Rapid drug increase and early onset of levodopa-induced dyskinesia in Parkinson’s disease

Jin Yong Hong; Mun Kyung Sunwoo; Jung Han Yoon; Suk Yun Kang; Young H. Sohn; Phil Hyu Lee; Seo Hyun Kim

doi:10.1371/journal.pone.0237472

Peer Review History

Original SubmissionMay 7, 2020
23 Jun 2020 Decision Letter - Véronique Sgambato, Editor PONE-D-20-13495 Rapid drug increase and early onset of levodopa-induced dyskinesia in Parkinson's disease PLOS ONE Dear Dr. Seo Hyun Kim, I 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. More presicely, the authors should add more details regarding the methods and the results sections. The paper would also be improved if the discussion could be expanded. Please submit your revised manuscript by two months. 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. 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In your Methods section, please provide additional information about the participant recruitment method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as: a) a description of how records were chosen, and b) descriptions of where the research took place. 3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information [Note: HTML markup is below. Please do not edit.] 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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: Yes ****** 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 ****** 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: Rapid drug increase and early onset of levodopa-induced dyskinesia in Parkinson's disease PONE-D-20-13495 Research article for the journal Plos One The authors conducted a retrospective multicenter study on the occurrence of levodopa induced dyskinesia (LID) in Parkinson Disease (PD) Patients. They studied the relationships between the increase in levodopa dose and levodopa equivalent dose (LED) over years and the time of LID onset. They included 150 PD patients from 4 centers and divided them in 3 subgroups, those who develop early LID (>2 years to � 4 years), those who develop middle LID (> 4 years and � 6 years) and late LID ( > 6 years). They found that the higher rate of increase in levodopa dose and LED, the earlier the onset of LID. They concluded that dopaminergic drug could induce LID or act as a trigger for onset. The study addresses an important issue for the management of PD patients. I have some comments and questions. Could the authors precise how they included the subjects in their study: did they select patients who were known to have early/middle and late LID onset or did they included consecutive patients followed in the different centers and then, classified them in 3 different groups, a posteriori? Could the authors argue the reason for which they excluded patients with very early LID? It would have been interesting to include them as they usually reflect severe dopamine depletion. Which criteria did they use to consider that patients were at LID onset? Did they took the medical observation into consideration? The (MDS)-UPDRS part IV for complications of treatment? The Marconi LID scale? Patients questionnaire? We know that slight dyskinesia may occur early in disease evolution but patients are lot always aware of them and are not always able to recognize them as dyskinesia. It may be, thus, a limit to define the precise onset of LID. In Table 1 the authors reported the number of patients with treatment other than levodopa: was it the treatment, patients had, at time of LID onset? In the results section the authors mentioned that female subjects were at higher risk of early LID but they wrote that male subjects were at higher risk in the abstract: please correct. The authors associated the risk of LID onset with the rapid rate of levodopa /LED increase. However, it is known that LID are also associated with pulsatile post-synaptic dopaminergic stimulation. If data is available, and in order to help interpreting the results of the study, the authors could study and report the way levodopa was prescribed and whether the increase in levodopa dose or LED was associated with an increase in levodopa/LED unitary dose (which may enhance pulsatile answer and promote LID) or whether the increase was associated an increase in the number of daily intakes (a more continuous dopaminergic administration, which may delay the onset of LID). If the authors could add these data, they could develop more precisely the discussion on the pathophysiology of LID and the way to manage PD patients to avoid the occurrence of LID, even in severely depleted patients. Reviewer #2: Manuscript Number: PONE-D-20-13495 Manuscript Title: Rapid drug increase and early onset of levodopa-induced dyskinesia in Parkinson's disease Authors assessed a retrospective sudy about the relationship between levodopa dose and time onset of Levodopa-induced dyskinesia (LID). This is an interesting paper that reinforces previous results . The article is well written and analyses are accurately performed. However, I have some comments about the data and their interpretation. Major comments MATERIALS AND METHODS Subjects : - Authors chose to perform the analyses with de novo PD patients. It is well known that some PD patients are in fact misdiagnosed (Coarelli et al, J Neurol Sci, 2019 ; Hustad E, Aasly JO. Front Neurol. 2020). How did they ensure that these patients were truly PD patients and not parkinsonian patients from other degenerative disorders such as PSP, MSA,… Which clinical criteria did they use? Did they check these criteria at the beginning of the « PD » disease but also during the follow-up of these patients? It seems strange that authors did not observe other parkinsonian disorders due to initial misdiagnosis, even if they are experts in movement disorders. - Did the authors use a score of dyskinesia such as the UDysRS? - In the sentence « Data of patients with… drug dose », the « for » seems not appropriate or something is missing. - How was performed the motor UPDRS by authors? Was it applied in the OFF state or in the ON state (or intermediate state)? How long after the last medication did the UPDRS have been carried out? Please detail the assessment of the UPDRS score. RESULTS - Demographic characteristics : it is probably more accurate to rename this part « Demographic and clinical characteristics » - The UPDRS motor score was available for only 89 out of 150 patients. Could you precise how many UPDRS motor scores were available in each group (E, M, L). Moreover, in which condition (On? OFF? intermediate?) were assessed these scores? - The UPDRS is relatively elevated at initiation of Levodopa and/or dopaminergic agonists. It seems that patients were not sufficiently treated. Could you please justify this point? - Entacapone increases the occurrence of dyskinesia (Ahn et al., J Clin Neurol. 2007 ; Trenkwalder et al., Neurology. 2019). Did authors observe any difference in dyskinesia occurrence between patients who took entacapone and those who did not take it? Did they look for a difference in each group (E, M, L)? - In the « Risk factor for early LID » section, second line, authors declared that there was a correlation between time to onset of LID and LED but the p value is 0.066 which is above 0.05… (you should also correct the sentence related with this result in the Discussion section) DISCUSSION Concerning the sentences from «However the present results… » to « … acts as a trigger for onset » : It is well established that the occurrence of LID is secondary both to the dopaminergic denervation AND the levodopa administration. Without one of this factor, LID could not appear. LID occur in patients (or animals) taking Levodopa but only in the presence of dopaminergic degeneration. Minor comments - Replace « Table 2 » by « Table 1 » in the « Drug » section of the Results. - Insert « Table 2 » at the end of the sentence « Multivariable linear regression models … were associated with early onset of LID ». Same remark for the next sentence. ****** 6. 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 [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. https://doi.org/10.1371/journal.pone.0237472.r001
Revision 1
2 Jul 2020 Author Response Reviewer #1 - Could the authors precise how they included the subjects in their study: did they select patients who were known to have early/middle and late LID onset or did they included consecutive patients followed in the different centers and then, classified them in 3 different groups, a posteriori? Answer) This study was conducted using medical record and study subjects were retrospectively selected according to the study criteria. Now we clarify and rewrite the Method section in revised manuscript. - Could the authors argue the reason for which they excluded patients with very early LID? It would have been interesting to include them as they usually reflect severe dopamine depletion. Answer) Importance of this study is on the method for assessment of drug dose. The rate of dose increase was calculated as (change in dose / treatment duration), therefore relatively short duration of treatment may make the rate of dose increase overestimated. To reduce this chance, we selected patients who encountered LID at least two years after initiation of levodopa. We declare this in Method section. - Which criteria did they use to consider that patients were at LID onset? Did they took the medical observation into consideration? The (MDS)-UPDRS part IV for complications of treatment? The Marconi LID scale? Patients questionnaire? We know that slight dyskinesia may occur early in disease evolution but patients are lot always aware of them and are not always able to recognize them as dyskinesia. It may be, thus, a limit to define the precise onset of LID. Answer) Because this study focused on the time to onset of dyskinesia, presence or absence of LID is the only data needed. Scales for dyskinesia is for assessment of severity of LID were not used in this study. As reviewer comment, many patients are not aware of their dyskinesia. Therefore, we defined the onset of LID based on clinicians’ observation. But when patients reported onset of dyskinesia and clinician also observed the dyskinesia, we accepted the day that patients indicated. Now we describe this content in Method section of revised manuscript. - In Table 1 the authors reported the number of patients with treatment other than levodopa: was it the treatment, patients had, at time of LID onset? Answer) Drug other than levodopa was assessed at the time of LID onset. In revised manuscript, we add this information in Table 1 and Result section. - In the results section the authors mentioned that female subjects were at higher risk of early LID but they wrote that male subjects were at higher risk in the abstract: please correct. Answer) We thank for reviewer’s correction. We correct the abstract. - The authors associated the risk of LID onset with the rapid rate of levodopa /LED increase. However, it is known that LID are also associated with pulsatile post-synaptic dopaminergic stimulation. - If data is available, and in order to help interpreting the results of the study, the authors could study and report the way levodopa was prescribed and whether the increase in levodopa dose or LED was associated with an increase in levodopa/LED unitary dose (which may enhance pulsatile answer and promote LID) or whether the increase was associated an increase in the number of daily intakes (a more continuous dopaminergic administration, which may delay the onset of LID). If the authors could add these data, they could develop more precisely the discussion on the pathophysiology of LID and the way to manage PD patients to avoid the occurrence of LID, even in severely depleted patients. Answer) We selected patients who was treated with levodopa initially, and almost all the patients took levodopa three time a day. And, no patient of this study was treated with continuous intestinal levodopa, subcutaneous apomorphine, rotigotine patch, or deep brain stimulation. Therefore, we think that influence of pulsatile dopaminergic stimulation on onset of LID cannot be explored using this study data and subanalysis suggested by reviewer seems to be impossible in this data Reviewer #2 Major comments MATERIALS AND METHODS Subjects : - Authors chose to perform the analyses with de novo PD patients. It is well known that some PD patients are in fact misdiagnosed (Coarelli et al, J Neurol Sci, 2019 ; Hustad E, Aasly JO. Front Neurol. 2020). How did they ensure that these patients were truly PD patients and not parkinsonian patients from other degenerative disorders such as PSP, MSA,… Which clinical criteria did they use? Did they check these criteria at the beginning of the « PD » disease but also during the follow-up of these patients? It seems strange that authors did not observe other parkinsonian disorders due to initial misdiagnosis, even if they are experts in movement disorders. Answer) We did not enroll study patients consecutively, but reviewed medical record and selected proper patients for study. During patient selection, other parkinsonian patients such as atypical parkinsonism, dementia with Lewy bodies, frontotemporal dementia, or unspecified disorders were excluded. Now we describe the process of patient selection in detail in Method section of revised manuscript. - Did the authors use a score of dyskinesia such as the UDysRS? Answer) This study focused on the time to onset of dyskinesia, so scales for assessment of severity of LID were not used. - In the sentence « Data of patients with… drug dose », the « for » seems not appropriate or something is missing. Answer) According to reviewer’s comment, we revise the sentence. - How was performed the motor UPDRS by authors? Was it applied in the OFF state or in the ON state (or intermediate state)? How long after the last medication did the UPDRS have been carried out? Please detail the assessment of the UPDRS score. Answer) UPDRS score rated at de novo status (just before initiation of levodopa) was used in this study. Now we add this content in Method section of revised manuscript. RESULTS - Demographic characteristics : it is probably more accurate to rename this part « Demographic and clinical characteristics » Answer) According to reviewer’s suggestion, we now rename the title of the paragraph and table 1. - The UPDRS motor score was available for only 89 out of 150 patients. Could you precise how many UPDRS motor scores were available in each group (E, M, L). Moreover, in which condition (On? OFF? intermediate?) were assessed these scores? Answer) As per reviewer’s suggest, we now present the number of patients of each group who had been assessed with UPDRS motor score and modified Hoehn and Yahr stage (footnote of Table 1). The used score rated at only drug-naïve status. - The UPDRS is relatively elevated at initiation of Levodopa and/or dopaminergic agonists. It seems that patients were not sufficiently treated. Could you please justify this point? Answer) First, the UPDRS score was rated at de novo status but not in treatment period. The mean UPDRS motor score at de novo status ranges 20 to 25 in most studies. Moreover, we selected patients who initiated medical treatment with levodopa, so patients with mild symptom who was suitable for dopamine agonist or MAO-B inhibitor monotherapy may be excluded from this study. - Entacapone increases the occurrence of dyskinesia (Ahn et al., J Clin Neurol. 2007 ; Trenkwalder et al., Neurology. 2019). Did authors observe any difference in dyskinesia occurrence between patients who took entacapone and those who did not take it? Did they look for a difference in each group (E, M, L)? Answer) The numbers of patients treated with entacapone are already presented in Table 1. There was no difference in number of patients treated with entacapone among E, M, and L groups. - In the « Risk factor for early LID » section, second line, authors declared that there was a correlation between time to onset of LID and LED but the p value is 0.066 which is above 0.05… (you should also correct the sentence related with this result in the Discussion section) Answer) As per reviewer’s comment, we revised the sentence for the data. DISCUSSION Concerning the sentences from «However the present results… » to « … acts as a trigger for onset » : It is well established that the occurrence of LID is secondary both to the dopaminergic denervation AND the levodopa administration. Without one of this factor, LID could not appear. LID occur in patients (or animals) taking Levodopa but only in the presence of dopaminergic degeneration. Answer) In the paragraph, we focused on the role of levodopa dose. In the clinical setting, levodopa dose was affected by severity of dopaminergic denervation, therefore it is unclear whether levodopa dose is an independent factor for LID or higher levodopa dose is just a consequence of severe dopamine depletion. We discussed this point in this paragraph. Now we revise the paragraph to make it less confusing. Additionally, as reviewer commented, both dopaminergic denervation and administration of dopaminergic drug are essential for onset of LID. But, Tagasaki et al. (Neuropharmacology 2005) showed that therapeutic dose of levodopa induced LID in DAT blocker-treated squirrel monkey without dopaminergic denervation, and Pearce et al. (Psycholpharmacology 2001) demonstrated that higher dose of levodopa induced LID in dose dependent manner in normal macaque monkey. Therefore, we think that the role of levodopa on LID should be reconsidered. Minor comments - Replace « Table 2 » by « Table 1 » in the « Drug » section of the Results. - Insert « Table 2 » at the end of the sentence « Multivariable linear regression models … were associated with early onset of LID ». Same remark for the next sentence. Answer) We appreciate reviewer’s correction. Now we edit that according to the comment. Attachments Attachment Submitted filename: Response to Reviewers.doc https://doi.org/10.1371/journal.pone.0237472.r002
15 Jul 2020 Decision Letter - Véronique Sgambato, Editor PONE-D-20-13495R1 Rapid drug increase and early onset of levodopa-induced dyskinesia in Parkinson's disease PLOS ONE Dear Dr. Seo Hyun Kim, 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, answer to the remaining minor comments adressed by the referees. Please submit your revised manuscript by one month. 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, Véronique Sgambato Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] 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: (No Response) Reviewer #2: All comments have been addressed ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 ****** 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 ****** 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: Rapid drug increase and early onset of levodopa-induced dyskinesia in Parkinson's disease PONE-D-20-13495 R1 Research article for the journal Plos One The authors have revised the manuscript of a retrospective multicenter study on the occurrence of levodopa induced dyskinesia (LID) in Parkinson Disease (PD) patients. They answered to all comments of the reviewers and corrected the errors in the previous version of the manuscript. They added data if available. They have developed more precisely the discussion section. The manuscript is now clearer than the first version. The authors did not add any comment on pharmacokinetics and the role of pulsatile administration of levodopa in sensitization and in the development of motor complications (see Nutt J, 1995, Clin Exp Pharmacol Physiol, Nutt J, 2007, Movement Disorders Journal, Sharma et al, 2015 Biomed Pharmacother for example). Most of the patients were taking treatment 3 times a day, as noted by the authors in the answers to comments. It did not seem to be different across groups. This would argue against the idea that high unitary doses of levodopa increase the risk of LID, whereas the rate of increase seem to be more important. They could perhaps add this comment in the limits of the study section. They could also add their answer on reviewer 2 comment on the discussion section. Even though the authors could not confirm that the risk to develop LID is associated with the rate of levodopa increase rather than the initial dose or the severity of dopamine denervation, these data are interesting as they provide clues for the management of patients when trying to avoid LID. Reviewer #2: Authors responded to all the queries. I just have few minor remarks : - Please use « levodopa » or « Levodopa » but authors should homogeneize this in all the manuscript - Lines 74-75, replace « Among them, we selected patients who medical treatment initiated with levodopa » by « Among them, we selected patients who initiated medical treatment with levodopa » - Lines 82-84 : I think authors should rewrite the sentence « When patient reported symptom suggesting LID or dyskinetic movement was observed in the clinic, clinicians have been recording the information for LID » ; « When patient reported symptom suggesting LID or dyskinetic movement was observed in the clinic, clinicians recorded the information for LID - Line 89 : « developed within 2 year … » ; add a « s » for years : « developed within 2 years … » - Line 94 : please put « de novo » in italic - Table 1 : « P-value » should be replaced by « p-value » ****** 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 [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. https://doi.org/10.1371/journal.pone.0237472.r003
Revision 2
23 Jul 2020 Author Response Reviewer #1 The authors did not add any comment on pharmacokinetics and the role of pulsatile administration of levodopa in sensitization and in the development of motor complications (see Nutt J, 1995, Clin Exp Pharmacol Physiol, Nutt J, 2007, Movement Disorders Journal, Sharma et al, 2015 Biomed Pharmacother for example). Most of the patients were taking treatment 3 times a day, as noted by the authors in the answers to comments. It did not seem to be different across groups. This would argue against the idea that high unitary doses of levodopa increase the risk of LID, whereas the rate of increase seem to be more important. They could perhaps add this comment in the limits of the study section. Answer) Now, we add the contents about the way levodopa was initiated and increased in Method section (lines 104-106 in revised manuscript). In this study, levodopa was usually prescribed three times a day with equal dose, and we increased the levodopa by 50mg per dose (150mg a day) when dose increased was needed. As we answered in previous response to review, there was no change in the number of daily intakes of levodopa during dose increase and there was no difference in number of daily intakes among patients. Therefore, we think that issue for the continuous dopaminergic stimulation is not applicable to this study. Reviewer #2 - Please use « levodopa » or « Levodopa » but authors should homogeneize this in all the manuscript Answer) Now we use “levodopa” in this revision. - Lines 74-75, replace « Among them, we selected patients who medical treatment initiated with levodopa » by « Among them, we selected patients who initiated medical treatment with levodopa » - Lines 82-84 : I think authors should rewrite the sentence « When patient reported symptom suggesting LID or dyskinetic movement was observed in the clinic, clinicians have been recording the information for LID » ; « When patient reported symptom suggesting LID or dyskinetic movement was observed in the clinic, clinicians recorded the information for LID Answer) We revise the sentences according to the suggestion. - Line 89 : « developed within 2 year … » ; add a « s » for years : « developed within 2 years … » - Line 94 : please put « de novo » in italic - Table 1 : « P-value » should be replaced by « p-value » Answer) We correct the errors. Attachments Attachment Submitted filename: Response to Reviewers_R2.doc https://doi.org/10.1371/journal.pone.0237472.r004
28 Jul 2020 Decision Letter - Véronique Sgambato, Editor Rapid drug increase and early onset of levodopa-induced dyskinesia in Parkinson's disease PONE-D-20-13495R2 Dear Dr. Seo Hyun Kim, 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, Véronique Sgambato Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0237472.r005
Formally Accepted
10 Aug 2020 Acceptance Letter - Véronique Sgambato, Editor PONE-D-20-13495R2 Rapid drug increase and early onset of levodopa-induced dyskinesia in Parkinson's disease Dear Dr. Kim: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Véronique Sgambato Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0237472.r006

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