JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2026

N-B06

Signalment (JPC #1492918): A monkey

HISTORY: This monkey developed seizures

HISTOPATHOLOGIC DESCRIPTION:Slide A: Cerebrum: Multifocally effacing 50% of the section, elevating the leptomeninges, and affecting both gray and white matter are multifocal to coalescing, granulomas that measure up to 5 mm in diameter. Granulomas are centered on a dense aggregate of eosinophilic cellular and basophilic karyorrhectic debris with loss of cellular architecture (liquefactive necrosis) admixed with basophilic, finely granular material (mineral) and necrotic neutrophils. Central necrosis is bordered by a rim of epithelioid macrophages and multinucleated giant cells (Langhans and foreign-body type) and are further bounded by a rim of lymphocytes and plasma cells. Previously described inflammatory cells extend the adjacent, less affected cerebral white and gray matter. At the periphery of the granulomas are increased numbers of small caliber vessels lined by hypertrophied (reactive) endothelium. In the intervening gray matter there are multifocal areas of liquefactive necrosis with loss of tissue architecture and replacement by necrotic cellular debris admixed with edema, hemorrhage, foamy macrophages (gitter cells), and lymphocytes. In parenchyma adjacent to granulomas and liquefactive necrosis there is a moderate increase in glial cells with reactive astrocytes that have abundant eosinophilic cytoplasm and eccentric nuclei with occasional multinucleation (gemistocytic astrocytes) and there are hypertrophied microglia (red cells) (gliosis). The leptomeninges are mildly expanded by lymphocytes, plasma cells, and macrophages.

Slide B: Acid fast stain: Cerebrum: Rarely, within necrotic cellular debris and within the cytoplasm of multinucleate giant cells, there are few 5-6µm in length acid-fast bacilli.

MORPHOLOGIC DIAGNOSIS: Cerebrum: Granulomas, multiple, multifocal to coalescing, with multifocal liquefactive necrosis, astrocytosis, gliosis, and rare intrahistiocytic acid-fast bacilli, monkey (species not specified), non-human primate.

CAUSE:Mycobacterium tuberculosis

ETIOLOGIC DIAGNOSIS: Cerebral mycobacteriosis

GENERAL DISCUSSION:

Mycobacterium Tuberculosis Complex (MTC) encompasses mycobacterial spp. that are capable of generating a tuberculoid granuloma, to include: Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium microti, Mycobacterium canettii, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium suricattae, Mycobacterium mungi, “dassie bacillus”, and Mycobacterium orygis

• Mycobacterium spp. are non-motile, gram-positive (do not stain well), acid-fast, non-spore forming, facultative intracellular, aerobic bacilli
• M. tuberculosis and M. bovisare the most common etiologies producing mediastinal lymphadenopathy in NHPs
• There is no apparent difference in distribution and character of the lesions produced by these two species
• Tuberculosis in NHP is most commonly acquired from humans via aerosolized bacteria
• M. tuberculosis affects Old World primates more than New World primates; cynomolgus macaques are best model of human disease
• MTC Mycobacterium spp. frequently cause granulomatous pneumonia (P-B10) and enteritis (D-B09, D-B10) in various species; CNS manifestations are rare
• In humans and mice, resistance to M. bovis is related to allelic variation in the natural resistance-associated macrophage protein (Nramp) genes 1 and 2

PATHOGENESIS:

• Transmission primarily by aerosol droplet inhalation (although ingestion of infected materials can occur)
• Mycobacterial cell wall contains a large hydrophobic layer of mycolic acids that generate hydrophobicity of the cell wall leading to environmental and antimicrobial resistance
• Important concepts in the pathogenesis of tuberculosis include the ability of mycobacteria to survive within macrophages, and the role of cellular immune responses in inciting granulomatous inflammation and enhancing the ability of macrophages to kill bacilli
• Macrophages exposed to mycobacterium stimulate production of IL-12 > skews immune response to favor secretion of IFN-γ and IL-2 by CD4+ T-hellper-1 lymphocytes > IFN-γ producing T-helper cells indicate development of cell-mediated immunity > this response is critical for the killing of intracellular bacilli > activated macrophages are epithelioid > surviving bacilli in the necrotic center can remain dormant for years > immunosuppression can allow proliferation and reactivation of the disease
• Cytokines TNF-α and IFN-γ act synergistically to promote formation of the tuberculoid granuloma
• Waxes and cell wall glycolipids induce the initial macrophage response
• Increased virulence is associated with increased glycolipid content in the cell wall, acid-fastness, and the amount of trehalose dimycolate (cord factor) in the cell wall
• Intrahistiocytic survival due to glycolipids/mycosides that form a barrier against lysosomal digestion and by preventing fusion of the phagosome and lysosomes
• Tuberculoproteins: Major category of immunoreactive mycobacterial substances
• Purified protein derivatives: Elicit delayed-type hypersensitivity (principle behind intradermal skin testing)

TYPICAL CLINICAL FINDINGS:

• Non-specific initially; followed by depression, vomiting, behavioral changes, cachexia
• Seizures
• Occasional sudden death
• In Old World monkeys, commonly results in a rapidly progressive, debilitating disease

TYPICAL GROSS FINDINGS:

• Pulmonary: Caseous (tuberculous) nodules in the hilar lymph nodes and lung that extend into the thoracic pleura; lesions may be cavitary; hallmark of disease is typical tubercle
• Widely disseminated, multifocal, pinpoint to large, nodular foci of confluent, caseous granulomas to most major organs (especially spleen, kidney, liver, and various lymph nodes); cerebral mycobacteriosis may manifest as meningitis or as an intraparenchymal tuberculoma
• Meningitis: Granular roughening or gelatinous appearance of the meninges; rare in non-human primates
• Granulomas may involve adjacent bone and dura

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Focal, typical granulomas may surround a necrotic, occasionally mineralized, core
• Lymphocytes, plasma cells and epithelioid macrophages surround the core
• Multinucleated giant cells common at the periphery of the granuloma
• Involved vessels exhibit obliterative endarteritis
• In chronic lesions, fibrous, adhesive arachnoiditis develops
• Acid fast bacilli are rarely detectable due to macrophage activation in killing M. tuberculosis as a process of granuloma formation

ULTRASTRUCTURAL FINDINGS:

• Mycobacterial features: Twisted bacillus shape; fibrillar, electron-opaque nuclear area; periphery is densely filled with ribosomes; capsule in close contact with cell wall

ADDITIONAL DIAGNOSTIC TESTS:

• Acid fast (depends on the amount and spatial arrangement of mycolic acids and their esters within the bacterial cell wall)
• Intradermal tuberculin skin test (eyelid or abdominal skin; I-M01)
• 2 different ELISA assay formats for M. bovis in detection of INF- γ (Chileshe, 2025)
• Culture and PCR necessary for speciation

DIFFERENTIAL DIAGNOSIS:

Meningitis in nonhuman primates:

• Streptococcus pneumoniae: the most common cause of fibrinopurulent meningitis/meningoencephalitis in non-human primates; dull, thickened and opaque leptomeninges; fibrinopurulent meningoencephalitis; necrotizing vasculitis, possibly with thrombosis
• Cytomegalovirus (CMV): Betaherpesvirus; suppurative to nonsuppurative meningoencephalitis with necrosis and fibrinous exudates and characteristic intranuclear inclusion bodies; usually observed with SIV
• Cryptococcus neoformans: Common opportunistic infection
• Neisseria meningitides
• Haemophilus influenzae
• Pseudomonas aeruginosa
• Pasteurella multocida
• Klebsiella pneumoniae
• Listeria monocytogenes

COMPARATIVE PATHOLOGY:

• Nontuberculous mycobacterial infections in nonhuman primates:
  • M. avium associated with SIV and chronic diarrhea
  • M. avium ss. paratuberculosis - Johne’s disease
  • M. avium-intracellulare
  • Atypical mycobacteria: M. marinum, M. kansasii, M. lepraemurium
• Cattle:
  • M. bovis –zoonotic, pneumonia
  • Endemic in Wood Buffalo National Park in Canada of free-ranging wood bison (Bison bison athabascae) – these bison are considered maintenance hostsM. avium ss. paratuberculosis - Johne’s disease
• Cervids
  • M. bovis reservoir for cattle
• Horses: Often alimentary with lesions in retropharyngeal and mesenteric lymph nodes and intestine
  • M. bovis most common in the horse
  • M. avium, proliferative tuberculoid granulation tissue resembling lardaceous or sarcomatous lesions described in equine tuberculosis
• Sheep and goats: Rare pneumonia
• Swine: Often systemic; M. bovis, similar lesions as in cattle;
• Dog and cat: Discrete tuberculoid granulomas are uncommon; lesions usually appear as granulation tissue with random scattered macrophages and giant cells
  • 20 cases of feline ocular granulomas from MTC pathogens M. bovis, M. microti, or non-speciated MTC (Mitchell, 2022)
  • M. lepraemurium in cats: Lepromatous leprosy is characterized by multibacillary sheets of large, pale, foamy epithelioid macrophages and a poor host immune response; dominant Th2 response
• African clawed frogs: M. marinum; sarcoma-like inflammatory response
• Birds: M. avium complex; CNS infection very rare; most often GI portal of entry
• Fish (“fish tank granuloma”): M. marinum, M. fortuitum; zoonotic; M. chelonae
• Guinea pigs: M. bovis and M. tuberculosis; highly susceptible to tuberculosis experimentally, natural disease is rare; disseminated caseating tubercles in lung, spleen, liver, lymph nodes (cervical, portal, inguinal, prescapular)
• Hamster: Rare
  • M. tuberculosis - laboratory inoculation.
  • M. chelonae - Single report: pet hamster with granulomatous swelling of feet and lymph nodes
• Mice:
  • Laboratory mice are susceptible to experimental infections with Mycobacteria, naturally occurring infections are rare
• Rabbits:
  • Highly susceptible to M. bovis and M. tuberculosis - extrapulmonary lesions typical of tuberculosis with granulomas, giant cell formation, multibacillary
  • Wild European rabbits are reservoir of M. avium ss. paratuberculosis (Johne’s)
  • Laboratory rabbits are valued models of TB due to cavitary pulmonary lesions
• Lemurs (ring-tailed, ruffed, black, and mongoose):
  • M. tuberculosis infection results in formation of granulomatous inflammation or granulomas, few intralesional acid-fast positive bacilli; pulmonary infection is most common
• Elephants: Pulmonary disease with spread to thoracic lymph nodes; Indian elephant > African elephant
• Free ranging rhinos: M. bovis or M. tuberculosis have been reported to cause granulomas in lungs and lymph nodes
• Hyrax:
  • Mycobacterium widely reported
  • MTC species known as “dassie bacillis”, M. microti, M. africanum,M. microti-like bacteria reported in some cases
  • Weight loss, lameness, pneumonia, reproductive failure
  • Granulomas found in the lungs, liver, spleen, and kidneys with acid-fast bacilli
• Cetaceans (whales):
  • Atypical mycobacteriosis; ulcerative dermatitis, panniculitis, pneumonia, lymphadenitis due to M. marinum, M. chelonae, M. abscessus
• Pinnipeds (seal/sea lions):
  • MTC member M. pinipedii generally respiratory disease either:
  • Granulomatous pleuropneumonia and thoracic lymphadenitis or
  • Caseating granulomas within the lungs and thoracic LNs
• Sirenia (manatees etc.)
  • Granulomas in lung, pleura, LN, testicle, skin
  • M. marinum, M. fortuitum, M. kansaii, M. chelonae
• Reptiles, bony fish, and amphibians: most commonly non-tuberculoid granulomatous dz. In skin/systemic, multiple species but M. marinum, M. fortuitum, M. chelonae are most common

References:

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2. Barthold S, Griffey S, Percy D. Pathology of Laboratory Rodents and Rabbits, 4^th ed. Ames, IA: John Wiley & Sons, Inc.; 2016:72, 185, 282.
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4. Chileshe J, Shury T, Chen JM. Optimization and validation of ELISAs for interferon-gamma determination in bison. J Vet Diagn Invest. 2025;37(5):764-770. 
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