Bleb-Independent Glaucoma Surgery to Activate the Uveolymphatic Route of Non-Trabecular Aqueous Humor Outflow: Short-Term Clinical and OCT Results

Round 1

Reviewer 1 Report

Kumar and colleagues report on the short-term outcomes of a bleb-independent technique in 38 eyes with open-angle glaucoma. The authors reported a significant reduction in post-operative IOP and anti-glaucoma medications and few complications over a 6-month follow up period. The manuscript reads very well and coherent, however, there are some concerns that need to be addressed.

 

General comments:

- The major drawback of this study is the lack of a control group. Hence, the superiority of this method over the conventional penetrating surgeries and the role of the collagen implant cannot be concluded from this study.

- A major concern is the lack of basic evidence for the safety, biocompatibility, and efficacy of the collagen implant used in this study. I encourage the authors to discuss whether there are previous studies (either experimental or clinical) using this implant. Also, the advantages and disadvantages of this implant compared with other implants should be discussed.

- Another major concern is the method of measurement of the IOP. Although iCare is widely used in glaucoma clinics, its accuracy and reliability in patients with glaucoma are questionable. Please explain why iCare was used instead of the Goldmann applanation tonometry and how the errors in IOP measurement using iCare may affect your findings.

- Line 394: “we initially expected formation of a bleb at the surgery site”. Is it possible that the site of the scleral flap (and incisions) was closed due to fibrosis? Since the laser trabeculotomy was performed 7-10 days after the surgery and anti-fibrotic agent was not used perioperatively, it can explain the lack of filtering bleb and activation of the lymphatic system because of the increased pressure in the intrascleral space. I wonder if there was any bleb in the initial case(s) where the trabeculotomy was performed 1 day after surgery?

 

Specific comments

- Line 40: define OAG

- Line 62: define OCT

- Line 65: define LV

- Line 78: visually significant cataract was an inclusion criterion. I suppose that this refers to patients who had combined surgery. If so, please reword the sentence to make it clear that significant cataract was not an inclusion criterion for the whole cohort.

- Line 106: define SC

- Line 109: define CI

- Line 115: should be “Argentinian flag”.

- Line 138: add the type of medication and frequency of usage

- Line 148: please use “millijoules” or “mj” instead of mjoules

- Line 159: add the number and distance between the B-scans

- Line 176: correct “(SCF)” to (SSF) in the figure legend.

- Figure 3: please add the direction of the B-scans shown in each panel.

- Table 1: Glaucoma types, I suppose that the second type is “Refractory” rather than “Refractive”. Please correct.

- Line 244: how was the improvement/worsening of VA defined?

- Line 255: “two cases refused to undergo the Nd: YAG trabeculotomy”. Were these 2 patients included in the analysis? Recognizing the critical role of the trabeculotomy in the success of this procedure, I recommend excluding these cases since they have not completed the procedure and cannot be considered failures.

- Figure 6: it seems that all failures occurred at the same time (around 40 weeks). If that was the case, please discuss possible mechanisms of failure at this specific time?

- Line 299-300: did the authors perform quantitative measurements and statistical analysis? If so, please include the results.

Author Response

I would like to thank the reviewer for taking pains and spending his/her valuable time in reviewing our paper. The comments were of immense value in upgrading the manuscript quality.

General comments:

- The major drawback of this study is the lack of a control group. Hence, the superiority of this method over the conventional penetrating surgeries and the role of the collagen implant cannot be concluded from this study.

This study was a clinical interventional study (non-comparative case series), describing outcomes of an intervention without a control group for comparison.

- A major concern is the lack of basic evidence for the safety, biocompatibility, and efficacy of the collagen implant used in this study. I encourage the authors to discuss whether there are previous studies (either experimental or clinical) using this implant. Also, the advantages and disadvantages of this implant compared with other implants should be discussed.

The implant used in this study is a certified medical item registered with competent authorities of the country where the study was conducted. They are ophthalmic collagen implants meant for use in glaucoma surgery.  They are permitted for use in human beings. Registration number is   РУ № ФС 01032006/3759-06 dated 23.10.2006. More detailed data may be downloaded from http://makmedi.ru/2010/04/20/microdrenaj.html. The comparison with other collagen implants has been added in the discussion section.

- Another major concern is the method of measurement of the IOP. Although iCare is widely used in glaucoma clinics, its accuracy and reliability in patients with glaucoma are questionable. Please explain why iCare was used instead of the Goldmann applanation tonometry and how the errors in IOP measurement using iCare may affect your findings.

Goldmann applanation tonometry is the suggested standard for IOP measurement.

Lately there is an increased interest in rebound tonometers (iCare tonometers). Recent published reports indicate lower measurement variability, good interoperator and interdevice reproducibility, good inter-device agreement among GAT and rebound tonometers [1,2,]. Icare ic100 rebound tonometer can measure IOP with relatively small measurement error and can provide a reliable and repeatable reading in comparison with GAT across a wide pressure range without hampering corneal health [3]. IOP readings from iCare are consistent with those from GAT [4].

1. Realini T.; McMillan B.; Gross R.L.; Devience E. Balasubramani G. K. Assessing the Reliability of Intraocular Pressure Measurements Using Rebound Tonometry. Journal of Glaucoma: August 2021 - Volume 30 - Issue 8 - p 629-633. doi: 10.1097/IJG.0000000000001892.
2. Kato Y.; Nakakura S.; Matsuo N.; Yoshitomi K.; Handa M.; Tabuchi H.; Yoshiaki K. Agreement among Goldmann applanation tonometer, iCare, and Icare PRO rebound tonometers; non-contact tonometer; and Tonopen XL in healthy elderly subjects. Int Ophthalmol. 2018; 38(2):687–696. doi: 10.1007/s10792-017-0518-2.
3. Jose J, Ve RS, Pai HV, Biswas S, Parimi V, Poojary P, Nagarajan T.Agreement and repeatability of Icare ic100 tonometer. Indian J Ophthalmol. 2020 Oct;68(10):2122-2125. doi: 10.4103/ijo.IJO_546_19.
4. Evelien Vandewalle, Sofie Vandenbroeck, Ingeborg Stalmans. Comparison of ICare, Dynamic Contour Tonometer, and Ocular Response Analyzer with Goldmann Applanation Tonometer in Patients with Glaucoma. Eur J Ophthalmol. Sep-Oct 2009;19(5):783-9. doi: 10.1177/112067210901900516.

 

Taking into consideration the above mentioned and taking account of the non-availability of fluoresceine dye (a necessary item for measuring IOP with GAT) in the country we opted for IOP measurement using iCare tonometer. To avoid any errors in IOP measurement we used the standard procedure. The median of three consecutive measurements was taken into consideration. The IOP values were adjusted for corneal thickness. This has been mentioned in the section “Methods and material”.

- Line 394: “we initially expected formation of a bleb at the surgery site”. Is it possible that the site of the scleral flap (and incisions) was closed due to fibrosis? Since the laser trabeculotomy was performed 7-10 days after the surgery and anti-fibrotic agent was not used perioperatively, it can explain the lack of filtering bleb and activation of the lymphatic system because of the increased pressure in the intrascleral space. I wonder if there was any bleb in the initial case(s) where the trabeculotomy was performed 1 day after surgery?

Yes, we fully agree with the comment. In all cases except 1 case a period of 7-10 days was allowed for wound healing before Nd:YAG laser trabeculotomy was attempted. The other case in whom laser trabeculotomy was performed the very next day after surgery resulted in conjunctival wound dehiscence requiring resuturing of the wound. There was another case with a bleb which lasted for 1 month. In other cases there was no bleb formation, which was confirmed by OCT.

Specific comments

- Line 40: define OAG – done

- Line 62: define OCT – done

- Line 65: define LV – done

- Line 78: visually significant cataract was an inclusion criterion. I suppose that this refers to patients who had combined surgery. If so, please reword the sentence to make it clear that significant cataract was not an inclusion criterion for the whole cohort. – done

- Line 106: define SC – done

- Line 109: define CI – done

- Line 115: should be “Argentinian flag”. – done

- Line 138: add the type of medication and frequency of usage – done

- Line 148: please use “millijoules” or “mj” instead of mjoules – done

- Line 159: add the number and distance between the B-scans – done

- Line 176: correct “(SCF)” to (SSF) in the figure legend. – done

- Figure 3: please add the direction of the B-scans shown in each panel. – They are shown in the right corner of the scans.

- Table 1: Glaucoma types, I suppose that the second type is “Refractory” rather than “Refractive”. Please correct. – done

- Line 244: how was the improvement/worsening of VA defined? – as per the “Guidelines on design and reporting of glaucoma surgical trials”. Editors. Shaarawy T.M.; Grehn F.; Sherwood M.B. World Glaucoma Association. Amsterdam: Kugler publications, 2008; 2009:1-14.

- Line 255: “two cases refused to undergo the Nd: YAG trabeculotomy”. Were these 2 patients included in the analysis? Recognizing the critical role of the trabeculotomy in the success of this procedure, I recommend excluding these cases since they have not completed the procedure and cannot be considered failures. – These cases were not failure cases. At this part of manuscript cases which needed instillation of additional hypotensive medications for IOP control were analyzed. Instillation of hypotensive eye drops resulted in control of IOP and these cases were classified as cases with qualified success.

- Figure 6: it seems that all failures occurred at the same time (around 40 weeks). If that was the case, please discuss possible mechanisms of failure at this specific time? – There was one failure case at 44 weeks.

- Line 299-300: did the authors perform quantitative measurements and statistical analysis? If so, please include the results. – No quantitative measurements of lymphatic vessels and statistical analysis were performed. 

 

On behalf of authors,

Prof. Kumar Vinod

Reviewer 2 Report

Scientific material represents original scientific research carried out at a high level and can be recommended for publication.

Author Response

On behalf of authors I would like to thank the reviewer for taking pains and spending valuable time in reviewing our article.

with regards,

Prof. Kumar Vinod

Reviewer 3 Report

This study beautifully demonstrated the appearance of lymphatic drainage vessels after the modified deep sclerectomy with suprachoroidal drainage. However, the description of the surgical outcome is not well-organized. Furthermore, in the Kaplan-Meyer curve, why most patients were censored while the survival probability is still 100% and the survival curve dropped abruptly to 80% once instead of a stepwise reduction. This finding probably indicated that many patients dropped out at the early stage of this study, and therefore not represent the actual clinical scenario. The result about the survival of this surgery in IOP reduction should be further clarified.

Furthermore, the ”observation during surgery” section should focus on the modified deep sclerectomy instead of the difficulties encountered during phacoemulsification or IOL exchange.

There should be more quantitative analysis regarding the postoperative formation of LVs. What is the relationship between the number and location of LVs with postoperative IOP reduction and temporal changes of the LVs?

As the author indicated that perioperative antimetabolites may cause a reduction in conjunctival and lymphatic vessels, how do they manage the use of antimetabolite in their modified surgery?

Some abbreviations were not spelled out when they were first cited in the article, such as CI, LV. Furthermore, abbreviations in Figure 3 are not consistent. It seems to me that both SSF vs SCF referred to superficial scleral flap.

In figure 3A, the appearance of the bicuspid lymphatic valves in the lymphatics is not convincing.

Author Response

On behalf of authors I would like to thank the reviewer for taking pains and spending valuable time in reviewing our paper. All comments have been answered and necessary changes have been made in the manuscript.

 

This study beautifully demonstrated the appearance of lymphatic drainage vessels after the modified deep sclerectomy with suprachoroidal drainage. However, the description of the surgical outcome is not well-organized. Furthermore, in the Kaplan-Meyer curve, why most patients were censored while the survival probability is still 100% and the survival curve dropped abruptly to 80% once instead of a stepwise reduction. This finding probably indicated that many patients dropped out at the early stage of this study, and therefore not represent the actual clinical scenario. The result about the survival of this surgery in IOP reduction should be further clarified.

Outcome measures have been duly described in the revised manuscript.

The Kaplan-Meyer curve was derived using the SPSS statistics (IBM) 28.0.0.0 software for windows 7 inputting the available data. A failure occurred at 44 weeks. Hence the sudden drop in the curve.  Afterwards there were no failure cases.

Furthermore, the “observation during surgery” section should focus on the modified deep sclerectomy instead of the difficulties encountered during phacoemulsification or IOL exchange.

Needed corrections have been made.

There should be more quantitative analysis regarding the postoperative formation of LVs. What is the relationship between the number and location of LVs with postoperative IOP reduction and temporal changes of the LVs?

We thank the reviewer for valuable comment. Quantitative analysis regarding the postoperative formation of LVs was not done in this case series. We did not explore any relationship between the number and location of LVs with postoperative IOP reduction and temporal changes of the LVs. Though we observed that with normalization of IOP level, the numbers and size of LV reduced. This is only an empirical observation.  We are planning to study this aspect in our future research.

As the author indicated that perioperative antimetabolites may cause a reduction in conjunctival and lymphatic vessels, how do they manage the use of antimetabolite in their modified surgery?

No antimetabolite was used in this case series. If indicated YAG laser trabeculotomy was attempted after a period of 7-10 days allowing enough time for wound healing.

Some abbreviations were not spelled out when they were first cited in the article, such as CI, LV. Furthermore, abbreviations in Figure 3 are not consistent. It seems to me that both SSF vs SCF referred to superficial scleral flap.

All abbreviations have been spelled out in the revised manuscript.

In figure 3A, the appearance of the bicuspid lymphatic valves in the lymphatics is not convincing.

In figure 3A, more attention was paid to show absence of filtering bleb and microcysts above the collagen implant and superficial scleral flap.

 

With regards,

on behalf of authors

prof. Kumar Vinod

Round 2

Reviewer 1 Report

All comments have been addressed appropriately.

Reviewer 3 Report

No further comments!