every study I read claimed MicroLactin to be a “miracle anti-inflammatory” that aided in cell regrowth. People were raving about this substance that is derived from cow’s milk. The studies dated back to the 80’s and not only suggested that MicroLactin truly was a natural cure all, but that it also had zero side effects or interactions.

I figured that I should give it a try. Again, I looked everywhere and nobody carried it. I looked online and saw that there was a brand called DuraLactin but that I would not be able to actually receive it for about a week. I began looking for supplements that contained the same ingredients as DuraLactin. Sure enough, I was able to find it!

The brand is called Vita-Flex Equinyl.

Vita Flex® Equinyl™ Combo is designed to help ease pain and inflammation associated with training and competition without causing gastrointestinal side effects. This supplement provides joint health support and increases flexibility. It shortens recovery time by reducing the emigration of neutrophils to the site of the inflammation. Contains glucosamine, which helps maintain synovial fluid that lubricates the joints for all day pain associated with daily exercise and activity. 5,000 mg glucosamine, 875 mg chondroitin. 7500 mg MSM. 3.75 lb (60-day supply).

How to we get there?

As I said previously, the idea of Chance collapsing and no one being there terrifies me. Vet4 is shipping me the Protazil and I am trying to find another vet to come and administer the DMSO before beginning treatment.  DMSO typically helps the Protazil adhere better, thus making the treatment more effective.

EPM: Is DMSO the Cure for Treatment Issues?

By Stacey Oke, DVM, MSc Aug 3, 2009

New research on treating horses with equine protozoal myeloencephalitis (EPM) has found dissolving toltrazuril sulfone, commercially known as ponazuril, in dimethylsulfoxide (DMSO) instead of water prior to oral administration in horses increases the bioavailability by three times and achieves therapeutic levels in both the blood and cerebrospinal fluid.
Ponazuril and related triazine-based antiprotozoal agents used to treat horses with EPM are highly lipid (fat) soluble. As a result, these agents dissolve poorly in the gastrointestinal systemand are therefore poorly absorbed.
Poor drug absorption results in variable drug concentrations in the bloodstream, which translates into a variable therapeutic effect in the treated horse, explained Levent Dirikolu, DVM, PhD, from the Department of Veterinary Biosciences at the University of Illinois, and co-researchers from the University of Kentucky Gluck Equine Research Center and the United States Department of Agriculture (USDA) Animal and Natural resources Institute.

I finally found a vet who was able to come to the farm to meet Chance and administer other medications.

Vet6 felt that DMSO wasn’t necessary and that Chance would be fine. I called Vet4, explained the situation, and he advised beginning Chance on 1/2 a dose of Protazil for the first couple days in conjunction with a mild anti-inflammatory.

So, that is what we did. I had also read that Vit E (only in its all natural form) was helpful during treatment, along with Ulcer Guard to keep his stomach safe from the medications.

I called 5 different vets and no one has what I was looking for in stock. I finally found it in Chantilly!

Other EPM Therapies

The below research was found athttp://www.epmhorse.org/Treatment/Other_Therapy.htm

Veterinarians should discuss other drug therapies, in addition to the protozoa killing drugs, to address symptomatic problems that may occur during treatment.  Limiting inflammation of the cerebrospinal column, stimulating the immune system, and anti-oxidants are three things that the owner should be prepared to handle during treatment.  If the veterinarian does not discuss these, ask about them.

Inflammation

An active S. neurona infection in the central nervous system (CNS) will produce both temporary inflammation and permanent nerve damage. The inflammation can get worse when the protozoa start to die during treatment.  This can happen as the treatment drug level builds in the CNS, and is known as a ‘treatment crisis’.  Watch for symptoms to get worse 7 to 14 days after the start of treatment drugs.

Inflammation by itself can cause permanent nerve damage, so treating it is important.  Veterinarians report that horses with higher neurologic deficiencies, and possibly higher levels of protozoa, tend to get treatment crises more often that horses with a Mayhew score of 1.  Some veterinarians will place a horse on anti-inflammatory drugs immediately, to prevent additional damage to the CNS.

Banamine   Many owners already have the non-steroidal anti-inflammatory drug (NSAID) Banamine at the barn.  Even if your horse is a 1 on the Mayhew scale, you may wish to have Banamine on-hand to deal with any worsening of the symptoms. Banamine can cause gastro-intestinal side effects such as ulcers when given in high doses, or longer than five days.  A January 2009 cost was $35 for 5 doses.

MicroLactin   This supplement is gaining recognition as an overall, mild anti-inflammatory.  This non-prescription supplement is a derivative of cows milk, and is known as Duralactin, or the ingredient ComfortX in Equinyl.  MicroLactin does not have side effects, so it can be used over the entire course of treatment.  It is possible to supplement with Banamine during a treatment crisis.  March 2009 price was $50 per month.

Dexamethazone   (Dex) This steroid suppresses the immune system, so it should not be used as an anti-inflammatory for EPM horses except in an extreme neurological case.  Used longer than 5 days, it can cause Laminitis.

DMSO   Dimethyl sulfoxide given intravenously, can be useful when the horse has extreme neurological symptoms.  The veterinarian should administer this drug, it should only be used for short time periods, and it can interact with other drugs.

Immune System

In many regions of the U.S. more than 50% of the horses have been exposed to EPM. Researchers do not know why less than 2% of them get an active infection in the CNS.  Studies on blood of EPM horses indicate a change in the immune system response and cells.  Relapse rates for EPM are high, often with the same symptoms. Some researchers believe that the relapses are latent infections which were never completely killed, and the immune system does not recognize.  Immune system stimulants have been suggested to help the horse fight the infection.

Levasimole   This drug has been used as part of a wormer, and anti-inflammatory.  It is known to increase immune response.  It has not been clinically tested specifically for use with EPM, but is being used for it.

Transfer Factor    This supplement has been around since the 1940’s for human use. The older studies on humans suggest it increases the cell-mediated immune response.  It has not been clinically tested in horses.  The supplement is suggested to increase the cell-mediated immune response (see research below).  It WILL NOT kill the protozoa; it is only an immune booster.  It is made from cow colostrum, eggs, and mushrooms.  At least two companies produce this for equine use, and while the main ingredients are the same, there are differences.  4 Life Research and Nutrition Horizons USA offer this at March 2009 prices of $150 to $200 per month.

Vitamin E

Vitamin E has been shown to relieve inflammation, promote regeneration of nerve cells, and is an anti-oxidant protecting the CNS.  This vitamin is suggested by many veterinarians for supplementation during and after drug treatment for EPM.  It crosses the blood-brain barrier to work in the CNS.  A deficiency in Vitamin E is thought to impair the blood-brain barrier.  It is suggested at therapeutic rates from 5,000 to 10,000 total IU per day.  Add the total Vitamin E content of all supplements and feed to reach the target rate.  Research has shown that natural source vitamin E (D-alpha tocopherol) is absorbed by the body better than manufactured E (DL-alpha-tocopherol).

Recent Research

A 2006 study published in Veterinary Parasitology indicated: “Our results demonstrated that naturally infected horses had significantly (P < 0.05) higher percentages of CD4 T-lymphocytes and neutrophils (PMN) in separated peripheral blood leukocytes than clinically normal horses.  The product MicroLactin has been shown to limit neutrophil activity thereby reducing the inflammation process in the CNS.  The study goes on to say, “Leukocytes from naturally infected EPM horses had significantly lower proliferation responses, as measured by thymidine incorporation, to a non-antigen specific mitogen than did clinically normal horses (P < 0.05).  Cell-mediated immunity is lowered in EPM positive horses.

An ongoing study by Dr. Bello, Journal of Equine Veterinary Science, vol. 28, issue 8 (2008), uses Marquis, MicroLactin, and transfer factor in a protocol.  The initial study involved 28 horses, and 8 more have been studied.  This study was presented at the AVMA conference in 2007, and was published in 2008. The full text article is available below with permission from Dr. Bello.

Continuing research by others indicates controlling inflammation is a large part of the treatment process, and immune system stimulation is critical to avoiding relapses.

January 2012

References:

Veterinary Parasitology 138 (2006) 200–210

J Appl Res Vet Med 2003;1:272-8.

J Eq Vet Sc, vol. 28, issue 8 (2008) 479-482
An Intensive Approach in the Treatment of Clinical Equine Protozoal Myeloencephalitis 

Am J Vet Research, June 2008  Vitamin E

J Eq Vet Sc, vol. 25, issue 9 (2005) 380-382

TheHorse.com articles # 12025, 4829