Injection Augmentation for Chronic Cough *Brianna K. Crawley, †Thomas Murry, and †Lucian Sulica, *Loma Linda, California, and yNew York, New York Summary: Objectives/Hypothesis. Chronic cough (CC) is a pervasive and expensive health problem in the United States. Almost as diverse as its etiologies are the available therapeutic options. When vocal fold paresis and CC coincide, injection augmentation may provide an alternative to standard medical and behavioral treatments for CC. Our objective was to assess the effect of injection augmentation in a selected group of patients with CC who had failed multiple medical and behavioral treatments. Study Design. The study design is a retrospective case review. Methods. Our study group included six subjects (1 male and 5 females; aged 24–84 y) who presented for laryngologic evaluation with a chief complaint of CC unresponsive to conventional medical and behavioral management. The cough severity index (CSI), reflux symptom index (RSI), dyspnea severity index (DSI), and voice handicap index-10 (VHI-10), as well as subjective evaluation were assessed before and after the injection augmentation of the vocal folds was undertaken. Results. Five of six patients reported subjective improvement in cough. CSI scores improved in all six (average change 7.3, range 2–13). RSI and DSI scores also improved significantly after injection, whereas VHI-10 scores did not significantly change. One patient reported transient hoarseness after injection that completely resolved. One patient received injection augmentation three times, as the material resorbed and symptoms returned. Conclusions. Injection augmentation effected relief from CC in a select group of patients with CC refractory to previous medical and/or behavioral treatments. This intervention is a novel option for such patients and offers an alternative approach to medical treatment. Key Words: Chronic cough–Vocal fold paresis–Laryngeal neuropathy–Vocal fold injection–Neurogenic cough. INTRODUCTION Chronic cough (CC) is a pathologic state consisting of persistent, unproductive, and irritating upper airway-related cough lasting at least 8 weeks.1 CC is estimated to occur in 9–30% of the population and is associated with significant comorbidities including anxiety, depression, sleep disturbance, and decreased quality of life.2–4 Available treatment regimens reflect the myriad causes of CC: sinonasal-directed therapy, antireflux medications and behavioral changes,5 asthma medication regimens,1 voice therapy,6,7 and botulinum toxin A.8 Recently, clinical connections have been drawn between sensory neuropathy and chronic refractory cough after upper respiratory infection (URI), and medical therapy for neuropathy has been applied to some effect.9–12 The very diversity of these remedies underscores their lack of universal success and the complexity of the clinical problem. Of the patients with CC who presented to our center, a subset displayed some degree of laryngeal asymmetry on examination, suggestive of laryngeal nerve paresis. Although these patients rarely had vocal complaints typical of glottic insufficiency, such as weak voice or breathiness, such findings drove us to consider whether a motor paresis may be significant in the pathophysiology of CC. Current concepts of neurogenic cough assume the presence of sensory dysfunction. This assumption is validated when the presentation or modification of chemical, Accepted for publication January 14, 2015. From the *Department of Otolaryngology – Head and Neck Surgery, Loma Linda University Health, Loma Linda, California; and the yDepartment of Otolaryngology – Head and Neck Surgery, Parker Institute for the Voice, New York, New York. Address correspondence and reprint requests to Brianna K. Crawley, Department of Otolaryngology - Head and Neck Surgery, Loma Linda University Health, 1895 Orange Tree Lane, Suite 102, Redlands, CA 92374. E-mail: [email protected] Journal of Voice, Vol. -, No. -, pp. 1-5 0892-1997/$36.00 Ó 2015 The Voice Foundation http://dx.doi.org/10.1016/j.jvoice.2015.01.001
thermal, or proprioceptive sensory stimuli prevents or exacerbates cough.13–16 Although neurogenic cough is commonly thought of as a solely sensory neuropathy, sensory and motor neuropathy are unlikely to be separate in reality. Considering the close association of sensory and motor fibers of the vagus nerve, an inflammatory or infectious process likely affects both afferent and efferent nerves. The notion of distinct afferent and efferent neuropathy of the larynx may be as artificial as the historically obsolete distinction between adductor and abductor paralysis. We then hypothesized that injection augmentation, an effective treatment for glottic insufficiency from motor paresis, might be effective in the relief of cough. The purpose of this article was to report treatment results in a small cohort of carefully selected patients with CC unresponsive to conventional treatment and pharmacologic measures directed at CC.
METHODS This study was approved by the Institutional Review Board of Weill Cornell Medical College. The study group consisted of six patients with CC who had failed pharmacologic and behavioral treatments and who had been diagnosed with vocal fold paresis on laryngeal videostroboscopic examination by an otolaryngologist. Paresis is a qualitative diagnosis for which no established criteria exist. At our center, diagnosis of paresis is considered in the presence of specific findings. In order of importance from greatest to least important, these are atrophy, as demonstrated by vocal fold thinning and/or dilatation of the ventricle; unilateral ventricular fold hyperfunction; presence of a contact lesion; impaired adduction; phase difference/asymmetry of the mucosal wave; and glottic axis deviation.17 Patients underwent injection augmentation via peroral approach if performed in the operating room and cricothyroid approach
2
Journal of Voice, Vol. -, No. -, 2015
if performed in the office; the latter technique has been described elsewhere.18 Age, gender, comorbidities, and smoking histories were extracted from the medical record. The history and duration of the cough and each patient’s studies and treatments before injection were recorded. We also noted the laterality of the vocal fold paresis perceived on clinical evaluation. Pretreatment and posttreatment voice handicap index (VHI-10),19 reflux symptom index (RSI),20 dyspnea severity index (DSI), and cough severity index (CSI)21 data were collected. Posttreatment data were collected at the patients’ first follow-up visit at 1 month after procedure. The number and type of procedures undertaken were documented as were their results, adverse effects, and duration of follow-up.
transient hoarseness (patient 1). Three patients underwent subsequent calcium hydroxylapatite (CaHA; Radiesse Voice; Merz Aesthetics, San Mateo, CA) injections based on the success of the initial injection, one on three occasions (8/30/ 12, 9/27/12, and 5/30/13). In each case, relief was replicated, and the duration of relief was consistent with the expected duration of the injectable material. Case study Patient 1 was a 53-year-old woman with a history of hypothyroidism, metabolic syndrome, and migraines. She presented with 2.5 years of chronic unproductive cough after an upper respiratory infection. She denied dysphagia, but noted intermittent hoarseness and dyspnea. She did not identify any specific cough triggers. She had seen several specialists and was treated for upper airway cough syndrome, pulmonary pathology, allergies, and gastroesophageal reflux disease (GERD). She tried several proton-pump inhibitors, steroid nasal sprays, oral steroids, amitriptyline, and gabapentin. Although she intermittently attained transient relief with new medications, her symptoms always returned, usually in a matter of days. She ascribed a 65-pound weight gain to her course of amitriptyline. She completed a remarkable 6 months of speech therapy, which reduced her nighttime coughing but did not appreciably improve her daytime coughing. She had never smoked or used angiotensin-converting enzyme (ACE) inhibitors, denied alcohol use, and her surgical history was noncontributory. The head and neck examination was unremarkable, with the exception of mucosal wave phase asymmetry and mildly impaired left vocal fold adduction on stroboscopy. Glottic closure was not obviously impaired (Figure 5A and B). Based on the laryngoscopic findings, the patient underwent bilateral methylcellulose injections. At her follow-up visit, she reported a dramatic improvement in her cough and stated that speaking and breathing seemed easier. She continued her behavioral therapy but returned in 3 months, complaining that her cough was beginning to return. She underwent bilateral repeat injections with calcium hydroxyapatite (CaHA), which gave her partial relief. Residual symptoms were successfully
RESULTS Five of six patients were females with ages ranging from 24– 84 years (mean 55.7). None were active smokers, although two quit more than 20 years before presentation, well before symptom onset. Four reported a respiratory infection associated with the onset of their symptoms. Comorbidities included depression in five patients and a history of pulmonary complaints (pneumonia, bronchiectasis, asthma, and bronchitis) in three. All had seen at least two specialists for the complaint of cough. Notably, one had consulted four pulmonologists, a gastroenterologist, an allergist, a rheumatologist, two otolaryngologists, a speech pathologist, and a hypnotist. Table 1 summarizes the inventory of patients’ treatments before injection. No lasting improvement was achieved with any these regimens. Each patient received an initial injection of methylcellulose (Radiesse Voice Gel; Merz Aesthetics, San Mateo, CA) as a trial treatment according to the principles outlined by Carroll and Rosen.22 Four injections were performed in the office and two in the operating room, these last by patient request. Preinjection and postinjection patient-reported VHI, RSI, DSI, and CSI scores are presented in Figures 1–4. In addition to index data, five of six patients reported a satisfactory reduction in cough after the injection. The only adverse effects were dissatisfaction with the degree of relief (patient 3) and
TABLE 1. Therapeutic Interventions Before Injection Trial Allergy Pulmonary/ Behavioral Patient Gabapentin Amitriptyline Tramadol Lyrica LPR* Steroidsy Medicationz Asthmax Botox Therapy Surgeryk 1 2 3{ 4 5 6
x x x x
x x x
x x
x x
* Laryngopharyngeal reflux therapy. y Oral PPI and H2-blocker. z Oral or topical nasal, desensitization therapy. x Oral or inhaled. k Nissen, septoplasty/turbinate reductions. { Patient 3 reported minimal benefit after injection augmentation.
x x x x x x
x
x
x
x x x
x x x x
x x x x
x
x
x
Brianna K. Crawley, et al
Injection Augmentation for Chronic Cough
3
FIGURE 1. Preprocedure and postprocedure cough severity index.
FIGURE 3. Preprocedure and postprocedure voice handicap index-10.
alleviated after the injection of additional CaHA 4 weeks later. On return of symptoms 9 months later, the patient underwent repeat injection. The patient experienced some hoarseness after injection, attributed to overinjection on the right side. However, her hoarseness resolved completely over 3 weeks, and her cough was again relieved. She is currently considering medialization laryngoplasty for more durable relief. DISCUSSION Injection augmentation may influence cough production in three ways. First, and most simply, augmentation may create a volume effect. This may remedy glottic insufficiency too mild to appreciate clinically, thereby preventing microaspiration and irritation that perpetuates cough and increasing cough efficiency. Injection augmentation has recently been shown to improve voluntary cough airflow measures, by increasing efficacy of cough and improving glottic closure.23 In a study of Botox injection into thyroarytenoid muscles for CC, significant relief was noted before the expected paresis could take effect, suggesting a volume component preceding a more durable change in neuropathic nociceptive cascades.8 We also observed an apparent volume effect in patient 1, when after partial relief from her second injection, she required additional volume to achieve complete relief.
In addition, coughing is a traumatic behavior that causes, exacerbates, or perpetuates voice disorders and even the cough itself.6 Improving glottic closure with injection laryngoplasty can interrupt the positive feedback loop incited by forceful or traumatic glottic closure, repeated vocal fold trauma, and release of neuropeptides.24,25 An improvement in glottic efficiency may also decrease a patient’s shortness of breath, especially during speech, which has been reported as a cough trigger in 53% of patients with CC.26 In that study, talking and telephone use were among the most important triggers of cough. Although most of our patients did not complain of vocal problems, or improve in their VHI-10 after intervention, a subtle change in vocal efficiency or the sensations associated with speaking may be responsible for success. Second, injection augmentation may alter sensory signaling. Patients with chronic refractory cough are hypersensitive both to known tussigens and nontussive agents, a pattern consistent with afferent reflex hypersensitivity (neuropathic sensory disorder).2,26 The success of neuromodulatory therapies in some of these patients supports this theory.10–12 Gabapentin has also been shown to reduce cough in the setting of recurrent and superior laryngeal motor neuropathy.10 Although injection augmentation is a mechanical rather than pharmacologic intervention, it may ultimately halt the cough reflex by altering
FIGURE 2. Preprocedure and postprocedure dyspnea severity index.
FIGURE 4. Preprocedure and postprocedure reflux symptom index.
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Journal of Voice, Vol. -, No. -, 2015
FIGURE 5. Laryngoscopy of patient 1 shows left vocal fold paresis, as demonstrated by atrophy of the left vocal fold (A) and dilatation of the left ventricle most evident in abduction (B). Other mild movement abnormalities were evident on dynamic examination. sensory receptor response. Potential mechanisms include alteration in proprioceptive input to the reflex, changes in upstream neuropeptide release as a result of decreased closing force or modification of the perception of laryngeal irritants because of a change in the position and exposure of laryngeal sensory nerve endings. Focal sensory change may even be more effective in reducing laryngeal hypersensitivity than pharmacologic neuromodulators, which diffusely target afferent neural function throughout the body. Finally, in cough especially, the placebo effect cannot be discounted. Placebo describes the phenomenon of a successful therapy that does not possess a component known or suspected to provide therapeutic relief. The placebo effect has been noted to be particularly vigorous in cough. In one review, the effect of the placebo in eight trials was noted to be an average of 85% of that of the antitussive medications under investigation. One study even reported a placebo effect greater than the effect of the trial medication.27 Our treatment was given without controls. The nature of the treatment, with the patient’s participation and ability to view the changing laryngeal anatomy as a result of the injection, precluded a blinded study. If we acknowledge the placebo effect to be related to the patient’s belief about the efficacy of the treatment, we provided our patients with powerful feedback that a change had occurred.28 However, we note that the success of our intervention was reliably reproducible with subsequent injections and consistent with the expected duration of the injectable when applied for the treatment of vocal fold paresis for voice complaints. The matter is somewhat obscured because neurologic changes that presumably occur with placebo may also be at work when neural relays involved in cough are altered by chemical or mechanical means. There may exist a final common pathway that includes placebo. Based on the experience reported in this article, we now consider injection augmentation in patients with refractory CC and laryngoscopic findings suggestive of motor paresis. We no longer propose trial injection with methylcellulose, using the more long-term CaHA at the initial treatment, and we tend to offer injection augmentation earlier in the treatment algorithm, sometimes concurrent with behavioral intervention and neuro-
modulating medication. As we use the treatment more widely, in a less highly selected group of patients who have perhaps not failed as many interventions, its efficacy may decrease. Further investigation is needed to identify clinical factors that predict success from this approach and elucidate the mechanism of effect. A prospective trial may help clarify this and the role of placebo. Given the injectables currently available, the duration of relief is suboptimal, and indefinite repeat injection is not a reasonable treatment plan for most patients. It remains to be seen if results can be duplicated in a more durable manner with medialization laryngoplasty. CONCLUSIONS Injection laryngoplasty appears to be a useful addition to the array of treatments for chronic refractory cough based on its effect in a small group of patients who failed multiple prior treatments. The mechanism remains to be determined, but this treatment response suggests that mild laryngeal motor paresis may play a role in the etiology of some CC in addition to the sensory mechanisms previously discussed in the literature. Further investigation is required to clarify the mechanism and whether effects may be duplicated by more durable interventions such as laryngeal framework surgery. Acknowledgments The authors have neither conflicts of interest nor financial relationships to disclose. REFERENCES 1. Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 suppl):1s–23s. 2. O’Neill J, McMahon SB, Undem BJ. Chronic cough and pain: Janus faces in sensory neurobiology? Pulm Pharmacol Ther. 2013;4:00140–00145. 3. Young EC, Smith JA. Quality of life in patients with chronic cough. Ther Adv Respir Dis. 2010;4:49–55. 4. Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008;371:1364–1374. 5. Altman KW, Simpson CB, Amin MR, Abaza M, Balkissoon R, Casiano RR. Cough and paradoxical vocal fold motion. Otolaryngol Head Neck Surg. 2002;127:501–511.
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Injection Augmentation for Chronic Cough
6. Vertigan AE, Theodoros DG, Gibson PG, Winkworth AL. Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy. Thorax. 2006;61:1065–1069. 7. Murry T, Tabaee A, Owczarzak V, Aviv JE. Respiratory retraining therapy and management of laryngopharyngeal reflux in the treatment of patients with cough and paradoxical vocal fold movement disorder. Ann Otol Rhinol Laryngol. 2006;115:754–758. 8. Chu MW, Lieser JD, Sinacori JT. Use of botulinum toxin type A for chronic cough: a neuropathic model. Arch Otolaryngol Head Neck Surg. 2010;136: 447–452. 9. Amin MR, Koufman JA. Vagal neuropathy after upper respiratory infection: a viral etiology? Am J Otolaryngol. 2001;22:251–256. 10. Lee B, Woo P. Chronic cough as a sign of laryngeal sensory neuropathy: diagnosis and treatment. Ann Otol Rhinol Laryngol. 2005;114:253–257. 11. Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomized, double-blind, placebo-controlled trial. Lancet. 2012;380:1583–1589. 12. Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. Laryngoscope. 2006;116:2108–2112. 13. Plevkova J, Kollarik M, Poliacek I, et al. The role of trigeminal nasal TRPM8-expressing afferent neurons in the antitussive effects of menthol. J Appl Physiol (1985). 2013;115:268–274. 14. Yu L, Xu X, Wang L, Yang Z, Lu H, Qiu Z. Capsaicin-sensitive cough receptors in lower airway are responsible for cough hypersensitivity in patients with upper airway cough syndrome. Med Sci Monit. 2013;19:1095–1101. 15. Blitzer A. Spasmodic dysphonia and botulinum toxin: experience from the largest treatment series. Eur J Neurol. 2010;17(suppl 1):28–30. 16. Gilio F, Curra A, Lorenzano C, Modugno N, Manfredi M, Berardelli A. Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia. Ann Neurol. 2000;48:20–26.
5
17. Estes C, Sulica L. Vocal fold pseudocyst: results of 46 cases undergoing a uniform treatment algorithm. Laryngoscope. 2014;124:1180–1186. 18. Sulica L, Rosen CA, Postma GN, et al. Current practice in injection augmentation of the vocal folds: indications, treatment principles, techniques, and complications. Laryngoscope. 2010;120:319–325. 19. Rosen CA, Lee AS, Osborne J, Zullo T, Murry T. Development and validation of the voice handicap index-10. Laryngoscope. 2004;114: 1549–1556. 20. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice. 2002;16:274–277. 21. Shembel AC, Rosen CA, Zullo TG, Gartner-Schmidt JL. Development and validation of the cough severity index: a severity index for chronic cough related to the upper airway. Laryngoscope. 2013;123: 1931–1936. 22. Carroll TL, Rosen CA. Trial vocal fold injection. J Voice. 2010;24: 494–498. 23. Ruddy BH, Pitts TE, Lehman J, Spector B, Lewis V, Sapienza CM. Improved voluntary cough immediately following office based vocal fold medialization injections. Laryngoscope. 2014;124:1645–1647. 24. Sant’Ambrogio G, Widdicombe J. Reflexes from airway rapidly adapting receptors. Respir Physiol. 2001;125:33–45. 25. Canning BJ. Central regulation of the cough reflex: therapeutic implications. Pulm Pharmacol Ther. 2009;22:75–81. 26. Vertigan AE, Gibson PG. Chronic refractory cough as a sensory neuropathy: evidence from a reinterpretation of cough triggers. J Voice. 2011;25: 596–601. 27. Eccles R. The powerful placebo in cough studies? Pulm Pharmacol Ther. 2002;15:303–308. 28. Morris D. Placebo, pain and belief: a biocultural model. In: Harrington A, ed. The Placebo Effect. An Interdisciplinary Approach. Cambridge, MA: Harvard University Press; 1999:187–207.
thermal, or proprioceptive sensory stimuli prevents or exacerbates cough.13–16 Although neurogenic cough is commonly thought of as a solely sensory neuropathy, sensory and motor neuropathy are unlikely to be separate in reality. Considering the close association of sensory and motor fibers of the vagus nerve, an inflammatory or infectious process likely affects both afferent and efferent nerves. The notion of distinct afferent and efferent neuropathy of the larynx may be as artificial as the historically obsolete distinction between adductor and abductor paralysis. We then hypothesized that injection augmentation, an effective treatment for glottic insufficiency from motor paresis, might be effective in the relief of cough. The purpose of this article was to report treatment results in a small cohort of carefully selected patients with CC unresponsive to conventional treatment and pharmacologic measures directed at CC.
METHODS This study was approved by the Institutional Review Board of Weill Cornell Medical College. The study group consisted of six patients with CC who had failed pharmacologic and behavioral treatments and who had been diagnosed with vocal fold paresis on laryngeal videostroboscopic examination by an otolaryngologist. Paresis is a qualitative diagnosis for which no established criteria exist. At our center, diagnosis of paresis is considered in the presence of specific findings. In order of importance from greatest to least important, these are atrophy, as demonstrated by vocal fold thinning and/or dilatation of the ventricle; unilateral ventricular fold hyperfunction; presence of a contact lesion; impaired adduction; phase difference/asymmetry of the mucosal wave; and glottic axis deviation.17 Patients underwent injection augmentation via peroral approach if performed in the operating room and cricothyroid approach
2
Journal of Voice, Vol. -, No. -, 2015
if performed in the office; the latter technique has been described elsewhere.18 Age, gender, comorbidities, and smoking histories were extracted from the medical record. The history and duration of the cough and each patient’s studies and treatments before injection were recorded. We also noted the laterality of the vocal fold paresis perceived on clinical evaluation. Pretreatment and posttreatment voice handicap index (VHI-10),19 reflux symptom index (RSI),20 dyspnea severity index (DSI), and cough severity index (CSI)21 data were collected. Posttreatment data were collected at the patients’ first follow-up visit at 1 month after procedure. The number and type of procedures undertaken were documented as were their results, adverse effects, and duration of follow-up.
transient hoarseness (patient 1). Three patients underwent subsequent calcium hydroxylapatite (CaHA; Radiesse Voice; Merz Aesthetics, San Mateo, CA) injections based on the success of the initial injection, one on three occasions (8/30/ 12, 9/27/12, and 5/30/13). In each case, relief was replicated, and the duration of relief was consistent with the expected duration of the injectable material. Case study Patient 1 was a 53-year-old woman with a history of hypothyroidism, metabolic syndrome, and migraines. She presented with 2.5 years of chronic unproductive cough after an upper respiratory infection. She denied dysphagia, but noted intermittent hoarseness and dyspnea. She did not identify any specific cough triggers. She had seen several specialists and was treated for upper airway cough syndrome, pulmonary pathology, allergies, and gastroesophageal reflux disease (GERD). She tried several proton-pump inhibitors, steroid nasal sprays, oral steroids, amitriptyline, and gabapentin. Although she intermittently attained transient relief with new medications, her symptoms always returned, usually in a matter of days. She ascribed a 65-pound weight gain to her course of amitriptyline. She completed a remarkable 6 months of speech therapy, which reduced her nighttime coughing but did not appreciably improve her daytime coughing. She had never smoked or used angiotensin-converting enzyme (ACE) inhibitors, denied alcohol use, and her surgical history was noncontributory. The head and neck examination was unremarkable, with the exception of mucosal wave phase asymmetry and mildly impaired left vocal fold adduction on stroboscopy. Glottic closure was not obviously impaired (Figure 5A and B). Based on the laryngoscopic findings, the patient underwent bilateral methylcellulose injections. At her follow-up visit, she reported a dramatic improvement in her cough and stated that speaking and breathing seemed easier. She continued her behavioral therapy but returned in 3 months, complaining that her cough was beginning to return. She underwent bilateral repeat injections with calcium hydroxyapatite (CaHA), which gave her partial relief. Residual symptoms were successfully
RESULTS Five of six patients were females with ages ranging from 24– 84 years (mean 55.7). None were active smokers, although two quit more than 20 years before presentation, well before symptom onset. Four reported a respiratory infection associated with the onset of their symptoms. Comorbidities included depression in five patients and a history of pulmonary complaints (pneumonia, bronchiectasis, asthma, and bronchitis) in three. All had seen at least two specialists for the complaint of cough. Notably, one had consulted four pulmonologists, a gastroenterologist, an allergist, a rheumatologist, two otolaryngologists, a speech pathologist, and a hypnotist. Table 1 summarizes the inventory of patients’ treatments before injection. No lasting improvement was achieved with any these regimens. Each patient received an initial injection of methylcellulose (Radiesse Voice Gel; Merz Aesthetics, San Mateo, CA) as a trial treatment according to the principles outlined by Carroll and Rosen.22 Four injections were performed in the office and two in the operating room, these last by patient request. Preinjection and postinjection patient-reported VHI, RSI, DSI, and CSI scores are presented in Figures 1–4. In addition to index data, five of six patients reported a satisfactory reduction in cough after the injection. The only adverse effects were dissatisfaction with the degree of relief (patient 3) and
TABLE 1. Therapeutic Interventions Before Injection Trial Allergy Pulmonary/ Behavioral Patient Gabapentin Amitriptyline Tramadol Lyrica LPR* Steroidsy Medicationz Asthmax Botox Therapy Surgeryk 1 2 3{ 4 5 6
x x x x
x x x
x x
x x
* Laryngopharyngeal reflux therapy. y Oral PPI and H2-blocker. z Oral or topical nasal, desensitization therapy. x Oral or inhaled. k Nissen, septoplasty/turbinate reductions. { Patient 3 reported minimal benefit after injection augmentation.
x x x x x x
x
x
x
x x x
x x x x
x x x x
x
x
x
Brianna K. Crawley, et al
Injection Augmentation for Chronic Cough
3
FIGURE 1. Preprocedure and postprocedure cough severity index.
FIGURE 3. Preprocedure and postprocedure voice handicap index-10.
alleviated after the injection of additional CaHA 4 weeks later. On return of symptoms 9 months later, the patient underwent repeat injection. The patient experienced some hoarseness after injection, attributed to overinjection on the right side. However, her hoarseness resolved completely over 3 weeks, and her cough was again relieved. She is currently considering medialization laryngoplasty for more durable relief. DISCUSSION Injection augmentation may influence cough production in three ways. First, and most simply, augmentation may create a volume effect. This may remedy glottic insufficiency too mild to appreciate clinically, thereby preventing microaspiration and irritation that perpetuates cough and increasing cough efficiency. Injection augmentation has recently been shown to improve voluntary cough airflow measures, by increasing efficacy of cough and improving glottic closure.23 In a study of Botox injection into thyroarytenoid muscles for CC, significant relief was noted before the expected paresis could take effect, suggesting a volume component preceding a more durable change in neuropathic nociceptive cascades.8 We also observed an apparent volume effect in patient 1, when after partial relief from her second injection, she required additional volume to achieve complete relief.
In addition, coughing is a traumatic behavior that causes, exacerbates, or perpetuates voice disorders and even the cough itself.6 Improving glottic closure with injection laryngoplasty can interrupt the positive feedback loop incited by forceful or traumatic glottic closure, repeated vocal fold trauma, and release of neuropeptides.24,25 An improvement in glottic efficiency may also decrease a patient’s shortness of breath, especially during speech, which has been reported as a cough trigger in 53% of patients with CC.26 In that study, talking and telephone use were among the most important triggers of cough. Although most of our patients did not complain of vocal problems, or improve in their VHI-10 after intervention, a subtle change in vocal efficiency or the sensations associated with speaking may be responsible for success. Second, injection augmentation may alter sensory signaling. Patients with chronic refractory cough are hypersensitive both to known tussigens and nontussive agents, a pattern consistent with afferent reflex hypersensitivity (neuropathic sensory disorder).2,26 The success of neuromodulatory therapies in some of these patients supports this theory.10–12 Gabapentin has also been shown to reduce cough in the setting of recurrent and superior laryngeal motor neuropathy.10 Although injection augmentation is a mechanical rather than pharmacologic intervention, it may ultimately halt the cough reflex by altering
FIGURE 2. Preprocedure and postprocedure dyspnea severity index.
FIGURE 4. Preprocedure and postprocedure reflux symptom index.
4
Journal of Voice, Vol. -, No. -, 2015
FIGURE 5. Laryngoscopy of patient 1 shows left vocal fold paresis, as demonstrated by atrophy of the left vocal fold (A) and dilatation of the left ventricle most evident in abduction (B). Other mild movement abnormalities were evident on dynamic examination. sensory receptor response. Potential mechanisms include alteration in proprioceptive input to the reflex, changes in upstream neuropeptide release as a result of decreased closing force or modification of the perception of laryngeal irritants because of a change in the position and exposure of laryngeal sensory nerve endings. Focal sensory change may even be more effective in reducing laryngeal hypersensitivity than pharmacologic neuromodulators, which diffusely target afferent neural function throughout the body. Finally, in cough especially, the placebo effect cannot be discounted. Placebo describes the phenomenon of a successful therapy that does not possess a component known or suspected to provide therapeutic relief. The placebo effect has been noted to be particularly vigorous in cough. In one review, the effect of the placebo in eight trials was noted to be an average of 85% of that of the antitussive medications under investigation. One study even reported a placebo effect greater than the effect of the trial medication.27 Our treatment was given without controls. The nature of the treatment, with the patient’s participation and ability to view the changing laryngeal anatomy as a result of the injection, precluded a blinded study. If we acknowledge the placebo effect to be related to the patient’s belief about the efficacy of the treatment, we provided our patients with powerful feedback that a change had occurred.28 However, we note that the success of our intervention was reliably reproducible with subsequent injections and consistent with the expected duration of the injectable when applied for the treatment of vocal fold paresis for voice complaints. The matter is somewhat obscured because neurologic changes that presumably occur with placebo may also be at work when neural relays involved in cough are altered by chemical or mechanical means. There may exist a final common pathway that includes placebo. Based on the experience reported in this article, we now consider injection augmentation in patients with refractory CC and laryngoscopic findings suggestive of motor paresis. We no longer propose trial injection with methylcellulose, using the more long-term CaHA at the initial treatment, and we tend to offer injection augmentation earlier in the treatment algorithm, sometimes concurrent with behavioral intervention and neuro-
modulating medication. As we use the treatment more widely, in a less highly selected group of patients who have perhaps not failed as many interventions, its efficacy may decrease. Further investigation is needed to identify clinical factors that predict success from this approach and elucidate the mechanism of effect. A prospective trial may help clarify this and the role of placebo. Given the injectables currently available, the duration of relief is suboptimal, and indefinite repeat injection is not a reasonable treatment plan for most patients. It remains to be seen if results can be duplicated in a more durable manner with medialization laryngoplasty. CONCLUSIONS Injection laryngoplasty appears to be a useful addition to the array of treatments for chronic refractory cough based on its effect in a small group of patients who failed multiple prior treatments. The mechanism remains to be determined, but this treatment response suggests that mild laryngeal motor paresis may play a role in the etiology of some CC in addition to the sensory mechanisms previously discussed in the literature. Further investigation is required to clarify the mechanism and whether effects may be duplicated by more durable interventions such as laryngeal framework surgery. Acknowledgments The authors have neither conflicts of interest nor financial relationships to disclose. REFERENCES 1. Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 suppl):1s–23s. 2. O’Neill J, McMahon SB, Undem BJ. Chronic cough and pain: Janus faces in sensory neurobiology? Pulm Pharmacol Ther. 2013;4:00140–00145. 3. Young EC, Smith JA. Quality of life in patients with chronic cough. Ther Adv Respir Dis. 2010;4:49–55. 4. Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008;371:1364–1374. 5. Altman KW, Simpson CB, Amin MR, Abaza M, Balkissoon R, Casiano RR. Cough and paradoxical vocal fold motion. Otolaryngol Head Neck Surg. 2002;127:501–511.
Brianna K. Crawley, et al
Injection Augmentation for Chronic Cough
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