Chin-Chang Huang

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.

Coenzyme Q10 treatment in mitochondrial encephalomyopathies. Short-term double-blind, crossover study.

We report a short-term double-blind, crossover study of CoQ10 in 8 patients with mitochondrial encephalomyopathies. Four patients had myoclonus epilepsy with ragged-red fibers syndrome, 3 had mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome, and 1 had chronic progressive external ophthalmoplegia with myopathy. A trend of effectiveness of CoQ10 in several parameters was noted. Fatigability of daily activities was alleviated. The endurance to muscle exercise was augmented. Global muscle strength scored by Medical Research Council scale was increased. The extent of elevation in serum lactate and pyruvate levels after exercise was decreased. However, only the global MRC index score had a statistical significance (p < 0.05). There were no side effects during therapy. The serum CoQ10 levels were significantly lower in patients than in normal controls before CoQ10 treatment and increased significantly after treatment.

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.

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.

MELAS syndrome with mitochondrial tRNA(Leu(UUR)) gene mutation in a Chinese family.

The clinical features of a patient in a Chinese family with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) are reported. The study revealed that hearing and visual impairments and miscarriages may be early clinical presentations in MELAS. A heteroplasmic A to G transition in the tRNA(Leu(UUR)) gene was noted at the nucleotide pair 3243 in the mitochondrial DNA of muscle, blood, and hair follicles of the proband and his maternal relatives. Quantitative analysis of the mutated mitochondrial DNA revealed variable proportions in different tissues and subjects of maternal lineage in the family. Muscle tissue contained a higher proportion of the mutant mitochondria than other tissues examined. The function of the reproductive system of the proband seems to be impaired. In one clinically healthy sibling, the 3243rd point mutation was found in sperm mitochondrial DNA, although sperm motility was not affected. It seems that biochemical defects in mitochondrial respiration and oxidative phosphorylation are tissue specific expressions of the 3243rd point mutation in the mitochondrial DNA of the affected target tissues.

Normal dopamine transporter binding in dopa responsive dystonia

Abstract We report the clinical manifestations of dopa responsive dystonia (DRD) in 2 patients from the same family. The brain magnetic resonance images (MRI) were normal. The dopamine transporter (DAT) imaging with 99mTc-TRODAT-1 was performed in the 2 probands, 8 patients with young onset Parkinson disease (YOPD) and 16 normal controls. The ratios of 99mTc-TRODAT-1 brain SPECT in the striatum were 2.40 ± 0.12 (right) and 2.30 ± 0.17 (left) in these 2 DRD patients as compared with 1.38 ± 0.18 (right), 1.41 ± 0.20 (left) in YOPD patients, and 2.15 ± 0.35 (right), 2.14 ± 0.32 (left) in normal controls respectively. A normal DAT uptake was found in DRD suggesting a normal presynaptic nigrostriatal dopaminergic terminal. We conclude that a normal DAT in parkinsonian patients can differentiate DRD from YOPD. In addition, DAT with 99mTc-TRODAT-1 is a reliable and convenient tool to study the function of the presynaptic dopaminergic axonal terminals.

Distinct features between longitudinally extensive transverse myelitis presenting with and without anti-Aquaporin 4 antibodies

Objectives: Longitudinally extensive transverse myelitis (LETM) with spinal cord lesions spanning three or more vertebral segments is a key feature of neuromyelitis optica (NMO). However, the role of anti-aquaporin 4 (anti-AQP4) antibody, a sensitive biomarker of NMO, in the conversion of LETM to NMO remains uncertain. Methods: Thirty first-ever LETM patients were retrospectively analysed and divided into two groups according to the presence of anti-AQP4 antibodies. Results: Eighteen (60%) patients presented with anti-AQP4 antibodies. Fifteen (83.33%) anti-AQP4 (+) LETM patients converted to NMO, while only three of 12 (25%, p = 0.002) anti-AQP4 (-) LETM patients progressed to NMO, over a mean follow-up period of 5.63 years. Seven (38.89%) anti-AQP4 (+) and one (8.33%) anti-AQP4 (-) LETM patients received interferon-β1a treatment, respectively. Anti-AQP4 (+) LETM patients demonstrated a higher immunogamma globulin (IgG) index (0.68 ± 0.43 versus 0.47 ± 0.19, p = 0.018), annual relapse rate (0.72 ± 0.31 versus 0.42 ± 0.17, p = 0.01) and Kurtzke Expanded Disability Status Scale (4.28 ± 2.22 versus 2.67 ± 2.26, p = 0.031), than anti-AQP4 (-) LETM patients. In spinal magnetic resonance imaging (MRIs), more than half (58.33%) of the anti-AQP4 (+) LETM patients were observed to have central grey matter-predominant involvement in the axial view, while peripheral white matter-predominant involvement (51.85%) was the most common pattern observed in the anti-AQP4 (-) LETM patients. Conclusion: Anti-AQP4 (+) LETM demonstrated a high conversion rate to NMO (83.33%), suggesting that anti-AQP4 (+) LETM may represent an early, isolated syndrome of NMO spectrum disorder. The greater number of patients receiving interferon-β treatment in anti-AQP4 (+) LETM may contribute to its high annual relapse rate.