Pathology in Practice

Daniel R. Rissi Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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 DVM, PhD, DACVP
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Leonardo Susta Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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 DVM, PhD, DACVP

History

In November 2010, a 1-year-old mixed-breed gelding from northern Georgia was submitted for necropsy after a 5-day history of climbing the stable wall and progressive blindness. According to the owner, another horse from the same farm had developed blindness and stupor a few days before. Both horses had been fed grain with large amounts of locally produced corn and died without medical intervention.

Clinical and Gross Findings

At necropsy, the most striking gross changes were observed in the brain. In the left cerebral hemisphere, throughout the corona radiata at the level of the basal nuclei and extending into the thalamus, there were multifocal to coalescing, irregular, depressed, and soft areas of cavitation (malacia) associated with hemorrhage (Figure 1). The adjacent parenchyma was compressed, swollen, and yellow owing to accumulation of fluid. Other changes observed on external examination were consistent with self-induced trauma and included conjunctival edema of the left eye, ulcerations of the rostral aspect of the lower gum line, and multiple areas of alopecia associated with subcutaneous edema and hemorrhage on the forehead and right flank.

Figure 1—
Figure 1—

Photograph of transverse section of the brain at the level of the basal nuclei of a horse that had a 5-day history of attempting to climb walls and progressive blindness. Notice the asymmetric appearance of the cerebral hemispheres (the left hemisphere is swollen by edema) and the focally extensive and granular area of malacia in the left subcortical white matter (arrow).

Citation: Journal of the American Veterinary Medical Association 243, 1; 10.2460/javma.243.1.57

Histopathologic Findings

Tissue samples from the brain were processed for histologic examination. The necrotic foci in the brain consisted of areas of loss and collapse of the white matter with accumulation of eosinophilic fluid and fibrin strands admixed with hemorrhage (Figure 2). The most severely affected areas contained large numbers of foamy macrophages (gitter cells) and fewer neutrophils (Figure 3). The adjacent neuroparenchyma at the junction between white and gray matter had decreased eosinophilia and vacuolation as a result of edema. Diffusely, throughout the perilesional areas, there were numerous swollen astrocytes, scattered foamy macrophages, few neutrophils, and numerous, well-defined, 10- to 20-ÎĽm-diameter, eosinophilic swollen axons (spheroids). Capillaries were prominent because of marked endothelial swelling, and there was multifocal perivascular accumulation of small numbers of lymphocytes, plasma cells, and neutrophils. Multifocally throughout the adjacent neuropil, occasional necrotic neurons with deeply eosinophilic, shrunken cytoplasm and pyknotic nuclei were evident. Small areas of perivascular hemorrhages and edema were observed in the mesencephalon.

Figure 2—
Figure 2—

Photomicrograph of a section of the left subcortical white matter and overlying gray matter obtained from the horse in Figure 1. Notice that the white matter (left) has collapsed and been replaced by edema fluid and fibrin strands. Multiple areas of hemorrhage (bottom left) are visible at the junction between white and gray matter. The adjacent cortical gray matter (right) contains numerous prominent vessels. H&E stain; bar = 250 ÎĽm.

Citation: Journal of the American Veterinary Medical Association 243, 1; 10.2460/javma.243.1.57

Figure 3—
Figure 3—

Photomicrograph of a section of the left subcortical white matter obtained from the horse in Figure 1. The necrotic white matter contains numerous foamy macrophages and scattered areas of hemorrhage. H&E stain; bar = 100 ÎĽm.

Citation: Journal of the American Veterinary Medical Association 243, 1; 10.2460/javma.243.1.57

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: severe multifocal hemorrhagic leukoencephalomalacia.

Case summary: leukoencephalomalacia in a horse.

Comments

The reported history and the gross and microscopic findings for the horse of the present report were consistent with equine leukoencephalomalacia (ELEM).1–8 Although these findings strongly suggested ELEM, the diagnosis may be confirmed by the isolation of the causative mycotoxin fumonisin from a suspected food source.6 Detection of fumonisin at a concentration of approximately 10 μg/g in feed given to horses with appropriate clinical signs raises a strong suspicion of ELEM.9 Fumonisin can be detected in feedstuffs via high-pressure liquid chromatographic assays or ELISA-based screening tests.10 In experimental settings, only sphingosine and sphingamine have been considered as useful biomarkers of this toxicosis in pigs, and concentrations of these in serum and frozen or formalin-fixed tissue samples are determined by high-pressure liquid chromatography.11 However, in situations where the source of toxin is no longer available, such as that which occurred in the case described in this report, a diagnosis of ELEM can be made on the basis of clinical and pathological findings.5,9

Equine leukoencephalomalacia, also known as moldy corn disease, blind staggers, corn stalk disease, and forage poisoning, is an acute to subacute, degenerative, and typically fatal neuromycotoxicosis of Equidae (horses, mules, and donkeys) that has been reported in the United States since the early 1900s.8 An isolated case of leukoencephalomalacia with epidemiological and clinicopathologic findings similar to ELEM has also been described in a white-tailed deer.12 Equine leukoencephalomalacia is associated with the ingestion of the mycotoxins fumonisin B1 and, less often, fumonisin B2 and B3 in moldy corn, corn by-products and, less often, other grains contaminated with the fungus Fusarium verticillioides (formerly Fusarium moniliforme) or Fusarium proliferatum13–16 Cases of ELEM have been reported worldwide1,2,4,8 and, similar to the case described in this report, involve horses in warm and moist climates during the late fall and early spring, when environmental conditions favor fungal growth and toxin production on feedstuffs.5,8 In affected animals, fumonisin B1 targets primarily the brain and inhibits sphingosine-N-acyltransferase and sphinganine-N-acyltransferase, leading to sphingolipid synthesis arrest with consequent cellular accumulation of free sphingosine and sphinganine and direct cellular damage.2,9 The toxin occasionally affects the liver and causes centrilobular degeneration and necrosis, with a mild degree of fibrosis and bile duct hyperplasia. However, hepatic changes rarely predominate in horses with naturally acquired ELEM.2,8,14

Clinical signs may be observed a few hours or days after ingestion of fumonisin-contaminated food.1 Typically, affected horses abruptly develop signs of anorexia and hyperexcitability that are rapidly followed by marked signs of depression, dullness, blindness, head pressing, lip and tongue paralysis, impaired masticatory movements, sweating, circling, ataxia, trembling, recumbency, paddling, and death.1,4–6,8 As evidenced by the horse of the present report, some affected horses may develop severe self-inflicted lesions secondary to violent involuntary movements.5 Almost all affected horses die, and animals that survive may have persistent neurologic signs as a result of the extensive brain lesions.15

In the horse of the present report, the gross changes in the brain, namely multifocal or extensive areas of softening and cavitation (malacia) with or without hemorrhages in the white matter of the cerebral hemispheres, were characteristic of ELEM. Lesions may develop in 1 or both sides of the brain and are predominantly located in the corona radiata and centrum semiovale, although they can extend to the basal nuclei and thalamus and, less frequently, to the mesencephalon, pons, and cerebellum. The necrotic foci are usually surrounded by soft and yellow areas of edema.8 In the horse of the present report, lesions extended from the corona radiata to the thalamus and only a few microscopic areas of hemorrhage were observed in the mesencephalon. In affected horses, microscopic findings include extensive areas of necrosis and accumulation of edema fluid and hemorrhages within the white matter. These areas are usually filled with variable numbers of foamy macrophages and are surrounded by variable degrees of astrocytosis and prominent blood capillaries with swollen endothelial cells. The adjacent gray matter may have perineuronal and perivascular vacuolation (edema) and prominent blood vessels. Accumulation of small numbers of macrophages, neutrophils, or less commonly eosinophils may be observed in the perivascular spaces within the brain or leptomeninges.1,2,8

Differential diagnoses for ELEM should include infection with Trypanosoma evansi17 or Aspergillus niger.18 Gross lesions in the brain of horses with trypanosomiasis in South America may resemble those of ELEM, including visible areas of necrosis with yellow discoloration in the white matter and flattening of the gyri. However, unlike ELEM-affected horses, horses with trypanosomiasis develop severe and diffuse necrotizing encephalomyelitis, with marked lymphoplasmacytic perivascular inflammation.17 Neurologic disease secondary to infection with neuroinvasive A niger in horses with enterocolitis has been reported.18 The severe enteric disease facilitates fungal invasion through the damaged intestinal wall and allows colonization of other tissues. In horses with A niger infection, gross findings in the brain may be similar to those of ELEM, but the areas of malacia may also affect the gray matter. Microscopically, those affected horses have multiple areas of necrosis and hemorrhage associated with vasculitis, thrombosis, and intralesional fungal hyphae.18 Inflammation, vasculitis, and fungal hyphae were not observed in tissue samples obtained from the horse of the present report.

For horses with ELEM, there is no specific treatment.6 Prevention of disease is important and can be effectively achieved if feeding potential sources of mycotoxin (mainly corn and corn by-products but also other poor-quality feedstuff1) to horses is eliminated.

References

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  • 18. Tunev SS, Ehrhart EJ, Jensen HE, et al. Necrotizing mycotic vasculitis with cerebral infarction caused by Aspergillus niger in a horse with acute typhlocolitis. Vet Pathol 1999; 36: 347–351.

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