Corneal Nerve Assessment by Aesthesiometry: History, Advancements, and Future Directions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Lines 24-26: I'd suggest also mentioning neuroimmune crosstalk and interaction directly. 

 

Lines 58-66: There is more nuance to nociceptor typing than is implied by this description.  I think that the references could be improved and some statements may tend to overgeneralization.  For instance, the authors say "The most abundant, polymodal nociceptors, communicate sharp and sus-59 tained pain through C-type nerve fibers in response to chemical stimuli. These comprise 60 approximately 70% of nociceptors." and this is correct per the reference used.  However, Yang et al.'s reference for their statement (doi:10.1016/0304-3940(93)90184-m) may have been a bit dated?  Another paper that is slightly newer gives the following description (https://doi.org/10.1016/j.exer.2003.09.023): "The majority of corneal sensory fibres (about 70%), named polymodal nociceptors, are equally activated by near-noxious mechanical energy but they also respond to heat, to exogenous chemical irritants and to a large variety of endogenous chemical mediators released by damaged corneal tissue, by resident inflammatory cells or originating from the plasma leaking from limbal vessels (protons, potassium ions, ATP, prostaglandins and other arachidonic acid metabolites, amino acids, amines, cytokines, kynins, growth factors (Belmonte et al., 1994, Chen et al., 1997a). Some of the polymodal nociceptor fibres belong to the thin myelinated group but most of them are of the C type." I have not double checked that all of the nuance in the second quote continued to be supported by subsequent work, but I would encourage the authors to please do so and update their statements accoridngly.

 

Line 106: There is an extra space after corneal sensitivity (typo).

 

Table 1: I suggest providing references at least for the disadvantages, and any other statement for which it is possible to do so.  Also, I would suggest that the disadvantages could be better described in the table.  I think that the major points are hit in the following text

 

Line 302: It feels like given the way the authors talk about the Brill Corneal Esthesiometer, they should at least describe it, how it works and what research has been done with it to date.  It's included in the table of methods, and there are some publications about it (doi:10.1177/11206721231210754).  Also, there are some statements that could be made--things like "it allows five levels of stimulation, and this is/isn't enough for a useful clinical assessment of x because of x", at the author's discretion.

 

General commentary:

 

I expected the authors to talk about how assessment of corneal function can guide treatments.  I'm not sure that it's necessary, but I didn't feel that the explanation for why measuring the degree of sensation is important was really flushed out.

 

The relationship between sensation and IVCM measurements was never really mentioned.  The authors mention morphological assessments, but it's a unconnected set of statements.  The relationships between morphology and sensitivity are unclear and likely vary from patient to patient.  This may be an argument for why measuring sensitivity is important alongside morphological measurements.  Please connect this better to the rest of the paper.

 

I felt like the authors made a repeated point about how expensive and complicated some of the tools are, but didn't really provide any nuance.  Some of them, like SLJA were never really adapted for actual use in the clinic.  The recent Brill device seems like it's been developed with some of the issues (cost, portability, complexity) that likely affected the Belmonte aesthesiometer's success as a clinical tool in mind, and comes following a greater appreciation for the limitation of the Cochet-Bonnet aesthesiometers than perhaps existed 25 years ago.  Some of the other technologies mentioned (OCT for instance) have only become useful clinical tools following decades of development work to output repeatable and clinically useful parameters.  None of the aesthesiometers mentioned are anywhere near as complicated as an OCT system, and it takes a while for the field to really study and understand how to use a tool before it can gain widespread use and acceptance.  I suggest reconsidering the framing of some of that commentary, but don't believe it to be absolutely necessary.

Author Response

We thank you for your thoughtful review and the constructive feedback that has led us to revise this narrative review, “Corneal Nerve Assessment by Aesthesiometry: History, Advancements, and Future Directions.” Taking your recommendations under careful consideration, we have updated our manuscript with particular focus on the evaluations given regarding the work 1) being a significant contribution to the field, 2) being well organized and comprehensively described, and 3) scientifically sound and not misleading. Please find our detailed responses to your recommendations and the corresponding revisions highlighted in our re-submitted file.

1. Lines 24-26: I'd suggest also mentioning neuroimmune crosstalk and interaction directly.
   1. We thank Reviewer 1 for drawing our attention to this point. We have included a discussion introducing the native immune cells present in the cornea and the factors and neurotransmitters suggested to regulate corneal homeostasis, as well as the only FDA-approved NK treatment, rh-NGF.

2. Lines 58-66: There is more nuance to nociceptor typing than is implied by this description. I think that the references could be improved and some statements may tend to overgeneralization.  For instance, the authors say "The most abundant, polymodal nociceptors, communicate sharp and sus-59 tained pain through C-type nerve fibers in response to chemical stimuli. These comprise 60 approximately 70% of nociceptors." and this is correct per the reference used.  However, Yang et al.'s reference for their statement (doi:10.1016/0304-3940(93)90184-m) may have been a bit dated?  Another paper that is slightly newer gives the following description (https://doi.org/10.1016/j.exer.2003.09.023): "The majority of corneal sensory fibres (about 70%), named polymodal nociceptors, are equally activated by near-noxious mechanical energy but they also respond to heat, to exogenous chemical irritants and to a large variety of endogenous chemical mediators released by damaged corneal tissue, by resident inflammatory cells or originating from the plasma leaking from limbal vessels (protons, potassium ions, ATP, prostaglandins and other arachidonic acid metabolites, amino acids, amines, cytokines, kynins, growth factors (Belmonte et al., 1994, Chen et al., 1997a). Some of the polymodal nociceptor fibres belong to the thin myelinated group but most of them are of the C type." I have not double checked that all of the nuance in the second quote continued to be supported by subsequent work, but I would encourage the authors to please do so and update their statements accoridngly.
   1. We thank Reviewer 1 for this comment and have expanded on our discussion of nociceptor characteristics in order to better convey our current mechanistic understanding of corneal sensation. We believe that doing so has added a stronger motivation for understanding why the stimulus of each aesthesiometer is important, and sincerely appreciate this constructive feedback.

3. Line 106: There is an extra space after corneal sensitivity (typo).
   1. This has been corrected in the manuscript. We thank Reviewer 1 for making us aware of this error.

4. Table 1: I suggest providing references at least for the disadvantages, and any other statement for which it is possible to do so. Also, I would suggest that the disadvantages could be better described in the table.  I think that the major points are hit in the following text
   1. We thank Reviewer 1 for this feedback and recommendation. Fields that risked ambiguity have been updated in this table (updated to table 2) to better reflect the information provided in the text of the review, and references have been added to the table for all possible disadvantages, as well as other columns where applicable.

5. Line 302: It feels like given the way the authors talk about the Brill Corneal Esthesiometer, they should at least describe it, how it works and what research has been done with it to date. It's included in the table of methods, and there are some publications about it (doi:10.1177/11206721231210754).  Also, there are some statements that could be made--things like "it allows five levels of stimulation, and this is/isn't enough for a useful clinical assessment of x because of x", at the author's discretion.
   1. We thank reviewer 1 for this comment. Given the recency of the device and paucity of peer-reviewed literature on its use, we had initially chosen to keep the discussion of the Brill esthesiometer brief. Upon reading reviewer recommendations, we agree that further discussion is warranted and have updated our review accordingly. The additional information included required the citation of literature available online ahead of print, as well as the device’s manufacturer website, which was an initial cause of hesitation. This information has been cross-checked to the best of our ability with currently available reputable literature.

General commentary:

7. I expected the authors to talk about how assessment of corneal function can guide treatments. I'm not sure that it's necessary, but I didn't feel that the explanation for why measuring the degree of sensation is important was really flushed out.
   1. We thank Reviewer 1 for drawing our attention to this aspect of our review that warranted further elaboration. To address this, we have placed greater emphasis on the impact of corneal nerves on epithelial homeostasis within the section titled “The cornea and Neurotrophic Keratopathy,” as well as an explicit discussion of the importance of their accurate assessment and appropriate escalation of treatment in the latter half of this section’s final paragraph
8. The relationship between sensation and IVCM measurements was never really mentioned. The authors mention morphological assessments, but it's a unconnected set of statements.  The relationships between morphology and sensitivity are unclear and likely vary from patient to patient.  This may be an argument for why measuring sensitivity is important alongside morphological measurements.  Please connect this better to the rest of the paper.
   1. We thank Reviewer 1 for drawing our attention to this perceived disconnection within the manuscript. To our understanding, the presence or absence of nerve fibers as assessed by IVCM provides insight into the diagnosis and severity of NK, but it does not measure the function of those nerve fibers, which is the main rationale for clinicians adopting formal aesthesiometry measurement. As a result, we have expanded on our discussion of current evidence for the relationship between IVCM and corneal sensation in an effort to bridge this section to the overall theme of the review.

8. I felt like the authors made a repeated point about how expensive and complicated some of the tools are, but didn't really provide any nuance. Some of them, like SLJA were never really adapted for actual use in the clinic.  The recent Brill device seems like it's been developed with some of the issues (cost, portability, complexity) that likely affected the Belmonte aesthesiometer's success as a clinical tool in mind, and comes following a greater appreciation for the limitation of the Cochet-Bonnet aesthesiometers than perhaps existed 25 years ago.  Some of the other technologies mentioned (OCT for instance) have only become useful clinical tools following decades of development work to output repeatable and clinically useful parameters.  None of the aesthesiometers mentioned are anywhere near as complicated as an OCT system, and it takes a while for the field to really study and understand how to use a tool before it can gain widespread use and acceptance.  I suggest reconsidering the framing of some of that commentary, but don't believe it to be absolutely necessary.
   1. We appreciate Reviewer 1’s feedback on our framing of this discussion, and have made a focused effort to refine the language used to describe the devices mentioned to better reflect their complexity. This has included adjusting statements to reflect cost and complexity relative to the Cochet-Bonnet device, and descriptions of the brill device with this framing in mind.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors present a review article about corneal nerve assessment by aesthesiometry. The article is very well writen, I would accept the article as presented. 

Author Response

We thank you for your thoughtful review and feedback regarding our narrative review, “Corneal Nerve Assessment by Aesthesiometry: History, Advancements, and Future Directions.” Taking the recommendations of all reviewers into consideration, we have provided a revised version of our submission with changes highlighted in the attached file. Please find our point-by-point responses to your comments below:

1. The authors present a review article about corneal nerve assessment by aesthesiometry. The article is very well writen, I would accept the article as presented.
   1. We thank Reviewer 2 for their time in evaluating our article and positive feedback. We hope that our additional revisions are accepted in a similar light, and appreciate any additional comments should they find them necessary.

Reviewer 3 Report

Comments and Suggestions for Authors

I want to thank you for the opportunity to review your manuscript. 

General comments:

- This is a very interesting topic. However, the review seems to very broad and non-specific. The review will benefit The authors did not discuss the specific details of the etiologies of corneal hypoesthesia, studies comparing one esthesiometer vs. the other, etc. Rather, they only provide a list of etiologies for corneal hypoesthesia and the very well-described characteristics of each esthesiometer, which are important, but the information could be summarized in a table. I would try to modify this review and make it more detailed. 

- The future directions section also lacks a thorough discussion about what's necessary in the field. It limits to summarize what was said in the manuscript.

 

Specific comments by section:

Abstract

- The abstract needs to expand a little bit more. It does not say much. Corneal sensitivity is not an indicator of eye health, but more of ocular surface disease. The authors should describe the main purpose of the review in the last sentence of the abstract. 

 

The cornea and neurotrophic keratopathy

- Lines 31-33: The reference the authors cite does not talk about the pathogenesis of the disease. It is a reference describing corneal neurotization. Two references describe this topic in detail (Reference 1: Cavanagh, H. Dwight, and Ann M. Colley. "The molecular basis of neurotrophic keratitis." Acta ophthalmologica 67.S192 (1989): 115-134; Reference 2: Ruiz-Lozano, Raul E., et al. "The molecular basis of neurotrophic keratopathy: diagnostic and therapeutic implications. A review." The ocular surface 19 (2021): 224-240).

- Lines 34-40: There is a new classification system that I think the authors should also mention (Reference: Mastropasqua, Leonardo, et al. "In vivo microscopic and optical coherence tomography classification of neurotrophic keratopathy." Journal of cellular physiology 234.5 (2019): 6108-6115.)

Etiologies of corneal hypoesthesia

- Overall, this section does not say much. It is just a list of pathologies that may lead to corneal hypoesthesia. I think the authors should include a table of this and, within the text, discuss the pathogenic mechanisms of the most relevant etiologies. Otherwise, this section is just a list.

- Lines 86-87: Herpes is, by far, the most common cause of NK. The authors should mention this. It is too broad and non-specific to just say "viral infections". 

History of corneal aesthesiometry and its advancements

- Lines 128-129: The Cochet-Bonett's nylon filaments measure 0.08 and 0.12 mm.

 

Author Response

We thank you for your thoughtful review and the constructive feedback that has led us to revise this narrative review, “Corneal Nerve Assessment by Aesthesiometry: History, Advancements, and Future Directions.” Taking your recommendations under careful consideration, we have updated our manuscript with particular focus on the evaluations given regarding the work 1) being a significant contribution to the field, 2) being well organized and comprehensively described, and 3) scientifically sound and not misleading. Please find our detailed responses to your recommendations and the corresponding revisions highlighted in our re-submitted file.

General comments:

1. This is a very interesting topic. However, the review seems to very broad and non-specific. The review will benefit The authors did not discuss the specific details of the etiologies of corneal hypoesthesia, studies comparing one esthesiometer vs. the other, etc. Rather, they only provide a list of etiologies for corneal hypoesthesia and the very well-described characteristics of each esthesiometer, which are important, but the information could be summarized in a table. I would try to modify this review and make it more detailed.
   1. We appreciate Reviewer 3’s constructive feedback regarding the content of our submission. At the outset of conducting this review, we hoped to compile comparative studies in a manner similar to that recommended, however experienced difficulty in finding studies of this type assessing aesthesiometry devices outside of those included here. We believe this may be due to a variety of reasons, including but not limited to variations in device designs throughout time, differences in the types of stimulus applied within variations of devices as well as between different devices, and commentary centered largely around comparison to the cochet-bonnet rather than other, more recently developed aesthesiometers. In an effort to address the concern regarding etiologies, we have added additional descriptions of the physiologic and pathologic alterations involved in the development of neurotrophic keratopathy in the section entitled “The cornea and neurotrophic keratopathy,” as well as a table to better elaborate on the mechanisms of the various categories of NK development. We hope that the inclusion of expected aesthesiometric findings within this table may provide additional nuance within our review, and thank Reviewer 3 for calling attention to this initial shortcoming.
2. The future directions section also lacks a thorough discussion about what's necessary in the field. It limits to summarize what was said in the manuscript.
   1. We thank Reviewer 2 for this constructive comment. As a result, we have added additional clarification to the future directions section of the needs we see most unmet but addressable in the future by further innovation, or improved understanding of the recently introduced Brill Esthesiometer, pasted here: “

      Future aesthesiometers should be ubiquitously and easily available to clinicians. Ophthalmologists and optometrists should have access to instruments that are affordable, easy to use, provide reliable measurements, and use an established standard. By encouraging the use of such devices, the accurate diagnosis of NK can be made earlier, thereby opening the door to preventing the otherwise inevitable deterioration of the ocular surface.”

Specific comments by section:

Abstract

3. The abstract needs to expand a little bit more. It does not say much. Corneal sensitivity is not an indicator of eye health, but more of ocular surface disease. The authors should describe the main purpose of the review in the last sentence of the abstract.
   1. We thank Reviewer 3 for their feedback and agree that the abstract of our paper benefitted from further elaboration. As such, we have updated the abstract to better reflect the content of our submission. Additionally, per Reviewer 3's recommendation, a statement has been added at the end of the abstract to explicitly describe the purpose of the review. 

The cornea and neurotrophic keratopathy

4. Lines 31-33: The reference the authors cite does not talk about the pathogenesis of the disease. It is a reference describing corneal neurotization. Two references describe this topic in detail (Reference 1: Cavanagh, H. Dwight, and Ann M. Colley. "The molecular basis of neurotrophic keratitis." Acta ophthalmologica 67.S192 (1989): 115-134; Reference 2: Ruiz-Lozano, Raul E., et al. "The molecular basis of neurotrophic keratopathy: diagnostic and therapeutic implications. A review." The ocular surface 19 (2021): 224-240).
   1. We thank reviewer 2 for their thorough review and attention to detail in evaluating our manuscript. Our submission has been updated to properly reflect our mechanistic understanding of how NK impacts the trophic regulation of the epithelium. We thank Reviewer 3 for their recommendation of references 1 and 2 above, and after critical evaluation have included Reference 2 in our resubmission. The previous reference describing corneal neurotization has been retained due to its discussion of the complications of untreated NK when this operation is not pursued. 

5. Lines 34-40: There is a new classification system that I think the authors should also mention (Reference: Mastropasqua, Leonardo, et al. "In vivo microscopic and optical coherence tomography classification of neurotrophic keratopathy." Journal of cellular physiology 234.5 (2019): 6108-6115.)
   1. We thank Reviewer 3 for providing this reference, and have updated our review to include its mention during our initial discussion of the Mackie classification system, as well as following the more detailed discussions of IVCM and OCT and their utilities in assessing ocular surface disorders.

Etiologies of corneal hypoesthesia

6. Overall, this section does not say much. It is just a list of pathologies that may lead to corneal hypoesthesia. I think the authors should include a table of this and, within the text, discuss the pathogenic mechanisms of the most relevant etiologies. Otherwise, this section is just a list.
   1. We thank Reviewer 3 for this feedback and have considered this recommendation at length. We agree that a table may be beneficial in this section, however, believe that it would be better suited for categories of etiologies of neurotrophic keratopathy rather than individual causes. While we recognize that this risks omitting some degree of the nuance involved in the many pathologies that can lead to NK, we feel that a discussion of shared mechanisms among similar pathologies, as well as the expected aesthesiometric manifestations fit the appropriate depth for the intended purpose of this review.

7. Lines 86-87: Herpes is, by far, the most common cause of NK. The authors should mention this. It is too broad and non-specific to just say "viral infections".
   1. We appreciate this recommendation from Reviewer 3 and have updated the manuscript accordingly to include herpes simplex and herpes zoster as the specific most common viral infections causing corneal hypoesthesia.

History of corneal aesthesiometry and its advancements

8. Lines 128-129: The Cochet-Bonett's nylon filaments measure 0.08 and 0.12 mm.
   1. We thank Reviewer 3 for making us aware of this mistyping. This has been corrected within the manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for the thoughtful revisions.

Reviewer 3 Report

Comments and Suggestions for Authors

I would like to thank the authors for the effort in addressing every comment I made.