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A 47-year-old Syrian woman arrives at an emergency department in Riyadh, Saudi Arabia, following attempted suicide using pyridostigmine (Mestinon), a medication she has been taking (60 mg orally, 3 times per day) to treat myasthenia gravis. On bringing her to the hospital, her husband and son explain that she has just received news that all of her family members have died in an accident related to the Syrian War.

They determine that an hour before their arrival at hospital, she had taken 120 (60 mg) tablets of pyridostigmine, for a total of 7,200 mg. They note that she vomited six times during the trip to the hospital. When she arrives at the resuscitation bay, she is conscious and distressed, and unable to speak. She is also confused as to where she is, ataxic, and sweating so profusely that her clothes are drenched in sweat as well as vomitus.

She is salivating heavily and has a frothy mouth discharge, excessive lacrimation, and bronchorrhea. All of her muscles are twitching, particularly those of her face. She is unable to talk. Her vision is blurred; her pupils are equally reactive bilaterally and are not constricted.

Her vital signs are as follows:

• Blood pressure: 121/76

• Heart rate: 50 beats per minute

• Respiratory rate: 16 breaths per minute

• Temperature: 36.7°C

• Oxygen saturation: 98% at room air

• Random blood sugar: 7.5 mmol/L

Physical examination reveals equal bilateral air entry with mild crackles and no wheezing. Findings of the cardiovascular examination are normal except for weak, thready, inconsistent pulses ranging from 25 to 140 bpm.

The patient's abdomen is neither distended nor sunken. Palpation identifies tenderness in the epigastric area, with guarding and no rigidity. She has urinary incontinence but no diarrhea or stool incontinence. Central nervous system examination shows general weakness, flaccidity, and fasciculations throughout her body, especially affecting her face.

The electrocardiograph performed on her arrival to hospital is normal.

Analysis of the patient's venous blood gas test shows metabolic alkalosis with the following results:

• pH of 7.43

• CO₂ of 30

• HCO₃ of 21

• Base excess is –4.0

Results of a chest x-ray are normal. Complete blood count findings include elevated white blood cells (14,400 cells/μL), hemoglobin (9.8 g/dL), and platelets (416,000 cells/μL).

Blood tests show that levels of serum urea and serum creatinine are normal. However, the patient has low serum potassium (3.1 meq/L), hyperglycemia (serum blood sugar of 7.5 mmol/L), and lactic acid of 3.2 mmol/L. (A test for blood cholinesterase was not available.)

Toxicology results are negative for co-ingestion of paracetamol, aspirin, ethanol, barbiturates, opiates, cocaine, benzodiazepines, amphetamines, and cannabis.

Test results are normal for liver function, amylase and lipase, and coagulation profile.

Treatment and Outcome

Because the patient has been vomiting and hypersalivating, the clinicians do not administer activated charcoal or undertake lavage. They treat the patient with 1 mg of intravenous atropine every 5 minutes; her symptoms appear to resolve after administration of a total of 3 mg. However, when she begins sweating and vomiting again, the clinicians add 0.5 mg atropine and 2 g pralidoxime delivered intravenously over 30 minutes.

In the emergency department the patient receives one liter of intravenous sodium chloride 0.9% bolus, one gram of intravenous paracetamol, and one gram of intravenous pantoprazole.

At this point, she is admitted for 2 days for observation. On the first day, she has intermittent symptoms, which are treated with 0.5 mg of intravenous atropine.

Her symptoms improve by the following day, and she is discharged free of symptoms after a psychiatric consultation.

Discussion

The authors of this of pyridostigmine poisoning following an attempted suicide with pyridostigmine by a patient with myasthenia gravis suggest it is the first such report in the literature. Given the lack of data on the toxicity of this medication, the case is a valuable addition to the literature.

Pyridostigmine is a quaternary amine parasympathomimetic inhibitor of acetylcholinesterase, which has been used to treat myasthenia gravis for many years. It is also used in other conditions such as postoperative ileus, Alzheimer's disease, glaucoma, and curariform drug toxicity.

Toxicity of pyridostigmine was initially documented during the Persian Gulf War when the troops took pyridostigmine in order to protect themselves from the effects of nerve gas agents. At that time, unwanted effects – primarily fatigue, muscle aches, gastrointestinal complaints, and memory problems – were reported as a multi-symptom condition named "Gulf War Illness."

Pyridostigmine is considered safe, with a maximum tolerated dose of 180 to 540 mg per day. A 1991 report of nine cases of self-poisoning with pyridostigmine during the Persian Gulf War involved doses ranging from 300 to 900 mg and the symptoms remained for 24 hours. All the patients underwent gastric lavage with activated charcoal and only three patients required atropine.

However, reports suggest that cholinergic and muscarinic side effects affect about 64% of myasthenia gravis patients on a daily dose of 150 to 900 mg/day. Elderly patients are particularly at risk of adverse effects including abdominal cramps, fasciculations, diaphoresis, urinary incontinence, blurred vision, bradycardia, cardiospasm, confusion, coma, and many more side effects.

And while in this reported case, the patient's heart function was not adversely affected by the high dose (7,200 mg) of pyridostigmine, the case report authors caution clinicians to be wary of the risk of sinus bradycardia due to stimulation of the muscarinic receptors in the sino-atrial node (particularly in children), and the risk of heart failure, syncope, or stress resulting from sino-atrial block and atrioventricular, particularly in the elderly.

Importantly, this patient had an excellent response to the classical antidote to pyridostigmine poisoning: She was symptom-free after receiving 3.5 mg of atropine and 2 g of pralidoxime. Immediate initiation of vomiting, prompt treatment with atropine and pralidoxime, and reversible inhibition of acetyl cholinesterase likely contributed to this positive outcome.

As well, the fact that she required pyridostigmine to treat her myasthenia gravis might have hampered the effects of the drug, the authors explained, adding, however, that no lethal effects or mortalities by pyridostigmine toxicity have yet been reported in the literature.

Atropine sulfate has been shown to counteract the severe cholinergic reactions to large dose ingestion and organophosphate, thus minimizing gastrointestinal side effects and helping to resolve arrhythmias. Nevertheless, vigilance is crucial since atropine sulfate can mask signs of overdosage and can lead to inadvertent induction of cholinergic crisis.

Given that the clinical symptomatology of myasthenic crisis and cholinergic crisis are very similar, distinguishing between the two remains a challenge. While rare, should always be considered when presented with an apparent myasthenic crisis, the case report authors emphasize, adding that a simple test to differentiate the two involves giving a dose of edrophonium, 2 mg intravenously. This will produce clinical improvement in the myasthenic crisis but worsen symptoms in cholinergic crisis.

The case authors conclude that while human toxicity with pyridostigmine is rare, prompt and specific management of pyridostigmine toxicity should lead to a safe outcome.

References

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