JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-F01

 

Slide A: 

Signalment (JPC #4019427): 7-year-old, male castrated, Russian Blue cat.

 

HISTORY: One year history of weight loss, left tarsal arthrodesis surgery 5 months prior. Most recent clinical presentation for ulcerated lip mass present for 8 weeks as well as stumbling, decreased menace, positional nystagmus, inappropriate mentation, and vocalization.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum: The leptomeninges are markedly expanded by an inflammatory infiltrate composed of macrophages, lymphocytes, plasma cells, fewer neutrophils, and occasional Mott cells and multinucleated giant cells. This inflammatory infiltrate multifocally extends into the adjacent white and gray matter, often centered on vessels. Frequently within macrophages and multinucleated giant cells there are one or more, 2-4µm basophilic, round, intracytoplasmic yeast that are surrounded by a 1µm clear capsule. Within adjacent, less affected tissue there is rarefaction of the neuropil, marked gliosis, macrophages containing foamy eosinophilic material (gitter cells), and rare gemistocytic astrocytes. Endothelial cells lining vessels in affected and adjacent areas are hypertrophied (reactive).

 

MORPHOLOGIC DIAGNOSIS: Cerebrum: Meningoencephalitis, granulomatous, multifocal, moderate, with intrahistiocytic yeast, Russian Blue, feline. 

 

Slide B:   

Signalment (JPC #1602214): Age and breed unspecified dog

 

HISTORY: Two-year history of progressive ataxia and posterior paresis. 

 

HISTOPATHOLOGIC DESCRIPTION: Cerebral cortex and diencephalon (GMS): There are numerous intrahistiocytic yeast with argyrophilic walls and occasional narrow based budding.

 

ETIOLOGIC DIAGNOSIS: Cerebral histoplasmosis 

 

CAUSE: Histoplasma capsulatum var. capsulatum 

 

CONDITION: Histoplasmosis

 

 

GENERAL

• Histoplasma capsulatum is dimorphic fungus with a life cycle that has an infectious mycelial (microconidia) phase, which occurs in extracellular environments (25° C), and a yeast phase which occurs intracellularly within cells of the monocyte-macrophage system (37° C); intracellular yeast are 2-4 μm in diameter 
• Common, soil-born, facultative intracellular fungus that infects macrophages and is a cause of granulomatous pneumonia and systemic disease affecting many organ systems in many domestic and wild animal species and humans; CNS involvement is rare
• Worldwide occurrence but predominately found in the United States along the St. Lawrence, Ohio, and Mississippi River valleys 
• Most animals are subclinically infected; clinical disease occurs most frequently in dogs and cats, but has been reported in other species, including humans, swine, cattle, horses, and birds.
  1. Dogs and cats are most susceptible to infection; typically infected with H. capsulatum variant capsulatum; the second most common fungal disease in cats in North America
• Thrives in moist, nitrogen-rich organic matter such as bird and bat excrement

 

 

PATHOGENESIS

• Dimorphic fungus with free-living, mycelial stages with infectious microconidia; inhalation of airborne conidia or rarely by ingestion or skin contact with infective spores 
• Inhalation or ingestion of microconidia àConvert to yeast forms (requirement for fungal pathogenicity), reproduce by budding à phagocytosis by neutrophils or macrophages, further replication à Yeast synthesize proteins inhibiting acidification of phagolysosome and lysosomal proteases, preventing killing à 
  1. Yeast outlive macrophages (6-16 day lifespan) and are released from dead macrophages into surrounding tissues (e.g. lamina propria of small intestines if ingested) à Yeast polysaccharides and chemokines/cytokines recruit additional pyogranulomatous inflammatory cells à Process repeats àVolume of inflammatory exudate grows
     • In intestines, results in thickening of tissues (e.g. intestinal wall), disruption of lymphatic vascular drainage, and disturbances of junctional complexes of villous epithelial cells, resulting in protein-losing enteropathy
  2. Dissemination via lymphatic and hematogenous routes to local/regional lymph nodes or other organs (leukocyte trafficking)
• Infection normally limited to respiratory system and local lymph nodes but dissemination may occur quickly in the immunocompromised or those with a high dose exposure
• Infection may become dormant within the phagocytic system and persist for years in immunocompetent hosts
• Target organs contain high numbers of monocyte/macrophage lineage cells and include lungs, lymph nodes, spleen, liver, bone marrow, gastrointestinal tract, adrenal glands, and mucous membranes of the oral cavity

 

TYPICAL CLINICAL FINDINGS:

• Cats: Non-specific signs (weight loss, mental depression, anorexia, dyspnea, tachypnea, pale mucous membranes, fever), splenomegaly, lymphadenopathy, hepatomegaly with icterus  
• Dogs: Similar to cats; most cases of disseminated disease involve GI tract à Emaciation, persistent large-bowel diarrhea, voluminous watery diarrhea with protein losing enteropathy, tenesmus, fresh blood in stool
  1. Other signs of disseminated histoplasmosis may include respiratory distress or lameness
• Clinical pathology abnormalities
  1. Normocytic, normochromic, nonregenerative anemia (chronic inflammation)
  2. Leukocytic changes vary with the reserves of the animal and the stage of the disease: 
     • If the animal is in good body condition and the bone marrow is competent, there is neutrophilic leukocytosis with some degree of monocytosis. 
     • With debilitation, the leukocyte count drops to normal levels or lower with left shift and marked toxic changes, including Döhle bodies 
     • There is usually lymphopenia and eosinopenia.

 

TYPICAL GROSS FINDINGS:

• CNS: Moderately well-demarcated, expansile, yellow-brown foci that displace normal tissue
• Lungs: Grey, round discreet to coalescing 1-2 cm nodules
• Intestine: Nodular thickening or corrugations of mucosa (similar to Johne’s disease) chiefly in lower small intestine and due to infiltration of lymphocytes, plasma cells, and macrophages; can progress to transmural thickening with loss of normal architecture (similar to lymphoma)
• Lymph nodes: Enlarged with grey nodular lesions effacing architecture
• Spleen and liver: Enlarged, grey, and firm
• Eyes: Ocular disease seen in 1/4 of cats (granulomatous blepharitis, conjunctivitis, chorioretinitis, panuveitis or panophthalmitis, retinal detachment, and optic nerve neuritis)
• Other: Adrenal gland involvement often seen in advanced histoplasmosis; dermatitis, osteomyelitis, and arthritis, as well as myelitis, are less common
• Necrosis of tissues is not often present, although central caseation without mineralization may occur in large, dense accumulations of macrophages

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Proliferation and infiltration of monocytes and epithelioid macrophages into tissue, often forming granulomas
• Yeast: Intrahistiocytic 2-4 μm diameter, oval to round, with a central 1-2 μm basophilic center surrounded by a 2 μm clear halo (part of the yeast’s cell wall); narrow-based budding
• Giant cells are rare and there is only mild fibrosis
• Specific tissues
  1. Eye: There is usually a diffuse granulomatous uveitis with little suppuration; in cats there is usually granulomatous conjunctivitis
  2. Bone and joints: Rarely involved; when present, often affects the metaphysis of long bones, especially around the carpal and tarsal joints of cats

 

ADDITIONAL DIAGNOSTIC TESTS:

• Cytology: Yeast are smaller than most other yeast (2-4 μm), ovoid, pale blue, surrounded by a thin clear halo, present within cytoplasm of macrophages (usually multiple yeast within a macrophage)
  1. Organisms are readily recognizable on rectal scrapings, fine needle aspirates of organs (e.g. liver, spleen, skin), lymph nodes, fluid preparations (e.g. pleural and peritoneal fluids, bronchoalveolar lavage fluids, or lavage of the turbinates in animals with sinusitis), bone marrow, skin, and CSF
• The glycogen-rich cell wall (the halo on cytology or histology) can be highlighted:
  1. PAS: Stains an empty red
  2. GMS: Stain black
  3. Giemsa: A light blue ring
• Immunohistochemistry is available
• Fungal culture: Zoonotic potential for lab workers from inhalation of microconidia
  1. Culture mimic environmental conditions, not tissue/host conditions, -> Results in formation of infective hyphae and conidia

 

DIFFERENTIAL DIAGNOSIS:

• Gross
  1. Neoplasia
• Microscopic:
  1. Histoplasma capsulatum var. duboisii (African histoplasmosis, I-F13): Only reported in baboons and humans, larger (8-15 μm), narrow-based budding
  2. Blastomyces dermatitidis: Larger (7-15 μm), multinucleated, thick “doubly contoured” walls, broad-based budding 
  3. Cryptococcus neoformans (N-F02): Variably-sized yeast (2-20 μm), uninucleate, pleomorphic shape, single narrow-based budding, thin mucicarmine-positive capsule, rare hyphae
  4. Candida (Torulopsis) glabrata: Slightly larger (2-5 μm), variably-sized, oval to elongate, broad-based budding, amphophilic, stain entirely with H&E, no “halo” or pseudocapsule
  5. Leishmania spp.: Amastigotes within macrophages are 2-4 μm diameter with kinetoplasts perpendicular to nuclei 
  6. Toxoplasma gondii: 2-6 μm crescentic bradyzoites, stain entirely with H&E, no “halo”, develops pseudocysts, usually found in somatic cells instead of phagocytic cells
  7. Neospora caninum (N-P03): Similar to Toxoplasma gondii, in CNS often within tissue cysts
  8. Pneumocystis carinii (pulmonary - intra-alveolar cyst form): 4-6 μm, primarily extracellular, lacks budding, GMS-positive
  9. Sporothrix schenckii: 2-6 μm, pleomorphic, mainly single narrow-based budding, thin cell wall, rare hyphae, uninucleate, extracellular and few yeast found in macrophages
  10. Aspergillus (I-F03, P-F06, U-F02): Fungal hyphae are 3-6 um in width, regularly septate, parallel walled, with dichotomous (branching at the terminal bud), progressive, acute angle branching

 

COMPARATIVE PATHOLOGY:

• Horses: Histoplasma farciminosum (epizootic lymphangitis of horses): Causes a chronic suppurative lymphadenitis of solipeds 
• Baboons: Histoplasma capsulatum var. duboisii (I-F13); only reported in baboons and humans
• Nubian goat: Histoplasma capsulatum recently reported in a Nubian goat (Schlemmer, 2019).
• ZEW
  1. Carnivores: Rarely reported in captive and free-ranging bears, somewhat frequently reported in coyotes with lesions similar to canines; disseminated systemic disease reported in 2 raccoon kits with granulomatous pneumonia, lymphadenitis, splenitis, enteritis, nephritis, encephalitis, and thymitis with intrahistiocytic yeast; reported as a cause of emaciation and lymphadenitis in sea otters and skunks (Terio)
  2. Systemic disease reported in a variety of NHPs and rodents (Terio)
  3. Bats can serve as reservoirs, although clinical disease is uncommon (Terio)

 

REFERENCES:

1. Church ME, Terio KA, Keel, MK.  BH, Burek Huntington KA. Procyonidae, Viverridae, Hyenidae, Herpestidae, Eupleridae, and Prionodontidae. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals. 1st ed. London, United Kingdom. Elsevier. 2018: 314.
2. Crain LE, Dittmer KE, Thompson KG. Bones and Joints. In: Maxie MG,ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Saunders. 2016:104, 104, 154.
3. Farina LL. Lankton JS. Chiroptera. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals. 1st ed. London, United Kingdom. Elsevier. 2018: 623.
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12. Schlemmer SN, Fratzke AP, Gibbons P, Porter BF, Mansell J, Ploeg RJ, Rodrigues Hoffmann A, Older CE, Clark SD. Histoplasmosis and multicentric lymphoma in a Nubian goat. Jour Vet Diagn Invest. 2019;31(5):770-773. 
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