Concise review

Laryngeal dysfunction - assessment and management for the clinician

J.H. Hull1, V. Backer2, P. G. Gibson3, S.J. Fowler4

1. Department of Respiratory Medicine and NIHR Respiratory Biomedical Research Unit, Royal

Brompton & Harefield NHS Foundation Trust London, UK

2. Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen, Denmark

3. Centre for Healthy Lungs, University of Newcastle; Department of Respiratory and Sleep

Medicine, John Hunter Hospital; Hunter Medical Research Institute, Newcastle, Australia

4. Centre for Respiratory Medicine and Allergy, University of Manchester, and Manchester

Academic Health Science Centre, Manchester, UK

Corresponding author:

Dr. James Hull FRCP PhD

Department of Respiratory Medicine, Royal Brompton Hospital, London, UK

Tel: +44 0207 351 8043

E-mail: j.hull@rbht.nhs.uk

Running Title: Clinical approach to laryngeal dysfunction

Word count: 4231

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Abstract word count: 194

Keywords: larynx, cough, vocal, dyspnea, wheeze

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ABSTRACT

The larynx is one of the most highly innervated organs in humans and serves a number of

vitally important, complex and highly-evolved biological functions. On a day-to-day basis,

the larynx functions autonomously, addressing several roles including airway protection,

swallowing and phonation.

In some situations the larynx appears to adopt a functional state that could be considered

maladaptive or ‘dysfunctional’. This laryngeal dysfunction can underpin and account for a

number of respiratory symptoms that otherwise appear incongruous with a clinical disease

state and/or contribute to the development of symptoms that appear ‘refractory’ to

treatment. These include conditions associated with a heightened tendency for

inappropriate laryngeal closure (e.g. inducible laryngeal obstruction), voice disturbance and

chronic cough.

Recognition of laryngeal dysfunction is important to deliver targeted treatment and failure

to recognize the condition can lead to repeated use of inappropriate treatment. Diagnosis is

not straightforward however and many patients appear to present with symptoms

attributable to laryngeal dysfunction, but in whom the diagnosis has been overlooked in

clinical work-up for some time.

This review provides an overview of the current state of knowledge in the field of laryngeal

dysfunction with focus on pragmatic clinical assessment and management.

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INTRODUCTION

The larynx is one of the most highly innervated organs in humans and serves a number of

vitally important, complex and highly-evolved biological functions (1). On a day-to-day basis,

the larynx functions autonomously and without requirement for excessive cortical

regulation, adapting to address a set of complex functional demands and the competing

interests of optimizing airflow, whilst protecting the airway and facilitating phonation and

swallowing.

In some situations the larynx may adopt a functional state that could be considered

maladaptive or ‘dysfunctional’ (2), not facilitating the aforementioned basic biological

requirements, and arising in the absence of any laryngeal structural abnormality or

neurological disease (1).

Over the past thirty years it has become increasingly well-recognized that ‘dysfunction’ of

the larynx may underpin and account for a number of respiratory symptoms that otherwise

appear incongruous with a clinical disease state (e.g. asthma), or contribute to the

development of symptoms that appear ‘refractory’ to treatment. These include conditions

associated with a heightened tendency for inappropriate glottic closure (e.g. vocal cord

dysfunction) and chronic cough. Other manifestations of laryngeal dysfunction may be

viewed in terms of a loss of normal function and include conditions associated with voice or

swallowing disturbance. Moreover, laryngeal dysfunction appears to be amplified under

conditions of heightened physiological (e.g. vigorous exercise (3)) or environmental (e.g.

mass-irritant exposure) stress (4).

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This laryngeal dysfunction varies in severity and intensity and can co-exist with other disease

states, such as severe asthma and nasal disease (e.g. polyposis). Temporally it can range

from short-lived paradoxical manifestations (e.g. acute vocal cord closure) to more chronic

indolent and persistent clinical states (e.g. refractory cough).

Timely recognition of laryngeal dysfunction is important to permit the delivery of targeted

and often very effective treatment. Yet, as judged by the delay to diagnosis reported in

several clinical series (5, 6), many patients appear to present with symptoms attributable to

laryngeal dysfunction, but in whom the diagnosis appears to have remained overlooked in

clinical work-up for some time. In fact some commonly prescribed medications in these

patients (e.g. inhaled corticosteroids) may exacerbate laryngeal dysfunction, and failure to

recognize the condition can lead to repeated use of inappropriate and potentially hazardous

treatment (e.g. intra-muscular adrenaline for supposed anaphylaxis).

The aim of this concise review is to provide an overview of the type of laryngeal functional

disorders encountered by pulmonologists, with a clinically pragmatic focus on assessment

and management.

LARYGNEAL DEVELOPMENT - DICTATING (DYS)FUNCTION

In order to understand the function and thus corollary of ‘dysfunction’ of the larynx, it is

helpful to understand the evolutionary and phylogenic development of the larynx in

humans.

The transition from aquatic to terrestrial existence dictated alterations in pulmonary

development, in order to allow gas exchange to occur directly from the air (7). These

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requirements resulted in the development of a respiratory organ internalized within the

thoracic cage and the requirement for a mechanism and conduit to protect the delicate gas

exchange surfaces from injury and desiccation.

Thus, whist the fundamental function of the larynx in more primitive species is thought to

be primarily protective, laryngeal development in humans has evolved to create an

abduction (i.e. dilation) mechanism, to facilitate ventilation. In later development and with

demand for effective phonation, the glottic aperture evolved to facilitate glottic narrowing

(8) with the laryngeal inlet becoming a major point of airflow resistance within the

respiratory tract (9). These developments in humans resulted in an upper airway that

crosses the upper gastrointestinal tract at the level of pharynx, an intersection that

compromises the primitive and primary protective laryngeal function (10) and contributes to

the development of ventilatory turbulence.

It is therefore not surprising that the larynx has evolved to have a rich motor and sensory

innervation and a highly developed glottic-closure reflex, acting via the superior laryngeal

nerve and triggered by proprioceptive, thermal and/or chemical triggers (11). The

consequence is a heightened tendency for ‘protective’ closure with an intricate network of

neural traffic and multiple muscular laryngeal adductors, yet only one laryngeal muscle, the

posterior crico-arytenoid, acting to abduct the glottis (11).

Typically the glottic aperture remains largely patent during passive respiration, with only a

minor reduction in aperture evident during the expiratory phase of the breath cycle.

Neuronal control of laryngeal movement is closely aligned and inter-dependent with the

ventilatory control of respiratory mechanics, such that bronchoconstriction and airflow

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obstruction are associated with an apparent reflex adjustment (i.e. narrowing) in glottic

aperture (12). In addition, neuronal adjustment responds in line with phrenic nerve activity,

such that acute laryngeal closure may be associated with apnea, and changes in ambient

carbon dioxide, hypoxia and resistive loading result in reflex changes in glottic aperture (13).

With growth and development there is increasing inhibition of the apnea reflex, likely due to

the development of inhibitory neural pathways. A clinical example of this is the higher

prevalence of ‘dry’ versus ‘wet’-drowning in toddlers compared to adults. The loss of a

inhibitory neural pathway may be a factor in disease states such as chronic cough (14).

THE CONCEPT OF CLINICAL LARYNGEAL DYSFUNCTION

Descriptions introducing the concept of clinically relevant ‘dysfunction’ of the larynx arise

from over one hundred years ago; Osler remarked that ‘some individuals develop spasms of

the [laryngeal] muscles’, associated with ‘violent inspiratory efforts and great distress’ (15).

In the modern era, Christopher et al. (16) provided the first classical description of

inspiratory wheeze from laryngeal closure being misdiagnosed as asthma.

Over time, conditions causing transient laryngeal obstruction have attracted many labels,

sometimes descriptive (e.g. paradoxical vocal cord motion / paradoxical vocal fold

movement disorder), and sometimes with pejorative implications (e.g. Munchausen stridor,

emotional croup, factitious asthma (17, 18)). In order to clarify and standardize the

terminology a recent broad-reaching international consensus group has recommended the

adoption of an umbrella term, inducible laryngeal obstruction (ILO), which will hopefully

improve diagnostic characterization, facilitate epidemiological understanding and

strengthen multi-center research collaboration (19). Moreover, the acronym ILO permits the

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addition of further descriptors to characterize ‘inducers’ or triggers, for example exercise-

induced laryngeal obstruction (EILO) (20).

Laryngeal dysfunction may manifest in several, often overlapping ways in the same

individual; e.g. the co-existence of chronic cough, ILO, globus pharyngeus and voice

disturbance (21) (Figure 1).

The term laryngospasm is a distinct clinical entity, associated with very rapid and complete

laryngeal closure, often associated with pre- or complete syncope. Laryngospasm is a

protective mechanism that mostly occurs when foreign bodies enter the endolarynx, or

when a stimulus mimicking a foreign body elicits the larynx to close. It is a recognized

complication of general anesthesia, and has been reported during both intubation and

extubation (22, 23).

Laryngeal hyperresponsiveness / hypersensitivity

An emerging concept is that of laryngeal hyperresponsiveness or hypersensitivity, in which

there is evidence of features consistent with a sensory hyperresponsiveness as a component

of laryngeal dysfunction syndromes (2, 24).

An analogy can be drawn with bronchial hyperresponsiveness in asthma; which comprises

both bronchial hypersensitivity, a reaction to a lower dose of stimulus, and hyperreactivity,

an exaggerated reaction. Likewise, in a proposed model of laryngeal hyperresponsiveness

causing laryngeal dysfunction the larynx may be more ‘sensitive’ to stimuli that would

otherwise be considered either innocuous (e.g. laughing) or mildly unpleasant (e.g. paint or

cleaning fluid fumes) in people who do not develop symptoms. In the presence of laryngeal

hypersensitivity however, on exposure, the exaggerated reaction of the larynx then

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manifests in a number of ways, that may be either specific to an individual, or as noted

above have overlapping clinical features (21).

The historical literature detailing laryngeal closure disorders and chronic cough (and indeed

muscle tension dysphonia and globus, although those presentations are somewhat out of

scope for a respiratory readership) does not explicitly address this overlap. However, it is

likely that the many terms used, such as cough hypersensitivity syndrome (25), the irritable

larynx syndrome (1), laryngeal hypersensitivity syndrome (2), and cough reflex

hypersensitivity (26) are in fact describing aspects and features of the same clinical problem.

As noted above, however, it is not just heightened sensitivity that is an issue in laryngeal

dysfunction, but also the exaggerated response to triggers. Such expression of laryngeal

dysfunction may be viewed and mapped to the loss of normal laryngeal function (Table 1).

Epidemiology

Although chronic cough is a common symptom amongst the general population [up to 18%

in the US (27)] and accountable for 10% of referrals to secondary care respiratory services

(28), the prevalence of laryngeal dysfunction within that group (as opposed to where the

cough is a result of normal laryngeal function) is unknown. It is however likely to make up a

significant proportion of patients with so-called idiopathic or refractory cough (29, 30).

Likewise the true prevalence of ILO is unknown but is certainly influenced by the varying

diagnostic criteria employed and lack of generally agreed and accepted terminology.

Moreover, ILO is most typically considered clinically in patients presenting with severe or

treatment refractory asthma, introducing a bias in understanding of the true prevalence.

Newman and co-workers reviewed the case records of 95 patients with ‘intractable asthma’

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and found 10% had vocal cord dysfunction alone and a further 30% evidence of both vocal

cord dysfunction and asthma (31). A more recent study using dynamic computer

tomography imaging found that half of patients with ‘difficult to treat’ asthma had evidence

of exaggerated laryngeal closure (32). In the general young population, the prevalence of

EILO is approximately 6–8% (33, 34) whilst in selected athletic populations the incidence of

EILO may be considerably higher, ranging from 22–77% (3, 35-37).

Both chronic cough and ILO are more common in women than men (38, 39), and there is

evidence of increased laryngeal sensitivity in women (40, 41). However, whilst the early

reports of ILO emphasized a high prevalence in young females with psychological

comorbidity, it should be noted that the majority of cases do not fit this classical stereotype

(42).

Etiology and co-morbidities

Patients with laryngeal dysfunction may report a sudden event at the onset of the condition,

such as an upper respiratory tract infection (29, 43), intubation events (23), or specific

exposure to a noxious substance (44, 45). In addition to asthma, ILO has been misdiagnosed

as reactive airways dysfunction syndrome (46) or anaphylaxis (16). Initiation of therapy with

angiotensin converting enzyme inhibitors is also a common reversible cause of chronic

cough, and laryngeal obstruction (47).

Whilst in many cases there may be no specific event preceding laryngeal dysfunction,

asthma, chronic rhinosinusitis (or postnasal drip), and gastroesophageal reflux have been

repeatedly associated with and implicated in the development of ILO and chronic cough (38,

48). Proof of a causative association is often lacking, and as these conditions are prevalent in

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the general population they may frequently coexist. Nevertheless intensive treatment may

result in improvement in some components of laryngeal dysfunction (49).

Anxiety and depression are commonly found in patients with laryngeal dysfunction (6, 50),

as they are in other chronic respiratory diseases (51, 52); it appears likely that the two are

interdependent rather than there being definitive proof of a direct causative relationship

from one to the other.

Irritant-induced VCD occurs after occupational or environmental exposure. Perkner et al.

first reported 11 cases of irritant-associated VCD (45), and a review of cases attending an

occupational lung disease clinic identified 10% with work-associated irritable larynx

syndrome (53). Vocal cord dysfunction has also been recognized in former rescue workers

and volunteers involved in the World Trade Centre disaster in 2001 (4, 54).

APPROACH TO ASSESSMENT

Overall, approach to diagnosis and assessment of laryngeal dysfunction should encompass a

thorough evaluation of clinical symptoms allied with careful review of supporting test

results. Historically, it has been proposed that diagnostic criteria, certainly for ILO, include

the presence of ‘noisy breathing’ arising from the upper airway, with confirmatory evidence

of compatible abnormalities on laryngoscopy and an attenuation of airflow on pulmonary

function testing.

In reality, the fluctuating temporal nature of laryngeal dysfunction means that whilst the

clinical manifestations of acute or sub-acute ILO may be evident on either pulmonary

function testing and/or with direct laryngeal visualization, at the time of assessment (e.g. in

a standard clinical office based setting), there may be little or indeed no commensurate

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objective evidence to support a diagnosis. Thus diagnosis is often made from detailed and

meticulous history taking, however a requirement for some form of provocation (e.g.

exercise) to precipitate typical symptoms and rule out other causes for symptoms (such as

asthma or dysfunctional breathing patterns) is an important component in a comprehensive

assessment.

Clinical assessment

Several clinical features serve to highlight the potential for laryngeal dysfunction to

underpin an individual’s symptoms. Classical features include symptoms that localize to the

throat or upper chest, that are highly-variable and often associated with rapid-onset and

inspiratory noise arising from the upper airway. In a comprehensive review of published ILO

cases, dyspnea, wheeze, stridor, cough, chest tightness, throat tightness and voice change

were found to be cardinal features, encountered in descending order respectively (55). The

fact that these symptoms may occur in a stereotyped, reproducible and predictable fashion

and be precipitated by exposure to certain triggers is a key feature. Despite this, several

features may overlap with classical bronchial hyper-responsiveness (Table 2).

The complexity of presentation and overlapping features can often lead to a delay in

diagnosis and indeed mistreatment as asthma (56). Yet a lack of efficacy of treatment may

often lead to a label of ‘refractory asthma’, rather than promote clinical focus on the

successful identification of laryngeal dysfunction as a potential underlying diagnosis (31, 32).

Several questionnaires are now available to aid objective clinical evaluation (Table 3). These

have been validated in a variety of contexts, with either the purpose of providing support

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for diagnostic evaluation of laryngeal dysfunction / ILO or for monitoring response to

treatment.

A detailed medication history is important and should focus on prescription of angiotensin

converting enzyme (ACE) inhibitors, inhaler therapy and other medications that have been

implicated in laryngeal disorders (Table 4). Cough is the most common side-effect of ACE-

inhibitor treatment, and is thought to be due to reduced enzymatic degradation of

tachykinins, and their subsequent tissue accumulation. The consequent extra-thoracic

airway hyperresponsiveness resolves after cessation of ACE-inhibitor therapy (47).

Clinical examination is typically normal in the clinic unless a structural laryngeal abnormality

is evident. Subtle voice changes (e.g. abnormal pitch) and visible neck tension may be

apparent. Associated abnormalities in breathing pattern (e.g. high-apical respiratory

pattern) may also be evident and co-exist. It is also important to consider clinical signs that

would be compatible with any associated extra-laryngeal neurological involvement, e.g.

tremor or gait disturbance.

Assessment of co-morbid and aggravating factors

An assessment of relevant co-morbid features forms an important part of clinical

assessment. Specifically, clinical interrogation focusing on symptoms of reflux and nasal

symptoms is important to facilitate targeted treatment. This assessment may not be

straightforward and will often mandate objective testing. For example the clinical features

of asthma or reflux can clearly overlap and co-exist in patients with laryngeal dysfunction.

Assessment and diagnosis, based on a clinical assessment alone, is therefore not likely to be

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precise in this context and robust objective testing algorithms are important (i.e. assessing

lower airways inflammation).

Diagnostic testing

Direct laryngoscopy

The gold-standard investigation for confirmation of ILO is flexible laryngoscopy, if necessary

performed in the presence of a typical trigger (e.g. exercise). Laryngoscopy is typically well-

tolerated and can be successfully employed by trained pulmonologists in a clinic-based

environment. It allows structural or neurological abnormalities to be detected and may

provide some insight regarding laryngopharyngeal reflux and general appearance of vocal

cords and laryngeal responses to phonatory tasks. The classical description of vocal cord

dysfunction details anterior closure of the vocal cords, with a visible posterior ‘chink’ (Figure

1), that occurs during the inspiratory phase of the breathing cycle and is associated with a

stridulous sound and symptoms.

A recent international nomenclature document (20) provides diagnostic guidance for

clinician’s performing laryngoscopy, indicating that the following should be assessed and

described: (i) location of the obstruction, i.e. supra-glottic (arytenoid area, epiglottis or false

vocal folds), glottic (true vocal folds) or both; (ii) phase of the respiratory cycle during which

the obstruction is present, i.e. inspiratory, expiratory or both; (iii) onset of the obstruction,

i.e. fast onset from one breath to the next or slow onset over several breaths; (iv) resolution

of the obstruction after cessation of exposure to the inducer (if the obstruction becomes

visible during exposure), i.e. fast resolution (i.e. within five minutes) or longer.

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A key limitation of laryngoscopy is the fact that any procedure only provides a ‘snapshot’ or

transient perspective and indeed if the triggering factor is not present then the examination

may appear entirely normal. Moreover, although the use of laryngoscopy, to evaluate

laryngeal dysfunction, appears to be more widely available, it is our experience that there

often remain limitations in timely access to the necessary equipment and certainly a lack of

dedicated training for pulmonogists to develop the requisite skills to evaluate laryngeal

structure and movement accurately.

Challenge laryngoscopy

Given the caveats described above, laryngoscopy has been performed in the context of

exposure to a relevant occupational and environmental trigger (44). There is unfortunately

no currently accepted guidance on how to best perform such challenge testing, however the

use of a ‘control’ / placebo exposure (i.e. visualizing stimulus) without inhalation / exposure

is important. Moreover, it should be noted that exposure to a stimulus may precipitate

other respiratory symptoms, but not laryngeal closure (e.g. acute hyperventilation). Perhaps

the most relevant and extensively described ‘challenge’ scenario is exercise. Continuous

laryngoscopic examination during exercise (termed the CLE test) provides a detailed

assessment of laryngeal movement and the nature of structures involved in precipitating

laryngeal closure, and informs management (Figure 3 and supplementary video file) (57). As

with all challenge tests however it should be noted that lower airway dysfunction (e.g.

exercise-induced bronchoconstriction) can co-exist with laryngeal dysfunction and this

possibility should be considered and addressed in physiological measurements during

challenge (e.g. with spirometric measurements)

Surrogate measures / indices of laryngeal dysfunction

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Several alternative diagnostic techniques have been employed and advocated as potential

‘surrogate’ markers of laryngeal dysfunction and specifically ILO (32). Of these, it is likely

most often that clinicians employ spirometric measurement of airflow, with a characteristic

attenuation in inspiratory flow being described as consistent with variable extra-thoracic

airflow obstruction. However, inspiratory flow may also be attenuated by poor effort or

respiratory muscle weakness and thus both the specificity and sensitivity of flow-volume

loop assessment in the diagnosis of ILO have been poor in several published assessments (5,

58).

Scrutiny of changes in resistance slopes obtained during body plethysmography and

measures obtained using the forced oscillometry technique may provide diagnostic value

(59, 60). However as described above, patients with laryngeal dysfunction may have no

abnormalities in the absence of provocation, and thus several researchers describe

assessment of flow-volume loops in the context of exposure to either standard

bronchoprovocation agents (e.g. histamine or hypertonic saline) or other noxious stimuli

(e.g. ammonia gas) (43, 61, 62). Typically a dose-dependent reduction in the forced

inspiratory flow at 50% (FIF50) by 25% is taken as evidence of extra-thoracic

hyperresponsiveness; as reported by Bucca et al. in almost 70 % of patients with

unexplained chronic cough (61).

Dynamic volume CT sequencing of the neck can provide detail regarding laryngeal

movement during respiration and has been used to identify possible laryngeal dysfunction

in patients with difficult to treat asthma. Limitations include radiation dose and the

requirement to image at a time of symptoms in order to detect abnormalities (32).

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APPROACH TO MANAGEMENT

At the current time the optimum approach to treating laryngeal dysfunction remains to be

determined and the published evidence base is heavily influenced by anecdotal report and

retrospective review. Further research is urgently needed in this field, although it is

generally accepted that treatment should proceed under the auspices of a multi-disciplinary

approach with clear focus on the benefit of therapy-based approach to management and

the removal of potential laryngeal irritants.

Successful management is dependent on obtaining the correct diagnosis, both of the

laryngeal disorder but also of any associated co-morbidities such as asthma, nasal disease

and reflux (63, 64); both because a significant number of patients can have their symptoms

relieved by this approach (49) but also because laryngeal dysfunction-specific therapies,

such as speech therapy, may not deliver sustained benefit if there is an on-going underlying

driver for symptoms. Indeed in some cases cough-suppression could theoretically do harm,

for example in bronchiectasis. Likewise expiratory vocal cord dysfunction most often occurs

in the presence of obstructive lung disease and / or obesity, and may well provide a degree

of positive expiratory pressure in order to maintain airway patency and optimize lung

emptying (12, 65, 66); treatment to reduce laryngeal closure in this setting, in our

experience, has usually resulted in a deterioration in symptoms (67).

Making the correct diagnosis in laryngeal dysfunction, excluding untreated comorbidities

and explaining the origin of symptoms acts to provide patients with reassurance, improved

understanding and reduces the frustration associated with clinical interaction. This is

particularly the case for ILO, which has the advantage of being associated with a recordable

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visible abnormality that can be shown to and discussed with the patient and potentially

used in a targeted biofeedback approach to treatment (68).

Education regarding avoidance of triggers and techniques to reduce exposure to laryngeal

irritants is important where possible. More formalized education is included in speech

therapy programs for laryngeal dysfunction detailed below.

Speech Therapy

A multicomponent speech therapy approach has been shown to be of benefit in chronic

cough and is recommended by current guidelines (63). The therapeutic approach

successfully employed by Vertigan and colleagues (69) comprised education, strategies to

reduce cough and laryngeal irritation, and psycho-educational counselling. This approach

resulted in a significant reduction in symptoms compared to control (i.e. lifestyle advice)

intervention.

Speech therapy has long been considered the mainstay of treatment for ILO (64) and is

associated with an improvement in symptoms and laryngoscopic appearances (70, 71). As

for cough, speech therapy for ILO usually comprises a multi-component and multi-

disciplinary approach that may also incorporate physiotherapy and clinical psychology (72,

73).

Pharmacotherapy

Several drugs have shown promise for treatment of refractory chronic cough, although only

gabapentin has been recommended as an option for a trial of treatment in recent guidelines

(63), in particular in light of its beneficial effect on cough-related quality of life (74). Oral

morphine is also commonly used, and has been associated with an improvement in cough

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symptoms, although not cough sensitivity (75). A combination of pregabalin and speech

therapy achieved a sustained improvement in cough as well as a reduction in both cough

sensitivity and laryngeal sensitivity (76). A recent phase II study of a novel P2X3 receptor

antagonist demonstrated a 75% reduction in cough frequency with the active treatment but

significant side effects, especially taste disturbance (77). Amitriptyline was also associated

with an improvement in cough-related quality of life in a randomized controlled trial versus

codeine/guaifenesin in patients with post-viral cough (78). In an uncontrolled study, Varney

and colleagues also noted benefits associated with amitriptyline in vocal cord dysfunction

(79).

Inhaled therapies used for asthma may have some benefits in chronic cough even where

there is no objective evidence of asthma. For example inhaled sodium cromoglycate has

been used with some success in cough related to ACE-inhibitors (80) and lung cancer (81),

and inhaled ipratropium bromide in post-infective cough (82). The latter has also been

reported to benefit some individuals with EILO.

Surgical Therapy

Local injection of botulinum toxin has long been used in muscle tension dysphonia (83), and

case reports have described benefit in ILO (84). In an uncontrolled study Baxter and

colleagues found a mean improvement in asthma control and laryngeal appearances in 11

patients with coexistent vocal cord dysfunction and asthma following botulinum toxin

injection, although there were no changes in physiological parameters, and a placebo effect

could not be ruled out particularly as benefit was only noted in those with local side effects

(85). It has also been used in selected patients with chronic cough (86), although again to

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date no controlled studies have been performed. In severe cases of vocal cord dysfunction

tracheostomy has been performed with mixed results (87).

Acute emergency management

Speech therapy for laryngeal dysfunction (both for chronic cough and ILO) includes

education on how patients can abort or at least minimize the severity and impact of acute

attacks (88, 89). Other treatments that have been used include heliox (90), which results in

lower inspiratory airflow resistance and may ease respiratory distress, and short acting

benzodiazepines such as midazolam (91, 92).

CONCLUSION

Laryngeal dysfunction can underpin many symptoms that may present as problematic or

refractory airway disease states. Through a common mechanism of ILO, laryngeal

dysfunction may be a component of asthma, chronic cough and symptoms induced by

exercise or irritant exposure. Recognition and treatment of laryngeal dysfunction can now

be achieved using behavioural and pharmacological approaches. Clinical airway

management programmes that include assessment and management of laryngeal

dysfunction can improve patient outcomes. The field remains in an embryonic state with a

great number of unanswered questions and hence many future research priorities (see box).

Specifically, further work is needed to establish robust diagnostic algorithms and to progress

consensus approach to management. These steps are important to allow clinicians to

detect, diagnose and successfully manage patients suffering with the debilitating

manifestations of laryngeal dysfunction, in a timely fashion.

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FIGURE LEGENDS

Figure 1. (A) Overlapping manifestations of laryngeal dysfunction [reproduced from (93)).

(B) Pictorial and figure representation of classical vocal cord closure [reproduced from (7)].

Definition of abbreviations: VCD: vocal cord dysfunction.

Figure 2. Schematic outlining the proposed relationship between etiological factors,

hypersensitivity, triggers and hyperreactivity.

Figure 3. Continuous laryngoscopy during exercise testing on a cycle ergometer to diagnose

exercise-induced laryngeal obstruction. Photo courtesy of Dr. Emil Walsted.

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Figure 1

23

Figure 2

24

Figure 3

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TABLE FOOTNOTES

Table 1. Normal function of the larynx and clinical manifestations arising from laryngeal

dysfunction.

Table 2. Key clinical and investigation features in inducible laryngeal obstruction and

discriminating features from lower airways disease. Definition of abbreviations: CT –

computerized tomography, FEV1 – forced expiratory volume in one second; FIF50 – forced

inspiratory flow at mid-point of inspiratory volume; PEF – peak expiratory flow

Table 3. Questionnaires addressing laryngeal dysfunction. Definition of abbreviations: VCD –

vocal cord dysfunction.

Table 4. Medications associated with laryngeal dysfunction. Source: Pneumotox.org

Definition of abbreviations:

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Table 1

Normal Function of the Larynx Manifestation of laryngeal dysfunction

Airway protection Inducible laryngeal obstruction

Chronic cough

Airway clearance Chronic cough

Vocalization / phonation Muscle tension dysphonia

Swallowing Globus

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TABLE 2

INDUCIBLE LARYNGEAL OBSTRUCTION ASTHMA / LOWER AIRWAY DYSFUNCTION

CLINICAL FEATURES

Onset Rapid (within seconds) Can be rapid but typically gradual

Duration / pattern Waxes and wanes and can regress rapidly Prolonged

Inhaled drug therapy for attacks Largely ineffective B2 agonist usually effective

Breathing characteristics Monophonic stridor, prolonged inspiratory phase Polyphonic expiratory wheeze, prolonged expiratory phase

Regional localization Upper airways, neck Lower airways, chest

Symptoms Breathlessness, cough, throat/chest tightness, voice disturbance Breathlessness, wheeze, cough, chest tightness

Precipitating factors Exercise, emotional stress, cold air, strong odors Exercise, infections, cold air, allergens, stress

INVESTIGATION FINDINGS

LaryngoscopyClassically - vocal cord closure on inspiration, associated with

symptoms and inspiratory noise. Precipitated by relevant trigger

Widely patent glottic aperture during inspiration. Some closure on

expiration; more pronounced in context of acute of chronic airflow

obstruction

Pulmonary function

-Resting state

May see attenuated inspiratory flow

Glottic closure signal on body plethysmography

Airflow obstruction pattern on spirometry but can be normal

Heightened airway resistance.

-Response to provocation (e.g.

histamine, hypertonic saline)Reduction in FIF50 >25% Reduction in FEV1 and PEF

Radiographic imaging CT findings of glottic closure on dynamic imaging Bronchial wall thickening, other CT findings of lung disease

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Table 3

QUESTIONNAIRE NAMEFIRST AUTHOR

(REF), YEAR

STUDY / VALIDATION

POPULATION / DESIGNREPORTED FINDINGS POTENTIAL UTILITY LIMITATIONS

VCD Questionnaire Fowler (70) 2015 Prospective two-stage study: 1.

focus groups (patients and

healthcare professionals) then; 2.

Prospective validation and testing

of 12-item questionnaire in

patients

VCDQ score different between

VCD, asthma and healthy controls,

and in VCD was sensitive to change

following speech therapy

Monitoring benefit of current

treatments and testing novel

treatments

Not yet tested as a diagnostic

questionnaire; likely to require

refinement in this regard as some

items non-specific

VCD screening checklist Pinto (94) 2015 Prospective observational study

in cohort (n=80) diagnosed with

severe asthma. 6 questions

identified to detect VCD and then

compared with laryngoscopic

findings.

The question “does pulmonary

auscultation reveal wheezing,

predominantly in the cervical

region, and/or stridor?” was

significantly higher for the VCD

group.

Simple screen to highlight VCD as

a cause of symptoms and thus

prompt consideration for work-

up with laryngoscopy.

Highly selected population. Lack

of information regarding other

contributory factors. Needs

replicating in other centers and

less selected cohort.

Newcastle laryngeal

hypersensitivity

Vertigan (95) 2014 Prospective evaluation in patients

with laryngeal dysfunction (n=82)

and controls (n=15). Evaluated

factor analysis, discriminant

analysis, responsiveness to

change

Discriminant validity: mean

difference between patients and

healthy was 5.5.

Responsiveness: score improves

after intervention , by 2.3 units

Identify patients with laryngeal

dysfunction;

Measure response to

intervention

Numbers tested are limited;

Needs evaluation in a second

validation population and in

different settings;

Assess reproducibility

29

Pittsburgh vocal cord

dysfunction index

Traister (96) 2014 Retrospective, subjects with

isolated VCD (n=89) versus

patients with asthma (n=59).

Model developed and applied to

additional cohort (n=72)

Based on 4 variables; (i) patient

reported history of symptoms of

throat tightness and (ii) dysphonia

(iii) absence of wheezing (iv)

presence of odors as a symptom

trigger. Cut-off score of 4 provides

positive predictive value of 96 and

negative predictive value of 77%.

Differentiate VCD from asthma Asthma patients had no

laryngoscopy performed.

Difficult to detect co-existing

asthma and VCD

Referred / selected population.

Potential difficulty interpreting

what is ‘wheeze’.

PPV dependent on prevalence.

Dyspnea index Gartner-Schmidt

(97) 2014.

Development of an upper airway

score using principle component

analysis in (n=369) during phases

of development. In final

development phase, subjects

(n=200) referred to voice service

with dyspnea. Final phase

evaluated intervention response.

10 point Likert scale developed.

Good test-retest reliability and

consistency. 10 deemed to be

abnormal upper airway dyspnea.

Tool to assess upper airway

symptom severity and follow-up,

rather than be used as diagnostic

tool.

Original questions based on

expert opinion / consensus expert

outcome and not generated

through patient interview.

Moderate correlation with other

dyspnea scores; this may be

expected.

30

Table 4.

Laryngeal abnormalityKey drug association

described / implicatedComment

Upper airway angioedema

Multiple agents associated

(including Salicylates, Penicillin,

Amlodipine, Amiodarone) as

manifestation of drug

anaphylaxis. ACEi important

and under-recognized cause of

presentation.

Careful drug history important for

patients presenting with intermittent

severe upper airway closure. Typically

other manifestations including visible

edema, rash.

Laryngospasm

Baclofen, β2 agonists,

Esomeprazole, Fentanyl,

Furosemide, Haloperidol, ACEi,

Ketamine, neuroleptics, N2O,

Vincristine, Risperidone

Acute severe laryngeal closure

implicated on exposure to many

agents, including inhaled therapies,

neuroleptics, and anesthetic agents. In

outpatient practice – focus should be

on inhaled therapies that may be

causing upper airway distress

Inducible laryngeal obstruction

Fentanyl, Flupentixol,

Hydralazine, anti-psychotic

medications, Propofol,

Sufentanil

Typically precipitated by agents used

or withdrawn in anesthesia. Anti-

psychotic agents associated with

laryngeal dystonia / dyskinesia.

Chronic cough

ACEi, angiotensin receptor

blockers, Latanoprost,

Linagliptin, Methotrexate,

statins, Topirimate, etc.

Multiple drugs implicated in cough

hypersensitivity. Detection and

removal of ACE inhibitors important.

Voice disturbance Axitinib, Inhaled corticosteroids

Inhaled corticosteroid implicated in

dysphonia. Some ICS agents may be

favorable as potency increased in lung.

31

Box: Future Research Priorities

Pathophysiology Role of TRP receptors – extension of cough / nerve research to ILO

Epidemiology Determination of prevalence of ILO in different settings:

community, primary care, secondary care, emergency department

Investigation Use of objective tests to diagnose laryngeal dysfunction:

quantification of effect, cut-points for diagnosis

How to address the episodic nature of ILO: provocation? Choice of

agents, etc. Means for assessing laryngeal movement over

prolonged period (e.g. hours).

Diagnosis (differentiation

from asthma)

Questionnaires with high negative / positive predictive value; role

of steroid trial, exhaled nitric oxide

Therapy Novel agents, long term outcomes of established therapies,

refinement of speech therapy. Evaluation of devices that promote

laryngeal abduction. Place of inhaled therapy in treating acute

episodes.

Definition of abbreviations: ILO – inducible laryngeal obstruction

32

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