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Reversal of diffusion abnormalities after ischemic stroke: Adding difficulty and complexity to the conundrum of acute stroke imaging

Diffusion-weighted magnetic resonance imaging (DWI) is increasingly used for the evaluation of acute stroke patients and provides important information about the location, extent and potential cause of the stroke. Combining DWI with susceptibility-weighted MRI appears to reliably distinguish between acute hemorrhagic and ischemic strokes. Beyond rapid confirmation of the stroke diagnosis, DWI can be combined with perfusion MRI to potentially approximate the ischemic penumbra and to choose patients more likely to respond to thrombolytic therapy. The tissue abnormality observed on DWI represents ischemic regions with a decline in the apparent diffusion coefficient of water. The precise mechanism for this apparent diffusion coefficient (ADC) decline remains unresolved, but it is apparent that with ischemia the ADC decline is associated with impairment of highenergy metabolism and the loss of ion homeostasis. Initially, it was thought that regions of ADC decline and hyperintensity on DWI represented regions of irreversible ischemic injury. Recent animal studies demonstrated that abnormal DWI regions could be largely reversed with early reperfusion, although late, secondary ADC declines occurred in a portion of the initial region of ischemia that normalized. The UCLA group previously demonstrated in a small group of stroke patients undergoing successful intraarterial thrombolysis that DWI abnormalities could be reversed and that late secondary DWI abnormalities also occur in humans. The study by Kidwell and colleagues extends the previous one and includes 18 ischemic stroke patients treated within 6 hours of stroke onset with intraarterial thrombolysis alone (n 12) or a combination of intravenous and intraarterial thrombolysis (n 6). Eight of 18 patients demonstrated some amount of ADC reversal when DWI was repeated several hours after thrombolysis. The day 7 MRI study showed that five of eight patients had partial or complete reappearance of a DWI abnormality that initially resolved and three of eight had no secondary ADC changes. Clinically, the latter group tended to have a better outcome than those patients with secondary ADC declines. The observations in this study and those derived from animal studies evaluating the phenomenon of ADC reversal and secondary reoccurrence have several intriguing implications. The study by Kidwell and colleagues and the recent one by Fichler and colleagues confirm the animal studies that early ADC declines, even relatively severe declines, can be reversed with early reperfusion. These observations support the contention that use of the so-called diffusion-perfusion mismatch, that is, that region appearing to be normal on DWI, but abnormal on perfusion MRI, to define the ischemic penumbra is indeed an oversimplification. If part of the diffusion abnormality is reversible early after stroke onset, then the ischemic penumbra, which has been operationally defined as ischemic tissue that is potentially reversible, must include part of the DWI abnormality as well. In the future, the ischemic penumbra will likely be defined on diffusion-perfusion MRI by relating time from stroke onset to absolute ADC and perfusion values and not just simply the region of abnormal perfusion that is normal on DWI. Recent histological studies in rats subjected to 30 minutes of temporary middle cerebral artery occlusion and mechanical reperfusion further complicate the issue of lesion reversal on DWI. Ringer and colleagues demonstrated partial or complete reversal of initial DWI abnormalities 5 hours after reperfusion. Loss of MAP2 immunostaining, a sensitive marker of irreversible neuronal, structural damage disclosed widespread changes in regions where ADC maps and T2 imaging were normal. Using the same stroke model, Li and colleagues observed abnormal neurons (shrunken neurons with swollen cellular processes) and astrocytes (swollen cytoplasm and vacuolation of the neuropil), changes consistent with ischemic injury in the majority of cells evaluated, 90 minutes after reperfusion when ADC values had completely normalized. These studies suggest that at the cellular level incomplete ischemic injury is present despite normal ADC and T2 values. One implication of these observations is that later ADC and T2 changes perhaps represent a continuum of ischemic lesion development and not a de novo process. Another implication of early DWI reversal and then late ADC decline after successful thrombolysis is that additional therapy may be useful. The mechanisms causing the secondary ADC decline and delayed ischemic injury have not been elucidated precisely. Potential causes for the secondary injury include free radical– mediated cell damage, recruitment of inflammatory mediators, delayed mitochondrial dysfunction related to secondary energy failure, and the initiation of programmed cell death pathways. It is certainly conceivable that more than one mechanism may contribute to the development of secondary cellular injury after EDITORIALS