IMR Press / JIN / Volume 22 / Issue 2 / DOI: 10.31083/j.jin2202052
Open Access Systematic Review
Predictors of Early Neurological Deterioration Occurring within 24 h in Acute Ischemic Stroke following Reperfusion Therapy: A Systematic Review and Meta-Analysis
Han-Xu Shi1,2,†Chen Li3,†Yi-Qun Zhang4,†Xia Li3,5Ao-Fei Liu3Yun-E Liu3Wei-Jian Jiang3,*Jin Lv1,3,*
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1 Central Laboratory of Research Department, the PLA Rocket Force Characteristic Medical Center, 100088 Beijing, China
2 School of Public Health, University of Hong Kong, 999077 Hong Kong, China
3 Department of Vascular Neurosurgery, New Era Stroke Care and Research Institute, The PLA Rocket Force Characteristic Medical Center, 100088 Beijing, China
4 Department of Critical Care Medicine, New Era Stroke Care and Research Institute, The PLA Rocket Force Characteristic Medical Center, 100088 Beijing, China
5 Department of Neurology, Baotou Central Hospital, 014040 Baotou, Inner Mongolia, China
*Correspondence: cjr.jiangweijian@vip.163.com (Wei-Jian Jiang); lvjin6630@hotmail.com (Jin Lv)
These authors contributed equally.
J. Integr. Neurosci. 2023, 22(2), 52; https://doi.org/10.31083/j.jin2202052
Submitted: 13 November 2022 | Revised: 12 December 2022 | Accepted: 15 December 2022 | Published: 23 March 2023
Copyright: © 2023 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Background: Early neurological deterioration (END), generally defined as the increment of National Institutes of Health Stroke Scale (NIHSS) score 4 within 24 hours, lead to poor clinical outcome in acute ischemic stroke (AIS) patients receiving reperfusion therapies including intravenous thrombolysis (IVT) and/or endovascular treatment (EVT). This systematic review and meta-analysis aimed to explore multiple predictors of END following reperfusion therapies. Methods: We searched PubMed, Web of Science and EBSCO for all studies on END in AIS patients receiving IVT and/or EVT published between January 2000 and December 2022. A random-effects meta-analysis was conducted and presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The quality of each included studies was assessed by calculating a total score according to the STROBE or CONSORT criteria. Publication bias and heterogeneity were also evaluated using the Eggers/Peters test, funnel plots and sensitivity analysis. Results: A total of 29 studies involving 65,960 AIS patients were included. The quality of evidence is moderate to high, and all studies have no publication bias. The overall incidence of END occurring after reperfusion therapy in AIS patients was 14% ((95% confidence intervals (CI), 12%–15%)). Age, systolic blood pressure (SBP), glucose levels at admission, the onset to treatment time (OTT), hypertension, diabetes mellitus, arterial fibrillation, and internal cerebral artery occlusion were significantly associated with END following reperfusion therapy. Conclusions: Numerous factors are associated with END occurrence in AIS patients receiving reperfusion therapy. Management of the risk factors of END may improve the functional outcome after reperfusion treatment.

Keywords
early neurological deterioration (END)
intravenous thrombolysis (IVT)
endovascular treatment (EVT)
reperfusion therapy
predictors
1. Introduction

The past decade has witnessed substantial advances in the treatment of acute ischemic stroke (AIS). Evidence-based reperfusion therapies such as intravenous thrombolysis (IVT) and mechanical thrombectomy have been shown to improve outcomes in AIS and become the standard care for AIS patients. However, despite these major improvement, only less than half of patients achieve functional independence (mRS 0–2) at 90 days as a result of treatment, leaving the others at a high risk of disability and death [1]. Most of the poor 90-day outcomes in AIS after reperfusion therapy (i.e., IVT and/or endovascular treatment) are reported to be largely associated with early neurological deterioration (END). END generally refers to a 4 point increase in the National Institutes of Health Stroke Scale (NIHSS) score between baseline and 24 hours after treatment. The estimates of END incidence vary widely in AIS patients, ranging from 8% to 28% of patients after IVT [2, 3, 4, 5, 6], and from 35% to 42% of patients after endovascular treatment (EVT) [7, 8, 9]. However, the reasons of END occurrence were not fully understood, some of which are related to symptomatic intracranial haemorrhage (sICH), malignant edema and early recurrent ischemic stroke, while others are remaining unexplained. Since END is closely related to the increase of disability and mortality following reperfusion therapy, it is desirable to identify factors associated with END and to explore the underlying mechanism, so that possible prevention and treatment could be done to improve clinical outcomes.

Thus far, END has only been addressed in either IVT or EVT setting. Few studies considered IVT and EVT as a whole for reperfusion therapy. Unfortunately, the latter is more like the cases in the real world. Furthermore, the exact rate and predictors of END have not been systematically investigated. Therefore, we present here a systematic review and meta-analysis of the predictors of END following reperfusion therapy (IVT and/or EVT) in AIS patients. Specifically, we categorized the predictors of END into three groups, IVT, EVT and overall reperfusion therapy, to study the treatment-specific risk factors.

2. Methods
2.1 Search Strategy

This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [10]. Studies published in English between January 2000 and December 2022 were identified by searching PubMed, Web of Science and EBSCO databases. Key search terms were ‘neurological deterioration’, ‘neurological deficit’, ‘neurological decline’, ‘thrombolysis’, ‘thrombolytic treatment’, ‘thrombolytic therapy’, ‘IV rtPA’, ‘endovascular treatment’, ‘endovascular therapy’, ‘mechanical thrombectomy’, ‘acute ischemic stroke’, ‘acute cerebral ischaemia’, ‘proximal vessel occlusion’, ‘proximal artery occlusion’, ‘large vessel occlusion’, ‘large artery occlusion’, ‘vertebrobasilar artery occlusion’, ‘basilar artery occlusion’, ‘middle cerebral artery occlusion’, ‘internal cerebral artery occlusion’. Details of the search algorithm is shown in Appendix I and the Supplementary Materials. Fig. 1 presents the specific screening process.

Fig. 1.

Flow diagram depicting the selection of studies eligible for analysis. END indicates early neurological deterioration; NIHSS indicates National Institutes of Health Stroke Scale.

2.2 Selection Criteria

We included all studies that investigated predictors of END for adult patients with AIS who received IVT and/or EVT if they met the following criteria: (1) age 18 years with AIS due to large vessel occlusion, including the anterior or posterior circulation; (2) arterial occlusion was confirmed by computed tomographic angiography (CTA), magnetic resonance angiography (MRA), or digital subtraction angiography (DSA); (3) studies reported the number of patients with END; (4) having clear definition of END (END was defined as an increment of NIHSS score of 4 points within 24 hours); (5) were published in English language.

We excluded studies (1) in animals and studies that did not provide sufficient information needed in the meta-analysis; (2) patients with baseline pre-stroke mRS score 3; (3) artery occlusion of non-atherosclerotic etiology such as dissection, moyamoya disease, vasospasm, or vasculitis; (4) reviews, letters, case reports, protocols or conference abstracts; (5) studies involved other definitions of END.

2.3 Data Extraction and Quality Assessment

Two authors (L.J. and S.H.X.) independently searched the literature, screened eligible studies, and extracted data on the first author’s name, year of publication, study design, sample size, number of patients in END and non-END groups, baseline characteristics, vascular comorbid conditions (history of hypertension, diabetes, atrial fibrillation), NIHSS on admission, Alberta Stroke Program Early CT Scores (ASPECT), lesion location (Internal Carotid Artery (ICA), Middle Cerebral Artery (MCA)), treatment strategy, and the onset to treatment time (OTT). Any disagreement was discussed and resolved by consensus among three other authors (L.C., Z.Y.Q., and L.X.). Three independent authors (L.A.F., L.Y.E, and W.S.) assessed the quality of each included study by using the CONSORT checklist for randomized controlled trials or the STROBE checklist for observational studies [11, 12]. Studies with quality scores of 8–10 were recognized as high quality whereas those who scored 7 or less were considered as low quality. Details of quality assessment scoring are shown in Appendix II and Supplementary Fig. 1.

2.4 Statistical Analysis

The risk ratio (RR) of the binary variable or the standardized mean difference (SMD) of the continuous variable with the 95% confidence intervals (CI) were calculated as summary statistics in this meta-analysis. The overall RR and SMD for all pooled data were calculated using the random effect method. Mean and standard deviation (SD) were calculated using the method described by Luo et al. [13] if the studies reported median and inter-quartile range (IQR). We assessed the publication bias using Egger’s test for continuous variables and Peters test for binary variables in addition to visual analysis of the funnel plots. The I2 statistic was used to evaluate the heterogeneity across included studies and considered as a low, moderate and high heterogeneity using thresholds of 25%, 50% and 75%, respectively [14]. The sensitivity analysis was conducted to explain the heterogeneity. We performed subgroup analyses for END by treatment administered to patients. All statistical analyses were performed using STATA 16.0 (StataCorp, College Station, TX, USA).

3. Results

The search yielded 6833 relevant records from PubMed, Web of Science, and EBSCO. Finally, a total of 29 studies involving 65,960 AIS patients suffering from END within 24 hours following IVT and/or EVT were included [1, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43]. The specific study selection process was reported in a PRISMA flowchart (Fig. 1). The basic characteristics of all included articles were shown in Table 6 (Ref. [15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43]).

Table 1.Participants’ characteristics of each study.
No. Source (Author/Year/Country) Sample size (Total, END, non-END) Age, year Study design Interventions Location lesion Time of stroke onset Quality score
1 Luo et al. 2022. China [15] T = 406 END A retrospective analysis of a prospectively maintained data EVT M1, M2, ICA, ACA, BA Within 4.5 h 9
END = 88 70 (60–78)
Non-END = 318 Non-END
71 (64–77)
2 Lattanzi et al. 2022. Italy [16] T = 211 END A retrospective analysis based a longitudinal study EVT M1, M2, internal carotid artery, internal carotid artery terminus, middle cerebral artery Within 4.5 h 9
END = 30 72 ± 10
Non-END = 181 Non-END
79 ± 5
3 Xu et al. 2022. China [17] T = 406 END A retrospective cohort analysis based on prospectively collected data IVT ICA, M1, basilar artery Within 4.5 h 9
END = 64 63.0 (56.0–69.5)
Non-END = 342 Non-END
64.5 (55.0–73.0)
4 Zhang et al. 2022. China [18] T = 591 END A multicenter, prospective, randomized, open-label trial EVT MCA, Intracranial ICA Within 4.5 h 10
END = 111 70 (63–78)
Non-END = 480 Non-END
69 (60–76)
5 Che et al. 2022. China [19] T = 1107 END A multicenter prospective stroke registry rtPA N/A Within 4.5 h 10
END = 81 64.47 ± 9.34
Non-END = 1026 Non-END
63.34 ± 11.48
6 Wang et al. 2022. China [20] T = 798 END A retrospective analysis of a prospectively maintained data IVT N/A Within 4.5 h 9
END = 139 69 ± 12.5
Non-END = 659 Non-END
66 ± 11.1
7 Shah et al. 2021. USA [21] T = 1238 END A retrospective analysis of a prospectively maintained data IV tPA ICA, M1, P1, and basilar artery, Vertebrobasilar Within 4.5 h 10
END = 91 72 ± 16
Non-END = 1147 Non-END
69 ± 15
8 Fabritius et al. 2021. Germany [22] T = 211 END A prospective consecutive cohort study EVT or bridging therapy (IVT plus EVT) Anterior circulation of LVO Within 4.5 h 9
END = 38 78 (72-80) ICA, MCA
Non-END = 173 Non-END
74 (63–81)
9 Li et al. 2021. China [23] T = 343 AD Retrospective analysis of prospectively collected observational study EVT Anterior circulation of LVO ND, 257 (210–300) 9
END = 90 70.7 ± 10.7 ICA, MCA
Non-END = 214 Non-ND
67.7 ± 10.9
10 Seners et al. 2021. France [24] T = 721 END A retrospective analysis based a longitudinal study IVT BA, ICA, M1 or M2 Within 4.5 h 10
END = 88 69 ± 15
Non-END = 633 Non-END
70 ± 15
11 Gong et al. 2021. China [25] T = 1060 END A prospective longitudinal study IVT Anterior circulation Within 4.5 h 10
END = 193 73.2 ± 11.5 Posterior circulation
Non-END = 469 Non-END
ENI = 398 69.6 ± 12.0
ENI
68.1 ± 12.1
12 Boulenoir et al. 2020. France [26] T = 74 END A multicenter retrospective analysis based on prospective study IVT iICAo, ICA, MCA, basilar artery Within 4.5 h 8
END = 22 62 (54–71)
Non-END = 52 Non-END
64 (54–74)
13 Girot et al. 2020. France [27] T = 1925 END Multicenter prospective observational registry EVT alone or bridging therapy (IVT plus EVT) ICA. M1/ M2 Within 4.5 h 10
END = 128 75.1 ± 11.8
Non-END = 1797 Non-END
69.8 ± 14.6
14 Tanaka et al. 2020. Japan [28] T = 744 END a retrospective design on Multicenter retrospective observational study IVT (IVT bridging EVT) ICA, MCA, BA Within 4.5 h 10
END = 79 H: 78 (67–87.5); I: 75 (64–81)
Non-END = 665 Non-END
75 (66–82)
15 Yu et al. 2020. United Kingdom [29] T = 50726 END a retrospective analysis on a multinational open registry project IVT Left hemisphere, posterior Within 4.5 h 9
END = 3415 76 (69–83)
Non-END = 47311 Non-END
72 (63–81)
16 Lee et al. 2020. USA [30] T = 81 END A prospective study IVT anterior circulation LVO as M1, M2, or carotid artery terminus (ICAT) Within 4.5 h 7
END = 28 70.8
Non-END = 53 Non-END
63.2
17 Zhong et al. 2020. China [31] T = 148 END A prospectively registered consecutive cohort study Basilar EVT BAO Within 24 h 9
END = 21 56 (49–65)
Non-END = 127 Non-END
61 (54–67)
18 He et al. 2020. China [32] T = 341 END A prospectively study IVT Within 4.5 h 8
END = 65 67.14 ± 10.06
Non-END = 276 Non-END
64.87 ± 11.38
19 Wang et al. 2020. China [33] T (END) = 581 END Single center retrospectively study IVT Within 4.5 h 9
END = 50 59.5 (53.5–67.5)
No END = 531 Non-END
62 (53–69)
20 Soomro et al. 2020. USA [34] T = 178 END Retrospective cohort EVT LVO Within 6 h for anterior; 6 to 24 h for posterior 9
END = 26 60.5 (53–69)
Non-END = 152 Non-END
63 (53–75)
21 Gong et al. 2019. China [35] T = 342 END Prospectively study IVT (IVT+EVT) proximal arte‐ rial occlusion Within 4.5 h 9
END = 86 70.9 ± 11.4
No-END = 256 Non-END
67.2 ± 12.7
22 Zhang et al. 2019. China [36] T = 563 END Multicenter, large prospective cohort study IVT (IVT+EVT) within 4.5 h 9
END = 83 69.1 ± 9.6
Non-END = 480 Non-END
66.2 ± 11.8
23 Mazya et al. 2018. Sweden [37] T = 587 END Secondary data analysis on an ongoing, prospective, multinational centers cohort study IVT occlusion of large proximal and distal cerebral arteries 9
END = 53 67 (59–75)
Non-END = 534 Non-END
67 (57–76)
24 Seners et al. 2017. France [38] T = 120 END Secondary analysis on a prospective cohort study IVT MCA Within 4.5 h 9
END = 22 75.7 ± 11.4
Non-END = 98 Non-END
68.0 ± 15.8
25 Simonsen et al. 2016. Denmark [39] T = 569 END A single center prospective cohort study IVT Small vessel disease, Large vessel disease Less than 3 hours, extended to 4.5 hours 10
END = 33 66 (61–74)
Non-END = 536 73 (60.5–80.75)
Non-END
66 (57–74)
26 Zinkstok et al. 2014. The Netherlands [40] T = 640 END A prospective, multi-center, randomized controlled trial IVT (Asprin + standard treatmetn) 113 (85–150) 9
END = 31 71.1 ± 12.4 115 (85–165)
Non-END = 609 Non-END
66.7 ± 13.5
27 Mori et al. 2012. Japan [41] T = 566 END A retrospective, multicenter, observational cohort study IVT AIS, ICA Within 3 h 10
END = 56 71.5 ± 9.3
Non-END = 510 Non-END
72.0 ± 11.9
28 Seners et al. 2014. France [42] T = 309 END A retrospective cohort IVT Anterior circulation (MCA) Within 4.5 h 9
END = 23 73.1 ± 12.6
Non-END = 276 Non-END
68.6 ± 14.7
29 Saqqur et al. 2007. Canada [43] T = 374 END A retrospective study IVT M1, M2, ICA, BA Within 3 h 9
END = 44 66.1 ± 14.7
Non-END = 330 Non-END
T = 374 68.8 ± 13.3
3.1 Incidence of END

Fig. 2 shows the pooled overall incidence of END following reperfusion therapy in AIS patients was 14% (95% CI, 12%–15%). In the subgroup analysis, the incidence of END occurring after IVT was 13% (95% CI, 11%–14%), and was 17% after EVT (95% CI, 11%–23%).

Fig. 2.

Forest plot of pooled incidence of END with random-effect method in AIS patients underwent reperfusion therapy (IVT and/or EVT). END indicates early neurological deterioration; IVT indicates intravenous thrombolysis; and EVT indicates endovascular therapy.

3.2 Predictors of END

The following risk factors of END in AIS patients after reperfusion therapies were evaluated: age, initial NIHSS, systolic blood pressure (SBP), glucose level at admission, OTT, ASPECT, history of hypertension, diabetes mellitus (DM), arterial fibrillation (AF), stroke subtype by TOAST criteria (large artery atherosclerosis, cardioembolism, others or unknown), occlusion site, and successful recanalization (SR).

For all included studies, the meta-analysis showed that higher age (Effect, overall: 0.16, 95% CI: 0.09–0.23), SBP (Effect, overall: 0.25, 95% CI: 0.14–0.37), glucose level at admission (Effect, overall: 0.44, 95% CI: 0.32–0.57), OTT (RR, overall: 0.07, 95% CI: 0.00–0.13), history of hypertension (RR, overall: 1.29; 95% CI: 1.17–1.42), DM (RR, overall: 1.37; 95% CI: 1.18–1.60) were significantly associated with END after reperfusion therapies (Figs. 3,4).

Fig. 3.

Forest Plots of (A) Age; (B) Initial NIHSS; (C) Systolic blood pressure; (D) Serum glucose; (E) Onset to treatment time; (F) ASPECT score. NIHSS indicates National Institutes of Health Stroke Scale; ASPECT indicates Alberta Stroke Early CT score. IVT indicates intravenous thrombolysis, and EVT indicates endovascular therapy. The solid squares denote the standardized mean differences (Effects), the horizontal lines represent the 95% confidence intervals (CIs), and the diamonds denote the pooled effect size.

Fig. 4.

Forest plots of (A) Hypertension; (B) Diabetes mellitus; (C) Etiology atherosclerosis; (D) Atrial fibrillation; (E) Lesion location; (F) Successful recanalization; (G) Lesion location_IVT; (H) Lesion location_EVT. IVT indicates intravenous thrombolysis, and EVT indicates endovascular therapy. The solid squares denote the risk ratios (RRs), the horizontal lines represent the 95% confidence intervals (CIs), and the diamonds denote the pooled RRs.

Analysis of the pooled data from studies on END following IVT demonstrated that higher age (Effect: 0.14, 95% CI: 0.06–0.22), SBP (Effect 0.24, 95% CI: 0.09–0.39), glucose level at admission (Effect 0.41, 95% CI: 0.28–0.54), OTT (Effect 0.07, 95% CI: 0.00–0.13), history of hypertension (Effect 1.33; 95% CI: 1.24–1.42), DM (Effect 1.37; 95% CI: 1.15–1.63), AF (Effect 1.20; 95% CI: 1.10–1.31), large artery atherosclerosis (Effect 1.18; 95% CI: 1.01–1.39), internal carotid artery occlusion (Effect 3.97; 95% CI: 1.51–10.43), middle cerebral artery M2 occlusion (Effect 0.34; 95% CI: 0.21–0.57) and bridging therapy (Effect 1.51; 95% CI: 1.18–1.94) were significantly associated with END after IVT (Figs. 3,4).

For studies focusing on END after EVT, four risk factors including SBP (Effect 0.30, 95% CI: 0.19–0.40), history of hypertension (RR 1.48; 95% CI: 1.09–2.02), internal carotid artery occlusion (RR 2.13; 95% CI: 1.67–1.72), and middle cerebral artery M1 occlusion (Effect 0.60; 95% CI: 0.45–0.80) were found to be significantly associated with END (Figs. 3,4).

3.3 END and Outcome

We noted that the risk of dependency or death (modified Rankin Score 3) at 3 months was considerably higher in patients with END after reperfusion therapies (Effect 0.13; 95% CI: 0.07–0.26). Similar results were observed in the IVT group (Effect 0.16; 95% CI: 0.07–0.39) or in the EVT group (Effect 0.07; 95% CI: 0.04–0.12) (Data not shown).

3.4 Publication Bias and Heterogeneity

We detected the publication bias by combining visual funnel plots inspection with the symmetry distributions and the quantitative analysis of Egger’s test and Peters test (p > 0.05), showing no sign of publication bias for all except age (Supplementary Figs. 2,3 and Appendix III).

Considering the high heterogeneity emerged at predictors of initial NIHSS, SBP, etiology of atherosclerosis, serum glucose, ASPECT, location of intracranial occlusion_IVT, and successful recanalization (Figs. 3,4), a sensitivity analysis was performed to detect which study resulted in such high heterogeneity. No high risk of bias for the studies were identified the other predictors [22, 26]. All the aforementioned results are shown in Supplementary Fig. 4.

4. Discussion

The main findings from this meta-analysis focused on investigating the predictors of END occurrence in AIS patients who receiving reperfusion treatments. Elderly, systolic blood pressure, glucose levels at admission, treatment onset, history of previous diseases (i.e., hypertension, diabetes mellitus, arterial fibrillation), internal carotid artery occlusion, and middle cerebral artery M2 occlusion significant associated with END in AIS patients who experienced overall reperfusion therapy. In addition, elderly, SBP, glucose level at admission, OTT, history of hypertension, DM, AF, large artery atherosclerosis, internal carotid artery occlusion, middle cerebral artery M2 occlusion and bridging therapy associated with END in patients who experienced IVT, and four risk factors including SBP, history of hypertension and internal carotid artery occlusion were found to be related with END in patients witnessed EVT.

The definition of END was not clear in existing studies because of the degree of symptom worsening and the time frame of the deterioration. Some literature adopted an increase of 2 points of the NIHSS score within the pre-defined time frame (ΔNIHSS 2) as the definition of END. View the fact that ΔNIHSS equals 2 seems to be too small changes in NIHSS out of a total score of 42 points and reflects inadequate reliability of the score itself rather than real symptom worsening, especially for severe stroke with high scores [44, 45]. We used ΔNIHSS 4 as the definition of END in this systematic review and meta-analysis, which was consistent with most studies on END. In terms of the time frame for END, although a number of END cases caused by malignant edema tended to occur beyond the first 24 hours, we adopted within 24 hours as the timeframe of END, which was consistent with most of the studies.

Within the currently acceptable timeframe and degree of worsening of END, multiple risk factors identified in this study were in line with several previous studies. Age has been identified as a risk factor for END onset in Birschel’s study [46]. In our study, the pooled data analysis showed that older AIS patients were at higher risk of END after revascularization treatment, especially more obviously presented underwent IVT treatment in the subgroup analysis, whereas no significant association between age and the occurrence of END was observed in patients receiving EVT treatment. This result might relate to a small number of studies included in the EVT group, limited by the number of patients. In addition, another reason might be that patients receiving EVT treatment have a more strict age restrictions and a smaller age span. Initial NIHSS score is used widely to measure a level of consciousness on admission, specifically, a larger initial NIHSS score indicated a declined consciousness which is related to a greater chance of END achieved [47]. However, in our analysis, the initial NIHSS score was not statistically significant in predicting the occurrence of END. In previous studies, the initial NIHSS score was a significant predictor of END24, both of which used a liberal definition of END24 (worsening of Scandinavian Stroke Scale, which might be more sensitive than NIHSS, and ΔNIHSS 1, respectively). Since a severe neurological deficit strongly predicts sICH and malignant oedema. In contrast, another study [41] using a more conservative definition (namely, ΔNIHSS 4) found the inverse association, that is, less severe deficits predicted END24, which might be explained by a ‘ceiling effect’ such that higher admission scores are less likely to further increase. Thus, the risk of END24 associated with admission to NIHSS might depend on the definition of END, including whether absolute or relative changes are considered. This is consistent with the definition of END in the included studies in our analysis, so the results are similar. Systolic blood pressure is a significant predictor of increased END risk in our meta-analysis. In both overall and subgroup analyses, in AIS patients treated with IVT or EVT, higher SBP was associated with a greater incidence of END. Augmented systolic blood pressure has been mentioned to predict early neurological deterioration in the preceding study [48]. The exact cause is not yet clear, but it may be related to the fact that high blood pressure can easily aggravate cerebral edema, which occurs after acute cerebral infarction, particularly in patients with extensive oligaemia due to proximal occlusion. This hypothesis has not been directly tested so far. Serum Glucose is a significant predictor of increased END risk.

History of diabetes mellitus is associated with a higher risk of END occurring [49, 50]. Notably, the poor neurological outcome (i.e., END) has resulted from persistently high level of serum glucose following reperfusion treatments [51]. One potential mechanism could be that it increased blood-brain barrier disruption and promoted sICH. However, hyperglycaemia might also facilitate neuronal damage. OTT (Onset to Treatment Time) was another significant predictor of increased END risk in our meta-analysis. Patients with longer OTT were more likely to have END, which is consistent with the concept of “time is brain” that we have known before. In the subgroup analysis, it was more obviously found in the IVT group, but in the EVT group, the association between age and the occurrence of END was not statistically different. We speculated that the reason was the large heterogeneity in OTT among patients receiving EVT. With the improved concept of thrombectomy, many AIS patients beyond the time window with salvage of brain tissue still received EVT. This might be the reason why OTT time did not fully predict the occurrence of END in EVT patients.

In addition, Kwan’s study [52] found atrial fibrillation aggrandized the risk of END attained, which was also a significant predictor of increased END risk in our meta-analysis. It might be due to the stroke etiology in patients with atrial fibrillation was cardiogenic embolism. The occlusion site was usually large vessel, with less collateral compensation and a larger infarct size. However, in another study [53], which focused on non-thrombolysis mild strokes, the incidence of END24 was 9% in lacunar infarcts as compared with 31% and 23% in large atherosclerosis and cardioembolic strokes, respectively, which showed a non-significant difference. Since stroke was caused by many reasons, the mechanism of END in various subtypes of stroke was completely different, yet remains largely unknown. Proximal arterial occlusion was observed more frequently in patients with END in our meta-analysis. One possible explanation for this association would posit that proximal occlusion predicts stroke severity, and therefore also END through its association with sICH and malignant oedema.

There are a few limitations in this meta-analysis that ought to be considered when interpreting the findings. Although we performed the meta-analysis for AIS cases with EVT, a sufficient subgroup analysis providing reliable results in the EVT group equivalent to IVT and total group may not be possible as scarce EVT studies are included. Due to insufficient data of re-occlusion and collateral circulation reported, it was difficult to analyze these two factors in this meta-analysis. Nevertheless, re-occlusion has been recognized as one of the important prognoses of END by clinical physicians [15], as well as playing a predominant role to improve the neurological functions for stroke patients. Another mechanism of END focuses on the insufficient collaterals with the adverse metabolic consequences among AIS patients in clinical practice [54]. Accordingly, collateral status described a linear relationship of the NIHSS score, implicating such the mechanism moderating symptoms in the hyperacute and post-therapeutic acute stroke phase [22]. Despite the ASPCT score contributing a lot to END occurring [1], we were not able to find a significant association of END as assigning the ASPECT score may vary by different physician.

The strength of this meta-analysis is that several large sample studies were involved to conduct the meta-analysis, providing convincing evidence of the associations, as well as depicting a complete picture to predict END occurring in stroke patients with medical or reperfusion therapies in clinical practice. We not only focused on END occurrence after EVT, but we also determined that the site of occlusion was linked with END after EVT.

5. Conclusions

This study contains some implications in clinical practice. END at 24 hours was associated with poor outcomes, hinting toward needs of the concentration on neurological deficit management. Understanding and monitoring older age, elevated systolic blood pressure, high levels of serum glucose, hypertension, diabetes mellitus and atrial fibrillation may elevate the early neurological worsening and achieve a satisfactory prognosis. Apart from this, other unmentioned factors, including collateral circulation, ASPECT score, CE stroke, are supposed to be thought about in decision-making protocols before reperfusion therapy conducting. Further studies ought to look into END occurring after EVT deeply because the exact proportion of END onset following EVT, and short-term/long-term prognosis still remain unclear at this stage.

Availability of Data and Materials

All data generated or analyzed during this study are included in this published article. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. PRISMA checklist is shown in supplementary materials.

Author Contributions

JL and WJJ take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualizing and designing the study—JL, HXS, CL and YQZ. Extracting, analyzing and interpreting the data—All authors. Drafting the study—HXS, CL and JL. Conducting meta-analysis—JL, HXS, CL, YQZ, XL, AFL,YEL. Critical revision of the study for important intellectual content—All authors. Obtaining funding—WJJ. Supervision—JL and WJJ.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This study was supported by the grants from National Key Basic Research Program of China (973 program) (grant No. 2013CB733805), and the National Natural Science Foundation of China (grant No. 81871464).

Conflict of Interest

The authors declare no conflict of interest.

Appendix

Appendix I: Detailed Search strategy

Pubmed

Free Text

Initial search performed on 3 August 2021

Search updated on 7 December 2022

English language limit applied

# Search Term No. of Results
1 ‘neurological deterioration’ or ‘neurological deficit’ or ‘neurological decline’ 724054
2 ‘thrombolysis’ or ‘thrombolytic treatment’ or ‘thrombolytic therapy’ or ‘IV-rtPA’ or ‘endovascular treatment’ or ‘endovascular therapy’ or ‘mechanical thrombectomy’ or ‘medical treatment’ or ‘medical management’ 3697171
3 ‘acute ischemic stroke’ or ‘acute cerebral ischaemia’ or ‘proximal vessel occlusion’ or ‘proximal artery occlusion’ or ‘large artery occlusion’ or ‘large vessel occlusion’ or ‘vertebrobasilar artery occlusion’ or ‘basilar artery occlusion’ or ‘middle cerebral artery occlusion’ or ‘internal cerebral artery occlusion’ 127348
4 #1 AND #2 AND #3 3648

Web of Science

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Initial search performed on 2 August 2021

Search updated on 6 December 2022

English language limit applied

# Search Term No. of Results
1 ‘neurological deterioration’ or ‘neurological deficit’ or ‘neurological decline’ ALL 64510
2 ‘thrombolysis’ or ‘thrombolytic treatment’ or ‘thrombolytic therapy’ or ‘IV-rtPA’ or ‘endovascular treatment’ or ‘endovascular therapy’ or ‘mechanical thrombectomy’ or ‘medical treatment’ or ‘medical management’ ALL 3459585
3 ‘acute ischemic stroke’ or ‘acute cerebral ischaemia’ or ‘proximal vessel occlusion’ or ‘proximal artery occlusion’ or ‘large artery occlusion’ or ‘large vessel occlusion’ or ‘vertebrobasilar artery occlusion’ or ‘basilar artery occlusion’ or ‘middle cerebral artery occlusion’ or ‘internal cerebral artery occlusion’ ALL 79075
4 #1 AND #2 AND #3 2547

EBSCO

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Initial search performed on 16 August 2021

Search updated on 10 December 2022

English language limit applied

# Search Term No. of Results
1 ‘neurological deterioration’ or ‘neurological deficit’ or ‘neurological decline’ ALL 31183
2 ‘thrombolysis’ or ‘thrombolytic treatment’ or ‘thrombolytic therapy’ or ‘IV-rtPA’ or ‘endovascular treatment’ or ‘endovascular therapy’ or ‘mechanical thrombectomy’ or ‘medical treatment’ or ‘medical management’ ALL 102745
3 ‘acute ischemic stroke’ or ‘acute cerebral ischaemia’ or ‘proximal vessel occlusion’ or ‘proximal artery occlusion’ or ‘large artery occlusion’ or ‘large vessel occlusion’ or ‘vertebrobasilar artery occlusion’ or ‘basilar artery occlusion’ or ‘middle cerebral artery occlusion’ or ‘internal cerebral artery occlusion’ ALL 46257
4 #1 AND #2 AND #3 638

Appendix II. Quality score

The quality score is composed of 5 items, and each item was allocated 0, 1 or 2 points. This allowed a total score between 0 and 10 points, 10 representing the highest quality. The following items are included in the score:

Objective

0 for no study objectives mentioned

1 for study objectives reported but non-specific

2 for specific study objectives reported

Design

0 for cross sectional studies

1 for case-control studies

2 for longitudinal studies (retrospective or prospective) or interventional studies

Population

Observational studies

0 if n <100

1 if n 100 to 500

2 if n >500

Outcome (see table below)

0 1 2
If not MRI or CT confirmation of AIS MRI or CT confirmation with clear location of lesions or stroke onset time With both clear location of lesions and stroke onset time

Adjustments

0 if findings are not controlled** for at least age and gender

1 if findings are controlled for age and gender

2 If findings are additionally controlled for covariates:

** ‘Controlled for’ here refers to: adjusted for in the statistical analyses (e.g. with multiple regression); stratified for in the analyses (e.g. males and females separately)

Appendix III Publication bias
Variables Egger test/Peters test
Total IVT EVT
Z score p Z score p Z score p
Age –3.44 0.002 –3.80 0.001 –0.86 0.423
Initial NIHSS –1.80 0.077 –1.15 0.264 –0.79 0.459
Systolic BP –0.43 0.670 –0.48 0.634 –0.17 0.873
Serum Glucose 1.56 0.207 1.34 0.190 NA
OTT –0.20 0.840 –0.34 0.741 0.21 0.851
ASPECT –0.74 0.672 –4.50 0.056 –0.17 0.807
HTN 9.34 0.003 9.80 0.002 1.21 0.273
Diabetes Mellitus 8.57 0.431 8.04 0.076 2.84 0.285
ET-atherosclerosis 5.23 0.209 5.87 0.098 –0.25 0.660
AF 5.68 0.180 5.31 0.287 3.71 0.531
SR –0.71 0.799 –0.78 0.657 –0.37 0.803
Bridging –0.53 0.612 –7.78 0.065 –0.178 0.135
ICA 0.109 0.912 4.10 0.419 1.21 0.510
M2 –3.09 0.553 –1.98 0.912 –3.87 0.199
90DmRS (0–2) –3.50 0.781 –6.80 0.097 NA
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