Title: Detection of Airbag Impact-induced Cone Photoreceptor Damage by Adaptive Optics Scanning Laser Ophthalmoscopy: A Case Report

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1 Author s response to reviews Title: Detection of Airbag Impact-induced Cone Photoreceptor Damage by Adaptive Optics Scanning Laser Ophthalmoscopy: A Case Report Authors: shintaro nakao (snakao@med.kyushu-u.ac.jp) Yoshihiro Kaizu (scott.foil.2013@gmail.com) Muneo Yamaguchi (m.yamaguchi123@gmail.com) Yusuke Murakami (ymuraka3@pathol1.med.kyushu-u.ac.jp) Hani Salehi-Had (hanisalehi@yahoo.com) Tatsuro Ishibashi (ishi@eye.med.kyushu-u.ac.jp) Version: 1 Date: 09 Jan 2016 Author s response to reviews: Author s response to reviews Title: Adaptive Optics Scanning Laser Ophthalmoscopy Detected Cone Photoreceptor Damage in Airbag-injured Eye: A Case Report Authors: Yoshihiro Kaizu (scott.foil.2013@gmail.com) Shintaro Nakao (snakao@med.kyushu-u.ac.jp) Muneo Yamaguchi (m.yamaguchi123@gmail.com)

2 Yusuke Murakami Hani Salehi-Had Tatsuro Ishibashi Version: 2 Date: Oct Author's response to reviews: see over Reviewer's report Title: Adaptive Optics Scanning Laser Ophthalmoscopy Detected Cone Photoreceptor Damage in Airbag-injured Eye: A Case Report Editor's Additional Request: 1. Requesting for Copy-Edit - We recommend that you ask a native English speaking colleague to help you copyedit the paper. If this is not possible, you may need to use a professional language editing service. For authors who wish to have the language in their manuscript edited by a native-english speaker with scientific expertise, BioMed Central recommends Edanz ( BioMed Central has negotiated a 10% discount to the fee charged to BioMed Central authors by Edanz. Use of an editing service is neither a requirement nor a guarantee of acceptance for publication. For more information, see our FAQ on language editing services at The authors would like to thank the reviewers for the constructive critiques and suggestions for improvements. To address all the points raised, we have thoroughly revised our manuscript. In the following we address in a point-by-point fashion each comment.

3 We had language editing by a native English speaker. Furthermore, we noticed the duration of follow-up period was wrong. Therefore, we also revised this point. 12 months after airbag injury 14 months after airbag injury 20 months after airbag injury 22 months after airbag injury Reviewer's report Title: Adaptive Optics Scanning Laser Ophthalmoscopy Detected Cone Photoreceptor Damage in Airbag-injured Eye: A Case Report Version:6 Date:10 July 2015 Reviewer:Yuhua Zhang Reviewer's report: This paper reports macular cone photoreceptor damage following the airbag deployment imaged by multimodal imaging featuring high resolution Adaptive Optics Scanning Laser Ophthalmoscopy (AOSLO). The authors examined the cone density and packing regularity at 12 and 20 months after the injury, identified disordered cone mosaic and reduced cone reflectivity corresponding to the area of the scotoma, and demonstrated the usefulness of AOSLO for assessment of cone photoreceptor damage in the case of closed globe blunt ocular trauma. The topic fits the scope of the BMC Ophthalmology well and the paper is reasonably clearly written. A few minor revisions are suggested. 1. Please add the technical information about the AOSLO instrument, e.g., imaging wavelength, field of view, frame rate, etc.

4 Thank you for your constructive comment. We agree with you, so we added the technical information about the AOSLO instrument as below. the AO-SLO device has the AO system which can measure and correct aberrations of subject eyes, a high-resolution confocal SLO imaging system and a wide-field imaging subsystem. The wavelength of AO-SLO is 845 nm, and the wavelength of beacon light for the measurement of wave front aberrations is 760 nm. The imaging light and the beacon light power are set at 400 and 100 μw, respectively, in accordance with the safety limits set by the American National Standards Institute. Images were recorded for one second per scan area with a field size of and The frame rate is 32 frames per second. 2. For figure 1, I suggest drawing a box in the color fundus photo and the AF image to indicate where the AO-SLO image was taken. A line indicating where the OCT was taken is also suggested to put on the color fundus photo. We appreciate your significant suggestion. We added boxes and line to indicate where AO-SLO and OCT was imaged on figure 1, respectively. 3. Figure legend, Figure 1, (E) The merged AO-SLO images suggested to use The AO- SLO image montage Thank you for your indication. We revised this part that this reviewer kindly pointed out. 4. Figure legend, Figure 1, indicate AO-SLO-image at the 0.25 μm, should be indicate AO-SLO image Thank you for pointing out our writing error. We revised this point. 5. Figure legend, Figure 1, (H) AO-SLO-image should be AO-SLO image We also revised this point. 6. As the authors used the AO-SLO image taken from a younger subject (29

5 years old) as control, a sentence discussing the caution of the age-related cone density difference should be added in the discussion. literature PMCID: PMC should be cited for this point.af Thank you for your significant comment. The paper by Song et al. has shown that aging could affect cone density using AO-SLO. We added this point in discussion with the citation of this paper. Level of interest: An article of outstanding merit and interest in its field Quality of written English: Needs some language corrections before being published Statistical review: Yes, and I have assessed the statistics in my report. Declaration of competing interests: I declare that I have no competing interests.reviewer's report Title: Adaptive Optics Scanning Laser Ophthalmoscopy Detected Cone Photoreceptor Damage in Airbag-injured Eye: A Case Report Version: 6 Date: 16 June 2015 Reviewer: John Flatter Reviewer's report: Reviewer s Report (Also attached as word doc) Major Compulsory Revisions 1. Page 3 Lines 14-17/ Page 9 Lines 2-8/Figure 1 Legend: Data presented on

6 cone densities, Voroni domains, and NND s is different in abstract, case presentation, and figure legend. These discrepancies must be resolved prior to publication. Thank you for pointing out our error. After the improvement of our analysis soft, we reanalyzed these index. The results in abstract was latest. We revised the writing error in figure legend. 2. Page 4 Lines 3-5: Please expand and further define conclusions. These conclusions are previously stated in work by Flatter et al. The last conclusion is too vague given the evidence presented in this case presentation. The conclusions should make better effort to describe the use of AOSLO in tracking ocular trauma longitudinally. We appreciate your critical comment. We revised our conclusion based on your comment as below. Conclusion. AO-SLO is a useful tool not only for the diagnosis but also long-term tracking of airbag-injured eyes. Using AO-SLO longitudinal tracking, we can document partial recovery of damaged cone photoreceptors following closed globe blunt ocular trauma. 3. This case report is strikingly similar to a 2014 ARVO meeting abstract published in IOVS Changes in Outer Retinal Structure Following Closed Globe Blunt Ocular Trauma. This abstract should be mentioned in the background for completeness. We appreciate your important information and fairness. We added this information in the background. 4. Page 6 Line 7: Please ensure the use of 0.5% tropicamide and phenylephrine. This is not standard dosing in the U.S. In Japan, we use 0.5% tropicamide and 0.5% phenylephrine hydrochloride for mydriasis. We also changed phenylephrine to phenylephrine hydrochloride.

7 5. Page 6 Lines 10-12: Change We also used an AO-SLO to We also used a confocal AO- SLO. Please cite the paper that describes the specifics of this prototype AO-SLO. The details such as light wave-length used, area of each acquired frame or video, post-acquisition image processing are critical to the publication of AOSLO data. Please also state how AOSLO montages were generated (using automatic methods or manually using blood vessel registration). Thank you for your suggestion. We changed an AO-SLO to a conical AO-SLO. Furthermore, we added the technical information about our AOSLO instrument with a citation of a ARVO presentation concerning our prototype AO-SLO. We also added an information that we generated AOSLO montages manually using blood vessel registration. 6. Methods: Choosing to compare Nasal and Superior data carries inherent differences in cone density (see histological data by Curcio et al and Carroll J et al Proc Natl Acad Sci U S A Also, your decision to internally control versus a normal area of photoreceptor mosaic and control versus one normal subject carry significant error. Please define this limitation in the discussion. Also consider comparing to a more extensive normative database; such as one described using the prototype AOSLO in your experiment or one previously published, such as Carroll et al (as above). Thank you for providing important information. We defined this limitation concerning control in the discussion. We also compared with a an extensive normative database (Chui et al. Invest Ophthalmic Vis Sci, 2012). 7. Methods: In Figure 1 legend you mention a 29 year old control, however this is not mentioned in the methods. Please further define this control in the methods. Thank you. We added description about a 29 year old control in the methods. 8. Page 10 Lines 13-17: Can you make claims of photoreceptor shortening and retinal thinning without properly manually segmenting the OCT s and measuring band thicknesses? Here you

8 fail to mention the role of the interdigitation zone, of which your subject s was discontinuous. Please reconsider wording here and limit discussion unfounded in data. Thank you for providing good point. We agree with you that we cannot conclude photoreceptor shortening and retinal thinning without any measurement. Therefore we deleted this point. We also added discussion about the interdigitation zone. 9. Figure 2 Legend: Each figure should be stand alone and include all relevant data, such as cone densities included in the text. Please make these changes. Thank you for your comment. As you suggested, we changed figure 2 legend and added all relevant data in the text. Minor Essential Revisions 1. Page 3 Line 10: Please define recorded in area. Does this mean the images are en-face or does it mean in the area of the scotoma. Thank you for your comment. I agree with this reviewer s comment that our description is not clear to indicate our imaged area. Because we imaged AO-SLO in the foveal area, we rewrote this part. 2. Page 3 Line 11: Please define the scotoma- Is it relative or fixed? When was the scotoma noticed? This patient noticed fixed scotoma at the first examination. 3. Page 3-4 Lines 19 and 1-2: The description of photoreceptor mosaic changes between 12 and 20 months post-trauma require expansion. The longitudinal tracking of your case is what

9 distinguishes this case report from those in Flatter et al. The data on this is what makes this case report novel and contributory. Thank you for your important comment. We added this point in the discussion as below. Flatter et al. also presented two subjects with closed globe blunt ocular trauma that were followed up by AO-SLO in a conference[11]. In the present study, we followed the course of the traumatic maculopathy with our prototype AO-SLO at two time points after the initial injury. Interestingly, AO-SLO detected partial improvement of cone mosaic although the scotoma still persisted. Several previous studies have shown temporal fluctuation in the reflectivity of individual cone photoreceptors[12]. In our case however, the change of reflectivity of cone mosaic was island shaped, suggesting that the alteration is due to improved cone structure or function in spite of the persistent scotoma. 4. Page 5 Lines 3-4: The citations for the various ocular injuries associated with ocular trauma are not nearly exhaustive and should be expanded. There is far more data on SD-OCT and commotion retinae following trauma, traumatic maculopathy, and retinal detachment following trauma. Also Stepien et al details a case of photoreceptor damage following a motor vehicle collision. We appreciate your insightful review. We agree with your comments. This sentence about airbag injury-related ocular complications described only retinal detachment and maculophaty. However, various papers have reported airbag injury could cause various ocular complications including commotio retinae. A review by Dr. Pearlman showed these ocular injuries as Table 1 (Pearlman JA et al. Surv Ophthalmol, 2001).We also added a citation about airbag injury-related commotio retinae (Vichnin MC et al. Ophthalmic Surg Lasers 26: 542, 1995). Stepien s case was photoreceptor damage following industrial accident but not airbag injury as shown below. Therefore we also cited a paper by Vichnin. 5. Page 5 Lines 8-9: Please consider re-wording to better describe longitudinally tracking subject at 12 and 20 months. Thank you for your suggestion. We revised this point.

10 6. Page 6 Line 6-10: Please consider re-wording this sentence, as it is initially confusing as to how each imaging modality was acquired. Please further define morphology. Does this mean topography? Please change were examined to were acquired with. Overall, the exact protocol of the SD-OCT data acquisition needs further explanation. For instance, how many scans were averaged per line scan? Or what is the size of OCT volumes? Thank you for indicating our mistake. We regret the mistake. After pupil dilation, FAF and SD- OCT were acquired with HRA. Therefore, we deleted a word morphology. We changed from were examined to were acquired with as you suggested. We also added the exact protocol of the SD-OCT acquisition as below. High-density five line raster scans were obtained with an SD-OCT (Cirrus HD; Carl Zeiss Meditec, Dublin, CA, USA). 7. Page 6 Line 13: Further define the area of AOSLO. Does this mean near the area of the scotoma, near the fovea, within the macula, or in the periphery? We imaged the area of the scotoma and the surrounding area within the macula using AO-SLO. We added the detailed description. 8. Methods: Please further detail your decision on which locations to sample photoreceptor metrics. Did you choose an area of disruption and find an equidistant region to sample. Thank you for your comment. We chose an area of photoreceptor disruption to examine photoreceptor metrics. We also chose an undisrupted region for internal control in the created montage of AO-SLO images. However, because the retinal eccentricity affects cone photoreceptor density, we added this point in the discussion.

11 9. Methods: There is no mention of how you define foveal center. Is it from maximum cone density or from foveal pit on OCT? Please expand. Thank you for your comment. We defined foveal center in the AO-SLO image with the fixation point and OCT. So we added the below description. The central fovea was defined as the location of the fixation point in the macula region. We also confirmed the central fovea from foveal pit on OCT. 10. Methods: Please define how data was gathered at 12 and 20 months. Were the same areas of retina sampled. Thank you for your comment. We recognized the same area from two different images with the fixation point and blood vessel registration. The description have been added in the methods. 11. Method: Include any clinical imaging acquired immediately post-trauma. If none is available, please state so. There is no available clinical imaging acquired immediately post trauma. We added this sentence in methods. 12. Methods: How did you ensure the same AOSLO sampling at 12 and 20only after extremely close inspection of individual cone patterns. Please make this more evident to the reader, either by marking the same cones at 12 and 20 months or describing how you ensured each area is the same. We have tried to detect the same individual cone, however, we could not detect it perfectly because of the altered reflectance of single cones as previously reported (Pallikaris et al. IOVS 2003; 44: 4580, Cooper et al. Biomed. Opt. Express 2011; 2: 2577). Therefore, we ensured each area is the same from the blood vessel registration. We described this point in the method.

12 We used blood vessel registration to confirm that the two images from the different time points were from the same area. 13. Page 8 Lines 10 and 11: Figure 1A and B are not slit-lamp and fundus examination photos. Please make this clear that those figures are fundus photography and auto fluorescence and that fundus and slit-lamp exams were normal. Thank you for pointing out our error. Figure 1A and B are fundus photography and auto fluorescence. We revised this part. 14. Page 8 Line 13: Please define disruption of the interdigitation zone. Is it mottled, discontinuous, thinned? Thank you for your comment. As we added magnified OCT image in Figure 1D, the interdigitation zone was discontinuous. We added this phrase in case presentation. 15. Page 8 Lines 14 to 16: Please include repeat fundus photo and SD-OCT in Figures as in Fig. 1 A-D. Thank you for your comment. We have only Cirrus OCT images both at 14 months and 22 months after the injury. We added the fundus photos and the SD-OCT images in Figure Page 9 Line 2 to 8: Consider rewording and defining figures within the text. revealed the con mosaic near within the disruption was discorded (Figure 1F and I) as compared with the normal area (Figure 1G and J) as well as in a healthy male (Figure 1H and F). Again, ensure that these data match those in abstract and figure 1 legend. Thank you for your suggestion. As this reviewer suggested, we revised this description. We also confirmed these data match those in abstract and figure 1 legend.

13 17. Page 9 Lines 12-16: analysis showed cone number consider further defining cone number. Is it cone density or total number within the exact same area (essentially density). In your description of the cone densities you state yellow A1, 12M; 6647/mm2 please better define the 12M and 20 M to be months. Consider rewording. Thank you. The cone number indicated cone density. We revised this point. We also changed from 12M and 20M to 12 months and 20 months. 18. Figure 2: Please change areas A1-A3 to have just dotted lines without inner shading as that does not allow closer inspection of the cone structure within each border. Thank you for your suggestion. We deleted the inner shading in Figure Page 11 Line 12: A longitudinal study was presented at ARVO 2014 by Flatter et al and is published in abstract form in IOVS. Please consider citing. Thank you again for your information. We added this indicated citation. 20. Page 11 Line 12 and 13: Please mention that although the photoreceptor mosaic partially improved the scotoma still persisted. We revised this point as below. AO-SLO detected partial improvement of cone mosaic although the scotoma still persisted. 21. Figure 1: Image D-Please indicate the location of disrupted interdigitation zone you describe in the text. You mention respectively after the first visit, is this after first clinical visit or trauma?

14 We agree with your point. It was difficult to find the location of disrupted interdigitation zone with the shown OCT image. Therefore, we added a magnified image and put arrows to indicate the the location of disrupted interdigitation zone. Furthermore, we changed from after the first visit to after the first clinical visit. Discretionary Revisions We appreciate your detailed review. 1. Page 2 Line 2 and Page 3 Line 2: consider changing maculopathy to traumatic maculopathy in the keywords and throughout the paper. We changed maculopathy to traumatic maculopathy throughout the paper including in the keyword. 2. Page 3 Line 12: observed on consider changing to observed in. We changed from observed on to observed in as you indicated. 3. Page 5 Line 2: Change death for to death from We changed from death for to death from as you suggested. 4. Page 5 Line 3: Change However, it has to However, airbags have We changed from However, it has to However, airbags have as you suggested.

15 5. Page 5 Line 6: Change trauma with to trauma using We changed from trauma with to trauma using as you suggested. 6. Page 6 Line 7: an eye drop of change to one drop each of We changed from an eye drop of to one drop each of as you suggested. 7. Page 8 Line 3: Was the subject wearing a restraint belt. Yes, the subject was wearing the seat belt. We added the information on this part. 8. Page 8 Line 3: Was the scotoma relative or fixed. What was the location of the scotoma (central or para-central)? We added the information about the scotoma as below. He immediately noticed a para-central fixed scotoma in his left eye. 9. Page 8 Line 6: Please define Normal. Consider Unremarkable. We changed from normal to unremarkable as you suggested. 10. Page 8 Lines 6 and 7: Define location of commotio retinae and retinal hemorrhages (within the macula or peripheral).

16 Commotio retinae and retinal hemorrhage could be observed around the optic nerve at the first visit to community ophthalmologist. I added this point. 11. Page 8 Lines 10 and 11: State if commotio retinae and retinal hemorrhages were resolved. We added statement commotio retinae and retinal hemorrhages were resolved. 12. Page 8 Line 18: in the foveal area change to within the macula We changed from in the foveal area to within the macula. 13. Page 8 Line 19: observed on consider changing to observed in. We changed from observed on to observed in as you indicated. 14. Page 9 Lines 8 to 12: Consider rewording two sentences to Furthermore, AOSLO imaging at 20 months (Figure 2B) as compared the same area at 12 months (Figure 2A) showed there were still certain areas with reduced cone reflectivity. Thank you for your advise. We revised this point as you suggested. 15. Page 10 Line 3-4: Mention of retinal detachment is not needed here as the paper is concerning photoreceptor damage and the patient never had a retinal detachment. We agree with this comment. We deleted description of retinal detachment.

17 16. Page 10 Line 4-5: Does the percentage of vitreoretinal injury include only cases where the airbag was deployed or all ocular trauma? The percentage of vitreoretinal injury is 20% in airbag-related ocular injury. We added description to make it clear. 17. Page 10 Line 6: Again, no an exhaustive list of publications. Flatter et al also lists patients with persistent scotomas following trauma. Thank you for your suggestion. We cited Flatter s report as a new reference. Level of interest: An article whose findings are important to those with closely related research interests Quality of written English: Needs some language corrections before being published Statistical review: No, the manuscript does not need to be seen by a statistician. Declaration of competing interests: In the past five years I have received funding to conduct research on outer retinal structure after ocular trauma using adaptive optics scanning laser ophthalmoscopy. The research was published in Retina and presented at ARVO 2013 and I have no other financial obligations, patents, or pending patents that would otherwise interfere in preclude a review of this publication.

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