Presentation
A 72-year-old patient was admitted for the first time to our internal medicine and geriatrics hospital on a Friday afternoon. His history was quite heavy: type II bipolarity, anxiety, depression, hypothyroidism, hypertension, gastroesophageal reflux, collagenous colitis…
On admission, she presented with a picture associating myoclonus with confusion and hallucinations. The interrogation was not contributory. On the other hand, her husband stated that three weeks earlier, she had complained of generalized dizziness, a drop in concentration and an ideo-motor slowing down. About 7 days later, he noted onset of tremor, episodes of confusion and hallucination.
Initial hospitalization and para-clinical assessments
The patient had been hospitalized in the neurology department for gait instability for about a week before her admission to our establishment. The clinical picture became more complicated with the appearance of myoclonus, an increase in delusional episodes and drowsiness. Brain imaging was ordered to exclude acute pathology. The EEG was in favor of moderate encephalopathy, without spikes or signs of epilepsy. The initial hypothesis of Creutzfeldt-Jakob disease was therefore ruled out.
No thyroid abnormality was noted. Analysis of cerebrospinal fluid after lumbar puncture showed a slight elevation of proteinorechia and the presence of ten lymphocyte elements. Herpes simplex virus (HSV) and Lyme virus serologies were negative. Serotonergic treatments (escitalopram, duloxetine and tramadol) were suspended, but his condition did not improve. The patient was transferred to our facility for post-acute care with a diagnosis of toxic encephalopathy.
Review history and look for clues
Upon arrival in post-acute care, the patient’s husband was interviewed again. This is how it was discovered that the patient had undergone a thyroidectomy a few years ago and that there was a family history of breast cancer.
The treatment had not been changed for years and included:
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Amlodipine 10mg once daily
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An antacid containing bismuth in drinkable sachets 3 times a day [ndlt : ce médicament est interdit en France depuis 1974. Mais on trouve du bismuth dans certaines associations médicamenteuses destinées au traitement de l’infection à Helicobacter pylori (Pylera ®, p.ex.)]
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Budesonide 2 puffs a day
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ZymaD 2 drops in the morning
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Calcium citrate 1000 mg twice daily
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Duloxetine 60mg twice daily
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Escitalopram 20mg once daily
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Esomeprazole 40mg once daily
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Lamotrigine 25 mg in the morning and 100 mg at bedtime
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Mesalazine 1 g 1 tab twice a day
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Metoprolol LP 50 mg once daily
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magnesium carbonate 100 mg twice daily
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Quetiapine 50 to 100 mg at bedtime
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Simethicone one tablet 3 to 4 times a day
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Tramadol 50 mg every 8 hours
On physical examination, the patient presents as a hyperactive woman with an incisive gaze in whom no sign of poor tolerance of her condition is detected. She presents with a combined deviation of her gaze, her teeth are greyish, her mucous membranes moist, no deviation of the tongue ― which she keeps in a protrusive position ― and a supple nape and neck without sensitivity or adenopathy. Pulmonary auscultation is clear while cardiac auscultation reveals a soft systolic murmur particularly present at the left edge of the sternum. The abdomen is soft and bowel sounds normal. She has slight tenderness along the right costal margin. Her stools are black on digital rectal examination and her sphincter tone is increased. His skin is characterized by the presence of prominent hair follicles, but they are not associated with any rash.
Neurologically, she presents with myoclonus associated with hyperreflexia of the upper and lower limbs. She is disoriented in time and space and does not recognize people who come to her. Not very concentrated during verbal exchanges, she seems to only understand part of the conversations and has difficulty concentrating her attention. His answers to questions are monosyllabic or monoverbal. The volume of her voice is normal, she speaks without dysarthria. His eye movements show no particularity: they are conjugated and without nystagmus. On motor examination, muscle strength and volume are preserved, but the muscles are more toned and stiffer than expected. She exhibits an intention tremor and overactive reflexes throughout her body. Babinski’s sign is bilaterally positive.
The patient’s husband says he is very worried: “We have been married for almost 40 years… I’ve never seen her act like that. Please let me find the one I love.”
I had the distinct impression of having omitted essential information. I mulled over this situation all weekend. I felt like Dr. Watson in a Sherlock Holmes story. Did I overlook something obvious?
Complete the interrogation and look into the smallest details
On Monday, the patient’s clinical condition was unchanged. I asked her husband if her medication had changed recently or if she had taken any over-the-counter medication. He replied that she had tried a herbal treatment containing black cohosh (usually suggested to combat menopausal disorders). I again hypothesized a serotonin syndrome yet all drugs with serotonergic activity had been suspended for more than a week and the patient’s condition had not improved.
So I went deeper into the matter, asking her husband:
“When was the last time your wife was as usual?”
“She was fine 3 months ago,” he replied.
“And did something happen just before his condition changed?”
“Nothing at all, doctor. She presented with a flare-up of colitis which resolved just before she became ill.”
The pieces of the puzzle suddenly fall into place
That’s when I understood. The patient’s black stools, grayish teeth and raised hair follicles were clues bismuth toxicity. Her husband confirmed that she had taken bismuth subsalicylate 45ml three times a day for her colitis. She had even increased the doses because the intestinal symptoms had worsened. Urine and serum samples were sent to the lab, and the results confirmed my suspicions. Bismuth levels in his serum (397 ng/ml) and urine (293 ng/ml) were particularly high. Normal serum bismuth levels should indeed be below 15 ng/mL; the toxicity threshold being reached when the levels reach 50 ng/mL. Mild symptoms have been documented in patients with serum levels between 30 ng/mL.
Excess bismuth leads to disorders in stages
Bismuth subsalicylate in the United States and potassium bismuth subcitrate in France are used in oral preparations as a treatment for many mild gastrointestinal disorders. The vast majority of ingested bismuth is not absorbed by the body and passes without chemical modification in the stool. The small percentage absorbed by the gastrointestinal tract is distributed in all tissues of the body; slightly increased concentrations can be detected in the liver and kidneys. The absorbed bismuth is in fact not metabolized and is eliminated by the renal or hepatic route.
When excessive amounts of bismuth are ingested or increasing doses are prescribed, an initial prodromal phase occurs which results in alterations in mood and sleep ― most specifically insomnia, lethargy, listlessness, malaise, anxiety, or irritability. . This phase can last for weeks or even months as bismuth levels continue to rise. At one point, there is a rapid escalation of symptoms, even to encephalopathy. Neurological symptoms may worsen markedly within 24 to 48 hours: disturbances of stability, ataxia, confusion, impaired short-term memory, dysarthria, hallucinations, paresthesias, convulsions or myoclonus. Sometimes, the patient even has drowsiness or even a coma. The toxicity may be such that hepatic and/or renal failure occurs.
This case is a typical example of bismuth toxicity.
The difference between Creutzfeldt-Jakob disease and bismuth toxicity leading to serotonin syndrome can be made. It is particularly advisable to look for a blackening of the tongue, dark or bluish lines on the gums, grayish teeth, black stools but not containing blood; finally, the follicular orifices may be the seat of blackish lesions. These can be removed by washing, but they reappear within 1 to 2 days.
After discontinuation of bismuth subsalicylate, the patient made a full recovery and was able to return home. Some patients take up to 12 months to recover from bismuth poisoning, others have mild residual short-term memory problems.
After reflexion
This case demonstrated that a detailed history and physical examination can provide subtle diagnostic clues that are sometimes hidden in plain sight.
[ndlt. En France, environ 1% de patients présentaient un taux excessif de bismuth dans le sang lors du traitement de l’infection par Helicobacter pylori avec Pylera ® (tétracycline + métronidazole + sous-citrate de bismuth potassique, Allergan) dans une étude post-autorisation de mise sur le marché présentée lors des Journées francophones d’hépato-gastroentérologie et d’oncologie digestive (JFHOD) en 2017. ]
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