Manganese in Whole Blood and Hair in Patients with Long-Term Home Parenteral Nutrition.

BACKGROUND: Manganese is an essential trace element and indispensable component of nutrition mixtures in long-term home parenteral nutrition (HPN) of patients. On the other hand, neurotoxic effects of excess manganese in the organism have been known for a long time. The objective of the present study was to determine manganese concentration in whole blood and hair of patients with long-term home parenteral nutrition. METHODS: We examined 16 patients (7 men and 9 women) aged from 28 to 68 years on long-term HPN lasting from 4 to 96 months. The short bowel syndrome was an indication for HPN. The daily dose of manganese ranged between 80 and 470 microg/day (1.2 to 8.5 pg/kg/day). RESULTS: In the investigated patients we detected approximately a doubled value of manganese concentration in whole blood in comparison to the control group (16.2 microg/L; 12.9-20.4 microg/L and 7.4 microg/L; 6.4-8.4 microg/L). In five patients with symptoms of cholestatic hepatopathy, Mn concentration in whole blood exceeded the value of 20.0 microg/L. Magnetic resonance of the brain in four of these patients detected a hyperintense T1-signal in the globus pallidus without any clinical symptoms similar to the Parkinson's syndrome. The content of manganese in the patients' hair was also significantly increased (p < 0.04). CONCLUSIONS: The results of our study corroborate the necessity of careful monitoring of the manganese concentration in the organism during HPN, especially in patients with liver disorders. Individualized HPN with greater accessibility of variable mixtures of trace elements would certainly be greatly beneficial, at least with regard to problems associated with manganese substitution.

The outcome of the movement disorder in methcathinone abusers: clinical, MRI and manganesemia changes, and neuropathology.

BACKGROUND AND PURPOSE: There is limited knowledge regarding the long-term outcome of the methcathinone/manganese-induced movement disorder. Our purpose was to define prognosis in intravenous methcathinone abusers affected by this distinctive disorder attributed to manganese (Mn) toxicity. Also, neuropathology from a globus pallidus region biopsy from a former user is reported. METHODS: Eighteen methcathinone abusers were categorized as active (five), discontinued (four) or former (nine) users. They were reassessed after a median of 32.5 months (range 3.4-59.6) clinically, on rating scales, and with MRI and blood Mn levels. The biopsy was examined ultrastructurally. RESULTS: Overall the group showed a slight tendency to deterioration at follow-up on clinical assessment of motor functioning, especially the active users. No significant change occurred on parkinsonian rating scale reassessment. Significant reduction in Mn levels occurred in former users, and decreased T1-weighted hyperintensity on basal ganglia MRI occurred in 3 of 4 former and 2 of 3 discontinued users, despite lack of clinical improvement. The biopsy consisted of white matter showing decompacted myelin sheaths and frequent abnormalities of mitochondria. CONCLUSIONS: No improvement in this Mn-induced movement disorder occurs after cessation of methcathinone abuse despite improvement of Mn blood levels and/or MRI abnormalities. Ultrastructural abnormalities in a former user confirm structural damage to white matter is associated with the disorder. Methcathinone/Mn toxicity is an important, disabling and permanent medical sequel of intravenous drug abuse in the former Soviet Union.

Prolactin levels in manganese-exposed male welders.

PURPOSE: Early studies on manganese (Mn) exposure have demonstrated that this transition metal affects dopamine neurotransmission. Dopamine serves as a tonic inhibitor of prolactin release in the anterior hypophysis. Our aim was to determine the relation between serum prolactin levels and manganese-exposure. METHODS: Whole blood was collected from 95 non-exposed control subjects and 179 manganese-exposed male welders. Whole blood manganese was analyzed by Inductively Coupled Plasma--Mass Spectrometer on Agilent 7700 (Agilent Technologies, USA). Serum prolactin levels (PRL), aspartate transaminase (AST), alanine transaminase (ALT), urea, creatinine, soduim (Na), potassium (K) were analyzed by immunological and spectrophotometric methods on Roche E170 Modular System (Roche Diagnostics, Mannheim, Germany). RESULTS: The mean ages for control and manganese-exposed group were 40.5 ± 7.8 and 39.5 ± 8.7, respectively (p = 0.258). The mean working period (years) for control and manganese-exposed group were 17.4 ± 9.8 and 18.2 ± 7.7 years, respectively (p = 0.581). Serum AST and potassium levels were significantly higher in control group than manganese-exposed group (p = 0.002 and p = 0.048, respectively) and body-mass index (BMI) was significantly lower in control group than manganese-exposed group (p = 0.033). There was a significantly positive correlation between whole blood manganese levels and serum prolactin (r = 0.860, p < 0.001). Serum ALT levels were positively correlated with serum AST, urea and sodium (r = 0.315, p < 0.001; r = 0.121, p = 0.046; r = 0.130, p = 0.031). CONCLUSIONS: Serum prolactin level is a diagnostic marker for determining the effect of manganese-exposure.

Manganese accumulation in red blood cells as a biomarker of manganese exposure and neurotoxicity.

Although overexposure to manganese (Mn) is known to cause neurotoxic damage, effective exposure markers for assessing Mn loading in Mn-exposed workers are lacking. Here, we construct a Mn-exposed rat model to perform correlation analysis between Mn-induced neurological damage and Mn levels in various biological samples. We combine this analysis with epidemiological investigation to assess whether Mn concentrations in red blood cells (MnRBCs) and urine (MnU) can be used as valid exposure markers. The results show that Mn exposure resulted in neurotoxic damage in rats and that MnRBCs correlated well with neurological damage, showing potential as a novel Mn exposure biomarker. These findings provide a basis for health monitoring of Mn-exposed workers and the development of more appropriate biological exposure limits.

A case of acute prochloraz-manganese complex intoxication treated with extracorporeal elimination.

BACKGROUND/AIM: We treated a patient with critical manganese intoxication with vigorous extracorporeal elimination. In this article, we describe the clinical characteristics and treatment modalities of the patient. PATIENT: A 65-year-old man was brought to the emergency room (ER) 5.5 h after ingesting prochloraz-manganese complex. He experienced circulatory collapse and went into a coma without self-breathing on arrival at the ER. Mechanical ventilation was initiated and hemoperfusion, hemodialysis and continuous venovenous hemodiafiltration were performed with the help of norepinephrine. MEASUREMENT AND RESULT: The manganese levels on the first, second and fourth hospital days were 34.1, 23.6 and 12.5 µg/l, respectively. He recuperated from the shock state within 7 hospital days. After 4 critical weeks, the patient regained full consciousness. CONCLUSION: Rigorous extracorporeal elimination by hemoperfusion, hemodialysis and continuous venovenous hemodiafiltration was an effective treatment modality for patients with acute manganese intoxication.

The association of bone and blood manganese with motor function in Chinese workers.

Manganese (Mn) is an essential element. However, Mn overexposure is associated with motor dysfunction. This cross-sectional study assessed the association between bone Mn (BnMn) and whole blood Mn (BMn) with motor function in 59 Chinese workers. BnMn and BMn were measured using a transportable in vivo neutron activation analysis system and inductively coupled plasma mass spectrometry, respectively. Motor function (manual coordination, postural sway, postural hand tremor, and fine motor function) was assessed using the Coordination Ability Test System (CATSYS) and the Purdue Pegboard. Relationships between Mn biomarkers and motor test scores were analyzed with linear regression models adjusted for age, education, current employment, and current alcohol consumption. BMn was significantly inversely associated with hand tremor intensity (dominant hand (ß=-0.04, 95 % confidence interval (CI):-0.07, -0.01; non-dominant hand ß=-0.05, 95 % CI:-0.08, -0.01) hand tremor center frequency (non-dominant hand ß=-1.61, 95 % CI:-3.03, -0.19) and positively associated with the Purdue Pegboard Assembly Score (ß = 4.58, 95 % CI:1.08, 8.07). BnMn was significantly inversely associated with finger-tapping performance (non-dominant hand ß=-0.02, 95 % CI:-0.04,-0.004), mean sway (eyes closed and foam ß=-0.68, 95 % CI:-1.31,-0.04), and positively associated with hand tremor center frequency (dominant hand, ß = 0.40, 95 % CI:0.002, 0.80). These results suggest BMn is related to better postural hand tremor and fine motor control and BnMn is related to worse motor coordination and postural hand tremor but better (i.e., less) postural sway. The unexpected positive results might be explained by choice of biomarker or confounding by work-related motor activities. Larger, longitudinal studies in this area are recommended.

Elevated manganese and cognitive performance in school-aged children and their mothers.

BACKGROUND: Growing evidence suggests that excess manganese (Mn) in children is associated with neurobehavioral impairments. In Brazil, elevated hair Mn concentrations were reported in children living near a ferro-manganese alloy plant. OBJECTIVES: We investigated these children's and caregivers' cognitive function in relation to bioindicators of Mn exposure. METHODS: In this cross-sectional study, the WISC-III was administered to 83 children aged between 6 and 12 years; the Raven Progressive Matrix was administered to the primary caregivers (94% mothers), who likewise responded to a questionnaire on socio demographics and birth history. Mn in hair (MnH) and blood (MnB) and blood lead (PbB) were measured by graphite furnace atomic absorption spectrometry (GFAAS). RESULTS: Children's mean MnB and MnH were 8.2 µg/L (2.7-23.4) and 5.83 µg/g (0.1-86.68), respectively. Mean maternal MnH was 3.50 µg/g (0.10-77.45) and correlated to children's MnH (rho=0.294, p=0.010). Children's MnH was negatively related to Full-Scale Intelligence Quotient (IQ) and Verbal IQ; ß coefficients for MnH were -5.78 (95% CI -10.71 to -0.21) and -6.72 (-11.81 to -0.63), adjusted for maternal education and nutritional status. Maternal MnH was negatively associated with performance on the Raven's (ß=-2.69, 95% CI -5.43 to 0.05), adjusted for education years, family income and age. CONCLUSIONS: These findings confirm that high MnH in children is associated with poorer cognitive performance, especially in the verbal domain. Primary caregiver's IQ is likewise associated to Mn exposure, suggesting that, in this situation, children's cognition may be affected directly and indirectly by Mn exposure.

Manganese encephalopathy: an under-recognized condition in the intensive care unit.

BACKGROUND: Manganese encephalopathy is a potential complication of parenteral nutrition. Lack of early recognition leads to unnecessary testing and to continued exposure to manganese. METHODS: Case report and review of the literature. RESULTS: We describe the clinical and imaging findings of a patient with manganese encephalopathy in whom the diagnosis was delayed due to lack of recognition of the characteristic imaging findings. CONCLUSION: Manganese encephalopathy has protean clinical and imaging findings that can easily be overlooked.

[Evaluating biomarkers of exposure to electric welding aerosol].

Biologic monitoring data in electric welders revealed reliable correlation between manganese concentration in the whole blood and manganese concentrations in the workplace air. The chronic manganese intoxication patients showed reliable lower levels of urinary iron, cobalt and manganese vs. those values in the reference group.

Preventive impacts of PAS-Na on the slow growth and activated inflammatory responses in Mn-exposed rats.

BACKGROUND: Sodium para-aminosalicylic acid (PAS-Na), an anti-tuberculosis drug, has been demonstrated its function in facilitating the Mn elimination in manganism patients and Mn-exposed models in vivo and improving the symptoms of Mn poisoning. But whether it can improve the growth retardation and inflammatory responses induced by Mn have not been reported. OBJECTIVES: This study was designed to investigate the preventive effects of PAS-Na on the development of retardation and inflammatory responses in Mn-exposed rats. METHODS: Male Sprague Dawley (SD) rats (8 weeks old, weighing 180 ± 20 g) were randomly divided into normal control group and Mn-exposed group in the 4 weeks experiment observation and normal control group, Mn-exposed group, PAS-Na preventive group and PAS-Na control group in the 8 weeks experiment observation. The Mn-exposed group received an intraperitoneal injection (i.p.) of 15 mg/kg MnCl2 and the normal control group i.p. physiological Saline in the same volume once a day for 4 or 8 weeks, 5 days per week. The PAS-Na preventive group i.p. 15 mg/kg MnCl2 along with back subcutaneous (s.c.) injection of 240 mg/kg PAS-Na once a day for 8 weeks, 5 days per week. PAS-Na control group received s.c. injection of 240 mg/kg PAS-Na along with i.p. injection of saline once daily. The body weight was determined once a week until the end of the experiment. The manganese contents in the blood were detected by graphite furnace atomic absorption spectrometry. The inflammatory factor levels (TNF-α, IL-1ß, IL-6, and PGE2) in the blood were detected by using enzyme-linked immunosorbent assay (Elisa) and each organ taking from rats were weighed and recorded. RESULTS: Mn exposure significantly suppressed the growth in rats and increased heart, liver, spleen and kidney coefficients as compared with the control group. The whole blood Mn level and serum levels of IL-1ß, IL-6, PGE2, and TNF-α in sub-chronic Mn-exposure group were markedly higher than those in the control group. However, preventive treatment with PAS-Na obviously reduced the whole blood Mn level, the spleen and liver coefficients of the Mn-exposed rats. And serum levels of IL-1ß and TNF-α were significantly reduced by 33.9% and 14.7% respectively in PAS-Na prevention group. CONCLUSIONS: PAS-Na could improve the growth retardation and alleviate inflammatory responses in Mn-exposed rats.

Latent subgroups of cognitive performance in lead- and manganese-exposed Uruguayan children: Examining behavioral signatures.

OBJECTIVES: Lead (Pb) and manganese (Mn) are confirmed neurotoxins but it is unclear to what extent low-level exposure produces a unique behavioral signature. The objective of this study was to investigate latent cognitive profiles among children (6-8 years) from Montevideo, Uruguay co-exposed to these metals. METHOD: Among 345 children, blood Pb and hair Mn were measured using atomic absorption spectroscopy and ICP-MS, respectively. Sixteen measures, reflecting multiple domains of cognitive functioning were gathered: (1) three tests from Cambridge Neuropsychological Test Automated Battery (CANTAB): Intra-Extra Dimensional Shift (IED), Spatial Span (SSP) and Stockings of Cambridge (SOC), (2) ten tasks from Woodcock-Muñoz Achievement Battery, Revised (WM): Visual-Motor Integration, Verbal Comprehension (Vocabulary, Synonyms, Antonyms, Analogies), Visual-Auditory Comprehension, Concept Formation, Visual Spatial Thinking, Number Inversion and Spatial Relations, (3) Bender Gestalt task, and (4) Weschler block design task. Scores were modeled using latent profile analysis (LPA). Association between blood Pb and hair Mn on performance profiles was assessed using ordinal regression, controlling for confounders. An interaction between Pb and Mn was tested. RESULTS: Mean ± SD of blood Pb was 4.1 ± 2.1 µg/dL and 35% of children had blood Pb ≥ 5 µg/dL. Median [5%, 95%] hair Mn level was 0.8 [0.3, 4.1] ppb. Three latent cognitive performance profiles were identified: high (n = 46, 13%), average (n = 209, 61%) and low (n = 90, 26%). Each one-unit increase in blood Pb was associated with a 28% greater likelihood of belonging to a poorer-performing profile. The association was non-linear, with the effect of Pb on profile membership strongest at lower levels of exposure. There was no meaningful interaction between Pb and Mn. CONCLUSIONS: A behavioral signature for low-level Pb & Mn exposure was not identified, but the likelihood of membership in low-performing profile was higher at lowest levels of blood Pb. There was no effect measure modification between Pb and Mn. Future research should address how complex environments created by chemical exposures and the social context relate to cognitive performance in young children.

Assessment of latent manganese toxicity as a prognostic factor following surgery for biliary atresia.

PURPOSE/BACKGROUND: The aim of this study was to investigate latent manganese toxicity in patients with biliary atresia and to use this tool to predict the prognosis of biliary atresia patients after Kasai's portoenterostomy. METHODS: 14 patients who underwent Kasai's portoenterostomy between 1993 and 2005 were included in the study. Whole blood manganese assays were performed using atomic adsorption spectroscopy (Philips PU 9200, Cambridge, UK) and verified by repeat analysis; these were done at the time of surgery and 6 months later. All blood samples were collected in an identical manner, blinded and then assayed by technicians. Whole blood manganese levels were correlated with the development of manganese deposits in the globus pallidus on T1-weighted images on magnetic resonance imaging (MRI) of the brain. Serum bilirubin of all 14 patients were noted both at the time of surgery and 6 months later. A hepatobiliary (HIDA) scan was done in all patients 6 months after Kasai's portoenterostomy. RESULTS: The bilirubin declined in all except 2 patients after surgery. Both these patients developed ascites and severe jaundice and 1 expired one year after surgery. HIDA scan was excretory in all 14 patients. Whole blood manganese ranged from 1.26 - 27.58 microg/dl (mean 4.63 +/- 7.00) at the time of surgery; the levels were normal in 11 patients and elevated in 3. The postoperative assay at 6 months after surgery demonstrated values from 1.08 - 74.46 microg/dl (mean 13.55 +/- 24.17); 4 patients showed an increase from the previous value. Globus pallidus hyperintensity on T1-weighted images was noted in 1 patient on MRI; this patient had a sharp rise in the postoperative manganese level. All other MRI examinations were normal. All 14 patients were neurologically intact. CONCLUSIONS: Although the study size is small, it shows that there is a risk of latent manganese toxicity in patients with biliary atresia who have undergone Kasai's portoenterostomy. Whole blood manganese assay in conjunction with brain MRI can be used to serially monitor these patients for early detection of these complications. This tool can be used for prognosis after Kasai's portoenterostomy and can also be extremely useful in selecting patients who will need a liver transplant on a priority basis.

Association of exposure to manganese and iron with relaxation rates R1 and R2*- magnetic resonance imaging results from the WELDOX II study.

OBJECTIVE: Magnetic resonance imaging is a non-invasive method that allows the indirect quantification of manganese (Mn) and iron (Fe) accumulation in the brain due to their paramagnetic features. The WELDOX II study aimed to explore the influence of airborne and systemic exposure to Mn and Fe on the brain deposition using the relaxation rates R1 and R2* as biomarkers of metal accumulation in regions of interest in 161 men, including active and former welders. MATERIAL AND METHODS: We obtained data on the relaxation rates R1 and R2* in regions that included structures within the globus pallidus (GP), substantia nigra (SN), and white matter of the frontal lobe (FL) of both hemispheres, as well as Mn in whole blood (MnB), and serum ferritin (SF). The study subjects, all male, included 48 active and 20 former welders, 41 patients with Parkinson's disease (PD), 13 patients with hemochromatosis (HC), and 39 controls. Respirable Mn and Fe were measured during a working shift for welders. Mixed regression models were applied to estimate the effects of MnB and SF on R1 and R2*. Furthermore, we estimated the influence of airborne Mn and Fe on the relaxation rates in active welders. RESULTS: MnB and SF were significant predictors of R1 but not of R2* in the GP, and were marginally associated with R1 in the SN (SF) and FL (MnB). Being a welder or suffering from PD or HC elicited no additional group effect on R1 or R2* beyond the effects of MnB and SF. In active welders, shift concentrations of respirable Mn>100µg/m3 were associated with stronger R1 signals in the GP. In addition to the effects of MnB and SF, the welding technique had no further influence on R1. CONCLUSIONS: MnB and SF were significant predictors of R1 but not of R2*, indicative of metal accumulation, especially in the GP. Also, high airborne Mn concentration was associated with higher R1 signals in this brain region. The negative results obtained for being a welder or for the techniques with higher exposure to ultrafine particles when the blood-borne concentration was included into the models indicate that airborne exposure to Mn may act mainly through MnB.

Effect of manganese on neural endocrine hormones in serum of welders and smelters.

BACKGROUND: Although manganese (Mn)-induced neurotoxicity effects are well known among occupational Mn exposure, few reports have investigated the effects on endocrine systems among welders and smelters. OBJECTIVE: To determine the effect of high level occupational manganese (Mn) exposure on neuropsychological parameters and hormonal status. METHODS: We used a cross-sectional design with 52 welders, 48 smelters and 43 age-matched office workers from the same factory in China. We analyzed serum endocrine hormones level and airborne Mn concentrations. Erythrocyte and urine Mn levels were quantified using inductively-coupled plasma atomic emission spectroscopy. RESULTS: The geometric mean of air Mn concentrations for the welders and smelters were 19.7 and 273.1 µg/m3, respectively. Mn concentrations in erythrocytes of smelters were markedly greater than those in controls and welders, but there was no difference between the erythrocytes Mn levels of Control and welders. We also found an increase of Mn levels in the urine of both welders and smelters vs. controls; Mn levels in urine of smelters were higher than in welders. Self-reported neurobehavioral symptoms were higher in welders and smelters than in controls. Finally, thyroid-stimulating hormone (TSH) levels of welders were significantly lower than in controls, whereas smelters had lower prolactin (PRL), testosterone (TST) and follicle-stimulating hormone (FSH) concentrations than either controls or welders. CONCLUSIONS: These results show that smelters have higher Mn exposure than do welders, and that Mn levels in erythrocytes or urine can be a marker for exposure. Moreover, high level occupational Mn exposure increases adverse neurobehavioral effects, and also may disrupt endocrine systems.

Cognitive function in a cohort of Danish steel workers.

OBJECTIVE: The aim of this study was to evaluate the level of possible cognitive impairment in a cohort of steel workers occupationally exposed to manganese and lead. MATERIAL: Ninety-two employees from an electro-steel works were examined in 1989 and 1995. Fifty-three were re-examined in 2003. Median age of the participants was 53 years, median duration of employment was 24 years, median blood manganese in 1989 and 1995 was 148 and 171 nmol/l, respectively, and median blood lead in 1989 was 0.79 micromol/l. Non-participants were comparable with participants, although they had a higher level of blood manganese in 1989 (186 nmol/l) and 1995 (186 nmol/l). Manganese level in the air was estimated below 1.9 mg/m3 in the 1970s. In the 1990s, manganese level in the air was below 0.28 mg/m3 in the majority of measurements. METHOD: Cognitive function was examined with the Cognitive Function Scanner, a computer-based neuropsychological test battery. From a published set of norms a subgroup (n=106) matched for gender, age and social status was extracted and used for comparison. RESULTS: Learning and memory, visuomotor and visuospatial function, concentration, attention, perception and vigilance were examined. Despite many statistically significant differences between the groups, it was not possible to interpret the results for the steel workers as being better or worse. In a visuomotor subtest, the pen-to-point test, the steel workers were much less accurate than the comparison group. This could be the result of an impaired ability to make fast accurate movements. There were no associations between pen-to-point test results and duration of employment or blood levels of manganese and lead. CONCLUSION: Intellectual impairment could not be shown with the Cognitive Function Scanner in this cohort of low to moderate manganese and lead exposed steel workers. A slight subclinical impairment of the visuomotor function was possibly found.

Neuromotor function in a cohort of Danish steel workers.

OBJECTIVE: With a longitudinal design to evaluate possible neuromotor impairment in a cohort of steel workers exposed to metal dust. MATERIAL: Ninety-two employees from a steel works were examined in 1989 and 1995. Sixty were re-examined in 2003. A non-matched control group was examined in 1996 (n=19) and in 2003 (n=14). Median blood manganese in 1989, 1995 and 2003 was 149, 171 and 155 nmol/l. Median blood lead in 1989 and 2003 was 0.76 and 0.22 micromol/l. Median air concentration of manganese at the steel works was estimated to be 0.11 mg/m3 in 1970s and was 0.03 mg/m3 in 1990s. Median air concentration of lead was estimated to be 0.13 mg/m3 in 1970s and was 0.01 mg/m3 in 1990s. METHOD: The Catsys 2000 system developed by Danish Product Development is computer-based device for measuring hand tremor, hand coordination and reaction time. RESULTS: Over all there were no statistically significant differences in neuromotor function between the participating steel workers, non-participating steel workers and controls in 1995/1996. Only reaction time for the right hand was slower for the participating steel workers. Compared with the control group the steel workers showed a decline in the ability to perform fast precise hand pronation/supination and finger tapping from 1995 to 2005. Correlation analysis showed no associations between test results for fast hand coordination and blood manganese and lead. Only seniority was associated with deterioration of beat regulation of fast pronation/supination of the hands. DISCUSSION: On a group basis the changes were subclinical, but they should none the less be taken seriously. CONCLUSION: Changes of neuromotor function measured as the ability to perform fast precise pronation/supination of the hands and fast precise finger tapping was shown in this cohort of steel workers. No causal relationships could be shown.

Massive intravenous manganese overdose due to compounding error: minimal role for hemodialysis.

CONTEXT: Manganese-associated parkinsonism is well described in occupational settings, in chronic methcathinone users, and in patients receiving long-term total parenteral nutrition. We present a unique case of acute intravenous manganese poisoning with a systematic evaluation of hemodialysis efficacy. CASE DETAILS: A 52-year-old woman was inadvertently administered a single intravenous dose of 800 mg compounded manganese chloride at an outpatient chelation center. In an attempt to minimize central nervous system (CNS) manganese deposition, she underwent urgent hemodialysis followed by five days of therapy with calcium disodium EDTA (1 g/m(2) over eight hours daily). Her initial whole blood manganese concentration, obtained six hours after exposure and prior to treatment, was 120 mcg/L (2.19 micromol/L); normal <5 mcg/L (< 0.09 micromol/L). Following the first four-hour hemodialysis session her blood manganese concentration decreased to 20 mcg/L (0.36 micromol/L). Despite the fall in her blood manganese concentration, analysis of dialysate revealed a total elimination of only 604 mcg (11 micromol) manganese (∼1.4% of manganese burden). Although she remained asymptomatic, an MRI on hospital day two revealed T1 hyperintensities within the bilateral globus pallidi, consistent with manganese exposure. DISCUSSION: Manganese poisoning is associated with irreversible neurologic toxicity. Hemodialysis did not appear to significantly enhance elimination in this case of acute intravenous manganese toxicity, beyond supportive care and calcium disodium EDTA chelation.

Grey matter abnormalities in methcathinone abusers with a Parkinsonian syndrome.

BACKGROUND: A permanent Parkinsonian syndrome occurs in intravenous abusers of the designer psychostimulant methcathinone (ephedrone). It is attributed to deposition of contaminant manganese, as reflected by characteristic globus pallidus hyperintensity on T1-weighted MRI. METHODS: We have investigated brain structure and function in methcathinone abusers (n = 12) compared to matched control subjects (n = 12) using T1-weighted structural and resting-state functional MRI. RESULTS: Segmentation analysis revealed significant (p < .05) subcortical grey matter atrophy in methcathinone abusers within putamen and thalamus bilaterally, and the left caudate nucleus. The volume of the caudate nuclei correlated inversely with duration of methcathinone abuse. Voxel-based morphometry showed patients to have significant grey matter loss (p < .05) bilaterally in the putamina and caudate nucleus. Surface-based analysis demonstrated nine clusters of cerebral cortical thinning in methcathinone abusers, with relative sparing of prefrontal, parieto-occipital, and temporal regions. Resting-state functional MRI analysis showed increased functional connectivity within the motor network of patients (p < .05), particularly within the right primary motor cortex. CONCLUSION: Taken together, these results suggest that the manganese exposure associated with prolonged methcathinone abuse results in widespread structural and functional changes affecting both subcortical and cortical grey matter and their connections. Underlying the distinctive movement disorder caused by methcathinone abuse, there is a more widespread pattern of brain involvement than is evident from the hyperintensity restricted to the basal ganglia as shown by T1-weighted structural MRI.

Neurologic spectrum of chronic liver failure and basal ganglia T1 hyperintensity on magnetic resonance imaging: probable manganese neurotoxicity.

BACKGROUND: An atypical form of parkinsonism has been described in patients with chronic liver disease, associated with increased T1 signal in the basal ganglia on magnetic resonance imaging. The magnetic resonance imaging signal changes are characteristic of manganese accumulation, which has been neuropathologically confirmed. Manganese neurotoxicity may result in additional neurologic findings besides parkinsonism. OBJECTIVE: To fully characterize patients with chronic central nervous system symptoms and chronic liver failure associated with basal ganglia T1 hyperintensity. DESIGN: Prospective and retrospective case study. SETTING: Mayo Clinic, Rochester, Minn. PARTICIPANTS: Eight patients referred for neurologic evaluation and studied prospectively, and 7 additional retrospectively identified patients who had been examined by Mayo Clinic neurologists. MAIN OUTCOME MEASURES: Neurologic syndromes identified. RESULTS: Three syndromes were recognized in these 15 patients with liver failure and basal ganglia T1 hyperintensity on magnetic resonance imaging: (1) isolated parkinsonism, (2) gait ataxia plus other neurologic findings (ataxia-plus), and (3) cognitive impairment with psychiatric features. All but 1 patient had elevated blood manganese levels. Ammonia levels were normal in most, and the neurologic syndromes did not appear to reflect the well-known toxic-metabolic encephalopathy of liver disease. CONCLUSIONS: Chronic liver failure may result in heterogeneous neurologic syndromes that cut across a variety of liver diseases. We selected cases on the basis of evidence of brain manganese accumulation, and this may be a crucial component of these syndromes. Further studies are necessary to explore this issue.

Neuroimaging identifies increased manganese deposition in infants receiving parenteral nutrition.

BACKGROUND: Manganese, an essential metal for normal growth and development, is neurotoxic on excessive exposure. Standard trace element-supplemented neonatal parenteral nutrition (PN) has a high manganese content and bypasses normal gastrointestinal absorptive control mechanisms, which places infants at risk of manganese neurotoxicity. Magnetic resonance (MR) relaxometry demonstrating short T1 relaxation time (T1R) in the basal ganglia reflects excessive brain manganese accumulation. OBJECTIVE: This study tested the hypothesis that infants with greater parenteral manganese exposure have higher brain manganese accumulation, as measured by MR imaging, than do infants with lower parenteral manganese exposure. DESIGN: Infants exposed to parenteral manganese were enrolled in a prospective cohort study. Infants classified as having high manganese exposure received >75% of their nutrition in the preceding 4 wk as PN. All others were classified as having low exposure. Daily parenteral and enteral manganese intakes were calculated. Whole-blood manganese was measured by high-resolution inductively coupled plasma mass spectrometry. Brain MR relaxometry was interpreted by a masked reviewer. Linear regression models, adjusted for gestational age (GA) at birth, estimated the association of relaxometry indexes with total and parenteral manganese exposures. RESULTS: Seventy-three infants were enrolled. High-quality MR images were available for 58 infants, 39 with high and 19 with low manganese exposure. Four infants with a high exposure had blood manganese concentrations >30 µg/L. After controlling for GA, higher parenteral and total manganese intakes were associated with a lower T1R (P = 0.01) in the globus pallidus and putamen but were not associated with whole-blood manganese (range: 3.6-56.6 µg/L). Elevated conjugated bilirubin magnified the association between parenteral manganese and decreasing T1R. CONCLUSION: A short T1R for GA identifies infants at risk of increased brain manganese deposition associated with PN solutions commonly used to nourish critically ill infants. These trials were registered at clinicaltrials.gov as NCT00392977 and NCT00392730.