ILS, PVFM, CC: When the Larynx Misbehaves

Transcription

1 ILS, PVFM, CC: When the Larynx Misbehaves Claudio F. Milstein, PhD Head and Neck Institute November 2012

2 ILS CC - PVMF Are these different manifestations of the same disorder? Do they share the same neural pathways? Do they have a similar pathophysiology?

3 Irritable Larynx Syndrome (ILS) Morrison and Rammage. University of British Columbia Vancouver - Canada Introduced by Morrison and Rammage 1999 hyperkinetic laryngeal dysfunction resulting from an assorted collection of causes in response to a definitive triggering stimulus Associated symptoms can include MTD Globus pharyngeus Dysphagia Throat clearing Cough PVFM

4 Australian Group Vertigan et al. Anne Vertigan Deborah Theodoros Peter Gibson Alison Winkworth University of Queensland, Brisbane University of Newcastle, Newcastle Charles Sturt University, Albury John Hunter Hospital, Newcastle To Vertigan and colleagues, CC and PVFM are features within the spectrum of one common, underlying syndrome

5 Vertigan et al., Relationship between CC and PVFM J of Voice 2006:20:

6 Sandage and Schroth Sandage and Schroth (2005) ASHA Short Course: ILS across the lifespan ILS: continuum Throat clearing Chronic cough PVFM Laryngospasm

7 Altman, Simpson, Amin, et al. Northwestern University, Chigago, IL.. Gastroesophageal reflux disease, vagal neuropathy, and paradoxical vocal fold motion are additional causes of chronic cough and disordered breathing that need to be considered, in the absence of obvious laryngotracheal and/or rhinologic pathology. Altman et al., Cough and Paradoxical Vocal Fold Motion Otol H&NS Dec 2002

8 Murry, Bransky, Cukier-Blaj, Aviv, et al. Weill Cornell Medical College, NY Memorial Sloan-Kettering Cancer Center, NY Columbia Presbyterian Medical Center, NY Mr. Sinai Medical Center, NY CC and PVFM: both associated with aberrant laryngeal sensation. Both respond to similar treatment modality Treatment results in improved sensation and reduction in symptoms Murry, Bransky, et al., Laryngeal Sensory Deficits in Patients With CC and PVFM. Laryngoscope When the 120; Larynx Aug Misbehaves: 2010 ILS, CC & PVFM

9 Most propone a relationship The pathophysiology remains elusive

10 Chronic Cough Cough is the single most common symptom for which patients worldwide seek medical attention (Schappert & Burt 2006, Office of Population Censuses and Surveys, 1995, Morice at al. 2007) Common problem that affects 11 to 16% of the population Can persist after extensive treatment for common causes, in 20-42% patients: chronic refractory cough

11 PubMed search on Cough Limits: English - Published in the last 5 years ( ) Cough: 6828 articles Humans: 5212 Animals: 606 Clinical Trials: 604 Chronic cough: 2454 articles Humans: 2149 Animals: 161 Clinical Trials: 139 VCD: 85 articles PVFM: 32 articles ILS: 4 articles 0 clinical trials

12 Cough Journal Cough is an open access, peer-reviewed, online journal Started in 2005 coughjournal.com

13 Chronic Cough Cough can be evoked in decerebrated or deeply anesthetized animals Animal models Known stimuli that trigger cough in animals and humans This allows for research on pathophysiology of cough

14 Multiple chemical and mechanical stimuli initiate cough Capsaicin Citric acid Hypertonic saline Low chloride buffers/ solutions Particulate/dust Chemical irritants (resiniferatoxin, cinnamaldehyde, allyl isothiocyanate Mechanic/vibratory stimulation of the airway mucosa (larynx or chest wall)

15 Cough challenge tests involving mechanical stimulation of the cervical trachea in patients with cough as a leading symptom. Kamimura et al., Respirology 2010

16 Initiators of cough reflex A variety of receptors and channels present in sensory nerve terminals Sense irritant stimuli - initiate protective reflex responses: cough Channels: transient receptor potential (TRP) ion channels Channels are sensors of airway irritation and initiators of the cough reflex vanilloid 1 (TRPV1) ankyrin 1 (TRPA1)

17 Cough Cough reflex can be measured: e/g., inhaling measured doses of capsaicin via dosimeter that elicit n # coughs Voluntary and involuntary pathways of cough Receptors in respiratory mucosa and vagus nerve Cough center in respiratory area of brainstem

18 Neural Pathways of Cough Reflex Intercostal Muscles Larynx Trachea Bronchi Efferent Pathways Spinal Cord Abdominal Muscles Intercostals Diaphragm Larynx Alveoli Abdominal Muscles + diaphragm Afferent Pathways Cough regulation center In brain stem Alveoli Bronchi Trachea Larynx Vagus Nerve

19 Which is the cough we are interested in?

20 Altman & Irwin Otolaryngologic Clinics of America Feb 2010

21 Altman & Irwin Otolaryngologic Clinics of America Feb 2010

22 Altman & Irwin Otolaryngologic Clinics of America Feb 2010

23 Altman & Irwin Otolaryngologic Clinics of America Feb 2010

24 Altman & Irwin Otolaryngologic Clinics of America Feb 2010

25 Altman & Irwin Otolaryngologic Clinics of America Feb 2010

26 Refractory Chronic Cough

27 CC: The most studied To certain extent the best understood Much more clear picture of CC than ILS or PVFM If CC and PVFM are different manifestations of same disorder, then what we know about CC may apply to PVFM If we understand the pathophysiology of refractory chronic cough, we are probably close to that of PVFM Third American Chronic Cough Conference NYC June 2011

28 3rd American Chronic Cough Conference NYC June 2011

29 3rd American Chronic Cough Conference NYC June 2011

30 3rd American Chronic Cough Conference NYC June 2011

31 3 rd Chronic Cough Conference NYC June 2011

32 Dr. Alyn Morice Cardiovascular and Respiratory Studies, University of Hull, Castle Hill Hospital, UK

33 Dr. Alyn Morice Cardiovascular and Respiratory Studies, University of Hull, Castle Hill Hospital, UK Dr. Lorcan McGarvey Centre for Infection and Immunity, Queen s University, Belfast, N. Ireland

34 Chronic Cough! Dr. Alyn Morice Cardiovascular and Respiratory Studies, University of Hull, Castle Hill Hospital, UK Dr. Lorcan McGarvey Centre for Infection and Immunity, Queen s University, Belfast, N. Ireland

35 Chronic Cough!! Cough Hypersensitivity Syndrome!! Dr. Alyn Morice Cardiovascular and Respiratory Studies, University of Hull, Castle Hill Hospital, UK Dr. Lorcan McGarvey Centre for Infection and Immunity, Queen s University, Belfast, N. Ireland

36 Cough hypersensitivity syndrome?? Ha ha ha! Dr. Alyn Morice Cardiovascular and Respiratory Studies, University of Hull, Castle Hill Hospital, UK Dr. Lorcan McGarvey Centre for Infection and Immunity, Queen s University, Belfast, N. Ireland

37 It s all reflux! Dr. Alyn Morice Cardiovascular and Respiratory Studies, University of Hull, Castle Hill Hospital, UK Dr. Lorcan McGarvey Centre for Infection and Immunity, Queen s University, When the Belfast, Larynx Misbehaves: N. Ireland ILS, CC & PVFM

38 Reflux??? You are crazy! Dr. Alyn Morice Cardiovascular and Respiratory Studies, University of Hull, Castle Hill Hospital, UK Dr. Lorcan McGarvey Centre for Infection and Immunity, Queen s University, Belfast, N. Ireland

39 Alyn H. Morice Head of Cardiovascular and Respiratory Studies University of Hull, Hull York Medical School, UK the overwhelming majority of patients with chronic cough have a single diagnosis: cough hypersensitivity syndrome A H Morice. Lung Jan; 188 Suppl 1:S87-90

40 the overwhelming majority of patients with chronic cough have a single diagnosis: cough hypersensitivity syndrome reflux A H Morice. Lung Jan; 188 Suppl 1:S87-90 As interpreted by Dr. Lorcan McGarvey Centre for Infection and Immunity The Queen s University of Belfast, N. Ireland

41 Reflux and association with CC and PVFM GER thought to be an important etiologic factor in PVFM and CC Studies looking at efficacy of standard therapies for reflux (PPI) are disappointing This suggests that mechanism that links CC and PVFM to reflux may be different from those responsible to symptoms like heartburn Jaclyn Smith, MB, ChB, PhD University Hospital of South Manchester, UK

42 Stimuli that initiate cough Canning, B Afferent Nerves Regulating the Cough Reflex Otolaryngol Clin N Am 43 (2010)

43 Stimuli that DO NOT initiate cough Canning, B Afferent Nerves Regulating the Cough Reflex Otolaryngol Clin N Am 43 (2010)

44 Stimuli that DO NOT initiate cough Canning, B Afferent Nerves Regulating the Cough Reflex Otolaryngol Clin N Am 43 (2010)

45 Mechanism that links GERD and cough is not simple GERD as a stimuli of afferent nerves is not a primary initiator of cough Other afferent nerves and afferent-nerve subtype interactions in GERD related cough

46 Mechanisms Linking Reflux and Cough Jaclyn Smith, MB, ChB, PhD University Hospital of South Manchester, UK Esophago-bronchial reflux Convergence of vagal afferents from the airway and esophagus allow esophageal stimuli to evoke cough and PVFM responses Laryngopharyngeal reflux Reflux into the larynx may cause chronic laryngeal inflammation, sensitising nerve terminals and stimulating cough receptors Micro aspiration Refluxate enters the airway, leading to chronic inflammation and stimulating airway cough receptors

47 Mechanisms Linking Reflux and Cough Micro-aspiration Laryngopharyngeal reflux Intra esophageal reflux Jaclyn Smith, MB, ChB, PhD University Hospital of South Manchester, UK

48 Terminology We know that PVFM has been given many labels: VCD PVFM

49 Adductor breathing dystonia Adult spasmodic croup Asthma-like disorder Asthmatic extra thoracic airway obstruction Atypical asthma Benign paradoxical vocal cord motion Bilateral abductor vocal cord paresis Emotional laryngeal wheezing Emotional laryngospasm Episodic laryngeal dyskinesia Episodic laryngospasm Episodic paroxysmal laryngospasm Exercise-induced laryngomalacia Expiratory laryngeal stridor Factitious asthma False croup Familial Munchausen stridor Fictitious asthma Functional abduction paresis Functional breathing disorder Functional laryngeal dyskinesia Functional stridor Functional upper airway obstruction Functional vocal cord paralysis Glottic dysfunction Hysteric croup Hysterical stridor Inspiratory vocal cord dysfunction Irritable larynx syndrome Psychogenic laryngeal dysfunction Psychogenic respiratory distress Psychogenic stridor Irritant-associated vocal cord dysfunction Psychogenic stridor caused by a Laryngeal asthma conversion disorder Laryngeal dysfunction Psychogenic upper airway obstruction Laryngeal dyskinesia Psychogenic wheezing Laryngeal respiratory dystonia Psychosomatic stridor Laryngeal spasm Psychosomatic wheezing Laryngeal stridor Respiratory glottic spasm Laryngismus fugax Reversible upper airway obstruction Laryngismus stridulous Sleep-related laryngospasm Laryngoneurosis Spasmodic croup Munchausen syndrome presenting Spasmodic croup in the adult as bronchospasm Stress-inducible functional laryngospa Munchausen stridor Suffocative laryngismus Nonorganic stridor Thymic asthma Nonorganic upper airway obstruction Upper airway dysfunction syndrome Paradoxical vocal cord adduction Upper airway obstruction misdiagnosed Paradoxical vocal fold dysfunction as asthma Paradoxical vocal fold motion Variable extrathoracic obstruction Paradoxical vocal cord movement Variable vocal cord dysfunction Paroxysmal laryngospasm Vocal cord dysfunction masquerading Paroxysmal vocal cord dysfunction as asthma Paroxysmal vocal cord motion Vocal cord dyskinesia Pseudoasthma Pseudo-steroid-resistant asthma Vocal cord malfunction Brugman, Chest, 2009

50 Adductor breathing dystonia Adult spasmodic croup Asthma-like disorder Asthmatic extra thoracic airway obstruction Atypical asthma Benign paradoxical vocal cord motion Bilateral abductor vocal cord paresis Emotional laryngeal wheezing Emotional laryngospasm Episodic laryngeal dyskinesia Episodic laryngospasm Episodic paroxysmal laryngospasm Exercise-induced laryngomalacia Expiratory laryngeal stridor Factitious asthma False croup Familial Munchausen stridor Fictitious asthma Functional abduction paresis Functional breathing disorder Functional laryngeal dyskinesia Functional stridor Functional upper airway obstruction Functional vocal cord paralysis Glottic dysfunction Hysteric croup Hysterical stridor Inspiratory vocal cord dysfunction Irritable larynx syndrome Psychogenic stridor Irritant-associated vocal cord dysfunction Psychogenic stridor caused by a Laryngeal asthma Laryngeal dysfunction Laryngeal dyskinesia Laryngeal respiratory dystonia Laryngeal spasm Laryngeal stridor Laryngismus fugax Laryngismus stridulous Laryngoneurosis Munchausen syndrome presenting 76 Different as bronchospasm Terms!! Munchausen stridor Nonorganic stridor Nonorganic upper airway obstruction Paradoxical vocal cord adduction Paradoxical vocal fold dysfunction Paradoxical vocal fold motion Paradoxical vocal cord movement Paroxysmal laryngospasm Paroxysmal vocal cord dysfunction Paroxysmal vocal cord motion Pseudoasthma Pseudo-steroid-resistant asthma Psychogenic laryngeal dysfunction Psychogenic respiratory distress conversion disorder Psychogenic upper airway obstruction Psychogenic wheezing Psychosomatic stridor Psychosomatic wheezing Respiratory glottic spasm Reversible upper airway obstruction Sleep-related laryngospasm Spasmodic croup Spasmodic croup in the adult Stress-inducible functional laryngospa Suffocative laryngismus Thymic asthma Upper airway dysfunction syndrome Upper airway obstruction misdiagnosed as asthma Variable extrathoracic obstruction Variable vocal cord dysfunction Vocal cord dysfunction masquerading as asthma Vocal cord dyskinesia Vocal cord malfunction Brugman, Chest, 2009

51 Terminology of Chronic Cough But chronic cough is chronic cough.

52 Chronic Refractory Cough Sensory Neuropathic Cough Cough Hypersensitivity Syndrome Laryngeal Sensory Neuropathy Irritable Larynx Syndrome Airway Hyperresponsiveness Cough Reflex Hypersensitivity Post Viral Vagal Neuropathy Bouts of cough triggered by relatively innocuous stimuli, exposure to aerosols, paint fumes, cleaners, etc

53 Recent publications The airway sensory hyperreactivity syndrome. Millqvist E. Pulm Pharmacol Ther. 2011; 24:263-6 The cough hypersensitivity syndrome: A novel paradigm for understanding cough. Morice AH. Lung 2010; 188 suppl 1:S87-90 Chronic cough hypersensitivity syndrome: A more precise label for chronic cough. Chung KF. Pulm Pharmacol Ther. 2011;24: Cough hypersensitivity syndrome: A distinct clinical entity. Morice, Faruki, et al., Lung 2011; 189:73-9

54 Morrison and Rammage 2010: ILS as a Central Sensitivity Syndrome Propose that ILS is a central sensitivity syndrome where laryngeal and paralaryngeal muscles overreact to normal sensory stimuli. N=195 patients with ILS High incidence of co-morbidity with IBS (57%) Fibromyalgia (28%) Chronic fatigue syndrome (42%) Migrane (49%) Morrison and Rammage; 2010 Revue cannadienne d orthophonie et d audiologie Vol. 34-4

55 Morrison and Rammage 2010: ILS as a Central Sensitivity Syndrome More than ½ of patients reported two or more comorbidities Conclusion: ILS is seen in patients manifesting a broad picture of disorder due to central nervous system hypersensitivity Morrison and Rammage; 2010 Revue cannadienne d orthophonie et d audiologie Vol. 34-4

56 Investigation of the Neural Control of Cough and Cough Suppression in Humans Using Functional Brain Imaging Suart B. Mazzone, Leonie J. Cole, Ayaka Ando, Gary F. Egan, and Michel J Farrell. The School of Biomedical Sciences, University of Queensland, the Centre for Neurosciences The Centre for Neuroscience, University of Melbourne, Australia Mid-cingulate cortex Anterior insula cortex Posterior cingulate cortex Postcentral gyrus Midbrain Thalamus Supplementary motor area Precentral gyrus Secondary somatosensory cortex. The Journal of Neuroscience, Feb 23, 2011

57 Representative BOLD signal responses associated with saline challenge and evoked cough, suppressed cough or voluntary cough after contrasting activations with saline challenge. Mazzone S B et al. J. Neurosci. 2011;31: by Society for Neuroscience

58 Investigation of the Neural Control of Cough and Cough Suppression in Humans Using Functional Brain Imaging CONCLUSION: This is the first time that it has been demonstrated that evoked cough is not only a brainstemmediated reflex response to irritation of the airways, but it requires active facilitation by cortical regions, and is further regulated by distinct higher order inhibitory processes. Mazzone S B et al. J. Neuroscience :

59 Neural Pathways of Cough Reflex Cortical Influence Intercostal Muscles Larynx Trachea Bronchi Efferent Pathways Alveoli Spinal Cord Abdominal Muscles Intercostals Diaphragm Larynx Abdominal Muscles + diaphragm Afferent Pathways Alveoli Bronchi Vagus Nerve Trachea Larynx Cough regulation center In brain stem

60 Neural Pathways of Cough Reflex Suppression of cough: anterior insula anterior mid-cingulate cortex inferior frontal gyrus Evoked cough: posterior insula posterior cingulate cortex Cortical Influence Intercostal Muscles Larynx Trachea Bronchi Efferent Pathways Alveoli Spinal Cord Abdominal Muscles Intercostals Diaphragm Larynx Abdominal Muscles + diaphragm Afferent Pathways Alveoli Bronchi Vagus Nerve Trachea Larynx Cough regulation center In brain stem

61 2012 Gabapentin for refractory chronic cough: a randomised double-blind, placebo-controlled trial. Ryan et al., The Lancet. Online 2012 August A cohort description and analysis of the effect of gabapentin on idiopathic cough. Van de Kerkhove et al, Cough 2012:8:9

62 Central System Theory Neuropathic Pain Paresthesia Abnormal sensation in absence of stimulus Hyperalgesia Pain triggered by low exposure to known painful stimulus Allodynia Pain triggered by non-painful stimulus Refractory Chronic Cough Laryngeal paresthesia Abnormal laryngeal sensation or tickle Hypertussia Increased cough sensitivity in response to known tussigens Allotussia Cough triggered by nontussive stimuli (e.g., talking or cold air) Ryan et al, Lancet 2012

63 Gabapentin Effective for neuropathic pain with central sensitisation Improves cough-specific QOL Effective in decreasing cough severity and frequency suggest that a central system sensitisation is a relevant mechanism in refractory chronic cough Ryan et al, Lancet 2012

64 Hypersensitivity? In recent research of ILS, CC and PVFM, most authors describe either central hypersensitivity sensory neuropathy (vagus nerve) hypersensitivity at the level of the respiratory or laryngeal mucosa

65 Hypersensitivity Wani and Woodson. Paroxysmal laryngospasm after laryngeal nerve injury Laryngoscope 1999 Altman, Simpson, Amin, et al., Cough and PFVM Otol H&N Surg 2002 Vertigan et al., The role of sensory dysfunction in the development of CC and PVFM. Intl J SLP 2008 Morrison and Rammage. ILS as a central sensitivity syndrome. RCDOEDA 2010

66 Proponents of Hyposensitivity Recent data demonstrates reduced laryngeal irritability with sensory stimuli in the presence of LPR Phua, McGarvey, et al., Patients with GERD and cough have impaired laryngopharyngeal mechanosensitivity. Thorax, 2005 Murry et al., Laryngeal sensory deficits in patients with CC and PVFM. Laryngoscope, 2010 Baseline LAR threshold significantly higher patients with GERD, as compared to healthy subjects suggests laryngeal hyposensitivity

67 Chest Nov, 138(5): The differential effect of gastroesophageal reflux disease on mechanistimulation and chemostimulation of the laryngopharynx. Phua SY, McGarvey L, Ngu M, Ing A Compared with the control subjects, subjects with GERD have: significantly increased thresholds to mechanical stimulation, suggesting reduced mechanosensitivity, and significantly reduced thresholds to chemical stimulation, suggesting heightened chemosensitivity

68 Differential Effect of GERD in Mechanostimulation and Chemostimulation of the Laryngopharynx Receptors are polymodal (respond to both mechanical and chemical stimuli) Inverse relationship between mechanosensitivity (hyposensitive) and chemosensitivity (hypersensitive) Authors postulate that in the presence of GER, receptors become sensitized to chemical stimuli and relinquish ability to detect mechanical stimuli Authors conclude this relationship may be integral in maintaining airway protection and prevention of aspiration Phua, McGarvey, et al. Chest 2010

69 Conclusion Evidence links PVFM, CC, ILS as different manifestations of similar disorder All involve sensory dysfunction New modalities of treatment effective for all (medical and behavioral)

70 Conclusion Lack of unifying terminology Described in separate bodies of literature Pulmonary, Allergy, ENT, SLP, GI, Neurology Most research comes from chronic cough, with animal models and healthy subjects A significant number of patients continue to have unexplained cough after exhaustive workup and failed empiric treatments. A growing body of literature supports sensory or motor neuropathy as the cause of PVFM, CC, ILS. New concept of CHS

71 Conclusion Inverse relationship between mechanosensitivity (hyposensitive) and chemosensitivity (hypersensitive) of the airway mucosa Complex interaction of peripheral and central processes with evidence of both having excitatory and inhibitory influences Pathophysiology remains elusive and not well understood Not likely to be resolved in the near future

72 PVFM: 2012 Articles Paradoxical vocal fold motion: respiratory retraining to manage long-term symptoms Hatzelis and Murry. Soc Bras Fonoaudiol. 2012;24(1):80-5. Paradoxical vocal fold motion: classification and treatment Forrest et al., Laryngoscope Apr;122(4): Vocal cord dysfunction in adolescents. Schulze et al, Pediatr Pulmonol Jun;47(6):612-9.

73 PVFM: 2012 Articles Cough and upper airway disorders in elite athletes: A critical review. Boulet, LP. Br J Sports Med May;46(6): Vocal cord dysfunction in athletes: Clinical presentation and review of the literature. Al-Alwan, A, Kaminsky D. Phys Sportsmed May;40(2):22-7. Etiology of dyspnea in elite and recreational athletes Hanks et al., Phys Sportsmed May;40(2): Exercise-induced paradoxical vocal fold motion disorder: Diagnosis and Management. Chiang et al., Laryngoscope Oct 24. doi: /lary