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Pyridostigmine-induced coronary artery spasm in early-onset myasthenia gravis: a case presentation and review of the literature
  1. Oranuch Chuapakdee1,
  2. Tanit Layangkool2 and
  3. Nonthikorn Theerasuwipakorn3
  1. 1Division of Neurology, Department of Medicine, Sunpasithiprasong Hospital, Ubon Ratchathani, Thailand
  2. 2Division of Cardiology, Department of Medicine, Sunpasithiprasong Hospital, Ubon Ratchathani, Thailand
  3. 3Division of Cardiovascular Medicine, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Cardiac Centre, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
  1. Correspondence to Dr Nonthikorn Theerasuwipakorn; n.theerasuwipakorn{at}


We present a case of pyridostigmine-induced coronary artery spasm in a woman with early-onset myasthenia gravis (MG) who suffered from acute chest discomfort a few days after pyridostigmine dose up-titration. Twelve-lead ECG demonstrated ST-segment elevation in inferior limb leads together with sinus arrest. Sublingual nitrate was immediately given, which rapidly relieved her symptoms concomitantly with the resolution of abnormal ECG findings. Coronary angiography showed normal coronary arteries reflecting the transient nature of the disease. A small dose of pyridostigmine was rechallenged under close monitoring in the coronary care unit and reproduced her chest discomfort. After the substitution of pyridostigmine with immunosuppressive agents and prescription of long-acting nitrate, she had no recurrence of chest discomfort, as well as well-controlled MG symptoms.

  • Arrhythmias
  • Ischaemic heart disease
  • Neurology (drugs and medicines)
  • Neuromuscular disease
  • Unwanted effects / adverse reactions

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Pyridostigmine, an acetylcholinesterase inhibitor used for controlling myasthenia gravis (MG) symptoms, is an uncommon trigger of coronary artery spasm (CAS).1–4 Although the prognosis of CAS is mostly benign, it can cause irreversible myocardial infarction and fatal arrhythmias such as ventricular fibrillation and sinus arrest.5 6 Hence, early recognition and diagnosis, promptly nitrate given, immediate exclusion of acute coronary syndrome (ACS), and identification with the withdrawal of triggers are essential strategies for preventing CAS recurrence and its serious complications. In addition to CAS, MG also influences the patient quality of life, particularly when pyridostigmine, as a symptoms controller, needs to be withdrawn. Alternative agents (eg, corticosteroid, azathioprine, mycophenolate mofetil, etc) should be prescribed at once to prevent an exacerbation of MG.

Case presentation

A woman in her 40s was referred to our hospital due to intermittent chest discomfort accompanied by palpitation and diaphoresis developed 3 days ago. Chest discomfort was characterised as a retrosternal tightness, which radiated to the left scapular region, occurred at rest and spontaneously resolved within 20 min. She was recently diagnosed with seropositive non-thymomatous generalised MG based on fluctuating symptoms of ptosis, diplopia, generalised proximal muscles weakness (Myasthenia Gravis Foundation of America (MGFA) clinical classification: IIA), positive decremental responses of muscle action potentials to repetitive nerve stimulation, an elevated serum antiacetylcholine receptor (AChR) antibody titre of 8 nmol/L (normal, <0.5) and the absence of thymus on CT of the chest. Due to the progression of MG symptoms despite initiation of pyridostigmine with a dose of 120 mg daily, the drug was up titrated to 180 mg daily, which was a few days before the onset of chest pain. She also had well-controlled hypertension treated with amlodipine 5 mg daily and asthma controlled with fluticasone/salmeterol inhaler. She had no history of smoking or illicit drug use. On admission, her vital signs revealed bradycardia with a regular pulse rate of 56 beats per minute and normal blood pressure of 130/60 mm Hg. Other examinations were unremarkable.


Twelve-lead ECG demonstrated sinus arrest and junctional escape rhythm with a rate of 60 beats per minute together with a 3 mm ST-segment elevation in limb leads II, III and aVF with a reciprocal ST-segment depression in limb leads I and aVL (figure 1A). According to the presentation and ECG findings, which were highly suspicious for ST-elevation ACS (STE-ACS), the patient was immediately treated with sublingual glycerine nitrate, intravenous heparin, dual antiplatelets including aspirin and ticagrelor and sent to the cardiac catheterisation laboratory without any delay. On the laboratory arrival, however, her chest pain was resolved, and ECG became sinus rhythm with the disappearance of ST-segment elevation (figure 1B). Coronary angiography (CAG) surprisingly showed normal coronary arteries (figure 2A and B). High-sensitivity cardiac troponin T collected at the emergency department was 72 ng/L (normal, <47). Transthoracic echocardiography (TTE) performed after CAG showed normal cardiac size, function and wall motion. Other blood tests were otherwise unremarkable.

Figure 1

Twelve-lead electrocardiography recorded during chest discomfort showed sinus arrest and junctional escape rhythm with a rate of 60 beats per minute together with a 3 mm ST-segment elevation in limb leads II, III and aVF with a reciprocal ST-segment depression in limb leads I and aVL (A) and recorded after the administration of sublingual nitrate showed complete resolution of ST-segment elevation and return of sinus rhythm (B).

Figure 2

Coronary angiography showed normal left anterior descending and left circumflex arteries in the right anterior oblique caudal view (A), normal right coronary artery in the left anterior oblique view (B).

Differential diagnosis

Given the history of acute retrosternal chest tightness along with a typical pattern of ST-segment elevation in inferior limb leads and sinus arrest, the first life-threatening condition that needed to be excluded was acute inferior wall STE-ACS from ruptured atheromatous plaque in the proximal right coronary artery (RCA). However, CAG revealed normal coronary arteries, which was suggestive of diseases under the condition named myocardial infarction with non-obstructive coronary arteries; for example, CAS, microvascular dysfunction (MVD), acute myocarditis and stress-induced cardiomyopathy. The most likely diagnosis was CAS according to the chest pain nature that intermittently occurred at rest and transient ST-segment deviation corresponding with the dynamic pain symptom. In spite of no evidence of vasospasm on CAG, this could be explained by the resolution of the symptom and ECG abnormalities before the procedure. Other differential diagnoses were less possible, although could not be totally excluded, due to many reasons; for instance, (1) angina from MVD is typically related to exertion and rarely caused sinus arrest and (2) TTE always demonstrates abnormal wall motion in stress-induced cardiomyopathy and usually in acute myocarditis.

After informing about the risks and benefits, the patient and family agreed and consented to undergo a pyridostigmine rechallenge. Pyridostigmine with a dose of 30 mg was rechallenged under close monitoring in the coronary care unit. The patient developed chest discomfort, and the ECG monitor showed that ST-segment deviation reproduced the previous episode 30 min after the first challenge dose. Again, sublingual glycerine nitrate was immediately given, then her symptom and abnormal ECG findings were rapidly resolved, which strengthened the diagnosis of CAS precipitated by pyridostigmine.


Long-acting glycerine mononitrate was prescribed for preventing a recurrent episode of CAS. Pyridostigmine was unavoidably withheld and substituted with immunosuppressive agents including prednisolone 15 mg/day which gradually escalated to 40 mg/day (0.75 mg/kg/day) and azathioprine 50 mg/day which gradually escalated to 100 mg/day (2 mg/kg/day). Prednisolone was planned to taper to the minimum effective dose after symptoms resolve, while azathioprine was planned to continue in minimum effective maintenance dose with monitoring of liver enzymes and complete blood count.

Outcome and follow-up

At a 1-month follow-up visit, the patient reported no recurrent angina episode along with satisfying MG symptoms control, MGFA clinical classification: I (mild weakness of ocular muscle), MGFA postintervention status: minimal manifestation-1 and MGFA MG therapy status: PR and IM (prednisolone and immunosuppression). The patient also agreed to undergo thymectomy, which was scheduled 1 month later.


CAS refers to a condition in the epicardial coronary artery that suddenly and severely constricts causing a significant reduction in coronary blood supply. Resting chest discomfort associated with transient ST-T segment deviation on ECG, which rapidly responds to nitrate, is the classical presentation.7 Vasospasm during CAG is crucial evidence for supporting the diagnosis, though, in the absence of vasospasm, this condition cannot be ruled out, especially when the symptom resolves as in our case. Acetylcholine, a muscarinic receptor agonist, is commonly used in a provocative test for CAS diagnosis. Although the exact mechanism of acetylcholine-induced CAS remains unclear and the response of the normal coronary artery is vasodilation, there is evidence that the damaged and hyper-reactive artery paradoxically constricts in response to acetylcholine.8 9 Pyridostigmine, a mandatory symptomatic treatment for MG, indirectly increases intrinsic acetylcholine level by inhibiting the acetylcholine hydrolysation pathway catalysed by acetylcholinesterase.

Unlike acetylcholine, pyridostigmine is rarely reported as a trigger of CAS, and only four published cases of pyridostigmine-induced CAS have been reported to date (table 1).1–4 One case is early-onset MG, age <50 years old, while others are late-onset MG. Gender preference in MG is bimodal; in other words, the prevalence of late-onset MG is higher in men and vice versa.10 From previous reports, moreover, men are more likely to have CAS.11 However, pyridostigmine-induced CAS astonishingly affects women in all reports including our case. Cigarette smoking, the major risk factor of CAS, is only described in two cases in accordance with its multifactorial nature. Atherosclerotic coronary artery disease coincided with CAS is related to increasing age as found in the general population. Compared with previous cases in which pyridostigmine-induced CAS affects the left anterior descending and left circumflex artery, our patient is the first case that involves proximal RCA causing sinus arrest. In regard to dose, CAS can be induced by a pyridostigmine dose of as small as 30 mg, which indicates that this may be a dose-independent condition.

Table 1

Literature review of pyridostigmine-induced coronary artery spasm

Given the lack of publication regarding the rechallenge of pyridostigmine in patients with suspected pyridostigmine-induced CAS, the neurocardiologist team decided to discuss rechallenge with the patient in light of the following reasons: (1) pyridostigmine is the first-line and effective management for controlling MG symptoms; (2) the patient had ever received pyridostigmine with a dose of 120 mg/day without developing CAS. Moreover, all of the previous publications reported that CAS occurs at a higher dose of pyridostigmine (180–240 mg/day)2 4; (3) pyridostigmine-induced CAS is very rare and is the provisional, not definite, diagnosis and (4) CAS can spontaneously occur without a precipitator. Hence, we cannot confidently conclude that pyridostigmine is the cause of CAS before the rechallenge. Once the patient decides to undergo rechallenge, we perform the re-administration of pyridostigmine within the close monitoring, coronary care unit for a prompt response to any adverse event.

Once the diagnosis is confirmed and the risk of myocardial infarction and fatal arrhythmia is compared with the benefit of MG symptoms control, pyridostigmine withdrawal is a preferred choice, particularly when alternative treatments are available.2 4 Apart from pyridostigmine, immunosuppressive agents (eg, corticosteroid, azathioprine, mycophenolate mofetil, etc) are indicated when MG symptoms cannot be controlled with pyridostigmine alone, or pyridostigmine is contraindicated. In addition, thymectomy should be considered in early-onset AChR antibodies positive generalised MG even without the presence of a thymoma.12 In our case, we decided to start an oral corticosteroid and steroid-sparing agent with azathioprine according to the AChR antibody result. Calcium-channel blockers, the first-line medication for preventing CAS, can aggravate MG symptoms; thus, we decide to avoid their use and prescribe long-acting nitrate instead.13

We report the first case of pyridostigmine-induced CAS in proximal RCA associated with sinus arrest. This case emphasises the important approaches for CAS, namely early nitrate given for relieving symptoms and preventing serious complications, immediate exclusion of ACS and identification with the withdrawal of CAS triggers. This case also discloses that pyridostigmine may trigger CAS in a dose-independent fashion; therefore, the rechallenge, even with a small dose of pyridostigmine, should be avoided.

Learning points

  • Coronary artery spasm (CAS) is an uncommon but serious adverse effect of pyridostigmine, an acetylcholinesterase inhibitor used for controlling myasthenia gravis symptoms.

  • Early recognition and diagnosis, promptly nitrate given, immediate exclusion of acute coronary syndrome, and identification with the withdrawal of triggers are essential strategies for preventing CAS recurrence and its serious complications.

  • Pyridostigmine may trigger CAS in a dose-independent fashion; therefore, the rechallenge, even with a small dose of pyridostigmine, should be avoided.

Ethics statements

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  • Contributors OC participated in the conception of the work, data acquisition and drafting of the manuscript. TL contributed to image acquisition and interpretation. NT participated in the conception of the work, figure preparation, editing and revising the manuscript. All authors read and approved the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.