Unusual Neuropsychiatric Presentation of Cryptococcus neoformans Meningoencephalitis in an Immunosuppressed Patient with Rheumatoid Arthritis: A Case Report

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript describes a case of a patient with rheumatoid arthritis who developed meningoencephalitis caused by Cryptococcus neoformans.

I recommend that the authors add some information:

- It is difficult to follow the clinical and laboratory course over time as described in the manuscript. Please add a chronological figure that includes clinical and laboratory tests, the time of cerebrospinal fluid collection for microbiological diagnosis and biochemical and cellular analyses, the start of treatment, and all results.

- Figures A1 and A2 are not shown in the text. Figure 1 was not shown either. The formatting of figures A1 and A2 should be improved. Do not place the letters on top of the images. Place the letters in the upper left/right corner. A scale bar (dimension bar) must be added to magnetic resonance images of the brain.

- Table 1 shows the test results for the patient in the study. Therefore, I recommend adding rheumatoid arthritis to the title.

- Please add italics to scientific names.

Author Response

Comments 1:  It is difficult to follow the clinical and laboratory evolution over time as described in the manuscript. Please add a chronological chart including clinical and laboratory tests, the time of cerebrospinal fluid collection for microbiological diagnosis and biochemical and cellular analyses, the start of treatment, and all outcomes.

Response 1: Thank you for pointing this out. We agree with this comment. The requested information is already included in the manuscript. Figure 1 presents the chronological history of the case, including the tests performed, the timing of cerebrospinal fluid collection for microbiological diagnosis, biochemical and cellular analyses, as well as the start of treatment and the results obtained.   Comments 2: Figures A1 and A2 do not appear in the text. Figure 1 also does not appear. The formatting of figures A1 and A2 should be improved. Do not place letters over the images. Place letters in the upper left/right corner. A scale bar (dimension bar) should be added to brain MRI images Response 2: We appreciate the reviewer’s comments. Figures A1, A2, and Figure 1 are now properly referenced within the text. The format of Figures A1 and A2 has been improved as suggested: the panel letters have been repositioned to the upper corner of each image   Comments 3: Table 1 shows the test results for the study patient. Therefore, I recommend adding rheumatoid arthritis to the title.   Response 3: Rheumatoid arthritis was adjusted to the title.   Comments 4: - Add italics to scientific names. Response 4: The text has been revised to improve readability and flow, correct the use of italics for scientific names, and adjust minor language issues for clarity

Reviewer 2 Report

Comments and Suggestions for Authors

This is a well-crafted case report of cryptococcal meningoencephalitis (CM) in a rheumatoid arthritis patient on long-term immunosuppressive therapy. The combination of immunosuppressive drugs has not been widely reported to be linked with CM, and the information provides, at a minimum, a solid contribution to the field of Medical Mycology.

While further genetic testing for specific immune-related gene polymorphism would further enhance this work, this is beyond the scope of the initial case report. Thus, ther are no concerns or requirements for further edits of this manuscript.

Author Response

Mentions that there are no concerns or requirements for further modifications to this manuscript

Reviewer 3 Report

Comments and Suggestions for Authors

In this case report, the authors describe a patient with rheumatoid arthritis (RA) receiving corticosteroids and TNF-α antagonists who developed a Cryptococcus infection. The patient’s symptoms began seven days prior to hospital admission and included progressive behavioral and affective changes—such as depression, frequent crying, irritability, anhedonia, social withdrawal, and severe anorexia.

The objective of this report is to present a case of cryptococcal meningoencephalitis in a patient with RA and chronic immunosuppression, emphasizing the clinical presentation, diagnostic workup, and therapeutic management. Importantly, the case highlights an atypical initial manifestation with prominent neuropsychiatric symptoms. The clinical findings underscore the need to consider cryptococcal infection in the differential diagnosis of acute psychiatric and cognitive disturbances among patients undergoing long-term corticosteroid and biologic therapy. This report reinforces the importance of maintaining a high index of suspicion for central nervous system (CNS) fungal infections in this immunosuppressed population.

Minor Comments:

• The organism’s name should be italicized throughout the manuscript.
• Figures A1 and A2 should be provided in higher resolution, as the current images appear pixelated.
• The authors should use arrows in Figures A1 and A2 to indicate the relevant areas described in the legend—such as the “focal hyperintense lesions in the right thalamus and globus pallidus”—to guide readers who may not be experts in interpreting MRI images.
• The authors note that cerebrospinal fluid (CSF) was negative for India ink staining and non-culturable. Since India ink is a commonly used diagnostic test for Cryptococcus, it may be worth discussing that the FilmArray® system’s high sensitivity could have detected low fungal loads. This might suggest that the infection involved a localized fungal burden in specific brain regions, potentially explaining the patient’s neuropsychiatric manifestations despite negative CSF findings.

 

Author Response

Comments 1: The name of the organization should be in italics throughout the manuscript.

 

Response 1: The name of the organization has been arranged in italics throughout the manuscript.

 

Comments 2: Figures A1 and A2 should be provided in higher resolution, as the current images appear pixelated.

 

Response 2: The quality of the figures has been improved

 

 

Comments 3: The authors should use arrows in Figures A1 and A2 to indicate relevant areas described in the legend—such as "focal hyperintense lesions in the right thalamus and globus pallidus"—to guide readers who are not experts in interpreting magnetic resonance imaging.

 

Response 3: Arrows were used to detail the figures

 

Comments 4:  The authors note that the cerebrospinal fluid (CSF) was negative for India ink staining and could not be cultured. Given that India ink is a common diagnostic test for Cryptococcus, it is worth mentioning that the high sensitivity of the FilmArray® system could have detected low fungal loads. This might suggest that the infection involved a fungal load localized to specific brain regions, which would explain the patient's neuropsychiatric manifestations despite the negative CSF results.

 

Response 4:  This comment was taken into account. Thank you for the suggestion.

 

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript presents a polished, concise, and quite well-written case report of Cryptococcus neoformans infection in a non-HIV patient with rheumatoid arthritis and, what is most interesting, highlights behavioral changes observed in the patient. In general, it was a pleasure to read such a nicely done case report.

There are only some minor editorial issues, for example: why are the figures labeled A1 and A2 instead of 1 and 2? Also, in several places, Cryptococcus neoformans is not italicized.

However, my major concern is that it is not entirely clear how the etiological agent (afromentioned C. neoformans) was confirmed? I ask the authors to clarify this point during the revision.

Author Response

Response 2: We appreciate the reviewer’s comments. Figures A1, A2, and Figure 1 are now properly referenced within the text. The format of Figures A1 and A2 has been improved as suggested: the panel letters have been repositioned to the upper corner of each image   Comments 3: Table 1 shows the test results for the study patient. Therefore, I recommend adding rheumatoid arthritis to the title.   Response 3: Rheumatoid arthritis was adjusted to the title.   Comments 4: - Add italics to scientific names. Response 4: The text has been revised to improve readability and flow, correct the use of italics for scientific names, and adjust minor language issues for clarity.   Author 2. Mentions that there are no concerns or requirements for further modifications to this manuscript.   Author 3 Comments 1: There are only a few minor editorial issues, for example: why are the figures labeled A1 and A2 instead of 1 and 2? Also, in several places, Cryptococcus neoformans is not italicized   Response 1: We appreciate the reviewer’s helpful comments. The figures have been renumbered according to the journal’s format (now Figures 1 and 2), and all text formatting has been corrected, including the use of italics for Cryptococcus neoformans throughout the manuscript.   Comments 2: However, my main concern is that it's not entirely clear how the etiologic agent (the aforementioned C. neoformans) was confirmed. I ask the authors to clarify this point during the review.   Response 2: We thank the reviewer for this valuable comment. In lines 91 and 177, we have corrected and clarified that the etiologic agent (Cryptococcus neoformans) was definitively identified through multiplex PCR (FilmArray®), which provided an early and specific diagnosis that enabled prompt, targeted antifungal therapy. This molecular finding was subsequently confirmed by cerebrospinal fluid (CSF) culture on day 27.