Ergot alkaloid (ergopeptine) toxicity in horse hay and pasture

Introduction

Losses of foals, at birth and early gestation, remind us that pregnant mares are very susceptible to a number of bacterial, viral and nutritional challenges. In 2001, a number of practitioners in Kentucky and Ohio reported two separate syndromes:

• Agalactia (little or no milk), difficult extended foaling, "red bag" placentas (premature separation of the placenta), edematous placentas, weak or dead foals with aspiration pneumonia.
• Mares diagnosed pregnant by ultrasound at 45 days post breeding were found with a dead fetus by day 60.

The first syndrome resembles fescue toxicity except that, in these cases, the gestation period was normal. The second syndrome has not been described in association with the mycotoxins of endophyte-infected fescue. Fescue, as well as most hay and grain crops, can be colonized by fungi which produce an array of mycotoxins. The ergot alkaloids and the fusarium mycotoxins are the main mycotoxin groups of concern. For this review, we will use the more general term ergot alkaloid(s) to also include the ergopeptine alkaloids. Colonization of both grain and hay crops and the tendency to produce mycotoxins by fungi is dependant on environmental conditions. The clinical conditions caused by these fungi are not well described for horses. The sequence of events leading to the natural occurrence of the fungi and their mycotoxins is often unknown.

Two types of colonization can occur. The endophytes live between the plant's cell walls and include the more common genera Balansia, Epichloe, Acremonium and Neotyphodium. The non endophytic fungi do not live intercellular and include the more common genera Claviceps, Stachybotrys, Fusarium and Penicillium. The endophytes, and Neotyphodium specifically, complete their entire life cycle within the plant. The spread of the endophyte from one generation of plant to another is by way of the seed. The non endophytic fungi generally have a sexual cycle outside of the plant. Claviceps, specifically, has a life cycle which consists of: an airborne ascospore infecting the inflorescences (flower) of the plant; followed by the formation of the honeydew and sclerotia which replace the ovary; sclerotia, which are masses of mycelium, mature and fall to the ground forming stalked stromata which in turn produce ascospores^{footnote 1[1]}.

In many ways these fungi are very similar, since sometimes they may be asexual and sometimes have a sexual cycle. This discussion will be limited to the genera of fungi, Neotyphodium and Claviceps. Most of the fungi in these two genera produce a similar array of ergot alkaloids. The fusarium mycotoxins will be discussed in another fact sheet since they are normally associated with concerns when harvesting wheat or corn. However, when investigating clinical problems, remember to analyse for the fusarium mycotoxins. Background levels of the fusarium mycotoxins are commonly found in hay and pasture grasses.

Fescue toxicity

Neotyphodium coenophialum was formerly called Acremonium coenophialum. The endophytic fungus produces mycotoxins, resulting in the disease condition called fescue toxicity. The mycotoxins of endophyte-infected fescue belong to the class of chemicals called ergot or more specifically ergopeptine alkaloids. They are well recognized as causing dystocia in mares and deaths of foals in the United States. The primary clinical signs of ergot alkaloid poisoning in the late-gestation mare include:

• an extended gestation length from 11 to 12 months
• dystocia, with mares sometimes trying to foal for many hours
• agalactia (little or no milk) with poor quality colostrum (low immunoglobulin levels)
• "red bag" placentas from premature separation
• thick edematous placentas with weights exceeding 6.5 kg for a thoroughbred mare
• weak or dead foals with aspiration pneumonia from struggling to get out through a thickened placenta

No studies have shown the effect of ergot alkaloids in horses other than with late-gestation mares. Fescue is grown extensively in the arid areas of the USA because of its ability to withstand drought and its resistance to many insect infestations. Fescue is not commonly grown for pasture or hay production in Ontario. Endophyte-free varieties have been developed to get away from the problems caused by these mycotoxins. Endophyte-infected varieties of fescues are commonly used for erosion control and golf greens. Occasionally, endophyte-infected seed will be accidentally sold to horse owners.

Neotyphodium lives in a symbiotic relationship with the plant, gaining nutrients to live on while providing chemical protection against grazers, both insect and higher life forms and some resistance to drought. Neotyphodium completes its entire life cycle within the plant. It passes from one generation of the grass to the next in the seeds of the plant. The main alkaloid produced by Neotyphodium is ergovaline. However, many other ergot alkaloids can be found.

Ergotism

Ergotism is the clinical syndrome caused by the genera, Claviceps. It is a non endophytic fungus which lives on the plant, utilizing the plant's nutrients without a recognizable benefit to the host. Claviceps can live on a variety of hays and pasture grasses and produce fruiting bodies on bluegrass and cereal rye. Ergotism is probably the oldest known mycotoxicosis. The ergot alkaloids of Claviceps purpurea are hallucinogenic. Consumption of infected rye bread has been associated with human outbreaks which date back some 2,000 years. Claviceps has a sexual life cycle as previously described with the ovary of the plant being replaced with a whitish mycelial mass which enlarges, darkens and eventually hardens into a sclerotium or fruiting body. The Claviceps sclerotia contain a large array of chemicals. Many of these same chemicals are also commonly found in the endophytic infected grasses^{footnote 1[1]}. Different genera of fungi produce the ergot alkaloids in different proportions. Claviceps commonly produces ergotamine, ergostine, ergocristine, ergocryptine and ergocornine^{footnote 2[2]}.

Two clinical cases involving the production of ergot alkaloids by Claviceps have been associated with fetal loss in late-gestation mares. The first case is from Brazil^{footnote 3[3]}. Late-gestation mares, which were fed oats containing ryegrass seed, suffered fetal losses similar to the clinical condition of fescue toxicity. The authors indicate that the ryegrass seed was the only source of ergot alkaloids. The second case is an investigation in which cereal rye straw bedding was being consumed by late-gestation mares^{footnote 4[4]}. The clinical syndrome was similar to fescue toxicity except that the mares foaled around their normal due date. Of the first 8 mares to foal, 7 had dead foals. High-performance liquid chromatography (HPLC) analysis of the bedding indicated the presence of two ergot alkaloids, each equivalent to 450 ppb. One was identified as ergocornine. A second laboratory tested the straw bedding and found a large peak just ahead of 2.2 minutes retention time. This peak was adjacent to the ergonovine standard.

Ergot alkaloid toxicity in the late-gestation mare

Mares are sensitive to ergopeptine alkaloids at levels as low as 50–100 ppb, while cattle do not show visible signs until 1000-2000 ppb. These alkaloids exert toxic effects on the reproductive tract and mammary gland of the mare and have been associated with depression of serum prolactin and progestagens (5 alpha-pregnanes), a prolonged gestation, a thickened edematous placenta and agalactia^{footnote 5[5]}. The ergopeptine alkaloids interfere with the normal rise of progestagens (mainly 5 alpha-pregnanes) and prolactin in the last 40 days of gestation. The progestagen levels normally increase from 300 days to birth (4.8 + 1.5 to 22.7 + 2.7 ng/ml). Suppression of progestagen levels indicates ergopeptine toxicity^{footnote 5[5]}. Dr. Brendemuehl, Oregon State University, uses a commercially available radioimmune assay (RIA) progesterone assay to measure total immunoreactive progestagens in pre-foaling sera of mares.

Foals born without the normal increases in maternal progestagens suffer hypoadrenocortical function and are small, weak or stillborn^{footnote 5[5]}. Edema of the placenta increases the placental weight. The placental weight of the normal thoroughbred mare is reported as 5.7 + 0.08 kg. or about 12.5 lbs or 11% of the foals body weight^{footnote 6[6]},^{footnote 7[7]}.

Sampling and analysis

When placental edema is diagnosed, the attending veterinarian will need to determine if it is caused by an ergot alkaloid. Samples of possible sources of ergot alkaloids including feed, grain and hay will all have to be tested. Laboratory testing for ergovaline (the ergot alkaloid of fescue toxicity) and lolitrem B (the ergot alkaloid of perennial rye grass) are commonly available. Dr. Morrie Craig's laboratory, Oregon State University, analyses thousand of samples annually for ergovaline. It is difficult to analyze for other ergopeptine alkaloids due to the lack of control standards.

Mares in the last 30 days of pregnancy can be monitored for placental edema by ultrasound. Low pre-foaling progestagen levels in the late-gestation mare are indicative of exposure to ergot alkaloids. Monitoring of progestagen levels is done by collecting serum samples from the mares when they enter the foaling barn (approximately 330 days gestation). A comparison with a second serum sample around day 335 of gestation would show whether there is a normal rise or peaking in progestagen level. Levels below 15 ng/ml. are suspicious of ergot alkaloid toxicity. A pre-foaling serum progestagen level below 5 ng/ml. is seen with fescue toxicity. In 50% of normal mares, progestagen levels drop 6–10 hours prior to foaling.

The Ontario situation

During the 1999 foaling season, an investigation found that cereal rye straw bedding containing ergot alkaloids was responsible for thickened edematous placentas, agalactia and seven perinatal deaths in foals. In the 2000 foaling season, four Ontario farms experienced edematous placentas. One placenta weighed 14 kg. One of the farms observed that 49% of the placentas from 78 mares weighed 6 kilograms or greater. The attending veterinarian observed edema in 18% of the 78 placentas^{footnote 8[8]}. A definitive cause of the edema was not determined in these cases. Preliminary analysis of the non-fescue hay revealed the sporadic presence of an ergopeptine alkaloid(s) which could not be identified. It is hypothesized that the sporadic occurrence of placental edema in foaling mares results from the presence of an ergot alkaloid(s) less pharmacologically active than ergovaline in non-fescue hays in Ontario.

Prevention and recommendations

1. Mow grass pastures to keep them in a vegetative state rather than letting them develop seed heads. This will minimize the opportunity for airborne ascospore from invading pasture plants.
2. Never feed sclerotia-containing grain to late-gestation mares.
3. Never allow late-gestation mares to eat cereal rye straw bedding or stubble.
4. Ensure that all pasture/hay seed mixes containing tall fescue and perennial rye grass are guaranteed endophyte free. A sample of the seed can be sent to a laboratory for testing prior to seeding.
5. Samples of hay and pasture can be tested for the presence of ergovaline and lolitrem B. The testing for other ergot alkaloids is dependant on the laboratory having adequate control standards to compare to.
6. Choose a laboratory which uses HPLC methodology. Thin layer chromatography (TLC) is not sensitive enough to identify ergot alkaloid levels less than 1 ppm. Pregnant mares are known to have foaling problems at half of this level.
7. Use a foaling record form and examine each placenta as suggested in the information sheet, Examining the Mare's Placenta and Keeping Foaling Records^{footnote 9[9]}. Pay particular attention to placenta weights. Placenta weights greater than 11% of the foal's weight are of concern. For thoroughbreds, the placenta weight should not exceed 6.5 kg.
8. Submit all heavy placentas and dead newborn foals to the laboratory for necropsy.
9. If placenta weights are high, collect pre-foaling sera from late-gestation mares and determine the progestagen (5 alpha-pregnanes) level and/or ultrasound the late-gestation mares for placental edema.
10. Mares can be treated with domperidone should an ergot alkaloid problem be suspected.