Clinical manifestations

Presentation and course

Symptoms and signs of disulfiram neuropathy are typical of many other toxic axonal neuropathies. Onset is usually 2 to 6 months after first taking disulfiram, but the earliest onset reported is 10 days (44). Development of the neuropathy may progress quickly, especially at higher doses. Progress is typically more rapid in onset and shows more large-diameter sensory involvement than with most cases of alcoholic polyneuropathy, but they can be confused. Involvement is length-dependent, producing the characteristic stocking-glove pattern. Distal paresthesias and numbness are often initial manifestations predominantly affecting large fiber modalities. The stocking-glove distribution progressively spreads rostrally as long as the medication is continued. Motor signs subsequently ensue, beginning in distal foot muscles, but significant weakness, including foot drop or tetraparesis with gait impairment, can develop, which is an unusual ethanol toxicity manifestation unless thiamine deficiency is coincident. Reflexes are diminished or lost distally, depending on severity. Recovery occurs after cessation but may be incomplete in more severe cases, especially in cases with clinically evident weakness.

Other neurologic manifestations include acute changes associated with the disulfiram-alcohol reaction. In addition, signs of chronic encephalopathy (including irritability, vertigo, dysarthria, disorientation, ataxia, confusion, and extrapyramidal signs) and personality or psychotic change may occur. Generalized seizures have been reported along with changes in preexisting EEG disturbances. The encephalopathic changes may coexist with neuropathy. Optic neuritis with chronic optic atrophy rarely develops, but this complication most often occurs in a separate population of patients. However, irreversible anterior ischemic optic neuropathy and coincident reversible peripheral neuropathy are reported (24). Severe sensorimotor axonal neuropathy and additional facial weakness, dysphagia, and dysarthria were reported in a 39-year-old Portuguese man on a dose of 500 mg/day of disulfiram (34).

Prognosis and complications

Prognosis is dependent on the severity and range of involvement. Involvement is not typically disabling with conventional dosage, but it can be severe with foot drop and significant tetraparesis at high dosage and more prolonged exposure. A fulminant case after overdose with both disulfiram and ethanol has been reported (33). As expected, with axonal loss and regeneration, recovery is slow and gradual. A different suicide attempt using 130 tablets produced severe peripheral neuropathy and additional hoarseness from vocal cord muscle denervation; the thyroarytenoid muscle demonstrated signs of denervation on EMG testing (02).

Predominately motor neuropathy was reported in a 37-year-old woman. She developed severe distal hand and leg weakness about 3 months after disulfiram use. Of note, nerve ultrasound demonstrated reduced nerve cross-sectional area, unlike many other neuropathy causes that cause nerve enlargement, such as vasculitic or inflammatory neuropathy and others (07). The cause is presumed to be acute axonal degeneration. She subsequently significantly but incompletely improved.

Biological basis

Etiology and pathogenesis

A minority of patients chronically taking disulfiram develop an axonal neuropathy. Unlike other idiosyncratic reactions to disulfiram, such as hepatitis and dermatitis, the peripheral neuropathy appears to be a dose-related phenomenon, with higher doses causing both a shorter latency of onset and more severe abnormalities. All cases reported have been at or above a 250 mg per day dosage, and some consequently have recommended the use of the lowest effective dose.

The true incidence of the neuropathy is unknown even though numerous case reports have been published; new cases continue to emerge (27; 12; 10; 08; 03; 11; 26; 43). Eighteen cases of disulfiram neuropathy were among 154 adverse disulfiram reactions reported by Enghusen Poulsen and colleagues (10).

The neurotoxin carbon disulfide is a metabolite of disulfiram through the intermediary diethyldithiocarbamate. This pathway has long been thought to mediate the neurotoxic effects. Neurofilament accumulations in distended axons are seen ultrastructurally with disulfiram and with experimental carbon disulfide toxicity cases (01; 04). Carbon disulfide and metabolites are significantly increased in patients on disulfiram, further strengthening the probable pathogenic association (20). Disulfiram and diethyldithiocarbamate also inhibit both aldehyde dehydrogenase and dopamine beta-hydroxylase, either or both of which could also play a causative role. However, some studies did not find the morphological changes or intermolecular cross-linking characteristic of carbon disulfide toxicity in a rat model, thus, questioning carbon disulfide as the mediating factor in the neuropathy (41). A model exposing rats directly to the major metabolite diethyldithiocarbamate (DEDC) demonstrated demyelinated axons and myelin splitting not seen with several other metabolites. This metabolite can proceed down two pathways, one to carbon disulfide and another to carbamylating sulfoxides and sulfones. These findings argue that cysteine carbamylation is not the primary mediator of demyelination and that diethyldithiocarbamate, not carbon disulfide, may be the primary disulfiram neurotoxin leading to demyelination (42). There is also evidence that DEDC promotes protein oxidative damage in peripheral nerves and produces sufficient lipid peroxidation to trigger an adaptive response; elevated copper levels may play a role in the process (45).

Interference with dopamine beta-hydroxylase has also been suggested as a probable factor in encephalopathy. Because of the possible inhibition of dopamine beta-hydroxylase, Karamanakos and colleagues studied disulfiram effects on rat biogenic amines to test the relationships between the pharmacological and neurotoxicological drug properties at different dosages (22). Their data showed that disulfiram increased norepinephrine and increased dopamine in a dose-dependent manner but at dose levels higher than those inhibiting aldehyde dehydrogenase activity. Karamanakos and colleagues suggest that lower doses may still cause the disulfiram reaction but fall short of affecting biogenic amine metabolism and potentially minimizing neurotoxicity (21). The effect on dopamine beta-hydroxylase is thought to be more important in central nervous system toxicity.

Disulfiram is garnering renewed attention as a possible form of chemotherapy. The agent, possibly through an active metabolite, inhibits cancer growth and perturbs protein degradation/turnover pathways (16). Combined with metformin, mouse esophageal squamous cell carcinoma tumor size shrunk significantly in vivo (19). When combined with a copper stabilizer, it shows promise as a radiosensitizing agent against glioblastoma multiforme. Disulfiram showed possible efficacy against refractory glioblastoma multiforme in combination with temozolomide. Twelve patients underwent a dose-escalation phase 1 study; some developed neuropathy said to be reversible (17). A more recent phase 1 trial in early glioblastoma multiforme combining disulfiram and adjuvant temozolomide found 500 mg but not 1000 mg of disulfiram daily to be tolerable, with or without the copper adjunct. Three of 18 patients developed significant neuropathy (18).

Epidemiology

No predisposition to the toxic manifestations is known. However, susceptibility is likely higher in patients with an existing axonal neuropathy of unrelated cause, such as alcoholic polyneuropathy, and in patients on higher dosages, especially if greater than 250 mg per day. No male-to-female discrepancy has been noted. However, large series have similar numbers of both sexes, raising the question of overrepresentation of the toxic effects in women, similar to alcoholic myopathy.

Prevention

Toxicity is unusual but dose-related. Tablets are supplied in scored 250 and 500 mg strengths. Toxic manifestations have been reported at 250 mg per day but are more common at 500 mg per day or higher. Palliyath reported progressive electrophysiologic abnormalities in asymptomatic patients taking 250 mg per day but not 125 mg per day over a 6-month period (30). The highest recommended dosage for routine use (and the recommended beginning test dosage) is 500 mg daily. The lower doses (less than 200 mg per day) have been advocated to avoid neurotoxic effects. Neurotoxicity at 125 mg per day has not been established, but this lower strength may be an insufficiently effective deterrent. Chloral hydrate also appears to enhance the neurotoxicity, possibly by secondarily increasing carbon disulfide metabolite concentration.

Differential diagnosis

The clinical pattern of involvement is indistinguishable from other symmetric toxic etiologies. Recognition of the temporal association is crucial for diagnosis. Another common issue involves separating this entity from underlying alcoholic polyneuropathy. Often, however, disulfiram patients have recently abstained from drinking and may have more well-rounded diets. Onset is faster, and signs of vasomotor and other small fiber dysfunction are typically lacking. Potential confusion could arise with the more acute form of alcoholic neuropathy associated with thiamine deficiency, which is clinically different than the more typical and common chronic alcoholic neuropathy (23). However, patients in this category are generally not compliant with disulfiram use.

Diagnostic workup

Recognition of the link between exposure and the ensuing toxicity is the primary means of diagnosis. Supportive tests, including electrodiagnostic studies demonstrating axonal neuropathy, may be useful. Both sensory and motor abnormalities are common with signs of distal denervation. Spinal fluid is generally normal, but slight increases in total protein have been noted. Nerve biopsy may show neurofilament aggregates in fusiform axonal swellings in addition to general evidence of an acute or subacute axonopathy. Nerve ultrasound is described as helpful in assisting the diagnosis of disulfiram neuropathy (39; 07). Distal nerve enlargement, asymmetric findings, and normal proximal cross-sectional area are described.

Management

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

Recognition and cessation of the exposure are key to management. Supportive care dependent on the degree and range of involvement is indicated; improvement may occur after discontinuation. Continued cessation of alcohol during recovery is also important.

Special considerations

Pregnancy

The safe use of disulfiram during pregnancy has not been established.

Anesthesia

No adverse effects of disulfiram and anesthesia have been established in humans.