Ergotism

Joseph C. Babrowicz, Jr., Richard F. Neville and Anton N. Sidawy

Ergot is a parasitic fungal disease that is caused by the organism Claviceps purpurea and that has a particular prevalence for infecting rye plants. Ergot and the ergot alkaloids have been linked to epidemic poisonings that manifested as ergotism and resulted from consumption of rye. History shows that ergotism was more common in Germany and Russia than it was in the United Kingdom. The ratio of rye to wheat production and consumption was many times greater in the Eastern European countries compared with the United Kingdom and mirrors the higher incidence of ergotism seen in Eastern Europe.

Observations from ergotism epidemics at the close of the 19th century led to the use of ergot as a therapeutic agent. Ergot and ergot alkaloid derivatives are now used routinely in the treatment of migraine headaches and the prevention of postpartum hemorrhage.

Pharmacology

Ergot alkaloids are derivatives of the tetracyclic compound 6-methyergoline. The therapeutically important ergot alkaloids include ergotamine tartrate (Ergomar) and ergonovine (Ergotrate). Semisynthetic ergot alkaloid derivatives include dihydroergotamine and bromocriptine. The hallucinogen lysergic acid diethylamide (LSD) and the serotonin antagonist methysergide are structurally similar to the ergot alkaloids.

Ergotamine is chemically similar to the endogenous catecholamines and indolamines. Therefore, ergotamine has activity similar to noradrenaline, adrenaline, dopamine, and serotonin (5-hydroxytryptamine [5-HT]). When applied clinically, ergotamine behaves as an agonist at α-adrenergic, serotoninergic, and dopaminergic receptors. Through activity with these various receptors, ergot can exert powerful vasoconstriction. Vasoconstriction is one of the proposed mechanisms by which ergots treat migraine headaches.

The cytochrome P450 (CYP) system is responsible for extensive first-pass metabolism of ergotamine. As a result of the rapid first-pass metabolism, ergotamine ingested orally routinely results in low systemic drug concentrations. Despite limited bioavailability of ergotamine and a half-life reported between 2 to 4 hours, the vasoconstrictive effects of ergot have been reported to last for 24 hours or longer. Tight receptor binding of the drug, poorly defined metabolites of the drug that might have lingering biologic activity, and drug interactions that can slow ergot metabolism have been proposed mechanisms for the prolonged vasoconstrictive activity observed clinically.

Clinical Presentation of Ergotism

Ergotism can manifest with signs and symptoms related to any vascular territory. However, two main forms of ergotism have been noted throughout history. The earliest written accounts of these two ergotism presentations—gangrenous and convulsive—are found in literature from the Middle Ages.

Convulsive ergotism initially manifests as heaviness in the limbs and head associated with diarrhea. As the illness progressed, complaints ranged from the pins and needles feeling of paresthesias to facial fasciculations. If the disease worsened, the victim could experience tonic–clonic spasms, opisthotonus, and status epilepticus. Eventually, 10% to 20% of patients died from severe convulsive ergotism. If patients recovered they were often left with dementia or delirium. A relatively recent account of convulsive ergotism comes from Pont Saint Esprit, France, in 1951. One in 20 of the small village inhabitants experienced hallucinations, convulsions, and burning sensations in their limbs. The illness left many of the villagers running mad in the streets. The cause of the villagers’ “madness” was diagnosed as ergotism caused by bread made with fungus-contaminated rye. The bizarre behavioral manifestations of convulsive ergotism are thought to be related to serotonin receptor antagonism by the lysergic acid diethylamide components found in ergot.

Historically, gangrenous ergotism was also known as holy fire or St. Anthony’s fire. Early descriptions tell of mild limb pain followed by burning pain shooting through the affected limbs. As the disease progressed the limbs became numb and painless. With even more time the tissues became darkened until they eventually became black. The limbs resembled charcoal and looked as if they had been burned by fire. Often the limbs would autoamputate without pain or bleeding. The gangrenous changes were attributed to the intense vasoconstrictive properties of the ergots.

The connection between ergotism and St. Anthony began in the late 11th century. The Hospital Brothers of St. Anthony, or Antonines, were a Roman Catholic order founded with the purpose of caring for those suffering from St. Anthony’s fire. The congregation was founded by Gaston of Valloire after his son’s miraculous cure from St. Anthony’s fire by praying to the relics of Saint Anthony the Great (Egyptian saint, c. 251–356). Pope Urban II confirmed the order in 1095. St. Anthony’s relics were subsequently housed at a church in La-Motte-Saint-Didier, France, with numerous patients treated at a hospital near the church. Many patients died there, but the survivors experienced “miracle cures” even though most lost limbs. The cures were thought to be a result of good nutrition and attentive wound care offered by the hospital. The work of St. Anthony is commemorated in the 16th-century Isenheim altarpiece by Matthius Grunewald (Figure 1).

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