Mechanisms

To understand why the larynx may close inappropriately and become ‘dysfunctional’, as is the case with ILO/VCD, it is important to consider normal laryngeal function.

The larynx is one of the most highly innervated organs and must successfully act to facilitate several important but conflicting functions including opening to optimise airflow and closing to permit phonation and swallowing.

The primary function of the larynx is to act to protect the inlet to the airway, and thus the more distal lung, from inhaling any real or perceived toxins (Hull et al., 2016). Accordingly, the larynx is the ‘gate-keeper’ to the airway. This is exemplified by the fact that most muscles situated close to the laryngeal inlet act to adduct or close the glottic inlet, yet there is only one major abductor muscle, the posterior cricoarytenoid (PCA). A highly evolved neural network acts to prompt activation of the muscles of laryngeal closure, via a laryngeal adductor or closure reflex (LAR).

Triggers of the LAR

1. Simple mechanical contact within the glottic inlet triggers the LAR and causes coughing with or without acute laryngeal closure. An example is laryngospasm following direct laryngeal contact during extubation.
2. Sensory triggers (e.g., noxious gases) can also cause LAR activation (Purdon et al., 2005).
3. The laryngeal area is also innervated by the autonomic nervous system. Thus, abnormalities in autonomic control have also been associated with laryngeal closure.
4. In animal models, laryngeal closure can be triggered by hypocarbia, precipitated by hyperventilation, emphasising the close relationship between control of the laryngeal inlet and other mechanisms underpinning breathing control (Bartlett et al., 1989).

In some scenarios, laryngeal closure appears to be adaptive or functional. For example, in patients with chronic obstructive pulmonary disease, laryngeal closure during expiration appears to act to maintain positive pressure in the more distal airways, thus acting in a similar way to pursed-lip breathing, functionally offsetting work of breathing and optimising ventilatory efficiency (Baz et al., 2016).

The reason why laryngeal dysfunction or ILO/VCD develops in some individuals remains to be determined. Experts (Leong et al., 2023) agree that ILO/VCD is a multi-factorial, complex condition, with no single overarching pathogenic mechanism. There appear to be multiple different, possibly parallel and interacting, pathways.

In 1999, it was proposed that conditions leading to closure of the larynx, in the absence of a pathological or neurological laryngeal disease, could be viewed as a form of ‘irritability’ of the larynx (Morrison et al., 1999). Clearly, any process which triggers the LAR, such as contact with sensory nerve fibres, can evoke closure. Intriguingly, there is considerable overlap between the type of stimuli patients report causing ILO/VCD, and those reported in other laryngeal-focused respiratory issues, such as in chronic cough (Smith et al., 2022; Vertigan et al., 2013).

Most experts believe that ILO/VCD develops from a form of sensory hyperresponsiveness of the larynx, where laryngeal adduction is triggered by stimuli at a lower-than-usual threshold. In this context, laryngeal neural control may be viewed as having become more ‘sensitive’ to stimuli that would otherwise be considered either innocuous (e.g, laughing) or only mildly unpleasant (e.g., paint or cleaning fluid fumes). For people with ILO/VCD, the exaggerated laryngeal response then manifests in different ways, that may be either specific to an individual or, as noted previously, have overlapping clinical features.

GORD & Nasal disease — Direct stimuli, driving a tendency to laryngeal irritation, and thus potentially ILO/VCD, include gastro-oesophageal reflux, acting both directly but also from distal activation of nerve fibres in the lower oesophagus, and nasal disease, nasal disease, altering airflow, mechanical and sensory factors, that may be contributory.

Ongoing hypersensitivity & Anaphylaxis — An expert roundtable group agreed that ILO/VCD could start with exposure, but after removal of the stimulus, there can be ongoing hypersensitivity. An example of this would be patients who have had an episode of true anaphylaxis and then have ongoing episodes of laryngeal closure, throat tightness, and laryngeal symptoms from ILO/VCD. Subsequent episodes of ILO/VCD in such patients are often treated as anaphylaxis, though there is no evidence of anaphylaxis. This clinical situation can be contrasted to patients who have short-lived symptoms after an initial exposure (such as an upper respiratory tract viral infection) that triggers symptoms. This leads to w ILO/VCD, but symptoms eventually resolve.

Incident-induced — Cortical level activation appears central to ILO/VCD pathogenesis in ‘incident-induced’ ILO/VCD, where administration of a drug, food or other putative ‘allergen’ can serve as a powerful psychogenic trigger to precipitate acute ILO/VCD  (Leong et al., 2023). The function and innovation of the larynx is closely aligned with primitive and ‘defensive’ centres in the brain, and thus, the larynx may also close in situations where there is a real or perceived emotional threat. This is poorly understood and the interplay between psychological distress and VCD/ILO is often overplayed in terms of the causative nature of any association. Cortical level processes involving behavioural, functional or cortical level activation are likely to play a role in reinforcement of behavioural input and thus anticipatory response patterns on exposure to recognised triggers.

Exercise — Exercise is a prevalent cause of EILO, but the reason this condition develops in some people remains unclear. EILO is most often encountered clinically in adolescent athletes and typically occurs during high intensity exercise. It seems likely that EILO develops in susceptible individuals, due to the development of a pressure gradient that encourages inward collapse of supraglottic structures, in susceptible individuals (Olin et al., 2016).

There remains a need for further research to understand the causes of ILO/VCD. To date, there is limited insight regarding  histological abnormalities, neuromuscular weakness, heightened neural sensitivity, or abnormal central processing pathways. Further studies are needed to advance understanding of the mechanism of ILO/VCD, to advance new treatment options.