PONE-D-20-08499

Idiopathic Intracranial Hypertension in Patients with Anemia: A Retrospective Cross-sectional Study

PLOS ONE

Dear Mr. Ma,

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.

The reviewers mention a several amount of issues that should be acknowledged before considering your manuscript for publication in Plos One, therefore I suggest you review each comment carefully, addressing the requested information.

We would appreciate receiving your revised manuscript by Jun 12 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Miguel A. Barboza, MD, MSc

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements:

1.    Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study, including: a) the date range (month and year) during which patients' medical records were accessed; and b) the source of the medical records analyzed in this work (e.g. hospital, institution or medical center name).

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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: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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: No

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: This retrospective cohort study has reviewed the records of adult patients with IIH from Jan 2014 - Aug 2019 at a single center, and performed a straight-forward separation into two groups based on the presence of anemia. Based on their findings, they make the conclusion that patients with anemia have an “subacute onset, shorter disease duration, tendency to suffer tinnitus and higher ICP, liable to develop TSS, and better clinical visual outcomes after timely treatments of anemia-correction and decreasing ICP”.

In general, this report provides a satisfactory picture that there is a trend that patients with anemia tend to do better. Unfortunately, the data collected is fairly minimalistic. All improvements are lumped into a simple yes or no category, and no further follow-up information is provided on the patients and their outcomes, despite having several criteria within that category as stated in the report. There is no follow-up Hb level showing that anemia was treated or not or what they were treated with, that a follow-up opening pressure was performed, or documentation of how many have papilledema and how many have shown improvement. The long-term follow-up characterization is also quite minimal and amounts to a simple “yes or no” data field and no granularity to clinical outcome data. Minor issues also include incorrectly used terms (referring to an opening pressure as ICP, eg). Clinical outcomes has been converted into a subjective criteria without evidence of the objective criteria, except for visual outcomes.

Overall this fares closer to empirical expert opinion, and lacks several aspects of rigorous research, as best as can be expected with a retrospective cohort study.

Reviewer #2: We thank the author for submitting their paper to PLOS ONE.

This manuscript describes a longitudinal cohort study done in patients with IIH and anemia. Their major objective is to define the clinical characteristics and prognosis of patients with IIH and anemia and without it during a period of 6 years and 7 months. The main conclusion given included that patients with IIH and anemia were more prone to a sub-acute onset, shorter disease duration, tinnitus, higher intracranial pressure, transverse sinus stenosis liability and better clinical visual outcome after treatment of anemia and lowering intracranial pressure.

The authors´s article inspires a lukewarm impression and the possibility of publication would be based in an overall improvement of the manuscript. I detail a general paragraph and some specific issues (major and minor) to be addressed to improve their article.

This is an significant topic and of interest to our readers. The article seems original in the sense of specific characterization of the patients with IIH and anemia; however, the appearance of anemia (specially microcytic/ferropenic) in IIH has been described before (casuistic has defined a prevalence of up to 10%) as well as the fact that only treating anemia would decrease intensity of headaches and even stop the course of the disease in some cases.

The writing is clear; however, general organization could be improved to provide an adequate flow and make the reading more comfortable. This will also aid the author to identify the major point of view in all the sections. More attention should be placed in specific areas such as criteria (diagnosis, inclusion and exclusion), treatments and limitations. The paper could be enhanced by tables and figures related to the data depicted.

Major issues:

1. Title: The author´s annotate a tittle suggesting a retrospective cross-sectional study and later define a longitudinal cohort study. A proper analysis and definition of the type of study design is a must.

2. Materials and methods: the means of getting to the information of the patients to the database should be provided in order to validate the author´s source of research: review of data charts, radiologic tests, laboratory records, direct or indirect contact with patients, surveys, etc.

3. Criteria: This paragraph could be improved greatly.

- Diagnostic criteria should be described in the article. Even though we assume that criteria for diagnosis is homogeneous internationally, some countries could variate their way to diagnose diseases according to their data and experience.

- The course of disease was defined as acute, sub-acute and chronic. It is important to describe why and how you defined the time frame for each category, either if you chose them based on prior studies or based on your own experience. The definition for acute course needs to be added.

- Even though it is also assumed, annotating that all patients had a complete and normal neurological exam (apart from CN VI palsy if any) is needed to ensure diagnostic criteria was met.

- Campimetry is also part of the diagnostic criteria of IIH and a significant number of the patients did not have a campimetric study. Explanation of the missing information should be addressed, as well as the repercussions in diagnosis, treatment and response to treatment, as well as inherent limitations to the conclusions study.

4. Treatment and prognosis:

- This section analyzed the treatments given. A clear approach step by step according to response should be described. Whether the patients were recommended to lose weight initially, followed by or accompanied by farmacologic treatment and / or surgical measures (depending of the severity, duration or accompanying features of the headache). Current guidelines indicate weight control, acetazolamide 500 BID up to 2-4 g qd, furosemide 20-40 mg qd as adjunctive medication and surgical treatments. If the guidelines were not followed, an explanation of the reason as well as the aftermath in prognosis (response) and your overall conclusions of the study is recommended.

5. Citations: the author´s citations pertinent and current. However, some of them do not coincide with the information in the text. It is very important that they support and expand the assertions of fact not addressed by the data presented.

6. Limitations: according to the aforementioned details, this section could be greatly enriched. The repercussions and possible solutions to these limitations should also be addressed.

Minor issues and other comments:

1. Discussion: Note that abbreviations and what they stand for need to be placed before using them alone in the article. It aids in a correct understanding of the text for all our readers.

2. Figures and tables: The use of tables and / or figures may improve greatly your paper, especially for diagnostic, inclusion and exclusion criteria. A flowchart is another possibility to strengthen the readers´ understanding and focus their attention on important facts.

3. Consider modifying the term renal anemia for anemia of chronic renal disease for better and correct understanding of the term.

4. Image quality could be improved in order to enhance your article.

5. If the power of the study was calculated prior to starting the research, a description of this process is important, since it can aid in searching for an appropriate sample size and increase the chances of getting significant results. If it was not it could be added to the limitations of the study.

6. A correction and re-review is advised for further analysis and possibility of publication.

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6. 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: No

Reviewer #2: Yes: KARLA ALEJANDRA MORA RODRIGUEZ MD Neurology Attending Physician

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-20-08499R1

Idiopathic Intracranial Hypertension in Patients with Anemia: A Retrospective Observational Study

PLOS ONE

Dear Dr. Ma,

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.

The manuscript improved substantially, and the authors reached all the suggestions from revisors, however, English quality should be improved in order to ease publication process, therefore, we suggest professional English editing services.

Please submit your revised manuscript by Aug 13 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Miguel A. Barboza, MD, MSc

Academic Editor

PLOS ONE

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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 #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 #2: Yes

**********

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

Reviewer #2: Yes

**********

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 #2: Yes

**********

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 #2: Yes

**********

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 #2: The authors improved their manuscript according to suggestions made by the editing committee and reviewers. Some minor orthographic and syntactic corrections should be done prior to publication. Usually, a native English speaking aid is recommended. Overall, my opinion on the corrected version is positive.

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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 #2: Yes: KARLA A. MORA RODRIGUEZ MD NEUROLOGY

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Idiopathic Intracranial Hypertension in Patients with Anemia: A Retrospective Observational Study

PONE-D-20-08499R2

Dear Dr. Wang,

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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Kind regards,

Miguel A. Barboza, MD, MSc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: