A Straightforward Approach to Analyze Skeletal Muscle MRI in Limb-Girdle Muscular Dystrophy for Differential Diagnosis: A Systematic Review

Round 1

Reviewer 1 Report

The manuscript is interesting, however it needs considerable improvements and rewriting before being eligible for publication.

1.     The introduction should be expanded and dystrophies should be briefly summarised.

2.     The method section should be more concise and better structured.

3.     Tables 1 and 2 are half missing so it is hard to evaluated them. Also, the abbreviations used in tables should be clarified in table captions. The tables are also too large and not easily appreciated. Consider keeping only data that is relevant to the reader to understand the conclusions in the manuscript and move all other to the supplementary.

4.     The discussion should be expanded and rewritten in a way that flows better and highlights the main findings of the study.

Author Response

The manuscript is interesting, however it needs considerable improvements and rewriting before being eligible for publication.

1.     The introduction should be expanded and dystrophies should be briefly summarised.

  > Thank you for your advice. We added a brief explanation of LGMD in the introduction

2.     The method section should be more concise and better structured.

  > Thank you for your suggestion. We have re-edited the entire paper, with the methods themselves described concisely and the detailed sections as supplements so that the flow of the paper is more straightforward to grasp.

3.     Tables 1 and 2 are half missing so it is hard to evaluated them. Also, the abbreviations used in tables should be clarified in table captions. The tables are also too large and not easily appreciated. Consider keeping only data that is relevant to the reader to understand the conclusions in the manuscript and move all other to the supplementary.

  > Thank you for your comment. The tables inserted in the text were limited to basic tables summarizing the number of people, ages, etc. of representative genotypes. Other data has been moved to the supplement as a reference for readers.

4.     The discussion should be expanded and rewritten in a way that flows better and highlights the main findings of the study.

  > Thank you for your comments. The discussion has been rewritten in its entirety, taking into account input from other reviewers.

Reviewer 2 Report

Morishima and Schoser reviewed articles on MRI images of adult limb-girdle muscular dystrophy (LGMD) cases. Dozens of causative genes for LGMD have been identified and clinical features alone are not sufficient to diagnose the subtype of LGMD. Hence, genetic testing is necessary for the final diagnosis. On the other hand, MRI imaging has revealed characteristic and sometimes unique patterns of affected muscles for each subtype. Therefore, a detailed analysis of MR image characteristics provides valuable diagnostic clues. The authors conducted a systematic review, searching for articles including grey literature. The methods of review are sound and well-described. The illustration in Fig.4 is clear and useful. 

Since the paper focused on LGMD, the number of the finally selected articles is smaller than the published papers of Leung. Given that clinicians cannot a priori discriminate LGMD from other myopathies, a broader scope is desirable for this type of study. Even though, discrimination among LGMD before or without genetic analysis would be helpful in clinical settings. Regarding the comparison with Alawneh's study, the description below is unclear to the reviewer. Please rephrase it to ensure readers can easily understand the meaning.

Lines 400-402,

These findings can be largely categorized as either [1] the present study was not sufficient in sample number (R9/R12/R19) or [2] describes a pattern of fat infiltration within the muscle, both of which could still be true simply

What is the subject of the phrase “describes a pattern of fat infiltration” ?  The brackets [1] and [2] are the same as the citation, causing potential confusion. Please use a different style of bracket, such as <1>.

The main concern is the discrepancy in the number of cited original papers between this manuscript and Alawneh’s paper. This is likely due to differences in inclusion and exclusion criteria. Please elaborate on these differences and explain the criteria used.

Minor points

The authors mentioned a total of 167 references in line 158, followed by “128 records” in line 159, and “39 studies” in line 162. The use of both terms “records” and “studies” might confuse readers. Please consider clarifying this.

The description “If the name of the individual muscle included in the image is known,” in line 251 is unclear. Does this sentence mean that “the name of muscle is explicitly stated”?

Please insert a line between lines 374-375 and 403-404 for improved formatting.

What does the letter “L” and the mark “X” in Fig.4 represent? Please explain in the legend.

In line 4, please add a punctuation mark after “adults”. (adults. The)

Author Response

Lines 400-402,

These findings can be largely categorized as either [1] the present study was not sufficient in sample number (R9/R12/R19) or [2] describes a pattern of fat infiltration within the muscle, both of which could still be true simply

What is the subject of the phrase “describes a pattern of fat infiltration” ?  The brackets [1] and [2] are the same as the citation, causing potential confusion. Please use a different style of bracket, such as <1>.

  > Thank you for your comments. I meant that the first part indicates the degree of disability within the same muscle. I have rewritten it to be more clear. I have also corrected the second half of your point.

The main concern is the discrepancy in the number of cited original papers between this manuscript and Alawneh’s paper. This is likely due to differences in inclusion and exclusion criteria. Please elaborate on these differences and explain the criteria used.

  > Thank you for your comment. I have noted in the Methods section and the Introduction the differences from Alawneh's study, with the significant difference being the inclusion or exclusion of a single case report (we have excluded a single case report from our study).

Minor points

The authors mentioned a total of 167 references in line 158, followed by “128 records” in line 159, and “39 studies” in line 162. The use of both terms “records” and “studies” might confuse readers. Please consider clarifying this.

  > Thank you for your comment. We have reviewed the full text and standardized everything to STUDY.

The description “If the name of the individual muscle included in the image is known,” in line 251 is unclear. Does this sentence mean that “the name of muscle is explicitly stated”?

  > Thank you for your comment. You correctly stated. This wording is easier to understand, and we have modified it as is.

Please insert a line between lines 374-375 and 403-404 for improved formatting.

  > Thanks for the comment, it seems the spaces were lost during the conversion to pdf. We have corrected it.

What does the letter “L” and the mark “X” in Fig.4 represent? Please explain in the legend.

  > Thank you for your comments. I have added each of them.

In line 4, please add a punctuation mark after “adults”. (adults. The)

  > Thank you for your comments. I have added a period.

Reviewer 3 Report

Ryo Morishima and Benedikt Schoser

An Approach to Make Skeletal Muscle MRI in limb-girdle Muscular Dystrophy a Simple and Useful Method for Differential Diagnosis: A Systematic Review.

Summary:
This exciting review focuses mainly on the skeletal muscle MRI in limb-girdle muscular dystrophy(LGMD). Overall this review is excellent as it summarizes the research done so far and it will be a very good resource for those interested in learning about MRI and LGMD. There are a lot of pieces of information and most of the tables are big and very hard to follow.

Minor comments:
- I know this review talks about the MRI aspect, but some introductions about LGMD and its types are missing.
-Is there any way to make Table 1 more readable?
-Figure 3 looks very complex and a lot of information and a few columns could be omitted to make it more clear.
-I really like the discussion section of this review. Similarly, I would like to see the author's future recommendations (it is there, although they are not highlighted well) in a different table or section that could be used as a guideline for future research or clinical trials. So, the data coming from various studies can be combined and analyzed.

Author Response

Summary:
This exciting review focuses mainly on the skeletal muscle MRI in limb-girdle muscular dystrophy(LGMD). Overall this review is excellent as it summarizes the research done so far and it will be a very good resource for those interested in learning about MRI and LGMD. There are a lot of pieces of information and most of the tables are big and very hard to follow.

  > Thank you for your comment. The tables inserted in the text were limited to basic tables summarizing the number of people, ages, etc. of representative genotypes. Other data has been moved to the supplement as a reference for readers.

Minor comments:
- I know this review talks about the MRI aspect, but some introductions about LGMD and its types are missing.

  > Thank you for your advice. We added a brief explanation of LGMD in the introduction.

-Is there any way to make Table 1 more readable?

　>Thank you for your comment, as I stated in my response to the Major Comment, I have made the large table a supplement.

-Figure 3 looks very complex and a lot of information and a few columns could be omitted to make it more clear.

　> Thank you for your comment. I have omitted some columns, especially those not included in figure 4, to make it easier to view the critical muscles.

-I really like the discussion section of this review. Similarly, I would like to see the author's future recommendations (it is there, although they are not highlighted well) in a different table or section that could be used as a guideline for future research or clinical trials. So, the data coming from various studies can be combined and analyzed.

　> We think this is an important point. We were not sure in the initial draft stage whether we should state this much. In response to your suggestion, we have included our recommendations throughout this study at the end of the discussion section.

Reviewer 4 Report

The manuscript “An Approach to Make Skeletal Muscle MRI in limb-girdle 2 muscular dystrophy a Simple and Useful Method for Differential Diagnosis: a systematic review.” provides an interesting review with a new perspective on the use of MRI as a tool in LGMD diagnosis.

The manuscript reports in a very detailed manner the literature on the use of MRI in LGMD diagnosis, makes an accurate collection and analysis of data, and attempts to uniform them to be used in LGMD diagnosis.

I suggest that the Authors make some changes to improve the current version.

-       The title suggests that Authors have a useful approach for differential diagnosis in LGMD, but then Authors do not clearly state why this is a good method. Moreover, in the Conclusions Authors write ‘We performed a quantitative synthesis in this systematic review and simply described the fatty infiltration patterns of the six major genotypes of LGMD’. I suggest the Authors to explain the usefulness of their approach in the discussion, or modify the title.

-       The Introduction is quite concise. Authors should mention the parameters used during the MRI dependent diagnosis. For example, there is no mention to the rationale of using fat infiltration. The introduction would profit of the description of the use of these (and others) parameters in muscular dystrophy diagnosis.

-       Table 1 caption should be modified to make Table1 easily readable, there are several abbreviations that cannot be found in the text.

-       A part of the paragraph ‘Synthesis’ (lines 238-271) repeats what already said in ‘Data synthesis and Analysis’

-       The Discussion should be revised because some parts are difficult to understand. Since in this part the Authors are comparing the present review with the precedent work (2 reviews), it is better to clearly mention them to avoid confusion. Moreover, as suggested in my first point, Authors should clearly justify why they think their approach makes MRI a simple and useful method.

-       Lines 365-369, the sentence is of difficult interpretation, it is better to rephrase it.

Minor editing

Author Response

-       The title suggests that Authors have a useful approach for differential diagnosis in LGMD, but then Authors do not clearly state why this is a good method. Moreover, in the Conclusions Authors write ‘We performed a quantitative synthesis in this systematic review and simply described the fatty infiltration patterns of the six major genotypes of LGMD’. I suggest the Authors to explain the usefulness of their approach in the discussion, or modify the title.

  > Thank you for pointing this out. We have added a discussion to clarify the significance of this paper and what makes it useful.

-       The Introduction is quite concise. Authors should mention the parameters used during the MRI dependent diagnosis. For example, there is no mention to the rationale of using fat infiltration. The introduction would profit of the description of the use of these (and others) parameters in muscular dystrophy diagnosis.

  > Thank you for your comments. We have added a note about the MRI parameters in the introduction.

-       Table 1 caption should be modified to make Table1 easily readable, there are several abbreviations that cannot be found in the text.

  > Thank you for your comment. The tables inserted in the text were limited to basic tables summarizing the number of people, ages, etc., of representative genotypes. Other data has been moved to the supplement as a reference for readers.

-       A part of the paragraph ‘Synthesis’ (lines 238-271) repeats what already said in ‘Data synthesis and Analysis’

  > Thank you for your comment. Some results were modified as it was thought appropriate to move them to the Methods section. The methods are described more concisely. Also, we believe the part you pointed out is part of the FIGURE caption, so we hope you understand there is some duplication.

-       The Discussion should be revised because some parts are difficult to understand. Since in this part the Authors are comparing the present review with the precedent work (2 reviews), it is better to clearly mention them to avoid confusion. Moreover, as suggested in my first point, Authors should clearly justify why they think their approach makes MRI a simple and useful method.

  > Thank you for your comment. The Discussion section has been substantially revised. We have decided to separate the new findings from the current study from comparisons with previous studies as a separate section. We have also added a section related to the point made in the title.

-       Lines 365-369, the sentence is of difficult interpretation, it is better to rephrase it.

  > Thank you for your comment. It has been revised.

Round 2

Reviewer 1 Report

The manuscript has been improved, however, the manuscript would in general still benefit from additional flow and language improvements.

Author Response

Thanks for the comment. The whole document has been checked by an English native colleague and we believe it is now more readable.

Reviewer 4 Report

Authors have responded to the raised points.

Minor editing

Author Response

Thanks for the comment. The whole document has been checked by an English native colleague and we believe it is now more readable.