Early brain magnetic resonance imaging can predict short and long-term outcomes after organophosphate poisoning in a rat model.
BACKGROUND
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.
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.
Shai
S
Shrot
School of Chemistry, The Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Maya
M
Tauber
Medical Corps HQ, IDF, P.O. Box - 02149, Tel-Hashomer Base, Ramat-Gan, Israel.
Arthur
A
Shiyovich
Medical Corps HQ, IDF, P.O. Box - 02149, Tel-Hashomer Base, Ramat-Gan, Israel.
Nadav
N
Milk
Medical Corps HQ, IDF, P.O. Box - 02149, Tel-Hashomer Base, Ramat-Gan, Israel.
Yossi
Y
Rosman
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.
Arik
A
Eisenkraft
The Israel Institute for Biological Research, P.O. Box 19, Ness Ziona 74100, Israel.
Tamar
T
Kadar
Medical Corps HQ, IDF, P.O. Box - 02149, Tel-Hashomer Base, Ramat-Gan, Israel.
Michael
M
Kassirer
School of Chemistry, The Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Yoram
Y
Cohen
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001285:Atropine / Q000494:pharmacology; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001929:Brain Edema / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000523:psychology; D002794:Choline / Q000378:metabolism; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D003071:Cognition; D003401:Creatine / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D042241:Early Diagnosis; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning; D008874:Midazolam / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009768:Obidoxime Chloride / Q000494:pharmacology; D062025:Organophosphate Poisoning / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000523:psychology; D010261:Paraoxon; D011237:Predictive Value of Tests; D066244:Proton Magnetic Resonance Spectroscopy; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000494:pharmacology; D013997:Time Factors; D015431:Weight Loss
D002801:Cholinesterase Reactivators; D018696:Neuroprotective Agents; D001224:Aspartic Acid; D009768:Obidoxime Chloride; D001285:Atropine; C000179:N-acetylaspartate; D012601:Scopolamine; D003401:Creatine; D002794:Choline; D010261:Paraoxon; D008874:Midazolam
Behavior; Biomarker; Neurotoxicity; Paraoxon; Seizures