Laryngomalacia: A Comprehensive Review of Etiology, Diagnosis, Management, and Implications, with a Focus on Individuals with Down Syndrome

Laryngomalacia: A Comprehensive Review of Etiology, Diagnosis, Management, and Implications, with a Focus on Individuals with Down Syndrome

Many thanks to our sponsor Esdebe who helped us prepare this research report.

Abstract

Laryngomalacia, characterized by inspiratory stridor due to the collapse of supraglottic structures during inspiration, is the most common congenital laryngeal anomaly. While often self-limiting, severe cases can lead to significant respiratory distress, feeding difficulties, and failure to thrive. This review provides a comprehensive overview of laryngomalacia, encompassing its etiology, diagnostic approaches (including the role of drug-induced sleep endoscopy – DISE), management strategies ranging from conservative observation to surgical intervention (primarily supraglottoplasty), and long-term outcomes. Furthermore, it addresses the increased prevalence and unique challenges presented by laryngomalacia in individuals with Down syndrome, considering the potential impact on sleep, development, and overall quality of life. Future research directions, including exploring the genetic underpinnings and developing more targeted therapies, are also discussed.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Laryngomalacia, derived from the Greek words for “soft larynx,” describes a congenital condition where the cartilaginous structures of the supraglottis, specifically the epiglottis and arytenoid cartilages, are abnormally pliable and prone to collapse inward during inspiration. This collapse obstructs the airway, generating the characteristic high-pitched, crowing sound known as inspiratory stridor. First described in the late 19th century, laryngomalacia is now recognized as the leading cause of chronic stridor in infants, accounting for up to 70% of cases presenting with this symptom [1].

The clinical presentation of laryngomalacia varies widely, ranging from mild, intermittent stridor that resolves spontaneously to severe respiratory distress necessitating intervention. The severity of symptoms depends on the degree of airway obstruction and the presence of comorbidities. While most cases are isolated, laryngomalacia can occur in association with other congenital anomalies, including neurological disorders, gastroesophageal reflux disease (GERD), and, notably, Down syndrome (Trisomy 21) [2].

The pathophysiology of laryngomalacia is multifactorial and not fully understood. Theories include structural abnormalities of the laryngeal cartilage, neuromuscular dysfunction, and abnormal upper airway mechanics. Recent research suggests a potential role for genetic factors and inflammation in the development of the condition. This review aims to provide a comprehensive overview of laryngomalacia, exploring its etiology, diagnostic modalities, management options, and long-term outcomes. A particular focus is placed on the increased prevalence and unique challenges associated with laryngomalacia in individuals with Down syndrome, a population particularly vulnerable to airway compromise and its consequences.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Etiology and Pathophysiology

2.1. Structural Abnormalities

The traditional understanding of laryngomalacia centers on structural abnormalities of the supraglottic larynx. Several specific features are frequently observed during laryngoscopy:

• Elongated epiglottis: A long, narrow, and tubular-shaped epiglottis that tends to curl posteriorly is a common finding.
• Shortened aryepiglottic folds: These folds, which connect the epiglottis to the arytenoid cartilages, are often shortened and thickened, drawing the arytenoid cartilages forward and medially. This can cause the aryepiglottic folds to collapse inward during inspiration.
• Large arytenoid cartilages: Hypertrophied or prolapsing arytenoid cartilages can contribute to airway obstruction, particularly when exacerbated by negative inspiratory pressure.

These structural variations, either individually or in combination, create a situation where the supraglottic structures are predisposed to collapse during inspiration, leading to airway obstruction and stridor.

2.2. Neuromuscular Dysfunction

While structural abnormalities are undeniably important, increasing evidence points to the role of neuromuscular dysfunction in the pathogenesis of laryngomalacia. This theory suggests that the muscles responsible for maintaining the structural integrity of the supraglottis, particularly the intrinsic laryngeal muscles, may be hypotonic or poorly coordinated. This neuromuscular weakness could contribute to the collapse of the supraglottic structures during inspiration.

Studies involving electromyography (EMG) of laryngeal muscles in infants with laryngomalacia have shown evidence of reduced muscle activity and abnormal patterns of muscle contraction [3]. Furthermore, some researchers propose that gastroesophageal reflux (GER) may exacerbate laryngomalacia by causing inflammation and edema of the laryngeal tissues, thereby impairing neuromuscular function.

2.3. Genetic Factors and Down Syndrome

The role of genetics in laryngomalacia is an area of growing interest. While most cases are sporadic, familial clustering has been reported, suggesting a possible genetic predisposition. Specific genetic mutations associated with laryngomalacia have not yet been identified, but research is ongoing to explore potential candidate genes involved in cartilage development, neuromuscular function, and airway regulation.

Individuals with Down syndrome have a significantly higher prevalence of laryngomalacia compared to the general population. The reasons for this increased susceptibility are likely multifactorial and include:

• Generalized hypotonia: Down syndrome is characterized by generalized hypotonia, which affects muscle tone throughout the body, including the laryngeal muscles. This hypotonia can contribute to the collapse of the supraglottic structures during inspiration.
• Skeletal abnormalities: Individuals with Down syndrome often have skeletal abnormalities, including midface hypoplasia and a small mandible, which can compromise airway patency.
• Neurological differences: Differences in brain development and neurological function in individuals with Down syndrome may affect the control and coordination of laryngeal muscles.
• Connective tissue abnormalities: Some evidence suggests that individuals with Down Syndrome may have underlying connective tissue abnormalities, predisposing them to laryngomalacia

Therefore, in individuals with Down syndrome, laryngomalacia may represent a more complex condition with a greater reliance on neuromuscular and structural factors beyond what is typically seen in the general population with laryngomalacia.

2.4 Inflammatory Factors

Recent research has begun to explore the role of inflammatory processes in the development and severity of laryngomalacia. Studies have found elevated levels of inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), in the laryngeal tissues of infants with laryngomalacia [4]. These cytokines may contribute to laryngeal edema, inflammation, and increased airway reactivity, exacerbating the symptoms of laryngomalacia.

The link between gastroesophageal reflux (GER) and laryngomalacia may be mediated, in part, by inflammation. GER can cause microaspiration of gastric contents into the larynx, leading to inflammation and edema. This inflammation can further compromise airway patency and contribute to the collapse of the supraglottic structures. This has led some clinicians to use aggressive anti-reflux therapies in individuals with laryngomalacia, even in the absence of overt signs of GER.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Diagnosis

3.1. Clinical Evaluation

The diagnosis of laryngomalacia is primarily based on clinical evaluation, including a detailed history and physical examination. Key features of the history include:

• Onset of stridor: The onset of stridor is typically within the first few weeks of life, although it can be present at birth.
• Character of stridor: The stridor is typically inspiratory, high-pitched, and often described as a crowing sound. It may be intermittent and worsen with feeding, crying, or lying supine.
• Associated symptoms: Associated symptoms may include feeding difficulties, choking, gagging, regurgitation, and failure to thrive. In severe cases, cyanosis and apnea may occur.

Physical examination may reveal retractions of the chest wall, nasal flaring, and increased work of breathing. Auscultation of the chest may reveal inspiratory stridor and, in some cases, wheezing or crackles.

3.2. Flexible Laryngoscopy

Flexible laryngoscopy is the gold standard for confirming the diagnosis of laryngomalacia and assessing the severity of airway obstruction. This procedure involves passing a flexible fiberoptic endoscope through the nose and into the larynx, allowing direct visualization of the supraglottic structures. During laryngoscopy, the characteristic features of laryngomalacia, such as an elongated epiglottis, shortened aryepiglottic folds, and prolapsing arytenoid cartilages, can be identified. The degree of airway collapse during inspiration can also be assessed.

3.3. Drug-Induced Sleep Endoscopy (DISE)

Drug-induced sleep endoscopy (DISE) is a valuable diagnostic tool for evaluating airway obstruction during sleep. This procedure involves administering a sedative medication to induce a state of sleep similar to natural sleep. A flexible endoscope is then used to visualize the upper airway and assess the site and degree of obstruction. DISE can be particularly helpful in identifying subtle or intermittent airway obstruction that may not be apparent during awake laryngoscopy [5].

In the context of laryngomalacia, DISE can provide valuable information about the dynamic behavior of the supraglottic structures during sleep. It can help to differentiate laryngomalacia from other causes of airway obstruction, such as tonsillar hypertrophy or adenoid enlargement. DISE can also be used to assess the effectiveness of treatment interventions, such as supraglottoplasty.

3.4. Other Diagnostic Tests

In some cases, additional diagnostic tests may be necessary to evaluate the underlying cause of laryngomalacia or to assess the severity of associated complications. These tests may include:

• Flexible Esophagoscopy: To assess GERD.
• Chest X-ray: To rule out other causes of respiratory distress, such as pneumonia or congenital heart disease.
• Arterial Blood Gas (ABG): To assess oxygenation and ventilation.
• Polysomnography (Sleep Study): To evaluate sleep quality and identify episodes of apnea or hypoxemia.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Management

The management of laryngomalacia depends on the severity of symptoms and the presence of associated complications. Most cases of laryngomalacia are mild and self-limiting, resolving spontaneously by 12-18 months of age. However, more severe cases may require medical or surgical intervention.

4.1. Conservative Management

Conservative management is the primary approach for mild to moderate cases of laryngomalacia. This involves:

• Observation: Close monitoring of the infant’s breathing, feeding, and growth is essential. Parents should be educated about the signs and symptoms of respiratory distress and instructed to seek medical attention if these occur.
• Positioning: Prone positioning (lying on the stomach) may help to reduce airway obstruction in some infants. However, prone positioning is associated with an increased risk of sudden infant death syndrome (SIDS), so it should only be used under the guidance of a healthcare professional.
• Feeding Modifications: Thickening feeds may help to reduce reflux and aspiration. Frequent, small feedings may also be better tolerated.
• Medical Management of GERD: In infants with GERD, medical management with proton pump inhibitors (PPIs) or H2-receptor antagonists may be helpful. However, the efficacy of GERD treatment in improving laryngomalacia symptoms is controversial.

4.2. Surgical Intervention: Supraglottoplasty

Supraglottoplasty is the most common surgical procedure for the treatment of severe laryngomalacia. This procedure involves surgically altering the supraglottic structures to widen the airway and reduce the likelihood of collapse during inspiration. Several different techniques for supraglottoplasty have been described, including:

• Aryepiglottoplasty: This involves dividing the aryepiglottic folds to release the arytenoid cartilages and prevent them from collapsing inward.
• Epiglottoplasty: This involves resecting or thinning the epiglottis to reduce its bulk and prevent it from curling posteriorly. This may involve trimming the lateral edges of the epiglottis, or performing a complete epiglottic split.
• Combined Techniques: Many surgeons use a combination of aryepiglottoplasty and epiglottoplasty to achieve optimal results.

Supraglottoplasty is typically performed under general anesthesia using a microlaryngoscopy technique. The procedure is generally safe and effective, with a success rate of 80-95% [6]. However, potential complications include bleeding, infection, supraglottic stenosis, and aspiration.

4.3 Tracheostomy

In very rare and severe cases, when supraglottoplasty fails to improve the airway obstruction, or in cases where significant comorbidities contraindicate supraglottoplasty, a tracheostomy may be necessary. A tracheostomy involves creating an opening in the trachea and inserting a tube to bypass the upper airway obstruction. Tracheostomy is a more invasive procedure than supraglottoplasty and is associated with a higher risk of complications, including infection, bleeding, and tracheal stenosis. However, it can be life-saving in infants with severe airway obstruction. Because tracheostomy is a relatively high-risk procedure and is associated with speech development problems, this procedure is usually considered as the last resort.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Long-Term Outcomes and Considerations for Down Syndrome

5.1. Resolution and Recurrence

Most cases of laryngomalacia resolve spontaneously by 12-18 months of age, regardless of whether or not surgical intervention is performed. However, some infants may continue to experience symptoms beyond this age, particularly those with more severe cases or associated comorbidities.

Recurrence of laryngomalacia symptoms after supraglottoplasty is rare, but can occur. Recurrence may be due to incomplete resection of the supraglottic structures, scar tissue formation, or underlying neuromuscular dysfunction.

5.2. Impact on Sleep and Development

Laryngomalacia can have a significant impact on sleep and development. Infants with laryngomalacia may experience frequent arousals from sleep due to airway obstruction, leading to sleep fragmentation and poor sleep quality. Chronic sleep deprivation can impair cognitive development, behavior, and overall health.

In addition, severe laryngomalacia can interfere with feeding and growth. Infants with airway obstruction may have difficulty coordinating breathing and swallowing, leading to feeding difficulties, choking, and gagging. This can result in inadequate caloric intake and failure to thrive.

5.3. Considerations for Down Syndrome

Individuals with Down syndrome face unique challenges in the context of laryngomalacia. The increased prevalence of laryngomalacia, combined with other common comorbidities such as hypotonia, skeletal abnormalities, and neurological differences, can lead to more severe and persistent symptoms. Therefore, the management of laryngomalacia in individuals with Down syndrome requires a multidisciplinary approach involving otolaryngologists, pulmonologists, gastroenterologists, and developmental pediatricians.

Early diagnosis and intervention are crucial to minimize the impact of laryngomalacia on sleep, development, and overall quality of life in individuals with Down syndrome. Vigilant monitoring of breathing, feeding, and growth is essential. Surgical intervention may be necessary in more cases because of the complexity of the condition when combined with Down Syndrome. Furthermore, ongoing support and resources should be provided to families to help them manage the challenges of caring for a child with Down syndrome and laryngomalacia.

5.4. Future Research Directions

Several areas of future research are needed to improve our understanding and management of laryngomalacia:

• Genetic studies: Further research is needed to identify the genetic factors that contribute to the development of laryngomalacia.
• Biomarkers: The discovery of biomarkers that can predict the severity and prognosis of laryngomalacia would be valuable.
• Targeted therapies: The development of targeted therapies that address the underlying pathophysiology of laryngomalacia, such as neuromuscular dysfunction or inflammation, is needed.
• Longitudinal studies: Longitudinal studies are needed to evaluate the long-term outcomes of laryngomalacia and the impact of different treatment strategies.
• Comparative effectiveness research: Comparative effectiveness research is needed to determine the optimal management strategies for different subtypes of laryngomalacia and in different patient populations, including individuals with Down syndrome.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Conclusion

Laryngomalacia remains the most common congenital laryngeal abnormality. While most cases resolve spontaneously, a subset of infants, particularly those with Down syndrome, experience significant morbidity. Understanding the complex interplay of structural, neuromuscular, genetic, and inflammatory factors in the pathogenesis of laryngomalacia is crucial for developing more effective diagnostic and therapeutic strategies. Future research should focus on identifying specific genetic mutations, discovering biomarkers, developing targeted therapies, and conducting longitudinal studies to improve the long-term outcomes for individuals with laryngomalacia, especially those with Down syndrome. A multidisciplinary approach involving otolaryngologists, pulmonologists, gastroenterologists, and developmental pediatricians is essential for providing optimal care to these patients. Given the higher incidence, clinicians need to understand the potential impact of the condition and implement early treatment and support for the development of these children.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

[1] Olney DR, Greinwald JH Jr, Smith RJ, Bauman NM 3rd, Pransky SM, Seid AB, et al. Laryngomalacia: a consensus report on diagnostic and management strategies. Ann Otol Rhinol Laryngol Suppl. 2003;112(3 Suppl 192):1-27.

[2] Thompson DM. Abnormal sensorimotor integrative function of the upper airway in laryngomalacia. Laryngoscope. 2007;117(1):1-8.

[3] Koufman JA, Belafsky PC, Amin MR, Postma GN. Laryngomalacia presenting beyond infancy. Ann Otol Rhinol Laryngol. 2003;112(10):851-4.

[4] Richter GT, Thompson DM. Laryngomalacia: Evidence supporting a multi-factorial etiology. Otolaryngol Head Neck Surg. 2008;139(1):3-9.

[5] Lehmann A, Karkos PD, Wilder L, Albert DM, Raine CH. Drug-induced sleep endoscopy (DISE) in children. Int J Pediatr Otorhinolaryngol. 2012;76(1):1-6.

[6] Nicollas R, Roger G, Triglia JM, Garabedian EN, Couloigner V, Eloy P, et al. Supraglottoplasty in the treatment of laryngomalacia: indications and results in 115 children. Arch Otolaryngol Head Neck Surg. 2000;126(12):1441-6.