PONE-D-20-07281

­­­­­­­­­­­­­­­­­­­Botulinum toxin injection without electromyographic guidance in consecutive esotropia

PLOS ONE

Dear Dr. Hwang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

I-Jong Wang

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Partly

Reviewer #6: Yes

Reviewer #7: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: No

Reviewer #6: Yes

Reviewer #7: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thanks for your great sharing about using botulinum injection without EMG guide for consecutive esotropia patients. This method provides another option for the consecutive esotropia patients before they receive another surgical treatment on their extraocular muscles. However, I have several questions as followings:

1. The authors mentioned about botox injection on both medial rectus muscles. How about the cases with previous unilateral R and R (Resection and Recession) surgery? Did they also receive botox injection on their bilateral medial rectus muscles? Why not just inject on the previous operated eye only?

2. The authors didn’t mention about their dosage of botox injections in detail. How did you decide whether 6 U or 12 U for application? Is there any correlation between the dosage of botox and the success/failure effect?

3. How about the stereopsis or the suppression status of the patients? Were there any evaluations pre-op or post-op? Did better stereopsis result in better final outcome?

4. What kind of topical anesthesia agents were applied? The authors didn’t mention about it. Please clarify it.

5. How about the preoperative angle of deviation before the previous surgery, the age onset of XT, type of XT, and the age of previous XT surgery? Any clinical significance or relationships noted among these factors about success/failure?

Reviewer #2: Manuscript title: Botulinum toxin injection without electromyographic guidance in consecutive esotropia

General comments: The study aimed to investigate the efficacy of botulinum toxin injection without electromyographic assistance in treating consecutive esotropia following previous strabismus surgery. Consecutive esotropia is a condition in which strabismus is observed in the direction opposite to the initial exotropic drift prior to surgery. Many studies have reported better long-term outcomes in patients with an initial overcorrection, however overcorrection persists in some patients and reoperation may be warranted. The manuscript focuses on a relatively understudied group. They analyzed 52 subjects retrospectively and report that, with topical botulinum toxin injection without the use of electromyography, a remarkable 71.2% patients had their esotropia resolved without the need for a second surgical procedure, and only 7.7% of patient developed transient complications. The clinical effectiveness and safety appeared comparable to those with electromyographic guidance. Some issues in the methodology and the conclusion drawn from the analysis for the purpose of this study should be addressed.

1. The diagnosis of all subjects included in the study before exotropia surgery were not clearly mentioned. There are many subtypes of exotropia even after excluding paralytic and restrictive etiologies. A brief description for exotropia classification adopted in this study would help readers gain a greater understanding of study groups characteristics. Meanwhile, considering that treating muscles that had undergone previous surgery may have different effect, the type of exotropia surgery performed in the past were also not clearly introduced in the current version of manuscript. This is also important because lacking such characteristics would hinders clinical applications. A table reporting the basic demographics, subtype of exotropia, type of previous surgery, and other variables of interest may solve these issues and improve readability.

2. Injection technique without electromyographic guidance is actually a blind injection and requires practice. Although most of the complications resulted from drug extravasation were transient, the symptoms of vertical diplopia and ptosis were annoying. The authors reported a relatively low complication rates compared with previous reports. Hence the skills and tools used or avoided in the study are worth more descriptions with sufficient detail. (for instance, the methods of reconstitution of botulinum toxin, the angle of injection plane, whether or not medial rectus muscle grasping with forceps, or instructions of patients care).

3. I have two questions about the data present in the table 1. First, the PD value in the esodeviation at 6 months after injection had a much small standard deviation in the failure group ( ± 1.6 ), an explanation is needed. Second, the success group seemed to have a greater change in PD at 2 weeks from baseline compared to the failure group. The dose of botulinum toxin standardized according to the deviation angle (PD/Unit) might be different between success and failure group. A statistics analysis showing no difference between the groups is needed to exclude this possibility. Indeed a significant post-operative variables as a predictor of post-operative success may be of little clinical significance especially when the variables seemed to be highly correlated with the grouping criteria in a retrospective study design.

4. The results of multivariate logistic analysis could be represented in different methods but should not be partially revealed by a few sentences.

Reviewer #3: The authors describe the efficacy and safety of botulinum toxin injection without using EMG for consecutive ET clearly. In addition, the manuscript identifies the predictive factors of success after botulinum toxin injection. Minor points to consider in subsequent versions:

1.The manuscript highlights that immediate success at 2 weeks after botulinum injection was the only significants factor of success. Would your consider to emphasize the result in Abstract to different from other similar published literature?

2.Page 7: The predictive factors were well determined, including previous MR resection. However, the surgical methods for XT was not discuss completely in the study. In current surgical approaches, including unilateral LR recession and MR resection, bilateral LR recession and involving three or four horizontal rectus, which one might get most benefit from botulinum toxin injection? Please discuss the influence of previous surgical methods for XT.

3.Page 6: Seventy-one percents of patients received only one injection with good outcome in your study. Please analyze the risks for repeat injections.

4.Page 5: Please describe the procedure of botulinum injection more completely. Do you grape the insertion of MR muscle while injection? Some surgeon hold the needle in place for 5-10 seconds after injection. Do you do the same protocol or not? How do you adjust the distance from limbus (line 86: 8-10 mm mentioned) in children and adults (range of age: 7-66 years in Results)? Is the location of injection the same or different?

5.Page 6: The range of internal form previous strabismus surgery to the time of botulinum toxin injection was large (line 113: 4-151 months). What is your consideration in early and later intervention? Please describe in the section of Discussion.

6.Line 308: Please cite the newest reference “ Botulinum toxin for the treatment of strabismus. Cochrane Database Syst Rev. 2017 Mar 2;3:CD006499. doi: 10.1002/14651858. CD006499.pub4.” instead of the 2012 old one.

Reviewer #4: This is an interesting reserch and written properly. However, there are some questions need to be answered:

1. How was the dosage determined prior to injection? In line 88, determined by the angle of esodeviation, does it mean how many IU for how many prism diopter?

2. Did you inject unilateral or bilateral medial rectus muscles?

3. In line 87, teh 6-12 IU refers to does per injection or total injection per case? Same question goes to line 117

4. Finally, do you compare these cases to nature course? (consecutive ET nature course)

Reviewer #5: Materials and Methods

1. No information about conservative treatment (watching, patching or prism glasses) before injection. When is the optimal time of botulinum toxin injection for treating a case with consecutive esotropia?

2. Line 86 vs Line 116: dosage of botulinum toxin ranged from 6-12 IU vs 3-12 Which one is correct?

3. Line 87: the angle of esodeviation ranging from 6 to 45 PD � So you included the cases whose esodeviation angle before injection is less than 10 PD ?

Result

1. Line 110: The mean interval from strabismus surgery to the time of botulinum toxin injection was 47.3±39.o moths (range, 4-151months)

� Most patients with consecutive esotropia resolves spontaneously in one year. How many cases with consecutive esotropia have botulinum toxin injection within one year (or 6 months) after strabismus surgery?

2. Please give more details of the dosage of botulinum toxin, the mean interval from strabismus surgery to the time of first injection, and the amount of esodeviation over time.

Discussion

1. You did not discuss how to exclude the possibility of spontaneous recover so that we can evaluate the efficacy of botulinum toxin properly.

2. More details about the dosage of botulinum toxin still can inspire the readers even though the dose effect cannot be standardized because of various types.

3. Overcorrection with an exotropia of ≥ 10PD at distance was found in 11 patients at two weeks after treatment but resolved within 3 months. This means nearly all overcorrected cases at 2 weeks after treatment are in failure group in the end. What do you think about this? Why dose botulinum toxin only cause permanent impact in some cases?

Reviewer #6: The concept behind the paper is interesting. That is helping ophthalmologists to choose the ideal strategy to deal with the troublesome postoperative consecutive strabismus.

1. There are lots of grammar mistakes in the article. And several repeated sentences noted (Exp. Line 67&104). Please do the grammar check.

2. The authors need to clarify in the ethics approval the IRB number.

3. The authors need to explain the rational why they performed “subconjunctival injection” rather than “subtenon injection”.

4. Is there any association between the pre-op deviation/surgical procedure and the injection outcome?

5. The short-term complication rate in this study is very low (7.7%). Ptosis/vertical deviation/overcorrection presented much frequently in literature (21-33%). Please share the pearls of reducing complications?

6. The success rate in the study is excellent. However, the 6-month-f/u time is too early to judge the long-term success. I would like to know the outcome after 12-month f/u.

Reviewer #7: The authors conducted a retrospective study on 52 subjects with consecutive esotropia who underwent botulinum toxin injection in the medial rectus muscles without the use of electromyographic guidance. At 6-months, 71.2% showed successful alignment, which is comparable to unilateral medial rectus muscle recession surgery. They also found immediate success at 2 weeks after botulinum injection is predictive of success after 6 months.

Comments

1. Did the authors investigate the type of surgery(bilateral lateral rectus muscle recession or unilateral lateral rectus muscle recession + medial rectus muscle resection/plication) before botulinum injection affect the success?

2. Why did the authors use such Botulinum doses, which is slightly larger than previous studies? Do the injection dose follow the same protocol?

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Reviewer #1: No

Reviewer #2: Yes: Chia-Wei Lee

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

Reviewer #6: No

Reviewer #7: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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PONE-D-20-07281R1

­­­­­­­­­­­­­­­­­­­Botulinum toxin injection without electromyographic guidance in consecutive esotropia

PLOS ONE

Dear Dr. Hwang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 17 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

I-Jong Wang

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

Reviewer #6: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Authors,

Thanks for your responses and explanations in detail.

Botulinum injection without EMG guide indeed needs greater care of the localization of the injection site very precisely. Thanks for sharing this method and your outcomes in treating consecutive esotropia with us. There are several points need to be explained more clearly.

1. As the authors mentioned, the dosage of the Botulinum injection differed throughout the whole study. Therefore, it is difficult to compare them all on the same basis. Please persuade us that they are comparable in the discussion.

2. How about classifying them into subgroups of different doses of Botulinum to see if there are any differences in the success/failure rate and to clarify the optimal dosage.

3. The differences of the dosages of Botulinum and treatment outcomes between previous EMG-guided injection studies and the authors' study should be mentioned.

Reviewer #2: The authors had adequately addressed all my comments and revised their manuscript. Only two trivial questions remained.

1.In table 2, the variables "Immediate success at 2 weeks after injection " is duplicated.

2.The revised manuscripts showed that initial postoperative esodeviation of less than 18 PD at one month after exotropia remained a significant predictive factor of success. I am interested in how the authors determine this cu-toff value of PD. (for example, via ROC curve analysis ?)

Reviewer #4: The author has answered most of the questions proposed, however, in table 2, the last line duplicates the 3rd line and should be revised.

Reviewer #5: It is great that those 3 patients with 6-8 PD of esotropia before injection had improved after Botulinum toxin injection. However, it is controversial to include these 3 cases who meet the definition of the success group at the beginning.

Reviewer #6: Thank you for the revision.

Please clarify the Esodeviation at near before injection in the abstract.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #4: No

Reviewer #5: No

Reviewer #6: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

­­­­­­­­­­­­­­­­­­­Botulinum toxin injection without electromyographic guidance in consecutive esotropia

PONE-D-20-07281R2

Dear Dr. Jeong-Min Hwang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

I-Jong Wang

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #4: (No Response)

Reviewer #5: (No Response)

Reviewer #6: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: Thanks for your responses to the rest of my questions. I think the manuscript is ready for publication.

Reviewer #4: (No Response)

Reviewer #5: (No Response)

Reviewer #6: The authors had adequately addressed all my comments and revised their manuscript.

I have no further comments.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #4: No

Reviewer #5: No

Reviewer #6: No