JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

February 2023

N-P02

 

Signalment (JPC #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 foci of liquefactive necrosis characterized by disorganization and loss of normal architecture with replacement by many gitter cells, fewer lymphocytes, plasma cells, gemistocytic astrocytes, and rare neutrophils. Necrotic foci contain occasional eosinophilic, 20x15µm, oval protozoal cysts that have a thin cyst wall encircling numerous 1-2 µm, elongate bradyzoites. Blood vessels within the necrotic foci are prominent and often lined by hypertrophic (reactive) endothelium; less affected blood vessels are surrounded by moderate numbers of lymphocytes, plasma cells, and fewer macrophages (perivascular cuffing). Randomly dispersed throughout less affected regions are glial nodules up to 250µm in diameter, mild spongiosis, and rare swollen axons surrounded by variably dilated myelin sheaths (spheroids). The meninges are moderately expanded by 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, obligate intracellular, coccidian parasite that causes disseminated disease (P-P01), central nervous system infections, and abortions (R-P01) in many species, except cattle
• Felids are the definitive host, and can uniquely serve as an intermediate host
• Sporozoites and tachyzoites are readily destroyed; tissue cysts (bradyzoites) are resistant and perpetuate the disease
• Tachyzoites (trophozoites) are rapidly dividing forms and occur in free groups
• Bradyzoites multiply slowly and are found in tissue cysts
• Oocysts contain infective sporozoites after being shed
• Contamination of feed by cat feces is a common transmission route
• 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:

• Transmission: Ingestion of infected prey tissue (tachyzoites, or cysts containing bradyzoites), ingestion of sporulated oocysts in contaminated food or water, or transplacental (common in sheep and goats)
• Definitive host, enteroepithelial (typical coccidian) cycle: Sexual replication occurs in feline intestinal epithelium, especially the ileum > unsporulated oocysts pass in feces and sporulate in 1-5 days; sporulated oocysts are infectious to intermediate hosts (includes cats)
• Intermediate host, extraintestinal cycle: After ingestion, sporozoites excyst, multiply intracellularly in the intestines and related lymph nodes by endodyogeny and form tachyzoites that spread to other tissues via blood and lymph > parasitemia develops in 3-4 days > tachyzoites actively penetrate host cell plasmalemma and reside within a parasitophorous vacuole derived from host cell membrane and the parasite > cell to cell spread continues until T-cell mediated immunity develops

• Intracellular tissue cysts form after 1-2 weeks and persist for months to years

 

PATHOGENESIS:

• T. gondii is able to infect all types of cells because it binds laminin (an extracellular matrix protein) and then binds to laminin receptors on the target cell
• Secretory organelles, called rhoptries, are important for cellular invasion; rhoptry membranes fuse with the anterior limiting membrane and a lytic product is secreted from fusion rosettes and facilitates invasion into the cell
• T. gondii has both catalase and glutathione peroxidase activity and is resistant to hydrogen peroxide, but is susceptible to hydroxyl radical and singlet oxygen (respiratory burst of inflammatory cells)
• In parasitophorous vacuoles, the protozoan initiates the production of the anti-inflammatory cytokines IL-10 and transforming growth factor-β (TGF-β), which inhibit the production of proinflammatory cytokines IL-12 and TNF-α
• T. gondii tachyzoites express glycosylphosphatidylinositol-linked surface proteins (SAGs, e.g. SAG1 and SAG3) that function in target cell attachment and immune modulation, and may also cause direct injury to enterocytes; SAG1 binds to enterocyte laminin, lectin, and SAG receptor proteins
• T. gondii can cross barrier systems (intestinal mucosa, blood-brain barrier, blood-retinal barrier, and placenta) using parasite motility (linear myosin, F-actin filaments, and gliding-associated proteins) and infect endothelial cells > vasculitis > ischemic necrosis
• In CNS infections: 
  • CNS infection occurs hematogenously; neurons and astrocytes are the primary targets
  • CD8+ T lymphocytes, once primed, produce IFN-g > activates astrocytes and microglia and inhibits Toxoplasma replication; IFN-g induces cytotoxic T lymphocytes to destroy infected cells, but also damages nearby neurons and axons
• Humoral and cell mediated immunity cause formation of tissue cysts within the CNS, skeletal muscle, and cardiac muscle
• 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, 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
• Systemic disease: Fever, lethargy, anorexia, ocular and nasal discharges, and respiratory distress
• Reproductive disease: Abortion 
• Clinical pathology: mild neutrophilic or mononuclear pleocytosis, and mildly elevated protein concentration, protein rich exudates

 

TYPICAL GROSS FINDINGS:

• CNS form: Malacia, hemorrhage, edema, roughening, and yellow/brown/grey discoloration of subependymal areas of brain
• Radiculoneuritis: Atrophy and discoloration of hind limb musculature
• Peracute cases: Brain edema +/- herniation
• Systemic disease: Interstitial pneumonia, focal hepatic necrosis, lymphadenitis, myocarditis, and nonsuppurative meningoencephalitis; pulmonary lesions are more often found, followed by CNS lesions

 

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, periventriculitis 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 mm) in brain +/- spinal cord; formation of microglial nodules; foci of mineralization

 

ULTRASTRUCTURAL FINDINGS:

• Zoites reside within a parasitophorous vacuole
• Pellicle (outer membrane) consists of 3 membranes: A plasmalemma and two closely applied membranes that form an inner membrane complex
• At the anterior surface is a cylindrical cone (conoid) consisting of microtubules wound like a spring and is used to probe host cell surface prior to entry
• Rhoptries are club-shaped excretory organelles between the anterior tip and nucleus that secrete a proteolytic enzyme used in host cell penetration
• Micronemes are rod-shaped structures found at the anterior end

ADDITIONAL DIAGNOSTIC TESTS:  

• Electron microscopy
• Immunohistochemistry (IHC): +/- crossreactivity with Neospora antibodies
• PCR testing in serum, tissue, CSF fluid
• Direct visualisation of organisms in CSF fluid  (Vet Diagn Invest 2021), aspirates of inflammatory focci, bronchoalveolar lavage, fecal examination
• Serology must be interpreted cautiously because IgG may remain elevated for up to 6 years after exposure; paired serum IgM-IgG titers, indicating more acute exposure, is more useful. 
• Tachyzoites and bradyzoites are PAS-positive, Gram-negative within PAS-negative cyst walls 

 

DIFFERENTIAL DIAGNOSIS:

• Neospora caninum: Causes encephalomyelitis, polymyositis, and polyradiculoneuritis in young dogs; it is indistinguishable by light microscopy but differentiated by IHC (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:

• Toxoplasma gondii can infect a wide variety of animals as intermediate hosts (extraintestinal life cycle) including fish, amphibians, reptiles, birds, human beings, and many other mammals
• Dogs: Disease is triggered by immunosuppression, such as with canine distemper virus infection, ehrlichiosis, and lymphosarcoma
• Sheep, goats, and reindeer:  Infection primarily causes abortion (see R-P01), with necrotizing placentitis affecting cotyledons; grossly, cotyledons have 1-2 mm white necrotic foci; fetal lesions include protozoal tissue cysts within the brain and myocardium, leukoencephalomalacia, loss of olidogendrocytes, increased numbers of astrocytes and microglia (Vet Path 2020)
• Horse: gastric mucosal masses, caecal necrosis, necrotizing granulomatous lymphadenitis with intrahistiocytic protozoal tachyzoites, splenitis, pneumonia, hepatitis (Comp Pathol 2021)
• Pigs: Develop devastating generalized disease with nonsuppurative encephalomyelitis
• Pet & aviary birds: bradyzoites and tachzyoites found in many organs;   myocarditis, myocardial necrosis, pneumonia, hepatic necrosis, muscle cysts, meningoencephalitis,   chorioretinitis, serous and fibrinous serositis 
• Wildlife and exotic species:  
  • Red kangaroo: Recent report of concurrent disease with amboebiasis and toxoplasmosis; T. gondii zoites present in the brain and multiple organs (stomach, cecum, adrenal gland, lymph nodes, thyroid gland, skeletal muscle, thymus, colon, and pancreas) (Ilha et. Al, J Comp Pathol 2019)
  • Patagonian maras: Fatal systemic infection with concurrent localized bacterial and fungal infections in a captive animal; lesions included lymphohistiocytic hepatitis, myocarditis, urinary cystitis, and adrenaliitis, with acute coagulative necrosis (Ostevik et.al, J Vet Diagn Invest 2019)
  • Red-Necked Wallaby: first report of T. cruzi and T. gondii co-infection; lymphohistiocytic and necrotizing pancarditis with intrasarcoplasmic protozoal tissue cysts with zoites morphologically compatible with Toxoplasma gondii;  intrasarcoplasmic pseudocysts containing amastigotes and intrahistiocytic amastigotes, morphologically compatible with Trypanozoma cruzi (Díaz-Delgado et. Al, J Comp Pathol 2020)
  • Mediterranean Monk Seal: Atypical Toxoplasmosis characterized by necrotizing arteritis of aorta and major pulmonary arteritis, hemorrhagic foci and non-suppurative meningoencephalitis, and protozoal cysts in brain; vascular lesions considered atypical as it has not been reported on other marine mammal species  (Mazzariol et.al,  J Comp Pathol 2021)
  • Pallas’ cats: are uniquely susceptible to infection with Toxoplasma, resulting in high neonatal mortality, and encephalomyelitis in aged cats, related to declining immune function and recrudescence of latent infections
  • Mustelids: especially free-ranging southern sea otters and black-footed ferrets, develop significant systemic disease
  • Meerkets, raccoons: are highly susceptible to infection, with high mortality in outbreaks in captive animals
  • Prosimians (lemurs, etc): are susceptible; infection in pregnant dams include placentitis, abortion or stillbirth, disseminated fetal infection, or neonatal death
  • Australian Marsupials: Increased susceptibility; encephalitis, pneumonia
  • Hyrax: Fatal infections reported in pregnant and young rock (cape) hyraxes and a tree hyrax
  • Cetaceans: Atlantic bottle‑nosed and Spinner dolphins: sporadic, significant cause of nonsuppurative meningoencephalitis, necrotizing placentitis, and abortion
  • Pinnipeds: California sea lions: Necrotizing and lymphohistiocytic meningoencephalitis, myocarditis, and myositis
  • Sirenia: Dugong, Antillian and Florida Manatee: necrotizing myocarditis, pneumonia, hepatitis, meningoencephalitis
  • Australian flying foxes: necrosis and granulomatous pneumonia, encephalitits, peritonitis, enteritis, myocarditis
  • Fatal infections occur in wild and captive species, including several fox species (red, gray, sand, Fennec, Blanford’s), giant pandas, and brown bears
  • Hawaiian forest birds and canaries:  Significant cause of mortality; ocular lesions common in canaries
  • New World monkeys: Increased susceptibility; Marmosets are very susceptible and may die within 5-6 days after contracting disease; necrotizing hepatitis, lymphadenitis, splenitis, nephritis, pneumonia; CNS: gliosis, focal hemorrhage, infarcts, cellular degeneration, perivascular cuffing
• Rats, cattle, and raptors are highly resistant to disease
• Mice: Can be congenitally infected generation after generation; rarely seen in laboratory mice since it requires cats as the definitive host

 

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