PONE-D-20-28449

Total Small Vessel Disease Burden and Functional Outcome in Patients with Ischemic Stroke

PLOS ONE

Dear Dr. Ryu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

1. Question about the reason for not adjusting the multivariate model with the NIHSS score.
2. English style needs some editing.
3. Provide more detail information based on reviewer’s suggestions.

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We look forward to receiving your revised manuscript.

Kind regards,

Quan Jiang, Ph,D.

Academic Editor

PLOS ONE

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 [WSR: This work was supported by the Dongguk University Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.].

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. 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: Yes

Reviewer #2: Partly

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

Reviewer #1: No

Reviewer #2: No

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3. 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: Yes

Reviewer #2: Yes

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4. 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: Yes

Reviewer #2: 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: Very interesting paper where the authors use a validated score to evaluate the role of cerebral small vessel disease on stroke outcome.

Major concerns

Could please the authors explain the reason for not adjusting the multivariate model with theNIHSS score?. Has this analysis been performed?. It is a common predictor of functional outcome in patients with stroke and patients with SVD 4 tend to have higher NIHSS scores (p75 is 10).

Minor concerns

Some of the English writing should be reviewed.

The authors use many times in the manuscript the expression “different subtypes of SVD” when they actually refer to different neuroimaging markers of SVD. I suggest use the expressions “SVD markers” or “neurimaging markers of SVD” instead. The “use of subtypes of SVD” can cause confusion to the readers, since SVD has several underlying etiologies such as hypertensive, amyloid angiopathy, CADASIL.. and the expression “SVD subtypes” is frequently used in this setting.

The authors perform a multivariate ordinal regression analysis. Therefore, it would be more correct if they say that “lacunes, MBS… independently increased the risk of worsening on the mRS scale” instead of “lacunes, MBS….were independently associated with unfavorable outcome”, because they analyze the whole spectrum of the scale and not only the unfavorable outcome categories(3-6).

Why have the authors selected the period 2012 to 2013 for the analysis of 90 days mRS?. Don’t they have more recent data?

How many centers participate in the study?. It is not clear from the methods section. At the beginning of this section, the authors say”patients who visited our center”, but lately they say “stroke subtypes were determined by the consensus experienced neurologists in each participating center”.

Reviewer #2: In this study authors evaluated the association between cerebral small vessel disease and functional outcome after ischemic stroke. The study is confirmative, since this observation is not novel in patients with ischemic stroke, but may be of interest because all patients had MR examination and SVD was therefore quantified with the gold standard. Furthermore, the study has been conducted within an Asian cohort of patients whereas many study on the topic were with Caucasian patients, therefore confirms the negative role of SVD on stroke outcome independently of the ethnicity.

The study could be improved and English style needs some editing.

Comments:

- Please report in the abstract number and strength of association rather than p values

- Please present general characteristics of population in the first part of results (age, sex, median NIHSS, etc.)

- Please state inclusion and exclusion criteria for study population. E.g. were included patients treated with acute stroke treatment?

- Please move the excluded patients paragraph from methods to results section

- a single reader rated all the scans

- Table 1 needs some editing (e.g. age, years, probably “mean” is missing). Please add a column with data from all the population.

- What “revascularization” means in the adjusted analysis?

- Although stroke severity (i.e. NIHSS) is a major determinant of stroke outcome, NIHSS is missing in the adjusted analysis. In table 1 there is a clear trend towards worse NIHSS in patients with higher SVD burden. Conversely, in the adjusted analysis

there are some variables that likely do not affect stroke outcome (e.g. smoke exposure, coronary heart disease-anamnestic, I suppose-). I would like to see a further multivariable analysis adjusted simply for age, sex, NIHSS, pre-stroke mRS.

- Figure 1 is rather confusing

- Discussion: there are also reports about no association between SVD and functional outcome after stroke (e.g. Boulouis G et al., Neurology 2019), please discuss your results comparing also with such studies.

- Discussion: as a limit, authors mentioned that patients that were eligible for endovascular treatment were excluded from the study. However, there are reports about SVD and outcomes in such patients (Arba F et al. Neurol Sci 2019; Boulouis G et al., Neurology 2019). Again, what about patients eligible for intravenous rt-PA (see Charidimou A et al., Stroke 2016; IST-3 collaborators, Lancet Neurol; Arba F et al., Acta Neurol Scand 2017)?

- Results apply only to patients who underwent MR, but the great majority of stroke patients receive only CT. Please discuss.

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Reviewer #1: Yes: Manuel Gomez-Choco

Reviewer #2: Yes: Francesco Arba

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Total Small Vessel Disease Burden and Functional Outcome in Patients with Ischemic Stroke

PONE-D-20-28449R1

Dear Dr. Ryu,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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.

Kind regards,

Quan Jiang, Ph,D.

Academic Editor

PLOS ONE

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 #2: 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 #2: Yes

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

Reviewer #1: (No Response)

Reviewer #2: 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 #2: 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 #2: 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 #2: No further comments, all issues have been addressed. The manuscript sounds more complete and limitations are fairly discussed.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Manuel Gómez-Choco

Reviewer #2: Yes: Francesco Arba