n-Hexane Neuropathy

n-Hexane neuropathy is a length dependent axonal sensorimotor polyneuropathy caused by inhaling n-hexane, whose metabolite 2,5-hexanedione damages peripheral axons. It occurs in occupational exposure and in solvent abuse.

Exposure. Glue and adhesive use in shoe, leather and furniture work, printing and cleaning solvents, lacquer and ink thinners, and petroleum extraction. Methyl n-butyl ketone gives the same metabolite. Methyl ethyl ketone increases toxicity.

Epidemiology. Clusters occur in small workshops with poor ventilation. Onset is gradual over weeks to months.

Course. Symptoms often worsen for 2 to 4 months after exposure stops (coasting). Recovery takes months to 2 years and may be incomplete after severe disease.

Severity. Mild sensory symptoms, to foot drop and quadriparesis in severe cases.

Pathophysiology.

2,5-Hexanedione forms pyrrole adducts with lysine residues in neurofilaments, causing cross-linking and axonal swelling with distal axonal degeneration.

Secondary demyelination reduces conduction velocity and can resemble an inflammatory demyelinating neuropathy. Optic and autonomic involvement can occur.

• Numbness, tingling and burning of the feet then hands, in a stocking and glove pattern.
• Distal weakness of the toes, ankles and later the hands, with loss of ankle reflexes.
• Muscle cramps, reduced vibration and pain sensation, and distal muscle wasting.
• Autonomic features, optic neuropathy or maculopathy in some patients.

Red flags.

• Rapidly ascending weakness, respiratory difficulty or bulbar signs.
• Marked autonomic instability.
• Persistent progression after weeks away from exposure.

• Exposure history including solvents, ventilation, skin contact, hobbies and co-worker cases.
• Examination of sensation, power and reflexes.
• Nerve conduction studies: reduced amplitudes with mild to moderate slowing of conduction velocity; conduction block can occur in severe cases.
• Urinary 2,5-hexanedione at the end of the shift after acid hydrolysis shows exposure; a level of about 0.4 mg/L is the usual workplace reference.
• Exclude other causes: glucose or HbA1c, vitamin B12, folate, TSH, renal and liver function, alcohol review, protein electrophoresis and vasculitis screen.
• Nerve biopsy only when the diagnosis is unclear: giant axonal swellings with neurofilament accumulation.

Differential diagnosis. Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, diabetic and alcoholic neuropathy, vitamin B12 deficiency, other toxic neuropathy (acrylamide, arsenic, lead, thallium), hereditary neuropathy, vasculitic neuropathy.

• Remove from exposure and replace n-hexane with non-neurotoxic solvents; improve ventilation and skin protection.
• Supportive care: physiotherapy, foot orthoses, falls prevention and occupational therapy.
• Neuropathic pain: pregabalin orally, 75 mg twice daily, increased after 3 to 7 days to 300 mg daily and, if needed after a further 7 days, to a maximum of 600 mg daily. Review at 4 weeks and stop if there is no meaningful benefit; withdraw over at least 1 week. Monitor sedation, dizziness, peripheral oedema, weight gain, mood and misuse. Adjust for renal function: creatinine clearance 30 to 60 mL/min, 75 to 300 mg daily in 2 or 3 divided doses; 15 to 30 mL/min, 25 to 150 mg daily; under 15 mL/min, 25 to 75 mg daily. Avoid in pregnancy unless benefit outweighs risk.
• Corticosteroids, immunoglobulin and plasma exchange have no proven benefit.
• Ventilatory support and intensive care for the rare respiratory failure.

Monitoring. Clinical review and nerve conduction studies at 3, 6 and 12 months; surveillance of co-workers.

Referral and escalation. Neurology and neurophysiology; occupational physician for workplace investigation; urgent admission for ascending weakness; notification and compensation where required.

Special groups. Pregnancy: avoid exposure; pregabalin is not advised unless necessary.