PONE-D-25-68588

Bullous Keratopathy Associated with a Shallow Anterior Chamber: An Anatomical Risk Phenotype for Corneal Endothelial Decompensation

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Response: We thank the editor for this comment. We reviewed the publications recommended by the reviewers, found them relevant to the present study, and incorporated the appropriate citations into the revised Discussion.

Location: manuscript p27-28 Line 340-347, 361-368

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Response: We thank the editor for this comment. We carefully reviewed the reference list for completeness and accuracy and revised it as needed in the updated manuscript. We also confirmed that no retracted articles are cited.

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Additional Editor Comments:

• Please address particularly the limitations inherent to small sample size.

Response: We thank the editor for this important comment. We revised the Discussion and Limitations sections to more clearly acknowledge the limitations related to the small sample size, particularly in the PAC/Unknown subgroup. Specifically, we emphasized the limited sample size, the relatively short follow-up, the possibility of limited statistical power in some analyses, and the exploratory nature of the findings, and we clarified that larger studies with longer follow-up are needed.

Location: manuscript p30 Limitations

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Reviewers' comments:

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Reviewer #1: The work highlights an important and often under-recognized phenotype, and the imaging documentation is excellent. To further strengthen the study and align it with current understanding of postoperative endothelial and stromal behavior, I would encourage you to address the following points.

-Please discuss the recent literature that it has demonstrated that PSR are not merely descriptive findings but structural biomarkers of stromal overhydration and lamellar micro-distortion. In particular, preoperative PSR correlate with slower visual recovery and postoperative PSR strongly predict rebubbling and graft instability (Ventura et al., Cornea 2024). Including this discussion will contextualize your observations and provide a more mechanistic interpretation of stromal morphology in your cohort.

Response: Thank you for this insightful comment. We have expanded the Discussion to incorporate the recent literature on posterior stromal ripples (PSR). Specifically, we clarified that PSR are not merely descriptive findings on anterior segment optical coherence tomography, but structural biomarkers of stromal overhydration and lamellar micro-distortion after DMEK. We also added discussion of the reported associations between preoperative PSR and slower visual recovery, as well as between postoperative PSR and rebubbling/graft instability. In addition, we related these findings to the posterior stromal irregularity observed in our illustrative case, while acknowledging that PSR were not systematically assessed in the present cohort.

Location: manuscript p27-28 Line 340-347, 361-368

-Discuss the role of subclinical inflammation. AS-OCT–based studies have shown that subclinical anterior chamber inflammation is almost universally present after DMEK, and higher postoperative inflammatory load (measured by ARI index and hyperreflective dots) is linked to the development of postoperative PSR and rebubbling (Vaccaro et al., Ophthalmology Science 2026). Incorporating this concept can help explain why some eyes demonstrate unexpected endothelial stress or postoperative behavior despite uneventful surgery.

Response: Thank you for this important comment. We have expanded the Discussion to address the role of subclinical postoperative inflammation after DMEK. Specifically, we added discussion of AS-OCT–based evidence showing that higher postoperative inflammatory load, reflected by the ARI index and hyperreflective dots, is associated with PSR and with postoperative rebubbling/graft instability. We also noted that this concept may help explain variable postoperative behavior despite apparently uneventful surgery.

Location: manuscript p27-28 Line 340-347, 361-368

-clarify the mechanistic link between anatomy and endothelial vulnerability. Your hypothesis of a shallow-anterior-chamber risk phenotype is intriguing, but discussing how crowding, micro-shear forces, and low-grade inflammation may contribute to chronic endothelial stress would strengthen the biological plausibility of the proposed mechanism.

Response: Thank you for this helpful suggestion. We have expanded the Discussion to clarify the potential mechanistic link between shallow anterior chamber anatomy and endothelial vulnerability. Specifically, we added discussion of anterior segment crowding, altered aqueous flow and micro-shear forces, intermittent IOP elevation, episodic iridocorneal contact, and low-grade inflammation as possible c

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Submitted filename: point-to-point.docx

Response to Academic Editor

Manuscript ID: PONE-D-25-68588R1

Title: Bullous keratopathy associated with a shallow anterior chamber: an anatomical risk phenotype for corneal endothelial decompensation

Dear Dr. Lalgudi,

We sincerely thank you and the reviewers for the careful evaluation of our manuscript and for the constructive comments. We have revised the manuscript accordingly to improve the clarity, reproducibility, and validity of the study. All changes have been incorporated into the revised manuscript and are indicated in the tracked-changes version.

Below, we provide a point-by-point response to each comment.

Comment 1

Editor’s comment:

Firstly, to improve the repeatability of the methodology, we need to have a clear explanation on how PAC was diagnosed. Was it just based on ACD, or based on gonioscopic findings as well? There seems to be no description of that. If gonioscopy was performed, was there any variation on the grade of the angle, including presence or absence and extent of PAS in the patients studied? Was ASOCT performed to analyze the trabecular iris angle (TIA)? And, please describe 'dark spots' on specular microscopy in the methodology.

Response:

Thank you for this important comment. We agree that the previous terminology may have been misleading. In the original manuscript, we used the terms “PAC/ALI” and “PAC/Unknown.” However, because the former “PAC/Unknown” group did not have sufficient documentation to support a strict diagnosis of PACD based on uniform gonioscopic criteria, we revised the terminology throughout the manuscript. Specifically, we renamed this group as the “shallow anterior chamber (shallow-AC) group” and clarified that this classification was intended to represent a shallow anterior chamber phenotype rather than a definitive diagnosis of PACD.

We also revised the Methods section to clarify how PACD was diagnosed. The PACD/ALI group was defined based on medical records documenting a history of argon laser iridotomy performed for a clinically diagnosed PACD-spectrum condition, supported when available by gonioscopic angle closure and/or a clinical diagnosis by glaucoma or corneal specialists. We further clarified that, because of the retrospective nature of the study, standardized gonioscopic grading and the extent of peripheral anterior synechiae were not consistently available and were therefore not included as analytic variables.

In addition, we clarified that AS-OCT was used to measure ACD and CCT, but angle parameters, including the trabecular iris angle, were not uniformly measured and were not used for group classification or statistical analyses. Finally, we added a definition of dark spots on specular microscopy and clarified that dark spots alone were not used as independent diagnostic criteria for FECD.

Location:

Abstract; Methods, Patients and data collection; Methods, Ophthalmic examinations; Results; Discussion; Figure legends; Supporting Information.

Comment 2

Editor’s comment:

As cornea specialists, when we see patients with BK without evidence of FECD (clinically/on specular of affected/fellow eye), the following are the differentials. Number 1 is cataract surgery or phaco energy induced endothelial loss or PBK. Especially in eyes with shallow ACD or with denser cataracts, the impact of phaco energy on the endothelium is significant. IOL position is a significant concern as well. Sulcus IOLs or UGH concerns or ACIOLs are known to increase the risk of corneal decompensation. Other aspects to rule out are a viral masquerade. Patients with a HSV or CMV endotheliitis in the past can also present with endothelial dysfunction and can improve with oral antivirals and topical steroids. While trying to describe a group of BK eyes with PAC without APAC or ALI, one of the major concerns is the fact that the authors seem to be completely ignoring the role and impact of cataract surgery and other above mentioned factors in these patients. The following parameters need to be added to the article. a) What was the timeline of the cataract surgery before presenting with corneal edema? b) Cataract surgery parameters including CDE (cumulative dissipated energy), IOL used and position of the IOL, c) How long prior to Cataract surgery was LPI performed? d) Pre-cataract surgery ECD on specular microscopy. e) Was any aqueous tap performed for ruling out HSV/CMV IgG/IgM PCR in BK patients with no evidence of FECD?

Response:

We thank the Editor for this important comment. We agree that cataract surgery-related endothelial injury, IOL-related factors, and viral endotheliitis are important differential considerations when evaluating bullous keratopathy without evidence of FECD. To address this concern, we reviewed additional cataract surgery-related variables in the shallow anterior chamber phenotype group and added these data to the Results section under “Patient characteristics” and to S2 Table.

Specifically, we added information on the timing of cataract surgery relative to corneal edema confirmation, cumulative dissipated energy, IOL type and position, the interval from ALI to cataract surgery, pre-cataract surgery ECD, and clinical findings and aqueous humor testing related to possible viral endotheliitis. Among the 28 eyes in the shallow anterior chamber phenotype group, 22 eyes underwent cataract surgery as part of a planned staged surgical approach before DMEK after corneal endothelial decompensation or BK had already been recognized. Cumulative dissipated energy was not available in the medical records. Among eyes with available IOL position data, all IOLs were placed in the bag, and no sulcus IOL or anterior chamber IOL was documented. The interval from ALI to cataract surgery and pre-cataract surgery ECD are summarized in S2 Table. Clinical findings suggestive of viral endotheliitis were noted in one eye, and aqueous humor testing, when performed, was negative.

These additions clarify that cataract surgery-related factors, IOL position, prior ALI, pre-cataract endothelial status, and possible viral masquerade were specifically reviewed in response to the Editor’s concern.

Although cumulative dissipated energy was not available because of the retrospective nature of the study, the newly added data indicate that most cataract surgeries in this subgroup were performed as planned staged procedures after endothelial decompensation or BK had already been recognized, and that no sulcus IOL or anterior chamber IOL was documented among evaluable eyes.

Location:

Results, Patient characteristics; Supporting Information, S2 Table.

Comment 3

Editor’s comment:

In the results section, what does 'baseline' visit represent? Is it prior to cataract surgery or prior to DMEK surgery?

Response:

Thank you for this important comment. To avoid ambiguity, we revised the Methods section and removed the term “baseline” from the relevant descriptions. We now specify that VA, CCT, IOP, the number of IOP-lowering medications, axial length, and preoperative donor ECD were recorded before DMEK. ACD was evaluated separately as pre-cataract surgery ACD and post-cataract surgery ACD. We also clarified that post-cataract surgery ACD was measured at the pre-DMEK assessment.

Location: Methods, Ophthalmic examinations; Results, Patient characteristics; Supporting Information, S4 and S5 Tables.

Comment 4

Editor’s comment:

Table 1 is confusing. After the row on 'Breakdown of BK', please create a separate table with new headers to make it easy for readers.

Response:

Thank you for this helpful suggestion. We revised Table 1 to improve readability. Specifically, we separated the original “Breakdown of BK” section from the main patient demographics and clinical characteristics table and created a separate table with new headers for BK cases. The main patient characteristics are now presented in Table 1A, and the breakdown of BK cases is presented separately in Table 1B. We also revised the corresponding text citation in the Results section.

Location: Results, Patient characteristics; Tables 1A and 1B.

Comment 5

Editor’s comment:

In table 1, 19 patients are mentioned to have Laser iridotomy. However, your PAC group with ALI is only 18. Why is this discrepancy?

Response:

Thank you for pointing this out. This discrepancy was due to a transcription error in the previous version of Table 1. We reviewed the dataset and confirmed that 18 eyes had a history of laser iridotomy, which is consistent with the number of eyes in the PACD/ALI group. We corrected the value in Table 1A accordingly.

Location: Table 1A.

Comment 6

Editor’s comment:

Line 315 mentions that PEX had deeper chambers than those with PAC eyes. However, Table 2 mentions PEX ACD mean as 2.09mm versus PAC group with 2.20 mm mean. Please fix this discrepancy.

Response:

We thank the editor for pointing out this discrepancy. We agree that the original statement was imprecise. In Table 2, the mean pre-cataract surgery ACD was 2.09 mm in the PEX subgroup and 2.20 mm in the shallow-AC subgroup; therefore, it was inappropriate to state that PEX was associated with deeper chambers in this context. We deleted the sentence “Conversely, FECD and PEX were associated with deeper chambers” and revised the Discussion to avoid this misleading interpretation. The revised sentence now reads: “Together, these findings suggest that eyes with the shallow anterior chamber phenotype may have anterior segment characteristics that differ from those of eyes with FECD.”

Location: Discussion, first paragraph.

Comment 7

Editor’s comment:

The following article has also previously described CECD cell loss in PACS eyes without ALI or angle closure attacks. Kusumi Y, Yamamoto M, Fukui M, Yamada M. Morphological Features in Eyes with Prominent Corneal Endothelial Cell Loss Associated with Primary Angle-Closure Disease. J Clin Med. 2025 Jul 29;14(15):5364. doi: 10.3390/jcm14155364. PMID: 40806986; PMCID: PMC12346976. This article points out the role of keratometry or radius of curvature in CECD loss in PACS eyes. Are you able to include corneal curvature in your patients in the study as well? Please also include this study in the discussion section.

Response:

We appreciate the Editor’s important suggestion. We agree that the study by Kusumi et al. is highly relevant, because it reported prominent corneal endothelial cell density loss in eyes with primary angle-closure disease, including primary angle-closure suspect eyes without a history of acute angle-closure attacks or laser iridotomy, and suggested a potential role of corneal curvature radius in endothelial vulnerability. We have incorporated this study into the Discussion.

Unfortunately, keratometric data and corneal curvature parameters were not consistently available because of the retrospective nature of this study and the long study period. Therefore, we were unable to perform a reliable corneal curvature analysis in the present cohort.

Location: Discussion.

Additional revisions

In addition to the changes made in response to the editor’s comments, we carefully reviewed the manuscript for clarity, consistency, and typographical errors.

Sincerely,

Takahiko Hayashi

On behalf of all authors

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