Ocular biometric parameters changes and choroidal vascular abnormalities in patients with neurofibromatosis type 1 evaluated by OCT-A

Aldo Vagge; Paolo Corazza; Lorenzo Ferro Desideri; Paola Camicione; Giulia Agosto; Roberta Vagge; Calevo Maria Grazia; Adriano Carnevali; Giuseppe Giannaccare; Massimo Nicolò; Carlo Enrico Traverso

doi:10.1371/journal.pone.0251098

Peer Review History

Original SubmissionJanuary 17, 2021
25 Feb 2021 Decision Letter - Alfred S Lewin, Editor PONE-D-21-01698 Ocular biometric parameters changes and choroidal vascular abnormalities in patients with neurofibromatosis type 1 evaluated by OCT-A PLOS ONE Dear Dr. Ferro Desideri, 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 correct referencing and formatting errors. Please provide brain MRI images or the results of brain MRI for NF1 patients. Focus on your specific results and don't conclude that this can be a diagnostic method at this stage. Please submit your revised manuscript by Apr 09 2021 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. 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Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ <h1> </h1> [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: Yes 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: Yes ****** 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: This is an interesting paper in an area of active research (biomarkers for NF1) that has rapidly progressed with multimodal imaging. The use of swept source and OCTA by the authors provides further knowledge on the topic. Some revision would greatly enhance the manuscript as follows: Abstract Specify “macular” RNFL, if this is the case. This needs to be specified in the methods section and throughout. In the conclusions avoid general comments (first sentence) and focus on specific results such as the major novel finding ie choroidal and retinal vascular flow area. The use of the term “diagnostic tool” may be appropriate once further studies are carried out, rather the findings of the authors provide further knowledge on the vascular alterations of the choroid using advance imaging, and thinning of the RNFL even in the absence of optic nerve gliomas In the results section please check language: the word “compared” is inserted twice Introduction Although the diagnosis of NF1 is clinical, some centers use genetic testing for assessment, please mention this. Please correct to: …contemporary presence of “the” following criteria… Please correct to: “The presence of choroidal nodules, detected as bright patchy areas by NIR, has previously been reported in 70% of pediatric patients with NF1.” Please correct to: Furthermore, in patients with NF1, the association between choroidal nodules and retinal vascular abnormalities (RVAs) has been reported. Please correct: OCTA has “enabled” us Methods Please state if IOP was measured and please state if patients with glaucoma or borderline IOP were excluded, as this can influence RNFL and GCL- IPL thickness values. Please correct: Remove the word “Furthermore”…… 3 different levels (l1, L2, and L3…) Results Please evaluate RNFL and GCL excluding patients with glioma in order to confirm significance results. If, following statistical analysis, the results change please comment accordingly in discussion. Discussion The authors state: “A reduced RNFL thickness was previously reported in patients with NF1 and optic pathway gliomas (17,18). Thus, the measurement of RNFL thickness has been proposed as a useful tool to screen NF1 patients for the presence of gliomas (17). However, only 3 patients in our cohort had a optic pathway glioma. Therefore, RNFL thickness may be reduced in patients with NF1 even in the absence of this complication.” There are publications on RNFL thinning in patients with optic nerve glioma (Chang L, et al. Optical coherence tomography in the evaluation of neurofibromatosis type-1 subjects with optic pathway gliomas. J AAPOS 2010;14:511-517.; Topcu-Yilmaz P, et al. Investigation of retinal nerve fiber layer thickness in patients with neurofibromatosis-1. Jpn J Ophthalmol 2014;88:172-176.) but also RNFL thinning in adult patients WITHOUT optic nerve glioma (Abdolrahimzadeh S, et al. Spectral domain optical coherence tomography evidence of retinal nerve fibre layer and ganglion cell loss in adult patients with neurofibromatosis type 1. Retina 2016; 36:75-81). Furthermore, some authors have studied the peripapillary RNFL and some also the macular RNFL. This section would benefit with some discussion, please mention the relevant references above when discussing the results on RNFL thickness. Citations and references Please correct citations in text: in some sections the citation in the text is the author name and year of publication, in other sections there are numbers. Furthermore, references are not identified by numbers in the reference section. Kindly correct citations and references according to journal instructions. Reference 16 is missing in the reference section when the authors refer to the previous study on choroidal thickness, Br J Ophthalmol 2015;99:789-793. References 17, and 18 are missing in the reference section when the authors refer to RNFL thinning, Chang L et al and Topcu-Yilmaz P et al. Please carefully check citations and reference list for accuracy throughout. Reviewer #2: Very interesting study one major remark: No data on MRI of the brain was given, if not all NF1 patients and NF1 suspected patients have undergone an MRI, no conclusions related to the RNFL can be drawn ****** 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.0251098.r001
Revision 1
10 Apr 2021 Author Response Reviewer #1: This is an interesting paper in an area of active research (biomarkers for NF1) that has rapidly progressed with multimodal imaging. The use of swept source and OCTA by the authors provides further knowledge on the topic. Some revision would greatly enhance the manuscript as follows: Abstract Specify “macular” RNFL, if this is the case. This needs to be specified in the methods section and throughout. We thank the reviewer for this comment; we specified it was the RFNL thickness measured in the macular region. In the conclusions avoid general comments (first sentence) and focus on specific results such as the major novel finding ie choroidal and retinal vascular flow area. The use of the term “diagnostic tool” may be appropriate once further studies are carried out, rather the findings of the authors provide further knowledge on the vascular alterations of the choroid using advance imaging, and thinning of the RNFL even in the absence of optic nerve gliomas We thank the reviewer for this insight. We avoided general comments as suggested, focusing on the possible importance of our findings and we agree with the fact that OCT-A ca not be considered a diagnostic tool yet considering the relatively small evidence in this regard to date. In the results section please check language: the word “compared” is inserted twice We corrected it as suggested. Introduction Although the diagnosis of NF1 is clinical, some centers use genetic testing for assessment, please mention this. We specified it as suggested by the reviewer Please correct to: …contemporary presence of “the” following criteria… We modified it as suggested by the reviewer Please correct to: “The presence of choroidal nodules, detected as bright patchy areas by NIR, has previously been reported in 70% of pediatric patients with NF1.” We modified it as suggested Please correct to: Furthermore, in patients with NF1, the association between choroidal nodules and retinal vascular abnormalities (RVAs) has been reported. We modified it as suggested Please correct: OCTA has “enabled” us We modified it as suggested by the reviewer. Methods Please state if IOP was measured and please state if patients with glaucoma or borderline IOP were excluded, as this can influence RNFL and GCL- IPL thickness values. Please correct: Remove the word “Furthermore”…… 3 different levels (l1, L2, and L3…) We added the corrections suggested Results Please evaluate RNFL and GCL excluding patients with glioma in order to confirm significance results. If, following statistical analysis, the results change please comment accordingly in discussion. We thank the reviewer for this comment. As correctly stated by reviewer cases of gliomas were present in our cohort; however, considering the post chiasmatic/optic radiations position of the finding, we did not rule out these patients from the statistical analysis. In this regard, no previous evidence has been reported in literature about a possible decrease in vascular density by OCTA in the choroid of patients with postchiasmatic gliomas. Moreover, we deem that n=3/31 patients does not represent a significant number of patients interfering with the significance of the findings in our study. Discussion The authors state: “A reduced RNFL thickness was previously reported in patients with NF1 and optic pathway gliomas (17,18). Thus, the measurement of RNFL thickness has been proposed as a useful tool to screen NF1 patients for the presence of gliomas (17). However, only 3 patients in our cohort had a optic pathway glioma. Therefore, RNFL thickness may be reduced in patients with NF1 even in the absence of this complication.” There are publications on RNFL thinning in patients with optic nerve glioma (Chang L, et al. Optical coherence tomography in the evaluation of neurofibromatosis type-1 subjects with optic pathway gliomas. J AAPOS 2010; 14:511-517.; Topcu-Yilmaz P, et al. Investigation of retinal nerve fiber layer thickness in patients with neurofibromatosis-1. Jpn J Ophthalmol 2014; 88:172-176.) but also RNFL thinning in adult patients WITHOUT optic nerve glioma (Abdolrahimzadeh S, et al. Spectral domain optical coherence tomography evidence of retinal nerve fibre layer and ganglion cell loss in adult patients with neurofibromatosis type 1. Retina 2016; 36:75-81). Furthermore, some authors have studied the peripapillary RNFL and some also the macular RNFL. This section would benefit with some discussion, please mention the relevant references above when discussing the results on RNFL thickness. We thank the reviewer for this comment. We added the suggested studies dealing with the study of RNFL thickness in NF1 patients without glioma, discussing its potential role for further studies. Citations and references Please correct citations in text: in some sections the citation in the text is the author name and year of publication, in other sections there are numbers. Furthermore, references are not identified by numbers in the reference section. Kindly correct citations and references according to journal instructions. We modified the references style as suggested by the reviewer Reference 16 is missing in the reference section when the authors refer to the previous study on choroidal thickness, Br J Ophthalmol 2015;99:789-793. References 17, and 18 are missing in the reference section when the authors refer to RNFL thinning, Chang L et al and Topcu-Yilmaz P et al. Please carefully check citations and reference list for accuracy throughout. All the references have been carefully checked and reordered Reviewer #2: Very interesting study one major remark: No data on MRI of the brain was given, if not all NF1 patients and NF1 suspected patients have undergone an MRI, no conclusions related to the RNFL can be drawn We thank the reviewer for the comment. We deem that our study has an ophthalmological perspective and the evaluation of MRI data, beside the individuation of 3 postchiasmatic gliomas in 3 out 31 patients with confirmed diagnosis of NF1, falls outside the topic of this study. Moreover, MRI findings are not very unlikely to interfere with the alterations reported in choroidal vasculature and RNFL thinning measure by OCT. We better discussed our findings dealing with RNFL thinning in the discussion paragraph. Attachments Attachment Submitted filename: PLOS one Answers reviewers.docx https://doi.org/10.1371/journal.pone.0251098.r002
20 Apr 2021 Decision Letter - Alfred S Lewin, Editor Ocular biometric parameters changes and choroidal vascular abnormalities in patients with neurofibromatosis type 1 evaluated by OCT-A PONE-D-21-01698R1 Dear Dr. Ferro Desideri, 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, Alfred S Lewin, Ph.D. Section Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0251098.r003
Formally Accepted
26 Apr 2021 Acceptance Letter - Alfred S Lewin, Editor PONE-D-21-01698R1 Ocular biometric parameters changes and choroidal vascular abnormalities in patients with neurofibromatosis type 1 evaluated by OCT-A Dear Dr. Ferro Desideri: 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. If we can help with anything else, please email us at plosone@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. Alfred S Lewin Section Editor PLOS ONE https://doi.org/10.1371/journal.pone.0251098.r004

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