Patient Perceptions of a Preventive Effect of Long-Term Botulinum Neurotoxin Therapy in Cervical Dystonia

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript addresses an original and clinically relevant question using an innovative, patient-centered approach. Its main strength lies in highlighting how long-term therapy shapes patient perceptions of disease progression. To maximize its scientific contribution, I recommend the following:

1. The introduction relies heavily on prior studies by the same research group. While these are relevant, the background would benefit from a broader engagement with independent literature on patient-reported outcomes, illness perception, and expectancy effects in chronic neurological disorders.
2. The cited references are largely relevant and up to date. Nonetheless, there is a noticeable concentration of citations from the same authors, particularly regarding the CoD graph methodology and the concept of a “preventive effect.” While this reflects continuity of research, it raises concerns about citation balance and external validation of the methodological approach.
3. Although patients with “clinically relevant disturbances of memory or mood” were excluded, no formal cognitive screening tools are reported. Clarify whether any standardized cognitive or psychological screening instruments were used. If not, acknowledge this explicitly as a methodological limitation.
4. The authors acknowledge several important limitations, including small sample size and the impossibility of controlled BoNT withdrawal studies. Additional limitations that merit explicit mention include reliance on hypothetical scenarios, potential recall bias regarding disease onset, and the absence of longitudinal follow-up data.
5. While the manuscript refers to BoNT-A injections in cervical dystonia, it does not provide any clinical context about what this entails. I recommend adding a concise subsection summarizing typical target muscles, noting that spastic muscles exhibit structural alterations that can affect muscle identification and injection strategy, and highlighting that emerging ultrasound-guided approaches improve targeting precision - enhancing efficacy and patient outcomes while reducing risks such as neurovascular injury and unintended toxin diffusion. Please see this paper: Popescu MN, Căpeț C, Beiu C, Berteanu M. The Elias University Hospital Approach: A Visual Guide to Ultrasound-Guided Botulinum Toxin Injection in Spasticity: Part I-Distal Upper Limb Muscles. Toxins (Basel). 2025 Feb 26;17(3):107. doi: 10.3390/toxins17030107.

Author Response

This manuscript addresses an original and clinically relevant question using an innovative, patient-centered approach. Its main strength lies in highlighting how long-term therapy shapes patient perceptions of disease progression. To maximize its scientific contribution, I recommend the following:

Thank you for the positive evaluation of our manuscript and for the constructive and insightful comments. All comments have been carefully considered, and the manuscript has been revised accordingly. Our detailed responses are provided below.

Comment 1

This manuscript addresses an original and clinically relevant question using an innovative, patient-centered approach. Its main strength lies in highlighting how long-term therapy shapes patient perceptions of disease progression. To maximize its scientific contribution, I recommend the following:

The introduction relies heavily on prior studies by the same research group. While these are relevant, the background would benefit from a broader engagement with independent literature on patient-reported outcomes, illness perception, and expectancy effects in chronic neurological disorders.

Response:
We agree that situating our work within a broader conceptual framework strengthens the manuscript. Accordingly, we have expanded the Introduction to include relevant literature on: patient-reported outcomes (PROs), illness perception models, and expectancy effects in chronic neurological disorders.

Introduction: … These observations highlight that patient form distinct expectations about disease progression, which may extend beyond their direct clinical experience. Patient-reported outcomes (PROs) and illness perception frameworks have increasingly been recognized as critical determinants of treatment adherence and perceived efficacy in chronic neurological disorders. Patients’ beliefs about disease progression and treatment effects are shaped not only by clinical experience but also by cognitive and psychological factors, including expectation and prior treatment response. Expectancy effects have been shown to influence perceived symptom severity and treatment outcomes across neurological and movement disorders. Therefore, understanding how long-term therapy shapes patient expectations provides important complementary insights beyond objective clinical measures….

Comment 2

The cited references are largely relevant and up to date. Nonetheless, there is a noticeable concentration of citations from the same authors, particularly regarding the CoD graph methodology and the concept of a “preventive effect.” While this reflects continuity of research, it raises concerns about citation balance and external validation of the methodological approach.

Response:
We have revised the manuscript to: include additional independent references supporting PROs and expectancy effects (Introduction section - please see the previous comment), clarify that the CoD graph methodology is exploratory and not yet externally validated.

Materials and Methods: The course-of-disease (CoD) graph methodology represents an exploratory, patient-centered approach designed to capture subjective illness trajectories. While this method has been applied in our previous work, it has not yet undergone extensive external validation and should therefore be interpreted as a hypothesis-generating tool.

Comment 3

Although patients with “clinically relevant disturbances of memory or mood” were excluded, no formal cognitive screening tools are reported. Clarify whether any standardized cognitive or psychological screening instruments were used. If not, acknowledge this explicitly as a methodological limitation.

Response:
No standardized cognitive or psychological screening instruments were applied. Instead, exclusion was based on clinical judgment during routine neurological evaluation. We have now clarified this explicitly and acknowledged it as a limitation.

Materials and Methods: …Exclusion of clinically relevant cognitive or mood disturbances was based on clinical assessment during routine neurological evaluation. No formal standardized cognitive or psychological screening instruments were applied.

Limitations: …In addition, no standardized cognitive or psychological screening tools were used, which may limit the ability to fully exclude subtle cognitive or affective biases influencing patient responses….

Comment 4

The authors acknowledge several important limitations, including small sample size and the impossibility of controlled BoNT withdrawal studies. Additional limitations that merit explicit mention include reliance on hypothetical scenarios, potential recall bias regarding disease onset, and the absence of longitudinal follow-up data.

Response:
We fully agree and have expanded the limitations section accordingly.

Limitations: …Additional limitations include the reliance on hypothetical scenarios, which may not accurately reflect real-world disease progression after treatment discontinuation. Furthermore, patient estimates of disease severity at onset are subject to recall bias. Finally, the cross-sectional design precludes longitudinal validation of the anticipated disease trajectories described by patients.

Comment 5

While the manuscript refers to BoNT-A injections in cervical dystonia, it does not provide any clinical context about what this entails. I recommend adding a concise subsection summarizing typical target muscles, noting that spastic muscles exhibit structural alterations that can affect muscle identification and injection strategy, and highlighting that emerging ultrasound-guided approaches improve targeting precision - enhancing efficacy and patient outcomes while reducing risks such as neurovascular injury and unintended toxin diffusion. Please see this paper: Popescu MN, Căpeț C, Beiu C, Berteanu M. The Elias University Hospital Approach: A Visual Guide to Ultrasound-Guided Botulinum Toxin Injection in Spasticity: Part I-Distal Upper Limb Muscles. Toxins (Basel). 2025 Feb 26;17(3):107. doi: 10.3390/toxins17030107.

Response:
We have added a concise paragraph describing: 1-typical injection targets, 2-structural muscle changes in dystonia/spasticity, 3-and the role of ultrasound guidance. We have also incorporated the suggested reference.

Introduction: ….BoNT injections are typically administered into overactive neck muscles—such as the sternocleidomastoid, splenius capitis, trapezius, and levator scapulae—depending on the individual pattern of dystonia. Chronic muscle overactivity may lead to structural alterations, including fibrosis and changes in muscle architecture, which can complicate accurate targeting. In recent years, ultrasound-guided injection techniques have increasingly been adopted to improve precision and safety, enhancing treatment efficacy while reducing the risk of neurovascular injury and unintended toxin diffusion….

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors • The basis on which the patient sample size was determined has not been clearly stated and should be justified. •The manuscript requires revision to ensure consistent use of the passive voice throughout the scientific writing. •The keywords should be revised to better reflect and focus on the main target and scope of the research. •The introduction should be strengthened by including relevant and up-to-date statistical data on idiopathic cervical dystonia. •Table 1 is missing a title and should be appropriately labeled. •The title of Figure 1 should be revised to clearly correspond with its subsections (A, B, and C). •Lines 117–118 require revision, as no graphs are provided to adequately support or ensure the presented data. •The discussion section should be expanded to provide a more detailed analysis of the coherent variables of the study, including other associated diseases. •The conclusion section is incomplete and should include future recommendations based on the study findings. •The methods section lacks a clear description of the study design, including well-defined inclusion and exclusion criteria. •The references require updating, and the repeated use of the same author should be reconsidered, as it does not add additional scientific value to the manuscript.

Author Response

Comment 1

• The basis on which the patient sample size was determined has not been clearly stated and should be justified.

Response:
We thank the reviewer for this important point. The sample size was not determined by formal power calculation, as this was an exploratory, hypothesis-generating study. Instead, the sample reflects all eligible patients meeting the inclusion criteria within the defined recruitment period.

Study Design: …This study was designed as an exploratory, hypothesis-generating analysis. No formal sample size calculation was performed. The sample size was determined by the number of eligible patients fulfilling the inclusion criteria during the predefined recruitment period.

Comment 2

•The manuscript requires revision to ensure consistent use of the passive voice throughout the scientific writing.

Response:
The manuscript has been carefully revised to ensure consistent use of passive voice throughout, in accordance with journal standards.

Comment 3

•The keywords should be revised to better reflect and focus on the main target and scope of the research.

Response:
The keywords have been revised to better reflect the conceptual and methodological focus of the study.

Keywords: cervical dystonia; preventive effect; botulinum neurogtoxin; patient perception; illness perception; patient-reported outcomes; disease progression; long-term therapy.

Comment 4

•The introduction should be strengthened by including relevant and up-to-date statistical data on idiopathic cervical dystonia.

Response:
We have expanded the Introduction to include epidemiological context.

Introduction: Cervical dystonia (CD) is the most common form of focal dystonia, with reported prevalence estimates ranging from approximately 5 to 30 cases per 100,000 individuals, depending on study design and population characteristics [1]. It typically presents in midlife and is associated with a substantial clinical burden, including abnormal head postures, involuntary muscle contractions, pain, and reduced quality of life. In addition to motor manifestations, non-motor features such as anxiety, depression, and social impairment further contribute to disease burden [2].

Comment 5

•Table 1 is missing a title and should be appropriately labeled.

Response:
A descriptive title has been added, and a comprehensive caption including definitions of all abbreviations has been provided: Table 1. Correlation matrix of patient-derived parameters (PAS measures) and physician-assessed TSUI score (ATSUI).

Comment 6

•The title of Figure 1 should be revised to clearly correspond with its subsections (A, B, and C).

Response:
The figure title has been revised for clarity. Figure 1. Distribution of patient-assessed cervical dystonia severity parameters: (A) PAS-%, (B) PAS-ST%, and (C) PAS-NO%. Histogram bars indicate the number of patients within each 5% interval. The y-axis is standardized from 0 to 16.

Comment 7

•Lines 117–118 require revision, as no graphs are provided to adequately support or ensure the presented data.

Response:
The figure caption has been updated to clearly describe panels (A), (B), and (C), improving alignment between the data and the graphical representation.

Comment 8

•The discussion section should be expanded to provide a more detailed analysis of the coherent variables of the study, including other associated diseases.

Response:
Thank you for this important suggestion. The Discussion has been expanded to provide a more detailed interpretation of the relationships between the study variables and to better contextualize the findings. In particular, additional text has been included to clarify the lack of correlation between experienced and anticipated disease severity, as well as to relate the observed perception patterns to findings from other chronic neurological disorders in which illness perception and expectancy effects influence patient-reported outcomes and treatment adherence.

Discussion: … The absence of a correlation between experienced disease severity (PAS-%) and anticipated disease severity under both hypothetical scenarios (PAS-ST% and PAS-NO%) suggests that patients’ expectations are not solely determined by their current clinical status. Rather, these expectations may reflect broader cognitive frameworks, including illness perception and expectancy effects [20, 21]. Similar phe-nomena have been described in other chronic neurological disorders, in which pa-tients’ beliefs about disease progression and treatment efficacy influence subjective outcome measures, coping behavior, and treatment adherence [22-24]. In this context, the perceived “preventive effect” of long-term BoNT therapy observed in the present study should be interpreted as a patient-centered construct that may contribute to sustained adherence and long-term treatment engagement, rather than as evidence of biological disease modification…

Comment 9

•The conclusion section is incomplete and should include future recommendations based on the study findings.

Response:
The Conclusion has been expanded to include future directions.

Conclusion: …Future studies should aim to validate these findings in larger, multicenter cohorts and to explore longitudinal changes in patient perceptions in relation to objective clinical outcomes.

Comment 10

•The methods section lacks a clear description of the study design, including well-defined inclusion and exclusion criteria.

Response:
The Methods section has been revised to clearly define study design, inclusion, and exclusion criteria.

… Between 20 January 2025 and 27 May 2025, 50 patients with CD were screened. Inclusion criteria were: (i) a diagnosis of idiopathic cervical dystonia; (ii) regular treatment with BoNT for more than 10 treatment cycles; and (iii) no interruption of BoNT therapy for more than one treatment cycle (corresponding to 3 months).
Exclusion criteria were: (i) clinically relevant disturbances of memory or mood; and (ii) BoNT treatment for disorders other than CD (e.g., hemifacial spasm or ble-pharospasm) at doses exceeding 10% of the dose used for CD. Exclusion of clinically relevant cognitive or mood disturbances was based on clinical assessment during rou-tine neurological evaluation. No formal standardized cognitive or psychological screening instruments were applied.

… This study was designed as an exploratory, hypothesis-generating analysis. No formal sample size calculation was performed. The sample size was determined by the number of eligible patients fulfilling the inclusion criteria during the predefined recruitment period.

Comment 11

•The references require updating, and the repeated use of the same author should be reconsidered, as it does not add additional scientific value to the manuscript.

Response:
Additional independent references have been incorporated to improve citation balance and contextualization. The use of prior work from our group has been retained where directly relevant to the methodology.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The article entitled

“Patient Perceptions of a Preventive Effect of Long-Term Botulinum Neurotoxin Therapy in Cervical Dystonia” is an interesting study on the patient notion of improvement or not under Botulinum neurotoxin in CD.

This article is suitable for publishing provided that some improvements are made.

1. It would be better to add the section “Materials and Methods” before results. Now it is misplaced.
2. The authors should determine the type of their study and this should be added in section Mat and Methods.
3. How do the authors choose the type of Bot Neurotoxin for each patient? Is it practitioner dependent?
4. How do the authors determine the dose for each patient?

The article is interesting and will add more information about the treatment of CD with Bot Neurotoxin.

 

 

Author Response

Comment 1

The article entitled “Patient Perceptions of a Preventive Effect of Long-Term Botulinum Neurotoxin Therapy in Cervical Dystonia” is an interesting study on the patient notion of improvement or not under Botulinum neurotoxin in CD. This article is suitable for publishing provided that some improvements are made.

Response:
We thank the reviewer for the positive evaluation of our manuscript and for the constructive suggestions. All comments have been carefully considered, and the manuscript has been revised accordingly.

Comment 2

It would be better to add the section “Materials and Methods” before results. Now it is misplaced.

Response:
The manuscript structure follows the journal’s required format, in which the Materials and Methods section is presented after the Results section. We have therefore retained this structure.

Comment 3

The authors should determine the type of their study and this should be added in section Mat and Methods.

Response:
The study design has now been explicitly defined in the Methods section. The following sentence has been added to Section 5.3 (“Study Design”):

This study was designed as a cross-sectional, exploratory, hypothesis-generating investigation. No formal sample size calculation was performed. The sample size was determined by the number of eligible patients fulfilling the inclusion criteria during the predefined recruitment period.

Comment 4

How do the authors choose the type of Bot Neurotoxin for each patient? Is it practitioner dependent?
How do the authors determine the dose for each patient?

Response:
Additional clarification has been added to the Methods section regarding both the choice of botulinum neurotoxin preparation and dose determination. In clinical practice, the selection of BoNT formulation is primarily based on physician experience, established treatment protocols within the center, and individual patient response and tolerability. Similarly, dosing is determined on an individual basis by the treating physician, taking into account the clinical presentation, including the pattern and severity of dystonia, the muscles involved, prior treatment response, and tolerability. Dose adjustments are made over time according to clinical response and the occurrence of side effects. In our cohort, treatment regimens reflect routine clinical practice in a specialized movement disorder center.

Materials and Methods: …The choice of BoNT preparation and dosing was based on routine clinical practice and determined by the treating physician, in accordance with established clinical ex-perience and published consensus recommendations. The following BoNT/A prepara-tions were used: onabotulinumtoxinA (Botox®, AbbVie), incobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals), and abobotulinumtoxinA (Dysport®, Ipsen). Selec-tion of BoNT formulation was guided by physician experience, established treatment protocols within the center, and individual patient response and tolerability. Dosing was individualized based on the clinical presentation, including the pattern and se-verity of dystonia, the muscles involved, prior treatment response, and tolerability, and was adjusted over time according to clinical response and the occurrence of side effects [6, 25]…

Comment 5

The article is interesting and will add more information about the treatment of CD with Bot Neurotoxin.

Response:
We thank the reviewer for this positive and encouraging comment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Thanks for doing modifications