Subacute Myelo-optic Neuropathy

A now largely historical neurological syndrome caused by clioquinol, an antidiarrhoeal and antiamoebic agent widely used through the mid twentieth century. A major epidemic occurred in Japan before the causative association was established and the drug was withdrawn from widespread use.

It is characterised by subacute onset of combined sensory peripheral neuropathy, myelopathy (spinal cord involvement, predominantly affecting the lateral and posterior columns) and optic neuropathy.

It retains clinical and educational relevance as an important historical example of a drug induced neurotoxic syndrome. Sporadic cases are still reported, though rarely, where clioquinol or related halogenated hydroxyquinoline compounds remain available or are used in unregulated settings.

Pathophysiology

• Clioquinol and related halogenated hydroxyquinoline compounds are believed to produce neurotoxicity through chelation of essential metal ions, important for mitochondrial and enzymatic function in neural tissue. Direct toxic effects on neural tissue are also believed to contribute.
• This produces the combined involvement of peripheral nerve, spinal cord and optic nerve that gives the syndrome its name.
• The precise molecular mechanism remains incompletely characterised, despite the well established clinical and epidemiological association with the drug.
• The historical epidemic occurred predominantly in Japan through the 1960s. It reflected widespread, often prolonged, use of clioquinol for gastrointestinal symptoms.
• Epidemiological investigation established a clear causal relationship between cumulative drug exposure and the neurological syndrome. This led to withdrawal from widespread clinical use in most jurisdictions.

• The typical combined presentation, from which the syndrome takes its name, has subacute onset, typically over weeks, of sensory disturbance affecting the lower limbs.
• The sensory disturbance reflects the peripheral neuropathy and posterior column myelopathy components.
• Progressive lower limb weakness and spasticity follow, reflecting the corticospinal tract (lateral column) myelopathy component.
• In a substantial proportion of affected individuals, visual impairment reflects associated optic neuropathy.
• Abdominal pain occurs in a proportion of cases and sometimes precedes the neurological manifestations.
• Together with the history of clioquinol or related drug exposure, it supported the historical epidemiological identification of the syndrome and its cause.
• The combination and relative severity of peripheral neuropathy, myelopathy and optic neuropathy vary between patients. Some show predominance of one component.
• The combined, multifocal involvement of these three distinct neural structures is the characteristic and defining feature.

• Diagnosis relies predominantly on recognising the characteristic combined pattern (peripheral neuropathy, myelopathy and optic neuropathy) in a patient with a history of exposure to clioquinol or a related halogenated hydroxyquinoline compound.
• No sensitive diagnostic biomarker or investigation finding is unique to this condition.
• Nerve conduction studies confirm the peripheral neuropathy component.
• Magnetic resonance imaging of the spinal cord may show corresponding posterior and lateral column signal change reflecting the myelopathy.
• Formal ophthalmological assessment, including visual evoked potentials, characterises the optic neuropathy.
• Together these allow objective characterisation of the full, combined pattern of neural involvement.
• The condition is now rare, so exclude alternative causes of combined peripheral neuropathy, myelopathy and optic neuropathy before considering it. These include vitamin B12 deficiency related subacute combined degeneration with optic involvement, certain hereditary and mitochondrial conditions, and other toxic or nutritional causes.
• The history of specific drug exposure is the essential distinguishing diagnostic feature.

• Immediate discontinuation of clioquinol or the related causative compound is the essential first step, given the established causal relationship between ongoing exposure and progressive neurological damage.
• There is no specific antidote or disease modifying treatment beyond discontinuation. Management thereafter is predominantly supportive and rehabilitative, addressing the functional consequences of the combined peripheral neuropathy, myelopathy and optic neuropathy.
• Rehabilitation is the central component of ongoing management. Physiotherapy addresses the combined sensory and motor deficits and associated spasticity.
• Occupational therapy support is provided. Where relevant, low vision support and rehabilitation address the optic neuropathy.
• Prognosis is variable. Some neurological recovery occurs in a proportion of individuals after discontinuation of the drug.
• Residual, sometimes significant, permanent neurological deficit is common. This reflects the often substantial cumulative neurotoxic exposure that typically occurred before diagnosis and discontinuation, particularly in the historical epidemic.
• The condition is now rare and largely historical. Its primary value is as an example of drug induced neurotoxicity. It is also a reminder of the importance of pharmacovigilance and ongoing monitoring for unexpected adverse effects after widespread introduction of any new pharmaceutical agent.
• It remains practically relevant in the rare contemporary patient with a compatible combined neurological syndrome and a history of exposure to clioquinol or related compounds. Such exposure may still occur in unregulated settings in certain regions.