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Equine protozoal myeloencephalitis

Preferred citation: Anipedia, www.anipedia.org: JAW Coetzer and P Oberem (Directors) In: Infectious Diseases of Livestock, JAW Coetzer, GR Thomson,
NJ Maclachlan and M-L Penrith (Editors). JP Dubey, Equine protozoal myeloencephalitis, 2018.
Equine protozoal myeloencephalitis

Equine protozoal myeloencephalitis

Previous authors: J P DUBEY

Current authors:
J P DUBEY - Senior scientist, MVSc, PhD, DSc, Animal Parasitic Diseases Laboratory, U.S. Department of Agriculture, Building 1001, Beltsville Agricultural Research Center, 10300 Baltimore Avenue, Beltsville, Maryland, 20705, United States of America

Introduction

Equine protozoal myeloencephalitis (EPM) is a neurological disease of horses in the Americas caused by Sarcocystis neurona. The clinical syndrome was recognized in the USA by Rooney125 in the 1960s and protozoa were first demonstrated in lesions in 1974.2, 19, 29 Initially, the protozoa were considered to be Toxoplasma gondii.2, 19, 29 Dubey et al. in 197429 reported lesions and protozoa in horses and distinguished the parasite from T. gondii. He also re-examined29, 30 the  original  cases of 19742, 19 and concluded that the parasite that causes EPM was not T. gondii but probably a species of Sarcocystis, which was later confirmed by ultrastructural examination.140 The protozoan was first cultured in 1991 from the spinal cord of an affected horse and was named Sarcocystis neurona.39 The development of a serological test in 199383 based on antigen prepared from in vitro cultured S. neurona merozoites led to the discovery that S. neurona infections are common in horses in the Americas.3, 4, 7, 148 The opossum was proposed as its definitive host74 and the life cycle was completed when the sarcocyst stage was identified.31 The development of an interferon gamma gene knock out (KO) mouse model for S. neurona made it possible to study its biology and chemotherapy.33, 50, 53, 54 Its genome was sequenced and annotated, potentially leading to development of  better diagnostic methods and therapies.6 The history of EPM and its biology have been fully reviewed.33, 37, 48

Aetiology and life cycle

Sarcocystis neurona is a coccidian belonging to the family Sarcocystidae. Opossums of the genus Didelphis (D. virginiana and D. albiventris) are the definitive hosts (Figure 1).31, 50, 53, 55, 72, 74 Many other mammals are aberrant or intermediate hosts.48 Aberrant hosts are those in which only part of the asexual cycle (only schizonts) is completed; horses are aberrant hosts. Intermediate hosts are those in which the full asexual cycle (schizonts and sarcocysts) takes place. Raccoons (Procyon lotor), skunks (Mephitis mephitis), armadillos, domestic cats, and sea otters (Enhydra lutris) are its proven intermediate hosts as evidenced by excretion of S. neurona sporocysts by laboratory-raised opossums fed infected tissues.16, 60, 62, 145, 150 Sarcocystis neurona-like sarcocysts have also been reported in two dogs,152 one horse,114 one mink (Neovison vison),120 one bobcat (Lynx rufus),153 and one fisher (Pekania pennanti). There is a report of brown-headed cowbirds (Molothrus afer) as intermediate host of S. neurona102 but it needs confirmation because S. neurona is usually not infectious to birds.50

The sarcocysts are microscopic in size (about 700 μm long) with a 1 - 2 μm thick cyst wall. They have villar protrusions that are up to 2.8 µm long that do not reach bradyzoites.48, 52, 135 The bradyzoites are slender and tiny (about 5 μm long).  The sporocysts are about 10 × 8 μm.93

A sexual cycle occurs in the lamina propria of the intestines of opossums. After gametogony, oocysts sporulate in the lamina propria of the small intestine and are excreted in the faeces. Sporocysts contain four sporozoites and a residual body.

Horses become infected by ingesting food and water contaminated with sporocysts. The only stages of S. neurona definitively identified in horses are schizonts and merozoites, which are confined to the brain and spinal cord.39, 48 (Figure 2) The precise time period and the route of dissemination of the parasite in horses are unknown.69 After oral inoculation of ponies with S. neurona sporocysts, evidence of invasion of brain occurred as early as seven days post- inoculation. In an experimental aberrant host, the KO mouse, sporozoites excyst in the small intestine and can be found in peripheral blood within one day of feeding sporocysts. Sarcocystis neurona first multiplies in visceral tissues and eventually resides in the central nervous system (CNS).32, 33, 52-54, 76 In the natural intermediate host (raccoon) schizogony occurred 7 to 22 days post- inoculation and mature sarcocysts were detected by 77 days post- infection.143 Sarcocystis bradyzoites are not infectious for intermediate hosts.65

Figure 1  Life cycle of Sarcocystis neurona

Figure 2 Sarcocystis neurona in sections of the spinal cord of a horse. Haematoxylin and eosin stain

  1. Perivascular infiltration and necrosis. Two infected neurons (arrows) but parasites are barely visible at this magnification
  2. Neuron containing several schizonts (arrows)
  3. Four schizonts (arrows) in various stages of development
  4. Intra- and extracellular individual merozoites (arrow heads)

Attempts to reproduce EPM after oral inoculation of horses with sporocysts were largely unsuccessful, including in immune-deficient foals.20, 21, 72, 98, 113, 129, 130, 137-139, 141

Sarcocystis neurona schizonts are found in neurons, various glial cells and resident macrophages in the brain and spinal cord.40, 48, 76, 142 They divide by endopolygeny:142 the  nucleus of the parasite becomes multilobed and eventually each nuclear lobe is incorporated into two budding merozoites (Figure 3 and Figure 4). Schizonts in tissue sections are approximately 5 -35 × 5 -20 μm in size and contain up to 40 merozoites, sometimes arranged in a rosette around a residual body.55 (Figure 4) Merozoites are approximately 5 × 1 μm in size. Ultrastructurally, S. neurona schizonts are located in the host cell cytoplasm without a parasitophorous vacuole (Figure 4). Merozoites contain a conoid, micronemes, a nucleus, a prominent lipid body posterior to the nucleus, but no rhoptries.55, 142 Schizonts have been identified in extraneural tissues of some hosts including the muscles of a dog,36 turbinates of a ferret11 and retina of a dog36 and a sea otter.66 (Figure 4)

There are no reports of congenital infection in any terrestrial mammal. However, S. neurona DNA was detected in foetal tissues of eight marine mammals.1

Figure 3 Transmission electron micrograph of a schizont of Sarcocystis neurona in a bovine monocyte showing merozoites budding from residual body (Rb). Some of the merozoites are still attached (arrowheads) to the residual body; conoid (Co); dense granule (Dg); host cell nucleus (Hcn); mitochondrion (Mi); microneme (Mn); micropore (Mp); nucleus of merozoite (N)

Figure 4 In vitro developmental stages of Sarcocystis neurona in bovine turbinate cells. Giemsa stain

  1. Immature schizonts with progressively differentiating nuclei from a-b. The nucleus in a and in b contains a single nucleolus whereas in c-e the nucleus has become lobed and has several nucleoli (arrows)
  2. Immature schizont with multilobed (arrrowheads) nucleus
  3. Three schizonts with merozoites arround a residual body (arrows)
  4. Mature schizont with peripherally situated merozoites (arrowheads). Some merozoites are at the centre of the schizont
  5. Free merozoites (arrowheads)

Epidemiology

Equine protozoal myeloencephalitis has been reported only in horses born and raised in the Americas, including Canada, USA, Panama and Brazil.8-10, 12, 15, 17, 24, 40, 56, 68, 72, 73, 77, 82, 84, 90, 94, 97, 99-101, 104-106, 112, 113, 131, 133, 149 Equine protozoal myeloencephalitis has been diagnosed on post-mortem  in other parts of the world, including South Africa;48, 81, 89, 124 it occurred only in horses imported from the Americas. The distribution of EPM follows the geographic range of the opossum (D. virginiana) in North America and its relative D. albiventris in Central and South America.48

Serological surveys indicated that up to 89 per cent of horses in the USA,3, 4, 7, 58, 119, 127, 128, 148, 151 Brazil49, 86, 117 Canada,58 Mexico,156 Costa Rica23 and Argentina67, 111 have been exposed to S. neurona.37, 48 Although antibodies to S. neurona have been found in horses, donkeys, and mules,132 bona fide clinical disease has not been reported in equids other than horses, with the exception of a pony and a Grant’s zebra (Equus burchelli bohmi).57, 103 The prevalence of S. neurona antibody increases with age and is not related to breed, sex, and category (race/draught) of horses.131-133 Although horses of any breed or age may suffer from EPM, clinical disease occurs most frequently in three- to five-year-old Thoroughbreds and Standardbreds; the youngest horse affected was six months old. There are no documented cases of congenital S. neurona infection in terrestrial mammals.

Sarcocystis neurona antibodies have been reported in many other hosts, which were recently summarized.48

Sarcocystis neurona-like organisms have been detected in the CNS of raccoons,43, 45, 63, 85, 144, 147 (Figure 5 and Figure 6), mink,46 skunk (Mephitis mephitis),13, 44 domestic cats,5, 34, 47 domestic dogs,18, 36, 38, 41, 64, 79, 152 ferrets (Mustela putorius furo),11 Canada lynx (Lynx canadensis),75 fisher,80 and a bald eagle (Haliaeetus leucocephalus).116

Figure 5 Degenerating host cell with eight individual merozoites and five developing schizonts (a to e) with single large nucleus. Sarcocystis neurona merozoites can form new schizonts without leaving the host cell. (From Dubey et al., 199139)

Figure 6 Transmission electron micrograph of a Sarcocystis neurona merozoite in the brain of the raccoon in Figure 5. Longitudinal section of a merozoite. Note the conoid (c), micronemes (m) and nucleus (n) but no rhoptries. (From Dubey et al., 199163, 64)

Sarcocystis neurona is also a major cause of mortality and encephalitis in several marine mammals in particular North American Southern sea otters.66, 95, 96, 107-109, 126, 146, 154, 155 Cases have been reported in Pacific harbour seals (Phoca vitulina).1, 91, 110, 115 However, viable S. neurona has been isolated only from horses, sea otters, harbour porpoise (Phocoena phocoena)1 and a California sea lion (Zalophus californianus).14 In most instances, the diagnosis was confirmed by immunohistochemical examination.

Opossums are also definitive hosts for at least three other species of Sarcocystis, namely, S. falcatula, S. speeri.31, 35, 50, 51 and S. lindsayi.59 Sporocysts of all three species are difficult to distinguish morphologically and progress has been made to develop genetic markers to distinguish them.48

Sarcocystis neurona sporocysts were reported in 6 to 31 per cent of opossums in USA.31, 42, 71, 122, 123 Sporocysts are found in the lamina propria of the intestines of opossums and can be excreted in their faeces for months. The excretion of sporocysts is irregular and they may be absent in faeces while present in the intestines.

Opossums can excrete millions of sporocysts in their faeces for months. Sporocysts are resistant to environmental influences, and most commonly used disinfectants do not kill S. neurona sporocysts. Heating to 60˚C for 1 minute will kill sporocysts, but exposure to 55˚C for 5 minutes will not.61 Although survival of sporocysts in different outdoor environmental conditions has not been tested, sporocysts may remain viable at 4˚C for months.

Clinical signs

Because S. neurona can infect any region of the CNS, clinical signs are related to the region affected.48, 55, 99, 100, 136 For example, lesions in the spinal cord may result in demarcated areas of spontaneous sweating or in loss of reflexes and cutaneous sensation.99 There may be foot dragging, difficulty in backing, or ataxia of the hind limbs or of all the limbs. Horses with lesions in the brain stem may be depressed, and have vestibular nerve dysfunction.99 There may be muscular atrophy, particularly of the gluteal muscles. Clinical signs may be sudden or progress over a period of weeks. Some horses have collapsed while racing.

Pathology

Lesions in horses are confined to the CNS, but occur more commonly in the spinal cord than in the brain.48 In the brain, the brain stem is affected more frequently than the cerebrum. Gross lesions consist of focal haemorrhages and areas of discolouration (from red to dark- brown) 1 to 30 mm in size (Figure 7). Any region of the spinal cord may be affected, and lesions may be confined to one segment of the spinal cord or be dispersed.2, 9, 17, 19, 25, 37, 40, 55

Microscopically, encephalomyelitis characterized by haemorrhages in and necrosis of the neuropil, as well as an infiltration of mononuclear cells in the neuropil and perivascularly, is observed. Chronic lesions consist of glial nodules and scattered areas of mononuclear cell infiltrations. Sarcocystis neurona parasites are usually associated with the lesions and may be scant or numerous, but some may be located away from the lesions.37 In most cases of EPM only a few organisms are found in the lesions.

Schizonts and merozoites are detected generally in the cytoplasm of neurons, glial cells and macrophages and rarely in vascular endothelial cells. Immunohistochemistry (IHC) reveals many more organisms than in sections stained only with haematoxylin and eosin (HE) (Figure 8).

Figure 7 Cross-section of the spinal cord of a horse that had suffered from equine protozoal myeloencephalitis. Note area of discoloration (arrow)

Figure 8 Histological sections of spinal cord of a horse with EPM. A and D, immunostaining with S. neurona antibody, B, C, haematoxylin and eosin stain

  1. Severe myelitis and numerous brownish stained parasites
  2. Myelin degeneration, and numerous parasites in an axon (arrow). Merozoites (arrowheads) are 2-3 mm long and difficult to observe
  3. Neuron with several schizonts
  4. Intraneuronal merozoites (arrowheads) and schizonts (arrow) in a neuron. (From Dubey et al., 2016)37

Diagnosis and differential diagnosis

The diagnosis of EPM is based on the clinical signs and the detection of S. neurona-specific antibodies in the cerebrospinal fluid (CSF).22, 55, 83, 99, 100, 121 The detection of antibodies in serum only indicates exposure and not necessarily clinical disease. A knowledge of the prevalence of subclinical S. neurona infections in the local equine population assists in the evaluation of serological results.

The diagnostic test used commercially to detect S. neurona-specific antibodies is an immunoblot using culture-derived S. neurona merozoite antigen.55, 83 Subsequently, an indirect fluorescent antibody test,26-28 various ELISAs48, 86-88, 157 and a direct agglutination test92 have been developed for the diagnosis of EPM.

The polymerase chain reaction (PCR) assay may also be used for the detection of S. neurona DNA in CSF.99 However, the sensitivity of the PCR appears to be much lower than initially estimated because intact merozoites rarely enter the CSF.48 Histopathology and IHC of CNS tissue section using S. neurona-specific antibodies can be useful in making a diagnosis.37 As stated earlier, EPM lesions are more common in spinal cord than the brain; however, any part of CNS can be affected (see Pathology).37

Microscopically, S. neurona may be confused with Neospora hughesi (see Neosporosis). Neospora spp. divide by endodyogeny and there is no schizont stage, whereas Sarcocystis spp. schizonts divide by endopolygeny.

As yet, no clinically confirmed cases of toxoplasmosis in horses have been diagnosed (see Toxoplasmosis). Equine protozoal myeloencephalitis should be considered in the differential diagnosis of diseases associated with impairment of function of the CNS, such as neosporosis, neurological involvement as a result of equid herpesvirus-1 infection, West Nile virus infection, rabies, equine encephalitides caused by alphavirus infections, and cervical stenosis.99, 100

Control

Horses with suspected EPM should be treated as soon as possible after the first clinical signs are recognized.48 Treatment results in recovery in 70 to 75 per cent of the affected horses, although these estimates may be somewhat high without prior confirmation of the diagnosis.48 Since it became evident that EPM has a protozoal aetiology, anti-protozoal drugs such as sulphonamides and pyrimethamine have been used to treat clinical cases. Nowadays, ponazuril (Marquis, Bayer), diclazuril (Protazil, Merck), and a sulphadiazine/pyrimethamine combination drug (ReBalance, PRN Pharmacal) are approved for treatment of EPM.42, 48, 118 Ponazuril and diclazuril are safe, with no side effects.78 Different supportive therapies have been used in affected horses70 including anti-inflammatory drugs such as phenylbutazone, flunixin meglumine, dimethylsulphoxide (DMSO) or steroids. Corticosteroids assist in stabilizing horses with serious neurologic involvement during the early period of treatment. Long-term treatment with steroids should be avoided due to their unknown effects in cases with EPM. Immuno-stimulants such as levamisole or Equimune have been recommended by some on the presumption that immunosuppression may play a role in the pathophysiological events of EPM but there is no information to suggest that these have any positive effects.48

The duration of treatment of clinical cases of EPM appears to be important. Horses should be evaluated clinically after one month of treatment with ponazuril or diclazuril. If there has been improvement but some clinical signs remain, then further treatment for at least a month is recommended. Recovered horses should be examined one month after treatment has been discontinued to ensure that there have not been relapses. Some horses may have severe relapses after prolonged therapy. The cause of relapses is unknown because the encysted stage, the sarcocyst, has not been confirmed. Whether schizonts can remain dormant in equine tissues is unknown.48

Preventing contamination of feed and water with opossum faeces is essential to prevent EPM as opossums can excrete millions of sporocysts in their faeces that may remain viable in the environment at 4oC for months (see Epidemiology).

There is no vaccine for EPM. A killed whole S. neurona merozoite vaccine was conditionally marketed by Fort Dodge in the USA but it has been withdrawn because of the difficulty of obtaining efficacy data.134

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