Use of Botulinum Toxin Type a for Chronic Cough a Neuropathic Model

ORIGINAL ARTICLE Use of Botulinum Toxin Type A for Chronic Cough A Neuropathic Model

Michael W. Chu, MD; John D. Lieser, MD; John T. Sinacori, MD

Objective: To review the experience and outcomes of Results: Three of the 4 patients (75%) were women, and a novel use of botulinum toxin type A (BtxA) in the treat- the mean patient age was 55.6 years (range, 38-64 years). ment of chronic cough. All patients had significant relief of cough after BtxA injection, with complete resolution after a median of 7 in- Design: Retrospective case series. jections (range, 4-16), using a mean dose of 4.0 U (range, 1.0-10.0 U) per treatment session for a mean duration Setting: Academic referral center. of 25.7 months (range, 7.2-42.9 months).

Patients : A total of 438 patients were diagnosed as hav- Conclusions: To our knowledge, this is the first re- ing laryngeal spasm and chronic cough, and 6 were docu- ported series in the literature of the use of BtxA in the treat- mented as having chronic cough treated with BtxA injec- ment of chronic cough in adults. In this small case series, tions. Two patients were excluded from the study because we report a neuropathic model for chronic cough caused of a history of tracheostomy or concurrent laryngeal and voice dysfunction. by neuroplastic changes and laryngeal hyperactivity as an explanation for the effectiveness of BtxA treatment. Fur- Intervention: Electromyography-guided BtxA injec- ther research and long-term follow-up are warranted, but tions of the thyroarytenoid muscles. BtxA is effective in directly decreasing laryngeal hypertonicity and possibly reducing neurogenic inflammation and Main Outcome Measures: Patient demographics (age neuropeptide-mediated cough. Botulinum toxin type A can and sex), voice-related quality-of-life scores, postproce- be considered for the treatment of chronic cough refrac- dure complications, number of BtxA units used, num- tory to other medical therapies. ber and length of treatments, and voice outcomes are reviewed. Arch Otolaryngol Head Neck Surg. 2010;136(5):447-452

OUGH IS ONE OF THE CHIEF sensory and motor mechanisms. The cough complaints in the pri- reflex begins when a stimulus activates a mary care setting. Cough sensory receptor to stimulate an afferent is a symptom, not a diag- signal to the brainstem through various nosis, and it usually re- neuropeptides. This information is inte- mitsC after the underlying condition re- grated in the brainstem, with possible solves. However, cough can persist in some interactions from the cerebral cortex, and patients despite extensive medical workup results in an efferent signal of motor in- and multiple therapies. The cough reflex structions to coordinate a cough.1 Cough- is mediated by a variety of afferent and ef- ing requires a sequence of several steps. ferent neurologic pathways and has nu- First, deep inspiration, glottic closure, and merous causes. relaxation of the diaphragm allow genera- Cough can be classified by anatomy, with tion of increased airway pressure. Sec- tracheobronchial (eg, asthma, bronchitis, ond, the thoracic muscles contract and Author Affiliations: or tracheal stenosis), laryngeal (eg, vocal bronchial smooth muscles constrict as the Department of fold paralysis or neoplasm), or sinonasal (eg, glottis opens. Third, a marked increase of Otolaryngology–Head & Neck allergies, postnasal drip, or rhinosinusitis) airway flow produces a cough, with shear- Surgery, Eastern Virginia causes.1 Cough can also be classified by ing forces for the expulsion of mucus or Medical School, Norfolk 1 (Drs Chu and Sinacori), and source of stimulus, including chemical, me- foreign material. 1 Ear, Nose, & Throat Center of chanical, or inflammatory mediators. The cough reflex helps protect the air- Fredericksburg, Fredericksburg, The neurologic pathway of the cough way by expelling mucus or noxious mate- Virginia (Dr Lieser). reflex involves a complex interaction of rial. When this normal process is dysfunc-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 tional, chronic cough can develop. Chronic cough is defined PATIENT 1 as cough that persists for more than 3 weeks2 despite treatment. The most common causes of cough are asthma, al- Patient 1 was a 64-year-old attorney who had a 30-month his- lergic rhinosinusitis, laryngopharyngeal reflux, chronic tory of chronic cough, which began after an episode of pneumo- bronchitis, and chronic rhinosinusitis. Proper diagnosis nia and pertussis infection. His cough was consistently triggered and treatment are effective in treating symptoms of cough. with initiation of phonation, which severely limited his ability to work and led to early retirement. He did not report hoarseness However, there is a small subset of patients for whom cough or other changes in voice quality. The results of his workup were persists despite treatment. These patients present a diag- negative for allergic rhinitis, reflux disease, shortness of breath, nostic and therapeutic challenge and are often given a non- or pulmonary origins. He did not use tobacco or alcohol. The pa- specific diagnosis of chronic cough. tient had previously been evaluated at 3 other tertiary medical Patients with chronic cough likely represent a hetero- facilities and treated with antireflux medications, allergy medi- geneous group of disorders with multifactorial causes and cations, multiple antibiotics, systemic and inhaled corticoste- a common laryngeal response. Chronic cough is often mis- roids, antitussive medications, mucolytics, cough suppressants, diagnosed as irritable laryngeal syndrome (ILS), paradoxi- and voice therapy. All previous treatments did not provide any cal vocal fold motion (PVFM), Munchausen stridor, fac- improvement. His chief complaint was the inability to speak with- titious asthma, hysterical or psychogenic asthma, episodic out coughing, which had caused him to retire from his work as an attorney and withdraw socially. Findings on physical exami- paroxysmal laryngospasm, functional laryngeal stridor, la- nation were unremarkable except that the patient had a dry cough ryngeal dyskinesia, or involuntary adduction during in- only when speaking. His initial voice-related quality-of-life 3 spiration. Chronic cough, also known as habit cough or (VRQOL) score was 20, and videostroboscopy revealed normal psychogenic cough, is believed to be caused by a dysfunc- vocal fold mobility with no mucosal abnormalities. tion in neurologic activity. This entity is poorly under- stood, and there is no consensus for diagnosis or manage- PATIENT 2 ment. Recent literature4-6 has suggested a neuropathic model for chronic cough, likened to other cranial nerve Patient 2 was a 38-year-old teacher who had an 8-month his- disorders, such as Bell palsy, trigeminal neuralgia, glos- tory of chronic cough. She had a history of asthma confirmed sopharyngeal neuralgia, and postviral vagal and olfactory by pulmonary function testing, allergic rhinosinusitis, and al- disorders. Vagal neuropathy can affect the larynx through lergies to trees, pollen, and mites confirmed by skin testing. She sensory and motor nerves by causing vocal fold paresis or also had a small hiatal hernia diagnosed by barium swallow. Her laryngeal pain or irritation. Behavioral therapy has been cough was triggered by phonation and worsened at night. Pre- suggested6 to address the neurologic and psychogenic com- vious treatment with albuterol sulfate, theophylline, mucolytics, cough suppressants, proton pump inhibitors, immuno- ponent, as well as other anecdotal therapies aimed at neu- 1,7-9 therapy, allergy medications, and voice therapy provided minimal ropathic pain or neurogenic hypersensitivity. improvement. Physical examination revealed signs of extra- We report a case series of 4 patients without any iden- esophageal reflux but normal vocal fold mobility and mucosa; tifiable cause of chronic cough who had thorough her initial VRQOL score was unavailable for review. workups and empirical treatment without success, including aggressive pharmacotherapy for reflux, asthma, PATIENT 3 allergies, and over-the-counter therapies. All 4 patients were successfully treated with botulinum toxin type A Patient 3 was a 55-year-old teacher with a 30-year history of (BtxA) injections, and we hypothesize laryngeal hyper- chronic cough. Her medical history was significant for laparo- tonicity and inappropriate neurologic feedback as the scopic fundoplication for reflux disease, seasonal allergies, and causes of chronic cough in these patients. We discuss the asthma. Previous treatment included proton pump inhibitors, mechanisms of cough and pharmacologic activity of BtxA albuterol, mucolytics, cough suppressants, and speech therapy. as a potential treatment of neuropathic chronic cough. Her chief complaint was a chronic cough that interfered with her quality of life. Physical examination results were nonfo- cal, with a normal laryngoscopy result that did not reveal any laryngeal disease. Her initial VRQOL score was 21. METHODS PATIENT 4 The institutional review board approved a review of all patient records from July 1, 2003, through March 31, 2009, at a single, Patient 4 was a 41-year-old woman with a 2-year history of chronic academic, tertiary referral center for diagnoses of laryngeal spasm cough, despite reflux and asthma treatments. She was a nonsmoker and chronic cough. A total of 438 patients were identified and, andnondrinkerwithnoothersignificantmedicalhistory.Themain of those, 6 were documented to have chronic cough treated with reason for her office visit was social embarrassment, causing her BtxA injections. One patient was excluded because of a his- to avoid dating and other social activities. Previous treatment with tory of multiple tracheostomies and another patient was ex- protonpumpinhibitors,mucolytics,coughsuppressants,andspeech cluded because she currently had spasmodic dysphonia treated therapy provided no relief of her symptoms. Physical examina- with BtxA injections. The remaining 4 patients had significant tion revealed normal laryngeal function and no pathological find- disruption of function and quality of life despite exhaustive ings. Her initial VRQOL score was 73. workup and conservative, empirical treatment of chronic cough. Botulinum toxin type A injections were offered as a possible RESULTS treatment after informed consent, rationale of therapy, explanation of off-label use, and disclosure of possible adverse effects, such as temporary breathiness and decreased voice qual- Of the 4 patients, 3 (75%) were women, and the mean pa- ity. The patients, treatment, and outcomes are reviewed. tient age was 55.6 years (age range, 38-64 years). All 4 pa-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 tients had significant relief of cough after BtxA injection. Table. Botulinum Toxin Type A Injection The median number of BtxA injections was 7 (range, 4-16), a and the mean amount of BtxA injected was 4.0 U (range, for Chronic Cough Case Series 1.0-10.0 U) per session. The mean duration of therapy was Duration 25.7months(range,7.2-42.9months)beforecompletesymp- of Botulinum tom resolution (Table). Patient No./ No. of Mean No. of Units Toxin Type A Sex/Age, y Injections Injected (Range) Injections, mo PATIENT 1 1/M/64 16 4.34 (1.00-5.00) 39.7 2/F/38 4 2.38 (2.00-2.50) 7.2 Patient 1 was treated with electromyography-guided per- 3/F/55 6 6.00 (2.50-10.00) 12.9 cutaneous injection of BtxA to the bilateral thyroaryte- 4/F/41 8 2.75 (2.00-3.00) 42.9

noid muscles. Breathiness was a mild, although not un- a expected, adverse effect after treatment and without All injections were made into the thyroarytenoid muscle. dyspnea or aspiration. His symptoms improved significantly, and he subsequently received unilateral injec- that involves stimuli activating sensory receptors, an af- tions to the thyroarytenoid muscles, which did not cause ferent signal, integration in the brainstem and cerebral breathiness in his voice while relieving his chronic cough. cortex, and coordinated motor actions sent through vari- He is now able to participate in social interactions, and ous efferent pathways. There are several possible mod- his VRQOL score increased from 20 to 80 after treat- els to explain chronic cough. Laryngeal causes of chronic ment. The patient’s chronic cough resolved after 16 treat- cough include gastroesophageal reflux disease, emo- ments for 39.7 months without any major complica- tional distress, vocal misuse, postviral cranial neuropa- tions, and he has remained symptom free. thy, PVFM,1 and ILS.8 However, the common mechanism for these etiologies is a hyperfunctional larynx owing PATIENT 2 to neuroplastic changes in the brainstem1,8 that control the cough reflex. The response to BtxA in our case series Patient 2 underwent electromyography-guided percuta- is consistent with this neuroplastic model of chronic neous BtxA injections to the bilateral thyroarytenoid cough. We discuss the mechanisms of cough and phar- muscles. This treatment resolved her chronic cough with- macologic activity of BtxA as a potential treatment of neu- out any complications. The patient required 4 injec- ropathic chronic cough. tions for 7.2 months before her chronic cough com- There are a multitude of stimulants that can trigger pletely resolved, and she has been asymptomatic since cough1-5 and at least 5 different vagal intraepithelial sen- then. Her VQROL scores were unavailable. sory receptors, the most important being rapidly adapting stretch receptors (RARs) and bronchial C-fiber re- PATIENT 3 ceptors. The C fibers can cause neurogenic inflammation, which can result in the RARs enhancing the strength of Patient 3 received percutaneous electromyography-guided the cough reflex. The larynx is dominated by mechano- sensitive receptors, whereas the distal airway and bron- BtxA injections to alternating thyroarytenoid muscles and 1 had significant improvement with minimal voice-related ad- chus are dominated by chemosensitive receptors. verse effects. Her VRQOL score increased from 21 to 31, and Activation of these receptors causes release of neuro- she required 6 injections for 12.9 months before her chronic peptides, including a group of tachykinins, such as sub- cough resolved without any complications. stance P, neurokinin A, and calcitonin gene-related peptide.1 These neuropeptides cause neurogenic inflam- 1 PATIENT 4 mation. Their role in cough is illustrated by cough caused by angiotensin-converting enzyme inhibitors, which pre- vent the breakdown of tachykinins, bradykinin, and sub- Patient 4 received 8 BtxA injections with electromyog- 1,10-12 raphy guidance to achieve complete resolution of her stance P. A relationship is thought to exist between chronic cough. She reported that the elimination of her neurogenic inflammation and hyperresponsiveness in the airway, which serves as a possible trigger for cough- cough had significantly improved her quality of life even 1,13 though her VRQOL score decreased from 73 to 48 after variant asthma and chronic cough. treatment because of the breathiness in her voice. She The afferent input of cough is mediated by the sensory wrote in her survey that despite these voice changes, “Bo- branch of the vagus nerve, which innervates various struc- tox has been wonderful for me and the cough. It made tures of the aerodigestive tract. This includes the Arnold me stop coughing....It’s given me a lot of relief.” She nerve from the ear canal, pharyngeal branches, superior is now able to interact socially and date again. She re- laryngeal branches, pulmonary branches, gastric branches from the stomach, and cardiac, diaphragmatic, and esoph- ceived 8 injections for 42.9 months and has been symp- 1 tom free with no reported complications. ageal branches. These inputs are received in the brainstem at the level of the nucleus tractus solitarius.1,14 The cough center in the brainstem is also influenced by vol- COMMENT untary cortical input because the cough reflex can be in- tentionally diminished. The efferent pathway of cough be- Coughing is an essential reflex that protects the aerodi- gins with motor information coordinated from the cerebral gestive tract. The cough reflex is a neurologic pathway cortex and cerebellum, as well as the nucleus ambiguus,1

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Cerebral cortex BtxA We believe that a change in the central nervous system likely causes the sensory and motor pathways of cough to be in a hyperexcitable state.5 This neural plasticity can Brainstem Efferents Cough – lower the threshold for cough stimulation and increase la- + + ryngeal tone. These changes are mediated through new axonal connections or changes in gene expression.5 Al- tered sensorimotor pathways are well documented in gus- BtxA tatory sweating, gustatory epiphora, and chronic neuropathic pain,16,17 all of which have been successfully treated Rapidly adapting Neuropeptides C-fiber with BtxA. This neuroplastic model of cough is also sup- receptors receptors ported by postviral vagal neuropathy.1,4,5,9 Review of patient history often reveals a previous upper respiratory tract

Cough stimulus infection, as seen in patient 1, which may alter the cough reflex. Other examples of virus-induced neuropathies also support this theory, such as postherpetic neuralgia, hu- Figure. Neurophysiology of cough reflex. BtxA indicates botulinum toxin man immunodeficiency virus neuropathy, and Guillain- type A; plus sign, excitatory; minus sign, inhibitory. Barré syndrome.1 Postviral neuropathy is thought to be caused by either direct infection of the nerve or an inflam- to produce the sequential events of a cough via the recur- matory response involving the nerve.1,4,5 For chronic cough, rent laryngeal nerve (Figure). the presumptive nerve injury would be cholinergic recep- There are several well-described models for chronic tors of the vagus nerve, causing changes in cough thresh- cough, including ILS,3,8 PVFM,3,6 sensory laryngeal neu- old and airway hyperactivity.1 ropathic cough,15 and postviral vagal neuropathy.4 Mor- It is also postulated that repeated noxious stimuli cause rison et al8 describe ILS as a neural plastic change to brain- release of neurotransmitters. Prolonged sensory distur- stem laryngeal control causing a hyperfunctional larynx, bances associated with tissue injury are thought to re- resulting in voice changes, laryngeal spasms, pain, fa- sult from reduction in nociceptor threshold, reduced in- tigue, globus, and cough. They proposed treatment mo- hibitory control, or increased excitability of central dalities based on likely etiologies, such as behavioral nervous system neurons. C-fiber neuropeptides and ex- therapy for psychogenic causes, breathing treatments for citatory amino acid neurotransmitters are thought to con- pulmonary and asthmatic causes, BtxA for neurologic and tribute to these changes in central nervous system func- dystonia causes, and antireflux medication for chemical tion1 (Figure). Chronic cough produces a harsh glottic causes.8 Cukier-Blaj et al6 proposed a sensory motor la- closure and vocal fold trauma with each cough. This re- ryngeal disorder to explain PVFM as a spectrum of dis- petitive trauma produces repeated release of neuropep- eases that manifest as a variety of clinical symptoms, in- tides and contributes to the feedback loop. cluding cough. They report laryngeal irritation caused Botulinum toxin type A is a potent neurotoxin pro- by reflux decreases laryngeal sensitivity and results in a duced by the anaerobic bacterium Clostridium botulinum. compensatory motor response with hyperadduction of There are 7 serotypes of the toxin based on immunologic the vocal folds during inspiration, cough, and dyspho- specificity, labeled types A through G.18 Botulinum toxin nia. They propose an inflammatory and neurogenic inhibits calcium-dependent release of acetylcholine chlo- basis of PVFM.6 Bastian et al15 reported a sensory neu- ride at the presynaptic neuromuscular junction and causes ropathic model for chronic cough. They suggested the local paralysis in a dose-dependent fashion until new nerve criteria to diagnose neuropathic cough as an idiopathic terminals are regenerated.18 Botulinum toxin can also act chronic cough, persistent irritable cervical and laryn- by inhibiting neurologic signaling markers, such as geal sensations, spontaneously occurring or with spe- substance P, glutamate, and modulate sensory feedback cific triggers, and a nonproductive cough, with exclu- loops.19 This is illustrated in its use for hyperhidrosis and sion criteria based on malingering, secondary gain, abrupt gustatory sweating, in which botulinum toxin inhibits re- onset or resolution, or periods of complete resolution. lease of acetylcholine from sympathetic nerves innervat- Rees et al5 describe postviral vagal neuropathy as an- ing eccrine sweat glands and salivary glands.20 However, other model of chronic cough that is similar to other cra- the only Food and Drug Administration–approved uses nial neuropathies, such as Bell palsy, trigeminal neural- for BtxA are for blepharospasm, strabismus, hyperhidro- gia, glossopharyngeal neuralgia, and postherpetic sis, glabellar rhytids, and cervical dystonias.18 neuralgia. They report that sensory and motor branches In several off-label uses of BtxA for focal muscle dys- of the vagus nerve may be affected to cause dysphonia, tonia, it was incidentally noted that BtxA produced pain vocal fatigue, paresis, pain, globus, laryngospasm, PVFM, relief before muscle decontraction,21 prompting investi- and cough.4,5 A common cause in these proposed mod- gators to explore its analgesic properties. Off-label uses els of chronic cough is neuroplasticity or central neu- were also encouraged by in vitro studies that showed BtxA ron adaptation to a stimulus or efferent signal causing a could inhibit neurogenic inflammation by attenuating the hyperexcitable sensorimotor state.5 The successful treat- release of neuropeptides (eg, substance P, calcitonin gene- ment of chronic cough with gabapentin, amitriptyline, related peptide, and glutamate) from C-fiber recep- BtxA, and behavioral therapy also supports such a neu- tors.21 However, other reports22 suggest that BtxA has mini- ropathic model for the pathophysiology of chronic cough. mal effect on pain on skin despite decreasing neurogenic

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 inflammation. These results indicate that BtxA may have nociceptive feedback.18,19 We believe that BtxA works on a selective effect on pathological pain, and Ranoux et al21 neuromuscular junctions to decrease the strength of cough hypothesize that BtxA may have a greater effect on sen- and severity of repeated glottic trauma by altering mo- sitized pain fibers by binding to nociceptive receptors with tor pathways and reducing neuropeptide release and neu- more affinity in patients with chronic neuropathic pain rogenic inflammation in afferent sensory pathways to treat compared with patients with acute pain or that another chronic cough. unknown central nervous system target was involved. They Further research is warranted to study the analgesic also reported that patients showed improved pain relief properties of BtxA and its ability to reduce neurogenic in- over time after 1-time injection of BtxA, suggesting a flammation in chronic neuropathies. Our report suggests change in neural plasticity and alteration of pain thresh- that BtxA may be considered a possible treatment option olds in chronic neuropathic pain. As in our case series, for chronic cough after thorough workup fails to find a many patients had significant relief of their cough be- treatable diagnosis and empirical treatment of the most fore the expected onset of muscle paresis caused by BtxA, common causes of chronic cough are unsuccessful. Other which also suggests an effect on sensory and possible neu- neuropathic medications have been reported to treat rogenic inflammatory pathways. chronic cough, such as gabapentin and amitriptyline, but Krämer et al22 reported that BtxA reduced neurogenic they are also not without risks or adverse effects, such as inflammation but only marginally reduced cutaneous pain sedation, anticholinergic effects, dizziness, and postural in otherwise healthy volunteers. However, this finding hypotension. Botulinum toxin type A injection is an in- is consistent with the ability of BtxA to selectively treat vasive procedure, but it is safe and effective and caused neurologic disease mediated through neuropeptides, such no major complications in our study. It can also be per- as chronic neuropathic pain and chronic cough, instead formed in the office setting. Some patients reported tem- of acute pain pathways. Krämer et al22 and Nichols et al23 porary breathiness and mild pain with injection of BtxA. speculated that release of neuropeptides from periph- After an average of 9 sessions during a mean span of 25.7 eral C fibers would cause vasodilation and neurogenic months, patients were successfully treated and had com- inflammation, but the neuropeptides in the spinal cord plete resolution of their chronic cough. and central nerves induce central nociceptive sensitiza- In conclusion, we report our early experience of treat- tion. These studies demonstrated that BtxA was effec- ing chronic cough with BtxA to support the neuro- tive in decreasing vasodilation and neurogenic inflam- pathic model for chronic cough caused by neuroplastic mation in cutaneous skin but did not test the effects of changes and laryngeal hyperactivity. Botulinum toxin type BtxA on central nerves. A was effective against both motor and sensory compo- We also speculate that injecting BtxA in the thyro- nents of the laryngeal neuropathy of chronic cough by arytenoid muscles acts on both sensory and motor com- directly decreasing laryngeal hypertonicity and possibly ponents of laryngeal neuropathy and chronic cough by reducing neurogenic inflammation and neuropeptide- reducing laryngeal hypertonicity through muscle pare- mediated cough. Botulinum toxin type A can be success- sis and diminishing the severity of trauma from re- fully used to treat chronic cough refractory to other medi- peated coughing. However, symptom relief occurred be- cal therapies. fore the expected paralytic effects of botulinum toxin on laryngeal musculature, suggesting another mechanism Submitted for Publication: June 18, 2009; final revi- of action of BtxA on neuropathic chronic cough, as de- sion received September 12, 2009; accepted November scribed by Ranoux et al21 and Krämer et al.22 Botulinum 25, 2009. toxin type A likely selectively affects chronic neuro- Correspondence: Michael W. Chu, MD, Department of pathic pathways instead of acute pain pathways by de- Otolaryngology–Head & Neck Surgery, Eastern Vir- creasing neuropeptide-mediated neurogenic inflamma- ginia Medical School, 600 Gresham Dr, Ste 1100, Nor- tion and interrupting the feedback cycle, allowing the folk, VA 23507 ([email protected]). larynx to regain baseline sensitivity to stimuli and de- Author Contributions: All authors had full access to all crease the exaggerated laryngeal response to cough stimuli. the data in the study and take responsibility for the in- The limits of this study are the small sample size and tegrity of the data and the accuracy of the data analysis. retrospective methods. However, to our knowledge, we re- Study concept and design: Lieser and Sinacori. Acquisi- port the first experience of BtxA injections used to treat tion of data: Chu, Lieser, and Sinacori. Analysis and in- chronic cough in adults and hope to encourage further dis- terpretation of data: Chu and Sinacori. Drafting of the manu- cussion and investigation of the pathophysiology of cough. script: Chu and Lieser. Critical revision of the manuscript The mechanisms of neural plasticity and a neuro- for important intellectual content: Lieser and Sinacori. Sta- pathic model of chronic pain provide valuable insight into tistical analysis: Chu. Administrative, technical, and ma- chronic cough. The neuropathic model of chronic cough terial support: Chu and Lieser. Study supervision: Lieser is consistent with ILS, postviral vagal neuropathy, PVFM, and Sinacori. and other neuropathic models, where neural plastic Financial Disclosure: None reported. changes cause hyperkinetic laryngeal dysfunction.8 It also shares similarities with chronic neuropathic pain disor- REFERENCES ders. The successful treatment with BtxA for chronic pain 7,23 and chronic cough also supports a neuropathic model. 1. Altman KW, Simpson CB, Amin MR, Abaza M, Balkissoon R, Casiano RR. Cough It has been reported that BtxA is effective in reducing neu- and paradoxical vocal fold motion. Otolaryngol Head Neck Surg. 2002;127 rogenic inflammation and possibly modulating central (6):501-511.

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 2. Irwin RS, Boulet L-P, Cloutier MM, et al. Managing cough as a defense mecha- 14. Jordan D. Central nervous mechanisms in cough. Pulm Pharmacol. 1996;9(5-6): nism and as a symptom: a consensus panel report of the American College of 389-392. Chest Physicians. Chest. 1998;114(2)(suppl):133S-181S. 15. Bastian RW, Vaidya AM, Delsupehe KG. Sensory neuropathic cough: a common 3. Andrianopoulos MV, Gallivan GJ, Gallivan KH. PVCM, PVCD, EPL, and irritable and treatable cause of chronic cough. Otolaryngol Head Neck Surg. 2006;135 larynx syndrome: what are we talking about and how do we treat it? J Voice. (1):17-21. 2000;14(4):607-618. 16. Kyrmizakis DE, Pangalos A, Papadakis CE, Logothetis J, Maroudias NJ, Helido- 4. Amin MR, Koufman JA. Vagal neuropathy after upper respiratory infection: a vi- nis ES. The use of botulinum toxin type A in the treatment of Frey and crocodile ral etiology? Am J Otolaryngol. 2001;22(4):251-256. tears syndromes. J Oral Maxillofac Surg. 2004;62(7):840-844. 5. Rees CJ, Henderson AH, Belafsky PC. Postviral vagal neuropathy. Ann Otol Rhi- 17. Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplas- nol Laryngol. 2009;118(4):247-252. ticity to pathological pain: review of clinical and experimental evidence. Pain. 1993; 6. Cukier-Blaj S, Bewley A, Aviv JE, Murry T. Paradoxical vocal fold motion: a sensory- 52(3):259-285. motor laryngeal disorder. Laryngoscope. 2008;118(2):367-370. 18. Cheng CM, Chen JS, Patel RP. Unlabeled uses of botulinum toxins: a review, 7. Sipp JA, Haver KE, Masek BJ, Hartnick CJ. Botulinum toxin A: a novel adjunct part 1. Am J Health Syst Pharm. 2006;63(2):145-152. treatment for debilitating habit cough in children. Ear Nose Throat J. 2007; 19. Therapeutics and Technology Assessment Subcommittee of the American Acad- 86(9):570-572. emy of Neurology. Assessment: the clinical usefulness of botulinum toxin–A in 8. Morrison M, Rammage L, Emami AJ. The irritable larynx syndrome. J Voice. 1999; treating neurologic disorders: report of the Therapeutics and Technology As- 13(3):447-455. sessment Subcommittee of the American Academy of Neurology. Neurology. 1990; 9. Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal 40(9):1332-1336. neuropathy. Laryngoscope. 2006;116(12):2108-2112. 20. Haider A, Solish N. Focal hyperhidrosis: diagnosis and management. CMAJ. 2005; 10. Visser LE, Stricker BH, van der Velden J, Paes AH, Bakker A. Angiotensin con- 172(1):69-75. verting enzyme inhibitor associated cough: a population-based case-control study. 21. Ranoux D, Attal N, Morain F, Bouhassira D. Botulinum toxin type A induces direct J Clin Epidemiol. 1995;48(6):851-857. analgesic effects in chronic neuropathic pain. Ann Neurol. 2008;64(3):274- 11. Trifilieff A, Da Silva A, Gies JP. Kinins and respiratory tract diseases. Eur Respir 283. J. 1993;6(4):576-587. 22. Krämer HH, Angerer C, Erbguth F, Schmelz M, Birklein F. Botulinum toxin A re- 12. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP duces neurogenic flare but has almost no effect on pain and hyperalgesia in hu- evidence-based clinical practice guidelines. Chest. 2006;129(1)(suppl):169S- man skin. J Neurol. 2003;250(2):188-193. 173S. 23. Nichols ML, Allen BJ, Rogers SD, et al. Transmission of chronic nociception by 13. Chang AB. Cough, cough receptors, and asthma in children. Pediatr Pulmonol. spinal neurons expressing the substance P receptor. Science. 1999;286(5444): 1999;28(1):59-70. 1558-1561.

Correction

Error in Byline. In the byline of Radiology Quiz Case 1, which appeared in the May 2009 issue of the Archives (2009;135[5]:516), the first author’s first name should have been spelled Navneet.

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