Clinical manifestations

Presentation and course

Single episodes of high-level acute exposure cause central nervous system depression and narcosis. However, with repeated massive exposure (ie, glue sniffing), a subacute, predominately motor neuropathy with cranial nerve dysfunction develops that may be confused with Guillain-Barré syndrome (16). This neuropathy may be associated with autonomic dysfunction including impotence, hyper- or anhidrosis, and vasomotor instability. Occupational or recreational exposure to lower doses over a longer time period results in a slowly developing central-peripheral axonopathy affecting the sensory and motor systems in a length-dependent fashion, as confirmed in a case report (26). In these cases, nerve fiber degeneration affects the distal portions of peripheral axons first, but, with continued exposure, leads to damage of distal corticospinal, dorsal column, and other central pathways. Vibratory, pinprick, and thermal sensations are impaired initially in the feet with dysfunction gradually progressing proximally with continued exposure. Although ankle reflexes are lost early in the course, the other reflexes may be surprisingly preserved relative to the degree of sensory loss. Distal leg and arm muscles may be weak and with neuropathy progression, weakness and atrophy may become the prominent complaint. In severe cases, the neuropathy is complicated by malaise, weight loss, abdominal pain, and leg cramps. Worsening of symptoms after removal from exposure (coasting) is frequently seen, including a report of 25 cases (37).

Prognosis and complications

Recovery depends on the severity of neuropathy. Patients with mild neuropathy usually make a complete and satisfactory recovery. A large case series found that all 102 cases that were identified recovered completely with minimal intervention except cessation of exposure (17). A large case series of automotive technicians found that there was no evidence for residual neuropathy but exposure levels were low (04). Residual distal atrophy, weakness, and sensory loss are not uncommon with severe neuropathies. This toxic neuropathy is well-known for the "coasting" phenomenon. Coasting is the continued worsening of the clinical manifestations even after removal from exposure. The effects of central damage (spasticity, long-tract weakness) may only become evident after resolution of the neuropathy.

Biological basis

Etiology and pathogenesis

Both n-hexane and methyl n-butyl ketone are clear, colorless, volatile liquids. They are metabolized to the toxic compound 2,5-hexanedione (25). 2,5-hexanedione is a gamma diketone in which the spacing of the ketone groups (3 carbons away, or gamma position) is critical for neurotoxicity (34). The toxic metabolite interacts with lysine in proteins in the nervous system to cause the damage (33). Methyl ethyl ketone is not neurotoxic by itself but is present in many solvent mixtures and may potentiate the neurotoxicity of n-hexane and methyl n-butyl ketone. Hexacarbons gain entry to the body through inhalation, dermal contact, and, rarely, ingestion. Ingestion of contaminated water is a rare cause of hexacarbon exposure.

A characteristic morphological abnormality is seen in the peripheral nerves of those with hexacarbon toxicity. This involves the formation of giant axonal swellings as a result of the accumulation of neurofilaments. Similar swellings are seen with exposure to acrylamide or carbon disulfide (09) and in the genetic giant axonal neuropathy (03). The accumulation of neurofilamentous material is most prominent at the paranodal region (35). The accumulation of neurofilaments is likely related to cross-linking and disruption of axonal transport, which leads to a distal-central dying back neuropathy (31). The role of neurofilaments in the neuropathy and axonal swellings has been proven in neurofilament-deficient quail. These animals do not develop neuropathy when exposed to 2,5-hexanedione and have no axonal swellings (13). The neurofilament abnormalities involve loss of neurofilament proteins, which may be due to these proteins being targeted for degradation by the ubiquitin proteosome system (36). Based on electrophysiologic evolution of the neuropathy, there is also some support for n-hexane–related neuropathy being a nodo-paranodopathy with demyelination, conduction block, and secondary axonal degeneration as with ganglioside antibodies and tetrodotoxin (02). The isoform of cytochrome P450 2E1 enzyme may be related to differential susceptibility of individuals exposed to similar levels of hexane (39).

Epidemiology

Two groups are affected by toxicity of these compounds: those exposed due to their occupation and those who intentionally inhale the vapors. The latter group tends to be adolescents or young adults who may be abusing other substances.

Prevention

Workers handling solvents containing n-hexane or methyl n-butyl ketone need to be informed regarding the toxic effects. In order to minimize dermal contact, gloves and other protective clothing should be worn (10). The work area should be well ventilated, especially in those areas where high concentrations are present. Ambient air levels can be monitored to gauge the risk of exposure (01). Measurement of 2,5-hexanedione in the urine can help detect exposure before significant toxicity occurs (05). The urinary levels of 2,5-hexanedione are tightly correlated with exposure levels (21; 20). Pyrrole adducts can also be detected as a marker of exposure (14) and it may be possible to determine a maximum level in hair for human exposure as has been determined in rats (19). Nerve conduction abnormalities can be seen in asymptomatic individuals in the sural and median sensory nerve action potential amplitudes that correlate with the urinary 2,5-hexanedione levels and may allow for early detection of hexane-induced neuropathy (24).

Differential diagnosis

The slowly developing neuropathy that occurs with prolonged occupational exposure is clinically similar to that produced by a number of other toxic and acquired conditions and, therefore, requires a low threshold of suspicion in the proper exposure setting. Because of the fairly rapid evolution and the presence of conduction slowing (16), the neuropathy associated with repeated high-level hexacarbon exposure needs to be differentiated from Guillain-Barré syndrome.

Diagnostic workup

Nerve conduction studies reveal marked slowing of distal motor conduction velocities, which is an unusual finding in other toxic neuropathies but characteristic of subacute hexacarbon neuropathy (16). A study of 25 cases of N-hexane related toxicity confirmed prolonged distal latency, although the findings appeared very mild (37). A case of occupational exposure in the pharmaceutical industry in China also showed evidence for distal predominant demyelination (26). Intentional inhalation has been associated with multifocal conduction block in addition to generalized slowing (18; 27). Slowed conduction velocities have also been reported in asymptomatic workers employed in factories with documented cases of solvent polyneuropathy. The nerve biopsy reveals the well-described giant axonal swellings. Spinal fluid protein is usually normal unless the nerve roots become involved, in which case cerebrospinal fluid protein may be elevated.

Management

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

Cessation of exposure is the primary form of treatment.