Cyproheptadine Treatment in Children and Adolescents with Migraine: A Retrospective Study in Japan

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a good study that seems to be prospective in nature.

Please clarify more about our static intolerance was this artistic hypertension measured with decreasing systolic pressures or was this subjective measurement by clinicians?

Also include the discussion that are static hypotension, and or static intolerance can lead to positional headache different from migraine and study. There weren’t any differentiation and this should be listed as a limitation.

 

 

in terms of morbid condition, it is clear how you concluded that comorbid condition such as attention deficit, hyperactivity disorder or conditions associated with the response crypt. It would be important to describe the medication patient and possible drug interaction. If you do not have this data then please this is a limitation in the study.

 

Consider using a metanalysis curve to show the different relationships of comorbid conditions and headache with response to crypto heptad and consider using graphs if possible. This will illustrate your point.

 

Brief discussion about lifestyle, modifications, and lifestyle. Modifications can also be effective in migraine treatment. Also discussed the role of cognitive therapy and it’s impact and controlling and helping Migraines. List these limitations as they were not included in the study.

 

This is publishable, but needs a few limitations listed, and some clarifications in your method and introduction. Try to put the definition tolerance, and this is different from our static hypertension and the methodology how you were able to a certain from the population studied.

If the date is available, state Tiffany, any of the children will replaced on Tylenol or ibuprofen, which is usually a class one recommendation or body placed on sumatriptan.

 

Generally, a good study and a good effort and would recommend publishing this page with minor edits.

Author Response

This is a good study that seems to be prospective in nature.

Comment 1:  Please clarify more about our static intolerance was this artistic hypertension measured with decreasing systolic pressures or was this subjective measurement by clinicians?

Response 1: Thank you for your insightful comments. In this study, the diagnosis of orthostatic intolerance (OI) was based on clinical symptoms rather than on measurements of blood pressure. Unfortunately, because this was a retrospective study, we were unable to include accurate blood pressure data in our analysis. As you correctly pointed out, orthostatic hypotension (OH) should be diagnosed using blood pressure measurements, and we have acknowledged this in the discussion and limitations section.

 

P7L299

The diagnosis of OH is typically confirmed by observing a decrease in blood pressure in response to orthostatic maneuvers. The extent of the blood pressure reduction varies across studies, with thresholds as low as a 20 mmHg decrease or a drop of 15% or more commonly reported. The standing test can be performed in two ways: either mechanically or actively. When performed mechanically, it is referred to as the head-up tilt test, while the active version is known as the active stand test or Schellong test. Although the Schel-long test was performed in all cases, the orthostatic test could not be incorporated into the diagnostic criteria because not all patients in the study had undergone this test at our fa-cility. Consequently, a detailed diagnosis based on blood pressure and pulse rate could not be established, which represents a limitation of the study.

 

P8L344

Third, because the diagnosis of OI as a comorbid condition was based on clinical symptoms alone, determining the precise pathophysiology proved challenging. Future studies should consistently implement established orthostatic tests.

 

Comment 2: Also include the discussion that are static hypotension, and or static intolerance can lead to positional headache different from migraine and study. There weren’t any differentiation and this should be listed as a limitation.

Response 2: Thank you for your valuable suggestion. As recommended, I have added a description regarding headaches caused by orthostatic maneuvers in the discussion and limitations sections.

 

P8L319

It has been reported that OI and headaches can coexist; however, it remains unclear whether OI directly causes headaches. Among the limited reports on this topic, Go et al. suggested that orthostatic maneuvers induce headaches due to reduced cerebral blood flow [49]. However, these headaches resolve within a shorter period and, therefore, do not meet the diagnostic criteria for a primary headache disorder.

 

P8L344

Third, because the diagnosis of OI as a comorbid condition was based on clinical symptoms alone, determining the precise pathophysiology proved challenging. Future studies should consistently implement established orthostatic tests.

 

Comment 3: in terms of morbid condition, it is clear how you concluded that comorbid condition such as attention deficit, hyperactivity disorder or conditions associated with the response crypt. It would be important to describe the medication patient and possible drug interaction. If you do not have this data then please this is a limitation in the study.

Response 3: Thank you for highlighting this important aspect. As you correctly noted, the discussion did not initially address the potential effects of other medications or drug interactions. We have now added the following clarification to the discussion section:

 

P7L287

The present study was unable to gather information on the medications used by the patients, which represents a limitation of this study.

 

Comment 4: Consider using a metanalysis curve to show the different relationships of comorbid conditions and headache with response to crypto heptad and consider using graphs if possible. This will illustrate your point.

Response 4: Thank you for your suggestion. We agree that a meta-analysis would be a valuable approach to illustrate the relationships between comorbid conditions, headaches, and response to cyproheptadine. However, due to the limitations of our current dataset, we were unable to perform a meta-analysis for this study.

While we appreciate the potential insights such an analysis could provide, the data we collected was not comprehensive enough to support a meta-analysis at this time. We will certainly consider this approach in future studies when more detailed and robust data are available.

 

Comment 5: Brief discussion about lifestyle, modifications, and lifestyle. Modifications can also be effective in migraine treatment. Also discussed the role of cognitive therapy and it’s impact and controlling and helping Migraines. List these limitations as they were not included in the study.

Response 5: Thank you for your valuable suggestions. In response, we have added a discussion on non-pharmacological treatments and their role in managing migraines.

 

P7L267

It is evident that non-pharmacological treatments should be initiated prior to the ad-ministration of drug therapy. [32,33] These non-pharmacological interventions include dietary modifications, nutraceuticals, neuromodulation, and cognitive-behavioral therapy (CBT). Among these, CBT has been shown to be an effective intervention for pediatric mi-graine, with strong evidence supporting its efficacy. Furthermore, research indicates that the effectiveness of CBT is enhanced when combined with pharmacological treatments. [34,35] Although some patients in the current study were undergoing non-pharmacological therapies, including CBT, it was not feasible to examine these inter-ventions in sufficient detail due to the retrospective nature of this study, which is a limita-tion.

 

Comment 6: This is publishable, but needs a few limitations listed, and some clarifications in your method and introduction. Try to put the definition tolerance, and this is different from our static hypertension and the methodology how you were able to a certain from the population studied.

Response 6: Thank you for your valuable feedback. In response to your suggestion, we have clarified the definition of orthostatic intolerance (OI) and distinguished it from orthostatic hypotension (OH) in the introduction and methods sections.

 

P2L68

OI has been identified as a condition characterized by autonomic nervous system dys-function, which manifests as difficulty tolerating an upright posture. The symptoms asso-ciated with OI typically subside when the patient returns to a supine position.[20] OI is broadly classified into orthostatic hypotension (OH), where blood pressure decreases up-on standing, and postural tachycardia syndrome (POTS), where the pulse rate increases. However, the detailed classification can vary among researchers. Although headaches have been reported in both OH and POTS, there are few studies on the effectiveness of pharmacological treatments for these headaches.

 

P8L324

The lack of standardization in diagnostic criteria for OI, OH, and POTS presents a significant barrier to further research. This inconsistency is also the reason these conditions are not listed as causes of secondary headaches in the ICHD, as previously stated.

 

Comment 7: If the date is available, state Tiffany, any of the children will replaced on Tylenol or ibuprofen, which is usually a class one recommendation or body placed on sumatriptan.

Response 7: Thank you for your suggestion. We agree that the information about acute medication was valuable. However, due to the limitations of our current dataset, we were unable to extract these data.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The author would like to declare no conflict of interest.

Generally, the manuscript is well written, although the study design can be considered quite simple for a full research article.

only 6 out of the 41 references are published after 2020. Some of the informations cited should be more updated, eg. the global burden of migraine, the latest classification of headache, the latest guidelines on migraine management, etc.

The title shouldl be improved. The current title of the manuscript is too generalised. The author should specify the scope of study (Japan) and it is a retrospective study.

Author Response

Reviewer 2

 

Comment 1:

The author would like to declare no conflict of interest.

Response 1: Thank you for your comment. I apologize for any confusion regarding the conflict of interest (COI) statement. The COI information is indeed provided on line 372 of the manuscript.

 

Comment 2:

Generally, the manuscript is well written, although the study design can be considered quite simple for a full research article.

Response 2: Thank you for your comment. As recommended, we have added a detailed description throughout the manuscript.

 

Comment 3:

only 6 out of the 41 references are published after 2020. Some of the informations cited should be more updated, eg. the global burden of migraine, the latest classification of headache, the latest guidelines on migraine management, etc.

Response 3: Thank you for your constructive comments. In response to your suggestion, we have updated several references to include more recent studies. These updates reflect the latest information on the global burden of migraine, headache classification, and migraine management guidelines.

 

[2] GBD 2021 Nervous System Disorders Collaborators Global, Regional, and National Burden of Disorders Affecting the Nervous System, 1990-2021: A Systematic Analysis for the Global Burden of Disease Study 2021. Lancet Neurol 2024, 23, 344–381, doi:10.1016/S1474-4422(24)00038-3.

 

[22]Ray, J.C.; Pham, X.; Foster, E.; Cheema, S.; Corcoran, S.J.; Matharu, M.S.; Hutton, E.J. The Prevalence of Headache Disorders in Postural Tachycardia Syndrome: A Systematic Review and Meta-Analysis of the Literature. Cephalalgia 2022, 42, 1274–1287, doi:10.1177/03331024221095153.

 

Additionally, we have incorporated a more recent paper, published after the manuscript was submitted, to ensure the citations reflect the latest research:

 

[5] Kohandel Gargari, O.; Aghajanian, S.; Togha, M.; Mohammadifard, F.; Abyaneh, R.; Mobader Sani, S.; Samiee, R.; Ker-manpour, A.; Seighali, N.; Haghdoost, F. Preventive Medications in Pediatric Migraine: A Network Meta-Analysis. JAMA Network Open 2024, 7, e2438666, doi:10.1001/jamanetworkopen.2024.38666.

 

P1L39

A recent meta-analysis on preventive medications for pediatric migraine [5] reported that topiramate and pregabalin were associated with a reduction in headache frequency and intensity. While other drugs, including flunarizine, riboflavin, amitriptyline, and cinnarizine, also demonstrated statistically significant outcomes, further investigation is need-ed to substantiate these findings. No correlation was identified between the use of these medications and improvements in quality of life or the duration of migraine attacks.

 

Comment 4:

The title should be improved. The current title of the manuscript is too generalised. The author should specify the scope of study (Japan) and it is a retrospective study.

Response 4: Thank you for your suggestion. Based on your feedback, we have revised the title to better reflect the scope and nature of the study. The updated title is:

 

Title

Cyproheptadine treatment in children and adolescents with migraine: a retrospective study in Japan

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript "Cyproheptadine treatment in children with migraine," authored by Hideki Shimomura et al., presented reasonable evidence that cyproheptadine could be efficient in preventing headaches, especially in children without NDDs or OI. 

Several recommendations: 

- The title should be more specific to the aim and conclusions of the study;

- There are some typos and punctuation misuse that need to be addressed (full stops before brackets and citations, more spaces than required between words or sentences, etc.);

- Please explain the difference between the affirmations in lines 150 and 153 ("No significant relationship was observed between the treatment effect and the headache frequency before treatment (p = 0.197)." versus "In the multiple logistic regression analysis (Table 4), cyproheptadine efficacy was significantly associated with the frequency of headaches before treatment, [...]"); 

- the Authors state that the adverse effects were present in 26% of the cases (line 223); more attention should be paid to this aspect, at least in the Discussion section (who else reported adverse effects, in what frequency, what adverse effects, why there are contrasts and similarities between Their study and others in regarding side effects); also, the Authors stated that the occurrence of the side effects were not correlated with comorbidities, yet the statistical data is not presented, as the only aspects on side effects are reported at lines 132-140 and mainly focus on somnolence.

Good luck!

Author Response

Reviewer3

The manuscript "Cyproheptadine treatment in children with migraine," authored by Hideki Shimomura et al., presented reasonable evidence that cyproheptadine could be efficient in preventing headaches, especially in children without NDDs or OI.

 

Several recommendations:

 

Comment 1:

- The title should be more specific to the aim and conclusions of the study;

Response 1: Thank you for your valuable feedback. In response to your suggestion, we have revised the title to more accurately reflect the aim and conclusions of the study.

 

The updated title is:

Title

Cyproheptadine treatment in children and adolescents with migraine: a retrospective study in Japan

 

 

Comment 2:

- There are some typos and punctuation misuse that need to be addressed (full stops before brackets and citations, more spaces than required between words or sentences, etc.);

Response 2: Thank you for bringing this to our attention. We have carefully reviewed the manuscript for typos and punctuation errors, including misplaced full stops before brackets, citations, and any extra spaces between words or sentences. These issues have been corrected throughout the manuscript.

 

 

Comment 3:

- Please explain the difference between the affirmations in lines 150 and 153 ("No significant relationship was observed between the treatment effect and the headache frequency before treatment (p = 0.197)." versus "In the multiple logistic regression analysis (Table 4), cyproheptadine efficacy was significantly associated with the frequency of headaches before treatment, [...]");

Response 3: Thank you for your insightful comments. As you pointed out, the description of the analysis was not sufficiently clear. To clarify, we meant to convey that there was no direct correlation between headache frequency and treatment effect when analyzed alone, but the multivariate analysis showed that headache frequency, among other factors, was significantly associated with treatment efficacy.

To address this, we have added the following clarifications to the Methods and Discussion sections:

 

P3L120

The correlation between comorbid conditions and age at first headache onset, as well as the correlation between cyproheptadine dose and treatment effect, and between the treatment effect and the headache frequency before treatment, were calculated using the Mann–Whitney U test.

 

P6L233

Despite the absence of a direct correlation between headache frequency prior to treatment and treatment efficacy, multiple logistic regression analyses of factors affecting the efficacy of cyproheptadine identified headache frequency before treatment, cyproheptadine dose, and the presence of comorbid neurodevelopmental disorders as significant risk factors.

 

 

Comment 4:

- the Authors state that the adverse effects were present in 26% of the cases (line 223); more attention should be paid to this aspect, at least in the Discussion section (who else reported adverse effects, in what frequency, what adverse effects, why there are contrasts and similarities between Their study and others in regarding side effects); also, the Authors stated that the occurrence of the side effects were not correlated with comorbidities, yet the statistical data is not presented, as the only aspects on side effects are reported at lines 132-140 and mainly focus on somnolence.

Response 4: Thank you for raising this important point. In response to your comments, we have expanded the discussion of adverse effects and their relationship to comorbid conditions in both the Results, Discussion, and Conclusion sections.

 

P2L80

We hypothesized that migraine associated with comorbid conditions reduce the therapeutic efficacy of prophylactic drugs and that the presence of comorbid conditions enhances the likelihood of adverse events.

 

P4L152

Among the seven patients who discontinued cyproheptadine treatment, only one had comorbid ND, and none had comorbid OI. No significant risk was detected for any of the established covariates of somnolence, which was the most observed adverse event. (Table 2). Among the three patients who reported adverse events of fatigue, none had comorbid OI or DD.

 

P6L242

Adverse events occurred in 26% of patients, and 4.5% of patients discontinued cyproheptadine, which is consistent with previous reports.[4,11] Tekin et al. reported that 51% of pediatric migraine patients receiving cyproheptadine at doses of 2 to 4 mg/day experienced side effects. Although comprehensive data were unavailable, the observed adverse events included somnolence and increased appetite. The authors indicated that these side effects did not impact patients' daily lives, and no patients discontinued the medication. In a prospective study of adolescents and adults, Rao et al. reported that 12% of patients experienced adverse events, such as drowsiness, sleep disturbances, weight gain, fatigue, and dry mouth, when treated with 2 mg/day of cyproheptadine.[9] While the authors reported that all adverse events were minor, they did not provide details. In the present study, the most frequently observed adverse event was somnolence. Compared to previous studies, this study demonstrated a higher incidence of adverse events, some of which resulted in the discontinuation of the drug. It was hypothesized that the higher dosage used in this study, when adjusted for body weight, may have contributed to the outcome. However, this could not be confirmed, as the detailed data from previous reports was unavailable. The initial hypothesis suggested that side effects were more likely to occur in the presence of comorbid conditions, particularly in patients with OI. However, this hypothesis was not supported by the evidence. none of the patients who discontinued treatment due to adverse events had comorbid OI, and only one patient had a comorbid neurodevelopmental disorder. Additionally, multivariate analysis did not identify any risk factors associated with the appearance of somnolence. Thus, However, predicting this outcome the appearance of adverse events was challenging due to the absence of identifiable risk factors. These results suggest that cyproheptadine is highly effective against migraine in patients without comorbid conditions, and the occurrence of adverse events was deemed acceptable and unrelated to comorbid conditions.

 

P8L352

Even in the presence of comorbid conditions, severe adverse events were uncommon, thereby establishing the drug as a safe and efficacious treatment option for migraine in children.

Author Response File: Author Response.docx

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors The quality of the manuscript "Cyproheptadine treatment in children with migraine" authored by Hideki Shimomura et al. have improved after revision.

Author Response

Comment 1:

The quality of the manuscript "Cyproheptadine treatment in children with migraine" authored by Hideki Shimomura et al. have improved after revision.

Answer 1:

I am highly appreciative of your constructive comments, which have improved the quality of our paper.

Author Response File: Author Response.docx