{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:58:49Z","timestamp":1760241529880,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2018,4,18]],"date-time":"2018-04-18T00:00:00Z","timestamp":1524009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Heavy metal poisoning is a rare but important cause of encephalopathy. Manganese (Mn) toxicity is especially rare in the modern world, and clinicians\u2019 lack of recognition of its neuropsychiatric manifestations can lead to misdiagnosis and mismanagement. We describe the case of a man who presented with recurrent episodes of confusion, psychosis, dystonic limb movement and cognitive impairment and was initially diagnosed with anti-voltage-gated potassium channel (VGKC) complex limbic encephalitis in view of previous positive autoantibodies. His failure to respond to immunotherapy prompted testing for heavy metal poisoning, which was positive for Mn. This is the first report to examine an association between Mn and VGKC antibodies and the effects of Mn on functional brain activity using functional near-infrared spectroscopy (fNIRS).<\/jats:p>","DOI":"10.3390\/ijerph15040783","type":"journal-article","created":{"date-parts":[[2018,4,18]],"date-time":"2018-04-18T03:51:13Z","timestamp":1524023473000},"page":"783","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Chronic Manganese Toxicity Associated with Voltage-Gated Potassium Channel Complex Antibodies in a Relapsing Neuropsychiatric Disorder"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7092-9566","authenticated-orcid":false,"given":"Cyrus S.H.","family":"Ho","sequence":"first","affiliation":[{"name":"Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9629-4493","authenticated-orcid":false,"given":"Roger C.M.","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy M.L.","family":"Quek","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore"},{"name":"Division of Neurology, University Medicine Cluster, National University Hospital, Singapore 119074, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0006-2952(03)00145-X","article-title":"Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese","volume":"66","author":"Roth","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/0021-9681(66)90094-4","article-title":"Essential trace metals in man: Manganese: A study in homeostasis","volume":"19","author":"Schroeder","year":"1966","journal-title":"J. Chronic Dis."},{"key":"ref_3","first-page":"205","article-title":"Nutrition versus toxicology of manganese in humans: Evaluation of potential biomarkers","volume":"20","author":"Greger","year":"1999","journal-title":"Neurotoxicology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3109\/10715769109145794","article-title":"Structure-function relationships in iron and manganese superoxide dismutases","volume":"12","author":"Stallings","year":"1991","journal-title":"Free Radic. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s40572-017-0136-1","article-title":"Relationships between Essential Manganese Biology and Manganese Toxicity in Neurological Disease","volume":"4","author":"Pfalzer","year":"2017","journal-title":"Curr. Environ. Health Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.taap.2004.10.003","article-title":"Alteration at translational but not transcriptional level of transferrin receptor expression following manganese exposure at the blood-CSF barrier in vitro","volume":"205","author":"Li","year":"2005","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0041-008X(92)90360-5","article-title":"Mn2+ sequestration by mitochondria and inhibition of oxidative phosphorylation","volume":"115","author":"Gavin","year":"1992","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s00706-011-0478-6","article-title":"The role of metal ions in dopaminergic neuron degeneration in Parkinsonism and Parkinson\u2019s disease","volume":"142","author":"Paris","year":"2011","journal-title":"Monatsh. Chem."},{"key":"ref_9","first-page":"946372","article-title":"The toxic effect of manganese on the acetylcholinesterase activity in rat brains","volume":"2014","author":"YousefiBabadi","year":"2014","journal-title":"J. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1002\/nbm.931","article-title":"Manganese toxicity upon overexposure","volume":"17","author":"Crossgrove","year":"2004","journal-title":"NMR Biomed."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.neuro.2005.11.002","article-title":"Manganese neurotoxicity: Connecting the dots along the continuum of dysfunction","volume":"27","author":"Martin","year":"2006","journal-title":"Neurotoxicology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7519","DOI":"10.3390\/ijerph120707519","article-title":"Manganese-Induced Parkinsonism and Parkinson\u2019s Disease: Shared and Distinguishable Features","volume":"12","author":"Kwakye","year":"2015","journal-title":"Int. J Environ. Res. Public Health"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1353-8020(99)00011-5","article-title":"A review of normal sleep and its disturbances in Parkinson\u2019s disease","volume":"5","author":"Pal","year":"1999","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.parkreldis.2006.09.002","article-title":"The natural history of neurological manganism over 18 years","volume":"13","author":"Huang","year":"2007","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1289\/ehp.0901748","article-title":"Manganese and Parkinson\u2019s disease: A critical review and new findings","volume":"118","author":"Guilarte","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1007\/s12017-009-8083-0","article-title":"Manganese and its role in Parkinson\u2019s disease: From transport to neuropathology","volume":"11","author":"Aschner","year":"2009","journal-title":"Neuromol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1097\/nen.0b013e31812503cf","article-title":"The neuropathology of manganese-induced Parkinsonism","volume":"66","author":"Perl","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_18","first-page":"189","article-title":"The role of heavy metals in autoimmunity","volume":"52","author":"Cojocaru","year":"2014","journal-title":"Rom. J. Intern. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1016\/j.autrev.2016.07.018","article-title":"From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time","volume":"15","author":"Schreurs","year":"2016","journal-title":"Autoimmun. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.nrl.2013.12.007","article-title":"Clinical spectrum and diagnostic value of antibodies against the potassium channel related protein complex","volume":"30","author":"Montojo","year":"2015","journal-title":"Neurologia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.seizure.2013.06.004","article-title":"VGKC complex antibodies in epilepsy: Diagnostic yield and therapeutic implications","volume":"22","author":"Lilleker","year":"2013","journal-title":"Seizure"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1212\/WNL.0000000000003300","article-title":"The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies","volume":"87","author":"Lilleker","year":"2016","journal-title":"Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1039\/c2tx20064c","article-title":"Mechanisms of lead and manganese neurotoxicity","volume":"2","author":"Neal","year":"2013","journal-title":"Toxicol. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1001\/archneur.1974.00490310061010","article-title":"Chronic manganese intoxication","volume":"30","author":"Cook","year":"1974","journal-title":"Arch. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s40572-015-0056-x","article-title":"Manganese Toxicity upon Overexposure: A Decade in Review","volume":"2","author":"Zheng","year":"2015","journal-title":"Curr. Environ. Health Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.neuro.2005.12.002","article-title":"Neuroimaging in manganism","volume":"27","author":"Kim","year":"2006","journal-title":"Neurotoxicology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuro.2010.10.002","article-title":"Biomarkers of Manganese Intoxication","volume":"32","author":"Zheng","year":"2011","journal-title":"Neurotoxicology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1289\/ehp.1002192","article-title":"In vivo measurement of brain GABA concentrations by magnetic resonance spectroscopy in smelters occupationally exposed to manganese","volume":"119","author":"Dydak","year":"2011","journal-title":"Environ. Health Perspect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1038\/jcbfm.2011.92","article-title":"Effect of manganese chloride on the neurochemical profile of the rat hypothalamus","volume":"31","author":"Just","year":"2011","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3389\/fpsyt.2016.00074","article-title":"Optical Topography in Psychiatry: A Chip off the Old Block or a New Look beyond the Mind-Brain Frontiers?","volume":"7","author":"Ho","year":"2016","journal-title":"Front. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1192\/apt.bp.115.015610","article-title":"Functional near-infrared spectroscopy in psychiatry","volume":"23","author":"Lai","year":"2017","journal-title":"BJPsych Adv."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1097\/01.jom.0000204114.01893.3e","article-title":"Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: A case of 17-year follow-up study","volume":"48","author":"Jiang","year":"2006","journal-title":"J. Occup. Environ. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/jat.3052","article-title":"Reversible cholinesterase inhibitors as pre-treatment for exposure to organophosphates: Assessment using azinphos-methyl","volume":"35","author":"Petroianu","year":"2015","journal-title":"J. Appl. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1172\/JCI105814","article-title":"Slow turnover of manganese in active rheumatoid arthritis accelerated by prednisone","volume":"47","author":"Cotzias","year":"1968","journal-title":"J. Clin. Investig."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/15\/4\/783\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:01:07Z","timestamp":1760194867000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/15\/4\/783"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,18]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,4]]}},"alternative-id":["ijerph15040783"],"URL":"https:\/\/doi.org\/10.3390\/ijerph15040783","relation":{},"ISSN":["1660-4601"],"issn-type":[{"type":"electronic","value":"1660-4601"}],"subject":[],"published":{"date-parts":[[2018,4,18]]}}}