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).

Epidemiology

In areas where arsenic exposure is endemic, a high proportion of individuals may be affected by arsenic toxicity (36; 37). A survey of more than 7600 people in West Bengal, India found that 45% were exposed to unsafe levels of arsenic (12). However, one study suggested that only a small percentage (approximately 6%) of patients with chronic arsenic exposure from drinking water will have neuropathy, and other manifestations such as skin (100%) and liver were more frequent (11). Sporadic cases or small epidemics occur from intentional exposure (19); occupational exposure is more common.

Prevention

Occupational Safety and Health Administration standards call for the posting of signs in areas where exposure to inorganic arsenic may occur. Respirators should be provided to employees who are likely to be exposed to high levels of arsine gas or arsenic trioxide. Monitoring of urinary levels may reveal excessive exposure before development of symptoms (27). Education of at-risk populations and avoidance of drinking water contaminated with arsenic may reduce the risk of long-term toxicity (37). In a case of attempted suicide, the administration of 2,3-dimercaptopropane-1-sulphonate intravenously after massive ingestion of arsenic with very high serum and blood levels completely prevented the development of peripheral neuropathy (24). An article evaluating symptoms of neuropathy suggested that levels in drinking water less than 10 parts per billion were less likely to cause symptoms and should be the target for arsenic concentration to prevent neurologic complications (25).

Differential diagnosis

Confusing conditions

The rapid presentation of neuropathy may mimic Guillain-Barré syndrome (34; 15). However, the associated gastrointestinal symptoms should help to distinguish arsenic poisoning. In addition, arsenic neuropathy does not cause demyelination; therefore, the electrophysiologic findings aid in the differentiation. Spinal fluid protein is normal in arsenic intoxication in contrast to Guillain-Barré syndrome.

Diagnostic workup

Arsenic levels may be measured in the urine. Urine arsenic levels may remain elevated for weeks. Levels greater than 25 µg per 24-hour specimen are considered abnormal unless there is recent seafood ingestion, a source of pentavalent arsenic. It is important to discuss seafood ingestion with patients and, if total arsenic level is elevated, to differentiate organic arsenic (found in high levels in seafood and non-toxic) from inorganic arsenic (29). A case report attributing neuropathy to mildly elevated arsenic levels without fractionation to organic versus inorganic forms points out the pitfall of erroneously attributing neuropathy to arsenic (32). More long-term exposure, or exposure that has since ceased, may only be detected by measuring levels in the hair and nails. Blood arsenic levels are not helpful because blood is cleared within 2 to 4 hours, even in massive intoxications. Rapid analysis (within 6 hours) of urine samples is important, especially when measuring the more toxic arsenic species methylarsonate and dimethylarsenate, because rapid oxidation of these compounds occurs even in frozen specimens (43).

Nerve conduction studies reveal low amplitude sensory responses with mild slowing of motor conduction velocities, typical findings for an axonopathy, with slowing not out of proportion to axon loss (42). EMG reveals active denervation acutely with reduced motor unit recruitment (31; 30). Some correlation has been found between urinary arsenic levels and vibratory perception thresholds (13; 33). Current perception is abnormal in individuals who live in areas with known arsenic contamination of drinking water when compared to those from other areas (41).

Management

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

Acute arsenic toxicity is life-threatening, and treatment in an intensive care setting with aggressive fluid and electrolyte resuscitation is indicated. Removal of arsenic from the body is facilitated by chelation therapy (16). The agents used are penicillamine and dimercaprol (British anti-Lewisite). British anti-Lewisite is a dithiol compound that allows excretion of arsenic by formation of a nontoxic ring. Another agent that has been used successfully to increase urinary excretion of arsenic in a severe case of arsenic intoxication is 2,3 dimercapto-1-propanesulphonic acid (44). Dimercapto-1-propanesulphonic acid has been shown in placebo-controlled studies to improve the recovery of arsenic-intoxicated patients (12), whereas dimercaptosuccinic acid did not. The treatment should be started as soon as possible after exposure (14) and continued for several months. Unfortunately, the fully developed neuropathy is unlikely to respond to therapy.