Glottal Gap As an Early Predictor for Permanent Laryngoplasty in Unilateral Vocal Fold Paralysis

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1 The Laryngoscope VC 2014 The American Laryngological, Rhinological and Otological Society, Inc. Glottal Gap As an Early Predictor for Permanent Laryngoplasty in Unilateral Vocal Fold Paralysis Tuan-Jen Fang, MD, FICS; Yu-Cheng Pei, MD, PhD; Hsueh-Yu Li, MD, FACS, FICS; Alice, M. K. Wong, MD; Hui-Chen Chiang, PhD Objectives/Hypothesis: To assess the possible predictive factors for permanent laryngoplasty (PL) in patients with acute unilateral vocal fold paralysis (UVFP), and to assess the effects of early vocal cord hyaluronic acid injection. Study Design: Prospective cohort study. Methods: Patients diagnosed with UVFP within the previous 6 months were enrolled. Initial and follow-up videolaryngostroboscopy, voice laboratory analysis, laryngeal electromyography, and Voice Outcome Survey were performed. Results: Fifty newly diagnosed UVFP patients were recruited. Eight were excluded after 12 months of follow-up and data for 42 patients were analyzed. In patients treated conservatively, the glottal gap was measured on presentation. Normalized glottal gap area (NGGA) was the only predictor of PL (P ) according to multivariate logistic regression analysis. A cutoff value of 7.36 resulted in sensitivity of 85.7% and specificity of 80.0% for predicting future PL. The PL rate was significantly higher in patients with an initial NGGA > 7.36 compared with (6/9 vs. 1/13; v ; P ). Among patients with an initial NGGA > 7.36, those who accepted early hyaluronic acid injection had a significantly lower rate of PL (1/11 vs. 6/9; v ; P ) and better social and emotional role functioning at follow-up. Conclusions: The glottal gap on presentation is a robust early predictor of PL. Early, office-based hyaluronic acid intracordal injection can reduce the need for PL in patients with a large NGGA. Key Words: Unilateral vocal fold paralysis, hyaluronic acid, injection laryngoplasty, glottal gap, Voice Outcome Survey. Level of Evidence: 4. Laryngoscope, 124: , 2014 INTRODUCTION Vocal function may change with time in patients with acute unilateral vocal fold paralysis (UVFP). Irrespective of the restoration of vocal fold motion, the voice and related quality of life generally improve spontaneously in most patients 1 ; therefore, most laryngologists prefer to postpone permanent laryngoplasty (PL) until vocal function stabilization. However, it is hard to predict which patients will regain adequate voice and which patients are at greater risk of requiring PL. The ability to identify patients at higher risk of PL could influence From the Department of Otolaryngology (T-J.F., H-Y.L.), the Department of Physical Medicine and Rehabilitation (Y-C.P., A.M.K.W.), Chang Gung Memorial Hospital at Taipei, Taipei; the Graduate School of Management, Ming Chung University (H-C.C.), Taipei; and the School of Medicine, Chang Gung University (T-J.F., Y-C.P., H-Y.L., A.M.K.W.), Taoyuan, Taiwan, Republic of China. Editor s Note: This Manuscript was accepted for publication March 24, Presented at the annual meeting of the American Academy of Otolaryngology Head and Neck Surgery, Vancouver, BC, Canada, from September 29 to October 2, The research was supported by a National Science Council Grant (NSC B , NSC B ) and Chang Gung Medical Foundation Grant (CMRPG 3B1031). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Tuan-Jen Fang, MD, FICS, No. 5 Fushing St., Taoyuan 333, Taiwan. fang3109@adm.cgmh.org.tw DOI: /lary the principles of management and potentially improve patient quality of life. Injection laryngoplasty was reportedly performed on awake patients several decades ago and was then moved to the operating room in line with advancements in general anesthesia. Since the development of the distal-chip laryngoscope, it is now feasible for some laryngeal interventions to be performed on awake patients in the office; injection laryngoplasty was one of the first procedures to be moved back into an office setting. 2 Office-based intracordal injection with temporary agents such as hyaluronic acid has now become a regular daily practice in our clinic. Friedman 3 found that the rate of permanent medicalization thyroplasty could be reduced by early intracordal injection compared with late intracordal injection. Another retrospective study reported a higher incidence of PL in patients without temporary agent injection. 4 However, the mechanism whereby the temporary agent intracordal injection impacts on PL and which patients can be spared PL after the procedure remain unclear. Based on the current evidence, it is not possible to conclude that all patients with acute UVFP patients would derive long-term benefit from this procedure. In this prospective cohort study, we investigated the natural course of acute UVFP in patients with a known cause of recurrent laryngeal nerve injury. Patients were either treated with the conventional wait-and-see followup policy or were administered early intracordal injection. The primary aim of the study was to identify early 2125

2 predictors of PL in patients following the conventional observation policy and to assess the impact of officebased early injection on PL. MATERIALS AND METHODS This prospective cohort study was approved by the ethics committee and the institutional review board at Chang Gung Medical Foundation. Written informed consent was obtained from each participant prior to recruitment. Patients with a diagnosis of acute UVFP (for <6 months) were invited to join the project between July 2011 and September The diagnosis of UVFP was based on the results of laryngoscopy and quantitative laryngeal electromyography (Q- LEMG). The technique of QLEMG has been described in our previous report. 5 Neuropathy was confirmed as denervation by laryngeal EMG examination. An abnormal LEMG was defined as the existence of spontaneous activities (such as fibrillation, positive sharp wave, and complex repetitive discharge), > 30% polyphasia, or decreased interference pattern (reduced, discrete, or no interference pattern). On presentation, patients had undergone assessments including Q-LEMG, voice laboratory analysis, videolaryngostroboscopy, and disease-specific quality-of-life questionnaires (Chinese version of Voice Outcome Survey [CVOS]). They were randomized into two groups. One group received conventional conservative management (CM), while the other group received early injection (EI) of hyaluronic acid (Restylane; Q-Med AB, Uppsala, Sweden) within 6 months from nerve injury. All patients received a second assessment at 12 months postinjury. The decision of whether or not to perform PL was made at their last visit (at least 12 months from nerve injury). In patients with early vocal fold injection, the decision of whether to conduct PL was made a minimum of 6 months after temporary vocal fold injection to reduce the confounding effect given that the agent was expected to be resorbed during the interval. The definition of PL used in this study was a surgical procedure intended to provide long-term correction of patient symptoms. The options in our hospital included transcervical medicalization thyroplasty with silastic blocks, arytenoid adduction, and autologous fat intracordal injection. The suggestion of PL was usually initiated by the patient, but the final decision was based on discussion and agreement between the patient and the surgeon (T.J.F.). Multiple factors were taken into consideration such as age, general health, risk of anesthesia, vocal demand, and present vocal/swallowing status. The related quality of life and possibility of recovery from PL were also taken into account. The relationships between demographic data, Q- LEMG, voice analysis, glottal gap, CVOS, and final therapy (i.e., PL or no PL) were analyzed in patients following the conventional observational watch-and-wait policy to identify predictors of PL. The identified predictors were then validated in the other group that received early intracordal hyaluronic acid (Restylane) injection. The influences of temporary injection on PL were also evaluated. Voice Laboratory Analysis Patients were asked to keep a constant mouth-tomicrophone distance of 10 cm and 45 off-axis positioning. Voice samples were captured in a sound-insulated room using a unidirectional dynamic microphone (Shure SM48; Shure Brothers Inc., Agua Prieta, Mexico). Each subject was asked to read a standard passage and sustained vowel at a conversational pitch and loudness. All voice inputs were recorded and sampled using a voice-analysis computer program (Computerized Speech Lab, model 4300B, version 5.05; Kay Elemetrics Corp., Lincoln Park, NJ) at a sampling rate of 25.6 khz and with 16-bit quantization. Fundamental frequency, jitter (perturbation of frequency), shimmer (perturbation of amplitude), and harmonic-to-noise ratio (HN) were tabulated from the recorded sample data. The maximal phonation time represented the interval of time that patients could sustain a vowel /a/. The S/Z ratio was the ratio of the duration of a /s/ to that of a /z/ sound, which characterized vocal cord control. The ideal value was close to 1. Measurement of Laryngeal Configuration An image was captured during the videolaryngoscopy examination while the patient vocalized /eee/ at modal pitch and regular loudness. The image of the narrowest glottal gap from several phonatory cycles was used in the calculations. The normalized glottal gap area (NGGA) was analyzed using imageprocessing computer software (Image J 1.44p, National Institutes of Health) using the method proposed by Omori et al. 6 The traced glottal gap was calculated and expressed in square pixels. Membranous vocal-fold length was measured from the point of the anterior commissure to the point of the tip of the vocal process and was expressed in linear pixels. The NGGA was computed using the following equation: NGGA 5 (narrowest glottal-gap area/membranous vocal fold length 2 ) units UVFP-Related Health: Voice Outcome Survey The VOS (Voice Outcome Survey) originally developed by Gliklich et al. 7 comprises a five-item survey that evaluates the physical and social problems associated with UVFP on a Likert scale. It was translated into Mandarin Chinese following a standard survey-validation process by the present research team. 8 The survey items and total scores were normalized on a 0 (worst) to 100 (best) scale based on published algorithms. Intracordal Hyaluronan Gel Injection Patients in the early injection group received intracordal hyaluronic acid (Restylane) injections within 6 months of their initial symptoms. Before injection, they were anesthetized with nasal 2% lidocaine with neosynephrine 1:100,000 spray. Lidocaine 10% was also sprayed onto the mucosa of the oral cavity and oropharynx. Patients were seated upright with their head extended in an examination chair. A distal-chip laryngoscope (laryngoscope ENF type V2; platform EVIS Exera II; Olympus Optical Co, Ltd, Tokyo, Japan) was passed transnasally by an experienced assistant and the glottis was viewed on the monitor. The hyaluronan gel (Restylane) was then injected into the vocal fold submucosally through the cricothyroid membrane until the glottal gap was completely closed when voicing. Statistical Analysis All study data were stored and analyzed using PASW statistics 18 (SPSS, Inc., Chicago, IL). Differences between the two groups were compared using Student s t tests for parametric data and Mann-Whitney U tests for nonparametric data. Differences in frequency distributions between groups were assessed using v 2 tests. The point-biserial correlation was used to evaluate the relationship between the measurements and PL. Furthermore, a stepwise multivariate logistic regression analysis was applied to identify significant independent variables. The variables were further analyzed by receiver operating characteristic (ROC) curve analysis to evaluate the predictor value 2126

3 TABLE I. Patient Demographics. Study Cohort (n 5 42) EI (n 5 20) CM (n 5 22) P Gender (M/F) 21/21 12/8 9/ Age (mean 6 SD) Vocal demand.212 High vocally demanding Routine vocally demanding Etiology.500 Heart surgery Lung/mediastinum surgery Esophageal surgery Carotid body tumor Thyroid-/parathyroidectomy Skull base surgery Cervical spine surgery Others CM 5 conservative management; EI 5 early injection (of hyaluronic acid [Restylane]). and best cutoff point. The level of significance was defined as P < RESULTS Fifty dysphonic patients were diagnosed with acute UVFP during the study interval. At the end of follow-up, eight patients were excluded from the analysis: Three patients had incomplete data; three patients died of cancer metastasis; and two patients were lost to follow-up. Data for 42 patients were therefore analyzed in the present study. The first assessment was performed at a mean of months postsymptom occurrence, and regular follow-up visits were carried out at our clinic. After a median of 15 months follow-up (range months), nine of the 42 (21%) patients had undergone PL. Among the study cohort, 22 patients followed the conservative management observation policy (CM group), and the other 20 patients received early office-based hyaluronan injection within 6 months from nerve injury (EI group). All of the patients in the EI group tolerated the injection well, and most completed the procedure within 20 minutes. No complications were noted during the follow-up period. The average interval between symptom occurrence and treatment in patients in the EI group was months. None of these patients had received repeated injections by the end of the follow-up period. The vocal demand of each patient was recorded and the level of vocal demand was categorized as professional user, high vocal demand, or routine vocal demand. 9 There were no professional voice users such as singers, actors, or students majoring in vocal performances in this cohort. Patients employed as teachers, sales staff, office administrators, and secretaries were included in the high vocaldemand group. Patients who did not need to give frequent group presentations or to talk frequently in loud, noisy environments were assigned to the routine vocaldemand group. Patient demographics, including etiology and vocal demand, are listed in Table I. There were no significant differences between the groups. Patient demographics, voice laboratory analysis, glottal gap, and CVOS at initial presentation were analyzed in patients without temporary EI to identify early predictors of PL in patients in the CM group. The decision to perform PL was modestly correlated with patient age (r ; P ), initial presentation of NGGA (r ; P ), and CVOS (r ; P ) (Table I). Stepwise multivariate logistic regression analysis identified initial NGGA as the single independent factor (P ) associated with PL. Furthermore, ROC curve analysis to detect the reliability of the predicting value revealed that initial NGGA had an excellent discriminatory role (area under curve ; P ) (Fig. 1). When the NGGA cutoff point was set at 7.36, the sensitivity was 85.7%, and the specificity was 80.0%. In the CM group, the rate of PL was significantly higher in patients with initial NGGA > 7.36 than in those with initial NGGA 7.36 (6/9 vs. 1/13; v ; P ) (Table III). To evaluate the influence of initial NGGA on PL in the EI group, the study cohort was further divided based on the cutoff (7.36) of initial NGGA (Fig. 2). However, unlike the CM group, the rates of PL were similar in patients with initially large and small glottal gaps following temporary injection (1/11 vs. 1/9; v ; P ) (Table III). Although patients in the CM group had a higher rate of PL, the difference was not significant (7/22 vs. 2/ 20; v ; P ). Interestingly, in patients with a large glottal gap at initial presentation, PL was carried out significantly less frequently in the EI group than in the CM group (1/11 vs. 6/9; v ; P ). In contrast, in patients with a small glottal gap at initial presentation, the incidences of PL were similar in the EI and CM groups (1/9 vs. 1/13; v ; P ) (Table III). Although there were no significant differences between 2127

4 TABLE II. The Correlation Between Presenting Measurements and Permanent Laryngoplasty in Patients Following Conservative Management (n 5 22). r P Fig. 1. Receiver operating characteristic curve analysis of various cutoff values for initial normalized glottal gap area. The best identified cutoff value (arrow) was 7.36, corresponding to sensitivity 85.7% and specificity 80.0%. [Color figure can be viewed in the online issue, which is available at the EI and CM groups in terms of objective evaluations at follow-up, including acoustic, aerodynamic and QLEMG measurements, patients in either group with a large initial glottal gap who received EI had significantly better final quality-of-life measurements in the domains of social functioning (P ) and emotional role functioning (P ) (Table IV). DISCUSSION Dysphonia and dysphagia associated with UVFP can be managed in various ways. Several treatment options such as laryngeal framework surgery and autologous fat injection laryngoplasty have been reported to be effective in the long term. 10,11 However, identification of those patients who will ultimately require PL remains a challenge during the early postnerve injury stage. Fig. 2. The examples in measuring of normalized glottal gap area (NGGA) in two patients. The left inset illustrates the film captured form the closed-phase of phonation cycle from the videostroboscopy and the right inset the processing from software. The NGGA in the first patient is 4.50 (A, B) and categorized to the small gap group. The second patient with NGGA as was categorized into the large gap group (C, D). [Color figure can be viewed in the online issue, which is available at Age * Sex Vocal demand Normalized glottal gap area * Maximum phonation time (seconds) S/Z ratio Jitter (%) Shimmer (db) Harmonic to noise ratio (db) Peak frequency at lesion Peak frequency at healthy Cricothyroid muscle dysfunction CVOS total score * *P < CVOS 5 Chinese version of Voice Outcome Survey; TA- LCA 5 thyroarytenoid-lateral cricoarytenoid muscle complex. Woodson 12 suggested that motor nerve function may be restored after recurrent laryngeal nerve injuries; paralyzed vocal cord position may change with time; and laryngeal function may also recover to some degree. 12 The general consensus thus involves performing treatment at 9 to 12 months from symptom onset, after which time most paralyzed cords would not be expected to recover their function. 13 For patients with high vocal demand, EI laryngoplasty with a temporary agent can improve their quality of life before making a decision regarding PL. EI laryngoplasty with a temporary agent in an office-based setting has become more popular since the development of the distal-chip laryngoscopy-imaging system. Percutaneous injection laryngoplasty for acute UVFP can provide immediate improvements in swallowing and voice status. 14 The long-term impacts of intracordal injection with a temporary agent have been discussed in recent reports. 3,4,15 Friedman et al. 3 reported that 62% of patients who underwent injection within 6 months remained in adequate voice compared with none who received late injection. They concluded that early transoral injection laryngoplasty with hyaluronic acid decreased the need for transcervical medialization laryngoplasty in patients with UVFP. However, because the above retrospective study only included patients who received injection laryngoplasty as their primary treatment, and only three cases received late injection, a possible selection bias existed by excluding the possibility that the patients voices may have recovered spontaneously before 6 months. It is difficult to draw any firm conclusions regarding the real effects of EI laryngoplasty with hyaluronic acid. The decision to perform PL may be multifactorial and may depend on voice outcomes and its impact on quality of life. In our study, after adjusting for confounding effects, 2128

5 TABLE III. The Rate of Permanent Laryngoplasty in Study Cohort (n 5 42). EI (n 5 20) CM (n 5 22) v 2 P Value NGGA /9 1/ (n 5 22) NGGA > /11 6/ * (n 5 20) v P Value * *p < 0.05; CM 5 conservative management; EI 5 early injection (of hyaluronic acid [Restylane]); NGGA 5 normalized glottal gap area. the NGGA at presentation was significantly correlated with later PL in patients who were treated with the conventional follow-up policy. Patients with an initially large glottal gap had a higher incidence of PL at later follow-up. To the best of our knowledge, this is the first report to identify the size of the glottal gap at presentation as a predictor of PL. Although the glottal gap can be used as a predictor of PL, the rate of PL can be reduced by early hyaluronic acid (Restylane) injection. Among patients with a large glottal gap, over 60% of patients without early injection needed PL after 12 months of follow-up compared with one out of 11 patients who received office-based EI with hyaluronic acid (Restylane). Our results also indicated that social functioning and emotional role functioning were significantly better in patients who received early office-based hyaluronic acid (Restylane) injection. Although there was no significant difference in voice laboratory measurements between the EI and CM groups, the relatively better voice in the former group resulted in a better quality of life. Based on these results, we suggest that patients presenting with acute UVFP with a large glottal gap should be offered early intracordal injection to reduce the risk of future PL. This study had some limitations. First, although it has been suggested that hyaluronic acid (Restylane) should be resorbed within 1 to 3 months, 16 it is possible that residual injectable material may have persisted in the vocal cords to assist vocal fold closure, in which case PL may still have become necessary after complete degradation of the agent. Further long-term follow-up is required to investigate this possibility. Second, the number of cases in the present study was limited. Although the distribution of the study sample was expected to be similar to that of the general patient population, the cutoff point based on this small sample size may not be applicable to the wider population, and further studies with larger sample sizes are needed to validate the cutoff value in terms of glottal gap area. CONCLUSION Patients with acute UVFP and a wide glottal gap at presentation are more likely to require subsequent PL. TABLE IV. Initial and Follow-up Measurements in Patients With Initial NGGA > 7.36 (n 5 20). Initial Follow-up EI (n 5 11) CM (n 5 9) P EI (n 5 11) CM (n 5 9) P Value Normalized glottal gap area Maximum phonation time (seconds) * S/Z ratio Jitter (%) Shimmer (db) Harmonic to noise ratio (db) Peak frequency at lesion Peak frequency at healthy CVOS total score Quality-of-Life Measurements by Short Form-36 Physical functioning * Physical role functioning Emotional role functioning * Vitality Mental health Social functioning * Bodily pain General health *p < 0.05; CM 5 conservative management; EI 5 early injection (of hyaluronic acid [Restylane]); NGGA 5 normalized glottal gap area; TA- LCA 5 thyroarytenoid-lateral cricoarytenoid muscle complex. 2129

6 The need for PL can be reduced by early office-based hyaluronic acid (Restylane) injection. Early injection can improve social functioning and emotional role functioning in these patients. Acknowledgment The authors thank Hsiu-Feng Chung, MS, for her supporting in voice laboratory measurement and Miss Chia-Fen Chang for collecting data. Author Contributions: Conceived and designed the experiments (T-J.F., Y-C.P.), performed the experiments (T-J.F., Y-C.P.), contributed materials and analysis tools (T-J.F., Y-C.P., H-Y.L., A.M.K.W., H- C.C.), wrote the article (T-J.F.). BIBLIOGRAPHY 1. Young N, Smith L, Rosen C. Voice outcome following acute unilateral vocal fold paralysis. Ann Otol Rhinol Laryngol 2013;122: Blitzer, A. Brin, MF. Ramig, LO. Neurologic Disorders of the Larynx 2nd ed. New York, NY: Thieme; Friedman AD, Burns JA, Heaton JT, Zeitels SM. Early versus late injection medialization for unilateral vocal fold paralysis. Laryngoscope 2010; 120: Yung KC, Likhterov I, Courey MS. Effect of temporary vocal fold injection medialization on the rate of permanent medialization laryngoplasty in unilateral vocal fold paralysis patients. Laryngoscope 2011;21: Pei YC, Fang TJ, Li HY, Wong A. Cricothyroid muscle dysfunction impairs vocal fold vibration in unilateral vocal fold paralysis. Laryngoscope 2014;124: Omori K, Kacker A, Slavit DH, Blaugrund SM. Quantitative videostroboscopic measurement of glottal gap and vocal function: an analysis of thyroplasty type I. Ann Otol Rhinol Laryngol 1996;105: Gliklich RE, Glovsky RM, Montgomery WW. Validation of a voice outcome survey for unilateral vocal cord paralysis. Otolaryngol Head Neck Surg 1999;120: Fang TJ, Li HY, Gliklich RE, Chen YH, Wang PC. Assessment of Chinese version voice outcome survey in patients with unilateral vocal cord paralysis. Otolaryngol Head Neck Surg 2007;136: Behrman A, Sulica L, He T. Factors predicting patient perception of dysphonia caused by benign vocal fold lesions. Laryngoscope 2004;114: Netterville JL, Stone RE, Luken ES, Civantos FJ, Ossoff RH. Silastic medialization and arytenoid adduction: the Vanderbilt experience. a review of 116 phonosurgical procedures. Ann Otol Rhinol Laryngol 1993;102: Fang TJ, Lee LA, Wang CJ, Li HY, Chiang HC. Intracordal fat assessment by 3-dimensional imaging after autologous fat injection in patients with thyroidectomy-induced unilateral vocal cord paralysis. Surgery 2009; 146: Woodson GE. Spontaneous laryngeal reinnervation after recurrent laryngeal or vagus nerve injury. AnnOtolRhinolLayngol2007;116: Sulica L. The natural history of idiopathic unilateral vocal fold paralysis: evidence and problems. Laryngoscope 2008;118: Song PC, Sung CK, Franco RA Jr. Voice outcomes after endoscopic injection laryngoplasty with hyaluronic acid stabilized gel. Laryngoscope 2010;120(suppl 4):S Prendes BL, Yung KC, Likhterov I, Schneider SL, Al-Jurf SA, Courey MS. Long-term effects of injection laryngoplasty with a temporary agent on voice quality and vocal fold position. Laryngoscope 2012;122: Lau DP, Lee GA, Wong SM, et al. Injection laryngoplasty with hyaluronic acid for unilateral vocal cord paralysis. Randomized controlled trial comparing two different particle sizes. J Voice 2010;24: