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. 2021 Feb 16;16(2):e0246906. doi: 10.1371/journal.pone.0246906

Posterior circulation acute stroke prognosis early CT scores in predicting functional outcomes: A meta-analysis

Wei-Zhen Lu 1,#, Hui-An Lin 2, Chyi-Huey Bai 3,4,5, Sheng-Feng Lin 3,6,7,*,#
Editor: Miguel A Barboza8
PMCID: PMC7886215  PMID: 33592055

Abstract

Background and purpose

Patients with posterior circulation acute ischemic stroke exhibit varied clinical presentations and functional outcomes. Whether posterior circulation acute stroke prognosis early computed tomography scores (PC-ASPECTS) predict unfavorable functional outcomes (UFO) for patients treated with different therapeutic regimens is unclear.

Methods

According to PRISMA guidelines, we performed a systematic search of electronic databases for studies assessing the functional outcomes of posterior circulation acute ischemic stroke using baseline PC-ASPECTS. The following three scales of PC-ASPECTS were retrieved: UFO prediction by using PC-ASPECTS per score decrease, UFO prediction by using binary PC-ASPECTS with a cut-off value, and the difference in PC-ASPECTS between patients with unfavorable and favorable functional outcomes. Moreover, a subgroup analysis was conducted for patients treated with intra-arterial endovascular treatment (IA-EVT) only. Sensitivity analysis with different definition of UFO and image modalities were also conducted.

Results

In total, 25 studies were included. In scale 1, PC-ASPECTS significantly predicted UFO (odds ratio [OR]: 1.66 per score decrease, 95% confidence interval [CI]: 1.32–2.07). In scale 2, binary PC-ASPECTS with a cut-off value between 6 and 9 significantly predicted UFO (OR: 3.91, 95% CI: 2.54–6.01). In scale 3, patients with UFO had lower PC-ASPECTS than those with favorable outcomes (standardized mean difference [SMD]: −0.67, 95% CI: −0.8 to −0.55). For patients treated with IA-EVT only, the scales demonstrated consistent results. Sensitivity analysis showed PC-ASPECTS significantly predicted UFO in both definitions of modified Rankin Scale ≥ 3 and ≥ 4, and magnetic resonance imaging was preferred imaging modality for PC-ASPECTS evaluation.

Conclusion

Baseline PC-ASPECTS is effective in predicting UFO for patients with posterior circulation acute ischemic stroke treated with different therapeutic regimens.

Introduction

Posterior circulation infarction accounts for one-fifth to one-fourth of all incidents of acute ischemic stroke [1,2] and has varied clinical presentations [3–5]. Acute basilar artery occlusion (BAO), the most devastating form of posterior circulation infarction, has a mortality rate of approximately 80% [6,7]. Prompt recanalization for BAO and other posterior circulation infarctions was proven to reduce morbidity and mortality [8,9]. Nevertheless, most scoring tools assessing whether stroke patients are candidates for thrombolytic therapy, such as the National Institutes of Health Stroke Scale (NIHSS; which is weighted more for anterior circulation symptoms and signs) [10] and the Alberta stroke program early computed tomography (CT) score (ASPECTS) (assessing the early ischemic changes in the middle cerebral artery territory) [11], are not universally applicable to posterior circulation infarction.

Similar to ASPECTS, posterior circulation Alberta stroke program early CT scores (PC-ASPECTS) allots 10 points to assess early ischemic changes on computed tomography angiography-source imaging (CTA-SI) or diffusion-weighted imaging (DWI) of magnetic resonance imaging (MRI) [12]. These 10 points provide semiquantitative estimates of the region of posterior circulation infarction, which include each side of the cerebellum (1 point), occipital lobe (1 point), thalamus (1 point), pons (2 point), and midbrain (2 point). Unlike anterior circulation stroke with a consensus ASPECTS of <6 as a robust predictor of unfavorable functional outcomes (UFO) and a relative contraindication of endovascular treatment [13,14], studies of posterior circulation infarction have demonstrated a discrepancy when predicting outcomes using baseline PC-ASPECTS. To address this issue, we performed a meta-analysis to determine whether baseline PC-ASPECTS effectively discriminate between unfavorable and favorable outcomes.

Materials and methods

Literature search

The first study to propose the scoring method of PC-ASPECTS was published on January 24, 2008. All relevant studies published in English were identified by searching PubMed, Embase, and Scopus from January 1, 2008, to July 31, 2020. The systematic search to identify eligible studies was conducted in accordance with PRISMA guidelines [15]. The keywords and MeSH terms within the search strategy included “stroke (MeSH),” “cerebrovascular disorders (MeSH),” “basilar artery (MeSH),” “vertebrobasilar insufficiency (MeSH),” “endovascular procedures (MeSH),” “thrombolytic therapy (MeSH),” “mechanical thrombolysis (MeSH),” “posterior circulation,” “PC-ASPECTS,” and their combination (S1 Table). Ethical approval for this study was waived by the Institutional Review Board of Far Eastern Memorial Hospital, New Taipei, Taiwan.

Study selection and quality assessment

The inclusion criteria were as follows: (1) studies reporting a series of patients with posterior circulation acute ischemic stroke and baseline PC-ASPECTS and (2) studies reporting the functional outcomes in terms of modified Rankin Scale (mRS) on day 90. The exclusion criteria were as follows: (1) abstract papers, (2) case reports, (3) review articles, (4) small studies with a sample size less than 10, (5) studies published in languages other than English, and (5) studies including pediatric populations. Independent screening of titles and abstracts was conducted by two authors (Lu WZ and Lin SF) to identify the studies that met the inclusion criteria. A final list was assembled based on their consensus (Lu WZ and Lin SF). The Newcastle–Ottawa Scale was used for quality assessment (S2 Table). Each retrieved study was critically appraised by two independent reviewers (Lu WZ and Lin SF). Disagreements between them were resolved by other two authors (Lin HA and Bai CH).

Data collection and outcomes

The study outcome was the prediction of UFO using baseline PC-ASPECTS for patients with posterior circulation acute ischemic stroke receiving any type of treatment. UFO was defined as an mRS of 3–6 or 4–6 on day 90. The association between UFO prediction and baseline PC-ASPECTS for patients was assessed using the following three scales: (1) UFO prediction by using PC-ASPECTS per score decrease, (2) UFO prediction by using binary PC-ASPECTS with a cut-off value, and (3) the difference in baseline PC-ASPECTS between posterior circulation infarction patients with UFO and those with favorable functional outcomes.

Statistical analysis

We estimated the odds ratio (OR) and standardized mean difference (SMD) and their 95% confidence interval (CI) for each cohort. Heterogeneity for each outcome was assessed using the Higgins index (I2); thereafter, the DerSimonian–Laird random effects model was applied. We defined the Higgins index value (I2) > 50% as substantial heterogeneity [16]. To evaluate heterogeneity and bias, a funnel plot was generated, followed by Begg’s test. Analyses were performed using metan package for Stata software, version 15 (StataCorp, Texas, USA). All reported P values were two-sided and were considered as statistically significant at <0.05. A step-down Bonferroni and Hochberg adjustment were used to address the problems of multiple testing.

Subgroup analyses

We conducted subgroup analyses assessed UFO prediction by using the baseline PC-ASPECTS for patients with intra-arterial endovascular treatment (IA-EVT). We also assessed UFO prediction by using baseline PC-ASPECTS in the above three scales. A random effects meta-regression test was performed to assess the heterogeneity caused by the potential modifiers of the imaging modality of CT or MRI and the definition of UFO based on an mRS of 3–6 or 4–6.

Sensitivity analyses

We performed two sensitivity analyses: (1) varied definition of UFO by mRS of 3–6 or 4–6, (2) varied imaging modalities of CT and MRI. The UFO Outcomes in three scales were analyzed as well.

Results

Search results

The flowchart describes the study selection process (Fig 1). During the initial search, a total of 2488 studies were identified, and only 25 studies met the inclusion and exclusion criteria. Characteristics of the included studies are summarized in Table 1. We included studies with prospective and retrospective cohort designs. In scale 1 (PC-ASPECTS per score decrease), a total of 8 studies with 609 patients were included. In scale 2 (binary PC-ASPECTS by a cut-off value), a total of 7 studies with 844 patients were enrolled. In scale 3 (SMD of PC-ASPECTS between patients with unfavorable and those with favorable functional outcomes), a total of 19 studies with 1186 patients were included in the analysis. For enrolled studies, the quality assessment was evaluated by Newcastle-Ottawa Scale. All of our included studies attained high quality with a total score of ≥ 8 (See online S2 Table).

Fig 1. PRISMA flowchart of search strategy.

Fig 1

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Table 1. Summary of methodological characteristics of included studies pertinent to the study outcomes.

Study Year Sample size (number) PC-ASPECTS cut-off Clinical Measures Imaging Patients treated with thrombolysis (number)
Scale 1: Unfavorable outcome prediction by PC-ASPECTS per score decrease
Junji Uno et al. [17] 2020 50 – 90-day mRS of 0–2 vs 3–6 CTP 50 with IA-EVT
Xuelei Zhang et al. [18] 2019 103 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 103 with IA-EVT
Sheng-Feng Lin et al. [19] 2018 125 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 1 with IV thrombolysis only
Chuanhui Li et al. [20] 2018 68 – 90-day mRS of 0–3 vs 4–6 CTA-SI or MRI (DWI) 68 with IA-EVT
Woong Yoon et al. [21] 2015 50 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 14 with IV thrombolysis, 50 with IA thrombectomy
Isabelle Mourand et al. [22] 2014 31 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 19 with IA-EVT and IV thrombolysis 12 with IA-EVT only
Simon Nagel et al. [23] 2012 50 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 41 with recanalization therapy
Hideaki Tei et al. [24] 2010 132 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) (No data provided)
Scale 2: Unfavorable outcomes prediction by binary PC-ASPECTS with a cut-off value
Volker Maus et al. [25] 2019 104 0–8, 9–10 90-day mRS of 0–2 vs 3–6 CTA-SI or MRI (DWI) 104 with IA EVT 49 with IV + IA thrombolysis
Sheng-Feng Lin et al. [19] 2018 125 0–7, 8–10 90-day mRS of 0–2 vs 3–6 MRI (DWI) 1 with IV thrombolysis only
Gang Luo et al. [26] 2018 69 0–5, 6–10 90-day mRS of 0–2 vs 3–6 MRI (DWI) 69 with IA EVT
Woo-Jin Lee et al. [27] 2017 292 0–6, 7–10 90-day mRS of 0–2 vs 3–6 MRI (DWI) 62 with recanalization therapy
Woong Yoon et al. [21] 2015 50 0–6, 7–10 90-day mRS of 0–2 vs 3–6 MRI (DWI) 50 with IA EVT
Puetz et al. [28] (BASIC registry) 2011 158 0–7, 8–10 90-day mRS of 0–2 vs 3–6 CTA-SI 15 with IV thrombolysis only 53 with IA EVT only 28 with IV and IA thrombolysis
Puetz et al. [12] (BASIC registry) 2008 46 0–7, 8–10 90-day mRS of 0–3 vs 4–6 CTA-SI 36 with any thrombolysis 19 with IV thrombolysis 29 with IA thrombolysis
Scale 3: PC-ASPECTS scores between unfavorable and favorable outcomes
Beilei Chen et al. [29] 2019 68 – 90-day mRS of 0–2 vs 3–6 CT 68 with IA-EVT
Xuelei Zhang et al. [18] 2019 103 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 103 with IA-EVT
Fana Alemseged et al. [30] 2019 60 – 90-day mRS of 0–3 vs 4–6 CTA-SI, CTP 28 with IV thrombolysis, 25 with IA-EVT
Francisco Antunes Dias et al. [31] 2019 27 – 90-day mRS of 0–3 vs 4–6 CTA 27 with IA-EVT
Sheng-Feng Lin et al. [19] 2018 125 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 1 with IV thrombolysis only
Alexandros Rentzos et al. [32] 2018 110 – 90-day mRS of 0–2 vs 3–6 CTA-SI 110 with IA-EVT
Chuanhui Li et al. [20] 2018 68 – 90-day mRS of 0–3 vs 4–6 CTA-SI or MRI (DWI) 68 with IA-EVT
Jun Young Chang et al. [33] 2017 59 – 90-day mRS of 0–3 vs 4–6 MRI (DWI) 20 with IV thrombolysis 59 with IA-EVT
Francisco Antunes Dias et al. [34] 2017 63 – 90-day mRS of 0–3 vs 4–6 NCCT 15 with IV thrombolysis 19 with IA-EVT 29 with no recanalization
Woo-Jin Lee et al. [35] 2017 98 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 98 with no recanalization
Robert Fahed et al. [36] 2017 34 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 34 with IA-EVT
Seungnam Son et al. [37] 2016 35 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 35 with IA-EVT
Valerio Da Ros et al. [38] 2016 15 – 90-day mRS of 0–3 vs 4–6 CTA-SI 15 with IA-EVT
Woong Yoon et al. [21] 2015 50 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 14 with IV thrombolysis, 50 with IA thrombectomy
S. Mundiyanapurath et al. [39] 2015 22 – 90-day mRS of 0–2 vs 3–6 MRI (DWI, SWI) 4 with IV thrombolysis only 4 with IA EVT 14 with IV and IA thrombolysis
Isabelle Mourand et al. [22] 2014 31 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 19 with IA-EVT and IV thrombolysis 12 with IA-EVT only
Simon Nagel et al. [23] 2012 50 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) 41 with recanalization therapy
Alexander Karameshev et al. [40] 2011 36 – 90-day mRS of 0–3 vs 4–6 MRI (DWI) 36 with IA-EVT
Hideaki Tei et al. [24] 2010 132 – 90-day mRS of 0–2 vs 3–6 MRI (DWI) (No data provided)
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BASIC, The Basilar Artery International Cooperative Study; CTP, Computed tomography perfusion scan; CTA-SI, computed tomography angiography-source imaging; ECASS: European Cooperative Acute Stroke Study; EVT, endovascular therapy; mRS, modified Rankin Scale; NCCT, non-contrast computed tomography; IA, intra-arterial; IV, intravenous; MRI, magnetic resonance imaging; SWI, susceptibility-weighted imaging. IV thrombolysis defined as treatment with tissue plasminogen activator.

Outcomes: PC-ASPECTS for patients with any treatment

(1) OR meta-analysis for PC-ASPECTS per score decrease

This meta-analysis compared the baseline PC-ASPECTS between patients with UFO and those with favorable functional outcomes on day 90. Meta-analysis results were expressed as ORs for UFO prediction by using PC-ASPECTS per score decrease (Fig 2A). All eight studies, except one, individually revealed that the baseline PC-ASPECTS significantly predicted UFO [22]. Overall, the meta-analysis of these studies revealed a significant association between UFO prediction and PC-ASPECTS (OR: 1.66, 95% CI: 1.32–2.07 per score decrease; I2 = 59.6%, P = 0.016). The funnel plot (Fig 2B) followed by Begg’s test exhibited no significant publication bias for the eight studies (P = 0.174).

Fig 2. Unfavorable functional outcome prediction by using PC-ASPECTS per score decrease.

Fig 2

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(A) The forest plot. (B) The funnel plot.

(2) OR meta-analysis for PC-ASPECTS by cut-off score

UFO prediction by using binary PC-ASPECTS with a cut-off value was analyzed for the included seven studies in this section (Fig 3). These included studies were classified into four subgroups according to their cut-off values. Of these studies, one, two, three, and one had PC-ASPECTS cut-offs of ≤6, ≤7, ≤8, and ≤9, respectively. All the studies individually revealed a significant association between UFO prediction and baseline binary PC-ASPECTS. The subgroup OR meta-analysis demonstrated a significant association between UFO prediction and binary PC-ASPECTS with cut-offs of ≤7 (OR: 4.22, 95% CI: 2.06–8.62; I2 = 0.0%, P = 0.808) and ≤8 (OR: 4.25, 95% CI: 1.5–12.07; I2 = 65.6%, P = 0.055).

Fig 3. The forest plot of unfavorable functional outcome prediction by using PC-ASPECTS with a cut-off value.

Fig 3

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Generally, the overall OR meta-analysis consistently displayed a significant association between UFO and binary PC-ASPECTS at any cut-off value, without heterogeneity (OR: 3.91, 95% CI: 2.54–6.01; I2 = 17.8%, P = 0.294). Besides, we performed a test of significance for effect size with by using step-down Bonferroni method and Hochberg adjustment. The adjusted P values by step-down Bonferroni and Hochberg adjustment methods showed PC-ASPECTS of ≤ 7 with the smallest adjusted P value (S4 Table).

(3) SMD between unfavorable and favorable outcomes of PC-ASPECTS

The difference in PC-ASPECTS between unfavorable and favorable functional outcomes was analyzed for studies that provided PC-ASPECTS using a continuous scale (Fig 4A). In total, 19 studies were eligible in this meta-analysis. Of these, 10 studies exhibited a significant difference in score of PC-ASPECTS for patients with unfavorable and favorable outcomes, whereas 9 studies demonstrated no significant difference. Among studies revealing no significant difference, one study [38] paradoxically displayed low PC-ASPECTS in the favorable functional outcome group (SMD: 0.55, 95% CI: −0.5 to 1.61). Generally, the overall SMD meta-analysis result showed significant differences in PC-ASPECTS despite significant heterogeneity (SMD: −0.67, 95% CI: −0.8 to −0.55; I2 = 73.4%, P = 0.000). The funnel plot of 19 studies (Fig 4B) followed by Begg’s test revealed no significant publication bias (P = 0.529).

Fig 4. The standardized mean difference in PC-ASPECTS scores between patients with unfavorable and favorable outcomes.

Fig 4

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Subgroup analyses: PC-ASPECTS for patients treated with IA-EVT

(1) OR meta-analysis for PC-ASPECTS per score

In total, three studies [18,22,23] involving patients treated with IA-EVT were included (Fig 5A). The overall results showed a significant association between UFO prediction and PC-ASPECT per score decrease for patients treated with IA-EVT, without heterogeneity (OR: 1.67, 95% CI: 1.09–2.58; I2 = 51.2%, P = 0.129).

Fig 5. Unfavorable functional outcome prediction for patients managed by intra-arterial endovascular treatment (subgroup analysis).

Fig 5

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(A) Scale by using PC-ASPECTS per score decrease. (B) Scale by using PC-ASPECTS with a cut-off value. (C) Scale by standardized mean difference in PC-ASPECTS scores between patients with unfavorable and favorable outcomes. (D) Funnel plot of scale by standardized mean difference.

(2) OR meta-analysis for binary PC-ASPECTS by cut-off score

Three studies [21,25,26] were included for PC-ASPECTS with cut-off points at 6, 7, and 9 (Fig 5B). The overall results demonstrated a significant association between UFO and binary PC-ASPECTS, with no heterogeneity (OR: 4.91, 95% CI: 2.40–10.05; I2 = 0.0%, P = 0.845).

(3) SMD meta-analysis between unfavorable and favorable outcomes of PC-ASPECTS

In total, 13 studies were eligible in this meta-analysis (Fig 5C). Of these, six studies showed no significance in scores of PC-ASPECTS for patients with unfavorable and favorable outcomes, whereas seven studies showed no significant difference. Consistent with the analysis for patients on any treatment regimen, the overall SMD meta-analysis result for IA-EVT displayed a significant difference in PC-ASPECTS between unfavorable and favorable outcomes (SMD: −0.54, 95% CI: −0.7 to −0.38; I2 = 78.7%, P = 0.000). The funnel plot (Fig 5D) followed by Begg’s test revealed no significant publication bias (P = 0.246). In addition, a meta-regression (S3 Table) exhibited a borderline significant association between the SMD of PC-ASPECTS and the imaging modality of CT or MRI (P = 0.05), with no significant differences between different definitions of mRS (P = 0.422).

Sensitivity analyses

We conducted two sensitivity analyses: (1) with varied imaging modalities of CT or MRI, and (2) definition of UFO according to an mRS 3–6 or 4–6.

(1) Different imaging modality

OR meta-analysis for PC-ASPECTS per score decrease. Six studies with MRI (OR: 1.81, 95% CI: 1.44–2.27; I2 = 26.3%, P = 0.237) and one study with CT (OR: 1.65, 95% CI: 1.09–2.73) showed scoring of PC-ASPECTS significantly associated with UFO (S1 Fig).

OR meta-analysis for binary PC-ASPECTS by cut-off score. Four studies with MRI showed PC-ASPECTS significantly associated with UFO (OR: 5.09, 95% CI: 2.96–8.78; I2 = 0.0%, P = 0.869), whereas two studies with CT revealed no significant association between PC-APSECTS and UFO (OR: 3.84, 95% CI: 0.70–20.90; I2 = 66.2%, P = 0.085) (S2 Fig).

SMD meta-analysis between unfavorable and favorable outcomes of PC-ASPECTS. Twelve studies with MRI showed PC-ASPECTS significantly predicted UFO (SMD: −0.93, 95% CI: −1.09 to −0.77; I2 = 69.9%, P = 0.000), whereas six studies with CT demonstrated no significant association between PC-ASPECTS and UFO (SMD: −0.19, 95% CI: −0.42 to 0.03; I2 = 0.0%, P = 0.524) (S3 Fig).

(2) Different definition of unfavorable outcomes by mRS

With different definitions of UFO, PC-ASPECTS showed significantly predicted the UFO with varied definitions of mRS of 3–6 and 4–6 in three scales (S4, S5 and S6 Figs).

Discussion

This meta-analysis confirmed that baseline PC-ASPECTS effectively predict functional outcomes for patients with posterior circulation acute ischemic stroke. We analyzed its association with UFO using the following three scales: (1) PC-ASPECTS per score decrease, (2) binary PC-ASPECTS with a cut-off value, and (3) difference in PC-ASPECTS between patients with unfavorable and favorable outcomes. Each decrease in the PC-ASPECTS score was significantly associated with UFO prediction. Although the results among all cut-off value demonstrated significance, we recommended a cut-off value of 7 for PC-ASPECTS effectively discriminated between patients with unfavorable and favorable functional outcomes. Furthermore, for patients treated with IA-EVT, subgroup analyses indicated a robust association between UFO prediction and PC-ASPECTS.

Different therapeutic regimens

The included studies revealed the following varied thrombolytic therapeutic regimens for patients with posterior circulation acute ischemic stroke: IV thrombolysis, IA-EVT, combination of both, and no recanalization. Subgroup analyses for patients with IA-EVT revealed consistent results with any therapeutic regimen, and the significant heterogeneity disappeared for IA-EVT only in scale 1. This suggested that the heterogeneity in these studies might have been resulted from different intervention regimens. Despite different therapeutic regimens, the results of this meta-analysis still indicated that PC-ASPECTS have a good predicting value for identifying UFO. However, we recommend that further studies should confirm the ability of PC-ASPECTS to predict functional outcomes in subgroups treated with no recanalization or IV thrombolysis because few studies were included in our meta-analysis.

Studies with different binary PC-ASPECTS cut-offs

The included studies displayed a diverse range of cut-off values of binary PC-ASPECTS for UFO prediction (from PC-ASPECTS of ≤6 to 9). Most studies adopted cut-off points of ≤7 to 8. Despite all cut-off values displaying a significant association between UFO prediction and PC-ASPECTS, we considered that a cut-off of ≤7 would be more appropriate because of a strong effect size. The statistical test for effect size (ES) supported a cut-off point of PC-ASPECTS ≤ 7 being the best cut-off value due to the smallest raw and adjusted P value (S4 Table).

Studies with varied definitions of UFO and imaging modalities

In total, 25 studies were included in our meta-analysis. We noted a discrepancy in the definitions of UFO based on the mRS score. Of these, 17 studies defined favorable outcome as mRS scores ≤2, and the rest defined favorable outcome as mRS scores ≤3. In our analyses, we applied each study’s individual UFO definition because of a vague boundary between mRS scores 2 and 3 in clinical practice. Our sensitivity analysis suggested PC-ASPECTS was applicable in predicting UFO for studies with a varied boundary of mRS.

Besides, we noted a disparity of imaging modalities of CT and MRI were used for evaluating PC-ASPECTS. The sensitivity analysis suggested MRI should be preferred modality for employing PC-ASPECTS. The association between PC-ASPECTS and UFO with MRI showed significant in three scales, whereas with CT demonstrated significant for OR meta-analysis for PC-ASPECTS per score decrease only.

At last, the meta-regression analysis (S3 Table) for patients treated with IA-EVT supports the negligible effect on heterogeneity by UFO definition (P = 0.412). Conversely, imaging modality of CT or MRI caused a significant effect on the heterogeneity of this study (P = 0.039).

Limitation

Our study had some limitations. First, high heterogeneity was observed in most of our analyses, which may be caused by study designs, therapeutic regimens, and imaging modalities. Second, none of the included studies involving patients treated with IA-EVT were randomized trials, and data were derived from cohort studies without control groups. However, publication bias was mostly eliminated in our analyses.

Conclusion

This meta-analysis of retrospective studies revealed that low baseline PC-ASPECTS are significantly associated with UFO. PC-ASPECTS of <7 was the most reasonable cut-offs for predicting UFO. Imaging modality and recanalization regimen were responsible for the heterogeneity in our meta-analysis. Even a one-point decrease in PC-ASPECTS significantly affects the outcome.

Supporting information

S1 Checklist

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S1 Fig. Unfavorable outcome prediction by PC-ASPECTS per score decrease (varied imaging modality).

(PDF)

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S2 Fig. Unfavorable outcome prediction with binary PC-ASPECTS (varied imaging modality).

(PDF)

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S3 Fig. PC-ASPECTS score difference between unfavorable and favorable outcome (varied imaging modality).

(PDF)

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S4 Fig. Unfavorable outcome prediction by PC-ASPECTS per score decrease (varied definition of mRS).

(PDF)

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S5 Fig. Unfavorable outcome prediction by binary PC-ASPECTS (varied definition of mRS).

(PDF)

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S6 Fig. PC-ASPECTS score difference between unfavorable and favorable outcome (varied definition of mRS).

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S1 Table. Search strategy.

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S2 Table. Quality measure of included studies by the Newcastle-Ottawa quality assessment scale.

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S3 Table. Meta-regression of standardized mean difference of PC-ASPECTS between unfavorable and favorable outcomes for patients with intra-arterial endovascular treatment.

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S4 Table. Significant test for effect size for each cut-off of PC-ASPECTS.

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S1 File

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Acknowledgments

Lin SF conceived the idea; all authors have contributed to the design of the study; Lu WZ, Lin HA, Bai CH, and Lin SF, collected and managed the data, including quality control. Lin SF provided statistical advice on study design and analyzed the data. Lin SF supervised the conduct of the study. Lu WZ and Lin SF drafted the manuscript, and all authors contributed substantially to its revision. Lu WZ and Lin SF contributed equally. Lin SF takes responsibility for the paper as a whole.

Abbreviations

ASPECTS

the Alberta stroke program early computed tomography computed tomography score

BAO

Basilar artery occlusion

CI

confidence interval

CT

computed tomography

CTA-SI

computed tomography angiography-source imaging

DWI

diffusion-weighted imaging

MRI

magnetic resonance imaging

mRS

modified Rankin Scale

NIHSS

National Institutes of Health Stroke Scale

OR

odds ratio

PC-ASPECTS

the posterior circulation Alberta stroke program early CT score

SMD

standardized mean difference

UFO

unfavorable functional outcomes

Data Availability

Datasets for this research are published literatures (please referred to the list of references) and the codes used for statistical analysis with Stata software, version 15 (StataCorp, Texas, USA) was available in the supplemental file.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Miguel A Barboza

27 Nov 2020

PONE-D-20-33033

Posterior Circulation Acute Stroke Prognosis Early CT Scores in Predicting Functional Outcomes: A Meta-analysis

PLOS ONE

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Reviewer #2: Yes

**********

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Reviewer #2: Yes

**********

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Reviewer #1: No

Reviewer #2: Yes

**********

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Reviewer #2: Yes

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Reviewer #1: This article innovates as it aims to establish if PC-ASPECTS may predict functional outcomes in patients with acute ischemic stroke. This has been an issue with NIHSS and ASPECTS as both scales are focused in anterior circulation strokes. The authors followed a systematic review (SR) approach for searching available articles with a meta-analyses (MA) that used a random effects modeling approach to account for heterogeneity. Even though the main objectives of this research were achieved, the presentation of results fails to be clear to the reader at several points of the article and this should be addressed prior to the approval for publication of this article.

1. The authors do not establish if their SR was previously registered at PROSPERO registry. Currently this is highly expected when attempting a SR in order to later compare the results obtained and the methodological approach performed with the protocol published at the beginning of the investigation. I did a search in the PROSPERO registry and could not find this SR registered, I would like to ask the authors if their review was previously registered and if they followed a previously determined protocol for this.

2. The authors confuse along the whole article between subgroups and sensitivity analysis in regards of their comparison of the results between patients with and without Intra-arterial endovascular treatment (IA-EVT). This by no means should be considered a sensitivity analysis, specially if you are reporting different outcomes obtained after a different intervention was applied. This should be formally analyzed and described as subgroup analysis. On the contrary, evaluating the differential effect of CT/MRI and different definitions of UFO based on mRS, could be better considered as sensitivity analysis as they would be assessing the same outcome but defined differently, yet not assessing the effect of different interventions. I highly recommend the authors to thoroughly review Cochrane Handbook of Systematic Reviews Chapter 10 to understand better the distinction between sensitivity and subgroup analysis, as both terms are commonly confused.

3. In similar terms, the results section should fully describe the results of sensitivity analysis. This was not described in any detail, yet it was referred to in the discussion part under "Studies with varied definitions of UFO and imaging modalities".

4. As I read the article, it becomes very confusing the cut-offs used by the authors for PC-ASPECTS that determined the best effect. In the discussion they chose 7-8 as the best cut-off but there should be more emphasis along the paper, as they describe the results of their analysis, in regards of what cut-offs should be taken as the main predictors, and specifying the effects sizes that lead into determining what cut-offs are best.

5. Some other minor changes that should be made:

- when describing the analysis of only 1 article, reporting 0.0% of heterogeneity (I2) is redundant and misleading. It is rather obvious that one article will not be heterogeneous on its own.

- it would be good for the reader to describe the authors cut-off points for heterogeneity, otherwise their interpretation of the I2 values seem rather arbitrary. I recommend Chapter 10 of Cochran SR Handbook where they establish cute-offs for heterogeneity.

- Please correct every time you refer to this search as "systemic search". This terminology is incorrect and should be "systematic research".

-Last paragraph of the discussion states "However, publication bias was excluded in our analyses". This is a daring phrase as funnel plots cannot fully exclude publication bias, please rephrase this sentence accordingly.

- It is highly expected in the PRISMA chart that the authors specify the reasons that made them exclude papers. Please list reasons for exclusion.

- Finally, I saw that the supplementary tables have a review of quality of the data retrieved yet there is no description of this in the results or discussion. I would like to know as a reader the quality of the data retrieved.

Reviewer #2: This is a very precise, informative and well written article. The predictive value of PC- ASPECTS is a very pertinent subject since the posterior circulation stroke are usually overlooked in the major trials.

I only have one question for the authors. Regarding the following statement

Furthermore, for patients treated with IA-EVT, sensitivity analyses only indicated a robust association between UFO prediction and PC-ASPECTS.

Why do you think there was only robust association between UFO and PC- ASPECTS when treated with AI EVT? Do you think this is due to the heterogenicity of the IA – EVT studies or perhaps that the therapy itself may modify the outcomes.

This is a high quality and pertinent paper; therefore, I recommend its publication.

**********

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Reviewer #1: No

Reviewer #2: Yes: Beatriz Mendez

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PLoS One. 2021 Feb 16;16(2):e0246906. doi: 10.1371/journal.pone.0246906.r002

Author response to Decision Letter 0

6 Jan 2021

We thank the reviewers for their constructive comments. We have made revisions to the manuscript to address all the questions and comments raised by the three reviewers. We highlights changes made to the original version by setting the text color to red. Our specific responses to each comment are as follows:

Responses to reviewers #1:

√ This article innovates as it aims to establish if PC-ASPECTS may predict functional outcomes in patients with acute ischemic stroke. This has been an issue with NIHSS and ASPECTS as both scales are focused in anterior circulation strokes. The authors followed a systematic review (SR) approach for searching available articles with a meta-analyses (MA) that used a random effects modeling approach to account for heterogeneity. Even though the main objectives of this research were achieved, the presentation of results fails to be clear to the reader at several points of the article and this should be addressed prior to the approval for publication of this article.

● We are grateful for all of your constructive comments. In the revised manuscript, we addressed the all of the additional points in the following sections.

√ 1. The authors do not establish if their SR was previously registered at PROSPERO registry. Currently this is highly expected when attempting a SR in order to later compare the results obtained and the methodological approach performed with the protocol published at the beginning of the investigation. I did a search in the PROSPERO registry and could not find this SR registered, I would like to ask the authors if their review was previously registered and if they followed a previously determined protocol for this.

● Thank you for the comment. We did not previously register this topic in the PROSPERO registry. However, we previously proposed this study to the research committee in the Far Eastern Memorial Hospital, New Taipei, Taiwan on Sep. 24, 2020. This study was also approved for exemption from the review of the Institutional Review Board, Far Eastern Memorial Hospital, New Taipei, Taiwan. The certificate of proposal on Sep. 24, 2020. was attached in the following page.

● Besides, all of the studies enrolled in our analysis were observational retrospective cohort studies. Neither randomized-controlled trial nor interventional study was included in our analysis. The analytic outcomes should not be changed despite no previous registry in the PROSPERO system. However, we were sincerely grateful for the reviewer’s kind reminder for PROSPERO registry to avoid repetitive topic.

● The certificate for proposal in the research committee in the Far Eastern Memorial Hospital, New Taipei, Taiwan (Chinese language).

√ 2. The authors confuse along the whole article between subgroups and sensitivity analysis in regards of their comparison of the results between patients with and without Intra-arterial endovascular treatment (IA-EVT). This by no means should be considered a sensitivity analysis, specially if you are reporting different outcomes obtained after a different intervention was applied. This should be formally analyzed and described as subgroup analysis. On the contrary, evaluating the differential effect of CT/MRI and different definitions of UFO based on mRS, could be better considered as sensitivity analysis as they would be assessing the same outcome but defined differently, yet not assessing the effect of different interventions. I highly recommend the authors to thoroughly review Cochrane Handbook of Systematic Reviews Chapter 10 to understand better the distinction between sensitivity and subgroup analysis, as both terms are commonly confused.

● Thank you for the comment. We thoroughly reviewed Cochrane Handbook of Systematic Reviews Chapter 10 for distinction between sensitivity analysis and subgroup analysis. The description for outcomes of IA-EVT treatment was revised as “subgroup analysis” in the manuscript. (Please see line 173-179, methods section; line 263-297, results section; line 333 discussion section; Fig 5A-5D)

√ 3. In similar terms, the results section should fully describe the results of sensitivity analysis. This was not described in any detail, yet it was referred to in the discussion part under "Studies with varied definitions of UFO and imaging modalities".

● Thank you for the comment. We added the additional analysis for studies with varied definitions of UFO and imaging modalities.

● Our result showed MRI was preferred for PC-ASPECTS evaluation. Sensitivity analysis showed significant association between UFO and PC-ASPECTS assessed by MRI in all three scales, whereas no significant association was found between UFO and PC-ASPECTS by CT in scales of binary PC-ASPECTS and SMD.

● Besides, both the definition of UFO by mRS 3-6 and 4-6 both showed lower PC-ASPECTS significantly predicted UFO in all three scales.

(Please see line 181-184, methods section; line 299-321, results section; line 359-378, discussion section; S1-S6 Fig)

√ 4. As I read the article, it becomes very confusing the cut-offs used by the authors for PC-ASPECTS that determined the best effect. In the discussion they chose 7-8 as the best cut-off but there should be more emphasis along the paper, as they describe the results of their analysis, in regards of what cut-offs should be taken as the main predictors, and specifying the effects sizes that lead into determining what cut-offs are best.

● Thank you for the comment. We revised this section by providing the test results for effect size (ES) for each cut-off for PC-ASPECTS. In the following figure, the test result for ES by STATA 15 software was shown. On considering the z score and raw P value, we thought PC-ASPECTS of ≤ 7 should be the best cut-off.

● Besides, we performed an adjustment for P value by using step-down Bonferroni method and Hochberg adjustment to address the problems of multiple testing. The adjusted P values by step-down Bonferroni and Hochberg adjustment methods also supported PC-ASPECTS of ≤ 7 being the best cut-off value due to the smallest adjusted P value. We summarized our findings in the following table and added this information to S4 Table. (Please see line 237-243, results section; line 355-357, discussion section; S4 Table)

√ 5. Some other minor changes that should be made:

- when describing the analysis of only 1 article, reporting 0.0% of heterogeneity (I2) is redundant and misleading. It is rather obvious that one article will not be heterogeneous on its own.

● Thank you for the comment. We revised our data reporting in Fig. 3 and Fig. 5.

√ - it would be good for the reader to describe the authors cut-off points for heterogeneity, otherwise their interpretation of the I2 values seem rather arbitrary. I recommend Chapter 10 of Cochran SR Handbook where they establish cute-offs for heterogeneity.

● Thank you for the comment. We referred to the Cochrane Handbook of Systematic Reviews Chapter 10. We also cited a reference for our objective judgement for heterogeneity. We defined the Higgins index value (I2) > 50% as substantial heterogeneity. (Please see line 165-166, methods section)

√ - Please correct every time you refer to this search as "systemic search". This terminology is incorrect and should be "systematic research".

● Thank you for the comment. We have corrected our terminology.

(Please see line 59, abstract section; line 130, methods section)

√ - Last paragraph of the discussion states "However, publication bias was excluded in our analyses". This is a daring phrase as funnel plots cannot fully exclude publication bias, please rephrase this sentence accordingly.

● Thank you for kind comment. We have revised our phrase for this sentence.

(Please see line 385, limitation section)

√ - It is highly expected in the PRISMA chart that the authors specify the reasons that made them exclude papers. Please list reasons for exclusion.

● Thank you for the comment. We have added the reasons for excluding papers.

(Please see Fig 1 PRISMA chart)

√ - Finally, I saw that the supplementary tables have a review of quality of the data retrieved yet there is no description of this in the results or discussion. I would like to know as a reader the quality of the data retrieved.

● Thank you for the comment. We added the description for a review of quality of the data.

(Please see line 146-149, methods section; line 196-198, results section)

Responses to reviewers #2:

√ This is a very precise, informative and well written article. The predictive value of PC- ASPECTS is a very pertinent subject since the posterior circulation stroke are usually overlooked in the major trials. I only have one question for the authors. Regarding the following statement:

Furthermore, for patients treated with IA-EVT, sensitivity analyses only indicated a robust association between UFO prediction and PC-ASPECTS. Why do you think there was only robust association between UFO and PC- ASPECTS when treated with AI EVT? Do you think this is due to the heterogenicity of the IA – EVT studies or perhaps that the therapy itself may modify the outcomes.

● Thank you for the comment.

● Our main analysis supported scoring of PC-ASPECTS was universally applicable for posterior circulation acute ischemic stroke with varied therapeutic regimens.

● In the literature reviews, we noted studies performing IA-EVT sharing higher conformance in their treatment plan. The subgroup analysis of IA-EVT was performed since previous studies reported that thrombectomy or stent-retriever therapy may greatly improve the functional outcomes for acute ischemic stroke than conservative medical therapy.

● In the subgroup analysis, we proved that PC-ASPECTS was still applicable for patients treated IA-EVT. Thus, the robustness of PC-ASPECTS in predicting unfavorable functional outcome was evident. However, this should not be interpreted as non-applicability of PC-ASPECTS for stroke patients treated with IV thrombolysis or conservative medical therapy.

(Please see line 336-348, discussion section)

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (303.4KB, docx)

Decision Letter 1

Miguel A Barboza

28 Jan 2021

Posterior Circulation Acute Stroke Prognosis Early CT Scores in Predicting Functional Outcomes: A Meta-analysis

PONE-D-20-33033R1

Dear Dr. Lin,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #1: Authors fully addressed all my concerns and the current manuscript reads better. They were able to describe better the statistic approach that led to their conclusions. To my appraisal this article is more understandable now as it was before, for the common reader that might not now about systematic reviews.

Reviewer #2: (No Response)

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Reviewer #2: Yes: Beatriz Mendez Gonzalez

Acceptance letter

Miguel A Barboza

4 Feb 2021

PONE-D-20-33033R1

Posterior Circulation Acute Stroke Prognosis Early CT Scores in Predicting Functional Outcomes: A Meta-analysis

Dear Dr. Lin:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Miguel A. Barboza

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist

    (PDF)

    Click here for additional data file. (91.8KB, pdf)
    S1 Fig. Unfavorable outcome prediction by PC-ASPECTS per score decrease (varied imaging modality).

    (PDF)

    Click here for additional data file. (512.4KB, pdf)
    S2 Fig. Unfavorable outcome prediction with binary PC-ASPECTS (varied imaging modality).

    (PDF)

    Click here for additional data file. (488.4KB, pdf)
    S3 Fig. PC-ASPECTS score difference between unfavorable and favorable outcome (varied imaging modality).

    (PDF)

    Click here for additional data file. (560.6KB, pdf)
    S4 Fig. Unfavorable outcome prediction by PC-ASPECTS per score decrease (varied definition of mRS).

    (PDF)

    Click here for additional data file. (541.6KB, pdf)
    S5 Fig. Unfavorable outcome prediction by binary PC-ASPECTS (varied definition of mRS).

    (PDF)

    Click here for additional data file. (535.4KB, pdf)
    S6 Fig. PC-ASPECTS score difference between unfavorable and favorable outcome (varied definition of mRS).

    (PDF)

    Click here for additional data file. (546.8KB, pdf)
    S1 Table. Search strategy.

    (PDF)

    Click here for additional data file. (75.4KB, pdf)
    S2 Table. Quality measure of included studies by the Newcastle-Ottawa quality assessment scale.

    (PDF)

    Click here for additional data file. (124.1KB, pdf)
    S3 Table. Meta-regression of standardized mean difference of PC-ASPECTS between unfavorable and favorable outcomes for patients with intra-arterial endovascular treatment.

    (PDF)

    Click here for additional data file. (91.6KB, pdf)
    S4 Table. Significant test for effect size for each cut-off of PC-ASPECTS.

    (PDF)

    Click here for additional data file. (90.8KB, pdf)
    S1 File

    (PDF)

    Click here for additional data file. (32.7KB, pdf)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (303.4KB, docx)

    Data Availability Statement

    Datasets for this research are published literatures (please referred to the list of references) and the codes used for statistical analysis with Stata software, version 15 (StataCorp, Texas, USA) was available in the supplemental file.

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