Is It Lupus? Is It Neuromyelitis Optica Spectrum Disorder (NMOSD)?—Why Not Both?

Round 1

Reviewer 1 Report

Thank you very much for giving me the opportunity to review the article “Case Report” titled “Is it Lupus? Is it NMOSD? - Why not both? “(sclerosis-2348878). The article describes a case report of a 41-year-old patient with a complex medical history, presenting with primary symptoms of seropositive Neuromyelitis Optica Spectrum Disorder (NMOSD), including paresthesia, paralysis of the lower extremities, and urinary incontinence. The patient was already undergoing treatment for a diagnosed systemic lupus erythematosus (SLE) with hydroxychloroquine, and the central nervous system manifestation of the disease was also considered.

However, I would like to provide some constructive feedback on the article. Firstly, I recommend avoiding the use of acronyms, especially in the title. Therefore, I suggest writing "Neuromyelitis Optica Spectrum Disorder (NMOSD)" instead of just NMOSD. Additionally, the introduction could be presented in a more structured way, stating the hypothesis and its significance before describing the objective of the study, which could help readers understand what can be learned from this situation.

Furthermore, it would be helpful to clarify the methodology, specifically whether the tests were performed simultaneously or as a decision tree, as the value of the tests differs for diagnosis. It would also be interesting to provide information on the duration of treatment to evaluate its effectiveness in controlling the underlying diseases.

Lastly, the conclusions should be based on the presented case, and should not overgeneralize beyond the scope of the report.

Thank you again for the opportunity to review this article.

Best regards,

Author Response

Reviewer 1:

 

Thank you very much for giving me the opportunity to review the article “Case Report” titled “Is it Lupus? Is it NMOSD? - Why not both? “(sclerosis-2348878). The article describes a case report of a 41-year-old patient with a complex medical history, presenting with primary symptoms of seropositive Neuromyelitis Optica Spectrum Disorder (NMOSD), including paresthesia, paralysis of the lower extremities, and urinary incontinence. The patient was already undergoing treatment for a diagnosed systemic lupus erythematosus (SLE) with hydroxychloroquine, and the central nervous system manifestation of the disease was also considered.

However, I would like to provide some constructive feedback on the article. Firstly, I recommend avoiding the use of acronyms, especially in the title. Therefore, I suggest writing "Neuromyelitis Optica Spectrum Disorder (NMOSD)" instead of just NMOSD.

 

Thank you very much for your constructive advice. We adopt your advice and changed the title accordingly:

“Is it Lupus? Is it Neuromyelitis Optica Spectrum Disorder (NMOSD)? - Why not both?

 

Additionally, the introduction could be presented in a more structured way, stating the hypothesis and its significance before describing the objective of the study, which could help readers understand what can be learned from this situation.

Thank you for this important comment. In order to highlight the hypothesis of our case study we added a short statement at the end of the introduction in order to clarify why this case was presented. Considering the fact that further information is given in the section ‘case presentation’, we found it important to primarily deliver a general description of the discussed autoimmune diseases in the introduction in order to emphasize on the subsequent hypothesis.

“Despite the already diagnosed SLE, extensive differential diagnostics were initiated as a competitive disease was suspected.”

 

Furthermore, it would be helpful to clarify the methodology, specifically whether the tests were performed simultaneously or as a decision tree, as the value of the tests differs for diagnosis.

 

We thank the reviewer for this important point. We made an addition to the ‘materials and methods’ section which states that most of the diagnostics were performed simultaneously.

“2.4        Diagnostic flow

Serum and CSF were aquired at the beginning of the inpatient stay for all of the in section 2.1 mentioned parameters. MRI and evoked potentials were initiated simultaneosly. All findings were received on the day of initiation, except the test results for AQP4-antibodies, anti-MOG-antibodies (done by an external laboratory) and neuropathological analysis (delay of nine days).”

 

It would also be interesting to provide information on the duration of treatment to evaluate its effectiveness in controlling the underlying diseases.

 

Thank you for this valuable comment. We would like to point to the section ‘discussion’ (see line 229 – 231). We also added the following part to the last sentence of the discussion, in order to clarify that the treatment had not been changed over the observational period.

“As the patient has not shown any signs of relapse within the observation period of twelve months, the combined treatment will be continued as primarily initiated.”

 

Lastly, the conclusions should be based on the presented case, and should not overgeneralize beyond the scope of the report.

 

We thank the reviewer for this comment. We reorganized the ‘conclusion’ in order to put emphasis on the conclusions made from the presented case and put a general ‘take-home-message’ at the end.

“5. Conclusion

In this case, the first detection of aPL-antibodies occurred four years prior to the first measurement of AQP4-antibodies. It is unclear whether AQP4-antibody synthesis had al-ready occurred in this regard. However, it should be noted that the previously presented clinical symptoms (hemolysis, thrombopenia etc.) were not compatible with a NMOSD-diagnosis. In our view, the possibility is given that the presence of aPL-antibodies may have led to microvascular damage of the blood-brain barrier and subsequently might have triggered an autoinflammatory reaction against AQP4.

Even though the formerly diagnosed SLE could also have sufficiently explained the symptoms of the patient, it is important to reconsider competitive diseases in order to establish an adequate immunotherapy.

In our view, this highlights the importance of thorough differential-diagnostics in patients presenting with myelitis and consideration of other autoimmune-diseases.”

 

Thank you again for the opportunity to review this article.

 

Best regards,

 

Author Response File: Author Response.docx

Reviewer 2 Report

You present and discuss a documented SLE case eventually developing features of NMO with confirmation of diagnosis. You carry a comprehensive assessment and discuss this case in a rather attractive and illustrative manner. The association of SLE and NMO is not a novel phenomenon, and indeed, the presence of autoimmune disorders (including SLE) in the NMO Spectrum Disorder (NMOSD) has been substantially addressed in the literature. This reviewer has several observations for your consideration:

1. In page 2, line 50, you mention "NMO patients who are seronegative AQP-4 antibodies....", ostensibly you do not address Myelin Oligodendrocyte antibody disease (MOGAD), the most common differential diagnosis with antibody negative NMOSD. Reports indicate between 20% to 40% of negative AQP-4 antibody individuals test positive for anti-MOG antibodies. There are substantial similarity in clinical symptoms among these two entities.

2. While brain MRI in your case show mild subcortical white matter abnormalities, generally the abnormal signals present in NMO (and ischemic lesions in lupus for that matter) are not present in the typical locations adjudicated to multiple sclerosis by different criteria (MAGNIMS, McDonald's, etc.,). The longitudinally extensive spinal cord lesion as shown by the MR images, is now part of the diagnostic criteria for NMO. Although older literature reports "myelopathy" associated to SLE (1%-3%, Kim et al. Ann Rehabil Med 2014), and > 4 spinal segments (Espinoza et al. Semin Arthritis Rheum 2010; Ferreira et al. Rheumatology 2010), the problem is that an AQP-IgG antibody was not performed in these cases. The NMO-IgG  discovered in 2004 and employed mainly for differential diagnosis from MS starting in 2006. I believe these aspects deserve discussion in your paper.

3. Just for the sake of discussion, some scholars feel the classifying term "NPSLE" is no longer applicable in people with SLE but without organic cerebral symptoms.   

None

Author Response

Reviewer 2:

 

You present and discuss a documented SLE case eventually developing features of NMO with confirmation of diagnosis. You carry a comprehensive assessment and discuss this case in a rather attractive and illustrative manner. The association of SLE and NMO is not a novel phenomenon, and indeed, the presence of autoimmune disorders (including SLE) in the NMO Spectrum Disorder (NMOSD) has been substantially addressed in the literature. This reviewer has several observations for your consideration:

 

1. In page 2, line 50, you mention "NMO patients who are seronegative AQP-4 antibodies....", ostensibly you do not address Myelin Oligodendrocyte antibody disease (MOGAD), the most common differential diagnosis with antibody negative NMOSD. Reports indicate between 20% to 40% of negative AQP-4 antibody individuals test positive for anti-MOG antibodies. There are substantial similarity in clinical symptoms among these two entities.

 

Thank you very much for this important comment. We expanded the introduction by discussing MOGAD as a possible differential diagnosis while indicating the possible overlapping features regarding seronegative NMOSD patients.

“NMO patients who are seronegative for AQP-4 antibodies might show a more heterogeneous clinical manifestation. In 30-70% of seronegative NMO patients antibodies directed against Myelin Oligodendrocyte Glycoprotein (MOG) can be detected. The detection of MOG-antibodies is not considered in the diagnostic criteria for NMOSD. It indicates the presence of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD), which is despite the possibility of overlapping clinical features and MRI-findings, thus complicating distinction from MS and NMO, considered a separate entity of disease. [5]”

5: Sechi E, Cacciaguerra L, Chen JJ, Mariotto S, Fadda G, Dinoto A, Lopez-Chiriboga AS, Pittock SJ, Flanagan EP. Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): A Review of Clinical and MRI Features, Diagnosis, and Management. Front Neurol. 2022 Jun 17;13:885218. doi: 10.3389/fneur.2022.885218. PMID: 35785363; PMCID: PMC9247462.

Additionally we report the negative results for MOG-Antibodies in the section ‘case presentation’ as well as we describe where the analysis was done in the ‘material and methods’ section.

“Later a 1:10240 serum titre of Aquaporin 4-antibodies was detected, while MOG-antibodies were tested negative.”

“Aquaporin 4-antibody and MOG-antibody analysis was done by an external laboratory (MVZ Labor PD Dr. Volkmann und Kollegen GbR, Karlsruhe, Germany).”

2. While brain MRI in your case show mild subcortical white matter abnormalities, generally the abnormal signals present in NMO (and ischemic lesions in lupus for that matter) are not present in the typical locations adjudicated to multiple sclerosis by different criteria (MAGNIMS, McDonald's, etc.,). The longitudinally extensive spinal cord lesion as shown by the MR images, is now part of the diagnostic criteria for NMO. Although older literature reports "myelopathy" associated to SLE (1%-3%, Kim et al. Ann Rehabil Med 2014), and > 4 spinal segments (Espinoza et al. Semin Arthritis Rheum 2010; Ferreira et al. Rheumatology 2010), the problem is that an AQP-IgG antibody was not performed in these cases. The NMO-IgG discovered in 2004 and employed mainly for differential diagnosis from MS starting in 2006. I believe these aspects deserve discussion in your paper.

 

We thank the reviewer for pointing out this important issue, which is indeed relevant to our reported case. We added the following part to the section ‘discussion’ considering the suggested literature:

“Regarding the formerly mentioned myelopathy as possible manifestation of SLE older reports have discussed several cases where SLE-patients suffered from myelopathy, even with extensive longitudinal myelitis over four or more spinal segments in some cases, which could also have indicated presence of NMOSD, unfortunately AQP4-antibodies had not been tested or taken in consideration.”

 

Kim, S.-Y.; Yoon, T.-S.; Suh, J.-H. Concomitant Occurrence of Cervical Myelopathy, Cerebral Infarction, and Peripheral Neuropathy in Systemic Lupus Erythematosus: A Case Report. Ann. Rehabil. Med. 2014, 38, 263–268, doi:10.5535/arm.2014.38.2.263.

Zotos, P.; Poularas, J.; Karakitsos, D.; Karabinis, A. Lupus Related Longitudinal Myelitis: Figure 1. J. Rheumatol. 2010, 37, 1776–1776, doi:10.3899/jrheum.100282.

Espinosa, G.; Mendizábal, A.; Mínguez, S.; Ramo-Tello, C.; Capellades, J.; Olivé, A.; Cervera, R. Transverse Myelitis Affecting More Than 4 Spinal Segments Associated with Systemic Lupus Erythematosus: Clinical, Immunological, and Radiological Characteristics of 22 Patients. Semin. Arthritis Rheum. 2010, 39, 246–256, doi:10.1016/j.semarthrit.2008.09.002.

Unfortunately we could not identify the publication ‘Ferreira et al. Rheumatology 2010’ given by the reviewer.

 

3. Just for the sake of discussion, some scholars feel the classifying term "NPSLE" is no longer applicable in people with SLE but without organic cerebral symptoms.

Thank you for addressing this issue with the term ‘NPSLE’, since we share your opinion about using a precise terminology. Within the scope of our literary research we noticed that the term is still very commonly used to summarize possible neurological and/or psychiatric manifestations of SLE in recent publications as well as the literature we cited in our case report. In order to maintain consistency towards other publications about this topic we decided to refer to ‘NPSLE’.

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Thank you very much for allowing me to review the new version of the article "Case Report" titled "Is it Lupus? Is it NMOSD? - Why not both?" (sclerosis-2348878), as well as the authors' response to the comments made. I believe they have conducted a comprehensive assessment and discussed this case on the association of SLE and NMO. After carefully reading this new version, I believe that some points have been clarified, although I think that other articles on this same topic should be referenced.

Author Response

Response to Reviewer 1 Round 2

„Thank you very much for allowing me to review the new version of the article "Case Report" titled "Is it Lupus? Is it NMOSD? - Why not both?" (sclerosis-2348878), as well as the authors' response to the comments made. I believe they have conducted a comprehensive assessment and discussed this case on the association of SLE and NMO. After carefully reading this new version, I believe that some points have been clarified, although I think that other articles on this same topic should be referenced.”

We thank the reviewer for carefully reading our revised manuscript. We added the following two articles to the manuscript to add even more cases, which discuss the association of SLE and NMOSD leading to a total number of five.

14. Ochi, M.G.S.; Shapiro, S.C.; Melamed, E. Lupus and NMOSD: The Blending of Humoral Autoimmunity. Case Rep. Rheumatol. 2020, 2020, 8820071, doi:10.1155/2020/8820071.
15. Aringer, M.; Costenbader, K.; Daikh, D.; Brinks, R.; Mosca, M.; Ramsey-Goldman, R.; Smolen, J.S.; Wofsy, D.; Boumpas, D.T.; Kamen, D.L.; et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Ann. Rheum. Dis. 2019, 78, 1151–1159, doi:10.1136/annrheumdis-2018-214819.

 

Author Response File: Author Response.docx