Multimodal Management and Prognostic Factors in Post-Traumatic Trigeminal Neuropathic Pain Following Dental Procedures: A Retrospective Study
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsABSTRACT
Include the number of implants placed among the procedures analyzed.
Define what is meant by "early treatment", mainly as it is used in correlation analyses.
Mention the main pharmacological therapies employed, particularly gabapentinoids.
Clearly state the main treatment approach recommended or observed to be most effective.
INTRODUCTION
Provide a clear explanation of the Sunderland classification, including the types or grades and their implications for prognosis.
Expand briefly on why timing of intervention is so critical for recovery, linking this to neuropathic mechanisms if possible.
MATERIALS AND METHODS
Consider aligning the methodology with the STROBE guidelines for observational studies and referencing this explicitly.
Clarify the average or median follow-up time for patients included between January 2014 and December 2024.
The description of the VAS interpretation is unclear. If 1.0 is “normal sensation,” how is zero or lower defined? Is it possible to have values below 1.0? Please clarify.
Indicate whether there was any randomization or blinding in the retrospective data analysis.
In the statistical analysis section, mention whether p = 0.05 was used as a significance threshold.
RESULTS
Report the total number of patients assessed during the inclusion period to contextualize the final sample (n = 120 with PTTN).
Clarify what are the “other traumatic causes” (n = 9), and describe them.
The correlation between symptom onset and treatment duration is confusing. Please explain this finding in more straightforward terms and interpret its clinical meaning.
If p = 0.05 was considered significant, please state this explicitly in the methods.
Include absolute values alongside all percentages (e.g., “41% [n = XX]”).
In Table 4, ensure that:
Parametric data are reported as mean ± standard deviation.
Non-parametric data are reported as median and interquartile range (IQR).
Indicate the software used to generate Figure 1, and consider whether the data presentation
would be clearer as a box plot or table.
DISCUSSION
It is not clear whether the cause of injury influenced the therapeutic approach. Were treatment strategies stratified by etiology (e.g., implant vs extraction vs endodontic injury)? If not, discuss whether this may have influenced outcomes.
When surgical decompression or implant removal was indicated, provide a more detailed description of these complex cases—how many required intervention, what were the outcomes, and what factors influenced the decision.
Author Response
Reviewer Comment:
Include the number of implants placed among the procedures analyzed.
Response:
Thank you for your comment. We have revised the Abstract to include the total number of implants analyzed. Specifically, 79 patients developed PTTNP following implant placement, involving a total of 121 dental implants.
Reviewer Comment:
Define what is meant by "early treatment", mainly as it is used in correlation analyses.
Response:
We have clarified in the Abstract that "early treatment" refers to interventions initiated within three months of symptom onset. This definition aligns with commonly accepted neuropathic pain management timelines and was used consistently in subgroup and correlation analyses.
Reviewer Comment:
Mention the main pharmacological therapies employed, particularly gabapentinoids.
Response:
We have revised the Abstract to specify that the main pharmacological therapies included gabapentinoids (e.g., gabapentin and pregabalin) and tricyclic antidepressants such as amitriptyline. These medications were the most commonly administered pharmacologic treatments in our study.
Reviewer Comment:
Clearly state the main treatment approach recommended or observed to be most effective.
Response:
We have clearly stated in the Abstract that combined therapy—comprising pharmacologic, physical, and surgical treatments—was associated with the greatest sensory improvement and is recommended over monotherapy for managing PTTNP.
Provide a clear explanation of the Sunderland classification, including the types or grades and their implications for prognosis.
Response:
We appreciate this valuable suggestion. In the revised Introduction, we have included a concise explanation of the Sunderland classification system. This system categorizes peripheral nerve injuries into five grades, ranging from Grade I (neurapraxia), which involves temporary conduction block with excellent prognosis, to Grade V (neurotmesis), indicating complete transection of the nerve and requiring surgical repair for any chance of recovery. The classification helps estimate the extent of structural damage and predict sensory or functional recovery outcomes.
Reviewer Comment:
Expand briefly on why timing of intervention is so critical for recovery, linking this to neuropathic mechanisms if possible.
Response:
Thank you for this important point. We have expanded the Introduction to explain that delayed intervention in cases of nerve injury increases the risk of central sensitization, persistent ectopic discharges, and maladaptive cortical reorganization—all of which contribute to the development and maintenance of chronic neuropathic pain. Early intervention, ideally within 3 months, may prevent these pathophysiological changes and improve sensory recovery.
Reviewer Comment:
“Consider aligning the methodology with the STROBE guidelines for observational studies and referencing this explicitly.”
Response :
As recommended, we have ensured that the study design, data collection, and reporting adhere to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for observational studies.
We have explicitly stated this alignment in the Materials and Methods section of the revised manuscript:
“This study was designed and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.”
In addition, we will submit the completed STROBE checklist as a supplementary file to further demonstrate compliance with these reporting standards.
Reviewer Comments: Clarify the average or median follow-up time for patients included between January 2014 and December 2024.
Response: Thank you for pointing this out. We have corrected the date range in the manuscript from "January 2014 to December 2024" to the accurate period of "January 2014 to December 2023." This was a typographical error in the previous version.
Regarding the follow-up duration, we have clarified this in the revised manuscript. Specifically, the average follow-up (F/U) period for the included patients was calculated based on the available data and found to be 7.86 ± 9.60 months. This value reflects the time interval between the onset of injury and the final clinical evaluation for sensory deficits. The manuscript has been updated accordingly.
Results
Comment:
Report the total number of patients assessed during the inclusion period to contextualize the final sample (n = 120 with PTTN).
Response:
We appreciate this suggestion. The total number of patients assessed during the study period (January 2014 to December 2023) was 122. This information has been added to the Results section for context. After excluding two patients (one who did not meet the inclusion criteria and one due to missing data), the final analytical sample comprised 120 patients diagnosed with post-traumatic trigeminal neuropathy (PTTN).
Comment:
Clarify what are the “other traumatic causes” (n = 12), and describe them.
Response:
Thank you for your comment. We have clarified the composition of the “other traumatic causes” group in the revised manuscript. Specifically, this group included cases such as facial bone fractures from traffic accidents or blunt trauma, and inferior alveolar nerve (IAN) injuries associated with regional nerve block anesthesia administered prior to dental procedures. This information has been added to the Results section to improve transparency and detail.
Comment:
The correlation between symptom onset and treatment duration is confusing. Please explain this finding in more straightforward terms and interpret its clinical meaning.
Response:
We have revised the relevant section of the Results to provide a clearer explanation. Specifically, we found a positive correlation between delayed symptom onset and prolonged treatment duration. In simpler terms, patients who experienced later onset of sensory symptoms after trauma tended to undergo longer periods of treatment. This may suggest that delayed symptom recognition or diagnosis could contribute to more protracted clinical courses. We have added this interpretation in the revised text.
Comment:
In Table 4, ensure that: – Parametric data are reported as mean ± standard deviation. – Non-parametric data are reported as median and interquartile range (IQR).
Response:
Thank you for your comment. We have reviewed the data in Table 4 and confirm that all variables presented are continuous and approximately normally distributed. Accordingly, parametric data are expressed as mean ± standard deviation, consistent with reporting guidelines. There were no non-parametric variables in Table 4 requiring median (IQR) representation. This has been clarified in the table footnote.
Comment:
Indicate the software used to generate Figure 1, and consider whether the data presentation would be clearer as a box plot or table.
Response:
Thank you for your helpful comment. The figure previously referred to as Figure 1 has been renumbered as Figure 4 in the revised manuscript. The software used to generate all figures, including Figure 4, has been specified at the end of Section 2.4 (Statistical Analysis) in the Materials and Methods.
As Figure 4 illustrates cumulative yearly patient enrollment, we believe that the current line chart format is appropriate for visualizing temporal trends. However, we are happy to reformat the figure as a table or box plot if the editor believes it would enhance clarity.
Discussion
Reviewer Comment :
It is not clear whether the cause of injury influenced the therapeutic approach. Were treatment strategies stratified by etiology (e.g., implant vs extraction vs endodontic injury)? If not, discuss whether this may have influenced outcomes.
Response:
Thank you for your thoughtful comment. In this study, treatment strategies were not systematically stratified by the cause of nerve injury. However, since implant-related cases constituted the largest subgroup (n = 79, 65.8%), we conducted a focused subgroup analysis for this population, as described in Sections 3.2 and 4.1.
We agree that the lack of etiology-based treatment stratification may have influenced outcome variability, as different mechanisms of injury (e.g., implant placement vs. extraction) can vary in anatomical severity, chronicity, and prognosis. We have added this point to the Discussion to acknowledge it as a limitation and suggest that future studies consider etiology-based treatment pathways to improve outcome interpretation.
Reviewer Comment :
When surgical decompression or implant removal was indicated, provide a more detailed description of these complex cases—how many required intervention, what were the outcomes, and what factors influenced the decision.
Response:
Thank you for this important suggestion. Among the implant-related cases, implant removal was performed in 32 of 79 patients (40.5%). The decision to remove implants was based on clinical symptoms (e.g., persistent numbness, pain), radiographic evidence of nerve proximity or compression, and the patient’s preference after clinical counseling.
Although greater VAS improvement was observed in the removal group (mean change −0.16) compared to the non-removal group (−0.08), the difference was not statistically significant (p = 0.625). No other surgical decompression procedures were performed in this cohort.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsFirst of all, I want to congratulate the authors regarding the scientific article.
The topic is very interesting, exhaustive, and with a huge potential for research. This review brings new data regarding PTTNP. The article is relevant to the field. So I consider that the results can fill a gap present now in the scientific literature.
On the introduction part -line29,30- please insert information regarding the IAN/LN injury by anesthesia techniques.
Please also discuss the aspects regarding the potential of mesenchymal stem cells derived from human periapical cysts to differentiate into neurons or repair neurons that can help PTTNP treatment (https://doi.org/10.3390/biomedicines11092436).
The materials and methods section is very well structured and the methodology is clear for the reader.
Line 112-patients with general diseases -like diabetes- that have neuropathy were excluded?
Tables must be limited in size.
Including MN in this study is a little bit confusing due to only 3 cases presented.
-line 238: the treatment options must be exhaustively presented. Please move some data from treatment consideration(4.1) in this section
The discussion section is clear.
The conclusions are consistent with the evidence and arguments presented
and they address the main question posed.
The references are appropriate.
Author Response
Comment 1
.
“First of all, I want to congratulate the authors regarding the scientific article... The article is relevant to the field...”
Response:
We sincerely thank the reviewer for the positive and encouraging feedback. We are grateful for your recognition of the relevance and scientific merit of our study, and we appreciate your constructive suggestions for further strengthening the manuscript.
Comment 2 (Discussion):
“Please also discuss the aspects regarding the potential of mesenchymal stem cells derived from human periapical cysts to differentiate into neurons or repair neurons that can help PTTNP treatment (https://doi.org/10.3390/biomedicines11092436).”
Response:
We sincerely appreciate the reviewer’s thoughtful suggestion regarding the regenerative potential of mesenchymal stem cells derived from human periapical cysts. While we agree that this represents a highly promising avenue for future research in neural repair and neuropathic pain, we believe that a detailed discussion of this topic may exceed the intended scope and clinical focus of the current study, which primarily emphasizes multimodal treatment outcomes in a retrospective cohort. Therefore, we respectfully decided not to include this content in the present manuscript, but we will certainly consider incorporating it into future work focused on regenerative approaches to PTTNP.
Comment 3
“Patients with general diseases—like diabetes—that have neuropathy were excluded?”
Response:
Thank you for this important clarification. In our study, patients with systemic conditions known to cause neuropathy were not excluded solely based on diagnosis, but rather based on documented history or clinical signs of neuropathy at baseline.
Specifically, patients with well-controlled diabetes mellitus were included, provided they had no prior history or symptoms suggestive of diabetic neuropathy. These cases were carefully reviewed during the chart screening process to ensure that the neuropathic symptoms under investigation were attributable to post-traumatic trigeminal nerve injury, not underlying systemic disease. This approach has been clarified in the revised Materials and Methods section.
Comment 4 (Tables):
“Tables must be limited in size.”
Response:
We acknowledge the reviewer’s concern. We have reviewed all tables and streamlined the content to ensure clarity and conciseness, while preserving essential information. If further reduction is required by the editor, we are happy to transfer specific sections to Supplementary Materials.
Comment 5 (Inclusion of Maxillary Nerve Cases):
“Including MN in this study is a little bit confusing due to only 3 cases presented.”
Response:
Thank you for the observation. We agree that the inclusion of maxillary nerve (MN) cases may be limited in significance due to the small sample size (n = 3). However, we have retained these cases for completeness and have addeacknowledge their limited impact on subgroup-level conclusions.
Comment 6 (Line 238 – Treatment Options):
“The treatment options must be exhaustively presented. Please move some data from treatment consideration (4.1) to this section.”
Response:
Thank you for your suggestion. The sentence located at line 238 states:
“Treatment-related changes in VAS are summarized, indicating minimal improvement with no treatment, modest reductions with pharmacologic and physical therapies, greater reduction with surgical treatment, and the largest improvement with combined therapy, albeit with greater variability.”
This passage serves as a summary and interpretation of treatment outcomes, rather than a detailed listing of treatment modalities. As such, we believe it is appropriately positioned in the Results section, where it contextualizes the findings presented in Table 4 and Figure 1.
We would also like to clarify that the treatment options themselves—pharmacologic agents, physical therapies, and surgical considerations—are thoroughly described in the Discussion, specifically in Section 4.4 (Treatment Considerations). To avoid redundancy and maintain a clear separation between results and interpretation, we have retained the treatment details in that section. However, if the editor deems it necessary, we are happy to relocate or duplicate selected content into the Results section.
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsAfter critically reviewing this Research Article titled "Multimodal Management and Prognostic Factors in Post-Traumatic Trigeminal Neuropathic Pain Following Dental Procedures: A Retrospective Study", I detected some MINOR flaws, which determined my recommendation of “ACCEPT UNDER REVIEW”. Below please find my detailed comments.
This study conducted a retrospective study of 120 patients diagnosed with post-traumatic trigeminal neuropathic pain (PTTNP), reviewing causal factors and post-traumatic clinical outcomes. Noting that rapid multidisciplinary intervention can improve the recovery of patients with PTTNP.
The study is well written and conducted, methodology applied is very appropriate and quite detailed and well described in the paper, with minor flaws and easily corrected and appropriate for the objectives of the work. Statistical analyzes of the results obtained were well conducted.
The results obtained were promising and the discussions were relevant to the results achieved, especially with regard to the general dentist being one of the main professionals responsible for the rapid detection of PTTNP cases.
Below are my comments:
- Abstract: the period in which the data was collected is very important to be included in the abstract.
- This advisor suggests that a graph be created showing how many initial patients there were and the number and causes of exclusions until reaching the number of 120 patients, like a PRISMA graph.
- In table 2, all acronyms must be detailed at the end of the table, even if they have already been mentioned throughout the text.
- Items 4.2 and 4.3 (first paragraphs) provide very similar data and could be improved to avoid repetitive information.
The conclusions are consistent with the results obtained, where the authors describe the limitations and are fair with their findings.
Author Response
Reviewer Comment 1: "The period in which the data was collected is very important to be included in the abstract."
Response:
Thank you for this important suggestion. We have now explicitly stated the data collection period (January 2014 to December 2023) in the Abstract to improve clarity and transparency of the study timeline.
Reviewer Comment 2: "This advisor suggests that a graph be created showing how many initial patients there were and the number and causes of exclusions until reaching the number of 120 patients, like a PRISMA graph."
Response:
We appreciate the recommendation. As suggested, we created a flow diagram illustrating the patient selection process, modeled after the PRISMA structure. This figure has been added to the manuscript as Figure 1, 2, providing a visual summary of the number of initially screened patients, exclusion criteria, and final cohort composition.
Reviewer Comment 3:
"In table 2, all acronyms must be detailed at the end of the table, even if they have already been mentioned throughout the text."
Response:
Thank you for your valuable comment. We would like to clarify that Table 2 does not contain any acronyms. However, upon reviewing Table 1, we identified that several acronyms—such as CPT (current perception threshold), Mx. (maxillary), and Mn. (mandibular)—were used in the table content and footnotes. To address this, we have now explicitly defined all abbreviations in the revised footnote of Table 1 as follows:
Abbreviations: CPT, current perception threshold; Mx., maxillary; Mn., mandibular.
This change ensures consistency and clarity for readers unfamiliar with these terms.
Reviewer Comment 4: "Items 4.2 and 4.3 (first paragraphs) provide very similar data and could be improved to avoid repetitive information."
Response:
We thank the reviewer for pointing out the redundancy between sections 4.2 and 4.3. While both sections originally included overlapping observations—such as the predominance of female patients and the benefits of early intervention—we have now revised the first paragraph of section 4.3 to minimize repetition. Section 4.2 focuses on comparing our results with previous studies, whereas section 4.3 has been edited to emphasize the clinical implications and recommendations for practitioners based on our findings. This revision improves clarity and avoids duplication.
Reviewer Comment 5: "The conclusions are consistent with the results obtained, where the authors describe the limitations and are fair with their findings."
Response:
We thank the reviewer for this positive feedback. We have ensured that the Conclusions section remains consistent with the study findings and accurately reflects both the strengths and limitations of our work.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsAs a minor suggestion, I recommend a light English language review of the Abstract, particularly to reduce the use of dashes (—), which may hinder readability. Replacing them with commas or appropriate sentence structure would improve fluency and alignment with standard academic style.
Author Response
Comments: As a minor suggestion, I recommend a light English language review of the Abstract, particularly to reduce the use of dashes (—), which may hinder readability. Replacing them with commas or appropriate sentence structure would improve fluency and alignment with standard academic style.
Response:
Thank you for your valuable suggestion. We have carefully reviewed the Abstract and revised the language to reduce the use of dashes, replacing them with commas or restructuring the sentences as appropriate. These changes have improved the fluency and alignment with standard academic writing conventions.
Additionally, we have reviewed and revised the relevant figures and tables to ensure consistency with the updated terminology and formatting, thereby improving overall clarity and presentation.
We appreciate your attention to detail and your helpful feedback.
Author Response File: Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript has been improved and can be publishex
Author Response
Thank you for your positive feedback and recommendation for publication.
We sincerely appreciate your time, thoughtful review, and valuable suggestions throughout the revision process, which greatly contributed to improving the quality of our manuscript.
