Clinical manifestations

Presentation and course

The peripheral neuropathy associated with thallium intoxication is a distal, symmetric axonopathy that affects small and large diameter fibers. The symptoms are sensory much more than motor with pain as a prominent feature. Degeneration affects the distal portion of the longest axons initially with sparing of the proximal segments. The most vulnerable are the large diameter sensory fibers. A delayed autonomic neuropathy due to involvement of small unmyelinated fibers may also appear after acute intoxication (19).

Three distinct syndromes of thallium neuropathy occur based on the temporal course and intensity of exposure (03). Acute, high dose poisoning is the most common scenario (28). This results in symptom onset within 1 to 2 days after a massive ingestion. Severe gastrointestinal distress with associated vomiting, abdominal pain, and diarrhea occurs within hours but may be delayed up to a day. Intense joint pain and severe burning distal paresthesias in the legs develop within 2 to 5 days. Small and large fiber sensory modalities are affected (12). The hands and trunk may occasionally be involved in the sensory disturbance. Weakness is evident on examination although it may not be a prominent complaint (16). A report of nine cases confirmed the sensory greater than motor predominance of acute thallium poisoning (24). In spite of the sensory dysfunction, tendon reflexes tend to be preserved early in the disease process, which may help to distinguish thallium neuropathy from Guillain-Barré syndrome (28). Severe cardiac and respiratory failure may occur with massive ingestion, leading to death (15). The mental status may decline to lethargy or coma and death may result (23). The classic sign of thallium intoxication is alopecia. This appears 15 to 39 days after ingestion and is not helpful in the acute setting (20). Alopecia is not always present and is not specific for thallium poisoning. Renal insufficiency and paralytic ileus may complicate acute thallium poisoning. A case report regarding a patient who was poisoned on two separate occasions highlighted a possible rapid evolution of the neurologic manifestations on second exposure in the absence of gastrointestinal symptoms and the possibility that this was related to delayed clearance of thallium from the nervous system (13).

With a somewhat smaller initial ingestion, the subacute variety of neuropathy is seen. In a family with three adults and six children affected by eating rice contaminated by thallium, symptom onset was delayed 1 to 2 weeks, and only two of nine had sensory neuropathy (27). Subacute thallium neuropathy evolves more slowly, beginning more than a week after exposure. The neuropathy is characterized by sensory greater than motor deficit. All modalities are affected (proprioception, light touch, and pin). Walking may be affected early on, primarily due to the painful paresthesias in the feet. Although some degree of distal weakness is usually detected, it is rarely severe. The deep tendon reflexes are slightly reduced or normal. Tachycardia or hypertension due to autonomic dysfunction may occur. Skin, hair, and nail changes may be associated. These include alopecia, hyperkeratosis, blackening of the hair roots (22), and Mees lines (white striae of the nails). Other neurologic features include cranial neuropathies, chorea, and ataxia (04). Cranial nerve involvement may include retinal damage or retrobulbar neuritis (21).

The chronic form of thallium neuropathy is rarely seen. This neuropathy results from prolonged low-level exposure to moderate levels of thallium. The neuropathy is the predominate finding here and is identical to that described above.

Prognosis and complications

In survivors of acute thallium intoxication, the recovery tends to be incomplete. Frequently, there is residual central nervous system dysfunction due to anoxic injury. The recovery of the peripheral nerves is slow and there is often permanent injury with persistent sensory loss (20; 02). One report indicated persistent psychiatric problems in five of nine victims of thallium poisoning (22). Subacute neuropathy tends to be milder and have a much better prognosis. With termination of exposure, the prognosis for recovery is excellent, and most patients recover within 6 months. Hair regrowth begins earlier at about 10 weeks after withdrawal.

Biological basis

Etiology and pathogenesis

Thallium enters the body through the gastrointestinal tract by inhalation or by dermal contact. It is distributed throughout the body similar to potassium, for which it substitutes in reactions (05; 06). Thallium also interacts with sulfhydryl groups (11). The entry of thallium into the CNS may be delayed as demonstrated in a patient that had serial blood and CSF measurements determined after his death from thallium poisoning (23).

The pathologic findings in acute thallium poisoning in terms of the effects on the nervous system have been described in a case of homicide (15). They reported that edema, necrosis of neurons, proliferation and necrosis of glial cells, focal neuronophagia, and satellitosis were seen in each part of the brain on microscopic examination. Amyloid corpuscles were deposited in the corpus callosum and hippocampus.

The mechanism of toxicity has not been clearly elicited and may not be due to its substitution for potassium. Thallium enters cells through potassium channels and can compete with potassium for sodium potassium adenosine triphosphatase. Thallium may interfere with energy metabolism in the Krebs cycle, oxidative phosphorylation, and glycolysis (11). In particular, the effects on intracellular organelles and mitochondria were apparent in autopsies performed on a married couple that were poisoned (15).

Epidemiology

Thallium toxicity is rare and more likely to be due to intentional (suicide or homicide) than occupational or accidental exposure. Case reports are very rare.

Prevention

Avoidance of excessive exposure is the primary means of prevention. This is accomplished by adherence to standards established for workplace exposure levels.

Differential diagnosis

Confusing conditions

The painful neuropathy caused by thallium is similar to that seen with arsenic. Both can also be associated with alopecia and other dermatological manifestations (18). Autonomic dysfunction is also seen with arsenic and, thus, autonomic dysfunction is not differentiating. With acute intoxication, the rapid onset of neuropathy can mimic Guillain-Barré syndrome. The presence of gastrointestinal symptoms in thallium intoxication distinguishes it from Guillain-Barré syndrome.

Diagnostic workup

Laboratory diagnosis includes testing for thallium in urine, blood, or body tissues. Sensitive methods capable of detecting microgram quantities are available. There are established blood levels that indicate toxicity, but this does not reflect the total body burden because it does not measure the thallium in tissue. The cerebrospinal fluid protein is normal in cases of thallium neuropathy.

Electrodiagnostic testing reveals low amplitude sensory responses with mild slowing of conduction velocities. There is evidence of axonal loss on EMG, and the electrodiagnostic abnormalities can be used to follow the peripheral nerve damage (07). If nerve conductions are performed very early in the course, abnormalities may not yet be maximal (12).

In cases without alopecia, giving a challenge of potassium chloride will cause the urinary excretion of thallium to rise and may allow a diagnosis even when the baseline level in blood and urine is normal. Sural nerve biopsy shows loss of large myelinated axons, whereas skin biopsy confirms damage to small sensory fibers (12).

In cases complicated by encephalopathy or mental status changes, MRI of the brain may reveal reversible changes in the corpus striatum (12).

Management

Supportive measures are discussed in Peripheral neuropathies: supportive measures and rehabilitation.

Treatment with Prussian blue or activated charcoal to bind thallium in the gut may help promote elimination (14; 22). Laxatives are helpful to correct constipation and paralytic ileus (18). Forced diuresis or administration of potassium chloride enhances urinary excretion. Thallium remains in the body for a prolonged period (half-life of 30 days) in the absence of measures to promote excretion. Use of British anti-Lewisite (BAL, dimercaprol) or penicillamine may actually be harmful because of redistribution of thallium to the CNS (11). Early diagnosis and treatment may keep thallium from entering tissues and causing more long-term damage (20). In several series of cases of acute thallium poisoning, hemodialysis and hemoperfusion were used and believed to be beneficial (28; 27). A publication on multiple patients with thallium poisoning indicated a dramatic reduction of thallium levels with the combined use of Prussian blue and hemoperfusion (25). Although thallium is felt to only be “slightly dialyzable,” a consensus group recommended that extracorporeal removal be attempted in severe cases of thallium poisoning (09).

Outcomes

With removal of thallium, the prognosis is generally good for recovery, particularly the sensory and cognitive effects. In cases with severe weakness, there may be persistent deficits (16).

Special considerations

Pregnancy

Thallium freely crosses the placenta, and toxicity in the pregnant mother has been linked to teratogenicity or fetal demise (11). Exposure early in pregnancy seems to correlate with prematurity and low birth weight (10). In addition, animal data suggest there is some risk of teratogenicity with thallium exposure.