Case Files of the Medical Toxicology Fellowship at the Oregon Poison Center: Thallotoxicosis

Case Presentation

An otherwise healthy, 19-year-old female university student presented to the emergency department in the early hours of January 5 after awakening with severe burning bilateral lower extremity arthralgias and abdominal wall myalgias, all unrelieved by ibuprofen. Urinalysis, complete blood count, and serum chemistry panels were unrevealing, and she was discharged home after initial pain control.

In the ensuing days, her lower extremity symptoms evolved to include symmetric distal extremity weakness with associated pain so severe she had trouble sleeping. Scalp-related hair loss began 10 days after initial symptom onset. Despite multiple additional acute healthcare visits and a diagnostic workup which included magnetic resonance imaging of her lumbar spine, the etiology of her symptoms remained unclear. With perceived emergent etiologies excluded, she was referred to a neurologist.

At the time of neurologist evaluation, she was noted to have profound alopecia, a symmetric sensorimotor neuropathy, and gait ataxia. An MRI of her thoracic spine was unremarkable. Electromyography indicated a marked, symmetric axonopathy with the lower extremity motor components most severely affected.

What Are the Toxicologic Etiologies of Peripheral Neuropathies? How Does the Development of Alopecia Help Determine the Likely Cause of the Patient’s Symptoms?

This patient presents with an uncommon symptom complex: a rapidly progressive peripheral neuropathy with delayed-onset alopecia. Although these findings are specific in combination, it is instructive to first develop a toxicologic differential diagnosis prior to focusing on her clinical presentation.

Peripheral Neuropathy

Peripheral neuropathies can be categorized in a variety of ways. From a pathophysiologic standpoint, neuronal dysfunction may result from demyelination (myelinopathy), nerve body damage (neuronopathy), impairment of the axonal projections (axonopathy), or dysfunction of impulse transmission [1]. Although clinical differentiation of neuropathies may be characterized based on the presence or absence of pain as well as relative sensory or motor involvement, there is significant heterogeneity and numerous exceptions to the classic categorizations. A thorough medical, environmental, and occupational history is crucial and may reveal one of the following exposures.

A handful of chemotherapeutics are implicated in neuronal dysfunction. Platinum-based xenobiotics directly damage both the neuronal cell body and axons [2], whereas the microtubule inhibitors vincristine and paclitaxel predispose to axonopathies [3]. Colchicine and podophyllin similarly impair cytoskeleton integrity and axonal transport. A sensorimotor neuropathy may develop, usually in the recovery phase after multisystem toxicity. Colchicine preferentially affects sensory nerves, whereas muscle weakness is myopathic in nature [4] [5]. Exposure can occur from overdose of the pharmaceutical xenobiotics as well as from consumption of their respective botanicals: Colchicine, Colchicum autumnale and Gloriosa superba, and Podophyllin, Podophyllum peltatum.

Cardiac patients prescribed amiodarone for dysrhythmias may develop either sensory or motor predominant neuropathic symptoms. These are characteristically myelinopathic in nature, although exceptions are noted [2]. Individuals taking tacrolimus for immunosuppression have developed demyelinating axonopathies [6]. Isoniazid, metronidazole, nitrofurantoin, and disulfiram (which is metabolized to carbon disulfide), among others, are all implicated in sensorimotor axonopathies [7].

Multiple vitamin deficiencies can lead to peripheral neuropathic symptoms. Deficiency of thiamine (vitamin B₁) is associated with malnutrition, characteristically among patients with alcohol use disorder, and manifests as a sensorimotor demyelinating neuropathy; interestingly neuropathic symptoms may occur in the setting of alcoholism even in the absence of overt vitamin deficiency [8]. Pyridoxine (vitamin B₆) is unique among the water-soluble B vitamins, since acute supratherapeutic exposure is associated with a pure sensory neuronopathy [1] [2]. Nitrous oxide [9] abuse predisposes to a functional vitamin B₁₂ deficiency which may precipitate central and peripheral demyelination. Descriptions of sensorimotor neuropathies were initially reported by healthcare workers who abused the gas anesthetic. Current presentations develop in those who huff nitrous oxide in the form of “whippets” [10].

Multiple heavy metals are implicated agents. Lead is encountered in both environmental and occupational settings. Neuropathy is usually portrayed as purely motor, although sensory symptoms may predominate particularly in the setting of chronic toxicity [11] [12]. Inorganic arsenic poisoning is most frequently noted in contaminated water supplies. It presents with a sensory neuropathy with subsequent motor involvement [13]. Significant non-organic mercurial exposure may be associated with an axonopathic sensorimotor neuropathy [14]. Thallium toxicity, historically from rodenticides exposure, is typified by excruciatingly painful sensorimotor dysfunction. Both demyelination and axonal degeneration are implicated in the pathophysiology underlying these heavy metal-related neuropathies [12] [13] [15].

Numerous occupational specific exposures may predispose to neurologic dysfunction. The hexacarbon solvents, n-hexane and methyl-n-butyl ketone, previously associated with rubber manufacturing but now more commonly found in household glues, are metabolized to the neurotoxic metabolite 2,5-hexanedione [16]. Acrylamide is the monomer required for the manufacture of polyacrylonitrile plastic [17]. Ethylene oxide is a common commercial gas sterilant [18]. Carbon disulfide is generated during viscose rayon production [7]. Methyl bromide is a fumigation hazard [7]. Polychlorinated biphenyl compounds are utilized for plasticizers and insulation and are also pervasive environmental contaminants, although data linking them to neuropathies in this setting is lacking [7]. These xenobiotics are all associated with sensorimotor neuropathies with primarily axonal degeneration. Trichloroethylene, which was historically used as a degreaser, is the main exception as it elicits primarily bulbar myelinopathic changes, although peripheral axonopathies have been described [7] [19].

Organophosphates are a broad class of xenobiotics implicated in two separate neuropathic syndromes that rarely occur in the same exposure cohort. Patients surviving the initial phase of acute cholinergic toxicity may develop the intermediate syndrome which is exemplified by a pure motor neuropathy secondary to post-synaptic downregulation of neuromuscular junction acetylcholine receptors [20]. The organophosphate-induced delayed peripheral neuropathy (OPIDN) is a pathophysiologically distinct process typified by exposure to tri-ortho-cresyl phosphate, the contaminant implicated in the “Jamaica Ginger Paralysis” epidemic during the US ethanol prohibition era [21]. It is classically associated with a sensorimotor axonopathy due to inhibition of neural target esterase [1].

Finally, many different biologic agents may predispose to neuronal dysfunction. Marine-related poisoning from consumption of ciguatoxin in reef fish, saxitoxin or brevetoxin in shellfish, and tetrodotoxin prototypically in pufferfish may all induce transmission neuropathies due to modulation of sodium channel function [22]. Elapid, [23] black widow, [24] or scorpion envenomation may also precipitate transmission neuropathies, although the pathophysiologic mechanisms are complex. Acute motor dysfunction may be triggered by tick envenomation [25] or exposure to botulinum toxin due to inhibition presynaptic acetylcholine release.

Alopecia

Alopecia is an uncommon yet highly specific sign. Thallium [26] and acute radiation syndrome [27] are the most iconic toxicologic etiologies. It is generally expected during chemotherapy—with doxorubicin, paclitaxel, and cyclophosphamide most frequently involved—and it is not uncommonly encountered in the setting of immune suppression with methotrexate [28]. Patients in the recovery phase after acute colchicine toxicity frequently note hair loss too [4].

Alopecia has also been documented in the setting of exposure to several less commonly encountered botanicals. Selenium poisoning may develop from the regular consumption of the nuts of the “Coco De Mano” tree (Lecythis ollaria) native to South America. [29]. Similarly, nuts of the “Miracle Tree” (Leucaena leucocephal), native to Madagascar, contain mimosine that is frequently associated with “Bald Lemur Syndrome” [30]. Wild species of the Cucurbitaceae family (squash and cucumbers), or fruit that was unknowingly cross-pollinated with wild cultivars, contain cucurbitacins which have been reported to lead to hair loss weeks after recovery of the acute gastrointestinal illness [31].

Other agents rarely implicated in hair loss include vitamin A excess [32] and boric acid [33].

Given the concurrence of symptoms, the most likely candidates for poisoning include thallium, colchicine, or paclitaxel. As the patient was otherwise healthy, paclitaxel toxicity is unlikely. Her symptom course is atypical for colchicine poisoning, where significant multisystem involvement including hematologic, cardiac, and gastrointestinal abnormalities is expected with a multiphasic illness.

Case Continuation

The neurologist was appropriately concerned for thallium poisoning based upon the constellation of a rapidly progressive, painful peripheral sensorimotor axonopathy, and concomitant alopecia. Twenty-one days after symptom onset, the blood thallium concentration returned at greater than 100 μg/L (ref < 2 μg/L).

She was evaluated by medical toxicology 4 days thereafter. A detailed temporal and social history leading up to the current evaluation was obtained:

Three weeks prior to symptom onset (one week before Christmas), she had completed her winter school term and returned to her hometown in the Portland Metro Area. She received a new metal ring as a gift from her family and wore it during the ensuing weeks. Starting on December 26, she drove down the Pacific Coast to San Diego along with her mother, grandfather, and grandmother. They visited the USS Midway and the San Diego Zoo and Safari Park. They began their return home on New Year’s Day, stopping in San Simeon and San Francisco. They spent their nights at motels. The patient denied any peculiarities regarding these endeavors nor anything suspicious about her meals. They finished the excursion 3 days prior to the onset of symptoms.

The following day, the patient and her family took down the Christmas decorations at her grandparents’ house and returned them to storage in the barn. The grandparents had lived at this location for the past 40 years. They did not believe there were any old unused rodenticides on the property and specifically noted that they only employed live rodent traps.

The patient returned to her college dorm room the following day and denied that any gifts were awaiting her. The evening prior to symptom onset, she went to a Rifle Club meeting on campus in which the team loaded their ammunition for the season. She went to bed that evening in her normal state of health before awakening early the following morning with the lower extremity and abdominal pains.

At college, she was pursuing a major in Fisheries and Wildlife and had spent time the previous summer on the Oregon Coast engaging in field work with salmon-fisheries and habitat maintenance. She was not enrolled in any chemistry or other laboratory courses. She did not have a job outside of school. She denied knowing anyone that wanted to harm her, including any prior significant others or friends.

On campus, she was president of the Rifle Club and was considered an accomplished markswoman. She worked with her own ammunition, made up of brass casings and gun powder with lead shot. She described that her relationship with her rifle team members was amicable and without perceived envy or rivalry.

When the patient returned home, she stayed with her grandparents in the rural Willamette Valley. She had intermittent contact with her mother. She had not had contact with her father for years.

The patient denied any tobacco, ethanol, or recreational substance use. No other family members developed symptoms. Her social history was otherwise unrevealing.

Vital signs during her toxicologic consultation were as follows: heart rate 127 beats per minute, blood pressure 153/121 mmHg, respiratory rate 14 breaths per minute, oxygen saturation 99% on room air, and an oral temperature 36.4 °C.

Physical exam was notable for a pleasant, well-groomed, and calm patient with scalp-restricted alopecia (Fig. 1). She specifically denied losing any other body hair, and her eyebrows appeared normal. Pupils were mid-range and equally reactive. Cardiopulmonary exam was only notable for tachycardia. Her abdomen was soft and non-tender. Extremities and skin were unremarkable and atraumatic. Her sensorium were clear. Upper extremity strength was 5/5 bilaterally. Lower extremities strength was noted as follows: 4/5 at her hips and knees and 3/5 bilaterally in her ankles. Tremor was absent. She exhibited a positive Romberg sign and an ataxic gait (Supplementary Video ESM).

Fig. 1.

Alopecia at the time of toxicology evaluation

Geiger counter exam of the patient and her urine was equal to the background reading. Exposure to Thallium-201, a therapeutic radioisotope, was excluded via consultation with the nuclear medicine team and the use of a well counter. These devices detect radioactivity by amplifying light generated from the gamma particles emitted by a radioisotope via interactions with a scintillating crystal (usually sodium iodide) and comparing it to a known standard. Her 24-h urinary thallium was significantly elevated at 159 μg/L but not radioactive. The ring that she received as a gift was taken by public health authorities but unfortunately was never tested.

How Have People Historically Been Exposed to Thallium? What Are Likely Sources of this Patient’s Exposure?

Historically, thallium was prescribed for the treatment of tinea capitis, tuberculosis, and venereal diseases including gonorrhea and syphilis [15]. Toxicity from oral administration of thallium acetate was noted in excess of 5% of patients [34]. Throughout the early twentieth century, topical formulation of thallium salts as an ointment gained popularity as a depilatory [34] [35]. However, the risk of toxicity and death endured [34], and by the 1930s its medicinal indications waned with the emergence of targeted antimicrobial and antifungal pharmaceuticals.

Medical encounters for thallium poisoning nevertheless continued due to its growing acceptance as an effective rodenticide. Reports of toxicity ranged from application misadventure in the occupational [34] and community [36] settings to deliberate poisonings [37]. However, these rodenticides are now banned in many countries, including the USA as of 1975 (where this case occurred), and exposure is generally considered to be intentional in nature, either with malicious or suicidal purpose [37] [38] [39] [40] [41].

Since thallium salts are white crystalline solids that are odorless and tasteless, ingestions are likely to occur undetected. It is well absorbed through all routes, although inhalational and dermal exposure are rare and restricted to niche occupational settings such as specialist glass manufacture and semi-conductor applications [42]. The thallium-201 radioisotope is occasionally used for cardiac scintigraphy; however, the dose required for imaging is far below the toxic threshold.

Given these considerations, the current patient’s social history provides a few possibilities for thallium exposure. The barn at her grandparent’s house raises the question of whether old, forgotten, thallium containing rodenticides remained on the property. However, without report of direct encounter or handling of old traps, this appears unlikely. Malicious intent therefore appears the most likely mode of exposure, although it is unclear who had motive or desire to harm her. Dermal exposure from her ring also seems unlikely; not only would sufficient metallic thallium need to be obtained, but then the ring would have to be forged.

What Is the Usual Presentation of Thallotoxicosis?

Acute thallotoxicosis is typified by a syndrome of painful ascending peripheral neuropathy and alopecia. However, the latency between the onset of neuropathic symptoms and hair loss frequently delays diagnosis, while more common etiologies, such as Guillain-Barré Syndrome, are investigated. Presentation is highly dependent on the acuity of the exposure and is dose-dependent. Significant exposure may lead to symptoms within hours, although a period of 2 to 5 days is more typical [43] [44] [15] [45].

Unless poisoning is severe, gastrointestinal complaints related to thallium ingestion are generally mild [26] [44]. Abdominal pain is the most frequently reported symptom and can be associated with either enteritis or constipation [41] [43]. This contrasts with poisoning from most other metal salts (such as arsenic or mercury) where severe chemical gastroenteritis is prominent and debilitating.

Neuropathic complaints predominate early in the disease course [43]. The sensorimotor neuropathy is excruciatingly painful and progresses rapidly in a centripetal fashion with distal lower extremities initially affected [43] [15] [45]. Larger diameter myelinated nerves are preferentially affected [44]. Severe or chronic exposures may precipitate cranial and optic neuropathies [15].

Central nervous system findings are variable; headache, lethargy, and tremors are common [41] and can progress to neurocognitive impairment, encephalopathy, and seizures [26]. Insomnia is frequently reported [43] and may manifest as day-night sleep reversal. Ataxia may develop in the setting of peripheral neuropathy and cerebellar dysfunction.

Alopecia is a hallmark symptom. Hair loss is generally scalp-restricted, begins about 10 days after exposure, and peaks within a month. Facial and axillary hair are classically spared [46] [26] although exceptions are noted [15]. Other dermatologic findings include nail erosions, skin hyperpigmentation, and Mees’ lines [41] [47].

Cardiovascular findings include tachycardia and hypertension but are delayed by 1 to 2 weeks after the initial symptom onset. Persistent tachycardia is considered a poor prognostic sign; it is likely multifactorial from a combination of vagal neuropathy [48] and impaired cellular energy generation [49]. ECG abnormalities, if present, are non-specific and related to altered repolarization.

Death results from seizure, coma, or respiratory arrest.

What Are the Biochemical Mechanisms Underlying Thallium Toxicity?

Thallium exists in two valence states, monovalent thallous (Tl⁺) and trivalent thallic (Tl³⁺) ions. Monovalent thallium is the most stable form and the most likely to be encountered [50]. Much of the pathophysiology underlying thallotoxicosis stems from the similar valance and ionic radii of the potassium (K⁺) and thallous (Tl⁺) ions. Cellular enzymes are unable to distinguish between them, and in many circumstances, these proteins exhibit a preferential affinity for Tl⁺ that is an order of magnitude greater than that for K⁺ [51] [52].

At low concentrations, thallium activates the Na⁺/K⁺-ATPase precipitating intracellular Tl⁺ accumulation; at higher concentrations, pump activity is inhibited [51] [53].

Rising intracellular thallium subsequently spoils intracellular energy generating processes. Tl⁺ hinders anaerobic glycolysis through pyruvate kinase inhibition [52]. Mitochondrial accumulation impedes the tricarboxylic acid cycle and electron transport chain, limiting ATP generation through oxidative phosphorylation at multiple stages [54].

With an inactivated Na⁺/K⁺ pump and limited ATP available, neurons and myocytes, which are exquisitely dependent on specific electrochemical membrane potentials, are unable to function properly. This likely underlies the predominant symptoms in thallotoxicosis–peripheral neuropathy, autonomic dysfunction (characterized by persistent tachycardia and constipation), central nervous system impairment, myalgias, and weakness.

Large diameter, highly myelinated neurons undergo Wallerian degeneration secondary to toxin-induced axonopathy, although secondary demyelination is occasionally noted [44] [45] [15]. Cranial nerves are similarly affected, although generally later in the disease course. [44]. Like other metals, thallium’s affinity for thiols can induce a glutathione deficiency which has been associated with increased rates of lipid peroxidation. In rodent brains, these effects were most notable in the cerebellum [55].

Hair loss and nail dystrophy are likely multifactorial as well. Thallium destabilizes ribosomes, preventing protein synthesis through its activity as a potassium analogue [56]. Evidence suggests that keratin formation is impeded [57] (theoretically from impaired sulfhydryl crosslinking) since these toxic effects are ameliorated by administration of cysteine [58].

What Is the Optimal Test for Detecting Thallium?

Multiple commercial laboratories can test for thallium. Twenty-four-hour urine atomic spectrophotometry is the preferred method of diagnosis [59]. Blood testing is an option, particularly in the setting of acute ingestion; however, spot tests are at increased risk for false negative results.

How Is Thallotoxicosis Treated?

Like other metals, the disposition pharmacokinetics for thallium follows a triphasic pattern. After absorption and redistribution, it is filtered by the kidneys or actively secreted into the gastrointestinal tract. Elimination is nevertheless slow and occurs over many weeks as it is subject to significant reabsorption in both organ systems [60] [61].

Prussian blue is the treatment of choice and specifically approved by the US Food and Drug Administration. It functions as an intraluminal ion exchange resin by substituting potassium within its crystal lattice for thallium. This impairs enterohepatic recirculation and offers a significant survival advantage in animal studies [62]. It is administered in divided doses totaling 250 mg/kg/day and is very well tolerated with minimal side effects aside from the expected bluing of secretions. Constipation is occasionally noted, but it is unclear if this is due to the underlying thallium toxicity itself [63]. Treatment should continue until the 24-h urine thallium is undetectable, which may take months depending on the extent of exposure.

Charcoal effectively adsorbs thallium [60] [64] and enhances clearance by interrupting enterohepatic recirculation similar to Prussian blue. Survival in animal models is also improved [61]. Although few present shortly after exposure, and evidence limited, it is reasonable to administer 50 g of activated charcoal followed by gastric lavage and whole bowel irrigation to help minimize absorption in the acute phase. In the more common setting of delayed presentation or diagnosis, multidose administration of 0.5 mg/kg/day in divided doses is appropriate.

A systematic review by the Extracorporeal Treatments in Poisonings (EXTRIP) Workgroup, a multidisciplinary consortium of toxicologists and nephrologists, recommends hemodialysis in those with acute or severe poisoning, based on clinical symptoms, or blood thallium concentrations over 400 μg/L. Intermittent hemodialysis is preferred and should be initiated within 48 h of acute exposure [65].

Systemic treatment with dimercaprol or EDTA, which are valuable chelators for other heavy metal exposures, is ineffective in thallotoxicosis [61] [58]. D-penicillamine is potentially harmful when administered alone due to increased tissue redistribution [66]. However, when given in conjunction with Prussian blue, investigations have noted both increased elimination [66] and improved survival [67]. Sulfur donors such as N-acetylcysteine may increase urinary excretion of thallium but do not significantly improve mortality in animal studies [61] [62].

Although potassium administration increases thallium excretion via displacement of intracellular thallium, this results in acute mobilization of the thallous ions into the systemic circulation [53]. This poses a danger of increasing central and peripheral nervous system concentrations. Treatment may acutely precipitate human neurologic toxicity [68], and it has been shown to heighten the risk of death in animal studies [69]. Sodium–potassium ion exchange resins, such as sodium polystyrene sulfonate, which are helpful in acute lithium exposure, are not clinically useful in thallium poisoning as they preferentially bind potassium [70].

Symptomatic management is also indicated. Since fecal excretion is the predominant mode of elimination, and because thallium can induce constipation, a cathartic may be necessary. Extremity discomfort can be managed with gabapentanoids, tricyclic antidepressants (TCAs), or serotonin and norepinephrine reuptake inhibitors (SNRIs), since mechanistically the pain is neuropathic in origin. Gabapentinoids were chosen as initial therapy in this case to reduce the added risk of adverse effects associated with TCAs or SNRIs [71]. For her insomnia, melatonin was suggested as an initial therapy due to its safety profile, with the plan that if it was ineffective, a non-benzodiazepine sedative would be considered [72]. Once improvement of pain was achieved with gabapentin, melatonin alone was sufficient to treat her insomnia.

What Is the Process for Obtaining Prussian Blue as an Antidote?

Unfortunately, most hospitals do not stock Prussian blue, hindering expeditious antidotal therapy. An emergency supply is stockpiled by the Radiation Emergency Assistance Center/Training Site (REAC/TS) for radiation disasters. Phone consultation with REAC/TS facilitated acquisition of enough Prussian blue for this patient’s treatment while awaiting a full therapeutic supply from McGruff Pharmaceuticals, which, at time of writing, is the only US supplier. Obtaining a therapeutic supply can be expected to take a few days. Interim treatment should be initiated with multidose activated charcoal [64].

What Is the Expected Course for Those Who Survive Toxicity?

Improvement is expected but the total extent is unpredictable. Initial ataxia, neuropathies, and alopecia appear to be of little prognostic value [26] [73]. One longitudinal study of thirty-one patients reported complete symptom resolution in over of 80% of those exposed [74]. Worse severity of presenting symptoms generally portends unfavorably for long-term recovery, particularly in those with coma, convulsions, and movement disorders. Neurocognitive impairment may become more prominent with time. Neuropathic symptoms generally improve, but resolution is often incomplete.

What Is the Role of Law Enforcement in Suspected Thallium Poisoning?

The USA outlawed thallium as an insecticide and rodenticide in 1975. Thus, toxicity not associated with a clear exposure should be presumed to be non-accidental in nature. Medical providers have an ethical, and frequently legal, duty to notify law enforcement when there is concern that a patient’s exposure to a toxic substance results from malicious intent [75]. In the USA, disclosure of protected health information to law enforcement is protected under the Health Insurance Portability and Accountability Act, Sect. 45 CFR 164.512(j)(1)(i). In nations where thallium remains publicly accessible, and etiology remains unclear, involvement of public health authorities is prudent to facilitate an epidemiologic investigation.

Case Conclusion

Law enforcement was notified; however, no source of exposure was ever identified. Prussian blue was discontinued after 4 weeks when repeat thallium urinary concentrations were undetectable. At 6-month follow-up, the patient reported significant improvement in her neuropathy, and strength had subjectively returned to 70% of baseline. Physical exam was notable for continued foot drop, albeit improved, which was managed with physical therapy.

Funding

None.

Declarations

Consent for publication of this case was obtained and provided to the journal in accordance with JMT policy.

Conflict of Interest

None.