Case Report Rapport de cas Optic neuropathy in a herd of beef cattle in Alberta associated with consumption of moldy corn Lynne S. Sandmeyer, Vladimir Vujanovic, Lyall Petrie, John R. Campbell, Bianca S. Bauer, Andrew L. Allen, Bruce H. Grahn Abstract — A group of beef cattle in eastern Alberta was investigated due to sudden onset of blindness after grazing on standing corn in mid-winter. Fumonisin-producing Fusarium spp. were isolated from the corn. Blindness was due to an optic nerve degeneration suspected to be secondary to fumonisin mycotoxin. Résumé — Neuropathie optique dans un cheptel de bovins de boucherie en Alberta associée à la consommation de maïs moisi. Un groupe de bovins de boucherie de l’est de l’Alberta a fait l’objet d’une enquête en raison de l’apparition soudaine de cécité après avoir brouté du maïs sur pied vers le milieu de l’hiver. Fusarium spp., qui produit la fumonisine, a été isolé dans le maïs. La cécité a été attribuable à la dégénération du nerf optique ayant pour cause suspectée la mycotoxine fumonisine.
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erd outbreaks of blindness and neurological disease may occur in cattle due to various infectious, nutritional, or toxic etiologies. Blindness may be the result of disease involving the globe, the optic nerve and its pathways, or the cerebral cortex, and may be temporary or permanent depending on the cause. Thromboembolic meningoencephalitis (TEME), caused by infection with the bacterium Histophilus somni may cause herd outbreaks, most commonly in feedlot cattle. Infection causes vasculitis and thrombosis and blindness may result from uveitis or retinal necrosis, or may be due to hemorrhage and necrosis within the brain (1). Fibrinopurulent meningitis and multifocal hemorrhagic necrosis of the brain at necropsy are pathognomonic. Deficiency of vitamin A is a well-known nutritional cause of blindness in cattle at any age. It occurs in cattle when plasma and liver levels fall below 0.7 mmol/L (0.2 ppm) and 2 mg/g respectively, and is often due to suboptimal amounts of green forage intake for a prolonged time (2–4). The pathogenesis of Department of Small Animal Clinical Sciences (Sandmeyer, Bauer, Grahn), Department of Large Animal Clinical Sciences (Petrie, Campbell), Department of Veterinary Pathology (Allen), Western College of Veterinary Medicine; Department of Food and Bioproduct Sciences, College of Agriculture and Bioresources (Vujanovic), University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B4. Address all correspondence to Dr. Lynne Sandmeyer; e-mail: [email protected] Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office ([email protected]) for additional copies or permission to use this material elsewhere. CVJ / VOL 56 / MARCH 2015
(Traduit par Isabelle Vallières)
blindness due to vitamin A deficiency varies with the age of the animal. Those younger than 6 mo develop blindness due to ischemic necrosis of the optic nerve that develops as a result of sphenoid bone overgrowth and thickening of the dura mater which compress the nerve as it passes through the optic canal (4,5), while retinal degeneration occurs in all ages due to lack of rhodopsin formation and subsequent photoreceptor degeneration (6,7). Increased cerebrospinal fluid pressure is also thought to be responsible for the neurological signs that accompany vitamin A deficiency (8). Polioencephalomalacia, due to nutritional or toxic etiologies, is also a common cause of blindness in herd outbreaks. Polioencephalomalacia develops secondary to thiamine deficiency, through inadequate consumption of vitamin B1, ruminal consumption of thiamine by bacterial thiaminase, or ingestion of antimetabolites such as thiaminases in plants (9); lead toxicity through ingestion from discarded automobile batteries or feed contamination by environmental pollutants (10,11); high sulfur intake (12); and water deprivation-sodium ion toxicity (13,14). These conditions result in swelling and necrosis of cerebral cortical gray matter. Clinical signs initially include anorexia, incoordination, and muscle tremors, and as the condition progresses animals develop blindness, head pressing and recumbency, and die. Blindness associated with polioencephalomalacia is due to cerebrocortical, rather than ocular or optic nerve disease (11,14,15). Herd outbreaks of blindness in cattle have also been reported in association with toxic plants such as Helichrysum argyrosphaerum, Dryopteris filix-mas (male fern), and Pteridium aquilinum (bracken fern) (16–18) and can be induced by chemical toxins such as acrylamide and rafoxanide (19,20). These agents are neurotoxins that cause myelin edema and compression of the optic nerve in the optic canal leading chronically to optic nerve atrophy. 249
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Table 1. Vitamin and mineral analysis 2 weeks after onset of blindness in 3 cows
Table 2. Serum biochemistry abnormalities 2 weeks after onset of blindness in 3 cows
Cow I.D.
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Cow I.D.
Parameter (units) Vitamin A (ppm) Vitamin E (ppm) Manganese (ppm) Magnesium (ppm) Iron (ppm) Cobalt (ppm) Copper (ppm) Selenium (ppm) Molybdenum (ppm) Lead
0.16a 0.20a 0.15a 3.24 2.53a 4.93 0.002b 0.003b 0.003b 19.4 17.8a 16.3 1.93 1.22a 1.72 0.23 1.41 0.78 0.71 1.04 1.03 0.16 0.16 0.20 0.057 0.033 0.037 0.006 0.007 0.006
a Marginal. b Deficient
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as reported by the laboratory.
This report describes an outbreak of blindness in a beef cattle herd in Alberta, due to an optic neuropathy, which was associated with consumption of fumonisin mycotoxin in standing corn. This is the first report of suspected mycotoxin toxicity associated with optic neuropathy in cattle.
Case description In a herd of 220 beef cattle, 184 mature pregnant cows had been placed on a pasture containing standing corn in March of 2010. Six days after being placed on this pasture 1 cow was found to be “acting blind.” On day 9 the owner noted gait abnormalities in approximately 35 cows (19% of cows on corn pasture); described as “stiffness in the hindquarters, walking as if they had dislocated hips, or walking in slow motion.” Between days 12 and 15 after being placed on the pasture an additional 4 cows were identified as blind (a total of 2.7% of cows on corn pasture). All cows were removed from the pasture on day 15. Those with blindness and gait abnormalities were placed in corrals and fed grass hay while the others were moved to standing oats supplemented with grass hay. The gait abnormalities resolved without therapy within 2 wk of cows being removed from the corn pasture and these animals were not examined by a veterinarian while they had gait abnormalities. On day 15, blood samples were collected from 9 cows, 7 with gait abnormalities and 2 that were blind, and submitted for lead analysis (Prairie Diagnostic Services, Saskatoon, Saskatchewan). Serum lead levels ranged from 0.006 to 0.012 ppm and were considered normal by the laboratory (Table 1). On day 21, blood from 3 blind cows was submitted for vitamin A and E, and mineral analysis (manganese, magnesium, iron, cobalt, copper, selenium, molybdenum, lead), as well as serum biochemistry (Prairie Diagnostic Services). Abnormalities present on serum biochemistry analysis from these cows are summarized in Table 2. Abnormalities were mild and not suggestive of organ dysfunction. Calving began 2 d after the animals were removed from the corn pasture. Over the following 3 wk, cows that were blind calved normally and had viable calves. In total approximately 200 calves were born during the season. About 20 calves died shortly after birth or were stillborn. This was slightly higher than normal perinatal mortality for the herd; however, minimal investigation into causes of death was carried out. 250
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Parameter (reference range) Urea (3.5 to 10.3 mmol/L) 3.2 3.0 2.8 Phosphorus (1.45 to 2.59 mmol/L) 1.18 1.54 1.05 Creatinine (49 to 95 mmol/L) 132 84 109 Glucose (1.6 to 4.4 mmol/L) 4.9 5.5 3.7 Total bilirubin (1 to 5 mmol/L) 3 5 6 GGT (12 to 39 U/L) 14 17 10 GLDH (7 to 36 U/L) 4 3 4 Total protein (68 to 87 g/L) 67 74 85 Albumin (32 to 38 g/L) 27 30 31 Globlulin (32 to 52 g/L) 40 44 54 SDH (5 to 30 U/L) 3 5 4 GGT — gammaglutamyl transaminase; GLDH — glutamate dehydrogenase; SDH — succinate dehydrogenase.
The 5 blind cows and 2 of their calves were examined by a veterinary ophthalmologist. One blind cow and her calf were examined at the Western College of Veterinary Medicine (WCVM) 4 wk after onset of blindness. Subsequently, the other 4 blind cows and 1 calf were available for examination onsite 6 wk after onset of blindness. Neuroophthalmic examination of the cows showed absent dazzle reflexes, absent menace responses bilaterally, and widely dilated and fixed pupils with no direct or consensual pupillary light reflexes. Intraocular pressures were estimated with a rebound tonometer (Tonvet; Tiolat, Helsinki, Finland) and ranged from 16 to 26 mmHg. Although rebound tonometry has not been verified in cattle, this range of pressures is within normal limits for other methods of tonometry (21). Biomicroscopic examination (Osram 64222; Carl Zeiss Canada, Don Mills, Ontario) revealed no anterior segment abnormalities in any cow. Indirect ophthalmoscopy (Heine Omega 200; Heine Instruments Canada, Kitchener, Ontario) revealed mild peripapillary depigmentation in the non-tapetal fundus which was unilateral in 1 cow, and bilateral in 3 of the 5 cows (Figure 1). Indirect ophthalmoscopic examination was normal in 1 affected animal. In all animals, the retinal vessels appeared to be of normal size (22). Clinical and ophthalmic examination (including a maze test) of the calves of 2 blind cows showed no abnormalities and these calves were determined to be visual. Electroretinography was completed on 4 of the blind cows; the first ERG was completed at the WCVM 4 wk after onset of blindness and 3 cows were tested on site approximately 2 wk later when the farm was visited. One of the blind cows was too fractious to allow ERG testing. Pharmacological dilation was not required prior to ERG testing as affected animals had fixed and dilated pupils. Two platinum electrodes (Cadwell Low Profile Needle electrodes; Cadwell Laboratories, Kennewick, Washington, USA) were placed subdermally with the ground electrode over the occipital tuberosity, and the reference electrode 2 cm from the lateral canthus. The active electrode was a corneoscleral contact lens (ERG-jet; Universo SA, La Chauxde-Fonds, Switzerland) which was placed on the cornea with 2% methycellulose (Methocell 2%; CIBA Vision, Mississauga, Ontario). The eyelids were manually retracted during the recording procedure. The ERGs were elicited with a white xenon strobe light. ERGs were recorded with a Cadwell Sierra II (Cadwell Laboratories). A single flash ERG was recorded CVJ / VOL 56 / MARCH 2015
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Figure 1. Fundus photographs of the left (a) and right (b) eyes of 1 blind cow. Note mild non-tapetal peripapillary depigmentation (arrows), which was unilateral in 1 cow, and bilateral in 3 of the 5 cows examined.
following a 10 min adaptation to ambient light at maximum light intensity (45 J/cm2) (photopic conditions). Cows were then dark-adapted for 10 min and single flash ERGs were then recorded using maximum light intensity (scotopic conditions). All blind cows had recordable a- and b-waves under photopic and scotopic conditions (Figure 2). The photopic and scotopic b-wave amplitudes of different cows ranged from 193–452 mv and 146–492 mv, respectively. The lowest b-wave amplitudes were recorded in the eye of a cow with depigmented foci in the peripapillary region and the highest b-wave amplitudes were recorded from an eye of a different blind cow with a normal ophthalmoscopic examination. The blind cow that was examined at the WCVM 4 wk after onset of blindness was euthanized and submitted for postmortem examination (Prairie Diagnostic Services). Immediately following euthanasia, the eyes and optic nerves were removed and each globe was injected with 1 mL of 10% neutral buffered formalin, placed in Bouin’s fixative for 18 h, rinsed in tap water for 2 min, then placed in 10% neutral buffered formalin. The brain, optic chiasm, pituitary gland, trigeminal ganglia, and lymph nodes of the head were placed in 10% neutral buffered formalin. Histologic sections were processed routinely and stained with hematoxylin-eosin (routine evaluation), Holmes stain (for axons), luxol fast blue (for myelin), and Masson’s trichrome (for collagen). Light microscopic examination of the eyes, optic nerve, and chiasm of this cow revealed spongiosis (dilated spaces), extensive axonal degeneration, and presumed histiocytic infiltration of the optic nerve and optic chiasm. CVJ / VOL 56 / MARCH 2015
Disorganization and thickening of the pial septa was also present (Figure 3). The optic nerve lesions were more severe near the optic chiasm compared with the intraocular portion which was essentially normal. The optic chiasm contained large, scattered foci of spongiosis (Figure 4). Changes were consistent with Wallerian degeneration. In addition, there was a region of inferior, peripapillary, full thickness retinal degeneration within the globe sections that was approximately 1.53 the diameter of the optic disc. No abnormalities were noted in the superior retina (Figure 5). Within the brain there was scattered, mild, perivascular, presumed histiocytic cell infiltration. Thorough evaluation of the environment for toxic chemicals and plants was completed 6 wk after the first blind cow was identified. Moldy corn was found in the pasture (Figure 6). This was collected and sent for fungal isolation and identification using translation elongation factor 1 alpha (EF1a) gene for Fusarium and ITS rDNA sequencing for other fungi (Food and Bioproduct Sciences, University of Saskathewan, Saskatoon, Saskatchewan), as well as mycotoxin analysis (Veterinary Diagnostic Laboratory, Fargo, North Dakota, USA). Fusarium acuminatum and Fusarium moniliforme (syn. F. verticillioides species) dominated in corn samples, showing EF-1alpha sequences similarity in GenBank to HM068315 (98%) and GU564300 (99%), respectively. Using culture-based and molecular methods, subsequent analysis of the corn samples from the pasture, on which affected animals had been grazing, detected the presence of several Fusarium spp. Based on EF1a and ITS rDNA gene sequences, our results 251
formis and F. proliferatum and demonstrated up-regulation of fumonisin coding genes in highly infected corn samples in this study (data not published).
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Discussion
Figure 2. Dark-adapted ERG with a bright light stimulus recorded from the left eye of 1 blind cow with a normal ophthalmoscopic examination (a). The b-wave (distance between A and B) is the result of both rod and cone activity and the amplitude is 358 mV. This confirms that retinal disease is not the cause of blindness in this animal. Inset is an ERG recorded from a normal, visual, cow under similar conditions for comparison (b). (100 mV, 50 ms/box).
confirmed the presence of Fusarium spp. as predominant, with an incidence of approximately 55%, followed by Alternaria alternata (27%) and Epicoccum nigrum (18%) (Figure 7). Fusarium spp. identified included Fusarium acuminata (also, Gibberella acuminatum with 98% EF1a gene similarity to HM068315, GenBank), Gibberella moniliformis (also, Fusarium moniliforme; syn. F. verticillioides with 100% EF1a gene similarity to GU564300) and Gibberella fujikuroi (also, F. proliferatum with 98% EF1a gene similarity to AF291058, GenBank). The corn was first analyzed for 17 different mycotoxins and results were negative. However, this lab (Veterinary Diagnostic Laboratory, Fargo) does not analyze for aflatoxins and fumonisins. Specific fumonisin primers for qPCR were developed based on F. monili252
The clinical manifestations and ERG results combined with histopathologic examination support the conclusion that blindness in these cows was due to optic nerve disease. Optic nerve toxicosis in this herd was thought to be caused by fumonisin mycotoxin consumed in the corn. Polioencephalomalacia and lead poisoning were thought unlikely as vision loss is due to a cerebrocortical lesion in these conditions rather than an optic nerve disease and lead concentrations were normal in the 9 animals tested. Vitamin A deficiency causes blindness in mature animals due to severe, diffuse retinal degeneration rather than optic nerve disease. Although vitamin A concentrations were marginal in the cows tested, the laboratory reported that these concentrations were common in cows at that time of year and retinal degeneration was not diffuse (3,4 6,7). The evidence for fumonisin mycotoxicosis in these animals is circumstantial. Up-regulation of fumonisin coding sequences was found in the corn samples. Fusarium spp. predominated in the consumed corn and several species were present including F. acuminatum, F. moniliformis, and F. fujikuroi. Apart from F. moniliformis, F. fujikuroi is considered as the most common corn pathogen, as well as the most effective producer of fumonisin mycotoxins (23,24). More than 10 types of fumonisins have been isolated and characterized. Of these, fumonisin B1 (FB1), fumonisin B2 (FB2), and fumonisin B3 (FB3) are the major fumonisins produced in nature on crops. The most prevalent of these mycotoxins in contaminated corn is FB1, which is believed to be the most toxic (25). FB1 can be produced at concentrations . 30 ppm by F. moniliforme or F. proliferatum (26). Alternaria alternata, which shows a high incidence of 27% in our study, was reported as a producer of fumonisin analogs (AAL) with toxigenic effects similar to FB1 (27). Both FB1 and AAL seem to cause disruption of sphingolipid metabolism and sphingolipid-mediated processes, thus producing neurotoxicosis in animals by oral administration (CAS Registry Number: 116355-83-0 Toxicity Effects). The toxic effects of fumonisin are species-dependent. The fumonisin toxin causes “crazy horse disease,” or leukoencephalomalcia in horses, a liquefaction necrosis of the white matter of the brain (28). Fumonisin toxicosis in swine causes porcine pulmonary edema (PPE) which appears to result from acute leftsided heart failure (29). In sheep, rabbits, and rats, fumonisin is associated with renal injury (30–32). Information on fumonisin toxicosis in cattle is minimal and manifestations of experimentally induced fumonisin toxicosis in cattle have been limited to hepatotoxicity (33,34). It has been speculated that cattle may have a lower sensitivity to the toxic action of fumonisins compared with other species. The results of serum biochemistry from blood samples obtained 2 wk after consumption of the presumed toxin in 3 affected cows were not consistent with findings in experimental fumonisin hepatotoxicity in cattle, but these were collected 3 wk after exposure. CVJ / VOL 56 / MARCH 2015
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Figure 3. Photomicrographs of proximal optic nerve in longitudinal section (a) and cross section of an affected cow (b). Compare to optic nerve of a normal cow of similar age in longitudinal (c) and cross section (d). Note significant loss of axons indicated by large spaces, cells within the dilated spaces of the degenerated optic nerve are presumed histiocytes. Pial septa are disorganized and thickened, possibly a manifestation of fibrosis. (Masson’s-trichrome stain).
Figure 4. Photomicrograph of optic chiasm of an affected cow. Dilated spaces are indicative of spongiosis. (Hematoxylin & eosin stain).
The clinical manifestations and histopathologic lesions in the retina and optic nerve are similar to those reported in various species following exposure to toxic plants (16–18,35–37) and CVJ / VOL 56 / MARCH 2015
chemical toxins (19,20,38–44). Histopathologic lesions following exposure to these agents typically include status spongiosis of white matter of the brain and spinal cord, and myelin edema associated with degeneration and loss of axons and myelin, as well as astrocytic gliosis in the intraorbital and intracranial portions of the optic nerves (20,35–37,39,40). More chronic lesions of optic nerve fibrosis and atrophy are found in the intracanalicular portions of the nerves suggesting the optic neuropathy occurs due to compression of the nerve in the optic canal as a result of myelin edema (35–37,39). In the blind cow that underwent necropsy, we found spongiosis and axon degeneration in the optic chiasm and optic nerve atrophy which was more apparent closest to the optic canal, compared to the intraocular portion. Therefore, the pathological mechanism of optic nerve degeneration following fumonisin toxicosis in cattle may be similar to that reported for these other toxins. Many of these same plant and chemical toxins are also reported to cause retinal lesions, most often distributed in the non-tapetal, peripapillary region (19,30,35–37,44). The lesions seen in some eyes of the blind cows in this herd were clinically and histologically similar in appearance and distribution to those described for these other toxins. Such retinal lesions are 253
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Figure 5. The intraocular portion of the optic nerve appears normal (a). Superior retina is normal (b). The inferior peripapillary retina shows focal full-thickness retinal degeneration extending approximately 1.53 the diameter of the optic disc (c). Hematoxylin & eosin stain.
Figure 6. Moldy corn found on the pasture where affected cows had been grazing.
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Figure 7. Frequency of isolation of Fusarium and other fungi from moldy corn samples (n = 9), Alberta, March 2010. Note: F.a — Fusarium acuminatum (teleomorph: Gibberella acuminata); F.m — Fusarium moniliforme, syn. F. verticillioides (teleomorph: G. moniliformis); F. torulosum (teleomorph: unknown); F.p — F. proliferatum (teleomorph: G. fujikuroi); F.g — F. graminearum (teleomorph: G. zeae); A.a — Alternaria alternata (teleomorph: unknown); E.n — Epicoccum nigrum (teleomorph: unknown). CVJ / VOL 56 / MARCH 2015
Acknowledgments The authors acknowledge Drs. Tracey Logan and Cecilia Ruschkowski for their help with this investigation. CVJ
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speculated to be due to either papilledema causing retinal separation, or to a direct toxic effect on retinal photoreceptors. As a direct toxic effect would be expected to be more diffuse, the retinal lesions in these cows may be more likely a consequence of papilledema, although the exact cause is not known. All blind cows manifested a complete lack of dazzle reflex and pupillary light reflex; therefore, one would expect extinguished ERG recordings if blindness was primarily due to retinal disease. ERG b-waves were recorded in all of the blind animals tested. However, statistical analysis was not done on the ERGs, due to the low number of animals studied and lack of controls. Histopathology was only available from 1 cow; however, all blind cows showed identical neuroophthalmic abnormalities and optic nerve degeneration was suspected in the other blind cows as well. In contrast, fumonisin-induced blindness in horses is central and manifests with or without abnormal pupillary light reflexes. This suggests a different pathological mechanism which may be species-dependent. Neuromuscular abnormalities such as hind limb weakness, ataxia, and tremors are also common features of toxicity with several blindness-inducing neurotoxins (19,20,42,44,45). Mechanisms include spongiosis of the white matter of the spinal cord and spinal nerve roots, and peripheral nerve axon degeneration (16,38,40). It is not uncommon for such abnormalities to resolve while blindness remains (19). Unfortunately, the gait abnormalities in this group of animals were uncharacterized as no veterinarian was consulted when they were present. They resolved following removal of the animals from the pasture. It is possible these were also a manifestation of toxicity within the herd. Although low numbers of animals in the herd appeared to be affected with blindness and gait abnormalities (2.7% and 19%, respectively), it is possible that subtle ocular or neurological signs may have been missed in other animals within the herd. Perinatal death can be a feature of various toxins. Although the incidence was slightly higher than normal during this season, perinatal death was not investigated thoroughly and therefore, could not conclusively be related to toxin exposure. This was an epidemiologic investigation carried out over several wk after the onset of abnormalities and thus, has obvious limitations. The evidence for fumonisin toxicity is circumstantial but compelling. Blindness in these animals is attributable to optic nerve degeneration which was likely the result of acute myelin edema causing compression of the intracanalicular optic nerves leading chronically to axon degeneration. Although not reported previously, fumonisin may be of concern in suspected neurological disorders in cattle.
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erd outbreaks of blindness and neurological disease may occur in cattle due to various infectious, nutritional, or toxic etiologies. Blindness may be the result of disease involving the globe, the optic nerve and its pathways, or the cerebral cortex, and may be temporary or permanent depending on the cause. Thromboembolic meningoencephalitis (TEME), caused by infection with the bacterium Histophilus somni may cause herd outbreaks, most commonly in feedlot cattle. Infection causes vasculitis and thrombosis and blindness may result from uveitis or retinal necrosis, or may be due to hemorrhage and necrosis within the brain (1). Fibrinopurulent meningitis and multifocal hemorrhagic necrosis of the brain at necropsy are pathognomonic. Deficiency of vitamin A is a well-known nutritional cause of blindness in cattle at any age. It occurs in cattle when plasma and liver levels fall below 0.7 mmol/L (0.2 ppm) and 2 mg/g respectively, and is often due to suboptimal amounts of green forage intake for a prolonged time (2–4). The pathogenesis of Department of Small Animal Clinical Sciences (Sandmeyer, Bauer, Grahn), Department of Large Animal Clinical Sciences (Petrie, Campbell), Department of Veterinary Pathology (Allen), Western College of Veterinary Medicine; Department of Food and Bioproduct Sciences, College of Agriculture and Bioresources (Vujanovic), University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B4. Address all correspondence to Dr. Lynne Sandmeyer; e-mail: [email protected] Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office ([email protected]) for additional copies or permission to use this material elsewhere. CVJ / VOL 56 / MARCH 2015
(Traduit par Isabelle Vallières)
blindness due to vitamin A deficiency varies with the age of the animal. Those younger than 6 mo develop blindness due to ischemic necrosis of the optic nerve that develops as a result of sphenoid bone overgrowth and thickening of the dura mater which compress the nerve as it passes through the optic canal (4,5), while retinal degeneration occurs in all ages due to lack of rhodopsin formation and subsequent photoreceptor degeneration (6,7). Increased cerebrospinal fluid pressure is also thought to be responsible for the neurological signs that accompany vitamin A deficiency (8). Polioencephalomalacia, due to nutritional or toxic etiologies, is also a common cause of blindness in herd outbreaks. Polioencephalomalacia develops secondary to thiamine deficiency, through inadequate consumption of vitamin B1, ruminal consumption of thiamine by bacterial thiaminase, or ingestion of antimetabolites such as thiaminases in plants (9); lead toxicity through ingestion from discarded automobile batteries or feed contamination by environmental pollutants (10,11); high sulfur intake (12); and water deprivation-sodium ion toxicity (13,14). These conditions result in swelling and necrosis of cerebral cortical gray matter. Clinical signs initially include anorexia, incoordination, and muscle tremors, and as the condition progresses animals develop blindness, head pressing and recumbency, and die. Blindness associated with polioencephalomalacia is due to cerebrocortical, rather than ocular or optic nerve disease (11,14,15). Herd outbreaks of blindness in cattle have also been reported in association with toxic plants such as Helichrysum argyrosphaerum, Dryopteris filix-mas (male fern), and Pteridium aquilinum (bracken fern) (16–18) and can be induced by chemical toxins such as acrylamide and rafoxanide (19,20). These agents are neurotoxins that cause myelin edema and compression of the optic nerve in the optic canal leading chronically to optic nerve atrophy. 249
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Table 1. Vitamin and mineral analysis 2 weeks after onset of blindness in 3 cows
Table 2. Serum biochemistry abnormalities 2 weeks after onset of blindness in 3 cows
Cow I.D.
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Cow I.D.
Parameter (units) Vitamin A (ppm) Vitamin E (ppm) Manganese (ppm) Magnesium (ppm) Iron (ppm) Cobalt (ppm) Copper (ppm) Selenium (ppm) Molybdenum (ppm) Lead
0.16a 0.20a 0.15a 3.24 2.53a 4.93 0.002b 0.003b 0.003b 19.4 17.8a 16.3 1.93 1.22a 1.72 0.23 1.41 0.78 0.71 1.04 1.03 0.16 0.16 0.20 0.057 0.033 0.037 0.006 0.007 0.006
a Marginal. b Deficient
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as reported by the laboratory.
This report describes an outbreak of blindness in a beef cattle herd in Alberta, due to an optic neuropathy, which was associated with consumption of fumonisin mycotoxin in standing corn. This is the first report of suspected mycotoxin toxicity associated with optic neuropathy in cattle.
Case description In a herd of 220 beef cattle, 184 mature pregnant cows had been placed on a pasture containing standing corn in March of 2010. Six days after being placed on this pasture 1 cow was found to be “acting blind.” On day 9 the owner noted gait abnormalities in approximately 35 cows (19% of cows on corn pasture); described as “stiffness in the hindquarters, walking as if they had dislocated hips, or walking in slow motion.” Between days 12 and 15 after being placed on the pasture an additional 4 cows were identified as blind (a total of 2.7% of cows on corn pasture). All cows were removed from the pasture on day 15. Those with blindness and gait abnormalities were placed in corrals and fed grass hay while the others were moved to standing oats supplemented with grass hay. The gait abnormalities resolved without therapy within 2 wk of cows being removed from the corn pasture and these animals were not examined by a veterinarian while they had gait abnormalities. On day 15, blood samples were collected from 9 cows, 7 with gait abnormalities and 2 that were blind, and submitted for lead analysis (Prairie Diagnostic Services, Saskatoon, Saskatchewan). Serum lead levels ranged from 0.006 to 0.012 ppm and were considered normal by the laboratory (Table 1). On day 21, blood from 3 blind cows was submitted for vitamin A and E, and mineral analysis (manganese, magnesium, iron, cobalt, copper, selenium, molybdenum, lead), as well as serum biochemistry (Prairie Diagnostic Services). Abnormalities present on serum biochemistry analysis from these cows are summarized in Table 2. Abnormalities were mild and not suggestive of organ dysfunction. Calving began 2 d after the animals were removed from the corn pasture. Over the following 3 wk, cows that were blind calved normally and had viable calves. In total approximately 200 calves were born during the season. About 20 calves died shortly after birth or were stillborn. This was slightly higher than normal perinatal mortality for the herd; however, minimal investigation into causes of death was carried out. 250
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Parameter (reference range) Urea (3.5 to 10.3 mmol/L) 3.2 3.0 2.8 Phosphorus (1.45 to 2.59 mmol/L) 1.18 1.54 1.05 Creatinine (49 to 95 mmol/L) 132 84 109 Glucose (1.6 to 4.4 mmol/L) 4.9 5.5 3.7 Total bilirubin (1 to 5 mmol/L) 3 5 6 GGT (12 to 39 U/L) 14 17 10 GLDH (7 to 36 U/L) 4 3 4 Total protein (68 to 87 g/L) 67 74 85 Albumin (32 to 38 g/L) 27 30 31 Globlulin (32 to 52 g/L) 40 44 54 SDH (5 to 30 U/L) 3 5 4 GGT — gammaglutamyl transaminase; GLDH — glutamate dehydrogenase; SDH — succinate dehydrogenase.
The 5 blind cows and 2 of their calves were examined by a veterinary ophthalmologist. One blind cow and her calf were examined at the Western College of Veterinary Medicine (WCVM) 4 wk after onset of blindness. Subsequently, the other 4 blind cows and 1 calf were available for examination onsite 6 wk after onset of blindness. Neuroophthalmic examination of the cows showed absent dazzle reflexes, absent menace responses bilaterally, and widely dilated and fixed pupils with no direct or consensual pupillary light reflexes. Intraocular pressures were estimated with a rebound tonometer (Tonvet; Tiolat, Helsinki, Finland) and ranged from 16 to 26 mmHg. Although rebound tonometry has not been verified in cattle, this range of pressures is within normal limits for other methods of tonometry (21). Biomicroscopic examination (Osram 64222; Carl Zeiss Canada, Don Mills, Ontario) revealed no anterior segment abnormalities in any cow. Indirect ophthalmoscopy (Heine Omega 200; Heine Instruments Canada, Kitchener, Ontario) revealed mild peripapillary depigmentation in the non-tapetal fundus which was unilateral in 1 cow, and bilateral in 3 of the 5 cows (Figure 1). Indirect ophthalmoscopic examination was normal in 1 affected animal. In all animals, the retinal vessels appeared to be of normal size (22). Clinical and ophthalmic examination (including a maze test) of the calves of 2 blind cows showed no abnormalities and these calves were determined to be visual. Electroretinography was completed on 4 of the blind cows; the first ERG was completed at the WCVM 4 wk after onset of blindness and 3 cows were tested on site approximately 2 wk later when the farm was visited. One of the blind cows was too fractious to allow ERG testing. Pharmacological dilation was not required prior to ERG testing as affected animals had fixed and dilated pupils. Two platinum electrodes (Cadwell Low Profile Needle electrodes; Cadwell Laboratories, Kennewick, Washington, USA) were placed subdermally with the ground electrode over the occipital tuberosity, and the reference electrode 2 cm from the lateral canthus. The active electrode was a corneoscleral contact lens (ERG-jet; Universo SA, La Chauxde-Fonds, Switzerland) which was placed on the cornea with 2% methycellulose (Methocell 2%; CIBA Vision, Mississauga, Ontario). The eyelids were manually retracted during the recording procedure. The ERGs were elicited with a white xenon strobe light. ERGs were recorded with a Cadwell Sierra II (Cadwell Laboratories). A single flash ERG was recorded CVJ / VOL 56 / MARCH 2015
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Figure 1. Fundus photographs of the left (a) and right (b) eyes of 1 blind cow. Note mild non-tapetal peripapillary depigmentation (arrows), which was unilateral in 1 cow, and bilateral in 3 of the 5 cows examined.
following a 10 min adaptation to ambient light at maximum light intensity (45 J/cm2) (photopic conditions). Cows were then dark-adapted for 10 min and single flash ERGs were then recorded using maximum light intensity (scotopic conditions). All blind cows had recordable a- and b-waves under photopic and scotopic conditions (Figure 2). The photopic and scotopic b-wave amplitudes of different cows ranged from 193–452 mv and 146–492 mv, respectively. The lowest b-wave amplitudes were recorded in the eye of a cow with depigmented foci in the peripapillary region and the highest b-wave amplitudes were recorded from an eye of a different blind cow with a normal ophthalmoscopic examination. The blind cow that was examined at the WCVM 4 wk after onset of blindness was euthanized and submitted for postmortem examination (Prairie Diagnostic Services). Immediately following euthanasia, the eyes and optic nerves were removed and each globe was injected with 1 mL of 10% neutral buffered formalin, placed in Bouin’s fixative for 18 h, rinsed in tap water for 2 min, then placed in 10% neutral buffered formalin. The brain, optic chiasm, pituitary gland, trigeminal ganglia, and lymph nodes of the head were placed in 10% neutral buffered formalin. Histologic sections were processed routinely and stained with hematoxylin-eosin (routine evaluation), Holmes stain (for axons), luxol fast blue (for myelin), and Masson’s trichrome (for collagen). Light microscopic examination of the eyes, optic nerve, and chiasm of this cow revealed spongiosis (dilated spaces), extensive axonal degeneration, and presumed histiocytic infiltration of the optic nerve and optic chiasm. CVJ / VOL 56 / MARCH 2015
Disorganization and thickening of the pial septa was also present (Figure 3). The optic nerve lesions were more severe near the optic chiasm compared with the intraocular portion which was essentially normal. The optic chiasm contained large, scattered foci of spongiosis (Figure 4). Changes were consistent with Wallerian degeneration. In addition, there was a region of inferior, peripapillary, full thickness retinal degeneration within the globe sections that was approximately 1.53 the diameter of the optic disc. No abnormalities were noted in the superior retina (Figure 5). Within the brain there was scattered, mild, perivascular, presumed histiocytic cell infiltration. Thorough evaluation of the environment for toxic chemicals and plants was completed 6 wk after the first blind cow was identified. Moldy corn was found in the pasture (Figure 6). This was collected and sent for fungal isolation and identification using translation elongation factor 1 alpha (EF1a) gene for Fusarium and ITS rDNA sequencing for other fungi (Food and Bioproduct Sciences, University of Saskathewan, Saskatoon, Saskatchewan), as well as mycotoxin analysis (Veterinary Diagnostic Laboratory, Fargo, North Dakota, USA). Fusarium acuminatum and Fusarium moniliforme (syn. F. verticillioides species) dominated in corn samples, showing EF-1alpha sequences similarity in GenBank to HM068315 (98%) and GU564300 (99%), respectively. Using culture-based and molecular methods, subsequent analysis of the corn samples from the pasture, on which affected animals had been grazing, detected the presence of several Fusarium spp. Based on EF1a and ITS rDNA gene sequences, our results 251
formis and F. proliferatum and demonstrated up-regulation of fumonisin coding genes in highly infected corn samples in this study (data not published).
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Discussion
Figure 2. Dark-adapted ERG with a bright light stimulus recorded from the left eye of 1 blind cow with a normal ophthalmoscopic examination (a). The b-wave (distance between A and B) is the result of both rod and cone activity and the amplitude is 358 mV. This confirms that retinal disease is not the cause of blindness in this animal. Inset is an ERG recorded from a normal, visual, cow under similar conditions for comparison (b). (100 mV, 50 ms/box).
confirmed the presence of Fusarium spp. as predominant, with an incidence of approximately 55%, followed by Alternaria alternata (27%) and Epicoccum nigrum (18%) (Figure 7). Fusarium spp. identified included Fusarium acuminata (also, Gibberella acuminatum with 98% EF1a gene similarity to HM068315, GenBank), Gibberella moniliformis (also, Fusarium moniliforme; syn. F. verticillioides with 100% EF1a gene similarity to GU564300) and Gibberella fujikuroi (also, F. proliferatum with 98% EF1a gene similarity to AF291058, GenBank). The corn was first analyzed for 17 different mycotoxins and results were negative. However, this lab (Veterinary Diagnostic Laboratory, Fargo) does not analyze for aflatoxins and fumonisins. Specific fumonisin primers for qPCR were developed based on F. monili252
The clinical manifestations and ERG results combined with histopathologic examination support the conclusion that blindness in these cows was due to optic nerve disease. Optic nerve toxicosis in this herd was thought to be caused by fumonisin mycotoxin consumed in the corn. Polioencephalomalacia and lead poisoning were thought unlikely as vision loss is due to a cerebrocortical lesion in these conditions rather than an optic nerve disease and lead concentrations were normal in the 9 animals tested. Vitamin A deficiency causes blindness in mature animals due to severe, diffuse retinal degeneration rather than optic nerve disease. Although vitamin A concentrations were marginal in the cows tested, the laboratory reported that these concentrations were common in cows at that time of year and retinal degeneration was not diffuse (3,4 6,7). The evidence for fumonisin mycotoxicosis in these animals is circumstantial. Up-regulation of fumonisin coding sequences was found in the corn samples. Fusarium spp. predominated in the consumed corn and several species were present including F. acuminatum, F. moniliformis, and F. fujikuroi. Apart from F. moniliformis, F. fujikuroi is considered as the most common corn pathogen, as well as the most effective producer of fumonisin mycotoxins (23,24). More than 10 types of fumonisins have been isolated and characterized. Of these, fumonisin B1 (FB1), fumonisin B2 (FB2), and fumonisin B3 (FB3) are the major fumonisins produced in nature on crops. The most prevalent of these mycotoxins in contaminated corn is FB1, which is believed to be the most toxic (25). FB1 can be produced at concentrations . 30 ppm by F. moniliforme or F. proliferatum (26). Alternaria alternata, which shows a high incidence of 27% in our study, was reported as a producer of fumonisin analogs (AAL) with toxigenic effects similar to FB1 (27). Both FB1 and AAL seem to cause disruption of sphingolipid metabolism and sphingolipid-mediated processes, thus producing neurotoxicosis in animals by oral administration (CAS Registry Number: 116355-83-0 Toxicity Effects). The toxic effects of fumonisin are species-dependent. The fumonisin toxin causes “crazy horse disease,” or leukoencephalomalcia in horses, a liquefaction necrosis of the white matter of the brain (28). Fumonisin toxicosis in swine causes porcine pulmonary edema (PPE) which appears to result from acute leftsided heart failure (29). In sheep, rabbits, and rats, fumonisin is associated with renal injury (30–32). Information on fumonisin toxicosis in cattle is minimal and manifestations of experimentally induced fumonisin toxicosis in cattle have been limited to hepatotoxicity (33,34). It has been speculated that cattle may have a lower sensitivity to the toxic action of fumonisins compared with other species. The results of serum biochemistry from blood samples obtained 2 wk after consumption of the presumed toxin in 3 affected cows were not consistent with findings in experimental fumonisin hepatotoxicity in cattle, but these were collected 3 wk after exposure. CVJ / VOL 56 / MARCH 2015
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Figure 3. Photomicrographs of proximal optic nerve in longitudinal section (a) and cross section of an affected cow (b). Compare to optic nerve of a normal cow of similar age in longitudinal (c) and cross section (d). Note significant loss of axons indicated by large spaces, cells within the dilated spaces of the degenerated optic nerve are presumed histiocytes. Pial septa are disorganized and thickened, possibly a manifestation of fibrosis. (Masson’s-trichrome stain).
Figure 4. Photomicrograph of optic chiasm of an affected cow. Dilated spaces are indicative of spongiosis. (Hematoxylin & eosin stain).
The clinical manifestations and histopathologic lesions in the retina and optic nerve are similar to those reported in various species following exposure to toxic plants (16–18,35–37) and CVJ / VOL 56 / MARCH 2015
chemical toxins (19,20,38–44). Histopathologic lesions following exposure to these agents typically include status spongiosis of white matter of the brain and spinal cord, and myelin edema associated with degeneration and loss of axons and myelin, as well as astrocytic gliosis in the intraorbital and intracranial portions of the optic nerves (20,35–37,39,40). More chronic lesions of optic nerve fibrosis and atrophy are found in the intracanalicular portions of the nerves suggesting the optic neuropathy occurs due to compression of the nerve in the optic canal as a result of myelin edema (35–37,39). In the blind cow that underwent necropsy, we found spongiosis and axon degeneration in the optic chiasm and optic nerve atrophy which was more apparent closest to the optic canal, compared to the intraocular portion. Therefore, the pathological mechanism of optic nerve degeneration following fumonisin toxicosis in cattle may be similar to that reported for these other toxins. Many of these same plant and chemical toxins are also reported to cause retinal lesions, most often distributed in the non-tapetal, peripapillary region (19,30,35–37,44). The lesions seen in some eyes of the blind cows in this herd were clinically and histologically similar in appearance and distribution to those described for these other toxins. Such retinal lesions are 253
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Figure 5. The intraocular portion of the optic nerve appears normal (a). Superior retina is normal (b). The inferior peripapillary retina shows focal full-thickness retinal degeneration extending approximately 1.53 the diameter of the optic disc (c). Hematoxylin & eosin stain.
Figure 6. Moldy corn found on the pasture where affected cows had been grazing.
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Figure 7. Frequency of isolation of Fusarium and other fungi from moldy corn samples (n = 9), Alberta, March 2010. Note: F.a — Fusarium acuminatum (teleomorph: Gibberella acuminata); F.m — Fusarium moniliforme, syn. F. verticillioides (teleomorph: G. moniliformis); F. torulosum (teleomorph: unknown); F.p — F. proliferatum (teleomorph: G. fujikuroi); F.g — F. graminearum (teleomorph: G. zeae); A.a — Alternaria alternata (teleomorph: unknown); E.n — Epicoccum nigrum (teleomorph: unknown). CVJ / VOL 56 / MARCH 2015
Acknowledgments The authors acknowledge Drs. Tracey Logan and Cecilia Ruschkowski for their help with this investigation. CVJ
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speculated to be due to either papilledema causing retinal separation, or to a direct toxic effect on retinal photoreceptors. As a direct toxic effect would be expected to be more diffuse, the retinal lesions in these cows may be more likely a consequence of papilledema, although the exact cause is not known. All blind cows manifested a complete lack of dazzle reflex and pupillary light reflex; therefore, one would expect extinguished ERG recordings if blindness was primarily due to retinal disease. ERG b-waves were recorded in all of the blind animals tested. However, statistical analysis was not done on the ERGs, due to the low number of animals studied and lack of controls. Histopathology was only available from 1 cow; however, all blind cows showed identical neuroophthalmic abnormalities and optic nerve degeneration was suspected in the other blind cows as well. In contrast, fumonisin-induced blindness in horses is central and manifests with or without abnormal pupillary light reflexes. This suggests a different pathological mechanism which may be species-dependent. Neuromuscular abnormalities such as hind limb weakness, ataxia, and tremors are also common features of toxicity with several blindness-inducing neurotoxins (19,20,42,44,45). Mechanisms include spongiosis of the white matter of the spinal cord and spinal nerve roots, and peripheral nerve axon degeneration (16,38,40). It is not uncommon for such abnormalities to resolve while blindness remains (19). Unfortunately, the gait abnormalities in this group of animals were uncharacterized as no veterinarian was consulted when they were present. They resolved following removal of the animals from the pasture. It is possible these were also a manifestation of toxicity within the herd. Although low numbers of animals in the herd appeared to be affected with blindness and gait abnormalities (2.7% and 19%, respectively), it is possible that subtle ocular or neurological signs may have been missed in other animals within the herd. Perinatal death can be a feature of various toxins. Although the incidence was slightly higher than normal during this season, perinatal death was not investigated thoroughly and therefore, could not conclusively be related to toxin exposure. This was an epidemiologic investigation carried out over several wk after the onset of abnormalities and thus, has obvious limitations. The evidence for fumonisin toxicity is circumstantial but compelling. Blindness in these animals is attributable to optic nerve degeneration which was likely the result of acute myelin edema causing compression of the intracanalicular optic nerves leading chronically to axon degeneration. Although not reported previously, fumonisin may be of concern in suspected neurological disorders in cattle.
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