PONE-D-24-11660Collateral assessment on magnetic resonance imaging/angiography up to 30 hours after stroke onsetPLOS ONE

Dear Dr. Tomari,

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper is a valuable report that focuses on two collateral flow indicators, HVS and PCA laterality, and compares them with two perfusion images.

Although relatively old, this dataset is unique because it is now ethically difficult not to perform thrombectomy in patients with acute onset large vessel occlusion. Another feature of the dataset is the relatively large number of tandem occlusions.

It is very interesting in that the classically known HVS is influencing recanalisation therapy decision making, but several areas require further consideration:

Major comments

1. It seems strange that there were no patients in the dataset who had undergone mechanical thrombectomy (MT), as there were already 5RCTs on MT in 2015 when this study was conducted. The inclusion criteria seem to include patients who would be good candidates for MT. Please clarify if any of the excluded patients had undergone MT or if there were any study design or institutional limitations.

2. In this report, it was reported that HVS and PCA laterality were assessed by two readers. Does this mean that two readers evaluated different patients or two readers evaluated the same patients, and if the latter, how were the discrepant cases handled?

3. Prestroke mRS should be reported because of the prognostic impact in the HVS high group and the HVS low group. The aetiology of stroke (e.g. TOAST classification) should also be included as the dataset is characterised by a relatively high number of ICA tandem occlusions. Time from onset to imaging should also be included in the table, as it may be related to HVS and PCA laterality.

Minor comments

1. Please describe the management of patients with M3 or more distal occlusions.

2. The scoring method for HVS seems to be the same as in ref. 11; it is advisable to add this to the METHOD.

Reviewer #2: This is a retrospective study of 49 stroke patients with ICA and/or proximal MCA occlusion with unfavorable recanalization, investigating the relationship between the hyperintense vessel sign (HVS) on FLAIR and PCA laterality on MRA, and their impact on stroke outcomes. The study found that a prominent HVS is associated with a smaller core volume and a larger penumbra volume at follow-up, and better clinical outcomes. In contrast, PCA laterality did not show significant differences in penumbra volumes or outcomes. In fact, it was associated with larger infarct volume at follow-up. The results suggest that HVS is a reliable indicator of good collateral status and favorable prognosis in late-window stroke patients, while PCA laterality does not correlate as strongly with these outcomes.

While the association between collateral status, good functional outcomes, and these radiographic markers was previously reported, those studies only evaluated patients within 4.5 hours from the onset of the stroke. The originality of this study lies in its examination of the same associations within a later time window, between 4.5 and 30 hours after stroke onset.

The clinical significance of these study results lies in the confirmed association between good collateral and penumbral status and the HVS. This finding suggests that HVS could serve as a surrogate marker for perfusion scans. Consequently, HVS could aid in the decision-making process for thrombectomy in patients with large vessel occlusion who are scanned using MRI/MRA but are unable to receive gadolinium contrast for perfusion scans due to medical conditions such as renal failure.

I found one major point of revision that may increase the study’s validity. The authors separated the 49 patients into two groups based on high versus low HVS, and positive versus negative PCA laterality. Since the same patient cohort was categorized using two different criteria, there is likely significant overlap between the groups. For instance, it is plausible that many patients with high HVS also exhibited positive PCA laterality—a correlation previously noted in the literature (PMID 23532013). Therefore, considering the strong correlation between these variables, an adjusted analysis may provide more insight. I recommend conducting an adjusted analysis with the core volume on follow-up scans (and other clinically meaningful aspects) as the dependent variable, incorporating the presence of HVS, PCA laterality, and clot location, especially since the positive PCA laterality group reportedly had a higher incidence of ICA occlusions. This approach would help clarify the independent effects of each variable on patient outcomes, given that the current results are based on unadjusted comparisons.

Here is the suggested minor edit points:

1) Page 2, Line 21, “a late time window up to 30 hours”. I assume the “late time window” means between 4.5h and 30h from the onset of the stroke. Please define the starting point of this “late time window” for clear understanding.

2) Page 2, Line 34, “TIMI grade”. I think TIMI was the typo of modified TICI score. However, if this was legitimate, please provide a reason why the scoring system for coronary revascularization was used to evaluate the result of cerebral thrombectomy.

3) For readers who are not familiar with MIStar, please consider adding a brief description of what Delay Time is and how it differs from Mean Transit Time and Time to Peak.

Reviewer #3: The authors evaluated the association between hypertensive vessel sign on FLAIR imaging (HVS) or PCA laterality on MRA within 30 hours form onset and outcome They showed that prominent HVS in later time was significantly associated with small core, and persistent penumbra volume, and favorable outcome. This study suggested useful imaging markers to predict short term outcome in patients with LVO in anterior circulation presented beyond 4.5 hours; however, there are some questions and comments about contents of the manuscript.

1.When considering the association between HVS and clinical outcome, the possibility of loss of HVS due to the completion of infarct at the same territory should be considered. This study showed the association between high score of HVS and good clinical outcome, but the volume of ischemic core was significantly larger in the low HVS group both at the initial visit and at follow-up. Significant and strong correlation between the low score of HVS and the large ischemic core is not surprising. What is the significance of using HVS rather than initial ischemic core as a predictor of clinical outcome? To elucidate the significance of HVS on clinical outcome, the effect of infarct core volume should be considered.

2.If the follow-up imaging performed within 30 hours after onset (median 20 hours) was used as surrogate for initial assessment of late presenting stroke, as the author mentioned as the limitation of study, the effect of acute treatment, especially intravenous thrombolysis, could not be ignored. Moreover, in this study, the final core volume at the follow-up would correspond to the initial ischemic core in late presenting stroke. If this study was designed for late presenting stroke, true ischemic core measured after follow-up visit should be analyzed. Similarly, clinical baseline parameters including initial NIHSS, were less meaningful. The author should present the NIHSS score obtained at follow-up.

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Reviewer #2: No

Reviewer #3: No

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Collateral assessment on magnetic resonance imaging/angiography up to 30 hours after stroke onset

PONE-D-24-11660R1

Dear Dr. Tomari,

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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Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #3: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #3: The authors have appropriately responded to the reviewer's comment. This manuscript is of satisfactory level for publication in this journal.

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Reviewer #1: No

Reviewer #3: No

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