Introduction
Laryngeal paralysis poses a distinct and diverse challenge that necessitates an individualised approach focused on the patient and a variety of treatment options tailored to both the type of laryngeal paralysis and the patient's individual factors. Laryngeal reinnervation is increasingly used as a surgical option for adults with unilateral vocal fold palsies and bilateral vocal fold palsies.Reference Misono and Merati1,Reference Fancello, Nouraei and Heathcote2 In unilateral vocal fold paralysis, non-selective reinnervation medially positions the affected vocal fold by restoring muscle tone and bulk, which improves phonation. This approach commonly involves direct anastomosis of the ansa cervicalis to the distal stump of the recurrent laryngeal nerve (ansa-RLN). In patients with bilateral vocal fold paralysis, airway compromise is common because of the loss of vocal fold abduction and often necessitates a tracheostomy. Selective reinnervation aims to re-establish physiologic inspiratory abduction while maintaining phonation in patients with bilateral vocal fold paralysis. Laryngeal reinnervation has several advantages over other treatment options. Reinnervation can be performed immediately in patients with pre-existing palsy or intra-operative nerve transection. In addition, patient safety can be ensured with injection augmentations prior to the procedure, which preserves glottic competence until the effects of reinnervation become evident. Despite modifications to reinnervation techniques, studies have produced varying reports on the efficacy of different approaches. The aim of our study was to review systematically existing published studies to determine the effectiveness and suitable applications of different techniques.
Material and methods
The systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (‘PRISMA’) guidelines. The main research question was developed as follows: What are the outcomes of existing laryngeal reinnervation techniques for managing adults with unilateral vocal fold paralysis and bilateral vocal fold paralysis?
The search
A literature search was conducted on 10 October 2022 in the Embase and Medline databases. The search terms used were ‘laryngeal’, ‘vocal cord’, ‘vocal fold’, ‘vocal ligament’ and ‘reinnervate’. No date restrictions were applied. The search was limited to human studies only. The reference lists of the identified articles were screened for additional relevant studies (Appendices 1 and 2).
Eligibility criteria
The eligibility criteria were: primary research studies, studies that included data on the adult population, studies that investigated unilateral vocal fold paralysis or bilateral vocal fold paralysis and reinnervation techniques, studies that documented the outcomes of the reinnervation techniques for unilateral vocal fold paralysis or bilateral vocal fold paralysis, and studies that did not have duplicate patients or were not based on similar datasets.
The exclusion criteria were: absence of outcome parameters, description of only alternative techniques or novel techniques, review articles, studies not in English and animal or post-mortem studies.
Study selection and data extraction
All three authors were involved in the study selection and data extraction. Two authors (AO and EV) read the articles identified in full and independently assessed each study based on the exclusion criteria. No disagreement occurred between the authors regarding which studies met the inclusion criteria (Κ = 1.0). Data extraction was performed independently by two authors (AO and EV) on piloted forms. The qualitative synthesis and descriptive statistics extracted from the results were reported.
The data extracted were: patient age range, gender, type of palsy, aetiology of vocal fold palsy, design, level of evidence, intervention, supplemental interventions, outcome measure and parameters, duration of paralysis before reinnervation, length of follow up and time until first signs of reinnervation.
Outcomes
The outcome measures recorded from each study included subjective and objective parameters: visual, subjective perceptual, acoustic, aerodynamic or laryngeal electromyography. For bilateral vocal fold paralysis, spirometry and decannulation rates were assessed for improvement in voice and airway. Data included mean values, standard deviations, confidence intervals and/or p values when available. Generalised scales were utilised across studies and are reported in the results section.
Meta-analysis
Average values of the pre- and post-operative maximum phonation time were obtained through meta-analysis, with a 95 per cent confidence interval (CI). Calculations were made for articles with raw data. Meta-analysis was performed with a random-effects model and inverse variance weighting because of the high data heterogeneity. I 2 determined the proportion of variance. Statistical heterogeneity was assessed by prediction interval. The prediction interval was analysed to determine how much the effects varied.Reference IntHout, Ioannidis, Rovers and Goeman3 Statistical significance was held at p ≤ 0.05. RevMan v5.4 software (Cochrane) was used to calculate the maximum phonation time effect size between reinnervation techniques. Jasp v16.4 software (University of Amsterdam, the Netherlands) was used to calculate Egger's regression test.
Assessment of the level of evidence and quality
The studies were classified according to the type and level of evidence specified in the 2011 Oxford classification.Reference Howick, Chalmers, Glasziou, Greenhalgh, Heneghan and Liberati4 The quality of each study was assessed by determining a score from 0 (low quality) to 8 (high quality) using the following system: data collection purpose (1 indicates patient care or not stated, 2 indicates research purposes); sample selection (consecutive or not: 1 indicates none or not stated, 2 indicates consecutive); follow-up period of one year or more (1 indicates less than one year or not stated, 2 indicates one year or more), post-operative or follow-up data status (1 indicates lack of data not accounted for or not stated, 2 indicates accounted for).
Results
Study selection
The initial search revealed 801 articles. After removing duplicate articles, title/abstract and full-text screening, and adopting the selection criteria, 27 articles were eligible for inclusion in the systematic review. Of these, 10 were included in the meta-analysis for maximum phonation time (Figure 1).Reference Miyauchi, Inoue, Tomoda, Fukushima, Kihara and Higashiyama5–Reference Ab Rani, Azman, Ubaidah, Yunus, Sani and Baki14
Preferred Reporting Items for Systematic Review and Meta-Analyses (‘PRISMA’) diagram. SD = standard deviation; IV = intravenous; CI = confidence interval
Methodological quality
All but two studies, one case-controlReference Wang, Chen, Chen, Li, Li and Xia15 and one prospective cohort,Reference Candelo, Borsetto, Obholzer, Clarke, MatBaki and Birchall16 were case series. Only four studies used consecutive samples.Reference Smith, Roy and Stoddard8,Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17,Reference Lee, Milstein, Hicks, Akst and Esclamado18 All but five studies had a median follow-up period of at least 12 months after reinnervation.Reference Paniello6,Reference Chou, Su, Jeng, Hsu and Lu7,Reference Crumley19–Reference El-Kashlan, Carroll, Hogikyan, Chepeha, Kileny and Esclamado21 One study did not describe the surgical technique.Reference Buyukatalay, Brisebois, Sirin and Merati22
Population characteristics
Study sample sizes ranged from 2 to 237 patients, totalling 803 patients (66.5 per cent female) with a mean age of 49.2 years (range, 12–82 years) who underwent reinnervation (Table 1). The median duration of paralysis before reinnervation was 2.7 months (range, 1–366 months). The median follow-up period was 14 months (standard deviation (SD) = 1.53) and 534 out of 803 patients had pre- and post-operative data reported. However, the patient characteristics describe all 803 patients because it was not possible to differentiate the data within the studies. Thyroid cancer and/or surgery accounted for most unilateral and bilateral vocal fold palsies, 74.8 per cent (559 of 747 cases) and 69.6 per cent (39 of 56 cases), respectively (Tables 2 and 3). This was followed by idiopathic (6.2 per cent, 46 of 747 cases) for unilateral vocal fold paralysis and laryngeal trauma (21.4 per cent, 12 of 56 cases) for bilateral vocal fold paralysis. Three studies described selective reinnervation in bilateral vocal fold paralysis using different nerve combinations,Reference Li, Chen, Zheng, Chen, Zhu and Wang11,Reference Li, Zheng, Chen, Chen and Zhu13,Reference Baki, Clarke and Birchall23 one study reported both selective and non-selective reinnervation,Reference Candelo, Borsetto, Obholzer, Clarke, MatBaki and Birchall16 and the remaining studies explored non-selective reinnervation. Ansa-RLN anastomosis was performed in 511 patients, supplemented with cricothyroid reinnervation in 74 high vagal injuries.Reference Miyauchi, Inoue, Tomoda, Fukushima, Kihara and Higashiyama5,Reference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17,Reference El-Kashlan, Carroll, Hogikyan, Chepeha, Kileny and Esclamado21 Seven studies reported two techniques with shared demographics.Reference Miyauchi, Inoue, Tomoda, Fukushima, Kihara and Higashiyama5,Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Candelo, Borsetto, Obholzer, Clarke, MatBaki and Birchall16,Reference Buyukatalay, Brisebois, Sirin and Merati22,Reference Maronian, Robinson, Waugh and Hillel24,Reference Mansor, Azman, Remli, Yunus and Baki25 Eleven studies involved supplementation with injection, using Permacol, AlloDerm or Gelfoam.Reference Smith, Roy and Stoddard8,Reference Candelo, Borsetto, Obholzer, Clarke, MatBaki and Birchall16–Reference Buyukatalay, Brisebois, Sirin and Merati22,Reference Maronian, Robinson, Waugh and Hillel24–Reference Olson, Goding and Michael26
Study characteristics
Primary RLN = primary recurrent laryngeal nerve anastomosis; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; Injection = injection laryngoplasty with Permacol, Alloderm or Gelfoam; SLR phrenic = SLR of bilateral posterior cricoarytenoid muscles with phrenic nerve; SLR left phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with left phrenic nerve; Medialisation = arytenoid medialisation; NMP = ansa cervicalis to thyroarytenoid neuromuscular pedicle; Vagus-RLN = vagus to recurrent laryngeal nerve anastomosis; FNG = free nerve grafting of supraclavicular, transverse cervical or ansa cervicalis to recurrent laryngeal nerve; SLR phrenic and hypoglossal = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and branch of hypoglossal nerve; SLR phrenic and ansa = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and ansa cervicalis; NMP + AA = ansa cervicalis to thyroarytenoid neuromuscular pedicle and arytenoid adduction; CT MNM = cricothyroid muscle-nerve-muscle neuromuscular pedicle; Implantation = ansa cervicalis to thyroarytenoid neural implantation; Hypoglossal-RLN = hypoglossal to recurrent laryngeal nerve anastomosis
Aetiologies of unilateral vocal fold paralysis patients who underwent non-selective laryngeal reinnervation
Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; CT MNM = cricothyroid muscle-nerve-muscle neuromuscular pedicle; NMP = ansa cervicalis to thyroarytenoid neuromuscular pedicle; Primary RLN = primary recurrent laryngeal nerve anastomosis; Vagus-RLN = vagus to recurrent laryngeal nerve anastomosis; Implantation = ansa cervicalis to thyroarytenoid neural implantation; Hypoglossal-RLN = hypoglossal to recurrent laryngeal nerve anastomosis; FNG = free nerve grafting of supraclavicular, transverse cervical or ansa cervicalis to recurrent laryngeal nerve
Aetiologies of bilateral vocal fold paralysis patients who underwent selective laryngeal reinnervation
SLR phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic nerve; SLR phrenic and ansa = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and ansa cervicalis; SLR phrenic and hypoglossal = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and branch of the hypoglossal nerve
Visual analysis
Glottic closure and vocal fold movement
Glottic closure was the most frequently described parameter. Data were collected using a scale from 0 to 3, where 0 indicated complete closure and 3 indicated severely incomplete closure. One study reported this using a different scale, with 0 indicating severely incomplete closure and 3 representing complete closure.Reference Lee, Park, Oh, Jung, Mok and Kim12 It was not possible to adjust this because of the lack of raw data. Nine of the 10 studies showed improvement in glottic closure/gap,Reference Chou, Su, Jeng, Hsu and Lu7,Reference Su, Hsu, Chen and Sheng9,Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Wang, Chen, Chen, Li, Li and Xia15,Reference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17,Reference Lee, Milstein, Hicks, Akst and Esclamado18,Reference Maronian, Robinson, Waugh and Hillel24,Reference Zheng, Li, Zhou, Cuan and Wen27 with p values in 5,Reference Chou, Su, Jeng, Hsu and Lu7,Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Wang, Chen, Chen, Li, Li and Xia15,Reference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17 4 of which demonstrated significant improvement (Table 4).Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Wang, Chen, Chen, Li, Li and Xia15,Reference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17,Reference Kodama, Sanuki, Kumai and Yumoto28 Three studies explored visual findings for two techniques collectively.Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Maronian, Robinson, Waugh and Hillel24 However, using the Mann–Whitney test, one study showed no significant differences in voice parameters between direct RLN and ansa-RLN reinnervation at baseline and 12 months, respectively.Reference Lee, Park, Oh, Jung, Mok and Kim12 One study showed no difference in glottal gap.Reference Li, Chen, Zheng, Chen, Zhu and Wang11 Only one study measured vocal fold movement and reported significant improvement in the functional abduction of both vocal folds.Reference Li, Chen, Zheng, Chen, Zhu and Wang11
Glottic closure
* Statistical significance noted;
† Confidence interval of 0.04 to 0.9 recorded;
‡ Supplementation with injection laryngoplasty: Permacol, micronised AlloDerm or Gelfoam;
** Supplementation with medialisation thyroplasty;
§ Pre-operative value is baseline probability, post-operative value is odds ratio.
SD = standard deviation; Primary RLN = primary recurrent laryngeal nerve anastomosis; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; CT MNM = cricothyroid muscle-nerve-muscle neuromuscular pedicle; NMP = ansa cervicalis to thyroarytenoid neuromuscular pedicle; Implantation = ansa cervicalis to thyroarytenoid neural implantation; SLR phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic nerve; SLR left phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with left phrenic nerve
Mucosal wave, true vocal fold edge and true vocal fold position
Data were collected using a scale from 0 to 3 (0, absent mucosal wave; 3, intact mucosal wave), except for one study in which the scale was used in reverse.Reference Crumley19 Three studies showed an improvement in the mucosal wave,Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Crumley19 with two demonstrating significanceReference Sanuki, Yumoto, Minoda and Kodama10,Reference Lee, Park, Oh, Jung, Mok and Kim12 (Table 5). One study showed no difference.Reference Baki, Clarke and Birchall23 True vocal fold edge was measured using a scale from 0 to 3 (0, straight; 1, mildly bowing; 2, moderately bowing; 3, severely bowing). Three studies recorded improved vocal fold edge,Reference Wang, Chen, Chen, Li, Li and Xia15,Reference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17,Reference Lee, Milstein, Hicks, Akst and Esclamado18 with two showing significance.Reference Wang, Chen, Chen, Li, Li and Xia15,Reference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17 No difference in vocal fold edge was found for bilateral vocal fold paralysis.Reference Li, Chen, Zheng, Chen, Zhu and Wang11 The true vocal fold position scale was 0 (midline) and 3 (lateral), with heterogeneous findings. One study showed significant improvement in vocal fold positionReference Wang, Chen, Chen, Li, Li and Xia15 and another reported an insignificant improvement.Reference Su, Hsu, Chen and Sheng9 Vocal fold position was worse in two studies,Reference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17,Reference Lee, Milstein, Hicks, Akst and Esclamado18 while another showed no difference.Reference Maronian, Robinson, Waugh and Hillel24
Vocal fold movement
* Statistical significance noted;
† Supplementation with injection laryngoplasty: Permacol, micronised AlloDerm or Gelfoam;
‡ Pre-operative value is baseline probability, post-operative value is the odds ratio;
** Confidence interval of 0.24 to 1.36 recorded.
SD = standard deviation; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; Primary RLN = primary recurrent laryngeal nerve anastomosis; CT MNM = cricothyroid muscle-nerve-muscle neuromuscular pedicle; SLR phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic nerve; NMP = ansa cervicalis to thyroarytenoid neuromuscular pedicle; Implantation = ansa cervicalis to thyroarytenoid neural implantation
Supraglottic effort and vertical height difference
Two studies recorded supraglottic effort and vertical height (Table 5).Reference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17,Reference Lee, Milstein, Hicks, Akst and Esclamado18 Both showed improvement in effort and an insignificant difference in height. The supraglottic effort scale ranged from 0 (normal) to 3 (severe effort). For vertical height, a scale from 0 (no change) to 1 (height difference) was used.
Perceptual analysis
The Overall Grade, Roughness, Breathiness, Asthenia and Strain rating scale and the Consensus Auditory-Perceptual Evaluation of Voice scale were used to measure severity, roughness, breathiness and strain. Apart from one study that used a scale ranging from 0 to 120 and was adjusted to a scale of 0 to 3,Reference Olson, Goding and Michael26 the Overall Grade, Roughness, Breathiness, Asthenia and Strain scores ranged from 0 (normal) to 3 (severe dysphonia). Three studiesReference Chou, Su, Jeng, Hsu and Lu7,Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Li, Zheng, Chen, Chen and Zhu13 showed significant improvement in the Overall Grade, Roughness, Breathiness, Asthenia and Strain score. Six studiesReference Chou, Su, Jeng, Hsu and Lu7,Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Li, Zheng, Chen, Chen and Zhu13,Reference Baki, Clarke and Birchall23,Reference Maronian, Robinson, Waugh and Hillel24,Reference Olson, Goding and Michael26 showed improvements in overall grade, five studiesReference Chou, Su, Jeng, Hsu and Lu7,Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Baki, Clarke and Birchall23,Reference Maronian, Robinson, Waugh and Hillel24,Reference Olson, Goding and Michael26 in roughness and breathiness, and in three studies,Reference Chou, Su, Jeng, Hsu and Lu7,Reference Maronian, Robinson, Waugh and Hillel24,Reference Olson, Goding and Michael26 asthenia and strain demonstrated improvements (Table 6). Two earlier studiesReference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17,Reference Lee, Milstein, Hicks, Akst and Esclamado18 used the Consensus Auditory-Perceptual Evaluation of Voice scale and demonstrated an improvement in all the categories (Table 7) on a scale from 0 (normal) to 100 (severe dysphonia).
Grade, Roughness, Breathiness, Asthenia, Strain scale analysis
* Statistical significance noted;
† Supplementation with injection laryngoplasty: Permacol, micronised AlloDerm or Gelfoam.
SD = standard deviation; Primary RLN = primary recurrent laryngeal nerve anastomosis; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; NMP = ansa cervicalis to thyroarytenoid neuromuscular pedicle; SLR phrenic and ansa = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and ansa cervicalis; SLR phrenic and hypoglossal = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and branch of hypoglossal nerve
Consensus Auditory-Perceptual Evaluation of Voice scale analysis
* Statistical significance noted;
† Supplementation with injection laryngoplasty: Permacol, micronised AlloDerm or Gelfoam.
SD = standard deviation; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; CT MNM = cricothyroid muscle-nerve-muscle neuromuscular pedicle
The Eating Assessment Tool – 10 was used to assess dysphagia. Two studies showed improvements following reinnervation (Table 8).Reference Buyukatalay, Brisebois, Sirin and Merati22,Reference Baki, Clarke and Birchall23
EAT-10 score
Voice-related quality of life was assessed using the Voice Handicap Index questionnaire in three studies,Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Ab Rani, Azman, Ubaidah, Yunus, Sani and Baki14,Reference Baki, Clarke and Birchall23 all of which showed improvements.
* Supplementation with injection laryngoplasty: Permacol, micronised AlloDerm or Gelfoam.
SLR phrenic and ansa = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and ansa cervicalis; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; NMP = ansa cervicalis to thyroarytenoid neuromuscular pedicle
Subjective assessment
Three studiesReference Lee, Park, Oh, Jung, Mok and Kim12,Reference Ab Rani, Azman, Ubaidah, Yunus, Sani and Baki14,Reference Mansor, Azman, Remli, Yunus and Baki23 reported improvements in the Voice Handicap Index (Table 9). One studyReference Lee, Park, Oh, Jung, Mok and Kim12 reported findings for two different techniques – Primary RLN and Ansa-RLN anastomosis. One studyReference Ab Rani, Azman, Ubaidah, Yunus, Sani and Baki14 was statistically significant.
Voice Handicap Index
* Statistical significance noted.
SD = standard deviation; Primary RLN = primary recurrent laryngeal nerve anastomosis; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; SLR phrenic and ansa = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and ansa cervicalis
Acoustic analysis
The mean noise-to-harmonics ratio and measures of phonation stability, namely jitter and shimmer, were reported as percentages. Statistical analysis using the Mann–Whitney test showed no significant differences in voice parameters between primary RLN and ansa-RLN at baseline and 12 months after reinnervation.Reference Lee, Park, Oh, Jung, Mok and Kim12 Four studies demonstrated improvement of noise-to-harmonics ratio p values (Table 10),Reference Li, Chen, Zheng, Chen, Zhu and Wang11–Reference Ab Rani, Azman, Ubaidah, Yunus, Sani and Baki14 and two studies were statistically significant.Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Li, Zheng, Chen, Chen and Zhu13 For jitter and shimmer, nine studies demonstrated an improvement (Table 11).Reference Paniello6,Reference Su, Hsu, Chen and Sheng9,Reference Li, Chen, Zheng, Chen, Zhu and Wang11–Reference Ab Rani, Azman, Ubaidah, Yunus, Sani and Baki14,Reference El-Kashlan, Carroll, Hogikyan, Chepeha, Kileny and Esclamado21,Reference Baki, Clarke and Birchall23,Reference Zheng, Li, Zhou, Cuan and Wen27 Four studies were statistically significant.Reference Su, Hsu, Chen and Sheng9,Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Li, Zheng, Chen, Chen and Zhu13,Reference Zheng, Li, Zhou, Cuan and Wen27
Noise-to-Harmonics ratio
* Statistical significance noted.
SD = standard deviation; Primary RLN = primary recurrent laryngeal nerve anastomosis; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; SLR left phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with left phrenic nerve; SLR phrenic and hypoglossal = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and branch of hypoglossal nerve
Jitter and shimmer
* Statistical significance noted;
† Injection medialisation supplementation with Permacol, AlloDerm or Gelfoam.
SD = standard deviation; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; CT MNM = cricothyroid muscle-nerve-muscle neuromuscular pedicle; Implantation = ansa cervicalis to thyroarytenoid neural implantation; Hypoglossal-RLN = hypoglossal to recurrent laryngeal nerve anastomosis; SLR phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic nerve; SLR left phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with left phrenic nerve; Primary RLN = primary recurrent laryngeal nerve anastomosis; SLR phrenic and ansa = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and ansa cervicalis; SLR phrenic and hypoglossal = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and branch of hypoglossal nerve
Aerodynamic analysis
All 10 studies measuring maximum phonation time values showed improvements (Table 12).Reference Miyauchi, Inoue, Tomoda, Fukushima, Kihara and Higashiyama5–Reference Ab Rani, Azman, Ubaidah, Yunus, Sani and Baki14 Four studies demonstrated statistical significance.Reference Chou, Su, Jeng, Hsu and Lu7,Reference Su, Hsu, Chen and Sheng9,Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Li, Zheng, Chen, Chen and Zhu13 The mean airflow rate from one study showed a significant improvement (Table 13).Reference Sanuki, Yumoto, Minoda and Kodama10
Maximum phonation time
* Statistical significance noted;
† Injection medialisation supplementation with Permacol, AlloDerm or Gelfoam.
MPT = maximum phonation time; SD = standard deviation; Primary RLN = primary recurrent laryngeal nerve anastomosis; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; Implantation = ansa cervicalis to thyroarytenoid neural implantation; Hypoglossal-RLN = hypoglossal to recurrent laryngeal nerve anastomosis; SLR phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic nerve; SLR left phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with left phrenic nerve; SLR phrenic and ansa = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and ansa cervicalis; SLR phrenic and hypoglossal = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and branch of hypoglossal nerve
Mean airflow rate
* Statistical significance noted. SD = standard deviation; Primary RLN = primary recurrent laryngeal nerve anastomosis; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis
Electromyography
A scale ranging from 0 (full interference) and 3 (no motor unit potential) was used to measure electromyography. Two studies showed a significant improvement in thyroarytenoid muscles,Reference Wang, Chen, Chen, Li, Li and Xia15,Reference Wang, Liu, Zhang, Li, Chen and Gao29 while another showed a significant improvement in bilateral posterior cricoarytenoids and no difference in thyroarytenoids (Table 14).Reference Li, Chen, Zheng, Chen, Zhu and Wang11 In one study, full interference of bilateral posterior cricoarytenoid during inspiration and bilateral thyroarytenoid during phonation were recorded, but moderate electric potentials were observed in the left interarytenoid muscle.Reference Li, Zheng, Chen, Chen and Zhu13
Electromyographic data
SD = standard deviation; Ansa-RLN = ansa cervicalis to recurrent laryngeal nerve anastomosis; TA = thyroarytenoid; PCA = posterior cricoarytenoid; SLR phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic nerve
Pulmonary function tests and decannulation rate
Two studies measuring pulmonary function parameters showed recovery to normal reference values within 12 months after reinnervation, except for PImax (Table 15).Reference Li, Chen, Zheng, Chen, Zhu and Wang11,Reference Li, Zheng, Chen, Chen and Zhu13 High decannulation rates were observed in both studies (Table 16). No significant pulmonary function morbidity with SLR was observed in one study.Reference Baki, Clarke and Birchall23
Pulmonary function parameters
SD = standard deviation; SLR phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic nerve; SLR phrenic and hypoglossal = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and branch of hypoglossal nerve; VC = vital capacity; FVC = forced vital capacity; FEV1 = forced expiratory volume in 1 second; PImax = maximal inspiratory pressure
Decannulation rate
SLR phrenic = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic nerve; SLR phrenic and hypoglossal = selective laryngeal reinnervation of bilateral posterior cricoarytenoid muscles with phrenic and branch of hypoglossal nerve
Meta-analysis
Ten studies describing 12 techniques were subjected to meta-analysis to assess pre- and post-operative maximum phonation time,Reference Miyauchi, Inoue, Tomoda, Fukushima, Kihara and Higashiyama5–Reference Ab Rani, Azman, Ubaidah, Yunus, Sani and Baki14 with 184 patients (Figure 2). Two studies were incalculable as a result of a lack of SD data.Reference Paniello6,Reference Smith, Roy and Stoddard8 Two studies described selective laryngeal reinnervation while all the others described non-selective laryngeal reinnervation.Reference Li, Chen, Zheng, Chen, Zhu and Wang11,Reference Li, Zheng, Chen, Chen and Zhu13 There was a statistically significant increase of 1.32 seconds (95 per cent CI 0.79–1.85). Two studiesReference Li, Chen, Zheng, Chen, Zhu and Wang11,Reference Ab Rani, Azman, Ubaidah, Yunus, Sani and Baki14 were outside the 95 per cent CI (Appendix 2), suggesting the presence of publication bias. I 2 is equal to 73 per cent with a prediction interval between –0.35 and 2.99 (Figure 2).
Forest plot: a comparison of reinnervation studies that assessed the maximum phonation time values
Discussion
The existing literature on adult reinnervation techniques mainly consists of case series, and only a few case-control studies have explored reinnervation for unilateral vocal fold paralysis, with a recent randomised, controlled trial (RCT) comparing reinnervation with medialisation for unilateral vocal fold paralysis.Reference Lee, Park, Oh, Jung, Mok and Kim12 The studies investigating bilateral palsies are limited to case series, indicating that reinnervation techniques are mostly supported by level 4 evidence. Our objective was to systematically review the literature on adult reinnervation techniques to assess their effectiveness.
• Significant improvements in multidimensional voice outcomes were observed in adults after reinnervation for both unilateral and bilateral palsies, as well as decannulation rates for bilateral vocal fold paralysis
• Reinnervation of bilateral palsies is more complex and supported by limited evidence compared to unilateral palsies
• A meta-analysis of 10 reinnervation techniques involving 184 patients demonstrated favourable outcomes in terms of maximum phonation time
• The studies included in the review were highly heterogeneous, mostly consisting of small case series without control groups
• Future studies should include larger sample sizes, differentiate between reinnervation techniques, separate unilateral and bilateral palsies, and incorporate control groups to provide more robust evidence
The distribution of true effects (Figure 3) shows that reinnervation primarily improves the maximum phonation time for unilateral and bilateral palsies. However, two studies were not statistically significant,Reference Li, Chen, Zheng, Chen, Zhu and Wang11,Reference Baki, Clarke and Birchall23 and another showed no significant difference.Reference Ab Rani, Azman, Ubaidah, Yunus, Sani and Baki14 For example, in one study a patient had a lack of vocal fold abduction, which may have been partly attributed to old age, leading to less vigorous axonal regrowth and an increased risk of general anaesthesia associated with elderly patients.Reference Li, Chen, Zheng, Chen, Zhu and Wang11 The inconsistency in results highlights the requirement for careful patient selection for reinnervation.
Distribution of true effects. d = standardised difference in means
Only two outliers are identified in the funnel plot (Appendix 3). When assessed visually, there is an asymmetrical pattern, with most studies scattered on the right side. This may be indicative of publication bias. In addition, this suggests the presence of a small-study effect. It is possible that the small subject case series included were only those with significant reinnervation effects, while unpublished studies with similar standard errors, but smaller and less significant reinnervation effects, were excluded.Reference Egger, Smith, Schneider and Minder30,Reference Sterne and Egger31
Other factors should be considered, such as selective reporting of outcomes and chance. For example, the operating surgeons may only report findings based on their experiences while the less favourable outcome parameters go unreported. This may have been the case in studies where raw data were unavailable. This can lead to an overestimation of the true reinnervation effects observed. Importantly, the funnel plot does not assess the existence of publication bias but instead provides a visual aid. Hence, statistical analysis with Egger's test was performed to further evaluate publication bias.Reference Harrer, Cuijpers, Furukawa and Ebert32
Egger's regression test detects publication bias in a meta-analysis by assessing the funnel plot for asymmetry. Because a p value of <0.05 was calculated (Figure 4), we can report the presence of publication bias. Importantly, the test only measures small study bias, which can include publication bias. The test also considers other features of small study bias, such as the differences in study designs.Reference Egger, Smith, Schneider and Minder30 By calculating Egger's test, we assume that the analysis consists of a sufficient number of studies and severe bias is absent, which is necessary for the test to have sufficient power. However, it is only applicable if a range of study sizes with a minimum of a medium-sized study are included.Reference Rothstein, Sutton and Borenstein33 One could therefore argue against its use because our studies are mostly limited to a small number of subjects. Another attempt was made to adjust for publication bias with the precision-effect test and precision-effect estimate with standard errors method. This is an approach aimed at small-study effects that adjusts for the correlation between effect sizes and standard errors.Reference Bartoš, Maier, Quintana and Wagenmakers34 We were unsuccessful in using this technique because of the inability to calculate the correlation for the effect size. Possible explanations include abnormal distribution of data, inadequate data and the presence of outliers.
Egger's test. sei = standard error of the intercept
The review showed improvements in voice and deglutition for unilateral vocal fold paralysis following reinnervation. Ansa-RLN anastomosis, the most studied approach, demonstrated significant improvement in glottic closure, mucosal wave, Eating Assessment Tool–10, Voice Handicap Index and the Consensus Auditory-Perceptual Evaluation of Voice scoring, jitter and shimmer, maximum phonation time, and laryngeal electromyography. Ansa-RLN was mostly associated with thyroid disease and/or surgery followed by idiopathic aetiology. To our knowledge, the largest study, published by Wang et al.,Reference Wang, Chen, Chen, Li, Li and Xia15 with improvements in voice quality, analysed 237 ansa-RLN anastomosis patients for unilateral vocal fold paralysis along with age- and gender-matched normal subjects. Ansa cervicalis to thyroarytenoid neuromuscular pedicle was the second most studied reinnervation technique. Vocal fold vibration, aerodynamic analysis and perceptual evaluation showed significant improvements. Laryngeal electromyography data for the neuromuscular pedicle technique was limited. One study showed positive outcomes when neuromuscular pedicle technique was combined with arytenoid adduction.Reference Kodama, Sanuki, Kumai and Yumoto28 The neuromuscular pedicle approach was more prevalent following aortic and mediastinal mass surgery, cerebrovascular accident, skull base tumours and neck trauma.
Primary RLN was the third most studied technique, and was almost exclusively reserved for thyroid cancer and/or surgical aetiology. The vagus-RLN anastomosis technique demonstrated an improvement in maximum phonation time and Overall Grade, Roughness, Breathiness, Asthenia and Strain score.Reference Yuan, Hou, Liao, Zheng, Wang and Wu35 Post-operative voice outcomes also improved when free nerve grafting was carried out.Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Yuan, Hou, Liao, Zheng, Wang and Wu35 A free nerve grafting study attributed voice improvements to the return of thyroarytenoid tone and bulk without providing any data on atrophy.Reference Sanuki, Yumoto, Minoda and Kodama10 However, only two studies recorded an improvement in the atrophy of the thyroarytenoid muscle so it was not possible to make a comparison.Reference Su, Hsu, Chen and Sheng9,Reference Maronian, Robinson, Waugh and Hillel24 One study performed hypoglossal-RLN anastomosis.Reference Paniello6 This could be possibly due to its association with high donor site morbidity.Reference Paniello6,Reference Manni36 Implantation of the ansa cervicalis into the thyroarytenoid was performed when the RLN could not be located, with improvements in 6 out of 10 patients.Reference Su, Hsu, Chen and Sheng9
Four articles reported outcomes following selective reinnervation with improvements in vocal fold abduction while maintaining phonation.Reference Li, Chen, Zheng, Chen, Zhu and Wang11,Reference Li, Zheng, Chen, Chen and Zhu13,Reference Candelo, Borsetto, Obholzer, Clarke, MatBaki and Birchall16,Reference Baki, Clarke and Birchall23 The phrenic nerve was used either solely or in combination with another (ansa cervicalis or hypoglossal nerve), with favourable results in vocal fold abduction, Overall Grade, Roughness, Breathiness, Asthenia and Strain rating score, laryngeal electromyography, pulmonary function tests and decannulation rates. For thyroid surgery or neck trauma, the left phrenic nerve was shown to improve several vocal function parameters and decannulation rates in 39 out of 44 patients without any posterior cricoarytenoid synkinesis. However, abnormal spontaneous activity was noted in the thyroarytenoid of the four failed patients.Reference Li, Chen, Zheng, Chen, Zhu and Wang11
Voice and swallowing improvements were demonstrated without any significant vocal fold abduction in vagal paragangliomas using the phrenic nerve and ansa cervicalis.Reference Baki, Clarke and Birchall23 The phrenic and a branch of hypoglossal nerve showed significant improvement in all parameters measured for six out of seven patients, with moderate electric potentials of the left interarytenoid in the failed patient.Reference Li, Zheng, Chen, Chen and Zhu13 The failure of vocal fold movement was likely due to moderate aberrant reinnervation. Importantly, this study showed mild aberrant reinnervation did not affect recovery of vocal fold movement. Another study using the phrenic nerve for selective reinnervation failed to produce any vocal fold abduction in three patients.Reference Candelo, Borsetto, Obholzer, Clarke, MatBaki and Birchall16
Reinnervation of bilateral palsies is far more complex than that of unilateral ones, with limited evidence. The existing literature involves a small group of surgeons who have made further improvements to their techniques. For example, in 2013, Li et al.Reference Li, Chen, Zheng, Chen, Zhu and Wang11 explored the reinnervation of bilateral posterior cricoarytenoid using the left phrenic nerve and in 2019Reference Li, Zheng, Chen, Chen and Zhu13 anastomosed the phrenic-hypoglossal nerves. As a result, improvements in voice and swallowing function were observed less often for bilateral palsies. In addition, the complexity of selective reinnervation makes it more difficult for otolaryngologists to learn and undertake the techniques which pioneering surgeons such as Roger Crumley and Professor Marie have shown to be beneficial. Some experts have suggested that the developments made in selective reinnervation have potential for global dissemination.Reference Fancello, Nouraei and Heathcote2 Our review found many studies describing multidimensional voice outcome parameters, which will help support this suggestion. However, larger studies are required to improve the safety and feasibility of reinnervation. Unfortunately, it remains difficult to recruit subjects for a sufficiently powered RCT. A potential solution was identified from a feasibility RCT to include controls with multidimensional voice and swallowing outcomes.Reference Blackshaw, Carding, Jepson, Baki, Ambler and Schilder37
Significantly, non-selective reinnervation seeks to maintain effective glottic closure, thereby preserving voice quality, while selective reinnervation aims to restore normal inspiratory abduction. Consequently, the outcomes of these two techniques differ, suggesting the need to analyse them as distinct entities. Nonetheless, if studied separately, the lack of reliable primary data makes obtaining substantial findings unlikely. The present study serves the purpose of providing a valuable resource for otolaryngologists interested in this field and emphasises the need for well-designed prospective studies with proper controls.
Limitations
Several limitations were identified in the study. Firstly, significant heterogeneity existed between the studies, including patient age, type and duration of paralysis, follow-up time, supplemental medialisation, surgeon's experience, outcomes measured and type of reinnervation. For example, we cannot clearly determine the effect of reinnervation when it is supplemented with augmentation. However, many agree that the effects of vocal fold augmentation are temporary and largely determined by the material used, with Restylane lasting for 6 months, fat for 12 months and calcium hydroxyapatite for 18 months.Reference Lagier, Polle-Pelletier, Giovanni and Marie38–Reference Zeleník, Walderová, Kučová, Jančatová and Komínek41 As a result, the lack of consistency between studies makes it challenging to generalise findings. Secondly, some studies that investigated multiple reinnervation techniques did not differentiate outcomes for each. Three studies pooled pre- and post-operative data for ansa-RLN and primary RLN.Reference Miyauchi, Inoue, Tomoda, Fukushima, Kihara and Higashiyama5,Reference Sanuki, Yumoto, Minoda and Kodama10,Reference Lee, Park, Oh, Jung, Mok and Kim12 Two studies combined ansa-RLN and NMP data.Reference Buyukatalay, Brisebois, Sirin and Merati22,Reference Maronian, Robinson, Waugh and Hillel24 Furthermore, two studies pooled data for ansa-RLN and ansa-RLN + cricothyroid muscle-nerve-muscle neuromuscular pedicle.Reference Lee, Park, Oh, Jung, Mok and Kim12,Reference Lorenz, Esclamado, Teker, Strome, Scharpf and Hicks17 This makes it impossible to attribute findings to one technique. Thirdly, as is generally the case, the review is limited by the quality of studies. Only one studyReference Lee, Park, Oh, Jung, Mok and Kim12 fulfilled all criteria for quality checks. Other studies had weaknesses in follow-up periods, data collection purposes and incomplete data. In addition, certain studies did not provide raw data and were excluded from quantitative synthesis. The authors were contacted to provide this information, but no response was received at the time of writing this paper.
Conclusion
Based on the review of 803 adults, surgical reinnervation demonstrated improvements in both voice and swallowing for unilateral and bilateral palsies, with improvements in decannulation rates also observed for bilateral palsies. Our meta-analysis provides clinical evidence supporting the effectiveness of reinnervation. However, the lack of control groups in most studies prevented a clear determination of the true effect of reinnervation.
Despite significant advances in standardisation for measuring outcome parameters and reinnervation, our study identified several limitations, such as small sample sizes and highly heterogeneous studies, which limit the generalisability of our findings to the broader adult population. Although reinnervation techniques are considered safe and viable alternatives, particularly when other treatments have failed to address vocal fold palsies, larger studies with control groups and more precise recordings of each technique are necessary to accurately determine their true effects. This information will be critical in identifying the patients who would most benefit from these techniques and enabling global dissemination of improved reinnervation techniques.
Moreover, non-selective reinnervation aims to preserve glottic closure and voice quality, while selective reinnervation focuses on restoring inspiratory abduction. Analysing these techniques separately is necessary because of their differing outcomes, but the lack of reliable data makes it challenging to obtain meaningful results. Our paper provides a valuable resource for otolaryngologists and highlights the importance of well-designed prospective studies.
Acknowledgements
The authors thank the librarians at Imperial College London, UK for their contribution to the systematic review search, notably Rebecca Jones.
Competing interests
None declared
Appendix 1. Ovid search terms
Appendix 2. Embase search terms
Appendix 3. Funnel plot for meta-analysis of maximum phonation time
SE = standard error; SMD = standardised mean difference
