Significance of age and sex in botulinum neurotoxin dosing for adductor spasmodic dysphonia

Abstract Objectives This study aims to analyze the impact of age and sex on botulinum neurotoxin (BoNT‐A) dosing and outcomes in adductor spasmodic dysphonia (AdSD). Methods A database review of all spasmodic dysphonia patients treated with BoNT from 1989 to 2018 at the Mayo Clinic in Arizona was performed. Only patients who had received ≥4 injections of BoNT‐A for AdSD were included. Patients were divided into two cohorts to analyze age, with an age of first treatment cutoff of 60 years. Patients were divided into male and female cohorts to analyze sex. Results The final analysis included 398 patients. The mean dose of BoNT‐A per treatment was significantly higher in the younger cohort (4.4 vs. 3.9 units, p = 0.048). The mean maximal benefit was similar (72% vs. 70%, p = 0.48); however, the mean length of benefit was significantly shorter in younger patients (3.0 vs. 3.6 months, p < 0.01). The mean BoNT‐A dose was significantly higher in the female cohort (4.2 vs. 3.6 units, p = 0.02). The mean maximal benefit was similar (69% vs. 75%, p = 0.58), as was the mean length of benefit (3.2 vs. 3.5 months, p = 0.11). Conclusions This study suggests that age and sex influence BoNT‐A dosing and outcomes in AdSD.


INTRODUCTION
Tourette's syndrome, and other voice disorders were excluded from the analysis.
Only patients who had received ≥4 injections of BoNT-A were included. Injections are performed using electromyography (EMG) guidance with the subcutaneous injection of local anesthetic. BoNT-A is injected into each thyroarytenoid muscle using a 37-mm, 27-guage Teflon-coated monopolar EMG injection needle.
A 100-unit vial of BoNT-A diluted with preservative-free saline to a concentration of two units per 0.1 ml is prepared for each patient. At our institution, patients are initiated at a dose of 1.2 units bilaterally with subsequent dose titration guided by patient response and preference. Some patients convert to unilateral injection. We elected to exclude the first two injections from the analysis. The third dose received is the first included in the analysis with a subsequent injection required to collect outcome data. To analyze the role of age, patients were divided into two cohorts: those with a first treatment aged 60 or younger and those with a first treatment over the age of 60. Patients who had previously received treatment at another institution were placed in the cohort based on the age of their first outside injection and their first two injections at our institution were excluded. To analyze the role of sex, patients were divided into two cohorts: male and female. Details recorded include sex, age of symptom onset, the time between first injection and last injection, number of injection sessions, presence of vocal tremor, presence of a coexisting movement disorder, and family history of SD or other dystonias.
Outcomes compared included mean BoNT-A dose, mean selfperception of maximal benefit (patients are asked to attribute a percentage to the maximum benefit received from the previous injection), mean perceived length of benefit from the previous injection (in weeks), mean time between injections, mean breathiness duration (patients are asked to provide a duration of breathiness in days or weeks), and mean duration of dysphagia to liquids (patients are asked to provide a duration of dysphagia to liquids in days or weeks). Data were collected at the patient's next injection appointment using a standardized questionnaire that remained unchanged over 30 years. Dose refers to the total amount administered in a treatment session (i.e., the cumulative dose in bilateral injections).
Individual patient averages were calculated and the averages of these were analyzed. This was performed to prevent analysis from being skewed by patients who have received many treatments (up to 80).
Linear regression was used to adjust for sex or age, coexistent vocal tremor, and other movement disorders. Analysis was conducted using advanced statistical software and a two-sample t-test or Wilcoxon rank sum test when applicable. A p-value < 0.05 was used to define statistical significance. Means are presented with the standard deviation in Tables 2, 4, and 5, and with the standard error in Table 3. Medians are presented with the interquartile range.

Analysis by age
Of the included patients, 199 received their first injection ≤60 years old (50%) and 199 received their first injection after their 61st birthday (50%). Demographic details are displayed in Table 1. Younger patients were more likely to be male than in the aged cohort (27% vs. 12%, p < 0.01). The length of follow-up was similar (median = 6 years) but younger patients received a higher median number of treatments (13 vs. 9, p < 0.01). Older patients were more likely to have coexistent vocal tremor (p < 0.01) or other movement disorders (p = 0.03). There was no difference in the family history of SD or other dystonias. Documentation of age of dysphonia onset was present in slightly more than half of patients, with means of 40 years and 62 years in the younger and older cohorts, respectively. Table 2 Table 3 displays these data.

Analysis by sex
Of the included patients, 320 (80%) were female and 78 (20%) were male. Demographic details are displayed in Table 4. The female cohort demonstrated older mean age at the first injection (60 vs. 54 years, p < 0.01). Female patients were more likely to exhibit a coexistent vocal tremor (59% vs. 27%, p < 0.01). Cohorts were similar regarding the length of follow-up, the number of treatments, additional movement disorders, and family history. The mean BoNT-A dose was significantly higher in the female cohort (4.2 vs.   This study aimed to analyze the influence of both age and sex on BoNT-A dosage and treatment outcomes in AdSD. For the analysis of age, patients were initially divided into three cohorts (<50, 50-60, and >60 years of age at first injection). The demographics, clinical characteristics, and outcomes between patients <50 years old and 50-60 years old were similar, and therefore these groups were combined to result in two cohorts that were evenly sized by chance.
Data pertaining to the age of dysphonia onset was unavailable for almost half of the patients in the study which limited its use as a metric for analysis. However, available data suggest that patients allocated to the first injection aged 60 years or younger cohort had significantly earlier disease onset compared to the older cohort.
The impact of age on BoNT-A treatment for AdSD has previously been studied. In 2009, Vasconcelos et al. retrospectively reviewed treatment outcomes in 155 patients who had received more than five treatments of BoNT-A for AdSD. 11 In their analysis, patients were divided into two cohorts by age at the first treatment being less than, or greater than, 50 years of age. Neither the dose of BoNT-A nor the length of benefit received were statistically significantly different. 11 Subsequently, Lerner, et al. selected patients who had received more than 5 years of treatments of BoNT-A for AdSD and divided by age <80 or >80 at the time of chart review. 12 These inclusion criteria yielded 201 patients with no statistically significant difference between the cohorts in terms of mean dosing. 12 These data differ from the findings of this study, where patients 60 years or younger at first injection tended to have a higher mean dose of BoNT-A per treatment and a shorter mean length of benefit, but the mean maximal benefit achieved by treatment was similar. Posttreatment breathiness affected each cohort equally and posttreatment dysphagia did not statistically significantly differ but was approaching significance, with older patients possibly more susceptible to longer posttreatment dysphagia to liquids.