Bilateral trial vocal fold injection with hyaluronic acid in patients with vocal fold atrophy with or without sulcus

In this study we evaluated the outcome of bilateral trial VFI with HA in 68 patients with vocal fold atrophy [atrophy only (n = 30) and atrophy with sulcus (n = 38)] and assessed the predictive value of trial VFI on the outcome of a durable medialization procedure. To our knowledge this is the largest study on trial VFI to date.

We found that the majority of patients reported a good response to the trial VFI, which was defined as enough subjective benefit to want to undergo a durable medialization procedure. The proportion of patients with a good response was not influenced by the type of pathology. We also found a statistically significant and clinically relevant improvement in the overall VHI-30 score. Looking at individual patients, the majority (58.8%) showed a clinically relevant improvement in the VHI-30.

These results demonstrate that the majority of patients with atrophy with or without sulcus experience less voice handicap after trial VFI, indicating that medialization is a valid treatment option in both these patient groups. However, the group of patients that chose to undergo a durable medialization procedure only partially corresponded to the group with a clinically relevant improvement in the VHI-30. Therefore, our findings show that even though the VHI-30 is indicative for voice improvement in this overall patient group, it does not adequately identify the subgroup of “true” good responders who will be motivated for a durable medialization procedure based on their subjective benefit of the trial VFI.

The concept of trial vocal fold injection was defined in 2010 [1]. Since then at least five studies have looked at the change in voice parameters after trial injection, with study populations ranging from 19 to 35 patients [1, 9, 17‐19]. The study by Young et al. was done in patients with atrophy, excluding patients with hypomobility, paresis or paralysis [17]. The other studies did include patients with hypomobility or paresis. One study also included one patient with a vocal fold paralysis [19]. Our proportion of patients with a good subjective response (57.8%) is comparable with those found by Carroll. He found a good response in 32–75% of patients in his three studies [1, 9, 19]. When including partial responses this proportion increased to 76–83% [1, 9, 19]. As for the VHI, it is not possible to compare our findings directly to those of other studies as they used either the VHI-10 version [1, 17, 19] or an alternative self-assessment tool [18]. However, when considering the proportion of patients with a clinically relevant change in the VHI in the different studies, our study (58.8%) has a relatively high percentage compared to earlier reports by Young (42%) and Carroll (30.4%) [17, 19]. Although the VHI scores improve it is important to realize that all studies show that the VHI does not normalize after trial VFI. Even the subgroups of good responders show elevated scores indicating an on-going burden on voice use in these patients. In our study good responders had a mean post-injection VHI-30 score of 26.7 (normal value VHI-30 Dutch version < 15) [12]. The mean post-injection VHI-10 score in good responders in the study by Young et al. was 12 and 20.5 in the study by Carroll et al. [17, 19] (normal value VHI-10 English version ≤ 11) [20].

Finally, the discrepancy that we found between the patients’ subjective experience and the VHI outcome has also been noted by others; a recent study showed that although 65% of the patients reported a subjective good response only five out of 15 (33%) had a clinically relevant improvement in their VHI-10 score (≥ 5 points improvement) [19]. The value of the VHI for assessing voice improvement in patients with glottic incompetence due to atrophy with or without sulcus is, therefore, unclear and needs to be further explored.

As for the acoustic and aerodynamic parameters, we found a statistically significant improvement in the melodic range from 16.5 to 19.6 ST. However, this would still classify as a limited range according to values for healthy subjects found by Wuyts. In this publication healthy subjects showed a melodic range between 22 and 44 ST [21]. Also, it is unclear what the clinical relevance of this increase in melodic range would actually mean to the patients. We found no statistically significant changes in the other voice parameters. The limited effect seen in acoustic and aerodynamic parameters in our study are reflected in other studies [17, 19].

As the effect of bilateral trial VFI is not reflected in the objective voice measures as described above and is only partially reflected in a clinically relevant VHI improvement two questions arise: (1) are the voice parameters used in these publications sufficiently valid and precise and (2) is the timing of the voice data acquisition optimal? The VHI is proven to be a reliable tool for measuring the general impact of a voice disorder and patient burden [10]. Also, as vocal effort is reflected in aerodynamic parameters, we expected these to change after trial VFI. However, some authors are currently pointing out that disease-specific outcome tools may be needed to accurately reflect voice impairment and to measure outcome of intervention [22, 23], which is in line with our findings. Alternative voice outcome measurements that better represent the voice problems of this patient group need to be identified. Two questionnaires for analyzing subjective voice change in patients with glottal insufficiency are mentioned in the literature: the glottal function index (GFI) and the vocal fatique index (VFI) [24, 25]. The GFI is a four-item symptom index, which can be used in the evaluation and treatment in patients with glottal dysfunction [24]. Although the questionnaire has not been designed for a specific clinical disease entity it has been used in several studies on non-paralytic glottic incompetence and its treatment [8, 18, 26, 27]. The VFI is a questionnaire designed specifically for detecting vocal fold fatigue and assessing the impact of treatment these patients [25].

These questionnaires could be of added value when assessing subjective voice change in patients with glottic incompetence, but validated Dutch versions have not yet been developed. Alternative aerodynamic parameters more suited for atrophy patients could be the phonation threshold pressure (PTP) and phonation threshold flow (PTF) reflecting the minimum pressure and flow required to sustain phonation. These parameters may better mirror the ease of phonation [28] [personal communication S. Thibeault and D. Phyland]. Frame-by-frame analysis (FBFA) of laryngovideostroboscopy in which subject’s average percentage of closed frames per glottic cycle is recorded may be another option [29]. The use of 2D digital kymography using laryngeal high-speed video-endoscopy allowed Bae to identify vibratory changes after VFI in patients with paresis and after speech therapy in patients with atrophy [30]. The benefit of these and other alternative voice outcome parameters as well as their clinical implications need to be further explored for patients with atrophy with or without sulcus. For now, we agree with the decision to continue to a definitive procedure is mainly based on the patient’s subjective experience and that additional voice data are of limited contribution [1].

Next to selecting suitable voice outcome parameters, the timing of evaluation is of great importance when evaluating the success of trial VFI. In our study post-trial injection data were collected at 1 month, with a spread from 2 to 8 weeks for a minority of patients. As the different substances used in the studies described have different lifespans it is difficult to compare results, although these other studies also raise concerns about the optimal timing of data collection. In our experience the window of benefit varies per patient even if the same substance is used and depends on factors such as the amount injected, possible oedema or temporary stiffness of the vocal folds and patient compliance with speech therapy. Due to these variations we assume that the voice outcome data in our study will not have been collected at the optimal time point in all patients. Interestingly some of the patients reported noticing a subjective benefit only after the effect of the injection had worn off. The confrontation with their “old” voice made them realize that the injection had been helpful. This subjective effect will, therefore, not have been captured in the VHI-30 filled in during voice analysis at 1 month. Ideally, evaluation should be done frequently to capture voice data at the time of patients’ optimal benefit from the trial VFI. However, for practical reasons we chose to evaluate at 1 month as (1) patients in our experience generally undergo an adjustment period the first few weeks when the voice is not optimal and (2) HA has an average lifespan of 3 months. We do agree that further studies are warranted determining the optimal timing for data collecting post-trial injection [19].

In our study we found that neither gender, nor the additional presence of a sulcus had any influence on voice outcome. We did find an association between age and two of the five voice parameters (VHI and dynamic range) showing an improvement in their outcome with increasing age. This influence of age has not been reported before. We hypothesized that a lower voice demand in the absence of work-related voice use may be underlying cause for increased VHI improvement with increasing age. In the literature, although the data are limited, poorer results after medialization procedures in patients with vocal fold scar have been reported [8, 27]. This poorer result may be well explained by the “double” pathology, not only affecting the glottic closure, but also affecting the vibratory potential of the layered anatomy of the vocal fold. However, although we conceptually agree with this assumption, these findings were not confirmed in our study for patients with sulcus undergoing trial VFI with HA. Our results may have been influenced by the fact that we included only patients with sulcus (Ford type II and III), which is a specific form of vocal fold scar. Further studies on patients with vocal fold scar and specifically with sulcus are needed to determine the value of (trial) medialization in this subcategory.

In this study the VHI-30 outcome did not always correspond to the patients’ subjective experience of the trial VFI. However, we did demonstrate the ability of the VHI-30 outcome after trial VFI to predict the VHI-30 outcome of a durable medialization procedure. 3 months after durable medialization procedure 90% of patients had a similar or better VHI-30 score compared to after trial VFI. This increased to 94% at 12 months. This is in line with previous studies that also have found a predictive value of trial VFI. In 2010 Carroll and Rosen described that all patients with a good subjective result after their trial VFI also had a good result after the durable medialization procedure [1]. In the study by Young et al., 75% of the patients with a good response to trial VFI (VHI-10 improvement of ≥ 5 points) also had a good response to the durable medialization procedure. 55% of patients with a poor response to trial VFI also had a poor response after the durable medialization procedure. Conversely 45% of patients had a good response after the durable procedure despite failing the trial VFI, indicating that the predictive value of a failed trial VFI might be lower than a successful one [17]. As theirs is the only study in which all patients with trial VFI underwent a durable medialization procedure this information cannot be compared to other studies. Interestingly, a recent study also showed the predictive value for trial VFI in patients with vocal fold scar. In this study 80% of good responders to trial VFI also showed clinically significant improvement after durable augmentation [9]. Dumberger et al., reported on predictability of trial VFI in 35 patients with non-paralytic glottic incompetency, including patients with paresis, who underwent trial VFI followed by type 1 medialization with Gore-Tex. They concluded that trial VFI is a useful tool, showing a good correlation (r = 0.55) with change in VRQOL, a strong correlation with change in GFI (r = 0.74) and excellent correlation with change in GRBAS (r = 0.90) [18].

Our study had some limitations. First, although the data were collected using a standardized protocol at set time points as a part of routine voice outcome registration, the study design was retrospective. This possibly led to more missing data than if the study had been prospective. We corrected for this where possible using a linear mixed model for analysis of change in pre- and post-trial VFI voice data. Additionally, there were missing data at the 12-month interval after the durable medialization procedure, mainly because nine patients were still not 12 months out from their operation. Second, the size of the patient group is a limitation. Although with 68 patients it is the largest series in this patient group to date, the isolated atrophy (n = 30) and atrophy with sulcus groups (n = 38) are still relatively small. A third limitation is that two different long-term procedures were used. It is still unclear which durable medialization procedure is the most beneficial for this patients group. We consider the current sample size too small to investigate the difference between the two procedures and this question was also beyond the scope of this study. Also, we did not investigate a possible difference for patients with atrophy versus atrophy with sulcus for the long-term procedure. Furthermore, the definition of a good responder in this study was based on the patient’s motivation to continue to a durable medialization procedure, which was in turn based on their subjective experience of the trial VFI. We recognize that there were five patients who initially opted for a durable procedure who had second thoughts and chose to cancel their procedure. As we had thorough discussions with each patient before consenting them for a long-term procedure, to make sure that the effect of the trial VFI was sufficient, and as we do not know the reason for their cancelation we have included them as good responders in analysis. Furthermore, a few patients with a good response did not opt to continue to a permanent procedure. Therefore, our estimation of good responders may be slightly over or under valued. We do not expect this deviation to be significant as in the group of poor responders the joint decision was always to refrain from a durable medialization procedure. Finally, we already mentioned our concerns about validity of the voice outcome parameters used and the timing of data collection. Further studies and consensus guidelines on the optimal voice outcome parameters for this patient group are warranted.