Fluorescein Angiography for Monitoring Neural Blood Flow in Chronic Nerve Compression Neuropathy: Experimental Animal Models and Preliminary Clinical Observations

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors    

The article “Fluorescein angiography for monitoring neural blood flow in chronic nerve compression neuropathy: in vivo and clinical study” by Kosuke Saito et al. investigates the utility of fluorescein angiography (FAG) in assessing neural blood flow in chronic nerve compression (CNC) neuropathy. The study compared FAG with laser Doppler flowmetry (LDF) in both animal models and clinical cases to evaluate their efficacy in detecting blood flow changes and correlating these with electrodiagnostic findings.

Comments:

1. Introduction (Lines 34-53): The introduction effectively outlines the significance of CNC neuropathies but could benefit from a clearer rationale for focusing on FAG over other established methods like LDF.
2. Results (Mostly Lines 177-199): The findings highlight FAG’s correlation with reduced blood flow and its alignment with electrodiagnostic findings. This is good at showing FAG’s utility but it needs a more direct critical comparison of FAG and LDF beyond the electrodiagnostic findings. Maybe addressing measurement depth limitations, and sensitivity, and explaining how FAG overcomes these issues would be beneficial. The figures are well-made and thoughtful.
3. Discussion Section (Lines 255-346: There is an in-depth analysis of FAG's advantages over LDF, particularly its superior detection in deeper neural tissues. However, FAG’s limitations or potential downsides should be more relevant. An example is its reliance on intraoperative settings or procedural variability concerns.

• General Feedback:
• The title is appropriate and accurate.
• The abstract effectively summarizes the study.
• The methods section may benefit from a clearer explanation of the choice of animal models and their relevance to human pathology would be beneficial.
• The conclusion is concise.

  Comments on the Quality of English Language

Minor editing required

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The main question addressed by the research is verification the effectiveness of monitoring the Fluorescein angiography (FAG) and laser Doppler flowmetry (LDF) application for real-time peripheral blood flow assessment in cases of neuropathies. The authors attempted to ascertain their reliability mainly in severe neuropathy models in animals or clinical cases with severe carpal tunnel syndrome (CTS).

The study is scientifically original and clinically important and addresses a specific gap in the field of pathophysiology of the neural transmission in the peripheral nervous system.  The combination of flow, neurophysiological and histological studies makes the results very interesting and convincing. When FAG was evaluated in two different chronic nerve compression neuropathies (CNC) in animal models in comparison with those of LDF, the authors observed significant blood flow reduction using both techniques in a newly developed severe CNC rabbit model. FAG correlated strongly with electrodiagnostic findings, unlike LDF. In clinical CTS cases, FAG correlated significantly with preoperative compound muscle action potential (CMAP) amplitude.

Comparing the reviewed study with other published material on the topic of the peripheral neuropathies, the authors concluded that FAG is important for assessing nerve blood flow during surgery, potentially improving diagnostic accuracy and surgical outcomes.

The work is very concise. Minor corrections should be considered to improve the report’s quality:

1. 1. I suggest changing the phrase “neural blood loss” to “blood loss related neuropathy” throughout the text, as closer to the truth. The authors summarize the necessity of this correction themselves, by providing the real scope of the study in lines 40-41 as follows …”The pathology of CNC neuropathies is associated with disturbances in neural blood flow [5–7].  “… .

2. I see the importance of changing the title “in vivo and clinical study” to “experimental animals and clinical human studies”, but “clinical studies” suggest observations in patients with CTS, which have been mentioned marginally.

3. The content of the Abstract should be revised; it is unclear and a little communicative in some parts to the reader, contrary to the content of the main text. For example, no data on the important electrodiagnostic results have been provided, as well as the blood flow evaluation results are summarized in a very general way. Results of studies on animals and humans should be clearly separated.

4. The Introduction section in the last paragraph should include the aim more explaining the importance of the diagnostic neurophysiological studies undertaken in this report.  Moreover, the authors use the scope of CTS studies only superficially. More available references on this issue in animal and human studies should be used.

5. Methods. Regarding the methodology, scarce data and principles of the electrodiagnostic evaluation of SNAP and CMAP are provided in lines 148-154. Principles of the recording conditions should be widely presented. The authors write about clinical studies by means of electroneurography recordings. Did they perform the classical clinical tests to confirm CTS (e.g. Tinel or Froment signs)?

6. Results. Considering the presentation on the tables and figures, photos of the nerves and histological sections are good, but screenshots from the recorders are poor quality and barely visible. The authors should subdivide the presentation of the results to studies in animals and separately in human subjects. Mixing them is confusing for the reader.

7. The discussion is very modest. Please provide some impressions on the reliability of the tested method of the blood flow evaluation. Studies have been reported to be performed on sciatic nerve model neuropathy; how is it related to CTS, which is related to the median nerve neuropathy in human subjects? Please discuss.

The authors promised to evaluate the reliability of FAG in severe neuropathy models in large  animals or clinical conditions  (see Abstract). I cannot understand this issue well in the Discussion section.

8. The Conclusions section should be rewritten, with conclusions on animal and human studies separated. In the current form, they are not consistent with the main aim of the study which was FAG LDF application reliability for real-time peripheral blood flow assessment in cases of neuropathies.

9. The references are appropriate, although their number is modest, especially for clinical neurophysiological studies on humans; e.g.

Comments on the Quality of English Language

Minor corrections are required

Author Response

Please see the attachment.

Author Response File: Author Response.docx