Sialorrhea in Parkinson’s Disease

Round 1

Reviewer 1 Report

I read with interest this review paper titled "sialorrhea and Parkinson's disease a systematic review" and found it very engaging. I would like to commend the authors on a well written comprehensive review paper with good flow in structure and easily readability. The article seems to be focused in covering all the appropriate points related to clinical practice.

My biggest concern for the paper is giving an impression of this being a systematic review which will be inappropriate. The information summarized here is very brief with a focus on clinical highlights. This paper should be more appropriately termed as a mini review, brief review or an overview. To explain my suggestion I encouraged authors to read paper titled "Rimabotulinumtoxin B in sialorrhea: systematic review of clinical trials" published in the Journal of clinical movement disorders in 2017 with PMID 28593050. That paper focuses just on one aspect of this current paper of type B botulinum toxin role in sialorrhea and reviews 7 selected studies out of 43 compared to only single study being discussed in this current paper. The same can be said for every single section of this paper.

Overall the paper is very well written but I encourage authors to consider reflecting on the abstract of this paper as the abstract is too vague and does not fully reflect the strength of this paper on what is being reviewed here.

I also suggest authors to consider adding some form of a picture in the section 6 on botulinum toxin mechanism of action and the structure of the toxin which is very appropriately summarized but may be hard to follow first reader not familiar with it.

On page 4 line 151 the mentions that the effects are diminished as SNAP proteins are restored. I think the authors should highlight here that the long duration of benefit of 8 to 12 weeks is likely because of degeneration of nerve endings from the blockade and regeneration of the nerve terminals which is a much more slower process than the half-life of the toxin would suggest.

On the same page in line 153 the authors rightly pointed out that increasing dose can result in increasing amount of weakness but then they mentioned that higher doses only provide modest additional paresis which is misleading. Authors might have meant that there is no further clinical benefit by keep increasing the doses but there is definitely increasing paresis to a point of complete paralysis by continuing to increase the doses, although not desirable. Similarly in the line 154-155 'can increase in duration of benefit with increasing doses' but again limit it at a maximum benefit of 12 weeks and could be misleading as the benefit could be even longer than that at the cost of getting weakness by increasing the dose and 12 weeks might be the maximum duration achievable without causing any significant or noticeable weakness.

In section 7 page 4 line 159 162 is a complete repetition of what has already been discussed in section 6 and may be removed to avoid redundancy.

The table 1 comparing form of botulinum toxin is well done. I would encourage the authors to put the reference on the 2 clinical trials listed in the table and also the side effects or cons listed in a Column is not clear if it is authors personally suggestions or the reported most common side effects in the trials as the 2 of the toxins do not have any clinical trials listed.

Section 9 line 202 reports that toxin is available as 100 units while it misses out that the Incobotulinum toxin is also availabil3 in 50 unit vial

Line 205 and 206 needs to be corrected as incobotulinumtoxin does not have any additional complexity protein and the way it is written misleads the reader as if the author mentions additional proteins which is only clarified later.

Section 13 conclusion line 275 and 276–the full title of the toxin trial for type B without listing for full title of the toxin trial of type A toxin which is confusing and full title may not be necessary.

There are also many other minor examples of need for removing redundancies with excessive wording and some indirect or passive language that actually does not fit with the overall writing style of this paper which is very direct precise and accurate and probably has been missed during a final review after editing of the dropped.

Overall the paper is brief, relevant and to the point and very useful for clinical practitioner and novice injector though requiring some editing as discussed above and a more appropriate title.

Author Response

Thank you for the very detailed and thorough recommendations. They are very much appreciated.

I will address each comment below:

Reviewer 1

1. Thank you for the comment regarding the title as a “Systematic review” as giving the wrong impression. I changed the title to reflect this. Thank you for the explanation of the suggestion, and I believe you are correct and the term “an overview” or a “mini review” is much more appropriate.
2. Thank you for your comment on the abstract being too vague. I have adjusted it to include the further scope of this overview.
3. Thank you for the suggestion of including a picture on mode of action of botulinum I have created a diagram to better illustrate the text.
4. Thank you for that suggestion. I have edited the paper and your suggestion was incorporated into the paper (See line 156).
5. Thank you for your suggestion about the misleading comment about a higher dose causing increased paresis. That was a typo, and I meant to say that there was not much more appreciable clinical benefit. Thank you for this comment.
6. Thank you for pointing out the redundancy. I have removed that sentence
7. Thank you for this comment regarding the table and references. Side effects were based on small studies, but given that the other two toxins have not had a large randomized trial I believe it is more correct to list side effects as unknown. Thank you for this suggestion. I have made those changes.
8. Thank you for this suggestion. I made this change.
9. Thank you for that comment on the complex proteins. I have removed that comment to ensure that the sentence is clear.
10. Thank you for this comment. I have changed the sentence.

Reviewer 2 Report

The manuscript “Efficacy and safety of botulinum toxin type A on persistent myofascial pain: a randomized clinical trial Sialorrhea in Parkinson’s Disease: A systematic review.” fits to the aims and scope of Toxins and may be suitable for publication after some very minor changes. Although sialorrhea is not one of the main symptoms of Parkinson's disease, it is perceived as stressful by affected patients and their families. The present manuscript summarizes the advantages and disadvantages of the treatment options, with special emphasis on the different botulinum toxins A and B. Overall, this is a well-written paper dealing with an interesting topic and maybe published after minor revision.

Specific comments

1. In several parts of the text there are excess or missing spaces, especially before round brackets:
   1. Page 3: lines 113, 119, 130 and 138
   2. Page 4: line 154
   3. Page 5: Table 1
   4. Page6: line 234
2. Page 3, line 133: Consider replacing “7” by “seven”
3. Table 1:
   1. last row, column “company”: incorrect formatting (brackets)
   2. why are “OnabotulinumtoxinA” and “RimabotulinumtoxinB” formatted bold instead of the headlines “botulinum toxin A” and “botulinum toxin B”?

I have no comments regarding the content of the manuscript.

Author Response

Reviewer 2

1. I have edited the excess spaces. Thank you for kindly pointing this out.
2. I have replaced 7 by “seven.” Thank you for this suggestion.
3. I have reformatted the table to appropriately highlight the category. Thank you for pointing out this typo.