Gold neurotoxicity

Steven Herskovitz MD

Peripheral Neuropathies

Updated 12.29.2023
Released 11.06.2001
Expires For CME 12.29.2026

Gold neurotoxicity

Author: Steven Herskovitz MD

See Contributor Disclosures

Editor: Louis H Weimer MD

Gold neurotoxicity

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Introduction

Overview

Historical note and terminology

Gold salt therapy (chrysotherapy) has been used in the treatment of rheumatoid arthritis for many years. Its use has declined in favor of methotrexate, chloroquine, and sulfasalazine (01). It shows efficacy as a second-line treatment in refractory pemphigus vulgaris (10). In its elemental form, it has been used for centuries as an antipruritic to relieve the itching palm (11). In the early part of the last century, Robert Koch used gold for the treatment of tuberculosis on the assumption that mycobacteria were the cause of rheumatoid arthritis. The most common gold preparations are aurothioglucose and sodium aurothiomalate; they contain 50% gold by weight, are water soluble, and are administered intramuscularly. Auranofin is the only available gold compound for oral use. Chrysotherapy is reported to decrease synovial inflammation and retard cartilage and bone destruction. Its mechanism of action may be based on effects on tumor necrosis factor-alpha (15). Neurotoxicity is uncommon, but includes encephalopathy, cranial neuropathy, myokymia, and peripheral neuropathy, including occasionally a Guillain-Barré-like clinical picture.

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).

References

01: Aletaha D, Smolen JS. Effectiveness profiles and dose dependent retention of traditional disease modifying antirheumatic drugs for rheumatoid arthritis. An observational study. J Rheumatol 2002;29(8):1631-8. PMID 12180721
02: Caldron PH, Wilbourn AJ. Gold neurotoxicity and myokymia (letter). J Rheumatol 1988;15:528-9. PMID 3379631
03: Cavany JA, Chaignot A. Accidents nerveux de la chrysotherapie. Presse Med 1934;42:478.
04: Delafuente JC, Osborn TG. Review of auranofin, an oral chrysotherapeutic agent. Clin Pharm 1984;3:121-7. PMID 6426843
05: Dick DJ, Raman D. The Guillain-Barré syndrome following gold therapy. Scand J Rheumatol 1982;11:119-20. PMID 7089501
06: Fam AG, Gordon DA, Sarzoki J, et al. Neurologic complications associated with gold therapy for rheumatoid arthritis. J Rheumatol 1984;11:700-6. PMID 6096543
07: Gambari P, Ostuni P, Lazzarin P, Tavolato B, Todesco S. Neurotoxicity following a very high dose of oral gold (auranofin) (letter). Arthritis Rheum 1984;27:1316-7. PMID 6093822
08: Gulliford MC, Archard NP, Vant Hoff W. Gold encephalopathy. Br Med J 1985;290:1744.
09: Heuer MA, Pietrusko RG, Morris RW. An analysis of worldwide safety experience with auranofin. J Rheumatol 1985;12:695-9. PMID 3932651
10: Iranzo P, Alsina MM, Martinez-de Pablo I, Segura S, Masacaro JM, Herrero C. Gold: an old drug still working in refractory pemphigus. J Eur Acad Dermatol Venereol 2007;21(7):902-7. PMID 17658998
11: Jackson Roberts L, Morrow JD. Analgesic-antipyretic and antiinflammatory agents. In: Hardman JG, Limbird LE, editors. Goodman LS and Gilman A. The pharmacologic basis of therapeutics. 10th ed. New York: McGraw Hill, 2001:716-8.
12: Katrak SM, Pollock M, O’Brien CP, et al. Clinical and morphological features of gold neuropathy. Brain 1980;103:671-93. PMID 6251941
13: Lampa J, Klareskog L, Ronnelid J. Effects of gold on cytokine production in vitro; increase of monocyte dependent interleukin 10 production and decrease of interferon-gamma levels. J Rheumatol 2002;29(1):21-8. PMID 11824965
14: Leiper EJ. A case of polyneuritis due to gold. Br Med J 1946;2:119-20. PMID 21284100
15: Mangalam AK, Aggarwal A, Naik S. Mechanism of action of disease modifying anti-rheumatic agent, sodium thiomalate (GSTM). Int Immunopharmacol 2001;1:1165-72. PMID 11407310
16: Meyer M, Haecki M, Ziegler W, et al. Autonomic dysfunction and myokymia in gold neuropathy. In: Canal N, Pozza G, editors. Peripheral neuropathies. Proceedings of the international symposium on peripheral neuropathies. Milan: Elsevier, 1978:475.
17: Mitsumoto H, Wilbourn AJ, Subramony SH. Generalized myokymia and gold therapy. Arch Neurol 1982;39:449-50. PMID 7103785
18: Myerson RM. Meningitis during gold therapy. JAMA 1950;143:1336-7.
19: Nicholson D, Scalettar R, Jacobs RP. Rheumatoid rigor: gold induced myokymia. A report and review of the literature. J Rheumatol 1986;13:195-6. PMID 3084775
20: Perry RP, Jacobsen ES. Gold induced encephalopathy: case report. J Rheumatol 1984;11:233-4. PMID 6327982
21: Querido A. Gold intoxication of nervous elements on the permeability of the blood-brain barrier. Acta Psychiatr Neurol Scand 1947;22:97.
22: Roquer J, Herriz J, Maymo J, Olive A, Carbonell J. Miller-Fisher syndrome (Guillain-Barré syndrome with ophthalmoplegia) during treatment with gold salts in a patient with rheumatoid arthritis (letter). Arthritis Rheum 1985;28:838-9. PMID 3925959
23: Schlumpf U, Meyer M, Ulrich J, Friede RL. Neurologic complications induced by gold treatment. Arthritis Rheum 1983;26:825-31. PMID 6409125
24: Vernay D, Dubost JJ, Thevenet JP, Sauvezie B, Rampon S. “Choree fibrillaire de Morvan” followed by Guillain-Barré syndrome in a patient receiving gold therapy (letter). Arthritis Rheum 1986;29:1413-4. PMID 3778549
25: Walsh JC. Gold neuropathy. Neurology 1970;20:455-8. PMID 4314824

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Steven Herskovitz MD

Dr. Herskovitz of Montefiore Medical Center, Albert Einstein College of Medicine, has no relevant financial relationships to disclose.
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Editor

Louis H Weimer MD

Dr. Weimer of Columbia University has no relevant financial relationships to disclose.
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Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Gold neurotoxicity

Associated Disorders

Cranial neuropathy
Encephalopathy
Myokymia
Peripheral neuropathy

Differential Diagnosis

toxic distal axonopathies
nontoxic distal axonopathies
rheumatoid vasculitic neuropathy
chronic deforming rheumatoid arthritis
subcutaneous nodules
- vasculitis
- myokymia
- Isaacs syndrome

Gold neurotoxicity

Gold neurotoxicity

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

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Peripheral nerve injuries

Gold neurotoxicity

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Chronic inflammatory demyelinating polyradiculoneuropathy

Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

Leukodystrophies

Neuroacanthocytosis

Peripheral nerve injuries

This is an article preview.
Start a Free Account
to access the full version.