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 (5–10). 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.

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.

The baseline characteristics of patients in both groups are demonstrated in Table 1. There were no statistically significant differences between baseline characteristics of the two groups including age (p = 0.031) and sex (p = 0.214), as well as risk factors, such as hypertension (p = 0.321), diabetes mellitus (p = 0.106), coronary artery disease (p = 0.545), atrial fibrillation (p = 0.641), stroke history (p = 0.791), and chronic kidney disease (p = 0.696). Smoking was less frequent in the FENI group compared to the ENI group (12.0% vs. 24.6%, p = 0.030). In addition, NIHSS at admission [FENI 15 (12–19) vs. ENI 14 (10–18), p = 0.15], premorbid mRS (FENI 0 vs. ENI 0, p = 0.051), baseline Alberta stroke program early CT score (ASPECTS) [FENI 8 (8–9) vs. ENI 8 (8–9), p = 0.362], and distribution of target vessel occlusion side (p = 0.11) were similar in both groups.

The rate of bridging intravenous (IV) thrombolysis before EVT was similar (FENI 53.2% vs. ENI 52.6%, p = 0.946) between the two groups. Patients with FENI required more attempts during EVT [2 (1–3) vs. 1 (1–2); p = 0.016], had longer last-known well-to-puncture time [251.50 min (183.75–299.25) vs. 200 min (136.50–265.50); p = 0.005] and door to recanalization time [230 min (169.75–295) vs. 195 min (149.50–240); p = 0.005]. Successful reperfusion defined by modified thrombolysis in cerebral infarction ≥2B was lower in the FENI compared to the ENI group [76.2% vs. 94.7%; p = 0.003]. Furthermore, symptomatic intracranial hemorrhage (sICH) occurred in 14.5% of patients with FENI, and there were no patients with ENI (p = 0.001) after EVT (Table 1).

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 (3–5) 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.

Differences in outcomes between ENI and FENI groups, including 90 days favorable outcome (p < 0.001) and 90 days mortality (p < 0.001) were present after adjusting for confounding factors, including age, current smoking status, diabetes mellitus, NIHSS pre-EVT, and premorbid mRS (Table 4).

Next, we decided to identify variables that can predict FENI outcomes. Eleven variables were assessed in a multiple logistic regression model, showing 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], longer last known well to puncture time [OR (95% CI), 1.010 (1.003–1.016), p = 0.002], lack of modified thrombolysis in cerebral infarction = 3 [OR (95% CI), 0.291 (0.122–0.692), p = 0.005], and the number of mechanical thrombectomy passes [OR (95% CI), 1.582 (1.087–2.302), p = 0.017] were predictors of FENI (Table 5).

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 blood-brain 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, multi-center 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).

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.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Foshan Sanshui District People’s Hospital in Foshan. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin because informed consents were not required due to the retrospective nature of the study in compliance with national laws and regulations.

FD, YnC, YL, and HM drafted the manuscript. MM, MA, and TN critically edited the manuscript. EJ, SZ, HS, JH, WY, YgC, MF, JC, JM, and XL analyzed the cases and edited the manuscript. All authors contributed to the article and approved the submitted version.

The study was supported by the Foshan Science and Technology Bureau (Grant No. 2220001005022), the Medical Science and Technology Research Foundation of Guangdong Province (Grant No. 20221027164016611), Foshan the 14th Five-Year Plan Key Discipline Foundation, the Guangdong Provincial TCM Bureau Key Discipline Foundation, and the Foshan Brain Heart Co-Therapy Foundation. The Foshan 14th Five-Year Priority Speciality Construction Project, The Foshan Nanhai District 14th Five-Year Priority Speciality Construction Project, Foshan Traditional Chinese Medicine Immune Health Technology Innovation Base.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The handling editor declared a shared affiliation with the author EJ at the time of review.

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