JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-B02

 

Slide A:

Signalment (JPC #1822362): 3-year-old, Yorkshire sow

 

HISTORY: This sow presented with a history of recent loss of condition, posterior weakness, and neuromuscular tics.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum at the level of the hippocampus and mesencephalon with subcommisural organ. Multifocally infiltrating the tunica adventitia and tunica media of small arteries and arterioles within the leptomeninges, cerebrum, and mesencephalon as well as filling Virchow-Robin spaces are moderate numbers of lymphocytes and plasma cells admixed with a small amount of proteinaceous fluid (edema) and scant fibrin. The leptomeninges are diffusely expanded by edema and contain ectatic lymphatics, congested blood vessels, and few hemosiderin laden macrophages. There are multifocal small areas of rarefaction characterized by edema and vacuolation of the neuropil, which are typically centered on vessels within the hippocampus and mesencephalon.

 

MORPHOLOGIC DIAGNOSIS: Cerebrum: Meningoencephalitis, lymphoplasmacytic, perivascular, multifocal, moderate, with perivascular and meningeal edema and multifocal neuropil rarefaction, Yorkshire, porcine.

 

Slide B:

Signalment (JPC #M0 4932): 3-week-old pig

 

HISTORY: This pig presented with clinical signs of a CNS disturbance. 

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum and lateral ventricle at the level of hippocampus. Within the gray matter there are multiple foci of rarefaction up to 2 mm in diameter characterized by increased pallor, increased clear space (edema), and vacuolated neuropil (spongiosis). Within these foci are few shrunken, angular, hypereosinophilic necrotic neurons and mild gliosis. Capillaries and small blood vessels are often lined by hypertrophied endothelial cells. Blood vessels are often surrounded by edema and few lymphocytes and plasma cells that occasionally infiltrate the vessel walls and expand Virchow-Robin space. Rarely, the vessel walls of small arteries and arterioles are expanded by proteinaceous fluid, fibrin, and scant cellular debris (necrotizing vasculitis). The leptomeninges are minimally expanded by low numbers of lymphocytes and plasma cells and mild edema.
 

MORPHOLOGIC DIAGNOSIS: Cerebrum: Vasculitis, necrotizing, fibrinoid, and lymphoplasmacytic, multifocal, mild, with multifocal mild neuropil rarefaction, gliosis, rare neuronal necrosis, and perivascular and meningeal edema, Yorkshire, porcine.

 

ETIOLOGIC DIAGNOSIS: Verotoxic meningitis

 

CAUSE: Shiga-like toxin type IIe (verotoxin)-producing Escherichia coli (VTEC)

 

CONDITION: Edema disease

 

SYNONYM: Enterotoxemic colibacillosis; cerebrospinal angiopathy

 

GENERAL DISCUSSION: 

• Syndrome unique to pigs
• Generally occurs after weaning (feeder piglets 6-14 weeks of age) or after a change in diet
• Disorder of rapidly growing, healthy feeder pigs being fed high energy ration
• Morbidity around 30%, with mortality approaching 100% of affected animals 
• Results in sudden death or nervous signs
• Caused by Enterohemorrhagic E. coli (EHEC); also known as Shiga toxin-producing E. coli [STEC]), which is a subset of Enteropatholgenic E. coli (EPEC) with specific O serotypes with Shiga-like toxin type IIe toxin production

 

PATHOGENESIS

• Bacterial spread via aerosols, direct contact, feed, and other vehicles
• EHEC colonization of the small intestine via F18 fimbrial mediated adherence to enterocytes > Shiga-like toxin (Stx2e) enters blood stream > toxin has affinity for endothelium expressing the receptors globotriaosylceramide (Gb3) and globotetraosylceramide (Gb4) > inhibition of protein synthesis > necrosis of endothelial and smooth muscle cells > vasogenic edema and encephalomalacia > secondary ischemia results in neuronal necrosis (especially brainstem nuclei)
• Stx2e toxin affinity for vessels in CNS, facial subcutis, colonic mesentery, and gastric cardia > damages endothelium and tunica muscularis (angiotoxin) 
• Colonization of the small intestine by specific O serotypes of E. coli (O138, O139, O140, O141):

• E. coli epithelial colonization (jejunum / ileum) is mediated by F18ab fimbriae
• Genetic susceptibility depends on the ability of E. coli to adhere to the intestine; receptors for E. coli (ie. F18) are not present in all pigs
• Diarrhea is not a common feature of edema disease, although some strains produce a secretory enterotoxin that causes diarrhea

• Enterotoxin (Shiga-like toxin type IIe [Stx2e], AKA verotoxin 2e)

• Endothelial cell sensitivity to Shiga-like toxin depends on the amount of Shiga-like toxin receptor (globotriaosylceramide and globotetraosylceramide)
• Exposure of endothelial cells to lipopolysaccharides or cytokines (TNF-alpha, IL-1) increases sensitivity of some endothelial cells to the cytotoxic effects of Stx2e
• Shiga-like toxin/verotoxin induces production of IL-8 > attracts neutrophils 

 

TYPICAL CLINICAL FINDINGS:

• Sudden death
• Subcutaneous edema, primarily of the eyelids, forehead, nose, throat (jowls), and lips; laryngeal edema may contribute to development of an abnormal “squeal”
• Nervous signs: Ataxia, convulsions, paralysis, aimless wandering and muscle tremors progressing to coma and death usually within 24 hours

 

TYPICAL GROSS FINDINGS:

• Sudden death may be associated with minimal or absence of significant lesions
• Variably severe edema may be present at multiple sites:

• CNS: Characteristic bilaterally symmetrical areas of malacia (tan-grayish discoloration) of the caudal medulla, may extend rostrally to the basal nuclei
• Integument:   Edematous subcutaneous regions may include the snout, palpebra, submandibular, and ventral trunk
• Alimentary: Edema of the stomach (especially the gastric cardia), mesentery of the spiral colon, and gallbladder
• Respiratory: Pulmonary edema with multifocal sublobular congestion; pleural effusions with white strands of fibrin; laryngeal edema
• Cardiac: Epicardial and endocardial petechiae; pericardial effusion 

• Edematous fluid is typically transparent and slightly viscous with minimal to absent hemorrhage 
• Stomach typically contains abundant ingesta with minimal digesta present in small intestine

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Edema within previously described sites of predisposition
• Degenerative/fibrinoid angiopathy/vasculitis affecting small arteries and arterioles (not a prominent feature in this case)

• Early:  Perivascular edema with protein-rich, eosinophillic droplets
• Late: Fibrinoid vascular necrosis is accompanied by infiltration of the tunica adventitia with neutrophils, lymphocytes, plasma cells and macrophages; endothelial hypertrophy; focal encephalomalacia in brainstem; necrotic foci eventually infiltrated by macrophages
• Thrombosis is usually not a feature (endothelium usually remains intact)

• Lesions are most frequent and most severe in the brainstem (caudal medulla to diencephalon) and cerebral and cerebellar meninges; spinal blood vessels also affected

 

ADDITIONAL DIAGNOSTIC TESTS:

• Culture
• Serology
• PCR

 

DIFFERENTIAL DIAGNOSIS:

For ataxia and recumbency in swine

• Pseudorabies/Aujeszky's Disease (porcine herpesvirus-1, N-V07):  Nonsuppurative meningoencephalomyelitis with ganglioneuritis, neuronal degeneration,  necrosis, and eosinophilic or basophilic intranuclear inclusion bodies  
• Bacterial meningoencephalitis (Streptococcus suis, Haemophilus parasuis. Salmonella spp.)
• Water deprivation/salt toxicity (N-T08):  Laminar cerebrocortical neuronal necrosis, with swollen astrocytes and perivascular eosinophilic cuffs in the leptomeninges
• Teschen's disease (Porcine enterovirus, N-V04):  Nonsuppurative polioencephalomyelitis
• Arsenic Toxicity:  Cerebral edema and hemorrhage from vascular necrosis,  but primarily degeneration of the peripheral and optic nerves, and the spinal cord, and a hemorrhagic gastroenteritis
• Dietary microangiopathy of swine (Vitamin E-selenium deficiency, N-M22):          Fibrinoid necrosis of small arteries and arterioles with fibrin thrombi; primary lesions include hydropericardium and cardiac hemorrhage (Mulberry heart disease) and massive hepatic necrosis (hepatosis dietetica)
• Porcine hemagglutinating encephalomyelitis virus (coronavirus):  This disease affects pigs less than a week old; nonsuppurative meningoencephalomyelitis and neuronal degeneration primarily within the gray matter of the caudal brain stem and spinal cord
• Rabies (rhabdovirus, N-V06):  Nonsuppurative encephalomyelitis with perivascular lymphocytic cuffing, gliosis and Negri bodies

 

COMPARATIVE PATHOLOGY:

 

References:

1. Cantile C, Youssef S.  Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th ed. St. Louis, MO: Elsevier, Inc: 2016: 298. 
2. Fairbrother JM, Gyles CL. Colibacillosis. In: Zimmerman JJ, Karriker LA, Ramirez A, Schwartz KJ, Stevenson GW, eds. Diseases of Swine. 10th ed. Ames, IA: Wiley-Blackwell; 2012: 735. 
3. Gal A, Castillo-Alcala F. Cardiovascular system and lymphatic vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7^th ed. St. Louis, MO: Mosby Elsevier; 2021: 689-690.      
4. Lopez A, Martinson SA. Respiratory system, thoracic cavities, mediastinum, and pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7^th ed. St. Louis, MO: Mosby Elsevier; 2021: 569.
5. Miller AD, Porter BF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6^th ed. St. Louis, MO: Mosby Elsevier; 2021: 975.
6. Spagnoli ST, Gelberg HB. Alimentary system and the peritoneum, omentum, mesentery, and peritoneal cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7^th ed. St. Louis, MO: Mosby Elsevier; 2021: 476.
7. Stanton JB, Zachary JF. Mechanisms of microbial infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7^th ed. St. Louis, MO: Mosby Elsevier; 2021: 201-2, 222-3, 234.
8. Uzal FA, Plattner BL, Hostetter JM.   Alimentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6^th ed. St. Louis, MO: Elsevier; Inc; 2016: 162-166. 
9. Welle MM, Linder KE. The integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7^th ed. St. Louis, MO: Mosby Elsevier; 2021: 1232.

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