Ocular Alignment and Strabismus-Related Findings Associated with Low-Dose Atropine for Myopia Control in Children: A Structured Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This structured narrative review examines the role of low-dose atropine (0.01–0.025–0.05%), used to slow the progression of myopia, in the development of ocular misalignment, strabismus. Its conclusions are very useful in daily practice when deciding whether to initiate atropine therapy to slow myopia.

Please incorporate the following suggestions and answers to the questions into the manuscript:

In the abstract, either do not use abbreviations or provide their meanings: the manuscript is
expected to be read by more than just pediatric ophthalmologists, and the abstract is not fully
understandable due to the abbreviations.

L105: Please define: low-dose atropine for myopia control

L113 Please define high-dose atropine

In the Tables 1 description, please provide a list of abbreviations Please also discuss: In the prospective studies, were binocular vision parameters assessed at baseline? In the prospective studies, when and at what intervals were ocular alignment, strabismus, and binocular vision parameters assessed? How old were the participants?

L426 Would you consider it necessary to conduct regular examinations of binocular vision and
strabismus concurrently with myopia control? Is there a high-risk age-grop?
Please provide a list of abbreviations for the entire manuscript.

Author Response

I am grateful to the Editor and Reviewers for their thoughtful and constructive feedback, which helped improve the clarity, methodological transparency, and clinical relevance of the manuscript. In accordance with the comments, I revised the Abstract, Methods, Results, Discussion, and Conclusions, and I provide a detailed point-by-point response below.

• Reviewer 1

This structured narrative review examines the role of low-dose atropine (0.01–0.025–0.05%), used to slow the progression of myopia, in the development of ocular misalignment, strabismus. Its conclusions are very useful in daily practice when deciding whether to initiate atropine therapy to slow myopia.

Please incorporate the following suggestions and answers to the questions into the manuscript:

Response: We sincerely thank the reviewer for the positive and encouraging assessment of our manuscript. We are pleased that the reviewer considered the topic clinically relevant and useful for daily practice. We have revised the manuscript according to the reviewer’s suggestions, as detailed below.

 

Comments 1:

In the abstract, either do not use abbreviations or provide their meanings: the manuscript is expected to be read by more than just pediatric ophthalmologists, and the abstract is not fully understandable due to the abbreviations.

Response 1:

We thank the reviewer for this helpful comment. We agree that the Abstract should be understandable to readers beyond pediatric ophthalmology specialists. Accordingly, we revised the Abstract by avoiding or spelling out abbreviations. Specifically, we replaced abbreviated terms such as “AC/A ratio,” “NPC,” and “NPA” with their full forms, namely “accommodative convergence/accommodation ratio,” “near point of convergence,” and “near point of accommodation.” These revisions were made to improve clarity and readability for a broader readership.

 

Comments 2:

L105: Please define: low-dose atropine for myopia control

Response 2:

We thank the reviewer for this helpful comment. We have added an explicit operational definition of low-dose atropine for myopia control in the Review design section. In the revised manuscript, low-dose atropine for myopia control was defined as topical atropine at concentrations from 0.01% to 0.05%, including 0.01%, 0.025%, 0.03%, and 0.05%. We used this range because the included studies evaluated concentrations within this range, including a study using 0.03% atropine. This clarification was added to define the scope of the review.

 

Comments 3:

L113 Please define high-dose atropine

Response 3:

We thank the reviewer for pointing this out. We have also defined high-dose, or higher-concentration, atropine in the Review design section. In this review, high-dose atropine was operationally defined as concentrations greater than 0.05%. We further clarified that reports involving dose escalation beyond 0.05% after initiation with low-dose atropine were interpreted separately from studies of fixed low-dose atropine regimens. This distinction was particularly important because one included case report involved escalating atropine concentrations rather than fixed 0.01%–0.05% treatment.

 

Comments 4:

In the Tables 1 description, please provide a list of abbreviations Please also discuss: In the prospective studies, were binocular vision parameters assessed at baseline? In the prospective studies, when and at what intervals were ocular alignment, strabismus, and binocular vision parameters assessed? How old were the participants?

Response 4:

We thank the reviewer for this helpful comment. We revised Section 3.2 and expanded Table 1 to include participant age, atropine regimen, baseline assessment, assessment timing, and main ocular alignment/binocular vision-related findings for each included study. We also added a list of abbreviations in the footnote to Table 1.

We clarified that, among the six clinical or interventional studies, participant ages ranged from 6 to 17 years, and baseline ocular alignment, binocular vision, accommodative function, or vergence-related parameters were assessed in all six studies. We also specified the assessment timing, which ranged from short-term assessments at 30 min, 60 min, and 24 h after instillation to follow-up over 3, 6, or 12 months, depending on the study.

Finally, we added a sentence in the Discussion noting that differences in baseline test batteries and follow-up intervals may affect the interpretation and comparison of prospective studies.

 

Comments 5:

L426 Would you consider it necessary to conduct regular examinations of binocular vision and

strabismus concurrently with myopia control? Is there a high-risk age-grop?

Response 5:

We thank the reviewer for this important comment. We revised the Discussion to address whether binocular vision and strabismus-related examinations should be performed concurrently with myopia control. We now state that baseline assessment and regular follow-up should be considered, particularly at treatment initiation, after dose escalation, and when symptoms such as near blur, diplopia, asthenopia, or reduced fusion develop. We also clarified that the current literature does not support a specific high-risk age group; rather, higher-risk profiles appear to be defined by baseline binocular status and ocular history, such as prior strabismus surgery, near esophoria or latent esodeviation, high or increasing AC/A ratio, unstable fusional ability, and early binocular symptoms.

 

Comments 6:

Please provide a list of abbreviations for the entire manuscript.

Response 6:

We thank the reviewer for this comment. We expanded the Abbreviations section before the References to provide a list of abbreviations used throughout the manuscript. Newly added or clarified abbreviations include AC/A, AMIXT, ATOM2, D, DIMS, PD, PFV, PRA, and RCT, in addition to the abbreviations already listed.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript addresses an important and underexplored topic: the potential impact of low-dose atropine therapy on ocular alignment, binocular vision, and strabismus-related outcomes in children undergoing myopia control treatment. The topic is clinically relevant given the increasing global use of atropine and the growing number of reports describing binocular vision disturbances associated with treatment.

The manuscript is generally well written, logically organized, and provides a useful synthesis of both case reports and prospective studies. However, several methodological and interpretative issues limit the scientific rigor of the review and should be addressed before publication 

 

Narrative review methodology:

The authors describe the paper as a “structured narrative review”. Many elements resemble a systematic review. Specifically:

1. The search strategy is only broadly described
2. Exact search strings are not provided
3. No assessment of study quality of risk of bias is performed

 

As only 11 studies were included, a more rigorous systematic review methodology may have been more feasible.

 

Recommendation: provide the complete search strategy (as an appendix) and discuss why a narrative rather than a systematic review methodology was chosen

 

 

 

Over-emphasis on case reports relative to higher level evidence

Five of the eleven included studies are case reports/case series, which form much of the discussion and ultimately drive the review's conclusions.

• Case reports are inherently subject to publication bias.
• The incidence of these events cannot be estimated.
• Children with pre-existing binocular instability may have been predisposed regardless of atropine use.

Several sections imply causality when only temporal association has been demonstrated. Examples include statements suggesting atropine may "unmask latent binocular imbalance" or induce "esophoric stress."

Recommendation:
Use more cautious language throughout and emphasize that current evidence is insufficient to establish causation 

 

Potential conflict between included and supporting literature

The review formally includes 11 studies but subsequently discusses numerous non-included studies in detail (e.g., Woodman-Pieterse, Hughes, Mitsukawa, Sun, Joachimsen, Loughman, Adhikari, Kuo). While this broadens the discussion, it creates ambiguity regarding:

• which studies contributed to the review findings,
• which studies merely informed mechanistic interpretation.

Recommendation: Provide some clear distinction between evidence included in the review and supporting literature cited in the discussion. A dedicated subsection or separate table would improve clarity

Lack of critical appraisal:

All included studies are presented with approximately equal weight despite substantial differences in methodological quality. For example:

• AMIXT (n=300 randomized clinical trial)
• Breliant et al. (randomized study)
• Single-patient case reports

are discussed almost equivalently.

Recommendation:
Provide a structured assessment of methodological quality, such as:

• Newcastle-Ottawa Scale
• JBI critical appraisal tools
• Cochrane RoB 2 (for RCTs)

Even a qualitative appraisal would substantially strengthen the review.

Other comments:

Clarification of definition of low-dose atropine

The manuscript includes concentrations ranging from 0.01-0.05% but also includes a case involving escalating concentrations. Provide a clear definition early in the manuscript

Inclusion/Exclusion of papers to review

Include details on why papers were excluded at the full-text review stage.

Table 1 – consider adding column for follow-up duration

 

Terminology: Be consistent with terminology to improve readability. For example all of the following terms are used:

• "ocular alignment abnormalities"
• "strabismus-related findings"
• "ocular misalignment"

AMIXT trial

This is arguably the strongest study included  - place greater emphasis on sample size, design and lack of adverse BV effects. Isolate case reports are disproportionately weighted currently

Summary

This manuscript provides a valuable overview of a clinically relevant issue that has received limited attention in the myopia-control literature. The review successfully highlights that while isolated reports describe esodeviation and binocular disturbances during low-dose atropine therapy. The authors do provide an acknowledgment that prospective studies do not demonstrate clinically significant alignment deterioration. Limitations are described in detail and provide a fair perspective. This topic is clinically relevant and provides practical relevant information for clinicians managing pediatric myopia.

Author Response

I am grateful to the Editor and Reviewers for their thoughtful and constructive feedback, which helped improve the clarity, methodological transparency, and clinical relevance of the manuscript. In accordance with the comments, I revised the Abstract, Methods, Results, Discussion, and Conclusions, and I provide a detailed point-by-point response below.

• Reviewer 2

This manuscript addresses an important and underexplored topic: the potential impact of low-dose atropine therapy on ocular alignment, binocular vision, and strabismus-related outcomes in children undergoing myopia control treatment. The topic is clinically relevant given the increasing global use of atropine and the growing number of reports describing binocular vision disturbances associated with treatment.

The manuscript is generally well written, logically organized, and provides a useful synthesis of both case reports and prospective studies. However, several methodological and interpretative issues limit the scientific rigor of the review and should be addressed before publication 

Response:

We sincerely thank the reviewer for the positive and constructive assessment of our manuscript. We are pleased that the reviewer considered the topic clinically relevant and useful for synthesizing the available evidence on low-dose atropine, ocular alignment, binocular vision, and strabismus-related outcomes. We also appreciate the reviewer’s comments regarding methodological and interpretative limitations. In response, we revised the manuscript to improve methodological transparency, clarify the distinction between included studies and supporting literature, use more cautious language regarding causality, and better align the conclusions with the strength of the available evidence. Detailed point-by-point responses are provided below.

 

• Narrative review methodology:

Comments 1:

The authors describe the paper as a “structured narrative review”. Many elements resemble a systematic review. Specifically:

The search strategy is only broadly described

Exact search strings are not provided

No assessment of study quality of risk of bias is performed

As only 11 studies were included, a more rigorous systematic review methodology may have been more feasible.

Recommendation: provide the complete search strategy (as an appendix) and discuss why a narrative rather than a systematic review methodology was chosen

Response 1:

We thank the reviewer for this important comment. We agree that methodological transparency needed to be improved. In response, we added the complete database-specific search strategies as Supplementary Table S1, including the exact search strings, search fields, search date, language restrictions, and number of records retrieved for PubMed/MEDLINE and Web of Science Core Collection.

We also clarified why a structured narrative review design was chosen rather than a full systematic review. The available evidence was highly heterogeneous in study design, atropine concentration, participant characteristics, follow-up duration, and outcome measures, and included randomized or prospective studies as well as case reports and case series. Because case reports were clinically relevant for identifying rare ocular alignment or strabismus-related findings but were not suitable for quantitative pooling, our aim was to provide a clinically focused synthesis using a structured search, study selection, and data extraction process rather than to generate a pooled estimate of effect.

Finally, we added a methodological appraisal approach to the Methods section. We evaluated the interpretative weight of the evidence based on study design, sample size, presence of a control group, prospective or retrospective data collection, baseline assessment, follow-up duration, and whether ocular alignment or binocular vision was a primary or secondary outcome. We also clarified that case reports and case series were considered hypothesis-generating evidence and were interpreted separately from randomized and prospective clinical studies.

 

 

• Over-emphasis on case reports relative to higher level evidence

Comments 2:

Five of the eleven included studies are case reports/case series, which form much of the discussion and ultimately drive the review's conclusions.

Case reports are inherently subject to publication bias.

The incidence of these events cannot be estimated.

Children with pre-existing binocular instability may have been predisposed regardless of atropine use.

Several sections imply causality when only temporal association has been demonstrated. Examples include statements suggesting atropine may "unmask latent binocular imbalance" or induce "esophoric stress."

Recommendation:

Use more cautious language throughout and emphasize that current evidence is insufficient to establish causation

Response 2:

We thank the reviewer for this important comment. We agree that the original manuscript gave relatively strong emphasis to case reports and that the language needed to more clearly distinguish temporal association from causation. We revised the Discussion and Conclusions to use more cautious wording throughout.

Specifically, we added text emphasizing that randomized and prospective clinical studies provide stronger group-level evidence, whereas case reports and case series are hypothesis-generating and are inherently subject to publication and selection bias. We also clarified that the incidence of ocular alignment abnormalities cannot be estimated from the current evidence and that causality cannot be established.

In addition, we revised mechanistic statements that could be interpreted as causal. For example, we softened language suggesting that atropine may “unmask” latent binocular imbalance or induce “esophoric stress,” and instead described these findings as temporal associations observed in selected children with potentially vulnerable binocular systems. We also expanded the Limitations section to note that pre-existing binocular instability may have contributed to the reported events independently of atropine exposure.

 

• Potential conflict between included and supporting literature

Comments 3:

The review formally includes 11 studies but subsequently discusses numerous non-included studies in detail (e.g., Woodman-Pieterse, Hughes, Mitsukawa, Sun, Joachimsen, Loughman, Adhikari, Kuo). While this broadens the discussion, it creates ambiguity regarding:

which studies contributed to the review findings,

which studies merely informed mechanistic interpretation.

Recommendation: Provide some clear distinction between evidence included in the review and supporting literature cited in the discussion. A dedicated subsection or separate table would improve clarity

Response 3:

We thank the reviewer for this helpful comment. We agree that the distinction between formally included studies and supporting literature needed to be clearer. We revised the Methods section to clarify that only the eleven original studies meeting the eligibility criteria were included in the focused evidence synthesis, whereas other articles were retained only as supporting literature for background, mechanistic interpretation, broader safety context, or clinical management discussion.

To further improve clarity, we added Table 2, which explicitly distinguishes the formally included studies [10–20] from supporting mechanistic literature [21–23] and supporting clinical or contextual literature [24–30]. We also revised the Discussion to use the term “supporting literature” consistently when referring to articles outside the formal focused evidence synthesis. These revisions clarify which studies contributed to the review findings and which were used only for contextual or mechanistic interpretation.

 

• Lack of critical appraisal:

Comments 4:

All included studies are presented with approximately equal weight despite substantial differences in methodological quality. For example:

AMIXT (n=300 randomized clinical trial)

Breliant et al. (randomized study)

Single-patient case reports

are discussed almost equivalently.

Recommendation:

Provide a structured assessment of methodological quality, such as:

Newcastle-Ottawa Scale

JBI critical appraisal tools

Cochrane RoB 2 (for RCTs)

Even a qualitative appraisal would substantially strengthen the review.

Response 4:

We thank the reviewer for this important suggestion. We agree that the included studies should not be presented with equivalent interpretive weight because they differed substantially in study design, sample size, control conditions, follow-up duration, and outcome focus.

Because the included evidence was heterogeneous and included randomized trials, prospective or interventional studies, case reports, and case series, we did not apply a single formal risk-of-bias instrument across all studies, such as Cochrane RoB 2, the Newcastle-Ottawa Scale, or JBI critical appraisal tools. Instead, we performed a structured qualitative methodological appraisal, as suggested by the reviewer as an acceptable approach.

We added Table 3 to summarize the study design and sample size, main methodological strengths, and main limitations or interpretive weight of each formally included study. In the revised manuscript, randomized and prospective clinical studies, particularly the AMIXT randomized clinical trial, are clearly distinguished from single-patient case reports and case series. Case reports and case series are now described as hypothesis-generating evidence, whereas randomized and prospective studies are given greater interpretive weight for group-level conclusions.

 

• Other comments:

Comments 5:

Clarification of definition of low-dose atropine

The manuscript includes concentrations ranging from 0.01-0.05% but also includes a case involving escalating concentrations. Provide a clear definition early in the manuscript

Response 5:

We thank the reviewer for this comment. We clarified the definition of low-dose atropine early in the manuscript. In this review, low-dose atropine was operationally defined as topical atropine at concentrations from 0.01% to 0.05%, including 0.01%, 0.025%, 0.03%, and 0.05%. High-dose or higher-concentration atropine was defined as concentrations greater than 0.05%. We also clarified that reports involving dose escalation beyond 0.05% after initiation with low-dose atropine were interpreted separately from fixed low-dose atropine regimens.

 

Comments 6:

Inclusion/Exclusion of papers to review

Include details on why papers were excluded at the full-text review stage.

Response 6:

We thank the reviewer for this helpful comment. We revised the literature search results section to clarify the disposition of full-text articles that were not formally included in the focused evidence synthesis. Of the 16 full-text articles that were not formally included, 10 were retained as supporting literature for mechanistic interpretation, broader safety context, clinical management discussion, or contextual interpretation, whereas six were excluded after full-text assessment. The main reasons for exclusion were insufficient ocular alignment, strabismus-related, binocular vision, accommodative, or vergence outcomes interpretable in relation to ocular alignment; lack of a suitable pediatric low-dose atropine myopia-control context; or a combined optical/pharmacologic intervention design that did not allow atropine-specific ocular alignment or strabismus-related effects to be evaluated.

 

Comments 7:

Table 1 – consider adding column for follow-up duration

Terminology: Be consistent with terminology to improve readability. For example all of the following terms are used:

"ocular alignment abnormalities"

"strabismus-related findings"

"ocular misalignment"

Response 7:

We thank the reviewer for this helpful suggestion. We revised Table 1 by adding a separate column for “Follow-up or assessment window” and updated the corresponding Table 1 title and description in the Results section to improve readability.

We also reviewed the manuscript for terminology consistency. We standardized the wording by using “ocular alignment abnormalities” to describe objective deviations or changes in ocular alignment and “strabismus-related findings” as the broader term for clinically related findings, including diplopia, reduced fusion, elevated AC/A ratio, and convergence excess-type deviation. We minimized the use of the less specific term “ocular misalignment” and replaced it with “ocular alignment abnormalities,” “ocular alignment changes,” or “deviation” where appropriate.

 

 

Comments 8:

AMIXT trial

This is arguably the strongest study included  - place greater emphasis on sample size, design and lack of adverse BV effects. Isolate case reports are disproportionately weighted currently

Response 8:

We thank the reviewer for this important comment. We agree that the AMIXT randomized clinical trial should be given greater emphasis because it represents the strongest group-level evidence among the included studies.

In response, we revised the manuscript to highlight the key strengths of AMIXT, including its placebo-controlled randomized design, enrollment of 300 children, 12-month follow-up, and direct assessment of exotropia condition and binocular vision. We also clarified that AMIXT did not demonstrate adverse effects of 0.01% atropine on exotropia condition or binocular vision in children with stable basic-type intermittent exotropia.

In addition, we revised the Discussion and Conclusions to better balance the interpretation of clinical/interventional studies and isolated case reports. We emphasized that case reports and case series are clinically important but should be interpreted as hypothesis-generating observations rather than evidence of a group-level adverse binocular vision effect.

 

 

 

Comments 9:

This manuscript provides a valuable overview of a clinically relevant issue that has received limited attention in the myopia-control literature. The review successfully highlights that while isolated reports describe esodeviation and binocular disturbances during low-dose atropine therapy. The authors do provide an acknowledgment that prospective studies do not demonstrate clinically significant alignment deterioration. Limitations are described in detail and provide a fair perspective. This topic is clinically relevant and provides practical relevant information for clinicians managing pediatric myopia.

Response 9:

We thank the reviewer for the positive and constructive assessment of our manuscript. We are pleased that the reviewer found the topic clinically relevant, the limitations balanced, and the review useful for clinicians managing pediatric myopia. We have revised the manuscript further to improve methodological clarity, evidentiary balance, and readability, as detailed in the responses above.

Reviewer 3 Report

Comments and Suggestions for Authors

1. The abstract includes contractions, but the original term must also appear the first time. AC/A, NPC, NPA
2.  The literature identification flowchart should be included in the materials and methods section.
3.  At the end of Table 1, the terms IXT, NRA, PFA, PFV and RCT should be explained.
4.  3.3.1. This heading: Case-based evidence of esodeviation associated with low-dose atropine, may be changed to something like this: Esodeviation 3.3.2. Intermittent exotropia5. 3.2 Characteristics of the included studies. This should also be included in Materials and Methods.3.3.2. Correct these signs: and  ¯ 0.75 D, ¯0.11 mm, ¯0.11 mm
5.  Line 246, 249: OK, enter the contraction value.
6.  3.4.1. Consider changing the title to: Binocular vision. Accommodation. Fusional vergence.
7. 3.5 Overall pattern of the evidence. This section should be merged with the conclusions and removed from the results.
8. The discussion is long and complex. Consider dividing it into sections. 4.1. Discrepancy between case-based reports showing abnormalities and comparative studies 4.2. Most studies exclude high-risk binocular cases 4.3. Studies with disparity in atropine concentration and results to be compared. 4.4. Disparate accommodative response in response to atropine doses 4.5.Response in intermittent esophoria and exophoria 4.6. Low-dose atropine and exclusion criteria with strabismus or binocular vision criteria. 4.7. Discontinuation of atropine and near addition. 4.8. Different accommodative response depending on iris pigmentation and atropine concentration. 4.9.  Strengths and weaknesses of the article4.10. Future research
9.  Discussion: It is surprising that with a dropout rate of 20%-30%, some of the causes studied are not mentioned.
10.  References. The DOI is not required for articles that have pagination.

Comments on the Quality of English Language Since this is not a quantitative study, similar descriptive results appear in the introduction,
results, and discussion sections. This reviewer has attempted to create subheadings to facilitate
the reader's understanding.

Author Response

I am grateful to the Editor and Reviewers for their thoughtful and constructive feedback, which helped improve the clarity, methodological transparency, and clinical relevance of the manuscript. In accordance with the comments, I revised the Abstract, Methods, Results, Discussion, and Conclusions, and I provide a detailed point-by-point response below.

• Reviewer 3

Comments 1:

The abstract includes contractions, but the original term must also appear the first time. AC/A, NPC, NPA

Response 1:

We thank the reviewer for this helpful comment. In the revised Abstract, we ensured that the original terms appear at first mention before the abbreviations. Specifically, we revised the relevant terms as “accommodative convergence/accommodation (AC/A) ratios,” “near point of convergence (NPC),” and “near point of accommodation (NPA).”

 

 

Comments 2:

The literature identification flowchart should be included in the materials and methods section.

Response 2:

We thank the reviewer for this helpful suggestion. We moved the literature identification flowchart from the Results section to the Materials and Methods section. Specifically, Figure 1 is now placed immediately after Section 2.4, Study selection, where the literature identification and study selection process is described. The Results section retains the numerical summary of the search and selection results, but the flowchart itself is now presented in the Materials and Methods section as requested.

 

Comments 3:

At the end of Table 1, the terms IXT, NRA, PFA, PFV and RCT should be explained.

Response 3:

We thank the reviewer for pointing this out. We revised the footnote to Table 1 and expanded the list of abbreviations. Specifically, the terms IXT, NRA, PFA, PFV, PRA, and RCT are now explained in the Table 1 footnote. We also checked the abbreviation list for consistency throughout the manuscript.

 

Comments 4:

3.3.1. This heading: Case-based evidence of esodeviation associated with low-dose atropine, may be changed to something like this: Esodeviation 3.3.2. Intermittent exotropia5. 3.2 Characteristics of the included studies. This should also be included in Materials and Methods.3.3.2. Correct these signs: and  ¯ 0.75 D, ¯0.11 mm, ¯0.11 mm

Response 4:

We thank the reviewer for these helpful suggestions. We changed the heading of Section 3.3.1 from “Case-based evidence of esodeviation associated with low-dose atropine” to “Esodeviation” and changed the heading of Section 3.3.2 to “Intermittent exotropia.” We also revised the Materials and Methods section to clarify that study characteristics, including study design, participant age, atropine regimen, follow-up or assessment window, baseline assessment, evaluated parameters, and main findings, were extracted and summarized descriptively. In addition, we corrected and standardized the minus signs for negative values, including −0.75 D and −0.11 mm.

 

Comments 5:

Line 246, 249: OK, enter the contraction value.

Response 5:

We thank the reviewer for this comment. We have already addressed this point in the revised manuscript by defining OK at first mention as “orthokeratology (OK)” in Section 3.2 and by adding “OK, orthokeratology” to the abbreviation footnote of Table 1.

 

 

Comments 6:

3.4.1. Consider changing the title to: Binocular vision. Accommodation. Fusional vergence.

Response 6:

We thank the reviewer for this helpful suggestion. We changed the title of Section 3.4.1 from “Studies showing no significant deterioration in alignment-related measures” to “Binocular vision, accommodation, and fusional vergence” to more clearly reflect the contents of the subsection.

 

Comments 7:

3.5 Overall pattern of the evidence. This section should be merged with the conclusions and removed from the results.

Response 7:

We agree with the reviewer. Section 3.5, “Overall pattern of the evidence,” contained interpretive synthesis rather than primary results, and we therefore removed it from the Results section. Because this section had been added to clarify the balance of evidence between clinical/interventional studies and case-based reports, we did not delete its content entirely. Instead, we integrated its main message into the Discussion and Conclusions. In particular, we retained the emphasis that the AMIXT randomized clinical trial provides the strongest group-level evidence, whereas case reports and case series should be interpreted as clinically important but hypothesis-generating observations rather than evidence of a group-level adverse binocular vision effect.

 

 

Comments 8:

The discussion is long and complex. Consider dividing it into sections. 4.1. Discrepancy between case-based reports showing abnormalities and comparative studies 4.2. Most studies exclude high-risk binocular cases 4.3. Studies with disparity in atropine concentration and results to be compared. 4.4. Disparate accommodative response in response to atropine doses 4.5.Response in intermittent esophoria and exophoria 4.6. Low-dose atropine and exclusion criteria with strabismus or binocular vision criteria. 4.7. Discontinuation of atropine and near addition. 4.8. Different accommodative response depending on iris pigmentation and atropine concentration. 4.9.  Strengths and weaknesses of the article4.10. Future research

Response 8:

We thank the reviewer for this constructive suggestion. We agree that the Discussion was long and complex. To improve readability, we divided the Discussion into subsections. The revised Discussion now includes subsections addressing the discrepancy between case-based reports and comparative studies, exclusion of high-risk binocular populations from comparative studies, heterogeneity in atropine concentration, outcome measures, and assessment timing, dose-related accommodative and vergence responses, responses in intermittent exotropia and esodeviation-prone patients, clinical monitoring and binocular-vision exclusion criteria, discontinuation and near addition, atropine concentration and iris pigmentation, strengths and limitations, and future research. We also added a brief statement on the strengths of the review before the limitations section.

 

Comments 9:

Discussion: It is surprising that with a dropout rate of 20%-30%, some of the causes studied are not mentioned.

Response 9:

We thank the reviewer for this important comment. We revised the Strengths and limitations subsection of the Discussion to acknowledge that attrition or dropout in some included studies may have affected interpretation. We added that reasons for discontinuation were not consistently reported or were not always categorized according to visual discomfort, accommodative symptoms, diplopia, asthenopia, near blur, or binocular vision problems. Therefore, treatment-related near-vision or binocular symptoms may have been underestimated, particularly in studies with substantial attrition.

 

Comments 10:

References. The DOI is not required for articles that have pagination.

Response 10:

We thank the reviewer for this formatting comment. We checked the MDPI/Children reference style and confirmed that DOI numbers are not mandatory but are highly encouraged. Therefore, to remain consistent with MDPI reference style and because DOI information was already consistently provided, we retained DOI information in the reference list while checking the references for consistency in formatting, pagination, article numbers, and DOI presentation. We will of course follow any additional formatting instructions from the Editorial Office during copyediting.

 

Comments on the Quality of English Language

Since this is not a quantitative study, similar descriptive results appear in the introduction,
results, and discussion sections. This reviewer has attempted to create subheadings to facilitate
the reader's understanding.

Response :

We thank the reviewer for this helpful comment. We agree that, because this is a narrative review rather than a quantitative study, similar descriptive statements could appear across the Introduction, Results, and Discussion if the manuscript is not carefully organized. We therefore revised the manuscript to improve section-level distinction and readability. Specifically, the Introduction focuses on the clinical background and rationale, the Results section presents the included-study findings, and the Discussion focuses on interpretation, evidence weighting, clinical implications, limitations, and future research.

In addition, as suggested by the reviewer, we divided the Discussion into subsections to facilitate the reader’s understanding and reviewed the manuscript to reduce unnecessary repetition between sections. The revised manuscript has also undergone professional English-language editing by Editage before resubmission.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for considering my suggestions.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have made significant changes to the manuscript resulting in a paper now ready for publication - well done 

Reviewer 3 Report

Comments and Suggestions for Authors The changes requested by the reviewer have been made. Comments on the Quality of English Language With the changes made, the expression of the article is clearer
and more understandable than in the initial version.