Shai Shrot1, Maya Tauber2, Arthur Shiyovich3, Nadav Milk3, Yossi Rosman3, Arik Eisenkraft4, Tamar Kadar5, Michael Kassirer3, Yoram Cohen2. 1. Medical Corps HQ, IDF, P.O. Box - 02149, Tel-Hashomer Base, Ramat-Gan, Israel; Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Address: 2 Sheba Rd, Ramat-Gan, 52621, Israel. Electronic address: shaishrot@gmail.com. 2. School of Chemistry, The Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel. 3. Medical Corps HQ, IDF, P.O. Box - 02149, Tel-Hashomer Base, Ramat-Gan, Israel. 4. Medical Corps HQ, IDF, P.O. Box - 02149, Tel-Hashomer Base, Ramat-Gan, Israel; NBC Protection Division, Israel Ministry of Defense, Hakiria, Tel-Aviv 61909, Israel; Institute for Research in Military Medicine, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel. 5. The Israel Institute for Biological Research, P.O. Box 19, Ness Ziona 74100, Israel.
Abstract
INTRODUCTION: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo alterations in brain structure and function after acute organophosphate (OP) poisoning. The goals of this study were to explore early imaging findings in organophosphate-poisoned animals, to assess the efficacy of centrally acting antidotes and to find whether early MR findings can predict post-poisoning cognitive dysfunction. METHODS: Sprague-Dawley rats were poisoned with the agricultural OP paraoxon and were treated with immediate atropine and obidoxime (ATOX) to reduce acute mortality caused by peripheral inhibition of acetylcholinesterase. Animals were randomly divided into three groups based on the protocol of centrally acting antidotal treatment: group 1 - no central antidotal treatment (n=10); group 2 - treated with midazolam (MID) at 30 min after poisoning (n=9), group 3 - treated with a combination of MID and scopolamine (SCOP) at 30 min after poisoning (n=9) and controls (n=6). Each animal had a brain MR examination 3 and 24 h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel (1)H MR spectroscopy (localized on the thalami, to measure total creatine [Cr], N-acetyl-aspartate [NAA] and cholines [Cho] levels). Eleven days after poisoning each animal underwent a Morris water maze to assess hippocampal learning. Eighteen days after poisoning, animals were euthanized, and their brains were dissected, fixed and processed for histology. RESULTS: All paraoxon poisoned animals developed generalized convulsions, starting within a few minutes following paraoxon injection. Brain edema was maximal on MR imaging 3 h after poisoning. Both MID and MID+SCOP prevented most of the cortical edema, with equivalent efficacy. Brain metabolic dysfunction, manifested as decreased NAA/Cr, appeared in all poisoned animals as early as 3h after exposure (1.1 ± 0.07 and 1.42 ± 0.05 in ATOX and control groups, respectively) and remained lower compared to non-poisoned animals even 24h after poisoning. MID and MID+SCOP prevented much of the 3h NAA/Cr decrease (1.22 ± 0.05 and 1.32 ± 0.1, respectively). Significant correlations were found between imaging findings (brain edema and spectroscopic changes) and clinical outcomes (poor learning, weight loss and pathological score) with correlation coefficients of 0.4-0.75 (p<0.05). CONCLUSIONS: MR imaging is a sensitive modality to explore organophosphate-induced brain damage. Delayed treatment with midazolam with or without scopolamine provides only transient neuroprotection with some advantage in adding scopolamine. Early imaging findings were found to correlate with clinical consequences of organophosphate poisoning and could be potentially used in the future to predict long-term prognosis of poisoned casualties.
INTRODUCTION: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo alterations in brain structure and function after acute organophosphate (OP) poisoning. The goals of this study were to explore early imaging findings in organophosphate-poisoned animals, to assess the efficacy of centrally acting antidotes and to find whether early MR findings can predict post-poisoning cognitive dysfunction. METHODS:Sprague-Dawley rats were poisoned with the agricultural OP paraoxon and were treated with immediate atropine and obidoxime (ATOX) to reduce acute mortality caused by peripheral inhibition of acetylcholinesterase. Animals were randomly divided into three groups based on the protocol of centrally acting antidotal treatment: group 1 - no central antidotal treatment (n=10); group 2 - treated with midazolam (MID) at 30 min after poisoning (n=9), group 3 - treated with a combination of MID and scopolamine (SCOP) at 30 min after poisoning (n=9) and controls (n=6). Each animal had a brain MR examination 3 and 24 h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel (1)H MR spectroscopy (localized on the thalami, to measure total creatine [Cr], N-acetyl-aspartate [NAA] and cholines [Cho] levels). Eleven days after poisoning each animal underwent a Morris water maze to assess hippocampal learning. Eighteen days after poisoning, animals were euthanized, and their brains were dissected, fixed and processed for histology. RESULTS: All paraoxon poisoned animals developed generalized convulsions, starting within a few minutes following paraoxon injection. Brain edema was maximal on MR imaging 3 h after poisoning. Both MID and MID+SCOP prevented most of the cortical edema, with equivalent efficacy. Brain metabolic dysfunction, manifested as decreased NAA/Cr, appeared in all poisoned animals as early as 3h after exposure (1.1 ± 0.07 and 1.42 ± 0.05 in ATOX and control groups, respectively) and remained lower compared to non-poisoned animals even 24h after poisoning. MID and MID+SCOP prevented much of the 3hNAA/Cr decrease (1.22 ± 0.05 and 1.32 ± 0.1, respectively). Significant correlations were found between imaging findings (brain edema and spectroscopic changes) and clinical outcomes (poor learning, weight loss and pathological score) with correlation coefficients of 0.4-0.75 (p<0.05). CONCLUSIONS: MR imaging is a sensitive modality to explore organophosphate-induced brain damage. Delayed treatment with midazolam with or without scopolamine provides only transient neuroprotection with some advantage in adding scopolamine. Early imaging findings were found to correlate with clinical consequences of organophosphatepoisoning and could be potentially used in the future to predict long-term prognosis of poisoned casualties.
Authors: Karen L G Farizatto; Sara A McEwan; Vinogran Naidoo; Spyros P Nikas; Vidyanand G Shukla; Michael F Almeida; Aaron Byrd; Heather Romine; David A Karanian; Alexandros Makriyannis; Ben A Bahr Journal: J Mol Neurosci Date: 2017-08-12 Impact factor: 3.444
Authors: Jason R Richardson; Vanessa Fitsanakis; Remco H S Westerink; Anumantha G Kanthasamy Journal: Acta Neuropathol Date: 2019-06-13 Impact factor: 17.088
Authors: Brad A Hobson; Sílvia Sisó; Douglas J Rowland; Danielle J Harvey; Donald A Bruun; Joel R Garbow; Pamela J Lein Journal: Toxicol Sci Date: 2017-06-01 Impact factor: 4.849