TrkA inhibitor promotes motor functional regeneration of recurrent laryngeal nerve by suppression of sensory nerve regeneration.

Recurrent laryngeal nerve (RLN) injury, in which hoarseness and dysphagia arise as a result of impaired vocal fold movement, is a serious complication. Misdirected regeneration is an issue for functional regeneration. In this study, we demonstrated the effect of TrkA inhibitors, which blocks the NGF-TrkA pathway that acts on the sensory/automatic nerves thus preventing misdirected regeneration among motor and sensory nerves, and thereby promoting the regeneration of motor neurons to achieve functional recovery. RLN axotomy rat models were used in this study, in which cut ends of the nerve were bridged with polyglycolic acid-collagen tube with and without TrkA inhibitor (TrkAi) infiltration. Our study revealed significant improvement in motor nerve fiber regeneration and function, in assessment of vocal fold movement, myelinated nerve regeneration, compound muscle action potential, and prevention of laryngeal muscle atrophy. Retrograde labeling demonstrated fewer labeled neurons in the vagus ganglion, which confirmed reduced misdirected regeneration among motor and sensory fibers, and a change in distribution of the labeled neurons in the nucleus ambiguus. Our study demonstrated that TrkAi have a strong potential for clinical application in the treatment of RLN injury.

Delayed Recurrent Laryngeal Nerve Palsy Following Anterior Cervical Discectomy and Fusion.

BACKGROUND: Vocal cord dysfunction resulting from recurrent laryngeal nerve palsy (RLNP) is a known complication following anterior cervical discectomy and fusion. RLNP occurs typically secondary to neurapraxia caused by intraoperative compression or traction on the nerve and less commonly from direct nerve injury intraoperatively in the setting of anterior cervical spine surgery. Patients with RLNP typically present with hoarseness immediately after surgery owing to unilateral vocal cord paralysis. In rare cases, there is late-onset, progressive development of RLNP that may potentially lead to permanent vocal cord paralysis or respiratory failure. CASE DESCRIPTION: A 75-year-old woman presented with myeloradiculopathy and chronic urinary incontinence. Imaging showed severe foraminal and central stenosis with T2 cord signal change. A C4-7 anterior cervical discectomy and fusion was successfully performed without immediate complications following surgery. The patient had a normal voice and was tolerating a regular diet well. On postoperative day 3, the patient developed new hoarseness and dysphagia. An otolaryngologist was consulted, and flexible nasolaryngoscopy showed left vocal cord paralysis consistent with left RLNP. The patient was treated with a course of steroids, and her hoarseness and dysphagia had resolved at the 6-month follow-up visit. CONCLUSIONS: To our knowledge, this is the first report of delayed RLNP in patients undergoing anterior cervical discectomy and fusion. This rare complication should be discussed during preoperative patient counseling. Previous literature indicates the underlying pathophysiology for delayed onset of RLNP may be small vessel ischemia, vasospasm, or viral resurgence that leads to recurrent laryngeal nerve dysfunction.

[Effect of cricothyroid and thyroarytenoid muscle botulinum toxin injection on patients with dyspnea caused by bilateral recurrent laryngeal nerve paresis].

Objective: To discuss the clinical effect of small dose of botulinum toxin injection in cricothyroid muscle and thyroarytenoid muscle on patients with incomplete bilateral recurrent laryngeal nerve paresis. Methods: Six patients were selected with Ⅰor Ⅱ or Ⅲ degree of dyspnea diagnosed as bilateral recurrent laryngeal nerve injury by laryngeal electromyography, and small dose of botulinum toxin injection was performed in cricothyroid muscle and thyroarytenoid muscle as a treatment. Degree of dyspnea was assessed one month before and after the treatment, and the stroboscopic laryngoscope results, acoustic parameters and CT image of the patients were collected in the 6 patients. The relevant parameters were also collected one month before and after treatment, including the degree of dyspnea, stroboscopic laryngoscope results, acoustic parameters and CT image of the patients. The angle between bilateral vocal cords in stroboscopy at full inspiratory was calculated, acoustic parameters (F0, jitter, shimmer) were analysed, and vocal length, width and the vocal region were measured. Then, the paired t test was performed for statistical analysis between before and after one month injection, the one way analysis of variance was performed among vocal parameters in CT image. Result: Botulinum toxin injection was successfully completed in the 6 patients, followed without any serious complications. The degree of dyspnea was alleviated to some extent after treatment in all 6 patients; the angle between bilateral vocal cords at the end of a deep inspiration was significantly increased (t=2.44, P<0.05) after the treatment. The changes of F0 and jitter between before and after treatment were not statistically significant (t=0.72, t=1.42, P>0.05). Shimmer was significantly decreased after treatment (t=2.61, P<0.05). Vocal fold length, width and vocal region increased with F0, there was a statistically significant difference between different F0 before injection, and there was no statistically significant difference between different F0 after injection. The follow-up time was respectively seven months, 1 year, 1 year, 18 months, 22 months and 2 years respectively. Conclusion: Small dose of botulinum toxin injection in bilateral cricothyroid muscles and thyroarytenoid muscles can relieve the dyspnea caused by bilateral vocal cords paresis to some extent, accompanied without serious complications, despite the sound quality was slightly worse.

Regenerative Effects of Basic Fibroblast Growth Factor on Restoration of Thyroarytenoid Muscle Atrophy Caused by Recurrent Laryngeal Nerve Transection.

OBJECTIVES: Vocal fold atrophy following unilateral vocal fold paralysis is caused by atrophy of the thyroarytenoid (TA) muscle and remains a challenge. Medialization procedures are popular treatment options; however, hoarseness often remains due to the reduction in mass or tension of the TA muscle. Therefore, in addition to medialization procedures, TA muscle reinnervation is desirable. In vivo studies have shown the potential for basic fibroblast growth factor (bFGF) to affect muscular and nerve regeneration. The present study aimed to examine the regenerative effects of bFGF on restoration of TA muscle atrophy caused by recurrent laryngeal nerve transection. STUDY DESIGN: Prospective animal experiments with controls. METHODS: TA muscle atrophy was induced by unilateral transection of the recurrent laryngeal nerve. One month after transection, different doses (200 ng, 100 ng, 10 ng) of bFGF in 50 µL were repeatedly injected into the TA muscle four times with an interval of 1 week between injections. Saline only was injected in the sham group. Larynges were harvested for histologic and immunohistochemical examination 4 weeks after the final injection. RESULTS: The cross-sectional TA muscle area was significantly larger in the bFGF-treated groups compared with the sham-treated groups. Immunohistochemistry indicated that bFGF significantly increases the number of neuromuscular junctions and satellite cells in the TA muscle. CONCLUSIONS: These results suggest that local application of bFGF to the TA muscle may improve TA muscle atrophy caused by recurrent laryngeal nerve paralysis. Furthermore, bFGF may have regenerative effects on both nerves and muscles.

Functional assessment of glottal insufficiency treated by hyaluronic acid injection: Retrospective 20-case series.

OBJECTIVES: The objectives of the present study were to describe hyaluronic acid injection to the vocal folds as treatment for glottal insufficiency, assess indications and report vocal results at 1 month and later than 6 months postoperatively. PATIENTS AND METHODS: A single-center retrospective study was performed for the period March 2012 to August 2015. Inclusion criteria comprised: unilateral recurrent nerve palsy or vocal fold closure defect with conserved mobility. Exclusion criteria comprised: previous thyroplasty, severe swallowing disorder, and cognitive disorder hindering subjective vocal assessment. Restylane® injection was performed under general or local anesthesia. The Vocal Handicap Index (VHI), maximum phonation time (MPT) and GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) score were assessed preoperatively and at 1 month and more than 6 months postoperatively. RESULTS: Twenty patients were included: 14 with unilateral recurrent nerve palsy and 6 with vocal fold closure defect. Restylane® injection was performed under general anesthesia in 16 patients and local anesthesia in 4 (20%). At 1-month assessment, there was significant reduction in VHI (by 36 points; P=0.0001) and GRBAS score (by 6.95 points; P=0.0001) and significant increase in MPT (by 4.95sec; P=0.0001). At 6 months, VHI, MPT and GRBAS scores remained significantly improved (respectively, P=0.0002, P=0.001 and P=0.0001), without significant difference from 1-month levels. Three patients had minor complications; two recovered normal vocal fold mobility. CONCLUSION: Hyaluronic acid injection was effective in treating glottal failure, improving objective and subjective vocal parameters, which remained satisfactory even 6 months postoperatively.

Paclitaxel inhibits post-traumatic recurrent laryngeal nerve regeneration into the posterior cricoarytenoid muscle in a canine model.

OBJECTIVES/HYPOTHESIS: To investigate the efficacy of paclitaxel, a potent microtubule inhibitor with a more favorable therapeutic index as compared with vincristine, in preventing post-traumatic nerve regeneration of the recurrent laryngeal nerve into the posterior cricoarytenoid muscle in a canine laryngeal model. STUDY DESIGN: Experimental animal study. METHODS: Forty-nine canine hemilaryngeal specimens were divided into five experimental groups. Under general anesthesia, a tracheostomy, recurrent laryngeal nerve (RLN) transection and repair, and laryngeal adductory pressures (LAP) were measured pre-RLN injury. The approach to the posterior cricoarytenoid (PCA) muscle for neurotoxin injection was transoral or open transcervical, at 0 or 3 months. At 6 months, postinjury LAPs were measured and the animals were sacrificed at 6 months to allow for laryngeal harvesting and analysis. RESULTS: Paclitaxel demonstrated increased mean laryngeal adductory pressures (70.6%) as compared with saline control (55.5%). The effect of paclitaxel was the same as observed with vincristine at 0 months and with a delayed injection at 3 months. There was no difference between transoral or open injection groups. CONCLUSIONS: PCA muscle injection with paclitaxel resulted in improved strength of laryngeal adduction. This effect was similar to that of vincristine at both 0 and 3 months following nerve injury. A single intramuscular injection of paclitaxel was well tolerated. Additional human studies are needed to determine the degree of clinical benefit of this intervention. LEVEL OF EVIDENCE: NA Laryngoscope, 127:651-655, 2017.

Neurotrophin expression and laryngeal muscle pathophysiology following recurrent laryngeal nerve transection.

Laryngeal palsy often occurs as a result of recurrent laryngeal or vagal nerve injury during oncological surgery of the head and neck, affecting quality of life and increasing economic burden. Reinnervation following recurrent laryngeal nerve (RLN) injury is difficult despite development of techniques, such as neural anastomosis, nerve grafting and creation of a laryngeal muscle pedicle. In the present study, due to the limited availability of human nerve tissue for research, a rat model was used to investigate neurotrophin expression and laryngeal muscle pathophysiology in RLN injury. Twenty-five male Sprague-Dawley rats underwent right RLN transection with the excision of a 5-mm segment. Vocal fold movements, vocalization, histology and immunostaining were evaluated at different time-points (3, 6, 10 and 16 weeks). Although vocalization was restored, movement of the vocal fold failed to return to normal levels following RLN injury. The expression of brain­derived neurotrophic factor and glial cell line-derived neurotrophic factor differed in the thyroarytenoid (TA) and posterior cricoarytenoid muscles. The number of axons did not increase to baseline levels over time. Furthermore, normal muscle function was unlikely with spontaneous reinnervation. During regeneration following RLN injury, differences in the expression levels of neurotrophic factors may have resulted in preferential reinnervation of the TA muscles. Data from the present study indicated that neurotrophic factors may be applied for restoring the function of the laryngeal nerve following recurrent injury.

Timing of nimodipine therapy for the treatment of vocal fold paralysis.

OBJECTIVES/HYPOTHESIS: To retrospectively determine optimal timing for initiation of nimodipine within a cohort of patients with acute vocal fold paralysis (VFP). STUDY DESIGN: Retrospective patient review. METHODS: Subjects were divided into three groups: initiation within 15 days postinjury (n = 19), between 15 and 30 days postinjury (n = 23), or greater than 30 days postinjury (n = 11). RESULTS: Fifty-one patients (53 paralyzed vocal folds [VFs]) met entrance criteria and were offered and started off-label nimodipine treatment. Thirty-six of 53 VFs recovered purposeful motion (67.9%). There was no significant difference in the rate of VF recovery among patients who began nimodipine within 15 days (68.4%), patients who started nimodipine between 15 and 30 days (73.9%) of nerve injury (P = .1405), and patients who initiated nimodipine after 30 days postinjury (54.5%). CONCLUSIONS: Nimodipine treatment for acute VFP yielded equal VF motion recovery rates regardless of when the medication was initiated. Time to recovery of motion was not different between groups studied.

Androgen treatment and recovery of function following recurrent laryngeal nerve injury in the rat.

PURPOSE: To investigate the effects of the androgen testosterone propionate (TP), on regeneration of the recurrent laryngeal nerve (RLN) after unilateral crush injury using assessment of vocal fold mobility (VFM) as a measure of behavioral recovery. METHODS: 48 adult male rats underwent standardized crush injury of left RLN and received treatment in the form of 2 silastic capsules containing TP or controls receiving a blank capsule (untreated). Direct laryngoscopic assessment of vocal cord mobility was performed before, immediately following and 1, 2, 3, 4, 5 or 6 weeks post injury. RESULTS: Treatment with TP enhanced the recovery of full VFM following crush injury of the RLN compared to controls. There was statistically significant improvement in VFM seen at the 1 and 2 week time points (p < 0.05). By 4 weeks TP-treated rats displayed a 100% recovery of VFM function, compared to only 50% by the control group. CONCLUSIONS: TP enhances RLN functional recovery following a crush injury, which further supports its potential general applicability as a therapeutic agent in peripheral nerve injury.