Morphological and ultrastructural investigation of the posterior atlanto-occipital membrane: Comparing children with Chiari malformation type I and controls

Vijay M. Ravindra; Lorraina Robinson; Hailey Jensen; Elena Kurudza; Evan Joyce; Allison Ludwick; Russell Telford; Osama Youssef; Justin Ryan; Robert J. Bollo; Rajiv R. Iyer; John R. W. Kestle; Samuel H. Cheshier; Daniel S. Ikeda; Qinwen Mao; Douglas L. Brockmeyer

doi:10.1371/journal.pone.0296260

Peer Review History

Original SubmissionSeptember 28, 2023
23 Oct 2023 Decision Letter - Sagar Panthi, Editor PONE-D-23-31525 Morphological and ultrastructural investigation of the posterior atlanto-occipital membrane: comparing children with Chiari malformation type I and controls PLOS ONE Dear Dr. Ravindra, 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. Please submit your revised manuscript by Dec 07 2023 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. 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Ethical Clearance: Please clarify in the ethical approval section that the hospital is affiliated to the university which approved the study as the hospital's name is not clearly indicated in the approval letter. 3. Figure captions Figure captions must be inserted in the text of the manuscript, immediately following the paragraph in which the figure is first cited (read order). Do not include captions as part of the figure files themselves or submit them in a separate document. [Note: HTML markup is below. Please do not edit.] 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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: No ****** 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 ****** 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: The authors performed a study of children undergoing posterior fossa craniotomy for Chiari 1 malformation or brain tumor resection. They then compared the PAOM between these two groups. Differences between Chiari and tumor were seen in posterior fossa volume and disorganization score, with Chiari patients showing higher degree of disorganization. There were no significant associations between most imaging measurements and the collagen disorganization score. Recruitment was 9/21 to 6/23. Why were these dates chosen? How was sample size determined for this prospective study? There were differences seen between the groups, but many were not statistically significant. Is this because the sample is too small? What would be considered a clinically relevant difference in the key variables? The primary outcome seems to be the score indicating the degree of disorganization of the collagen (0 to 3). Has this score been validated? Any testing of reliability? How likely is it that the difference in posterior fossa volume observed here is related to the presence of a mass in the posterior fossa? This seems an odd control group for the volume measurement. Non-pathological controls might be more appropriate. In the Discussion and Conclusion, the authors state that their findings suggest that the collagen findings are more likely to be an adaptation rather than a cause of Chiari pathology. It is not clear what they base this statement on? How to the present results support this conclusion? This point is made in several places, including the Abstract. More justification of this statement is needed, or the conclusion should be revised. Reviewer #2: 1. A well written article. However the sample size is small and the cases and controls are unevenly distributed. A total of 35 children with 11 as controls. Were they matched? Pls explain. 2. As the number of patients were few, I suggest the authors to list all 24 patients with age sex, preop imaging findings, post op complications and histological findings. 3. Pls describe in the discussion section, the implication of this research to clinical practice. Will it affect the way we perform surgery or any medicines you theorize to address the disorganized membrane? ****** 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: No ******** [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. https://doi.org/10.1371/journal.pone.0296260.r001
Revision 1
9 Nov 2023 Author Response November 1, 2023 Sagar Panthi, MBBS Academic Editor PLOS ONE Dear Dr. Panthi: Thank you for sending us the reviewers’ comments regarding our paper, "Morphological and ultrastructural investigation of the posterior atlanto-occipital membrane: comparing children with Chiari malformation type I and controls” (PONE-D-23-31525). We are very pleased that the reviewers found the paper to be of interest. In response to their comments, we have made the following changes to the paper. RESPONSE TO REVIEWERS Reviewer #1 1. The authors performed a study of children undergoing posterior fossa craniotomy for Chiari 1 malformation or brain tumor resection. They then compared the PAOM between these two groups. Differences between Chiari and tumor were seen in posterior fossa volume and disorganization score, with Chiari patients showing higher degree of disorganization. There were no significant associations between most imaging measurements and the collagen disorganization score. Recruitment was 9/21 to 6/23. Why were these dates chosen? How was sample size determined for this prospective study? There were differences seen between the groups, but many were not statistically significant. Is this because the sample is too small? What would be considered a clinically relevant difference in the key variables? RESPONSE: Recruitment for the study was based on the study timeline proposed as part of the funding mechanism. The original study was set to be completed over a 12-month period with the intention of examining and analyzing 40 specimens. Because of the COVID-19 pandemic, we had a difficult time enrolling patients and, therefore, obtaining specimens. The study was extended to June 2023, but the final enrollment was only 35 patients. This is the first study of its type, and therefore there was no specific primary outcome measure. Instead, we performed a comparative analysis of children with and without CM-I that required surgical treatment. Based on the findings of this exploratory study, there is no obvious clinically relevant difference per se. Additionally, no metric exists for disorganization scoring or thickness with respect to minimal clinically important difference. The results of this study, do, however, shed light on the potential pathophysiologic mechanism of CM-I and its effect on other mesodermal structures, in this case the PAOM. The sample size is small and a larger-scale study of the phenomena is warranted. As a result of the reviewer’s request, we have added this to the limitations section of the paper (page 24). 2. The primary outcome seems to be the score indicating the degree of disorganization of the collagen (0 to 3). Has this score been validated? Any testing of reliability? RESPONSE: The outcome/variable of membrane disorganization was used to describe the structure of the PAOM in a clinically relevant manner. Initially, percentage of fat content and fiber organization were considered for use, but we determined that describing the structure that way would have very little meaning to the readership or clinicians. Because, to the knowledge of the authors, no published criteria for organization/disorganization is available, the ordinal disorganization index was derived by a senior, fellowship-trained neuropathologist and used with clear definitions and criteria. Each specimen was independently reviewed by two fellowship-trained neuropathologists who tested the method and consistently arrived at consensus; however, the grading system has not been formally validated. This information has been added to the methods (page 8) and limitations (page 23) sections of the paper. 3. How likely is it that the difference in posterior fossa volume observed here is related to the presence of a mass in the posterior fossa? This seems an odd control group for the volume measurement. Non-pathological controls might be more appropriate. RESPONSE: The use of posterior fossa tumor patients as controls is a limitation, but for a surgical pathology study there is no other comparison with respect to membrane histology/ultrastructural properties. Chiari malformation is a congenital anomaly except in cases where a secondary malformation develops from a tumor, CSF leak, etc. On the other hand, posterior fossa tumor/mass lesion growth that occurs after development of the compartments of the cranium is not congenital. Thus, we would expect the volumetric measurements of the posterior fossa in patients with tumor/mass lesion growth to be a reasonable proxy for “normal,” despite not being ideal. In calculating posterior fossa volume, the goal was to compare the histological measures to the volumetric measure to correlate the specimens to the imaging findings. A third population of non-pathological controls would not allow us to achieve this goal. Additionally, non-pathological controls with imaging in the setting of TBI/concussion/epilepsy would not have the three-dimensional, fine-cut, high-resolution sequences available that are necessary to calculate posterior fossa volume. Had we included non-pathological control patients, additional recruitment and imaging studies would have been needed, which were outside the scope of and exceeded the financial constraints of the current study. The limitations of the use of posterior fossa tumor patients as the control population has been added to the paper (page 23). 4. In the Discussion and Conclusion, the authors state that their findings suggest that the collagen findings are more likely to be an adaptation rather than a cause of Chiari pathology. It is not clear what they base this statement on? How to the present results support this conclusion? This point is made in several places, including the Abstract. More justification of this statement is needed, or the conclusion should be revised. RESPONSE: In patients with CM-I, the posterior fossa compartment is small (a), which is part of what leads to the clinical presentation—headaches, syringomyelia, bulbar symptoms, etc.—of children with the malformation. The small posterior fossa leads to crowding at the foramen magnum with associated hyperdynamic local CSF pulsation with nonlaminar flow at the foramen magnum (b,c,d). The surgical treatment for symptomatic CM-I involves expansion of the space at the foramen magnum via opening of the bone (suboccipital bone, C1 lamina), dura, and posterior atlanto-occipital membrane. Based on the findings of this study, the thinning and disorganization of the PAOM is an acquired mechanism or adaptation that is a physiologic response attempting to compensate for the malformation with auto-expansion of the posterior compartment. As a result, we posit that the membrane thins and becomes more disorganized with increased fat content (a chronic sign of tissue fatigue). This information, including references is included in the discussion portion of the paper (page 21). a. Botelho RV, Heringer LC, Botlho PB, Lopes RA, Waisberg J. Posterior fossa dimensions in chiari malformation patients compared with normal subjects: systematic review and meta-analysis. World Neurosurg. 2020 Jun: 138: 521-529. b. Heiss JD. Cerebrospinal fluid hydrodynamics in chiari i malformation and syringomyelia: modeling pathophysiology. Neurosurg Clin N Am. 2023 Jan; 34(1): 81-90. c. Chiari H. Ueber Veränderungen des Kleinhirns infolge von Hydrocephalie des Grosshirns. Dtsch Med Wochenschr 1891;17:1172–5. d. Wilkins RH, Brody IA. The Arnold-Chiari malformation. Neurological classics 38. Arch Neurol 1971;25:376–9. Reviewer #2: 1. A well written article. However the sample size is small and the cases and controls are unevenly distributed. A total of 35 children with 11 as controls. Were they matched? Pls explain. RESPONSE: We thank the reviewer for their compliment. We recognized that the sample size is small with uneven distribution of cases and controls. As noted in response 1 to Reviewer #1, patient enrollment was interrupted by the COVID-19 pandemic and recruitment goals were necessarily altered. Given the desire to recruit as many subjects/pathological specimens as possible, the patients were not matched. Although disparities in body mass index, sex, and age were a concern, our post hoc analysis (Table 1) did not reveal any differences in age, sex distribution, or BMI. Thus, we believe a relative comparison is reasonable for this anatomic structure analysis. We have added the lack of formal matching to the limitations portion of the paper (page 24). 2. As the number of patients were few, I suggest the authors to list all 24 patients with age sex, preop imaging findings, post op complications and histological findings. RESPONSE: We appreciate the suggestion, however because of the homogeneity in age and sex as well as histopathological findings and the lack of postoperative complications within the CM-I cohort we do not think that a table with this information would add to the paper. 3. Pls describe in the discussion section, the implication of this research to clinical practice. Will it affect the way we perform surgery or any medicines you theorize to address the disorganized membrane? RESPONSE: Please see responses 1 and 4 to Reviewer #1 above. Our findings further the current understanding of the pathophysiology of CM-I and the role of the PAOM. This study is not likely to impact clinical practice directly, but thinning of the membrane as an adaptive response may represent a potential for therapeutic targets in the future to locally improve the flow of CSF and pulsatility at the foramen magnum (i.e., agents administered directly or indirectly to thin the membrane). We have added this to the discussion section of the paper, but we have kept this insertion brief so as not to overstate the clinical implications of our results (page 24). We thank the editor for the opportunity to revise the paper and believe that with the aforementioned changes it is significantly improved. We hope it meets the standard for publication in PLoS One and look forward to your decision. Attachments Attachment Submitted filename: responsetoreviewers.docx https://doi.org/10.1371/journal.pone.0296260.r002
16 Nov 2023 Decision Letter - Sagar Panthi, Editor PONE-D-23-31525R1Morphological and ultrastructural investigation of the posterior atlanto-occipital membrane: comparing children with Chiari malformation type I and controlsPLOS ONE Dear Dr. Ravindra, 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. Please submit your revised manuscript by Dec 31 2023 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Sagar Panthi, MBBS Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Thank you to the authors for sending us with the revisions addressing the suggestions and queries as asked by the reviewers. There are still a few suggestions from Reviewer 1 which needs addressing. In addition, please also address the suggestions made by the editorial team in the previous revision. 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 ******** 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: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ****** 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: Yes 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 #1: Yes 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 #1: The authors have addressed the reviewer comments. One additional suggestion: Recommend removing the final statement in conclusion regarding refutation of prior hypotheses. Because the abstract does not make reference to these hypotheses, it is difficult to understand what is meant by this comment. Also, in the Conclusion section, while the refuted hypotheses have now at least been mentioned in the Discussion, this statement is probably a bit too strong given the provided data. Removing that clause about refutation would do nothing to weaken this report. Reviewer #2: The authors have satisfactorily addressed my queries and I approve this manuscript for publication in the PLOS ONE ****** 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: No Reviewer #2: Yes: Mohan Raj Sharma ******** [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. https://doi.org/10.1371/journal.pone.0296260.r003
Revision 2
17 Nov 2023 Author Response We thank the reviewer and have made the suggested change and have removed the sentence about refutation of prior hypotheses from the conclusion section of the abstract and the conclusion of the manuscript itself. We agree the suggested removal does nothing to weaken the report. We thank the editor for the opportunity to revise the paper and believe that with the changes it is improved. We hope it meets the standard for publication in PLoS One and look forward to your decision. Sincerely, Vijay M. Ravindra, MD, MSPH Attachments Attachment Submitted filename: PLoS One R2 Letter to Reviewers.docx https://doi.org/10.1371/journal.pone.0296260.r004
10 Dec 2023 Decision Letter - Sagar Panthi, Editor Morphological and ultrastructural investigation of the posterior atlanto-occipital membrane: comparing children with Chiari malformation type I and controls PONE-D-23-31525R2 Dear Dr. Ravindra, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Sagar Panthi, MBBS Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0296260.r005
Formally Accepted
5 Jan 2024 Acceptance Letter - Sagar Panthi, Editor PONE-D-23-31525R2 PLOS ONE Dear Dr. Ravindra, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Sagar Panthi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0296260.r006

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