Vet 961_2131 ld.pmd
Pesq. 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
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:[email protected]
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.
[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
, 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.
spp.), trauma and toxic substances (e.g. fumonisins
and yellow starthistle - Centaurea solstitialis
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
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.
Several authors reported a seasonal occurrence of
Leucoencefalomalacia em equinos no Rio Grande do Sul. Pesq. Vet.
ELEM with a peak of cases occurring between late fall to
early spring (Rooney & Robertson 1996, Riet-Correa et al.
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. &
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
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eosinophilia in human post-mortem brains: A change indicative of
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plasma extravasation. Acta Neuropathol 100:688-694.
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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
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