Altered Cardiac Autonomic Regulation in Individuals with Myasthenia Gravis—A Systematic Review and Meta-Analysis
, Łukasz Rzepiński 2,3, Małgorzata Tafil-Klawe 1, Nicola Veronese 4, Mario Barbagallo 4, Mario Habek 5,6 and Nils E. Gilhus 7,8Round 1
Reviewer 1 Report
This is an important and well-designed rewiev on the topic. It would be ineresting also a short comment, in the discussion, on cerebrovascular risk of MG.
Author Response
Response to Reviewer: 1
Reviewer #1: This is an important and well-designed review on the topic. It would be interesting also a short comment, in the discussion, on cerebrovascular risk of MG.
Answer: We thank the reviewer for this valuable comment. Appropriate information has been added as suggested in Discussion paragraph.
Results of retrospective study in Taiwan revealed that individuals with MG exhibited higher prevalence of hypertension, coronary artery disease, diabetes mellitus, dyslipidemia, thyroid and cerebrovascular diseases. These comorbidities could potentially be linked to the prolonged use of immunosuppressive treatments for MG [51]. High-quality studies designed to examine the relationship between immunosuppressive/glucocorticoid treatments (such as azathioprine) and ischemic stroke are lacking [52].
Reviewer 2 Report
Authors present an interesting review and meta analysis of the autonomic alterations in MG. It is important to give attention to such aspect of the disease which is often neglected. It often happens that the main feature of a disease (e.g., fatigue and fatiguability) takes all the attention of researchers and clinicians, while the patient experiences several other symptoms that may cause burden and need to be investigated. The manuscript is very well written and organized, I have just few suggestions that I believe may improve the quality of the manuscript.
As a major concern, in line 214 authors state that "All studies included medicated participants", and in the discussion affirm that pyridostigmine may alter autonomic testing results. Hence, I believe that in the discussion it should be highlighted that some alterations may depend on the received therapy (being cholinesterase inhibitors, steroids, or immunosuppressive drugs). Moreover, I believe that such absence of therapy naïve patients should be addressed among the limitations of the study, together with the retrospective nature of the included studies.
As a minor concern, authors should try to be uniform in describing the number of studies in actual Arabic numbers (e.g., "6") or in the extended form in letters (i.e., "six"), with the exception of when starting a sentence. Particularly, I am referring to lines 213-216.
Author Response
Response to Reviewer: 2
Reviewer #2: Authors present an interesting review and meta-analysis of the autonomic alterations in MG. It is important to give attention to such aspect of the disease which is often neglected. It often happens that the main feature of a disease (e.g., fatigue and fatiguability) takes all the attention of researchers and clinicians, while the patient experiences several other symptoms that may cause burden and need to be investigated. The manuscript is very well written and organized, I have just few suggestions that I believe may improve the quality of the manuscript.
- As a major concern, in line 214 authors state that "All studies included medicated participants", and in the discussion affirm that pyridostigmine may alter autonomic testing results. Hence, I believe that in the discussion it should be highlighted that some alterations may depend on the received therapy (being cholinesterase inhibitors, steroids, or immunosuppressive drugs). Moreover, I believe that such absence of therapy naïve patients should be addressed among the limitations of the study, together with the retrospective nature of the included studies.
Answer: We thank the reviewer for this valuable comment. Appropriate information has been added as suggested in Discussion paragraph.
There is evidence of autonomic involvement in individuals with MG [6,15] before and after pharmacological treatment. Cholinergic stimulation induced by AChE inhib-itor treatment influences autonomic function including cardiac function and im-proveimprove BRS, HRV, in both humans and animal disease models. AChE inhibitors also increase the HF while decreasing the LF and sympathovagal balance [35-36]. Moreover, immunosuppressive agents could potentially affect autonomic function [37], thereby increasing the potential risk of arrhythmia, cardiac hypertrophy, and ab-normal vascular remodeling [38]. Corticosteroids hold the potential to impact cardio-vascular autonomic function, resulting in improved responses in terms of sympathovagal balance (Prednisone/Prednisolone), as observed in patients with Duchenne Muscular Dystrophy [39].
The limitations of the MG studies include their relatively small sample sizes, retrospective design, and the absence of therapy-naïve patients.
- As a minor concern, authors should try to be uniform in describing the number of studies in actual Arabic numbers (e.g., "6") or in the extended form in letters (i.e., "six"), with the exception of when starting a sentence. Particularly, I am referring to lines 213-216.
Answer: We thank the reviewer for this valuable remark. The manuscript has been changed as You suggested.
Reviewer 3 Report
The paper presented: ALTERED CARDIAC AUTONOMIC REGULATION IN INDIVIDUALS WITH MYASTHENIA GRAVIS – A SYSTEMATIC REVIEW AND META-ANALYSIS - is a review on the subject of cardiac autonomic dysregulation (CAD) in Myasthenia Gravis (MG). The occurrence of CAD in MG is long known, but results of systematic studies have been inconsistent or even controversial, so this review and analysis is timely and welcome.
This review has the following main strengths: 1) the subject is interesting and not well studied; 2) methodically, it is flawless, the methods used for selection of source and processing the data for the meta review are clearly defined and are entirely adequate to the research standards; 3) the results from quite a number of different tests, in heterogeneous populations, that may be confusing, are systematised and presented clearly and logically; 4) the authors are experts in the corresponding fields (autonomic testing, Myasthenia Gravis), have themselves authored valuable research in this field and the discussion and interpretation they provide is objective and balanced; 5) the language the paper is most readable and clear.
After carefully reviewing the manuscript, I would recommend the publication of the paper "as is".
My only remark concerns the acceptance of quantitative parameters of sympathetic skin responses as a reliable outcome (as used in reference 16, Nalbantoglu et al 2021, discussed in the manuscript line 364). Routine SSR are too prone to habituation, inter- and intraindividual assessment to be used in quantitative way (review Kucera 2004). For this reason, the modification by Emmer et al 2012 (SSR evoked by train of stimuli that do not habituate) was introduced. It seems only the presence/absence of SSR may be a reliable finding (Hubli 2015). The authors could mention that the use of SSR amplitudes and latencies as a quantitative measure is considered disputable. However, I understand my opinion itself may be debatable and don't insist on any revision, unless accepted by the authors.
PS. Some of the references lack the DOI, a technical omission that can be easily corrected.
Author Response
Response to Reviewer: 3
Reviewer #3: The paper presented: ALTERED CARDIAC AUTONOMIC REGULATION IN INDIVIDUALS WITH MYASTHENIA GRAVIS – A SYSTEMATIC REVIEW AND META-ANALYSIS - is a review on the subject of cardiac autonomic dysregulation (CAD) in Myasthenia Gravis (MG). The occurrence of CAD in MG is long known, but results of systematic studies have been inconsistent or even controversial, so this review and analysis is timely and welcome.
This review has the following main strengths: 1) the subject is interesting and not well studied; 2) methodically, it is flawless, the methods used for selection of source and processing the data for the meta review are clearly defined and are entirely adequate to the research standards; 3) the results from quite a number of different tests, in heterogeneous populations, that may be confusing, are systematised and presented clearly and logically; 4) the authors are experts in the corresponding fields (autonomic testing, Myasthenia Gravis), have themselves authored valuable research in this field and the discussion and interpretation they provide is objective and balanced; 5) the language the paper is most readable and clear.
After carefully reviewing the manuscript, I would recommend the publication of the paper "as is".
My only remark concerns the acceptance of quantitative parameters of sympathetic skin responses as a reliable outcome (as used in reference 16, Nalbantoglu et al 2021, discussed in the manuscript line 364). Routine SSR are too prone to habituation, inter- and intraindividual assessment to be used in quantitative way (review Kucera 2004). For this reason, the modification by Emmer et al 2012 (SSR evoked by train of stimuli that do not habituate) was introduced. It seems only the presence/absence of SSR may be a reliable finding (Hubli 2015). The authors could mention that the use of SSR amplitudes and latencies as a quantitative measure is considered disputable. However, I understand my opinion itself may be debatable and don't insist on any revision, unless accepted by the authors.PS. Some of the references lack the DOI, a technical omission that can be easily corrected.
Answer: We thank the reviewer for this valuable comment. Appropriate information has been added as suggested in Discussion paragraph.
Utilization of SSR amplitudes and latencies as a quantitative measure is regarded as debatable [40-41]. Evaluating sudomotor function through the qualitative analysis of SSR based on its presence/absence could potentially be a more reliable method [42].
