Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript explores the use of greater and lesser occipital nerve blocks in adolescents with medically refractory migraine, addressing a clinically relevant and under-investigated area in pediatric neurology. The topic is of potential interest, and the authors report notable improvements in headache frequency and severity. However, after careful evaluation, there are substantial methodological and analytical limitations that significantly weaken the validity of the conclusions.

1. Lack of Control Group: The absence of a control or comparator group represents a fundamental limitation. Without a control arm, it is not possible to determine whether the observed improvements are attributable to the intervention rather than placebo effects, regression to the mean, or the natural variability of migraine. This severely limits causal interpretation.
2. Absence of Inferential Statistical Analysis: The study relies exclusively on descriptive statistics, without applying appropriate inferential statistical methods. The lack of hypothesis testing, confidence intervals, and effect size estimation prevents a rigorous assessment of the reported outcomes and undermines the scientific robustness of the findings.
3. Heterogeneity of Intervention Without Subgroup Analysis: Participants received different intervention approaches (GON alone versus combined GON + LON), yet the outcomes are analyzed collectively. The absence of subgroup analysis introduces heterogeneity that complicates interpretation and reduces clarity regarding treatment-specific effects.
4. Unclear Study Design and Risk of Bias: The manuscript does not clearly specify whether the study was conducted prospectively or retrospectively. This lack of clarity limits the ability to assess potential biases and overall study quality.
5. Outcome measures rely primarily on VAS and a non-validated questionnaire, without inclusion of standardized pediatric migraine disability scales.
6. The discussion does not sufficiently address placebo effects or contextualize findings within controlled studies.

Author Response

Response to Reviewer 1

We sincerely thank the reviewer for the thorough and constructive evaluation of our manuscript. We have carefully addressed all comments and revised the manuscript accordingly.

1. Comment: Lack of control group

Response:

We thank the reviewer for this important evaluation. Our study was designed as a retrospective observational pilot study aimed at evaluating the effectiveness of peripheral nerve blocks in adolescents with treatment-refractory migraine. Due to its retrospective nature and the limited number of patients, a control group could not be established. We acknowledge that this represents a significant limitation of the study. Therefore, statements have been added to the Limitations section explicitly indicating that the observed effects cannot be fully distinguished from placebo effects, regression to the mean, or the natural course of the disease. In addition, the need for future randomized controlled studies has been emphasized.

2. Comment: Absence of inferential statistical analysis

Response:

We thank the reviewer for this valuable comment. In response, we have revised the statistical analysis of the manuscript. Inferential statistical methods have now been incorporated to strengthen the robustness of our findings. Specifically, changes in VAS scores across multiple time points were analyzed using the Friedman test, followed by post hoc pairwise comparisons using the Wilcoxon signed-rank test with Bonferroni correction. These analyses demonstrated a statistically significant reduction in pain severity over time (p < 0.001), supporting the effectiveness of the intervention. The relevant statistical methods and results have been clearly described in the Methods and Results sections of the revised manuscript.

3. Comment: Heterogeneity of intervention without subgroup analysis

Response:

We thank the reviewer for this valuable comment. We agree that analyzing outcomes separately for GON and combined GON + LON interventions would provide additional insights. However, due to the limited sample size, performing a reliable subgroup analysis was not statistically feasible. Therefore, all patients were analyzed collectively to preserve statistical validity. This limitation has now been explicitly acknowledged and discussed in the revised manuscript.

4. Comment: Unclear study design and risk of bias

Response:

We thank the reviewer for this important comment. We acknowledge that the study design was not clearly specified in the original manuscript. To address this issue, the study design has now been explicitly stated as a retrospective observational study in the Methods section. In addition, the potential sources of bias inherent to retrospective studies have been more clearly addressed in the Limitations section.

5. Comment: Outcome measures and lack of validated scales

Response:

We thank the reviewer for this valuable comment. We agree that the use of standardized pediatric migraine disability scales, such as PedMIDAS, would strengthen the assessment of treatment outcomes. However, due to the retrospective design of our study, data collection was limited to the available clinical records, which included VAS scores and a structured questionnaire routinely used in our clinical practice. The questionnaire was designed to capture key aspects of pain relief and functional improvement but was not formally validated. This limitation has now been explicitly acknowledged in the Limitations section of the revised manuscript. Future prospective studies incorporating validated pediatric migraine disability scales are warranted to provide a more comprehensive evaluation of treatment efficacy.

6. Comment: Insufficient discussion of placebo effects and lack of contextualization

Response:

We thank the reviewer for this insightful comment. Although randomized placebo-controlled studies have demonstrated the efficacy of greater occipital nerve (GON) block in adults with chronic migraine, studies in pediatric and adolescent populations remain limited. The available pediatric literature largely consists of retrospective and open-label studies. Therefore, while a placebo effect cannot be entirely excluded in our study, the observed clinical improvement should be interpreted with caution. Nonetheless, our findings suggest that peripheral nerve block may represent a potentially beneficial therapeutic option for adolescents with refractory migraine. In line with the reviewer’s suggestion, this issue has been discussed in greater detail in the revised Discussion section.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This paper is an interesting study that demonstrates the usefulness of peripheral nerve block for migraines in adolescents. The manuscript is well constructed and easy to understand.

I would like to suggest some revisions to the authors.

#1 Obtaining consent for treatment in adolescent cases

Since 18-year-olds are considered adults internationally, it is advisable to clearly state that consent for intervention has been obtained not only from the parents but also from the patients.

 

#2 The distribution of data for continuous variables

It would be better to present the distribution of data for continuous variables. The VAS scores are shown as the mean only in Table 2, but it would be better to show the mean and standard deviation, or the median and IQR.

Author Response

Response to Reviewer 2

We sincerely thank the reviewer for the positive and constructive comments. We have carefully addressed all suggestions and revised the manuscript accordingly.

1. Comment: Distribution of continuous variables

Response:

We thank the reviewer for this valuable comment. The presentation of continuous variables has been revised. VAS scores and other continuous variables are now reported with appropriate measures of distribution, including mean ± standard deviation (or median and interquartile range where applicable). These changes have been incorporated into the Results section.

2. Comment: Presentation of VAS scores

Response:

We thank the reviewer for this helpful suggestion. In response, VAS scores are now reported using appropriate measures of distribution, including mean ± standard deviation and median with interquartile range (IQR). These changes have been incorporated into the Results section.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript evaluates the efficacy and safety of peripheral nerve blocks, primarily greater and lesser occipital nerve blocks, in adolescents with medically refractory migraine. The topic is clinically relevant, as therapeutic options for adolescents with frequent or chronic migraine remain limited, while long-term preventive pharmacotherapy may be associated with tolerability and adherence issues. The presented data are potentially of interest as a description of local clinical experience. However, in its current form, the manuscript has substantial methodological, statistical, and interpretative limitations that do not allow such confident conclusions regarding the efficacy of the intervention.

The principal limitation of the study lies in its design. The work represents a small retrospective observational case series of 28 patients without a control group, randomization, blinding, or comparison with sham procedures or standard therapy. Under such conditions, it is impossible to reliably distinguish the specific effect of the nerve block from placebo effects, regression to the mean, natural fluctuations in migraine course, the influence of ongoing preventive therapy, or the effect of increased clinical attention. Although the authors partially acknowledge these issues in the Limitations section, the Abstract, Discussion, Highlights, and Conclusions still contain overly confident statements regarding the safety and efficacy of the procedure.

A critically important issue is that all patients continued or had previously received preventive therapy, including topiramate, flunarizine, and magnesium; 20 of 28 patients were receiving dual therapy. However, it remains unclear whether medication dosages changed during follow-up, whether preventive treatment remained stable, whether acute rescue medications were used, or whether behavioral recommendations, sleep patterns, school workload, or other lifestyle factors changed during the observation period. Without such information, the reduction in attack frequency cannot be confidently attributed specifically to the nerve block intervention.

The inclusion criteria are insufficiently rigorous. The authors state that they included patients with migraine lasting more than six months and inadequate control despite treatment, as well as patients with medically refractory chronic migraine or status migrainosus. However, no clear definition of refractory migraine is provided: which medications, at what dosages, for what duration, and with what assessment of adherence were considered adequate preventive therapy. In addition, combining chronic migraine and status migrainosus may create a clinically heterogeneous cohort.

The description of the intervention also requires clarification. In one section, the manuscript states that each injection site received 0.5 mL of 1% lidocaine, with a maximum total daily dose of 2 mL, whereas later the lesser occipital nerve block is described as bilateral injections of 1 mL. The protocol should therefore be described more clearly, including the injected volume per nerve, the number of injection points, whether procedures were unilateral or bilateral, and the criteria used to select GON, LON, or combined blockade. At present, the intervention appears heterogeneous.

 

The statistical analysis is limited. The authors applied the Friedman test and Wilcoxon signed-rank test for VAS analysis, whereas migraine frequency was essentially presented descriptively only. However, reduction in attack frequency represents the primary outcome of the study. Confidence intervals, effect sizes, individual patient trajectories, the proportion of patients achieving ≥50% reduction in migraine frequency, handling of missing data, and criteria for clinically meaningful response are not reported. In addition, discrepancies in the reported numbers are present: the Abstract states 18 patients with marked improvement, 6 with partial benefit, and 4 with no response, whereas the Results section reports 19 patients with marked reduction, 4 with partial improvement, and 5 without clinically meaningful reduction. These inconsistencies must be corrected.

 

Quality-of-life assessment was based on a “structured questionnaire,” which the authors themselves acknowledge was not validated. Therefore, statements regarding improvement in quality of life should be substantially softened. It would be more appropriate to describe these findings as subjectively reported improvement based on a non-validated questionnaire rather than demonstrated improvement in quality of life.

 

The safety section also requires a more cautious interpretation. The absence of serious complications across 84 procedures in 28 patients does not establish the safety of the method; it merely indicates that no major complications were observed within this small case series. Accordingly, categorical statements such as “safe and effective” should be replaced with more cautious wording such as “appeared to be well tolerated” and “may be associated with improvement.”

 

The ethical aspect also requires clarification. The study was reportedly conducted between October 2023 and April 2025, whereas ethics committee approval is dated June 24, 2025. The authors should clarify whether this represented retrospective approval for analysis of previously collected data or approval of the procedural protocol itself. Furthermore, no registration of the study in a clinical trial or observational study registry is reported.

 

Overall, the study may have value as a preliminary retrospective description of clinical experience with GON/LON blockade in adolescents with refractory migraine. However, in its current form, the conclusions substantially exceed the strength of the presented data. The manuscript requires major revision, including a more rigorous description of the study design and inclusion criteria, clarification of the intervention protocol, correction of inconsistencies in the reported results, a more cautious interpretation of efficacy and safety, and clearer distinction between observational findings and evidence of therapeutic effectiveness.

Author Response

Comment 1: General methodological limitations and overly strong conclusions

Response:
We thank the reviewer for this important evaluation. We acknowledge that the retrospective and uncontrolled design of our study has methodological limitations. Accordingly, the statements in the Abstract, Discussion, Highlights, and Conclusions sections have been revised to adopt a more cautious tone.

? Comment 2: Study design (lack of control group and risk of bias)

Response:
We thank the reviewer for this important comment. We acknowledge that the retrospective and uncontrolled design of our study represents a significant limitation. Accordingly, it has been clearly stated in the Limitations and Discussion sections that the observed effects cannot be fully distinguished from placebo effects, regression to the mean, or the natural course of the disease.

? Comment 3: Concomitant treatments (potential confounders)

Response:
We thank the reviewer for this valuable comment. It has been clearly stated in the Methods section that all patients continued their existing prophylactic treatments at the same dosage prior to the procedure and that no treatment changes were made during the follow-up period. In addition, it has been added to the manuscript that paracetamol was used for acute attacks and that no additional lifestyle recommendations were provided. Furthermore, the potential confounding effects of these factors have been emphasized in the Limitations section.

? Comment 4: Inclusion criteria (definition of refractory migraine)

Response:
We thank the reviewer for this important comment. The definition of refractory migraine has been revised to be clearer. It has been specified that patients were defined as those who had a diagnosis of migraine for at least six months and had an inadequate response to at least two different prophylactic treatments. In addition, the medications used and treatment characteristics have been described in more detail in the Methods section.

? Comment 5: Heterogeneous patient group

Response:
We thank the reviewer for this valuable comment. It is acknowledged that the study group may include clinical heterogeneity. However, due to the limited sample size, it was not possible to perform subgroup analysis.

? Comment 6: Intervention protocol

Response:
We thank the reviewer for this important comment. The intervention protocol has been revised and rewritten in a clearer and more consistent manner. The injected volume per nerve, bilateral/unilateral application, injection points, and the criteria for selecting GON, LON, or combined blockade have been described in detail in the Methods section.

? Comment 7: Numerical inconsistencies

Response:
We thank the reviewer for this important point. The reported numerical inconsistencies have been corrected, and full consistency between the Abstract and Results sections has been ensured.

? Comment 8: Quality of life assessment

Response:
We thank the reviewer for this valuable comment. It is acknowledged that the questionnaire used was not validated, and statements regarding quality of life have been revised to adopt a more cautious tone.

? Comment 9: Safety interpretation

Response:
It has been emphasized that the small sample size represents a limitation in terms of safety evaluation.

? Comment 10: Ethical approval timing

Response:
We thank the reviewer for this important issue. It has been clearly stated in the manuscript that ethical approval was obtained for the retrospective analysis of previously collected data. This has been clarified in the Methods section.

? Comment 11: Overall interpretation

Response:
We thank the reviewer for this valuable evaluation. All Results and Discussion sections have been revised to ensure a more cautious interpretation consistent with observational data. It has been clearly emphasized that the findings reflect clinical observations rather than evidence of causal effectiveness.

The requested revisions have been highlighted in red in the revised manuscript.

The original manuscript has been re-uploaded along with the revised version.

Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

The authors appear to have comprehensively addressed reviewer comments. It would be helpful to review the English language at this time. 

Comments on the Quality of English Language

Please review and edit English.

Author Response

Reviewer Comment:
The reviewers indicate that the English requires improvement.

Response:
Thank you for this valuable comment. The manuscript has undergone comprehensive English language editing by a professional scientific editing service. The language, grammar, and overall readability of the manuscript have been revised throughout the text to improve clarity and ensure consistency with academic writing standards.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors provided thoughtful revisions and detailed responses to the reviewer comments. Although the manuscript has improved, concerns remain that the overall level of evidence provided by the study is not sufficiently strong to support reliable clinical conclusions. The remaining limitations continue to substantially affect the scientific rigor and interpretability of the findings.

Author Response

Response to Reviewer Comments

We sincerely thank the reviewer for re-evaluating our manuscript and for taking into consideration the extensive revisions and detailed responses we have provided.

The aim of our study was not to definitively demonstrate the efficacy of occipital nerve blocks, but rather to present our real-world clinical experience in adolescents with medically refractory migraine, a population for whom available evidence remains limited. We have also emphasized throughout the manuscript that larger prospective randomized controlled studies are needed to establish the efficacy, safety, and long-term clinical value of peripheral nerve blocks.

We thank the reviewer again for the constructive comments and believe that these suggestions have contributed significantly to improving the scientific balance and transparency of our manuscript.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have substantially revised the manuscript compared with the previous version. The revised manuscript provides a significantly improved description of the study design, inclusion criteria, peripheral nerve block protocol, concomitant treatments, and statistical analyses. Importantly, the authors have acknowledged the major methodological limitations of the study and have substantially moderated the interpretation of their findings. The manuscript now includes a detailed discussion of the study limitations, including the absence of a control group, the retrospective design, the small sample size, and the inability to fully exclude placebo effects, regression to the mean, and the natural variability of disease course. These limitations are now clearly reflected in the appropriate section of the manuscript. The authors also explicitly acknowledge that meaningful subgroup analyses could not be performed because of the limited sample size and recognize the use of a non-validated questionnaire for quality-of-life assessment. The description of refractory migraine has been substantially improved. The authors clarified that the study included patients who had failed to achieve meaningful clinical improvement despite at least two preventive therapies administered at appropriate doses and durations. In addition, details regarding previous treatments and the exclusion of secondary headache causes have been expanded. Another strength of the revised manuscript is the more detailed description of the intervention protocol, including anatomical landmarks, injection volumes, criteria for selecting GON and LON blocks, and the intervals between treatment sessions. The authors have also corrected the previously identified numerical inconsistencies and ensured consistency of the reported results throughout the manuscript.

Nevertheless, several issues remain:

1. Despite the substantial moderation of the interpretation in the Discussion and Limitations sections, the Conclusions remain somewhat stronger than warranted by the study design. In particular, the statement that greater and lesser occipital nerve blocks “appear to be safe and effective treatment options” seems overly definitive for a retrospective uncontrolled study. It would be more appropriate to use wording that emphasizes an association between the intervention and the observed improvements rather than implying demonstrated effectiveness.

2. The Conclusions continue to state that the intervention improved patients’ quality of life. However, the authors themselves acknowledge that the questionnaire used was not a validated quality-of-life instrument. Therefore, these findings should be interpreted more cautiously, and the wording should preferably refer to patient-reported improvements in well-being or daily functioning rather than quality of life per se.

Author Response

We sincerely thank the reviewer for the careful re-evaluation of our manuscript and for recognizing the substantial improvements made in response to the previous review round.

In accordance with the reviewer’s recommendations, we have further revised the Conclusions section to ensure that the interpretation of the findings remains fully consistent with the retrospective and uncontrolled design of the study.

1. The statement suggesting that greater and lesser occipital nerve blocks are “safe and effective treatment options” has been modified. The revised text now emphasizes the observed association between the intervention and reductions in headache frequency and pain severity, without implying proven treatment effectiveness.
2. We agree that the questionnaire used in this study was not a validated quality-of-life instrument. Therefore, the term “quality of life” has been removed from the Conclusions and related sections of the manuscript. It has been replaced with more appropriate wording referring to “patient-reported daily functioning,” consistent with the nature of the collected data and the limitations of the assessment tool.

All revisions requested by the reviewer have been incorporated into the revised manuscript and are highlighted in blue for ease of review.

We appreciate the reviewer’s valuable comments, which have helped further improve the accuracy and scientific rigor of our manuscript.

Author Response File: Author Response.docx