PROSPECTIVE INVESTIGATION OF NIMODIPINE FOR ACUTE VOCAL FOLD PARALYSIS CLARK A. ROSEN, MD,1 LIBBY SMITH, DO,1 VYVY YOUNG, MD,1 PRIYA KRISHNA, MD,2 MATTHEW F. MULDOON, MD, MPH,3 and MICHAEL C. MUNIN, MD1,4 1
University of Pittsburgh Voice Center, Department of Otolaryngology, University of Pittsburgh School of Medicine, UPMC Mercy Building B, Suite 11500, 1400 Locust Street, Pittsburgh, Pennsylvania 15219 USA 2 Department of Otolaryngology, Loma Linda University, Loma Linda, California, USA 3 Heart and Vascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 4 Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA Accepted 28 October 2013 ABSTRACT: Introduction: Nimodipine has been shown to be beneficial for recovery from acute vocal fold paralysis (AVFP) in an animal model. Methods: prospective, open-label trial of patients with AVFP was performed using nimodipine. Consecutive patients were evaluated and offered nimodipine therapy. Results: Fifty-three patients were considered for treatment with nimodipine. Thirteen did not qualify for inclusion, 5 were lost to follow-up, and 7 had side effects requiring cessation of treatment. Thus 28 patients (30 paralyzed vocal folds) were analyzed. Eighteen of the paralyzed vocal folds experienced recovery of purposeful motion (60%). Historical controls and laryngeal electromyography meta-analysis suggest no more than a 20% recovery rate from AVFP. Conclusions: This open label study using nimodipine for treatment of AVFP demonstrates tripling of the recovery rate of vocal fold motion compared with historical controls. Further study in a randomized, controlled manner is warranted. Muscle Nerve 50: 114–118, 2014
Vocal fold paralysis typically occurs from injury to the recurrent laryngeal and/or vagus nerves, resulting in difficulties such as dysphonia and dysphagia. Often this condition arises from iatrogenic injury, although idiopathic vocal fold paralysis from presumed viral infection to the recurrent laryngeal and/or vagus nerves is reported.1,2 Acute management of unilateral vocal fold paralysis is characterized by an expectant approach, with use of an intervening temporary static repositioning of the paralyzed vocal fold on an as-needed basis. Once the vocal fold has been paralyzed for greater than 6 months in a symptomatic patient, treatment is aimed at permanent static repositioning of the paralyzed vocal fold by means of vocal fold injection or a laryngeal framework procedure.3,4 Controversy exists over the value of laryngeal reinnervation, which has been suggested to provide increased tone but does not offer a solution that results in a dynamic, mobile vocal fold.5 Presently, there are no proactive treatments for patients with acute Abbreviations: AVFP, acute vocal fold paralysis; LEMG, laryngeal electromyography; MUP, motor unit potential; TA-LCA, thyroarytenoid-lateral cricoarytenoid Key words: laryngeal electromyography; laryngeal muscle innervation; nerve regeneration/drug effects; nimodipine; vocal cord paralysis Correspondence to: C.A. Rosen; e-mail: [email protected] C 2013 Wiley Periodicals, Inc. V
Published online 6 November 2013 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24111
114
Nimodipine VF Paralysis
vocal fold paralysis (AVFP) aimed to recover purposeful vocal fold motion. Nimodipine is a calcium channel antagonist that has been suggested to enhance vocal fold motion recovery in an animal model of VFP and a small clinical series of AVFP.6–8 It is thought to promote nerve regeneration following peripheral nerve injury with subsequent restoration of neural function.6–8 The proposed mechanism of nimodipine involves assisting growth cones of regenerating axons arising from nodes of Ranvier. Growth cones of regenerating axons have been shown to be affected by intracellular calcium levels.9 Increased axonal growth can occur by administering antagonists to voltage-gated calcium channels. Nimodipine has this effect and thus may play a role in the reinnervation process in patients following a peripheral nerve injury, such as AVFP.10 The purpose of this study was to undertake an open label, prospective investigation into the utility of nimodipine for treatment of AVFP. MATERIALS AND METHODS
The study was an open-label, prospective, nonrandomized design, using nimodipine as an offlabel medication for AVFP. Individuals were identified after they sought treatment through the University of Pittsburgh Voice Center. Patients with acute unilateral or bilateral vocal fold paralysis were offered nimodipine. Eligibility to be treated with a 2–3 month nimodipine treatment regimen included unilateral or bilateral vocal fold paralysis of less than 4 months duration, no contraindications (Table 1), and laryngeal electromyography (LEMG) evidence of axonal injury that connoted a poor or fair prognosis for spontaneous recovery (Table 2).11,12 Patients were evaluated initially with a comprehensive history and otolaryngologic examination, including video-recorded flexible laryngoscopy (and stroboscopy when appropriate). When clinically indicated, imaging of the path of the vagus/ recurrent laryngeal nerve was performed with a computed tomography scan to exclude compressive or infiltrative lesions. Date of onset of VFP was MUSCLE & NERVE
July 2014
Table 1. Contraindications to nimodipine. 1. Pregnancy. 2. Current breast feeding. 3. Malignant invasion of the recurrent laryngeal nerve/vagus nerve causing vocal fold paralysis. 4. Recent stroke or transient ischemia attack. 5. Recent acute coronary syndrome. 6. Unstable/uncontrolled hypertension. 7. Chronic liver disease. 8. Use of more than 2 antihypertensive medications. 9. No laryngeal electromyography study for prognosis and determination of existing neuropathy. 10. Good prognostic criteria met on laryngeal electromyography.
determined by onset of voice symptoms (i.e., day of surgery for the iatrogenic patient group). Baseline blood pressure was measured, and if preliminary study eligibility was met and patients agreed to treatment, they were placed on oral nimodipine, 30 mg, 3 times daily and scheduled for an LEMG shortly thereafter. Patients were initially placed on nimodipine before LEMG, because diagnostic LEMG was performed only every other week at our facility. Animal studies have suggested that the sooner nimodipine was started, the greater the chance for vocal fold paralysis recovery.13 All patients were given information regarding the medication and for monitoring of blood pressure. Blood pressure was monitored 3 times during the first 7 days of nimodipine therapy, and if systolic blood pressure remained within 15 mmHg from baseline and the patient did not report other drug-related side effects, the dose was then increased to 60 mg 3 times daily. Blood pressure was measured and called in at days 3 and 7 after the dose increase to 60 mg 3 times daily, and it was monitored subsequently at each clinical follow-up visit. LEMG was performed using a 37 mm concentric electrode and a Teca Synergy, T-Series electromyography machine (Natus Neurology, Middleton, Wisconsin) using both qualitative and quantitative analysis.14 The thyroarytenoid-lateral cricoarytenoid
(TA-LCA) muscle complex (and the cricothyroid muscles when appropriate) were evaluated within 2 weeks of starting nimodipine. To quantify motor unit potential (MUP) recruitment, we measured mean turns per second when sufficient recruitment was present.14,15 The board certified electromyographer (M.C.M.) was blinded to the side of the lesion, and to the results of flexible laryngoscopy. LEMG prognosis was based upon the description of axonal pathology as determined by electrodiagnostic findings.11 To document signs of axonal loss, LEMG must demonstrate fibrillation potentials and/or positive sharp waves at rest. If MUP recruitment is significantly decreased or absent, in combination with signs of acute axonal loss, the prognosis for spontaneous recovery is typically poor.11 Fair and poor prognoses were distinguished by the degree of voluntary MUP recruitment present and the configuration of the MUPs. Specifically, fair prognosis had evidence of 3 or more MUPs upon activation with a firing frequency of at least 20 HZ with either normal or polyphasic configuration, whereas poor prognosis was assigned for absent or only 1 or 2 rapidly firing MUPs observed during vocalization (Table 2). Patients with poor or fair prognosis on LEMG were continued on nimodipine. Subjects with a favorable prognosis, indicating a higher likelihood of natural recovery, were instructed to stop nimodipine. A favorable prognosis was given if no abnormal spontaneous activity was observed, and motor unit recruitment was only mild to moderately decreased with at least 3 MUPs activated during vocalization. For this study, we did not include testing for synkinesis when determining prognosis, as we studied patients very early in their clinical timeline.12 Quantified turns were measured for 10 epochs for each patient who had more than a few MUPs recruiting to task. This method of EMG quantitation allows assessment of the number and size of the MUPs at various force levels. A 500-ms epoch was used for quantification, and 400 turns per second or greater was considered normal.14,15
Table 2. LEMG characteristics of prognostic categories. Good prognosis
Fair prognosis
Poor prognosis
Fibrillation potentials/ positive waves MUP recruitment
None
Present in at least 1 field
Present in more than 1 field
Slightly decreased with 3 MUPs observed. Incomplete interference pattern
Quantified turns per second
>400 per sec
3–4 MUPs with a firing frequency of at least 20 HZ with either normal or polyphasic configuration (indicating peripheral sprouting)
University of Pittsburgh Voice Center, Department of Otolaryngology, University of Pittsburgh School of Medicine, UPMC Mercy Building B, Suite 11500, 1400 Locust Street, Pittsburgh, Pennsylvania 15219 USA 2 Department of Otolaryngology, Loma Linda University, Loma Linda, California, USA 3 Heart and Vascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 4 Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA Accepted 28 October 2013 ABSTRACT: Introduction: Nimodipine has been shown to be beneficial for recovery from acute vocal fold paralysis (AVFP) in an animal model. Methods: prospective, open-label trial of patients with AVFP was performed using nimodipine. Consecutive patients were evaluated and offered nimodipine therapy. Results: Fifty-three patients were considered for treatment with nimodipine. Thirteen did not qualify for inclusion, 5 were lost to follow-up, and 7 had side effects requiring cessation of treatment. Thus 28 patients (30 paralyzed vocal folds) were analyzed. Eighteen of the paralyzed vocal folds experienced recovery of purposeful motion (60%). Historical controls and laryngeal electromyography meta-analysis suggest no more than a 20% recovery rate from AVFP. Conclusions: This open label study using nimodipine for treatment of AVFP demonstrates tripling of the recovery rate of vocal fold motion compared with historical controls. Further study in a randomized, controlled manner is warranted. Muscle Nerve 50: 114–118, 2014
Vocal fold paralysis typically occurs from injury to the recurrent laryngeal and/or vagus nerves, resulting in difficulties such as dysphonia and dysphagia. Often this condition arises from iatrogenic injury, although idiopathic vocal fold paralysis from presumed viral infection to the recurrent laryngeal and/or vagus nerves is reported.1,2 Acute management of unilateral vocal fold paralysis is characterized by an expectant approach, with use of an intervening temporary static repositioning of the paralyzed vocal fold on an as-needed basis. Once the vocal fold has been paralyzed for greater than 6 months in a symptomatic patient, treatment is aimed at permanent static repositioning of the paralyzed vocal fold by means of vocal fold injection or a laryngeal framework procedure.3,4 Controversy exists over the value of laryngeal reinnervation, which has been suggested to provide increased tone but does not offer a solution that results in a dynamic, mobile vocal fold.5 Presently, there are no proactive treatments for patients with acute Abbreviations: AVFP, acute vocal fold paralysis; LEMG, laryngeal electromyography; MUP, motor unit potential; TA-LCA, thyroarytenoid-lateral cricoarytenoid Key words: laryngeal electromyography; laryngeal muscle innervation; nerve regeneration/drug effects; nimodipine; vocal cord paralysis Correspondence to: C.A. Rosen; e-mail: [email protected] C 2013 Wiley Periodicals, Inc. V
Published online 6 November 2013 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24111
114
Nimodipine VF Paralysis
vocal fold paralysis (AVFP) aimed to recover purposeful vocal fold motion. Nimodipine is a calcium channel antagonist that has been suggested to enhance vocal fold motion recovery in an animal model of VFP and a small clinical series of AVFP.6–8 It is thought to promote nerve regeneration following peripheral nerve injury with subsequent restoration of neural function.6–8 The proposed mechanism of nimodipine involves assisting growth cones of regenerating axons arising from nodes of Ranvier. Growth cones of regenerating axons have been shown to be affected by intracellular calcium levels.9 Increased axonal growth can occur by administering antagonists to voltage-gated calcium channels. Nimodipine has this effect and thus may play a role in the reinnervation process in patients following a peripheral nerve injury, such as AVFP.10 The purpose of this study was to undertake an open label, prospective investigation into the utility of nimodipine for treatment of AVFP. MATERIALS AND METHODS
The study was an open-label, prospective, nonrandomized design, using nimodipine as an offlabel medication for AVFP. Individuals were identified after they sought treatment through the University of Pittsburgh Voice Center. Patients with acute unilateral or bilateral vocal fold paralysis were offered nimodipine. Eligibility to be treated with a 2–3 month nimodipine treatment regimen included unilateral or bilateral vocal fold paralysis of less than 4 months duration, no contraindications (Table 1), and laryngeal electromyography (LEMG) evidence of axonal injury that connoted a poor or fair prognosis for spontaneous recovery (Table 2).11,12 Patients were evaluated initially with a comprehensive history and otolaryngologic examination, including video-recorded flexible laryngoscopy (and stroboscopy when appropriate). When clinically indicated, imaging of the path of the vagus/ recurrent laryngeal nerve was performed with a computed tomography scan to exclude compressive or infiltrative lesions. Date of onset of VFP was MUSCLE & NERVE
July 2014
Table 1. Contraindications to nimodipine. 1. Pregnancy. 2. Current breast feeding. 3. Malignant invasion of the recurrent laryngeal nerve/vagus nerve causing vocal fold paralysis. 4. Recent stroke or transient ischemia attack. 5. Recent acute coronary syndrome. 6. Unstable/uncontrolled hypertension. 7. Chronic liver disease. 8. Use of more than 2 antihypertensive medications. 9. No laryngeal electromyography study for prognosis and determination of existing neuropathy. 10. Good prognostic criteria met on laryngeal electromyography.
determined by onset of voice symptoms (i.e., day of surgery for the iatrogenic patient group). Baseline blood pressure was measured, and if preliminary study eligibility was met and patients agreed to treatment, they were placed on oral nimodipine, 30 mg, 3 times daily and scheduled for an LEMG shortly thereafter. Patients were initially placed on nimodipine before LEMG, because diagnostic LEMG was performed only every other week at our facility. Animal studies have suggested that the sooner nimodipine was started, the greater the chance for vocal fold paralysis recovery.13 All patients were given information regarding the medication and for monitoring of blood pressure. Blood pressure was monitored 3 times during the first 7 days of nimodipine therapy, and if systolic blood pressure remained within 15 mmHg from baseline and the patient did not report other drug-related side effects, the dose was then increased to 60 mg 3 times daily. Blood pressure was measured and called in at days 3 and 7 after the dose increase to 60 mg 3 times daily, and it was monitored subsequently at each clinical follow-up visit. LEMG was performed using a 37 mm concentric electrode and a Teca Synergy, T-Series electromyography machine (Natus Neurology, Middleton, Wisconsin) using both qualitative and quantitative analysis.14 The thyroarytenoid-lateral cricoarytenoid
(TA-LCA) muscle complex (and the cricothyroid muscles when appropriate) were evaluated within 2 weeks of starting nimodipine. To quantify motor unit potential (MUP) recruitment, we measured mean turns per second when sufficient recruitment was present.14,15 The board certified electromyographer (M.C.M.) was blinded to the side of the lesion, and to the results of flexible laryngoscopy. LEMG prognosis was based upon the description of axonal pathology as determined by electrodiagnostic findings.11 To document signs of axonal loss, LEMG must demonstrate fibrillation potentials and/or positive sharp waves at rest. If MUP recruitment is significantly decreased or absent, in combination with signs of acute axonal loss, the prognosis for spontaneous recovery is typically poor.11 Fair and poor prognoses were distinguished by the degree of voluntary MUP recruitment present and the configuration of the MUPs. Specifically, fair prognosis had evidence of 3 or more MUPs upon activation with a firing frequency of at least 20 HZ with either normal or polyphasic configuration, whereas poor prognosis was assigned for absent or only 1 or 2 rapidly firing MUPs observed during vocalization (Table 2). Patients with poor or fair prognosis on LEMG were continued on nimodipine. Subjects with a favorable prognosis, indicating a higher likelihood of natural recovery, were instructed to stop nimodipine. A favorable prognosis was given if no abnormal spontaneous activity was observed, and motor unit recruitment was only mild to moderately decreased with at least 3 MUPs activated during vocalization. For this study, we did not include testing for synkinesis when determining prognosis, as we studied patients very early in their clinical timeline.12 Quantified turns were measured for 10 epochs for each patient who had more than a few MUPs recruiting to task. This method of EMG quantitation allows assessment of the number and size of the MUPs at various force levels. A 500-ms epoch was used for quantification, and 400 turns per second or greater was considered normal.14,15
Table 2. LEMG characteristics of prognostic categories. Good prognosis
Fair prognosis
Poor prognosis
Fibrillation potentials/ positive waves MUP recruitment
None
Present in at least 1 field
Present in more than 1 field
Slightly decreased with 3 MUPs observed. Incomplete interference pattern
Quantified turns per second
>400 per sec
3–4 MUPs with a firing frequency of at least 20 HZ with either normal or polyphasic configuration (indicating peripheral sprouting)
