SLIPPERS Reconsidered: Clinical, Radiological, and Pathological Overlap with PACNS—A Case Report

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript presents two instructive cases initially classified as supratentorial lymphocytic inflammation with parenchymal perivascular enhancement responsive to steroids (SLIPPERS) that, upon longitudinal clinical, radiological, and histopathological reassessment, fulfill diagnostic criteria for primary angiitis of the central nervous system (PACNS). The authors address a clinically important and underexplored diagnostic gray zone with significant therapeutic implications. The integration of clinical course, imaging findings, histopathology, and treatment response—particularly with extended follow-up—constitutes a notable strength.

However, while the central hypothesis is plausible and compelling, several methodological, diagnostic, and reporting limitations currently preclude acceptance. In particular, the absence of vascular imaging data, incomplete histopathological documentation in one case, limited cerebrospinal fluid (CSF) characterization, and insufficient discussion of key differential diagnoses (notably lymphoproliferative disorders) weaken the evidentiary basis of the reclassification. Substantial revisions are required to strengthen transparency, reproducibility, and clinical applicability.

Overall, this is a potentially valuable contribution that would benefit from major revision before being considered suitable for publication.

Major Strengths

1. The manuscript highlights a clinically relevant and high-stakes diagnostic overlap between SLIPPERS and PACNS, challenging the presumed nosological distinctness of SLIPPERS.

2. Multimodal integration of radiological, histopathological, and longitudinal treatment-response data supports the proposed diagnostic reassignment.

3. Open brain biopsy was performed in both cases, including immunohistochemistry and, in one case, elastic staining demonstrating transmural vascular involvement.

4. Long-term follow-up (up to seven years in one patient) provides meaningful insight into relapse patterns and treatment course.

5. The case-based narrative structure is clear and facilitates comprehension.

6. The inclusion of a literature summary table provides useful contextualization of previously reported SLIPPERS cases.

7. The manuscript addresses an important management issue, as misclassification may lead to inadequate intensity or duration of immunosuppression.

Major Concerns

1. Absence of Vascular Imaging Data

A central recommendation of the manuscript is the systematic use of angiography and intracranial vessel-wall imaging (VWI) to avoid misclassification. However, no magnetic resonance angiography (MRA), digital subtraction angiography (DSA), or vessel-wall MRI findings are presented for either patient. This significantly weakens the argument that these modalities would have altered the initial diagnostic classification.

• If such imaging was performed, the findings should be reported and illustrated.

• If not performed, the authors should clearly explain the constraints and discuss whether retrospective imaging could be obtained.

2. Incomplete Histopathological Evidence in Case 1

While case 2 demonstrates convincing transmural vascular involvement supported by elastic staining, the histopathological narrative for case 1 emphasizes perivascular inflammation without clearly documented transmural changes.

• If transmural involvement was identified upon review, corresponding histologic images (e.g., elastic van Gieson or equivalent stains) should be provided.

• If not, the authors should temper the strength of the PACNS reclassification for this case or explicitly discuss diagnostic uncertainty.

3. T-Cell Clonality in Case 2

The detection of T-cell clonality in case 2 raises an important differential diagnosis of T-cell lymphoproliferative disorders, which is insufficiently addressed.

• Please specify the clonality assay (target locus, methodology such as PCR vs. NGS, and interpretive thresholds).

• The authors should expand the discussion on how clonality may be observed in reactive inflammatory conditions and clearly justify why a lymphoproliferative process was excluded in this case.

4. Lack of Explicit Mapping to PACNS Diagnostic Criteria

The manuscript would benefit from a systematic, item-by-item mapping of each case to established PACNS diagnostic criteria (e.g., Calabrese and Mallek; Birnbaum and Hellmann).

• Explicitly stating which criteria were fulfilled and how mimics were excluded would substantially enhance diagnostic transparency.

• Consider including this mapping as a table or structured subsection.

5. Incomplete CSF Characterization

CSF findings are insufficiently detailed, despite their importance in excluding infectious, neoplastic, and inflammatory mimics.

• Please provide comprehensive CSF data, including cell counts and differential, IgG index, cytology and/or flow cytometry results, and relevant autoimmune/paraneoplastic and infectious studies.

6. Treatment Reporting and Rationale

Treatment details are currently narrative and incomplete.

• Induction and maintenance regimens (steroid dosing, duration, tapering strategy, methotrexate and cyclophosphamide doses, monitoring, and relapse criteria) should be systematically reported.

• The rationale for choosing methotrexate versus cyclophosphamide at different disease phases should be aligned with current guideline-based practice.

Minor Concerns and Editorial Issues

1. There are inconsistencies between the main text and figure captions (e.g., hemispheric involvement in case 2) that require correction.

2. Figure legends contain typographical errors and ambiguities; histology panels for case 1 lack vascular elastic stain images.

3. The literature summary table includes missing data fields, inconsistent terminology (e.g., punctate vs. pseudonodular enhancement), and future-dated or incomplete references that need reconciliation.

4. The discussion of vessel-wall MRI literature in PACNS is limited; a more granular appraisal of sequence choice and diagnostic yield would improve practical relevance.

5. Minimal discussion is provided on other steroid-responsive mimics, including CLIPPERS-to-lymphoma evolution.

Overall Recommendation

This manuscript offers an important and clinically meaningful perspective on the diagnostic overlap between SLIPPERS and PACNS. The longitudinal follow-up and histopathological evidence—particularly in case 2—support the central premise. Nevertheless, the lack of vascular imaging data, incomplete histopathologic documentation in case 1, limited CSF detail, and insufficient discussion of T-cell clonality necessitate major revision.

With substantial additions addressing these points, clarification of inconsistencies, and a more structured diagnostic and therapeutic framework, this work has the potential to provide valuable guidance for clinicians confronting steroid-responsive supratentorial enhancement.

Author Response

We sincerely thank the reviewers for their meticulous review of our manuscript and for highlighting these important points.

MAJOR CONCERNS:

Comment 1: A central recommendation of the manuscript is the systematic use of angiography and intracranial vessel-wall imaging (VWI) to avoid misclassification. However, no magnetic resonance angiography (MRA), digital subtraction angiography (DSA), or vessel-wall MRI findings are presented for either patient. This significantly weakens the argument that these modalities would have altered the initial diagnostic classification.

If such imaging was performed, the findings should be reported and illustrated.

If not performed, the authors should clearly explain the constraints and discuss whether retrospective imaging could be obtained.

Response 1: thank you for pointing this out. We acknowledge that the lack of magnetic resonance angiography (MRA), digital subtraction angiography (DSA), and intracranial vessel-wall imaging (VWI) in the initial workup is a limitation of this retrospective study.

However, we believe this absence reinforces our central thesis: the strong clinical and radiological resemblance to SLIPPERS syndrome can lead clinicians to inadvertently omit the vascular sequences necessary to detect PACNS.

In both cases, the initial diagnosis was directed towards SLIPPERS due to the characteristic nodular, steroid-responsive enhancement pattern. Consequently, only standard structural MRI sequences were obtained.

Regarding the reviewers’ suggestion for retrospective data, we must clarify that DSA and VWI are active acquisition modalities that cannot be reconstructed from existing standard MRI data. While this remains a constraint, we have updated the manuscript to explicitly discuss how the omission of these sequences contributed to the initial misclassification, thereby strengthening our recommendation for their systematic use in suspected SLIPPERS cases (Page 10, line 256).

Comment 2: While case 2 demonstrates convincing transmural vascular involvement supported by elastic staining, the histopathological narrative for case 1 emphasizes perivascular inflammation without clearly documented transmural changes.

If transmural involvement was identified upon review, corresponding histologic images (e.g., elastic van Gieson or equivalent stains) should be provided.

If not, the authors should temper the strength of the PACNS reclassification for this case or explicitly discuss diagnostic uncertainty.

Response 2: We would like to clarify that a vascular elastic stain was not performed during the initial workup of Case 1 because the clinical and radiological phenotype was highly suggestive of SLIPPERS syndrome, an entity primarily defined by its perivascular inflammation. Consequently, the initial pathological evaluation focused on characterizing the perivascular infiltrate and excluding neoplastic mimics rather than looking for signs of primary vasculitis.

Upon identifying transmurality in Case 2 and subsequently re-evaluating Case 1, we encountered a technical constraint: the original tissue block for Case 1 had been exhausted following two separate open brain biopsies and multiple immunohistochemical stains.

However, a meticulous retrospective review of the original hematoxylin and eosin slides by our neuropathology team definitively confirmed that the lymphocytic infiltrate was not merely restricted to the perivascular space but invaded and disrupted the full thickness of the vessel walls.

We have added changes in the text to address this point (page 4, line 111).

Comment 3: The detection of T-cell clonality in case 2 raises an important differential diagnosis of T-cell lymphoproliferative disorders, which is insufficiently addressed.

Please specify the clonality assay (target locus, methodology such as PCR vs. NGS, and interpretive thresholds).

The authors should expand the discussion on how clonality may be observed in reactive inflammatory conditions and clearly justify why a lymphoproliferative process was excluded in this case.

Response 3: As requested, we have clarified the technical parameters of the clonality assay and expanded our discussion on the phenomenon of monoclonality in reactive inflammatory states. While clonality is a hallmark of malignancy, it is not pathognomonic; in the context of our patient, the clinical course, radiological evolution, and detailed histomorphology favored Primary Angiitis of the Central Nervous System (PACNS) over a neoplastic process

Changes in the “results” and the “discussion” section have been included to address this question (Page 6, line 217 and Page 9, line 342).

Comment 4: The manuscript would benefit from a systematic, item-by-item mapping of each case to established PACNS diagnostic criteria (e.g., Calabrese and Mallek; Birnbaum and Hellmann).

Explicitly stating which criteria were fulfilled and how mimics were excluded would substantially enhance diagnostic transparency.

Consider including this mapping as a table or structured subsection.

Response 4: As requested, we have provided a systematic, item-by-item mapping of our cases against the Calabrese and Mallek (1988) criteria and the Birnbaum and Hellmann (2009) diagnostic certainty levels.

A table and structured text have been integrated into the revised manuscript (Page 7, line 263 and page 7, line 274).

Comment 5: CSF findings are insufficiently detailed, despite their importance in excluding infectious, neoplastic, and inflammatory mimics.

Please provide comprehensive CSF data, including cell counts and differential, IgG index, cytology and/or flow cytometry results, and relevant autoimmune/paraneoplastic and infectious studies.

Response 5: We include detailed CSF biochemistry, microbiology, cytology, and flow cytometry. Furthermore, we have expanded on the extensive autoimmune and paraneoplastic panels performed in both cases, which showed no immunoreactivity for onconeural or cell-surface antibodies.

A table and structured text have been integrated into the revised manuscript (Page 2, line 81; Page 5, line 179 and Page 6, line 204)

Comment 6: Treatment details are currently narrative and incomplete.

Induction and maintenance regimens (steroid dosing, duration, tapering strategy, methotrexate and cyclophosphamide doses, monitoring, and relapse criteria) should be systematically reported.

The rationale for choosing methotrexate versus cyclophosphamide at different disease phases should be aligned with current guideline-based practice.

Response 6: In accordance with the reviewers, we have revised the Case Presentation section to include specific dosing, durations, and titration schedules (Page 4, line 139 and Page 6, line 231).

Moreover, as requested, we have expanded our explanation regarding the selection of MTX versus CYC. In both cases, the initial clinical and radiological presentations were strongly suggestive of SLIPPERS syndrome. Since it is considered a supratentorial variant of CLIPPERS, our initial management followed the therapeutic paradigm for CLIPPERS, where methotrexate is advocated as an effective first-line steroid-sparing agent to facilitate glucocorticoid tapering and maintain remission [Taieb et al., 2017].

The subsequent transition to cyclophosphamide in Case 2 occurred only after radiological progression revealed the more aggressive nature of the underlying disease, which was then histopathologically confirmed as Primary Angiitis of the Central Nervous System (PACNS). This approach aligns with PACNS guidelines which reserve CYC for severe or progressive disease patterns.

(Page 9, line 354)

MINOR CONCERNS:

Comment 7: There are inconsistencies between the main text and figure captions (e.g., hemispheric involvement in case 2) that require correction.

 

Response 7: It was an error in the wording, the text in the figure has been revised to ensure consistency with the main manuscript (Page 5, line 192)

 

Comment 8: Figure legends contain typographical errors and ambiguities; histology panels for case 1 lack vascular elastic stain images

 

Response 8: A vascular elastic stain was not performed during the initial workup as the clinical suspicion was focused on the perivascular inflammation characteristic of SLIPPERS syndrome. After that, due to the limited residual tissue in Case 1's biopsy, years later it was technically impossible to perform all the additional stains. However, subsequent meticulous re-evaluation of the H&E sections demonstrated the transmural nature of the infiltrate, consistent with PACNS

Comment 9: The literature summary table includes missing data fields, inconsistent terminology (e.g., punctate vs. pseudonodular enhancement), and future-dated or incomplete references that need reconciliation.

Response 9: The DWI column was removed due to numerous missing data fields (Page 10, line 364)

Terminology was standardized, replacing the term “pseudonodular” with “nodular” and “punctate” with “puntiform.”

 

Comment 10: The discussion of vessel-wall MRI literature in PACNS is limited; a more granular appraisal of sequence choice and diagnostic yield would improve practical relevance.

 

Response 10: The discussion section has been edited for better understanding (Page 8, line 306)

 

Comment 11: Minimal discussion is provided on other steroid-responsive mimics, including CLIPPERS-to-lymphoma evolution.

Response 11: The possibility of other neurological entities responding to steroids was considered, such as primary lymphoma of the central nervous system, but the course of the disease, with no new recurrences in years in the first case and clinical stability in the second case, allowed us to rule out this diagnostic option (Page 7, line 258)

Reviewer 2 Report

Comments and Suggestions for Authors

This report describes a rare case of SLIPPERS syndrome which is a rare case, providing a insight its differential diagnosis. I have some suggestions for this case report to make it more interest for the readers.

1. In both cases, do the patients have another underlying medical conditions (e.g. DM, heart disease etc.). If they do not have please mention it.
2. In case 1, line 69 please give the full name of T2/FLAIR because using the abbreviation.
3. Figure 1, The MRI image shows several hyperintense foci, can you please arrow this in the MRI image. It will make more clear where the hyperintense foci located.
4. Figure 2 reveals the nice staining of brain biopsy. However, can you arrow the  CD20, CD3, CD5, CD8, CD138 positive staining in the images. That will draw an attention for the readers.
5. Figure 3, as mention in figure1 , please arrow the foci of hyperintense.
6. Figure 4, please arrow where the gliosis and other positive staining located.

Author Response

We sincerely thank the reviewers for their meticulous review of our manuscript and for highlighting these important points.

Comment 1: In both cases, do the patients have another underlying medical conditions (e.g. DM, heart disease etc.). If they do not have please mention it.

 

Response 1: As requested, we have clarified that apart from the specific risk factors already described—smoking in Case 1 and hypertension, dyslipidemia, and chronic alcohol use in Case 2—neither patient had other underlying medical conditions (Page 2, line 66 and Page 5, line 168)

 

Comment 2: In case 1, line 69 please give the full name of T2/FLAIR because using the abbreviation.

 

Response 2: We have clarified the full name of the sequence in the text as requested: ”T2‑weighted spin‑echo sequence and Fluid Attenuated Inversion Recovery (FLAIR) sequence.

 

 

Comment 3: Figure 1, The MRI image shows several hyperintense foci, can you please arrow this in the MRI image. It will make clearer where the hyperintense foci located.

 

Response 3: Arrows have been added in the image to make clearer de location of the hyperintense foci.

 

 

Comment 4: Figure 2 reveals the nice staining of brain biopsy. However, can you arrow the CD20, CD3, CD5, CD8, CD138 positive staining in the images. That will draw an attention for the readers.

 

Response 4: Arrows have been added in the image to make clearer the positive staining in the images.

 

 

Comment 5: Figure 3, as mention in figure1, please arrow the foci of hyperintense.

 

Response 5: Arrows have been added in the image to make clearer the location of the hyperintense foci.

 

 

Comment 6: Figure 4, please arrow where the gliosis and other positive staining located.

 

Response 6: Arrows have been added in the image to make clearer the positive staining in the images.

Reviewer 3 Report

Comments and Suggestions for Authors

Review of the article “SLIPPERS Reconsidered: Clinical, Radiological, and 2

Pathological Overlap with PACNS”

The article presents two new cases of PACNS initially misdiagnosed as SLIPPERS. The article is relevant as there is “ongoing discussion whether SLIPPERS constitutes a disease entity on its own or just an acronym encompassing many underlying diagnoses” [doi.org/10.3390/brainsci13081191] and only few cases of well documented SLIPPERS were reported. Thus, any new information about diagnostic criteria and differential diagnosis of similar but different syndromes will help doctors in making a correct diagnosis for the patient. The article highlights the important sign for differential diagnosis of the SLIPPERS disease.

There are several minor points that should to be addressed before publication.

1. It would be better to give a slightly clearer description of SLIPPERS at the beginning of the article.
2. For better understanding by the reader, it would be useful to more clearly describe in the “Case” or “Discussion” section: 1) on what basis exactly both patients were diagnosed with SLIPPERS syndrome and 2) what results led to reassessment of the diagnose as PACNS.
3. For better understanding by the reader, it would be great to give visual representation (e.g. a table) of characteristics of SLIPPERS and PACNS – what are the same and what differs.
4. It is preferable to use greater uniformity in the description of the figures (the way of description for Fig.2, 4 differs from the one for Fig.1, 3).
5. Why the markers panel differs between the two presented cases (in case 1 it is the set of CD3,5,8,20,138 but in case 2 the set is CD4,8,20,79a)? This raises the question about the uniformity of the applied diagnostic process.

Author Response

We sincerely thank the reviewers for their meticulous review of our manuscript and for highlighting these important points.

Comment 1: It would be better to give a slightly clearer description of SLIPPERS at the beginning of the article.

 

Response 1: As requested, we have revised the first paragraph of the Introduction to include a concise yet comprehensive clinical, radiological, and pathological description of this entity (Page 2, line 46)

 

Comment 2: For better understanding by the reader, it would be useful to more clearly describe in the “Case” or “Discussion” section: 1) on what basis exactly both patients were diagnosed with SLIPPERS syndrome and 2) what results led to reassessment of the diagnose as PACNS.

 

Response 2: The first paragraph in the discussion section has been edited for better understanding (Page 7, line 251)

 

 

Comment 3: For better understanding by the reader, it would be great to give visual representation (e.g. a table) of characteristics of SLIPPERS and PACNS – what are the same and what differs.

 

Response 3: As requested, we have developed a comparative table that highlights the hallmark features of both conditions, emphasizing the transition from an initial "perivascular" suspicion to a "transmural" definitive diagnosis (Page 12, line 378).

 

 

Comment 4: It is preferable to use greater uniformity in the description of the figures (the way of description for Fig.2, 4 differs from the one for Fig.1, 3).

 

Response 4: To achieve greater uniformity, we have revised the legends for Figures 2 and 4 to match the descriptive style of the MRI figures:

 

Figure 2: H&E stain (40x) demonstrating intense chronic perivascular inflammatory infiltrates within the meninges and cortex (A and B). H&E stain (20x) showing evidence of slight erythrocyte extravasation (C). CD20 immunohistochemistry (20x) revealing isolated B-cell presence (D). T-cell markers (CD3, CD5, and CD8, 40x) confirming an intense T-cell predominant infiltrate (E). CD138 stain (40x) highlighting occasional reactive plasma cells (F).

 

Figure 4: H&E stain (20x, 60x) revealing a prominent perivascular sleeve-like arrangement of inflammatory cells (A and B). Elastic stain (60x) confirming the transmural nature of the infiltrate, invading and disrupting the vascular wall (C, D). CD79a (5x) and CD20 (20x) stains showing partial B-cell lineage markers (E, F). CD4 (10x) and CD8 (20x) stains highlighting the predominance of T-lymphocytes within the vascular wall (G, H).

 

 

Comment 5: Why the markers panel differs between the two presented cases (in case 1 it is the set of CD3,5,8,20,138 but in case 2 the set is CD4,8,20,79a)? This raises the question about the uniformity of the applied diagnostic process.

 

Response 5: We would like to clarify that this variation reflects the retrospective and comparative nature of our study, as well as the practical constraints inherent in the availability of pathological material over time:

Case 1 was initially evaluated several years prior to Case 2 and had achieved prolonged clinical remission under the diagnostic protocols in place at that time. The more recent presentation and subsequent radiological recurrence of Case 2 prompted us to perform a retrospective of the first case.

When we reevaluated the histopathology of Case 1 using the more modern and expanded panel employed for Case 2, due to the limited residual tissue in Case 1's biopsy, it was technically impossible to perform all the additional stains.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I congratulate the authors on their efforts and this valuable article. I believe that the article should be accepted in its current form.

Author Response

Dear reviewer,

We greatly appreciate your time and consideration during the evaluation process, as your kind message and the positive evaluation of our manuscript. 

Best regards.

Reviewer 3 Report

Comments and Suggestions for Authors

Thank the author for the thorough work on the new version of the article.

 

Now there are a few additional minor points:

1. In the new version of the article, the resolution of all images is worse than before.
2. There is one grammatical error – “moloclonallity” instead of “monoclonality” (line 342).

Author Response

Dear reviewer,

Thank you very much for your careful review and helpful comments on our revised manuscript. We have now improved the resolution of all images and are submitting them in high-quality TIFF format.

In addition, the grammatical error has been corrected accordingly.

We appreciate your continued guidance and the opportunity to further refine our submission.

Best regards.