Timing of Nimodipine Therapy for the Treatment of Vocal Fold Paralysis

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1 The Laryngoscope VC 2014 The American Laryngological, Rhinological and Otological Society, Inc. Timing of Nimodipine Therapy for the Treatment of Vocal Fold Paralysis Shaum S. Sridharan, MD; Clark A. Rosen, MD; Libby J. Smith, DO; VyVy N. Young, MD; Michael C. Munin, MD 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 5 19), between 15 and 30 days postinjury (n 5 23), or greater than 30 days postinjury (n 5 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 ), 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. Key Words: Nimodipine, vocal cord paralysis, laryngeal electromyography, laryngeal muscle innervation, nerve regeneration/drug effects, timing. Level of Evidence: 4 Laryngoscope, 125: , 2015 INTRODUCTION Recent efforts in the care of vocal fold paralysis (VFP) have focused on specific interventions that could promote the recovery of purposeful vocal fold motion (VFM) in the acutely injured recurrent laryngeal nerve (RLN) without transection. 1 3 Nimodipine, an L-type voltage-gated calcium channel blocker, has been utilized in an attempt to improve functional recovery after peripheral nerve injury. 2,4,5 It is postulated that by blocking the transient intracellular influxes of Ca11 ions within neurons, propagation of the growth cones in the injured nerve is improved. 6 There are currently no randomized clinical studies available that definitively prove the effectiveness of nimodipine in restoring VFM after paralysis. However, previous nonrandomized clinical investigations into the use of nimodipine in acute VFP have demonstrated significant VFM recovery rates From the Department of Otolaryngology, University of Pittsburgh Voice Center (S.S.S., C.A.R., L.J.S., V.N.Y.), Department of Physical Medicine and Rehabilitation (M.C.M.), and Department of Otolaryngology (M.C.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Editor s Note: This Manuscript was accepted for publication August 4, Presented at the American Laryngological Association 135th Annual Meeting at COSM, Las Vegas, Nevada, U.S.A., May 14, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Clark A. Rosen, MD, University of Pittsburgh Voice Center, Department of Otolaryngology, UPMC Mercy Building B, Suite 11500, 1400 Locust Street, Pittsburgh, PA rosenca@upmc.edu DOI: /lary compared to historical control groups. 2,7 Increases in nerve fiber growth rate and size have been confirmed by animal studies after crush injury to the RLN and facial nerve. 8,9 Moreover, improved nerve growth was observed in rats with transection injury to the RLN with reanastomosis. 10 Animal studies suggest that the earlier nimodipine was started, the greater the chance for VFP recovery following injury. 8,10 In the clinical setting, starting nimodipine therapy immediately after RLN injury can be challenging. Hydman et al. were able to start nimodipine on six of their patients immediately after iatrogenic nerve injury. The three patients who remained on the nimodipine therapy all had return of VFM. 2 In our previous cohort of 28 patients enrolled in our treatment protocol, patients were started on nimodipine therapy if they were evaluated anytime within 4 months of RLN injury. Recovery rates for purposeful VFM in patients taking nimodipine after paralysis was 60% compared to <20% in historical controls. 7,11 13 Although nimodipine may be useful in recovery after VFP, it is unclear at this time if there is an optimal time to begin nimodipine therapy after an RLN injury. The purpose of this study was to investigate whether vocal fold recovery rates and time until recovery were affected by when nimodipine therapy was initiated postinjury. MATERIALS AND METHODS This study retrospectively reviewed the results of an openlabel, prospective, nonrandomized study that used nimodipine as an off-label medication in the treatment of acute VFP. There

2 TABLE I. Contraindications to Using Nimodipine. Pregnancy Current breast feeding Malignant invasion of the recurrent laryngeal nerve/vagus nerve causing the vocal fold paralysis/immobility Recent stroke or transient ischemia attack Recent acute coronary syndrome Unstable/uncontrolled hypertension Chronic liver disease Use of more than two antihypertensive medications No laryngeal electromyographic study for prognosis and determination of existing neuropathy Good prognosis criteria met on laryngeal electromyography are no financial disclosures to report for this study. A smaller subset of this cohort was used for our initial study, and recovery rates and demographic data were published in our previous work. 7 Eligibility to be treated with nimodipine included unilateral or bilateral VFP of <4 months duration, no contraindications (Table I), and laryngeal electromyography (LEMG) evidence of axonal injury that connoted a poor or fair prognosis of spontaneous recovery of VFM (Table II) Patients with known transection injury were enrolled in the protocol but are not included in this review. Institutional review board approval for the retrospective review of the results of this therapy was obtained from the University of Pittsburgh. Patients were initially evaluated with a comprehensive history and otolaryngologic examination including videorecorded flexible laryngoscopy (and stroboscopy when appropriate). When clinically indicated, imaging of the path of the vagus/rln was performed with a computed tomography scan to exclude compressive and infiltrative lesions. Date of onset of VFP was 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 nimodipine 30 mg by mouth, three times per day, and scheduled for an LEMG within the next 14 days. As per our previous protocol, patients underwent standardized, blinded LEMG studies of the thyroarytenoid lateral cricoarytenoid (TA-LCA) muscle complex of both vocal folds. In all cases, the board-certified electromyographer was blinded to the clinical history and laryngoscopy findings, and in most situations the same was true for the fellowship-trained laryngologist who performed the LEMG. LEMG was performed using a 37- mm concentric electrode and a Teca Synergy, T-Series electromyography machine (Natus Neurology, Middleton, WI). The TA- LCA muscle complex (and the cricothyroid muscles when appropriate) was evaluated within 2 weeks of starting nimodipine. Quantitative and qualitative analysis of the LEMG findings were conducted on each patient as appropriate. 12 Based on these findings, the patients were stratified into those with unfavorable (poor or fair) or favorable prognosis for spontaneous recovery (Table II). Only patients with an unfavorable prognosis were continued on nimodipine, because our goal was to evaluate the potential to improve VFM recovery outcomes in those with the least favorable prognosis for spontaneous recovery. All patients were given information regarding the medication and for monitoring of blood pressure. Blood pressure was monitored three times during the first 7 days of nimodipine (30 mg three times per day) therapy, and if systolic blood pressure remained within 15 mm Hg from baseline and the patient did not report other drug-related side effects, the dose was then increased to 60 mg three times per day. Blood pressure was remeasured and reported to the office on day 3 and day 7 after increasing to 60 mg three times per day, and then subsequently monitored with each clinical follow-up visit. Patients were monitored with repeat flexible laryngoscopy at 1- to 2-month intervals. If recovery of purposeful gross VFM was identified, nimodipine was stopped. Purposeful motion of the vocal fold was defined as substantive and coordinated VFM with respiration (abduction) and/or phonation (adduction). If persistent vocal fold immobility was noted after 2 to 3 months following the initiation of nimodipine, a second LEMG was performed for prognostic purposes. Nimodipine was stopped in individuals who showed no improvement in their second LEMG and/or who had been on nimodipine for 3 months. Vocal fold recovery was stratified based on when nimodipine therapy was initiated from the time of injury. Patients were grouped into an early (1 15 days postinjury), middle (15 30 days postinjury) or late (>30 days postinjury) category for statistical analysis. A v 2 test, Mann-Whitney U test, and Kruskal-Wallis test were used for statistical analysis (IBM SPSS-19 Statistics; IBM, Armonk, NY). RESULTS A total of 103 patients were offered nimodipine as per the described protocol. This represents 109 paralyzed vocal folds, because six patients had bilateral VFP. Nine patients (nine vocal folds) were excluded from this analysis because they had known transection of the RLN. Nineteen patients (21 vocal folds) were excluded after their initial LEMG revealed a good prognosis, making them ineligible for continued nimodipine therapy. Two patients (three vocal folds) were removed from analysis due to not having or tolerating an LEMG. Fifteen patients (16 vocal folds) were not included after developing side effects of nimodipine requiring them to stop the medication. Last, seven patients (seven vocal folds) were lost to follow-up. The remaining cohort was composed of 51 patients representing 53 paralyzed vocal folds, because two patients had bilateral VFP. Twenty-one patients were males; demographic information of each of the three groups (early, middle, and late) is shown in Table III. Forty-eight of the 53 (90%) paralyzed vocal folds were related to surgical injury to the recurrent laryngeal or vagus nerve. Age (P 5.21) and sex (P 5.61) were not significantly different among the early group, middle group, and late groups. The early group (0 15 days postinjury) was composed of 19 patients, with 13 patients recovering VFM (68.4% recovery rate). The middle group (16 30 days postinjury) had 23 patients, of whom 17 patients had return of VFM (73.9% recovery rate). Last, the late group was composed of 11 patients who started the medication after 30 days (range, days). Six of the 11 patients in this group recovered motion (54.5%), the latest of which initiated therapy at 86 days postinjury. Overall, 36 of the 53 patients had return of purposeful VFM (67.9%). When comparing the early group versus the middle group, there was no significant difference in recovery rates (P 5.74). Similarly when the early and middle groups were combined and compared to the late group, 187

3 Fibrillations/ positive waves Motor unit recruitment TABLE II. Laryngeal Electromyography Characteristics of Prognostic Categories. Good Prognosis Fair Prognosis Poor Prognosis None Present in at least one field Present in more than one field Slightly decreased with three or more motor units observed; incomplete interference pattern Three to four units with a firing frequency of at least 20 Hz with either normal or polyphasic configuration (indicating peripheral sprouting) Absent or one to two units with firing frequency at least 20 Hz observed during vocalization; normal configuration if units present Quantified turns >400 <400 <400 or not tested if no per second 12 motor unit recruitment observed there was no statistical difference (P 5.30). The early group was compared to the entire cohort of patients treated with nimodipine, and differences in recovery rates did not meet statistical significance (P 5.45). No statistical difference was found when the middle group recovery rates were compared to the entire cohort (P 5.54). When groups were compared against one another, there was no difference in recovery rates among all three groups (P 5.67). The average duration of treatment for all 53 patients was days, whereas the average duration of treatment in patients who had return of purposeful VFM was days. These values were not statistically different (P 5.59). When comparing the patients who had vocal fold recovery, the early group and middle group average days until recovery were and days, respectively. Again, the difference between these values did not show statistical significance (P 5.54). Also, when comparing the time to recovery between those patients in the early group compared to the entire cohort, there was no statistical difference (P 5.60). Last, when time to recovery was compared among all three groups, there was no difference in number of days (P 5.56). DISCUSSION Nimodipine treatment produced a 67.9% rate of recovery of VFM in our cohort of patients with acute, severe RLN injury. This is similar to our published results in the smaller cohort of patients included in this study. 7 There was no difference in recovery rates between patients who began treatment between 1 to 15 days postinjury and those who started the medication between 15 to 30 days postinjury. Patients who started nimodipine after 30 days postinjury had a slightly decreased recovery rate of 54%, but this was not statistically significant when compared to the other cohorts. This later treatment group was rather small (n 5 11) and varied in initiation times ( days), making comparison to the other groups more challenging. Thus, we cannot definitively state that late administration of nimodipine is similar to other time frames. The early group was individually compared to the entire cohort, and there was no significant difference in recovery rates. 188 Time to recovery was not significantly different when comparing the early and middle group (75.3 and 68.9 days). Average time to recovery in the late group was 66.5 days. An exact date for return of function is known in only a few patients who had a sudden improvement in their voice and asked to be seen in the office as soon as possible. Otherwise, patients were examined as per the protocol described. Our times to recovery are similar to those published by Hydman et al., who treated six patients immediately after iatrogenic RLN nerve injury without nerve transection. 2 Three of the six patients were found to have severe nerve injury on LEMG and remained on nimodipine, whereas the remaining patients were taken off the medication. All three patients who remained on nimodipine had return of some vocal fold function at 2 months, and near normal movement by 6 months. 2 Several theories suggest that earlier administration of the drug is beneficial. Nerve regeneration could be limited by muscle acetylcholine (ACh) receptors being occupied by autonomic nerves or misguided efferent nerves. 15,16 As our understanding of laryngeal innervation expands, it is clear that there are numerous connections between branches of the superior laryngeal nerve and RLN. 17 These connections may serve as pathways and provide foreign invader nerve fibers in lieu of native injured nerves, which can result in synkinetic innervation. 18 Other theories suggest that the effects of nimodipine therapy can be effective weeks after nerve injury. In an animal model, ACh receptors appear to decrease in number 10 weeks after denervation. 19 If nimodipine can hasten nerve regrowth and ACh receptor occupation, it is possible that initiation of nimodipine before 10 weeks could preserve the greatest number of ACh receptors. Due to its ability to cross the blood brain barrier, nimodipine may help prevent the gradual somatotopical rearrangement of neurons within the nucleus ambiguus after severe RLN injury. This preserved organization within the motor nucleus could encourage proper nerve regrowth. 8,20 Mattson et al. studied the effect of nimodipine therapy on neuromuscular junctions after RLN injury in animals. 10 Rats were divided between those who had no medical therapy and those who were immediately started on nimodipine. Of note,

4 TABLE III. Patient Demographics and Results by Cohorts. Early (1 15 Days) Middle (16 30 Days) Late (>30 Days) Total No. of patients Male Female Average age, yr Type of injury Iatrogenic Idiopathic No. of vocal folds recovered No. of vocal folds without recovery % recovery Average duration of treatment, d Average time to recover, d neuromuscular junctions (NMJs) in both cohorts were nearly depleted at 1 week, starting to recover at 2 weeks, and returning to normal levels at 6 weeks. This large fluctuation in NMJs could support our positive results in the middle and late groups, because nimodipine may have maximal benefit as the number of NMJs returns to normal. Though nimodipine therapy did not alter the number of recovered NMJs in that study, laryngeal electromyographic findings were improved in the treatment group. Nimodipine has been used in the treatment of facial nerve injury for some time. Clinical timing for administration of nimodipine therapy has been varied. In vestibular schwannoma surgery, nimodipine therapy was shown to alleviate cerebral vasospasm while also improving facial and cochlear nerve outcomes in these patients. 4,21 24 Scheller et al. conducted an open-label, randomized trial with patients receiving nimodipine prophylactically or after evidence of possible intraoperative nerve injury. 4 They reported improved facial nerve and cochlear nerve functional outcomes in their prophylactic treatment cohort. With respect to extracranial facial nerve injury, the same group used nimodipine therapy in patients with postoperative facial paresis (average of 20 days postinjury) after maxillofacial surgery. The authors noted that the treated patients had improved facial motion and faster rates of recovery when compared to those who did not receive nimodipine. 5 In regard to RLN injury, clinical efficacy of prophylactic or intraoperative initiation of nimodipine is unknown. Though our data suggest that nimodipine therapy started anytime before 4 months postinjury to the RLN may be beneficial to recovery of VFM, there are limitations to this study. A larger sample size in our late group would help better differentiate the possible benefits of nimodipine therapy among the three groups. Also, LEMG was performed soon after nerve injury in the early and middle group. It should be mentioned that historical controls as cited in this publication were based on LEMG studies obtained 3 to 4 weeks after RLN injury, which is in contrast to some patients in our study ,25 Early EMG may show decreased recruitment due to conduction block (neuropraxia) and may be falsely labeled as poor prognosis, when in reality it has a favorable recovery rate. To avoid this pitfall, we avoided categorizing this decreased recruitment as a poor prognosis by insisting that signs of active denervation (fibrillations) were necessary for inclusion. Last, although the results indicate that nimodipine positively influences recovery of VFM after paralysis, this has not been proven by level 1 evidence. At this time, we do not advocate the routine clinical use of nimodipine therapy for VFP until more evidence is available. A randomized clinical trial is necessary to fully elucidate the benefits of nimodipine therapy in acute VFP. Due to the results of our study, future trials should include all eligible patients who present within 4 months of RLN injury. CONCLUSION In our patient cohort, nimodipine therapy initiated within 4 months of acute VFP improves VFM recovery rates compared to historical controls. At present, there does not appear to be a significant difference in recovery rates between those patients in the early, middle, or late group. Further studies are needed to elucidate the benefit of nimodipine therapy, the optimal timing of the medication, and proper dosage in the treatment of acute VFP. At present, nimodipine therapy should be used in a clinical protocol until randomized clinical trial results have been published. Acknowledgments The authors thank Tina Harrison for her assistance with data management. BIBLIOGRAPHY 1. Halum SL, McRae B, Bijangi-Vishehsaraei K, Hiatt K. Neurotrophic factor-secreting autologous muscle stem cell therapy for the treatment of laryngeal denervation injury. Laryngoscope 2012;122:

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