Clinical Characteristics of Myasthenia Gravis Patients with COVID-19 in Guangxi, China: A Case-Control Study.

Purpose: With the adjustment of prevention strategies in December 2022, coronavirus disease 2019 (COVID-19) became widely prevalent in China. This study is aimed to describe the clinical characteristics of myasthenia gravis (MG) patients with COVID-19 and identify risk factors of exacerbation in MG patients with COVID-19 in Guangxi. Patients and Methods: A total of 489 MG patients and 587 control subjects in Guangxi during the COVID-19 pandemic were enrolled in this case-control study. After contacting the participants, the clinical data of MG patients and the control group were analyzed. The clinical characteristics of MG patients with COVID-19 were described. Multivariable logistic regression analysis was used for discovering independent risk factors of MG exacerbation in the patients with MG and COVID-19. Results: A total of 311 (75.30%) MG patients and 428 (72.91%) control subjects were infected with COVID-19, and 64.31% of MG patients with COVID-19 were women. The median age at the time of interview was 41 (IQR: 28, 54) years old, and median onset age was 36 (IQR: 24, 51), both of which were lower than those in MG patients without COVID-19. MG duration was 24 (IQR: 9, 72) months. About 44.69% of patients were generalized MG (GMG). About 11.90% of MG patients with COVID-19 showed severe COVID-19 symptoms and the duration of symptomatic COVID-19 was 9.57 ± 6.79 days, higher than those in the control group. About 35.69% MG patients with immunosuppressive drugs were infected with COVID-19, which is higher than those in the non-infected MG patients (21.57%). A total of 120 (38.59%) MG patients with COVID-19 had comorbidities. About 21 (20.19%) of the 104 MG patients without vaccination showed severe COVID-19 symptoms. Multivariable logistic regression analysis showed that baseline MG activities of daily living profile (MG-ADL, OR 1.280, 95% CI: 1.010-1.621, p = 0.041), duration of COVID-19 (OR 1.158, 95% CI: 1.100-1.220, p < 0.001), GMG (OR 2.331, 95% CI: 1.228, 4.426, p = 0.010), and lack of COVID vaccination (OR 2.075, 95% CI: 1.152, 3.738, p = 0.015) were independent factors of exacerbation in MG patients with COVID-19. Conclusion: MG patients with immunosuppressive drugs, younger onset, longer MG duration, or comorbidities are more susceptible to COVID-19. The baseline MG-ADL, duration of symptomatic COVID-19, GMG, and lack of COVID-19 vaccination are independent risk factors of exacerbation in MG patients with COVID-19.

Inhibiting PI3K/Akt-Signaling Pathway Improves Neurobehavior Changes in Anti-NMDAR Encephalitis Mice by Ameliorating Blood-Brain Barrier Disruption and Neuronal Damage.

The disruption of the blood-brain barrier (BBB) is hypothesized to be involved in the progression of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, but its mechanism is still unclear. Recently, the phosphatidylinositol 3-kinase (PI3K)/threonine kinase (Akt) pathway is involved in the regulation of the BBB in various diseases. This study is aimed to investigate the mechanism of BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. Female C57BL/6J mice were actively immunized to establish an anti-NMDAR encephalitis mouse model and evaluate the neurobehavior changes of mice. To study its potential mechanism, LY294002 (PI3K inhibitor, 8 mg/kg) and Recilisib (PI3K agonist, 10 mg/kg) were treated by intraperitoneal injection, respectively. Anti-NMDAR encephalitis mice showed neurological deficits, increased BBB permeability, open endothelial tight junctions (TJs), and decreased expression of TJ-related proteins zonula occludens (ZO)-1 and Claudin-5. However, administration of PI3K inhibitor significantly reduced the expression of p-PI3K and p-Akt, improved neurobehavior function, decreased BBB permeability, and upregulated the expressions of ZO-1 and Claudin-5. Furthermore, PI3K inhibition reversed the decline of NMDAR NR1 in the membranes of hippocampal neurons, which reduced the loss of neuron-specific nucleoprotein (NeuN) and microtubule-associated protein 2 (MAP2). In contrast, administration of the PI3K agonist Recilisib showed a tendency to exacerbate BBB breakdown and neurological deficits. Our results showed that the activation of PI3K/Akt, along with the changes in TJ-related proteins ZO-1 and Claudin-5, may be closely related to BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. PI3K inhibition attenuates BBB disruption and neuronal damage in mice, thereby improving neurobehavior.

miR-548k regulates CXCL13 expression in myasthenia gravis patients with thymic hyperplasia and in Jurkat cells.

Myasthenia gravis (MG) is a B cell-mediated and T cell-dependent autoimmune disease. Thymic hyperplasia has great significance for MG pathogenesis and treatment. MicroRNAs (miRNAs) are a newly recognized type of gene expression regulatory factor that regulate gene expression at the post-transcriptional level. Additionally, miRNAs are involved in immune regulation of the thymus and the occurrence and development of autoimmune diseases. In this study, we found 33 miRNAs that were significantly dysregulated in thymic tissues from MG patients with thymus hyperplasia (MGH) compared with thymic tissues from normal controls using a miRNA microarray chip. We found a negative correlation between the miR-548k and CXCL13 mRNA levels in a large set of samples using quantitative real-time polymerase chain reaction (qRT-PCR). We found that the CXCL13 3'-untranslated region (UTR) was a target of miR-548k using bioinformatics analysis. Next, we obtained direct evidence that CXCL13 is a target of miR-548k using a luciferase reporter assay. Finally, we demonstrated negative regulation between mir-548k and CXCL13 in Jurkat cells. Thus, miR-548k regulates the mRNA expression of its target gene CXCL13 in the thymus of MGH patients and plays an important role in MGH pathogenesis.

[Mutation analysis of presenilin 1 gene in a Chinese family affected with early-onset familial Alzheimer's disease].

OBJECTIVE: To explore the clinical phenotype and genotype in a Chinese family affected with early-onset familial Alzheimer's disease (EOFAD). METHODS: Potential mutation of beta-amyloid precursor protein (APP) gene, presenilin 1 (PSEN1) gene and apolipoprotein E (APOE) gene was detected with polymerase chain reaction (PCR) and direct sequencing. RESULTS: Homozygous APOE ε 2 allele and no gene mutation of APP gene were detected in the proband (III1). A 488A>G mutation (His163Arg) of the PSEN1 gene was found in the proband and other 4 family members (IV1, IV12, IV21, V2). CONCLUSION: A mutation (c.488A>G, p.His163Arg) of PSEN1 gene was found in a Chinese family affected with EOFAD.

Altered expression of miR-125a-5p in thymoma-associated myasthenia gravis and its down-regulation of foxp3 expression in Jurkat cells.

Myasthenia gravis is an autoantibody-mediated and T cell-dependent autoimmune disease of neuromuscular junctions. Thymomas may play a crucial role in the pathogenesis of thymoma-associated myasthenia gravis (TAMG), but the thymic pathogenesis of TAMG is unknown. MicroRNAs (miRNAs) are non-coding RNA molecules 21-24 nt in length that regulate the expression of their target genes in a post-transcriptional manner. In this study, we used a miRNA microarray chip to identify, for the first time, 137 miRNAs in normal tissue adjacent to the thymoma from TAMG patients that were significantly dysregulated compared with normal thymus controls. We confirmed the differential expression of miR-125a-5p in larger samples using quantitative real-time polymerase chain reaction (qRT-PCR). Using bioinformatics analysis, we identified the foxp3 3' untranslated region (UTR) as a target of miR-125a-5p. Importantly, miR-125a-5p expression exhibited a negative correlation with foxp3 expression in normal tissue adjacent to the thymoma from TAMG patients. Furthermore, we demonstrated that the expression of the foxp3 gene was modulated by miR-125a-5p in Jurkat cells. Taken together, our results suggest that the abnormal expression of miR-125a-5p and its effect on foxp3 expression are likely involved in the pathogenesis of TAMG.

LPS Induces Occludin Dysregulation in Cerebral Microvascular Endothelial Cells via MAPK Signaling and Augmenting MMP-2 Levels.

Disrupted blood-brain barrier (BBB) integrity contributes to cerebral edema during central nervous system infection. The current study explored the mechanism of lipopolysaccharide- (LPS-) induced dysregulation of tight junction (TJ) proteins. Human cerebral microvascular endothelial cells (hCMEC/D3) were exposed to LPS, SB203580 (p38MAPK inhibitor), or SP600125 (JNK inhibitor), and cell vitality was determined by MTT assay. The proteins expressions of p38MAPK, JNK, and TJs (occludin and zonula occludens- (ZO-) 1) were determined by western blot. The mRNA levels of TJ components and MMP-2 were measured with quantitative real-time polymerase chain reaction (qRT-PCR), and MMP-2 protein levels were determined by enzyme-linked immunosorbent assay (ELISA). LPS, SB203580, and SP600125 under respective concentrations of 10, 7.69, or 0.22 µg/mL had no effects on cell vitality. Treatment with LPS decreased mRNA and protein levels of occludin and ZO-1 and enhanced p38MAPK and JNK phosphorylation and MMP-2 expression. These effects were attenuated by pretreatment with SB203580 or SP600125, but not in ZO-1 expression. Both doxycycline hyclate (a total MMP inhibitor) and SB-3CT (a specific MMP-2 inhibitor) partially attenuated the LPS-induced downregulation of occludin. These data suggest that MMP-2 overexpression and p38MAPK/JNK pathways are involved in the LPS-mediated alterations of occludin in hCMEC/D3; however, ZO-1 levels are not influenced by p38MAPK/JNK.

Rosiglitazone suppresses HIV-1 Tat-induced vascular inflammation via Akt signaling.

Peroxisome proliferator-activated receptor gamma (PPARƔ) contributes to human immunodeficiency virus (HIV)-1-induced dysfunction of brain endothelial cells. The aim of the present study was to evaluate the protection mechanism of PPARƔ against Tat-induced responses of adhesion molecules. We measured the protein expressions of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in human brain microvascular endothelial cells (hCMEC/D3) and C57BL/6J mouse brain microvessels with Western blotting and immunofluorescent labeling. The mRNA levels of ICAM-1 and VCAM-1 were determined by real-time reverse-transcriptase polymerase chain reaction. HIV-1 Tat induced overexpression of ICAM-1 but not VCAM-1 in both hCMEC/D3 and brain microvessels, this response was attenuated by treatment with the PPARƔ agonist rosiglitazone. Tat-mediated upregulation of ICAM-1 and VCAM-1 levels were abolished by the addition of PPARƔ antagonist GW9662 and the Akt inhibitor KP3721, indicating that Akt signaling is involved in the PPARƔ-mediated protection of Tat-induced adhesion molecule upregulation. These results show that Akt signaling plays a key role in PPARƔ's vascular inflammatory effects that contribute to blood-brain barrier damage.

Transplantation of differentiated bone marrow stromal cells promotes motor functional recovery in rats with stroke.

OBJECTIVE: To investigate the effects of transplantation into rats with stroke of bone marrow-derived mesenchymal stem cells (MSCs) induced by brain-derived neurotrophic factor (BDNF). MATERIALS AND METHODS: MSCs were harvested from 6-week-old Sprague-Dawley male rats, and transplanted into adult Sprague-Dawley male rats with transient middle cerebral artery occlusion. At 48 hours after stroke, the adult rats, weighing 250-280 g, were injected via the tail vein with 1×10(7) MSCs or MSCs induced by BDNF (BDNF-MSCs) suspended in 1 ml phosphate-buffered saline. All animals underwent the neurological function test for 14 days. Infarct volume and blood-brain barrier permeability assay were assessed on day 14 post-middle cerebral artery occlusion. Western blotting and immunohistochemical staining were used to detect the protein expression of neuron-specific enolase (NSE). RESULTS: Both BDNF-MSCs and MSCs produced improvement in neurological deficits compared with vehicle controls on day 14 (P<0·05). In particular, the group transplanted with BDNF-MSCs exhibited significant recovery of motor function compared with the group transplanted with MSCs alone (P<0·05). Both BDNF-MSCs and MSCs, but particularly the former, reduced infarct volume, improved blood-brain barrier dysfunction, reduced serum NSE levels, activated the NSE activity, and inhibited neuronal apoptosis in the ischemic boundary zone. CONCLUSIONS: BDNF-MSCs might contribute to the motor function improvement partly by reducing neuronal damage via upregulating the NSE expression level and inhibiting neuronal apoptosis.

How does an occupational neurologist assess welders and steelworkers for a manganese-induced movement disorder? An international team's experiences in Guanxi, China Part II.

The Occupational Medicine Forum is prepared by the ACOEM Occupational and Environmental Medical Practice Committee and does not necessarily represent an official ACOEM position. The Forum is intended for health professionals and is not intended to provide medical or legal advice, including illness prevention, diagnosis or treatment, or regulatory compliance. Such advice should be obtained directly from a physician and/or attorney.

Incidence of thymoma in myasthenia gravis: a systematic review.

BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is usually comorbid with thymoma. More accurate estimates of the incidence thymoma in MG will help inform patients and their physicians, facilitate health policy discussions, provide etiologic clues, and optimize the management of MG. METHODS: We conducted a systematic review search of relevant English-language studies published between 1960 and 2012 using MEDLINE and Embase. We identified additional studies by reviewing the bibliographies of the retrieved articles and hand searched the main neurology journals. Only incidence studies and case series of unselected MG patients in which information about thymoma were included. RESULTS: Out of 2206 potentially relevant studies, 49 met the inclusion criteria. Although there was a considerable degree of heterogeneity, the pooled estimate of the incidence of thymoma in MG was 21% (95% confidence interval, 20-22%). The pooled incidence was significantly higher for surgery-based studies than for population- and hospital-based studies. A large proportion of the reported thymomas were noninvasive. Furthermore, thymoma appears to occur significantly more frequently among male MG patients and those older than 40 years at the onset of MG. CONCLUSIONS: Thymoma is common in MG patients, but appears to be found more often in male MG patients and those older than 40 years at the onset of MG. Further research is needed to expand our understanding of these association conditions.

Expression of laminin ß1 and integrin α2 in the anterior temporal neocortex tissue of patients with intractable epilepsy.

We investigated the expression of laminin ß1 and integrin α2 in the anterior temporal neocortex tissue of patients with intractable epilepsy and explored the role of these molecules in the pathogenesis of this disease. Immunohistochemistry and immunofluorescence were used to test the expression of laminin ß1 and integrin α2 in samples (from the brain bank of our department, n=32) of surgically removed anterior temporal neocortex tissues from intractable epilepsy patients, and the results were compared with those of controls (n=10). We found that laminin ß1 and integrin α2 protein expression was significantly increased in the anterior temporal neocortex as compared with controls (immunohistochemistry optical density: laminin ß1 = 0.36 ± 0.01 vs. 0.10 ± 0.03 for control; integrin α2=0.42 ± 0.02 vs. 0.04 ± 0.01 for control; p<.05). Immunofluorescence staining indicated that laminin ß1 and integrin α2 accumulated in the plasma membrane and cytoplasm, with strong fluorescence intensity in the anterior temporal neocortex tissue of patients with intractable epilepsy. Thus, our work demonstrates that laminin ß1 and integrin α2 expression is elevated in the anterior temporal neocortex tissue from patients with intractable epilepsy.

Frequency of autoimmune diseases in myasthenia gravis: a systematic review.

The course of myasthenia gravis (MG) may get complicated by the development of other autoimmune diseases. Estimates of the frequency of autoimmune diseases will help inform patients and physicians, direct health policy discussion, provide etiologic clues, and optimize the management of MG. However, the frequency of autoimmune diseases in people with MG is still uncertain. A systematic search for English language studies was conducted by MEDLINE and EMBASE from 1960 through 2010. Incidence studies and case series of all MG subtypes with information about autoimmune diseases were included; 25 studies met the inclusion criteria. Although there was considerable heterogeneity, the pooled estimate of the coexisting autoimmune diseases in MG was 13% (95% confidence interval, 12%-14%). Autoimmune thyroid disease seems to occur more frequently than other autoimmune conditions in MG patients. Heterogeneity in study estimates could be explained by ascertainment bias and case mix. Furthermore, autoimmune diseases occurred significantly more often in females and anti-acetylcholine receptor seropositive MG patients. Patients with MG have an increased frequency of coexisting autoimmune diseases. Autoimmune diseases seem to occur more often in female and seropositive MG patients. Further research is needed to expand our understanding of these associations.

In vivo measurement of brain GABA concentrations by magnetic resonance spectroscopy in smelters occupationally exposed to manganese.

BACKGROUND: Exposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable. OBJECTIVES: Our goal was to determine whether in vivo brain levels of γ-aminobutyric acid (GABA), N-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure. METHODS: We used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)]. RESULTS: Seven of 10 exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = -0.93; p < 0.001). CONCLUSIONS: We demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity.

[Variations of brain magnetic resonance imaging among manganese-exposed workers].

OBJECTIVE: Variations of the signal intensities in the magnetic resonance (MR) T(1)-weighted image (T(1)WI) of globus pallidus among manganese(Mn)-exposed workers were explored to provide a scientific basis for exposed biomarker of manganese-injured central nervous system (CNS). METHODS: The brain MR T(1) and T(2) WI in eighteen male asymptomatic Mn-exposed, eight manganism and nine healthy control workers were examined routinely by adopting a 1.5 Tesla signal superconducting system. The SIGP and the signal intensity in frontal white matter (SIFWM) in the same side were determined, then pallidal index (PI) was calculated. Concentration of MnO(2) in workplaces and content of manganese in red blood cell (MnRBC) among workers were respectively determined by flame atomic absorption spectrometer (AAS) and inductively coupled plasma-atomic emission spectrophotometry (ICP-AES). The follow-up investigation in the eight high Mn-exposed workers was made one year later. RESULTS: The results showed that the median of air MnO(2) in smelting workplace was 0.64 mg/m(3)(0.07 - 5.40 mg/m(3)), which were respective 0.56 mg/m(3)(0.09 - 1.71 mg/m(3)) in power distribution room (low Mn-exposure) and 0.89 mg/m(3) (0.07 - 5.40 mg/m(3)) in furnace (high Mn-exposure). PI in the Mn-exposed and high Mn-exposed workers were both higher than those of the manganism and control workers(116.4 +/- 8.2, 119.0 +/- 7.9, 105.3 +/- 8.4 and 102.2 +/- 1.5, respectively. Mn vs control, t' = 7.146, P = 0.000; Mn vs manganism, t = 3.181, P = 0.004. High Mn-exposure vs control, t' = 7.446, P = 0.000; high Mn-exposure vs manganism, t = 3.763, P = 0.001). The increased signal in T(1)WI of globus pallidus was observed in Mn-exposed workers, especially in high Mn-exposed workers. The content of manganese in red blood cell of Mn-exposed and control workers was significantly higher than those of the manganism workers [(151.6 +/- 40.5) ng/ml, (149.2 +/- 21.3) ng/ml, (154.5 +/- 46.6) ng/ml, (144.4 +/- 14.2) ng/ml, (20.8 +/- 7.4) ng/ml respectively. The difference was significant in statistics. Manganism vs control, t = 20.206, P = 0.000; manganism vs Mn, t' = 13.144, P = 0.000; manganism vs low and high Mn, t' = 12.964, 9.957, respectively, P = 0.000]. Only a decreased median of air MnO(2) in furnace was found one year later (0.89, 0.31 mg/m(3), Z = -2.142, P = 0.032). The difference was significant in statistics. CONCLUSION: Our data suggests that SIGP of MR T(1)WI among workers was obviously increased by manganese-exposure. PI may be taken as the signal of CNS injury which was induced by manganese-exposure.

Expression of laminin beta1 in hippocampi of patients with intractable epilepsy.

We investigated laminin beta1 expression in the hippocampi of patients with intractable epilepsy and explored the role of laminin beta1 in the pathogenesis of this condition. Fluorescence quantitative PCR, immunofluorescence, immunohistochemistry and Western blotting were used to measure laminin beta1 expression in surgically removed hippocampi of patients with intractable epilepsy, and the results were compared with control hippocampi. Fluorescence quantitative PCR showed increased expression of laminin beta1 mRNA in patient hippocampi compared with control tissues. Immunohistochemical staining demonstrated that laminin beta1 protein expression was significantly increased in patient hippocampi, and immunofluorescence microscopy showed accumulation of laminin beta1 in the cell membrane and cytoplasm of patient hippocampi. These findings were confirmed by Western blotting of protein preparations from patient hippocampi. Elevated expression of laminin beta1 mRNA and protein in the hippocampus suggests that laminin beta1 may play a role in the development of epileptic seizures in patients with intractable epilepsy.

Brain magnetic resonance imaging and manganese concentrations in red blood cells of smelting workers: search for biomarkers of manganese exposure.

The MRI technique has been used in diagnosis of manganism in humans and non-human primates. This cross-sectional study was designed to explore whether the pallidal signal intensity in T1-weighted MRI correlated with Mn levels in the blood compartment among Mn-exposed workers and to understand to what extent the MRI signal could reflect Mn exposure. A group of 18 randomly selected male Mn-exposed workers of which 13 were smelting workers with high exposure (mean of airborne Mn in work place: 1.26 mg/m3; range: 0.31-2.93 mg/m3), and 5 power distribution control workers with low exposure (0.66 mg/m3 and 0.23-0.77 mg/m3) from a ferroalloy factory, and another group of 9 male subjects as controls from a non-smelting factory who were office or cafeteria workers (0.01 mg/m3 and 0-0.03 mg/m3) were recruited for neurological tests, MRI examination, and analysis of Mn in whole blood (MnB), plasma (MnP) or red blood cells (MnRBC). No clinical symptoms and signs of manganism were observed among these workers. MRI data showed average increases of 7.4% (p<0.05) and 16.1% (p<0.01) in pallidal index (PI) among low- and high-exposed workers, respectively, as compared to controls. Fourteen out of 18 Mn-exposed workers (78%) had intensified PI values, while this proportion was even higher (85%) among the high Mn-exposed workers. Among exposed workers, the PI values were significantly associated with MnRBC (r=0.55, p=0.02). Our data suggest that the workers exposed to airborne Mn, but without clinical symptoms, display an exposure-related, intensified MRI signal. The MRI, as well as MnRBC, may be useful in early diagnosis of Mn exposure.

Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study.

OBJECTIVE: Chronic manganese (Mn) intoxication induces syndromes resembling Parkinson disease. The clinical intervention has largely been unsuccessful. We report a 17-year follow-up study of effective treatment of occupational Mn parkinsonism with sodium para-aminosalicylic acid (PAS). METHODS: The patient, female and aged 50 at the time of treatment, was exposed to airborne Mn for 21 years (1963-1984). The patient had palpitations, hand tremor, lower limb myalgia, hypermyotonia, and a distinct festinating gait. She received 6 g PAS per day through an intravenous drip infusion for 4 days and rested for 3 days as one therapeutic course. Fifteen such courses were carried out between March and June 1987. RESULTS: At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal. Recent follow-up examination at age 67 years (in 2004) showed a general normal presentation in clinical, neurologic, brain magnetic resonance imaging, and handwriting examinations with a minor yet passable gait. CONCLUSIONS: This case study suggests that PAS appears to be an effective drug for treatment of severe chronic Mn poisoning with a promising prognosis.