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In most species thiamin deficiency is expressed as central nervous system dysfunction due to the dependence of the brain on glycolysis for energy production. Clinical signs include an apparent weakness that is usually first characterized by poor leg coordination, especially of the forelimbs, and by inability to rise and stand. The head is frequently retracted (i.e., "star-gazing") ( Illus. 1), and cardiac arrhythmia may occur. Affected animals may also display blindness and convulsions. Specific signs are usually accompanied by growth depression, anorexia and severe diarrhea, followed by dehydration and death (NRC, 1996). Signs in calves can be either acute or chronic. Acutely affected calves displayed anorexia with severe diarrhea and died within 24 hours of onset. These signs appeared after two to four weeks on a low-thiamin diet (Johnson et al., 1948). Growing cattle display dullness and neural aberrations such as circling, head pressing, apparent blindness, excitability and convulsions. These symptoms may be confused with those of certain bacterial or viral diseases (e.g.. clostridial infections, listeriosis, encephalitis), heavy metal poisoning, hypomagnesemia or vitamin A deficiency. Mortality can be sudden and significant if animals are not treated. This condition, polioencephalomalacia (PEM) or cerebrocortical necrosis (CCN), is also observed in sheep and goats. The condition is often precipitated by feeding high grain feedlot rations or by the sudden introduction of livestock to lush pasture. Low copper status and high intakes of sulfur, especially sulfate, in feed or water are risk factors. In some instances similar symptoms arise as a result of sulfur toxicity and the production and inhalation of hydrogen sulfide gas, a neurotoxin (Kandylis, 1984).
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PEM affects mainly calves and young cattle between four months and two years of age and lambs, young sheep and goats between two and seven months of age. The incidence of PEM is reported to be between 1% and 20%, and mortality may reach 100%. Clinical signs in mild cases include dullness, blindness, muscle tremors, especially of the neck, and opisthotonos ("star-gazing"). Other progressive symptoms include circling, head pressing and convulsions; in severe cases, collapse within 12 to 72 hours after the onset of the disease (Illus. 2). In the final stages, the ears droop and the limbs and head are extended, which is a parallel of "star-gazing" in thiamin-deficient chicks. Trembling and twitching of the musculature of the ears and eyelids, waving of the head and neck and grinding of the teeth with groaning may be observed. Without treatment, death usually occurs within a few days. The main lesions in these animals are necrotic areas in both cerebral hemispheres.
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PEM may appear as an acute disease with high mortality or in milder forms that run a more protracted course. Not all animals in a group will be affected. It is probable that, particularly in its mild form, the condition is often not diagnosed and may in fact occur more frequently than is recognized. Clinical signs of central nervous system (CNS) disorders associated with PEM are more readily recognized than the nonspecific symptoms such as scouring, reduced growth and anorexia. However, these signs are also exhibited at later stages of thiamin deficiency (Rammell and Hill, 1986). Thornber et al.(1979) reported that lambs fed a thiamin-deficient diet may not show clinical signs of a CNS disorder for three to five weeks or longer, although depressed blood thiamin levels and other clinical signs may be observed. Without treatment, mortality is about 50% with the mild form and may be up to 100% in the acute form of PEM. The incidence and death rate are highest in young animals from two to five months of age.
A number of experiments have shown that PEM can be caused by naturally occurring thiamin antagonists, reduced thiamin synthesis or increased destruction of thiamin in the rumen. Several researchers report that most field cases of PEM result from a progressive thiamin deficiency, likely the result of bacterial thiaminases in the rumen or lower intestine (Loew, 1975; Frye et al., 1991). Clinical reports indicate that high concentrate rations or sudden introduction of lush pasture results in production of rumen thiaminases and predisposes young cattle and sheep to PEM (Edwin and Lewis, 1971). There is also evidence that disruptions of rumen function by sudden diet change can result in production of anti-thiamin analogs. Thiaminases can be produced by bacterial and fungal contamination of feeds (Davies and Pill, 1968). Clostridium sporogenes and Bacillus thiaminolyticus have been isolated from the rumen of PEM-affected cattle and sheep (Loew, 1975; Cushnie et al., 1979; Haven, et al., 1983). Both organisms produce thiaminase type I. Thiaminases are found in certain plant species, such as the bracken fern. This is a special problem in Australia, where PEM occurs under pasture conditions, apparently due to grazing of certain fern species. Furazolidone at high doses produces a thiamin-responsive neuropathology including head tremors, ataxia, visual impairment and convulsions (Ali et al., 1984; Merck, 1991).
The anticoccidial mode of action of amprolium is apparently through inhibition of thiamin phosphorylation. Loew and Dunlop (1972) found that high levels of amprolium (considerably above the levels needed to prevent coccidiosis) could produce the physical signs and the histological lesions of PEM. Amprolium-induced PEM produces abnormal changes in brain waves and is thiamin responsive (Itabisashi et al., 1990). Wernery et al.(1998) reported that amprolium induced PEM in dromedary camels but only when a barley diet was fed and not when the camels were fed hay ad libitum. However, serum thiamin was depressed equally in both groups, indicating an interaction between amprolium and diet in producing PEM.
From Colombia, a wasting disease known as "secadera" or "drying up" (Illus. 3) is alleviated by thiamin injections (Mullenax, 1983). Mullenax (1983) suggested that a fungus associated with native forage produces a thiaminase. On the contrary, Miles and McDowell (1983) report that the wasting disease secadera can be successfully controlled with a highly fortified complete mineral supplement. It is possible that supplementation of this wasting disease is controlled by either thiamin or trace minerals through different mechanisms (McDowell, 1985). More recent data show an effect of copper on thiamin metabolism in cattle (Olkowski et al., 1991), suggesting that marginal copper status is a factor in PEM, and other related neural degenerative diseases (Frank et al., 1992).
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High sulfur diets or water sources are associated with thiamin deficiency and PEM symptoms (Kandylis, 1984; Olkowski, 1991b; Gould, 1998). The toxicology of sulfur in ruminants has been reviewed in detail by Kandylis (1984). Gould et al. (1991) reported that in steers the highest rumen fluid sulfide concentrations coincided with the onset of clinical signs of PEM. McAllister et al.(1997) investigated a field case of PEM induced by high sulfate water and reported no reduction in blood thiamin in affected steers. Controlled studies have reported both significant reductions (Goetsch and Owens, 1987) and small reductions (Alves de Oliveira et al., 1997) in rumen thiamin production in response to high sulfate intakes. Olkowski et al. (1991b), in a large field study, reported that beef cattle consuming high sulfate water sources had reduced blood thiamin status. Several cases of PEM have occurred when gypsum (CaSO4) has been used as a feed intake-limiting factor. It would appear that the sulfate ion of gypsum, during its conversion to sulfide, must pass through sulfite, which itself may destroy thiamin or produce anti-thiamine analogs (Bartley and Brent, 1982). Feedlot cattle that received 0.72% sulfate had 50% less gain than controls and some developed PEM (Sadler et al., 1983). For sheep, high sulfur intake was shown to have a detrimental effect on in vitro polymorphonuclear leukocyte function. Thus, ruminants consuming diets or water high in sulfur may have reduced immune function and increased risk of disease (Olkowski et al., 1990). Low copper status appears to play a role in development of PEM in sheep (Olkowski et al., 1991a). High dietary sulfur and molybdenum can induce copper deficiency through formation of thiomolybdates in the rumen (Maynard et al., 1979). Thus, low dietary copper, high dietary or water sulfate and molybdenum are predisposing factors for PEM. Brassica plant species contain high levels of sulfur and can produce low copper status in ruminants (Taljaard, 1993). The symptoms of PEM are not entirely specific to thiamin deficiency although thiamin deficiency is clearly one of several causative factors, along with high concentrate diets, excess sulfur intakes and low copper status.
Livestock grazing tall fescue infected by endophyte (Acremonium coenophiatum) can suffer from tall fescue toxicosis. The symptoms resemble those caused by elevated rumen thiaminase activity, for example, PEM (Edwin et al., 1968; Lauriault et al., 1990), and are alleviated by thiamin supplementation (Dougherty et al., 1991). Response to supplemental thiamin was found to be greater when cattle grazing endophyte-infected tall fescue were exposed to heat stress (Lauriault et al., 1990). Results suggest that oral thiamin supplementation may alleviate tall fescue toxicosis of beef cattle during hot weather. An earlier study (Fontenot et al., 1988) found that in cattle grazing fescue moderately infected by endophytes, supplemental thiamin did not have any beneficial effect.
Diagnosis of thiamin deficiency initially depended upon recognition of the clinical signs in live animals, followed by confirmatory brain histopathology or clinical response to thiamin administration (Rammell and Hill, 1986). Moreover, affected animals react so promptly to treatment with thiamin (sometimes within hours) that early treatment with thiamin is used to confirm the diagnosis of PEM.
Biochemical changes indicating that PEM is associated with thiamin deficiency include reduced blood, urine and tissue thiamin concentrations, dramatic elevation of blood pyruvate and lactate, and markedly reduced erythrocyte transketolase activity (Braunlich and Zintzen, 1976). Brin (1969) showed that blood transketolase activity (particularly in the red cells) is a reliable index of the availability of coenzyme TPP, and thus is well correlated with the degree of deficiency in animals. Transketolase activity is an excellent indicator of a marginal thiamin deficiency. The best transketolase assay for assessing thiamin deficiency is based on the so-called TPP effect, which is the percentage increase in transketolase activity following addition of excess TPP to the sample. Values of 120% to 250% have been reported for animals diagnosed as having PEM (Edwin et al., 1979). Benevenga et al. (1966) performed a classical experiment on thiamin deficiency in Holstein calves fed a purified diet. Deficiency symptoms appeared 27 to 48 days after initiation of a thiamin-free diet. Anorexia, heart arrhythmia, respiratory distress, lacrimation and grinding of teeth were clinical symptoms. Blood pyruvate and lactate levels were elevated, hemoglobin and PCV depressed and, activities of several liver enzymes were reduced 30% to 50%. Re-feeding thiamin relieved all symptoms.
Zintzen (1974) concludes that PEM can be definitely established if the following four situations exist:
- Case history: Animals maintained on high energy feeds rich in soluble carbohydrates died after showing central nervous system disorders.
- Biochemical evidence: Blood pyruvate has steeply increased and the activity of erythrocyte-transketolase has been reduced.
- Diagnostic therapy: Animals thought to have PEM will react promptly to early treatment with thiamin.
- Pathological changes: Necropsy shows typical pathological, anatomical changes , i.e., bilateral cortical necrosis in the brain.
Seasonal trends have been associated with PEM, which may be due to increased metabolic demands of gestation, lactation and growth, or changes in rumen microbial populations. Additionally, feeding of high-concentrate, low-fiber rations may induce PEM. Polioencephalomalacia generally occurs in feedlot cattle about three weeks after a diet change. Research suggests that PEM is associated with lactic acid acidosis and with the adaptation to high-grain rations. Oltjen et al.(1962) reported that thiamin in the rumen is decreased by a reduction in rumen pH; a low ruminant pH is characteristic of cattle fed high-concentrate diets. However, this effect was not observed in vitro using rumen simulation techniques (Alves de Oliveira et al., 1997).
PEM has caused significant economic losses in tropical countries, not only in feedlots where high-grain diets are fed, but also where high levels of molasses are fed. When molasses is provided ad libitum together with diets containing little crude fiber, a disease referred to as "molasses toxicity" or "molasses drunkenness" appears (Losada et al., 1971). Clinical signs of this condition closely resemble PEM, and some studies completed in Cuba have suggested that thiamin treatment, together with additional roughage, may be an effective cure. Mella et al. (1976) induced PEM by feeding a molasses-urea diet to cattle.
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