Manganism

Manganism is chronic neurotoxicity from excess manganese, causing a psychiatric prodrome followed by parkinsonism with dystonia. It differs from Parkinson disease in its course, signs and poor response to levodopa.

Exposure. Manganese mining and ore processing, steel and ferroalloy production, welding, dry battery manufacture and some fungicide work. Non-occupational causes include intravenous ephedrone (methcathinone) use, long term parenteral nutrition and chronic liver failure with portosystemic shunting.

Epidemiology. Cases arise after months to years of exposure to high levels of respirable manganese. Iron deficiency increases uptake.

Course. Deficits often progress or persist after exposure stops. Imaging changes may regress while clinical signs do not.

Staging. Early psychiatric and non-specific phase, followed by an established movement disorder.

Pathophysiology.

Inhaled manganese enters the brain via the olfactory tract and transporters shared with iron, and accumulates in the globus pallidus, striatum and substantia nigra pars reticulata.

Mitochondrial dysfunction, oxidative stress and glutamatergic and dopaminergic disturbance follow. Damage is mainly pallidal and postsynaptic, so dopamine terminals are often preserved.

• Early: irritability, emotional lability, compulsive behaviour, hallucinations, headache, fatigue and sleep disturbance (so called manganese psychosis).
• Later: bradykinesia, mask like face, monotone speech, micrographia, postural instability with retropulsion, tremor (often less than in Parkinson disease), and dystonia.
• Characteristic gait on the toes with the elbows flexed (cock walk), and facial grimacing.
• Poor or short lived response to levodopa.

Red flags.

• Rapid deterioration, falls or swallowing difficulty.
• Severe psychiatric disturbance or suicidal thoughts.
• Signs of liver failure or other cause of manganese accumulation.

• Exposure history: process, duration, ventilation, respiratory protection and co-worker cases; check non-occupational sources.
• Neurological examination with rating of parkinsonism and dystonia.
• MRI brain: bilateral symmetric T1 hyperintensity of the globus pallidus, striatum and midbrain, with normal T2 signal. T1 change reduces over about 6 months after exposure ends.
• Dopamine transporter imaging: usually normal presynaptic uptake, which helps separate it from Parkinson disease.
• Whole blood manganese reflects recent exposure only and correlates poorly with clinical disease. Normal levels are generally under about 15 micrograms/L.
• Liver function, ferritin and iron studies, copper and caeruloplasmin, and nutrition review.

Differential diagnosis. Parkinson disease, Wilson disease, atypical parkinsonism (progressive supranuclear palsy, multiple system atrophy), drug induced parkinsonism, acquired hepatocerebral degeneration, ephedrone encephalopathy, other toxic parkinsonism.

• Remove from exposure permanently and control the source; stop ephedrone use and correct parenteral nutrition manganese content when relevant.
• Correct iron deficiency, which increases manganese absorption.
• Levodopa test course: carbidopa/levodopa 25/100 mg orally, 1 tablet three times daily after food, increased by 1 tablet daily every 2 to 3 days if needed to a maximum of 8 tablets daily (levodopa 800 mg, carbidopa 200 mg) in divided doses, for 3 months. Continue only if there is clear benefit; otherwise withdraw over 1 to 2 weeks. Monitor postural hypotension, nausea, dyskinesia, hallucinations and mood. Avoid with non-selective MAO inhibitors and in angle closure glaucoma; caution in hepatic impairment; no renal adjustment. Response is usually poor.
• Chelation with edetate calcium disodium has produced inconsistent results and carries renal toxicity; reserve it for specialist toxicology advice.
• Physiotherapy, speech and occupational therapy, falls prevention and psychological support.

Monitoring. Neurological review every 3 to 6 months; repeat MRI after 6 to 12 months if the diagnosis is uncertain.

Referral and escalation. Neurology and toxicology at diagnosis; occupational physician for workplace investigation and surveillance of co-workers; notification and compensation where required.

Special groups. Pregnancy: levodopa only when the benefit is clear. Liver failure and long term parenteral nutrition: review manganese content and hepatic function.