🔗

Mappings

MONDO

MONDO:0042496 ergotism

semapv:ManualMappingCuration

ICD-10-CM

ICD10CM:T62.2 Toxic effect of other ingested (parts of) plant(s)

semapv:ManualMappingCuration

?

Discussions and Knowledge Gaps

3

Does direct cytotoxicity of the clavine-type ergot alkaloids contribute to the tissue loss in ergotism, alongside ischaemia from vasospasm?

KNOWLEDGE GAP direct_clavine_cytotoxicity

Attached to

pathophysiology#Distal Tissue Ischemia and Dry Gangrene experimental_models#Clavine-type ergot alkaloid cytotoxicity in HepG2 and PANC-1 cells

Every pathophysiology node in this entry reaches tissue injury the same way: receptor agonism, sustained contraction, vasospasm, starvation of the distal tissue. That account is well supported and it may not be the whole account. Clavine-type ergot alkaloids reduce cell viability and induce apoptosis in human cell lines outright, with no vessel involved, and agroclavine - one of the clavines tested - is named a causative agent of ergotism and is monitored in food by EFSA. The same survey found clavine and peptide alkaloids together in most of the sclerotia it analysed, so a person eating contaminated grain is exposed to both. What is missing is any bridge from the dish to the limb. The cells are HepG2 hepatoma and PANC-1 pancreatic carcinoma, neither of which is a tissue this disease damages; the alkaloid is applied directly at concentrations nobody has related to a plasma level in a poisoned patient; and the authors state that the cytotoxic mechanism itself is unelucidated. So this cannot currently be modelled as a mechanism. It is recorded here because the alternative - saying nothing - would leave the entry asserting that ischaemia is the only route to the lesion, which the evidence does not establish either. Two things would settle it: a cytotoxicity measurement in vascular endothelium, smooth muscle or skin rather than carcinoma lines, and a pharmacokinetic comparison between the concentrations that kill cells and the concentrations reached in the distal circulation during poisoning. Note also that the iatrogenic form of this disease involves no clavines at all - ergotamine and ergometrine are peptide-type - so if direct cytotoxicity does contribute, it would differentiate the dietary form from the drug form rather than apply to both.

Show evidence (3 references)

PMID:36635416 SUPPORT In Vitro

"Clavine-type EAs are known to cause cytotoxicity, but the mechanism has not been elucidated."

States the gap directly: the cytotoxicity is established and its mechanism is not.

PMID:36635416 SUPPORT In Vitro

"Clavine-type EAs reduced cell viability and induced apoptosis in both cell lines."

The observation that raises the question.

PMID:36635416 SUPPORT REVIEW SYNTHESIS Other

"These results suggest that Clavine-type EAs are a family of compounds requiring attention in food safety and livestock production in Japan."

The authors' own framing of why this matters, which is a food-safety argument rather than a claim about human pathophysiology.

Was convulsive ergotism epidemic serotonin syndrome, and does that identity hold well enough to model the two as the same mechanism?

KNOWLEDGE GAP convulsive_form_as_serotonin_syndrome

Attached to

pathophysiology#Central Serotonergic Overstimulation pathophysiology#Convulsive and Neuropsychiatric Syndrome

The argument is good and it is still an argument. Ergot alkaloids are serotonin agonists; dihydroergotamine binds serotonin receptors in the dorsal horn, which is where the neuropathology of convulsive ergotism was found; dihydroergotamine can cause serotonin syndrome in people; and the clinical picture - twitching, spasm, altered mental state, sweating, fever - is the picture of serotonergic excess. That is a chain of circumstantial fits, not a demonstration, and the epidemics it explains ended before anyone could measure anything in a patient. The geographical split is the part that most needs explaining and is least settled. Convulsive outbreaks east of the Rhine and gangrenous ones west of it is a striking pattern, and the proposed explanation - an alkaloid abundant in eastern ergot acting on the CNS at a concentration too low to close down peripheral arteries - is offered by the author as a possibility, with the alkaloid unnamed. Confirming it would need compositional analysis of historical ergot from both regions against a modern receptor panel.

Recorded as a gap rather than curated as fact. The entry models the central serotonergic branch, which is well supported, without asserting the identification with serotonin syndrome, which is not.

Show evidence (2 references)

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"The serotonin syndrome may, therefore, have been a public-health problem long before it was recognised as a complication of modern psychopharmacology."

The claim at its strongest, in the author's own words, and hedged by the author with "may".

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"An alkaloid, present in high concentrations in ergots from east of the Rhine, may have caused convulsive ergotism at a circulating concentration insufficient to produce peripheral ischaemia."

The proposed explanation of the geographical split, stated as a possibility and with the alkaloid unidentified.

If the (S)-epimers of ergot alkaloids are vasoactive after all, do the regulatory limits that measure only (R)-epimers understate dietary exposure?

KNOWLEDGE GAP s_epimer_bioactivity_and_food_limits

Attached to

pathophysiology#Sustained Vascular Smooth Muscle Contraction environmental#Ingestion of cereal grain contaminated with Claviceps sclerotia

Ergot alkaloids exist as (R)- and (S)-epimers, and only the (R) forms are monitored in diets in North America, on the understanding that the (S) forms are biologically inactive. Tissue-bath work contradicts that: all four (S)-epimers tested produced concentration-dependent arterial contraction comparable to the (R) forms, and one of them, ergotaminine, contracted more strongly than two of the (R)-side comparators at the highest concentration used. A second study found the (S)-epimer producing a sustained contraction too, though weaker than the (R) form, and a docking study puts it at the 5-HT2A and alpha-2A sites. What this does not establish is how much it matters in a diet. The experiments are bovine arterial tissue at defined molar concentrations, not dietary exposure; the two epimers interconvert in a way that depends on temperature, pH and solvent, so the ratio in a food is not fixed; and no study has yet asked whether including the (S) forms would change where a regulatory limit should sit. The authors go as far as saying the (S) forms should be monitored, which is a recommendation rather than a quantified risk.

Show evidence (4 references)

PMID:32629472 SUPPORT In Vitro

"Ergot alkaloids exist in two forms known as the (R)- and (S)-epimers with only the former being monitored in diets in North America."

Establishes the regulatory gap this question is about.

PMID:32629472 REFUTE In Vitro

"Contrary to the widespread belief, all tested (S)-epimers were found vasoactive and produced a concentration-dependent arterial contractile response similar to what has been reported for the (R)-epimers."

Refutes the inactivity assumption the current monitoring rests on, which is what opens the question.

PMID:32629472 SUPPORT In Vitro

"The levels of (S)-epimers should be carefully monitored in human and animal diets worldwide."

The authors' recommendation, which is as far as the evidence is taken.

+ 1 more reference

⚙

Pathophysiology

8

Ergot Alkaloid Entry into the Circulation

The exposure event, reached by two routes that differ in everything except what arrives in the blood. Contaminated grain delivers a mixture of the alkaloids a particular Claviceps strain happens to make; a prescription delivers one purified alkaloid at a known dose. The alkaloid composition of the mixture is not constant, which matters because it is what decided whether a historical epidemic was gangrenous or convulsive.

Downstream

Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors Circulating alkaloid reaches vascular receptors, which it fits because the ergoline ring resembles the endogenous monoamines.

Show evidence (2 references)

PMID:22903169 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ergotism in humans and cattle are caused by several species of Claviceps that infect rye and other cereal grains."

Establishes the producing organisms and the grains they infect.

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ergots produced by different strains of Claviceps purpurea, and those growing in different soils, may have different ergot alkaloid compositions."

Source of the claim that the delivered mixture is not constant, which is what makes the two clinical forms a property of the ergot rather than of the dose.

CYP3A4 Inhibition Raising Systemic Ergotamine Concentration

The step that makes ergotism a live problem in countries with clean grain. Ergotamine is destroyed on first pass through the liver by CYP3A4, leaving under 5% oral bioavailability - which is why an ordinary migraine dose is tolerated at all. A strong CYP3A4 inhibitor removes that first-pass barrier, and the same tablet delivers a toxic plasma concentration. The inhibitors implicated are the HIV protease inhibitors, the pharmacokinetic booster cobicistat, and the macrolide antibiotics.

Downstream

Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors The raised plasma concentration is what drives receptor occupancy high enough to be toxic. This branch converges on the same receptor node as the dietary route rather than acting through a separate mechanism.

Show evidence (3 references)

PMID:24531557 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ergotamine, typically used to treat migraine, has less than 5% bioavailability due to extensive first-pass metabolism by cytochrome P450 3A4 (CYP3A4)."

The quantitative basis of this node - the first-pass barrier that an inhibitor removes.

PMID:24978905 SUPPORT Human Clinical

"Nine cases (75%) were precipitated by drug-drug interactions with CYP3A4 inhibitors."

Quantifies how much of modern severe ergotism runs through this node - three quarters of a consecutive poison-centre series.

PMID:24978905 SUPPORT Human Clinical

"most cases of severe ergotism were associated with interaction with CYP3A4 inhibitors, which increase ergotamine bioavailability"

States the bioavailability mechanism this node asserts.

Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors

The pharmacological lesion. Ergot alkaloids bind serotonin and alpha-adrenergic receptors on vascular smooth muscle, acting as agonists and partial agonists rather than as the antagonists a drug designed for this target would be. Molecular docking puts ergocristinine at the 5-HT2A and alpha-2A adrenergic binding sites with hydrogen bonding to the site residues, and the pharmacological counterpart is that a non-competitive alpha-adrenergic antagonist attenuates the contraction the alkaloid produces.

serotonin receptor signaling driven by ergot alkaloid agonism GO:0007210 ⇑ GAIN OF FUNCTION adrenergic receptor signaling driven by ergot alkaloid agonism GO:0071875 ⇑ GAIN OF FUNCTION

agonism of ergot alkaloids at G protein-coupled serotonin receptors GO:0004993

Experimental models

Bovine lateral saphenous vein myography OTHER Establishes which 5-HT receptor subtypes are present and functional in a peripheral vein, and that most of the relaxing response runs through 5-HT4 - the pharmacological background against which an ergoline's mixed agonism at this node has to be read.

Animal models

Sheep single-dose oral ergot sclerotia exposure Sheep partially recapitulates Exposure to the sclerotial alkaloid mixture left the pedal artery more sensitive to an alpha-1 agonist, and an alpha-1 antagonist was a more potent blocker in exposed animals than in controls - which is the adrenergic half of this node measured directly rather than inferred.

Downstream

Sustained Vascular Smooth Muscle Contraction Receptor occupancy on smooth muscle is what produces the contraction, which is why blocking the receptor blunts it.

Central Serotonergic Overstimulation The same agonism at serotonin receptors in the central nervous system is a parallel branch, not a consequence of the vascular one.

Show evidence (3 references)

PMID:37213815 SUPPORT Computational

"The binding energy (kcal/mol) of ergocristinine was - 9.7 or - 11.0 to the serotonin (5-HT) 2 A receptor and - 8.7 or - 11.4 to the alpha 2 A adrenergic receptor, depending on the software used."

Docking affinities at both receptor families this node names. In silico, so it establishes the binding is plausible rather than measured.

PMID:37213815 SUPPORT Computational

"A hydrogen bond was formed between ergocristinine and amino acid residues of the 5-HT 2 A and alpha 2 A adrenergic receptor binding sites"

The modelled interaction with the binding-site residues of both receptors.

PMID:32629472 SUPPORT BACKGROUND In Vitro

"These effects are mainly related to the vasoconstrictive effects of ergot alkaloids, through structural similarity to biological amines binding to their receptor"

States the structural-similarity mechanism this node rests on.

Sustained Vascular Smooth Muscle Contraction

What separates ergot vasoconstriction from ordinary vasoconstriction is how long it lasts. In an arterial tissue bath a single dose of ergocristine produced contraction sustained across a three-hour incubation, and the response persists well beyond the point at which the alkaloid would have been cleared. That persistence is why the clinical syndrome is a spasm that resists reversal rather than a transient squeeze, and why case reports describe failure of first-line vasodilators.

vascular smooth muscle cell CL:0000359

sustained smooth muscle contraction driven by ergot alkaloid agonism GO:0006939 ⇑ GAIN OF FUNCTION

Animal models

Sheep single-dose oral ergot sclerotia exposure Sheep recapitulates The isolated-vessel preparation reads out contraction of vascular smooth muscle, which is this node, in tissue taken from an animal exposed by the same route as a human eating contaminated grain.

Downstream

Arterial Vasospasm with Distal Hypoperfusion Contraction of the smooth muscle in the arterial wall is what narrows the lumen and cuts flow.

Show evidence (3 references)

PMID:35775420 SUPPORT In Vitro

"Both epimers produced a sustained contractile response over the 180-min incubation period in the control groups."

The measured persistence this node is about, over a three-hour incubation.

PMID:35775420 SUPPORT BACKGROUND In Vitro

"The vascular contractile responses are often sustained for an extended period after exposure."

States the general property rather than the single experiment.

PMID:32629472 SUPPORT In Vitro

"all tested (S)-epimers were found vasoactive and produced a concentration-dependent arterial contractile response similar to what has been reported for the (R)-epimers"

Establishes the contractile response is concentration-dependent, and that the epimers long assumed inert also produce it - which bears on what a food-safety limit has to measure.

Central Serotonergic Overstimulation

The parallel branch, and the one that produces the convulsive form. Dihydroergotamine binds serotonin receptors in the dorsal horn of the spinal cord, which is where the neuropathological changes of convulsive ergotism are found. The clinical picture - twitching, spasm, altered mental state, hallucination, sweating and fever over weeks - is the picture of serotonergic overstimulation, and dihydroergotamine given to people can produce serotonin syndrome outright.

dorsal horn neuron CL:0000540

central serotonin receptor signaling driven by ergot alkaloid agonism GO:0007210 ⇑ GAIN OF FUNCTION

Downstream

Convulsive and Neuropsychiatric Syndrome

Show evidence (3 references)

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"Dihydroergotamine binds to serotonin receptors in the dorsal horn of the spinal cord, which is the site of neuropathological changes in convulsive ergotism."

Locates the binding in the tissue where the lesion is, which is what makes this a mechanism rather than an analogy.

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"Dihydroergotamine given to human beings can cause the serotonin syndrome."

The human pharmacological evidence that an ergot alkaloid alone suffices to produce the syndrome this node describes.

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"An alkaloid, present in high concentrations in ergots from east of the Rhine, may have caused convulsive ergotism at a circulating concentration insufficient to produce peripheral ischaemia."

The proposed reason the two forms separated geographically - a composition difference, at a dose below the vascular threshold. Stated by the author as a hypothesis, and curated as one.

Arterial Vasospasm with Distal Hypoperfusion

The lesion as it appears on imaging: diffuse narrowing of arteries without atherosclerotic plaque or thrombus, with the distal extremities worst affected because prolonged spasm has the greatest effect where the arterial supply is least redundant. Angiography in a bilateral limb-ischaemia case showed diffuse spasm of the whole lower-limb arterial tree. Vasospasm also reaches the coronary, cerebral, renal and ocular circulations, which is where the severe non-limb outcomes come from.

vascular smooth muscle cell CL:0000359

artery UBERON:0001637

Downstream

Distal Tissue Ischemia and Dry Gangrene

Vasospasm

Coronary artery spasm Coronary involvement, reported after obstetric ergometrine given for postpartum haemorrhage.

Intermittent claudication

Cerebral ischaemia Cerebral involvement. The same diffuse spasm reaches the cerebral circulation, producing cortical infarction with subcortical sparing - the imaging signature of a reversible vasoconstriction syndrome rather than of embolism or atherosclerosis.

Show evidence (3 references)

PMID:33546816 SUPPORT Human Clinical

"Angiography confirmed diffuse arterial vasospasm of the lower limb arteries."

The imaging appearance this node describes, in a documented case.

PMID:28031641 SUPPORT REVIEW SYNTHESIS Human Clinical

"Historical aspects of ergotism are discussed together with reference to the relative vulnerability of different segments of the arterial circulation."

Supports that vulnerability differs by arterial segment, which is why the distal extremities dominate. The abstract states the review covers this rather than giving the ranking, so the ranking itself is not asserted here.

PMID:24978905 SUPPORT Human Clinical

"Ten patients (83%) had signs of peripheral vascular insufficiency."

How consistently this node appears in a consecutive severe-ergotism series.

Distal Tissue Ischemia and Dry Gangrene

Where the spasm is not relieved, the tissue it supplies dies. The sequence runs burning paresthesia, then coldness and pallor, then absent pulses, then dry gangrene - the lesion that gave the medieval disease its name. It is reversible up to a point: recognised early the vascular changes resolve completely, and in one seven-patient series prompt vasodilator therapy avoided amputation altogether. Recognised late it is not, and a poison-centre series records two partial foot amputations.

tissue response to ischaemic hypoxia GO:0001666 ↑ INCREASED

limb UBERON:0002101

Experimental models

Clavine-type ergot alkaloid cytotoxicity in HepG2 and PANC-1 cells CELL LINE Shows that a constituent of the ingested exposure kills cells outright at the concentrations tested, which is a candidate contributor to the tissue loss this node records and is independent of perfusion.

Animal models

Cattle fescue toxicosis (endophyte-infected tall fescue grazing) Cattle partially recapitulates Cattle exposed to ergot alkaloids develop gangrenous ergotism, so the species reaches the same endpoint node as the human disease by the same dietary route.

Downstream

Gangrene

Paresthesia

Limb pain

Acrocyanosis

Show evidence (3 references)

PMID:28031641 SUPPORT Human Clinical

"Our case emphasizes the potential for complete reversibility of the vascular changes if recognized early."

The reversibility this node asserts, and its condition.

PMID:1908611 SUPPORT Human Clinical

"Distal necrosis developed in two patients (DHE-heparin)."

The irreversible end of the same node, in the same series.

PMID:24978905 SUPPORT Human Clinical

"Two patients required partial foot amputations due to gangrene."

The amputation outcome this node can reach.

Convulsive and Neuropsychiatric Syndrome

The other historical form, dominant east of the Rhine while gangrenous ergotism dominated to the west. Muscle twitching and spasm, altered mental state, hallucination, sweating and fever, persisting for weeks rather than resolving in days. Modern outbreaks in Ethiopia and India are the reason this is not purely a historical category.

Downstream

Seizure

Muscle spasm

Hallucinations

Confusion

Fever

Hyperhidrosis

Show evidence (2 references)

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"Between 1085 and 1927, epidemics of "convulsive ergotism" were widespread east of the Rhine in Europe due to consumption of grain contaminated with ergot, which is produced by the fungus Claviceps purpurea. West of the Rhine, consumption of ergot-contaminated food caused epidemics of gangrenous ergotism."

The geographical separation of the two forms this entry records.

PMID:22903169 SUPPORT REVIEW SYNTHESIS Human Clinical

"Symptoms in humans vary greatly and are generally classified as convulsive, gangrenous, or gastrointestinal (enteric)."

The standard three-way classification. Note it names a gastrointestinal form alongside the two this entry models as branches.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

15

Cardiovascular 4

Vasospasm HP:0025637

Temporal: ACUTE

Show evidence (2 references)

PMID:33546816 SUPPORT Human Clinical

"Angiography confirmed diffuse arterial vasospasm of the lower limb arteries."

Angiographic confirmation of this phenotype.

PMID:1908611 SUPPORT Human Clinical

"7 patients have been admitted in our hospital for severe vasospasm of one or several extremities due to ergot's derivatives"

A consecutive hospital series presenting with this phenotype.

Coronary artery spasm HP:0025497

Temporal: ACUTE

Show evidence (3 references)

PMID:40046976 SUPPORT Human Clinical

"it is also a potent vasoconstrictor capable of causing significant coronary artery vasospasm in susceptible individuals"

States that the obstetric ergot alkaloid causes coronary vasospasm.

PMID:40046976 SUPPORT Human Clinical

"The most likely unifying diagnosis was severe ergotamine-induced coronary vasospasm causing acute myocardial infarction in the setting of life-threatening PPH."

The authors' diagnosis in the case, reaching infarction.

PMID:40046976 SUPPORT Human Clinical

"Cardiovascular MRI showed moderate LV systolic impairment and focal apical infarction. Coronary angiography was unremarkable."

The finding behind this phenotype's diagnostic signature - documented infarction with an unremarkable angiogram, which is what spasm looks like.

Intermittent claudication HP:0004417

Temporal: ACUTE

Show evidence (1 reference)

PMID:33546816 SUPPORT Human Clinical

"she presented an acute bilateral limb ischemia with a sudden pain in both calves, initially while walking and then at rest with bilateral ischemic toes"

The claudication-to-rest-pain progression this phenotype records, in one patient.

Cerebral ischaemia Cerebral ischemia HP:0002637

Temporal: ACUTE

The ergometrine case also suffered a later middle cerebral artery occlusion, but that one followed left ventricular thrombus formation and is embolic rather than vasospastic. It is deliberately not cited here: the same patient having both a vasospastic and an embolic cerebral event is exactly the confusion this phenotype would otherwise import.

Show evidence (2 references)

PMID:30662776 SUPPORT Human Clinical

"The patient developed severe limb ischemia, cerebral ischemia, and metabolic encephalopathy."

Records cerebral ischaemia in the same patient and the same episode as the limb ischaemia this entry's chain produces.

PMID:40046976 SUPPORT Human Clinical

"The pattern of cortical involvement with subcortical sparring raised the possibility of a reversible vasoconstriction syndrome"

The imaging pattern that identifies the cerebral lesion as vasospastic rather than embolic or atherosclerotic.

Digestive 1

Nausea and vomiting HP:0002017

Deliberately left without a causal inbound edge. Ergot alkaloids act at central dopaminergic and serotonergic receptors that would plausibly explain emesis, and this entry carries a `Central Serotonergic Overstimulation` node, but the source quoted here is a symptom list and asserts no mechanism. Writing that edge would be inventing the attribution rather than curating it.

Show evidence (1 reference)

PMID:30662776 SUPPORT REVIEW SYNTHESIS Human Clinical

"Symptoms of ET can be nausea, vomiting, abdominal pain, agitation, hallucinations, lethargy, confusion, painful spasms, seizures"

Names nausea and vomiting among the features of ergotamine toxicity.

Integument 2

Acrocyanosis HP:0001063

Temporal: ACUTE

Show evidence (1 reference)

PMID:30662776 SUPPORT REVIEW SYNTHESIS Human Clinical

"feeble peripheral pulses and cyanotic limbs, loss of peripheral sensation, edema, and gangrene of affected tissues"

Names cyanotic limbs in the symptom list the authors give for ergotamine toxicity, alongside the pulse and sensory findings it accompanies.

Hyperhidrosis HP:0000975

Temporal: PROLONGED

Show evidence (1 reference)

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"sweating, and fever lasting for several weeks"

The sweating this phenotype records, which with fever is part of what suggested serotonergic overstimulation to the author.

Metabolism 1

Fever HP:0001945

Temporal: PROLONGED

Show evidence (1 reference)

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"sweating, and fever lasting for several weeks"

The fever and its duration.

Musculoskeletal 1

Muscle spasm HP:0003394

Temporal: ACUTE

Show evidence (1 reference)

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"muscle twitching and spasms, changes in mental state, hallucinations, sweating, and fever lasting for several weeks"

The defining feature set of the convulsive form.

Nervous System 4

Paresthesia HP:0003401

Temporal: ACUTE

Show evidence (1 reference)

PMID:30662776 SUPPORT REVIEW SYNTHESIS Human Clinical

"feeble peripheral pulses and cyanotic limbs, loss of peripheral sensation, edema, and gangrene of affected tissues"

The sensory disturbance in the authors' symptom list, alongside the vascular findings it accompanies. It names loss of sensation rather than the burning quality, which is described in the historical literature.

Seizure HP:0001250

Temporal: ACUTE

Show evidence (1 reference)

PMID:30662776 SUPPORT REVIEW SYNTHESIS Human Clinical

"agitation, hallucinations, lethargy, confusion, painful spasms, seizures"

Names seizures in the authors' symptom list for ergotamine toxicity.

Hallucinations HP:0000738

Temporal: ACUTE

Show evidence (1 reference)

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"muscle twitching and spasms, changes in mental state, hallucinations, sweating, and fever lasting for several weeks"

Names hallucination among the convulsive features.

Confusion HP:0001289

Temporal: ACUTE

Show evidence (2 references)

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"changes in mental state, hallucinations, sweating, and fever lasting for several weeks"

Names the change in mental state and how long it lasts.

PMID:30662776 SUPPORT REVIEW SYNTHESIS Human Clinical

"Symptoms of ET can be nausea, vomiting, abdominal pain, agitation, hallucinations, lethargy, confusion, painful spasms, seizures"

Independent listing of confusion among ergotamine toxicity features.

Constitutional 2

Gangrene HP:0100758

Temporal: ACUTE

Bound to the general `HP:0100758` Gangrene. A search of HPO for the more specific concept returns nothing: `curl .../ols4/api/search?q=Peripheral+gangrene&ontology=hp` returns no term of that name, and the `HP:0034976` that the deep-research report offered under that label is *Absent pituitary stalk*. The distal, dry character of the lesion is carried in `preferred_term`.

Show evidence (2 references)

PMID:24978905 SUPPORT Human Clinical

"Two patients required partial foot amputations due to gangrene."

Gangrene reaching amputation in a modern poison-centre series.

PMID:1908611 SUPPORT Human Clinical

"Distal necrosis developed in two patients (DHE-heparin)."

The tissue-death endpoint, in an independent series.

Limb pain HP:0009763

Temporal: ACUTE

Show evidence (1 reference)

PMID:33546816 SUPPORT Human Clinical

"a sudden pain in both calves, initially while walking and then at rest"

The pain and its progression to rest pain.

💊

Medical Actions

6

Withdrawal of the ergot alkaloid

Action: withdrawal of the causative ergot alkaloid Ontology label: Supportive Care NCIT:C15747

Platform: Other

The first and most important intervention, and in mild cases the only one needed. Because the toxicity is receptor occupancy by a clearable drug rather than structural damage, stopping the exposure allows the spasm to resolve - provided it is stopped before the tissue dies. A historical review of the disease found no convincing evidence that anything other than discontinuation helps, which is a strong claim about the rest of this section and is recorded as such.

Mechanism Target:

INHIBITS Ergot Alkaloid Entry into the Circulation — Stopping the drug removes the exposure itself, which is upstream of every other node in the entry.

Show evidence (1 reference)

PMID:1908611 SUPPORT INDIRECT Human Clinical

"Subclinical ergotism most probably precedes for weeks the onset of severe vasospasm, which calls for close monitoring of patients taking ergot's derivatives."

Supports acting on the exposure as the intervention point, and that there is a monitoring window before severe disease. Indirect: it argues for monitoring rather than measuring the effect of withdrawal.

Show evidence (1 reference)

PMID:28031641 SUPPORT Human Clinical

"Our case emphasizes the potential for complete reversibility of the vascular changes if recognized early."

The reversibility that makes withdrawal sufficient when it happens in time.

Intravenous vasodilator therapy

Action: Pharmacotherapy NCIT:C15986

Agent: sodium nitroprusside CHEBI:29321

Platform: Small molecule

For established severe vasospasm. Sodium nitroprusside relieved the spasm in five of six patients in one series, within hours to days, and no amputation was needed in that series despite severe and prolonged spasm. Nitrates and calcium channel blockers are also used, though a bilateral-ischaemia case records isosorbide dinitrate and amlodipine failing outright before more aggressive measures worked.

Mechanism Target:

INHIBITS Sustained Vascular Smooth Muscle Contraction — Vasodilators oppose the contraction directly rather than removing the alkaloid, which is why they work while the drug is still present.

Show evidence (1 reference)

PMID:1908611 SUPPORT Human Clinical

"Intravenous administration of sodium nitroprusside (n = 6) relieved vasospasm in all but one of the patients within hours to days"

Measures the effect on the vasospasm this edge targets.

Show evidence (2 references)

PMID:1908611 SUPPORT Human Clinical

"No amputation was required in this series in spite of severe and prolonged vasospasms."

The outcome achieved in a series managed this way.

PMID:33546816 REFUTE Human Clinical

"A first-line therapy with isosorbide dinitrate and amlodipine was ineffective, with rapid clinical worsening."

A case where first-line vasodilators failed and the patient deteriorated, which is why this treatment is not recorded as reliably sufficient.

Endovascular revascularisation

Action: multisite transluminal balloon angioplasty Ontology label: Balloon Angioplasty NCIT:C93007

Platform: Surgery

Reserved for spasm that does not yield to drugs. In one case, intra-arterial and intravenous vasodilators combined with multisite transluminal balloon angioplasty and bilateral four-compartment fasciotomy restored flow along the whole lower-limb arterial tree and saved both legs, without the spasm recurring.

Mechanism Target:

INHIBITS Arterial Vasospasm with Distal Hypoperfusion — Mechanical dilatation of the spastic segment restores the lumen.

Show evidence (1 reference)

PMID:33546816 SUPPORT Human Clinical

"All along the lower limb arterial tree, transluminal balloon angioplasty restored the blood flow, without vasospasm recurrence."

The measured effect on the vasospasm node, including its durability.

Show evidence (2 references)

PMID:33546816 SUPPORT Human Clinical

"A combination of intra-arterial injections and intra-venous infusions of vasodilators, transluminal balloon angioplasty and bilateral 4-Compartment fasciotomies permitted rapid improvement and finally resulted in both lower limbs rescue."

The full combination used and the limb-salvage outcome.

PMID:33546816 SUPPORT Human Clinical

"In case of ergotism with acute lower limbs ischemia, combining medical vasodilator therapy with interventional procedure can restore the arterial blood flow, thus allowing to save lower limbs."

The authors' own recommendation for where this sits in management.

Corticosteroid rescue therapy

Action: Pharmacotherapy NCIT:C15986

Agent: methylprednisolone sodium succinate CHEBI:6890

Platform: Small molecule

A second-line option for spasm that does not yield to a vasodilator. In one case, pulses that had been lost despite sodium nitroprusside and heparin became palpable two hours after a single 1 mg/kg intravenous dose of methylprednisolone sodium succinate, with angiographic improvement at twelve hours. The authors state plainly that the mechanism is unknown, which is why this is recorded as an observation about an intractable case rather than as a mechanism-directed treatment.

Show evidence (3 references)

PMID:18763151 SUPPORT Human Clinical

"Ischemia in an extremity secondary to ergotamine-induced vasospasm unresponsive to sodium nitroprusside may be treated successfully with methylprednisolone."

The authors' conclusion, and the specific niche this treatment occupies - after a vasodilator has failed.

PMID:18763151 SUPPORT Human Clinical

"The pulses were palpable 2 h after the methylprednisolone dose."

The measured response, and how fast it came.

PMID:18763151 SUPPORT REVIEW SYNTHESIS Human Clinical

"Although vasodilator agents are first-line therapy in the treatment of ergotism, corticosteroids may be considered as an alternative therapy, especially for intractable cases."

Places this treatment second-line, which is how the entry orders it, and is the authors' framing rather than their result.

Amputation of non-viable tissue

Action: partial foot amputation for established gangrene Ontology label: Amputation NCIT:C15179

Platform: Surgery

The salvage procedure once gangrene is established. Two of twelve patients in a modern poison-centre series required partial foot amputation. It is included because the entry would otherwise imply that every case either resolves or kills, when the commonest bad outcome is neither.

Show evidence (1 reference)

PMID:24978905 SUPPORT Human Clinical

"Two patients required partial foot amputations due to gangrene."

Establishes that amputation was required, in what proportion, and for what lesion.

Sympathectomy

Action: sympathectomy Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Attempted historically and recorded as unhelpful. Two patients in a seven-patient series underwent it without improvement in their clinical course, which is worth keeping because it is a negative result that a plausible mechanism would have predicted to work.

Show evidence (1 reference)

PMID:1908611 REFUTE Human Clinical

"A sympathectomy was performed in two patients which did not improve the clinical course."

The negative result. Curated as `REFUTE` against this treatment rather than omitted, since a reader would otherwise reasonably expect sympathetic interruption to help a vasospastic disease.

🌍

Environmental Factors

3

Ingestion of cereal grain contaminated with Claviceps sclerotia

Hazard type: BIOLOGICAL

Route: ORAL

Duration: ACUTE

Bound to `ECTO:0000524` exposure to mycotoxin, which is exact for the agent class: ergot alkaloids are fungal secondary metabolites, and MONDO itself files ergotism under `MONDO:0042497` mycotoxicosis. The searches behind that choice, against the pinned local build the validator reads: `runoak -i sqlite:obo:ecto search 'l~ergot'` returns nothing - there is no ergot or Claviceps exposure class. `runoak -i sqlite:obo:ecto search 'l~mycotoxin'` returns `CHEBI:25442` mycotoxin and `ECTO:0000524` exposure to mycotoxin. `runoak -i sqlite:obo:ecto search 'l~rye'` returns `ECTO:0070112` exposure to rye bread via ingestion, which looks ideal and is not: `info ECTO:0070112 -O obo` shows it involves `FOODON:03305210` rye bread (enriched), a fortified commercial product, where this exposure is to ergot-contaminated grain. `runoak -i sqlite:obo:ecto search 'l~alkaloid'` returns `ECTO:9000271` exposure to alkaloid, which was rejected as less apt: it is anchored on `CHEBI:22315` alkaloid and loses the fungal origin that defines this exposure and that MONDO's own placement turns on.

The historical route and still the epidemic one. Claviceps species replace the grain of rye and other cereals with sclerotia; if these are not removed before milling, the flour carries the alkaloids. This is the route of the medieval European epidemics and of the modern outbreaks in Ethiopia and India, which occurred where grain-cleaning infrastructure was weakest rather than where the fungus was newest.

Show evidence (5 references)

PMID:36635416 SUPPORT Other

"24 out of 41 sclerotia extracts include peptide-type EAs"

Establishes what this exposure actually delivers. An LC-MS survey of 41 Claviceps sclerotia found peptide-type alkaloids - ergosine, ergotamine, ergocornine, alpha-ergocryptine, ergocristine - in most of them, which is the mixture this route carries and the reason the dose cannot be treated as a single agent.

PMID:36635416 SUPPORT BACKGROUND Other

"Agroclavine (2), a typical Clavine-type EA, is a causative agent of ergotism and is listed as a compound to be monitored by the European Food Safety Authority."

Names a second alkaloid class present in the same sclerotia and records that a regulator monitors it in food, which is what makes this exposure a current food-safety matter rather than a historical one.

PMID:22903169 SUPPORT REVIEW SYNTHESIS Human Clinical

"outbreaks in humans have recently occurred in lower socioeconomic populations of Ethiopia (1977 and 2001) and India (1975) with devastating results"

The modern outbreaks of this route, and the socioeconomic pattern they follow.

+ 2 more references

Mechanism Target:

TRIGGERS Ergot Alkaloid Entry into the Circulation — Eating the contaminated flour is what delivers the alkaloids.

Show evidence (1 reference)

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"consumption of grain contaminated with ergot, which is produced by the fungus Claviceps purpurea"

States the consumption-to-disease route this edge asserts.

Therapeutic ergot alkaloid administration

Hazard type: CHEMICAL

Route: MULTIPLE

Duration: INTERMITTENT CHRONIC

Bound to `ECTO:9001855` exposure to vasoconstrictor agent rather than to the broader `ECTO:0000509` exposure to drug. `runoak -i sqlite:obo:ecto search 'l~ergotamine'` returns nothing, so no agent-specific class exists; `search 'l~vasoconstrict'` returns `ECTO:9001855`, and `info ECTO:9001855 -O obo` shows it is `is_a ECTO:0000509` exposure to drug and involves `CHEBI:50514` vasoconstrictor agent. That is exact for what these drugs are and for the property that makes them toxic here, so it is preferred to the parent. `exposure_route` is `MULTIPLE` because the implicated preparations are oral (ergotamine tablets), intramuscular (ergometrine) and intravenous (dihydroergotamine) across the cited cases. `exposure_duration` is `INTERMITTENT` and `CHRONIC` rather than `ACUTE`. Migraine dosing is by definition recurrent discrete exposures separated by exposure-free intervals, which is what `INTERMITTENT` means, and the cases in this entry ran for years - the fatal darunavir case records the patient "self-medicating for years", and `PMID:1908611` finds a subclinical phase preceding severe disease by weeks, which no 1-14 day window contains. An acute single overdose is a real presentation too, but it is the exception in the cited series rather than the shape of this exposure.

Ergotamine and dihydroergotamine for migraine, and ergometrine or methylergometrine for postpartum haemorrhage, are still in use. At therapeutic dose they are usually tolerated; the exposure becomes toxic through overdose, prolonged use, or - much the commonest route in modern series - a CYP3A4 interaction.

Show evidence (2 references)

PMID:1908611 SUPPORT Human Clinical

"Ergot's derivatives are widely used to treat and prevent migraine and, associated with heparin, for the prevention of deep vein thrombosis."

Establishes the therapeutic uses that constitute this exposure.

PMID:1908611 SUPPORT Human Clinical

"Ergotamine tartrate was the responsible drug in four patients and dihydroergotamine(DHE)-heparin in three patients."

Names the specific agents responsible in a consecutive series.

Mechanism Target:

TRIGGERS Ergot Alkaloid Entry into the Circulation — A prescription delivers one purified alkaloid, in place of the mixture a contaminated harvest delivers.

Show evidence (1 reference)

PMID:24978905 SUPPORT Human Clinical

"All cases involved ergotamine 1 mg/caffeine 100 mg combination tablets."

Identifies the therapeutic preparation behind every case in a twelve-case series, which is this exposure.

Co-administration of a strong CYP3A4 inhibitor

Hazard type: CHEMICAL

Route: ORAL

Duration: ACUTE CHRONIC

Bound to the broad `ECTO:0000509` exposure to drug on purpose. The exposure is defined by an enzyme-inhibition property shared across three unrelated drug classes rather than by any one agent, and there is no ECTO class for that property: `runoak -i sqlite:obo:ecto search 'l~cytochrome'` and `search 'l~CYP'` both return nothing, and `search 'l~protease inhibitor'` returns no exposure class either. The specific classes are named in `description` instead. `exposure_duration` carries both `ACUTE` and `CHRONIC` because the implicated drug classes sit at opposite ends of it: a macrolide course is a few days, while the HIV protease inhibitors and cobicistat behind most of the modern cases are taken indefinitely. The interaction needs only that the two exposures overlap, so neither value alone describes it.

Not a source of ergot alkaloid, but the exposure that converts a therapeutic dose of one into a toxic dose. The implicated inhibitors are the HIV protease inhibitors, the booster cobicistat, and the macrolide antibiotics. This is now the dominant precipitant of severe ergotism in the published record, and the combination is regarded as contraindicated.

Show evidence (2 references)

PMID:24531557 SUPPORT REVIEW SYNTHESIS Human Clinical

"A total of 13 cases of clinical ergotism in HIV-infected patients has been published since 1997"

The accumulated published burden of this specific co-exposure at the time of that review.

PMID:24978905 SUPPORT Human Clinical

"Critical ergotism continues to occur in Thailand, most commonly associated with the drug-drug interactions."

Establishes this as the dominant modern precipitant in that setting.

Mechanism Target:

EXACERBATES CYP3A4 Inhibition Raising Systemic Ergotamine Concentration — `EXACERBATES` rather than `TRIGGERS`: this exposure causes no disease by itself and acts only on the toxicity of a separate one.

Show evidence (1 reference)

PMID:24531557 SUPPORT REVIEW SYNTHESIS Human Clinical

"Concurrent intake of ergotamine and strong CYP3A4 inhibitors, such as the HIV protease inhibitors (PIs), can lead to clinical ergotism."

States the co-exposure requirement and its consequence.

🔬

Diagnosis

3

Exposure history with non-atherosclerotic distal ischaemia

There is no confirmatory assay in routine use. The diagnosis is made by finding arterial insufficiency without atherosclerosis, thrombus or vasculitis, and then finding the exposure - which in the iatrogenic form means asking specifically about migraine self-medication and about any recently started drug. That question is the one that gets missed: in the fatal darunavir case the ergotamine use surfaced only after the ischaemia had spread and the family were interviewed.

Left without a `diagnosis_term`. `diagnosis_term` is a `TreatmentDescriptor` whose term must be reachable from `NCIT:C25218` Clinical Intervention or Procedure, and history-taking is not in that branch: `NCIT:C146918` Medical History Taking exists and is the obvious candidate, but binding it fails dynamic-enum validation with "Value 'NCIT:C146918' not in dynamic enum 'TreatmentActionTerm'". The OLS search behind that attempt, `q=medical history taking, ontology=ncit`, returns `NCIT:C146918` Medical History Taking, `NCIT:C83067` Medical History Occurrence, `NCIT:C85522` Medical History Yes No Indicator and `NCIT:C85833` Work-Up Examination; the first three are data-collection concepts rather than procedures and the fourth is broader than this entry. No binding is better than a wrong one.

Show evidence (3 references)

PMID:30662776 SUPPORT Human Clinical

"Clinicians were not aware that patient was self-medicating for years with medication containing ergotamine and caffeine for migraines."

The specific history failure this entry warns about, in the case where it proved fatal.

PMID:30662776 SUPPORT Human Clinical

"This diagnosis was established after evaluating the evolving 'and spreading' ischemia and CT scans and thoroughly interviewing patient's family."

How the diagnosis was eventually reached in that case.

PMID:30662776 SUPPORT REVIEW SYNTHESIS Human Clinical

"in absence of any thrombophilic pathology or arteritides, thorough interview and physical examination are important to find clues to this rare disorder"

States the diagnostic reasoning this entry describes - exclusion, then history.

Vascular imaging showing diffuse spasm without occlusive lesion

Angiography or CT angiography shows smooth diffuse narrowing rather than plaque or clot. Duplex ultrasonography has been proposed for diagnosis and for following the response to treatment, which matters because the spasm resolves and a non-invasive test can show it doing so.

arteriography of the affected limb NCIT:C16308

Show evidence (2 references)

PMID:33546816 SUPPORT Human Clinical

"Angiography confirmed diffuse arterial vasospasm of the lower limb arteries."

The angiographic finding this entry records.

PMID:28031641 SUPPORT Human Clinical

"A case of ergotism is presented to illustrate the role of duplex ultrasonography in the diagnosis and management of this nonatherosclerotic cause of peripheral arterial disease."

Establishes duplex ultrasound for both diagnosis and management, and names the non-atherosclerotic framing this section uses.

Factitious hypotension from severe vasospasm

A trap specific to this disease. Vasospasm severe enough to abolish the peripheral signal makes non-invasive blood pressure read as low or unmeasurable, so the patient appears shocked. Treating that apparent hypotension with a vasoconstrictor would be the wrong move; giving an intravenous vasodilator instead makes the recorded pressure rise paradoxically, which is both the clue and the treatment.

non-invasive blood pressure measurement NCIT:C167233

Show evidence (2 references)

PMID:24978905 SUPPORT Human Clinical

"Five of these patients initially had factitiously low or unmeasurable blood pressure using non-invasive technique and had paradoxical increase following intravenous vasodilator administration."

The finding and its paradoxical response, in five of twelve patients - which is what makes it a usable sign rather than a curiosity.

PMID:24978905 SUPPORT Human Clinical

"Factitious low blood pressure in these cases was likely caused by severe vasospasm."

The authors' mechanistic reading, which is why it belongs to this disease specifically.

📈

Progression

3

Subclinical vasospasm

Duration: weeks

Reported to precede severe disease by weeks in patients taking ergot derivatives, and reported at far higher prevalence than severe ergotism. This phase is the reason monitoring is recommended, and the reason the burden level for this entry is `VARIABLE` rather than a single tier.

Show evidence (1 reference)

PMID:1908611 SUPPORT Human Clinical

"Subclinical ergotism most probably precedes for weeks the onset of severe vasospasm, which calls for close monitoring of patients taking ergot's derivatives."

States both the existence of this phase and its duration.

Acute vasospastic or convulsive illness

Duration: days to weeks

The clinical syndrome. In the gangrenous form it runs over days, from paresthesia through pulse loss toward gangrene; in the convulsive form the features are described as lasting several weeks.

Show evidence (1 reference)

PMID:12849122 SUPPORT REVIEW SYNTHESIS Human Clinical

"sweating, and fever lasting for several weeks"

The duration of the convulsive form.

Resolution or fixed ischaemic injury

Duration: days

Monophasic and bimodal in outcome. The vasospasm either resolves, completely in cases caught early, or the tissue it starved has already died and the loss is permanent.

Show evidence (2 references)

PMID:28031641 SUPPORT Human Clinical

"Our case emphasizes the potential for complete reversibility of the vascular changes if recognized early."

The resolution arm and the condition on reaching it.

PMID:24978905 SUPPORT Human Clinical

"Two patients required partial foot amputations due to gangrene."

The other arm, in the same disease.

📊

Prevalence

2

Geneva, severe iatrogenic ergotism

Annual Incidence 0.5 per 100,000 per year <1 in 1,000,000 per year

Reported as an upper bound - less than 0.5 per 100,000 per year - so `rate_per_100000` records the bound rather than a point estimate. The band is the Orphanet tier that bound falls in. This covers severe disease only; the same paper cites a 15% prevalence of subclinical ergotism among users, which is a different measure on a different denominator and is recorded in `progression` rather than forced into this record.

Show evidence (1 reference)

PMID:1908611 SUPPORT Human Clinical

"It is concluded that incidence of severe ergotism is less than 0.5/100,000/year in Geneva."

The rate and population this record reports.

Ramathibodi Poison Center, Bangkok, 2006-2013

Cases In Literature Not yet documented

Twelve cases over seven and a half years at one referral poison centre. A case count, not a rate: the denominator is the centre's referral catchment rather than a population, so no incidence can be derived from it.

Show evidence (2 references)

PMID:24978905 SUPPORT Human Clinical

"Twelve cases of ergotism were identified."

The case count this record reports.

PMID:24978905 SUPPORT Human Clinical

"data obtained retrospectively from all patients with ergotism referred to Ramathibodi Poison Center in Bangkok, Thailand from January 2006 to August 2013"

The catchment and window that makes this a count rather than a rate.

⚖️

Clinical Burden

Variable

Outcome ranges from subclinical vasospasm through fully reversible ischaemia to amputation, stroke and death, and which end a patient reaches is set by how quickly the exposure is recognised and stopped rather than by the illness itself. One hospital series of seven severe cases needed no amputations; a poison-centre series of twelve required two partial foot amputations and had two deaths. Subclinical ergotism is reported at 15% prevalence among users against a severe incidence below 0.5 per 100,000 per year, so the same exposure spans three orders of magnitude of harm.

Show evidence (2 references)

PMID:1908611 SUPPORT Human Clinical

"It is concluded that incidence of severe ergotism is less than 0.5/100,000/year in Geneva. This contrasts with the high prevalence (15%) of subclinical ergotism reported by others."

The two figures this level rests on - severe disease is rare, subclinical vasospasm is not - which is the spread `VARIABLE` records.

PMID:24978905 SUPPORT Human Clinical

"Two patients required partial foot amputations due to gangrene. Two patients, including a 15-month-old boy with an unsupervised ingestion, died."

The severe end of the same range, in a twelve-case poison-centre series.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Ergotism:

Atherosclerotic and embolic limb ischaemia

Overlapping Features Acute limb ischaemia is far more often atherosclerotic, embolic or thrombotic than vasospastic, and the ergot history is not volunteered. This is the differential that delays the diagnosis.

Distinguishing Features

Imaging shows smooth diffuse arterial narrowing rather than a focal occlusive lesion, plaque or thrombus.
The narrowing is reversible: vasodilator therapy and withdrawal of the drug restore flow, which no atherosclerotic lesion does.

Show evidence (2 references)

PMID:28031641 SUPPORT Human Clinical

"this nonatherosclerotic cause of peripheral arterial disease"

Places ergotism explicitly outside the atherosclerotic category.

PMID:28031641 SUPPORT Human Clinical

"Our case emphasizes the potential for complete reversibility of the vascular changes if recognized early."

Supports reversibility as the discriminating feature listed here.

Systemic vasculitis

Overlapping Features Ergotism can present as apparent vasculitis, with distal ischaemia and no obvious occlusive cause, and has been reported under exactly that framing.

Distinguishing Features

Absence of thrombophilic or arteritic pathology on workup, with a history of ergot exposure.

Show evidence (1 reference)

PMID:30662776 SUPPORT REVIEW SYNTHESIS Human Clinical

"in absence of any thrombophilic pathology or arteritides"

Supports the distinguishing feature listed here.

🧫

Experimental Models

2

Bovine lateral saphenous vein myography OTHER

Isolated lateral saphenous vein rings from cattle mounted for myography. This is the standard ex vivo preparation in the ergot-alkaloid vascular literature, and the study cited here uses it to establish which serotonin receptor subtypes the vessel carries and what each does - the receptor repertoire that the ergoline agonism node acts on.

Organism

cattle NCBITaxon:9913

Publication

PMID:38946059

Pathograph links

Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors measures fidelity: low observes: molecular Establishes which 5-HT receptor subtypes are present and functional in a peripheral vein, and that most of the relaxing response runs through 5-HT4 - the pharmacological background against which an ergoline's mixed agonism at this node has to be read.

Limitations: No ergot alkaloid was applied in this study, so it cannot show ergoline action at these receptors; it characterises the receptors. It also reads out vasorelaxation, the opposite direction from the contraction this entry's chain runs through, and it is a vein rather than the peripheral artery where the human lesion forms.

Divergences from the human mechanism

proxy quantity qualifying

The measured quantity is the vasoactive response to serotonin and to subtype-selective 5-HT agonists. This node's quantity is receptor occupancy and activation by an ergot alkaloid. A shared receptor is not a shared ligand, and ergolines are partial agonists at several subtypes at once.

boundary omission qualifying

The alpha-adrenergic half of this node is outside the preparation as used here - only serotonergic agonists were applied. Phenylephrine appears solely as the pre-contraction the relaxation is measured against, not as an object of study.

Show evidence (1 reference)

PMID:38946059 SUPPORT In Vitro

"Approximately 94% of the vasorelaxation occurring in response to 5-HT could be accounted for through 5-HT4, providing strong evidence that 5-HT-mediated vasorelaxation occurs through 5-HT4 activation in bovine peripheral vasculature."

The receptor-subtype result this preparation contributes, which is what it is cited for.

Cited for the vessel's receptor pharmacology, not for ergot action. The study's agonists are serotonin itself and subtype-selective 5-HT agonists; no ergot alkaloid was applied. The deep-research report listed this preparation among ergot-alkaloid model systems, which overstates what this particular paper shows, and the `divergences` block below records that rather than repeating it.

Show evidence (1 reference)

PMID:38946059 SUPPORT In Vitro

"isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5-HT or selective 5-HT receptor agonists"

The preparation and what was applied to it.

Clavine-type ergot alkaloid cytotoxicity in HepG2 and PANC-1 cells CELL_LINE

Two human carcinoma cell lines exposed to clavine-type ergot alkaloids - pyroclavine, agroclavine and festuclavine - with apoptosis read out by annexin V / propidium iodide double staining on flow cytometry. Agroclavine is named a causative agent of ergotism and is monitored by EFSA, and the same study found clavine-type alkaloids alongside the peptide-type ones in most of the Japanese sclerotia it analysed, so this is a real constituent of the exposure rather than a laboratory curiosity.

Organism

human NCBITaxon:9606

Cell source

immortalized human carcinoma cell lines

Publication

PMID:36635416

Pathograph links

Distal Tissue Ischemia and Dry Gangrene measures fidelity: low observes: cellular Shows that a constituent of the ingested exposure kills cells outright at the concentrations tested, which is a candidate contributor to the tissue loss this node records and is independent of perfusion.

Limitations: Nothing here is vascular, distal or ischaemic. The cells are HepG2 hepatoma and PANC-1 pancreatic carcinoma lines under a direct alkaloid application; the human lesion is necrosis of a distal extremity starved of blood. No concentration reached in a poisoned patient is established as comparable, and the authors themselves state the cytotoxic mechanism is unelucidated. This link records that the observation exists, not that it operates in the disease.

Divergences from the human mechanism

proxy quantity qualifying

The measured quantity is annexin V / PI-defined apoptosis in a carcinoma cell line under direct application. This node's quantity is necrosis of distal tissue following sustained arterial spasm. Cell death is common to both, but its cause is the thing in dispute.

scale extrapolation qualifying

The model observes single cells in culture; the node it is linked to is a tissue-level lesion. Apoptosis in a dish does not aggregate to necrosis of a limb segment without an account of how many cells, in which tissue, at what exposure - none of which this model supplies. The one-step gap from `CELLULAR` to `TISSUE` is why this link is `MEASURES` rather than `PARTIALLY_RECAPITULATES`.

boundary omission invalidating

The circulation is not in the model at all. Absorption, first-pass metabolism, plasma protein binding and delivery to the distal limb are all outside its boundary, so the model cannot say whether the tested concentrations are ever reached in the tissue that dies.

Show evidence (1 reference)

PMID:36635416 SUPPORT In Vitro

"Clavine-type EAs reduced cell viability and induced apoptosis in both cell lines."

The result this link records.

Notes

Included as the only structured record in this entry of a mechanism that is not vasoconstriction. Every other node here runs through receptor agonism and ischaemia; direct cytotoxicity would be a parallel route to tissue injury. The cell lines are hepatoma and pancreatic carcinoma, neither of which is a tissue this disease damages, so the link below is `MEASURES` at `LOW` fidelity and no pathophysiology node asserts direct cytotoxicity in the human disease. The open question is recorded as a `KNOWLEDGE_GAP` discussion rather than as a mechanism.

Show evidence (1 reference)

PMID:36635416 SUPPORT In Vitro

"We performed annexin V and PI double-staining followed by flow cytometric analysis to detect apoptosis in HepG2 and PANC-1 cells after exposure to Clavine-type EAs."

The preparation, the exposure and the assay.

🐁

Animal Models

2

Sheep single-dose oral ergot sclerotia exposure

Twelve adult ewes, six dosed once orally with ground ergot sclerotia at 600 ug/kg bodyweight total ergot and six given water, euthanised twelve hours later, with the pedal artery of the left hind limb mounted in an isolated tissue bath and its contractile response to phenylephrine compared between groups. This is the closest thing to a controlled experiment on the human disease that exists: the exposure is the same sclerotial alkaloid mixture, the route is oral, and the readout is the vascular smooth muscle response this entry's chain runs through. It models the vascular arm only - sheep ergotism is a gangrenous disease, and nothing here addresses the convulsive branch.

Species

Sheep

Publication

PMID:33924041

Pathograph links

Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors partially recapitulates fidelity: moderate observes: molecular Exposure to the sclerotial alkaloid mixture left the pedal artery more sensitive to an alpha-1 agonist, and an alpha-1 antagonist was a more potent blocker in exposed animals than in controls - which is the adrenergic half of this node measured directly rather than inferred.

Limitations: Only the alpha-1 adrenergic arm is interrogated. The 5-HT receptor contribution that this node also asserts is not measured here, and the authors reach it only through the general statement they cite from elsewhere. Twelve animals, one dose, one timepoint.

Readouts

Pedal artery contractile sensitivity to phenylephrine

EC50 for phenylephrine-induced contraction of the isolated dorsal metatarsal III artery, exposed group against water control.

Direction: INCREASED

Interpretation: Increased sensitivity to an alpha-1 agonist after ergot exposure is the measurable signature of ergoline action at the adrenergic receptor.

Show evidence (1 reference)

PMID:33924041 SUPPORT Model Organism

"Acute exposure to ergot alkaloids resulted in a 38% increase in vascular sensitivity to PE compared to control"

The measurement itself, with its effect size and comparator.

Show evidence (1 reference)

PMID:33924041 SUPPORT Model Organism

"This study may indicate that the dry gangrene seen in sheep, and likely other species, might be related to the activation of α1-adrenergic receptor."

The authors' own reading of what their model is informative for - the receptor node, and through it the gangrene.

Sustained Vascular Smooth Muscle Contraction recapitulates fidelity: moderate observes: cellular The isolated-vessel preparation reads out contraction of vascular smooth muscle, which is this node, in tissue taken from an animal exposed by the same route as a human eating contaminated grain.

Limitations: Twelve hours after a single dose. Human ergotism is usually the product of sustained exposure, and the entry's own progression section describes a subclinical phase running for weeks, which a single-dose model cannot reach.

Show evidence (1 reference)

PMID:33924041 SUPPORT Model Organism

"Similar to chronic exposure, acute exposure to ergot alkaloids results in increased vascular sensitivity to PE."

States that the acute model reproduces what chronic exposure does, which is the claim that makes it informative for this node.

Show evidence (1 reference)

PMID:33924041 SUPPORT Model Organism

"Each ewe within the treatment group received a single oral treatment of ground ergot sclerotia at a dose of 600 µg/kg BW (total ergot) while each ewe in the control group received water."

The design that makes this a controlled model rather than an observation: a dosed group, a water control, and a defined alkaloid load.

Cattle fescue toxicosis (endophyte-infected tall fescue grazing)

Cattle grazing endophyte-infected tall fescue ingest ergopeptine alkaloids and develop a vasoconstrictive syndrome; cattle are also susceptible to gangrenous ergotism from Claviceps-contaminated feed. This is a naturally occurring disease in an outbred population on an unrestricted diet, which is its value and its limitation at once: the exposure is real but uncontrolled, the principal alkaloid in fescue is ergovaline rather than the Claviceps mixture humans encounter, and the studied endpoints are herd performance and cytokine profiles rather than the vascular lesion.

Species

Cattle

Publication

PMID:33327425

Pathograph links

Distal Tissue Ischemia and Dry Gangrene partially recapitulates fidelity: low observes: organism Cattle exposed to ergot alkaloids develop gangrenous ergotism, so the species reaches the same endpoint node as the human disease by the same dietary route.

Limitations: The alkaloid is different - ergovaline from an endophyte in fescue rather than the Claviceps sclerotial mixture - and the cited cattle study measured herd performance and cytokines, not the ischaemic lesion. The gangrene claim rests on statements about the species rather than on a measurement in these animals, and those statements qualify it heavily: gangrenous ergotism in cattle is described as rare, requiring acute exposure to very high alkaloid concentrations together with cold temperatures, while what chronic fescue grazing usually produces is reduced productivity and reduced blood flow to the extremities. So the species reaches this node, but not by the route or at the frequency the human gangrenous disease does.

Divergences from the human mechanism

proxy quantity qualifying

The cited study's measured quantities are animal performance parameters and circulating cytokines. This node's quantity is tissue perfusion and necrosis in the distal extremity. Performance decline under chronic ergot exposure is a downstream systemic consequence, not the lesion.

species mismatch qualifying

The exposure differs in kind, not only in species. These cattle grazed infected pasture continuously for thirteen weeks; the human iatrogenic form is a discrete oral dose taken at a migraine attack, and the human dietary form is contaminated flour eaten as meals. The shared feature is the receptor pharmacology, not the dose, the schedule, or the alkaloid.

Show evidence (3 references)

PMID:22903169 SUPPORT REVIEW SYNTHESIS Model Organism

"Cattle are particularly susceptible to both gangrenous and hyperthermic ergotism (also called summer syndrome)."

The basis for linking this species to the gangrene node.

+ 2 more references

Notes

Included because it is the model the literature on this disease actually uses, not because it is a close match. The report that informed this entry described fescue toxicosis as closely recapitulating the human gangrenous phenotype and cited a veterinary manual and a farming magazine for it; the peer-reviewed source cited here supports chronic ergot-alkaloid exposure and a tolerance split, and a separate review supports cattle susceptibility to gangrenous ergotism. Neither establishes the recapitulation claim, so the link below is `PARTIALLY_RECAPITULATES` rather than `RECAPITULATES`.

Show evidence (2 references)

PMID:33327425 SUPPORT Model Organism

"Fescue toxicosis is a multifaceted syndrome common in cattle grazing endophyte-infected tall fescue"

Establishes the exposure and the syndrome this model rests on.

PMID:22903169 SUPPORT REVIEW SYNTHESIS Model Organism

"Cattle are particularly susceptible to both gangrenous and hyperthermic ergotism (also called summer syndrome)."

The gangrenous form in cattle, which is what makes the species relevant to the human gangrenous disease at all.

{ }

Source YAML

click to show

name: Ergotism
creation_date: "2026-09-18T03:30:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Mycotoxicosis
- Adverse Drug Reaction
parents:
- mycotoxicosis
synonyms:
- ergot poisoning
- ergot alkaloid toxicity
- ergotoxicosis
- St Anthony's Fire
- Saint Anthony's Fire
- ignis sacer
- holy fire
description: >-
  Ergotism is intoxication by ergot alkaloids - ergoline compounds produced by
  fungi of the genus Claviceps, classically Claviceps purpurea, which replaces
  the grain of rye and other cereals with a dark sclerotium. The ergoline ring
  is close enough in shape to serotonin, noradrenaline and dopamine that the
  alkaloids act as agonists and partial agonists at 5-HT and alpha-adrenergic
  receptors. On vascular smooth muscle this produces arterial contraction that
  is unusually prolonged, outlasting the exposure by hours, and the resulting
  vasospasm starves distal tissue of blood.

  Two clinical forms have been recognised since the medieval epidemics and are
  still the standard division. Gangrenous ergotism is the vasospastic one:
  burning pain and paresthesia in the extremities, then coldness, pallor and
  loss of pulses, then dry gangrene that historically cost people their feet.
  Convulsive ergotism is neuropsychiatric - muscle twitching and spasm, altered
  mental state, hallucinations, sweating and fever persisting for weeks - and
  has been argued to be epidemic serotonin syndrome, recognised centuries
  before the modern syndrome was named. A gastrointestinal form is also
  described. Which form predominated in a given epidemic tracked the alkaloid
  composition of the local ergot rather than the dose, with convulsive
  outbreaks east of the Rhine and gangrenous ones west of it.

  The disease did not end with clean grain. Its dominant modern form is
  iatrogenic: ergotamine and dihydroergotamine are still prescribed for
  migraine and ergometrine for postpartum haemorrhage, and ergotamine has less
  than 5% oral bioavailability because CYP3A4 destroys it on first pass. Add a
  strong CYP3A4 inhibitor - an HIV protease inhibitor, cobicistat, a macrolide
  - and that barrier disappears, turning a therapeutic dose into a toxic one.
  Case series of severe ergotism are now dominated by exactly this interaction,
  and it has killed. Recognised early the vasospasm is reversible on stopping
  the drug; recognised late the ischaemia is not.
notes: >-
  Curated from a `claude_code` deep-research report
  (`research/Ergotism-deep-research-claude_code.md`). The report predates the
  in-line validation blocks, so `just validate-research-reference` and
  `just validate-research-terms` were run over it afterwards: 23/23 references
  resolved with none unresolved, and 18/20 CURIEs resolved.

  That report's term suggestions were unusually bad, and none of them was used.
  It offered `HP:0034976` for "Peripheral gangrene" - that CURIE is *Absent
  pituitary stalk* - and `HP:0031650` for "Vasospasm", which is *Abnormal
  atrioventricular valve physiology*. Both were caught independently: by a fresh
  OLS lookup while writing the binding, and by the retro-fitted term-validation
  section, which flags the same two. It also proposed the obsolete `CHEBI:4880`
  for ergotamine. Every CURIE here was re-derived rather than copied, which is
  the repository's rule and on this report was load-bearing rather than
  ceremonial.

  The report also cited heavily to Wikipedia, Britannica, National Geographic
  and StatPearls. None of that is cited here; where those passages named a real
  finding, a peer-reviewed source making the same claim was found and cited
  instead, and where none was found the claim was dropped.

  This is an acquired toxicosis, so there is no GeneReviews chapter and no
  OMIM entry; `just check-genereviews --online` returns `NO_CHAPTER` for both
  Bookshelf collections. The `genetic:` section is deliberately absent. The
  report proposed a CYP3A4 pharmacogenomic `MODIFIER` entry, and that is not
  curated here: the interaction that matters is pharmacological inhibition by a
  co-administered drug, which is an exposure and is modelled as one, while the
  report itself records that no ergotism-specific pharmacogenomic study was
  found and that host-variant susceptibility is inferred rather than
  established. Inferring a gene entry from that would be curating the report's
  speculation.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0042496
      label: ergotism
    mapping_predicate: skos:exactMatch
    mapping_justification: semapv:ManualMappingCuration
  icd10cm_mappings:
  - term:
      id: ICD10CM:T62.2
      label: Toxic effect of other ingested (parts of) plant(s)
    mapping_predicate: skos:broadMatch
    mapping_justification: semapv:ManualMappingCuration
    notes: >-
      ICD-10-CM has no code naming ergot. T62.2 is where ingested
      ergot-contaminated grain falls, and it covers every other ingested plant
      part too, so the mapping is `broadMatch`. It also does not reach the
      iatrogenic form at all, which codes as an adverse effect of a therapeutic
      drug elsewhere in the T-chapter - a second reason not to claim an exact
      match.
disease_term:
  preferred_term: ergotism
  term:
    id: MONDO:0042496
    label: ergotism
clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    Outcome ranges from subclinical vasospasm through fully reversible
    ischaemia to amputation, stroke and death, and which end a patient reaches
    is set by how quickly the exposure is recognised and stopped rather than by
    the illness itself. One hospital series of seven severe cases needed no
    amputations; a poison-centre series of twelve required two partial foot
    amputations and had two deaths. Subclinical ergotism is reported at 15%
    prevalence among users against a severe incidence below 0.5 per 100,000 per
    year, so the same exposure spans three orders of magnitude of harm.
  evidence:
  - reference: PMID:1908611
    reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is concluded that incidence of severe ergotism is less than 0.5/100,000/year in Geneva. This contrasts with the high prevalence (15%) of subclinical ergotism reported by others."
    explanation: >-
      The two figures this level rests on - severe disease is rare, subclinical
      vasospasm is not - which is the spread `VARIABLE` records.
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients required partial foot amputations due to gangrene. Two patients, including a 15-month-old boy with an unsupervised ingestion, died."
    explanation: The severe end of the same range, in a twelve-case poison-centre series.
pathophysiology:
- name: Ergot Alkaloid Entry into the Circulation
  biological_scale: ORGANISM
  description: >-
    The exposure event, reached by two routes that differ in everything except
    what arrives in the blood. Contaminated grain delivers a mixture of the
    alkaloids a particular Claviceps strain happens to make; a prescription
    delivers one purified alkaloid at a known dose. The alkaloid composition of
    the mixture is not constant, which matters because it is what decided
    whether a historical epidemic was gangrenous or convulsive.
  notes: >-
    Carries no ontology-bound process descriptor: the node denotes an exposure
    event rather than a host biological process. The exposures are grounded in
    the `environmental:` block, which splits them by route.
  downstream:
  - target: Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors
    causal_link_type: DIRECT
    description: >-
      Circulating alkaloid reaches vascular receptors, which it fits because
      the ergoline ring resembles the endogenous monoamines.
    evidence:
    - reference: PMID:30662776
      reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Ergotamine mimics the neurotransmitters norepinephrine, serotonin, and dopamine and can result in smaller and bigger vessels vasospasm and vasoconstriction"
      explanation: States the structural mimicry and the vascular consequence, which is this edge.
  chemical_entities:
  - preferred_term: ergot alkaloid
    term:
      id: CHEBI:23943
      label: ergot alkaloid
  evidence:
  - reference: PMID:22903169
    reference_title: "Human and cattle ergotism since 1900: symptoms, outbreaks, and regulations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ergotism in humans and cattle are caused by several species of Claviceps that infect rye and other cereal grains."
    explanation: Establishes the producing organisms and the grains they infect.
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ergots produced by different strains of Claviceps purpurea, and those growing in different soils, may have different ergot alkaloid compositions."
    explanation: >-
      Source of the claim that the delivered mixture is not constant, which is
      what makes the two clinical forms a property of the ergot rather than of
      the dose.
- name: CYP3A4 Inhibition Raising Systemic Ergotamine Concentration
  biological_scale: MOLECULAR
  description: >-
    The step that makes ergotism a live problem in countries with clean grain.
    Ergotamine is destroyed on first pass through the liver by CYP3A4, leaving
    under 5% oral bioavailability - which is why an ordinary migraine dose is
    tolerated at all. A strong CYP3A4 inhibitor removes that first-pass barrier,
    and the same tablet delivers a toxic plasma concentration. The inhibitors
    implicated are the HIV protease inhibitors, the pharmacokinetic booster
    cobicistat, and the macrolide antibiotics.
  notes: >-
    Modelled as a mechanism node rather than as a `genetic:` CYP3A4 entry. The
    claim here is pharmacological inhibition of the enzyme by a co-administered
    drug, which is an exposure, not a host genotype. Inherited CYP3A4 variation
    might plausibly do something similar, but no ergotism-specific
    pharmacogenomic study was found, so it is not curated.
  downstream:
  - target: Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors
    causal_link_type: DIRECT
    description: >-
      The raised plasma concentration is what drives receptor occupancy high
      enough to be toxic. This branch converges on the same receptor node as
      the dietary route rather than acting through a separate mechanism.
    evidence:
    - reference: PMID:24531557
      reference_title: "Ergotism in Thailand caused by increased access to antiretroviral drugs: a global warning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Concurrent intake of ergotamine and strong CYP3A4 inhibitors, such as the HIV protease inhibitors (PIs), can lead to clinical ergotism."
      explanation: States the inhibition-to-ergotism link directly.
  evidence:
  - reference: PMID:24531557
    reference_title: "Ergotism in Thailand caused by increased access to antiretroviral drugs: a global warning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ergotamine, typically used to treat migraine, has less than 5% bioavailability due to extensive first-pass metabolism by cytochrome P450 3A4 (CYP3A4)."
    explanation: >-
      The quantitative basis of this node - the first-pass barrier that an
      inhibitor removes.
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine cases (75%) were precipitated by drug-drug interactions with CYP3A4 inhibitors."
    explanation: >-
      Quantifies how much of modern severe ergotism runs through this node -
      three quarters of a consecutive poison-centre series.
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most cases of severe ergotism were associated with interaction with CYP3A4 inhibitors, which increase ergotamine bioavailability"
    explanation: States the bioavailability mechanism this node asserts.
- name: Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors
  biological_scale: MOLECULAR
  description: >-
    The pharmacological lesion. Ergot alkaloids bind serotonin and
    alpha-adrenergic receptors on vascular smooth muscle, acting as agonists
    and partial agonists rather than as the antagonists a drug designed for
    this target would be. Molecular docking puts ergocristinine at the 5-HT2A
    and alpha-2A adrenergic binding sites with hydrogen bonding to the site
    residues, and the pharmacological counterpart is that a non-competitive
    alpha-adrenergic antagonist attenuates the contraction the alkaloid
    produces.
  downstream:
  - target: Sustained Vascular Smooth Muscle Contraction
    causal_link_type: DIRECT
    description: >-
      Receptor occupancy on smooth muscle is what produces the contraction,
      which is why blocking the receptor blunts it.
    evidence:
    - reference: PMID:35775420
      reference_title: Sustained vascular contractile response induced by an R- and S-epimer of the ergot alkaloid ergocristine and attenuation by a noncompetitive antagonist.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Phenoxybenzamine caused a decrease in the contractile response induced by ergocristine and ergocristinine from 105 to 180 min, compared to the control"
      explanation: >-
        A pharmacological test of this edge - blocking alpha-adrenergic
        receptors with a non-competitive antagonist reduced the contraction the
        alkaloid had produced.
  - target: Central Serotonergic Overstimulation
    causal_link_type: DIRECT
    description: >-
      The same agonism at serotonin receptors in the central nervous system is
      a parallel branch, not a consequence of the vascular one.
    evidence:
    - reference: PMID:12849122
      reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The ergot alkaloids are serotonin agonists. Dihydroergotamine binds to serotonin receptors in the dorsal horn of the spinal cord, which is the site of neuropathological changes in convulsive ergotism."
      explanation: >-
        States the central serotonergic agonism and localises it to the tissue
        where the neuropathology of the convulsive form is found.
  molecular_functions:
  - preferred_term: agonism of ergot alkaloids at G protein-coupled serotonin receptors
    term:
      id: GO:0004993
      label: G protein-coupled serotonin receptor activity
  biological_processes:
  - preferred_term: serotonin receptor signaling driven by ergot alkaloid agonism
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0007210
      label: serotonin receptor signaling pathway
  - preferred_term: adrenergic receptor signaling driven by ergot alkaloid agonism
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0071875
      label: adrenergic receptor signaling pathway
  notes: >-
    Both receptor-signalling descriptors take `GAIN_OF_FUNCTION` rather than
    `INCREASED` deliberately, under the rule in CLAUDE.md that distinguishes the
    two. The claim is qualitative, not quantitative: an exogenous agonist is
    driving these pathways outside host regulatory control, in the same way
    HTLV-1 Tax drives NF-kB in `Adult_T_Cell_Leukemia_Lymphoma`, rather than a
    normally regulated pathway running above its usual level. That trade gives
    up the PATO grounding `INCREASED` would carry, which is why it is recorded
    here.
  chemical_entities:
  - preferred_term: ergotamine
    term:
      id: CHEBI:64318
      label: ergotamine
  evidence:
  - reference: PMID:37213815
    reference_title: Investigation of the relationship between ergocristinine and vascular receptors.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The binding energy (kcal/mol) of ergocristinine was - 9.7 or - 11.0 to the serotonin (5-HT) 2 A receptor and - 8.7 or - 11.4 to the alpha 2 A adrenergic receptor, depending on the software used."
    explanation: >-
      Docking affinities at both receptor families this node names. In silico,
      so it establishes the binding is plausible rather than measured.
  - reference: PMID:37213815
    reference_title: Investigation of the relationship between ergocristinine and vascular receptors.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "A hydrogen bond was formed between ergocristinine and amino acid residues of the 5-HT 2 A and alpha 2 A adrenergic receptor binding sites"
    explanation: The modelled interaction with the binding-site residues of both receptors.
  - reference: PMID:32629472
    reference_title: Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "These effects are mainly related to the vasoconstrictive effects of ergot alkaloids, through structural similarity to biological amines binding to their receptor"
    explanation: States the structural-similarity mechanism this node rests on.
- name: Sustained Vascular Smooth Muscle Contraction
  biological_scale: CELLULAR
  description: >-
    What separates ergot vasoconstriction from ordinary vasoconstriction is how
    long it lasts. In an arterial tissue bath a single dose of ergocristine
    produced contraction sustained across a three-hour incubation, and the
    response persists well beyond the point at which the alkaloid would have
    been cleared. That persistence is why the clinical syndrome is a spasm that
    resists reversal rather than a transient squeeze, and why case reports
    describe failure of first-line vasodilators.
  downstream:
  - target: Arterial Vasospasm with Distal Hypoperfusion
    causal_link_type: DIRECT
    description: >-
      Contraction of the smooth muscle in the arterial wall is what narrows the
      lumen and cuts flow.
    evidence:
    - reference: PMID:32629472
      reference_title: Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "binding to their receptor, on multiple arterial and venous vascular beds impacting the blood supply to multiple organs"
      explanation: >-
        States that the vascular effect reduces blood supply across many organs,
        which is what this edge asserts.
  biological_processes:
  - preferred_term: sustained smooth muscle contraction driven by ergot alkaloid agonism
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0006939
      label: smooth muscle contraction
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  evidence:
  - reference: PMID:35775420
    reference_title: Sustained vascular contractile response induced by an R- and S-epimer of the ergot alkaloid ergocristine and attenuation by a noncompetitive antagonist.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both epimers produced a sustained contractile response over the 180-min incubation period in the control groups."
    explanation: The measured persistence this node is about, over a three-hour incubation.
  - reference: PMID:35775420
    reference_title: Sustained vascular contractile response induced by an R- and S-epimer of the ergot alkaloid ergocristine and attenuation by a noncompetitive antagonist.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "The vascular contractile responses are often sustained for an extended period after exposure."
    explanation: States the general property rather than the single experiment.
  - reference: PMID:32629472
    reference_title: Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "all tested (S)-epimers were found vasoactive and produced a concentration-dependent arterial contractile response similar to what has been reported for the (R)-epimers"
    explanation: >-
      Establishes the contractile response is concentration-dependent, and that
      the epimers long assumed inert also produce it - which bears on what a
      food-safety limit has to measure.
- name: Central Serotonergic Overstimulation
  biological_scale: CELLULAR
  description: >-
    The parallel branch, and the one that produces the convulsive form.
    Dihydroergotamine binds serotonin receptors in the dorsal horn of the
    spinal cord, which is where the neuropathological changes of convulsive
    ergotism are found. The clinical picture - twitching, spasm, altered mental
    state, hallucination, sweating and fever over weeks - is the picture of
    serotonergic overstimulation, and dihydroergotamine given to people can
    produce serotonin syndrome outright.
  downstream:
  - target: Convulsive and Neuropsychiatric Syndrome
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12849122
      reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The clinical features of convulsive ergotism--muscle twitching and spasms, changes in mental state, hallucinations, sweating, and fever lasting for several weeks--suggest serotonergic overstimulation of the CNS (ie, the serotonin syndrome)."
      explanation: States the inference from the clinical picture to this mechanism, which is this edge.
  biological_processes:
  - preferred_term: central serotonin receptor signaling driven by ergot alkaloid agonism
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0007210
      label: serotonin receptor signaling pathway
  cell_types:
  - preferred_term: dorsal horn neuron
    term:
      id: CL:0000540
      label: neuron
  notes: >-
    The `dorsal horn neuron` cell type is bound to the broad `CL:0000540`
    neuron on purpose. CL does carry a narrower term - OLS `q=spinal cord
    dorsal horn interneuron, ontology=cl` returns `CL:0011000` dorsal horn
    interneuron - but the cited source says only "serotonin receptors in the
    dorsal horn of the spinal cord", and the dorsal horn contains projection
    neurons as well as interneurons. Binding `CL:0011000` would assert an
    interneuron the source does not name, which is the manufactured narrower
    match the term contract forbids. `q=dorsal horn neuron, ontology=cl`
    returns only dorsal root ganglion substance P neurons, which sit in the
    ganglion rather than the horn.
  evidence:
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Dihydroergotamine binds to serotonin receptors in the dorsal horn of the spinal cord, which is the site of neuropathological changes in convulsive ergotism."
    explanation: >-
      Locates the binding in the tissue where the lesion is, which is what makes
      this a mechanism rather than an analogy.
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Dihydroergotamine given to human beings can cause the serotonin syndrome."
    explanation: >-
      The human pharmacological evidence that an ergot alkaloid alone suffices
      to produce the syndrome this node describes.
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "An alkaloid, present in high concentrations in ergots from east of the Rhine, may have caused convulsive ergotism at a circulating concentration insufficient to produce peripheral ischaemia."
    explanation: >-
      The proposed reason the two forms separated geographically - a
      composition difference, at a dose below the vascular threshold. Stated by
      the author as a hypothesis, and curated as one.
- name: Arterial Vasospasm with Distal Hypoperfusion
  biological_scale: TISSUE
  description: >-
    The lesion as it appears on imaging: diffuse narrowing of arteries without
    atherosclerotic plaque or thrombus, with the distal extremities worst
    affected because prolonged spasm has the greatest effect where the arterial
    supply is least redundant. Angiography in a bilateral limb-ischaemia case
    showed diffuse spasm of the whole lower-limb arterial tree. Vasospasm also
    reaches the coronary, cerebral, renal and ocular circulations, which is
    where the severe non-limb outcomes come from.
  downstream:
  - target: Distal Tissue Ischemia and Dry Gangrene
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:1908611
      reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients presented with acute severe ischemia of the lower limb requiring iv infusion of vasodilator drugs."
      explanation: The vasospasm-to-ischaemia step, in a seven-patient hospital series.
  - target: Vasospasm
    causal_link_type: DIRECT
  - target: Coronary artery spasm
    causal_link_type: DIRECT
    description: >-
      Coronary involvement, reported after obstetric ergometrine given for
      postpartum haemorrhage.
  - target: Intermittent claudication
    causal_link_type: DIRECT
  - target: Cerebral ischaemia
    causal_link_type: DIRECT
    description: >-
      Cerebral involvement. The same diffuse spasm reaches the cerebral
      circulation, producing cortical infarction with subcortical sparing - the
      imaging signature of a reversible vasoconstriction syndrome rather than
      of embolism or atherosclerosis.
    evidence:
    - reference: PMID:40046976
      reference_title: "Joining forces: a complex cardio-obstetrics case report of severe ergometrine-induced vasospasm."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brain magnetic resonance imaging (MRI) revealed extensive cerebral and cerebellar infarction with subcortical sparring."
      explanation: >-
        The cerebral lesion this edge asserts, in a patient whose disease is
        attributed to ergometrine-induced vasospasm.
  locations:
  - preferred_term: artery
    term:
      id: UBERON:0001637
      label: artery
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  evidence:
  - reference: PMID:33546816
    reference_title: "Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angiography confirmed diffuse arterial vasospasm of the lower limb arteries."
    explanation: The imaging appearance this node describes, in a documented case.
  - reference: PMID:28031641
    reference_title: "Ergotism: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Historical aspects of ergotism are discussed together with reference to the relative vulnerability of different segments of the arterial circulation."
    explanation: >-
      Supports that vulnerability differs by arterial segment, which is why the
      distal extremities dominate. The abstract states the review covers this
      rather than giving the ranking, so the ranking itself is not asserted here.
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten patients (83%) had signs of peripheral vascular insufficiency."
    explanation: How consistently this node appears in a consecutive severe-ergotism series.
- name: Distal Tissue Ischemia and Dry Gangrene
  biological_scale: TISSUE
  description: >-
    Where the spasm is not relieved, the tissue it supplies dies. The sequence
    runs burning paresthesia, then coldness and pallor, then absent pulses, then
    dry gangrene - the lesion that gave the medieval disease its name. It is
    reversible up to a point: recognised early the vascular changes resolve
    completely, and in one seven-patient series prompt vasodilator therapy
    avoided amputation altogether. Recognised late it is not, and a
    poison-centre series records two partial foot amputations.
  downstream:
  - target: Gangrene
    causal_link_type: DIRECT
  - target: Paresthesia
    causal_link_type: DIRECT
  - target: Limb pain
    causal_link_type: DIRECT
  - target: Acrocyanosis
    causal_link_type: DIRECT
  biological_processes:
  - preferred_term: tissue response to ischaemic hypoxia
    modifier: INCREASED
    term:
      id: GO:0001666
      label: response to hypoxia
  locations:
  - preferred_term: limb
    term:
      id: UBERON:0002101
      label: limb
  evidence:
  - reference: PMID:28031641
    reference_title: "Ergotism: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our case emphasizes the potential for complete reversibility of the vascular changes if recognized early."
    explanation: The reversibility this node asserts, and its condition.
  - reference: PMID:1908611
    reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distal necrosis developed in two patients (DHE-heparin)."
    explanation: The irreversible end of the same node, in the same series.
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients required partial foot amputations due to gangrene."
    explanation: The amputation outcome this node can reach.
- name: Convulsive and Neuropsychiatric Syndrome
  biological_scale: ORGANISM
  description: >-
    The other historical form, dominant east of the Rhine while gangrenous
    ergotism dominated to the west. Muscle twitching and spasm, altered mental
    state, hallucination, sweating and fever, persisting for weeks rather than
    resolving in days. Modern outbreaks in Ethiopia and India are the reason
    this is not purely a historical category.
  downstream:
  - target: Seizure
    causal_link_type: DIRECT
  - target: Muscle spasm
    causal_link_type: DIRECT
  - target: Hallucinations
    causal_link_type: DIRECT
  - target: Confusion
    causal_link_type: DIRECT
  - target: Fever
    causal_link_type: DIRECT
  - target: Hyperhidrosis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Between 1085 and 1927, epidemics of \"convulsive ergotism\" were widespread east of the Rhine in Europe due to consumption of grain contaminated with ergot, which is produced by the fungus Claviceps purpurea. West of the Rhine, consumption of ergot-contaminated food caused epidemics of gangrenous ergotism."
    explanation: The geographical separation of the two forms this entry records.
  - reference: PMID:22903169
    reference_title: "Human and cattle ergotism since 1900: symptoms, outbreaks, and regulations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Symptoms in humans vary greatly and are generally classified as convulsive, gangrenous, or gastrointestinal (enteric)."
    explanation: >-
      The standard three-way classification. Note it names a gastrointestinal
      form alongside the two this entry models as branches.
phenotypes:
- category: Vascular
  name: Vasospasm
  description: >-
    The core lesion, seen on angiography as diffuse arterial narrowing without
    plaque or thrombus. It is what makes ergotism a non-atherosclerotic cause of
    peripheral arterial disease.
  phenotype_term:
    preferred_term: Vasospasm
    term:
      id: HP:0025637
      label: Vasospasm
    temporality: ACUTE
  evidence:
  - reference: PMID:33546816
    reference_title: "Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angiography confirmed diffuse arterial vasospasm of the lower limb arteries."
    explanation: Angiographic confirmation of this phenotype.
  - reference: PMID:1908611
    reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "7 patients have been admitted in our hospital for severe vasospasm of one or several extremities due to ergot's derivatives"
    explanation: A consecutive hospital series presenting with this phenotype.
- category: Vascular
  name: Gangrene
  description: >-
    Dry gangrene of the extremities, the lesion that named St Anthony's Fire and
    still the outcome when vasospasm is not relieved in time.
  phenotype_term:
    preferred_term: dry gangrene of the extremities
    term:
      id: HP:0100758
      label: Gangrene
    temporality: ACUTE
  notes: >-
    Bound to the general `HP:0100758` Gangrene. A search of HPO for the more
    specific concept returns nothing:
    `curl .../ols4/api/search?q=Peripheral+gangrene&ontology=hp` returns no term
    of that name, and the `HP:0034976` that the deep-research report offered
    under that label is *Absent pituitary stalk*. The distal, dry character of
    the lesion is carried in `preferred_term`.
  evidence:
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients required partial foot amputations due to gangrene."
    explanation: Gangrene reaching amputation in a modern poison-centre series.
  - reference: PMID:1908611
    reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distal necrosis developed in two patients (DHE-heparin)."
    explanation: The tissue-death endpoint, in an independent series.
- category: Vascular
  name: Coronary artery spasm
  description: >-
    Coronary vasospasm, reported after obstetric ergometrine given for
    postpartum haemorrhage - the same pharmacology reaching the coronary bed
    while acting on its intended uterine target. The diagnostic signature is
    myocardial infarction with unremarkable coronary angiography, since the
    obstruction is spasm rather than plaque.
  phenotype_term:
    preferred_term: Coronary artery spasm
    term:
      id: HP:0025497
      label: Coronary artery spasm
    temporality: ACUTE
  evidence:
  - reference: PMID:40046976
    reference_title: "Joining forces: a complex cardio-obstetrics case report of severe ergometrine-induced vasospasm."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is also a potent vasoconstrictor capable of causing significant coronary artery vasospasm in susceptible individuals"
    explanation: States that the obstetric ergot alkaloid causes coronary vasospasm.
  - reference: PMID:40046976
    reference_title: "Joining forces: a complex cardio-obstetrics case report of severe ergometrine-induced vasospasm."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most likely unifying diagnosis was severe ergotamine-induced coronary vasospasm causing acute myocardial infarction in the setting of life-threatening PPH."
    explanation: The authors' diagnosis in the case, reaching infarction.
  - reference: PMID:40046976
    reference_title: "Joining forces: a complex cardio-obstetrics case report of severe ergometrine-induced vasospasm."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiovascular MRI showed moderate LV systolic impairment and focal apical infarction. Coronary angiography was unremarkable."
    explanation: >-
      The finding behind this phenotype's diagnostic signature - documented
      infarction with an unremarkable angiogram, which is what spasm looks like.
- category: Vascular
  name: Intermittent claudication
  description: >-
    Limb pain on walking, progressing to rest pain as the spasm worsens - the
    presenting complaint in the drug-interaction case that went on to bilateral
    ischaemia.
  phenotype_term:
    preferred_term: Intermittent claudication
    term:
      id: HP:0004417
      label: Intermittent claudication
    temporality: ACUTE
  evidence:
  - reference: PMID:33546816
    reference_title: "Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she presented an acute bilateral limb ischemia with a sudden pain in both calves, initially while walking and then at rest with bilateral ischemic toes"
    explanation: >-
      The claudication-to-rest-pain progression this phenotype records, in one
      patient.
- category: Vascular
  name: Acrocyanosis
  description: Cyanotic discolouration of the digits as distal perfusion fails.
  phenotype_term:
    preferred_term: Acrocyanosis
    term:
      id: HP:0001063
      label: Acrocyanosis
    temporality: ACUTE
  evidence:
  - reference: PMID:30662776
    reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "feeble peripheral pulses and cyanotic limbs, loss of peripheral sensation, edema, and gangrene of affected tissues"
    explanation: >-
      Names cyanotic limbs in the symptom list the authors give for ergotamine
      toxicity, alongside the pulse and sensory findings it accompanies.
- category: Neurologic
  name: Paresthesia
  description: >-
    Burning pain and tingling in the extremities, the earliest feature of the
    gangrenous form and the sensation the disease's old name refers to.
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
    temporality: ACUTE
  evidence:
  - reference: PMID:30662776
    reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "feeble peripheral pulses and cyanotic limbs, loss of peripheral sensation, edema, and gangrene of affected tissues"
    explanation: >-
      The sensory disturbance in the authors' symptom list, alongside the
      vascular findings it accompanies. It names loss of sensation rather than
      the burning quality, which is described in the historical literature.
- category: Neurologic
  name: Limb pain
  description: Ischaemic pain in the affected extremity, at rest in severe cases.
  phenotype_term:
    preferred_term: Limb pain
    term:
      id: HP:0009763
      label: Limb pain
    temporality: ACUTE
  evidence:
  - reference: PMID:33546816
    reference_title: "Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a sudden pain in both calves, initially while walking and then at rest"
    explanation: The pain and its progression to rest pain.
- category: Neurologic
  name: Seizure
  description: Part of the convulsive form.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    temporality: ACUTE
  evidence:
  - reference: PMID:30662776
    reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "agitation, hallucinations, lethargy, confusion, painful spasms, seizures"
    explanation: Names seizures in the authors' symptom list for ergotamine toxicity.
- category: Neurologic
  name: Muscle spasm
  description: >-
    Muscle twitching and painful spasm, the feature that named the convulsive
    form.
  phenotype_term:
    preferred_term: Muscle spasm
    term:
      id: HP:0003394
      label: Muscle spasm
    temporality: ACUTE
  evidence:
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "muscle twitching and spasms, changes in mental state, hallucinations, sweating, and fever lasting for several weeks"
    explanation: The defining feature set of the convulsive form.
- category: Neuropsychiatric
  name: Hallucinations
  description: >-
    Hallucination during the convulsive form, the feature that made medieval
    accounts read as possession.
  phenotype_term:
    preferred_term: Hallucinations
    term:
      id: HP:0000738
      label: Hallucinations
    temporality: ACUTE
  evidence:
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "muscle twitching and spasms, changes in mental state, hallucinations, sweating, and fever lasting for several weeks"
    explanation: Names hallucination among the convulsive features.
- category: Neuropsychiatric
  name: Confusion
  description: Altered mental state, persisting for weeks in the convulsive form.
  phenotype_term:
    preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
    temporality: ACUTE
  evidence:
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "changes in mental state, hallucinations, sweating, and fever lasting for several weeks"
    explanation: Names the change in mental state and how long it lasts.
  - reference: PMID:30662776
    reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Symptoms of ET can be nausea, vomiting, abdominal pain, agitation, hallucinations, lethargy, confusion, painful spasms, seizures"
    explanation: Independent listing of confusion among ergotamine toxicity features.
- category: Neurologic
  name: Cerebral ischaemia
  description: >-
    Vasospasm is not confined to the limbs. Cerebral ischaemia is recorded
    alongside limb ischaemia in the fatal darunavir interaction, and an
    ergometrine case shows extensive cortical infarction whose pattern was read
    as a reversible vasoconstriction syndrome - the same lesion as the limb
    disease, in the cerebral circulation.
  phenotype_term:
    preferred_term: Cerebral ischemia
    term:
      id: HP:0002637
      label: Cerebral ischemia
    temporality: ACUTE
  notes: >-
    The ergometrine case also suffered a later middle cerebral artery
    occlusion, but that one followed left ventricular thrombus formation and is
    embolic rather than vasospastic. It is deliberately not cited here: the
    same patient having both a vasospastic and an embolic cerebral event is
    exactly the confusion this phenotype would otherwise import.
  evidence:
  - reference: PMID:30662776
    reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient developed severe limb ischemia, cerebral ischemia, and metabolic encephalopathy."
    explanation: >-
      Records cerebral ischaemia in the same patient and the same episode as
      the limb ischaemia this entry's chain produces.
  - reference: PMID:40046976
    reference_title: "Joining forces: a complex cardio-obstetrics case report of severe ergometrine-induced vasospasm."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pattern of cortical involvement with subcortical sparring raised the possibility of a reversible vasoconstriction syndrome"
    explanation: >-
      The imaging pattern that identifies the cerebral lesion as vasospastic
      rather than embolic or atherosclerotic.
- category: Gastrointestinal
  name: Nausea and vomiting
  description: >-
    Listed among the features of ergotamine toxicity. Recorded because the
    gastrointestinal form is one of the three classical presentations of this
    disease and was otherwise absent from this entry.
  phenotype_term:
    preferred_term: Nausea and vomiting
    term:
      id: HP:0002017
      label: Nausea and vomiting
  notes: >-
    Deliberately left without a causal inbound edge. Ergot alkaloids act at
    central dopaminergic and serotonergic receptors that would plausibly
    explain emesis, and this entry carries a `Central Serotonergic
    Overstimulation` node, but the source quoted here is a symptom list and
    asserts no mechanism. Writing that edge would be inventing the
    attribution rather than curating it.
  evidence:
  - reference: PMID:30662776
    reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Symptoms of ET can be nausea, vomiting, abdominal pain, agitation, hallucinations, lethargy, confusion, painful spasms, seizures"
    explanation: Names nausea and vomiting among the features of ergotamine toxicity.
- category: Constitutional
  name: Fever
  description: Fever accompanying the convulsive form, described as lasting weeks.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
    temporality: PROLONGED
  evidence:
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "sweating, and fever lasting for several weeks"
    explanation: The fever and its duration.
- category: Constitutional
  name: Hyperhidrosis
  description: Sweating, alongside fever, in the convulsive form.
  phenotype_term:
    preferred_term: Hyperhidrosis
    term:
      id: HP:0000975
      label: Hyperhidrosis
    temporality: PROLONGED
  evidence:
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "sweating, and fever lasting for several weeks"
    explanation: >-
      The sweating this phenotype records, which with fever is part of what
      suggested serotonergic overstimulation to the author.
environmental:
- name: Ingestion of cereal grain contaminated with Claviceps sclerotia
  description: >-
    The historical route and still the epidemic one. Claviceps species replace
    the grain of rye and other cereals with sclerotia; if these are not removed
    before milling, the flour carries the alkaloids. This is the route of the
    medieval European epidemics and of the modern outbreaks in Ethiopia and
    India, which occurred where grain-cleaning infrastructure was weakest rather
    than where the fungus was newest.
  exposure_term:
    preferred_term: dietary exposure to ergot alkaloids in Claviceps-contaminated grain
    term:
      id: ECTO:0000524
      label: exposure to mycotoxin
  exposure_classifications:
    hazard_agent_type:
    - classification_value: BIOLOGICAL
    exposure_route:
    - classification_value: ORAL
    exposure_duration:
    - classification_value: ACUTE
  influences_mechanisms:
  - target: Ergot Alkaloid Entry into the Circulation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: Eating the contaminated flour is what delivers the alkaloids.
    evidence:
    - reference: PMID:12849122
      reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "consumption of grain contaminated with ergot, which is produced by the fungus Claviceps purpurea"
      explanation: States the consumption-to-disease route this edge asserts.
  notes: >-
    Bound to `ECTO:0000524` exposure to mycotoxin, which is exact for the agent
    class: ergot alkaloids are fungal secondary metabolites, and MONDO itself
    files ergotism under `MONDO:0042497` mycotoxicosis. The searches behind that
    choice, against the pinned local build the validator reads:

    `runoak -i sqlite:obo:ecto search 'l~ergot'` returns nothing - there is no
    ergot or Claviceps exposure class.
    `runoak -i sqlite:obo:ecto search 'l~mycotoxin'` returns `CHEBI:25442`
    mycotoxin and `ECTO:0000524` exposure to mycotoxin.
    `runoak -i sqlite:obo:ecto search 'l~rye'` returns `ECTO:0070112` exposure
    to rye bread via ingestion, which looks ideal and is not: `info ECTO:0070112
    -O obo` shows it involves `FOODON:03305210` rye bread (enriched), a
    fortified commercial product, where this exposure is to ergot-contaminated
    grain.
    `runoak -i sqlite:obo:ecto search 'l~alkaloid'` returns `ECTO:9000271`
    exposure to alkaloid, which was rejected as less apt: it is anchored on
    `CHEBI:22315` alkaloid and loses the fungal origin that defines this
    exposure and that MONDO's own placement turns on.
  evidence:
  - reference: PMID:36635416
    reference_title: "Ergot alkaloids in sclerotia collected in Japan: synthetic profiles and induction of apoptosis by Clavine-type compounds."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "24 out of 41 sclerotia extracts include peptide-type EAs"
    explanation: >-
      Establishes what this exposure actually delivers. An LC-MS survey of 41
      Claviceps sclerotia found peptide-type alkaloids - ergosine, ergotamine,
      ergocornine, alpha-ergocryptine, ergocristine - in most of them, which is
      the mixture this route carries and the reason the dose cannot be treated
      as a single agent.
  - reference: PMID:36635416
    reference_title: "Ergot alkaloids in sclerotia collected in Japan: synthetic profiles and induction of apoptosis by Clavine-type compounds."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Agroclavine (2), a typical Clavine-type EA, is a causative agent of ergotism and is listed as a compound to be monitored by the European Food Safety Authority."
    explanation: >-
      Names a second alkaloid class present in the same sclerotia and records
      that a regulator monitors it in food, which is what makes this exposure a
      current food-safety matter rather than a historical one.
  - reference: PMID:22903169
    reference_title: "Human and cattle ergotism since 1900: symptoms, outbreaks, and regulations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "outbreaks in humans have recently occurred in lower socioeconomic populations of Ethiopia (1977 and 2001) and India (1975) with devastating results"
    explanation: >-
      The modern outbreaks of this route, and the socioeconomic pattern they
      follow.
  - reference: PMID:22903169
    reference_title: "Human and cattle ergotism since 1900: symptoms, outbreaks, and regulations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The prevalence of ergotism has decreased as knowledge of the fungus has increased, mainly through implementation of regulations and advances in milling procedures."
    explanation: >-
      What suppressed this route, which is also why its failure is an
      infrastructure question rather than a biological one.
  - reference: PMID:34920829
    reference_title: Ergotism and Saint Anthony's fire.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ingestion of infected rye grains containing ergot alkaloids-usually in the form of contaminated rye bread-causes poisoning, also known as ergotism."
    explanation: Names the specific vehicle of the historical epidemics.
- name: Therapeutic ergot alkaloid administration
  description: >-
    Ergotamine and dihydroergotamine for migraine, and ergometrine or
    methylergometrine for postpartum haemorrhage, are still in use. At
    therapeutic dose they are usually tolerated; the exposure becomes toxic
    through overdose, prolonged use, or - much the commonest route in modern
    series - a CYP3A4 interaction.
  exposure_term:
    preferred_term: therapeutic exposure to ergot alkaloid vasoconstrictors
    term:
      id: ECTO:9001855
      label: exposure to vasoconstrictor agent
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: MULTIPLE
    exposure_duration:
    - classification_value: INTERMITTENT
    - classification_value: CHRONIC
  influences_mechanisms:
  - target: Ergot Alkaloid Entry into the Circulation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      A prescription delivers one purified alkaloid, in place of the mixture a
      contaminated harvest delivers.
    evidence:
    - reference: PMID:24978905
      reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All cases involved ergotamine 1 mg/caffeine 100 mg combination tablets."
      explanation: >-
        Identifies the therapeutic preparation behind every case in a
        twelve-case series, which is this exposure.
  notes: >-
    Bound to `ECTO:9001855` exposure to vasoconstrictor agent rather than to the
    broader `ECTO:0000509` exposure to drug. `runoak -i sqlite:obo:ecto search
    'l~ergotamine'` returns nothing, so no agent-specific class exists;
    `search 'l~vasoconstrict'` returns `ECTO:9001855`, and `info ECTO:9001855
    -O obo` shows it is `is_a ECTO:0000509` exposure to drug and involves
    `CHEBI:50514` vasoconstrictor agent. That is exact for what these drugs are
    and for the property that makes them toxic here, so it is preferred to the
    parent. `exposure_route` is `MULTIPLE` because the implicated preparations
    are oral (ergotamine tablets), intramuscular (ergometrine) and intravenous
    (dihydroergotamine) across the cited cases.

    `exposure_duration` is `INTERMITTENT` and `CHRONIC` rather than `ACUTE`.
    Migraine dosing is by definition recurrent discrete exposures separated by
    exposure-free intervals, which is what `INTERMITTENT` means, and the cases
    in this entry ran for years - the fatal darunavir case records the patient
    "self-medicating for years", and `PMID:1908611` finds a subclinical phase
    preceding severe disease by weeks, which no 1-14 day window contains. An
    acute single overdose is a real presentation too, but it is the exception
    in the cited series rather than the shape of this exposure.
  evidence:
  - reference: PMID:1908611
    reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ergot's derivatives are widely used to treat and prevent migraine and, associated with heparin, for the prevention of deep vein thrombosis."
    explanation: Establishes the therapeutic uses that constitute this exposure.
  - reference: PMID:1908611
    reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ergotamine tartrate was the responsible drug in four patients and dihydroergotamine(DHE)-heparin in three patients."
    explanation: Names the specific agents responsible in a consecutive series.
- name: Co-administration of a strong CYP3A4 inhibitor
  description: >-
    Not a source of ergot alkaloid, but the exposure that converts a
    therapeutic dose of one into a toxic dose. The implicated inhibitors are the
    HIV protease inhibitors, the booster cobicistat, and the macrolide
    antibiotics. This is now the dominant precipitant of severe ergotism in the
    published record, and the combination is regarded as contraindicated.
  exposure_term:
    preferred_term: co-exposure to a strong CYP3A4 inhibitor
    term:
      id: ECTO:0000509
      label: exposure to drug
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: ORAL
    exposure_duration:
    - classification_value: ACUTE
    - classification_value: CHRONIC
  influences_mechanisms:
  - target: CYP3A4 Inhibition Raising Systemic Ergotamine Concentration
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      `EXACERBATES` rather than `TRIGGERS`: this exposure causes no disease by
      itself and acts only on the toxicity of a separate one.
    evidence:
    - reference: PMID:24531557
      reference_title: "Ergotism in Thailand caused by increased access to antiretroviral drugs: a global warning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Concurrent intake of ergotamine and strong CYP3A4 inhibitors, such as the HIV protease inhibitors (PIs), can lead to clinical ergotism."
      explanation: States the co-exposure requirement and its consequence.
  notes: >-
    Bound to the broad `ECTO:0000509` exposure to drug on purpose. The exposure
    is defined by an enzyme-inhibition property shared across three unrelated
    drug classes rather than by any one agent, and there is no ECTO class for
    that property: `runoak -i sqlite:obo:ecto search 'l~cytochrome'` and
    `search 'l~CYP'` both return nothing, and `search 'l~protease inhibitor'`
    returns no exposure class either. The specific classes are named in
    `description` instead.

    `exposure_duration` carries both `ACUTE` and `CHRONIC` because the
    implicated drug classes sit at opposite ends of it: a macrolide course is a
    few days, while the HIV protease inhibitors and cobicistat behind most of
    the modern cases are taken indefinitely. The interaction needs only that
    the two exposures overlap, so neither value alone describes it.
  evidence:
  - reference: PMID:24531557
    reference_title: "Ergotism in Thailand caused by increased access to antiretroviral drugs: a global warning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A total of 13 cases of clinical ergotism in HIV-infected patients has been published since 1997"
    explanation: >-
      The accumulated published burden of this specific co-exposure at the time
      of that review.
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Critical ergotism continues to occur in Thailand, most commonly associated with the drug-drug interactions."
    explanation: Establishes this as the dominant modern precipitant in that setting.
diagnosis:
- name: Exposure history with non-atherosclerotic distal ischaemia
  notes: >-
    Left without a `diagnosis_term`. `diagnosis_term` is a `TreatmentDescriptor`
    whose term must be reachable from `NCIT:C25218` Clinical Intervention or
    Procedure, and history-taking is not in that branch: `NCIT:C146918` Medical
    History Taking exists and is the obvious candidate, but binding it fails
    dynamic-enum validation with "Value 'NCIT:C146918' not in dynamic enum
    'TreatmentActionTerm'". The OLS search behind that attempt, `q=medical
    history taking, ontology=ncit`, returns `NCIT:C146918` Medical History
    Taking, `NCIT:C83067` Medical History Occurrence, `NCIT:C85522` Medical
    History Yes No Indicator and `NCIT:C85833` Work-Up Examination; the first
    three are data-collection concepts rather than procedures and the fourth is
    broader than this entry. No binding is better than a wrong one.
  description: >-
    There is no confirmatory assay in routine use. The diagnosis is made by
    finding arterial insufficiency without atherosclerosis, thrombus or
    vasculitis, and then finding the exposure - which in the iatrogenic form
    means asking specifically about migraine self-medication and about any
    recently started drug. That question is the one that gets missed: in the
    fatal darunavir case the ergotamine use surfaced only after the ischaemia
    had spread and the family were interviewed.
  evidence:
  - reference: PMID:30662776
    reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinicians were not aware that patient was self-medicating for years with medication containing ergotamine and caffeine for migraines."
    explanation: >-
      The specific history failure this entry warns about, in the case where it
      proved fatal.
  - reference: PMID:30662776
    reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This diagnosis was established after evaluating the evolving 'and spreading' ischemia and CT scans and thoroughly interviewing patient's family."
    explanation: How the diagnosis was eventually reached in that case.
  - reference: PMID:30662776
    reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "in absence of any thrombophilic pathology or arteritides, thorough interview and physical examination are important to find clues to this rare disorder"
    explanation: States the diagnostic reasoning this entry describes - exclusion, then history.
- name: Vascular imaging showing diffuse spasm without occlusive lesion
  diagnosis_term:
    preferred_term: arteriography of the affected limb
    term:
      id: NCIT:C16308
      label: Arteriography
  description: >-
    Angiography or CT angiography shows smooth diffuse narrowing rather than
    plaque or clot. Duplex ultrasonography has been proposed for diagnosis and
    for following the response to treatment, which matters because the spasm
    resolves and a non-invasive test can show it doing so.
  evidence:
  - reference: PMID:33546816
    reference_title: "Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angiography confirmed diffuse arterial vasospasm of the lower limb arteries."
    explanation: The angiographic finding this entry records.
  - reference: PMID:28031641
    reference_title: "Ergotism: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A case of ergotism is presented to illustrate the role of duplex ultrasonography in the diagnosis and management of this nonatherosclerotic cause of peripheral arterial disease."
    explanation: >-
      Establishes duplex ultrasound for both diagnosis and management, and names
      the non-atherosclerotic framing this section uses.
- name: Factitious hypotension from severe vasospasm
  diagnosis_term:
    preferred_term: non-invasive blood pressure measurement
    term:
      id: NCIT:C167233
      label: Blood Pressure Measurement
  description: >-
    A trap specific to this disease. Vasospasm severe enough to abolish the
    peripheral signal makes non-invasive blood pressure read as low or
    unmeasurable, so the patient appears shocked. Treating that apparent
    hypotension with a vasoconstrictor would be the wrong move; giving an
    intravenous vasodilator instead makes the recorded pressure rise
    paradoxically, which is both the clue and the treatment.
  evidence:
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five of these patients initially had factitiously low or unmeasurable blood pressure using non-invasive technique and had paradoxical increase following intravenous vasodilator administration."
    explanation: >-
      The finding and its paradoxical response, in five of twelve patients -
      which is what makes it a usable sign rather than a curiosity.
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factitious low blood pressure in these cases was likely caused by severe vasospasm."
    explanation: The authors' mechanistic reading, which is why it belongs to this disease specifically.
differential_diagnoses:
- name: Atherosclerotic and embolic limb ischaemia
  description: >-
    Acute limb ischaemia is far more often atherosclerotic, embolic or
    thrombotic than vasospastic, and the ergot history is not volunteered. This
    is the differential that delays the diagnosis.
  distinguishing_features:
  - >-
    Imaging shows smooth diffuse arterial narrowing rather than a focal
    occlusive lesion, plaque or thrombus.
  - >-
    The narrowing is reversible: vasodilator therapy and withdrawal of the drug
    restore flow, which no atherosclerotic lesion does.
  evidence:
  - reference: PMID:28031641
    reference_title: "Ergotism: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this nonatherosclerotic cause of peripheral arterial disease"
    explanation: Places ergotism explicitly outside the atherosclerotic category.
  - reference: PMID:28031641
    reference_title: "Ergotism: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our case emphasizes the potential for complete reversibility of the vascular changes if recognized early."
    explanation: Supports reversibility as the discriminating feature listed here.
- name: Systemic vasculitis
  description: >-
    Ergotism can present as apparent vasculitis, with distal ischaemia and no
    obvious occlusive cause, and has been reported under exactly that framing.
  distinguishing_features:
  - >-
    Absence of thrombophilic or arteritic pathology on workup, with a history of
    ergot exposure.
  notes: >-
    Kept short and cited to one source. PMID:28661928, titled "Ergotism
    Masquerading Systemic Vasculitis", is the paper this differential is named
    after and is deliberately not cited: its cached record has no abstract at
    all, so there is no sentence to quote, and quoting the title would assert a
    finding from a string that only states a topic. The differential is
    supported instead by the exclusion reasoning below, which a cited abstract
    does state.
  evidence:
  - reference: PMID:30662776
    reference_title: "Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "in absence of any thrombophilic pathology or arteritides"
    explanation: Supports the distinguishing feature listed here.
treatments:
- name: Withdrawal of the ergot alkaloid
  description: >-
    The first and most important intervention, and in mild cases the only one
    needed. Because the toxicity is receptor occupancy by a clearable drug
    rather than structural damage, stopping the exposure allows the spasm to
    resolve - provided it is stopped before the tissue dies. A historical review
    of the disease found no convincing evidence that anything other than
    discontinuation helps, which is a strong claim about the rest of this
    section and is recorded as such.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: withdrawal of the causative ergot alkaloid
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Ergot Alkaloid Entry into the Circulation
    treatment_effect: INHIBITS
    description: >-
      Stopping the drug removes the exposure itself, which is upstream of every
      other node in the entry.
    evidence:
    - reference: PMID:1908611
      reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Subclinical ergotism most probably precedes for weeks the onset of severe vasospasm, which calls for close monitoring of patients taking ergot's derivatives."
      explanation: >-
        Supports acting on the exposure as the intervention point, and that
        there is a monitoring window before severe disease. Indirect: it argues
        for monitoring rather than measuring the effect of withdrawal.
  evidence:
  - reference: PMID:28031641
    reference_title: "Ergotism: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our case emphasizes the potential for complete reversibility of the vascular changes if recognized early."
    explanation: >-
      The reversibility that makes withdrawal sufficient when it happens in
      time.
- name: Intravenous vasodilator therapy
  description: >-
    For established severe vasospasm. Sodium nitroprusside relieved the spasm in
    five of six patients in one series, within hours to days, and no amputation
    was needed in that series despite severe and prolonged spasm. Nitrates and
    calcium channel blockers are also used, though a bilateral-ischaemia case
    records isosorbide dinitrate and amlodipine failing outright before more
    aggressive measures worked.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium nitroprusside
      term:
        id: CHEBI:29321
        label: sodium nitroprusside
  target_mechanisms:
  - target: Sustained Vascular Smooth Muscle Contraction
    treatment_effect: INHIBITS
    description: >-
      Vasodilators oppose the contraction directly rather than removing the
      alkaloid, which is why they work while the drug is still present.
    evidence:
    - reference: PMID:1908611
      reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Intravenous administration of sodium nitroprusside (n = 6) relieved vasospasm in all but one of the patients within hours to days"
      explanation: Measures the effect on the vasospasm this edge targets.
  evidence:
  - reference: PMID:1908611
    reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No amputation was required in this series in spite of severe and prolonged vasospasms."
    explanation: The outcome achieved in a series managed this way.
  - reference: PMID:33546816
    reference_title: "Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "A first-line therapy with isosorbide dinitrate and amlodipine was ineffective, with rapid clinical worsening."
    explanation: >-
      A case where first-line vasodilators failed and the patient deteriorated,
      which is why this treatment is not recorded as reliably sufficient.
- name: Endovascular revascularisation
  description: >-
    Reserved for spasm that does not yield to drugs. In one case, intra-arterial
    and intravenous vasodilators combined with multisite transluminal balloon
    angioplasty and bilateral four-compartment fasciotomy restored flow along
    the whole lower-limb arterial tree and saved both legs, without the spasm
    recurring.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: multisite transluminal balloon angioplasty
    term:
      id: NCIT:C93007
      label: Balloon Angioplasty
  target_mechanisms:
  - target: Arterial Vasospasm with Distal Hypoperfusion
    treatment_effect: INHIBITS
    description: Mechanical dilatation of the spastic segment restores the lumen.
    evidence:
    - reference: PMID:33546816
      reference_title: "Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All along the lower limb arterial tree, transluminal balloon angioplasty restored the blood flow, without vasospasm recurrence."
      explanation: The measured effect on the vasospasm node, including its durability.
  evidence:
  - reference: PMID:33546816
    reference_title: "Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A combination of intra-arterial injections and intra-venous infusions of vasodilators, transluminal balloon angioplasty and bilateral 4-Compartment fasciotomies permitted rapid improvement and finally resulted in both lower limbs rescue."
    explanation: The full combination used and the limb-salvage outcome.
  - reference: PMID:33546816
    reference_title: "Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In case of ergotism with acute lower limbs ischemia, combining medical vasodilator therapy with interventional procedure can restore the arterial blood flow, thus allowing to save lower limbs."
    explanation: The authors' own recommendation for where this sits in management.
- name: Corticosteroid rescue therapy
  description: >-
    A second-line option for spasm that does not yield to a vasodilator. In one
    case, pulses that had been lost despite sodium nitroprusside and heparin
    became palpable two hours after a single 1 mg/kg intravenous dose of
    methylprednisolone sodium succinate, with angiographic improvement at twelve
    hours. The authors state plainly that the mechanism is unknown, which is why
    this is recorded as an observation about an intractable case rather than as
    a mechanism-directed treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methylprednisolone sodium succinate
      term:
        id: CHEBI:6890
        label: Methylprednisolone sodium succinate
  notes: >-
    No `target_mechanisms`. An edge would have to name the node the steroid
    acts on, and the cited source explicitly declines to: "The mechanism by
    which corticosteroids dilate arteries is not clear." Leaving the treatment
    unlinked records what is known; guessing at the receptor node would not.

    Heparin was co-administered in this case and is named in the same sentence
    as the nitroprusside, but no outcome is attributed to it and the recovery
    followed the steroid. It is therefore not curated as a separate treatment
    here - a treatment whose only support is that it was given alongside
    something else is not a treatment claim.
  evidence:
  - reference: PMID:18763151
    reference_title: Reversal of ergotamine-induced vasospasm following methylprednisolone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ischemia in an extremity secondary to ergotamine-induced vasospasm unresponsive to sodium nitroprusside may be treated successfully with methylprednisolone."
    explanation: >-
      The authors' conclusion, and the specific niche this treatment occupies -
      after a vasodilator has failed.
  - reference: PMID:18763151
    reference_title: Reversal of ergotamine-induced vasospasm following methylprednisolone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pulses were palpable 2 h after the methylprednisolone dose."
    explanation: The measured response, and how fast it came.
  - reference: PMID:18763151
    reference_title: Reversal of ergotamine-induced vasospasm following methylprednisolone.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although vasodilator agents are first-line therapy in the treatment of ergotism, corticosteroids may be considered as an alternative therapy, especially for intractable cases."
    explanation: >-
      Places this treatment second-line, which is how the entry orders it, and
      is the authors' framing rather than their result.
- name: Amputation of non-viable tissue
  description: >-
    The salvage procedure once gangrene is established. Two of twelve patients
    in a modern poison-centre series required partial foot amputation. It is
    included because the entry would otherwise imply that every case either
    resolves or kills, when the commonest bad outcome is neither.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: partial foot amputation for established gangrene
    term:
      id: NCIT:C15179
      label: Amputation
  notes: >-
    No `target_mechanisms`, and none of the `TreatmentEffectEnum` values fits.
    Amputation does not inhibit, activate, modulate, bypass or restore any node
    in this entry; it removes the tissue that the last node in the chain has
    already killed. The absence is the accurate record.
  evidence:
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients required partial foot amputations due to gangrene."
    explanation: >-
      Establishes that amputation was required, in what proportion, and for
      what lesion.
- name: Sympathectomy
  description: >-
    Attempted historically and recorded as unhelpful. Two patients in a
    seven-patient series underwent it without improvement in their clinical
    course, which is worth keeping because it is a negative result that a
    plausible mechanism would have predicted to work.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: sympathectomy
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  notes: >-
    Bound to the generic `NCIT:C15329` because NCIT has no sympathectomy term.
    OLS `q=sympathectomy` returns `SNOMED:57071006`, `mesh:D013562`,
    `OMIT:0014426` and four further SNOMED children, and no NCIT identifier at
    all; `q=sympathectomy, ontology=ncit`, `q=sympathetic denervation,
    ontology=ncit` and `q=lumbar sympathectomy, ontology=ncit` each return
    nothing. `NCIT:C21110` Sympathetic Block exists but names an anaesthetic or
    chemical block rather than the surgical division performed in the cited
    series, so it is not a substitute. The specificity is carried in
    `preferred_term`.
  evidence:
  - reference: PMID:1908611
    reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "A sympathectomy was performed in two patients which did not improve the clinical course."
    explanation: >-
      The negative result. Curated as `REFUTE` against this treatment rather
      than omitted, since a reader would otherwise reasonably expect
      sympathetic interruption to help a vasospastic disease.
progression:
- phase: Subclinical vasospasm
  duration: weeks
  notes: >-
    Reported to precede severe disease by weeks in patients taking ergot
    derivatives, and reported at far higher prevalence than severe ergotism.
    This phase is the reason monitoring is recommended, and the reason the
    burden level for this entry is `VARIABLE` rather than a single tier.
  evidence:
  - reference: PMID:1908611
    reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subclinical ergotism most probably precedes for weeks the onset of severe vasospasm, which calls for close monitoring of patients taking ergot's derivatives."
    explanation: States both the existence of this phase and its duration.
- phase: Acute vasospastic or convulsive illness
  duration: days to weeks
  notes: >-
    The clinical syndrome. In the gangrenous form it runs over days, from
    paresthesia through pulse loss toward gangrene; in the convulsive form the
    features are described as lasting several weeks.
  evidence:
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "sweating, and fever lasting for several weeks"
    explanation: The duration of the convulsive form.
- phase: Resolution or fixed ischaemic injury
  duration: days
  notes: >-
    Monophasic and bimodal in outcome. The vasospasm either resolves, completely
    in cases caught early, or the tissue it starved has already died and the
    loss is permanent.
  evidence:
  - reference: PMID:28031641
    reference_title: "Ergotism: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our case emphasizes the potential for complete reversibility of the vascular changes if recognized early."
    explanation: The resolution arm and the condition on reaching it.
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients required partial foot amputations due to gangrene."
    explanation: The other arm, in the same disease.
prevalence:
- population: Geneva, severe iatrogenic ergotism
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.5
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    Reported as an upper bound - less than 0.5 per 100,000 per year - so
    `rate_per_100000` records the bound rather than a point estimate. The band
    is the Orphanet tier that bound falls in. This covers severe disease only;
    the same paper cites a 15% prevalence of subclinical ergotism among users,
    which is a different measure on a different denominator and is recorded in
    `progression` rather than forced into this record.
  evidence:
  - reference: PMID:1908611
    reference_title: "Severe iatrogenic ergotism: incidence and clinical importance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is concluded that incidence of severe ergotism is less than 0.5/100,000/year in Geneva."
    explanation: The rate and population this record reports.
- population: Ramathibodi Poison Center, Bangkok, 2006-2013
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Twelve cases over seven and a half years at one referral poison centre. A
    case count, not a rate: the denominator is the centre's referral catchment
    rather than a population, so no incidence can be derived from it.
  evidence:
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twelve cases of ergotism were identified."
    explanation: The case count this record reports.
  - reference: PMID:24978905
    reference_title: Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "data obtained retrospectively from all patients with ergotism referred to Ramathibodi Poison Center in Bangkok, Thailand from January 2006 to August 2013"
    explanation: The catchment and window that makes this a count rather than a rate.
animal_models:
- name: Sheep single-dose oral ergot sclerotia exposure
  species: Sheep
  description: >-
    Twelve adult ewes, six dosed once orally with ground ergot sclerotia at 600
    ug/kg bodyweight total ergot and six given water, euthanised twelve hours
    later, with the pedal artery of the left hind limb mounted in an isolated
    tissue bath and its contractile response to phenylephrine compared between
    groups. This is the closest thing to a controlled experiment on the human
    disease that exists: the exposure is the same sclerotial alkaloid mixture,
    the route is oral, and the readout is the vascular smooth muscle response
    this entry's chain runs through. It models the vascular arm only - sheep
    ergotism is a gangrenous disease, and nothing here addresses the convulsive
    branch.
  publication: PMID:33924041
  evidence:
  - reference: PMID:33924041
    reference_title: Vasoactive Effects of Acute Ergot Exposure in Sheep.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Each ewe within the treatment group received a single oral treatment of ground ergot sclerotia at a dose of 600 µg/kg BW (total ergot) while each ewe in the control group received water."
    explanation: >-
      The design that makes this a controlled model rather than an observation:
      a dosed group, a water control, and a defined alkaloid load.
  modeled_mechanisms:
  - target: Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Exposure to the sclerotial alkaloid mixture left the pedal artery more
      sensitive to an alpha-1 agonist, and an alpha-1 antagonist was a more
      potent blocker in exposed animals than in controls - which is the
      adrenergic half of this node measured directly rather than inferred.
    limitations: >-
      Only the alpha-1 adrenergic arm is interrogated. The 5-HT receptor
      contribution that this node also asserts is not measured here, and the
      authors reach it only through the general statement they cite from
      elsewhere. Twelve animals, one dose, one timepoint.
    readouts:
    - name: Pedal artery contractile sensitivity to phenylephrine
      target: Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors
      description: >-
        EC50 for phenylephrine-induced contraction of the isolated dorsal
        metatarsal III artery, exposed group against water control.
      direction: INCREASED
      interpretation: >-
        Increased sensitivity to an alpha-1 agonist after ergot exposure is the
        measurable signature of ergoline action at the adrenergic receptor.
      evidence:
      - reference: PMID:33924041
        reference_title: Vasoactive Effects of Acute Ergot Exposure in Sheep.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Acute exposure to ergot alkaloids resulted in a 38% increase in vascular sensitivity to PE compared to control"
        explanation: The measurement itself, with its effect size and comparator.
    evidence:
    - reference: PMID:33924041
      reference_title: Vasoactive Effects of Acute Ergot Exposure in Sheep.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This study may indicate that the dry gangrene seen in sheep, and likely other species, might be related to the activation of α1-adrenergic receptor."
      explanation: >-
        The authors' own reading of what their model is informative for - the
        receptor node, and through it the gangrene.
  - target: Sustained Vascular Smooth Muscle Contraction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The isolated-vessel preparation reads out contraction of vascular smooth
      muscle, which is this node, in tissue taken from an animal exposed by the
      same route as a human eating contaminated grain.
    limitations: >-
      Twelve hours after a single dose. Human ergotism is usually the product
      of sustained exposure, and the entry's own progression section describes
      a subclinical phase running for weeks, which a single-dose model cannot
      reach.
    evidence:
    - reference: PMID:33924041
      reference_title: Vasoactive Effects of Acute Ergot Exposure in Sheep.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Similar to chronic exposure, acute exposure to ergot alkaloids results in increased vascular sensitivity to PE."
      explanation: >-
        States that the acute model reproduces what chronic exposure does,
        which is the claim that makes it informative for this node.
- name: Cattle fescue toxicosis (endophyte-infected tall fescue grazing)
  species: Cattle
  description: >-
    Cattle grazing endophyte-infected tall fescue ingest ergopeptine alkaloids
    and develop a vasoconstrictive syndrome; cattle are also susceptible to
    gangrenous ergotism from Claviceps-contaminated feed. This is a naturally
    occurring disease in an outbred population on an unrestricted diet, which
    is its value and its limitation at once: the exposure is real but
    uncontrolled, the principal alkaloid in fescue is ergovaline rather than
    the Claviceps mixture humans encounter, and the studied endpoints are herd
    performance and cytokine profiles rather than the vascular lesion.
  notes: >-
    Included because it is the model the literature on this disease actually
    uses, not because it is a close match. The report that informed this entry
    described fescue toxicosis as closely recapitulating the human gangrenous
    phenotype and cited a veterinary manual and a farming magazine for it; the
    peer-reviewed source cited here supports chronic ergot-alkaloid exposure
    and a tolerance split, and a separate review supports cattle susceptibility
    to gangrenous ergotism. Neither establishes the recapitulation claim, so
    the link below is `PARTIALLY_RECAPITULATES` rather than `RECAPITULATES`.
  publication: PMID:33327425
  evidence:
  - reference: PMID:33327425
    reference_title: Evaluation of Resistance to Fescue Toxicosis in Purebred Angus Cattle Utilizing Animal Performance and Cytokine Response.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Fescue toxicosis is a multifaceted syndrome common in cattle grazing endophyte-infected tall fescue"
    explanation: Establishes the exposure and the syndrome this model rests on.
  - reference: PMID:22903169
    reference_title: "Human and cattle ergotism since 1900: symptoms, outbreaks, and regulations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cattle are particularly susceptible to both gangrenous and hyperthermic ergotism (also called summer syndrome)."
    explanation: >-
      The gangrenous form in cattle, which is what makes the species relevant
      to the human gangrenous disease at all.
  modeled_mechanisms:
  - target: Distal Tissue Ischemia and Dry Gangrene
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Cattle exposed to ergot alkaloids develop gangrenous ergotism, so the
      species reaches the same endpoint node as the human disease by the same
      dietary route.
    limitations: >-
      The alkaloid is different - ergovaline from an endophyte in fescue rather
      than the Claviceps sclerotial mixture - and the cited cattle study
      measured herd performance and cytokines, not the ischaemic lesion. The
      gangrene claim rests on statements about the species rather than on a
      measurement in these animals, and those statements qualify it heavily:
      gangrenous ergotism in cattle is described as rare, requiring acute
      exposure to very high alkaloid concentrations together with cold
      temperatures, while what chronic fescue grazing usually produces is
      reduced productivity and reduced blood flow to the extremities. So the
      species reaches this node, but not by the route or at the frequency the
      human gangrenous disease does.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The cited study's measured quantities are animal performance
        parameters and circulating cytokines. This node's quantity is tissue
        perfusion and necrosis in the distal extremity. Performance decline
        under chronic ergot exposure is a downstream systemic consequence, not
        the lesion.
      evidence:
      - reference: PMID:33327425
        reference_title: Evaluation of Resistance to Fescue Toxicosis in Purebred Angus Cattle Utilizing Animal Performance and Cytokine Response.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "could accurately distinguish between tolerant and susceptible animals based on the performance parameters in cattle chronically exposed to ergot alkaloids"
        explanation: >-
          Names what this study measured - performance parameters - which is
          the quantity standing in for the lesion.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The exposure differs in kind, not only in species. These cattle grazed
        infected pasture continuously for thirteen weeks; the human iatrogenic
        form is a discrete oral dose taken at a migraine attack, and the human
        dietary form is contaminated flour eaten as meals. The shared feature
        is the receptor pharmacology, not the dose, the schedule, or the
        alkaloid.
      evidence:
      - reference: PMID:33327425
        reference_title: Evaluation of Resistance to Fescue Toxicosis in Purebred Angus Cattle Utilizing Animal Performance and Cytokine Response.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Angus cows grazed endophyte-infected tall fescue at two locations for 13 weeks starting in mid-April 2016."
        explanation: The exposure schedule this divergence contrasts with the human one.
    evidence:
    - reference: PMID:22903169
      reference_title: "Human and cattle ergotism since 1900: symptoms, outbreaks, and regulations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "Cattle are particularly susceptible to both gangrenous and hyperthermic ergotism (also called summer syndrome)."
      explanation: The basis for linking this species to the gangrene node.
    - reference: PMID:33327425
      reference_title: Evaluation of Resistance to Fescue Toxicosis in Purebred Angus Cattle Utilizing Animal Performance and Cytokine Response.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "the symptoms of this multifaceted disease range from acute outbreaks of gangrenous ergotism to more subtle and chronic decreases in livestock productivity"
      explanation: >-
        Places gangrenous ergotism at one end of the cattle syndrome's range,
        which is what makes the species informative for this node.
    - reference: PMID:33327425
      reference_title: Evaluation of Resistance to Fescue Toxicosis in Purebred Angus Cattle Utilizing Animal Performance and Cytokine Response.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "While the gangrenous ergotism is rare and most likely due to acute exposure to very high concentrations of ergot alkaloids, combined with cold temperatures"
      explanation: >-
        Cuts against treating this as a faithful model of the human gangrenous
        disease: in cattle the lesion is rare and needs an acute high dose plus
        cold, where the human dietary and iatrogenic forms need neither. Kept
        as a `REFUTE` on the link rather than buried in prose, because it is
        the strongest argument against the link it sits on.
experimental_models:
- name: Bovine lateral saphenous vein myography
  experimental_model_type: OTHER
  description: >-
    Isolated lateral saphenous vein rings from cattle mounted for myography.
    This is the standard ex vivo preparation in the ergot-alkaloid vascular
    literature, and the study cited here uses it to establish which serotonin
    receptor subtypes the vessel carries and what each does - the receptor
    repertoire that the ergoline agonism node acts on.
  organism:
    preferred_term: cattle
    term:
      id: NCBITaxon:9913
      label: Bos taurus
  publication: PMID:38946059
  notes: >-
    Cited for the vessel's receptor pharmacology, not for ergot action. The
    study's agonists are serotonin itself and subtype-selective 5-HT agonists;
    no ergot alkaloid was applied. The deep-research report listed this
    preparation among ergot-alkaloid model systems, which overstates what this
    particular paper shows, and the `divergences` block below records that
    rather than repeating it.
  evidence:
  - reference: PMID:38946059
    reference_title: Serotonin receptor-mediated vasorelaxation occurs primarily through 5-HT(4) activation in bovine lateral saphenous vein.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5-HT or selective 5-HT receptor agonists"
    explanation: The preparation and what was applied to it.
  modeled_mechanisms:
  - target: Ergoline Agonism at Vascular 5-HT and Alpha-Adrenergic Receptors
    relationship: MEASURES
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      Establishes which 5-HT receptor subtypes are present and functional in a
      peripheral vein, and that most of the relaxing response runs through
      5-HT4 - the pharmacological background against which an ergoline's mixed
      agonism at this node has to be read.
    limitations: >-
      No ergot alkaloid was applied in this study, so it cannot show ergoline
      action at these receptors; it characterises the receptors. It also reads
      out vasorelaxation, the opposite direction from the contraction this
      entry's chain runs through, and it is a vein rather than the peripheral
      artery where the human lesion forms.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The measured quantity is the vasoactive response to serotonin and to
        subtype-selective 5-HT agonists. This node's quantity is receptor
        occupancy and activation by an ergot alkaloid. A shared receptor is
        not a shared ligand, and ergolines are partial agonists at several
        subtypes at once.
      evidence:
      - reference: PMID:38946059
        reference_title: Serotonin receptor-mediated vasorelaxation occurs primarily through 5-HT(4) activation in bovine lateral saphenous vein.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5-HT or selective 5-HT receptor agonists"
        explanation: >-
          Names the ligands actually applied, which is what makes this a proxy
          for ergoline action rather than a measurement of it.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The alpha-adrenergic half of this node is outside the preparation as
        used here - only serotonergic agonists were applied. Phenylephrine
        appears solely as the pre-contraction the relaxation is measured
        against, not as an object of study.
      evidence:
      - reference: PMID:38946059
        reference_title: Serotonin receptor-mediated vasorelaxation occurs primarily through 5-HT(4) activation in bovine lateral saphenous vein.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre-contraction."
        explanation: >-
          Shows the alpha-1 agonist used only to set the baseline, with every
          test agonist serotonergic.
    evidence:
    - reference: PMID:38946059
      reference_title: Serotonin receptor-mediated vasorelaxation occurs primarily through 5-HT(4) activation in bovine lateral saphenous vein.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Approximately 94% of the vasorelaxation occurring in response to 5-HT could be accounted for through 5-HT4, providing strong evidence that 5-HT-mediated vasorelaxation occurs through 5-HT4 activation in bovine peripheral vasculature."
      explanation: >-
        The receptor-subtype result this preparation contributes, which is what
        it is cited for.
- name: Clavine-type ergot alkaloid cytotoxicity in HepG2 and PANC-1 cells
  experimental_model_type: CELL_LINE
  description: >-
    Two human carcinoma cell lines exposed to clavine-type ergot alkaloids -
    pyroclavine, agroclavine and festuclavine - with apoptosis read out by
    annexin V / propidium iodide double staining on flow cytometry. Agroclavine
    is named a causative agent of ergotism and is monitored by EFSA, and the
    same study found clavine-type alkaloids alongside the peptide-type ones in
    most of the Japanese sclerotia it analysed, so this is a real constituent
    of the exposure rather than a laboratory curiosity.
  cell_source: immortalized human carcinoma cell lines
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:36635416
  notes: >-
    Included as the only structured record in this entry of a mechanism that is
    not vasoconstriction. Every other node here runs through receptor agonism
    and ischaemia; direct cytotoxicity would be a parallel route to tissue
    injury. The cell lines are hepatoma and pancreatic carcinoma, neither of
    which is a tissue this disease damages, so the link below is `MEASURES` at
    `LOW` fidelity and no pathophysiology node asserts direct cytotoxicity in
    the human disease. The open question is recorded as a `KNOWLEDGE_GAP`
    discussion rather than as a mechanism.
  evidence:
  - reference: PMID:36635416
    reference_title: "Ergot alkaloids in sclerotia collected in Japan: synthetic profiles and induction of apoptosis by Clavine-type compounds."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We performed annexin V and PI double-staining followed by flow cytometric analysis to detect apoptosis in HepG2 and PANC-1 cells after exposure to Clavine-type EAs."
    explanation: The preparation, the exposure and the assay.
  modeled_mechanisms:
  - target: Distal Tissue Ischemia and Dry Gangrene
    relationship: MEASURES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Shows that a constituent of the ingested exposure kills cells outright at
      the concentrations tested, which is a candidate contributor to the tissue
      loss this node records and is independent of perfusion.
    limitations: >-
      Nothing here is vascular, distal or ischaemic. The cells are HepG2
      hepatoma and PANC-1 pancreatic carcinoma lines under a direct alkaloid
      application; the human lesion is necrosis of a distal extremity starved
      of blood. No concentration reached in a poisoned patient is established
      as comparable, and the authors themselves state the cytotoxic mechanism
      is unelucidated. This link records that the observation exists, not that
      it operates in the disease.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The measured quantity is annexin V / PI-defined apoptosis in a
        carcinoma cell line under direct application. This node's quantity is
        necrosis of distal tissue following sustained arterial spasm. Cell
        death is common to both, but its cause is the thing in dispute.
      evidence:
      - reference: PMID:36635416
        reference_title: "Ergot alkaloids in sclerotia collected in Japan: synthetic profiles and induction of apoptosis by Clavine-type compounds."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "We performed annexin V and PI double-staining followed by flow cytometric analysis to detect apoptosis in HepG2 and PANC-1 cells after exposure to Clavine-type EAs."
        explanation: The assay and cell types that constitute the proxy quantity.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        The model observes single cells in culture; the node it is linked to is
        a tissue-level lesion. Apoptosis in a dish does not aggregate to
        necrosis of a limb segment without an account of how many cells, in
        which tissue, at what exposure - none of which this model supplies. The
        one-step gap from `CELLULAR` to `TISSUE` is why this link is `MEASURES`
        rather than `PARTIALLY_RECAPITULATES`.
    - divergence_type: BOUNDARY_OMISSION
      materiality: INVALIDATING
      description: >-
        The circulation is not in the model at all. Absorption, first-pass
        metabolism, plasma protein binding and delivery to the distal limb are
        all outside its boundary, so the model cannot say whether the tested
        concentrations are ever reached in the tissue that dies.
      evidence:
      - reference: PMID:36635416
        reference_title: "Ergot alkaloids in sclerotia collected in Japan: synthetic profiles and induction of apoptosis by Clavine-type compounds."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Clavine-type EAs reduced cell viability and induced apoptosis in both cell lines."
        explanation: >-
          The whole of what the model reports: a direct application to cells in
          culture, with no absorption or delivery step anywhere in it.
    evidence:
    - reference: PMID:36635416
      reference_title: "Ergot alkaloids in sclerotia collected in Japan: synthetic profiles and induction of apoptosis by Clavine-type compounds."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Clavine-type EAs reduced cell viability and induced apoptosis in both cell lines."
      explanation: The result this link records.
discussions:
- discussion_id: direct_clavine_cytotoxicity
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does direct cytotoxicity of the clavine-type ergot alkaloids contribute to
    the tissue loss in ergotism, alongside ischaemia from vasospasm?
  attaches_to:
  - pathophysiology#Distal Tissue Ischemia and Dry Gangrene
  - experimental_models#Clavine-type ergot alkaloid cytotoxicity in HepG2 and PANC-1 cells
  rationale: >-
    Every pathophysiology node in this entry reaches tissue injury the same
    way: receptor agonism, sustained contraction, vasospasm, starvation of the
    distal tissue. That account is well supported and it may not be the whole
    account. Clavine-type ergot alkaloids reduce cell viability and induce
    apoptosis in human cell lines outright, with no vessel involved, and
    agroclavine - one of the clavines tested - is named a causative agent of
    ergotism and is monitored in food by EFSA. The same survey found clavine
    and peptide alkaloids together in most of the sclerotia it analysed, so a
    person eating contaminated grain is exposed to both.

    What is missing is any bridge from the dish to the limb. The cells are
    HepG2 hepatoma and PANC-1 pancreatic carcinoma, neither of which is a
    tissue this disease damages; the alkaloid is applied directly at
    concentrations nobody has related to a plasma level in a poisoned patient;
    and the authors state that the cytotoxic mechanism itself is unelucidated.
    So this cannot currently be modelled as a mechanism. It is recorded here
    because the alternative - saying nothing - would leave the entry asserting
    that ischaemia is the only route to the lesion, which the evidence does not
    establish either.

    Two things would settle it: a cytotoxicity measurement in vascular
    endothelium, smooth muscle or skin rather than carcinoma lines, and a
    pharmacokinetic comparison between the concentrations that kill cells and
    the concentrations reached in the distal circulation during poisoning. Note
    also that the iatrogenic form of this disease involves no clavines at all -
    ergotamine and ergometrine are peptide-type - so if direct cytotoxicity
    does contribute, it would differentiate the dietary form from the drug
    form rather than apply to both.
  evidence:
  - reference: PMID:36635416
    reference_title: "Ergot alkaloids in sclerotia collected in Japan: synthetic profiles and induction of apoptosis by Clavine-type compounds."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Clavine-type EAs are known to cause cytotoxicity, but the mechanism has not been elucidated."
    explanation: >-
      States the gap directly: the cytotoxicity is established and its
      mechanism is not.
  - reference: PMID:36635416
    reference_title: "Ergot alkaloids in sclerotia collected in Japan: synthetic profiles and induction of apoptosis by Clavine-type compounds."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Clavine-type EAs reduced cell viability and induced apoptosis in both cell lines."
    explanation: The observation that raises the question.
  - reference: PMID:36635416
    reference_title: "Ergot alkaloids in sclerotia collected in Japan: synthetic profiles and induction of apoptosis by Clavine-type compounds."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "These results suggest that Clavine-type EAs are a family of compounds requiring attention in food safety and livestock production in Japan."
    explanation: >-
      The authors' own framing of why this matters, which is a food-safety
      argument rather than a claim about human pathophysiology.
- discussion_id: convulsive_form_as_serotonin_syndrome
  kind: KNOWLEDGE_GAP
  prompt: >-
    Was convulsive ergotism epidemic serotonin syndrome, and does that identity
    hold well enough to model the two as the same mechanism?
  attaches_to:
  - pathophysiology#Central Serotonergic Overstimulation
  - pathophysiology#Convulsive and Neuropsychiatric Syndrome
  rationale: >-
    The argument is good and it is still an argument. Ergot alkaloids are
    serotonin agonists; dihydroergotamine binds serotonin receptors in the
    dorsal horn, which is where the neuropathology of convulsive ergotism was
    found; dihydroergotamine can cause serotonin syndrome in people; and the
    clinical picture - twitching, spasm, altered mental state, sweating, fever -
    is the picture of serotonergic excess. That is a chain of circumstantial
    fits, not a demonstration, and the epidemics it explains ended before
    anyone could measure anything in a patient.

    The geographical split is the part that most needs explaining and is least
    settled. Convulsive outbreaks east of the Rhine and gangrenous ones west of
    it is a striking pattern, and the proposed explanation - an alkaloid
    abundant in eastern ergot acting on the CNS at a concentration too low to
    close down peripheral arteries - is offered by the author as a possibility,
    with the alkaloid unnamed. Confirming it would need compositional analysis
    of historical ergot from both regions against a modern receptor panel.
  notes: >-
    Recorded as a gap rather than curated as fact. The entry models the central
    serotonergic branch, which is well supported, without asserting the
    identification with serotonin syndrome, which is not.
  evidence:
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The serotonin syndrome may, therefore, have been a public-health problem long before it was recognised as a complication of modern psychopharmacology."
    explanation: >-
      The claim at its strongest, in the author's own words, and hedged by the
      author with "may".
  - reference: PMID:12849122
    reference_title: "Convulsive ergotism: epidemics of the serotonin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "An alkaloid, present in high concentrations in ergots from east of the Rhine, may have caused convulsive ergotism at a circulating concentration insufficient to produce peripheral ischaemia."
    explanation: >-
      The proposed explanation of the geographical split, stated as a
      possibility and with the alkaloid unidentified.
- discussion_id: s_epimer_bioactivity_and_food_limits
  kind: KNOWLEDGE_GAP
  prompt: >-
    If the (S)-epimers of ergot alkaloids are vasoactive after all, do the
    regulatory limits that measure only (R)-epimers understate dietary
    exposure?
  attaches_to:
  - pathophysiology#Sustained Vascular Smooth Muscle Contraction
  - environmental#Ingestion of cereal grain contaminated with Claviceps sclerotia
  rationale: >-
    Ergot alkaloids exist as (R)- and (S)-epimers, and only the (R) forms are
    monitored in diets in North America, on the understanding that the (S)
    forms are biologically inactive. Tissue-bath work contradicts that: all four
    (S)-epimers tested produced concentration-dependent arterial contraction
    comparable to the (R) forms, and one of them, ergotaminine, contracted more
    strongly than two of the (R)-side comparators at the highest concentration
    used. A second study found the (S)-epimer producing a sustained contraction
    too, though weaker than the (R) form, and a docking study puts it at the
    5-HT2A and alpha-2A sites.

    What this does not establish is how much it matters in a diet. The
    experiments are bovine arterial tissue at defined molar concentrations, not
    dietary exposure; the two epimers interconvert in a way that depends on
    temperature, pH and solvent, so the ratio in a food is not fixed; and no
    study has yet asked whether including the (S) forms would change where a
    regulatory limit should sit. The authors go as far as saying the (S) forms
    should be monitored, which is a recommendation rather than a quantified
    risk.
  evidence:
  - reference: PMID:32629472
    reference_title: Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ergot alkaloids exist in two forms known as the (R)- and (S)-epimers with only the former being monitored in diets in North America."
    explanation: Establishes the regulatory gap this question is about.
  - reference: PMID:32629472
    reference_title: Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Contrary to the widespread belief, all tested (S)-epimers were found vasoactive and produced a concentration-dependent arterial contractile response similar to what has been reported for the (R)-epimers."
    explanation: >-
      Refutes the inactivity assumption the current monitoring rests on, which
      is what opens the question.
  - reference: PMID:32629472
    reference_title: Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The levels of (S)-epimers should be carefully monitored in human and animal diets worldwide."
    explanation: The authors' recommendation, which is as far as the evidence is taken.
  - reference: PMID:32629472
    reference_title: Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "the transformation of (R)-epimers to their respective (S)-epimers being complex and dependent on several factors, including temperature, pH, and solvent"
    explanation: >-
      The interconversion that makes the epimer ratio in a real food unstable,
      and so makes the exposure question harder than the tissue-bath result
      alone suggests.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Curated from a `claude_code` deep-research report (`research/Ergotism-deep-research-claude_code.md`). The report predates the in-line validation blocks, so `just validate-research-reference` and `just validate-research-terms` were run over it afterwards: 23/23 references resolved with none unresolved, and 18/20 CURIEs resolved. That report's term suggestions were unusually bad, and none of them was used. It offered `HP:0034976` for "Peripheral gangrene" - that CURIE is *Absent pituitary stalk* - and `HP:0031650` for "Vasospasm", which is *Abnormal atrioventricular valve physiology*. Both were caught independently: by a fresh OLS lookup while writing the binding, and by the retro-fitted term-validation section, which flags the same two. It also proposed the obsolete `CHEBI:4880` for ergotamine. Every CURIE here was re-derived rather than copied, which is the repository's rule and on this report was load-bearing rather than ceremonial. The report also cited heavily to Wikipedia, Britannica, National Geographic and StatPearls. None of that is cited here; where those passages named a real finding, a peer-reviewed source making the same claim was found and cited instead, and where none was found the claim was dropped. This is an acquired toxicosis, so there is no GeneReviews chapter and no OMIM entry; `just check-genereviews --online` returns `NO_CHAPTER` for both Bookshelf collections. The `genetic:` section is deliberately absent. The report proposed a CYP3A4 pharmacogenomic `MODIFIER` entry, and that is not curated here: the interaction that matters is pharmacological inhibition by a co-administered drug, which is an exposure and is modelled as one, while the report itself records that no ergotism-specific pharmacogenomic study was found and that host-variant susceptibility is inferred rather than established. Inferring a gene entry from that would be curating the report's speculation.

Create: Ergotism · 2026-09-18T04:01:54Z · View source

New Disease entry for ergotism (MONDO:0042496), intoxication by the ergot alkaloids of Claviceps purpurea. Curated on a branch cut fresh from origin/main. Duplicate preflight clean on all three surfaces: no entry or stub on origin/main, no PR, no issue. Deep research: one claude_code run (research/Ergotism-deep-research-claude_code.md). The report predates the in-line validation blocks, so validate-research-reference and validate-research-terms were run over it afterwards - 23/23 references resolved with none unresolved, 18/20 CURIEs resolved with one obsolete and one unverifiable. That report's term suggestions were unusually poor and none was used. It offered HP:0034976 for 'Peripheral gangrene', which is actually Absent pituitary stalk, and HP:0031650 for 'Vasospasm', which is Abnormal atrioventricular valve physiology. Both were caught twice over: by a fresh OLS lookup performed while writing the binding, and independently by the retro-fitted term-validation section, which flags the same two. It also proposed the obsolete CHEBI:4880 for ergotamine. This is the second consecutive entry where re-deriving every CURIE rather than copying it was load-bearing rather than ceremonial. The report also cited heavily to Wikipedia, Britannica, National Geographic and StatPearls. None is cited in the entry; where such a passage named a real finding a peer-reviewed source was located and cited instead, and where none was found the claim was dropped. Ontology bindings, with the queries recorded rather than the conclusions, per the dismech-terms step 3a rule added since the previous entry. All against the pinned local build the validator reads: runoak -i sqlite:obo:ecto search 'l~ergot' -> nothing runoak -i sqlite:obo:ecto search 'l~mycotoxin' -> CHEBI:25442, ECTO:0000524 runoak -i sqlite:obo:ecto search 'l~rye' -> ECTO:0070112 runoak -i sqlite:obo:ecto search 'l~alkaloid' -> ECTO:9000271 runoak -i sqlite:obo:ecto search 'l~vasoconstrict' -> ECTO:9001855 runoak -i sqlite:obo:ecto search 'l~ergotamine' -> nothing runoak -i sqlite:obo:ecto search 'l~cytochrome' -> nothing The dietary route binds ECTO:0000524 exposure to mycotoxin, exact for the agent class and matching MONDO's own placement of ergotism under mycotoxicosis. ECTO:0070112 exposure to rye bread via ingestion looks ideal and was rejected after reading its record: it involves FOODON:03305210 rye bread (enriched), a fortified commercial product rather than contaminated grain. ECTO:9000271 exposure to alkaloid was rejected as losing the fungal origin the disease turns on. The therapeutic route binds ECTO:9001855 exposure to vasoconstrictor agent, which info -O obo confirms is is_a ECTO:0000509 exposure to drug and involves CHEBI:50514, so it is preferred to the broader parent. The CYP3A4-inhibitor co-exposure binds the broad ECTO:0000509 because the exposure is defined by an enzyme-inhibition property shared across three unrelated drug classes and no ECTO class exists for it. Neither bound term is flagged Not4Curation. Content: an eight-node causal chain running from exposure through ergoline agonism at 5-HT and alpha-adrenergic receptors, then branching into a vascular arm (sustained smooth muscle contraction, arterial vasospasm, distal ischaemia and dry gangrene) and a central serotonergic arm producing the convulsive form. The CYP3A4-inhibition node sits as a parallel amplifier converging on the receptor node, which is what makes the modern iatrogenic form the same disease as the medieval one. 13 phenotypes, all causally connected. Three environmental exposures - contaminated grain, therapeutic ergot alkaloid, and the CYP3A4-inhibitor co-exposure, the last using EXACERBATES rather than TRIGGERS because it causes no disease alone. Four treatments including two REFUTE items: first-line vasodilators failing in a documented case, and sympathectomy recorded as not improving the clinical course, which is a negative result a plausible mechanism would have predicted to work. Three diagnosis entries, including factitious hypotension - vasospasm severe enough to make non-invasive blood pressure read as unmeasurable, with a paradoxical rise after intravenous vasodilator. Two discussions: whether convulsive ergotism was epidemic serotonin syndrome, and whether regulatory limits that measure only (R)-epimers understate dietary exposure now that the (S)-epimers have been shown vasoactive. Two title-quoting evidence items were written and then removed rather than baselined, after check-title-snippets flagged them. One quoted PMID:40046976's title when that paper has a full abstract, and was replaced with three real sentences including 'Coronary angiography was unremarkable', which is a better piece of evidence than the title was. The other quoted the title of PMID:28661928 'Ergotism Masquerading Systemic Vasculitis', whose cached record has no abstract at all; that reference is now cited nowhere, and the differential it names records in notes why. Three snippets under the five-word floor were lengthened to propositional spans rather than baselined. Validation: validate-disorders passed (schema, terms, references batched), 91/91 snippets verified offline; compliance 89.1% weighted; check-genereviews --online returns NO_CHAPTER for both Bookshelf collections, as expected for an acquired toxicosis, which is why there is no genetic: section. The report proposed a CYP3A4 pharmacogenomic MODIFIER gene entry; that is not curated, because the interaction that matters is pharmacological inhibition by a co-administered drug and the report itself records that no ergotism-specific pharmacogenomic study was found. All offline gates pass: folded-hyphens, snippet-length, title-snippets, snippet-grading, environmental-evidence, enum-values, case-collisions, duplicate-keys, entity-refs, causal-targets, qualifier-terms.

Claude Code ▸

Ergotism: Comprehensive Disease Characteristics Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 41 citations 2026-09-18T03:36:01.230353

Ergotism: Comprehensive Disease Characteristics Research Report

1. Disease Information

Overview. Ergotism (also called ergot poisoning, ergotoxicosis, or historically "St. Anthony's Fire" / "holy fire" / "ignis sacer") is a toxicological syndrome caused by ingestion of ergot alkaloids — indole (ergoline) alkaloids produced by fungi of the genus Claviceps, most classically Claviceps purpurea, which parasitizes rye and other cereal grains, forming dark sclerotia ("ergots") in place of normal grain kernels Wikipedia: Ergotism; Britannica: Ergotism. The disease is not a Mendelian/genetic disorder but an environmental/toxicological entity — an acquired intoxication from either (a) contaminated food (classic/epidemic ergotism) or (b) pharmaceutical ergot-alkaloid derivatives used therapeutically (iatrogenic ergotism, the dominant modern form) ScienceDirect: Ergotism overview.

Key identifiers. - ICD-10-CM: T62.2 (toxic effect of ingested mycotoxin food contaminants; ergot-specific subcodes exist in some national modifications), typically paired with an external-cause code bionity.com: Ergotism. - MeSH: "Ergotism" is an indexed MeSH descriptor (used extensively across the PubMed literature retrieved above). - MONDO: MONDO:0042496 was supplied as the target identifier for this curation; the general web search did not surface a public-facing MONDO term page distinct from the ontology's general documentation, so this identifier should be independently confirmed against the current MONDO release before binding (just validate-terms-equivalent check) rather than asserted from this report. - Orphanet: no dedicated rare-disease Orphanet entry was located in this search; ergotism is a toxidrome rather than a genetically-defined rare disease, so Orphanet coverage may not exist — this should be verified directly against Orphanet rather than assumed absent.

Synonyms: St. Anthony's Fire, holy fire, ignis sacer, ergot poisoning, ergotoxicosis, ergotized-grain poisoning; the two principal clinical subtypes are named gangrenous ergotism and convulsive ergotism Wikipedia: Ergotism; National Geographic: St Anthony's fire.

Data derivation. Modern knowledge is derived overwhelmingly from (1) aggregated case reports/case series of iatrogenic ergotism from therapeutic ergotamine/dihydroergotamine/methylergonovine use (individual-patient case reports, PMID-indexed), (2) historical and modern epidemic outbreak investigations of food-borne (grain-contamination) ergotism, especially in Ethiopia and India, and (3) veterinary/agricultural toxicology of livestock "fescue toxicosis"/"ergotism in animals," which is a well-studied natural-disease analog in cattle Human and cattle ergotism since 1900 — PMID:22903169; Merck Veterinary Manual: Ergotism in Animals.

2. Etiology

Disease causal factors. Ergotism is exogenous/environmental, not intrinsic-genetic: it is caused by exposure to ergot alkaloids, either from (a) fungal contamination of food grain by Claviceps spp. sclerotia, or (b) pharmacological/iatrogenic overdose or drug-interaction-potentiated toxicity of ergot-derived medications (ergotamine, dihydroergotamine, methylergonovine/methylergometrine, ergonovine/ergometrine) ASM.org: From Poisoning to Pharmacy.

Risk factors — environmental/exposure: - Consumption of rye or other cereal (wheat, barley, oats) contaminated with Claviceps purpurea sclerotia — historically the dominant cause of mass poisoning in medieval Europe, with cool, wet climates favoring fungal growth on grain Ergotism — Wikipedia; a 9th-century Rhine Valley outbreak reportedly killed tens of thousands National Geographic. - Poor food-safety/grain-cleaning infrastructure and lower socioeconomic status — modern outbreaks have occurred in Ethiopia (1977–78 and 2001, Arsi Zone, from ergotized wild-oat–contaminated barley) and India (1975) Laboratory studies on the outbreak of Gangrenous Ergotism… Arsi, Ethiopia. - Therapeutic ergot-alkaloid use (migraine treatment with ergotamine/dihydroergotamine; obstetric use of methylergonovine/ergometrine for postpartum hemorrhage) — the principal modern human risk exposure in industrialized settings Severe iatrogenic ergotism: incidence and clinical importance — PMID:1908611. - Drug-drug interaction risk factor: co-administration of ergot alkaloids with potent CYP3A4 inhibitors — protease inhibitors (ritonavir, darunavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, amprenavir/fosamprenavir) and macrolide antibiotics (clarithromycin, telithromycin) — dramatically raises plasma ergotamine/DHE concentrations, converting a therapeutic dose into a toxic one; this is now considered a contraindicated combination Drug Interaction Interaction of Ergotamine with Darunavir/Abacavir/Lamivudine — PMC6313968; case of coronary vasospasm with ergotamine + cobicistat + darunavir (PMID search, J Int Med Res 2022). - HIV-positive patients on antiretroviral protease-inhibitor regimens are a specifically flagged modern at-risk population A potentially lethal interaction: Migraine, HIV and ergotism — PMC11910312. - Concurrent tobacco/caffeine use has been implicated in exacerbating iatrogenic ergotism (cessation of these is part of first-line management).

Genetic risk factors. No Mendelian causal gene exists (this is an acquired toxidrome), but genetic variability in hepatic CYP3A4/CYP3A5 metabolic capacity (≈20 characterized variants, ~350 SNPs, most reducing enzyme activity) plausibly modulates individual susceptibility to ergotamine toxicity by altering systemic ergot-alkaloid clearance, though disease-specific pharmacogenomic studies for ergotism specifically were not found in this search and should be treated as inferred rather than established CYP3A4 and CYP3A5: crucial roles in clinical drug metabolism — PMC11625447.

Protective factors. - Modern grain-safety practices: fungicide use, crop rotation, planting of clean/inspected seed, and seed-flotation separation of ergot sclerotia from healthy kernels before milling Medical News Today: Ergot poisoning. - Regulatory maximum limits on ergot sclerotia/alkaloid content in traded grain (see Prevention, §13). - Avoidance of concomitant strong CYP3A4 inhibitors in patients prescribed ergot-derivative medications.

Gene-environment interactions. The principal documented interaction is pharmacogenomic/pharmacokinetic rather than germline-susceptibility: CYP3A4 inhibition (by co-administered drugs, a chemical/environmental factor) interacting with the pharmacologically active ergot-alkaloid "gene product" target profile (5-HT, dopamine, and α-adrenergic receptors) to produce toxic vasoconstriction at otherwise sub-toxic doses Ergotamine/Caffeine — StatPearls NBK555953.

3. Phenotypes

Ergotism presents as two overlapping but classically distinguished symptom clusters, first well documented in Renaissance/medieval European epidemics and confirmed in modern case series:

A. Gangrenous ergotism (vasospastic form)

Peripheral vasospasm/ischemia of the extremities — cold, pale, painful hands/feet progressing to cyanosis, and dry gangrene with tissue necrosis, historically requiring limb amputation Ergotism — Wikipedia. Suggested HP term: HP:0034976 (Peripheral gangrene) / general HP:0025637 (Vasospasm) if present in the enum; verify against the current HPO release before binding.
Burning pain/paresthesia in the extremities ("St. Anthony's Fire" burning sensation) — precedes overt ischemia. Candidate HP:0003401 (Paresthesia).
Diminished/absent peripheral pulses (radial, ulnar, popliteal, tibial) — documented in case report of a 25-year-old with ergotamine-induced vasospasm Reversal of ergotamine-induced vasospasm following methylprednisolone — PMID:18763151.
Myocardial/coronary vasospasm and infarction — reported in an obstetric case following intramuscular ergometrine for postpartum hemorrhage Joining forces: cardio-obstetrics case of severe ergometrine-induced vasospasm — PMC11879452. Candidate HP:0001677 (Coronary artery atherosclerosis) is not quite right — better: free-text/CHEBI-linked vasospasm phenotype; consider HP:0031650 (Vasospasm) if present.
Cerebral ischemia/stroke from vasospasm of cerebral arteries, in severe drug-interaction cases Drug-Drug Interaction of Ergotamine… Fatal Vasospastic Ischemia — PMC6313968.
Transient monocular blindness and renal arterial spasm — unusual manifestations documented in a historical review of ergot intoxication Ergot Intoxication: Historical Review — PMC1343691.
Bilateral foot drop from ischemic common peroneal nerve damage — an unusual, previously undocumented presentation in the same review.

B. Convulsive ergotism (neuropsychiatric form)

Muscle spasms/twitching and painful seizures — candidate HP:0001250 (Seizure).
Hallucinations and psychosis/mania — psychiatric manifestations historically mistaken for demonic possession in medieval accounts Convulsive ergotism: epidemics of the serotonin syndrome? — PMID:12849122. The paper's title itself argues convulsive ergotism may represent a historical analog of serotonin syndrome, given ergot alkaloids' serotonin-receptor agonism.
Paresthesias and itching (formication) — a tactile hallucination of insects crawling under the skin, documented in the 2001 Ethiopian outbreak Laboratory studies on the outbreak of Gangrenous Ergotism, Arsi, Ethiopia.
Diarrhea, nausea, vomiting — gastrointestinal symptoms common to both forms.
Headache — frequently reported, consistent with the serotonergic/vasoconstrictive mechanism also underlying ergotamine's therapeutic anti-migraine effect.
Fever and diaphoresis (sweating), lasting weeks in some accounts.
Weakness and burning sensations — reported general prodromal symptoms in the 2001 Ethiopian outbreak.
Infant mortality from starvation, attributed to maternal lactation failure during the outbreak — a distinctive, population-level secondary phenotype in the Ethiopian epidemic [same source].

Phenotype characteristics: - Onset: acute-to-subacute after ingestion of contaminated grain (epidemic form) or after days-to-weeks of excessive/interacting ergot-medication use (iatrogenic form); in the case report above, symptoms began after ~1 week of ergotamine use for migraine and progressed over 2 days [PMID:18763151]. - Severity: highly variable — from mild paresthesia/headache to limb-threatening gangrene, blindness, stroke, or myocardial infarction, and (rarely) death. - Progression: in gangrenous ergotism, progressive vasospasm → ischemia → dry gangrene → possible auto-amputation/surgical amputation if untreated; convulsive ergotism can show a fluctuating/relapsing course. - Frequency: exact population frequencies are not established (this is an exposure-driven toxidrome rather than a fixed-penetrance disease); case-series literature is the primary quantitative source. - Reversibility: iatrogenic ergotism is often reversible with prompt discontinuation of the causative agent — "recovery may occur within 4 days of stopping the ergot-containing medication" — but ischemic complications (gangrene, infarction, stroke) can be permanent if treatment is delayed ScienceDirect: Ergotism treatment overview; [Ergot Intoxication historical review, PMC1343691] ("no convincing evidence that any treatment other than discontinuation… is of benefit").

Quality of life impact: Limb amputation, chronic ischemic pain, and (in the psychotic/convulsive form) lasting neuropsychiatric sequelae are the major QoL burdens; specific validated QoL instrument data (EQ-5D/SF-36) for ergotism were not identified in this search and would need dedicated retrieval.

4. Genetic/Molecular Information

Ergotism has no primary causal human gene — it is a toxin-mediated disease. The "genetic/molecular" content that is relevant is almost entirely about (a) the fungal biosynthetic genes producing the toxin, and (b) the human drug-metabolizing/pharmacogenomic genes modulating host susceptibility.

Fungal causal genetics: Claviceps purpurea ergot alkaloids are synthesized from a 14-gene biosynthetic gene cluster in the fungal genome producing the ergoline/lysergic-acid-derived alkaloid metabolites Bionity.com: Ergotism.
Host pharmacogenomics: CYP3A4 (and CYP3A5) — the human hepatic enzyme responsible for ergotamine/dihydroergotamine metabolism — carries ~20 characterized genetic variants and ~350 SNPs, most reducing enzymatic activity and thereby plausibly elevating individual susceptibility to ergotism when ergot-alkaloid drugs are used [PMC11625447]. Candidate gene: CYP3A4 (HGNC:2637).
Not applicable: somatic/germline variant classification (ClinVar/ACMG), chromosomal abnormalities, epigenetic disease drivers, and modifier genes in the classic Mendelian sense do not apply to this entity, since it is not a genetically caused disease. If the dismech schema requires a genetic: section, it should likely be limited to the CYP3A4 metabolic-susceptibility modifier framed as relationship_type: MODIFIER (pharmacogenomic host factor), not a causal gene.

5. Environmental Information

This is the dominant etiological category for ergotism and should anchor the environmental: section of the entry.

Fungal/mycotoxin contamination: Claviceps purpurea (and related Claviceps spp.) infecting rye, wheat, barley, oats, and other cereal grasses, forming sclerotia ("ergots") that, if not removed before milling, contaminate flour and food products with ergot alkaloids Ergot — Wikipedia; APS: Ergot Alkaloids.
Ergot alkaloid classes: two principal chemical groups — clavine alkaloids and lysergic acid alkaloids (amides and peptide/ergopeptine alkaloids), sharing a tetracyclic ergoline ring core. Key compounds found in Claviceps sclerotia: ergometrine (ergonovine), ergotamine, ergosine, ergocristine, ergocryptine, and ergocornine Ergoline — Wikipedia; Analysis of Ergot Alkaloids — PMC4488688. LSD (lysergic acid diethylamide) is chemically related but is a semi-synthetic derivative, not a natural sclerotial contaminant. Candidate CHEBI terms: ergotamine (CHEBI:4880-family), ergometrine, ergosine, ergocristine, ergocryptine, ergocornine (specific CHEBI IDs should be confirmed via runoak lookup per project convention rather than asserted here).
Iatrogenic/pharmaceutical exposure: ergotamine tartrate, dihydroergotamine, methylergonovine/methylergometrine, and ergometrine used therapeutically (migraine abortive therapy; obstetric hemorrhage control) are the principal modern environmental exposure route in industrialized countries Ergotamine/Caffeine — StatPearls NBK555953.
Climate factor: cool, wet growing conditions favor Claviceps sporulation and sclerotia formation on grain heads, historically concentrating outbreaks in northern/central Europe and linked in the literature to periods of unusually wet weather preceding epidemic years National Geographic: St Anthony's Fire.
Socioeconomic/food-security factor: contaminated-grain outbreaks recur in settings of food insecurity and inadequate grain-cleaning infrastructure — documented in Ethiopia (1977–78, 2001) and India (1975) EJHD: Arsi Ethiopia outbreak.
Infectious agent: Claviceps purpurea is technically a plant-pathogenic ascomycete fungus, not a human/animal infectious pathogen — ergotism is a toxicosis/mycotoxicosis, not an infection of the human host. NCBI Taxonomy: Claviceps purpurea (NCBITaxon — specific ID should be confirmed by lookup).
Drug-drug interaction as an environmental/exposure amplifier: concomitant strong CYP3A4 inhibitors (protease inhibitors, macrolide antibiotics) are a well-documented environmental co-exposure that converts therapeutic ergot dosing into toxic exposure [PMC6313968]; [Cheng-En Wu et al., coronary vasospasm with ergotamine + cobicistat + darunavir, J Int Med Res 2022].

6. Mechanism / Pathophysiology

Ordered causal chain

Ingestion or therapeutic administration of ergot alkaloids (ergotamine, dihydroergotamine, ergometrine/methylergonovine, or a mixture from contaminated grain) leads to systemic absorption of ergoline-ring compounds structurally similar to endogenous monoamine neurotransmitters (serotonin, dopamine, norepinephrine) Ergot Alkaloid Pharmacology — pharmacology2000.com.
[Amplifying/optional branch] Co-administration of a strong CYP3A4 inhibitor (protease inhibitor or macrolide) inhibits hepatic ergot-alkaloid metabolism, which results in markedly elevated plasma ergot-alkaloid concentrations even at otherwise-therapeutic oral doses [PMC6313968].
Elevated ergot-alkaloid concentration leads to simultaneous partial-agonist/agonist binding at multiple G-protein-coupled receptor families on vascular smooth muscle and neurons: α1/α2-adrenergic receptors, serotonin 5-HT1B/5-HT1D/5-HT2A receptors, and dopamine D2-like receptors Investigation of the relationship between ergocristinine and vascular receptors — PMC10199403; Naunyn-Schmiedeberg's: non-peptide ergot alkaloids at 5-HT1-like and 5-HT2 receptors.
Simultaneous activation of α-adrenergic and 5-HT2 receptors on vascular smooth muscle results in sustained arterial and arteriolar vasoconstriction — this dual-receptor mechanism is specifically cited as the basis of ergot-induced vasospasm ScienceDirect: Ergotism — Pharmacology/Toxicology topic.
Sustained arterial vasoconstriction leads to regional tissue hypoperfusion/ischemia, particularly in the distal extremities (fingers, toes, hands, feet) where arterial supply is most vulnerable to prolonged spasm, and, in severe or drug-potentiated cases, in coronary, cerebral, renal, and ocular circulations [PMC1343691]; [PMC11879452 — coronary vasospasm/MI]; [PMC6313968 — cerebral ischemia].
Prolonged ischemia results in tissue hypoxia, oxidative/metabolic injury, and, if uncorrected, dry gangrene and tissue necrosis — historically the defining lesion of "gangrenous ergotism"/St. Anthony's Fire [Wikipedia: Ergotism].
In parallel (branch), direct agonism of ergot alkaloids at central/peripheral serotonin receptors (5-HT) in the CNS leads to the neuropsychiatric/"convulsive ergotism" phenotype — muscle spasms, seizures, hallucinations, and psychosis — proposed in the literature to represent a historical epidemic analog of serotonin syndrome [Convulsive ergotism: epidemics of the serotonin syndrome? — PMID:12849122].
In the specific case of postpartum ergometrine/methylergonovine administration, ergot-receptor agonism also acts directly on uterine smooth muscle (the intended oxytocic/uterotonic pharmacological target) in parallel with unintended coronary/systemic vasospasm, explaining reports of peripartum myocardial infarction after obstetric ergot use [PMC11879452].

Category detail

Molecular pathways: GPCR signaling downstream of α-adrenergic, 5-HT (serotonergic), and dopaminergic receptor agonism on vascular and neuronal cell membranes. Candidate GO terms: GO:0003085 (negative regulation of systemic arterial blood pressure) is not quite right; more precise: GO:0042311 (vasodilation) [negatively implicated] and its antonym vasoconstriction processes — GO:0042310 (vasoconstriction) is a strong candidate for the primary node's biological process, and GO:0007210 (serotonin receptor signaling pathway) / GO:0007212 (dopamine receptor signaling pathway) / GO:0071875 (adrenergic receptor signaling pathway) for the receptor-signaling steps. (Confirm exact IDs/labels via OAK lookup before binding.)
Cellular processes: vascular smooth muscle contraction (sustained, pathological — a "gain-of-function-like" qualitative overactivation rather than a quantitative INCREASED reading of a normally regulated process, given the exogenous receptor agonist driving it outside physiological regulatory constraints); ischemic cell injury/necrosis in distal tissue.
Protein dysfunction: not a protein-structural disease — the mechanism is receptor agonism by an exogenous small molecule (ergot alkaloid) rather than any host protein misfolding or intrinsic dysfunction.
Tissue damage mechanisms: ischemia-driven dry gangrene/coagulative necrosis of distal extremities; possible myocardial infarction from coronary vasospasm; possible cerebral infarction/stroke from intracranial arterial vasospasm; renal arterial spasm.
Biochemical abnormalities: no primary enzyme deficiency; secondary biochemical consequences of ischemia (lactic acidosis in ischemic tissue) may occur but are non-specific.
Immune system involvement: not a primary immune-mediated mechanism, although chronic gangrenous tissue may become secondarily infected/septic ("gangrene and sepsis of limbs" as a late-stage complication) [Wikipedia: Ergotism].
Cell types involved: vascular smooth muscle cells (candidate CL:0000359, vascular associated smooth muscle cell, exact CL ID to confirm), and CNS neurons expressing serotonergic/dopaminergic receptor targets.

7. Anatomical Structures Affected

Organ level: primary — peripheral vasculature of the extremities (hands, feet, digits); secondary — coronary arteries (myocardial ischemia/infarction), cerebral arteries (stroke), renal arteries, retinal/ophthalmic artery (transient monocular blindness), uterine vasculature (in obstetric ergot use), and peripheral nerves (ischemic mononeuropathy, e.g., common peroneal nerve → foot drop) [PMC1343691]. Body systems: cardiovascular, nervous, and (in convulsive form) central nervous/psychiatric.
Tissue/cell level: vascular smooth muscle of small-to-medium arteries and arterioles is the direct pharmacological target; distal skin and subcutaneous tissue undergo ischemic/gangrenous change.
Subcellular level: GPCR signal transduction at the plasma membrane of vascular smooth muscle cells and neurons (α-adrenergic, 5-HT, dopamine receptor complexes); no organelle-specific pathology is described in the literature reviewed.
Localization: classically bilateral and symmetric in the epidemic/gangrenous form (both feet/hands), though case reports also document unilateral presentations (e.g., unilateral leg ischemia) [PMC1343691]. Candidate UBERON terms: extremities (UBERON:0002542, appendage skeleton — too broad; prefer digit/limb-specific terms), coronary artery (UBERON:0001621), cerebral artery, uterus (UBERON:0000995).

8. Temporal Development

Onset: variable by route — epidemic/food-borne ergotism can present within days of consuming contaminated grain; iatrogenic ergotism has been reported after as little as ~1 week of therapeutic ergotamine use, and drug-interaction-potentiated cases can occur even with standard single/short-course dosing once a CYP3A4 inhibitor is added [PMID:18763151].
Progression: gangrenous ergotism progresses through a recognizable sequence — burning paresthesia → coldness/pallor/cyanosis → absent pulses → dry gangrene, over a timescale of days; convulsive ergotism may show a fluctuating course with fever/sweating persisting for "several weeks" in some historical accounts.
Disease course pattern: iatrogenic ergotism is generally self-limited/reversible upon cessation of the causative agent, with recovery reported within about 4 days in many cases; but ischemic complications that progress to gangrene or infarction before treatment become fixed, irreversible lesions.
Recurrence: documented "recurrent ergotism" case reports exist in patients who resumed or continued using ergot-derivative medications after an initial episode Recurrent Ergotism: A Case Report, J Fam Pract 1978.
Critical window: early recognition and cessation of the causative ergot exposure, plus prompt vasodilator therapy, represent the critical intervention window before irreversible ischemic tissue loss.

9. Inheritance and Population

Inheritance pattern: not applicable — ergotism is an acquired toxicological disease, not a Mendelian/heritable condition. No penetrance, expressivity, anticipation, mosaicism, founder-effect, or carrier-frequency concepts apply in the conventional genetic sense.
Epidemiology: exact modern incidence/prevalence figures were not located in this search (expected, given the sporadic/case-report nature of modern disease); historically, epidemic outbreaks affected many thousands in medieval Europe (e.g., the 9th-century Rhine Valley outbreak reportedly killing "tens of thousands") [National Geographic]. Modern documented outbreaks: Ethiopia 1977–78 and 2001 (Arsi Zone, gangrenous ergotism from ergotized-wild-oat–contaminated barley, ~0.75% ergot content in affected grain) and India 1975 [EJHD Arsi Ethiopia study]; [Human and cattle ergotism since 1900 — PMID:22903169].
Population demographics: modern iatrogenic ergotism disproportionately affects individuals prescribed ergot-alkaloid migraine therapy (historically more common in women, consistent with migraine epidemiology) and obstetric patients receiving ergometrine/methylergonovine for postpartum hemorrhage (exclusively female by indication). HIV-positive patients on protease-inhibitor regimens represent a specific modern at-risk subgroup due to the CYP3A4 drug-interaction mechanism [PMC11910312].
Geographic distribution: historically concentrated in northern/central Europe (rye-dependent diet, cool wet climate favoring Claviceps); modern food-borne outbreaks concentrated in regions with less-regulated grain supply chains (Ethiopia, India).

10. Diagnostics

Clinical tests:
Angiography — the primary diagnostic imaging modality, revealing characteristic segmental vasospastic narrowing of peripheral (and occasionally coronary/cerebral/renal) arteries, distinguishing ergotism from fixed atherosclerotic or embolic occlusion [PMC1343691]; angiographic pattern is also a key differentiator from thromboangiitis obliterans (Buerger disease), which shows distal segmental occlusive lesions with normal proximal arteries and a smooth, regular arterial wall without calcification Thromboangiitis obliterans — PMC1523324.
Peripheral pulse examination (radial, ulnar, popliteal, tibial) — diminished/absent pulses support the diagnosis in the acute setting.
Toxicological/analytical confirmation — detection of ergotamine and ergometrine in contaminated grain samples was used to confirm etiology in the Ethiopian outbreak investigation [EJHD Arsi Ethiopia study].
Differential diagnosis: thromboangiitis obliterans (Buerger disease), Raynaud phenomenon, other vasculitides (ergotism is specifically flagged as a vasculitis-mimic warranting careful differentiation in imaging reviews of medium/large-vessel disease) AJR: Imaging of Primary and Secondary Inflammatory Diseases, scleroderma/CREST syndrome, and hypercoagulable states — recommended work-up includes CBC, liver function tests, creatinine, fasting glucose, ESR, ANA, rheumatoid factor, and hypercoagulability screening to exclude these mimics.
Genetic testing: not applicable as a diagnostic modality for this condition (no causal gene); pharmacogenomic CYP3A4 genotyping is not a standard diagnostic test for ergotism itself but could theoretically inform risk stratification before prescribing ergot-derivative drugs.
Clinical criteria: diagnosis is principally clinical — history of ergot-alkaloid exposure (medication or contaminated grain) plus compatible vasospastic/ischemic or convulsive/neuropsychiatric findings, supported by angiography and (in epidemic settings) toxicological confirmation of ergot alkaloids in the implicated food source.

11. Outcome/Prognosis

Reversibility with treatment: the historical-review literature states plainly that "there is no convincing evidence that any treatment other than discontinuation of ergotamine is of benefit in the treatment of iatrogenic ergotism," and case reports document full recovery (e.g., complete resolution of ischemic foot drop within months) after cessation of the offending agent [PMC1343691].
Complications: limb gangrene with risk of surgical amputation, myocardial infarction, cerebral infarction/stroke, transient or permanent monocular blindness, ischemic mononeuropathy, and (in untreated gangrenous cases) secondary sepsis [Wikipedia: Ergotism]; [PMC6313968 — fatal vasospastic ischemia case].
Mortality: modern iatrogenic cases treated promptly generally have good outcomes; however, severe drug-interaction-potentiated cases (e.g., ergotamine + protease inhibitor) have been reported as fatal [PMC6313968 title: "…Causing a Fatal Vasospastic Ischemia"]. Historical epidemic ergotism carried substantial mortality, including reported infant deaths from lactation failure during the 2001 Ethiopian outbreak.
Prognostic factors: speed of recognition and cessation of the causative ergot exposure; presence/absence of a potentiating CYP3A4-inhibitor interaction; severity/duration of ischemia before treatment; response to vasodilator therapy.

12. Treatment

First-line/supportive management: immediate discontinuation of the causative ergot-alkaloid medication (and cessation of caffeine/tobacco, which may exacerbate vasospasm) [ScienceDirect: Ergotism treatment].
Vasodilator pharmacotherapy:
Sodium nitroprusside (intravenous or intra-arterial infusion) — the most extensively documented treatment, described across multiple case series as effective in relieving vasospasm, often combined with forced diuresis and hydroxocobalamin administration to manage cyanide-release risk from prolonged nitroprusside use Sodium Nitroprusside in the Treatment of Ergotism — Radiology 1977; Intraarterial sodium nitroprusside infusion in the treatment of severe ergotism — PMID:3802106. NCIT candidate: pharmacotherapy (NCIT:C15986) with therapeutic_agent sodium nitroprusside (CHEBI lookup required).
Calcium channel blockers and prostaglandins — cited as alternative direct vascular-smooth-muscle vasodilators for severe vasospasm [ScienceDirect: Ergotism treatment overview].
Nitroglycerin — studied experimentally in vitro and in migraine patients, and used to treat an overt ergotism case Nitroglycerin for ergotism — Eur J Clin Pharmacol.
Corticosteroids (methylprednisolone) — reported as successful in a case unresponsive to sodium nitroprusside, suggested as alternative therapy especially for intractable cases [PMID:18763151].
Anticoagulation: heparin, to prevent secondary thrombosis in ischemic vascular beds.
Interventional/surgical: balloon angioplasty/dilatation, and surgical intervention (including amputation) for cases progressing to established gangrene despite medical therapy.
Treatment algorithm summary: stop causative agent → vasodilator therapy (sodium nitroprusside first-line) ± heparin → escalate to corticosteroids or interventional/surgical management for refractory or advanced ischemic disease.
Experimental/investigational: no dedicated clinical trials (NCT-registered) specifically for ergotism treatment were identified in this search; management is derived from case reports and small case series rather than randomized trial evidence.
Genetic-counseling/screening interventions: not applicable (non-genetic disease).

13. Prevention

Primary prevention (food safety):
EU Regulation (EU) 2021/1399 (amending Regulation (EC) No 1881/2006) sets maximum levels for ergot sclerotia and for the sum of 12 toxicologically relevant ergot alkaloids in cereals and cereal products, effective 1 January 2022; unprocessed-cereal sclerotia limits were tightened (e.g., ≤0.5 g/kg for rye, with further reduction to 0.2 g/kg from 1 July 2024 for certain categories), because milling can grind sclerotia into "ergot dust" that contaminates grain even without visible sclerotia, necessitating separate alkaloid (not just sclerotia) limits Europe sets new ergot alkaloids limits — Food Safety News; Commission Regulation (EU) 2021/1399 text.
Modern agricultural practice: fungicide application, crop rotation, use of clean/certified seed, and mechanical seed-cleaning (flotation separation of sclerotia) before milling [Medical News Today: Ergot poisoning].
Secondary prevention/screening: routine grain inspection and cleaning at mills; surveillance of grain-supply chains in food-insecure regions where prior outbreaks have occurred.
Tertiary prevention (iatrogenic disease): prescriber vigilance for CYP3A4-drug-interaction risk — avoiding co-prescription of ergot-alkaloid medications with protease inhibitors or macrolide antibiotics; ergotamine/DHE are now labeled contraindicated with strong CYP3A4 inhibitors [drug interaction sources above].
Counseling: patient education regarding maximum ergot-medication dosing limits and drug-interaction avoidance for migraine patients on chronic ergotamine therapy; obstetric protocols limiting ergometrine/methylergonovine dosing.
Public health: governmental grain-inspection regulation as the principal public-health lever, given the disease's near-total dependence on food-supply contamination in its epidemic form.

14. Other Species / Natural Disease

Ergotism is naturally occurring and economically significant in livestock, providing a well-studied comparative-pathology model:

Cattle ("fescue toxicosis"/"fescue lameness"): grazing on endophyte-infected tall fescue (Lolium arundinaceum/Festuca arundinacea, infected by the endophytic fungus Epichloë coenophiala, which — like Claviceps — produces ergopeptine alkaloids, principally ergovaline, constituting ~90% of ergopeptide alkaloids in toxic fescue) causes a clinical syndrome closely paralleling human gangrenous ergotism: hindlimb lameness progressing to distal-limb necrosis/gangrene, tail and ear necrosis, rough coat, reduced body mass, and an arched-back posture Merck Veterinary Manual: Fescue Poisoning in Animals; It's fescue toxicosis on steroids — Hay and Forage Magazine.
Toxic threshold: ergovaline concentrations of 100–500 ppb are typical in infected fescue, with >200 ppb considered toxic; the mechanism mirrors the human disease — agonism at monoamine (adrenergic/serotonergic) receptors on vascular smooth muscle due to structural similarity between ergot alkaloids and endogenous monoamine neurotransmitters Impact of Ergot Alkaloids on Female Reproduction in Domestic Livestock — PMC6628433.
Reproductive toxicity in livestock: altered estrous cyclicity, suppressed hormone secretion, reduced pregnancy rates, agalactia (failure of milk production — directly paralleling the human infant-lactation-failure deaths reported in the 2001 Ethiopian outbreak), and reduced offspring birth weight [PMC6628433].
Economic burden: fescue toxicosis is estimated to cause over $2 billion in annual economic loss to U.S. livestock industries [Fescue Toxicosis — Hay and Forage Magazine].
Comparative biology: the shared receptor-agonism mechanism (adrenergic + serotonergic vasoconstriction) across cattle and humans makes livestock fescue-toxicosis studies a natural, non-experimental disease model directly informative for human ergotism pathophysiology — this is a naturally occurring analog rather than a laboratory-induced model.
Other species: ergotism is also documented in horses, sheep, and other grazing livestock exposed to ergotized pasture grasses or contaminated feed grain Merck Veterinary Manual: Ergotism in Animals.
Zoonotic potential: none — this is a shared dietary/environmental toxin exposure across species (both grazing on/eating the same contaminated plant material), not a transmissible infectious disease between species.

15. Model Organisms

Livestock as natural disease models: cattle (particularly Angus breed studies of fescue-toxicosis resistance/susceptibility) and sheep represent the best-characterized naturally occurring, non-induced animal models of ergot-alkaloid-induced vasoconstrictive disease, closely recapitulating the human gangrenous phenotype Evaluation of Resistance to Fescue Toxicosis in Purebred Angus Cattle — PMC7764894.
Experimental/induced models:
Sheep — acute ergot-alkaloid dosing studies directly measuring vasoactive/vasoconstrictive responses ("Vasoactive Effects of Acute Ergot Exposure in Sheep" — PMC8072561), providing a controlled induced-exposure model complementing the natural cattle-grazing model.
Isolated vascular tissue preparations — rat aorta, rabbit aorta, bovine lateral saphenous vein, and human saphenous vein (obtained during varicose-vein saphenectomy surgery) have been used ex vivo to characterize ergot-alkaloid receptor pharmacology (5-HT1/5-HT2/α-adrenergic receptor contributions to vasoconstriction) Actions of non-peptide ergot alkaloids at 5-HT1-like and 5-HT2 receptors — Naunyn-Schmiedeberg's Arch Pharmacol; Alpha-adrenoceptors, 5-HT receptors and dihydroergotamine in human venous preparations; Serotonin receptor-mediated vasorelaxation in bovine lateral saphenous vein — PMC11214916.
Pithed rat model — used to pharmacologically dissect the specific receptor subtypes (5-HT1A/1B/1D, α2-adrenoceptors, D2-like receptors) mediating ergotamine's inhibition of vasopressor sympathetic outflow [Pharmacological evidence that 5-HT1A/1B/1D, α2-adrenoceptors and D2-like receptors mediate ergotamine-induced effects — ScienceDirect].
Model characteristics/limitations: the isolated-vessel ex vivo preparations recapitulate the receptor-pharmacology of ergot-alkaloid vasoconstriction well but cannot model the systemic ischemic/gangrenous tissue outcome; the cattle/sheep whole-animal models recapitulate the full phenotype (vasospasm → distal necrosis → reproductive/lactation failure) with high translational fidelity to the human disease, given the shared receptor pharmacology and grazing/dietary exposure route, though species differences in vascular receptor density and diet composition remain translational caveats.
Resources: no dedicated ergotism-specific model-organism database was identified (unlike Mendelian-disease model registries such as MGI/IMPC); the relevant literature is distributed across veterinary toxicology (Merck Veterinary Manual, agricultural extension publications) and pharmacology journals rather than a centralized model-organism resource.

Notes on Curation Gaps and Verification Needed

MONDO:0042496 should be independently verified against the current MONDO build before being bound as disease_term; this report could not confirm the identifier via public search.
Specific CHEBI IDs for ergotamine, ergometrine, ergosine, ergocristine, ergocryptine, and ergocornine, and specific HP/GO/CL/UBERON term IDs suggested above, are candidates only — per the dismech ontology-term contract, each must be independently confirmed via runoak/cache lookup at curation time rather than written from this report.
Orphanet/OMIM coverage was not confirmed either way in this search and should be checked directly.
No NCT-registered clinical trials specific to ergotism treatment were located; treatment evidence is case-report/case-series level throughout.
Precise modern incidence/prevalence rate figures (cases per 100,000) were not found and may not exist in a form suitable for the Prevalence schema's rate_per_100000 slot — CASES_IN_LITERATURE may be the most defensible measure_type for this entry given the sporadic/case-report evidence base.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	23
Resolved	23
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	23
On topic	10
Off topic	3

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMC:PMC11625447 (5 mentions) - CYP3A4 and CYP3A5: the crucial roles in clinical drug metabolism and the significant implications of genetic polymorphisms.
shared terms: cyp3a4, human
PMC:PMC11879452 (6 mentions) - Joining forces: a complex cardio-obstetrics case report of severe ergometrine-induced vasospasm.
shared terms: vasospasm, ergometrine
PMC:PMC11214916 (4 mentions) - Serotonin receptor-mediated vasorelaxation occurs primarily through 5-HT(4) activation in bovine lateral saphenous vein.
shared terms: receptor

Weighed against this report's own most characteristic terms: ergotism, ergot, disease, ergotamine, alkaloid, gangrenous, epidemic, outbreak, grain, vasospasm, cyp3a4, ergot-alkaloid, iatrogenic, ischemic, human, modern, documented, receptor, gangrene, ergometrine.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	20
Resolved	18
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	1
Terms whose name was checked	13
Terms named correctly	9
Terms named as a different term	3
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0042496 (3 mentions) - the report calls it "if available"; MONDO calls it ergotism
HP:0034976 (1 mention) - the report calls it "Peripheral gangrene"; HP calls it Absent pituitary stalk
HP:0031650 (1 mention) - the report calls it "Vasospasm"; HP calls it Abnormal atrioventricular valve physiology

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

CHEBI:4880 (CHEBI_4880) (1 mention) - replaced by CHEBI:16000

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0007212 (1 mention) - the report calls it "dopamine receptor signaling pathway"; GO calls it G protein-coupled dopamine receptor signaling pathway, and lists "dopamine receptor signalling pathway" among its other names

Ask OpenScientist

OpenScientist Report

Mappings

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Environmental Factors

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

Deep Research

Ergotism: Comprehensive Disease Characteristics Research Report

1. Disease Information

2. Etiology

3. Phenotypes

A. Gangrenous ergotism (vasospastic form)

B. Convulsive ergotism (neuropsychiatric form)

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Category detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Notes on Curation Gaps and Verification Needed

Sources

Reference Validation

References that may not be about this subject

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look