Four-month-old Hampshire ewe (Ovis
aries).One of a number
of young meat sheep showing neurological signs and hyperthermia. This sheep
progressed through phases of straight legs, muscle fasciculations, and
recumbency. A neurological examination revealed cranial nerves normal,
mentation normal, recumbency, good muscle tone, head turn to left, normal to
increased muscle tone. Localized to cervical spinal cord. This sheep was
treated with flunixin and antibiotics with no response by owner.
the superficial pectoralis muscle is green-black, dry, and firm with
surrounding red tissue in an oval area measuring 8 x 5 x 1cm on the right and 7
x 6 x 1cm on the left (Figs1,2.: severe, myonecrosis and hemorrhage). The left
quadriceps and the left lateral head of the triceps are irregularly pale pink
to gray (Fig3.: myodegeneration/myonecrosis).
Numerous Hemonchus and Trichostrongyles are in the abomasum.
and cross sections of triceps muscle are examined. On cross section, round,
large sometimes hyalinized, hypereosinophilic or flocculant fibers are seen
with central, large nuclei. Some fibers remain as aggregates of activated satellite
cells in a shrunken endomysium. On longitudinal section, swollen, hyalinized,
broken, flocculent fibers with myocyte nuclear loss and contraction bands are
prominent. Satellite cells are activated and proliferating with a large
vesiculate chromatin and blue-grey cytoplasm. Macrophages and small clusters
of degenerate neutrophils enter pockets of broken fibers. Capillaries are
lined by endothelial cells with hypertrophied nuclei.
Subacute, monophasic myopathy with
severe myofiber necrosis and satellite cell activation and early regeneration.
No monensin or lasalocid in rumen contents.
analysis: 3.4% lasalocid (this 10,000 times the legal limit of 30g/ton,
section shows a nice monophasic toxic myopathy. Ionophores are added to feeds
for growth promotion and as a coccidiostat.6,9 However, if toxic
doses are achieved, they permit free cationic movement, especially calcium into
myocytes and necrosis. Monogastrics such as the horse and dog are more
This breeder had been having a chronic, sporadic, neurologic problem in the flock of show sheep. It affected sheep taken off pastured and pushed nutritionally for the show season. Upon opening this ewe, it was obvious that a myopathy was the problem, and given the history, we analyzed the rumen content (negative for ionophores additives), and then, the feed from the bag used to fed these ewes was tested (toxic levels of lasalocid). The levels of lasalocid the feed were extremely high, and it is presumed a pocket of unmixed, lasalocid salt was included in the test sample. In some reports2 and in this contributors experience, once the ionophore is over a certain con-centration, these additives are unpalatable, and animals refuse the feed rather than consume myotoxic levels. Unfortunately, toxicity studies are based on bolus feedings.1,4
In spontaneous, ionophore (usually monensin) intoxications of sheep2,7,8,9,10 display an acute onset of signs of anorexia, dyspnea, muscle weakness, ataxia, a stiff gait and deaths follow feed changes. Firm or atrophic rear limb muscles are sometimes reported. A variety of autopsy lesions are reported including: cavitary effusions, pale-streaked hearts, diarrhea and pale-streaked skeletal muscles especially semi-membranosus and semitendinosus. While some acute gastrointestinal lesions are reported, consistent macroscopic and/or histologic lesions are in cardiac and skeletal muscles. In ovine monensin toxicity studies1,4, it was commented that acute myopathies were not visible in H&E-stained sections, but that lesions were demonstrable using electron microscopy. Early ultra-structure changes include mitochondrial swelling and myofibrillar disarray. Chronic histologic lesions include atrophy, fibrosis, and calcification. The severity of the present case is impressive, and the minimal cardiac lesion is unexplained. Is it possible that hypoxia from hemonchosis-exacerbated lesions?
Finally, many ionophore intoxications present as CNS disease. Although in light of the muscle lesions, the signs could be explained as muscular pain and weakness, we should remember that an ionophore neuropathy is observed in some toxicity trials.5 Our ewe had no lesions in the sciatic or femoral nerves, but some conduction problems may be occurring.
Diagnosis: Skeletal muscle:
Degeneration and necrosis, diffuse, severe, Hampshire ewe, Aries ovis.
As mentioned by the contributor, this case is an excellent
example of extensive monophasic skeletal muscle necrosis. Classification of muscle degeneration and necrosis is
based on the distribution of the lesion and the duration of the insult.
Characterization of the type of skeletal muscle necrosis gives insight on the
potential cause and helps narrow down the list of differential diagnoses. As a
result, a classification scheme breaks muscle necrosis into four broad
categories, including focal monophasic, multifocal monophasic, focal
polyphasic, and multifocal polyphasic. Focal monophasic is the result of a
single mechanical injury, such as intramuscular injection or focal trauma. This
case is representative of the multifocal monophasic pattern, which is caused by
a single massive exposure of myotoxic drugs, such as ionophores (monensin and
lasalocid), or metabolic disorder.11 Exertional capture myopathy
also produces widespread monophasic skeletal muscle necrosis with a similar
histologic appearance to this case. Polyphasic reactions are the result of
repeated and ongoing skeletal muscle insult occurring over a prolonged period
as a result of repeated trauma (focal) or nutritional deficiencies,
inflammatory myopathies, or genetic disorders (multifocal). Skeletal muscle
regeneration, mineralization, and deposition of fibrous connective tissue, all
key features of polyphasic necrosis, are not prominent in this case.3,11
Nice examples of multinucleated satellite cells are scattered throughout this
tissue section and represent only the beginning stages of regeneration.
Conference participants briefly reviewed the stages of skeletal muscle necrosis, re-generation, and repair. Myofibers are long and multinucleated and thus often undergo segmental necrosis rather than necrosis of the entire muscle fiber; however, extreme pressure, trauma, or ischemia can produce global myofiber necrosis. Necrosis is commonly triggered by increased intracellular calcium concentration, often released from high levels stored in the sarcoplasmic reticulum. Initially, segmental changes are represented by myofiber hyper-contraction, and cross sections appear large and dark with hyalinization and loss of cross striations. Further insult results in sarcoplasmic fragmentation that can lead to dystrophic myofiber mineralization, often seen in chronic myopathies.3,11
Skeletal myofibers are classified as permanent cells and are not capable of cell division. As a result, skeletal muscle regeneration depends on the activation of satellite cells, normally resting between the sarcolemma and the basement membrane. These cells are highly resistant to injury and are activated by necrosis of adjacent myofibers.3,11 Satellite cells begin proliferation and differentiation into myoblasts in the early stages of skeletal muscle regeneration. Concurrently, macro-phages migrate from the peripheral blood and phagocytose necrotic debris leaving a potential space within the damaged muscle. The initial infiltrating macrophages are of the M1 inflammatory phenotype but later switch to the M2 anti-inflammatory phenotype.11 If the basement membrane is intact, the potential space is filled by a scaffold, called the sarcolemmal tube, which prevents the local migration of fibroblasts and instead acts as a guide for proliferating myoblasts. Within the sarcolemmal tubes, satellite cells, known as activated myoblasts at this stage, can be observed undergoing mitoses. Within hours, sarcolemmal tubes fuse end-to-end and form myotubes that eventually mature into skeletal myofibers over the course of a few days. Initial infiltrating M1 macrophages are tough to stimulate proliferation of the myoblasts, while M2 macrophages promote the formation of the myotubes.3,11
In contrast, if large enough numbers of satellite cells are killed and if the basement membrane is destroyed, the sarcolemmal tube is not formed, and there is no proliferation of myoblasts. This allows the influx of fibroblasts into the areas of necrosis resulting in healing by fibrosis rather than regeneration. Additionally, in cases where there is disruption of the basement membrane but satellite cells are still viable, regeneration is disorganized and ineffective due to disorganization of proliferating myotubes. This is typified by the presence of muscle giant cells (large, pleomorphic multinucleated giant myoblastic cells) and fibrous connective tissue.3,11
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10. Nation PN, Crowe SP, Harries WN. Clinical signs and pathology of accidental monensin poisoning in sheep. Can Vet J. 1982; 23: 323-326.
11. Valentine BA. Skeletal muscle. In: McGavin MD,ed. Pathologic basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Mosby; 2017:922-926.