Irritable Larynx Syndrome

This article provides a detailed review of the terminology, pathogenesis, and causes of irritable larynx syndrome in adults. It describes the diagnosis of irritable larynx syndrome based on medical history, symptoms, and laryngoscopic findings. The article also presents contemporary treatment principles, including recognition of the condition, voice therapy, psychotherapy, behavioral therapy, and treatment with neuromodulators. The benefits of vocal hygiene and hydration are also discussed.

The larynx becomes irritable when exposed to excessive levels of exogenous and endogenous irritants, which cause long-lasting neuroplastic changes in the brain and lead to inappropriate use of the laryngeal muscles [1]. Patients with irritable larynx syndrome (ILS) experience recurrent episodes of laryngospasm, during which inspiration is usually impaired [1, 2]. Patients with ILS report dyspnea, stridor, dysphonia, chronic persistent cough, a sensation of a lump in the throat, and/or frequent throat clearing. Because laryngeal hyperfunction causes episodic acute airway obstruction, these patients are often misdiagnosed with asthma, airway foreign bodies, organic laryngeal disorders, or laryngeal paralysis.

Consequently, numerous unnecessary investigations are performed, patients undergo unnecessary surgical interventions, such as intubation or tracheostomy, and they are prescribed various medications that are often ineffective [3–5]. Studies have shown that more than two-thirds of these patients are diagnosed with highly treatment-resistant asthma [3]. Examination of patients with ILS reveals signs of laryngeal muscle hypertonicity, including anteroposterior compression of the vocal folds, paradoxical vocal fold movements, and tension in the neck and shoulder girdle muscles. These patients are also frequently diagnosed with laryngopharyngeal reflux associated with gastroesophageal reflux disease (GERD), and psychoemotional imbalance may be present [2, 6]. This article discusses the causes, diagnosis, and contemporary treatment principles of ILS.

Terminology

Historically, numerous terms have been used to describe this condition, including paradoxical vocal fold movement, functional airway obstruction, pseudoasthma, paradoxical vocal fold dysfunction, episodic laryngeal dyskinesia, psychogenic stridor, laryngeal hypersensitivity, laryngeal hypersensitivity syndrome, and episodic paroxysmal laryngospasm. Since 1999, the term irritable larynx syndrome, introduced by Morrison and colleagues, has become the most widely used designation [1–6]. This syndrome is also associated with terms such as laryngopharyngeal neuropathy, postviral vagal neuropathy, idiopathic laryngeal sensory neuropathy, and neurogenic cough [7–13].

According to contemporary reviews of the scientific literature, ILS is classified among episodic laryngeal breathing disorders [5]. Patients with this syndrome frequently exhibit paradoxical vocal fold movements, which in this context represent a component of irritable larynx syndrome. ILS may also overlap with other syndromes. When persistent chronic cough is present, cough hypersensitivity syndrome may be diagnosed. This syndrome involves not only the upper respiratory tract, particularly the larynx, which contains the highest concentration of cough receptors, but also the lower respiratory tract and shares a pathogenesis similar to that of ILS [14–16].

Table 1. Main Causes of Paradoxical Vocal Fold Movement [3]

Category	Causes
Primary paradoxical vocal fold movements	Psychological and social factors, anxiety, and stress (70% of cases)
	Simulation (5%)
Secondary paradoxical vocal fold movements (25% of cases)	Other diseases
	Asthma
	Reflux
	Allergic laryngitis
	Dry laryngitis
	Laryngeal candidiasis
	Nasal and paranasal sinus diseases
	Undiagnosed obstructive sleep apnea
	Laryngeal sensory neuropathy
Neurological disorders	Brainstem dystonia or spasmodic dysphonia; autonomic dysfunction
Differential diagnosis	Bilateral/unilateral vocal fold paralysis
	Laryngeal stenosis
	Laryngomalacia/tracheomalacia
	Physical features of vocal fold movement
	Tonsillar (tumor-related) upper airway hypertrophy
	Benign/malignant airway tumors
	Atrophy of the vocal fold

OSA – obstructive sleep apnea.

Irritable larynx syndrome is characterized by episodic recurrent laryngospasm, respiratory dysphonia, cough, and laryngeal paresthesias associated with increased laryngeal sensitivity to irritants of various origins [1, 2, 5, 6].

Paradoxical vocal fold movement refers to inappropriate adduction (narrowing) of the larynx, specifically the vocal folds and/or structures of the laryngeal inlet, during inspiration and/or expiration, which may be primary or secondary [3].

Cough hypersensitivity syndrome is a disorder of the sensory nerves of the upper and lower respiratory tract, characterized by a persistent chronic cough triggered by nontussive and toxic irritants due to increased sensitivity of cough receptors, particularly transient receptor potential vanilloid type 1 (TRPV1) and A1 receptors [14, 15, 17].

Pathogenesis of Irritable Larynx Syndrome

Scientific studies have demonstrated that irritable larynx syndrome develops as a result of acquired neuroplastic changes in the brain, particularly in the periaqueductal gray matter [1, 2]. Repeated exposure to respiratory irritants causes marked excitation of afferent neurons, predisposing patients to laryngospasm and persistent cough, and alters the central neural control of the larynx and surrounding tissues. This process is referred to as neuroplasticity [2, 14]. Consequently, the response to an appropriate sensory stimulus becomes impaired.

Nonspecific inflammatory mediators of various origins sensitize the afferent nerves in the mucous membranes of organs innervated by the vagus nerve through rapidly conducting impulses in their nerve endings, including unmyelinated C fibers, thereby lowering sensory receptor thresholds [2, 9]. In patients with persistent chronic cough, this process is associated with increased expression of transient receptor potential vanilloid type 1 (TRPV1) receptors in nonadrenergic, noncholinergic nerve endings [9].

Central nervous system sensitization is characterized by increased excitability within central sensory pathways. Central sensitization is indicated by changes detected during objective laryngeal sensory testing; laryngeal hypersensitivity or paresthesias, manifested by altered sensations in the pharynx, such as tickling, itching, or a sensation of a lump in the throat; an exaggerated laryngeal response, including spasmodic coughing, to appropriate stimuli such as smoke, smoking, and aspirated material; and an increased laryngeal response to inappropriate stimuli, including temperature fluctuations, voice use, and physical exercise [9, 18].

Furthermore, recent studies have demonstrated increased cerebral cortical activity in these patients, as detected by functional magnetic resonance imaging [9]. Altered pain thresholds have also been observed [9].

Causes of Irritable Larynx Syndrome

Among the most common laryngeal irritants associated with ILS, as described by Morrison and colleagues, are repeated exposure of the laryngeal mucosa to refluxed gastric contents and a history of viral infection, reported in nearly half of patients [1, 2]. The significance of these irritants has also been confirmed in subsequent studies by other researchers [4, 8, 9, 12].

Other external triggers described in the scientific literature include various odors, smoke, temperature changes, and occupational irritants. Episodic laryngospasm may also be provoked by speaking, singing, and coughing [1–7, 11, 12].

Andrianopoulos and colleagues investigated 27 patients with ILS and found that more than one-third associated their symptoms with emotional factors, particularly stress and anxiety. In 22% of patients, symptom onset coincided with the consumption of certain foods, including peanut butter, salad dressings, grapefruit, nuts, and others [4].

According to most authors, ILS occurs significantly more frequently in middle-aged women than in men [1, 2, 4, 12, 19]. This may be explained by greater sensitivity of transient receptor potential cough receptors in women or by declining estrogen levels during the premenopausal period, which may contribute to increased cough reflex activity [9].

Table 2. Summary of Data From a Systematic Review of Neuromodulators Used to Treat Refractory Chronic Cough [13]

Medication (number of publications)	Dosage	Treatment Duration	Improvement (% of patients)
Amitriptyline (3/8)	10–100 mg/day	10–21 days	75–86%
Gabapentin (3/8)	100–1,800 mg/day, divided into 2–3 doses	4–12 weeks	69–83%
Pregabalin (1/8)	150–300 mg/day, divided into 2 doses	4 weeks	60%
Baclofen (1/8)	30 mg/day, divided into 3 doses	4 weeks	90%
Carbamazepine (1/8)	200 mg/day, divided into 2 doses	4 weeks	69%

These medications are initiated at low doses and increased to the optimal dose; treatment is discontinued by gradually reducing the dose.

The number of patients studied was very small.

Diagnosis of Irritable Larynx Syndrome

The main diagnostic criteria for irritable larynx syndrome (ILS) are as follows [1, 2, 12]:

• Symptoms associated with laryngeal muscle tension:
  • Dysphonia and/or laryngospasm (stridor/dyspnea).
  • A sensation of a lump in the throat and/or chronic cough.
• Signs of head and neck muscle tension detected during examination:
  • Laryngoscopy reveals laryngeal muscle tension during phonation, including hyperadduction of the vocal folds and vestibular folds (ventricular phonation, characterized by medial-to-lateral approximation of laryngeal structures) and/or varying degrees of anteroposterior laryngeal compression. A posterior triangular or diamond-shaped glottic opening may also be observed due to persistent tension of the posterior thyroarytenoid muscle (m. thyroarytenoideus posterior), described as responsible for vocal fold abduction, or opening, during phonation.
  • Palpation reveals painful, tense suprahyoid and infrahyoid muscles. An elevated laryngeal position and tender points in the laryngeal region may also be detected.
• An association between symptoms and specific irritants, including inhaled substances, esophageal irritants, and odors.

Symptoms

ILS is characterized by sudden episodes of tickling or irritation in the throat, accompanied by dyspnea with stridor and persistent coughing associated with lacrimation, rhinorrhea, and facial flushing [12].

Stridor, episodes of dyspnea, and persistent cough are the most common symptoms and represent the primary complaints in approximately two-thirds of patients with ILS [1–4]. However, approximately half of these patients may also develop acute or recurrent aphonia (loss of voice) [4].

Unlike patients with laryngopharyngeal reflux associated with gastroesophageal reflux disease (GERD), patients with ILS more commonly experience a dry daytime cough, often described as barking and associated with speaking [3]. In these patients, coughing frequently occurs during phonation as part of the clinical examination.

(Video) Laryngoscopy

In addition to signs of laryngeal muscle tension (Figure 1), laryngoscopy may reveal paradoxical vocal fold movements. These movements involve inappropriate adduction of the vocal folds during breathing, resulting in respiratory disturbances that may sometimes be considered life-threatening [2, 3].

Consequently, as mentioned earlier, these patients frequently undergo numerous unnecessary investigations, receive various medications, and may be subjected to unnecessary surgical interventions.

It is important to remember that paradoxical vocal fold movements have multiple causes and are not exclusive to patients with ILS. Secondary paradoxical vocal fold movements associated with laryngeal hypersensitivity may be triggered by irritation of the laryngeal mucosa or changes in laryngeal sensitivity [3].

Table 1 presents the main currently recognized causes of paradoxical vocal fold movements, which are important in the differential diagnosis of ILS [3].

In some patients, video laryngoscopy may also reveal subtle or clearly visible neurological abnormalities, such as paresis, as well as signs caused by refluxed gastric contents [8, 12].

Patients with ILS may also have dry pharyngeal and laryngeal mucosa, most commonly due to adverse effects of medications or dehydration, which is characteristic of these patients [9].

Flexible fiberoptic laryngoscopy plays an important role in diagnosing ILS and distinguishing it from other conditions. Since 2004, the perfume provocation test has been used in the United States to diagnose ILS [20].

During this test, the larynx is examined using a flexible fiberoptic endoscope while the patient breathes and phonates before and after inhaling the provocative stimulus.

A positive test is characterized by paradoxical vocal fold movements that cause coughing and inspiratory dyspnea. Studies have demonstrated that strong perfume is the most reliable stimulus when inhaled through either the nose or the mouth [20].

Based on clinical symptoms and findings, the Canadian researcher Hoy and colleagues proposed a simple screening method for ILS in 2010.

ILS is suspected when at least one major symptom is present. Major symptoms include dysphonia associated with laryngeal muscle tension and dyspnea, while minor symptoms include a sensation of a lump in the throat and chronic cough.

A definite diagnosis of ILS is established when at least one major symptom is present, a laryngologist objectively confirms signs of laryngeal tension, and obvious organic laryngeal pathology has been excluded [6].

When clear occupational exposure to airborne irritants and odors is also identified, occupational ILS is diagnosed.

In 2014, the Newcastle Laryngeal Hypersensitivity Questionnaire was developed and validated to facilitate the diagnosis of ILS. It consists of 14 specific questions covering three domains: obstruction, pain/temperature sensations, and irritation [21].

The questionnaire helps diagnose ILS and provides a reliable means of monitoring treatment effectiveness.

Other Investigations

Laryngeal sensitivity, which is altered in patients with ILS, can be assessed using objective methods. These include hypertonic saline solution or mechanical stimulation of the arytenoid tubercles during fiberoptic endoscopy, using an air pulse or touching them with the tip of the fiberscope to elicit the vocal fold adductor reflex [4, 8, 9, 18].

ILS is characterized by increased chemoreceptor sensitivity and decreased mechanoreceptor sensitivity in the laryngeal mucosa [17].

Although the classical criteria established by Morrison require the absence of obvious organic laryngeal pathology, clearly defined neurological disease, or psychiatric illness, contemporary studies indicate that ILS may coexist with neurological laryngeal disorders, laryngeal edema, other conditions capable of causing laryngeal obstruction, asthma, and various psychiatric disorders [1–4].

Nevertheless, to ensure appropriate treatment, it is essential to distinguish and diagnose ILS even when comorbid conditions are present.

Traister and colleagues recently proposed the Pittsburgh Vocal Cord Dysfunction Index to differentiate ILS from asthma and facilitate timely, appropriately targeted treatment [19].

According to the authors, when all four index variables are positive—dysphonia, a sensation of throat tightness or a lump in the throat, absence of wheezing, and sensitivity to odors—ILS is identified in the vast majority of patients studied, with a reported probability of 77.8%.

A contemporary review of the scientific literature conducted by American researchers, covering the period from 1983 to 2015, led to the development of a theoretical diagnostic model for irritable larynx syndrome [5].

This conceptual model includes the factors that trigger ILS, as well as its characteristic symptoms and laryngeal findings (Figure 2).

Treatment Principles for Irritable Larynx Syndrome

The main principles of effective ILS treatment include:

• Conscious recognition of the condition and vocal hygiene, including patient education about the causes of the disorder and their elimination, adherence to an appropriate voice-use regimen, avoidance of irritants, systemic and topical hydration, and dietary measures.
• Voice therapy, including learning and reinforcing appropriate breathing and speaking behaviors with the assistance of biofeedback.
• Treatment with neuromodulators.
• Psychotherapy and behavioral therapy.
• Treatment of comorbid conditions, including laryngopharyngeal reflux associated with GERD.
• Other measures, including topical treatment aimed at modifying laryngeal sensitivity.

At the beginning of the 21st century, an effective educational neurolinguistic programming system was proposed for patients with ILS at the University of Massachusetts Center for Language, Voice and Hearing [4].

The program consists of three stages:

1. Conscious recognition of the problem, during which patients are taught to understand the causes and nature of their condition and the goals of treatment.
2. The associative stage, during which patients learn to control breathing and laryngeal dysfunction automatically through auditory, visual, instrumental, and proprioceptive biofeedback. Video laryngoscopy sessions aimed at modifying responses to stimuli through biofeedback are popular internationally, with two to five sessions typically prescribed.
3. The autonomous stage, during which the acquired control skills are reinforced and become automatic.

Patient education should also establish long-term vocal hygiene practices. These include phonatory and nonphonatory measures designed to protect the voice from injury, such as voice rest, hydration, avoidance of laryngeal irritants (including smoking and industrial irritants), appropriate speaking techniques, and basic voice-strengthening and training exercises [8, 9].

Hydration

Hydration is one of the primary measures for protecting the voice.

Recommendations include humidifying indoor environments, maintaining adequate fluid intake, avoiding dehydrating substances such as coffee, black tea, and alcohol, and avoiding medications that may cause dehydration, including antihistamines, anticholinergics, and diuretics.

Nasal hygiene and topical moisturizing agents are also recommended. Both systemic and topical hydration play an important role in treating patients with ILS [4, 6, 8, 9, 18].

Because coughing and throat clearing are characteristic of ILS, patients are advised to take a sip of water or consciously swallow saliva whenever they feel the urge to cough and/or clear their throat. This technique is known as the cough suppression swallow method.

In addition, because of laryngeal hypersensitivity, topical agents that reduce mucosal excitability may be recommended, including sucralfate elixir and topical moisturizers containing hyaluronic acid [3].

Topical Moisturizing Agents

Scientific studies have demonstrated that products with mucosal moisturizing properties play an important role in the comprehensive treatment of laryngeal disorders. Topical moisturizing agents containing hyaluronic acid have been developed, and studies have shown that locally applied hyaluronic acid retains moisture in the oropharyngeal and hypopharyngeal mucosa and forms a protective layer over these areas and the laryngeal inlet. Its hygroscopic properties promote mucosal regeneration and wound healing, making it suitable for treating dry and irritated mucous membranes, as well as acute, chronic, and ulcerative inflammation [22, 23].

Recent studies conducted in Germany have demonstrated that a topical preparation combining hyaluronic acid with minerals that stimulate salivary secretion (sodium, potassium, zinc, and silicon), formulated as lozenges (GeloRevoice), forms a hydrogel complex. This complex coats the mucosal surfaces of the oropharynx, hypopharynx, epiglottis, and posterior larynx (laryngeal inlet) with a protective layer enriched with hyaluronic acid.

Within three days, the preparation significantly reduced symptoms of pharyngeal and laryngeal irritation, including throat irritation, tickling, coughing, throat clearing, a sensation of a lump or dryness in the throat, difficulty swallowing, and hoarseness [23, 24]. Therefore, this preparation is considered suitable as part of the comprehensive treatment of irritable larynx syndrome.

An analysis of data from 965 patients examined at 326 medical centers showed that the hydrogel complex remained on the mucosal surfaces for more than one hour in the majority of patients (60%) [24].

Voice Therapy

Developing appropriate speaking techniques primarily involves learning diaphragmatic breathing [25]. Techniques such as sighing, sniffing, blowing, and other breathing exercises are used [4].

Special physical and orthophonic exercises are also employed to reduce head and neck muscle tension, establish gentle vocal onset and correct articulation, and synchronize breathing with phonation. Treatment includes manual therapy and orthophonic exercises based on various techniques.

Scientific studies have demonstrated that voice therapy is effective in treating irritable larynx syndrome [9]. Meta-analyses have shown that voice therapy reduces episodes of laryngospasm and persistent coughing while improving quality of life [26].

Treatment With Neuromodulators

Episodes of persistent coughing are treated with neuromodulators [13]. Medication doses are gradually increased until a therapeutic response is achieved. If treatment is effective, it is continued for up to three months. Medications are also discontinued gradually by reducing the dose.

Neuromodulator treatment for ILS is expected to produce substantial improvement rather than complete recovery.

A recent systematic review by Cohen and colleagues, analyzing eight published articles on this topic, revealed that the most commonly prescribed contemporary neuromodulator is gabapentin, a gamma-aminobutyric acid analogue. Its dose is gradually increased according to the therapeutic response, starting at 100 mg daily and reaching an optimal dose of 900–1,800 mg daily, divided into two or three doses (Table 2).

Neuromodulators may cause adverse effects such as drowsiness, dizziness, and mucosal dryness. Patients should therefore be informed about these potential side effects [13].

Antireflux Medications

Empirical short-term treatment with proton pump inhibitors (PPIs) for three months is recommended when a patient with ILS also exhibits signs of chronic laryngitis on video laryngoscopy or experiences typical symptoms of gastroesophageal reflux disease (GERD), such as heartburn and regurgitation [25].

According to FDA recommendations, calcium supplementation is recommended for at-risk patients receiving long-term PPI treatment (more than one year), particularly older individuals, postmenopausal women, and patients with osteoporosis [27].

Contemporary approaches to treating laryngopharyngeal reflux associated with GERD also include agents that inhibit pepsin activity, such as magnesium and sodium alginates, alkaline water (pH >8), pepsin-neutralizing phytochemicals, and a pH-based antireflux diet [28].

Local Treatment of Laryngeal Sensitivity

Local treatment of laryngeal sensitivity involves intralaryngeal lidocaine injections [29]. This approach is indicated when voice therapy is ineffective in patients with laryngeal muscle tension.

Dworkin and colleagues proposed injecting 1 mL of a 1–2% lidocaine solution into the larynx (vocal folds) through a trans laryngeal approach via the cricothyroid membrane (membrana cricothyroidea).

According to the original technique, the lidocaine injection is followed by a five-minute voice therapy session.

Lidocaine acts on mechanoreceptors in the laryngeal mucosa and interrupts the mechanism responsible for hyperfunctional phonation.

Summary

Irritable larynx syndrome is a multifactorial disorder associated with increased laryngeal sensitivity to various irritants. It causes recurrent episodes of laryngospasm accompanied by dysphonia, coughing, and laryngeal paresthesia.

The diagnosis of irritable larynx syndrome is based on characteristic symptoms, laryngoscopic findings, and external examination of the neck demonstrating increased tension in the laryngeal and cervical muscles, as well as an identifiable association between symptoms and specific irritants.

Treatment is comprehensive and includes patient education, voice therapy, neuromodulator treatment, and vocal hygiene.

Prof. Habil. Dr. Nora Šiupšinskienė, Department of Otorhinolaryngology, Lithuanian University of Health Sciences Medical Academy; Klaipėda University

Lithuanian Doctor's Journal: Expert Recommendations, 2016/2017