Quality of Life After Botulinum Toxin Injection in Patients With Adductor Spasmodic Dysphonia; a Systematic Review and Meta-analysis

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Quality of Life After Botulinum Toxin Injection in Patients With Adductor Spasmodic Dysphonia; a Systematic Review and Meta-analysis *,†Maryam Faham, ‡Akram Ahmadi, §Erin Silverman, ║Gholamreza Ghaedamini Harouni, and ¶Payman Dabirmoghaddam, *yShiraz, zBabol, and ║{Tehran, Iran, and xGainesville, Florida Summary: Introduction. Adductor spasmodic dysphonia is an extremely disabling voice disorder that negatively impacts a patient’s quality of life (QOL). We performed a systematic review to determine if Botulinum Toxin (BT) injections improved voice related QOL in patients with this disorder. Methods. PubMed, EMBASE, Web of Science, Cochrane Library, ProQuest, and Scopus from 2000, to and including November 1st, 2018, were searched. We identified randomized controlled trials, controlled trials, and observational studies of the effects of BT injections on the QOL in patients with adductor spasmodic dysphonia. The two authors, separately and individually chose the studies based on inclusion criteria, assessed study quality, and relevant extracted data. Results. Nine studies used the Voice Handicap Index (VHI). The results showed significant changes pre- to post-BT injection (SMD = 0.357; 95% CI: 0.579, 0.136; z = 3.16; P = 0.002; I-squared = 0.000%). Five studies used the Voice-Related QOL; their results also showed a significant improvement pre- to postinjection (SMD = 2.99; 95% CI: 3.27, 1.32; z = 4.61; P < 0.001; I-squared = 87%). Three other studies used other, shortened versions of the VHI, VHI-10. They also showed significant results (SMD = 0.145; 95% CI: 0.349, 0.06; z = 1.38; P = 0.17; I-squared = 0.000). Conclusion. BT injections positively affect patients’ QOL. However, patients’ QOL scores may never be normalized, in line with perceptual voice quality and acoustic parameters. Key Words: Laryngeal dystonia−Adductor Spasmodic Dysphonia−Botulinum toxin injection−Quality of life −Voice disorder.

INTRODUCTION Spasmodic Dysphonia (SD) is a focal laryngeal dystonia with no clear pathophysiology. Evidence exists of central nervous system dysfunction (both higher and lower than average).1−4 Genetic factors,5 in combination with environmental factors6,7 have been suggested as causes of SD. SD is a rare chronic condition8 with a prevalence of 14 per 100,0009; and manifests as three types: adductor SD (ADSD), abductor SD, and mixed SD.10−12 ADSD is more common than the two other types3,11 and is characterized by involuntary spasms of the true vocal folds. These spasms lead to voice breaks and a perceptually hoarse, tight, strained, or strangled voice quality.13−15 There is no permanent cure for SD; however, botulinum toxin (BT)

Accepted for publication July 31, 2019. Funding: This study was funded by Shiraz University of Medical Sciences (grant number 95-01-106- 13865). From the *Department of Speech and Language Pathology, Shiraz University of Medical Sciences, Shiraz, Iran; yRehabilitation Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; zDepartment of Speech Therapy, School of Rehabilitation, Babol University of Medical Sciences, Babol, IR Iran; xDivision of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida; ║Social Welfare Management Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran; and the {Otolaryngology Research Center, Tehran University of Medical Sciences, Tehran, Iran. Address correspondence and reprint requests to Maryam Faham, Department of Speech and Language Pathology, Shiraz University of Medical Sciences, Chamran Blvd, Abiverdi 1st, Shiraz 7194733669, Iran. E-mail addresses: [email protected], [email protected] Journal of Voice, Vol. &&, No. &&, pp. &&−&& 0892-1997 © 2019 The Voice Foundation. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jvoice.2019.07.025

injections are considered the gold standard treatment for ADSD and generally last 3−4 months.1,16,17 Several prospective studies have indicated that voice quality improves after BT injection; although patients typically never achieve a “normal voice”−whether acoustically or perceptually.16−18 Symptoms generally return after approximately 3 months, on average, and patients may require reinjection.19,20 ADSD negatively affects voice-related quality of life (QOL),1,18,21 and past studies found that patients with ADSD who were treated with BT showed improved QOL and speech-related attitudes18,21−23; although, as expressed by Tanner et al, their scores were still below normal levels.7 Patients have reported that this disorder limits their professional activities resulting in lower socio-economic status and poor self-perception.21,24 Meyer et al reported that 58.3% of patients with SD reported reduced work productivity because of their poor voice quality.25 Baylor et al found that SD restricted patients’ professional and social roles, reduced their self-consciousness, and caused them to feel embarrassed because of their voice quality.26 These adverse effects of SD on voice-related QOL may change positively after receiving BT injections. There are various instruments that quantify the effects of voice disorders on QOL. These measures have been used as treatment outcome measures for patients with SD. The Voice Handicap Index (VHI) is the most popular instrument for measuring the voice-related QOL in patients with dysphonia. Jacobson et al validated this tool, and then it was translated and adapted for several languages. This instrument includes thirty items distributed

ARTICLE IN PRESS 2 across three subscales: physical, functional, and emotional. Total VHI score varies between 0 and 120, with zero meaning no effect of a voice disorder on a patient’s QOL.27 There are two other forms of the VHI: the VHI-1028 and VHI-1223 which are shorter than original VHI and can be administered quickly. These versions have shown good reliability and validity and are used as treatment outcome measures. The Voice Related QOL (V-RQOL) instrument was designed and validated by Hogikyan and Sethuraman and includes 10 items in two domains: social-emotional and physical-functional. All of the items are rated on a five point Likert scale. The V-RQOL total score is extracted by an algorithm and varies between 0 and 100. In contrast to the VHI, “0” indicates worse QOL because of a voice disorder.29 The Voice Activity Participation Profile (VAPP) questionnaire contains 28 items across four domains; including job, daily communication, social interaction, and emotional effects. VAPP total scores range from 0 to 280, with “0” indicating the lowest effect of a voice problem on a patient’s QOL.30 The questionnaires mentioned above were used in different studies to track the changes due to ADSD regards to the researchers' preferences and study designs at different time intervals and have produced different results. Most studies used the VHI-30, VHI-10,19,21−23,31 or the V-RQOL.12,18,24 There are some systematic review studies of the effects of BT injections on patients with SD. Van Esch et al systematically compared the results of BT injections with surgical treatment in patients with ADSD. They only selected studies which used the VHI-30 and VHI-10 questionnaires; so they were not able to compare results that were measured with other scales.32 A recent systematic review by Rumbach et al comprehensively reviewed various outcome measurements of BT injection effects for all types of SD.33 They did not include any meta-analysis of the studies used in their systematic review. Former systematic reviews by Watts et al34,35 and Whurr and Lorch36 provide a good source of information about the history, characteristics, differential diagnosis, assessment, and treatment options for SD. In 1998 the first meta-analysis was administered by Whurr et al. The authors examined 22 studies and considered all treatment outcome measures stated in the articles to evaluate the efficacy of BT injections.37 In 2002 another metaanalysis was performed on 30 studies. This analysis showed that BT injections were moderately effective, at best, at ameliorating the symptoms of ADSD. However, the lack of standardized, disease-specific assessment tools may be driving such conclusions.38 Today, additional reliable subjective and objective voice assessment tools have been developed to analyze voice acoustics. These include the Acoustic Voice Quality Index39 and the Cepstral Spectral Index of Dysphonia40 which track the deviation from normal more accurately than traditional acoustic analysis approaches. However, to the best of our knowledge, these measures have not been used to measure acoustic changes in patients with ADSD pre-to-post BT injection. Audio-perceptual assessments were used in

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most studies and are integral to the initial diagnosis of SD.36,41 However, these assessments yield varying results. In order to comprehensively examine the effects of BT injections on changes in QOL for patients with ADSD, we carried out a systematic review and quantitative meta-analysis of papers which studied QOL changes after BT injections in these patients. METHODS This systematic review and meta-analysis study is reported per the Preferred Reporting Items for Systematic Review and Meta-Analyses statement.42 This review was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) on 6 July 2017 (CRD42017052980). We performed a systematic search of the literature in PubMed, EMBASE, Web of Science, Cochrane Library, ProQuest, and Scopus (publications from 2000 to and including November 1st, 2018) using the search strategy outlined below. This search strategy was developed by M.F. and is provided in Appendix 1. Titles and abstracts were reviewed independently by two authors (M.F. and A.A.) to assess for relevance. Eligibility criteria We included all randomized controlled trials, controlled trials, and observational studies that evaluated the effects of BT injections on QOL measures in patients with ADSD. We included articles that (1) studied the effects of BT injections in patients with ADSD, (2) did not combine BT injections with any other treatment like voice therapy (3) injected BT into the thyroarytenoid muscles but not into any other muscles, and finally (4) used an official self-assessment or voice-related QOL tool, but not other unofficial assessments, either before or after injection. We excluded review papers, editorial letters, animal models, papers which mixed ADSD with other forms of SD, and non-English language papers. Study selection The titles and abstracts of studies identified by the search strategy were screened independently by two authors (M.F. and A.A.). The reviewers discussed any discrepancies in opinion regarding screening, and if they did not reach a mutual agreement, a third author was asked to help. The full texts of appropriate articles were obtained for final review, and a decision regarding inclusion against the eligibility criteria was independently obtained. Title and abstract screening were done following final paper selection. Data extraction Data were extracted by M.F. and included the following outcomes: mean and standard deviation of pre-BT injection QOL scores, post-BT QOL scores, mean, and standard deviations of patients' ages, sample size, and assessment tools. In cases where mean and standard deviations were

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QOL After BT Injections in ADSD Patients

not included in the article, we attempted to contact the authors over three separate emails. If no reply was received, we attempted to derive the data using the formula of Wan et al 43 If the formula did not work, the study was subsequently excluded. Critical appraisal M.F. critically appraised the studies, which were further verified by A.A. using the Newcastle-Ottawa Scale for cohort studies. Articles were scored according to their selection, comparability, and exposure. Assessments included stars, ranging from zero to nine. Articles that scored six or more stars were graded as high-quality studies,12,22,23,44−51 moderate for score 4−521,31,52 and weak for scores below three.53 The Delphi list54 was used for randomized clinical trials and clinical trials.18,55,56 In cases of any disagreement, a third author was asked to contribute to the final decision. Statistical analysis A random-effects model was used to calculate changes in QOL from pre-to-post BT injection time. In experimental studies that contrast treatments and employ continuous outcome variables, the standardized mean difference (SMD: the difference between the treatment and control group means divided by the within-group standard deviation) is often used.57 Therefore, in this study, SDM was used for computing effect size. A forest plot was used for illustrating effect sizes and corresponding indexes. A forest plot displays effect estimates and confidence intervals for both individual studies and meta-analyses. A block represents each study at the point estimate of intervention effect with a horizontal line extending either side of the block. The area of the block indicates the weight assigned to that study in the meta-analysis while the horizontal line depicts the confidence interval (usually with a 95% level of confidence). The area of the block and the confidence interval convey similar information, but both make different contributions to the graphic. The confidence interval depicts the range of intervention effects compatible with the study’s result and indicates whether each was individually statistically significant. The size of the block draws the eye towards the studies with larger weight (usually those with narrower confidence intervals), which dominate the calculation of the pooled result.58 Study heterogeneity greater than 50% indicated severe heterogeneity. Begg’s test, Egger’s test, and funnel plots were used to assess publication bias. All meta-analytical methods were performed using STATA (Release 12. statistical software. College Station, Texas: STATA Corp LP). RESULTS Study selection We selected 2267 papers from the searched databases. Of these, 1000 papers were duplicates. In the title screening phase, 1267 titles were assessed, resulting in 89 papers for

3

abstract screening. We excluded papers that did not use any formal QOL tool, those that did not assess QOL pre-and postinjection, those that mixed results obtained from patients with all types of SD or different types of treatments combined with BT injection. Finally, 37 papers were selected for full-text assessment. By this stage, selected papers studied QOL in patients with ADSD who were treated with BT injections. Three papers were excluded as they pooled all types of SD in the final results. We additionally excluded two papers that used a nonstandardized or nonvalidated QOL tool, 11 that did not state pre- or postscores and one was excluded as injections were made to the supraglottic space, but not the thyroarytenoid muscles. For studies that did not report QOL scores, we attempted to communicate to the first and corresponding authors of the paper three times over 3 weeks. If the study authors did not respond, we excluded the studies. Two papers with inaccessible full texts were excluded. Finally, 17 papers were selected for a critical appraisal (Figure 1). Study designs Of the 17 papers that were selected for appraisal, three papers were clinical trials,18,55,56 14 were prospective cohorts and longitudinal pre-post studies.12,21−23,31,44−52 Fourteen were prospective cohort studies and longitudinal pre-post studies. The number of patients varied from 133 to 9 patients with ADSD. Most studies included predominantly female study cohorts, except Faham et al.45 In total, 474 patients were recruited to the studies, including 347 females. The mean patients’ age was 55.47 (SD = 9.04). Most of the studies examined the effects of bilateral BT injections22,23,44−46,51,52,55,56 while in some studies both types of unilateral and bilateral injections were applied.12,47,48,50 Silverman et al,18 Neumann et al,21 and Benninger et al31 did not mention the type of injections. The minimum postinjection assessment interval was 1 week.31 Some of the papers did not state a clear time for postinjection assessments.12,44,47 The details of the studies are presented in Table 1. Assessment tool The studies mainly used the VHI, V-RQOL, VHI-10, VHI12, and VAPP-Persian (VAPPP) to assess changes in QOL before and after BT injections. Out of 17 studies, seven (44%) only used the VHI to investigate the effects of BT injections on QOL in patients with ADSD, five studies (33%) only used V-RQOL, two studies (5%) only used VHI-10, one study (5%) only used the VHI-12, and one study (5%) only used the VAPPVAPPP version. Morzaria et al used the V-RQOL, VHI, and VHI-10 questionnaires simultaneously; this was the only study which used more than one QOL tool.12 The V-RQOL scores were exactly in another study by Morzaria et al47 which was included in this meta-analysis. Consequently, we only used the data in the earliest paper in order not to reduplicate any data. Based on the V-RQOL algorithm for measuring QOL, the higher score means a better situation in contrast to other

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Identification

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Records idenfied through database searching (n = 2667)

Addional records idenfied through other sources (n = 0 )

Eligibility

Screening

Records aer duplicates removed (n = 1267)

Records screened (n =1267)

Records excluded (n =1178)

Full-text arcles assessed for eligibility (n =89)

Full-text arcles excluded, with reasons (n =72)

Included

Studies included in qualitave synthesis (n =17)

Studies included in quantave synthesis (meta-analysis) (n =17)

FIGURE 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 flow diagram. tools like VHI, VHI-10, and VAPP. So, we inversed the V-RQOL mean scores using the following formula: Maximum score−Minimum score−Old Variable score59 The new scores that were generated were compared to other studies. Meta-analysis Data were analyzed using the Random Effect Model and Cohen’s d. First, all the studies were pooled together; then, in cases of any heterogeneity, subgroup analyses were applied. The first step analysis showed significant differences between pre- and post-BT injection QOL (SMD = 0.885; 95% CI: 1.327, 0.442; z = 3.92; P < 0.001). Please refer to Table 2 and Figure 2. The I-squared was 89.8%, indicating a high degree of heterogeneity, so subgroup analysis was needed based on tools used in different studies. A minimum of three and a maximum of nine studies were included in each group. Two single studies stood alone in two separate groups.

In the first group, there were nine studies which used the VHI. The results showed significant changes from pre to post-BT injection (SMD = 0.357; 95% CI: 0.579, 0.136; z = 3.16; P = 0.002; I-squared = 0.000%). This finding is provided in Table 3 and Figure 3. Five studies used the V-RQOL and also produced significant pre- to postinjection differences (SMD = 2.99; 95% CI: 3.27, 1.32; z = 4.61; P < 0.001; I-squared = 87%). The heterogeneity in this subgroup was still high after subgroup analysis. The third group consisted of three studies which used a shortened version of the VHI (VHI-10). These studies showed no significant results (SMD = 0.145; 95% CI: 0.349, 0.06; z = 1.38; P = 0.17; I-squared = 0.000). The I-square value improved after subgroup analysis which means the subgroup analysis were qualified; However, there were two studies where patients were separated into groups based on the QOL tool that was used [VHI-1223 and VAPPP45]. Because these studies passed study inclusion criteria, they were not excluded from statistical analysis.

Maryam Faham, et al

TABLE 1. Study Characteristics; QOL Tool, Time of Assessment.

Benninger Wingate Dejonckere Kim

2001 2005 2012 2014

Prospective Prospective ? Prospective

Esposito Rojas Singh Hogikyan Rubin Gama Morzaria Silverman Morzaria

2015 2016 2016 2001 2004 2010 2011 2012 2012

Prospective Prospective Prospective Prospective Prospective Prospective Prospective Prospective Prospective

Naumann

2009

Hartmann Novakovic Faham

2013 2011 2018

Prospective Prospective Retrospective

Participants (No. of Females)

Mean Age

Injection Type: Uni/Bi*

Previous Injection

Postinjection Time:

Postinjection Sample-size

QOL Tool

Mea (SD) Preinjection

Mean (SD) Postinjection

VHI VHI VHI VHI

67.6 (14.7) 63.64 (27.18) 64.17 (21.98) 81.9 (19.7) 77.5 (24.3) 82 (7.72) 67.79 (26.52) 78.7 (11.63) 28.68 (17.14) 31.81 (18.43) 34.09 (21.97) 47.5 (19.26) 31 (19) 69.95 (22.23) 24.54 (7.19) 69.58 (12.99) 24.42 (4.85) 24 (11.69) 22.3 (7.84) 138.80

22 (14.3) 49.76 (33.87) 48.75 (22.54) 23.3 (6.3) 23.4 (5.2) 66.38 (3.71) 58.21 (27.3) 45.8 (7.98) 85.6 (9.52) 80.62 (15.42) 57.95 (25.34) 87.64 (12.05) 56 (29) 51.11 (21.14) 15.64 (6.90) 45.25 (16.6) 16.25 (5.23) 42 (23.50) 12.66 124.60 91.20 131.76

30 (24) 13 (13) 19 (11) 15 (?) 15 (?) 13 (10) 14 (10) 10 (6) 27 (23) 42 (36) 11 (11) 37 (26) 31 (25) 37 (26)

50 73.3 60.6 34.9 31.9 61 57.2 47.4 51.9 51.5 56.54 56.2 48.45 56.2

?** Bi Bi Bi

? Yes ? No

1-3 W* 4W ? 1-3-6 M*

Bi Uni Bi Bi Uni&Bi Bi Uni&Bi ? Uni&Bi

Yes Yes No No Yes No Yes No Yes

2W 136 D* 8W 6-8 W 6-8 W 2W 2-22W 3W 2-22 W

22 13 19 15 15 13 14 10 21 36 11 37 10 37

15 (9)

60.6

?

?

?

13

17 (13) 133 (96) 15 (3)

68.64 ? 47.7

Bi Uni&Bi Bi

Yes Yes Yes

4-8 W ? 1M 3M 6M

17 133 15

VHI VHI VHI VRQOL VRQOL VRQOL VRQOL VRQOL VHI VHI-10 VHI VHI-10 VHI-12 VHI-10 VAPPP

* Bi, Bilateral; Uni, Unilateral; W, Week; M, Month; Y, Year. ** ?: did not mention in the paper.

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Year

QOL After BT Injections in ADSD Patients

Study Design

Authors

5

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TABLE 2. Meta-analysis Results for All Studies 95% CI Study Benninger (2001) Dejonckere (2012) Esposito (2015) Gama (2010) Hartmann (2013) Hogikyan (2001) Kim (2014) Morzaria (2011) Morzaria (2012) Morzaria (2012) Faham (2018) Naumann (2009) Novakovic (2011) Rojas (2016) Rubin (2004) Silverman (2012) Singh (2016) Wingate (2005) Naumann (2009) D+L pooled SMD

SMD

LB

UB

% Weight

0.808 0.234 0.171 1.006 0.094 4.111 1.003 2.499 0.309 0.060 1.685 0.379 0.075 0.109 2.853 1.031 0.496 0.247 0.369 0.885

1.381 0.872 0.942 1.898 0.578 5.126 1.766 3.110 0.767 0.516 2.526 1.129 0.316 0.850 3.488 1.948 1.388 1.018 1.092 1.327

0.236 0.404 0.599 0.114 0.767 3.095 0.241 1.887 0.149 0.396 0.844 0.370 0.165 0.633 2.217 0.114 0.395 0.525 0.353 0.442

5.54 5.42 5.15 4.89 5.35 4.62 5.17 5.47 5.73 5.73 5.00 5.19 6.00 5.21 5.42 4.84 4.89 5.15 5.25 100

Publication bias Egger and Begg regression analysis were applied to analyze publication bias. The results showed that the risk of bias was low to moderate, maybe because of heterogeneity of the studies rather than publication bias, as depicted in Tables 4 and 5 and Figures 4 and 5. The funnel plot indicates that, in the absence of availability bias, the average effect size is expected to be the same in large- and small-sample studies, while varying more widely in small-sample studies due to greater sampling error. This plot depicts effect sizes (d values or correlations) against study sample size (or the standard error of the study estimate, which is an inverse function of sample size). In the absence of bias, the resulting figure should take the form of an inverted funnel. However, if there is a publication or other availability bias based on the statistical significance (P value) of the studies, then small-sample studies reporting small effect sizes will be disproportionately absent because these are the studies that will fail to attain statistical significance. These are the studies in the lower left-hand corner of the funnel plot (Figure 5).60 DISCUSSION This systematic review and meta-analysis study attempted to determine changes in voice-related QOL in patients with ADSD. Self-assessed outcome scales are generally recommended for studying the effects of therapeutic procedures on these patients.33 SD can affect different aspects of patients’ daily lives, mostly because of the poor voice quality, which characterizes this disorder. Also, SD is a chronic

disabling and often progressive condition.7 SD symptoms interfere with different aspects of personal life and reduce patients’ QOL and job status, both of which appear to be sensitive to changes in voice quality after BT injection.26,61 Many patients with SD claimed that SD reduced their productivity and work-related activities. They also reported experiencing negative emotions due to their poor voice quality.62 On the other side, there were many situations where patients expressed dissatisfaction with their treatment outcomes, in complete disagreement with real clinical outcome measures. It may be more important to know what will happen after treatment and how long the effects of treatment will last in cases of severe disorders like SD where there is no permanent cure, but only a temporary symptomatic treatment. Many self-assessment questionnaires have been developed to assess voice-related QOL in patients with voice disorders like the VHI,27 V-RQOL,29 and the VAPP.63 Another questionnaire was developed to assess coping strategies related to voice disorders called the Voice Disability Coping Questionnaire.45,64 This questionnaire was first validated on patients with SD and muscle tension dysphonia; however, as far we know, no studies have assessed the effect of BT injections on ADSD characteristics. For all the scales mentioned above, the first aim is to assess the patient-specific impact of the voice disorder, since the patient is the one living with the condition. The VHI is one of the most popular voice assessment tools and has been used in different studies for different populations of patients with voice disorders. The VHI has been validated in different languages like Portuguese,65 Spanish,66 Italian,67 and so on. The VHI consists of 30 items distributed across three subscales: emotional, functional, and physical. The scores vary from 0 to 120, with 120 indicating the worst possible voice impairment. The developers stated that a reduction in VHI overall score equal to or greater than 18.5 indicates significant changes pre- post-treatment.27 In many studies, the mean reduction was less than 18.5 points22,44,49,52; and in others, the changes were greater than 18.5 points.12,21,31,51,56 Among studies that used VHI as an outcome measure, Wingate et al52 first reported that their patients did not improve in terms of overall VHI score. They found that three out of 13 patients had large negative scores from pre to postinjection. The authors claimed that two of those three patients had experiences of long-term injections; that may increase the level of expectations. Neumann and Dejonckere also reported that the VHI total scores of two patients increased after injection.21 None of the other 15 studies report any negative changes from pre-to postinjection. The postinjection assessments were done at different time intervals, from 1 week to about 6 months. Consequently, it is not easy to group studies based on the time interval. Kim et al56 and Singh et al51 followed patients for 6 months, but Benninger et al study,31 followed their patients between 3 and 31 weeks and showed statistically significant positive postinjection changes. However, in studies like Esposito et al22 or Rojas et al49 which reported more

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FIGURE 2. Forest plot for meta-analysis of all studies. than one follow-up records; we selected the first records to be included in the meta-analysis. Regards to type (unilateral/bilateral) of BT injection and any probable effect on amount of VHI score reduction, we can see that both bilateral and unilateral BT injection leads to a significant positive effect. Esposito et al,22 Singh et al,51 and Kim et al56 applied bilateral BT injection while Rojas et al49 applied unilateral BT injection. Morzaria et al12 used both types of injection methods depending on patients need. The rest did not report the type of injection. So no differences were seen in these studies regard to the type of injection to achieve higher than 18.5 VHI score changes from pre to postinjection. Some other studies12,18,46,50,55 used the V-RQOL, which is a 10-item questionnaire consisting of two sub-scales: social-emotional and physical-functioning. A logarithm and range derive the final scores from 0 to 100. On the VRQOL, a score of 100 means that the voice disorder did not affect the patient’s QOL.29 Results obtained from studies that used the V-RQOL are in line with studies that used the

VHI; the data revealed significant changes over a short time postinjection. However, the I-Square value did not improve in these groups after subgroup analysis (I-Square = 87%). It was not possible to do any further subgroup analysis based on other outcome measurements. The most significant changes were recorded by Morzaria et al who followed their patients up until 22 weeks postinjection.12 Other studies produced similar results but followed patients over shorter time intervals. The mean total VRQOL score showed lower-magnitude changes in two studies which repeated the evaluation after the first month of postinjection.18,46 We considered this as a potential source of a higher level of heterogeneity; however, it should be considered in future meta-analysis with more included papers; especially regards to the type of injection. As we can see, with the exception of Silverman et al18 which did not report the type of injection, the rest of the studies applied bilateral injection or combination of bilateral-unilateral injections based on patients' needs. So, postinjection assessment times may play a more salient role.

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TABLE 3. Meta-analysis Results After Grouping Based on QOL Tool 95% CI Assessment Tool 1

VHI

VRQOL2

VHI-12 VHI-10

VAPP3 Total

Study

SMD

LB

UB

% Weight

Benninger (2001) Dejonckere (2012) Esposito (2015) Kim (2014) Morzaria (2012) Rojas (2016) Singh (2016) Wingate (2005) Naumann (2009) D+L pooled SMD Gama (2010) Hogikyan (2001) Morzaria (2011) Rubin (2004) Silverman (2012) D+L pooled SMD Hartmann (2013) D+L pooled SMD Morzaria (2012) Naumann (2009) Novakovic (2011) D+L pooled SMD Faham (2018) D+L pooled SMD D+L pooled SMD

0.808 0.234 0.171 1.003 0.060 0.109 0.496 0.247 0.369 0.357 1.006 4.111 2.499 2.853 1.031 2.299 0.094 0.094 0.309 0.379 0.075 0.145 1.685 1.685 0.885

1.381 0.872 0.942 1.766 0.516 0.850 1.388 1.018 1.092 0.579 1.898 5.126 3.110 3.488 1.948 3.276 0.578 0.578 0.767 1.129 0.316 0.349 2.526 2.526 1.327

0.236 0.404 0.599 0.241 0.396 0.633 0.395 0.525 0.353 0.136 0.114 3.095 1.887 2.217 0.114 1.322 0.767 0.767 0.149 0.370 0.165 0.060 0.844 0.844 0.442

5.54 5.42 5.15 5.17 5.73 5.21 4.89 5.15 5.25 47.50 4.89 4.62 5.47 5.42 4.84 25.23 5.35 5.35 5.73 5.19 6.00 16.92 5.00 5.00 100.00

1: Voice Handicap Index; 2: Voice-Related Quality of Life; 3: Voice Activity and Participation Profile (VAPP).

As shown in Table 1, few studies followed patients for more than 8−12 weeks in order to investigate the effects of BT even though the injections may continue to exert some positive effects beyond that time. Geneid et al stated that, based on their experiences, the clinical effects of BT injections exceeded the expected pharmacological effects by approximately 3 months in some instances.19 Davidson and Ludlow examined electromyographic signals and found that BT-related reinnervation continued for 12 months postinjection.62 In a recent study, Faham et al reported that patients exhibited improvements relative to their preinjection statuses, even at 6 months postinjection.45 Therefore, extended postinjection assessments and patient follow-ups may help us to better understand the effects of a single injection. This is important because many patients do not intend to receive more injections for many reasons. Understanding the longer effects of BT injections helps practitioners prepare patients for likely treatment effects in individuals with SD. There were no significant changes in pre-to-post injection scores in studies that used the VHI-10; however, there were only three studies in this subgroup, and more data will be needed to drive a more solid conclusion. Morzaria and Damrose used the VHI, VHI-10, and V-RQOL in a group of patients with ADSD. They found that the VHI-10

showed post-treatment changes like the other two instruments.12 The original VHI-10 study by Rosen et al found that the VHI-10 score was representative of the full VHI score. The mean ratio of VHI-10 to VHI for patients with ADSD was not out of the range of other voice disorders,28 but final subgroup analysis in this meta-analysis showed that post-treatment changes were not significant after pooling the results. Comparing the results obtained from the VHI, V-RQOL, and VHI-10, we found that only the VHI showed significant results from pre-to-post injection with a low level of heterogeneity. The high level of heterogeneity in the V-RQOL subgroup may be related to questionnaire parameters. The VHI has 30 items, while the V-RQOL contains 10 items. Given the wide range of functional, social, and emotional problems that patients with ADSD may encounter, a more detailed questionnaire may draw a better profile of changes that occur after treatment. Studies which used the VHI-10 could be interpreted as above. This does not mean V-RQOL or VHI-10 are not able to track the changes after treatment, or should not be used. Both are valuable questionnaires that consider the most important aspects of QOL in patients with dysphonia. However, in patients with extremely severe voice disorder symptoms like ADSD, a more detailed questionnaire may be preferable.

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QOL After BT Injections in ADSD Patients

FIGURE 3. Forest plot for subgroup meta-analysis. There was only one study that used the VHI-1223 and only one study that used the VAPPP.45 Both showed significant improvement after receiving BT injection. Hartmann

TABLE 4. Begg’s Results for Publication Bias Adj. Kendall’s Score (P−Q) SD of Score Z (P value) Z (P value)

65 26.40 2.46 (0.014) 2.42 (0.015)

et al followed patients for 4−8 weeks,23 and Faham et al repeated outcome measurements three times postinjection (at 1, 3, and 6-months).45 The first postinjection month data

TABLE 5. Egger Results for Publication Bias 95% CI

(Corrected for Ties) Std_Eff Coefficient (Continuity corrected) (Continuity corrected)

Slope Bias

0.41 3.76

SE

t

p

LB

UB

0.49 0.84 0.41 0.63 1.45 1.68 2.24 0.04 7.320 0.19

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Journal of Voice, Vol. &&, No. &&, 2019

FIGURE 4. Funnel plot for all studies’ publication bias.

FIGURE 5. Funnel plot for publication bias in subgroups. had been used for meta-analysis in this study. As shown by authors, patients reported the best overall VAPPP (Persian version of original VAPP) score at the third postinjection month in comparison with months one and six postinjection. The positive effects of BT injection continued up to 6 months after injection.45 The VAPP63 was not used in any other study. One advantage of the VAPP is that it contains a “job” subscale, which tries to evaluate the impact of a voice disorder on a patient’s employment status. The job subscale had the least changes, which implied that the BT injection was not associated with significant improvement to this subscale in comparison to as other subscales.45 Rojas

et al had similar findings. Here the functional part of VHI did not change significantly from pre- postinjection assessment times.49 In contrast, the physical-functional domain of the V-RQOL improved as much as the socio-emotional domain (81.8%) after injection in the Gama et al study.46 There were insufficient data on changes to functional domains in QOL tools, which is very important for younger patients with ADSD. Functional subscales measures the effects of treatment on key life domains like how voice functions in workplace settings. Many patients with ADSD lose their jobs or have to change careers because of their voice symptoms.

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QOL After BT Injections in ADSD Patients

Because of this, it is critically important to have a specific tool that evaluates work productivity in patients with voice disorders. Isetti and Meyer administered a qualitative study with two work productivity scales: the Stanford Presenteeism Scale-668 and Work Productivity and Activity Impairment Questionnaire- Specific Health Problem69 to a group of individuals with SD. Their results showed that the two questionnaires were able to track work productivity in patients with SD within clinical practice settings.70 Finally, in all included studies, patients with ADSD had higher QOL scores after injection; however, these scores did not reach normal levels. This may mean that patients never feel completely satisfied with their voice quality. BT injections appear to help patients improve their voice quality and related aspects of their daily living, including work productivity and general activity by temporarily relieving spasms and thereby enabling more comfortable phonation. Some variables like injection type (unilateral or bilateral), previous injection, number of injections, and injection dosage varied across the included studies. The effects of BT injections are influenced by these factors.32 However, in line with perceptual and acoustic assessment results, most patients did not achieve a normal QOL because of the quality of their voices and the chronic nature of the disorder. This important matter should be considered by health, and insurance systems as this group of patients requires repeated injections to maintain even this level of voice quality. It is also essential to evaluate the perceptions of patients' friends and families who bear witness to each patient's voice-related challenges. Additionally, clinicians should explain the expected outcomes of BT injection to their patients. Other subjective and objective voice assessments To follow the changes after BT injection in patients with ADSD, the researchers used a variety of assessment methods depending on the designs of the studies. Harmonic-to-noise ratio,22,51,56 percentage of signal types,18 perturbation of intensity,51,56 jitter,51,56 percentage of voice breaks,18,49 maximum phonation time,22,51,56 and audio perceptual assessments by specialists18,44,45,52 and by patients.50,55 Some comments for future We require additional information about patients with ADSD, beyond their acoustic and perceptual voice qualities. Future, well-powered studies are needed if we are to improve our understanding of the effects of BT injections in patients with ADSD. These individuals are at increased risk of poor QOL and negative feelings resulting from their voice condition. Baylor et al tried to show the effects of BT injections for SD on different aspects of patients’ lives, beyond the concept of QOL.26,61,71,72 Lower self-consciousness and feeling embarrassed were mentioned by six patients with SD in a qualitative study26; they also use some coping strategies as well as avoidance (more common), passive coping, and information seeking.26 As mentioned by Epstein et al, patients with SD often exhibit avoidance strategies and do not like to

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talk on the phone. Others prefer to pursue jobs with minor vocal demands.64 Communication Participation is another concept studied by Baylor et al, and it seems negatively affected by ADSD72; however, more studies are needed. Also, as a chronic disorder, a very disease-specific QOL tool may be more helpful, rather than other general voice-related ones. Limitations One limitation of this work was the lack of high-quality studies, including randomized controlled trials. Such studies are needed to examine the effectiveness of intervention procedures for this population.32 The papers we reviewed differed greatly in terms of outcome measures, postinjection times, use of control groups, and study design. Each of these factors may substantially influence findings. CONCLUSION BT injections may improve QOL in patients with ADSD, at least over the short term; however, these changes are not permanent, and the effects from the BT typically wear off after 3 or 4 months. The positive changes associated with BT injections for ADSD include (temporarily) higher QOL. Unfortunately, we do not know much about how these QOL changes continue over time because most studies only follow patients for a short time postinjection. Studying other parts of QOL rather than emotional and functional parts will lead to having a more holistic view of the impact of SD and also BT injection on patients. From a clinical point of view, clinicians should discuss what patients should expect from injection and how they may feel after BT with particular attention to voice quality, voice function, and physical effects of spasm relief. Also, patients should be aware of how the positive changes faded as time passes. APPENDIX 1: PUBMED SEARCH STRATEGY The keywords for the search were basically: Spasmodic Dysphonia, Laryngeal dysphonia, Botulinum toxin, and Botox. To define the search strategies, all MeSH terms were checked, and after modifying the final PubMed search strategy was as below: (“Spasmodic Dysphonia” [ti] OR “Phonation Disorder” OR “Organic Tremor Dysphonia” OR (Dysphonia AND Organic Tremor) OR (Spastic Dysphonia AND Neurologic Adductor) OR “Neurologic Adductor Spastic Dysphonia” OR “Hyperkinetic Dysphonia” OR (Dysphonia AND Hyperkinetic) OR “Spastic Dysphonia” OR (Dysphonia AND Spastic) OR “Task-Specific Focal Dystonia” OR “Task-Specific Dystonia” OR “Focal Task-Specific Dystonia” OR “laryngeal dystonia”) AND (“Botulinum Neurotoxin A”[tiab] OR (Neurotoxin A AND Botulinum) OR “Clostridium botulinum A Toxin” OR “Clostridium Botulinum Toxin Type A” OR “Botulinum A Toxin”[tiab] OR (Toxin AND Botulinum A) OR “Botulinum Toxin Type A” OR Meditoxin OR Neuronox OR Oculinum OR Botox

ARTICLE IN PRESS 12 OR “abobotulinumtoxin A” OR “abobotulinumtoxinA” OR bocouture OR “BoNT A”[tiab] OR “BoNT A DS” OR “BoNT serotype A” OR “botox (100 U) injection” OR “botox (oculinum)” OR “botox 100E” OR “botox a”[tiab] OR “botulin A”[tiab] OR “botulin toxin a” OR “botulinum a exotoxin” OR “botulinum a toxin” OR “botulinum neurotoxin type A” OR (botulinum toxins AND type A) OR BTXA OR “clostridium botulinum endotoxin” OR “Clostridium botulinum neurotoxin A” OR “Clostridium botulinum neurotoxin type A” OR “Clostridium botulinum type A neurotoxin” OR “daxibotulinumtoxin A” OR “daxibotulinumtoxinA” OR dysport OR “evabotulinum toxin A” OR “evabotulinumtoxin A” OR “incobotulinum toxin A” OR “incobotulinumtoxin A” OR “incobotulinumtoxinA” OR “letibotulinumtoxin A” OR meditoxin OR “onabotulinum toxin A” OR “onabotulinumtoxin A” OR onaclostox OR prosigne OR purtox OR reloxin OR xeomin) AND 2000: 2017/06/01[dp].

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