JPC SYSTEMIC PATHOLOGY
NERVOUS SYSTEM
March 2023
N-T10
Signalment (JPC #1640747): A horse
HISTORY: This horse died following sudden onset of a neurological syndrome characterized by drowsiness, visual impairment, partial pharyngeal paralysis, weakness, staggering, and circling.
HISTOPATHOLOGIC DESCRIPTION: Cerebrum, cerebral cortex: Affecting approximately 80% of cerebral cortical white matter and often centered on blood vessels, there are extensive coalescing areas of rarefaction and cavitation, with loss of neuroparenchyma and replacement by necrotic debris, gitter cells, fibrin, hemorrhage, and edema (liquefactive necrosis). Adjacent white matter, at the interface with overlying gray matter, is characterized by increased vacuolization (spongiosis), dilated myelin sheaths that contain swollen, degenerate axons (spheroids), and increased glial cells (gliosis) including moderate numbers of reactive, sometimes gemistocytic astrocytes. Blood vessels are congested, lined by markedly reactive endothelium, and surrounded by abundant eosinophilic proteinaceous fluid (edema), hemorrhage, and fibrin. Few macrophages, lymphocytes, and eosinophils expand Virchow-Robin space. The adjacent gray matter is characterized by mild gliosis, rare neuronal necrosis with occasional satellitosis, and few small perivascular foci of hemorrhage, fibrin, and edema. Multifocally, the leptomeninges contain small aggregates of lymphocytes, plasma cells, and macrophages.
MORPHOLOGIC DIAGNOSIS: Cerebrum, cortical white matter: Necrosis, liquefactive, multifocal to coalescing, with cavitation, spongiosis, gliosis, hemorrhage, and edema, breed unspecified, equine.
ETIOLOGIC DIAGNOSIS: Mycotoxic leukoencephalomalacia
CAUSE: Fumonisin B1 mycotoxin
CONDITION: Equine leukoencephalomalacia (ELEM); “Moldy corn poisoning”
GENERAL DISCUSSION:
- Mycotoxicosis caused by fumonisin B1 is usually associated with consumption of moldy corn contaminated with the saprophytic fungus Fusarium verticillioides (formerly F. moniliforme) or F. proliferatum
- Isolated fumonisins include: B1, B2, B3, B4, A1, and A2; only B1 and B2 appear to be toxic, and B1 is considered most important
- Many species are susceptible to fumonisins, with the liver being a target in all species; leukoencephalomalacia is produced in equids (horses, donkeys, mules)
- Two most important syndromes associated with fumonisins are ELEM in equids, and porcine pulmonary edema (PPE) in swine
- Outbreaks of ELEM are seasonal, late fall through early spring, most common when a dry growing season is followed by a wet period
- Horses get leukoencephalomalacia at low doses of fumonisins and (less frequently) hepatotoxicity at high doses
PATHOGENESIS:
- Fumonisin (B1 most common) produced in moldy corn > competitively inhibits sphinganine and sphingosine N-acyltransferase (same as ceramide synthase) > inhibits sphingolipid biosynthesis > buildup of sphinganine and sphingosine and decreased synthesis of sphingolipids (sphingolipids are critical for maintenance of membrane structure and function in regulation of cell growth, metabolism, cell-to-cell communication, differentiation, neoplastic transformation) > sphingosine inhibits L-type calcium channels that mediate:
- Vascular tone in cerebral arterioles > inability to maintain cerebral blood pressure > vasogenic cerebral edema (ELEM in horses)
- Myocardial contractility > left heart failure > pulmonary edema (PPE in swine)
- Fumonisins are also associated with lipid peroxidation of cellular membranes and inhibiting synthesis of macromolecules and DNA.
TYPICAL CLINICAL FINDINGS:
- Clinical manifestations in horses depend on dose, duration of exposure (~1 month or longer), and tolerance of individual to fumonisin; most common manifestations relate to neurologic and hepatic toxicosis
- Neurologic signs: Acute onset depression or hyperexcitability, blindness, pharyngeal paralysis, paresis, ataxia, circling; death in 2-3 days; no recovery from clinical signs
- Hepatotoxic signs: Icterus, mucous membrane petechiae, facial edema, marked elevations in total bilirubin and serum AST
- Impaired cardiovascular function (cardiotoxicity)
TYPICAL GROSS FINDINGS:
- Lesions are primarily confined to the white matter of the frontal and parietal lobes, but can extend through the cortex to the meninges; regions adjacent to necrosis are edematous
- Brain swelling can be marked, with flattening of the cerebrocortical gryi
- Liquefactive necrosis and degeneration of the subcortical white matter of one or both cerebral hemispheres, yellow-orange gelatinous malacia (color due to the lipid breakdown and hemorrhage); lesions often bilateral, though not symmetric
- In contrast to cerebrum, when lesions extend to brainstem and spinal cord, they occur in gray matter
- Microcirculatory damage: hemorrhages throughout the CNS, pleural, and abdominal cavities
- Swollen, discolored (yellowish brown) liver with irregular foci or nodules scattered throughout the parenchyma. Alternatively, small liver due to hepatic fibrosis.
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- White matter necrosis and edema; +/- bilateral, irregular cavitations follow damaged vasculature with eosinophilic proteinaceous fluid
- Transition zone between rarefied and normal neuropil is characterized by perivascular hemorrhage and edema, congestion, satellitosis, and neuronophagia
- Blood vessels: Vessel walls degenerate, necrotic, infiltrated with neutrophils, plasma cells, eosinophils +/- thrombosis; adventitia may be thickened, especially in the brainstem; cellular infiltrates extend to perivascular spaces
- Liver: Centrilobular necrosis and fibrosis, portal fibrosis, bile stasis, bile duct proliferation, and fatty deposition in hepatocytes (similar to aflatoxicosis)
ADDITIONAL DIAGNOSTIC TESTS:
- Cerebrospinal fluid (CSF): Elevated protein, albumin, and IgG; no change in erythrocyte, leukocyte, glucose, or creatine kinase
- Definitive diagnosis: Demonstration of fumonisin B1 and/or B2 in feed via high performance liquid chromatography (HPLC) or ELISA
- Sphinganine to sphingosine (Sa:So) ratio: Increases in horses and pigs exposed to fumonisin and may be useful when feed analysis not available
DIFFERENTIAL DIAGNOSIS:
Equine encephalitides:
- Equine herpes virus type I myeloencephalopathy (EHV-1): Brain and spinal cord; leptomeningeal congestion, hemorrhage, malacia
- EEE, VEE, and WEE (alphavirus, togaviridae; N-V09): Cerebral hyperemia, edema, petechiation and focal necrosis
- West Nile virus (flavivirus; N-V19): Lymphocytic polioencephalomyelitis in medulla oblongata, pons, basal nuclei, thalamus, mesencephalon, ventral and lateral horns of thoracolumbar spinal cord
- Rabies (rhabdovirus; N-V06): Cattle and horses may hemorrhage into spinal cord
- Other: Hepatoencephalopathy, heat trauma, bacterial or parasitic meningoencephalitis, brain abscess, equine protozoal myeloencephalitis, tetanus
COMPARATIVE PATHOLOGY:
Fumonisin toxicity in other species:
- Liver is a target in many species (horses, pigs, cattle, sheep, baboons, rabbits)
- Other species-specific target organ toxicosis: Lung (pigs), kidney (horses, cattle, sheep, rabbits, rats), esophagus (pigs, rats)
- Pigs: Lung, liver, kidney are major targets; porcine pulmonary edema (severe interlobular edema, hydrothorax); death typically 1-10 days after onset of clinical signs, hepatic megalocytosis. In pigs liver affected at low doses, then lung (pulmonary edema) at higher doses of fumonisins; cardiotoxicity is also reported
- Cattle: Relatively resistant to fumonisin due to different mechanism of action; mild hepatotoxicity in adults, kidney toxicity in milk-fed calves (experimental)
- Rats: Hepatocellular carcinomas in laboratory rats
- Poultry
- Turkeys: Increase in hepatic sphinganine to sphingosine ratio in turkeys fed diets containing FB, with no apparent consequences
- Chickens and turkeys: Decreased bodyweight gain, diarrhea, hepatotoxicity
- Chicks: Spiking mortality syndrome (likely associated with moniliformin toxin of F. verticillioides)
- White-tailed deer: Leukoencephalomalacia associated with fumonisin toxicosis reported
- Liver lesions in equine fumonisin toxicity resemble aflatoxicosis in other species (D-T03)
- Fumonisin B1 and B2 induce lymphocytolysis in the thymic cortex (unclear species predilection, PBVD 7th Ed.)
References:
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