JPC SYSTEMIC PATHOLOGY
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: Affecting approximately 80% of cerebral white matter and often centered on blood vessels, there are extensive coalescing areas of rarefaction and cavitation, with loss of neuropil (necrosis), and replacement by necrotic debris, gitter cells, fibrin, and hemorrhage. Adjacent white matter, at the interface with overlying gray matter, there is increased vacuolization (spongiosis), swollen, degenerate axons within dilated myelin sheaths (spheroids) and 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, fibrin, and few macrophages, lymphocytes, and eosinophils which expand Virchow-Robin space. The adjacent gray matter contains mild gliosis, rare neuronal necrosis with occasional satellitosis, and few small perivascular foci of hemorrhage. Multifocally, the meninges contain small aggregates of lymphocytes, plasma cells and macrophages.
MORPHOLOGIC DIAGNOSIS: Cerebrum, white matter: Necrosis, 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”
· 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 only 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
· Fumonisin (B1 most common) production in moldy corn > competitively inhibits sphinganine and sphingosine N-acyltransferase (ceramide synthase) > inhibits sphingolipid biosynthesis > increased sphinganine and sphingosine and decreased complex sphingolipids (sphingolipids are critical for maintenance of membrane structure and function in regulation of cell growth, cell-to-cell communication, differentiation, neoplastic transformation) > sphingosine inhibits L-type calcium channels that mediate:
1) Vascular tone in cerebral arterioles > inability to maintain cerebral blood pressure > vasogenic cerebral edema (ELEM)
2) Myocardial contractility > left heart failure > pulmonary edema (PPE)
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 usually within three days
· Hepatotoxic signs: Icterus, mucous membrane petechiae, facial edema, marked elevations in total bilirubin and serum AST
· Impaired cardiovascular function in experimentally induced disease in horses
TYPICAL GROSS FINDINGS:
· Liquefactive necrosis and degeneration of the subcortical white matter of one or both cerebral hemispheres, yellow-orange gelatinous malacia (due to the breakdown of lipids accompanied by hemorrhage)
· Lesions are primarily confined to the white matter, but can extend through the cortex to the meninges; regions adjacent to necrosis are edematous
· In contrast to cerebrum, when lesions extend to brainstem and spinal cord, they occur in gray matter
· Hemorrhages throughout the CNS, pleural and abdominal cavities
· Swollen, discolored (yellowish brown) liver with irregular foci or nodules scattered throughout the parenchyma
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· White matter necrosis and edema; irregular cavitations follow vasculature
· 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 of hepatocytes (similar to aflatoxicosis)
ADDITIONAL DIAGNOSTIC TESTS:
· Cerebrospinal fluid (CSF): Elevated protein, albumin, and IgG; no change in erythrocyte, leukocyte, glucose, or creatine kinase in CSF of affected horses
· 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): Cerebral hyperemia, edema, petechiation and focal necrosis
· West Nile virus (flavivirus): Lymphocytic polioencephalomyelitis in medulla oblongata, pons, basal nuclei, thalamus, mesencephalon, ventral and lateral horns of thoracolumbar spinal cord
· Rabies (rhabdovirus): Cattle and horses may hemorrhage into spinal cord
· Other: Hepatoencephalopathy, heat trauma, bacterial or parasitic meningoencephalitis, brain abscess, equine protozoal myeloencephalitis, tetanus
· Liver is a target in many species (pigs, horses, cattle, rabbits, primates)
· Other species specific target organ toxicosis: Lung (pigs), kidney (rats, rabbits, sheep), esophagus (rats, pigs); esophageal neoplasia (human); hepatocarcinogen (rats, mice)
· Pigs: Lung and liver are major targets; PPE (severe intralobular edema, hydrothorax); hepatic toxicity at much lower doses than for PPE
· Cattle: Relatively resistant to fumonisin due to different mechanism of action; mild hepatotoxicity in adults, kidney toxicity in milk-fed calves (experimental)
· Poultry: Toxic to both chickens and turkeys; decreased weight gain, diarrhea, hepatotoxicity; acute death syndrome in young chicks (“spiking mortality syndrome”) attributed to moniliformin (another mycotoxin of F. verticillioides)
· Rats: Potent renal and hepatocarcinogen
· Dogs: One reported case of meningoencephalitis caused by Fusarium solani
· Humans: Fumonisins have been associated with human esophageal cancer in areas of China and southern Africa
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