Corneal Confocal Microscopy in the Diagnosis of Small Fiber Neuropathy: Faster, Easier, and More Efficient Than Skin Biopsy?

Round 1

Reviewer 1 Report

The manuscript “Corneal confocal microscopy in the diagnosis of small fiber neuropathy: faster, easier, and more efficient?” is a nice primer on using the technique of corneal confocal microscopy to quantify small fiber losses. The history and description of the technique are succinctly presented, as well as some background material concerning “small fiber neuropathy” (SFN). It will give an excellent overview for the reader who is not familiar with the technique.

My comments for this short but very readable paper are:

1. Since it is to be included in a special issue “Pathophysiology of Autoimmune Diseases” and the abstract states that “recent research suggests that autoimmune disease may be one of the most common causes of small nerve fiber damage”, I expected some discussion of this would take place. The only exposition concerning autoimmune diseases is in the Table. Unless there are another manuscript in the special issue which develops this topic in some detail, I suggest adding a more comprehensive paragraph about autoimmune-mediated small fiber damage, as this will likely be an unfamiliar topic for many readers.
2. There is a focus on “pure” SFN, i.e., small nerve fiber loss with demonstrated lack of large nerve fiber involvement. This is misleading as the typical patient with pain and other symptoms of small fiber involvement will commonly have polyneuropathy, i.e., including large fiber involvement. Obviously, CCM is just as useful in these patients for assessing small fiber damage and losses. I think this should be pointed out more clearly.
3. There are abbreviations which should be spelled out (e.g., QST, QSART, etc) for the unfamiliar reader.
4. There is a typo in the conclusion (“disaease”).

Author Response

Dear Sir or Madam, please, find our deepest gratitude for your valuable comments!

1. Several paragraphs were added to the paper, that discussed the autoimmune etiology of SFN, as well as specific issues of the diagnostic of such pathology with CCM.
2. The topic of pure and mixed SFN was clarified with a special paragraph.
3. The abbreviations were spelled out carefully.
4. A typo in the conclusion (“disaease”) was checked with gratitude.

Thank you very much for your time and efforts,

Best regards, Natalia Gavrilova

Reviewer 2 Report

The authors provide a review of corneal confocal microscopy (CCM) in the diagnosis of small fiber neuropathy (SFN), taking into account recent literature.

This elegant technique allows intravital examination of corneal innervation representative of the entire peripheral nervous system. The topic is interesting and clinically relevant. The paper covers the anatomical, pathophysiological, and clinical basis of SFN. Furthermore, the technique of confocal microscopy is highlighted.

The text is very condensed. Before publication, please consider the following minor edits. Thank you.

The title suggests a comparison, but it is unclear what CCM is compared to. To biopsy technique?

1. The introduction gives a good introduction to the topic. The second paragraph might belong in the following section and uses abbreviations that are not explained (NCS, LF, SFN SIQ, SFN-RODS, DN4, COMPASS-31) or are explained later (IENFD). It seems questionable whether the former abbreviations contribute to understanding.

2. The section could describe SFN more comprehensively and could benefit from a clearer structure.

- What is the definition of the SFN?

- Please provide data on epidemiology. For which clinical subjects is the technique relevant and should be more widely publicized?

- The etiologic factors and clinical presentation are already well presented in the text

3. The technological evolution of confocal microscopy is presented in brief chronological form. The confocal imaging principle (incident light, point illumination with laser light, pinholes in the beam path) and image construction using scanning techniques could be concisely described. If relevant, the listed techniques for contrast enhancement could be discussed. However, it probably makes more sense to highlight the technical specifications of the established HRT-RCM (Heidelberg corneal module) system in more detail.

4. The section on the application of CCM in the diagnosis of SFN is presented in a very condensed manner. Since its introduction about 20 years ago (Oliveira-Soto and N. Efron, 2001), numerous studies on the role of CCM in the diagnosis of various local and systemic diseases were published. The text coherently discusses the changes in idiopathic and diabetic SFN. The autoimmunologically mediated, toxic, and degenerative forms are mentioned together in one sentence. A second section presents exemplary comparative studies on the specificity and sensitivity of CCM versus biopsy.

- it would be interesting to present the study results for individual entities in more detail in separate paragraphs. Are there differences among the entities?

- since the summary also includes the suitability for diagnosis of central neurodegenerative diseases, the studies on these entities should be mentioned.

- the section on iSFN uses abbreviations that have not been explained (PREP, QST, QSART).

- existing studies about the limitations and pitfalls of the method (variability between working groups, small field of view lacking consensus for cut off values) should be addressed.

- the figures seem to be external images from cited publications. Perhaps this should be noted in the legend.

Author Response

Dear Sir or Madam, please, find our deepest gratitude for your valuable comments!

- The title was slightly changed for the purpose of readability.

1. All abbreviations that are checked and explained (NCS, LF, SFN SIQ, SFN-RODS, DN4, COMPASS-31).

2. In the section, describing SFN in general, were added paragraphs on clearer definition and epidemiology. 

3. The technological evolution of confocal microscopy is a fascinating topic, however, the authors are not aware of the technical differences between the Heidelberg microscope and other microscopes of this type. In order to preserve the readability of the text, the authors decided not to expand the paragraph with technical and physical aspects of the topic.

4. the authors added paragraphs about the currently studied features of autoimmune SFN, features of its diagnosis by confocal microscopy, both separately and in comparison with other methods.

- the mention of neurodegenerative diseases was deleted from the summary in order to avoid destructions for the reader. We will address this topic separately in the next papers.

- all abbreviations were checked and explained (PREP, QST, QSART).

-the limitations were discussed in a separate paragraph.

- the figures, shown in the paper were kindly provided by our colleagues and are our intellectual property. We are considering this remark as a compliment since they are of really good quality.

Thank you so much for your time and efforts!

Best regards, Natalia Gavrilova