JPC SYSTEMIC PATHOLOGY
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: There is multifocal liquifactive necrosis within the white matter of the internal capsule with focal extension into the gray matter, characterized by loss of tissue architecture, scattered cellular and karyorrhectic debris, edema, numerous gitter cells with abundant foamy cytoplasm and phagocytized debris, and few lymphocytes and plasma cells. At the periphery of the areas of rarefaction, there is spongiosis, characterized by vacuolation of the neuropil admixed with many dilated axon sheaths with swollen, pale, eosinophilic axons (spheroids) that are surrounded by increased numbers of glial cells (gliosis). Vessels are multifocally congested with marked expansion of Virchow-Robins space by increased clear space and proteinaceous fluid (edema) and plump, reactive endothelial cells. The meninges are moderately expanded by edema and few lymphocytes and plasma cells.
MORPHOLOGIC DIAGNOSIS: Cerebrum, internal capsule: Leukoencephalomalacia, multifocal, with gitter cells, axonal spheroids, gliosis and perivascular edema, 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
· Clostridium perfringens type D is a gram positive, anaerobic commensal bacteria in the intestinal tract of most ruminants; it causes sporadic disease in lambs and sheep
· Reported in cattle and goats but only sheep 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; two clinical courses:
· Acute form: Sudden death
· Subacute or chronic form: Focal symmetric encephalomalacia; occasionally signs of enterocolitis precede CNS signs
· C. perfringens is classified into 5 major types (A, B, C, D, and E), based on the production of 4 major lethal toxins:
- Type A produces alpha toxin
- Type B produces alpha toxin, beta toxin, and epsilon toxin
- Type C produces alpha toxin and beta toxin
- Type D produces alpha toxin and epsilon toxin
o Epsilon toxin (ETX) is the third most potent clostridial toxin (after botulinum and tetanus toxins)
o 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 produces alpha toxin and iota toxin
· Sheep of all ages, except newborns, are susceptible; newborns lack pancreatic proteolytic enzymes necessary for activation of the epsilon toxin; trypsin inhibitors in colostrum
· Presence of undigested starch in small intestine stimulates growth of Clostridium perfringens type D; however, absence of glucose stimulates epsilon toxin production
· Alterations in intestinal environment due to diet changes such as sheep fed on diets high in fermentable carbohydrates (lush spring pastures or high grain diet) > some starch passes into intestine and acts as a substrate for bacteria> C. perfringens type D proliferation > 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-ishemic mechanisms
· Some effects of ETX are mediated by the adenyl cyclase/cAMP system
· ETX binds receptors on distal renal tubular epithelial cells> renal tubular degeneration; however rapid postmortem autolysis may also play a role in “pulpy” kidneys
· ETX also causes microvascular endothelial injury in the retina leading to vasogenic edema; large doses of toxin may cause visual deficits
· Recently shown that ETX binds directly to mouse cell body and dendrites of granule cells and oligodendrocytes but not astrocytes; toxin may also be directly toxic to these cells
· Gene for epsilon toxin (and many other clostridial toxins) located on plasmids (extrachromosomal DNA molecules that are usually circular)
· Plasmids can self-replicate and are distributed to daughter cells by conjugation (typically via a pilus) when the bacterium divides
· Vaccination of ewes before lambing imparts passive protection in lambs
TYPICAL CLINICAL FINDINGS:
· Hyperglycemia is common; glucosuria is a useful but non-specific diagnostic indicator when detected
· 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: sudden death
· 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; renal autolysis is less rapid, so kidneys less “pulpy”
TYPICAL GROSS FINDINGS:
· Subacute/chronic form- focal, bilaterally symmetric encephalomalacia:
· Corpus striatum, thalamus, cerebellar pedunclesmost 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)
· Characteristic soft, “pulpy” kidneys
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Sharply demarcated areas of focal symmetrical encephalomalacia (FSE); degeneration of white matter, hemorrhage, astrocyte and axonal swelling
· Perivascular protein-rich edema (microangiopathy), surrounding small and medium sized arteries and veins, is seen in 90% of cases (though not a prominent feature in this case) 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
· Severe damage to vascular endothelium; swelling of protoplasmic astrocytes
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
· Listerial encephalitis: Perivascular cuffs, neutrophils (microabscesses), glial nodules, +/- vasculitis, +/- presence of bacteria
· Lead toxicity: 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
· Calves: Similar age, clinical signs, 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
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