Encephalopathy Following ingestion of Lead-Contaminated Opium; Magnetic Resonance Imaging Findings

Encephalopathy Following ingestion of Lead-Contaminated Opium; Magnetic Resonance Imaging Findings | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Encephalopathy Following ingestion of Lead-Contaminated Opium; Magnetic Resonance Imaging Findings Maryam Haghighi-Morad, Nasim Zamani, Hossein Hassanian-Moghaddam, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.19790/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 May, 2020 Read the published version in BMC Neurology → Version 2 posted 8 You are reading this latest preprint version Show more versions Abstract Background Encephalopathy is an uncommon but serious presentation of lead toxicity. Objective We aimed to determine and follow-up the brain magnetic resonance imaging (MRI) abnormalities in the patients with lead encephalopathy due to ingestion of lead contaminated opium. Methods In a cross-sectional study during lead-contaminated opium outbreak, all lead-poisoned patients with any signs/symptoms of encephalopathy were included. Results Of 19 patients with lead encephalopathy, five died early and other five could not be sent to MRI during their hospitalization period. Mean age was 51±11 years and males were dominant (89%). Median [IQR] blood lead level (BLL) was 101 [81, 108] µg/dL (range; 50 to 200 µg/dL). There was no correlation between MRI findings and signs/symptoms. MRI was normal in six and abnormal in three. Bilateral symmetric involvement of parieto-occipital lobes was observed. Gray matter, gray-white matter junction, and subcortical white matter were also affected. Follow-up MRI was performed in two with abnormal MRI which showed complete and near complete resolution of the abnormalities after cessation of opium use and treatment. Conclusion: There was no correlation between MRI findings and BLL. Complete recovery of brain MRI lesions was detected after cessation of opium use. Neurology Neurosurgery lead toxicity outbreak encephalopathy magnetic resonance imaging opioid Figures Figure 1 Figure 2 Figure 3 Introduction Encephalopathy is an uncommon but serious presentation of lead toxicity [1]. Lead encephalopathy is generally described by sudden commence of the manifestations including severe headache, vomiting, convulsions, mental aberration and excitement [2]. Although blood lead levels (BLLs) of higher than 100 μg/dL generally accompany with lead encephalopathy, much lower levels (as low as 38 μg/dL) may also result in encephalopathy in chronic toxicities [1]. During an outbreak in Iran, opium users were evaluated at Loghman-Hakim Hospital, and found to have high BLLs. Lead-contaminated opium was considered as the source of oral contamination [3-5]. Lead-contaminated opium has been recently discussed in the literature [6]. The objective of the current report was to determine the magnetic resonance imaging (MRI) characteristics of lead encephalopathy due to ingestion of lead-contaminated opium. We also aimed to perform a follow-up MRI after treatment in these patients to see if treatment improved their MRI abnormalities. Methods 2.1. Study design and setting This cross-sectional study was carried out during an outbreak of lead toxicity due to lead-contaminated opium in Tehran between September 2016 and August 2017 [3]. All data was pooled from a referral center for poisoned patients with annual admissions of almost 24000 intoxicated patients supposed to be the biggest in-patient clinical toxicology center of the world [7]. 2.2. Selection of participants All lead-poisoned patients who referred with any signs/symptoms of encephalopathy including loss of consciousness or seizure were considered as the potential participants through a chart review of the admitted patients during outbreak [3]. Diagnosis of lead toxicity was made based on BLLs higher than normal (normal range;<10 µg/dL) checked by atomic absorption technique (Graphite Furnace Atomic Absorption Spectrometry [GFAAS]). After termination of treatment, BLL was followed using Lead Care II device. Our MRI unit has recently been established with no supporting ventilator for comatose patients. Therefore, only patients who were stable and not intubated could be sent for MRI. If a comatose intubated patient improved and could be extubated, he/she would also be considered to be transferred to MRI unit where MRI was performed at the earliest convenient time. Bedside electroencephalogram (EEG) was done based on the treating physician’s decision. Our primary outcome was MRI findings of the patients with lead encephalopathy while determination of the demographic characteristics of the patients and follow-up results of the abnormal MRIs were the secondary outcomes. MRI was performed using Vantage Elan 1.5T MR system (Toshiba Medical Systems Corporation [TMSC]). 2.3. Statistical Analysis For the description of quantitative variables with normal and non-normal distribution, mean (±SD) and median [IQR interquartile range] were used, respectively. For qualitative variables, percent of frequency was used. To compare normal/abnormal MRI findings with categorical variables, Fisher’s exact test was applied. For comparing continuous variables with normal/abnormal MRI findings, t-test or Mann-Whitney U test was used. A P value less than 0.05 was considered to be statistically significant. Statistical package for social sciences (SPSS) version 17.0 (SPSS Inc., Chicago, Ill, USA) was used for analysis. Our institutional ethics committee approved this study. Results Almost 3800 lead-poisoned opium user patients were admitted to our center [3]. Of the 19 patients who were eligible to be entered, five died early and MRI was out of service for another five patients because of technical reasons. Finally nine patients were evaluated by MRI. Lab tests for other medications/toxins that could affect brain MRI (including carbon monoxide, methanol, pesticides, cyanide, and sympathomimetics) were negative. Hypoxic encephalopathy was also excluded using cases without a period of hypoxia greater than 3 minutes or an out of hospital respiratory arrest as a clinical finding. Table 1 shows epidemiological characteristics of the patients. Their mean age was 51±11 years (range; 39 to 72) and males were dominant (89%). Median [IQR] blood lead level was 101 [81, 108] µg/dL (range; 50 to 200) with a mean hemoglobin level of 9.2±1.7 mg/dL (range; 7.6 to 12.8). EEG was performed in three and was normal in one and abnormal in two of those who had MRIs (Table 1). MRI was normal in six cases (67%) and showed pathologic changes in three cases (Figures 1-3). There was no statistically significant difference between those with and without MRI abnormalities in terms of BLL, hemoglobin level, age and clinical manifestations. Figures 1-3 show MRI findings of three patients during hospitalization. On follow-up, all patients became symptom-free after quitting the lead-contaminated opium or initiation of lead chelating agents. Two, out of three patients with abnormal MRI accepted to undergo the follow-up MRI. The time interval between the two MRIs was three and twelve months in cases 3 and 1, respectively. MRI findings resolved with no major neurological damage. BLLs were 8 and 25 µg/dL on follow-up evaluations of these two patients, respectively. We could not find any correlation between MRI findings and BLLs, age, Hb, EEG, and signs/symptoms. Limitations: We could only evaluate 5 out of 19 potentially eligible patients due to mortality and technical reasons. We have no access to the follow-up information of the patients that did not undergo the MRI, to know if all these patients presented reversible neurological symptoms. Discussion Opioid abuse causes acute and chronic effects on neurovascular system. The most common encountered acute neurovascular effect of opioids on central nervous system is ischemia which is more often observed with intravenous injection of the drugs in comparison to oral ingestion or inhalation. The suggested mechanisms for acute ischemia due to opioids are reversible vasospasm, vasculitis and embolic events. Reversible vasospasm is the result of stimulation of mu-opioid receptors of the vascular smooth muscles. Immune mediated response to opioids or impurities causes vasculitis. Also embolization of small insoluble particles is a potential mechanism of ischemic events due to opioids. Globus pallidus and after that hippocampus and cerebellar water shed areas are the most commonly reported location of ischemic infarctions due to opioids. Chronic neurovascular abnormalities from opioid abuse are represented with diffuse, symmetric bilateral T2W hyper intensities in the subcortical and peri ventricular white mater which are secondary to microvascular ischemic changes [8, 9]. None of these findings due to opioids toxicity are observed in our patients. MRI findings of lead encephalopathy due to regular ingestion of opium have not been reported to date. In our study, three patients (33.3%) showed abnormal MRI findings. Atre and colleagues reported encephalopathy due to Ayurvedic medicine with bilateral symmetric involvement of the parasagittal occipital, temporal, parietal and frontal lobes and a right cerebellar lesion. In the first patient of our study, the lesions dramatically resolved without chelation therapy. This may emphasize on the importance of cessation of lead exposure as the most effective treatment in lead encephalopathy [10]. Lead encephalopathy is usually associated with BLLs higher than 100 μg/dL; but, there are few reports of encephalopathy with levels even lower than 70 μg/dL [11]. The minimum BLL in our study was 50 μg/dL and encephalopathy due to such low BLL might be due to the chronic nature of the toxicity. Lead encephalopathy can be seen even as low as 38 μg/dL in chronic cases suggesting demyelination process of lead toxicity [1]. This might be in accordance with previous study of Bouldin et al. indicating cumulative brain lead exposure and the best predictor of the prevalence of demyelination [12]. Bilateral symmetric involvement of the thalami and lentiform nuclei were reported in two patients with abnormal signal in external capsule and subcortical white matter in one patient [13]. Bilateral thalamic and T2-weighted high signal areas in the basal ganglia, posterior thalamus, pons, insula, and periventricular white matter have also been reported [11, 14]. In our patients, bilateral symmetric involvement of occipital, parietal and to a less extent, frontal and temporal lobes were observed. Gray matter, gray-white matter junction, and subcortical white matter were also affected. Our patients' imaging results are similar to regular findings in posterior reversible encephalopathy syndrome (PRES) which is an acute neurotoxic state characterized by temporary neurological symptoms including acute headache, altered mental status, visual loss, and coma. PRES is mainly due to hypertension but other conditions including immunosuppression therapy, hypercalcemia, and chronic renal/hepatic failure can also lead to it. It is suggested that PRES is associated with endothelial damage and blood brain barrier (BBB) disruption [15]. Interestingly, organic lead is able to cross blood-brain barrier, accumulate in the brain tissue, and mimic or mobilize calcium ions. Lead can enter the brain not only by passive transport but also as the consequence of changed BBB permeability. “Leaky microvessels” following endothelial dysfunction in lead excitotoxicity and PRES have the same MRI findings [16]. The data obtained in the study, although limited by the number of patients, is interesting because the patients' encephalopathy improved after discontinuation of the contaminated opium. Response to treatment ruled out other opioid-related complications such as “chasing the dragon” or hypoxic encephalopathy in our patients. Conclusions One-thirds of our encephalopathy patients, that could be retrieved for follow-up MRI, had reversible abnormal MRI findings. MRIs of the more severely poisoned patients would have been worse, but as these patients did not undergo MRIs, this cannot be known. With the knowledge on our limited cases, no correlation exists between the MRI findings and BLLs or clinical signs. BBB disruption is the same mechanism for imaging findings in lead encephalopathy and PRES. List of Abbreviations BBB=Blood brain barrier, BLL=Blood lead level, CNS=Central Nervous System, EEG= Electroencephalography, Hb=Hemoglobin, IQR= Inter Quartile Range, MRI=Magnetic Resonance Imaging, PRES= Posterior Reversible Encephalopathy Syndrome, SPSS=Statistical package for social sciences Declarations Ethics approval and consent to participate: This study approved by Shahid Beheshti University of Medical Sciences ethics committee (IR.SBMU.RETECH.REC.1396.74). The informed consent from was waved due to retrospective nature of the study by ethics committee. Consent to publish: Available. Availability of data and materials: The data is all presented in the text. Competing interests: None. Funding: This study was supported by Social Determinants of Health Research Center, Shahid Beheshti University of Medical sciences, Tehran, Iran (Grant no. 10307). Authors' Contributions: HHM is the guarantor of integrity of the entire study. MHM and MS gave the study concepts and designed the study. NZ, and MHM did the literature research. MHM and HHM performed the data and statistical analysis. NZ prepared the manuscript draft and HHM did edit the final manuscript. All authors have read and approved the manuscript. Acknowledgements: None References Rao, J.V.B., Vengamma, B., Naveen, T. and Naveen, V., 2014. Lead encephalopathy in adults. J Neurosci Rural Pract. 5,161–163. Bramwell, B., 1879. The Differential Diagnosis of Lead Encephalopathy and Intra-Cranial Tumours. Edinb Med J. 25, 510-514. Ghane, T., Zamani, N., Hassanian-Moghaddam, H., Beyrami, A. and Noroozi, A., 2018. Lead poisoning outbreak among opium users in the Islamic Republic of Iran, 2016‒2017. Bull World Health Organ. 96, 165-172. Zamani, N., Hassanian-Moghaddam, H., 2018. Lead Contamination of Opium— Iran, 2016. MMWR Morb Mortal Wkly Rep. 66, 1408-9. Zamani, N., Hassanian-Moghaddam, H., Latifi, M., 2017. Abdominopelvic CT in a patient with seizure, anemia, and hypocalcemia. Gastroenterology. 152, 27–28. Alinejad, S., Aaseth, J., Abdollahi, M., Hassanian‐Moghaddam, H. and Mehrpour, O., 2018. Clinical Aspects of Opium Adulterated with Lead in Iran: A Review. Basic Clin Pharmacol Toxicol. 122, 56-64. Hassanian-Moghaddam, H., Zamani, N., Rahimi, M., Shadnia, S., Pajoumand, A., Sarjami, S., 2014. Acute Adult and Adolescent Poisoning in Tehran, Iran; the Epidemiologic Trend between 2006 and 2011. Arch Iran Med. 17, 534-538. Geibprasert, S., Gallucci, M., Krings, T., 2010. Addictive Illegal Drugs : Structural Neuroimaging. AJNR. 31, 803-808. Borne, J., Riascos, R., Cuellar, H.,Vargas, D., Rojas, R., 2005. Neuroimaging in Drug and Substance Abuse Part II: Opioids and Solvents. Top Magn Reson Imaging.16, 239-245. Atre, A.L., Shinde, P.R., Shinde, S.N., Wadia, R.S., Nanivadekar, A.A., Vaid, S.J., Shinde, R.S., 2006. Pre and posttreatment MR imaging findings in lead encephalopathy. AJNR Am J Neuroradiol. 27, 902-903. Mani, J., Chaudhary, N., Kanjalkar, M. and Shah, P.U., 1998. Cerebellar ataxia due to lead encephalopathy in adult. J Neurol Neurosurg Psychiatry. 65, 797-798. Bouldin, T.W., Meighan, M.E., Gaynor, J.J., Goines, N.D., Mushak, P., Krigman, M.R., 1985. Differential vulnerability of mixed and cutaneous nerves in lead neuropathy. J Neuropathol Exp Neurol. 44, 384-96. Bhaskara Rao, J.V.,Vengamma, B., Naveen, T., Naveen, V., 2014. Lead encephalopathy in adults. J Neurosci Rural Pract. 5, 161-163. Schröter, C., Schröter, H. and Huffmann, G., 1991. Neurologic and psychiatric manifestations of lead poisoning in adults (case report and review of literature) ]in German]. Fortschr Neurol Psychiatr. 59, 413-424. Demirel, İ., Kavak, B.S., Özer, A.B., Bayar, M.K. and Erhan, Ö.L., 2014. An intensive care approach to posterior reversible encephalopathy syndrome (PRES): An analysis of 7 cases. J Turk Ger Gynecol Assoc. 15, 217-221. Strużyńska, L., Walski, M., Gadamski, R., Dabrowska-Bouta, B. and Rafałowska, U., 1997. Lead-induced abnormalities in blood-brain barrier permeability in experimental chronic toxicity. Mol Chem Neuropathol. 31, 207-224. Tables Table 1: Selected characteristics of patients with lead encephalopathy No Age (Year) Gender BLL (µg/dL) Hgb (mg/dL) Signs & Symptoms EEG Interpretation Chelating agents MRI finding 1 52 M 50 12.8 Seizure, abdominal pain, agitation, constipation mild diffuse encephalopa thy No abnormal 2 72 M 200 8.7 Delirium, abdominal pain, weakness, constipation not done BAL+EDTA abnormal 3 39 M 68 7.6 Abdominal pain, constipation, confusion, seizure moderate diffuse encephalopa thy BAL+EDTA abnormal 4 45 M 95 8.1 Abdominal pain, weakness, myalgia, confusion, seizure, insomnia, loss of appetite, dysarthria, gait disturbance, steering, delirium, seizure, constipation, ventricular tachycardia and cardiac arrest before arrival diffuse alpha activity BAL+EDTA normal 5 40 M 101 10.2 Consciousness fluctuation, delirium, hallucination, disorientation, upper motor neuron weakness moderate diffuse encephalopa thy (cortical dysfunction) BAL+EDTA normal 6 51 M 107 8.4 Repeated seizure, weakness, agitation, loss of appetite, abdominal pain, constipation mild diffuse cortical dysfunction BAL+EDTA normal 7 57 M 105 7.6 Abdominal pain, confusion, disorientation to time, constipation Normal BAL+EDTA normal 8 48 M 110 10.6 Agitation, seizure, delirium not done BAL+EDTA normal 9 52 F >65 9.1 Seizure, delirium, severe agitation, nausea and vomiting, confusion mild diffuse encephalopathy BAL+EDTA normal Cite Share Download PDF Status: Published Journal Publication published 01 May, 2020 Read the published version in BMC Neurology → Version 2 posted Review # 1 received at journal 31 Mar, 2020 Review # 2 received at journal 15 Mar, 2020 Reviewer # 2 agreed at journal 10 Mar, 2020 Reviewer # 1 agreed at journal 09 Mar, 2020 Reviewers invited by journal 06 Mar, 2020 Editor assigned by journal 05 Mar, 2020 Submission checks completed at journal 04 Mar, 2020 Editor invited by journal 04 Mar, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-10402","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":397355,"identity":"85131a32-cd5b-441d-949f-93858067edbd","order_by":1,"name":"Maryam Haghighi-Morad","email":"","orcid":"","institution":"Shahid Beheshti University of Medical Sciences School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Maryam","middleName":"","lastName":"Haghighi-Morad","suffix":""},{"id":397356,"identity":"a67e9729-bcd2-404e-97f2-65b0f95cd77b","order_by":2,"name":"Nasim Zamani","email":"","orcid":"","institution":"Shahid Beheshti University of Medical Sciences School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Nasim","middleName":"","lastName":"Zamani","suffix":""},{"id":397357,"identity":"4657845c-f54c-4d4b-81e2-3d11c7742b92","order_by":3,"name":"Hossein Hassanian-Moghaddam","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYBACAwglwcDA3sAGFWNsIFILzwHStIB0JbDhUYcEzNmPP/7wc4eFvLnk82ePbrYxyPM3MLd9wKfFsifHTLL3jIThztk55sa5bQyGMw4wNs/A67ADOWwMvG0SjBtu57BJA7UwbmBgbMbvl/PPH3/82yZhv+Hm8WcgLfaEtdxIMJAG2pK44QaDGUhLIhFa3phJy7ZJJG84A/RLzjmJ5BmHCTos/fHHt211thuOH3/2OKfMxra/vf0xXi3oABinzCRpGAWjYBSMglGADQAAUpBHUPjfJaYAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-4370-0544","institution":"Shahid Beheshti University of Medical Sciences School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hossein","middleName":"","lastName":"Hassanian-Moghaddam","suffix":""},{"id":397358,"identity":"fe5a7ef4-ea59-47ad-bb10-a044df8cf9b9","order_by":4,"name":"Maziar Shojaei","email":"","orcid":"","institution":"Shahid Beheshti University of Medical Sciences School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Maziar","middleName":"","lastName":"Shojaei","suffix":""}],"badges":[],"createdAt":"2019-12-26 15:47:24","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.2.19790/v2","doiUrl":"https://doi.org/10.21203/rs.2.19790/v2","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12883-020-01750-z","type":"published","date":"2020-05-01T21:00:08+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":632400,"identity":"b98187ec-1098-42c1-aa04-6653d40596ba","added_by":"auto","created_at":"2020-03-11 18:06:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":171108,"visible":true,"origin":"","legend":"(Case1):\nOn admission MRI: MRI shows bilateral symmetric involvement of two areas in parasagittal parietal and occipital lobes. Gray matter, gray white matter junction, and the subcortical white matter are involved. The lesions are bright on T2-weighted and FLAIR images and hypointense on T1-weighted images. No evidence of diffusion restriction is noted. \nFollow-up MRI: Lesions completely resolved on the repeat MRI without chelation therapy.","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-10402/v2/1.png"},{"id":632401,"identity":"4c943ee0-4f66-4469-b22f-65ae4b77a9be","added_by":"auto","created_at":"2020-03-11 18:06:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":156106,"visible":true,"origin":"","legend":"(Case 3): \nAdmission MRI: MRI shows symmetric involvement of the parietal lobes in the parasagittal region. Gray matter, gray white matter junction, and subcortical white matter are affected. The lesions were bright on T2-weighted and FLAIR images and hypointense on T1-weighted images. Mild to moderate edema is associated with these lesions. No evidence of diffusion restriction is noted in mentioned areas.\nFollow-up MRI: Complete recovery of the lesions are seen in the repeat MRI after chelation therapy.","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-10402/v2/2.png"},{"id":632402,"identity":"01d8318d-b31f-4a00-be96-728076ea086f","added_by":"auto","created_at":"2020-03-11 18:06:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":255382,"visible":true,"origin":"","legend":"(Case 2):\nAdmission MRI: MRI shows symmetric involvement of the parasagittal areas of bilateral parietal and occipital lobes. Asymmetric involvement of bilateral posterior temporal lobes is also evident. The affected areas are gray matter, gray white matter junction, and subcortical white matter. The lesions signal on T2-weighted and FLAIR sequences are high and low on T1-weighted sequence. No evidence of Diffusion restriction is depicted in involved areas.\nThis patient refused follow-up MRI after chelation therapy as he believed to be completely fine.","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-10402/v2/3.png"},{"id":13493033,"identity":"ada6a01e-62db-4966-bf7f-c63cd4d956c4","added_by":"auto","created_at":"2021-09-16 22:33:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":805813,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-10402/v2/c25ca486-4add-4d80-807d-30345884ae33.pdf"}],"financialInterests":"","formattedTitle":"Encephalopathy Following ingestion of Lead-Contaminated Opium; Magnetic Resonance Imaging Findings","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEncephalopathy is an uncommon but serious presentation of lead toxicity [1]. Lead encephalopathy is generally described by sudden commence of the manifestations including severe headache, vomiting, convulsions, mental aberration and excitement [2]. Although blood lead levels (BLLs) of higher than 100 \u0026mu;g/dL generally accompany with lead encephalopathy, much lower levels (as low as 38 \u0026mu;g/dL) may also result in encephalopathy in chronic toxicities [1]. During an outbreak in Iran, opium users were evaluated at Loghman-Hakim Hospital, and found to have high BLLs. Lead-contaminated opium was considered as the source of oral contamination [3-5]. Lead-contaminated opium has been recently discussed in the literature [6]. The objective of the current report was to determine the magnetic resonance imaging (MRI) characteristics of lead encephalopathy due to ingestion of lead-contaminated opium. We also aimed to perform a follow-up MRI after treatment in these patients to see if treatment improved their MRI abnormalities.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003e2.1.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Study design and setting\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis cross-sectional study was carried out during an outbreak of lead toxicity due to lead-contaminated opium in Tehran between September 2016 and August 2017 [3]. All data was pooled from a referral center for poisoned patients with annual admissions of almost 24000 intoxicated patients supposed to be the biggest in-patient clinical toxicology center of the world [7].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.2.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Selection of participants\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll lead-poisoned patients who referred with any signs/symptoms of encephalopathy including loss of consciousness or seizure were considered as the potential participants through a chart review of the admitted patients during outbreak [3]. Diagnosis of lead toxicity was made based on BLLs higher than normal (normal range;\u0026lt;10 \u0026micro;g/dL) checked by atomic absorption technique \u003cem\u003e(Graphite Furnace Atomic Absorption Spectrometry\u003c/em\u003e [GFAAS]). After termination of treatment, BLL was followed using Lead Care II device.\u003c/p\u003e\n\u003cp\u003eOur MRI unit has recently been established with no supporting ventilator for comatose patients. Therefore, only patients who were stable and not intubated could be sent for MRI. If a comatose intubated patient improved and could be extubated, he/she would also be considered to be transferred to MRI unit where MRI was performed at the earliest convenient time. Bedside electroencephalogram (EEG) was done based on the treating physician\u0026rsquo;s decision.\u003c/p\u003e\n\u003cp\u003eOur primary outcome was MRI findings of the patients with lead encephalopathy while determination of the demographic characteristics of the patients and follow-up results of the abnormal MRIs were the secondary outcomes. MRI was performed using Vantage Elan 1.5T MR system (Toshiba Medical Systems Corporation [TMSC]).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.3.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Statistical Analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFor the description of quantitative variables with normal and non-normal distribution, mean (\u0026plusmn;SD) and median [IQR interquartile range] were used, respectively. For qualitative variables, percent of frequency was used. To compare normal/abnormal MRI findings with categorical variables, Fisher\u0026rsquo;s exact test was applied. For comparing continuous variables with normal/abnormal MRI findings, t-test or Mann-Whitney U test was used. A \u003cem\u003eP\u003c/em\u003e value less than 0.05 was considered to be statistically significant. Statistical package for social sciences (SPSS) version 17.0 (SPSS Inc., Chicago, Ill, USA) was used for analysis.\u003c/p\u003e\n\u003cp\u003eOur institutional ethics committee approved this study.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAlmost 3800 lead-poisoned opium user patients were admitted to our center [3]. Of the 19 patients who were eligible to be entered, five died early and MRI was out of service for another five patients because of technical reasons. Finally nine patients were evaluated by MRI. \u0026nbsp;Lab tests for other medications/toxins that could affect brain MRI (including carbon monoxide, methanol, pesticides, cyanide, and sympathomimetics) were negative. Hypoxic encephalopathy was also excluded using cases without a period of hypoxia greater than 3 minutes or an out of hospital respiratory arrest as a clinical finding. Table 1 shows epidemiological characteristics of the patients.\u003c/p\u003e\n\u003cp\u003eTheir mean age was 51\u0026plusmn;11 years (range; 39 to 72) and males were dominant (89%). Median [IQR] blood lead level was 101 [81, 108] \u0026micro;g/dL (range; 50 to 200) with a mean hemoglobin level of 9.2\u0026plusmn;1.7 mg/dL (range; 7.6 to 12.8).\u003c/p\u003e\n\u003cp\u003eEEG was performed in three and was normal in one and abnormal in two of those who had MRIs (Table 1).\u003cbr /\u003e MRI was normal in six cases (67%) and showed pathologic changes in three cases (Figures 1-3). There was no statistically significant difference between those with and without MRI abnormalities in terms of BLL, hemoglobin level, age and clinical manifestations.\u003c/p\u003e\n\u003cp\u003eFigures 1-3 show MRI findings of three patients during hospitalization. On follow-up, all patients became symptom-free after quitting the lead-contaminated opium or initiation of lead chelating agents. Two, out of three patients with abnormal MRI accepted to undergo the follow-up MRI. The time interval between the two MRIs was three and twelve months in cases 3 and 1, respectively. MRI findings resolved with no major neurological damage. BLLs were 8 and 25 \u0026micro;g/dL on follow-up evaluations of these two patients, respectively. We could not find any correlation between MRI findings and BLLs, age, Hb, EEG, and signs/symptoms.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLimitations: \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe could only evaluate 5 out of 19 potentially eligible patients due to mortality and technical reasons.\u003c/p\u003e\n\u003cp\u003eWe have no access to the follow-up information of the patients that did not undergo the MRI, to know if all these patients presented reversible neurological symptoms.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOpioid abuse causes acute and chronic effects on neurovascular system. The most common encountered acute neurovascular effect of opioids on central nervous system is ischemia which is more often observed with intravenous injection of the drugs in comparison to oral ingestion or inhalation. The suggested mechanisms for acute ischemia due to opioids are reversible vasospasm, vasculitis and embolic events.\u003c/p\u003e\n\u003cp\u003eReversible vasospasm is the result of stimulation of mu-opioid receptors of the vascular smooth muscles. Immune mediated response to opioids or impurities causes vasculitis. Also embolization of small insoluble particles is a potential mechanism of ischemic events due to opioids. Globus pallidus and after that hippocampus and cerebellar water shed areas are the most commonly reported location of ischemic infarctions due to opioids. Chronic neurovascular abnormalities from opioid abuse are represented with diffuse, symmetric bilateral T2W hyper intensities in the subcortical and peri ventricular white mater which are secondary to microvascular ischemic changes [8, 9]. None of these findings due to opioids toxicity are observed in our patients.\u003c/p\u003e\n\u003cp\u003eMRI findings of lead encephalopathy due to regular ingestion of opium have not been reported to date. In our study, three patients (33.3%) showed abnormal MRI findings. Atre and colleagues reported encephalopathy due to Ayurvedic medicine with bilateral symmetric involvement of the parasagittal occipital, temporal, parietal and frontal lobes and a right cerebellar lesion. In the first patient of our study, the lesions dramatically resolved without chelation therapy. This may emphasize on the importance of cessation of lead exposure as the most effective treatment in lead encephalopathy [10].\u003c/p\u003e\n\u003cp\u003eLead encephalopathy is usually associated with BLLs higher than 100 \u0026mu;g/dL; but, there are few reports of encephalopathy with levels even lower than 70 \u0026mu;g/dL [11]. The minimum BLL in our study was 50 \u0026mu;g/dL and encephalopathy due to such low BLL might be due to the chronic nature of the toxicity. Lead encephalopathy can be seen even as low as 38 \u0026mu;g/dL in chronic cases suggesting demyelination process of lead toxicity [1]. This might be in accordance with previous study of Bouldin et al. indicating cumulative brain lead exposure and the best predictor of the prevalence of demyelination [12].\u003c/p\u003e\n\u003cp\u003eBilateral symmetric involvement of the thalami and lentiform nuclei were reported in two patients with abnormal signal in external capsule and subcortical white matter in one patient [13]. Bilateral thalamic and T2-weighted high signal areas in the basal ganglia, posterior thalamus, pons, insula, and periventricular white matter have also been reported [11, 14]. In our patients, bilateral symmetric involvement of occipital, parietal and to a less extent, frontal and temporal lobes were observed. Gray matter, gray-white matter junction, and subcortical white matter were also affected.\u003c/p\u003e\n\u003cp\u003eOur patients' imaging results are similar to regular findings in posterior reversible encephalopathy syndrome (PRES) which is an acute neurotoxic state characterized by temporary neurological symptoms including acute headache, altered mental status, visual loss, and coma. PRES is mainly due to hypertension but other conditions including immunosuppression therapy, hypercalcemia, and chronic renal/hepatic failure can also lead to it. It is suggested that PRES is associated with endothelial damage and blood brain barrier (BBB) disruption [15].\u003c/p\u003e\n\u003cp\u003eInterestingly, organic lead is able to cross blood-brain barrier, accumulate in the brain tissue, and mimic or mobilize calcium ions. Lead can enter the brain not only by passive transport but also as the consequence of changed BBB permeability. \u0026ldquo;Leaky microvessels\u0026rdquo; following endothelial dysfunction in lead excitotoxicity and PRES have the same MRI findings [16].\u003c/p\u003e\n\u003cp\u003eThe data obtained in the study, although limited by the number of patients, is interesting because the patients' encephalopathy improved after discontinuation of the contaminated opium. Response to treatment ruled out other opioid-related complications such as \u0026ldquo;chasing the dragon\u0026rdquo; or hypoxic encephalopathy in our patients.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOne-thirds of our encephalopathy patients, that could be retrieved for follow-up MRI, had reversible abnormal MRI findings. MRIs of the more severely poisoned patients would have\u0026nbsp;been worse, but as these patients did not undergo MRIs, this cannot be known. With the\u0026nbsp;knowledge on our limited cases, no correlation exists between the MRI findings and BLLs or clinical signs. BBB disruption is the same mechanism for imaging findings in lead encephalopathy and PRES.\u003c/p\u003e"},{"header":"List of Abbreviations","content":"\u003cp\u003eBBB=Blood brain barrier, BLL=Blood lead level, CNS=Central Nervous System, EEG= Electroencephalography,\u0026nbsp; Hb=Hemoglobin, IQR= Inter Quartile Range,\u0026nbsp; MRI=Magnetic Resonance Imaging, PRES= Posterior Reversible Encephalopathy Syndrome, SPSS=Statistical package for social sciences\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e This study approved by Shahid Beheshti University of Medical Sciences ethics committee (IR.SBMU.RETECH.REC.1396.74). The informed consent from was waved due to retrospective nature of the study by ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish: \u003c/strong\u003eAvailable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials: \u003c/strong\u003eThe data is all presented in the text.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests: \u003c/strong\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding: \u003c/strong\u003eThis study was supported by Social Determinants of Health Research Center, Shahid Beheshti University of Medical sciences, Tehran, Iran (Grant no. 10307).\u003cstrong\u003e\u003cbr /\u003e \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' Contributions: \u003c/strong\u003eHHM is the guarantor of integrity of the entire study. MHM and MS gave the study concepts and designed the study. NZ, and MHM did the literature research. MHM and HHM performed the data and statistical analysis. NZ prepared the manuscript draft and HHM did edit the final manuscript. All authors have read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements: \u003c/strong\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRao, J.V.B., Vengamma, B., Naveen, T. and Naveen, V., 2014. Lead encephalopathy in adults. J Neurosci Rural Pract. 5,161\u0026ndash;163.\u003c/li\u003e\n\u003cli\u003eBramwell, B., 1879. The Differential Diagnosis of Lead Encephalopathy and Intra-Cranial Tumours. Edinb Med J. 25, 510-514.\u003c/li\u003e\n\u003cli\u003eGhane, T., Zamani, N., Hassanian-Moghaddam, H., Beyrami, A. and Noroozi, A., 2018. Lead poisoning outbreak among opium users in the Islamic Republic of Iran, 2016‒2017. Bull World Health Organ. 96, 165-172.\u003c/li\u003e\n\u003cli\u003eZamani, N., Hassanian-Moghaddam, H., 2018. Lead Contamination of Opium\u0026mdash; Iran, 2016. MMWR Morb Mortal Wkly Rep. 66, 1408-9.\u003c/li\u003e\n\u003cli\u003eZamani, N., Hassanian-Moghaddam, H., Latifi, M., 2017. Abdominopelvic CT in a patient with seizure, anemia, and hypocalcemia. Gastroenterology. 152, 27\u0026ndash;28.\u003c/li\u003e\n\u003cli\u003eAlinejad, S., Aaseth, J., Abdollahi, M., Hassanian‐Moghaddam, H. and Mehrpour, O., 2018. \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/28802093\"\u003eClinical Aspects of Opium Adulterated with Lead in Iran: A Review.\u003c/a\u003e Basic Clin Pharmacol Toxicol. 122, 56-64.\u003c/li\u003e\n\u003cli\u003eHassanian-Moghaddam, H., Zamani, N., Rahimi, M., Shadnia, S., Pajoumand, A., Sarjami, S., 2014. Acute Adult and Adolescent Poisoning in Tehran, Iran; the Epidemiologic Trend between 2006 and 2011. Arch Iran Med. 17, 534-538.\u003c/li\u003e\n\u003cli\u003eGeibprasert, S., Gallucci, M., Krings, T., 2010. Addictive Illegal Drugs : Structural Neuroimaging. AJNR. 31, 803-808.\u003c/li\u003e\n\u003cli\u003eBorne, J., Riascos, R., Cuellar, H.,Vargas, D., Rojas, R., 2005. Neuroimaging in Drug and Substance Abuse Part II: Opioids and Solvents. Top Magn Reson Imaging.16, 239-245.\u003c/li\u003e\n\u003cli\u003eAtre, A.L., Shinde, P.R., Shinde, S.N., Wadia, R.S., Nanivadekar, A.A., Vaid, S.J., Shinde, R.S., 2006. Pre and posttreatment MR imaging findings in lead encephalopathy. AJNR Am J Neuroradiol. 27, 902-903.\u003c/li\u003e\n\u003cli\u003eMani, J., Chaudhary, N., Kanjalkar, M. and Shah, P.U., 1998. Cerebellar ataxia due to lead encephalopathy in adult. J Neurol Neurosurg Psychiatry. 65, 797-798.\u003c/li\u003e\n\u003cli\u003eBouldin, T.W., Meighan, M.E., Gaynor, J.J., Goines, N.D., Mushak, P., Krigman, M.R., 1985. Differential vulnerability of mixed and cutaneous nerves in lead neuropathy. J Neuropathol Exp Neurol. 44, 384-96.\u003c/li\u003e\n\u003cli\u003eBhaskara Rao, J.V.,Vengamma, B., Naveen, T., Naveen, V., 2014. Lead encephalopathy in adults. J Neurosci Rural Pract. 5, 161-163.\u003c/li\u003e\n\u003cli\u003eSchr\u0026ouml;ter, C., Schr\u0026ouml;ter, H. and Huffmann, G., 1991. Neurologic and psychiatric manifestations of lead poisoning in adults (case report and review of literature) ]in German]. Fortschr Neurol Psychiatr. 59, 413-424.\u003c/li\u003e\n\u003cli\u003eDemirel, İ., Kavak, B.S., \u0026Ouml;zer, A.B., Bayar, M.K. and Erhan, \u0026Ouml;.L., 2014. An intensive care approach to posterior reversible encephalopathy syndrome (PRES): An analysis of 7 cases. J Turk Ger Gynecol Assoc. 15, 217-221.\u003c/li\u003e\n\u003cli\u003eStrużyńska, L., Walski, M., Gadamski, R., Dabrowska-Bouta, B. and Rafałowska, U., 1997. Lead-induced abnormalities in blood-brain barrier permeability in experimental chronic toxicity. Mol Chem Neuropathol. 31, 207-224.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style=\"margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\u0026quot;Times New Roman\u0026quot;,serif;text-align:center;line-height:200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eTable 1:\u0026nbsp;\u003c/span\u003e\u003c/strong\u003eSelected characteristics of patients with lead encephalopathy\u003c/p\u003e\n\u003ctable align=\"left\" border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:503.1pt;border-collapse:collapse;border:none;margin-left:6.75pt;margin-right:6.75pt;\" width=\"671\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.05pt;border: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"4.626865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eNo\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"7.611940298507463%\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;font-family:\u0026quot;Times New Roman\u0026quot;,serif;\"\u003e\n \u003cbr\u003e\u0026nbsp;\n \u003c/span\u003e\u0026nbsp;\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eAge\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e(Year)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47.4pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.402985074626866%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eGender\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43.25pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.656716417910447%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eBLL\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e(µg/dL)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.8pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.104477611940299%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eHgb\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e(mg/dL)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110.25pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"21.940298507462686%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eSigns \u0026amp; Symptoms\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.1pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"16.26865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eEEG Interpretation\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.1pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"12.537313432835822%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eChelating agents\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.55pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.850746268656716%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eMRI finding\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"4.626865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"7.611940298507463%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e52\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.402985074626866%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eM\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.656716417910447%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e50\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.104477611940299%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e12.8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"21.940298507462686%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eSeizure, abdominal pain, agitation, constipation\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"16.26865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003emild diffuse encephalopa\u003c/span\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003ethy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"12.537313432835822%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eNo\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.850746268656716%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eabnormal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"4.626865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"7.611940298507463%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e72\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.402985074626866%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eM\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.656716417910447%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e200\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.104477611940299%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e8.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"21.940298507462686%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eDelirium, abdominal pain, weakness, constipation\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"16.26865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003enot done\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"12.537313432835822%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eBAL+EDTA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.850746268656716%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eabnormal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"4.626865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"7.611940298507463%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e39\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.402985074626866%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eM\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.656716417910447%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e68\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.104477611940299%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e7.6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"21.940298507462686%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eAbdominal pain, constipation, confusion, seizure\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"16.26865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003emoderate diffuse encephalopa\u003c/span\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003ethy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"12.537313432835822%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eBAL+EDTA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.850746268656716%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eabnormal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"4.626865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"7.611940298507463%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e45\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.402985074626866%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eM\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.656716417910447%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e95\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.104477611940299%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e8.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"21.940298507462686%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eAbdominal pain, weakness, myalgia, confusion, seizure, insomnia, loss of appetite, dysarthria, gait disturbance, steering, delirium, seizure, constipation, ventricular tachycardia and cardiac arrest before arrival\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"16.26865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003ediffuse alpha activity\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"12.537313432835822%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eBAL+EDTA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.850746268656716%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003enormal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"4.626865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"7.611940298507463%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e40\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.402985074626866%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eM\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.656716417910447%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e101\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.104477611940299%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e10.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"21.940298507462686%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eConsciousness fluctuation, delirium, hallucination, disorientation, upper motor neuron weakness\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"16.26865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003emoderate diffuse encephalopa\u003c/span\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003ethy (cortical dysfunction)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"12.537313432835822%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eBAL+EDTA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.850746268656716%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003enormal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"4.626865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"7.611940298507463%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e51\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.402985074626866%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eM\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.656716417910447%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e107\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.104477611940299%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e8.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"21.940298507462686%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eRepeated seizure, weakness, agitation, loss of appetite, abdominal pain, constipation\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"16.26865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003emild diffuse\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003ecortical dysfunction\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"12.537313432835822%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eBAL+EDTA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.850746268656716%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003enormal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"4.626865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"7.611940298507463%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e57\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.402985074626866%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eM\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.656716417910447%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e105\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.104477611940299%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e7.6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"21.940298507462686%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eAbdominal pain, confusion, disorientation to time, constipation\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"16.26865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eNormal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"12.537313432835822%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eBAL+EDTA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.850746268656716%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003enormal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"4.626865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"7.611940298507463%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e48\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.402985074626866%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eM\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.656716417910447%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e110\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.104477611940299%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e10.6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"21.940298507462686%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eAgitation, seizure, delirium\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"16.26865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003enot done\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"12.537313432835822%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eBAL+EDTA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.850746268656716%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003enormal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.05pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"4.626865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"7.611940298507463%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e52\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.402985074626866%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eF\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.656716417910447%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e\u0026gt;65\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45.8pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.104477611940299%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003e9.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"21.940298507462686%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eSeizure, delirium, severe agitation, nausea and vomiting, confusion\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"16.26865671641791%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003emild diffuse\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eencephalopathy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"12.537313432835822%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003eBAL+EDTA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.55pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"9.850746268656716%\"\u003e\n \u003cp style=\"text-align:center;line-height:150%;\"\u003e\u003cspan style=\"font-size:13px;line-height:150%;\"\u003enormal\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"lead; toxicity; outbreak; encephalopathy; magnetic resonance imaging; opioid","lastPublishedDoi":"10.21203/rs.2.19790/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.19790/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground Encephalopathy is an uncommon but serious presentation of lead toxicity. Objective We aimed to determine and follow-up the brain magnetic resonance imaging (MRI) abnormalities in the patients with lead encephalopathy due to ingestion of lead contaminated opium. Methods In a cross-sectional study during lead-contaminated opium outbreak, all lead-poisoned patients with any signs/symptoms of encephalopathy were included. Results Of 19 patients with lead encephalopathy, five died early and other five could not be sent to MRI during their hospitalization period. Mean age was 51±11 years and males were dominant (89%). Median [IQR] blood lead level (BLL) was 101 [81, 108] µg/dL (range; 50 to 200 µg/dL). There was no correlation between MRI findings and signs/symptoms. MRI was normal in six and abnormal in three. Bilateral symmetric involvement of parieto-occipital lobes was observed. Gray matter, gray-white matter junction, and subcortical white matter were also affected. Follow-up MRI was performed in two with abnormal MRI which showed complete and near complete resolution of the abnormalities after cessation of opium use and treatment. Conclusion: There was no correlation between MRI findings and BLL. Complete recovery of brain MRI lesions was detected after cessation of opium use.\u003c/p\u003e","manuscriptTitle":"Encephalopathy Following ingestion of Lead-Contaminated Opium; Magnetic Resonance Imaging Findings","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2020-03-11 18:06:17","doi":"10.21203/rs.2.19790/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-03-31T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"editorInvitedReview","content":"","date":"2020-03-15T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"reviewerAgreed","content":"","date":"2020-03-10T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-03-09T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-03-06T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-03-05T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-03-04T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-03-04T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-01-01 21:23:38","doi":"10.21203/rs.2.19790/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-03-04T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-02-27T12:00:00+00:00","index":2,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nThe authors report a series of patients with neurological symptoms following a lead intoxication and describe the MRI findings. The subject is interesting because it is uncommon to see lead intoxications nowadays and published information about MRI findings and neurological symptoms of these patients, is scarce. Overall, the manuscript is well written. However thera are some issues that should be addressed before considering this work for publication:\n\n*Major revisions:\nMETHODS\n- The study design seems correct to me. Inclusion criteria are well defined and description of the statistical analysis is well provided. However the description of the population study is confusing. The sentence \"This cross-sectional study was carried out during an outbreak of lead toxicity due to leadcontaminated opium in Tehran between September 2016 and August 2017 with a BLL range of 47.3-1124 μg/dL in a sample of 80 patients\" is confusing. Firstly because this information (\"...range of 47.3-1124 μg/dL in a sample of 80 patients\") should be placed in the Results section. Secondly, because in the Results section the authors report that 3800 patients were admitted to their centre during this period and then, they selected 19 that fullfilled the inclusion criteria. And the 80 samples? Where do they come from? I would strongly recommend to attach a Flow-Chart describing the study population selection. I guess that there were 3800 patients admitted during the study period --\u003e 80 blood samples available ---\u003e 19 patients included following the inclusion criteria. But this should be clarified by the authors.\n- Also in Methods the authors should specify how do they identify the study subjects: by chart review? Prospective database?\nRESULTS\n- Authors state that \"Hypoxic encephalopathy was also excluded\". Please describe how (by MRI? by clinical history? both?)\n- Also, it is stated in Results that: \"On follow-up, all patients became symptom-free after quitting the lead-contaminated opium and initiation of treatment.\" Please specify which treatment.\nDISCUSSION\n- The sentence: \"Atre and colleagues reported bilateral symmetric involvement of the parasagittal occipital temporal, parietal and frontal lobes and a right cerebellar lesion.\" right after affirming that the MRI findings of lead encephalopathy due to regular ingestion of opium have not been reperted to date, is confusing. I guess that the study population of Atre et al was differents. Please clarify the sentence.\n- The authors report that \"The minimum BLL in our study was 50 μg/dL and encephalopathy due to such low BLL might be due to the chronic nature of the toxicity.\" Why? Could you please develop more your hypothesis?\n- Also, it is stated that: \"Interestingly, organic lead is able to cross blood-brain barrier, accumulate in the brain tissue, and mimic or mobilize calcium ions. The consequence would be apoptosis following excessive influx of calcium that could lead to death.\" However in these patients the DWI sequence is normal and the neurological symptoms are reversible with the treatment. Therefore, it looks like there should not be much neuronal death (otherwise neurological deficits would not be reversible). After this sentence the authors state that \"\"Leaky microvessels\" following endothelial dysfunction in lead excitotoxicity and PRES have the same MRI findings\". That make more sense to me. Probably the MRI abnormalities are secondary to endothelial dysfunction rather than cell death. What do you think? Please, explain better your hypothesis.\n- Please include a paragraph in the discussion section describing the study limitations.\nCONClUSIONS\n- \"Substitution of lead on calcium channels in CNS can mimic hypercalcemia and subsequent PRES-like imaging.\" This conclusion does not come from your study results.\n\n*Minor revisions/suggestions:\nABSTRACT\n- BLL is not defined in the abstract\nINTRODUCTION\n- Change the sentence \"We also would like to perform a follow-up MIR...\" for \"We also aimed to perform a follow-up MRI...\"\nFIGURE 1\n- The authors describe findings on T1 but the figure only shows FLAIR images. Please consider adding a T1 picture of the patient to better show the changes.\nFIGURE 2\n- The authors describe symmetric involvement of the occipital, parietal, and frontal lobes in the parasagittal region, but in the images I can only see the parasagital parietal hyperintensities. Could you please revise that the images shown really demonstrate the abnormalitites of the patient? Maybe adding an arrow in the figure may help the reader to identify the abnormalitites.\n\n*Other suggestions\n- If you have the follow-up information of the patients that did not undergo the MRI, it would be really interesting to know also if all these patients presented reversible neurological symptoms.\n\n\n* Are the methods appropriate and well described?: **No**\n* Does the work include the necessary controls?: **Yes**\n* Are the conclusions drawn adequately supported by the data shown?: **No**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **I am able to assess the statistics**\n* Quality of written English: **Needs some language corrections before being published**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n"},{"type":"reviewerAgreed","content":"","date":"2020-01-16T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-01-16T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nVery interesting case series report.\nThe final population evaluated by MRI was 9 patients, because 5 die early and another 5 could not be evaluated by RMI given technical reasons; If we have understood correctly.\nThis implies that out of 19 potentially eligible patients, MRI was evaluated in 25.7% (5/19). I think it would be convenient to improve the wording to make more clear the involuntary selection bias\nOn the other hand, I would recommend article review by S. Geibprasert, M. Gallucci, T. Krings. Addictive Illegal Drugs: Structural Neuroimaging. AJNR Am J Neuroradiol 2010 31: 803- 08 in order to enrich the discussion of the cases presented* Are the methods appropriate and well described?: **Yes**\n* Does the work include the necessary controls?: **Yes**\n* Are the conclusions drawn adequately supported by the data shown?: **Yes**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **Not relevant to this manuscript**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n"},{"type":"reviewerAgreed","content":"","date":"2020-01-14T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-01-05T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2019-12-25T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-12-19T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2019-12-18T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-12-18T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0ffb1ad3-4450-48c6-81af-09ae7c714be3","owner":[],"postedDate":"March 11th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":46089,"name":"Neurology"},{"id":46090,"name":"Neurosurgery"}],"tags":[],"updatedAt":"2021-07-27T21:00:08+00:00","versionOfRecord":{"articleIdentity":"rs-10402","link":"https://doi.org/10.1186/s12883-020-01750-z","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2020-05-01 21:00:08","publishedOnDateReadable":"May 1st, 2020"},"versionCreatedAt":"2020-03-11 18:06:17","video":"","vorDoi":"10.1186/s12883-020-01750-z","vorDoiUrl":"https://doi.org/10.1186/s12883-020-01750-z","workflowStages":[]},"version":"v2","identity":"rs-10402","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-10402","version":["v2"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}