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UPDATE ON EQUINE PROTOZOAL MYELOENCEPHALITIS by Joseph J. Bertone, D.V.M., MS, Diplomate ACVIM This article summarizes conclusions drawn from a recent symposium concerning Equine Protozoal Myeloencephalitis sponsored by the Grayson-Jockey Club Research Foundation, held March 5 through 8, 1996, in Lexington, Kentucky. Attendees were invited as experts in this or related areas. The Grayson-Jockey Club Foundation and the American Association of Equine Practitioners invited Dr.JosephBertone to attend this symposium as a regulatory representative, taking into account his clinical expertise. Equine protozoal myeloencephalitis (EPM) is a progressive debilitating neurologic disease of horses associated with migration of Sarcocystis falcatula (neurona). It can affect any portion of the central nervous system. Clinical signs are related to focal (single site) or multifocal (many sites) neuropathology. Varied clinical signs may be present depending on the neural anatomic location of parasite migration and the ensuing inflammatory process. Distribution EPM occurs in much of the Western Hemisphere. Over 3000 horses have been diagnosed with the condition, by immunologic analysis of cerebral spinal fluid samples, since 1992. The number of affected horses is most likely greater. Surveys in Kentucky, Pennsylvania, Ohio, and Oregon identified that 50 to 60 percent of horses are seropositive for this organism (identifies exposure). The incidence of clinical disease involving the spinal cord is far lower. Climatic factors may affect exposure rates. The frequency of seropositive horses appears to be less in areas with greater numbers of freezing days, or with hot, dry climates. EPM is often sporadic (individual cases), but herd outbreaks have been reported in Kentucky, Ohio, Indiana, Michigan, Florida, and Maryland. Life Cycle The clinical disease and associated pathology have been recognized for over 20 years. However, the organism was not successfully cultured until recently (J.P.Dubey, et al. 1991). Once cultured, the organism was titled Sarcocystis neurona. Strong evidence suggests that the organism is Sarcocystis falcatula. The definitive host of this organism is the opossum, and various birds (brown headed cowbird, boat tailed grackle, and probably others) act as intermediate hosts. The horse is a dead-end, aberrant host. Infectious forms of the parasite are not passed from horse to horse, or from horse to the definitive or true intermediate hosts. Recent investigation indicates that opossum feces is the major source of infection. Opossums acquire the infection by eating infected birds. Birds and insects may contribute to feed contamination, but the importance of this to equine infection is unclear. Aberrant migration of Sarcocystis falcatula has been described in free-range chickens. Signalment and Clinical Signs EPM often progresses to loss of neural and musculoskeletal function and may lead to death. In many cases, the abnormal neurologic deficit is so subtle that abnormal function is attributed to other causes. EPM can affect any breed or sex. To date, the youngest horse identified was 2 months of age, and the oldest was over 30years old. Clinical signs may be triggered or worsened by physiologic stress (e.g., shipping), or the administration of corticosteroids. Clinical signs associated with neuropathology of any sort relate to the specific site (neural anatomic location) of pathology. Neurologic control of musculoskeletal activity can be divided into 3 general categories that include the upper and lower motor neuron and proprioceptive functions. Lower motor neurons directly stimulate muscle contraction. Upper motor neurons are inhibitory and control the extent of lower motor neuron induced muscle activity. Proprioceptive neurons provide for limb and trunk positional awareness. An example of proprioceptive dysfunction is the inability to touch one's nose when blind-folded (loss of positional awareness) in association with alcohol consumption. Since EPM can affect all 3 of these systems (separately or in combination), the disease may present as any gait or function deficit. Clinical signs of EPM include weakness (lower or upper motor neuron deficit), hypermetria (upper motor neuron deficit), poor limb position awareness (proprioceptive deficit), muscle atrophy (lower motor neuron deficit), and various cranial nerve deficits. In addition, many horses whose presenting chief complaint is poor performance, lameness, weakness, and/or behavioral changes may have this condition. In many cases, horses with EPM are lame secondary to musculoskeletal pathology. This is believed to be secondary to neurologic gait abnormalities that place these animals at higher risk for injury. Therefore, any horse that is demonstrating neurologic and/or musculoskeletal abnormalities of any kind may have EPM. Abnormal behavior and seizures have been associated with EPM. Severely affected horses may be recumbent and unable to rise. In most cases, affected horses are bright and alert, with a normal appetite. Hematological and biochemical blood values are usually within reference ranges. Diagnosis Diagnosis of EPM is based on clinical signs, and cerebrospinal fluid (CSF) positive for antibodies to the organism (western-blot analysis) or organism DNA (polymerase-chain reaction, PCR). The PCR analysis appears to be most useful in very early, or late stages of the disease when the western-blot analysis may be negative. False positive CSF samples most commonly occur with blood admixture during CSF collection. Blood admixture can be confidently excluded by use of protein electrophoresis and protein indices. The commercial laboratory performing the western-blot and PCR analyses will perform the analysis for blood contamination (Equine Biodiagnostics, Lexington, Kentucky). The meeting attendees strongly suggest that to be confident of the results of CSF testing, the analysis for blood contamination must be performed to guarantee that the CSF sample has not been contaminated regardless of the gross appearance or of the cytologic analysis of the CSF sample. False negatives (horses with EPM and a negative test) are extremely rare. Treatment Currently, treatment of EPM includes a combination of antimicrobials that inhibit folic acid metabolism. Antimicrobial treatment simply clears the organisms and their associated inflammation. It does not guarantee return to function (see prognosis). Pyrimethamine, administered orally at 1 mg/kg, once per day, acts by inhibiting dihydrofolate reductase. The most common form of this drug used for EPM is a tablet approved for use in people. However, pharmacokinetic data, which is the basis for the dose, was collected by evaluating oral administration of bulk chemical and relating that information to the effects of this drug on other similar pathogens (C.R. Clark, et al. 1992). This drug is combined with sulfamethoxazole (oral, 12.5 to 25 mg/kg, once or twice per day) or sulfadiazine (oral, 20 mg/kg, once per day). The doses of these drugs are based on pharmacokinetic analysis as well. The only veterinary formulations of the two sulfonamides are in combination with trimethoprim. Trimethoprim is not useful for treatment of this condition and may contribute to increased risk of adverse drug reactions. Folic acid metabolism inhibitors should be administered 1 hour prior to feeding hay. The average duration of treatment is 90 to 120 days, and may exceed 6 months in some instances. The appropriate length of treatment and the methods to determine adequate treatment duration are unknown. Negative western-blot analysis, or PCR on CSF may be useful to determine the time to withdraw treatment. Premature withdrawal of treatment often leads to relapse, which is often associated with a poorer prognosis for improvement or recovery. Sub-optimal dosing or intermittent therapy (for treatment or prophylaxis) has no proven efficacy and may lead to increased resistance of the organisms within the treated individual. If resistant organisms develop, they will most likely reside in that affected horse, since they cannot multiply in aberrant hosts. Adverse side effects of drug therapy may include anemia, abortion, diarrhea, and leukopenia (low white blood cell counts). In some cases, the initiation of therapy may be associated with worsened signs. This response is believed to be associated inflammation, secondary to death of organisms within the spinal tract. Administration of a nonsteroidal anti-inflammatory drug in the initial stage of treatment has been recommended to alleviate this situation. Folic acid supplementation, administered at 40 mg orally, once a day, may help prevent adverse side effects associated with bone marrow suppression and may also reduce the risk of abortion. This quantity of folic acid supplementation will not inhibit the effect of the absorbed drug. Supra-pharmacologic concentrations of folic acid are required to overcome the effects of drug-inhibited folic acid metabolism. Folic acid should not be administered at the same time as the antimicrobial drugs as it may inhibit antimicrobial drug absorption. In cases with severe neurologic signs, nonsteroidal anti-inflammatory medications (labeled doses), dimethylsufoxide (intravenous, diluted 5 to 1 in saline solution), and supportive care are often added to the treatment regimen. Prognosis Antimicrobial treatment simply clears the organism and its associated inflammation and does not guarantee return to function. The specific site and extent of the lesion, the horse's use, duration of disease, and physical therapeutics are the most important contributors to prognosis once the organism has been cleared. Early detection and treatment increases the chance of success. Response to treatment is highly variable. Many treated horses return to their original level of function; however, many respond incompletely. It is estimated that approximately 10 percent of cases relapse after treatment is discontinued. CVM Response CVM is aware of the severity and prevalence of this condition, and intends to act in response to the needs of horse owners and veterinarians. CVM has contacted the American Association of Equine Practitioners (AAEP) and suggested that they submit a request for Investigational New Animal Drug status for the above drug combinations, which are now being compounded. This will allow continued data collection for this drug formulation. In addition, CVM has suggested that the AAEP encourage the pharmaceutical industry to sponsor these drug combinations. Since there is no approved therapy for this severe, debilitative disease, CVM will grant expedited review status to such applications and otherwise work with NADA sponsors to facilitate the data generation and review process. In addition, a great deal of information is available to support efficacy and safety of the therapeutic combination to provide for an expedient development plan. For further information, please contact Dr. Joseph J. Bertone, at 301-594-1692.
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