SARS-CoV-2 Infection Causes Relapse of Kleine-Levin Syndrome: Case Report and Review of Literature

Round 1

Reviewer 1 Report

Marcic et al, reports a case of Klein-Levin syndrome (KLS) patient, where KLS relapses after the patient contracted with SARS-CoV-2 virus. The authors here tried to establish an association between KLS and SARS-CoV-2. The SARS-CoV-2 has been associated with other neurological disorders in the recent past, hence, it is logical to argued that SARS-CoV-2 is the cause of the relapse in the presented case. Since we are still in the infancy of understanding the consequences of SARS-CoV-2, its association with other diseases cannot be missed by scientific fraternity. Although the manuscript is easy to follow, presentation quality of this case report can be improved greatly.

General:

• Overall, it appears that the report was written very carelessly.
• In my opinion, English language needs improvement. Please check the manuscript carefully as there are some typos and verb
  tenses disagreements (e.g.line 41 give, line 49 get, line 49 It, line
  150 te...). 
• Discussion as a whole makes no senses, except 2-3 lines there is no discussion about the possible association between KLS and SARS-CoV-2. It mostly looks like copy and paste from previous published reviews, e.g. line 135-144 copied as such from reference no. 19. Whole discussion needs re-writing. It gives the impression of introduction only.

Specific comments:

• Line 23, the statement “it can cause any neurological disease”, looks too broad. List the known neurological diseases affected by SARS-CoV-2.
• Line 35, list the fluid test conducted
• Line 36, expend “DAT scan” should be abbreviated on fist use.
• Line 36, it says Figure-1 is DAT scan but Figure legend says it is MSCT, needs correction.
• There is no labeling on the images. Consider labelling, it will help readers to understand the exact details.
• Figure-2, Cite this figure and consider pointing the lesions with arrows or another type of sign in the images of Figure 2. Moreover, Figure 2 images have sub-labelling (B and C) continued from Figure-1. Needs correction.
• Line 79, Expand TCCD
• The patient shows higher values in some parameters of the TCCD (EDV, MV, RI) in the rest state when compared with the subjects in the previous study by the authors (Ref.15) that also suffer from COVID. Have the authors some insights about this? 
• Table-4, Why rest values of BHTM(s) and BHI are missing?
• Table titles should be established based on the order of appearance in
  the text. 
• MRI scan is shown only post SARS-CoV-2 onset, there is no comparative MRI scan from before the onset of SARS-CoV-2. Hence authors cannot rule out the possibility of prior existence of the brain legions. Hence, this partial information could be misleading and needs to be modified.
• Discussion, 1^st paragraph is best suited for introduction.
• Please check sentence meaning in line 89 (sleeps about 10 hours per day
  and in the waking state).
• The authors choose hypersexuality as a keyword, but this symptom is not
  described for the case studied.

 

Author Response

Dear Editor and Reviewers,

In this letter I want to clarify the changes suggested to me by your editors and reviewers to my case report entitled „SARS-CoV-2 infection causes relapse of Klein-Levin syndrome: case report and review of literature“

1.As reviewer asked, we remove the keyword hypersexuality.

2. As requested in a another e-mail by the editor of the journal, at the end of the article we added the approval of the Ethics Committee of UHC Split and the informed consent for the patient. We also added authors contributions.
3. As requested by another rewiever, we corrected spelling errors in lines 41, 49, and 150 (we inserted words gave, got, He, to).
4. At the suggestion of the reviewer, we inserted the word many (neurological diseases) in line 28. Although the rewiever asked us to list all these diseases, this is an introduction and we emphasize them in the discussion.
5. As requested by the reviewer, we wrote the full name of DaTSCAN, and deleted the part of the text that indicates that Figure 1 shows DaTSCAN
6. As requested by the rewiever, we have added Figure 1 in the text at the point where his pneumonia is described.
7. According to rewiver suggestions, we changed the appearance and layout of the images — we added brain images taken 18 months before the COVID infection, and we highlighted the lesions in the images showing the brain MR after the infection. As the rewiever suggested, we changed Figure 2.and now it shows an brain MRI of our patient from September 2019. (A, D) that was without pathological changes and brain MRI scans from March 2021. (B, E),same MR slices, which showed white matter lesions bilaterally frontally. We marked the lesions with arrows in Figures 2.B and 2.E
8. As the rewiver suggested, in line 79 we wrote the full name of the TCCD
9. As the rewiver suggested, first paragraph from discussion we incorporated into the introduction. We also redesigned the introduction

10.In line 66, as second rewiever suggested, we changed words feeding disorders to overeating.

11. In line 89, at the suggestion of the reviver, we changed the text to better point out that the patient now sleeps less with therapy during the day and night, but is still sleepy when awake.
12. In Table 4, our patient data are listed after TCCD measurement and after breath holding test. As the rewiever rightly observed, our patient has slightly higher velocity parameter values ​​(PSV, EDV, MV, PI) than respondents from our paper published in the MDPI Journal of Personalized Medicine. This is not uncommon because our patient is much younger than the subjects in that study, and in younger people there is greater elasticity of blood vessels which in turn leads to slightly increased flow rates through cerebral arteries that can be registered on the TCCD.
13. In Table 4. the values ​​of breath holding time (BHTM) are shown, which is measured after the breath holding test, it is not measured during the rest period, so it is not possible to enter the data in the table.
14. Breath holding index is a measure of cerebral vasoreactivity, it is calculated by dividing the values ​​of flow velcity rates (PSV, EDV, MV) by the values ​​of breath holding time (BHTM). Breath holding index does not exist in rest period, so in Table 4 it could not be entered for the rest period.
15. As requested by the reviewer, we completely rearranged the discussion. We moved the first paragraph to the introduction.
16. At the beginning of the discussion, we briefly repeat the basic characteristics of the patient

17.We added a section that talks about the effect of the virus on Klein Levin syndrome.

18. We pointed out in detail that diseases precede respiratory infections, but we also emphasized other risk factors for the disease.
19. According to rewiever's suggestions, we have listed in detail the neurological symptoms that can be caused by the SARS-CoV-2 virus.
20. In the following paragraph, we tried to explain our view of how the SARS-CoV-2 virus can cause a relapse of Klein Levin syndrome.
21. In the next paragraph, we tried to explain what changes in the brain MRI can occur in patients after COVID infection, and we pointed out what changes our patient had.
22. In the paragraph before Table 2, we tried to point out the similarity of the clinical picture in our patient when he was diagnosed with the disease and in relapse after COVID infection.
23. In a passage explaining the basic symptoms of KLS, we noted that our patient did not have hypersexuality.

24.Finally, we have made changes to the counting tables: Table 1. is in the introduction and talks about the diagnostic criteria for KLS, Table 2. describes the TCCD and BHT parameters for our patient, Table 3. lists the frequency of individual symptoms in this syndrome, and Table 4. presents the differential diagnosis of KLS

Thank you for your cooperation on this manuscript.

Sincerely,

Marino Marcic

 

Author Response File: Author Response.docx

Reviewer 2 Report

This is an interesting case report providing novel findings. To the best of my knowledge this is the first report on relapse of Kleine-Levin syndrome associated with SARS-CoV-2 infection. It is well written. 

I have only one minor crtizism- line 66 - "feeding disorders" does not appear to be the appropriate wording as it decribes disturbed feeding in babies. I recommend to replace it by  "overeating".

Author Response

Dear Editor and Reviewers,

In this letter I want to clarify the changes suggested to me by your editors and reviewers to my case report entitled „SARS-CoV-2 infection causes relapse of Klein-Levin syndrome: case report and review of literature“

1.As reviewer asked, we remove the keyword hypersexuality.

2. As requested in a another e-mail by the editor of the journal, at the end of the article we added the approval of the Ethics Committee of UHC Split and the informed consent for the patient. We also added authors contributions.
3. As requested by another rewiever, we corrected spelling errors in lines 41, 49, and 150 (we inserted words gave, got, He, to).
4. At the suggestion of the reviewer, we inserted the word many (neurological diseases) in line 28. Although the rewiever asked us to list all these diseases, this is an introduction and we emphasize them in the discussion.
5. As requested by the reviewer, we wrote the full name of DaTSCAN, and deleted the part of the text that indicates that Figure 1 shows DaTSCAN
6. As requested by the rewiever, we have added Figure 1 in the text at the point where his pneumonia is described.
7. According to rewiver suggestions, we changed the appearance and layout of the images — we added brain images taken 18 months before the COVID infection, and we highlighted the lesions in the images showing the brain MR after the infection. As the rewiever suggested, we changed Figure 2.and now it shows an brain MRI of our patient from September 2019. (A, D) that was without pathological changes and brain MRI scans from March 2021. (B, E),same MR slices, which showed white matter lesions bilaterally frontally. We marked the lesions with arrows in Figures 2.B and 2.E
8. As the rewiver suggested, in line 79 we wrote the full name of the TCCD
9. As the rewiver suggested, first paragraph from discussion we incorporated into the introduction. We also redesigned the introduction

10.In line 66, as second rewiever suggested, we changed words feeding disorders to overeating.

11. In line 89, at the suggestion of the reviver, we changed the text to better point out that the patient now sleeps less with therapy during the day and night, but is still sleepy when awake.
12. In Table 4, our patient data are listed after TCCD measurement and after breath holding test. As the rewiever rightly observed, our patient has slightly higher velocity parameter values ​​(PSV, EDV, MV, PI) than respondents from our paper published in the MDPI Journal of Personalized Medicine. This is not uncommon because our patient is much younger than the subjects in that study, and in younger people there is greater elasticity of blood vessels which in turn leads to slightly increased flow rates through cerebral arteries that can be registered on the TCCD.
13. In Table 4. the values ​​of breath holding time (BHTM) are shown, which is measured after the breath holding test, it is not measured during the rest period, so it is not possible to enter the data in the table.
14. Breath holding index is a measure of cerebral vasoreactivity, it is calculated by dividing the values ​​of flow velcity rates (PSV, EDV, MV) by the values ​​of breath holding time (BHTM). Breath holding index does not exist in rest period, so in Table 4 it could not be entered for the rest period.
15. As requested by the reviewer, we completely rearranged the discussion. We moved the first paragraph to the introduction.
16. At the beginning of the discussion, we briefly repeat the basic characteristics of the patient

17.We added a section that talks about the effect of the virus on Klein Levin syndrome.

18. We pointed out in detail that diseases precede respiratory infections, but we also emphasized other risk factors for the disease.
19. According to rewiever's suggestions, we have listed in detail the neurological symptoms that can be caused by the SARS-CoV-2 virus.
20. In the following paragraph, we tried to explain our view of how the SARS-CoV-2 virus can cause a relapse of Klein Levin syndrome.
21. In the next paragraph, we tried to explain what changes in the brain MRI can occur in patients after COVID infection, and we pointed out what changes our patient had.
22. In the paragraph before Table 2, we tried to point out the similarity of the clinical picture in our patient when he was diagnosed with the disease and in relapse after COVID infection.
23. In a passage explaining the basic symptoms of KLS, we noted that our patient did not have hypersexuality.

24.Finally, we have made changes to the counting tables: Table 1. is in the introduction and talks about the diagnostic criteria for KLS, Table 2. describes the TCCD and BHT parameters for our patient, Table 3. lists the frequency of individual symptoms in this syndrome, and Table 4. presents the differential diagnosis of KLS

Thank you for your cooperation on this manuscript.

Sincerely,

Marino Marcic

 

Author Response File: Author Response.docx