JPC SYSTEMIC PATHOLOGY
Signalment (AFIP #1769598): 3-month-old great Dane
HISTORY: This dog exhibited nervous signs prior to death.
HISTOPATHOLOGIC DESCRIPTION: Cerebellum: Multifocally and randomly affecting the molecular layer, granular cell layer and white matter tracts are areas of necrosis characterized by disruption and loss of the normal architecture with replacement by many gitter cells, fewer lymphocytes, plasma cells, gemistocytic astrocytes and rare neutrophils. Within necrotic foci there are occasional hypereosinophilic oval protozoal cysts which measure approximately 20x15 um, having a thin cyst wall bounding numerous, 1-2 um, elongate bradyzoites. Blood vessels within the necrotic foci are prominent and often lined by hypertrophic (reactive) endothelium while those adjacent to necrotic areas are surrounded by moderate numbers of lymphocytes, plasma cells and fewer macrophages (perivascular cuffing). Randomly dispersed throughout less affected areas, there are aggregates of glial cells up to 250 um in diameter (glial nodules), mild spongiosis and rare swollen axons (spheroids). The meninges are moderately expanded by a few lymphocytes, plasma cells and macrophages.
MORPHOLOGIC DIAGNOSIS: Cerebellum: Encephalitis, necrotizing, subacute, multifocal, moderate, with few protozoal cysts, gliosis, and lymphoplasmacytic meningitis, great Dane, canine
CAUSE: Toxoplasma gondii
ETIOLOGIC DIAGNOSIS: Cerebellar toxoplasmosis
· Apicomplexan parasite that causes disseminated disease, central nervous system infections, and abortions in a wide range of intermediate hosts
· Felids are the only definitive host, and can also serve as intermediate hosts
· Most neurologic infections in young puppies/kittens present as nonsuppurative meningococcal encephalitis; radiculoneuritis is also possible.; fetal infection generally presents as multifocal necrotizing encephalomyelitis; peracute disease can result in vasculitis with brain edema +/- herniation
· Infection occurs by three pathways: 1) Ingestion of tissue containing cysts, 2) ingestion of food containing sporulated oocysts from cat feces, or 3) transplacental infection; it may also be possible for tachyzoites from lung lesions to be spread in respiratory secretions
· Ingestion of bradyzoites in tissue cysts or sporozoites from oocytes that enter into the intestinal epithelium and multiply
· Organisms multiply by endodyogeny within a parasitophorous vacuole inside cells, forming tachyzoites
· Spreads via leukocyte trafficking within lymphocytes, macrophages and granulocytes to Peyer’s patches and lymph nodes, then tachyzoites disseminate to distant organs via the blood and lymphatics (either by leukocyte trafficking or free protozonemia)
· With the development of an antibody response, tachyzoites transform into slow-growing bradyzoites within tissues
· T. gondii is capable of infecting all cell types; tachyzoites express SAGs which attach to laminin, lectin, and SAG receptor proteins on host cells
· Rhoptries in apex of tachyzoites produce substances to facilitate cell invasion and form a parasitophorous vacuole, a “hybrid” membrane with the host cell
· Parasitophorous vacuole also avoids fusions with macrophage lysozymes, effects release of IL-10 and TGFb (inhibiting IL-12, IFNgand TNFa)
· CNS infection occurs hematogenously; neurons and astrocytes are the primary targets
· T. gondii can cross blood-brain barrier by infecting endothelial cells > vasculitis > ischemic necrosis
o Parasite motility (linear myosin, F-actin, gliding proteins) and leukocyte trafficking also allow organism to reach brain tissue
· Humoral and cell mediated immunity cause formation of tissue cysts within the CNS, skeletal and cardiac muscle
· CD8+ T lymphocytes, once primed, produce interferon gamma > activates astrocytes & microglia and inhibits Toxoplasma replication
· IFNg induces cytotoxic T lymphocytes destroy infected cells, but also damages nearby neurons and axons
· Immunosuppression of latently infected hosts allows cysts to rupture with reactivation of acute disease
TYPICAL CLINICAL FINDINGS:
· CNS infection: Neurologic signs vary with age, species, and lesion localization; may include seizures, paresis, weakness, tremors, depression, circling, blindness, and ataxia
· Radiculoneuritis: Affects puppies less than 3 months old; acute paraparesis with rigid extension of hind limbs, loss of patellar and withdrawal reflexes, pain, and muscle wasting
· Disseminated disease: Fever, lethargy, anorexia, ocular and nasal discharges, and respiratory distress
TYPICAL GROSS FINDINGS:
· CNS form: Malacia, hemorrhage, edema, and roughening and yellow/brown/grey discoloration of subependymal areas of brain
· Radiculoneuritis: Atrophy and discoloration of hind limb musculature
· Peracute cases: Brain edema +/- herniation
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· CNS form: Nonsuppurative meningoencephalitis of gray and white matter (especially perivascular), vasculitis, hemorrhage, necrosis, tissue cysts, tachyzoites surrounded by neutrophils and mononuclear inflammation, leptomeningitis, periventricular in young animals; gliosis and tissue cysts in chronic cases
· Radiculoneuritis: Lymphoplasmacytic and histiocytic inflammation, most severe in the roots of the lumbosacral spinal cord
· Peracute cases: Hemorrhagic infarcts and vasogenic edema
· Fetal brains: Multifocal discrete foci of necrosis (100-300 um) in brain +/- spinal cord; formation of microglial nodules; foci of mineralization
· Tachyzoites are present within a parasitophorous vacuole
· Anterior apical complex consisting of a polar ring, conoid, rhoptries and micronemes
· Also contains amylopectin granules, dense bodies, microtubules, and micropores
ADDITIONAL DIAGNOSTIC TESTS:
· Electron microscopy
· Immunohistochemistry- crossreactivity with Neospora antibodies possible
· Neospora caninum: Causes encephalomyelitis, polymyositis and polyradiculoneuritis in young dogs; it is indistinguishable by light microscopy but differentiated by immunohistochemistry (some cross-reactivity possible) or by the presence of more numerous micronemes and rhoptries on electron microscopy
· Neospora hughesi: Specific to horses; T. gondii usually not clinical in horses
· Sarcocystis spp.: Typically there is limited tissue necrosis compared to T. gondii
· Sheep, goats and reindeer: The infection primarily causes abortion, with necrotizing placentitis affecting cotyledons; grossly, cotyledons have 1-2 mm white foci; fetal lesions include tissue cysts within the brain and myocardium and leukoencephalomalacia
· Bottlenose , Risso’s and striped dolphins: Reported cases of meningoencephalitis
· New World monkeys and Australian marsupials are very susceptible
· Pigs develop devastating generalized disease with nonsuppurative encephalomyelitis
· Combined ocular and encephalic form reported in canaries
· Old World monkeys, rats, cattle, raptors, and horses are highly resistant to disease
· Mice can be congenitally infected generation after generation
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