On the Quest for Ophthalmological Biomarkers for Long COVID: A Scoping Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript "On the quest for ophthalmological biomarkers for long COVID: a scoping review" presents an innovative review of studies registering ophthalmological and neurological problems after prolonged COVID. The authors emphasize the fact that additional diagnostics and monitoring are needed to track eye damage and the use of an objective biomarker for this. In general, data from 15 relevant studies from the last 5 years were used for the proposed innovative study. The authors highlight the established ophthalmological signals - such as saccadic movements and pupillary reflexes - and their significantly altered levels in patients with long COVID. To propose the study, the correlated signals were measured using various methods, including infrared cameras and eye tracking systems. The study is entirely medically oriented and emphasizes the need to develop standardized biomarkers for the long-term diagnosis and monitoring of COVID-infected patients.
The submitted manuscript is written in standard English, in accordance with the journal's requirements, and completely provides a new approach in clinical practice for preliminary determination of risk categories.
Minor remarks:
1. The proposed abstract is satisfactory. The use of a graphic version would increase the understanding of the problem.
2. The proposed introduction is accessible and sufficient. In order to increase the readability of the proposed work, the introduction of a graphic scheme for stating the problem would be appropriate.
.....lines 101-106 to observe the necessary spacing and font; to be unified.
3. Materials and methods are well systematized and described.
2.2. Search strategy - to be revised; to be unified with the text as a whole;
4. Results
Figure 1 and Figure 2 - to supplement the descriptive part in detail
Table 1 to correct the caption. All additional subtitles and additions should be inserted below the table.
Is it possible to submit Figure 3 in different colors for better readability of SPSS or Statistics?
Is Table 1 repeated twice? Correct the caption. All additional subtitles and additions should be inserted below the table - the probable technical error should be avoided.
...line 281...... rewrite the paragraph;
5. Discussion
Is it possible to present a summarized scheme for patients - analyses - biomarkers - results in order to increase readability and interest of the reader?
5. The conclusion is good.
All texts abstracted in yellow should be corrected.
6. The proposed literature presents new research on the proposed issue; the requirements of the journal are met and 56% of the research is from the last 5 years.

Author Response

Comments 1: The proposed abstract is satisfactory. The use of a graphic version would increase the understanding of the problem.
Response 1: Thank you for pointing this out. While we agree with this comment, we decided to provide a graphic figure to increase the understanding and readability on page 3 line 93 as part of our reply to comment 2. We hope this will improve the presentation of our work.

Comments 2: The proposed introduction is accessible and sufficient. In order to increase the readability of the proposed work, the introduction of a graphic scheme for stating the problem would be appropriate......lines 101-106 to observe the necessary spacing and font; to be unified.
Response 2: Agree. We have added a figure to emphasize this point (page 3 line 92). Lines 101-106 have been reformatted to be consistent. They are now on page 2 line 87-92.

Comments 3: Search strategy - to be revised; to be unified with the text as a whole.
Response 3: Agree. We have put the search terms and the text in the same paragraph on page 3 line 108-117. 
 
Comments 4: Figure 1 and Figure 2 - to supplement the descriptive part in detail. 
Response 4: Thank you for this suggestion. We agree that figure 1 and figure 2 need more descriptive details. We have illustrated the screening process step by step and provided the inclusion and exclusion criteria. The modified part for figure 1 is on page 5 line 154-160. Figure 2 has been removed according to other comments but the updated explanation is on page 6 line 165-170.
 
Comments 5: Table 1 to correct the caption. All additional subtitles and additions should be inserted below the table.
Is it possible to submit Figure 3 in different colors for better readability of SPSS or Statistics?
Is Table 1 repeated twice? Correct the caption. All additional subtitles and additions should be inserted below the table - the probable technical error should be avoided.
...line 281...... rewrite the paragraph;
Response 5: Agree. We have, accordingly, corrected the captions for all tables on page 6 line 182-184 and page 9 line 216. Figure 3 is presented in different colors for better readability on page 7 line 192.

Comments 6: Discussion
Is it possible to present a summarized scheme for patients - analyses - biomarkers - results in order to increase readability and interest of the reader?
Response 6: The summary information like patients and biomarkers can be found in Table 1 and Table 2. If the reader needs more information, the full extraction table is in Supplementary Material 1, which offers more details including patients - analyses - biomarkers – results. Therefore, we believe that it is not necessary to summarize it again at the beginning of Discussion.

Comments 7: All texts abstracted in yellow should be corrected.
Response 7: Agree. This article is not yet published and we do not know the URL link for supplementary materials. This will be sorted out at proofreading stage. We have cancelled the yellow highlight of the text on page 13 line 389-391. 

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

It is not quite clear what you want to tell the reader of this manuscript - too many different topics, not connected and very unspecific - the symptoms you described can be found in different neurological diseases and are not specific for Long Covid.

Please structure the manuscript and have an ophthalmologist looking at it: VEP has nothing to do with visual field and there are other issues concerning the scientific content. 

Comments on the Quality of English Language

Needs intensive English editing

Author Response

Comments 1: It is not quite clear what you want to tell the reader of this manuscript - too many different topics, not connected and very unspecific - the symptoms you described can be found in different neurological diseases and are not specific for Long Covid.
Response 1: Thank you for this comment, we have expanded the introduction to add clarity on page 2 line 56-70. This makes the point that Long Covid symptoms are many and variable, overlap with predisposing conditions, and there are no defining disease-specific symptoms. To manage the inherent complexity, we have structured the manuscript according to three fundamental mechanisms that can be measured with digital ophthalmic biosignals (network connectivity, resting network thresholds, and altered neuromodulation). We have added citations that allow interested readers to further explore various mechanisms by which brain pathology results in Long Covid symptoms.

Comments 2: Please structure the manuscript and have an ophthalmologist looking at it: VEP has nothing to do with visual field and there are other issues concerning the scientific content. 
Response 2: Thank you for pointing out the error. We think the confusion stemmed from table 2 in which “Reduced VEP amplitude” seems to befalling under “Visual Field Test” column, but actually it does fall under “VEP feature”. This is due to formatting requirements. We have now corrected this and adjusted Table formatting for clarity and avoiding confusion on page 8-9 line 216. As suggested, we have sought further proof reading of the corrected manuscript from colleagues with ophthalmology and neuroscience expertise.

4. Response to Comments on the Quality of English Language
Point 1: Needs intensive English editing
Response 1: Authors include native English language speakers with much clinical academic and editorial experience of clear and concise scientific writing.  We were surprised at the suggestion that intensive English editing is required. We have been thorough in proofreading the revised manuscript and are confident that the written English will meet the high standard required. 

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript represents a fair attempt to summarize ophthalmological biomarkers for long
COVID. Although it is well-written and comprehensive some issues need to be addressed. In particular:

1. The beginning of the introduction mentions the general guidelines on how to write the paper. This should be erased.
2. The introduction section is very long and should be made more concise omitting unrelated information.
3. In the second step of the PRISMA flowchart, why were 236 studies excluded? The authors should mention the reasons.
4. Figure 2 does not provide any additional information besides what is mentioned in the manuscript and can be omitted.

Author Response

Comments 1: The beginning of the introduction mentions the general guidelines on how to write the paper. This should be erased.
Response 1: Thank you for pointing this out. We agree with this comment. Therefore, we have removed the first paragraph of the introduction.

Comments 2: The introduction section is very long and should be made more concise omitting unrelated information.
Response 2: Agree. We have, accordingly, cut down the content detailing the psychological and neuropsychiatric effects of long COVID and removed the paragraph of the potential benefits of digital ophthalmological signals in line 90-100 from the original manuscript. The updated first part is on page 2 line 51-55.

Comments 3: In the second step of the PRISMA flowchart, why were 236 studies excluded? The authors should mention the reasons.
Response 3: Agree. We have changed PRISMA flowchart figure (Figure 2 on page 5 line 161) to emphasize this point. The detailed reasons for screening 236 papers by title/abstract are added.

Comments 4: Figure 2 does not provide any additional information besides what is mentioned in the manuscript and can be omitted.
Response 4: We agree that figure 2 is not necessary considering the study type is explained in the text. We have removed figure 2 from the original manuscript and we have also supplemented the description of the text on study types on page 6 line 165-170. 

 

Reviewer 4 Report

Comments and Suggestions for Authors

This review explores the potential of ophthalmological signals as biomarkers for the diagnosis and monitoring of long COVID. The potentials of eye-tracking technology as an objective tool for long COVID diagnosis and monitoring were considered. The paper employed the PRISMA methodology to select papers systematically (15 papers were selected). However, inclusion and exclusion criteria need to be more clearly defined and justified. Other minor corrections:

The first paragraph of the Introduction includes general explanations about this section, it has to be removed.

Line 99 – “Illustrative examples are presented in Table 2” – Table 2 should be mentioned in the text closely to the table presentation (the table is presented a few pages below).

Please explain Fig. 1 in the text.

Figure 2 – only 20% (orange, case control study) is out of the pie.

Line 154 – “After applying the inclusion and exclusion criteria…” – all inclusion and exclusion criteria should be listed in detail.

Lines 527-529 – these lines are general instructions for authors.

Author Response

Comments 1: The first paragraph of the Introduction includes general explanations about this section, it has to be removed.
Response 1: Thank you for pointing this out. We agree with this comment. Therefore, we have removed the first paragraph of the introduction.

Comments 2: Line 99 – “Illustrative examples are presented in Table 2” – Table 2 should be mentioned in the text closely to the table presentation (the table is presented a few pages below).
Response 2: Agree. We think that this paragraph is not necessary and thus have removed this statement from the manuscript.

Comments 3: Please explain Fig. 1 in the text.
Response 3: Thank you for this suggestion. We agree that figure 1 need more descriptive details. We have illustrated the screening process step by step and provided the inclusion and exclusion criteria. The modified part for figure 1 is on page 5 line 154-160. 
 
Comments 4: Figure 2 – only 20% (orange, case control study) is out of the pie.
Response 4: Agree. We think that figure 2 in the original manuscript did not provide additional information. Therefore, figure 2 has been removed but the updated explanation is on page 6 line 165-170.

Comments 5: Line 154 – “After applying the inclusion and exclusion criteria…” – all inclusion and exclusion criteria should be listed in detail.
Response 5: Agree. We have modified the 2.3 Study eligibility part and offered a detailed inclusion/exclusion criteria on page 4 line 121-138.

Comments 6: Lines 527-529 – these lines are general instructions for authors.
Response 6: This is part of the template. We will edit this part during proofreading.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Thanks for the changes - the manuscript has improved a lot