1	Transient Cytotoxic Edema and　Delayed Ischemic Neuronal Injury after Early Reperfusion Masahiro Ida, Keiko Hino, Naoya Yorozu, Yuko Kubo, Syunsuke Sugawara, Yuko Kawaguchi Department of Radiology and Comprehensive Stroke Center, Tokyo Metropolitan Ebara Hospital, Tokyo, Japan RX00500@nifty.com Disclosure; none
2	Introduction We present two patients with transient cytotoxic edema and delayed neuronal injury after prompt recanalization of acute arterial occlusion. Those patients showed reversal of bright signal on diffusion-weighted imaging (DWI) and a restoration of ADC immediately after early reperfusion by prompt t-PA thrombolysis; However, the lesions with the initial ischemic insult subsequently evolved again into irreversible infarction by the second hospital day.
3	Materials We performed intravenous throbmolysis in 11 patients, during 3 hours of onset, since April 2007 to March 2008. Among them, case 6 and 9 showed transient reversal of DWI lesion and secondary delayed neuronal injury after recanalization.
4	Methods MR System and Parameters
5	Methods Emergency MR Protocol for Hyperacute Ischemia + Optional imaging if enough time. Sequences Purpose and Findings To detect and evaluate To exclude Diffusion Cytotoxic edema FLAIR Intraarterial high signal Subarchnoid Hx T2WI Main trunk occlusion Old infarct, Acute Hx TOF MRA Main trunk occlusion the circle of Willis SWI⁺ Intraarterial low signal Acute and old Hx Misery perfusion T2*WI⁺ Susceptibility sign Acute and old Hx When combination of DWI, FLAIR, MRA and SWI suggests diffusion-perfusion mismatch, Gd-Perfusion Vascular reserve
6	Case 6 46 year-old woman Sudden onset, right hemiparesis and aphasia. NIHSS; 8 points Emergency CT reveals no acute intracranial hemorrhage. Early CT sign can be detected. Left basal ganglia Slightly lower attenuation The contour unclear No hyperdense MCA sign
7	Case 6. 46 year-old woman MR images 80 minutes after onset MRA shows complete occlusion of the proximal portion of the left MCA M1 FLAIR intraarterial signal was identified in the left MCA hemispheric branches, suggesting acute occlusion and perfusion deficit. Susceptibility-weighted imaging (SWI) demonstrates relative increase of deoxyhemoglobin in the draining veins from the left MCA territory, representing misery perfusion state.
8	Case 6. 46 year-old woman Diffusion Imaging Mild hyperintensity was seen on DWI in the territories fed by the left lateral striate arteries (LSA) and the middle hemispheric trunk of the left MCA. ADC was also reduced Corresponding to hyperintensity on DWI
9	Case 6. 46 year-old woman Diffusion-perfusion mismatch An area with TTP elongation is identified in the left MCA territory, larger than an area with DWI abnormality. Marked reduction of rCBV and rCBF is noted in the left LSA territory corresponding to DWI lesion. However, rCBV and rCBF are relatively well reserved within the mismatch area.
10	"After iv t-PA thrombolysis" After iv t-PA thrombolysis, recanalization of the left M1 was confirmed on the postthrombolytic MR 7 hrs. Diffusion abnormality was reversed. The patient was improved neurologically. However, the initial LSA lesion finally evolved into irreversible infracted tissue on the 3rd MR 24 hrs., in spite that there was no recurrence of occlusion in the left MCA M1. No neurological deterioration was recurrent.
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13	Case 9; 75 year-old Woman Sudden onset left hemiparesisa and total aphasia NIHSS; 20 points Emergency CT 54 minutes after onset demonstrates No acute intracranial hemorrhage Chronic ischemic changes in the bilateral deep white matter No early CT sign of hyperacute ishcemia. No hyperdense MCA sign
14	Case 9; 75 year-old woman MR imaging 66 minutes after onset MRA shows right MCA M1 occlusion T2*WI demonstrates susceptibility sign in the right M1, representing thromboembolism. FLAIR intraarterial signal was also identified in the right MCA hemispheric branches, suggesting acute occlusion and perfusion deficit.
15	Case 9; 75 year-old woman Diffusion Imaging DWI hyperintensity was seen in the territories fed by the right lateral striate arteries (LSA) and the upper trunk of the right MCA hemispheric branches ADC was also reduced corresponding to hyperintensity on DWI
16	Case 9; 75 year-old woman Diffusion-perfusion mismatch Gd-perfusion study represents a large area with diffusion-TTP mismatch in the right MCA territory. Marked reduction of rCBV and rCBF was noticed in the right LSA region, corresponding to the DW lesion However, rCBV and rCBF are well reserved within the mismatch area.
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20	Discussion Various biophysical processes are considered to contribute to ADC reduction in hyperacute ischemia Membrane depolarization caused by failure of ATP-dependent ion pumps, and water shift from extracellular to intracellular space Cytoxic edema and restricted intracellular diffusion Decreased extracellular spaces and increased tortuosity DWI lesions are initially located in the ischemic core where the depth of ischemia is greatest. The ADC decreases further and the DWI lesions are getting larger and continue to enlarge within penumbral regions during the initial 24 hours. In general, almost DWI lesions are irreversible and finally evolve into infracted tissue by 24 hours after occlusion. Early detection of the area with diffusion-perfusion mismatch before enlargement of DWI lesion is necessary for effective thrombolytic therapy and improvement of clinical outcome. In some cases, early reversal of hyperintensity on DWI and normalization of ADC can be observed, when prompt recanalization of the occluded artery and reperfusion into tissue capillary occur.
21	"Pan J" Pan J. Neuroradiology. 2007;49:93-102. Olah L. J Cereb Blood Flow Metab 20:1474–1482, 2000 Li F. Stroke 31:946–954 2000 Recanalization usually minimize infarct volume and result in better clinical outcome; however, tissue reperfusion may cause secondary delayed neuronal injury Olah et al. evaluated the dynamics of the ADC in a rat model the ADC was decreased at the end of ischemia, and then improved during the first 2 hours after reperfusion , but the ADC reduce again at later time points with a secondary increase of hemisphere lesion volume. There is a secondary deterioration likely as a consequence of the reperfusion-related injury Li et al. examined the dynamic changes of DWI using a rat model with temporary occlusion of MCA DWI hyperintensity seen during the initial ischemic insult reverted to normal approximately 60–90 minutes after the start of reperfusion And then secondary hyperintensities appear 12 hours after reperfusion .
22	"In two cases out of..." In two cases out of the eleven in whom iv. t-PA thrombolysis was performed during 3 hours of onset, the initial DWI lesion and ADC reduction reverted to normal after prompt recanalization on the 2^nd MR obtained 6 hours of onset However, in the reversal areas from the initial ischemic insult, secondary hyperintensity on DWI and ADC reduction was confirmed again after reperfusion, on the 3^rd MR obtained 24 hours of onset. In our series, the secondary deterioration of ADC can be predicted by marked reduction of rCBV and rCBF on the initial MR study before recanalization. A marked decrease in rCBV and rCBF is the best indicator of irreversible ischemic core.
23	"Pan J et al" Pan J et al. reviewed and summarized various pathophysiological mechanisms producing reperfusion injury Leukocyte infiltration, platelet activation, complement-mediated activation, postischeic hypertension and breakdown of blood brain barrier (BBB). Hemorrhagic transformation and severe vasogenic edema are significant complications after recanalization by t-PA thrombolysis. Those conditions follows postischemic hyperperfusion and subsequent BBB disruption, and result in poor clinical outcome. In our series, no hemorrhagic transformation or severe edema was observed within the lesions with secondary deterioration of ADC reduction. Finally both cases demonstrated better clinical outcome (NIHSS; from 8 to 0 in case 6, and from 20 to 6 in case 9), because almost mismatched areas were rescued completely by recanalization. The reversibility of ADC reduction after early recanalization does not necessarily indicate complete restoration and salvage of brain tissue from acute ischemic insult. Pre-thombolytic rCBV and rCBF should be evaluated to predict reperfusion injury.
24	Conclusion I DWI hyperintensity and reduction in ADC can revert to almost normal by prompt recanalization and reperfusion. However, the reversibility of DWI hyperintensity and ADC reduction in the hyperacute stage does not necessarily reveal complete restoration and salvage of brain tissue from acute ischemic damage.
25	Conclusion II So-called, “reperfusion injury” is considered to be a process of secondary delayed neuronal injury Neutrophil infiltration, platelet accumulation, complement activation, no-reflow phenomen Secondary accelerated deterioration of DWI lesion and ADC reduction can be predicted by marked reduction of rCBV and rCBF on the initial perfusion study before reperfusion.