Review Reports

Round 1

Reviewer 1 Report

All the comments have been added to the Word file. Use track changes to incorporate your response.

All the comments have been added to the Word file. Use track changes to incorporate your response.

Comments for author File: Comments.pdf

Author Response

Thank you for the comments.  I'm working on that.

Author Response File: Author Response.pdf

Reviewer 2 Report

This narrative review provides a timely and comprehensive synthesis of the neurological sequelae associated with Long COVID, drawing on mechanisms such as direct viral invasion, immune dysregulation, and vascular complications. It effectively highlights clinical impacts, including cognitive impairments and sensory disturbances, and discusses emerging therapies like antivirals and rehabilitation. The discussion of biomarkers (e.g., NFL and GFAP) and risk factors (e.g., ACE2/TMPRSS2 genetics) adds value, particularly for clinicians managing post-COVID patients. As a neurologist specializing in Long COVID, I appreciate the multidisciplinary approach, which aligns with current evidence showing persistent neuroinflammation in up to 30% of survivors.

Positive aspects include the broad coverage of cohort studies and meta-analyses, offering practical insights for diagnosis and management. The review's emphasis on ongoing research needs is relevant, given the evolving nature of Long COVID variants.

Potential for improvement: The manuscript could incorporate more recent data on post-Omicron sequelae, as pre-Omicron variants are overemphasized. Expand on neuroimaging findings (e.g., MRI evidence of hippocampal atrophy in cognitive fog cases) and differentiate pediatric vs. adult presentations more clearly, as the provided text blends them. Additionally, discuss limitations of current biomarkers, such as GFAP's non-specificity in differential diagnosis from other neuroinflammatory conditions. 

• "1. Introduction": The description of Long COVID as a "new normal" is apt but could reference recent WHO updates on prevalence, noting a decline in new cases but persistence in unvaccinated populations.
• "4. Neurological Symptoms and Conditions Associated with Long COVID-19": The overview of primary neurological effects is strong; however, i would add that "long-COVID" symptoms like fatigue may overlap with other disease which may share common pathophysiological mechanism like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with shared immune pathways (e.g., elevated IL-6) (e.g. https://link.springer.com/article/10.1007/s10072-024-07566-w).
• "3. Hypothetical Mechanisms of Neurological Damage in COVID-19 and Long-term COVID-19": Hypothetical mechanisms section is well-structured. Suggest adding discussion on persistent viral reservoirs in the CNS. No inaccuracies noted.
• "9. Long-term neurological implication": "Female patients often reported limitations in per- 597 forming their usual daily activities and experienced pain, discomfort, or anxiety [56]." I would encourage the authors to provide more detail regarding female susceptibility toward Long-Covid implications, base upon the presence of an additional X chromosome in females which elevate the expression of ACE2, contributing to the sustained presence of COVID-19 in the system (e.g. https://karger.com/ned/article/59/4/426/912067/Gender-Disparities-in-Neurological-Symptoms-of) As this review delves into the "3. Hypothetical Mechanisms of Neurological Damage in COVID-19 and Long-term COVID-19" it would be wiseful to add this important notion.
• General:Mild english improvements needed for conciseness (e.g., avoid repetitive phrases like "ongoing long-term research"); some sentences are lengthy and could be split for clarity. Ensure all references are up-to-date; the provided citations seem relevant but check for 2024-2025 publications on therapeutics. Base on the fact that Long-Covid research has drastically been updated year by year.

Author Response

Thank you for the comments.  I'm working on that.

Author Response File: Author Response.pdf

Reviewer 3 Report

The review is interesting, clearly presented, and suitable for publication in this journal pending minor revisions.

1. Tables: While conceptually well designed, the tables are difficult to read. Column margins should be better defined and the layout made more schematic for clarity.
2. Abbreviations: A table of abbreviations has been included, but it is incomplete. The following entries should be added: IL6, IL10, TLR4, OAS1, NICE, MRI, NFL, and ICU. Moreover, the use of abbreviations is inconsistent—some appear in the table, others are written in full in the text, and others are not explained at all. A uniform approach is recommended.

Conclusions: The conclusions section would be stronger if it included a concise summary of the main findings from the individual chapters, in addition to highlighting the overall importance of the review

1. Column margins should be better defined and the layout made more schematic for clarity.
2. Abbreviations: A table of abbreviations has been included, but it is incomplete. The following entries should be added: IL6, IL10, TLR4, OAS1, NICE, MRI, NFL, and ICU. Moreover, the use of abbreviations is inconsistent—some appear in the table, others are written in full in the text, and others are not explained at all. A uniform approach is recommended.
3. Conclusions: The conclusions section would be stronger if it included a concise summary of the main findings from the individual chapters, in addition to highlighting the overall importance of the review.

Author Response

Thank you for the comments.  I'm working on that.

Author Response File: Author Response.pdf