Correlation of optic nerve and optic nerve sheath diameter with intracranial pressure in pigs

R. Mija; I. Zubak; A. Schuetz; M. Glas; C. Fung; S. M. Jakob; J. Beck; W. J. Z’Graggen; Andreas Bloch

doi:10.1371/journal.pone.0228242

Peer Review History

Original SubmissionJuly 31, 2019
6 Sep 2019 Decision Letter - Nimesh Patel, Editor PONE-D-19-21626 Correlation of optic nerve and optic nerve sheath diameter with intracranial pressure in pigs PLOS ONE Dear Dr. Bloch, 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. We would appreciate receiving your revised manuscript by Oct 21 2019 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, Nimesh Patel Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 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.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 1. To comply with PLOS ONE submissions requirements, please provide methods of sacrifice in the Methods section of your manuscript. Additional Editor Comments (if provided): The work presented is important for understanding intracranial pressure. However, as pointed out by both expert reviewers, there is need to accurately describe the methodology used. Please address this major concern, along with other comments the reviewers have made. [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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ****** 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: No 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: Dear Authors, I enjoyed reviewing your interesting and novel work. The finding that the optic nerve diameter changes with changes in ICP is intriguing. I would like the following issues addressed that will help make this manuscript more compelling. 1. Given the known technical challenges with visualizing optic nerve anatomy in humans, it is necessary for including a figure showing the actual ultrasound images of the relevant anatomy, not just a diagram. This will give the reader the important information regarding the technical aspects of the ultrasonic technique. 2. Throughout the manuscript, please include 95% CIs whenever the p-values are reported, this will give one a better idea of the precision of the results. 3. In the introduction, pg 3, line 65. "capillaries may become congested" I am not sure I understand why the capillaries would be selectively congested, and not the venules, please clarify, and correct if indicated 4. Page 5, line 102, "left decubitus position" Do you mean, "left lateral decubitus position"? 5. Please include a picture of the experimental setup if possible for illustration 6. What methods were employed to ensure the ICP readings were accurate? Was there any calibration performed. Were the ICP waveforms evaluated for responsiveness to physiological changes in pulse and respiration to determine the accuracy and patency of the transduction system? 7. Page 10 , line 1, "perineural space" I believe this is an error and should be "optic nerve sheath" please check. 8. The discussion is inadequate with regards to the measurement of optic nerve diameter. Please elaborate on why this structure has not been measured before, or whether it has in humans and or animals in relationship to the ICP, or even as an anatomical measurement with ultrasound. Consider incorporating the article, "Chen, Q et al High-resolution transbulbar ultrasonography helping differentiate intracranial hypertension in bilateral optic disc oedema patients. Acta Ophthalmologica. 2017 9. page 9, "Further, elevated ICP levels cause additional vasogenic edema..." I do not understand the physiological mechanism referred to here. Vasogenic edema does not accompany all ICP elevation, especially if the ICP elevation does not disrupt the blood brain barrier, consider omitted this statement or clarifying it. 10. Please correct multiple typographical errors for example... pg 4, line 83, "intracompartimental" Pg 9, line 8, "extend" should be "extent" pg 9, "liquor" is usually referred to cerebrospinal fluid, please correct Reviewer #2: Thanks for the opportunity to review this article. Since the entire work is relying on ultrasound image-based measurement values, it is imperative that representative images are shown, along with the measurement points. This is even more important since 40 kg porcine optic nerve at baseline should be smaller (human ON rarely exceeds 3 mm). The diagram (Figure 1) is clearly insufficient. Porcine optic nerve imaging is very difficult due to a number of impediments, including positional instability of the eyes, near-impossibility to bypass the large lens, limited probe positioning options, and others. These difficulties, combined with unexpected results, make it even more important for the reader to see the actual images of the measured structures with the measuring technique. ****** 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: Yes: Eric Bershad 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 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. https://doi.org/10.1371/journal.pone.0228242.r001
Revision 1
23 Oct 2019 Author Response Editor comments To comply with PLOS ONE submissions requirements, please provide methods of sac-rifice in the Methods section of your manuscript. Response In order to comply with PLOS ONE submissions requirements we have added details concerning sacrifice of the pigs in the methods section. The following sentence was added. “… At the end of the experiment a bolus of 40 mmol potassium chloride was given to sacrifice the animal.” Reviewer #1: Dear Authors, I enjoyed reviewing your interesting and novel work. The finding that the optic nerve diameter changes with changes in ICP is intriguing. I would like the following issues addressed that will help make this manuscript more compelling. Reviewer comment 1. Given the known technical challenges with visualizing optic nerve anatomy in hu-mans, it is necessary for including a figure showing the actual ultrasound images of the relevant anatomy, not just a diagram. This will give the reader the important infor-mation regarding the technical aspects of the ultrasonic technique. Response We have included the following figure showing two actual ultrasound images with the relevant anatomy marked with arrows and stars. One image was recorded at baseline ICP (9 mmHg) and the second one at an ICP of 40mmHg. We have therefore excluded the previous schematic figure 1. This will hopefully improve the illustration of the tech-nical aspects. Fig 1: The upper transbulbar ultrasound image was recorded at baseline ICP – the lower image was recorded at ICP of 40mmHg. All measurements were obtained 3 mm behind the papilla as indicated by the two stars connected with the dotted line. Optic nerve diameter increased from 0.36 cm to 0.48 cm as illustrated by the black arrow. Op-tic nerve sheath diameter increased from 0.79 cm to 0.86 cm as illustrated by the white arrow. Reviewer comment 2. Throughout the manuscript, please include 95% CIs whenever the p-values are re-ported, this will give one a better idea of the precision of the results. Response We have followed your valid input and we have added the respective 95% confidence intervals when p- values were reported. Reviewer comment 3. In the introduction, pg 3, line 65. "capillaries may become congested" I am not sure I understand why the capillaries would be selectively congested, and not the venules, please clarify, and correct if indicated Response Thanks to your input we have corrected the obviously physiological inprecise state-ment “capillaries may become congested” to “capillaries and venules within ON may become congested…” Reviewer comment 4. Page 5, line 102, "left decubitus position" Do you mean, "left lateral decubitus posi-tion"? Reponse We have revised the term “left decubitus position” to “left lateral decubitus position”. Reviewer comment 5. Please include a picture of the experimental setup if possible for illustration Response We did not take any picture during the trial so we cannot accommodate this demand. Reviewer comment 6. What methods were employed to ensure the ICP readings were accurate? Was there any calibration performed. Were the ICP waveforms evaluated for responsiveness to physiological changes in pulse and respiration to determine the accuracy and patency of the transduction system? Response For ICP-monitoring a bolt-kit silver-bearing EVD catheter system (Silverline-Bolt-Kit-catheter; Spiegelberg GmbH & Co. KG; Hamburg, Germany) was implanted. This cathe-ter type is equipped with an intraparenchymal/intraventricular ICP measurement sys-tem via an air-pouch mounted close to the tip of the drainage catheter. The air-pouch is connected via a separate lumen to a standalone ICP monitor. This monitor itself is connected to the multi-modular monitor (S/5 Critical Care Monitor®; Datex-Ohmeda, GE Healthcare, Helsinki, Finland) where the ICP waveform is displayed. The Spiegel-berg ICP measurement system has an automatic calibration algorhythm and a ne-glectable drift over time. In addition, conventional ICP measurement is also possible via the drainage catheter. After implantation of the EVD catheter, the ICP measured with the Spiegelberg monitor was compared with the conventional ICP measurement via the CSF coupled pressure transducer to check for accuracy. Furthermore, the ICP waveform was evaluated for responsiveness to manoevers reducing the venous back flow. For the further experimental procedures, the Spiegelberg ICP monitoring system was used. Reviewer comment 7. Page 10 , line 1, "perineural space" I believe this is an error and should be "optic nerve sheath" please check. Response Given that the effective area (see calculations below) of the perineural space increas-es, the statement is correct. However in order to clarify and specify this we have changed the sentence from “Despite stable perineural space diameter the area of the perineural space still increases due to the overall increase of the combined diameters of the ON and perineural space” to “Despite stable perineural space diameter the area of the perineural space still increases due to the increase of inner and outer circumfer-ence of the perineural space” . Calculations: Calculating the areas of the components ON and ONS from baseline to values at 60 mmHg using the formula area = π / diameter 2 results in the following values: Area ON (optic nerve) at baseline = 10.2 mm2 Area ON (optic nerve) at ICP 60 mmHg = 36.3 mm2 Area ONS (optic nerve sheath) at baseline = 60.8 mm2 Area ONS (optic nerve sheath) at 60 mmHg = 120.8 mm2 The area of the perineural space can be calculated by subtracting the optic nerve area from the optic nerve sheath area. This results in the following values: Area PNS (perineural space) at baseline = 50.6 mm2 Area PNS (perineural space) at 60 mmHg = 84.5 mm2 We have further tried to emphasize this finding by integrating the calculation and the results of the respective changes of the different areas into the manuscript. Reviewer comment 8. The discussion is inadequate with regards to the measurement of optic nerve diame-ter. Please elaborate on why this structure has not been measured before, or whether it has in humans and or animals in relationship to the ICP, or even as an anatomical measurement with ultrasound. Consider incorporating the article, "Chen, Q et al High-resolution transbulbar ultrasonography helping differentiate intracranial hypertension in bilateral optic disc oedema patients. Acta Ophthalmologica. 2017 Response Thank you for providing this interesting reference article. It is in fact difficult to find op-tic nerve diameter measurements in articles concerning transbulbar sonography. It is somewhat hard to elaborate the reasons for that. The most obvious explanation might be that no difference in optic nerve diameter was found which was also the case in the paper from “Chen et al”. Most studies on transbulbar sonography were conducted in patients with mild to maximally moderately increased ICP levels. Given the much smaller diameter of the optic nerve compared with the optic nerve sheath differences might be missed in these ICP ranges. In the present study, the increase in ON was significant only with ICP levels ≥40 mmHg Further, most authors only considered the cerebrospinal fluid shifts as a change detectable by ultrasound and they therefore fo-cused on optic nerve sheath diameter changes only. The article from “Topcuoglo M et al, Transorbital Ultrasonographic Measurements of Optic Nerve Sheath Diameter in Brain Death. Journal Neuroimaging. 20151” measured optic nerve diameter and optic nerve sheath diameter in brain-death and non brain-death patients. Optic nerve diameter was significantly larger (p < 0.001) in brain-death patients compared to non brain-death patients. This finding might support our finding that also non cerebrospinal fluid changes attributed to elevated intracranial pressure can be detected by transbulbar ultrasound by measuring optic nerve diameter. We have adjusted the discussion part of the manuscript. The abstract related to your comment reads as follows: So far most published literature consider CSF shifts as a change detectable by ultra-sound and therefore the focus is on optic nerve sheath diameter without measuring optic nerve diameter2,3. However optic nerve diameter measurements have been assessed and validated. A high intra- and interobserver reliability was documented for OND measurements in healthy subjects4. In patients with multiple sclerosis OND can depict optic nerve atro-phy5. Two studies conducted in patients with idiopathic intracranial hypertension found no significant difference in optic nerve diameter between control groups and patients with elevated intracranial pressure6,7. However intracranial pressure levels in these studies were mildly to maximum moderately increased (ICP levels between 18 and 25 mmHg). Given the much smaller diameter of optic nerve compared with optic nerve sheath, differences might have been too small to be detected. We acknowledge, that in our study the increases in ON diameter became statistically significant only at ICP values of ≥40 mmHg. The study from Topcuoglo M et al measured different diame-ters within the orbit in brain death and non brain death patients1. Optic nerve diameter was significantly larger (p < 0.001) in brain death patients compared to non brain death patients. This finding might support our finding that also non cerebrospinal fluid changes attributed to elevated intracranial pressure can be detected by measuring op-tic nerve diameter using transbulbar ultrasound. Reviewer comment 9. page 9, "Further, elevated ICP levels cause additional vasogenic edema..." I do not understand the physiological mechanism referred to here. Vasogenic edema does not accompany all ICP elevation, especially if the ICP elevation does not disrupt the blood brain barrier, consider omitted this statement or clarifying it. Response We have omitted this statement due to your valid comment. Thank you. Reviewer comment 10. Please correct multiple typographical errors for example... pg 4, line 83, "intracompartimental" Pg 9, line 8, "extend" should be "extent" pg 9, "liquor" is usually referred to cerebrospinal fluid, please correct Response We have thoroughly reviewed the manuscript with regards to typographical errors. We thankfully integrated your corrections. Reviewer #2: Reviewer comment Reviewer #2: Thanks for the opportunity to review this article. Since the entire work is relying on ultrasound image-based measurement values, it is imperative that repre-sentative images are shown, along with the measurement points. This is even more important since 40 kg porcine optic nerve at baseline should be smaller (human ON rarely exceeds 3 mm). The diagram (Figure 1) is clearly insufficient. Porcine optic nerve imaging is very difficult due to a number of impediments, including positional instability of the eyes, near-impossibility to bypass the large lens, limited probe positioning options, and others. These difficulties, combined with unexpected results, make it even more important for the reader to see the actual images of the measured structures with the measuring technique. Response Thank you for your valid comment. We have included the following figure showing two actual ultrasound images with the relevant anatomy marked with arrows and stars. One image was recorded at baseline ICP (9 mmHg) and the second one at an ICP of 40mmHg. We have therefore excluded the previous schematic figure 1. As pointed out in the discussion our findings and our setup have clear limitations in-cluding inherent problems in transmissibility to humans. The differences in optic nerve vascularization might have significantly influenced our findings. However our setup with stable left lateral decubitus position and deep sedation of the animals might have facilitated the difficulties that you had pointed out. Hopefully the current figure will help the reader to better understand and to be able to relate to the described method. Fig 1: The upper transbulbar ultrasound image was recorded at baseline ICP – the lower image was recorded at ICP of 40mmHg. All measurements were obtained 3 mm behind the papilla as indicated by the two stars connected with the dotted line. Optic nerve diameter increased from 0.36 cm to 0.48 cm as illustrated by the black arrow. Op-tic nerve sheath diameter increased from 0.79 cm to 0.86 cm as illustrated by the white arrow. References 1. Topcuoglu MA, Arsava EM, Bas DF, Kozak HH. Transorbital Ultrasonographic Measurement of Optic Nerve Sheath Diameter in Brain Death. Journal of neuroimaging : official journal of the American Society of Neuroimaging. 2015;25(6):906-909. 2. Dubourg J, Javouhey E, Geeraerts T, Messerer M, Kassai B. Ultrasonography of optic nerve sheath diameter for detection of raised intracranial pressure: a systematic review and meta-analysis. Intensive care medicine. 2011;37(7):1059-1068. 3. Fernando SM, Tran A, Cheng W, et al. Diagnosis of elevated intracranial pressure in critically ill adults: systematic review and meta-analysis. Bmj. 2019;366:l4225. 4. Lochner P, Coppo L, Cantello R, et al. Intra- and interobserver reliability of transorbital sonographic assessment of the optic nerve sheath diameter and optic nerve diameter in healthy adults. Journal of ultrasound. 2016;19(1):41-45. 5. Candeliere Merlicco A, Gabaldon Torres L, Villaverde Gonzalez R, Fernandez Romero I, Aparicio Castro E, Lastres Arias MC. Transorbital ultrasonography for measuring optic nerve atrophy in multiple sclerosis. Acta neurologica Scandinavica. 2018;138(5):388-393. 6. Chen Q, Chen W, Wang M, et al. High-resolution transbulbar ultrasonography helping differentiate intracranial hypertension in bilateral optic disc oedema patients. Acta ophthalmologica. 2017;95(6):e481-e485. 7. Jeub M, Schlapakow E, Ratz M, et al. Sonographic assessment of the optic nerve and the central retinal artery in idiopathic intracranial hypertension. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2019. https://doi.org/10.1371/journal.pone.0228242.r002
11 Nov 2019 Decision Letter - Nimesh Patel, Editor PONE-D-19-21626R1 Correlation of optic nerve and optic nerve sheath diameter with intracranial pressure in pigs PLOS ONE Dear Dr. Bloch, 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. We would appreciate receiving your revised manuscript by Dec 26 2019 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, Nimesh Patel Academic Editor PLOS ONE Additional Editor Comments (if provided): Thank you for your revisions. Please address carefully the requested change by the second reviewer. [Note: HTML markup is below. Please do not edit.] 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: (No Response) ******** 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: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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 #1: Yes Reviewer #2: No ****** 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: (No Response) Reviewer #2: Thanks for replacing a diagram with actual ultrasound images. However, these provided images are not much superior compared to the diagram. While a slight variation of the imaging plane is acceptable, I find it disappointing that only fragments of the images are shown. The probe that you are using is excellent for this purpose, and could probably allow bypassing the lens; Judging by the similarity and quality of the patterns in the two images, it seems like the lens was indeed bypassed (or at least, transected with a similar aberration). But the reader should not have to guess (or remain oblivious to the fact that the lens may introduce major distortions and affect the measurements of the posterior structures). The reader does not learn from these images, nor do these images serve to assure the reader of proper technique hence accurate results. I would strongly recommend providing full images with a depth scale, otherwise my concerns are not alleviated. ****** 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: Eric Bershad 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 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. https://doi.org/10.1371/journal.pone.0228242.r003
Revision 2
25 Dec 2019 Author Response Editor comments Thank you for your revisions. Please address carefully the requested change by the second reviewer. Response Thank you for the possibility to address this important issue recognised by the second reviewer. The figure 1 has been replaced by a new figure 1. Reviewer #2: Thanks for replacing a diagram with actual ultrasound images. However, these provid-ed images are not much superior compared to the diagram. While a slight variation of the imaging plane is acceptable, I find it disappointing that only fragments of the imag-es are shown. The probe that you are using is excellent for this purpose, and could probably allow bypassing the lens; Judging by the similarity and quality of the patterns in the two images, it seems like the lens was indeed bypassed (or at least, transected with a similar aberration). But the reader should not have to guess (or remain oblivious to the fact that the lens may introduce major distortions and affect the measurements of the posterior structures). The reader does not learn from these images, nor do these images serve to assure the reader of proper technique hence accurate results. I would strongly recommend providing full images with a depth scale, otherwise my concerns are not alleviated. Response Thank you for this very valid comment. We have followed your recommendation and we have provided the full images with a depth scale. As you can see both images rep-resent images made from high definition zooms with a zoom box size of 2 cm – there-fore the depth scale does not start at 0. In both ultrasound images the lenses were indeed bypassed and therefore no major distorsions were caused by the lens nor were the measurements affected. We have further supplemented the legend of the figure as follows: The upper transbulbar ultrasound image was recorded at baseline ICP – the lower im-age was recorded at ICP of 40mmHg. All measurements were obtained 3 mm behind the papilla as indicated by the two stars connected with the dotted line. Optic nerve di-ameter increased from 0.36 cm to 0.48 cm as illustrated by the black arrow. Optic nerve sheath diameter increased from 0.79 cm to 0.86 cm as illustrated by the white arrow. In both ultrasound images the lens was bypassed in order to obtain the most accurate display of the posterior structures of the eye. Further both images were made by using a high definition zoom box of 2 cm size. https://doi.org/10.1371/journal.pone.0228242.r004
13 Jan 2020 Decision Letter - Nimesh Patel, Editor Correlation of optic nerve and optic nerve sheath diameter with intracranial pressure in pigs PONE-D-19-21626R2 Dear Dr. Bloch, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. 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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 #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: 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 #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: (No Response) Reviewer #2: Thanks for clarifications and a detailed response to reviewer concerns. Congratulations with successful completion of a technically challenging experiment. Best wishes to the team. ****** 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: Eric Bershad Reviewer #2: No https://doi.org/10.1371/journal.pone.0228242.r005
Formally Accepted
21 Jan 2020 Acceptance Letter - Nimesh Patel, Editor PONE-D-19-21626R2 Correlation of optic nerve and optic nerve sheath diameter with intracranial pressure in pigs Dear Dr. Bloch: I am 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 notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Nimesh Patel Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0228242.r006

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