Ergotamine-Induced Leg Ischemia: A Case Report & Review

349
St.
Anthony’s Fire
(Ergotamine Induced Leg Ischemia)
A Case Report and Review of the Literature
Zavaleta, MD,* Bernardo B. Fernandez, MD,† Mark K. Grove, MD,‡ and
Kaye, MD,§ Fort Lauderdale, FL
Ernesto G.
Marc D.
Ergotism, once an epidemic disease, is now a rare disorder. The most common manifestation is
acute peripheral ischemia due to vasospasm,
2 We report a case
1with an incidence of 0.001%.
of a middle-age woman who presented with ergotamine-induced leg ischemia, due to chronic
use of ergotamine-containing medications for migraine headaches. The diagnosis was confirmed
with arteriography results, and she responded well to vasodilator therapy. The pharmacology,
clinical presentation, diagnostic approach, and therapy of ergotism are reviewed.
Introduction
Case Report
epidemic disease in the Middle Ages,
This entity is usually related to the chronic use of drugs containing ergot
alkaloids (EA). While ergotism may have different
presentations, the most common manifestation is1
acute peripheral ischemia due to vasospasm,
which occurs in 0.001% to 0.002% of patients
who use EA.2 We report a case of ergotamine-induced leg ischemia, occurring in conjunction with
clinical and ultrasonographic signs of carotid vasospasm without neurologic compromise.
A
Ergotism,
is very
an
uncommon now.
Angiology 52:349-356, 20011
From the Departments of *Internal Medicine, 1 Vascular
Medicine, ’Vascular Surgery, and ~Interventional Radiology;
The Cleveland Clinic Florida, Fort Lauderdale, FL
Presented at the 45th Annual Meeting of the American
of Angiology, New Orleans, Louisiana, October 1998
College
Bernardo B. Fernandez, MD, Chairman,
Department of Vascular Medicine, Cleveland Clinic Florida,
3000 W. Cypress Creek Rd., Fort Lauderdale, FL 33309
©2001 Westminster Publications, Inc., 708 Glen Cove Avenue,
Glen Head, NY 11545, USA
Correspondence:
48-year-old Guatemalan woman with recent
of hypertension and intermittent right calf
onset
claudication
was
evaluation, after
referred
a
to our
institution for
cold, painful, and pulseless
right leg, developed. She was a nonsmoker and
had no identifiable risk factors for atherosclerosis.
She had a history of migraine headaches, for
which she took different types of over-the-counter
medications for headaches for several years. She
reportedly stopped taking these drugs 2 weeks
prior to her visit to our clinic. Arteriography attempted in her country was aborted when the
right femoral artery could not be cannulated. The
review of systems was unremarkable. No history
of collagen vascular disease was present.
On examination, the right femoral, popliteal,
dorsalis pedis, and posterior tibialis pulses were
absent and the right leg and foot were cool and
pallorous. A loud 2/6 left systolic carotid bruit
was noted. The pulses on the left leg were nonpalpable. A pulse volume recording study demonstrated flat waveform tracings at the right calf
and ankle levels. The ankle-brachial index was
not obtainable (Figure 1). Atherosclerotic plaques
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350
Figure 1. Pulse volume
recording results showing flat
waveforms in the right calf
and ankle. The ankle/brachial
index was unobtainable since
no pressure could be
measured in the right ankle.
during duplex ultrasound imaging
right iliac, common femoral, and superficial
femoral arteries. A duplex ultrasound of the
were not seen
of the
carotid arteries demonstrated increased velocities
consistent with bilateral 60% to 79% stenosis. No
discreet plaques were discerned at the bifurcation. Westergreen sedimentation rate and complete blood cell counts were normal, raising the
suspicion of ergotamine abuse. This was confirmed when the patient admitted that some of
the medications that she took for her migraine
headaches contained ergotamine derivatives and
caffeine. Hypercoagulable studies and antinuclear
antigen profile were also normal.
Arteriography was performed via the contralateral femoral artery. Initial films of the right
lower extremity demonstrated severe stenosis of
the superficial femoral artery and small collateral
vessels from the profunda femoris artery (Figure
2A). The tibial vessels could not be identified
(Figure 2B). Following the initial runoff, 100 Ag
nitroglycerin was injected intraarterially into the
right femoral artery. Repeat arteriography was
performed 5 minutes following the injection of nitroglycerin and showed marked improvement of
the stenosis in the
common femoral, superficial
femoral, deep femoral, and popliteal arteries
(Figure 3A). The tibial vessels were seen, and
three-vessel runoff to the foot was seen (Figure
3B). The patient was admitted to the hospital for
further
treatment.
She received intravenous ni-
troprusside for 48 hours in conjunction with heparin infusion, oral calcium channel blocker
(nifedipine), and alpha blocker (prazosin) that resulted in prompt return of pedal pulses and resolution of symptoms. Results of the physical examination following therapy were normal, and
the carotid bruit disappeared. Follow-up pulse
volume recording and the ankle brachial-index
were normal (Figure 4). Serum ergotamine levels measured on admission to the hospital were
undetectable.
Discussion
The first references to ergot alkaloid intoxication
due to ergot-tainted rye is found on an Assyrian
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351
Figure 2. A. Initial runoff of the arterial circulation on the right thigh, revealing severe stenosis of
the superficial femoral artery and multiple small collateral vessels from the profunda femoris artery.
B. The tibial vessels were not seen during the initial runoff of the right leg. Few small collateral
vessels
are
present.
3.
A. After intraarterial injection of nitroglycerin, the spasm in the superficial femoral
marked
shows
improvement. The small collateral vessels from the profunda femoris artery are
artery
no longer visible. B. Following injection of nitroglycerin, the tibioperoneal vessels are now visible.
Figure
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352
Figure
volume
Follow-up pulse
recording after
4.
with vasodilator
The
waveforms and
therapy.
the ankle/brachial index show
marked improvement.
treatment
dating from 600 BC. In the Middle Ages,
epidemics of &dquo;gangrenous ergotism&dquo; were common in Europe due to ingestion of rye contaminated with the ergot fungus Claviceps purpurea.
Claudication and painful burning of the affected
tablet
limb occurred in less advanced cases. The disease
called Holy Fire or St. Anthony’s fire, the latter being in honor of the saint at whose shrine re-
was
said to be obtained.’ The frequency of
epidemics declined after the relationship with the
contaminated rye was recognized.
lief
was
Pharmacology
Ergot alkaloids can be divided in three categories:
amino-acid alkaloids (ergotamine), amine alkaloids (ergonovine), and dihydrogenated amino
acid alkaloids.3The first
oxytocic properties,
two
groups have direct
can cause
vasoconstriction,
central emetic effect. Ergotamine, in
particular, increases peristalsis of the gastrointestinal tract. 3,4 Those in the first group are also
alpha-adrenergic blocking agents and can cause
vasodilatation by inhibition of norepinephrine-induced vasoconstriction. 4,5 Dihydroergotamine is
and have
a
synthesized by hydrogenation of the alkaloids.
This modification increases the alpha-adrenergic
blocking effect and decreases the vasoconstrictor
and emetic effects.5
The major pharmacologic effects of EA include smooth muscle stimulation (most evident
as vasoconstriction and uterine contraction), central sympatholytic activity, and peripheral alpha-
adrenergic blockade.66
Ergot-containing products interact with multiple receptors, such as norepinephrine, epinephrine, dopamine, and serotonin receptors. They
cause vasoconstriction by stimulating alphaadrenergic and 5-hydroxytryptamine (5-HT) receptors, which is responsible for the development
of ischemic side effects.5
While ergot alkaloids are poorly absorbed
orally (less than 2%), the concentration required
to produce appropriate pharmacologic effects is
very low. Absorption via the rectum has been
shown to be more complete. 4,7 Contrasting with a
rapid clearance of the administered drug from the
plasma, a protracted effect of the EA in the vasculature has been documented and this appears
to be a characteristic property of EA.’-11These
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353
findings suggest that an extremely slow dissociation from the receptor sites and/or the presence
of active metabolites may account for the proof action of these compounds in
longed duration
the periphery.88
Ergot alkaloids and their metabolites are primarily metabolized in the liver ( > 90%) and are
excreted in the feces via biliary elimination. Only
a small fraction of these drugs is excreted through
the renal system.’ Several drugs with hepatic metabolism have been reported to increase the potential for ergotism associated with ischemic complications. The use of macrolide antibiotics, oral
contraceptives, and ampicillin has been associated with cases of ergotism. 12-14 Beta blockers can
increase the risk of severe peripheral ischemia
with concomitant EA administration due to inhibition of beta-2 receptor-mediated vasodilatation.l5 Smoking has also been reported to increase the incidence/likelihood of ergot-induced
peripheral
ischemia. 12
Ergotamine-Induced Vasoconstriction
Ergotism is a rare disorder that may be associated
with the use of ergot derivatives either at therapeutic doses (iatrogenic) or with chronic abuse.
The incidence of ergotism is estimated to be
0.001%-0.002% in patients using ergotamine
preparations for migraine headaches, for postparturition hemorrhage, or in combination with
heparin for deep vein thrombosis prophylaxis.22
Ischemic manifestations can occur in any part
of the circulatory system. Symptoms secondary to
arterial spasm and ischemia induced by ergotamine have been reported in the brachial,4,15-17 radial, 15 iliac,18~19 femoral, 6,12,15,18,20 coronary, 21,22
renal,23 popliteal, 6,18 mesenteric,24 retinal,6and
carotid arteries.25,26
Ergotamine
intoxication
can
be
principally
observed in three conditions: (a)
acute intoxica(b) acute intoxi-
tion via an allergic mechanism;
cation via the use of high doses of ergot derivatives ; or (c) chronic intoxication after prolonged
therapy at therapeutic doses, 1,17 the latter being
the
presentation.
ergotism may be manifested by nausea, vomiting (due to dopaminergic stimulation
on the emetic center), diarrhea, thirst, paresthesias, confusion, rapid and weak pulse, unconsciousness, convulsions (&dquo;convulsive ergotism&dquo;),
most common
Acute
sudden death. 3,6,7 In chronic intoxication, ischemia of the extremities is the most common form of presentation. In a review of controlled clinical trials in the use of ergotamine for
and
even
migraine, Meyler found
that more than two
thirds of serious side effects attributable to ergotamine were caused by vasoconstriction.’ The
remainder were caused by fibrosis (cardiac
valves, anorectal ulcers, retroperitoneal or pulmonary fibrosis).
As previously mentioned, the biologic effects
of the EA can persist for days following adminis-
tration,8°9 but the plasma levels will be detected
only for a short time after dosing. This dissociation between plasma concentrations of the parent
drug and the observed biologic effects of EA make
the diagnosis of ergotism more difficult. The
physician must therefore base the diagnosis on
the history of migraine and EA intake, the clinical
findings, and a high index of suspicion.
In our review of the literature of reported
cases of vascular insufficiency secondary to ergotism, a pattern of EA use could be identified. Most
patients were chronic users of EA for migraine
therapy who increased the intake of these drugs
due to worsening of migraine attacks before developing classical symptoms of vascular insufficiency. It is likely that most of these patients had
subclinical ergotism that became symptomatic
when they increased EA intake, exacerbating the
vasospasm.
Diagnosis
high index of suspicion and a history of possible chronic use (and possible abuse) of EA are
necessary to make the diagnosis. Physical findings compatible with arterial ischemia in a young
patient with history of migraines and no risk factors for atherosclerosis should raise the possibility of ergotism.
The differential diagnosis of ischemic limbs
includes atherosclerosis, vasculitis, Buerger’s disease, thromboembolic events, aneurysms, and
drug-induced vasospasm (Table I).
Pulse volume recording (PVR) and anklebrachial index (ABI) are helpful tests that may
help confirm the diagnosis of ischemia, but will
not help to identify the cause. In contrast, duplex
ultrasound and plethysmography are noninvasive
imaging tests that can be used to help identify the
causes of ischemia.
The lack of atherosclerotic plaques in a patient with ultrasonographic evidence of occlusive
disease increases the suspicion for vasospasm due
A
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354
to
vasculitis or ergotism. These two conditions
be differentiated with results of specific labo-
can
ratory tests.
Arteriography, the gold standard test for the
diagnosis of vasospasm, can be therapeutic in patients with EA-induced ischemia. If relief of
va-
sospasm is obtained with the use of intraarterial
vasodilators in a patient with antecedent EA intake, the diagnosis of ergotism-induced ischemia
is corroborated. Three angiographic findings can
be present: (1) arterial spasm, usually bilateral
and symmetric with abrupt or smooth areas of
narrowing; (2) collateral vessels, which may disappear following withdrawal of the medication;
and (3) thrombi formation, the latter being rarely
reported. 18 In one unusual case, the angiogram
showed
Table I. Differential
ischemic limbs.
diagnosis
of
pseudoaneurysms. 27
Why collateral vessels do not prevent vasospasm is unknown, but as suggested by Enge et
al, this can be due to a difference between the
composition of the muscular layers of the vessels.l6 It has been proposed that vessel sensitivity
to EA may predispose some patients to ergotism.28 Similar factors may also explain why vasospasm develops in different arteries in different
patients.
Subclinical Ergotism
The vasospasm induced by EA may, in the early
stages of this condition, be largely asymptomatic.
In some cases, the patients had symptoms of vascular insufficiency for years before the diagnosis
was
made. 4,16
Bongard et al reported four patients with ergotamine-induced vasospasm who had moderate
symptoms for weeks before the onset of acute ischemia .30 Diege-Petersen et al reported subclinical ergotism (ergotamine-induced physiologic
vascular changes without clinical symptoms) in
30 patients taking ergotamine daily for more than
1 year. When ankle blood pressures were measured with strain-gauge plethysmography, all patients had abnormal low foot systolic blood pressures or values in the lower range of normal. 31
Other authors have reported the effect of ergotamine in the vascular system. 21,27,32 The toearm systolic blood pressure gradients were decreased at 24 hours in 10 patients receiving ergotamine suppositories within therapeutic doses.
ergotamine produced coronary vapatients with recurrent
angina pectoris at rest. Four of these patients had
ECG changes compatible with myocardial ischemia. Acute myocardial infarction secondary to
the use of ergotamine, probably caused by severe
Intravenous
sospasm in nine of 10
coronary vasospasm, has been reported,22 and exacerbation of angina in patients with coronary
6
artery disease is not uncommon.6
Several risk factors for ergotamine intoxication have been reported, including sepsis, febrile
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355
malnutrition, avitaminosis, coronary heart
disease, hepatic disease, renal insufficiency, thyrotoxicosis, hypertension, pregnancy, peripheral
vascular disease, and smoking. 4,18
states,
Therapy
The first therapeutic measure is discontinuation
of the EA; however, the vasospasm may be prolonged for up to a week following withdrawal of
these agents .30 The use of heparin and antiplatelet agents is also recommended as prophylaxis to
prevent secondary thrombosis related to stasis.
While there are no clinical trials showing the
benefits of oral or intravenous vasodilator therapy in patients with ergotamine-induced vasospasm, these medications have been used extensively to treat the ischemic complications and
appear to be the most effective therapy.
Vasodilator therapy should be continued for few
days, since the vasospasm usually recurs.29
There are reports of some refractory cases.
Since ergotamine is tightly bound to alpha receptors, the vasospasm due to these compounds
may not respond to vasodilators.6Intravenous or
intraarterial nitroprusside, 22,26,33 nitroglycerin,34
nifedipine,35 and prostaglandins36 have been
used. The latter have been reported to be effective in refractory cases of ergotism.23 Oral medications such as captopril, prazosin, and nifedipine have been tried successfully. In our patient,
we used a combination of all these medications
because of the severity and duration of symptoms. Sympathetic blockade has been attempted
when vasodilator therapy has failed, but the efficacy is controversial. 16 Other forms of therapy include hyperbaric oxygen, mechanical intraarterial vasodilatation, 37 and epidural spinal cord
stimulation.38
The patient described in this report had signs
and symptoms of chronic ischemia of both lower
extremities related to the use of ergotamine.
Furthermore, the carotid duplex ultrasound on
admission showed significant stenosis from vasospasm correlating the clinical findings of
carotid bruits, which disappeared after therapy
was initiated. It is remarkable that the patient
used oral ergotamine products intermittently for
her migraine attacks in therapeutic doses, and
that her symptoms persisted for 2 weeks after she
stopped taking these medications.
Conclusion
Ergotamine-induced ischemia, although
rare,
should still be considered in the differential diagnosis of ischemic limbs, especially in younger patients with a history of headaches that present
with symptoms of progressive ischemia. A history
of ergotamine use should always be obtained, including dosages, frequency, and when the last
time these medications were used.
In most of the Latin American countries, ergotamine-containing medications can be purchased without a prescription. Finally, a high
index of suspicion is required to make the diagnosis of this rare condition.
Acknowledgment
To Mr. Robert Cravero from the
photography de-
partment at Cleveland Clinic Florida for preparing
the pictures and photographs for this manuscript.
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