Recently, there have been some reports that MRI shows characteristic brain lesions in patients with parenteral nutrition containing manganese (Mn), or hepatic failure, and that the serum or whole blood Mn concentration is often increased.1-3 T1 weighted MRI in these patients has shown hyperintensity, always in the bilateral globus pallidus and sometimes in part of the brainstem, although no abnormalities have been found on T2 weighted MRI. The Mn concentrations of CSF in these patients, however, have not been previously measured, because values in control subjects were previously undetermined. The present study was designed to investigate the CSF Mn concentrations in control subjects, and to evaluate the concentrations in patients with symmetric pallidal hyperintensities on T1 weighted MRI.

We examined five patients with the appropriate hyperintensity on T1 weighted MRI, aged from 31 to 72 years (mean 55.8 (SD 16.9) years); two with parenteral nutrition containing Mn (patients 1 and 2), two with Child’s grade B cirrhosis (patients 3 and 5), and one without any specific factors relating to Mn or hepatic failure (patient 4, who had parkinsonism). In addition, we investigated 10 age matched control subjects without hyperintensity, aged from 28 to 78 years (mean 54.2 (SD 15.9) years) (table). The MRI was performed on a 1.5 Tesla magnet. In all five patients, T1 weighted MRI in the patients showed hyperintensity in the bilateral globus pallidus and in the region of the substantia nigra or the quadrigeminal plate, although T2 weighted MRI and brain CT showed no abnormalities. Ten control subjects from the neurology and psychiatry service with no history of parenteral nutrition containing Mn, or hepatic failure, showed no abnormal findings on T1 weighted MRI. We obtained blood and CSF samples from the five patients and 10 control subjects with informed consent. The serum, whole blood, and CSF Mn concentrations were measured by a standard method using graphite furnace atomic absorption spectrometry (Model VARIAN SPECTRA A-40) within 1 month after recognition of the symmetric pallidal hyperintensities. The CSF Mn concentrations were measured by diluting the sample with 0.5% (v/v) nitric acid to yield absorbance values within the linear range and injecting 200 μl into the furnace. The mean serum, whole blood and CSF Mn concentrations were calculated for the patients and control subjects. The non-parametric Mann-Whitney U test was used to assess the significance of differences between the two groups.

The serum, whole blood and CSF Mn concentrations of the patients and control subjects are listed in the table. All the serum and whole blood concentrations of the control group were within the normal range, and their CSF concentrations were mean 0.47 (SD 0.25)μg/l, a relatively narrow range. The CSF Mn concentration (2.1 μg/l) of patient 4, which was the lowest in the patient group, was much higher than 2 SD above the mean of the control group, but the serum Mn concentration of patient 4 and the whole blood Mn concentrations of patients 1, 3, and 4 were all within the normal range. The serum and CSF Mn concentrations of the patient group were significantly higher (p=0.023 and p=0.002 respectively) than those of the control group, whereas the whole blood Mn concentrations were not significantly different (p=0.086) between the two groups.

This is the first study to evaluate the CSF Mn concentrations in patients with symmetric pallidal hyperintensities on T1 weighted MRI. Hyperintensity on T1 weighted MRI is associated with many factors, including calcification, lipid, haemorrhage, and Mn, but the pattern of MRI abnormalities in all the five patients was identical with that seen because of Mn deposition and the serum or whole blood Mn concentrations were often increased.1-3 In the blood, Mn can bind to transferrin in the trivalent state and to albumin or α2-macroglobulin or low weight solutes in the divalent state. The blood Mn is transferred to the brain through the blood-brain barrier by several transport systems.4 Recently, increased Mn concentrations were recognised in postmortem tissue samples from the brains of patients with long term parenteral nutrition containing Mn, or severe cirrhosis.2 5 From our study, the CSF Mn concentrations were increased more than those in serum and whole blood in all patients and, in particular, patient 4, who had no parenteral nutrition or hepatic failure, showed an increase only in CSF Mn concentration. The CSF Mn concentrations are considered to reflect the accumulation of Mn in the brain tissue most directly of the three Mn concentrations. The reason why patient 4 is connected with Mn may be individual susceptibility.6 Moreover, Mn neurotoxicity caused neuropsychiatric symptoms including pyramidal and extrapyramidal signs.1-3 The findings suggest that a high degree of correlation exists between hyperintensity and the CSF Mn concentration, and that the increase may be a most useful marker and predictor of Mn neurotoxicity in patients with symmetric pallidal hyperintensities on T1 weighted MRI. Further studies with more patients are necessary to elucidate a precise correlation between Mn neurotoxicity and the CSF Mn concentration.