Laryngeal electromyography findings of vocal fold immobility in patients after radiotherapy for nasopharyngeal carcinoma

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1 ORIGINAL ARTICLE Laryngeal electromyography findings of vocal fold immobility in patients after radiotherapy for nasopharyngeal carcinoma Yi-Ling Hsieh, MD, 1 Ming-Hong Chang, MD, 2 Chen-Chi Wang, MD 1,3,4* 1 Department of Otolaryngology Head and Neck Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, 2 Department of Neurology, Taichung Veterans General Hospital, Taichung, Taiwan, 3 School of Medicine, National Yang Ming University, Taipei, Taiwan, 4 School of Speech Language Pathology and Audiology, Chung Shan Medical University, Taichung, Taiwan. Accepted 15 May 2013 Published online 29 May 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The clinical features of vocal fold immobility (VFI) after radiotherapy for nasopharyngeal carcinoma (NPC) have seldom been reported. Methods. We retrospectively reviewed laryngeal electromyography (LEMG) and tumor study findings to elucidate the common clinical features of patients who presented with VFI after radiotherapy for NPC. The LEMG signals obtained from the cricothyroid and thyroarytenoid muscles were used to confirm superior laryngeal nerve (SLN) and recurrent laryngeal nerve (RLN) injury. Results. The medical records of 13 patients were reviewed and 11 of them had evidence of RLN injury. Six of the 11 patients also had SLN injury, indicating possible vagus nerve (VN) injury. Two patients had cricoarytenoid joint fixation without evidence of nerve injury. None of the nerve injuries were caused by skull base recurrence or tumor metastasis. Conclusion. VFI is usually caused by nerve injury, but it is not a malignant sign of tumor recurrence or metastasis. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: laryngeal electromyography, nasopharyngeal carcinoma, nerve paralysis, radiotherapy, vocal fold immobility INTRODUCTION Cranial nerve paralysis (CNP) is a rare complication among patients with head and neck cancer receiving conventional radiotherapy because the cranial and peripheral nerves are relatively radio-resistant in contrast to the brain and spinal cord. Nevertheless, all of the cranial nerves are potentially at risk of injury during radiotherapy. In the literature, the reported incidence after radiotherapy for nasopharyngeal carcinoma (NPC) ranges from 0.3% to 9%. 1 A cohort study of 1032 Taiwanese patients with NPC showed that 1% of them developed CNP after receiving radiotherapy. 2 In a study by Lin et al 3 on radiation-related CNP in patients with NPC, hypoglossal nerve paralysis was the most frequent complication, followed by vagus nerve (VN) paralysis and recurrent laryngeal nerve (RLN) paralysis. Radiation-induced VN or RLN paralysis can cause vocal fold immobility (VFI), then hoarseness or airway problems. However, VFI can also occur after cricoarytenoid joint ankylosis and posterior glottis stenosis, which are possible complications of radiotherapy. 2 Which scenario is the most common in patients who present with VFI after radiotherapy for NPC remains unclear. *Corresponding author: C.-C. Wang, Department of Otolaryngology Head and Neck Surgery, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Boulevard, Taichung 40705, Taiwan. entccwang@msn.com Laryngeal electromyography (LEMG) was introduced in 1944 by Weddel and Pattle, 4 and it is helpful for clinical differentiation between nerve paralysis and cricoarytenoid joint fixation. 5 It can also provide information about the site of the nerve lesion and prognosis in patients with vocal fold paralysis. 6 8 However, to date, only Lau et al 1 reported LEMG findings on patients (n 5 3) who presented with VFI after radiotherapy for NPC. CNP caused by tumor involvement is also a common presenting manifestation of NPC. When patients with a history of radiotherapy for NPC present with VFI, tumor recurrence should be considered in the differential diagnosis. 3 Furthermore, extralaryngeal malignancies, such as lung or esophageal cancer, are common etiologies of VFI. 9 Therefore, it is important to exclude a second malignancy or distant metastasis. In this study, we retrospectively reviewed the LEMG and tumor study findings to elucidate the common clinical features of patients who presented with VFI after radiotherapy for NPC. MATERIALS AND METHODS After institutional review board approval, this study was conducted at Taichung Veterans General Hospital, a tertiary referral center in central Taiwan. We retrospectively reviewed the medical records of 13 patients who received radiotherapy for NPC in the past and who presented with a chief manifestation of VFI without HEAD & NECK DOI /HED JUNE

2 HSIEH ET AL. FIGURE 1. Normal to nearly normal recruitment pattern of immobile vocal fold muscles examined by laryngeal electromyography. We asked patients to phonate the vowel /i/ with maximal intensity for maximal voluntary contraction of the thyroarytenoid muscle or asked patients to phonate the vowel /i/ with the highest pitch for maximal voluntary contraction of the cricothyroid muscle. If the recruitment of the immobile vocal fold (A) was 80% to 100% of the recruitment of the normal mobile vocal fold (B), we defined the recruitment pattern of the immobile vocal fold as a normal to nearly normal recruitment pattern. nasopharyngeal tumor, as shown on nasopharyngoscope between December 2004 and December The demographic data including patient s sex, age, NPC initial TNM stage, laterality of primary NPC, irradiation dose to the nasopharynx, and neck metastasis were collected. The VFI was confirmed by flexible laryngoscope and videostroboscopy. The laterality of immobile vocal fold, and the interval between symptom onset and the end of previous irradiation were also recorded. All 13 patients received LEMG, which was performed by corresponding author C.-C.W., a laryngologist familiar with the anatomy of the intrinsic laryngeal muscles. The LEMG findings were interpreted by M.-H.C., a neurologist with 20 years experience in electrodiagnostic medicine. All LEMG examinations were performed by the same machine (Cadwell Sierra 6200A; Cadwell Laboratories Inc., Kennewick, WA) using a computer-based electrodiagnostic system. LEMG signals were monitored on a FIGURE 2. Obvious reduction in the recruitment pattern of immobile vocal fold muscles examined by laryngeal electromyography. We asked patients to phonate the vowel /i/ with maximal intensity for maximal voluntary contraction of the thyroarytenoid muscle or asked patients to phonate the vowel with the highest pitch for maximal voluntary contraction of the cricothyroid muscle. If the recruitment of the immobile vocal fold (A) was less than 80% of the recruitment of the normal mobile vocal fold (B), we defined the recruitment pattern of the immobile vocal fold as an obvious reduction in the recruitment pattern. 868 HEAD & NECK DOI /HED JUNE 2014

3 LARYNGEAL ELECTROMYOGRAPHY FINDINGS OF VOCAL FOLD IMMOBILITY AFTER RT FOR NPC FIGURE 3. Spontaneous activity, such as (A) fibrillation potentials (FIBs) or (B) positive sharp waves (PSWs), detected by laryngeal electromyography (LEMG) when the patients kept silent. Both FIBs and PSWs represent ongoing axonal degeneration and indicate significant nerve injury. computer screen and by means of a speaker simultaneously. The procedure and diagnosis were described in detail in our previous retrospective study. 7 Briefly, the thyroarytenoid (TA) muscle was punctured with a monopolar electrode and the signals obtained from the TA muscle represented the RLN function. The position of the needle was validated by asking the patient to repeat a sustained vowel /i/with highest intensity. The neurologist compared the recruitment pattern of the immobile vocal fold to the normal vocal fold and estimated the percentage of normal motor unit recruitment left in the immobile vocal fold. The recruitment pattern of the immobile vocal fold was dichotomized to normal to nearly normal (80% to 100% of normal motor unit recruitment) (Figure 1) and obvious reduction (<80% of normal motor unit recruitment) (Figure 2). Finally, we asked the patient to keep silent to see if there were any spontaneous activities such as fibrillation potentials (FIBs) or positive sharp waves (PSWs; Figure 3). The preset overall LEMG diagnostic rule first set forth by Munin et al, 8 and adopted in our previous study, 7 was used to define the level of RLN injury. Normal or nearly normal motor unit recruitment and absence of spontaneous activities such as FIBs or PSWs determine a negative test (no significant nerve injury); otherwise, it is a positive test (significant nerve injury; Table 1). The same procedure was performed on the cricothyroid muscle and the position of the needle was validated by asking the patient to sustain a highest pitch vowel /i/. The signals obtained from the cricothyroid muscle represent the superior laryngeal nerve (SLN) function. Because the SLN and the RLN both branch from the VN, evident injury to both of them must have occurred either at the skull base above the takeoff of the SLN or diffusely in both nerves. 1 After long-term follow-up, the outcome of VFI (recovery of motion or no recovery), and the interval between outcome measurement and LEMG examination were archived. After long-term follow-up with comprehensive tumor studies from images and nasopharyngoscopy, the evidence of NPC recurrence, second malignancy, or distant metastasis was analyzed. RESULTS The medical records of 13 patients with VFI were reviewed after radiotherapy for NPC. The aforementioned demographic data are summarized in Table 2. There were 11 men and 2 women, and their ages ranged from 46 to 71 years with a mean age of 58. The initial NPC was located on both sides of the nasopharynx in 1 patient, the right side in 6 patients, and the left side in 6 patients. One patient had stage I, 1 patient had stage III, and 9 patients had stage IV disease according to the Union Internationale Contre le Cancer/American Joint Committee on Cancer staging system. The other 2 patients had no initial staging or irradiation data because they received treatment at other hospitals. The irradiation dosage to the primary site ranged from 6600 cgy to 7400 cgy with a TABLE 1. injury. The diagnostic rule of laryngeal electromyography for nerve Negative test (no significant nerve injury) Positive test (significant nerve injury) Abbreviations: FIBs, fibrillation potentials; PSWs, positive sharp waves. 1. normal or nearly normal recruitment pattern (80% to 100% normal motor unit recruitment) and 2. absence of spontaneous activities (FIBs, PSWs) 1. obvious reduction in recruitment pattern (less than 80% of normal motor unit recruitment) or 2. presence of spontaneous activities (FIBs, PSWs) HEAD & NECK DOI /HED JUNE

4 HSIEH ET AL. TABLE 2. The demographics, laryngeal electromyography findings, and outcome measurements of the 13 patients. Patient no Sex M M F M M M M M M M M M F Age NPC primary site R R L L R L R L R L R B L TNM stage T2N2cM0 T2bN2cM0 NA NA T4N2cM0 T4N2cM0 T1N1M0 T3N2cM0 T2N2cM0 T2N2cM0 T1N0M0 T4N0M0 T1N3M0 Overall stage IV IV NA NA IV IV III IV IV IV I IV IV RT dose to NP, cgy NA NA RT dose to right neck, cgy NA NA NA NA RT dose to left neck, cgy NA NA NA NA Laterality of VFI L R B L R R R L R L R R L VFI timing after RT, y LEMG timing after symptoms, mo LEMG R SLN function G G G G G G G G G G G LEMG R RLN function G G G G G G G LEMG L SLN function G G G G G G G G LEMG L RLN function G G G G G G G G Recovery nil nil NA nil nil nil nil nil nil nil nil nil nil VFI outcome measurement NA timing after LEMG, mo NPC recurrence nil nil NA nil nil nil nil nil nil nil nil nil nil Second malignancy nil nil NA nil nil nil nil nil nil nil nil nil nil Lung metastasis nil nil NA nil nil nil nil nil nil nil nil nil nil Abbreviations: NPC, nasopharyngeal carcinoma; R, right; L, left; NA, not available; RT, radiotherapy; NP, nasopharynx; VFI, vocal fold immobility; B, bilateral; LEMG, laryngeal electromyography; SLN, superior laryngeal nerve; G, good;, injury; RLN, recurrent laryngeal nerve. 870 HEAD & NECK DOI /HED JUNE 2014

5 LARYNGEAL ELECTROMYOGRAPHY FINDINGS OF VOCAL FOLD IMMOBILITY AFTER RT FOR NPC patients who received tumor studies, none had lung metastasis at presentation. Two patients had lung metastasis long after the onset of VFI, but the VFI was not related to the lung metastasis. Neither one of these patients had a second primary esophageal cancer. FIGURE 4. The nerve injury sites in the 13 patients. Stars show evidence of nerve injury based on laryngeal electromyography, and diamonds show possible injury sites at the vagus nerve when both the superior laryngeal nerve (SLN) and the recurrent laryngeal nerve (RLN) were injured (group 1). There was only evidence of RLN injury in group 2 and no evidence of nerve injury in group 3. mean dosage of 7122 cgy. The details of radiation dose to the neck are listed in Table 2. The aforementioned data on the VFI are summarized in Table 2 and the nerve injury sites are illustrated in Figure 4. One patient had bilateral VFI, and the other 12 patients had unilateral VFI (5 left sided and 7 right sided). The time interval between immobility onset and radiation therapy ranged from 2 years to 17 years with a mean of 7.3 years. The only patient (no. 3) with bilateral VFI had normal LEMG signals from the bilateral cricothyroid and TA muscles, indicating that the immobility probably was caused by cricoarytenoid joint fixation. Another patient (no. 9) with right VFI had a contralateral left SLN injury but no evidence of ipsilateral right SLN or RLN injury. On videostroboscopy, he had no jostle sign, a movement of the arytenoid on the affected side during vocalization. The passive movement of the arytenoid on the affected side occurs as a result of contact with the other arytenoid, which presses against it during adduction. If no jostle sign can be seen in VFI, the VFI might be caused by a joint problem. 10 Of the other 11 patients with unilateral VFI, 5 patients (nos. 5, 6, 7, 11, and 13) had ipsilateral RLN injury, and 6 patients (nos. 1, 2, 4, 8, 10, and 12) had both ipsilateral SLN and RLN injury from LEMG. Of the 13 patients with VFI, 1 patient was lost to follow-up after LEMG, but the other 12 patients were followed up from 6 months to 88 months with a mean follow-up of 42.9 months. None of these 12 patients had recovered vocal fold mobility at the last follow-up. All of the patients were examined with flexible nasopharyngoscopy and none had evidence of nasopharyngeal tumor at presentation. Except for 1 patient (no. 3), they all received tumor studies including images such as CT or MRI to exclude nasopharynx submucosa recurrence or skull base recurrence. However, no patients had tumor recurrence around the nasopharynx or skull base either at presentation or after long-term follow-up. Of the 12 DISCUSSION VFI is a common disorder seen in the practice of otolaryngology. Normally, the vocal folds abduct in order to open the glottis when we breathe, and adduct to close the glottis for airway protection and phonation. However, the movement of vocal folds may be impaired by neurological injury or mechanical conditions in the cricoarytenoid joint of the vocal folds. 11 The RLN and SLN are branches of the 10th cranial nerve, or VN. The SLN innervates the cricothyroid muscle, which controls the longitudinal tension of the vocal folds and then the pitch of the voice. The RLN innervates other intrinsic laryngeal muscles and controls the motion (abduction and adduction) of vocal folds (Figure 4). In VFI with neurologic etiology, the impairment of RLN function can be caused by heterogeneous conditions. 9 If patients have a history of NPC after radiotherapy, the possibility of tumor recurrence should be considered 3 and differential diagnosis will become more complicated. In this regard, the present study may help to elucidate the clinical features of this specific disease entity. In the English-language literature, occurrence of CNP in patients with a history of NPC after radiotherapy has seldom been reported. 3 The nerve injury sites in such patients can vary because both VN injury with downstream SLN and RLN paralysis and isolated RLN injury can cause VFI. However, the location of the lesion along the nerve in these patients was usually inferred clinically without electrophysical evidence from LEMG. 3,12 In 2003, Lau et al 1 first used LEMG to identify the possible nerve injury sites in 3 patients who presented with VFI after radiotherapy for NPC. Two of the patients had both SLN and RLN injuries, indicating that the VN above the takeoff of the SLN nerve at the skull base could also be injured. Six of our patients (nos. 1, 2, 4, 8, 10, and 12) had both SLN and RLN injuries. The possibility of VN injury raised the suspicion of tumor recurrence at the skull base level. However, none of them had evidence of tumor recurrence at the skull base on comprehensive image studies. Five patients (nos. 5, 6, 7, 11, and 13) had RLN injury alone. The paralyzed RLN also had no relationship to tumor recurrence at the neck or chest level in these patients. In 2 of our 13 patients, the VFI might have developed from joint problems. According to our observation, VFI delayed long after radiotherapy for NPC is commonly caused by nerve injury but it is usually not a malignant sign indicating tumor recurrence or metastasis. All of our patients were older than 40 years with a mean age of 58 years. The mean interval between completion of radiotherapy and symptom onset was 7.3 years, which indicates that VFI is usually a delayed complication of irradiation. This phenomenon was also reported by Delanian et al, 13 who described radiation-induced peripheral neuropathy as a chronic handicap, usually appearing several years after radiotherapy. A possible mechanism for radiation-induced peripheral neuropathy may be initial microvascular injury, with subsequent radiation-induced fibrosis (RIF). 14 Marked HEAD & NECK DOI /HED JUNE

6 HSIEH ET AL. fibrosis surrounding the nerve trunk with fibrous infiltration and replacement of nerve fibers was noted in the autopsy results of 2 patients with breast cancer with brachial plexopathy after postoperative radiotherapy. 15 Another vascular concept based on a theory of gradual ischemia-hypoxia has been proposed to account for capillary network destruction after radiotherapy. 16 The aforementioned theories may explain the delayed onset of VFI in our patients. Of our 13 patients, 10 had VFI ipsilateral to the NPC primary site laterality. Only 3 patients (nos. 1, 3, and 6) had VFI contralateral to the primary NPC side. Patient no. 3 had no TNM staging record; the other 2 patients (nos. 1 and 6) had bilateral neck metastasis and received bilateral neck irradiation, which may account for the development of contralateral VFI. In addition to nerve paralysis, 2 of our patients had nearly normal RLN function at the immobile vocal fold, indicating that the immobility might have been caused by cricoarytenoid joint synechia. It seems that RIF not only damages nerves but also joints. The irreversibility of RIF may also explain why no patients recovered their vocal fold motion after long-term follow-up. Our study had some limitations. First of all, it was a retrospective study and the sample size was small. Besides, some medical records at other hospitals from a long time ago were not available. However, our results can still serve as a valuable clinical reference. In summary, most of the cases of VFI after radiotherapy for NPC occurred long after the completion of irradiation of advanced-stage tumors. VFI commonly develops ipsilateral to the primary NPC laterality and is usually caused by nerve injury rather than mechanical joint fixation. According to LEMG studies, about half of the nerve lesions are located at VNs and half of the lesions are located at RLNs. Therefore, the injury could be caused by irradiation to primary nasopharyngeal tumors or metastatic cervical lymph nodes. No matter where the lesions are, the prognosis for vocal fold motion recovery is poor even after long-term follow-up. However, VFI is usually not a malignant sign indicating skull base tumor recurrence or neck and chest metastasis. Acknowledgment The authors thank Ms. An-Ting Yu for her assistance in the preparation of the images and figures. REFERENCES 1. Lau DP, Lo YL, Wee J, Tan NG, Low WK. Vocal fold paralysis following radiotherapy for nasopharyngeal carcinoma: laryngeal electromyography findings. J Voice 2003;17: Huang S, Chu G. Nasopharyngeal cancer: study II. Int J Radiat Oncol Biol Phys 1981;7: Lin YS, Jen YM, Lin JC. Radiation-related cranial nerve palsy in patients with nasopharyngeal carcinoma. Cancer 2002;95: Weddel GB, Pattle RE. The electrical activity of voluntary muscle in man under normal and pathological conditions. Brain 1944;67: Rontal E, Rontal M, Silverman B, Kileny PR. The clinical differentiation between vocal fold paralysis and vocal cord fixation using electromyography. Laryngoscope 1993;103: Koufman JA, Walker FO. Laryngeal electromyography in clinical practice: indications, techniques and interpretation. Laryngoscope 1998;105: Wang CC, Chang MH, Wang CP, Liu SA. Prognostic indicators of unilateral vocal fold paralysis. Arch Otolaryngol Head Neck Surg 2008;134: Munin MC, Rosen CA, Zullo T. Utility of laryngeal electromyography in predicting recovery after vocal fold paralysis. Arch Phys Med Rehabil 2003;84: Benninger MS, Gillen JB, Altman JS. Changing etiology of vocal fold immobility. Laryngoscope 1998;108: Rubin AD, Sataloff RT. Vocal fold paresis and paralysis. Otolaryngol Clin North Am 2007;40: Sataloff RT, Mandel S, Manon Espaillant R, Heman Ackah YD, Abaza M. Laryngeal electromyography. Philadelphia, PA: Thomas Jefferson Medical College; Cheng VS, Schultz MD. Unilateral hypoglossal nerve atrophy as a late complication of radiation therapy of head and neck carcinoma: a report of four cases and a review of the literature on peripheral and cranial nerve damages after radiation therapy. Cancer 1975;35: Delanian S, Lefaix JL, Pradat PF. Radiation-induced neuropathy in cancer survivors. Radiother Oncol 2012;105: Cavanagh JB. Effects of x-irradiation on the proliferation of cells in peripheral nerve during Wallerian degeneration in the rat. Br J Radiol 1968;41: Stoll BA, Andrews JT. Radiation-induced peripheral neuropathy. Br Med J 1966;1: Delanian S, Lefaix JL. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother Oncol 2004;73: HEAD & NECK DOI /HED JUNE 2014