Current Management of Amblyopia with New Technologies for Binocular Treatment

Round 1

Reviewer 1 Report

The authors have addresses all of my concerns in their revised version.

Author Response

We thank the reviewer for such gratifying comment.

Author Response File: Author Response.docx

Reviewer 2 Report

The authors have made several modifications, but the manuscript includes little critical analysis, which is an important part of any review. Improvements in visual acuity of about 1 to 1.5 lines are reported as significant, and they may well be statistically significant, but it is important to question whether they are clinically significant. They are within test-retest levels for amblyopes, which suggests they might be largely due to practice or similar effect.

Author Response

We thank the reviewer for such constructive comment, which clearly improves our work. We are agree that improvements fewer than 1.5 lines could be due to practice or test-retest repeatability for amblyopes. In this review we had highlight this aspect in page 8 lines 15-17. Furthermore, we had included this annotation at the beginning of the conclusions (page 14 lines 20-22). 

Author Response File: Author Response.docx

Reviewer 3 Report

I consider this MS as an interesting review of amblyopia treatment that could be of interest for our readers (espacially updating modern technologies). However it needs a major revision before further consideration of publication process. The major problem is the structure of manuscript, specific: 1. The introdcution section is too short and should include both the definition and types of amblyopia. 2. In the material and methods section please add information about the number of articles found and the ethical statement 3. The following results section or treatments section should be divided into two subsections classical & modern treatments or monocular & binocular treatments. 4. The discussion section is too short and should include the comparison of previous subsections (classical vs modern treatments or monocular vs binocular treatments) and also the limitations. 5. Current shape of conclusions sections looks rather like a part of discussion section so the authors should re-write it and draw only conclusions supported by the review results (one or two not too many)

Author Response

1. The introduction section is too short and should include both the definition and types of   amblyopia. 

  

Response: We thank the reviewer for such constructive comment. We had made several modifications and now the introduction contains the definition and types of amblyopia (page 1 lines 26-39; page 2 lines 1-32).  

  

2. In the material and methods section please add information about the number of articles found and the ethical statement.

 

Response: We thank the reviewer for such positive comment and valuable input. We had completed the methods section with an explanation about the process followed in the search carried out. The number of articles found and the ones that had been used is specified in this section (page 2 lines 40-42; page 3 lines 1-2). Besides, a brief ethical statement had been included (page 3 line 3). 

  

3. The following results section or treatments section should be divided into two subsections classical & modern treatments or monocular & binocular treatments.  

 

Response: We thank the reviewer for such useful comment, which clearly improves our work. The treatment section had been divided into two subsections: classical (from page 3 line 16) and modern treatment (from page 5 line 24), which improves the understanding of the topic. 

  

4. The discussion section is too short and should include the comparison of previous subsections (classical vs modern treatments or monocular vs binocular treatments) and also the limitations.

  

Response: We thank the reviewer for such constructive annotation. We have enhanced the discussion section including comparisons between classical treatments (such as patching and optical correction) with modern treatments, and also, we have compared placebo and active video games (page 13 lines 26-36; page 14 lines 1-11). 

 

5. Current shape of conclusions sections looks rather like a part of discussion section so the 

authors should re-write it and draw only conclusions supported by the review results (one or two not too many). 

 

Response: We thank the reviewer for such constructive comment, which clearly complete our work. We have rewritten the conclusion section highlighting the effects of visual acuity after binocular treatments, the importance of the compliance and the treatment hours and the necessity of future investigations (page 14 lines 20-31). 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The revisions include additional wording in the Conclusion to the effect that innovative treatments for amblyopia do improve visual acuity, yet the improvements are not necessarily significant. In addition to concerns I have raised in previous rounds of review, this is problematic because it suggests the improvements are important while they are not significant.

Author Response

Response: We thank the reviewer for such constructive comment. We had rewritten some paragraphs for the purpose of clarify this subject (page 7 lines 12-15; page 10 lines 33-35; page 11 line 29). It is true that it was mentioned that in general there was a visual acuity improvement –being or not being statistically significant-. Currently, in the discussion section it is specified this aspect and we had mention all the studies that had an improvement not statistically significant and the ones where the improvement was greater than or equal to 1.5 logMAR lines (page 14 lines 28-32). 

Author Response File: Author Response.pdf

Reviewer 3 Report

I am partially satisfied with authors reply. The MS still needs a minor correction. Specific 1. Introduction- paragraph 1.5 should be added before the types of amblyopia. 2. There should be the aim of the study at the end of introduction 2. The numeration of sections should be corrected 3. The first two paragraphs of the conlusions section should be added into the discussion section as well as the limitations of the present study 4. Please leave only last paragarph as conclusions in the conclusion section

Author Response

I am partially satisfied with authors reply. The MS still needs a minor correction. Specific  

1. Introduction- paragraph 1.5 should be added before the types of amblyopia. 

 

Response: We thank the reviewer for such useful comment, which clearly improves our work. We had changed the paragraph 1.5 before the types of amblyopia (page 1 line 26). 

 

2. There should be the aim of the study at the end of introduction.

 

Response: We thank the reviewer for such constructive comment. We had written the aim of the study (page 1 line 37-39). 

 

2. The numeration of sections should be corrected 

 

Response: We thank the reviewer for highlight this aspect. The numeration had been corrected (page 1 line 26; page 2 lines 1, 6, 14, 25, 31). 

 

3. The first two paragraphs of the conclusions section should be added into the discussion section as well as the limitations of the present study.

 

Response: We thank the reviewer for such constructive comment, which clearly improves our work. The first two paragraphs had been improved and added into the discussion section (page 14 lines 28-37). Furthermore, we had written the primary limitation of this study in the discussion section (page 14 lines 26-27). 

 

4. Please leave only lastparagraphas conclusions in the conclusion section. 

 

Response: We thank the reviewer for such constructive annotation. Now in the conclusion section there is only the mentioned paragraph (page 14 lines 40-44). 
 

Author Response File: Author Response.pdf

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

This is an interesting review on new approaches for amblyopia treatment. No information is provided on methods used in literature search or appraisal of previous research, and this is fine because it is a narrative rather than systematic review, but there is no evidence of critical appraisal of the research. Previous findings on amblyopia treatment are stated and references appropriately cited but there is no indication of the reliability of the research. As a result the reader cannot judge whether the findings discussed here are flawed.

On page 2, amblyopia treatments based on perceptual learning are introduced, and they are discussed on page 3. The main technique included here is the 'rotating grating' method. It is stated that visual acuity is improved with this method, but in fact subsequent research showed that similar improvements are found with or without the gratings. No specific mention is made of this, and there is no discussion of a large body of more recent research testing a range of perceptual learning approaches for amblyopia. 

When patching is discussed, it is stated that near tasks are also used, but in fact the PEDIG group (2008) found near and distance tasks to have similar effects on amblyopia treatment success.

In discussion of the 'falling blocks' game for amblyopia treatment, a 1.5 line improvement is reported  (end of page 7), but this level of improvement may be similar to test-retest repeatability (systematic review and meta-analysis by Tsirlin et al, 2015) and may not be clinically significant for amblyopes. Points such as this should be considered.

Other points:

The writing needs to be improved throughout; currently spelling is good but grammar and expression is poor in places, and there is some repetition (page 6: description of falling blocks at interocularly different contrast).

Figure 2 seems superfluous.

Reviewer 2 Report

General comments

 

This is a review on novel binocular treatments for amblyopia, which presents in detail several new technologies. Although the main studies in the field are mentioned, the paper should also include the authors’ own opinion / conclusion on the topics discussed. The main problem of this paper is that it simply lists previous studies without comparing them, making any suggestions for future improvements.

I would strongly suggest editing by a native English speaker, as there are many grammatic and syntax errors throughout the paper.

Detailed comments

In the definition of amblyopia in introduction, I suggest also adding the term “lazy eye”, as it is widely used by healthcare personnel as well.

 

Line 30

The authors state “Moreover, is possible to have an isoametropic amblyopia if both eyes have a similar refractive error and both become amblyopic.” It should be specified that this holds true for cases where a high degree of refractive error occurs in both eyes.

 

Line 34

Which are the “… certain types of anisometropia” where suppression is observed?

 

Line 57, please rewrite

“It may be the result of iatrogenic excessive patching or atropine penalization of the dominant or non-amblyopic eye during amblyopia treatment.”

 

Line 61, please insert title for paragraph, i.e. suppression and cortical plasticity

 

Line 61 “Amblyopia has a direct impact on visual confusion and diplopia”. Amblyopia does not have a direct “impact” on confusion and diplopia. I would rather state that Amblyopia is associated with….

 

Line 63, please rewrite “neural suppression removes the worst image so the owning eye becomes amblyopic.”, to “the brain suppresses or ignores the inputs from the weaker eye under binocular viewing conditions, so it becomes amblyopic.”

 

Lines 64-66 please rewrite the sentences “Suppression was a secondary consequence of the monocular loss of function in amblyopia, so a weaker suppression is associated with poorer monocular vision in the amblyopic eye. This is because there would be less information to suppress in patients with deeper amblyopia (10).”

It is very difficult to understand the meaning.

 

Line 86 Optical treatment is also called refractive adaptation

 

Line 89

Please correct “have demonstrated”

 

Line 92

What does “increased with treatment duration” mean? Please explain. I guess the authors try to summarize that refractive adaptation works gradually for up to 30 weeks. However, it has been suggested that the improvement in visual acuity in the amblyopic eye is considerable at 4 to 12 weeks

then reaches a plateau, after which it improves only slowly.  Literature [11] and [12]

 

line 111

correct “the most common…”

 

Lines 113-115

The authors refer to a study by Seol et al. regarding the use of atropine. However, there is considerably more publishes papers on this issue and the authors could add 2-3 sentences on that, i.e. weekend vs daily atropine etc.

• Pediatric Eye Disease Investigator Group (2002) A randomized

trial of atropine vs. patching for treatment of moderate amblyopia

in children. Arch Ophthalmol 120:268–278

• Repka MX, Cotter SA, Beck RW, Kraker RT, Birch EE, Everett

DF, Hertle RW, Holmes JM, Quinn GE et al (2004) A randomized

trial of atropine regimens for treatment of moderate amblyopia in

children. Ophthalmology 111:2076–2085

• Pediatric Eye Disease Investigator Group (2003) The course of

moderate amblyopia treated with atropine in children: experience

of the amblyopia treatment study. Am J Ophthalmol 136:630–639

 

Line 116

Please explain the mechanism of action of levodopa/carbidopa and relevant literature. i.e.

For the retinal mechanism of action, it has suggested that increased dopamine levels lead to shrinkage in the size of the receptive field, thereby improving visual acuity. For cortical mechanism, it has been hypothesized that increased dopamine levels produce a reduction in the size of the suppression scotoma, thereby, improving visual acuity.

 

Line 133, please include further limitations for perceptual learning, i.e. The criticism of the perceptual learning approach includes the small number of study participants, the task-specific gains that do not transfer to novel situations, the need for homebased training systems, and the lack of sustained effects and long-term follow-up. From Papageorgiou E, Asproudis I, Maconachie G, Tsironi EE, Gottlob I. The treatment of amblyopia: current practice and emerging trends. Graefes Arch Clin Exp Ophthalmol. 2019 Jun;257(6):1061-1078.

 

Line 138

Please explain the rationale of using binocular treatments for amblyopia, i.e. These novel strategies are based on simultaneous binocular visual stimulation (dichoptic treatment) and aim not only to improve visual acuity in the amblyopic eye, but also to promote binocular function and stereoacuity.

• Sengpiel F. Plasticity of the visual cortex and treatment of amblyopia. Curr Biol. 2014 Sep 22;24(18):R936-R940.

 

 

Which are the references for the developers of Dig Ruch game, falling blocks, Occlu-Pad and vivid vision?

 

Can you provide figures for Occlu-Pad and vivid vision?

 

For each of these types of binocular treatments, the authors should state the advantages and disadvantages of the methods along with their personal judgement of the effectiveness, instead of simply listing other studies’ results.

 

Conclusions

The authors strongly favor the use of binocular treatments in amblyopia therapy. However, this is not clearly supported by randomized controlled trials and this should be mentioned. i.e. from Papageorgiou et al. “Research on binocularity systems in adults and children have yielded promising results, but the most recent RCTs have shown small effects on VA and have failed to demonstrate non-inferiority over standard treatments.”

 

• Tsirlin I, Colpa L, Goltz HC, Wong AM (2015) Behavioral training

as new treatment for adult amblyopia: a meta-analysis and

systematic review. Invest Ophthalmol Vis Sci 56:4061–4075

• Holmes JM, Manh VM, Lazar EL, Beck RW, Birch EE, Kraker

RT, Crouch ER, Erzurum SA, Khuddus N et al (2016) Effect of a

binocular iPad game vs part-time patching in children aged 5 to 12

years with amblyopia: a randomized clinical trial. JAMA

Ophthalmol 134:1391–1400

• Manh VM, Holmes JM, Lazar EL, Kraker RT,Wallace DK, Kulp

MT et al (2018) A randomized trial of a binocular iPad game

versus part-time patching in children aged 13 to 16 years with

amblyopia. Am J Ophthalmol 186:104–115

• Gao TY, Guo CX, Babu RJ, Black JM, Bobier WR, Chakraborty

Aet al (2018b) Effectiveness of a binocular video game vs placebo

video game for improving visual functions in older children, teenagers,

and adults with amblyopia: a randomized clinical trial.

JAMA Ophthalmol 136:172–181

• Holmes JM, Manny RE, Lazar EL, Birch EE, Kelly KR, Summers

AI et al (2018) A randomized trial of binocular Dig Rush game

treatment for amblyopia in children aged 7 to 12 years of age.

Ophthalmology S0161-6420:32304–32302.

Reviewer 3 Report

The aim of this paper was to review the effectiveness of recently developed treatments for amblyopia. This is an interesting topic, which has been recently reviewed by Pineles et al (Binocular Treatment of Amblyopia: A Report by the American Academy of Ophthalmology. Ophthalmology. 2020 Feb;127(2):261-272. doi: 10.1016/j.ophtha.2019.08.024. Epub 2019 Oct 13. PMID: 31619356.)

I'm afraid the submitted manuscript overlaps significantly with the published article, and the current work does not add any new insights. Furthermore, the manuscript lacks depth and critical synthesis. The description of studies reviewed was not consistent in terms of sample studies (ages, acuity deficits, stereo measures, etc) - sometimes these variables were reported but not in all cases. The effects of studies are not reported in a meaningful way, for example, effect size is an important outcome to report which conveys the clinical importance, rather than saying that an effect is significant or not. Most importantly, a discussion of potential factors that could influence the variability of findings across different studies was included.