Manganism may be difficult to differentiate from other neurodegenerative disorders. Several tests may contribute to establishing the diagnosis, but each has important limitations. Careful consideration of plausible sources of exposure, findings on neurologic and neuropsychologic examinations, and determining hepatic function and iron reserve status are important. If movement abnormalities are present, then failure of sustained response to levodopa therapy is highly suggestive of manganism. Genetic mutations in the manganese transporter SLC30A10 have recently been linked to a neurodegenerative syndrome, and family history should also be explored.66,83
Normal reference values for manganese in blood and urine are published (see above) and measurements may be helpful, but concentrations are poorly correlated with total body manganese burden. Whole blood manganese concentrations are the most reliable values for biomonitoring purposes, although they only correlate with group and not with individual exposures.7,9 Manganese concentrations in blood are most commonly determined by flame or furnace atomic absorption spectrophotometry. Whole blood manganese concentrations should be elevated after acute overexposure, but abnormal concentrations are neither sensitive nor specific for chronic manganese toxicity because manganese is rapidly cleared from the blood.86 Signs and symptoms of manganism are insidious and may occur long after concentrations in urine or blood have normalized.
Urine manganese concentrations are not well correlated with either symptoms or extent of exposure.7 Increased urinary elimination of manganese after chelation challenge with calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) occurs but cannot be interpreted. In most situations, it is unclear whether the increased excretion signifies mobilization of physiologic manganese, an increased body burden of manganese, or toxicity. The utility of hair, nail clippings, and saliva as biomarkers of chronic manganese exposure is not clearly established.7,44,78,84
Patients with manganese associated movement disorders often have a characteristic pattern of abnormalities on magnetic resonance imaging (MRI) that includes a bilateral, symmetric, hyperintense signal in the basal ganglia, particularly in the globus pallidus, on T1-weighted images.4,37,38,61,79 This pattern is also reported in patients with iatrogenic manganism from long-term parenteral nutrition,10,24,36,55,81 and is sometimes seen in cirrhotic patients with impaired dietary manganese elimination.32,65,77 MRI studies in patients receiving total parenteral nutrition (TPN) have shown a positive correlation between the concentration of manganese in TPN mixtures and the intensity of increased basal ganglia signal on T1-weighted MRI images.10,81 An increased T1-weighted MRI signal throughout the basal ganglia has been demonstrated in welders and correlates with the length of welding exposure.21 These changes on MRI are reversible with TPN discontinuation in patients without neurologic symptoms.55,80 While highly suggestive of manganism in the correct clinical context, an increased T1-weighted signal in the basal ganglia is a nonspecific finding that may also reflect iron, copper or lipid deposition, hemorrhage, or neurofibromatosis.9
By contrast to these radiographic abnormalities, MRI findings in PD typically demonstrate a hypointense signal in the substantia nigra on T2-weighted images.43,82 Some evidence suggests that SPECT and PET may also help differentiate these two clinical entities. For example, molecular imaging studies of patients with chronic manganese exposure and extrapyramidal symptoms have largely failed to demonstrate abnormal nigrostriatal dopaminergic activity and projections, although these are clearly abnormal in patients with PD.30,61,85