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New Treatments for EPM
Submitted by Harold Schott DVM, PHD; Diplomate ACVIM,
Department of Large Animal Clinical Sciences
-College of Veterinary Medicine - Michigan State University-East Lansing, MI 48824
Everyone agrees that treating horses afflicted with EPM
is problematic: the results are frustrating, horses have to be treated for months, and its
not cheap. As a consequence, there has been a lot of activity since the last edition
of this newsletter in use of different drugs as well as alternative therapies in the
management of horses with EPM. However, before we talk about new medications for
treating EPM, there are a few facts about EPM that we should revisit. First,
diseases that affect the nervous system are bad diseases because nervous
tissue, in comparison to other body tissues, has a poor ability to recover once it
has been damaged. Thus, when EPM damages the central nervous system, it is unrealistic to
expect full recovery in all affected horses. Thus, treatment results are frustrating.
Second, the protozoa responsible for EPM, Sarcocystis neurona and Neospora hughesii,
hide out inside neuronal cells in the central nervous system. As a result, they can
effectively evade the immune system. Further, only drugs that can pass through cell
membranes are effective against protozoa. For these reasons, long term treatment is
usually required. Thus, an accurate diagnosis must be established before treatment
is pursued! This point cannot be emphasized enough because more than 50% of horses
currently being treated for EPM (a conservative estimate based on horses we have examined
at MSU) probably do not have EPM. As an example, I will never forget the response of one
client that had spent nearly $6,000 on diagnosis and unsuccessful treatment of EPM as a
cause of stumbling in a horse when we diagnosed ringbone in both front pasterns as a more
likely cause of the problems
Sulfadiazine/Pyrimethamine
One daily oral administration of sulfadiazine/pyrimethamine suspension
remains the recommended treatment for new cases of EPM. Both drugs inhibit production of
folic acid by the protozoa and thereby, result in inhibition of growth (termed static
drugs) and eventual slow death of the parasite. The latter drug (pyrimethamine) is
also referred to as the anti-malarial drug and may be better known by its trade name
Daraprim. The treatment ranges from 3-6 months in duration and the drug combination
is most economically acquired from compounding pharmacies and sold at costs of $100-$200
for a months supply for a full-sized horse. Licensed compounding pharmacies in your area
can be found by contacting the International Academy of Compounding Pharmacies at
1-800-927-4227 or via the internet at
http://www.iacprx.org,
. Your veterinarian can help you with this task. Two-thirds of affected horses can be
expected to improve with this treatment, but only about 50% of all affected horses are
likely to return to performance at their prior level of competition (frustrating results).
Treatment should continue for 30 days beyond resolution of neuralgic deficits or
stabilization of clinical signs (in the case of incomplete recovery). To date, there
is no information to support any benefits of prolonged treatment for stable cases of EPM
or prophylactic use of these medications in an attempt to prevent EPM. Once
medication is stopped, horses have a l0-20% chance of relapse. Although unproved, clinical
signs similar to the initial disease support incomplete killing of the protozoa during the
first round of treatment, rather than a new infection as the cause of relapse. Initially,
dietary supplementation with folic acid was widely recommended for horses being treated
with Sulfadiazine/pyrimethamine suspensions. However, horses actually absorb folic acid in
a slightly different chemical form, tetrahydrofolate, which is plentiful in pasture and
good quality hay. Supplementation with folic acid may actually inhibit intestinal
absorption of tetrahydrofolate and has been incriminated as a cause of birth defects in a
few foals whose dams were receiving sulfadiazine/pyrimethamine suspensions and folic acid
during pregnancy. The best treatment is pasture turn-out for the horse showing signs of
folic acid deficiency during therapy with anti-folate drugs. Signs they may show include
mild depression or anemia due to bone marrow suppression. Alternatively, supplementation
with folinic acid, rather than folic acid, can be helpful, but is expensive (nearly $1,000
per month) (This is not a misprint folks, Folinic Acid runs $1K)
Since the use of sulfadiazine/pyrimethamine suspensions produces rather
poor results (one-third of affected horses fail to respond), demand for other drugs and
alternative (holistic/nutriceutical) treatments has been high. In response,
researchers and veterinarians have tried medications termed coccidiostats and
coccidiocides that are fed to various farm animals as growth promotants. Coccidiostate are
drugs that inhibit growth of protozoal organisms (coccidia) to allow the immune system to
clear them from the body. Coccidiocides are drugs that kill protozoal organisms
(coccidia). They have been used in animals raised for food production.
Diclazuril
Diclazuril is a widely used feed additive from growing chickens and has
been the second most widely used treatment for EPM. Its advantages are that it is a
cidal (killing) drug that is given for only 28 days. Although undocumented, relapse
rates should also be lower than for sulfadiazine/pyrimethamine. Its drawbacks are:
1) That it is not available for use in the United States (but your
vet can legally import the drug from Canada for use on your horse with appropriate FDA
approval
2) That it is very unpalatable necessitating daily administration by a
stomach tube to some horses. The cost of the medication alone is about $600. This does not
include any fees for stomach intubation to deliver the drugs.
Although some anecdotal reports have praised this drug, a limited drug
trial performed by researchers at the University of Kentucky found a similar treatment
response as with sulfadiazine/pyrimethamine suspensions. Remember, EPM is a bad
disease.
Toltrazuril
Toltrazuril is a drug similar to diclazuril that has been formulated into
a more palatable oral paste. It is also given daily for 28 days. Although results are not
yet in, a multi-center FDA trial has recently been completed and information about this
drug should be available in the near future. Since protozoa are an important component of
the normal large intestinal fermentation process that allows horses to digest hay, use of
disclazuril or toltrazuril is not without risk of side effects. These include
gastrointestinal upsets displayed as loss of appetite, colic or diarrhea.
Nitozoxamide
Most recently, the broad spectrum Anthelmintic (anti-worm parasite drug)
nitozoxamide has been undergoing a FDA efficacy trial in cooperation with Blue Ridge
Pharmaceuticals, Inc of North Carolina. This drug is currently used to combat
intestinal parasites of humans in developing countries and in patients with AIDS
complicated by secondary protozoal infections. Similar to diclazuril and
toltrazuril, it is a cidal drug administered as a daily oral paste for 28 days.
Although efficacy results are not yet available, horses can be enrolled in an open field
study using this drug. Unfortunately, the medication costs $895. Contact your veterinarian
for further details. Side effects with this drug have been more serious than with other
medications. The side effects are thought to be cause by killing of other parasites
during the treatment for EPM. This has led to recommendations for deworming with
another Anthelmintic prior to starting this treatment. Further, documentation of a
significant number of intestinal upsets in horses in the early stages of use of this drug
prompted the dose to be decreased in half for the initial few days of treatment.
In addition to the specific anti-protozoal drugs discussed above, a number
of supplemental therapies have been used on horses afflicted with EPM. For example,
the anti-oxidant vitamin E is widely recommended because it could be helpful for
essentially any neuralgic disease in horses. In addition, because protozoa can hide from
the immune system, use of various immunostimulants has been attempted. However, there is
no information demonstrating improved responses with use of these agents.
Finally, whenever we are faced with a disease as debilitating and
frustrating as EPM in which a substantial number of patients fail to respond to treatment,
individuals (many who are untrained charlatans) will promote use of alternative therapies
and claim miracle cures in chronically disabled individuals. Although most of us trained
in Western medicinal societies typically disregard such therapies (including this
author), I will admit that I am becoming more open-minded to such approaches.
(yeah!!)
However, before alternative approaches are pursued it is first important to establish an
accurate diagnosis of EPM and to consider alternative therapies as an supplemental
treatment rather than the sole treatment for EPM (yes!). Next, ask the individual
recommending alternative therapies about their training and credentials. (yes!) Reputable
individuals should have licensure within that state if not a veterinarian, they should
work closely with your veterinarian in the management of the case.
Also, use common sense when considering these treatment options. I have
yet to understand acupuncture or a chiropractic manipulation can kill a protozoa hiding in
a nerve cell; however, they may be adjunctive tools in management of pain and
inflammation. Use of so-called holistic medications (herbs and nutriceuticals) is less
clear cut. Many approved drugs are plant extracts; herbs may have medicinal properties
that have simply been undocumented by scientific studies. However, one certainty is that
herbs are less rigidly controlled than medications approved and monitored by the FDA.
Several studies have documented that the chemical agents suspected to impart medicinal
qualities to some herbs vary widely in their content between different batches and sources
of herbs (yes again-that's herbal medicine).
In closing, treatment of horses afflicted with EPM can be an emotional and
financial roller coaster ride. Before buying a ticket, make sure that problems other than
EPM that could cause your horse's problems have been ruled out. Also, have a clear
picture as to what an acceptable outcome is for you. Remember that many horses can recover
yet may not return to their previous level of athletic competition.
Improved Western Blot Test
By Linda Mansfield, MS. VMD, PHD, Section Chief Clinical Parasitology Lab,
Animal Health Diagnostic Lab-Michigan State University
A new Western Blot test for equine protozoal myeloencephalitis that
substantially reduces the number of false positive results is available at the Clinical
Parasitology Laboratory at the Animal Health Diagnostic Laboratory at Michigan State
University. The test detects antibody reactive with Sarcocystis neurona in
equine cerebrospinal fluid and/or serum. A positive serum test indicates active or chronic
infection with the parasite. A positive cerebrospinal fluid test indicates active
infection.
Definitive diagnosis of EPM can only be established by finding the organism
in sections of brain or spinal cord using histopathology or by culturing the organism from
these tissues (Murphy and Mansfield, in press) during postmortem examination. In 1993,
testing of living animals was established with the development of a Western Blot test
which detected antibody in the serum or cerebrospinal fluid of horses that were exposed to
the parasite (Granstom, et al., 1993). This Western Blot test uses antibody reactivity to
13, 11, 10.5 and 10 kDa proteins of Sarcocystis neurona Merozoites as the
criteria for a positive test. Our work in the Emerging Parasitic Diseases Laboratory
at Michigan State University along with others demonstrated that this current criteria for
a positive test includes reactivity to proteins that are not specific to Sarcoystis
neurona (Marsh el al., 1997) Rossano el al., in review). In our studies, Sarcocystis
neurona Merozoites harvested from cell cultures were heat denatured and the proteins
separated by SDS-PAGE in a 12-20% grandient gel. Separated proteins were
electrophorectically transferred to Westran PVDF membranes and blocked in 1% bovine serum
albumin. Serum and cerebrospinal fluid samples from 8 horses with S. neurona (cultured
from neural tissue) and 59 horses without (horses from countries with no S. neurona)
were tested using these Western blots. Horses from both groups had reactivity to the 13,11
10.5 and 10 kDa bands indicating that these bands are not specific to S neurona. Testing
was repeated with another step. Blots were incubated with purified IgG antibody to Sarcocystis
cruzi, then treated as above. Sarcocystis cruzi is a related Sarcocystis
spp. parasite affecting cattle and dogs to which horses are commonly exposed. This
treatment blocked reactivity to the nonspecific 11, 10.5 and 10 kDa bands. Retesting of
the known positive and negative samples showed that positive infection status correlated
with reactivity to the 30 and 16 kDa bands (Fisher's Exact test p<0.001) and that the
16 kDa band represented the 13 kDa reported band in the original Western blot test. The
blocked Western blot had a sensitivity of 100% and a specificity of 98% We conclude that
the specificity of the Western blot test is improved by blocking nonspecific Sarcocystis
reactivity and using the 30 and 16 kDa bands as the criteria for a positive test. If
horses have antibody in serum that reacts with the 30 and 16 kDa bands, the horse
has been exposed to the parasite sometime during its lifetime. If horses have the same
antibodies in cerebrospinal fluid, active infection of the parasite in the nervous tissue
is supported. Thus, antemortem diagnosis of EPM is established when clinical signs
of neurological disease are found along with positive cerebrospinal fluid Western blot
results. Use of the MSU Western blot with high specificity will reduce the rate of false
positive tests.
It is important to apply this test in the proper way. The predictive value of the
Western blot test is much greater if the horse that is tested has neurological disease.
The Western blot test is less meaningful in a normal horse. For example, the Western
blot test has been used to check horses for exposure to Sarcocystis neurona at
pre-purchase examinations. Serum samples of many normal horses test positive for Sarcocystis
neurona . In fact, this may mean that these horses are resistant to the parasite.
Further information is needed to understand what this result means in a normal horse. The
same is true for normal horses that test positive for S. neurona in cerebrospinal
fluid. This may be a false positive test result. It may mean that the horse was
successfully treated, but antibodies against the parasite are still present. Other
interpretations can also be made. More work is needed to understand the biology of the Sarcocystis
neurona organism in the horse before we can interpret these test results
accurately. For these reasons, we do not recommend testing of normal horses at this
time. Please contact the Clinical Parasitology Laboratory at the College of Veterinary
Medicine at Michigan State University with your questions about diagnosis of EPM.
Pathologic Diagnosis of EPM
by Jon S Patterson, DVM, PhD, DACVP
Pathology Laboratory, Animal Health Diagnostic Lab
Michigan State University, Lansing MI
Necropsy diagnosis of equine protozoal myeloencephalitis (EPM) is often
difficult. Thorough neuralgic examination of the live horse is necessary to
adequately localize the lesions, and thorough gross and microscopic examination of the
brain and spinal cord after death or euthanasia of the animal is required to identify the
tissue changes. Lesions are focal ormulti-focal, are usually asymmetric, and may be
present in the gray matter and/or the white matter. Any portion of the central nervous
system may be involved, although infection and inflammation are more common in the spinal
cord than in the brain, and are reportedly more common in the cervical and lumbar
intumescences (where the large motor nerves to the limbs arise) than in other regions of
the spinal cord.
Grossly, the areas of tissue damage may be discolored yellow brown or
red (if hemorrhage is present) and may be softer than normal. In cases in which
lesions are not severe or extensive, however, there may be no detectable gross
abnormalities in the brain or spinal cord. Microscopically, the pathologist looks
for areas of "nonsuppurative" or "granulomatous" inflammation.
Typically, mononuclear inflammatory cells (lymphocytes, plasma cells, and macrophages)
surround small blood vessels or form dense aggregates int he nervous tissue and are
present in the leptomeninges (the thin connective tissue layer covering the brain and
spinal cord). Areas of necrosis (irreversibly damaged tissue) also may be present.
Protozoal organisms are rarely identified; it is reported that stages of the
causative agent, Sarcocystis neurona, are found microscopically in only 12 to 36%
of cases, and in horses which have been given specific treatment for EPM, detection of
organisms is even less likely. Pathologic diagnosis, then, is usually based on the
presence of characteristic focal ormulti-focal lesions rather than on identification of
the parasite. Staining of histologic sections for Sarcocystis organisms,
using specific antiserum, may be helpful in revealing the protozoan, or culturing the
agent from cerebrospinal fluid in the live horse or from spinal cord tissue at the time of
necropsy may prove diagnostic.
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