Clinical manifestations

Presentation and course

Acute or subacute high-level exposure results in predominant CNS dysfunction including confusion, hallucinations, memory impairment, and emotional lability (06; 11). Additional chronic, low-level exposure causes a combination of peripheral neuropathy and CNS abnormalities. The neuropathy may be asymptomatic and detected only by electrophysiologic testing when exposure is low. As the concentration increases, a progressive sensorimotor distal polyneuropathy emerges. CNS manifestations of prolonged exposure include headache, dizziness, depression, memory impairment, and impaired sexual arousal (04). Exposed individuals may also have extrapyramidal signs of tremor, bradykinesia, and cogwheel rigidity, as well as hemiparesis or spasticity. Tremor, reduced speed of finger tapping, and neurocognitive effects were seen in workers exposed chronically to carbon disulfide in a study, and the effects were dose dependent (05).

Prognosis and complications

The degree of recovery depends greatly on the severity of the CNS and peripheral nerve dysfunction at the time of removal from exposure. In mild cases, once exposure is terminated, an almost complete recovery from neuropathy takes place, and most of the CNS abnormalities can be expected to resolve. Occasionally, CNS recovery is incomplete, probably due to residual damage of the distal portions of corticospinal and posterior column axons in the spinal cord. Those who suffer from severe neuropathy may not completely recover. In 1 cohort of subjects, more than one third of patients with severe carbon disulfide neuropathy continued to display symptoms and signs of neuropathy 10 years later (13).

Biological basis

Etiology and pathogenesis

Carbon disulfide is a clear liquid that becomes a vapor at room temperature and is readily absorbed by inhalation. Furthermore, carbon disulfide is a major metabolite in the breakdown of the drug disulfiram (Antabuse), which is used as a deterrent for alcohol abuse (10). Carbon disulfide is absorbed by inhalation and dermal contact. Although less common, carbon disulfide can be absorbed through the gastrointestinal tract if swallowed (04).

The toxicity of this compound is most likely related to its reactivity with amine, sulfhydryl, and hydroxyl groups in biological systems (07). This results in the formation of reactive sulfur atoms that bind with and suppress the activity of the cytochrome P-450 enzymes. The formation of di- and tri-thiocarbamates can lead to chelation of copper, which serves to inactivate metalloenzymes such as dopamine beta-hydroxylase that are vital to norepinephrine production. These compounds are also metabolized to isothiocyanates that can covalently bind to and cross-link cytoskeletal proteins such as neurofilaments. Potentially, this process may be related to the formation of giant axonal swellings apparent in experimental studies performed in rats. Carbon disulfide has been shown to alter the cytoskeletal profiles in the spinal cord of rats (15). Covalent cross-linking of erythrocyte spectrin (a surrogate protein to neurofilament) has been demonstrated in a mouse model of carbon disulfide toxicity (14).

Epidemiology

The toxic effects of carbon disulfide result almost exclusively from occupational exposure. This exposure has historically been in those employed in manufacturing. Rarely, an overdose of disulfiram may be the etiology for exposure.

Prevention

As with most occupational exposure problems, education and employee protection are both important. The toxin enters invariably through the respiratory system; thus, use of fume hoods and sufficient ventilation are vital safety measures. Moreover, the monitoring of air samples and use of respirators should be part of a good prevention program (04). Urinary levels of its metabolite, 2-thiothiazolidine-4-carboxylic acid, have proved to be a sensitive measure of carbon disulfide exposure, and improved methods have been developed to detect this compound (01). However, care must be used in analysis of these levels because alcohol consumption may cause false positive results (09).

Differential diagnosis

Carbon disulfide toxicity should be suspected when individuals in the proper clinical setting present with both a sensorimotor neuropathy and CNS dysfunction. Acute exposure may initially demonstrate only nonspecific CNS abnormalities. Historical attention to potential toxic exposures is a vital aspect of uncovering the underlying etiology. In some instances there may be multiple chemical exposures. Other etiologies of distal axonopathy should be considered and are far more common than carbon disulfide toxicity, including diabetes, B12 deficiency, and monoclonal gammopathy.

Diagnostic workup

Conduction slowing and prolongation of motor and sensory latencies are seen in nerve conduction studies (13; 02). The effects on nerve conduction are dose-dependent and most prominently demonstrated in the sural sensory nerve (05). Carbon disulfide also impairs the sympathetic skin response of exposed workers (05). Needle electromyography reveals acute and chronic denervation changes in distal leg muscles, reflecting axonal degeneration and chronic motor unit reinnervation. Sural nerve biopsy performed 2 years after exposure to carbon disulfide showed loss of large myelinated axons (03). The spinal fluid profile is unremarkable.

Management

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

Removal from exposure is the only intervention and early recognition prevents further decline.