Previous studies have revealed that the free radical scavenger, edaravone, is neuroprotective following acute ischemic stroke in both animal and human models [9, 10]. Moreover, the protective effect of edaravone against oxidative stress has been reported to not be limited to neurons, but to also extend to astrocytes and endothelial cells. Thus, edaravone treatment results in protection of the neurovascular unit [11, 12]. In the EDO study, edaravone reduced the incidence of recurrent stroke following acute treatment compared with the anti-platelet drug, sodium ozagrel . However, a recent trial with NXY-059, another free radical scavenger, showed no significant neuroprotection when administered to stroke patients (SAINT II) . Collectively, these findings suggest that edaravone may have efficacy in ischemic stroke treatment, but with limitations in its therapeutic capability .
In our study, patients treated with edaravone exhibited a significant reduction in ischemic lesion size compared with those not treated with edaravone. However, this finding was limited to specific time frames, or the subacute, early chronic and late chronic phases. Generally, edaravone is administrated twice a day for 2 weeks from the onset of the ischemic insult. Because of its ability to restrict inflammation, edaravone may potentially limit the ischemic insult during the early phases and, thus, restrict the expansion of the stroke lesion faster than those not treated with the free radical scavenger. In support of this finding, edaravone has been reported to reduce delayed neuronal death after middle cerebral artery occlusion by limiting N-acetyl aspartate signaling in humans . Further supporting our findings, brain edema following stroke with internal carotid artery stenosis has also been reported to be limited to the acute period if patients were treated with edaravone .
Upon closer examination of our results, lesion reduction elicited by edaravone was most effective in the small-vessel occlusion stroke subtype. In this study, lesions due to small-vessel occlusion were mostly located in corona radiata (white matter) and some were in basal ganglia (gray matter). Anatomically, white matter contains more astrocytes and microglia which participate in the inflammatory response, and more phospholipids which are vulnerable to oxidative stress . Therefore, it is reasonable that edaravone treatment excerted a significant effect on the small-vessel occlusion subtype due to its actions on inflammation. Actually, a recent study reported that edaravone reduced the extent of damage in both the gray and white matter caused by global ischemia , supporting the theory that edaravone may act by limiting inflammation.
While effective in the small-vessel occlusion stroke subtype, edaravone failed to elicit statistically significant reductions in lesion sizes in the cardioembolism and the large-artery atherosclerosis subtype groups in our study. It is possible that reductions of lesional expansion by edaravone may be limited by the hemodynamic worsening, which occurs in these specific stroke subtypes. Moreover, because our data included patients with both mild and severe neurological deficits, the effects of edaravone may be masked by its inability to treat ischemic insults unconditionally. In support of this notion, it has been reported that edaravone improves the outcome of embolic strokes only in patients with mild neurological deficits . Furthermore, edaravone treatment appeared to trend towards lesion size reductions in all subtypes, and not just the small-vessel occlusion stroke subtype, suggesting that the small sample sizes in this study may have prevented the identification of statistical significance between the treatment groups. This was overcome when the stroke subtypes were grouped collectively.
Our findings indicate that treatment with edaravone did not cause any significant differences in clinical outcomes, such as the NIHSS at discharge point, duration of hospital days, and the mRS at one year after the onset. However, a significant improvement in clinical outcome at discharge was observed in the small-vessel occlusion stroke subtype treated with edaravone. These findings are supported by a recent study on acute lacunar infarctions in which Ohta et al. found that a protective effect of edaravone was not identified using NIHSS scores but could be identified when using palsy scores .
A limitation of our study is that we examined a retrospective cohort that was gathered from a two year period, and the patients were consecutively treated according to the typical treatment regimens with and without edaravone, as described in the methods section. A fully-powered, prospective, randomized control trial may expand on our findings and demonstrate the full benefits of edaravone in patients with ischemic insults. Indeed, current clinical trials are being conducted with free radical scavengers, including a study of the safety and pharmacokinetics of MCI-186 in subjects with acute ischemic stroke in Europe .