This case highlights the fact that bismuth encephalopathy, while rare, should be considered in patients with subacute progressive encephalopathy, even after a chronic exposure. Recognition of bismuth encephalopathy was not straightforward mainly due to the rarity of this entity and the fact that encephalopathies of other aetiologies may present with a similar neurologic picture and CSF findings. Ali F. et al. [7] suggest a list of differential diagnoses: Creutzfeldt-Jakob disease and other neurodegenerative etiologies, other toxic/metabolic encephalopathy, neoplasms, infectious causes, vascular disorders, and systemic autoimmune disease with nervous system involvement. Although classically associated with a subacute clinical presentation, bismuth neurotoxicity can also manifest acutely. Brigandì A. et al. [8] reported a recent case of sudden onset neurological signs mimicking a stroke caused by bismuth subcitrate toxicity.

In addition to the diagnostic difficulties associated with a rare cause of encephalopathy, the patient and her family members initially omitted medication with bismuth, because they considered bismuth subsalicylate an innocuous drug, leading us to consider other causes such as infectious and autoimmune encephalitis. Only when we considered the hypothesis of bismuth encephalopathy, based on the absence of clinical response to antiviral and immune therapy and the presence of exuberant myoclonus, in a patient with a prior medical history of irritable bowel syndrome, did they report the use of this drug.

Bismuth subsalicylate (Pepto-Bismol®), marketed in the United States but not in Portugal, is an over-the-counter medication readily available via the internet, commonly used in the treatment of various gastrointestinal conditions, including dyspepsia, acute diarrhoea and in the prevention of traveller’s diarrhoea [9, 10]. In the age of online supplement use, with easy access to these substances, it is not clear that the general public or health care providers are fully aware that bismuth compounds can be toxic [5].

Since its initial development in 1918, Pepto-Bismol has become a widely known drug. Between 1973 and 1980, about 1000 cases of bismuth-related neurotoxicity were reported in France (among 942 patients, there were 72 deaths) [11], 40 in Australia and 26 in Belgium, Switzerland, and Spain [12]. These patients had ingested large doses of bismuth subnitrate or subgallate for long periods. (from 4 weeks to 30 years). However, only few of these cases has been published. Since the epidemic in France and Australia, a few other cases of bismuth-related neurotoxicity have been published, despite the continued use of bismuth salts worldwide [12, 13]. It is clearly established that many different types of bismuth preparation have caused the syndrome [13]. Neurotoxicity from use of topical bismuth dressing for burns also has been reported [14]. Previous authors observed similar symptoms in nine case reports of bismuth subsalicylate induced encephalopathy, summarized in Table 1.

Table 1 Summary of encephalopathy cases associated with bismuth subsalicylate Full size table

Our patient was going through a moment of intense stress and we know that psychological stress may have a critical effect on the gut-brain axis. Irritable Bowel Syndrome is considered a stress sensitive disorder. The effects of stress are mainly on intestinal motility, permeability, visceral sensitivity, immune responses and gut microbiota composition [22]. After oral administration, bismuth subsalicylate is nearly completely hydrolyzed in the gastrointestinal tract into bismuth and salicylic acid. Less than 1% of the bismuth in this compound is absorbed [12]. Cases of bismuth subsalicylate neurotoxicity reported have been marked by chronic overexposure, high-dose, or both. [6]. Why the disease appears so suddenly in patients with a chronic consumption is a question that cannot be fully answered satisfactorily [13]. Abnormal gut permeability (leading to increased absorption) and renal impairment (with decreased elimination) may predispose to bismuth toxicity [6]. Another theory is that this is not a toxic phenomenon directly proportional to bismuth consumption. Some authors believe in a modification of the intestinal microorganism that can convert the bismuth salt into an absorbable form, perhaps by methylation, and bismuth administered as an insoluble substance would become soluble and pass through the bloodbrain barrier [13, 23]. In our case, we hypothesized that a period of stress in a patient with Irritable Bowel Syndrome might have increased bismuth absorption and/or have changed the gut microbiota composition contributing to the neurotoxicity.

Subacute encephalopathy usually begins with a prodromal phase, which progresses over a few weeks or months, characterized by nonspecific cognitive and neuropsychiatric symptoms such as changes of mood and sleep, followed by a rapid deterioration over days with altered mental status, myoclonic jerks and ataxia [17, 19]. In our patient, insomnia lasted for years and we believe that it could be, at least in part, attributed to bismuth intake, mainly because it improved substantially after bismuth interruption.

Chronic use of bismuth-containing products can result in encephalopathy, whereas acute toxicity can manifest as nephrotoxicity [24]. Blackening of the tongue and teeth has been reported as a harmless side effect of bismuth toxicity [25]. Our patient had dark teeth, with no change in tongue coloration and no evidence of gingival bismuth line (Fig. 1). This discoloration of teeth, not so evident as previously described, probably should also be considered as an adverse effect of bismuth.

The levels of bismuth in urine, blood and CSF samples confirm the intoxication by this agent [5, 13]. Brain CT scan and MRI were both normal. Most of the other reported cases also didn’t show imaging changes [7, 16, 18,19,20]. However, Siram R. et al. [21] described a case of 25-year-old women who developed bismuth encephalopathy after taking high doses of bismuth subsalicylate for 15–20 days. Brain MRI showed signal changes in the dorsomedial thalamus and a repeated MRI, three months later, showed cerebral and cerebellar atrophy. Imaging changes result of the accumulation of bismuth in gray matter with edema in the surrounding white matter [21]. Buge A. et al. [26] also described a radiographic pattern of CT scan showing heterogeneous diffuse areas of cortical hyperdensity.

Treatment of bismuth encephalopathy consists of interruption of the offender along with supportive care. By removing bismuth-containing products, bismuth encephalopathy generally improves progressively over weeks to months [19]. Our patient returned three months after discharge without neurological symptoms. The role of chelators such as D,L-2,3-dimercaptopropane-1-sulfonic acid and 2,3-dimercapto-succinic acid is not well established [27, 28].

In conclusion, our case highlights that toxic encephalopathy should be considered when dealing with subacute encephalopathy. Bismuth encephalopathy may be difficult to recognize due to its rarity, infrequent documentation in the literature and because this drug is not considered medically relevant and therefore omitted by patients and relatives. Even when exposure to neurotoxins is not reported, the hypothesis of toxic encephalopathy should remain present and potential neurotoxic agent intake should be sought after. Chronic use of bismuth can cause neurotoxicity with devastating consequences and; however, its discontinuation is associated with a full recovery in weeks to months.