JPC SYSTEMIC PATHOLOGY
NERVOUS SYSTEM
February 2023
N-P01
Signalment (JPC #2019041): A 9-year-old, standardbred mare
HISTORY: This mare had a history of multiple skin nodules for the past two and a half years. In recent months she had been treated with systemic corticosteroids. Posterior paresis developed to the extent that the horse required assistance to stand. Grossly, the lumbar spinal cord was swollen, friable, and gray.
HISTOPATHOLOGIC DESCRIPTION: Spinal cord, lumbar: Multifocally affecting both the white and gray matter, there is perivascular cuffing composed of low to moderate numbers of lymphocytes, macrophages, fewer plasma cells, and neutrophils, that expands the Virchow Robin space and multifocally extends into the surrounding neuroparenchyma. Multifocally, similar inflammatory cells infiltrate the leptomeninges and ventral nerve roots, mixed with hemorrhage, fibrin, edema, and cellular debris. Affecting the white matter, predominantly within the ventral funiculus, there are dilated myelin sheaths that often contain cellular debris and/or gitter cells (digestion chamber) or myelin sheaths are swollen and hypereosinophilic axons (spheroids); there are also occasional swollen astrocytes with abundant eosinophilic cytoplasm (gemistocytes). The gray matter contains multifocal glial nodules; foci of hemorrhage, fibrin, and edema; and occasional swollen neurons with central chromatolysis (neuronal degeneration). Within the white matter and occasionally in the grey matter, there are few 10x40 μm diameter schizonts with an indiscernible outer wall that contain many 2x4 μm, oval, basophilic merozoites. Neurons often contain golden-brown, finely granular, intracytoplasmic pigment (lipofuscin).
MORPHOLOGIC DIAGNOSIS: Spinal cord, lumbar: Meningomyelitis and radiculitis, lymphoplasmacytic and histiocytic, multifocal, moderate, with hemorrhage, necrosis, axonal degeneration, gliosis, and protozoal schizonts, standardbred, equine.
ETIOLOGIC DIAGNOSIS: Sarcocystal meningomyelitis
CAUSE: Sarcocystis neurona
CONDITION: Equine protozoal myeloencephalitis (EPM)
CONDITION SYNONYMS: Equine protozoal meningomyelitis; protozoal encephalomyelitis (PE)
GENERAL DISCUSSION:
- Sarcocystis sp. is an apicomplexan protozoan parasite
- Neospora caninum and Neospora hughesi can cause identical lesions
- Exposure is widespread, but prevalence of classic progressive disease is low
- Seropositivity does not necessarily indicate that clinical disease will develop
- Most cases appear in the summer and fall; there is no sex or age predilection
PATHOGENESIS:
- Horses are both aberrant dead-end hosts; may also act as intermediate hosts
- Definitive hosts: Opossums (Didelphis spp.) shed sporocysts in feces
- Sporocysts are infective to intermediate hosts and are found in tongue and other skeletal muscles
- Natural intermediate hosts: armadillos, sea otters, raccoons, skunks and cats
- In intermediate hosts sarcocysts tend to develop in muscle rather than CNS; EPM-like disease is possible in intermediate hosts
- Definitive hosts: Opossums (Didelphis spp.) shed sporocysts in feces
- Life cycle (dead-end; neurologic): Opossums shed sporocysts in feces à horse and other intermediate hosts ingest sporocysts à gain access to intestinal mucosa à sporozoites are excyst from sporulated oocysts à sporozoites infect enterocytes à mature from sporozoites to schizonts containing merozoites in endothelial cells à endothelial cells rupture and release merozoites into the blood and ECM à cycle of endothelial infection, replication, and release repeats à focal vascular inflammation recruits macrophages à merozoite trafficking to CNS à infection of neurons, glial cells, and mononuclear cells à cell lysis à inflammation à hemorrhagic, necrotizing, nonsuppurative myeloencephalitis
- Mechanism of injury in EPM is disruption and lysis of neurons and neural cells from replication and release of protozoan and from inflammation, chemical mediators, and degradative enzymes
- Postulated mechanisms for migration from GI lumen to capillaries in the lamina propria
- Most likely: Sporozoites may be phagocytized by mucosa-associated macrophages, then spread locally and encounter capillaries
- Sporozoites may interact with and penetrate mucosa and gain direct access to endothelial cells
- Potential methods of merozoite spread to brain
- Cell-free travel via blood vessels
- Cell-free travel via lymphatics
- Intracellular travel via leukocyte trafficking; phagocytized by macrophage, travel to CNS endothelium, then infect endothelium
TYPICAL CLINICAL FINDINGS:
- Depression, behavioral changes, seizures, gait abnormalities, ataxia, facial nerve paralysis, head tilt, paralysis of the tongue, urinary incontinence, dysphagia, atrophy of masseter and/or temporal muscles, and atrophy of the quadriceps and/or gluteal muscles
TYPICAL GROSS FINDINGS:
- Only present in severe cases
- Multifocal acute hemorrhage; discrete multifocal gray to dark yellow areas in fixed sections (brainstem, obex, pons, and cervical and thoracic spinal cord)
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Multifocal areas of necrosis, malacia with aggregation of gitter cells, gliosis, and infiltration of large numbers of lymphocytes, histiocytes, plasma cells, and fewer eosinophils and neutrophils; severe involvement of the meninges
- Blood vessels have swollen, activated endothelium with dense perivascular cuffs of mononuclear cells and occasional eosinophils
- In cord sections there may be axonal swelling or loss with appearance of spheroids and digestion chambers
- Chronic cases: inflammation can be predominantly histiocytic with few eosinophils and multinucleated giant cells
- Finding merozoites or schizonts is challenging and may require serial sections
- Schizonts (most common near areas of inflammation and necrosis): oval or irregularly round, have very thin walls (<0.5 µm), are up to 20 µm in diameter and contain a few basophilic ovoid merozoites that are 5 µm x 1.5 µm
ADDITIONAL DIAGNOSTIC TESTS:
- Definitive diagnosis of EPM is challenging
- Seropositivity combined with clinical signs of weakness and acute ataxia usually indicate active disease; seropositivity only indicates exposure
- IHC kits for S. neurona are available commercially
- Cytology: Merozoites can be found within neutrophils and extracellular on CSF cytology or radially arranged merozoites forming schizonts within impression smears of lungs in systemic infections
DIFFERENTIAL DIAGNOSIS:
Clinical:
- Cervical vertebral myelopathy (N-M02)
- Equine herpes virus myelitis (EHV-1)
- Equine motor neuron disease (EMND; N-M24)
- Rabies (Rhabdoviridae; lyssavirus; N-V06)
- Western and eastern equine encephalomyelitis (Flaviviridae; alphavirus; N-V09)
- West Nile virus (Flaviviridae; flavivirus; N-V19))
- Idiopathic polyradiculoneuritis (cauda equina syndrome; N-M18)
- Rhodococcus equi myeloencephalitis (secondary to vertebral osteomyelitis)
- Leukoencephalomalacia [Fusarium verticillioides (fumonisin B1 toxicosis); N-T10]
Microscopic:
- Toxoplasma gondii (N-P02)
- Neospora spp. (N-P03)
- Neospora caninum and Neospora hughesi can cause identical lesions
- Other Sarcocystis sp.
- Microsporidian parasites
COMPARATIVE PATHOLOGY:
- Protozoal encephalomyelitis: Sporadic in cattle and sheep
- Harbor seals can develop severe fatal disease from S. neurona infection; develop nonsuppurative meningoencephalitis most severe in the cerebellum; Rosette-form schizonts can differentiate organisms from T. gondii; novel genotype, Type XIII associated with increased severity of encephalitis in multiple marine mammal species
- Associated with lesions and mortality in cetaceans from the Pacific Northwest
- A captive Grant’s zebra was diagnosed with encephalomyelitis and S. neurona merozoites identified in brainstem
- S. neurona-like disease (encephalomyelitis) occurs in a variety of mammals including cats, mink, raccoons, skunks, dogs
- Cats are susceptible to natural infection, but overt disease is reported only sporadically
- Protozoal infections, including with S. neurona, are common secondary infections in racoons with canine distemper virus infections
References:
- Boes KM. Respiratory System. In: Raskin RE, Meyer DJ, Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:224.
- Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. 6th ed. Vol 1. St. Louis, MO: Elsevier; 2016: 386-388.
- Church ME, Terio KA, Keel MK. Procyonidae, Viverridae, Hyenidae, Herpestidae, Eupleridae, and Prionodontidae. In: Terio KA et al, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:312.
- Colegrove KM, Burek-Hungtingon KA, et al. Pinnipediae. In: Terio KA et al, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:586-7.
- Duncan M. Perissodactyls. In: Terio K et al, ed. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:450.
- Levine GJ, Cook JR. Cerebrospinal Fluid and Central Nervous System Cytology. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:218.
- Miller AD, Porter BF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:290-291,962-963.
- St. Leger J, Raverty S, Mena A. Cetacea. In: Terio KA et al, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:564.