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The interrelationships between vocal cord dysfunction and laryngeal hyperresponsiveness may have profound implications in the diagnosis and management of patients with difficult respiratory symptoms.
The ability of land animals to oxygenate via the lung as they developed from aquatic species means that a system also evolved for protecting the lung from flooding—the glottis. Although in man this is considered primarily as an organ of speech, disturbance of its protective function will threaten the integrity of the lung. While obstructive conditions in the larynx can cause breathlessness, abnormal function of an otherwise structurally normal larynx can also lead to symptoms. Such a condition is vocal cord dysfunction, characterised by paradoxical movement of the vocal cords resulting in marked reductions in airflow and breathlessness.1
During normal respiration the false vocal cords move very little while the true cords abduct slightly during both inspiration and expiration.2 In vocal cord dysfunction, paradoxical movement of the true and/or false cords occur during inspiration, expiration, or both.2,3 Vocal cord dysfunction frequently co-exists with asthma4,5 and is usually considered as being exclusively associated with psychopathology,1,4 a view which is perpetuated in part by the diagnosis only being considered in that situation. However, vocal cord dysfunction can occur in psychologically normal patients—for example, after upper respiratory tract infections6 or thyroid surgery.7 Diagnostic confirmation is not always easy. The flow-volume loop may reveal either extrathoracic upper airway obstruction8 or ending of the inspiratory limb below total lung capacity,9,10 while direct visualisation of the cords may detect paradoxical cord adduction but usually only after exposing the subject to a known trigger such as perfume.11 However, both these methods have low sensitivity, albeit high specificity.
LARYNGEAL HYPERRESPONSIVENESS
Laryngeal hyperresponsiveness (analogous to bronchial or nasal hyperresponsiveness in asthma or allergic rhinitis) may underlie vocal cord dysfunction, as shown by Bocca et al.12 They found laryngeal hyperresponsiveness in the majority of patients who presented with recurrent episodes of wheeze by showing deformation of the changes in the flow-volume loop after histamine challenge, although the reproducibility of this measure can be questioned. However, inhalation of histamine or methacholine has been shown to cause laryngeal narrowing in both normal and asthmatic subjects (using photography,13 fluoroscopy,14 or laryngeal sounds15,16) and in those with acute severe asthma14,15,17 and with chronic asthma on exercise.18 Conversely, laryngeal widening occurs in normal subjects following mechanical stimulation19 and in both normal and mild asthmatic subjects on exercise18 and during panting.14,20 Panting overrides the glottic narrowing induced by methacholine in stable asthma but not that seen in acute severe asthma.14 Inflammatory and irritant stimuli can thus cause a transient or a longer lasting tendency to laryngeal narrowing—that is, laryngeal hyperresponsiveness—which will thus contribute to wheezy breathlessness. In addition, antigen handling cells can be found in the laryngeal mucosa,21 which suggests that allergens may be important in the development of laryngeal hyperresponsiveness. However, the presence of inflammation alone does not explain why this irritable state is maintained over time.
ALTERED AUTONOMIC BALANCE
An altered state of autonomic balance, maintained by the activity of more central brain regions with the potential strongly to influence autonomic function, could underlie this response. These areas include sites in the medulla, midbrain and the prefrontal cortex, particularly medial areas 25 and 32 of Brodmann,22 and are polysynaptically linked with the larynx. Both true and false vocal cords derive motor innervation from the vagus, while sensory fibres from M3 muscarinic receptors (among others) in the laryngeal mucosa23 pass via the vagus to the medulla. Activity within these areas directly influences autonomic functions such as the respiratory and cardiac cycles and gut motility. Area 25 also receives inputs resulting from a variety of factors such as stress, emotion, and changes in ambient temperature, and is thus well positioned to act as a modulator of autonomic output in response to inputs both from sensory mucosal nerves and to these less specific inputs.24,25
But what evidence is there for an altered autonomic preset in certain individuals? Asthmatic subjects exposed to sulphur dioxide at rest show a reduction in parasympathetic tone while normal subjects show an increase in tone,26 perhaps mediated through rapidly adapting receptors27 in the larynx.28 While such an increase in vagal tone in normal subjects in response to an inhaled irritant can be construed as bronchoprotective, this apparently paradoxical asthmatic response may be due to an initial induction of neurogenic inflammation by the irritant followed by vagal inhibition.26 Once upper airway hyperresponsiveness (on the background of the change in autonomic preset) is established, the absence of quick recovery from an initiating episode could result in this autonomic preset becoming persistent. Subsequent further irritant stimuli would prevent or slow recovery leading to persistent symptoms.
VOCAL CORD DYSFUNCTION
Clinically, vocal cord dysfunction often overlaps with the hyperventilation syndrome, a condition also deemed to be largely psychological in origin29 in which tachypnoea could be explained by the presence of laryngeal hyperresponsiveness and consequent glottic narrowing. Vocal cord dysfunction can mimic or co-exist with severe asthma1,5 and apportioning the symptoms of the two can be difficult. Preliminary findings in severe asthma30 suggest that the increase in parasympathetic tone on lying flat is exaggerated in severe asthma compared with mild asthma, which could contribute to nocturnal symptoms in asthma and in vocal cord dysfunction.
Vocal cord dysfunction may thus be caused by laryngeal hyperresponsiveness, initiated by an initial inflammatory insult and resulting in altered autonomic balance which may be short lived or become persistent. If persistent, subsequent stimuli (such as psychological stressors or cold air) will induce local parasympathetic reflexes causing airway narrowing either at the glottic level and/or in patients with asthma in the lower airways. As such, this represents an exaggeration of the role of the larynx in lung protection. The altered autonomic preset is likely to be primarily driven by the highest centres of the central nervous system such as area 25 of the prefrontal cortex. These complex interrelationships now need to be explored, as this may have profound implications in the diagnosis and management of patients with difficult respiratory symptoms.
The interrelationships between vocal cord dysfunction and laryngeal hyperresponsiveness may have profound implications in the diagnosis and management of patients with difficult respiratory symptoms.