Manganese-Induced Parkinsonism

Manganese induced parkinsonism is an atypical parkinsonian syndrome caused by excessive manganese accumulating in the basal ganglia. It differs from idiopathic Parkinson disease by symmetric onset, early gait and postural problems, dystonia, little rest tremor and poor response to levodopa.

Sources. Mining and ore processing, steel and ferroalloy work, welding, dry battery manufacture and fungicides. Non-occupational sources are intravenous ephedrone (methcathinone) use, long term parenteral nutrition, chronic liver disease with portosystemic shunting, and contaminated well water.

Epidemiology. Cases follow months to years of high exposure. Whether lower level welding exposure increases idiopathic Parkinson disease risk remains uncertain.

Course. Deficits often persist or progress after exposure stops, even when imaging changes fade.

Risk modifiers. Iron deficiency, liver disease and male sex.

Pathophysiology.

Manganese is carried into the brain by 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. Injury is mainly pallidal and postsynaptic, so nigrostriatal terminals are usually preserved.

• Bradykinesia, rigidity, mask like face, monotone speech, micrographia and early postural instability with falls.
• Dystonia of the limbs, face or trunk, and a toe walking, high stepping gait (cock walk).
• Rest tremor is infrequent; action tremor may occur.
• Earlier psychiatric features: irritability, emotional lability, compulsions and hallucinations.
• Poor or short lived response to levodopa.

Red flags.

• Rapid progression, severe dysphagia or recurrent falls.
• Evidence of liver failure or ongoing exposure (for example continuing ephedrone use).
• Severe psychiatric disturbance.

• Exposure history including non-occupational sources and diet or parenteral nutrition composition.
• Neurological examination with rating of parkinsonism and dystonia.
• MRI brain: bilateral symmetric T1 hyperintensity of the globus pallidus, with changes in the striatum and midbrain, and normal T2 signal. T1 change often regresses within about 6 months of exposure ending.
• Dopamine transporter imaging: usually normal, unlike Parkinson disease.
• Whole blood manganese reflects recent exposure and correlates poorly with disease; usual general population levels are about 4 to 15 micrograms/L.
• Liver function, ferritin, iron studies, copper and caeruloplasmin.

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

• Stop exposure permanently; correct parenteral nutrition manganese content and stop ephedrone use; control the workplace source.
• Correct iron deficiency, which increases manganese uptake.
• 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 in divided doses, for 3 months. Continue only with 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 or para aminosalicylic acid rests on case reports and carries toxicity; use only on specialist toxicology advice.
• Physiotherapy, speech and occupational therapy, falls prevention and psychological support.
• Treat liver disease and shunts where possible, because they allow manganese clearance to recover.

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

Referral and escalation. Neurology and toxicology; hepatology when liver disease contributes; occupational physician for workplace investigation and co-worker surveillance; notification and compensation where required.