Nai-Shin Chu

Manganism and idiopathic parkinsonism : similarities and differences

From the comparison we have made between PD and manganism, we draw the following conclusions: 1. There are similarities between PD and manganism, notably the presence of (a) generalized bradykinesia and (b) widespread rigidity. 2. There are also dissimilarities between PD and manganism, notably the following in manganism: (a) less-frequent resting tremor, (b) more frequent dystonia, (c) a particular propensity to fall backward, (d) failure to achieve a sustained therapeutic response to levodopa, and (e) failure to detect a reduction in fluorodopa uptake by PET. Further studies are likely to yield more discriminants between PD and manganism. For example, PET with raclopride may be useful in early cases of manganism, and MRI may be helpful in patients with advanced manganism.

Progression after chronic manganese exposure

We report a longitudinal follow-up study on six patients with chronic manganese-induced parkinsonism following cessation of manganese exposure. Compared with the 1987 study, their parkinsonian symptoms showed a slow progression, particularly in gait disturbances such as freezing during turning and walking backward with retropulsion. The mean disability scores on the Kings College Hospital Rating Scale were 15.0 ± 4.2 in 1987 and 28.3 ± 6.7 in 1991 (p = 0.003, paired t test). Review of the video records also confirmed a worsening of parkinsonism, especially in difficulty turning. Three of six patients receiving levodopa treatment had an initial improvement. The response decreased after 2 to 3 years. During the therapy, they did not develop on-off fluctuation or dyskinesia. We conclude that patients with manganese-induced parkinsonism may develop increasing neurologic dysfunction long after cessation of exposure and that their responses to levodopa are different from those of patients with Parkinsons disease.

Long-term progression in chronic manganism: Ten years of follow-up

We studied the long-term clinical course of five patients with chronic manganese intoxication. The mean scores of the Kings College Hospital Rating Scale for Parkinsons disease increased from 15.0 ± 4.2 in 1987 to 28.3 ± 6.70 in 1991 and then to 38.1 ± 12.9 in 1995. The deterioration was most prominent in gait, rigidity, speed of foot tapping, and writing. Tissue concentrations of manganese in blood, urine, scalp hair, and pubic hair returned to normal. Follow-up MRIs did not show paramagnetic high-signal intensity on T1-weighted images. The data indicate that clinical progression in patients with manganese parkinsonism continues even 10 years after cessation of exposure.

Presynaptic and postsynaptic striatal dopaminergic function in patients with manganese intoxication A positron emission tomography study

We performed PET on four patients with chronic industrial Mn intoxication; presynaptic and postsynaptic dopaminergic function were measured with [18F]6-fluoro-l-dopa (6FD) and [11C]raclopride (RAC). All patients had a rigid-akinetic syndrome; they had no sustained benefit from l-dopa. Influx constants (Ki) of 6FD were normal in the caudate and putamen. RAC binding was mildly reduced in the caudate and normal in the putamen. We conclude that nigrostriatal dopaminergic dysfunction is not responsible for the parkinsonism caused by chronic Mn intoxication. The pathology is likely to be downstream of the dopaminergic projection.

Levodopa failure in chronic manganism

We report a placebo-controlled study of levodopa in four patients with extrapyramidal deficits caused by chronic manganese intoxication. Their parkinsonism and dystonia had progressed slowly over a period of 5 years after they left the site of exposure. Initially the patients appeared to respond to levodopa in open observations, but this apparent benefit was not sustained. This short-term, double-blind study indicates that their parkinsonism and dystonia failed to respond to levodopa.

Epileptic seizures in thrombotic stroke.

SummaryEpileptic seizures due to thrombotic cerebral infarction were studied in 118 patients. The occurrence of seizures had a bimodal distribution with one peak period within 2 weeks and another peak period from 6 to 12 months after stroke. Four patients had seizures preceding stroke, while 23 patients without a history of previous stroke had “silent infarct” on the CT scan. Fifteen patients (13%) had status epilepticus. Simple partial seizures occurred in 56% of patients, complex partial seizures in 24% and generalized tonic-clonic seizures in 4%. Epilepsy developed in 35% of patients with early seizures and in 90% of patients with late seizures.

Dopamine transporter binding in chronic manganese intoxication.

Abstract.Chronic exposure to manganese may induce parkinsonism similar to idiopathic Parkinson’s disease (PD). However, clinical manifestations of manganism also have some features different from PD. The mechanisms of manganese-induced parkinsonism remain not fully understood. 99mTc-TRODAT-1 is a cocaine analogue that can bind to the dopamine transporter (DAT) site reflecting the function of presynaptic dopaminergic terminals. The purpose of this study was to evaluate DAT function using 99mTc-TRODAT-1 to investigate the integrity of the presynaptic dopaminergic terminals in manganese-induced parkinsonism. Brain 99mTc-TRODAT-1 single photon emission computed tomography was performed in 4 patients with chronic manganese intoxication in a ferromanganese smelting plant in Taiwan. Twelve PD patients and 12 healthy volunteers served as abnormal and normal controls, respectively. Clinically, all manganism patients had a bradykinetic-rigid syndrome. The scores of the Unified Parkinson’s Disease Rating Scale ranged between 19 and 64. The uptake values of the 99mTc-TRODAT-1 were 0.868±0.136 in the right corpus striatum and 0.865±0.118 in the left, as compared with 0.951±0.059 and 0.956±0.058, respectively for the normal controls. The data were significantly higher than 0.250±0.070 and 0.317±0.066 respectively for the PD patients. Interestingly, there was a mild decrease in the uptake of 99mTc-TRODAT-1 in the putamen and the ratio of putamen and caudate when compared with the normal controls. Although the DAT shows a slight decrease in the putamen of manganism patients as compared with that of the normal controls, the data indicate that the presynaptic dopaminergic terminals are not the main target of chronic manganese intoxication. In addition 99mTc-TRODAT-1 SPECT can provide a useful, convenient and inexpensive tool for differentiation between chronic manganism and PD.

Isolated involvement of substantia nigra in acute transient parkinsonism: MRI and PET observations.

A woman, aged 27 years, developed acute headache and fever followed by tremor, rigidity, and bradykinesia. Masked face, drooling saliva, monotonous voice, and dysphagia were observed. She was totally bedridden during the worst period because of marked generalized rigidity and bradykinesia. There was no neurological disturbance other than parkinsonism. Several herpetic vesicles were noticed at the left angle of her mouth. The cerebrospinal fluid revealed a mononuclear pleocytosis with a normal concentration of sugar and protein. The antibody test for Type I herpes simplex virus was positive in the serum but negative in the cerebrospinal fluid. Brain CT and EEG were normal. However, MRI study showed markedly increased signals in the bilateral substantia nigra on T2-weighted, proton density, and in gradient recall acquisition imagings. Those abnormal findings had almost disappeared in a follow-up MRI study 2 months later. Her parkinsonian symptoms were substantially resolved by the time. However, PET scans, performed 8 months later, disclosed: (1) mild reduction of fluorodopa uptake; and (2) increased raclopride binding, predominantly in the putamen. These findings suggest a subclinical nigrostriatal dopaminergic deficit and a relative excess of the D2 receptors, with a pattern similar to that found in typical idiopathic parkinsonism.

Dopamine transporter binding in Wilson's disease.

INTRODUCTION In Wilsons disease (WD), brain magnetic resonance images (MRI) show increased signal intensity in T2 weighted images in the lenticular nuclei, thalamus and brainstem, including the substantia nigra. A poor therapeutic response to levodopa in WD suggests the mechanism of a postsynaptic abnormality. However positron emission tomography studies show an involvement of the nigrostriatal presynaptic dopaminergic pathway. CASE REPORT We report the clinical manifestations in a case of WD with akinetic-rigid syndrome and initial hesitation. The brain MRI showed an increased signal intensity lesion in the substantia nigra region, in addition to basal ganglion and thalamic lesions. However, dopamine transporter (DAT) imaging with 99mTc-TRODAT-1 revealed a nonsignificantly increased DAT uptake, suggesting a normal presynaptic nigrostriatal dopaminergic terminal. CONCLUSION We suggest that significant heterogeneity can be found in WD patients and a normal presynaptic dopaminergic pathway may occur in some patients, even those with typical akinetic-rigid syndrome and evidence of substantia nigra involvement in the brain on MRI.

Random mitotic segregation of mitochondrial DNA in MELAS syndrome.

We describe the heterogeneity of clinical features and molecular genetic characteristics of the probands and other members in two families with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes (MELAS) syndrome. A point mutation at the 3243rd nucleotide position of mtDNA was found only in some of the maternal lineage members of the two families. Furthermore, the proportions of mutant mtDNA were varied and found only in some tissues of the individuals. Intriguingly, in some subjects, the mutant mtDNA was found in blood cells or hair follicles but was absent in muscles. The data do not support the notion of a selective advantage of wild‐type mtDNA to rapidly replicating cells. We suggest that a rapid replicative segregation may occur in early embryogenesis.