JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2026

N-B01

 

Signalment (JPC #1292462): A sheep

 

HISTORY: This sheep presented with hyperesthesia. Significant lesions included a pale-yellow liver and kidneys. The brain was grossly normal.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum: Affecting ~ 20% of the tissue section, there is multifocal liquefactive necrosis that is predominantly within the cerebral white matter with focal extension into the cortical gray matter. Liquefactive necrosis is characterized by loss of tissue architecture that is replaced by cellular and karyorrhectic debris, edema, numerous gitter cells, and fewer lymphocytes and plasma cells. Gitter cells have abundant foamy cytoplasm and phagocytized debris. At the periphery of the areas of rarefaction there is vacuolation of the neuropil. In the adjacent less affected white matter, there are many dilated myelin sheaths that contain swollen, pale eosinophilic axons (spheroids) and myelin debris. Affected regions are surrounded by increased numbers of gitter cells, reactive astrocytes, and oligodendrocytes (gliosis). Vessels are multifocally congested, lined by hypertrophic endothelial cells, and there is marked expansion of Virchow-Robins space by increased clear space and occasional bright eosinophilic proteinaceous fluid (edema). Less frequently there is expansion of vessel walls by eosinophilic plasma proteins (hyalinization). The meninges are moderately expanded by edema and few lymphocytes and plasma cells.

 

MORPHOLOGIC DIAGNOSIS: Cerebrum: Encephalomalacia, subacute, multifocal, marked, with perivascular edema, gliosis, myelin degeneration, and spheroids, breed not specified, ovine.

 

CAUSE: Clostridium perfringens type D epsilon toxin

 

ETIOLOGIC DIAGNOSIS: Clostridial enterotoxemic encephalomalacia

 

CONDITION: Focal symmetrical encephalomalacia

 

SYNONYMS: Clostridium perfringens type D encephalopathy, pulpy kidney disease, overeating disease, blind staggers, enterotoxemia

 

GENERAL DISCUSSION:

• C. perfringens are gram positive, anaerobic bacteria classified into 5 major types (A, B, C, D, and E), based on the production of 4 major lethal toxins:
• Type A – alpha toxin
• Type B – alpha toxin, beta toxin, and epsilon toxin
• Type C – alpha toxin and beta toxin
• Type D – alpha toxin and epsilon toxin
  • Epsilon toxin (ETX) is the third most potent clostridial toxin (after botulinum and tetanus toxins)
  • Some isolates produce up to five different toxins, which may also play a role in virulence, although ETX is necessary to induce disease
• Type E – alpha toxin and iota toxin
• Type F – alpha toxin and C. perfringens enterotoxin (CPE)
• Type G – alpha toxin and netB toxin
• Clostridium perfringens type D is a commensal bacteria in the intestinal tract of most ruminants; it causes sporadic disease in lambs and sheep (sheep most commonly exhibit the neurologic manifestations of the disease)
• Often a sequela to overeating disease and enterotoxemia in sheep, although enterocolitis is not usually a characteristic feature as it is in goats 
• Sheep of all ages are susceptible; however, newborns typically unaffected as they lack pancreatic proteolytic enzymes (trypsin and trypsin-chymase) necessary for activation of the epsilon toxin (trypsin inhibitors in colostrum prevent breakdown of immunoglobulins during passive transfer)
• There have been recent reports of enterotoxemia affecting newborns due to lambda toxin-positive strains (protease that activates ETX) (Acevedo, 2023) (Moctezuma, 2025)

 

PATHOGENESIS:

• Alterations in intestinal environment due to sudden diet changes (e.g. sudden feeding of large amounts of grain or lush pastures) > inadequate ruminal flora for digestion of starch > undigested starch passes into intestine and acts as a substrate for bacteria, promoting C. perfringens type D growth >  C. perfringens type D proliferation > glucose in environment is low due to poor digestion of feed > decreased glucose stimulates Epsilon exotoxin production > activated by trypsin cleavage > facilitates its own absorption through the intestinal mucosa > endothelial damage and increased vascular permeability (especially in lungs and brain) > vasogenic brain edema > hypoxic-ischemic necrosis
• ETX binding to endothelial cells results in:
• Opening of tight junctions
• Disturbed transport processes
• Increased vascular permeability
• Swelling of astrocytic foot processes
• Necrosis due hypoxic-ischemic mechanisms
• Some effects of ETX are mediated by the adenyl cyclase/cAMP system
• ETX also causes microvascular endothelial injury in the retina leading to vasogenic edema; large doses of toxin may cause visual deficits

 

TYPICAL CLINICAL FINDINGS:

• Two clinical courses:
• Acute form: Sudden death; 3-10 week-old, fast-growing lambs on a high nutritional plane or with a sudden change in feed (e.g. feedlot) are most commonly affected by type D enterotoxemia
• Subacute or chronic form: Focal symmetric encephalomalacia; occasionally signs of enterocolitis precede CNS signs; affects older sheep; similar signs to lambs, but more consistent and advanced; some develop CNS signs including blindness, ataxia, head pressing, seizures, and death; mild intestinal signs
• Hyperglycemia is common; glucosuria is a useful but non-specific diagnostic indicator when detected 

 

TYPICAL GROSS FINDINGS:  

• Subacute/chronic form: focal, bilaterally symmetric encephalomalacia:
• Corpus striatum, thalamus, cerebellar peduncles most common
• White matter is preferentially affected
• Cerebellar coning (herniation of the cerebellar vermis)
• Pulmonary edema 
• Pericardial, thoracic, abdominal fluid with fibrin
• Serosal petechiation (epicardium, endocardium, thymus, intestines, renal cortex)
• Occasionally soft, “pulpy” kidneys (U-B06), but this is nonspecific

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Sharply demarcated areas of focal symmetrical encephalomalacia (FSE); degeneration of white matter, hemorrhage, astrocyte and axonal swelling with spheroid formation
• Perivascular protein-rich edema (microangiopathy), surrounding small and medium sized arteries and veins, is seen in 90% of cases and is considered diagnostic in sheep; with hypertrophied vascular endothelium and hyalinization of arteriolar walls
• Perivascular edema and FSE are always bilateral and roughly symmetrical; most common in corpus striatum, thalamus, midbrain, cerebellar peduncles, and cerebellar white matter
• Neuropil interstitial (vasogenic) edema – light-pink, spongy appearance to CNS parenchyma
• Infiltrates of lymphocytes and plasma cells in Virchow-Robin space 
• Intestinal erosion and congestion and cardiac Purkinje fiber degeneration, with subepicardial and subendocardial hemorrhage
• Kidneys: nonspecific hemorrhage/edema (Giannitti, 2023)
• Heart: subepicardial/endocardial hemorrhage and degeneration in the Purkinje network

 

ULTRASTRUCTURE

• Severe damage to vascular endothelium; swelling of protoplasmic astrocytes foot processes around blood vessels and the processes around neurons are most severely swollen

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Detection of epsilon toxin of C. perfringens type D in intestinal contents or other tissue fluids; gram-stained smears of intestinal mucosa
• History, clinical signs, and histopathologic lesions in brain

 

DIFFERENTIAL DIAGNOSIS: 

• Listerial encephalitis (N-B04):  Perivascular cuffs, neutrophils (microabscesses), glial nodules, +/- vasculitis, +/- presence of bacteria
• Lead toxicity (N-T05):  Cerebral edema with endothelial/vascular damage; laminar necrosis and astrocytosis of deep cortical gray matter; focal malacia of basal nuclei and brain stem
• Infarction due to emboli; ischemic encephalomyelopathy

 

COMPARATIVE PATHOLOGY:  

• C. perfringens associated with acute gastric dilatation in NHPs
• C. perfringens type D is also reported in cattle and goats:
• Calves:  Similar age, clinical signs to lambs, with variable degrees of perivascular proteinaceous edema in the internal capsule, thalamus, and cerebellum (white – grey matter junction and granular layer)
• Recent report of microangiopathy in a calf, associated with C. perfringens type D- epsilon toxin detected in intestinal contents
• Goats:  Diarrhea and severe abdominal discomfort are the most common clinical signs; CNS lesions (similar to those in sheep) are reported but rare
• Lesions usually confined to gastrointestinal tract: fibrinonecrotic enterocolitis
• Recent report of 2 neonatal kids with enterotoxemia caused by C. perfringens type D; isolate encoded gene for lambda toxin, a protease that may allow activation of ETX in neonates (Acevedo, 2023)
• Diseases caused by C. perfringens:

 

Clostridium perfringens – Types, toxins, and diseases
Type	Toxin						Diseases
	Alpha	Beta	Epsilon	Iota	CPE	NetB
A	+	-	-	-	-	-	Gas gangrene Yellow lamb disease – enterotoxemia (western US) Colitis X – horses Hemorrhagic bowel syndrome – dairy cattle Food Borne Illness - humans Necrotic enteritis - chickens Gastroenteritis - ferrets  Necrotizing enterocolitis-piglets Enterotoxemia-calves and lambs Canine hemorrhagic gastroenteritis
B	+	+	+	-	-	-	Lamb dysentery Hemorrhagic enteritis – calves, foals, GPs (UK, S. Africa, Middle East) Hemorrhagic enterotoxemia-sheep
C	+	+	-	-	+/-	-	Enterotoxic hemorrhagic enteritis - neonatal lambs, goats, cattle, pigs Struck – adult sheep, hemorrhagic enteritis & peritonitis (UK)
D	+	-	+	-	+/-	-	Overeating disease/pulpy kidney - Sheep, cattle, goats Enterocolitis-goats Focal symmetric encephalomalacia – Sheep, goats
E	+	-	-	+	+/-	-	Enterotoxemia - calves, lambs. guinea pigs, rabbits Enteritis-lagomorphs
F	+	-	-	-	+	-	Food borne illness - humans
G	+	-	-	-	-	+	Necrotic enteritis in chickens
Table adapted from Barker et al, 1993 p.237 & Jones et al, 1997 p. 421 & Rood, Uzal et al., Anaerobe 2018

 

 

References:  

1. Acevedo HD, Schlesinger MS, Streitenberger N, Henderson E, Asin J, Beingesser J, Uzal FA. Enterotoxemia produced by lambda toxin-positive Clostridium perfringens type D in 2 neonatal goat kids. J Vet Diagn Invest. 2023;35(4):448-451. 
2. Agnew D. Camelidae. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:198
3. Gelberg HB. Alimentary system and the peritoneum, omentum, mesentery and peritoneal cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:398.
4. Giannitti F, García JP, Adams V, Armendano JI, Beingesser J, Rood JI, Uzal FA. Experimental acute Clostridium perfringens type D enterotoxemia in sheep is not characterized by specific renal lesions. Vet Pathol. 2023;60(4):412-419.
5. Giannitti F, García JP, Rood JI, Adams V, Armendano JI, Beingesser J, Uzal FA. Cardiopulmonary Lesions in Sheep Produced by Experimental Acute Clostridium Perfringens Type D Enterotoxemia. Vet Pathol. 2021;58(1):103-113.
6. Manavis, J, Blumbergs P, Jerrett I, Hanshaw D, Uzal F, Finnie J. Heterogeneous immunoreactivity of axonal spheroids in focal symmetrical encephalomalacia produced by Clostridium perfringens type D epsilon toxin in sheep. Vet Pathol. 2022;59(2):328-332.
7. Matz-Rensing K, Lowenstine LJ. New World and Old World Monkeys. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:363.
8. Miller AD and Porter BF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 974-975.
9. Moctezuma K, Acevedo HD, Henderson EE, Asin J, Adaska JM, Uzal FA. Enterotoxemia in a 2-day-old lamb produced by a Clostridium perfringens type D lambda toxin-positive strain. J Vet Diagn Invest. 2025;37(3):504-506.
10. Simmons J, Gibson S. Bacterial and mycotic diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research Volume 2: Diseases. 2nd ed. London, UK: Academic Press; 2012:122-123.
11. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsev5ier Ltd; 2015:188-191.

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