JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

April 2023

N-V13

 

Slide A: Signalment (JPC: #1366104): 2.5‑year‑old Corriedale ewe

 

HISTORY: Prior to death, a ewe from a small flock in Connecticut had a two-month history of a unilateral head tilt.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum and thalamus: Multifocally within the periventricular white matter there are extensive areas of rarefaction and loss of neuropil (liquefactive necrosis) with replacement by numerous gitter cells, fewer reactive astrocytes, lymphocytes, rare plasma cells, and minimal hemorrhage, fibrin, and edema. Multifocally myelin sheaths are lost and replaced by gitter cells (demyelination), or are markedly dilated (spongiosis) and contain swollen axons with hypereosinophilic axoplasm (spheroids). Adjacent gray matter contains increased numbers of astrocytes and microglial cells (reactive gliosis) and numerous vessels are lined by hypertrophic endothelium (reactive) and are surrounded by moderate to high numbers of macrophages, lymphocytes, and plasma cells expanding Virchow-Robin space (perivascular cuffing). Multifocally within the gray matter and subependymal neuroparenchyma, there are few glial nodules that occasionally surround swollen or vacuolated (degenerate) neurons (satellitosis). Moderate numbers of lymphocytes and plasma cells expand the subependymal neuroparenchyma with fewer throughout the choroid plexus. 

 

MORPHOLOGIC DIAGNOSIS: Cerebrum and thalamus, white matter: Demyelination and liquefactive necrosis, multifocal, marked, with gliosis, periventricular glial nodules, and lymphoplasmacytic choroiditis, Corriedale, ovine.

 

ETIOLOGIC DIAGNOSIS: Lentiviral encephalitis

 

CAUSE: Small ruminant lentivirus subgroup A; Ovine lentivirus; Visna virus (VISNA)

 

CONDITION: Visna-maedi disease complex

 

Slide B: Signalment (JPC #2332604): Four-month-old male pygmy goat

 

HISTORY: This goat presented afebrile with posterior paresis and ataxia. The paresis progressed to the front limbs.

 

HISTOPATHOLOGIC DESCRIPTION: Brainstem (myelencephalon): Multifocally affecting the submeningeal white matter and, to a lesser extent, the periventricular region, are foci of lytic necrosis characterized by loss of neuropil and replacement by numerous gitter cells, reactive astrocytes, few lymphocytes, many variably sized acicular cholesterol clefts, and scattered eosinophilic cellular and karyorrhectic debris. There is multifocal discontinuity of the ependymal lining. Myelin sheaths are multifocally either lost (demyelination), dilated and empty, or contain eosinophilic debris and degenerate macrophages (digestion chambers). Rarely dilated myelin sheaths contain swollen axons with hypereosinophilic axoplasm (spheroids). Virchow-Robin spaces are multifocally moderately expanded by lymphocytes and macrophages, and to a lesser extent, the meninges are multifocally expanded by a similar inflammatory infiltrate. Capillaries are multifocally lined by reactive endothelium.

 

MORPHOLOGIC DIAGNOSIS: Brainstem: Leukoencephalitis, necrotizing, lymphohistiocytic, periventricular and submeningeal, multifocal, moderate, with demyelination, reactive astrocytosis, and gliosis, pygmy goat, caprine.

 

ETIOLOGIC DIAGNOSIS: Lentiviral leukoencephalitis

 

CAUSE: Small ruminant lentivirus subgroup B; Caprine arthritis-encephalitis virus

 

CONDITION: Caprine arthritis-encephalitis

 

GENERAL DISCUSSION:  

• Visna-maedi virus (VISNA) of sheep and Caprine arthritis encephalitis virus (CAEV) of goats are small-ruminant lentiviruses (SRLV) in the family Retroviridae; enveloped, single-stranded RNA viruses; some strains of virus affect both species and there is viral overlap especially in gag and pol genes
  • Lentiviruses are non-oncogenic retroviruses that cause chronic progressive disease with long incubation periods and lifelong persistent infection; SRLVs do not cause immunosuppression like other lentiviral infections
  • CAEV is SRLV subgroup B
  • VISNA is SRLV subgroup A
• SRLVs have the following viral genes:
  • pol – encodes reverse transcriptase and other enzymes
  • gag – encodes for group-specific nucleocapsid & matrix glycoproteins; detected by antibody-based tests
  • env – encodes for surface glycoprotein that mediates receptor binding and virus entry into cells; target for neutralizing antibody
  • vif, rev, and tat – encodes for regulatory proteins
• The virus causes four clinical syndromes; a single animal can show multiple forms but typically one syndrome predominates in endemic situations:
  1. Arthritis: In many herds this is the only clinical manifestation of infection; typically affects adult goats (see M-V02)
  2. Encephalomyelitis: Occurs in young goats 2-4 months old and in sheep over 2 years old (visna)
  3. Mastitis: Frequent subclinical lesion 
  4. Interstitial pneumonia: Maedi or ovine progressive pneumonia (see P-V17)
• Sheep: Pulmonary, mammary, and nervous forms are the most common
• Goats: Nervous and articular forms are typically observed 
  • Young goats (<4-6 months):  Neurological disease with ascending paralysis and nonsuppurative leukoencephalomyelitis and often interstitial pneumonia
  • Adult goats:  Animals that survive the initial infection later develop chronic, nonsuppurative arthritis and synovitis (most common presentation), mastitis (usually subclinical), and chronic interstitial pneumonia (usually subclinical)

 

PATHOGENESIS:  

• Transmission: 1) to kids via infected macrophages in milk and colostrum (most common), 2) adult to adult aerosol spread (less common in goats; more common in Maedi-Visna of sheep), and 3) in utero transmission (rare/never) à virus likely infects mucosal dendritic cells à virus to regional lymph node à virus enters macrophages likely via mannose receptor à spread to monocyte precursor cells in the bone marrow à migration to regional lymph nodes and hematogenous dissemination mainly to lung, mammary gland, CNS, and joints à dysregulation of cytokines produced by infected macrophages and lymphocytes results in lymphoid recruitment (IL-16 expression increased; TNF alpha, IL-1 beta, IL-6, and IL-12 expression are all reduced)
• The virus infects a variety of cell types including choroid plexus, mammary epithelium, fibroblasts, endothelial cells, and monocytes; however, replication primarily takes place in mature macrophages; the virus is activated when monocytes mature into macrophages and is persistent in macrophages, microglia, monocytes, and dendritic cells
• Prolonged incubation up to 2 years 
• Most goats naturally infected with CAEV are asymptomatic but remain life-long carriers, excreting virus into the environment via colostrum, milk, and respiratory secretions
• Proinflammatory cytokines from concurrent infection with other pathogens hasten disease onset
• Lesions have been shown to be at least partially immune-mediated as well as due to direct destructive effect of virus 

 

TYPICAL CLINICAL FINDINGS:  

• Most infected goats are asymptomatic
• Neurologic syndrome in sheep (>2 years old) and goats (2-4 months old):
  • Neurologic signs are due to motor spinal dysfunction without signs of cerebral disease
  • Clinical signs are progressive: Caudal ataxia and trembling of the lips à Afebrile; progressive posterior ataxia and extensor paralysis and tetraplegia à death from starvation (wasting) or secondary infection
  • Once paralytic signs develop, death is certain
  • CSF marked lymphocytosis, pleocytosis, increased protein; clinical course corresponds to degree of CSF lymphocytosis
• Arthritis: Lameness, joint effusion, enlarged carpal joints, high prevalence of carpal hygromas
• Interstitial pneumonia: Dyspnea and coughing, cachexia
• Mastitis: Udder firm, swollen; reduced milk production 

 

TYPICAL GROSS FINDINGS:  

CNS lesions:

• Typically no gross lesions
• If present: Foci of yellow-white malacia distributed randomly in the CNS, especially the spinal cord

Other lesions:

• Joints: Chronic proliferative arthritis/synovitis of carpal, stifle, hock joints; carpal hygromas
• Lung: Interstitial pneumonia most severe in caudal lobes
• Mammary gland: Indurative mastitis (“hard udder”), agalactia

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

For CNS lesions:

• Chronic inflammation and demyelination primarily involving the white matter (unlike other neurotropic viruses)
• Early inflammatory CNS lesions:
  • Intense mononuclear/lymphohistiocytic inflammation of the white matter  (leukoencephalomyelitis) with mononuclear perivascular cuffing (more prominent in kids than sheep) and gliosis; mononuclear infiltrates may form tertiary lymphoid follicles in the choroid plexus
  • Lesions begin in and just beneath the ependyma
  • Myelin remains relatively intact even within inflammatory foci at this time
  • Spinal cord grey matter may have irregular but intense nonsuppurative inflammation
• Later inflammatory CNS lesions, in paralytic and terminal animals:
  • Periventricular destruction of white matter of cerebrum and cerebellum; almost all white matter may be destroyed, leaving the grey matter relatively free of lesions
  • Inflammatory lesions may persist for years in goats that survive
• Demyelination leading to malacia:  
  • Mild to severe myelin destruction principally involving the white matter  especially of the spinal cord (most severe from mesencephalon caudally), resulting in “myelinoclastic lesions”
  • Patchy, asymmetrical, characteristically peripheral, triangular shaped demyelinated plaques with base on the pia mater; contain numerous reactive astrocytes and microglia
  • Spinal nerve roots also affected
  • Evidence of remyelination can be found
  • Not caused by progressive spread of pericentral inflammation
    • Dorsal and lateral tracts are most often involved; yet there is no selectivity for particular fiber tracts and no symmetry

 

ULTRASTRUCTURAL FINDINGS:  

• Difficult to identify virus particles via EM (most of the virus is present as a provirus)
• Demyelination with macrophages stripping myelin from axons 

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Serology (AGID or ELISA): Useful for herd-level diagnosis; can be performed on bulk tank milk
• Immunohistochemistry: Antigen is typically within macrophages in lesions
• PCR of blood, milk, or tissue
• Virus isolation

 

DIFFERENTIAL DIAGNOSIS:  

Progressive ataxia:

• Rabies (lyssavirus, N-V06): Nonsuppurative encephalomyelitis; Negri bodies

• Pseudorabies (N-V07): Intranuclear inclusion bodies in neurons and astroglia
• Scrapie (sheep, N-M08): Demonstration of scrapie prion by immunostaining; no pleocytosis of cells in the CNS; spongiform encephalopathy

• Copper deficiency (enzootic ataxia, swayback, N-T04): Axonal degeneration and

demyelination of lateral (dorsal aspect) and ventral (ventromedial aspect) funiculi of spinal cord 

• Neuronal vacuolar degeneration of Angora goats: Scrapie-like neuronopathy in young Angora goats in Australia

• Listeria monocytogenes (N-B04): Affinity for brainstem; microabscesses, vasculitis

 

COMPARATIVE PATHOLOGY:  

• Other Lentiviruses:
  • Equine infectious anemia virus (EIA) 
  • Feline immunodeficiency virus (FIV)
  • Bovine immunodeficiency virus (BIV)
  • Simian immunodeficiency virus (SIV)
  • Human immunodeficiency virus (HIV)

 

References:  

1. Cantile C, et al.  Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th ed. Philadelphia, PA: Elsevier Saunders; 2016: 378-380. 
2. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:558-560.
3. Craig 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. St. Louis, MO: Elsevier; 2016:154-155.
4. Gayo E, Polledo L, Balseiro A, et al. Inflammatory lesion patterns in target organs of visna/maedi in sheep and their significance in the pathogenesis and diagnosis of the infection. Jour Comp Pathol. 2018;159:49-56.
5. Highland, MA. Small ruminant lentiviruses: Strain variation, viral tropism, and host genetics influence pathogenesis. Vet Pathol. 2017;54(3):353-354.
6. López A, Martinson SA.  Respiratory system, mediastinum, and pleurae.  In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Mosby, Inc.; 2022:620-621.
7. Miller AD, Porter BF. Nervous system. In: Zachary JF, eds.  Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Mosby Elsevier; 2022: 969-970.
8. Nardelli S, Bettini A, Capello K, et. al. Eradication of caprine arthritis encephalitis virus in the goat population of South Tyrol, Italy: analysis of the tailing phenomenon during the 2016-2017 campaign. J Vet Diagn Invest. 2020; 32(4): 589-593.
9. Pérez M, et al. Small ruminant lentivirus-induced arthritis: Clinicopathologic findings in sheep infected by a highly replicative SRLV B2 genotype. Vet Pathol. 2015; 52(1):132-139.
10. Pinczowski P, et al. Small ruminant lentiviruses in sheep: Pathology and tropism of 2 strains using bone marrow route. Vet Pathol. 2017;54(3):413-424.
11. Vandevelde M, et al. Veterinary Neuropathology. Ames, IA: Wiley-Blackwell; 2012: 50, 58-59, 63.
12. Zachary JF.  Mechanisms of microbial infections.  In: Zachary JF, eds.  Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Mosby Elsevier; 2022:254.

 

Click the slide to view.

---