Discussion

Our analysis highlights the prognostic value of a simple early neurological assessment after MT to predict the 3-month clinical outcome. We found that an improvement of at least four points in the NIHSS score 24 hours after MT can accurately predict the 3-month outcome (AUC 0.93) with high specificity and sensitivity. Despite quite good diagnostic accuracy, the threshold of 1 point in NIHSS improvement 2 hours after MT seemed to be not relevant clinically because of the possibilities of inter-rater variability in the NIHSS assessment.12 13 Indeed, although being simple, quick and a robust stroke deficit scale, the NIHSS also contains items with poor reliability and redundancy such as the level of consciousness, facial palsy, limb ataxia, and dysarthria.9 However, in our study the correlation between ENI and 3-month outcome was clearly stronger for an assessment performed at 24 hours.

The predictive power of ENI has been widely evaluated in large cohorts of patients treated with IVT. Unlike our study, NIHSS changes at 2 and 24 hours showed fair accuracy (AUC 0.65–0.75) for predicting final outcome.1 2 These studies underlined that no single definition of ENI provides optimal values for both specificity and sensitivity1; indeed, the earlier ENI occurred, the higher specificity and the lower sensitivity in general.2 The role of ENI in patients treated with MT has been poorly studied. In line with our results, an International Management Stroke III post hoc analysis (where 50% of patients were treated endovascularly) found that the evaluation of NIHSS at 24 hours showed a high level of accuracy (AUC 0.91) in predicting the final outcome.5 We hypothesize that such differences in the final outcome prediction may result from different kinetics of neurological recovery after MT or IVT. First, MT provides higher rates of rapid recanalization with subsequent early clinical improvement,14 while chemical lysis of the thrombus may be more progressive in large vessel occlusions. This may allow a higher amount of DWI reversal, a factor that strongly influences ENI.9 10 Second, in studies evaluating ENI after IVT, patients did not always have a large vessel occlusion whereas our patients had large vessel occlusions and higher baseline NIHSS scores. Although indicating a poor prognosis, higher scores also allowed a more significant decrease after early recanalization, meaning a higher chance of achieving ENI. Indeed, in a population of patients treated with IVT, Hemmen et al reported better accuracies of ENI while baseline NIHSS scores increased.1

Another important goal of our study was to define the optimal time point to determine if the patient shows ENI. We found that assessment at 24 hours was more valuable at predicting final outcome than at 2 hours. It is widely acknowledged that the NIHSS score often changes during the first 24 hours, and that the relationship between the neurological examination and final functional outcome strengthens after the initial hours and then begins to plateau.15 Indeed, in some recanalized patients a ‘stunned brain’ phenomenon (ie, no response to recanalization during a few hours) with delayed recovery can be observed.16 Consequently, we hypothesize that NIHSS testing at 2 hours may have been influenced by greater variability. Also, because MT necessitates anesthetic support to prevent patient movement, a very early neurological assessment may be impacted due to altered levels of consciousness, especially in patients treated under general anesthetic. However, in our study, conscious sedation was always offered as a first-line option, thus limiting the number of patients treated under general anesthesia. But a consequence is also that the impact of general anesthesia on 2-hour and 24-hour NIHSS assessment is difficult to determine in the present study, so our ENI thresholds need further validation cohorts of patients treated under general anesthesia.

While ENI seems to be a practical tool, a concern is whether it has the same meaning in patients with low and high NIHSS. We found a greater proportion of patients reaching ENI at 2 and 24 hours with increasing baseline NIHSS (p for trend=0.14 and 0.02, respectively). Higher baseline NIHSS allowed greater improvement of the score after early recanalization. However, this was counterbalanced by the smaller proportion of patients with a high baseline NIHSS score achieving a good functional outcome. Finally, we did not observe better accuracy of ENI while baseline NIHSS scores increased (online supplemental table 2). Additionally, we found that ENI seems to be a practical tool for routinely following patients with a high baseline NIHSS score, while using total NIHSS may be preferable for patients with a low baseline NIHSS score (online supplemental table 3).

The role of IVT combined with MT (bridging therapy) remains a matter of debate. Indeed, some studies comparing patients treated by bridging versus MT alone suggested similar clinical outcomes, revascularization, symptomatic intracranial hemorrhage, and mortality rates.17–19 In contrast, other studies with the same design suggested that prior IVT facilitates successful recanalization by MT.20–22 This suggests the pressing need for a randomized trial to compare direct MT with bridging therapy. In this situation of clinical uncertainty, we noted in our population a higher proportion of patients with IVT in the ENI group (p=0.02). One possible explanation is that successful arterial recanalization does not guarantee by itself good reperfusion, as distal blood flow may be compromised and not accessible to mechanical treatment but only to the synergistic effect of IVT. While waiting for a randomized trial comparing IVT+MT with MT alone, IVT should be started as early as possible for all eligible patients with stroke without delaying access to MT.

Our study has potential limitations. First, the single-center design may weaken the generalizability of our results. Second, despite an honorable sample, some analyses lacked precision, with wide CI. Ideally, larger studies are needed to confirm the clinical utility of ENI in patients treated by MT. Third, we did not test definitions of ENI based on percent change in NIHSS score, as has been done previously.2 4 23 24 However, we obtained significant results with absolute NIHSS changes which are more pragmatic. Our study is affected by some limitations of retrospective analyses of registry data, especially bias due to lack of blinding to treatment. Indeed, the NIHSS assessment was performed by stroke neurologists not blinded to the result of MT, but we believe this was unlikely to introduce a measurement bias because they were not aware of the study at that time. On the other hand, it is impossible to determine whether knowledge of the baseline NIHSS score may have influenced the neuroradiologist in some way during MT; however, the neuroradiologists were similarly not aware of the study at that time. Also, we did not assess the accuracy of the final infarct volume compared with ENI in the prediction of 3-month functional outcome because we focused on the analysis of pre-therapeutic factors affecting ENI. As the final infarct volume is a strong predictor of the final outcome,25 a future study comparing the ROCs of final infarct volume with ENI at 2 and 24 hours will be meaningful. Finally, we did not evaluate whether combining ENI with other variables available at 24 hours (eg, hemorrhagic transformation, infarct volume) could potentiate the final outcome prediction.

While a consideration of all possible pre-stroke and post-stroke variables in a predictive model might be ideal, it would likely be highly complex and the resulting tool impractical to use in clinical settings. Instead, it is possible that a complex variable such as ENI, that is influenced by several factors,23 26 27 could serve as a single determinant of clinical outcome.28 29 ENI at 24 hours after MT could provide a straightforward and reliable substitute for long-term endpoints in future research.