Predictors of failure of early neurological improvement in early time window following endovascular thrombectomy: a multi-center study

Background and objective Endovascular thrombectomy (EVT) has become the gold standard in the treatment of acute stroke patients. However, not all patients respond well to this treatment despite successful attempts. In this study, we aimed to identify variables associated with the failure of improvements following EVT. Methods We retrospectively analyzed prospectively collected data of 292 ischemic stroke patients with large vessel occlusion who underwent EVT at three academic stroke centers in China from January 2019 to February 2022. All patients were above 18 years old and had symptoms onset ≤6 h. A decrease of more than 4 points on the National Institute of Health Stroke Scale (NIHSS) after 24 h compared with admission or an NIHSS of 0 or 1 after 24 h was defined as early neurological improvement (ENI), whereas a lack of such improvement in the NIHSS was defined as a failure of early neurological improvement (FENI). A favorable outcome was defined as a modified Rankin scale (mRS) score of 0–2 after 90 days. Results A total of 183 patients were included in the final analyses, 126 of whom had FENI, while 57 had ENI. Favorable outcomes occurred in 80.7% of patients in the ENI group, in contrast to only 22.2% in the FENI group (p < 0.001). Mortality was 7.0% in the ENI group in comparison to 42.1% in the FENI group (p < 0.001). The multiple logistic regression model showed that diabetes mellitus [OR (95% CI), 2.985 (1.070–8.324), p = 0.037], pre-stroke mRS [OR (95% CI), 6.221 (1.421–27.248), p = 0.015], last known well to puncture time [OR (95% CI), 1.010 (1.003–1.016), p = 0.002], modified thrombolysis in cerebral infarction = 3 [OR (95% CI), 0.291 (0.122–0.692), p = 0.005], and number of mechanical thrombectomy passes [OR (95% CI), 1.582 (1.087–2.302), p = 0.017] were the predictors of FENI. Conclusion Diabetes mellitus history, pre-stroke mRS, longer last known well-to-puncture time, lack of modified thrombolysis in cerebral infarction = 3, and the number of mechanical thrombectomy passes are the predictors of FENI. Future large-scale studies are required to validate these findings.


Introduction
Stroke is one of the major causes of global mortality and patient disability (1).Treatment of stroke has improved significantly over the past few decades, and endovascular thrombectomy (EVT) has become the gold standard for the treatment of acute ischemic stroke (AIS) (2,3).However, a significant proportion of AIS patients do not benefit from EVT despite successful attempts (4).
Multiple studies have reported that early neurological improvements (ENI) can be used as a surrogate in predicting functional outcomes of AIS patients (5)(6)(7)(8)(9)(10).For example, a decrease in the National Institute of Health Stroke Scale (NIHSS) score of greater than 4 points or NIHSS was 0 or 1 at 24 h after EVT, defined as ENI, was considered as a surrogate of long-term outcomes after mechanical thrombectomy (11).Conversely, a failure of early neurological improvement (FENI) was defined as an unchanged or decrease in the NIHSS score <4 points at 24 h after EVT (11).However, variables that can predict early ENI within 24 h after EVT remain understudied (11,12).Identifying markers of early neurological improvement can be important in predicting longer-term outcomes in patients with large vessel occlusion undergoing endovascular therapy.The objective of this study was to investigate factors that contribute to ENI in patients with large vessel occlusion presenting in the early time window following EVT.

Patients
We included consecutive patients with AIS who underwent EVT from January 2019 to February 2022 at three academic comprehensive stroke centers in China.We used data from the Big Data Observatory Platform for stroke in China, a prospectively collected data platform registry for stroke patients following EVT and the hospital data platforms.The inclusion criteria were as follows: (1) patients with AIS who underwent EVT; (2) age ≥18 years old at the time of treatment; (3) symptom onset ≤6 h.The exclusion criteria were as follows: (1) pre-EVT NIHSS <6; (2) missing data of follow-up; (3) symptoms onset >6 h.

Study outcome and assessment
Patients were divided into two groups according to their evolution of neurological deficits.A decrease of more than 4 points on the National Institute of Health Stroke Scale (NIHSS) after 24 h compared with admission or an NIHSS of 0 or 1 after 24 h was defined as early neurological improvement (ENI), whereas a lack of such improvement in the NIHSS was defined as a failure of early neurological improvement (FENI).We collected the following data: age, sex, vascular risk factors, premorbid modified Rankin scale (mRS), door-to-needle time (DNT), onset-to-needle time (ONT), door-to-puncture time (DPT), last known well-to-puncture time (LKWPT), door to recanalization time (DRT), puncture to recanalization (PRT), site of arterial occlusion, number of thrombectomy passes, and modified thrombolysis in cerebral infarction (mTICI) post-thrombectomy.Successful reperfusion was defined as an mTICI of ≥2B, and complete reperfusion was defined as an mTICI of 3. Experienced attending neurologists measured and recorded the NIHSS of all consecutive patients at the admission, while the interventionist recorded the NIHSS after the EVT.Patients' outcomes were evaluated by mRS at 90 days.Stroke nurses and/or the attending neurology physicians routinely assessed the mRS during in-person appointments or remotely by telephone during outpatient follow-up.A favorable outcome was defined as an mRS of 0-2 after 3 months, and an mRS of 6 was defined as mortality.

Statistical analysis
IBM SPSS version 26 was performed to analyze and draft the figure.The Mann-Whitney U-test was performed for non-normally distributed continuous data, recorded as medians along with the interquartile range (IQR).Normally distributed variables were reported as means with corresponding standard deviations (SD) and compared using the student's t-test.Results were considered statistically significant if the p-value was <0.05.

Ethics
The study protocol was approved by the Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Guangdong Province, China.Informed consent was not required due to the retrospective nature of the study in compliance with national laws and regulations.All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Results
From January 2019 to February 2022, we treated 292 consecutive AIS patients who had large vessel occlusion and underwent EVT.A total of 103 patients were treated with an LKWPT >360 min, four patients were lost to follow-up, one had a pre-EVT NIHSS <6, and one did not have the 24 h NIHSS documented.Therefore, 183 patients were included in the final analysis.Among them, 126 patients had FENI, while 57 had ENI.
Functional outcome was significantly different between the two groups (Table 2).Patients with ENI were more likely to experience a good outcome at discharge [median mRS 5 (3)(4)(5) in the FENI group vs. 2 (1-3) in the ENI group, p < 0.001] and at the 3 months follow-up (mRS of 0-2 in 22.2% of FENI vs. 80.7% of ENI, and mRS of 6 in 42.1% of FENI vs. 7% of ENI; p < 0.001).Furthermore, mortality was 7.0% (n = 4) in the ENI group in comparison to 42.1% (n = 53) in the FENI group (p < 0.001).The distribution of 90 days mRS of FENI and ENI groups is shown in Figure 1 and Table 3.

Discussion
This study analyzed the clinical variables for their association with FENI in patients with AIS due to LVO who underwent EVT.We found that diabetes history, pre-stroke mRS, LKWPT, absence of complete (TICI 3) reperfusion, number of MT passes, and ICH were independent predictors of FENI.Predictors of FENI were consistent with predictors of reperfusion without functional independence (RFI), a frequent phenomenon that may occur in the extended time window.Indeed, a multi-center cohort study recently demonstrated that higher baseline NIHSS, higher pre-stroke disability, transfer to a comprehensive stroke center, and a longer interval to puncture were independent predictors of RFI in patients with late presentation AIS (13).Conversely, in agreement with previous studies (12,14), we showed that ENI was strongly associated with good functional outcomes, low rates of sICH, and reduced mortality.Thus, we may argue that predictors of FENI can be considered surrogate parameters of long-term clinical outcomes in patients with AIS who underwent MT.Recognizing such factors can help to identify patients who may be at risk of FENI and establish future studies to circumvent these limitations.
As previously demonstrated in multiple studies (15-18), diabetes mellitus did not influence recanalization; nevertheless, it was a predictor of poor outcomes at 90 days.Moreover, a higher admission glucose value was an independent predictor of sICH (17).As recanalization rates do not explain the worse outcome of patients with diabetes mellitus, the mechanisms accounting for this are likely to be on the capillary, cellular, or metabolic level.Potential mechanisms leading to more extensive neuronal cell damage and worse outcomes in stroke patients with higher glucose levels include accumulation of extracellular glutamate (18), intracellular acidosis, increased bloodbrain barrier disruption (19,20), and formation of brain edema (21).
Furthermore, longer last known normal to puncture time was an independent predictor of FENI and strategies to optimize treatment time are critical to improving patient outcomes (22,23).
.The limitations of this study are related to the retrospective design.Furthermore, uncertainty might arise because of the imputation of missing values.A confirmation and analysis of independent predictors of FENI can be achieved with larger, multicenter cohort studies.Despite such limitations, our findings can help identify factors that can predict the successful outcome of EVT, which can provide pragmatic points for randomized controlled trials, facilitate surrogacy for patients who are unlikely to follow-up, and establish predictive models for ischemic stroke patients' outcomes (24).

Conclusion
Early neurological improvement was a reliable surrogate to predict 90 days favorable outcomes and mortality.Diabetes, premorbid mRS, longer last known well time to puncture time, absence of mTICI 3, sICH, and more EVT passes predicted the failure of early neurological improvement in the early time window following endovascular therapy.Future randomized controlled trials are required to validate these findings.

FIGURE 1
FIGURE 1Distribution of 90 days modified Rankin scale (mRS) of failure of early neurological improvement (FENI) and early neurological improvement (ENI).

TABLE 1
Comparison of baseline and failure of early neurological improvement (FENI) and early neurological improvement (ENI) groups.

TABLE 3
Distribution of 90 days mRS of FENI and ENI.

TABLE 2
Comparison of mRS at discharge, 90 days favorable outcome and mortality in failure of early neurological improvement (FENI), and early neurological improvement (ENI) groups.

TABLE 5
Independent predictors of FENI by logistic regression analysis.