Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I found this review to be easy to follow along and well written. References and case studies are appropriate, and the organization is satisfying. I did find a few technical issues that might need to be addressed before publication of the manuscript. 
1. The list of abbreviations at the end of the manuscript is not comprehensive. For example: MRA, BMD, CT, DIC, and SAH are missing in the list. Please include these and any others that are not present.

2. For section number seven, I believe that pathogen name is incorrect. This is likely a typo. Please make the required changes.

Apart from these minor changes, I found no other issues with this manuscript and recommend it for publication.

Author Response

Please see the attachment. Thank you for your time!

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript titled “Cerebrovascular Disease as a Manifestation of Tick-Borne Infections: A Narrative Review” provides an in-depth examination of the correlation between tick-borne infections and cerebrovascular events, addressing historical context, specific pathogens, mechanisms of vascular damage, and contemporary treatments; nonetheless, its overall efficacy is diminished by several issues that require rectification in a comprehensive revision. The methods section does not clearly explain the search approach, such as the databases used, the search keywords used, the criteria for including or excluding studies, and the time periods studied. This makes it harder to repeat the research and raises concerns about possible bias in study selection. The quality of the study and the handling of conflicting facts are also not discussed. Furthermore, while the manuscript is organized by pathogen and clinical aspect, it has unnecessary repeated sections (like two on "Borrelia burgdorferi and Cerebrovascular Disease"). Also, the visual aids, like Table 1 and Figure 1, need clearer captions and consistent formatting to make them easier to read. The methodological part lacks clear information on the search technique, such as the databases used, the search keywords, the criteria for inclusion and exclusion, and the time span covered. This makes it hard to reproduce the results and raises issues about selection bias. Furthermore, there is an absence of discussion on research quality or the assessment of contradictory findings. The paper is rationally divided into parts based on pathogen and clinical feature, however it is hard to read since there are too many subsections (for example, there are two sections on "Borrelia burgdorferi and Cerebrovascular Disease"). Additionally, visual aids like Table 1 and Figure 1 need better captions and more uniform style to make them easier to understand. The discussion about mechanistic insights, such as the roles of direct endothelial invasion versus immune-mediated injury, is good, but it would be better if there were a deeper critical analysis of disagreements and gaps in understanding, especially when it comes to conditions like Ehrlichia-induced cerebrovascular events. Moreover, a brief mention of new treatments or diagnostic improvements would make the information even better. Additionally, the review does not include a dedicated limitations section to point out the biases that come with narrative reviews, the differences across source research, and areas with not enough data. The historical analysis is interesting, but it would be better if it were more balanced by focusing more on how it affects modern medicine. In the end, minor issues like inconsistent reference formatting, uneven spacing, unnecessary numbering, and the inconsistent definition and use of abbreviations make the manuscript less clear. A full editorial review to get rid of unnecessary statements and fix these typographical and stylistic mistakes is strongly recommended to follow the style guidelines of the target journal and greatly improve the paper's overall professionalism and clarity.

Author Response

Please see the attached document. We are thankful for your time and believe you have greatly improved this manuscript.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

This narrative review addresses an often overlooked but therapeutically significant subject: the cerebrovascular consequences associated with tick-borne illnesses (TBDs). The extensive range of diseases addressed—from spirochetes to viruses and protozoa—offers readers a valuable summary. The paper requires a more rigorous approach, improved organization, enhanced mechanistic insights, and a critical synthesis of the clinical data to augment its effect.

Principal Observations Examination Methodology and Clarity:
The Boolean search approach is robust; nonetheless, the review is deficient in a PRISMA flowchart or a comparable summary of article selection.
No quality assessment or evaluation of bias risk was conducted. A concise table categorizing the degree of evidence (e.g., case report, observational series, mechanistic research) would assist readers in assessing the strength of each link, even in a narrative review.
Indicate the date range for the searches, the total number of records evaluated, and the number included or excluded at each phase.

Quantification and Summary of Cases:
The Results and pathogen-specific sections depend mostly on narrative descriptions of individual reports. Propose the inclusion of a summary table enumerating each pathogen:
Count of documented cerebrovascular incidents:
Demographics of patients (age range, concomitant conditions)
Classification of cerebrovascular incident (ischemic vs hemorrhagic)
Imaging results (e.g., multifocal stenoses, vessel wall enhancement)
Therapeutic intervention and results
This organized summary will make trends and deficiencies clearly apparent.

Mechanistic Profundity:
Numerous sections define "endothelial injury" in general terms. To enhance the review, include further molecular information or cite significant experimental models:

Which cytokines have been associated with Rickettsia-induced vasculitis?
Is there in vitro evidence about Borrelia surface proteins that stick to cerebral endothelium?
What is understood about the breakdown of the blood-brain barrier or viral replication in microvascular cells by viral pathogens?
A succinct graphic table correlating pathogen, molecular process, and vascular lesion type would enhance readers' comprehension.
Algorithm for Diagnosis and Management
Clinicians facing inexplicable strokes should possess a definitive strategy. Propose a diagnostic approach outlining indicators for suspecting TBD (e.g., endemic exposure, prodromal fever); suggest appropriate serologic/PCR assays; and establish neuroimaging priorities (vessel-wall MRI vs standard MRA).
A succinct segment on acute care (empiric doxycycline vs ceftriaxone; the function of steroids; stroke-specific interventions) structured as a decision tree would enhance practical applicability.
Illustrations and Charts:
Figure 1: The existing schematic is too general.
Annotate the left and right paths directly on the diagram.
Incorporate a tick symbol, instances of pathogens, and annotations for major mediators (e.g., “TNF-α”, “immune complexes”).
Table 1:
Eliminate superfluous language for conciseness. List the characteristics of each disease in bullet points instead of using whole words.
Guarantee consistent formatting (e.g., uniform capitalization, alignment).
Identifying Research Deficiencies and Prospective Avenues
The Conclusions briefly reference "future investigation" but lack specific recommendations.
Suggest certain research, including:
Anticipated incidence of tick-borne cerebrovascular accidents in endemic regions
Standardized imaging techniques for vessel walls
Animal models to differentiate contributions of coagulopathy and vasculitis
Identification of biomarkers (e.g., endothelium activation markers in cerebrospinal fluid)
Minor Observations Language and Typographical Errors:
Page 2, line 62 “frequently demonstrated multifocal stenoses and a vessel-wall inflammation.”
Define each abbreviation upon its first use (e.g., DIC, SAH).
Consistently use the past tense when detailing case reports.
Introduction:
The classical history of ticks is intriguing but may be succinctly summarized in 2–3 words to ensure coherence.
References:
Certain references lack issue numbers or page ranges. Ensure adherence to MDPI formatting standards.
Section of Abbreviations:
Position this immediately behind the Abstract or at the conclusion of the Introduction to enhance readability.

Author Response

Thank you for your time. We believe you greatly enhanced the quality of our manuscript. Please find comments attached. 

Author Response File: Author Response.pdf