JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

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 a focally extensive, 6mm X 7mm area of rarefaction, predominantly affecting the gray matter, characterized by loss of neuropil, proteinaceous fluid accumulation and abundant clear space (edema). This focus is infiltrated by abundant viable and degenerate neutrophils, fewer gitter cells, lymphocytes, and abundant cellular and karyorrhectic debris (necrosis). Within surrounding, less affected areas are numerous nodules of viable and degenerate neutrophils that are occasionally centered on a focus of liquefactive necrosis (microabscesses), spongiosis, and swollen axons (spheroids) within dilated myelin sheaths. Multifocally, vascular endothelial cells are hypertrophied and vessel walls are transmurally expanded by neutrophils, fibrin, and cellular and karyorrhectic debris (fibrinonecrotizing vasculitis). Multifocally, Virchow-Robin space and to a lesser extent the leptomeninges are expanded up to three times normal by lymphocytes, plasma cells, and macrophages with few neutrophils.

 

MORPHOLOGIC DIAGNOSIS: Brainstem: Meningoencephalitis, necrosuppurative, subacute, multifocal, moderate, with fibrinonecrotizing vasculitis, microabscesses, and mononuclear perivascular cuffing, Holstein, bovine. 

 

ETIOLOGIC DIAGNOSIS: Listerial meningoencephalitis

                       

CAUSE: Listeria monocytogenes

 

CONDITION: Listeriosis, “Circling disease”

 

GENERAL DISCUSSION:   

• Gram-positive, small (0.4-0.5um x 0.5-2um), 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 dies 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 à phagocytized and grows within splenic and hepatic macrophages à 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; lesions most severe in the medulla and pons
    • Commonly, extensive tissue destruction associated with suppurative inflammation
    • 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 rumenal 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
• Immunohistochemistry: bacteria in axons, neurons, endothelium, and microabscesses 

 

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:   

• Sheep and goats: common
• Horses, swine, dogs, and rodents: less common
• 
  
  • Horses:  abortion in mares; septicemia in foals
  • Dogs:  encephalitis
  • Backyard poultry: L. monocytogenes has been reported as a cause of infectious mortality in backyard poultry within 8 states in the US (Cadmus, J Vet Diagn Invest 2019)
  • Cat: Recent report of L. monocytogenes infection with concurrent pleural mesothelioma (Elbert, J Vet Diagn Invest 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: used as a 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, J Comp Path 2022)

 

References:

1. 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.
2. Barthold SW, Griffey SM, Percy DH.  Pathology of Laboratory Rodents and Rabbits.  4th ed.  Ames, IA: Wiley-Blackwell; 2016: 203, 226-227, 280-281.
3. Cadmus KJ, Mete A, Harris M, et al.  Causes of mortality in backyard poultry in eight states in the United States.  J Vet Diagn Invest. 2019;31(3):318-326.
4. 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; 2016:362-363.
5. 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. 2^nd ed. Waltham, MA: Elsevier; 2012: 525.
6. 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.
7. 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.
8. 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.
9. 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.

1. 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.
2. 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.
3. 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.

13. 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.
14. 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. 2^nd ed. Waltham, MA: Elsevier; 2012: 111-112.

16. Struthers JD, Kucerova Z, et al. Septicaemic Listeriosis in a White-Faced Saki (Pithecia Pithecia).  J Comp Path. 2022;194:7-13.

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