Arsenic neuropathy …

Michael T Pulley MD PhD

Peripheral Neuropathies

Updated 02.06.2024
Released 12.03.1999
Expires For CME 02.06.2027

Arsenic neuropathy

Author: Michael T Pulley MD PhD

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Editor: Louis H Weimer MD

Arsenic neuropathy

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Introduction

Overview

Arsenic toxicity has predominately been the result of suicidal or homicidal ingestion of massive quantities of arsenic. However, in India and Taiwan, the presence of arsenic in drinking water has made the problem endemic. There is also the risk of developing neurotoxicity, primarily peripheral neuropathy, from therapeutic use of arsenic for acute promyelocytic leukemia (23). In this article, the authors discuss the clinical manifestations, diagnosis, and management of acute and chronic arsenic poisoning. The focus of the article is on the effects of arsenic on the peripheral nervous system.

Key points

	• Although arsenic is more commonly known for intentional poisonings in homicides or suicides, the most common etiology of arsenic toxicity worldwide is ingestion of contaminated drinking water in endemic areas.
	• As with other heavy metal intoxications, the neuropathy related to arsenic is rarely seen without other systemic manifestations, including abdominal pain and skin changes.
	• Arsenic neuropathy causes painful paresthesias and, with higher level or continued exposure, length-dependent weakness.

Historical note and terminology

Arsenic is a metallic compound known for its use as a poison in both homicides (39) and suicide attempts, where the usual case is massive acute exposure. However, toxicity can also result from chronic low-grade exposure. Occupational exposure may occur in the smelting of lead and copper ore (07), mining, and in the manufacture of integrated circuits or microchips. Other potential sources include contaminated well water (20; 28), tainted illicit drugs (02), arsenic-contaminated fossil fuels, high arsenic-containing coal (22), or the burning of preserved wood (35). Trivalent arsenate has greater human toxicity than pentavalent arsenate.

Reports have demonstrated a large-scale problem in Bangladesh and India due to groundwater contamination, causing exposure to become endemic (36; 37; 28; 04; 05). In these areas, a high proportion of individuals (10% to 20%) examined have evidence of arsenical toxicity. Of those with toxicity, peripheral neuropathy is a common finding (37% to 87%) (36). This group of patients represents the largest cohort reported to date with arsenic toxicity. Similarly, a report from Taiwan indicates that individuals living in areas with groundwater contamination are at markedly increased risk for abnormalities of nerve function (41).

Suspicions of arsenic poisoning have been advanced for a number of historical figures, including several United States presidents. Arsenic levels from the exhumed remains of Zachary Taylor measured in 1991 were found to be insufficient to cause death. Arsenic was a treatment for various disorders in earlier eras in various tonics and in Chinese herbs. It has been implicated in cases of traditional medication-related toxicity in India (42). Arsenic is still in use against acute promyelocytic leukemia, for which neuropathy has been reported as a complication (38; 21).

Clinical manifestations

Presentation and course

The clinical manifestations of arsenic exposure depend on the level of exposure (25). Also, the severity of the neuropathy and prognosis for recovery may be influenced by underlying conditions, including thiamine deficiency (21). High-dose exposure results in rapid onset of severe gastrointestinal disturbance (eg, abdominal pain, vomiting, and diarrhea), as well as tachycardia, hypotension, and vasomotor collapse with possible death (10; 02). In addition, CNS dysfunction may occur, which can be transient (eg, organic psychosis, somnolence, or stupor) (31) or prolonged (eg, behavioral and cognitive problems). If the subject survives acute high-level exposure, the neuropathy begins to manifest within weeks and may continue to worsen for a period of weeks after removal from exposure (coasting). Sensory symptoms, including painful paresthesias and numbness, predominate. Burning, aching, and tingling are positive sensory phenomena that occur first in the toes and feet but later in the fingers. Similarly, weakness follows a length-dependent pattern, starting with the feet and later involving the hands. With high-dose exposure or inadequate treatment, the weakness may progress to involve the respiratory muscles and mimic Guillain-Barré syndrome. The deep tendon reflexes are depressed or absent early in the process. In addition to nervous system manifestations, high-dose toxicity often causes bone marrow suppression and skin changes.

Chronic exposure to lower levels of arsenic results in dermatologic manifestations before overt clinical neuropathy. The patient may complain about symptoms of anorexia, malaise, generalized weakness, and vomiting. This is followed by hyperpigmentation of the skin, white transverse lines in the nails (Mee lines), hyperkeratosis, and irritation of the mucous membranes. Although asymptomatic at this point, neuropathy may be detected by careful examination and electrophysiologic testing. Clinical neuropathy characterized by burning and numbness of the feet and later the hands results from continued exposure. This involves both small and large fiber sensory disturbance with resultant difficulties with proprioception and dysesthesias. Weakness tends to be mild and limited to the most distal muscles. Recovery is related to the severity of the neuropathy at the onset of treatment. Mild cases recover completely, whereas more severe cases may have significant residua.

The large group of arsenic toxicity patients identified in India by Mukherjee and colleagues and Rahman and colleagues was divided into those that had chronic exposure and those that had subacute evolution of toxicity (36; 28). Those with subacute exposure had a much higher incidence of neuropathy (33 of 38 vs. 154 of 413). The neuropathy manifestations were similar in both groups, with painful paresthesias and other sensory complaints occurring more commonly than motor symptoms or signs. The prognosis of patients in this large cohort conforms to previous experience as described above. In one reported series of a large group of workers in a copper smelting facility in China, 45 of 104 workers developed symptoms suggestive of peripheral neuropathy approximately 3 weeks after a subacute (3- to 5-day) exposure to arsenic, and 25 of those 45 workers had abnormal sensory and motor nerve conduction velocity (46).

Prognosis and complications

Although treatment with chelating agents is usually helpful, patients with advanced cases of peripheral neuropathy may not recover (14; 34). The CNS effects of arsenic poisoning may also be persistent after treatment (08). Although cases of neuropathy associated with arsenic treatment of acute promyelocytic leukemia are usually mild and recover completely, a case in which a patient had undiagnosed thiamine deficiency had poor recovery (21).

Biological basis

Etiology and pathogenesis

Arsenic enters the body through inhalation (particulate arsenic and arsine gas), gastrointestinal absorption, and dermal contact. This exposure may be occupational, accidental (eg, burning treated lumber), or intentional (homicide or suicide). Arsenic trioxide is now being used to treat disease recurrence in acute promyelocytic leukemia. Kim and colleagues analyzed 115 patients treated over 10 years and found a 10% incidence of neuropathy in patients treated with a combination of arsenic trioxide and all-trans retinoic acid with or without cytotoxic chemotherapy; they did not further analyze which agent was causative (17). An analysis found that the incidence of neurotoxicity, primarily peripheral neuropathy, was related to dose and that obese patients were at higher risk as dosing is not capped and obese patients receive higher doses (23). Arsenic-containing compounds have also caused neuropathy when used for homeopathic purposes (03; 18). A case report from the United Kingdom of worsening neuropathy suggested that over-the-counter supplements may be contaminated by arsenic (01). Topical traditional Chinese herbal treatments containing arsenic and other heavy metals have been found to cause neuropathy and other systemic complications (45).

The underlying pathophysiology of arsenic neuropathy may be related to the affinity of this compound for thiol groups (06). This affinity leads to binding with lipoic acid, which interferes with the conversion of pyruvate to acetyl CoA and, thus, energy metabolism. The accumulation of arsenic in hair and skin is also related to the thiol affinity in keratin molecules. The pharmacokinetics of arsenite binding to biologically relevant sulfur-containing compounds such as glutathione have been determined (40). Toxic effects of inorganic arsenite may be mediated by oxidative stress and attenuated by treatment with alpha-tocopherol in rats (09). Evidence also indicates that arsenic interferes with cell migration in vitro and inhibits phosphorylation of an adhesion kinase (47). Children may have a higher body arsenic burden than adults with similar exposure (36).

References

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Contributors

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

Author

Michael T Pulley MD PhD

Dr. Pulley of the University of Florida, Jacksonville received consulting fees from Argenx, Alexion, and UCB/Ra.
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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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Former Authors

Alan R Berger MD

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: lumberyard workers

power plant workers

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Arsenic neuropathy

Differential Diagnosis

Guillain-Barré syndrome

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Arsenic neuropathy …

Arsenic neuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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

Questions or Comment?

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Arsenic neuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

References

Contributors

Author

Editor

Former Authors

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

Clinical evaluation of peripheral neuropathies

Hypothyroidism

Monoclonal gammopathy of neurologic significance

Chronic inflammatory demyelinating polyradiculoneuropathy

Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

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