Clinical manifestations

Presentation and course

The more common toxicities of gold therapy include mucocutaneous lesions, nephropathy, and blood dyscrasias (11). Auranofin is generally better tolerated but has a high incidence of gastrointestinal disturbances (04; 09). There is a relationship between gold doses and toxicity but no clear correlation with gold plasma concentration. Neurotoxicity is uncommonly reported and may appear with or without other systemic signs of gold toxicity.

Duration of treatment and total dose of gold vary widely in cases of gold neuropathy. The clinical course in most cases is that of a progressive, symmetric, distal polyneuropathy, with predominant sensory, motor, or sensorimotor features evolving over days to weeks (14; 25; 12; 23; 06; 07). Weakness may be severe, and all sensory modalities may be involved. Dysesthesias are common. Clinical and electrophysiologic evidence of myokymia may be prominent, described in the French literature as choree fibrillaire de Morvan (03; 17; 19; 24; 02). Autonomic involvement can occur (16). Cases with rapid progression, areflexia, and albuminocytologic dissociation have mimicked Guillain-Barré syndrome (05; 23). One case of Fisher syndrome is reported (22). Various cranial neuropathies may rarely occur, either in association with polyneuropathy or in isolation (06). One case of gold-induced aseptic meningitis is reported (18). A few reports of gold-induced encephalopathy are described with delirium, psychiatric features, or focal abnormalities including hemiparesis, aphasia, or seizures (06; 07; 20; 08). In one case, reversible, contrast-enhancing white matter lesions were demonstrated on CT (06).

Prognosis and complications

Recovery over weeks to months is almost invariable after withdrawal of gold treatment, but neurologic residua can occur in severe cases (06). It is unclear whether chelating therapy influences the course.

Biological basis

Etiology and pathogenesis

The mechanism of gold neurotoxicity (whether a hypersensitivity reaction or a direct toxic effect) is debated but not yet established. Experimental studies in hens showing dose-related neuropathy suggest a direct toxic effect (12).

Aurothioglucose and sodium aurothiomalate are rapidly absorbed after intramuscular injection (11). Peak serum concentration is reached in 2 to 6 hours; 95% is bound to albumin. The plasma half-life is about 7 hours for a 50 mg dose but lengthens substantially with successive doses. Tissue distribution is widespread but variable. It has been shown to cross the blood-brain barrier into cerebrospinal fluid. Residual gold can be found in the liver and skin many years after treatment cessation. Excretion is 60% to 90% renal, 10% to 40% fecal, and increased by sulfhydryl agents such as dimercaprol, penicillamine, and N-acetylcysteine. Auranofin is more lipid-soluble and absorbed orally, has plasma steady-state concentrations reached after 8 to 12 weeks, accumulates less in tissues, and has an elimination half-life of about 80 days.

Animal studies of gold neurotoxicity are limited. A dose-related neuropathy, similar to that observed in human studies, is demonstrated after prolonged exposure in hens, with both axonal degeneration and segmental demyelination (12). Mice can develop paralysis, ataxia, and disorientation after repeated injections of aurothiosulphate (21).

In humans, electrophysiologic studies are scanty and not detailed, with most reports describing signs of axonal degeneration, occasional slowing of motor conductions, and sometimes myokymia. Morphologic studies of sural nerve biopsies, including teased fibers, show both axonal degeneration and segmental demyelination (12) or almost exclusively axonal degeneration (25). The cerebrospinal fluid protein varies from normal to (more typically) mildly or moderately elevated, occasionally even up to several gm/dl. In vitro, gold salt has differential effects on cytokine production, with marked stimulatory effect on interleukin-10 and interleukin-6 (13).

Epidemiology

Neurotoxicity from chrysotherapy appears to be rare, estimated to occur in 0.2% to 0.5% of patients with rheumatoid arthritis who are treated with gold (06).

Prevention

No specific agent is known to prevent gold neurotoxicity.

Differential diagnosis

The symptoms, signs, and electrophysiologic features are not specifically distinguishable from other toxic or nontoxic distal axonopathies, and screening blood work is generally advisable. The major issue will be distinguishing rheumatoid vasculitic neuropathy, usually seen in patients with chronic deforming rheumatoid arthritis, often with subcutaneous nodules and clinical signs of vasculitis (06). In cases with generalized myokymia, other associations with Isaacs syndrome will need to be considered.

Diagnostic workup

The neuropathy should be established by clinical examination and characterized electrophysiologically. The temporal relationship to drug administration should generally be clear, and improvement with withdrawal of the drug should establish the diagnosis. Rarely, a sural nerve biopsy may be necessary when vasculitic neuropathy is a serious consideration.

Management

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

Patients should be clinically monitored regularly for the development of neuropathic signs or symptoms, and the drug dose adjusted or discontinued as necessary. Carbamazepine is reported to be useful in the management of myokymia in these cases (17).