JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

March 2017

N-P02

 

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

 

CONDITION:  Toxoplasmosis

 

GENERAL DISCUSSION:

·         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

 

LIFE CYCLE:

·         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

 

PATHOGENESIS:

·         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, ahybrid” 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

·         Abortion

 

 

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

 

ULTRASTRUCTURAL FINDINGS:

·         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

·         PCR

 

DIFFERENTIAL DIAGNOSIS:

·         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

 

COMPARATIVE PATHOLOGY:

·         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

 

References:

1.     Antoniassi NA, Boabaid FM, Souza RL, Nakazato L, Pimentel MF, Filho JO, Pescador CA, Driemeier D, Colodel EM. Granulomatous meningoencephalitis due to Toxoplasma gondii in a black-headed night monkey (Aotus nigriceps).  J Zoo Wildl Med. 2011;42(1):118-20.

2.     Cheville NF. Pathogenic protozoa. In: Cheville NF, ed. Ultrastructural Pathology. 2nd ed. Ames, IA: Wiley-Blackwell; 2009:552-555.

3.     Cohen ND, MacKay RJ, Toby E, et al. A multicenter case-control study of risk factors for equine protozoal myeloencephalitis. J Am Vet Med Assoc. 2007;231(12):1857-1863.Di Guardo G, Mazzariol, S.  Toxoplasma gondii: clues from stranded dolphins. Vet Pathol. 2013: 50(5):737.

4.     Di Guardo G, Proietto U, Di Francesco CE, et al. Cerebral toxoplasmosis in striped dolphins (Stenella coeruleoalba) stranded along the Ligurian sea coast of Italy. Vet Pathol. 2010;47(2):245-253.

5.     Dubey JP, Lewis B, Beam K, Abbitt B.  Transplacental toxoplasmosis in a reindeer (Rangifer tarandus) fetus. Vet Parasitol. 2002;110(1-2):131-135.

6.     Fayaad A, Kummerfeld M, Davina I, Wohlsein P, Beineke A, Baumgärtner W, Puff C.  Fatal Systemic Toxoplasma gondii infection in a red squirrel (Sciurus vulgaris), a Swinhoe's striped squirrel (Tamiops swinhoei) and a New World porcupine (Erethizontidae sp.). J Comp Pathol. 2016;154(2-3):263-7.

7.     Levine ND.  Veterinary Protozoology. Ames, IA: Iowa State University Press; 1985: 233-260.

8.     Love D, Kwok OC, Verma SK, Dubey JP, Bellah J.  Antibody prevalence and isolation of viable Toxoplasma gondii from raptors in the Southeastern USA.  J Wildl Dis. 2016;52(3):653-6.

9.     Mikaelian I, Boisclair J, Dubey JP, Kennedy S, Martineau D. Toxoplasmosis in beluga whales (Delphinapterus leucas) from the St. Lawrence estuary: Two case reports and a serological survey.  J Comp Path. 2000;122(1):73-76.

10.  Cantile C, Youssef S. Nervous System. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier; 2016:352, 387-389.

11.  Summers BA, Cummings JF, de Lahunta A. Veterinary Neuropathology. St. Louis, MO: Mosby; 1995.

12.  Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier; 2016:236-238.

13.  Williams SM, Fulton RM, Render JA, Mansfield L, Bouldin M. Ocular and encephalic toxoplasmosis in canaries.  Avian Dis. 2001;45(1):262-267.

14.  Zachary JF. Nervous system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby-Elsevier; 2017:844-845.

15.  Zachary JF. Mechanisms of microbial infections. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby-Elsevier; 2017:238-239.


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