JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2026

N-B04

Signalment (JPC #2239642): 5-year-old Holstein cow

HISTORY: This cow exhibited anorexia and mental confusion followed by recumbency and nervous signs. The animal was sick for two days.

HISTOPATHOLOGIC DESCRIPTION: Brainstem: There is an extensive central focus of liquefactive necrosis that measures 6 mm x 7 mm and is characterized by loss of intact white and grey matter and replacement by abundant eosinophilic cellular debris, fragmented myelin debris, swollen and pale eosinophilic axons (spheroids), abundant intact and necrotic neutrophils, and fewer gitter cells and lymphocytes. Neurons within the area of liquefactive necrosis are necrotic with indistinct borders, pale eosinophilic cytoplasm, and a faded or lost nucleus and necrotic neurons are frequently phagocytosed by many neutrophils and fewer gitter cells (neuronophagia). Dense neutrophilic inflammation extends into surrounding intact parenchyma and occasionally forms small, discrete neutrophilic nodules centered on focal areas of liquefactive necrosis (microabscesses). Multifocally, vascular endothelial cells are hypertrophied and vessel walls are transmurally expanded by neutrophils, fibrin, and cellular and karyorrhectic debris (fibrinonecrotic vasculitis). Multifocally, Virchow-Robin space and to a lesser extent the leptomeninges are expanded up to three times normal by lymphocytes, plasma cells, macrophages, and fewer neutrophils.

MORPHOLOGIC DIAGNOSIS: Brainstem: Meningoencephalitis, necrotizing and suppurative, subacute, multifocal, marked, with fibrinonecrotic vasculitis, microabscesses, and mononuclear perivascular cuffing, Holstein, bovine.

ETIOLOGIC DIAGNOSIS: Listerial meningoencephalitis

CAUSE: Listeria monocytogenes

CONDITION: Listeriosis, “Circling disease”

GENERAL DISCUSSION:

• Gram-positive, small (0.4-0.5 um x 0.5-2 um), nonspore-forming, motile, facultatively intracellular, facultatively anaerobic, catalase-positive bacillus with more than 11 serotypes; occur singly or in short chains
  • Almost all animal infections are caused by serotypes 1/2a, 1/2b, 4b, and 5
• Ubiquitous in the environment as a saprophyte, especially temperate zones
• Resistant to harsh environmental conditions
• Sporadic disease in a variety of animals, including man
• Economically important in ruminants; seasonal occurrence (winter and early Spring)
• Associated with poorly preserved silage (improper fermentation with silage pH >5), big-bale silage, moist feed; bacteria killed at pH lower than 5.5
• Commonly isolated from tissues of normal animals (e.g. lymphoid tissues) and in large numbers in the feces of ruminants
• Intracellular pathogen within macrophages, neutrophils, and epithelial cells

PATHOGENESIS:

• Exact pathogenesis unclear; penetrates intestinal epithelial barrier phagocytized and grows within splenic and hepatic macrophages dissemination to other tissues including CNS and pregnant uterus
• Three main distinct disease syndromes in animals (syndrome seldom overlap; likely separate pathogeneses):
  • Encephalitis: Disease of adult ruminants; associated with heavy feeding of silage
    • Bacterial invasion through wounds in oral mucosa (pathologic or physiologic) > invade the trigeminal nerves and travel centripetally via retrograde axonal transport to the brain (medulla oblongata and midbrain) > actin-based motility into adjacent cells including endothelial cells > acute inflammation > necrosuppurative meningoencephalitis with vasculitis
    • Remarkable affinity for brainstem (reticular formation); lesions most severe in the medulla and pons
    • Commonly, extensive tissue destruction associated with suppurative inflammation
    • Inhibition of P-glycoprotein (efflux protein) increases tissue invasiveness
    • Hematogenous spread usually only under experimental circumstances
  • Abortion:
    • Gravid uterus is highly susceptible to infection
    • Hematogenous spread to gravid uterus > organisms penetrate placenta and spread to fetal liver > focal hepatic necrosis, focal necrosis of spleen or brain, and focal necrotizing interstitial pneumonia
      • Gross lesions in fetus consist of tiny pinpoint yellow foci in the liver, and focal-to-diffuse red-to-brown exudative intercotyledonary placentitis
    • Can cause third trimester abortion
    • Retention of fetal membranes causes mild clinical illness by the dam but is quickly cleared
  • Septicemia:
    • Transported by macrophages
    • Liver: multifocal necrosis or miliary microabscesses; rarely heart and other tissues
    • Principally in neonates up to one week of age as a continuation of the fetal infection
    • Characterized by tissue lytic necrosis with infiltration of neutrophils and fewer macrophages
  • Enteric:
    • Severe necrotizing colitis in bovine fetus with clusters of colonizing gram-positive bacteria
    • Extremely rare; reported in humans, cattle, and sheep
    • Severe congestion of entire digestive tract with prominent muscularis mucosa neutrophilic inflammation, mucosal necrosis, and villous blunting
• Virulence factors:
  • Internalin (types A and B) internalizes via E-cadherin; required to overcome intestinal, placental, and blood-brain barriers
  • Utilizes cholesterol-binding hemolysin to lyse phagocytic cell phagosomes and escape into the host cytoplasm
  • Listeriolysin O (LLO) is a pore-forming cytolysin that lyses phagocytic cell phagosomes, allowing escape into cytoplasm where the organism multiplies
  • One of the few organisms known to co-opt host cell actin using ActA protein, allowing cell-to-cell transfer

TYPICAL CLINICAL FINDINGS:

• Encephalitic form:
• Mental confusion and depression, head pressing, turning or twisting of head to one side (without rotation), walking in circles (“circling disease”)
• Unilateral facial nerve (CN VII) paralysis causing drooping eyelid, ear, lips
• Paralysis of masticatory muscles and pharynx leading to drooling
• Strabismus, nystagmus, hemiparesis, decreased ruminal motility
• Purulent endophthalmitis, usually unilateral, often in association with meningoencephalitis in ruminants

TYPICAL GROSS FINDINGS:

• Gross brain lesions are rare; parenchymal lesions occur initially (microabscesses), then meningeal lesions
• Occasionally, medullary meninges thickened by greenish gelatinous material
• Occasionally, gray foci of softening (malacia) in cross sections of medulla (caused by inflammatory cells/thrombi occluding vessels)

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Microabscesses and glial nodules infiltrated by neutrophils and gitter cells that may contain bacteria and have a center of liquefactive necrosis (rhombencephalitis) centered on the pons and medulla, involving both the gray and white matter
• The parenchyma surrounding microabscesses and glial nodules may be minimally affected, or may be edematous and rarefied with areas of malacia and prominently swollen axons
• Acute vasculitis with fibrin exudation in the white matter near inflammatory foci, secondary to drainage of the parenchymal foci into the Virchow-Robin space
• Mononuclear leptomeningitis and densely cellular mononuclear perivascular cuffs (lymphocytes and histiocytes with fewer neutrophils and eosinophils)
• Neuronal necrosis
• Cranial nerves may have intrafascicular and perineural accumulations of inflammatory cells (lymphocytes, macrophages, plasma cells, and neutrophils)

ADDITIONAL DIAGNOSTIC TESTS:

• Gram-positive intrahistiocytic or intraneutrophilic bacilli in tissue, in association with typical light microscopic findings, is pathognomonic
• CSF analysis: Protein concentration greater than 40ug/dL and WBC count greater than 12 mononuclear cells per uL (mononuclear pleocytosis) with consistent clinical signs is suggestive of listeriosis
• Culture
• PCR and Immunohistochemistry: Bacteria in axons, neurons, endothelium, and microabscesses
• Fluorescent antibody test (FAT) IHC and PCR significantly more reliable (Rissi, 2024)

DIFFERENTIAL DIAGNOSIS:

• Clinical signs:
  • Nervous ketosis in cattle
  • Middle ear disease
  • Malignant catarrhal fever (purulent endophthalmitis; D-V15, S-V01)
  • Cerebral theileriosis (N-P08): “turning sickness” or “East Coast Fever”; present in Kenya, Tanzania, and India; caused by piroplasm Theileria annulata and Theileria parva
• Microscopic:
  • Polioencephalomalacia (N-T02; thiamine deficiency): marked laminar cerebral cortical necrosis
  • Malignant catarrhal fever (ovine herpesvirus 2; D-V15, S-V01): perivascular edema, nonsuppurative meningoencephalomyelitis, lymphocytic perivascular cuffing
  • Thrombotic meningoencephalitis (Histophilus somni; N-B03): fibrinonecrotic vasculitis with fibrin thrombi; meningoencephalitis, neutrophilic inflammation, bacterial colonies
  • Rabies (Rhabdoviridae: Lyssavirus; N-V06): nonsuppurative polioencephalomyelitis with ganglionitis, Negri bodies in Purkinje cells

COMPARATIVE PATHOLOGY:

• Same triad of syndromes in many mammals and birds
  • Sheep and goats: common
  • Horses, swine, dogs, and rodents: less common
    • Horses: abortion in mares; septicemia in foals
    • Dogs: encephalitis
  • Gray foxes: hepatitis with intralesional G+ bacilli with concurrent canine distemper virus (Weyna, 2022)
  • Poultry: two forms visceral and neural listeriosis
    • Neural- young birds
      • Hatchlings- become septic, have necrosis of multiple organs and brain has congested meninges, edema in the subarachnoid space, a few lymphocytic perivascular cuffs, extensive neuronal degeneration and satellitosis, and spongiform changes in the cerebellar arbor vitae
      • Broilers- similar histologic findings in other animals: extensive multifocal necrosis, large perivascular lymphocytic cuffs, axonal degeneration, heterophilic granulomas covered with multinucleated giant cells, diffuse gliosis, thrombosis, and hemorrhage in the brain, especially the brain stem, and spinal cord.
    • Visceral- mature birds
    • Some birds can have both
    • Septicemic form multifocal necrotizing myocarditis
  • Pet and aviary birds: listeria causes systemic disease that involves liver can infect kidney, and CNS
    • Passerine outbreak:
      • 50% mortalitiy in two weeks-multifocal necrotizing and partly granulomatous hepatitis, splenitis, myocarditis, interstitial nephritis, and exudative pericarditis.
  • Wild turkeys: 8 cases hepatocellular necrosis (3 of 8), heterophilic hepatitis (1 of 8), heterophilic granulomas (1 of 8), intrasinusoidal gram positive bacilli without hepatic lesions (1 of 8), granulomatous dermatitis (1 of 8), and/or granulomatous myocarditis, with Lymphoproliferative disease viral DNA 5/6 and reticuloendotheliosis viral DNA detected in 2/3 turkeys (Weyna, 2022)
  • Cervids: 2 cases systemic listeriosis (Weyna, 2022)
  • Cat: Recent report of L. monocytogenes infection with concurrent pleural mesothelioma (Elbert, 2021)
• Rabbits: Abortion (very susceptible), sudden death in does in advanced pregnancy; tropism for gravid uterus (adult bucks and nonpregnant does are resistant); histologic lesions include hepatic necrosis, cerebral and cerebellar microabscesses, mononuclear leptomeningitis with prominent perivascular cuffs, neuronal necrosis, cranial nerve neuritis; report in Canadian wild hares include necrotizing and fibrinosuppurative transmural metritis and septicemia
• Guinea pigs: Model of human maternal-fetal listeriosis; rarely occurs naturally, manifesting as either conjunctivitis or multisystemic disease
• Bushy-tailed jerds: Report of an acute outbreak resulting in necrotizing lesions in multiple organs and acute death without clinical signs
• Humans/nonhuman primates: causes septicemia, meningitis, and abortion; one of the most common causes of meningitis in humans
  • New-World and Old-World Monkeys: clinical disease uncommon; typically, signs include reproductive failure (abortion, stillbirth, neonatal death due to septicemia or cerebral complications); the mother displays absent to mild influenza-like symptoms; lesions most often include diffuse fibrinopurulent placentitis, and multifocal hepatic and lung necrosis of the fetus
    • Free-ranging colobus monkeys: Report of cause of death for two animals with petechial to ecchymotic hemorrhages of the intestinal tract, lymphadenopathy, and multifocal 2mm tan foci throughout the liver
• White-faced saki: Recent report of septicemic listeriosis (Struthers, 2022)
• Monotremes and marsupials: Reported in several species; in the antechinus (Australian marsupial), often associated with post mating die off of males secondary to physiological exhaustion, with multifocal pinpoint hepatic (primarily), and myocardial and adrenal necrosis, and splenic lymphoid depletion
• Pinnipeds: initial report of Listeria m in pinnipeds, severe disease including sepsis, neurological disease and abortion (Baily, 2024)

References:

• Abdul-Aziz T, Fletcher OJ. Chapter 5: Cardiovascular System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016: 146.
• Bagatella S, Tavares-Gomes L, and Oevermann A. Listeria monocytogenes at the interface between ruminants and humans: A comparative pathology and pathogenesis review. Vet Pathol. 2022; 59(2):186-210.
• Baily JL, Paterson GK, Foster G, Davison NJ, Begeman L, Hall AJ, Dagleish MP. The first report of Listeria monocytogenes detected in pinnipeds. J Comp Pathol. 2024;208:54-60.
• Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley-Blackwell; 2016:203, 226-227, 280-281.
• Cantile C, Youssef S. Nervous system. In: Maxie, MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Vol I. 6th ed. Philadelphia, PA: Elsevier Ltd; 2016:350, 362-363.
• Cline JM, Brignolo L, and Ford EW. Urogenital System. In: Abee CR, Mansfield K, Tardif S, and Morris T, eds. Nonhuman Primates in Biomedical Research, Volume 2: Diseases. 2nd ed. Waltham, MA: Elsevier; 2012:525.
• Delaney MA, Treuting PM, and Rothenburger JL. Lagomorpha In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:493.
• Delaney MA, Treuting PM, and Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:509.
• Elbert JA and Rissi DR. Systemic Listeria monocytogenes infection and concurrent pleural mesothelioma in a cat. J Vet Diagn Invest. 2021;33(1):120-123.
• Jerry CF. Liver. In: Schmidt RE, Struthers JD, and Phalen DN. Pathology of Pet and Aviary Birds. 3rd ed. Hoboken, NJ: John Wiley & Sons, Inc.; 2024:207.
• Higgins D, Rose K, and Spratt D. Monotremes and Marsupials. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:469.
• Lopez A and Martinson SA. Respiratory System, thoracic Cavities, Mediastinum, and Pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:592.
• Matz-Rensing K and Lowenstine LJ. New World and Old World Monkeys. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:362.
• Miller AD and Porter BF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO:Elsevier; 2022:966-967.
• Rissi DR, McKinney AS, Fishburn JD, Mendes RE, Velayudhan BT. Comparison of fluorescent antibody test, immunohistochemistry, and PCR testing for diagnostic confirmation of neurolisteriosis in 25 goats. J Vet Diagn Invest. 2024 Nov;36(6):896-901.
• Schlafer DH and Foster RA. Female Genital System. In: Maxie, MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Vol I. 6th ed. Philadelphia, PA: Elsevier Ltd; 2016:408-409.
• Simmons J and Gibson S. Bacterial and Mycotic Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, and Morris T, eds. Nonhuman Primates in Biomedical Research, Volume 2: Diseases. 2nd ed. Waltham, MA: Elsevier; 2012:111-112.
• Schmidt RE. Passerine Birds. In: Schmidt RE, Struthers JD, and Phalen DN. Pathology of Pet and Aviary Birds. 3rd ed. Hoboken, NJ: John Wiley & Sons, Inc.; 2024:524.
• Stanton JB and Zachary JF. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:232-234.
• Struthers JD, Kucerova Z, et al. Septicaemic Listeriosis in a White-Faced Saki (Pithecia Pithecia). J Comp Path. 2022;194:7-13.
• Swayne DE, Barnes HJ, Abdul-Aziz T, Fletcher OJ. Chapter 10: Nervous System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016: 477.
• Weyna AAW, Niedringhaus KD, Kunkel MR, Fenton HMA, Keel MK, Webb AH, Bahnson C, Radisic R, Munk B, Sánchez S, Nemeth NM. Listeriosis with viral coinfections in 8 gray foxes, 8 wild turkeys, and 2 young cervids in the southeastern United States. J Vet Diagn Invest. 2022;34(4):654-661.

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