UNIVERSITE EUROPEENNE JEAN MONNET ASSOCIATION INTERNATIONALE SANS BUT LUCRATIF BRUXELLES - BELGIQUE "SCIENCES CRIMINOLOGIQUES" IL CASO NADALINI Un caso ancora aperto Dott.ssa Chiara Bucchignoli Bruxelles, June 2009 ISTITUTO MEME S.R.L. - MODENA ASSOCIATO UNIVERSITÉ EUROPÉENNE JEAN MONNET A.I.S.B.L. BRUXELLES DOTT.SSA CHIARA BUCCHIGNOLI – SST IN SCIENCES CRIMINOLOGIQUES - TERZO ANNO A.A. 2008 – 2009
Vet 961_2131 ld.pmdPesq. Vet. Bras. 31(5):407-412, maio 2011 Equine leukoencephalomalacia (ELEM) due to fumonisins
B1 and B2 in Argentina1
Federico Giannitti2* , Santiago Sain Diab3, Ana Maria Pacin4,5, Maria Barrandeguy6, Carlos Larrere7, Joaquin Ortega3 and Francisco Alejandro Uzal3 ABSTRACT.- Giannitti F., Diab S.S., Pacin A.M., Barrandeguy M., Larrere C., Ortega J. &
Uzal F.A. 2011. Equine leukoencephalomalacia (ELEM) due to fumonisins B1 and
B2 in Argentina. Pesquisa Veterinária Brasileira 31(5):407-412. Laboratorio de Diagnóstico
Veterinario, calle 25 de Mayo 139, Bahía Blanca (8000), Buenos Aires, Argentina. E-mail:
In August 2007 an outbreak of neurological disease and sudden death in Arabian horses occurred in a farm located in Coronel Rosales County, Buenos Aires Province, Argentina.
The animals were on a pasture of native grasses and supplemented ad libitum with cornkernels and wheat bran. Three horses were observed having acute neurologic signs includingblindness, four leg ataxia, hyperexcitability, aimless walking and circling, followed by deathin two of them. Four other horses were found dead overnight without a history of neurologicsigns. The morbidity, mortality and lethality rates were 11.6%, 10% and 85.7%, respectively.
Grossly, the brain showed focal areas of hemorrhage, brown-yellow discoloration andsoftening of the sub-cortical white matter. The microscopic brain lesions consisted ofextensive areas of malacia within the white matter of the cerebral hemispheres, brainstemand cerebellum, characterized by rarefaction of the white matter with cavitations filled withproteinaceous edema, multifocal hemorrhages and mild infiltration by neutrophils, and rareeosinophils. Swollen glial cells with abundant eosinophilic cytoplasm, distinct cell borders,intracytoplasmic deeply eosinophilic globules and eccentric, hyperchromatic, occasionallypyknotic nucleus were present throughout the areas of rarefaction hemorrhage, edemaand necrosis. The feed supplements contained 12,490μg/kg of fumonisin B1 and 5,251μg/kg of fumonisin B2. This is the first reported outbreak of ELEM associated with consumptionof feed supplements containing high concentrations of fumonisins in Argentina.
INDEX TERMS: Mycotoxins, horse, equine leukoencephalomalacia, fumonisins, pathology, Argentina.
RESUMO.- [Leucoencefalomalacia equina devida a
Received on November 23, 2010.
fumonisinas B1 e B2 na Argentina.] Em agosto de 2007,
Accepted for publication on December 11, 2010.
ocorreu um surto de doença neurológica e morte súbita em Laboratorio de Diagnóstico Veterinario (LDV), calle 25 de Mayo 139, Bahía Blanca (8000), Buenos Aires, Argentina. *Corresponding cavalos árabes em uma propriedade localizada no municí- pio de Coronel Rosales, na província de Buenos Aires, 3 California Animal Health and Food Safety Laboratory System Argentina. Os animais estavam em pasto nativo e eram (CAHFS), San Bernardino and Davis Branches, University of California suplementados ad libitum com grãos de milho e farelo de Davis, 105 West Central Avenue, San Bernardino (92408), CA, and trigo. Três cavalos foram observados com sinais neuroló- West Health Science Drive, Davis (95616), CA, USA.
4 Fundación de Investigaciones Científicas Teresa Benedicta de la gicos agudos, incluindo cegueira, ataxia nas quatro per- Cruz, calle Dorronzoro 141, Luján (B6700), Buenos Aires, Argentina.
nas, hiperexcitabilidade, e andar sem rumo e em círculo, 5 Comisión de Investigaciones Científicas de la Provincia de Buenos seguidos de morte em dois animais. Outros quatro cava- Aires, calle 526 e/10 y 11, La Plata (1900), Buenos Aires, Argentina.
los foram encontrados mortos durante a noite sem históri- 6 Instituto Nacional de Tecnología Agropecuaria (INTA), calle De los co de distúrbios neurológicos. A mortalidade, morbidade e reseros y Las cabañas s/n (1712), Castelar (1712), Buenos Aires, letalidade foram de 11,6%, 10% e 85,7%, respectivamen- te. Macroscopicamente, o cérebro tinha áreas focais de Veterinarian, Private Practice, Bahía Blanca, Buenos Aires, Argen- hemorragia, coloração amarelada e amolecimento da subs- Federico Giannitti et al.
tância branca sub-cortical. Microscopicamente, as lesões Beasley 1999, Foreman et al. 2004). The clinical signs include cerebrais consistiram de extensas áreas de malácia na decreased tongue tone and mobility, propioceptive deficit, substância branca dos hemisférios cerebrais, do tronco ataxia, anorexia, lethargy, blindness, circling, aimless encefálico e do cerebelo. Estas lesões da substância bran- walking, head-pressing, hyperexcitability, diaphoresis and ca se caracterizaram por rarefação, cavidades contendo coma (Summers et al. 1995, Beasley 1999, Foreman et al.
fluido proteináceo (edema), hemorragias multifocais e mo- 2004, Maxie & Youssef 2007). Affected animals that develop derado infiltrado por neutrófilos e raros eosinófilos. Células clinical signs but survive usually show some degree of gliais tumefeitas com abundante citoplasma eosinifílico, neurologic deficit for life (Summers et al. 1995, Beasley 1999, limites celulares evidentes, globules citoplasmáticos eosi- Maxie & Youssef 2007).
nofílicos, e núcleo excéntrico, hipercromático e ocasional- The pathogenesis of ELEM is not yet completely under- mente picnótico foram observadas nas areas de rarefacção, stood. The enzyme sphingosine-N-acyltransferase (whose edema, hemorragias e necrose. Os suplementos alimen- substrates are sphingosine and fatty acyl-CoA) is structurally tares continham 12.490μg/kg de fumonisina B1 e 5.251μg/ inhibited by fumonisins. This enzyme is involved in sphingo- kg de fumonisina B2. Este é o primeiro surto reportado na lipids biosynthesis and it is hypothesized that the accumul- Argentina de leucoencefalomalácia equina associado ao ation of the enzyme substrates as well as the depletion of consumo de suplementos alimentares contendo altas con- complex sphingolipids, may account for the toxicity of these centrações de fumonisinas.
fumonisins (Merril et al. 1996, Beasley 1999).
The characteristic gross lesion of ELEM is restricted to TERMOS DE INDEXAÇÃO: Micotoxinas, cavalo, leucoencefa-lomalacia equina, fumonisinas, patologia, Argentina.
the white matter of the cerebral hemispheres and consists of softening, cavitation and yellow discoloration (leukoence- phalomalacia). The lesion may be focal or multifocal, uni or bilateral (Summers et al. 1995), and mild cases may not Equine leukoencephalomalacia (ELEM), also known as show gross lesions at all (Beasley 1999). Histologically, the equine mycotoxic encephalomalacia or moldy corn poiso- most characteristic lesions consist of areas of liquefactive ning is a devastating neurologic diseases of equidae cha- necrosis, edema and hemorrhage affecting the encephalic racterized by acute central neurological clinical signs asso- white matter (Maxie & Youssef 2007). A presumptive ciated with liquefactive necrosis of the cerebral sub-cortical diagnosis is established based on clinical signs and on gross white matter. The disease has been reported in several and/or histological findings. Confirmation of the diagnosis countries and it is caused by ingestion of one or more type relies on detection of toxic concentrations of fumonisins in of fumonisins (Marasas et al. 1988, Kellerman et al. 1990), feed (Beasley 1999). We describe here a cluster of cases of mycotoxins produced by several species of fungi of the genus ELEM in Argentina, a country in which no cases of the Fusarium, including F. proliferatum and F. verticillioides disease associated with consumption of fumonisins have (formerly F. moniliforme) (Shephard et al. 1996), that are been reported before.
frequent corn (Zea mays) and corn by-products contaminants(Cawood et al. 1991, Ross et al. 1991). More than 28 types MATERIALS AND METHODS
of fumonisins have been isolated and characterized (Rheeder et al. 2002). Of these, fumonisins B1 (FB1), B2 (FB2) and In August 2007 an outbreak of neurological disease and B3 are the most common in nature and FB1 is the most sudden death in Arabian horses occurred in a farm located in frequently detected in corn worldwide (Beasley 1999, FDA Coronel Rosales County, Buenos Aires Province, Argentina. A 2001, Wu 2006) and the most commonly associated with herd of 60, 2 to 4-year-old male Arabian horses was grazing on ELEM outbreaks. Fumonisins are responsible for a variety natural pastures in a 160 hectare paddock. In addition, the ani- of health problems in several animal species, including mals were supplemented ad libitum with a mixture of corn kernelsand wheat bran administered in silo feeders. Within ten days humans. These compounds are carcinogenic in laboratory after the horses began consuming the supplement, 4 horses were rodents (NTP 2001) and the International Agency for found dead and 3 others were seen showing acute neurological Research on Cancer of the World Health Organization has signs. The animals had been seen the day before by the caretaker included them in the list of probable carcinogenic substances and they appeared healthy. The clinical signs of the sick animals for humans (WHO 2002).
were of variable severity and included blindness, circling, aimless Amongst the domestic animals, horses are the most walking, ataxia and hyperexcitability. The clinical signs worsened sensitive to fumonisin intoxication, the toxic effects of FB1 until the horses became laterally recumbent and two of them in this species being dose-dependent (Foreman et al. 2004).
died 24h after the onset of the clinical signs. The third horse, Most naturally occurring cases of ELEM have taken place which presented milder clinical signs, was treated with thiamine, with feed containing FB1 concentrations above 10,000μg/ antibiotics, dexamethasone and flunixin, and it showed a slowpartial recovery. The morbidity, mortality and lethality rates were kg (Ross et al. 1991). Affected horses develop acute 11.6%, 10% and 85.7%, respectively.
neurological clinical signs after a variable exposure time,which ranges between 7 and 180 days, or die suddenly and unexpectedly after only mild neurologic clinical alteration or Post-mortem examinations of one of the horses found dead without clinical signs being observed (Wilson et al. 1992, (Horse # 1) and one of the animals that had been observed Pesq. Vet. Bras. 31(5):407-412, maio 2011 Equine leukoencephalomalacia (ELEM) due to fumonisins B1 and B2 in Argentina presenting neurological signs (Horse # 2) were performed. Both philic globules, and/or multifocal areas of hemorrhage.
animals were 3 years old. The estimated elapsed time between Throughout the areas of rarefaction, hemorrhage, edema death and necropsy was 12h and 3h, respectively. Samples from and necrosis there were: (1) swollen astrocytes with large, brain, liver, spleen, kidney, intestine, lung, stomach, heart, lymph vesicular nuclei; (2) a moderate number of activated glial node, adrenal gland and urinary bladder were collected and cells with abundant eosinophilic cytoplasm, well-demarcated fixed in 10% neutral buffered formalin for 48h. The brains were cell boundaries, frequently containing intracytoplasmic, fixed whole for 48h after which they were sliced at 5mm intervalsand fixed for another 48h in fresh formalin, and the following deeply eosinophilic, small globules and occasionally areas were obtained: cortex, brain stem, cerebellum and medulla eccentric, hyperchromatic sometimes pyknotic nucleus oblongata. The tissues were embedded in paraffin, sectioned at (Fig. 4); (3) scattered neutrophils; and (4) rare eosinophils.
5ìm and stained routinely with hematoxylin and eosin (HE).
Vascular changes were present in small arteries and veins A blood sample was collected from Horse # 2 and the serum within the areas of rarefaction and necrosis, and included was processed by capture ELISA for West Nile Virus (WNV) hypertrophy and degeneration of the vascular endothelium, IgM antibody detection as previously described (Ostlund 2008).
perivascular edema and hemorrhage, and thrombosis. Oc- Cerebrospinal fluid (CSF) was collected from both horses casionally, there were perivascular cuffs consisting of a and used for WNV IgM antibody detection using the same low to moderate number of lymphocytes, histiocytes, fewer technique described above for the serum of Horse # 2.
neutrophils and rare eosinophils (Fig.1-6). The urinary From Horse # 2, a pool of brain tissue (cerebrum, cerebellum and medulla oblongata) was collected and frozen immediately bladder of Horse # 2 had severe, acute, diffuse, sub- at -20oC until it was processed for virus isolation, and WNV and epithelial hemorrhage. No other significant histological ab- Equine Herpesvirus 1 (EHV-1) PCR. For virus isolation, brain normalities were observed.
pool tissue homogenates were inoculated onto RK13 cells; theinoculated cell cultures were observed daily and a blind passage onto new cells was done after 7 days. Polymerase chain reaction The feed supplement appeared grossly normal and no (PCR) and reverse transcriptase PCR (RT-PCR) for EHV-1 evidence of mold was observed. Determination of fumonisins (Lawrence et al. 1994) and WNV (Johnson et al. 2001) genome by the liquid chromatographic method revealed a concentra- detection were performed on DNA and RNA, respectively, tion of 12,490μg/kg of FB1 and 5,251μg/kg of FB2.
extracted from the same tissue homogenates.
Samples from the feed supplement (mixture of corn kernels and wheat bran) were collected and analysed to determine the No cytopathic viruses were isolated from brain tissue presence of FB1 and FB2 by liquid chromatography (AOAC pool of Horse # 2; RT-PCR for EHV-1 and PCR for WNV 2000). Limits of Detection (LOD) were 10 ng/g for FB1 and 6 ng/g for FB2 (Signal-to-noise ratio = 3:1). Limits of Quantification genome detection resulted negative. No WNV IgM antibo- (LOQ) were 18ng/g for FB1 and 30ng/g for FB2 (Signal-to-noise dies were detected in blood serum or CSF of Horse # 2.
ratio = 5:1). Average recoveries at 100, 200, 400 and 600 μg/kgof spiked sample were greater than 99% for FB1 and the same level for FB2 was 103%. The precision of the methods was Acute central neurological disease in horses can be caused calculated in terms of relative standard deviation and were by several viruses (e.g. WNV, EHV-1 and encephalitides ranged between 7.5 and 17.0% for both fumonisins.
viruses), protozoa (e.g. Sarcocystis neurona), bacteria (e.g.
Listeria spp.), trauma and toxic substances (e.g. fumonisins and yellow starthistle - Centaurea solstitialis - intoxication).
In this case, infectious encephalitides were ruled out by Both necropsied horses were in very good nutritional histology and also by the negative result of virus isolation.
condition, and in a mild to moderate state of post-mortem WNV and EHV-1 were also ruled out by the negative results decomposition. Grossly, the brain of Horse # 2 had multiple of the PCR specific for these diseases and, in the case of to coalescing foci of hemorrhage, brown-yellow discolorati- WNV, by the negative serological results. No evidence of on and softening of the sub-cortical cerebral white matter.
trauma was evident on necropsy.
No gross lesions were found in the brain of Horse # 1. The The gross and histological features of ELEM, including urinary bladder mucosa of Horse # 2 was diffusely reddened.
the anatomical location of these changes are very The only other gross findings observed in these two horses characteristic of this condition. In this study a preliminary consisted of multifocal, shallow, chronic ulcerations and diagnosis of ELEM was established based on the gross presence of numerous larvae of Gasterophilus sp. attached lesions in the brain of Horse # 2 and on the histological to the non-glandular gastric mucosa.
changes observed in the brain of both horses. This Histological lesions were seen in the cerebral hemis- diagnosis was confirmed by detection of toxic concentrati- pheres, brainstem and cerebellum only and they were si- ons of FB1 and FB2 (17,741μg/kg) in the feed supplement milar in both animals (Horses # 1 and 2). They consisted of that the animals were eating. This value is well over the extensive multifocal to coalescing areas of white matter amount of fumonisin considered toxic for horses. Most rarefaction and necrosis, which occasionally extended into naturally occurring cases of ELEM have been seen in ani- the adjacent gray matter. Affected white matter had severe mals eating feedstuff with fumonisins concentrations above eosinophilic proteinaceous edema, with scattered eosino- 10,000μg/kg (Ross et al. 1991, Wilson et al. 1992).
31(5):407-412, maio 2011
Federico Giannitti et al.
Fig.1. Cerebral cortex, horse # 2. Areas of malacia and Fig.2. Brainstem, horse # 2. Multifocal, severe hemorrhage.
hemorrhage affecting the white matter (WM) and sparing the gray matter (GM). HE, 20x.
Fig.4. Cerebral cortex, horse # 2. White matter malacia with Fig.3. Cerebral cortex, horse # 2. Abundant, eosinophilic edema and extracytoplasmic eosinophilic globules (thick homogeneous material (edema) and hemorrhage within arrow), reactive glial cells with abundant eosinophilic cyto- the white matter. HE, 400x.
plasm, distinct cell borders, intracytoplasmic deeply eosi-nophilic globules and eccentric hyperchromatic nucleus (thin Fig.5. Cerebral cortex, horse # 2. Vascular thrombosis and pe- arrows), and hypertrophied vascular endothelium (*). HE, rivascular hemorrhage within the white matter. H&E, 600x.
Fig.6. Cerebral cortex, horse # 2. Perivascular inflammatory infiltrate. HE, 600x.
Pesq. Vet. Bras. 31(5):407-412, maio 2011 Equine leukoencephalomalacia (ELEM) due to fumonisins B1 and B2 in Argentina To the best of our knowledge, lesions compatible with ELEM is not frequently reported in Argentina despite ELEM were diagnosed only once before in Argentina the high frequency of fumonisins contamination detected (Monina et al. 1981). However in that case the diagnosis in corn and corn by-products destined to animal and human was established based on clinical signs, gross and consumption in this country (Solovey et al. 1999, Broggi et histological findings, and isolation of Aspergillus flavus, al. 2002, Broggi et al. 2007, Pacin et al. 2009). This situation Penicillum spp., and Fusarium spp. from feed, but no me- may be due to the low frequency with which corn is used to asurement of fumonisins was performed. Isolation of feed horses or to the limited number of horse necropsies Fusarium spp. from feed samples is no longer considered and/or toxicological studies performed, which are necessary of diagnostic significance since this fungus is a frequent to confirm the diagnosis.
contaminant of corn and it does not always producefumonisins (Uhlinger 1997, Beasley 1999, Galey 2009).
In the previous case reported in Argentina by Monina et This is the first confirmed outbreak of ELEM in Argentina al. (1981) the authors describe the presence of sub-epithelial in which toxic levels of fumonisins were detected in feed.
hemorrhage in the urinary bladder which was also present Nevertheless, we believe the disease may be under-reported in one of the horses in our study. These lesions have been and it should be an important differential diagnosis in horses previously reported to occur in ELEM confirmed cases that develop acute neurologic signs and are consuming (Rooney & Robertson 1996).
feedstuffs containing corn. Findings in this report emphasize The swollen glial cells with abundant eosinophilic cyto- the importance of detection of fumonisins and other myco- plasm, distinct cell borders, intracytoplasmic deeply eosi- toxins related to health problems in feeds destined to ani- nophilic globules and eccentric, hyperchromatic, occasio- mal and human consumption. This and other mycotoxicoses nally pyknotic nucleus present throughout the areas of should not be underestimated in animal production systems, hemorrhage, edema and necrosis are referred to as oligo- mainly those using grains and cereals as feedstuffs.
dendrocytes or clasmatodendritic astroglia in the humanpathology literature. It has been proposed that these Acknowledgements.- The authors wish to thank Dr. Ingeborg Lan-
macroglial cells incorporate plasma proteins and edema fluid gohr from Michigan State University, and Gabriela Cano and Daniela that have been released into the brain parenchyma around Taglieri from "Comisión de Investigaciones Científicas de la Provincia areas of hemorrhage and phagocytose cellular debris in de Buenos Aires" for their technical assistance.
patients with cerebrovascular disease, which likely represents a homeostatic mechanism that tends to maintain thecomposition of the extracellular environment (Tomimoto et Abbas H.K. & Riley R.T. 1996. The presence and phytotoxicity of fumonisins and AAL-toxin in Alternaria alternata. Toxicon 34:133-136.
al. 1997, Del Bigio et al. 2000). The presence of this celltype has been previously described in cases of AOAC International 2000. AOAC-IUPAC (1998) AOAC Official Method 995.15 Fumonisins B1, B2, and B3 in corn. Liquid Chromatographic leukoenephalomalacia in horses (Riet-Correa et al. 1998, Method, AOAC-IUPAC Method, First Action 1995, Revision March Câmara et al. 2008) and mules (Riet-Correa et al. 2007, Câmara et al. 2008).
Barros C.S.L., Barros S.S., Dos Santos M.N. & Souza M.A. 1984.
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Beasley V. 1999. Toxicants with mixed effects on the central nervous 1998). This is consistent with the time of the year when the system. In: Ibid. (Ed.), Veterinary Toxicology <http://www.ivis.org/advances/Beasley/toc.asp> International Veterinary Information currently reported case occurred (August; middle of the Service (IVIS), Ithaca, NY (www.ivis.org).
winter in the Southern hemisphere).
Broggi L.E., Pacin A.M., Gasparovic A., Sacchi C., Rothermel A., Gallay ELEM cases have also been associated to wet climate A. & Resnik S.L. 2007. Natural occurrence of aflatoxins, conditions during the corn production period (Barros et al.
deoxynivalenol, fumonisins and zearalenone in maize from Entre 1984, Rooney & Robertson 1996). In our case no information Rios Province, Argentina. Mycotoxin Res. 23(2):59-64 about year of harvesting and storage conditions of the corn Broggi L.E., Resnik S.L., Pacin A.M., González H.H.L., Cano G. & was available.
Taglieri D. 2002. Distribution of fumonisins in dry-milled corn fractionsin Argentina. Food Additives and Contaminants 19(5):465-469.
Although most fumonisins are produced by fungi of the Câmara A.C.L., Bastos Alfonso J.A., Riet-Correa F., Dantas A.F.M., genus Fusarium, other fungi such as Aspergillus niger Lopes de Mendonça C., de Acevêdo Costa N., Cruz Dantas A., (Frisvad et al. 2007) and Alternaria alternata (Abbas & Riley Araújo Costa Neto H., Silva Siqueira Campos A.G. & de Souza M.I.
1996, Mirocha et al. 1996), are capable of producing FB1 2008. Leucoencefalomalácia em eqüídeos no estado de Pernambu- and FB2. Although it is most likely that the fumonisins co. Ciência Animal Brasileira. 9(2):470-479.
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Pesq. Vet. Bras. 31(5):407-412, maio 2011
BACK TO BASICS MECHANISM OF ACTION OF THE MAJOR ANTIBIOTIC GROUPS CELL WALL SYNTHESIS INHIBITORS In a recent survey1, vets identified that remembering the intricacies of every different Penicillins antibiotic could sometimes be a challenge. • Bactericidal • Bactericidal