Organophosphate-Induced Delayed Neuropathy

Organophosphate induced delayed neuropathy is a distal axonopathy that appears 1 to 3 weeks after acute exposure to certain organophosphorus compounds. It affects long, large diameter axons in peripheral nerves and spinal cord tracts and is independent of cholinesterase inhibition.

Causative agents. Tri-ortho-cresyl phosphate, mipafox, leptophos, trichlorfon, methamidophos and some chlorpyrifos and dichlorvos cases. Only some organophosphates carry this property.

Epidemiology. Rare. Historical outbreaks followed contaminated ginger extract and cooking oil. Current cases follow deliberate ingestion, heavy occupational exposure or spills.

Timing. Symptoms start about 7 to 21 days after an acute exposure, often after recovery from the cholinergic phase.

Course. Peripheral recovery takes months to years. Upper motor neurone signs and spasticity often persist.

Pathophysiology.

Inhibition and subsequent ageing of neuropathy target esterase in neurons, with about 70% or more inhibition required, triggers axonal degeneration.

The longest axons degenerate first. Peripheral nerves can regenerate, whereas corticospinal tract damage does not.

• Calf cramping and pain, then distal paraesthesia.
• Symmetric distal weakness with foot drop, wrist drop and an ataxic or high stepping gait.
• Loss of ankle reflexes at first, then spasticity, hyperreflexia and extensor plantar responses as peripheral nerves recover.
• Mild sensory loss, with relative sparing of cranial nerves and respiratory muscles.

Red flags.

• Rapidly ascending weakness, bulbar involvement or respiratory difficulty (intermediate syndrome or other cause).
• Sphincter disturbance.

• History of acute exposure with timing of onset, the agent and the severity of the cholinergic phase.
• Nerve conduction studies: reduced sensory and motor amplitudes with mild slowing; electromyography shows denervation.
• Lymphocyte neuropathy target esterase assay, where available, shows exposure but is not essential.
• Exclusion of other causes: glucose, B12, thyroid, renal and liver function, vasculitis screen, and cerebrospinal fluid analysis when Guillain-Barre syndrome is a concern.
• MRI of the spine when the upper motor neurone picture is unexplained.

Differential diagnosis. Guillain-Barre syndrome, intermediate syndrome (24 to 96 hours after poisoning, with proximal and respiratory weakness), other toxic neuropathy (n-hexane, acrylamide, arsenic, thallium, lead), hereditary spastic paraparesis, transverse myelitis, vitamin B12 deficiency.

• No treatment prevents or reverses the neuropathy. Atropine and oximes do not alter it.
• Remove from further exposure and avoid neuropathic organophosphates.
• Physiotherapy, orthoses for foot drop, occupational therapy and falls prevention.
• 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.
• Spasticity: baclofen orally 5 mg three times daily, increased every 3 days by 5 mg each dose to a usual 30 to 75 mg daily in 3 divided doses. Maximum 100 mg daily. Monitor sedation, weakness and mood; withdraw slowly over at least 1 to 2 weeks because abrupt stopping causes seizures and hallucinations. Reduce dose and extend the interval when eGFR is under 50, and use with great caution under 30. Use caution in epilepsy and peptic ulcer.

Monitoring. Neurological review and nerve conduction studies at 3, 6 and 12 months.

Referral and escalation. Neurology and rehabilitation; occupational physician for workplace and agent review; notification and compensation where required.