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. 2023 Mar 15;18(3):e0283111. doi: 10.1371/journal.pone.0283111

Health-related quality of life of daily-life-affected benign essential blepharospasm: Multi-center observational study

Parima Hirunwiwatkul 1,2,*, Wajamon Supawatjariyakul 1,2, Supharat Jariyakosol 1,2, Supanut Apinyawasisuk 1,2, Jiruth Sriratanaban 3, Yuda Chongpison 4,5, Priya Jagota 6, Nipat Aui-aree 7, Juthamat Witthayaweerasak 7, Suwanna Setthawatcharawanich 8, Kitthisak Kitthaweesin 9, Niphon Chirapapaisan 10, Piyawadee Chaimongkoltrakul 11, Poramaet Laowanapiban 11, Linda Hansapinyo 12, Suthida Panpitpat 13, Sireedhorn Kurathong 14, Jirat Nimworaphan 14, Suntaree Thitiwichienlert 15, Kavin Vanikieti 16, Narong Samipak 17, Worapot Srimanan 18, Nattapong Mekhasingharak 19, Pareena Chaitanuwong 20
Editor: Tommaso Martino21
PMCID: PMC10016646  PMID: 36920965

Abstract

Purpose

To compare Thais’ health-related quality of life (HRQOL) and severity grading, efficacy and safety in daily-life-affected benign essential blepharospasm (BEB) patients at baseline and after Botulinum toxin type A (BTX-A) treatment.

Design

Prospective-observational study.

Participants

BEB patients with Jankovic rating scale (JRS) at least 3 in both severity and frequency graded from 14 institutes nationwide were included from August 2020 to June 2021.

Methods

Demographic data, HRQOL evaluated by the Thai version of EQ-5D-5L and NEI-VFQ-25 questionnaires, and severity grading score evaluated by Jankovic rating scale (JRS) at baseline, 1, and 3 months after the treatment were collected. The impact of the BTX-A injections and their complications were recorded.

Results

184 daily-life-affected BEB patients were enrolled; 159 patients (86.4%) had complete data with a mean age of 61.40±10.09 years. About 88.05% were female, and 10.1% were newly diagnosed. Most of the patients had bilateral involvement (96.9%) and 12.6% had history of BEB-related accident. After BTX-A treatment, HRQOL improved significantly in 4 dimensions of EQ-5D-5L, except self-care. The EQ_VAS (mean±SD) was 64.54±19.27, 75.13±15.37, 73.8±15.85 (p<0.001) and EQ-5D-5L utility score was 0.748±0.23, 0.824±0.19 and 0.807±0.19 at baseline, 1, 3 months after treatment, respectively. From NEI-VFQ-25, HRQOL also improved in all dimensions, except eye pain. The JRS improved in all patients. Self-reported minor adverse events were 22.6%, which mostly resolved within the first month.

Conclusion

Daily-life-affected BEB impacted HRQOL in most dimensions from both generic and visual-specific questionnaires. BTX-A treatment not only decreased disease severity, but also improved quality of life.

Introduction

Benign essential blepharospasm (BEB) is an abnormal bilateral contraction of eyelid muscles leading to episodic closure of the eyelids. The etiology of BEB is unknown with prevalence ranging from 1.6-30/100,000 worldwide and 1.6/100,000 in Thailand [1]. BEB is more commonly found in females (50–85%) [2–6] with age of onset of 40–60 years old. There is a higher degree of symptom severity and frequency of BEB in female than male [5]. Blepharospasm is one of focal dystonias whose symptoms commonly spread to other group of muscles beyond orbicularis oculi, mostly involving oromandibular and neck muscles [7–9]. Disease affects both motor and non-motor function including psychiatric problems, sleep quality, cognitive and ocular symptoms [5, 10, 11]. In severe cases, unpredicted abrupt forceful eyelid closure causes functional blindness, which may lead to life-threatening accidents while working or controlling vehicles [12, 13]. Symptoms gradually progress and could finally affect patient’s physical and psychological health. Although there is no curative treatment for BEB, the standard symptomatic treatment is periodic injection of Botulinum toxin type A (BTX-A) every 3–4 months. The estimated cost is 2,000–3,000 Thai Baht (approximately 60–90 USD) per injection. Even though there have been many studies about health-related quality of life (HRQOL) in BEB patients [14–17], the use of BTX-A for BEB is not covered by Thai universal health care coverage because there has been no previous study investigating the cost and benefits of BTX-A injection for BEB in Thai population. We evaluated HRQOL in Thai patients who had daily-life-affected BEB before and after BTX-A treatment, including efficacy and safety of the treatment. The results of the study might provide supporting evidence for amending the Nation’s reimbursement policy for daily-life-affected BEB treatment.

Methods

This is a prospective multicenter, observational study recruiting BEB patients treated with BTX-A from 14 centers across Thailand from August 2020 to June 2021. The study protocol was approved by the Central Research Ethics Committee (Certificate number: COA-CREC070/2020), and an Institutional Review Board of each site. The study protocol adhered to the tenets of the Declaration of Helsinki. The inclusion criteria were daily-life-affected BEB patients who had Jankovic rating scale (JRS) of at least 3 in both severity and frequency scores (JRS ≥ 6), graded by a neuro-ophthalmologist or neurologist and required BTX-A treatment. We diagnosed blepharospasm by excessive contractions of muscles around the eyes, especially orbicularis oculi. The spasm is episodic, involuntary, and unpredictable [18].

We use the JRS, which is widely used for clinical research and is easy to use [19], to assess the severity and frequency of blepharospasm. The score ranges from 0–4 in each severity and frequency rating scales. Grade 0 is no spasm. Grade 1 and 2 are defined by increased blinking or eyelid fluttering without functional disabilities. Grade 3 and 4 are defined by increased severity and frequency that disturb normal function of daily activities [20]. Then we used at least 3 in both severity and frequency scores as the inclusion criteria in this study.

We excluded patients who (1) received BTX-A treatment less than 12 weeks before enrollment, (2) aged under 18 years old, (3) were pregnant, (4) had other neurological problems or other serious physical problems, and (5) could not understand Thai language. In each center, all patients were invited to join the study by trained research assistants or treating physicians with a standard invitation script. All participants received BTX-A treatment from each center to control the spasm, and the dose depended on the severity, previous response and type of BTX-A.

Demographic and clinical data collection included: age, gender, involved eye(s), underlying disease, history of BTX-A use, current medication, previous BEB related surgery, and history of BEB related accident. Socioeconomic data included marital status, education level, occupation or employment status, income, transportation cost per healthcare visit, and health insurance.

HRQOL was evaluated by 2 questionnaires covering both vision and general health status. First, a Thai version of the 25-item National Eye Institute visual function questionnaire (NEI VFQ-25) was used. This visual specific questionnaire covered 11 subscales including: 1) general vision, 2) ocular pain, 3) difficulty with near-vision activities, 4) difficulty with distance-vision activities, 5) limitation of social functioning due to vision, 6) mental health problems due to vision, 7) role limitations due to vision, 8) dependency on others due to vision, 9) driving difficulties, 10) difficulty with color vision, and 11) difficulty with peripheral vision [21, 22]. The composite score from NEIVFQ-25 was analyzed as the mean score of all items except for the general health item. The general health was evaluated by overall health status, depends on the patients’ perception. The second questionnaire was the Thai version of the European Quality of Life Five Dimension Five levels (EQ-5D-5L) which related to general health questions comprising five different dimensions including: 1) mobility, 2) self-care, 3) usual activities, 4) pain/discomfort and 5) anxiety/depression [23, 24]. Both versions of the Thai questionnaires were validated in previous studies [22, 24].

We evaluated the JRS, NEI-VFQ-25, EQ-5D-5L at baseline before the treatment, 4 to 6 weeks (the maximal effect of BTX-A), and 12 to 16 weeks after the treatment (the end of BTX-A’s duration of action). In order to collect NEI-VFQ-25, EQ-5D-5L data, participants were asked to complete a case record form. Trained research assistants assisted illiterate participants to complete the form. JRS (both severity and frequency scores) and treatment complications were evaluated and recorded by the same physician for each participant throughout the 3 visits. Complications and their durations were recorded at the second and final visit. Type and amount of BTX-A, site of injection, and other prescribed medications were also documented. During the COVID-19 pandemic, some of the follow-up visits were performed via video conferencing by a single physician for each participant.

Statistical analysis

Sample size was calculated by using data from the validated Thai NEI-VFQ-25 questionnaires study [14]. To achieve power of 80% at significant level of 0.05, the calculated sample size was 146 patients with 10% loss to follow up. Thus, we aimed to include 165 patients.

Descriptive statistics were used to describe patients’ characteristics including demographic data, clinical data, and complication of BTX-A injection. Box plot over time and linear mixed model analysis were used to describe and compare HRQOL and JRS pre and post treatment, respectively. NEI-VFQ-25 and EQ-5D-5L were analyzed and adjusted with JRS summarized scores. We tested the interaction between each QoL domain and JRS with a significance level of 0.05. When significant, the interaction term is included in the reported model. Employment, sex, age, and underlying disease were evaluated as confounding factors. To determine efficacy, durations of action of BTX-A were compared by types of BTX-A using Kaplan-Meier estimates.

Results

Demographic data

A total of 184 participants were enrolled. One hundred and fifty-nine participants (86.41%) had complete data until the final follow-up visit. In COVID-19 endemic situation, 25 patients were loss to follow up and unable to be contacted by phone during the follow-up period: 11 patients on 1st month and 14 patients on 3rd month after treatment visit. There was no significant difference in age, sex, presence of comorbid diseases, and JRS severity grading between patients with complete data and those who were loss to follow-up. Demographic data are showed in Table 1. Participants who had complete follow-up data had a mean age of 61.40 years and were female predominate. The average duration of BEB was 5.05 ± 4.25 years and 96.86% of BEB was bilateral. Approximately half of the participants (48.43%) had prior BTX-A treatment of more than 10 times. A longer duration of the disease was found in females (5.3 years) than males (3.02 years). The minority of participants (10.06%) were newly treated with BTX-A. The majority of participants (71.70%) had comorbid diseases. Hypertension, dyslipidemia and diabetes mellitus were the three most common conditions. The JRS at baseline was 3.41 (SD 0.49, range 3–4) for severity, 3.40 (SD 0.49, range 3–4) for frequency, and 6.82 (SD 0.88, range 6–8) for summative score. There are 12.58% of participants had history of BEB-related accidents consisting of motor vehicle accidents, which was the most common accident type (68.42%), followed by falls and bumping into others. The employment rate in the complete-to-follow-up group was about two times higher than in the loss-to-follow-up group (60.38% versus 32.00%, respectively).

Table 1. Demographic data of patients with daily-life-affected BEB at baseline.

General Total Included N = 184 Complete follow up N = 159 Lost-to-follow up N = 25
Age (years) (Mean, SD) 61.57 (10.47) 61.40 (10.09) 62.68 (12.81)
Sex (Female) 87.50% 88.05% 84.00%
Presence of U/D 71.74% 71.70% 72.00%
    DM 13.59% 15.09% 4.00%
    HT 38.04% 36.48% 48.00%
    DLP 32.61% 32.70% 32.00%
    Old CVA 1.09% 0.63% 4.00%
    Thyroid diseases 2.17% 1.89% 4.00%
    CAD 1.63% 1.89% 0%
    CKD 1.63% 1.26% 4.00%
    Other 25.00% 26.42% 16.00%
Number of previous injections
    0 11.48% 11.95% 8.33%
    1–5 20.77% 21.38% 16.67%
    6–10 17.49% 18.24% 12.50%
    11–20 29.51% 28.30% 37.50%
    >20 20.77% 20.13% 25.00%
Jankovic Rating Scale; JRS (Mean, SD)
    Frequency grading 3.41 (0.49) 3.40 (0.49) 3.52 (0.51)
    Severity grading 3.40 (0.49) 3.41 (0.49) 3.36 (0.49)
    Total grading 6.82 (0.88) 6.81 (0.87) 6.88 (0.93)
Presence of BEB-related accident 11.96% 12.58% 8.00%
Presence of other med. 21.20% 18.87% 36.00%
New case 9.78% 10.06% 8.00%
Employment* 56.52% 60.38% 32.00%
Total income* (THB/month) (Med (Q2, Q3)) 6,000 (600, 23,150) 8,000 (600, 30,000) 700 (0, 8,000)
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*p-value < 0.01 for comparisons between complete follow up and lost-to-follow up groups.

CAD = Coronary artery disease, CKD = Chronic kidney disease, CVA = Cerebrovascular accident, DLP = Dyslipidemia, DM = Diabetes mellitus, HT = Hypertension, med. = medication, THB = Thai baht, U/D = Underlying diseases.

Effect of botulinum toxin treatment on clinical outcome

The results showed a significant improvement in JRS summary scores after BTX-A treatment. Means ± SD of JRS summary scores were 6.81 ± 0.87, 1.46 ± 1.75, 5.20 ± 2.06 at 0, 1, 3 months, respectively (Fig 1). The predicted JRS scores using linear mixed model were 6.72 (95%CI 6.48–6.95, p < 0.001), 1.41 (95%CI 1.16–1.66, p < 0.001), 5.18 (95%CI 4.92–5.43, p < 0.001) at 0, 1, 3 months, respectively (Fig 2).

Fig 1. Box plot JRS, EQ-5D-5L, and NEI-VFQ-25 at each visit.

Fig 1

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Fig 2. JRS, EQ-5D-5L, and NEI-VFQ-25 at each visit with 95% confidence interval.

Fig 2

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All models were adjusted for employment, sex, age, and underlying disease.

Effect of Botulinum toxin treatment on HRQOL

EQ-5D-5L and NEI-VFQ-25 improved at 1 month and did not decline to pre-treatment level after 3 months in all dimensions except for self-care and ocular pain (Fig 1). EQ-5D-5L utility scores were 0.75 ± 0.23, 0.82 ± 0.19, 0.81 ± 0.19 at baseline, post-treatment 1, and 3 months, respectively; and predicted values were 0.74 (95%CI 0.72–0.77, p < 0.001), 0.83 (95%CI 0.80–0.86, p < 0.001), and 0.81 (95%CI 0.78–0.84, p < 0.001) respectively. NEI-VFQ-25 composite scores were 58.70 ± 19.07, 68.79 ± 17.37, and 66.52 ± 18.71, respectively, and predicted values were 59.53 (95%CI 56.95–62.10, p < 0.001), 69.54 (95%CI 66.85–72.23, p < 0.001), and 67.15 (95%CI 64.43–69.88, p < 0.001), respectively. The most significant improvement in the NEI-VFQ-25 subscale were role limitations, difficulty with near-vision activities, mental health problems, and limitation of social functioning with differing scores between pre and post-treatment at 1 month of 16.78 (95%CI 13.08–20.48, p < 0.001), 13.81 (95%CI 10.06–17.57, p < 0.001), 13.79 (95%CI 10.04–17.54, p < 0.001), and 11.80 (95%CI 7.81–15.79, p < 0.001), respectively. By subgroup analysis, pre-treatment HRQOL scores were lower in female, unemployed participants with underlying diseases and in participants with higher JRS severity scores.

After testing and finding interaction terms between HRQOL, JRS, and time, we used covariate JRS summary scores with linear mixed model. In JRS = 8 group, the utility scores (EQ-5D-5L) were 0.68 (95%CI 0.64–0.72), 0.75 (95%CI 0.66–0.85), and 0.78 (95%CI 0.73–0.82) (p-value < 0.001) at baseline, 1 month, and 3 months, respectively. There was better improvement in utility and composite scores in higher JRS summary scores than lower scores (Fig 3).

Fig 3. EQ-5D-5L, and NEI-VFQ-25 at each JRS scores with 95% confidence interval.

Fig 3

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Estimated QoL were from models with an interaction term between JRS and time.

Our study selected OnabotulinumtoxinA (Botox®, Allergan) or Abobotulinum toxin A (Dysport®, Galderma Laboratories, LP) which varied among institutes based on physician’s preference. The average dose of OnabotulinumtoxinA was 13.11 units per eye per treatment and the average dose of AbobolutinumtoxinA was 39.41 units/eye/treatment. Duration of action is defined as time from BTX-A injection to the time participants started to feel eyelid spasm. We found that 50 percent of participants reported that they started to feel the beginning of blepharospasm at 10th week after treatment (i.e., median duration of action is approximately 10 weeks). Almost all participants had recurring symptoms at the end of the 12th week after treatment. There was no significant difference in duration of action between the two types of BTX-A (Log-rank test, p >0.99) (Fig 4). About 22% (36 participants) reported minor complications; ptosis (10.69%) and lagophthalmos (5.66%) were the first and second most common complications. Others included diplopia (2.52%), lips ptosis (1.26%), and others complication (5.03%) which included: dry eyes, lid edema, dizziness and neck pain. All complications were completely resolved within 4 weeks after BTX-A treatment.

Fig 4. Kaplan-Meier estimates of the duration of action of BTX-A treatment.

Fig 4

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Discussion

We started our study in 2020 when the new diagnostic criteria [25] have not been published. We thus used our criteria which was an involuntary spasm of the orbicularis oculi with sensory trick without abnormal contraction of the lower face. With this inclusion criteria, we recruited 5 unilateral blepharospasm in our studied population. All 5 participants had onset of 3 years or less at the time of inclusion and possibly progressed to bilateral blepharospasm or hemifacial spasm in the future. Grandas et al. reported that 19.7% of the participants in their study had unilateral involvement, which mostly progressed to bilateral blepharospasm [26]. BEB had approximately 50% risk of symptoms spreading to other muscles beyond orbicularis oculi in 5 years [7, 8].

This condition can cause accidents, injury, and loss of health. In our study, accidents associated with suddenly severe blepharospasm occurred while operating motor vehicles, walking and bumping into others, and falling while walking. These accidents lead to injury and limited daily activities, especially hindering driving and working abilities. Employment or job duties were key factors in seeking BTX-A treatment. Unemployment and low income were major factors in the loss to follow-up group. Co-medication was used more in the loss to follow-up group for relief symptoms than the BTX-A treated patients. This study revealed the female-to-male ratio was higher than in previous studies [3, 27, 28]. Since our project recruited participants with high-severity grading score, 88% of our patients were female because our study included only severe cases who need botulinum toxin treatment. The prevalence of female in daily-life-affected BEB are mostly the same in 14 nationwide institutes of Thailand, with median prevalence of 90% (83.92%, 95%). In general, the female preponderance in BEB is approximately 60–71% [4, 27–30]. Evidence showed higher degree of symptom severity and frequency of BEB in female than in male [31, 32]. The use of Botulinum toxin A in BEB treatment was associated with the efficacy and cost of botulinum toxin A treatment. Male and female patients may perceive the affected quality of life differently, even if the severity is the same. Female patients might be more concerned about their symptoms and thus seek medical attention more than male patients.

We chose the NEI-VFQ25 and EQ5D5L questionnaires to evaluate HRQOL in the Thai population because we would like to determine the effect of DL-BEB on vision abilities and general health to assess utility score to compare the health-related effect with other diseases. In pre-treatment DL-BEB, vision effects of HRQOL measured by the NEI-VFQ-25 questionnaires were decreased to lower than 50% in role limitation, driving difficulties and general health. Ocular pain and difficulties with color vision have less effect (about 20% decrease). In Europeans, ocular pain has significant effect after BTX-A treatment [15, 33]. However, in our study, it had no effect because our patient’s baseline score was higher, and there was no statistical difference in the mean scores for ocular pain between the baseline and the after-treatment measurement in our study. From NEI-VFQ25, mental health, difficulty with near-vision activities, distance-vision activities and peripheral vision had effects in the 50–60% range. Although vision itself is unaffected by BEB, spasms, repositioning and movement of eyelids during tonic-clonic spasms can disrupt vision. Hall et al. used the same BEB questionnaires in hemifacial spasm patients and found similar affected role limitation, mental health, and color vision as in our study. The general health and composite score in Thai DL-BEB was less than the US DL-BEB (34.39, 59.53% in Thais and 54, 70% in US, respectively) [15]. From the generic HRQOL by EQ-5D-5L, utility index at baseline was 0.74 (VAS 63.60%) which improved in the optimal period of BTX-A (UI 0.83, VAS 74.84%) and dropped at 3 months after treatment. In a previous study in Germans, HRQOL had the same pattern. However, the baseline utility index was lower than in Thais [34]. It seems that quality of life is affected in the same way, but the degree of decline in HRQOL varies by race, culture and the patient’s environment.

Blepharospasm affected mental health and socializing, which has been reported in many previous studies [15, 35–37]. However, our study found that moderate to severe blepharospasm which is affected daily-life activities, also decreased QoL in visual function and general health. BTX-A treatment not only reduces physical severity but also enhances quality of life, including in non-physical aspects. The higher severity grading at baseline, the more HRQOL improvement after BTX-A treatment.

The strength of this study is that we conducted a prospective multicenter, observational study from neuro-ophthalmologists and neurologists in 14 centers nationwide with large population that included participants from all parts of Thailand. Data on quality of life, collected through generic and visual-specific questionnaires, broadened the scope of data collection. However, this study did have some limitations. BEB is mostly bilateral and unpredictable. A recent multicenter study has proposed new diagnostic criteria for BEB which include 4 items: stereotyped, bilateral, and synchronous orbicularis oculi muscle spasms inducing eyelids closure/ narrowing as item 1, effective sensory trick as item 2, increased blinking as item 3, and inability to voluntarily suppress the spasms as item 4. Item 1 yields high sensitivity (96%) and relatively low specificity (76%). Combinations of more than 1 item increase sensitivity and specificity [25]. If our inclusion criteria for DL-BEB differ from these new criteria, we may include a few unilateral cases that could be misdiagnosed by the new criteria. The new patients who self-pay their medical expenses might deny Botulinum toxin treatment due to financial limitation. They, thus, were not including into the study. This resulted in another potential selection bias. This study was conducted on a short-term basis because data for only one cycle of BTX-A treatment was collected. Future study warrants a follow up of these cases to identify progression and long-term effects. Another limitation was that this study was conducted during the COVID-19 pandemic, which may have impacted the HRQOL [38–41]. The peak of the COVID-19 outbreak occurred mostly during the follow up visit period of 1 or 3 months. This timing could imply that the actual HRQOL after treatment might be higher than reported in our results.

Conclusion

Daily-life-affected BEB treated with BTX-A significantly improved disease severity and HRQOL in most dimensions in both generic and visual-specific questionnaires, with the exception of the self-care dimension in the EQ-5D-5L and ocular pain subscale in the NEI-VFQ-25. The factors that affected QoL improvement after BTX-A treatment were gender, age, underlying diseases and employment. BTX-A treatment not only decreased disease severity, but also improved QoL.

Supporting information

S1 Table. Baseline quality of life by generic (EQ-5D-5L) and condition-specific (NEI-VFQ25) questionnaires (Mean, SD).

(DOCX)

Click here for additional data file. (24.8KB, docx)
S2 Table. Daily-life-affected BEB patients’ health-related quality of life by EQ-5D-5L questionnaires in subscales.

(DOCX)

Click here for additional data file. (24.5KB, docx)
S3 Table. Estimated EQ-5D-5L, NEI-VFQ-25 and JRS at each visit and coefficient with 95% confidential interval of patients with daily-life-affected blepharospasm.

(DOCX)

Click here for additional data file. (27KB, docx)

Acknowledgments

We would like to express our gratitude to the Thai Neuro-ophthalmology Society (TNOS) for their team support. The EuroQol Foundation and The Health Intervention and Technology Assessment Program (HITAP) for their permission to use the Thai version of EQ5D5L questionnaires, Associate Professor Suwanna Setthawatcharawanich for her permission to use the Thai version of National Eye Institute Visual Functioning Questionnaire (NEI-VFQ25) [14, 22] in this study. Special thanks to Mr. Phanupong Phutrakool who advised the use of the REDCap program for data collection from multi-centers.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

PH received funding form Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University, grant number RA64.2.2.2/504.1 The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Tommaso Martino

16 Nov 2022

PONE-D-22-27465Health-related quality of life of daily-life-affected benign essential blepharospasm: multi-center observational studyPLOS ONE

Dear Dr. Hirunwiwatkul,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Dec 31 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Tommaso Martino, M.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors reported an interesting study about quality of like in patients with benign essential blepharospasm (BEB). I have some comments to the authors:

- In the methods the authors should specify that the diagnosis of BEB was made in accordance with the recent criteria. Here the paper that should be included:

Defazio G, et al. Diagnostic criteria for blepharospasm: A multicenter international study. Parkinsonism Relat Disord. 2021 Oct;91:109-114. doi: 10.1016/j.parkreldis.2021.09.004. Epub 2021 Sep 8. PMID: 34583301; PMCID: PMC9048224.

- Please specify whether all the patients had focal dystonia. The phenomenon of spread in BEB is a frequent condition, so it would be better if the authors expanded this point in the methods. There are several studies on the topic that might be helpful:

Berman BD, et al. Risk of spread in adult-onset isolated focal dystonia: a prospective international cohort study. J Neurol Neurosurg Psychiatry. 2020 Mar;91(3):314-320. doi: 10.1136/jnnp-2019-321794. Epub 2019 Dec 17. PMID: 31848221; PMCID: PMC7024047.

Ercoli T, et al. Spread of segmental/multifocal idiopathic adult-onset dystonia to a third body site. Parkinsonism Relat Disord. 2021 Jun;87:70-74. doi: 10.1016/j.parkreldis.2021.04.022. Epub 2021 May 12. PMID: 33991781.

- Among the strengths of the study, the author may also add that the Jankovic rating scale is one of the best tool to assess BEB, as recently reported in this recent international study:

Defazio G, et al. Measurement Properties of Clinical Scales Rating the Severity of Blepharospasm: A Multicenter Observational Study. Mov Disord Clin Pract. 2022 Aug 15;9(7):949-955. doi: 10.1002/mdc3.13530. PMID: 36247913; PMCID: PMC9547140.

- The results should better organize adding the p value in the text and the findings from the statistic.

- “In our study, the female to male ratio was higher than previous studies.” Please expand this point.

Reviewer #2: The authors present data about quality of life of Thai patients with blepharospasm treated with

Botulinum toxin type A. The manuscript might have important clinical message and may be of great

interest to the readers who are interested in this specific topic.

However, I do believe that the manuscript would benefit from a second round of major revisions in order to

improve it before being considered for publication. Below are some recommendations:

Q1. Line 63: “Most of the patients had bilateral involvement (96.9%)”

Please discuss why you consider few patients with unilateral involvement as having blepharospasm rather

than hemifacial spasm taking into account that all more accepted definitions describe blepharospasm as a

bilateral disturb.

Q2. Line 97-98 : “We evaluated 98 HRQOL in Thai patients who had daily-life-affected BEB before and

after…”

What do you mean by “daily-life-affected” when you consider a disease with continuous symtpoms like

blepharospasm? Do you refer to more severe forms of BEB? Please specify

Q3. Lines 107-108 “Inclusion criteria were daily-life-affected BEB patients who had Jankovic rating scale

(JRS) of at least 3 in both severity and frequency scores graded…”

Please provide a brief sentence on the scoring graduation of the Jankovic rating scale (for istance : The JRS

ranges from 0 to 8 points (sum score) and includes 2 categories:… etc etc). Moreover, a score of at least 3

for both severity and frequency on the Jankovic rating scale is relatively high as compared to those present

in several case series from the literature (see works by Jankovic J, et al. 10.1002/mds.22368; and Jankovic

J, et al. 10.1002/mds.23658), where Mean JRS sum score was less than 6 despite of a disease duration of

more than 6 years (5.05 ± 4.25 years in the present study). It would be of great interest to report which

rate of patients from the 14 centers across Thailand reached a Jankovic rating scale total score more than 6.

Had all patients higher severity scores? why was the severity of the blepharospasm in this study population

higher than that of the general population (as you stated – line 243)? The blepharospasm is a disorder

almost exclusively managed in tertiary centers worldwide and this should not be a reason why the severity

scores are so high in BEB patients in this study. Consider this in the discussion.

Q.4 Line 130: “Both versions of the Thai questionnaires were validated in previous studies”.

please report reference of the previous studies were a the Thai version of the 25-item National Eye

Institute visual function questionnaire (NEI VFQ-25) was validated.

Q5. Line 179: “Table 1: Demographic data of patients with daily-life-affected BEB”

Please specify in the table that JRS scores refer to baseline state.

Q6. Lines 221-222-223 : “Duration of action analyzed by Kaplan-Meier estimates, 50% of participants

reported the beginning of recurrent BEB symptoms at 10 weeks after the treatment.”

Please give sense to the first part of the sentence.

Q7. the General health item and composite score of the 25-item National Eye Institute visual function

questionnaire (NEI VFQ-25) are first described in the results and discussion. It would be better to introduce

them in the methods firstly. In particular, unlike the other scores, Composite scores increase after

treatment, so it should be better defined in methods section.

Q8. Figures:

most Y-X graphs’ legends are almost unreadable. Please increase graphs’ quality or limit the number of

graphs/figures in order to increase size (fig. 4 is a good solution)

Q9. Statistical analysis and results:

It would be more appropriate to specify coefficient and significance values when comparing pre and posttreatment data (both in text and tables)

Reviewer #3: This research is an accurate description of demographic and clinical features of BEB in Thailand. Authors show with adeguate statistical tools how quality of life improves after treatment with botulinum toxin. Authors used different and validated scales with reliable results.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

**********

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PLoS One. 2023 Mar 15;18(3):e0283111. doi: 10.1371/journal.pone.0283111.r002

Author response to Decision Letter 0

30 Dec 2022

Dear Editor, Tommaso Martino, and my 3 reviewers,

Thank you very much for your kind reviews. Your comments are very useful for us to improve our manuscript. Thank you for give us an opportunity to correct many points in manuscripts for improve the quality.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (27.2KB, docx)

Decision Letter 1

Tommaso Martino

2 Feb 2023

PONE-D-22-27465R1Health-related quality of life of daily-life-affected benign essential blepharospasm: multi-center observational studyPLOS ONE

Dear Dr. Hirunwiwatkul,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: I received positive evaluation from our eminent referees. There are still some minor comments that needs to be addressed (see below). A further revision of your english writing style is needed. 

==============================

Please submit your revised manuscript by Mar 19 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tommaso Martino, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

​

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Academic Editor Comments:

In addition to the comments of our eminent referees, please consider the following:

- Line 63: add p-values.

- Line 77: change "depends of multifactor" with "are multifactorial".

- Line 78: change "another" with "one of".

- Line 86: change "that" with "whose".

- Line 108: remove the sentence from "we would like..." to "... then the". Start with inclusion and exclusion criteria, which should be reported in a more systematic way.

- Line 121: change "was pregnant" with "were pregnant".

- Line 125: explain what is the most common "standard routine" used in your centers.

- Line 178 and 185: change "underlying diseases" with "comorbid diseases" or "comorbidity".

- Line 188: I would not say "significant number" if the percentage is 12.5%.

- Line 190: what do you mean by "transportation cost"? And why is it reported?

- Line 196-198: acronyms should be listed in alphabetical order.

- Line 203-205: why are you reporting the predicted scores using the linear mixed model? What is the meaning to give to the predicted scores, compared to the actual scores? Similarly for the other reported scores (line 219, etc.)

- Line 214: remove the opening parenthesis.

- Line 257-262: move the paragraph from "a recent multicenter..." to "... and specificity [27]" in the limitations section of the article.

- Line 262-291: move the sentences after the discussion of your results. The discussion section should be focused on the results of YOUR paper, and then a comparison with previous literature.

- Line 318: start a new paragraph when reporting the strength and limitations of your paper. Another limitation is the fact that some interview (how many?) were performed by remote, due to COVID19 pandemia.

- In the introduction it is said that the treatment with BTX-A is not covered by your health system. How do you treated the patients included in your study? Do they payed the treatment? This could also be a selection bias, that should be included in the limitations section.

Tommaso Martino, M.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed all the points, and they have strengthen the manuscript.

Reviewer #2: The authors aswered to most of the comments. However, I have further recommendations in order to get acceptable english language. Please check the following sentences:

1. line 86: “Blepharospasm is one of focal dystonias that symptoms commonly spread to…”

2. lines 114-115 : “We use the JRS, worldwide for clinical research and easy to use [21], for assess the severity and frequency of the blepharospasm”

3. line 288 : “Male and female patients might aware of the…”

4. lines 301-302 : “Mental health and difficulties with vision activities in near, distance and peripheral had effects…”

5. line 316: “BTXA treatment is useful for decreased physical severity…”

6. lines 320-322 : “The large 320 network of cooperation from participating neuro321

ophthalmologists and neuro-medicine units to deploy both generic and visual-specific

322 questionnaires allowed for broader data collection however, this study did have some limitations”

Moreover, Martino et al., 2012 and Weiss et al.,2006 references are reported twice in refercences list. (9-30 and 8 – 29 , respectively); Yang et al., 2021 reference is reported three times (5-7-12);

Reviewer #3: I did non ask for revision of the previous version, the revised version is still accurate and I can confirm that the current version of the manuscript is worthy of publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

**********

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Mar 15;18(3):e0283111. doi: 10.1371/journal.pone.0283111.r004

Author response to Decision Letter 1

19 Feb 2023

Dear Editors and Reviewers,

Thank you for your kind comments. I got many points of view and grammar to improve my manuscript. Here is my explanations and additional contents which already added in the 2nd revised manuscript.

Additional Academic Editor Comments:

In addition to the comments of our eminent referees, please consider the following:

- Line 63: add p-values.

>> Done (p<0.001)

- Line 77: change "depends of multifactor" with "are multifactorial".

>> Done

- Line 78: change "another" with "one of".

>> Done

- Line 86: change "that" with "whose".

>> Done

- Line 108: remove the sentence from "we would like..." to "... then the". Start with inclusion and exclusion criteria, which should be reported in a more systematic way.

>> Done

- Line 121: change "was pregnant" with "were pregnant".

>> Done

- Line 125: explain what is the most common "standard routine" used in your centers.

>> Done. Change to “All participants received BTX-A treatment from each center to control the spasm, and the dose depended on the severity, previous response and type of BTX-A.”

- Line 178 and 185: change "underlying diseases" with "comorbid diseases" or "comorbidity".

>> Done

- Line 188: I would not say "significant number" if the percentage is 12.5%.

>> Done.

- Line 190: what do you mean by "transportation cost"? And why is it reported?

>> In this project, we plan to use the information from this study to do the economic analysis in the future, then we collect cost of transportation from the patients. In this article, we showed about QOL in patients with daily-life affected blepharospasm and improvement after Botulinum toxin treatment. Then, we removed the cost of transportation from this article, in results and in the table 1.

- Line 196-198: acronyms should be listed in alphabetical order.

>> Done

- Line 203-205: why are you reporting the predicted scores using the linear mixed model? What is the meaning to give to the predicted scores, compared to the actual scores? Similarly for the other reported scores (line 219, etc.)

>> We did not aim to compare the predicted score to the actual scores. Since the quality-of-life scores were measured repeatedly in three visits within each patient. Thus, the data for each patient is correlated. To adjusted for correlated data, we use a linear mixed model to estimate the scores and we called the scores estimated from the linear mixed model as a predicted score. We just would like to show the value of scores after adjusting for the correlated nature of the data.

- Line 214: remove the opening parenthesis.

>> Done

- Line 257-262: move the paragraph from "a recent multicenter..." to "... and specificity [27]" in the limitations section of the article.

>> Already moved and rearranged to line 315-321

- Line 262-291: move the sentences after the discussion of your results. The discussion section should be focused on the results of YOUR paper, and then a comparison with previous literature.

>> Already rearranged in line 258-279

- Line 318: start a new paragraph when reporting the strength and limitations of your paper. Another limitation is the fact that some interview (how many?) were performed by remote, due to COVID19 pandemia.

>> Already restarted paragraph of strength and limitations. Also rewrite in some part of the limitation 315-330

- In the introduction it is said that the treatment with BTX-A is not covered by your health system. How do you treated the patients included in your study? Do they payed the treatment? This could also be a selection bias, that should be included in the limitations section.

>> Done. Already added in limitation. “The new patients who self-pay their medical expenses might deny Botulinum toxin treatment due to financial limitation. They, thus, were not including into the study. This resulted in another potential selection bias.” Line 322-4

Reviewer #2:

Reviewer #2: The authors aswered to most of the comments. However, I have further recommendations in order to get acceptable english language. Please check the following sentences:

1. line 86: “Blepharospasm is one of focal dystonias that symptoms commonly spread to…”

>> Done. Blepharospasm is one of focal dystonias whose symptoms commonly spread to… as editor suggested.

2. lines 114-115 : “We use the JRS, worldwide for clinical research and easy to use [21], for assess the severity and frequency of the blepharospasm”

>> Done. We use the JRS, which is widely used for clinical research and is easy to use [21], to assess the severity and frequency of blepharospasm.

3. line 288 : “Male and female patients might aware of the…”

>> Done. Male and female patients may perceive the affected quality of life differently, even if the severity is the same. Line 280-281

4. lines 301-302 : “Mental health and difficulties with vision activities in near, distance and peripheral had effects…”

>> Done. From NEI-VFQ25, mental health, difficulty with near-vision activities, distance-vision activities and peripheral vision had effects in the 50-60% range. Line 293-4

5. line 316: “BTXA treatment is useful for decreased physical severity…”

>> Done: BTX-A treatment not only reduces physical severity but also enhances quality of life, including in non-physical aspects. Line 308-9

6. lines 320-322 : “The large network of cooperation from participating neuro ophthalmologists and neuro-medicine units to deploy both generic and visual-specific questionnaires allowed for broader data collection however, this study did have some limitations”

>> Done. The strength of this study is that we conducted a prospective multicenter, observational study from neuro-ophthalmologists and neurologists in 14 centers nationwide with large population that included participants from all parts of Thailand. Data on quality of life, collected through generic and visual-specific questionnaires, broadened the scope of data collection. Line 311-4

Moreover, Martino et al., 2012 and Weiss et al.,2006 references are reported twice in refercences list. (9-30 and 8 – 29 , respectively); Yang et al., 2021 reference is reported three times (5-7-12);

>> Thank you very much for your information. I already revised all the references.

Response for all reviewers:

Thank you very much for your kind reviews. Your comments are very useful for us to improve our manuscript.

Attachment

Submitted filename: Response to Reviewers2_190223.docx

Click here for additional data file. (20.4KB, docx)

Decision Letter 2

Tommaso Martino

2 Mar 2023

Health-related quality of life of daily-life-affected benign essential blepharospasm: multi-center observational study

PONE-D-22-27465R2

Dear Dr. Hirunwiwatkul,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Tommaso Martino, M.D.

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have no further comments to this manuscript.

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

Acceptance letter

Tommaso Martino

6 Mar 2023

PONE-D-22-27465R2

Health-related quality of life of daily-life-affected benign essential blepharospasm: multi-center observational study

Dear Dr. Hirunwiwatkul:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Tommaso Martino

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Baseline quality of life by generic (EQ-5D-5L) and condition-specific (NEI-VFQ25) questionnaires (Mean, SD).

    (DOCX)

    Click here for additional data file. (24.8KB, docx)
    S2 Table. Daily-life-affected BEB patients’ health-related quality of life by EQ-5D-5L questionnaires in subscales.

    (DOCX)

    Click here for additional data file. (24.5KB, docx)
    S3 Table. Estimated EQ-5D-5L, NEI-VFQ-25 and JRS at each visit and coefficient with 95% confidential interval of patients with daily-life-affected blepharospasm.

    (DOCX)

    Click here for additional data file. (27KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (27.2KB, docx)
    Attachment

    Submitted filename: Response to Reviewers2_190223.docx

    Click here for additional data file. (20.4KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.

    Articles from PLOS ONE are provided here courtesy of PLOS

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