Hexacarbon neuropathy …

Michael T Pulley MD PhD

Peripheral Neuropathies

Updated 04.01.2024
Released 12.15.1994
Expires For CME 04.01.2027

Hexacarbon neuropathy

Author: Michael T Pulley MD PhD

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Editor: Louis H Weimer MD

Hexacarbon neuropathy

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Introduction

Overview

The author reviews the clinical features of an interesting toxic neuropathy. This neuropathy was fairly common in the past, related to recreational glue sniffing, but is primarily occupational currently. The axonal swellings seen in hexacarbon neuropathy are similar to those seen in carbon disulfide and acrylamide neuropathy.

Key points

	• Hexacarbons are present in many solvents and glues, and exposure is most commonly occupational.
	• The neuropathy associated with hexacarbon exposure results in giant axonal swellings and distal slowing of conduction velocity.
	• Hexacarbon neuropathy may continue to worsen for some time after cessation of exposure (coasting).

Historical note and terminology

Hexacarbons are used as solvents and are components of lacquers and glues. Exposure to the hexacarbons occurs in petroleum production and refining industries. Glues and lacquers are widely used in the shoe and cabinet-making industries (12; 08). Initial reports of occupational exposure to hexacarbons centered on the sandal- and shoe-making industries of Japan (15; 38). Subsequent similar outbreaks of hexacarbon neuropathy were reported in Italy and in cabinet-finishing plants in the United States (12). Substitution of methyl n-butyl ketone for methyl ethyl ketone and methyl isobutyl ketone in the manufacturing of plastic-coated and color-coated fabrics prompted an epidemic of peripheral neuropathy in 1974 and 1975 (22). Other reports have pointed out the risk of n-hexane neuropathy among automotive technicians using degreasing and cleaner solvents (06), screen printers in India (29; 30; 28), and in the pharmaceutical industry in China (26). Intentional inhalation (glue sniffing) is also a cause of high-level exposure (11; 07). Hexacarbon-related neuropathy is less common at present because of the removal of hexacarbons from many industrial and commercial products. However, recreational abuse, usually by means of glue sniffing, remains a substantial epidemiologic problem. Occupational exposures are still the most common cause in less developed countries (23; 32).

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).

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: automotive technicians

cabinet makers

leather goods manufacturers

paint thinner manufacturers

petroleum workers

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Hexacarbon neuropathy

Differential Diagnosis

Guillain-Barre syndrome

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Hexacarbon neuropathy …

Hexacarbon 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

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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Hexacarbon 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

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.