TY - JOUR
T1 - Early brain magnetic resonance imaging can predict short and long-term outcomes after organophosphate poisoning in a rat model
AU - Shrot, Shai
AU - Tauber, Maya
AU - Shiyovich, Arthur
AU - Milk, Nadav
AU - Rosman, Yossi
AU - Eisenkraft, Arik
AU - Kadar, Tamar
AU - Kassirer, Michael
AU - Cohen, Yoram
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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 30min after poisoning (n = 9), group 3 - treated with a combination of MID and scopolamine (SCOP) at 30min after poisoning (n = 9) and controls (n = 6). Each animal had a brain MR examination 3 and 24h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel 1H 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 3 h 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 24 h after poisoning. MID and MID + SCOP prevented much of the 3 h 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.
AB - 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 30min after poisoning (n = 9), group 3 - treated with a combination of MID and scopolamine (SCOP) at 30min after poisoning (n = 9) and controls (n = 6). Each animal had a brain MR examination 3 and 24h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel 1H 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 3 h 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 24 h after poisoning. MID and MID + SCOP prevented much of the 3 h 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.
KW - Behavior
KW - Biomarker
KW - Neurotoxicity
KW - Paraoxon
KW - Seizures
UR - http://www.scopus.com/inward/record.url?scp=84941275718&partnerID=8YFLogxK
U2 - 10.1016/j.neuro.2015.04.003
DO - 10.1016/j.neuro.2015.04.003
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AN - SCOPUS:84941275718
SN - 0161-813X
VL - 48
SP - 206
EP - 216
JO - NeuroToxicology
JF - NeuroToxicology
ER -