JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-M19 (NP)

 

Signalment (JPC #1852981): A 4-year-old Rhesus macaque

 

HISTORY: After a week of water deprivation, this animal drank water heavily but ate poorly.   Over the course of a week, it became depressed and died despite supportive care.

 

HISTOPATHOLOGICAL DESCRIPTION: Cerebrum, cortex: Diffusely in the meninges and multifocally in the white and gray matter, veins are dilated up to 1mm, are congested, and are often partially to completely occluded by fibrin thrombi. Occasionally, the walls of the thrombosed veins are expanded by hyalinized fibrin and edema (fibrinoid change), and affected vessels are lined by variably hypertrophied endothelium (reactive). Multifocally within the white matter surrounding affected veins, there are moderate numbers of gemistocytes, increased numbers of microglial cells (microgliosis), and hemosiderin-laden macrophages admixed with hemorrhage, fibrin, and edema. There is mild vacuolation in the adjacent white matter (edema) and rare swollen, rounded, hypereosinophilic axons (spheroids).   

 

MORPHOLOGIC DIAGNOSIS: Cerebrum, veins: Thrombosis, multifocal, moderate, with congestion, vascular fibrinoid change, hemorrhage, hemosiderosis, gemistocytosis, and rare spheroids, rhesus macaque, nonhuman primate. 

 

CONDITION: Idiopathic cerebral venous thrombosis

 

GENERAL DISCUSSION:

 

PATHOGENESIS:

• The etiology is unknown but it has been reported with diseases leading to hypercoagulability such as diarrhea and water deprivation; it can also be an incidental finding at necropsy
• Hypovolemia/endotoxemia from colitis > vasodilatation, vascular stasis, and elaboration of inflammatory cytokines (TNF and IL-1) > activation of the clotting cascade and thrombosis > venous occlusion > perivascular edema, infarction, demyelinating lesions
• Proposed that degenerate axonal terminals in center of lesion release excessive amounts of neurotransmitter glutamate leading to injury of still viable neurons on periphery; glutamate binds to viable neuron > calcium flows into cell > cell death
• Neurons (especially Purkinje cells) and oligodendroglia are most sensitive to ischemia; astrocytes are moderately resistant; microglia and blood vessels are most resistant
• Gray matter and deeper lamina are more sensitive to ischemia than white matter and superficial lamina due to higher metabolic rate and dependence on oxygen

 

TYPICAL CLINICAL FINDINGS:

• Signs reflect the primary disease present and the location and extent of injury; can range from nonexistent to moderate
• CNS signs include depression, ataxia, loss of reflexes or proprioception, and seizures; diarrhea common
• CSF usually normal

 

TYPICAL GROSS FINDINGS:

• Due to normal CNS physical characteristics (abundance of lipid and lack of fibrous connective tissue), gross lesions become soft due to liquefactive necrosis; gray matter lesions tend to be hemorrhagic and white matter lesions tend to be soft due to less dense capillary meshwork
• Multifocal congestion, thrombi, hemorrhage, and malacia occurs primarily in the white matter of the cerebrum and may rarely occur in the cerebellum
• Typically bilateral, but not always symmetrical 
• With chronicity, affected region is depressed, shrunken, variably cystic, often dark brown-yellow

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Common to see acute and chronic lesions; chronic lesions may be characterized by recanalization of thrombi adjacent to acute lesions
• Major CNS lesions include multiple cerebral and dural thrombi, hemorrhage, fibrin, perivascular demyelination, reactive gemistocytic astrocytes

 

DIFFERENTIAL DIAGNOSIS:

• Venous infarcts have more extensive hemorrhage and affect the white matter; arterial infarcts usually affect the gray matter due to its high metabolic rate
• Cerebral infarction (see N-M25): More often associated with arteries; results in cerebral necrosis, with less extensive hemorrhage than venous lesions 
  • With loss of blood supply, neurons undergo irreversible damage within 3 to 4 minutes (Kumar, Pathologic Basis of Veterinary Disease, 2015) 

 

COMPARATIVE PATHOLOGY:

Thrombotic/ischemic CNS conditions in other animals:

• Horse
  • Equine herpesvirus-1 (EHV-1; see P-V10):  May have "strokes" secondary to necrotizing vasculitis and thrombosis; characteristic lesion is non-suppurative necrotizing vasculitis and thrombosis
  • Neonatal maladjustment syndrome (“barker foal” syndrome):  Lesions range from perivascular and petechial hemorrhage throughout the brain to ischemic laminar necrosis of the cerebral cortex with necrosis in paired grey nuclei of brainstem; etiology is unknown
  • Strongylus aberrant larval migration:  Thrombosis of superior sagittal and transverse sinuses
• Dog
  • Cerebral infarction secondary to venous thrombosis associated with metastatic carcinoma
  • Cerebral infarction due to aberrant migration of Dirofilaria immitis
  • Amyloid degeneration of meningeal and cerebral vessels occurs in aged dogs
  • Atherosclerosis secondary to hypothyroidism or diabetes mellitus
  • Vasculitis associated with systemic lupus erythematosus (see I-M28), or Rocky Mountain spotted fever (Rickettsia rickettsia; see N-B09)
  • Steroid-responsive meningo-arteritis (polyarteritis nodosa) has a predilection for spinal arteries (AKA “beagle pain syndrome”)
  • Fibrocartilaginous embolism (N-M03) primary affects spinal cord

 

• Cat
  • Feline ischemic encephalopathy (see N-M23):  Unilateral, ischemic neuronal necrosis within the hippocampus +/- brainstem; associated with Cuterebra larval migration; more severe lesions tend to be around the middle cerebral artery
• Pig
  • Organomercurial poisoning (N-T07):  Hyaline necrosis of meningeal vessels
  • Polyarteritis nodosa:  Predilection for the cerebral arteries
  • Edema disease (N-B02, Shiga-like toxin producing Escherichia coli):  Important cause of cerebrospinal angiopathy
• Cattle
  • Noninflammatory thrombosis of the cranial dural sinuses associated with polioencephalomalacia (N-T02) and head injuries
  • Thrombotic meningoencephalitis (Histophilus somni, see N-B03):  Vasculitis, thrombosis and neutrophilic inflammation

 

References:

1. Cantile C, Youssef S.  Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:296-301.
2. Fahey MA, Westmoreland SV. Nervous system disorders of nonhuman primates and research models. In: Abee CR, Mansfield K, Tardif S, et al., eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2nd ed. London, UK: Elsevier; 2012:756-757.
3. Harber ES, O’Sullivan MG, Jayo MJ, et al. Cerebral infarction in two cynomolgus macaques (Macaca fascicularis) with hypernatremia. Vet Pathol. 1996;33(4):431-434.
4. Musio F, Older SA, Jenkins T, et al. Case report: Cerebral venous thrombosis as a manifestation of acute ulcerative colitis. Am Jour Med Scien. 1993;305(1):28-35.
5. Swayne DE, Tyler DE, Batker J. Cerebral infarction with associated venous thrombosis in a dog. Vet Pathol. 1988;25(4):317-320.

 

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