Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This study examined the efficacy and safety of PE in patients with autoimmune neurological disorders, which is an interesting topic. There are some issues that should be addressed before considering publication. The following are the reviewer’s comments.

 

1. Please specify the period of this study.

 

2. How did you diagnose each disease? Please specify diagnostic criteria for each disease.

 

3. Please spell out abbreviations at their first appearance (Page 4: PNS, POEMS, and PN)

 

4. The number of patients of each disease is unclear. Please specify the number of patients, not just the percentage.

 

5. Please indicate A-D and full spell of PLEX in Figure 2

 

6. If PE is performed after IVIg, IgG is removed. Such sequence is not desirable and not recommended. In patients who received IVIg before PE, how long was the interval of IVIg and PE?

 

7. The authors compared parameters of multiple diseases (e.g. Figure 2). Please specify how did you addressee the multiple comparison.

 

8. Which scale did you use to evaluate effectiveness of PE in patients with NMOS? EDSS or MRC score? If you used MRC score, you should add NMOSD on figure 4D.

 

9. I felt that it’s unreasonable to use MRC score evaluate all diseases other than MS and MG. Clinical manifestations vary from disease to disease and included diseases that don’t necessarily cause muscle weakness.

 

10. No adverse events leading to life-threatening conditions or death occurred?

 

11. Discussion should be divided into paragraphs as appropriate. This will make it easier to read.

Author Response

We thank the respectable reviewer for his careful reading of our manuscript as well as for his precious comments. Here we provide a point-to point reply to reviewer’s comments. All the changes throughout the manuscript are highlighted in red.

Comment 1. Please specify the period of this study.

         R: We added the study period in the methods section (ln 100-101): “from July 2011 to July 2022”.

Comment2. How did you diagnose each disease? Please specify diagnostic criteria for each disease.

 R: Accordingly, the reviewer comment we added the diagnostic criteria employed for the diagnosis     of included diseases in a dedicate paragraph included in methods section (see ln 106-123): “The final diagnoses of patients included in this study were carried out according to the disease-specific and currently used diagnostic criteria. Particularly, MS, NMOSD and MOGAD diagnoses were carried out according the 2017 McDonald criteria, International Panel for NMO diagnosis and International MOGAD Panel criteria respectively (17-19). MG diagnosis was performed since the finding of decremental U-shaped response at 3 Hz repetitive nerve stimulation and/or increased jitter at single-fiber electromyography and positive testing for autoantibodies against AChRs, MuSK or LRP4 (20). GBS and CIDP were recognized according to the Asbury and European Federation of Neurological Socie-ties/Peripheral Nerve Society Guideline, respectively (21,22). The diagnosis of ADEM was carried out according to the Bradford Hill causality criteria since the finding of a temporal relationship between infectious disease and acute myelitis/EM without other positive serological testing (23). The diagnosis of paraneoplastic syndromes (PNSs) was done by the presence of circulating onconeural antibodies and the related neurological manifestation with or without tumor (24). The patients with SPS had a higher serum titer of anti-GAD 65 IgG (>20 mmol/l) as well as he had the typical neurological manifestations such as hypertonia, rigidity and exaggerated startle reaction, therefore the definite diagnosis of SPS was carried out (25).”

Comment 3. Please spell out abbreviations at their first appearance (Page 4: PNS, POEMS, and PN)

                R: all the abbreviation at their first appearance have been clarified.

Comment 4. The number of patients of each disease is unclear. Please specify the number of patients, not just the percentage.

R: We thank the reviewer for this comment. We rearranged Figure 1 into Table 1 reporting the clinical indications to perform TPE with number and the relative percentage of patients included. We also clarified the number and relative percentage of specific diagnosis after the diagnostic work-up as well as the final diagnosis (see ln 207-213): “After diagnostic work-up, patients with unknown diagnosis were diagnosed as MS (n=5/14; 35.7%), seronegative NMOSD (n=1/14; 7.1%), ADEM (n=3/14; 17.6%), CIDP (n=2/14; 14.3%) and PNSs (n=3/14; 17.6%). Finally, out of n=59 individuals included in this study, n=25 (42.4%) patients underwent TPE due to MS relapses, n=9 (15.3%) had MG crisis, n=9 (15.3%) had GBS, n=5 (8.5%) had CIDP, n=5 (8.5%) had PNSs, n=3 (5.1%) had ADEM while n=1 (1.7%) had seronegative NMOSD, n=1 (1.7%) had MOGAD and n=1 (1.7%) had SPS.”

Comment 4. Please indicate A-D and full spell of PLEX in Figure 2

R: According to the 7^th point of this revision, we rearranged tables and figures since in the previously submitted Figure 2 we compared parameters of multiple diseases. Now the past Figure 2 was replaced by an easier to read Table 3 with the aim to report the descriptive statistic of TPE features and demographic parameters. All the Figures are now titled with an upper-case letter as well as all the abbreviations are spell in the figure legend.

Comment 6. If PE is performed after IVIg, IgG is removed. Such sequence is not desirable and not recommended. In patients who received IVIg before PE, how long was the interval of IVIg and PE?

R: We thank the reviewer for his precious comment. We added the median time between last corticosteroids and IVIg administration and the TPE initiation (see ln454-458) as following: “Notably, the median time from the last IVIg administration and TPE initiation was 41.5 days. Although the sequency from IVIg to TPE is not recommended due to the clearance of circulating immunoglobulin operated by TPE, in our study the time between IVIG admin-istration and TPE appeared long enough to avoid the Ig removal.”

Comment 7. The authors compared parameters of multiple diseases (e.g. Figure 2). Please specify how did you addressee the multiple comparison.

R: we rearranged tables and figures since in the previously submitted Figure 2 we compared parameters of multiple diseases, but we agree to the fact that the figure was not easy to understand. Now the past Figure 2 was replaced by an easier to read Table 3 with the aim to report the descriptive statistic of TPE features and demographic parameters. Table 2 was unchanged, and it reported the clinical and demographic features of all participants included in this study The clinical and demographic features outlined in Table 3 and the comparison between patients’ groups may help the understanding of some results as stated throughout the discussion section (see ln 345-349; see ln 405-407, etc).

Comment 8. Which scale did you use to evaluate effectiveness of PE in patients with NMOS? EDSS or MRC score? If you used MRC score, you should add NMOSD on figure 4D.

R: We thank the reviewer for this comment. Indeed, we clarified throughout the manuscript, including tables and figures, the distinction between MS and NMOSD/MOGAD, especially in the case of the effectiveness evaluation. Accordingly, EDSS was only computed for patients with MS while NMOSD patients were evaluated only through mRS (Figure 2). We also clarified this issue in the methods section (see ln 159) “. In other cases, mRS was the only study outcome measure”.

 

Comment 9. I felt that it’s unreasonable to use MRC score evaluate all diseases other than MS and MG. Clinical manifestations vary from disease to disease and included diseases that don’t necessarily cause muscle weakness.

R: we agree with this precious comment, and we thank the reviewer for his highly qualified comment. In clinical practice we calculated routinary MRC for patients with GBS , CIDP and other neuropathies causing motor impairment. Indeed, MRC seems to be a good measure in GBS (Kleyweg et al, see ref 29). However, we agree to the fact that some polyneuropathy may involve mainly sensory fibers resulting in a normal or slightly reduced MCR and in a lower-than-expected TPE effectiveness when evaluated through MRC. Moreover, some disease such as SPS, ADEM and NMOSD may have a normal MRC. Due to this reason, we rearranged statistical analyses and Figure 2 accordingly by using mRS for the evaluation of TPE effectiveness in patients with PNSs, ADEM, NMOSD/MOGAD, instead MRC and we limited the pre vs post TPE evaluation to patients with GBS and CIDP (Figure 2). We also updated methods section accordingly (see ln 126-236). Furthermore, we deserved a brief argumentation on the difference between mRS and MRC as outcome measure in GBS into the discussion section thus supporting strongly the reviewer comments (see ln 419-426): “However, the discordance between the significant mRS reduction and the not significant MRC increasing in patients with GBS may be due to interoperator variability of neurological examination as well as to the fact that MRC may turn inappropriate in some cases (e.g., GBS with predominant sensory impairment). Furthermore, it has been shown that TPE is higly effective in axonal form of GBS and less in demyelinating ones (9). Due to the lower number of GBS patients we could not conducted a subgroup analysis testing whether TPE effectiveness was different between axonal and demyelinating GBS variants”.

Comment 10. No adverse events leading to life-threatening conditions or death occurred?

R: in the appropriate paragraph of Result section, we stated that no life-threatening conditions or death occurred in this study (see ln 315).

Comment 11. Discussion should be divided into paragraphs as appropriate. This will make it easier to read.

R: we agree with the reviewer, and we divided discussion into paragraphs accordingly. In each paragraph we critically discussed the main finding of our study and compared with the current literature.

Reviewer 2 Report

Comments and Suggestions for Authors

I would like to congratulate the authors for a comprehensive approach to TPE in immune-mediated neurological diseases and for the development of a timely article for clinical practice. As the strengths of the article, I would detail the following:

1)     The article details the reason for using this treatment based on the pathophysiological mechanisms of the diseases, providing a suitable foundation for understanding the practical applicability of this therapy.

2)     The reported data includes clinical and demographic characteristics, treatment effect, and clinical evolution. Adverse effects are also mentioned, the statistical method used is appropriate.

3)     In the same time, the existing gaps are highlighted, justifying further research in this area.

Aspects to be improved include the following

1)     Although the efficacy of IVIg and TPE treatments in immune-mediated neurological diseases is relatively similar, some authors mention that treatment should be patient-tailored and based on available clinical resources (Pinto AA, De Seze J, Jacob A, Reddel S, Yudina A, Tan K. Comparison of IVIg and TPE efficacy in the treatment of neurological disorders: a systematic literature review. Ther Adv Neurol Disord. 2023 Mar 29;16:17562864231154306. doi: 10.1177/17562864231154306).  

2)     You mentioned that sometimes the indication for IVIg or TPE for certain acute immune-mediated diseases is not clear. However, some authors argue that axonal forms of GBS benefit more from TPE if initiated rapidly after disease onset compared to IVIg treatment (Stoian A, Șerban G, Bajko Z, Andone S, Mosora O, Bălașa A. Therapeutic plasma exchange as a first-choice therapy for axonal Guillain-Barré syndrome: A case-based review of the literature (Review). Exp Ther Med. 2021 Mar;21(3):265. doi: 10.3892/etm.2021.9696). The same authors mention allergic reactions to plasma as potential adverse effects that may occur when plasma is used as the replacement fluid for TPE and the management approach for these complications. We suggest addressing these aspects mentioned in the discussion section. The introduction could benefit from a more detailed comparison between TPE and treatment with IVIG or corticosteroids.

3)     Please specify the amount of plasma exchanged in plasma volumes. You mentioned that between 1000-1500 ml of plasma were exchanged per session. Have you calculated this in terms of plasma volumes per session or the total plasma volumes exchanged over the hospitalization period? If you haven't done this, please mention it as a limitation of the study along with the other aspects addressed earlier.

Author Response

We thank the reviewer for appreciating our work as well as for its precious comments. We provide a point-to-point reply to its comments. All the changes throughout the manuscript are highlighted in red.

Comment 1.Although the efficacy of IVIg and TPE treatments in immune-mediated neurological diseases is relatively similar, some authors mention that treatment should be patient-tailored and based on available clinical resources (Pinto AA, De Seze J, Jacob A, Reddel S, Yudina A, Tan K. Comparison of IVIg and TPE efficacy in the treatment of neurological disorders: a systematic literature review. Ther Adv Neurol Disord. 2023 Mar 29;16:17562864231154306. doi: 10.1177/17562864231154306).  

R: This interesting paper has been extensively read. We added this reference accordingly (see ln 73-78): “Thus, both IVIg and TPE, by removing the pathogenetic antibodies and immune media-tors from systemic circulation seems to have a similar effectiveness in neuroimmunologi-cal disorders. However, the choice between these two approaches is often tailored to pa-tient according to some features such as the presence of concomitant infections, comorbid-ity, availability of TPE equipment and trained medical personnel or cost in local setting “

Comment 2.  You mentioned that sometimes the indication for IVIg or TPE for certain acute immune-mediated diseases is not clear. However, some authors argue that axonal forms of GBS benefit more from TPE if initiated rapidly after disease onset compared to IVIg treatment (Stoian A, Șerban G, Bajko Z, Andone S, Mosora O, Bălașa A. Therapeutic plasma exchange as a first-choice therapy for axonal Guillain-Barré syndrome: A case-based review of the literature (Review). Exp Ther Med. 2021 Mar;21(3):265. doi: 10.3892/etm.2021.9696). The same authors mention allergic reactions to plasma as potential adverse effects that may occur when plasma is used as the replacement fluid for TPE and the management approach for these complications. We suggest addressing these aspects mentioned in the discussion section. The introduction could benefit from a more detailed comparison between TPE and treatment with IVIG or corticosteroids.

R: We appreciated the highly expert comments provided by the reviewer. Accordingly, we added further comparison study between IVIg, corticosteroids and TPE thus enriching the introduction section and provide to the reader the basis for understanding our study (see ln 52-72): “Several studies explored the effectiveness of TPE and IVIg in the case of GBS although a clear superiority of one therapy over the other has not emerged. Since the conduction of the first randomized trial, IVIg and TPE appear to have a similar effectiveness (7). These studies, however, included predominantly patients with demyelinating GBS form (8). Recently, some authors reported that TPE was more effective in patients with axonal form of GBS (9). Conversely, it seems that treatment with IVIg is less commonly associated with the occurrence of adverse events (AEs) when compared to TPE (10,11). It is also well known that corticosteroids have no effect on GBS course (12). Regarding the treatment of MG cri-sis, corticosteroids may cause transient worsening of myasthenic crisis therefore starting immediately with IVIg or TPE is immediately indicated. However, also in this case, data from comparison studies were not meaningful. Indeed, Mandawat et al. found that the ef-fectiveness of IVIg and TPE were similar in MG crisis although therapy with IVIg was less expensive as well as less associated with adverse events (AEs) making it preferable in pa-tients with comorbidity (13). Other authors confirmed these data and suggested that the choice between IVIg and TPE should be based upon the availability of resources (14).………… A brief mention should be deserved to CIDP. In this case, corticosteroids and IVIg are em-ployed as maintenance therapy while TPE is commonly used in refractory-patients (16).” We also address the issue of TPE effectivenes in demyelinating vs axonal GBS form into the discussion session as follows (see ln 412-415): “Furthermore, it has been shown that TPE is higly effective in axonal form of GBS and less in demyelinating ones (9). Due to the lower number of GBS patients we could not con-ducted a subgroup analysis testing whether TPE effectiveness was different between ax-onal and demyelinating GBS variants.”.

Finally, we reserved also a brief discussion on the allergic reaction as suggested by the reviewer (see ln 510-511): “Of note, all the patients included in this study received 5% human albumin and electrolyte solution as replacement after TPE. For this reason, probably, we did not observe allergic reaction which are common when plasma is used as replacement fluid (9).”

Comment 3. Please specify the amount of plasma exchanged in plasma volumes. You mentioned that between 1000-1500 ml of plasma were exchanged per session. Have you calculated this in terms of plasma volumes per session or the total plasma volumes exchanged over the hospitalization period? If you haven't done this, please mention it as a limitation of the study along with the other aspects addressed earlier.

R: We stated in the methods section that 1000 to 1500 mL of plasma volume was exchanged in each TPE cycle. Patients received three to five cycles of TPE per session. Each session comprised three to five TPE cycle as indicated in the methods section. We understand the confusion generated by the terms cycle and session thus we clarified these aspects throughout the manuscript by replacing the term “session” with “hospital admission” since in our view a TPE session was referred to a single HA. See changes in methods section (ln144-145). We replaced the term session with cycle throughout the manuscript. However, according reviewer’s comment, in the limitation section (see ln 526-528), we stated as follow: “Finally, we did not calculate the total volume of plasma exchanged at each TPE session.”

Thank you.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors revised the manuscript appropriately according to the reviewers' comments. I have no further comments.