Fire in the Rain
Want to know what toxin has killed hundreds of thousands of people, has been associated with the Salem Witch Trials and is the source of modern hallucinogens?
This is the Pick Your Poison podcast. I’m your host Dr. JP and I’m here to share my passion for poisons in this interactive show. Will our patients survive this podcast? It’s up to you and the choices you make. Our episode today is called Fire in the Rain. Want to know what toxin has killed hundreds of thousands of people, has been associated with the Salem Witch Trials and is the source of modern hallucinogens? Then stay tuned!
A 39-year-old woman presents to the emergency department complaining of severe pain in her legs. It’s been hurting for weeks, maybe a month, and is worsening. Initially it was only with walking several blocks, but now she gets it even just walking from her bedroom to the bathroom. It gets better if she sits down and rests.
She denies other symptoms including back pain, leg weakness, fever or falls. No chest pain or shortness of breath. She has a history of migraines and gets them frequently, but there’s been no recent change in the headaches. With the migraines, she experiences scotoma, or visual changes associated with the migraines, and vomiting, but doesn’t get other focal neurological problems.
The chart says she doesn’t take any medicines and has no known drug allergies. It notes she smokes, but denied alcohol and illicit drugs.
Her vital signs are normal. She looks comfortable sitting on the stretcher. You move onto the physical exam, focusing on her legs. She doesn’t have any tenderness to palpation, there’s no redness or swelling, and sensation is intact. Everything seems fine until you check the pulses in her feet. They aren’t there. You put your fingers on the arch of her foot, after a minute or two you move it to the inside of her ankle. Nothing.
Is she dead? Obviously not, but something is wrong with the circulation in her feet. You get the doppler, a small probe used to locate a pulse that can't be palpated ie felt. You might have seen it used on the stomach of pregnant women to check a fetal heartbeat. You put the small probe atop the arch of the patient’s foot and listen. First, static, but then you hear the steady whooshing sound of arterial flow. Good news, she has some blood circulation. But the lack of a palpable pulse means its severely compromised. Why? Good question.
The diagnosis here is easy. The history of exertional leg pain improving with rest is the classic description of claudication, indicating poor circulation. The legs get enough blood flow with sitting, but not enough to support exercise. Even minimal muscle movement is too much, like walking a few steps to the bathroom in our patient’s case. It’s just like angina, chest pain with exertion due to cardiac disease.
While the diagnosis is easy, the cause is the confounding problem here. If she were 80 years old with heart disease, high blood pressure, diabetes and high cholesterol, plaque buildup and blockage in her arteries would be no surprise. In a young, otherwise healthy person this is unusual. Very unusual. Smoking is definitely a risk factor for vascular disease. You don’t need me to tell you about the association between smoking and heart attacks. Nevertheless, smoking causing circulatory failure isn’t something I’d expect to see in a 39-year-old.
You ask her specifically about a history of high blood pressure, autoimmune disease, or blood clots, all of which she denies. While it’s unclear what’s happening, it is clear what she needs. You call the vascular surgeon who plans an angiogram for further evaluation. An angiogram is when dye is injected into the arterial system to check for blockages, narrowing, tears or clots. If you know what a cardiac catheterization is, it’s essentially an angiogram of the coronary arteries. If the cardiologist identifies a blockage they can intervene with a stent, for example. Vascular surgery will inject our patient’s legs to determine the cause and potentially intervene.
After putting that next step in motion, you talk to the patient again to search for clues to the cause of this surprising illness. In fact, she is taking a medication. Did I hear you say hey that’s not fair, you mislead me earlier by saying no medicines? In truth, this is a real-life, every day scenario. The patient did tell the triage nurse no meds. We toxicologists aren’t the only physicians who always take our own detailed histories. Patients often say they have no medical problems and don’t take any medicines, but on closer questioning reveal more information. Why? Sometimes they don’t realize the relevance of their prior history. Sometimes they don’t count over-the-counter medicines, thinking we mean only prescriptions and routinely they won’t mention supplements. Sometimes they’re concerned about disclosing sensitive topics like substance use or HIV.
Our patient says she’s taking Tylenol for pain relief, though it wasn’t working. This is definitely not acetaminophen toxicity. She also takes a medicine for migraines, though she’s forgotten the name. Ah ha. Migraine medicines could be relevant here.
Migraines are a common problem, and a fascinating disease, but sadly one we don’t know much about. The symptoms range from simple headaches, classic scotoma, to vomiting, to vertigo and all the way up to focal neurological deficits. With severe migraines patients can have visual loss and unilateral weakness mimicking a stroke.
The patient says she doesn’t know the name of the medicine and she doesn’t have a prescription, her family in Mexico sends the pills to her. Ok, this expands the differential diagnosis to just about anything. You ask if someone can text a picture of the bottle.
What kinds of medicine can you take for a migraine? There are a lot of options. First and most commonly, anti-inflammatories like acetaminophen, ibuprofen, and naproxen. None of these will impair circulation. Caffeine helps migraines and does cause vasoconstriction, but not enough to cause this level of ischemia. Ischemia, in case I forgot to mention, is poor blood flow, causing problems to surrounding tissues or organs. In the ER, we often use antinausea medicines for migraines. They work well, but don’t cause ischemia.
A class of drugs I’d definitely have on my list are triptans, like sumatriptan. They work by constricting blood vessels and are contraindicated in patients with heart disease and other vascular problems. Another category are ergotamines, used to treat migraines for more than 100 years and definitely a cause of vasoconstriction. These absolutely fascinating toxins have killed hundreds of thousands of patients in horrific epidemics, but have also saved many, many lives.
Her phone beeps with a picture. You can read the label, caffeine and ergotamine. This drug is sold in the US under the name Cafergot. Dosing recommendations are to start with two tablets then take one additional tablet every half hour until the headache is better, maximum six tablets per episode, and 10 per week.
You ask how much she’s taking. She says four to six pills per day, and she has a migraine almost every day. Uh oh. This is a definite overdose, even though it’s unintentional. Cafergot carries a black box warning in the US about the risk of peripheral ischemia, though it’s specifically warning about increased risk with drug interactions. Ergotamine toxicity and overdose is extremely rare in modern times. I’ve only given IV ergot derivatives a few times, and only in consultation with a neurologist to treat refractory migraines. I wanted to discuss ergots not because they’re common, but because they and their history are so fascinating. Let’s move to the history and come back to our patient in a bit.
I could just as easily have started this episode in the Middle Ages with the following patient. A 20-year-old man presents to the hospital, located in a monastery, with black legs. He reports his symptoms started weeks ago with unbearable burning pain in his legs. After the pain ceased, the legs turned black. He can’t use them, he arrived at the hospital using crutches and dragging the useless limbs behind him. On exam, the extremities are withered, the skin is leathery and black. He has no pulses or sensation. When you hold up the leg to look underneath, two toes fall off. You’d be horrified, except this is a regular occurrence. You’re silently relieved it’s just the toes and not the whole leg.
Question #1. What disease are both our modern and medieval patients suffering from?
A. Leprosy
B. The black death
C. Tuberculosis
D. St. Anthony’s fire
Answer: D. This is egotism, or St. Anthony’s fire as it was called in the Middle Ages.
It’s one of the syndromes caused by ergot toxicity. Terrible, recurrent outbreaks occurred in the Middle Ages. The first documented outbreak was in 857 AD in Germany. Another in 944 in the Aquitaine region of France reportedly killed 20,000 people or half—half—of the population. Fifty years later another 40,000 people died. How were so many people exposed to and poisoned by this toxin?
It comes from contaminated food, often bread. In modern times, ergots are medicine. However, for most of its history ergotism was a foodborne illness.
Question number 2. Where do ergots come from?
A. Bacteria
B. Viruses
C. Fungi
Answer: C.
Ergotism comes from a fungus infecting grasses. I’m using the term ergots, because the fungus can have as many as 200 different compounds, of which ergotamine itself is one. The fungus is classically Claviceps purpurea, though other species are implicated. Outbreaks increase during wet, rainy growing seasons. The fungus infects wheat, rye, corn, rice and other grasses. It’s very common in rye, thus the disease, as with so many others, often affected the poor as they were more likely to eat cheaper rye bread, then more expensive grains, like wheat.
As I mentioned, St. Anthony’s fire is one of the syndromes caused by ergot toxicity. Interestingly, in the Middle Ages, location contributed significantly to what symptoms developed. West of the Rhine River, in France, the gangrenous form of ergotism, was predominant.
It was called holy fire, then became known as St. Anthony’s fire. It’s caused by peripheral vasoconstriction, like with our modern patient. First, severe pain due to neuropathy develops. Once the circulation is completely cut off, the pain stops and dry gangrene develops. Eventually gangrene leads to auto-amputation of extremities. Meaning the limbs literally fall off. This is painless, because the limbs are already dead. In some patients, this happened in all four limbs, which is just devasting to even think about. Side note dry gangrene is different than wet gangrene. Dry gangrene isn’t due to infection, but vascular compromise for example due to frostbite. Wet gangrene is due to infection and suppurates and oozes with discharge and pus.
East of the Rhine River, in Germany and Eastern Europe, a different syndrome of ergotism was prevalent, known as the convulsive form). It’s characterized by an altered mental status, including delirium and hallucinations, as well as painful muscle spasms and seizures.
It's unclear why different locations resulted in different symptoms. One thought is that different alkaloids were present in different geographic regions due to variation in weather, infected plants and conditions after harvesting.
Why did our patient from the Middle Ages present for care at a monastery? The Order of St. Anthony cared for patients stricken with ergotism, thus the name St. Anthony’s fire. They had as many as 400 hospitals throughout Europe. Apparently the monasteries, displayed detached gangrenous limbs above the entrances to identify themselves and were called hospitals of the dismembered. I have to say I’d think twice about entering a hospital displaying severed limbs. To treat our medieval patient, you’d prescribe a healthy diet and wound care, including topical application of St. Anthony’s water. An ointment made from pig fat. Glad we’ve moved on from that.
Eventually observant scientists began to establish the cause of these devastating epidemics and the disease was ultimately linked to Claviceps purpurea in 1676. Outbreaks declined thereafter, but haven’t disappeared.
The reason we don’t see foodborne ergotism in modern times is thanks to regulatory control and testing. For example, in the US grain is allowed to have some ergotamine, but only in low quantities. For wheat, lower than 0.05% and for rye less than 3%.
Back to our modern patient. She gets the angiogram, and the vascular surgeon sees very narrowed arteries in both legs. They also note pruning of the arterial trees, loss of smaller blood vessels, a classic finding associated with ergotamine toxicity.
How do we treat it? First, let me touch briefly on what they do. Ergots have very complex receptor physiology with numerous effects on the body. Let’s focus on their two major mechanisms of action. First is stimulation of serotonin receptors in the brain. This causes delirium and hallucinations, and is the same mechanism of many hallucinogens. If we had a patient with these symptoms, we’d give benzodiazepines for sedation. The second major action is alpha-adrenergic receptor stimulation causing vasoconstriction.
This is the problem affecting our patient. Treatment includes several options, but the most important is stop ergot exposure. In this case our patient is given nitroprusside, a strong relaxer of blood vessels to help until the ergots are metabolized and their effects dissipate. Other options include calcium channel blockers, a class of antihypertensive drugs and phentolamine, an alpha blocker, which works to reverse the alpha stimulation causing vasoconstriction. Blood clots may be present, likely due to damage to the vessels and if so can be treated with blood thinners.
In a few weeks, the patient’s claudication has completely resolved. Unfortunately, she hasn’t stopped smoking. Luckily, for our patient, the vascular damage was reversible. In some cases, repeat angiogram shows a return to normal circulation. In other cases, damage is permanent.
Just as fascinating as the historical outbreaks are the early uses of ergotism in medicine. What have we used ergot derived drugs for? Medicines as well as drugs of abuse. We’ve discussed ergots for headaches, both oral and IV forms are available, though rarely used since the development of triptans and other medicines. There is one area of the hospital where we use ergotamines more frequently, that’s on labor and delivery. You may have heard of methergine, or methylergonovine which induces uterine contractions and reduces postpartum bleeding.
The earliest reference to ergotamine use in obstetrics was documented in 1100 BCE in Chinese medicine. Around 350 BCE, a Parsee text described ‘noxious grasses that cause pregnant women to drop the womb and die in childbed.” This refers to the increased risk of fetal distress, stillbirth and uterine rupture if given during labor, thus the reason it’s generally used after the baby is delivered to reduce hemorrhage.
In the Middle Ages, use of the fungus by midwives developed after it was noted that pigs who ingested contaminated grain developed miscarriages and preterm labor. Slow recovery of areas in the Middle Ages after ergot outbreaks is interestingly enough attributed to low birth rates due to ergot- induced miscarriages.
Another drug derived from ergots is bromocriptine which I mention because it’s an antidote for muscle rigidity caused by neuroleptic malignant syndrome, due to antipsychotic medicines.
Question # 3. Which historical events have been associated with ergotism?
A. Salem Witch Trial in the US
B. Norway Witch Trials
C. French Revolution
D. Dancing plague
Answer: E all of the above.
A number of ancient phenomenon and historical events attributed to ergot poisoning, some convincingly, some less so. Scholars have postulated the Salem witchcraft trials were the result of ergot intoxication by the young girls and women seeing visions, though others feel more inhabitants would’ve been affected and that ergotism would’ve been easily recognized and diagnosed in those times. Similar questions have been raised about trials in Norway.
In France a period described as the Great Fear, characterized by panic and riots led up to the French Revolution. Could this have been ergotism? And did it keep the Russians from their goal of a port on the Black Sea? In 1772, Peter the Great’s Army was marching to fight the Turks when the men and their horses became ill, forcing a retreat.
Ergotism has also been raised as a cause of the very medieval bizarre “dancing epidemics.” strange occurrences were the afflicted couldn’t stop dancing and were treated with music. They’ve been attributed to everything from tarantula bites, to the neurologic problem chorea to ergotism to mass hysteria.
In fact, the hallucinogenic power of ergots is still harnessed in modern times. What drug is derived from ergot?
A. Peyote
B. LSD
C. PCP
D. Psilocybin
Answer B. LSD.
Albert Hoffman, the chemist who synthesized the drug, ingested and reported its hallucinogenic effects, called LSD his “problem child.”
Today’s cases, as are all our cases, are fictional to protect the innocent. But it is based on real poisonings that have occurred throughout history.
Last question in today’s podcast. Which of the following artwork or artworks includes depictions of ergotism?
A. Hieronymus Bosch's The Temptation of St. Anthony
B. Matthias Grunewald’s Isenheim Altarpiece
C. Pieter Bruegel’s The Triumph of Death
D. Salvator Rosa’s Human Frailty
Follow the Instagram and twitter feeds @pickpoison1 and you’ll see the answer along with these incredible paintings when I post it. Remember, never try anything on this podcast at home or anywhere else.
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