Laryngeal Clefts

Etiology

Normal embryological development of the upper aerodigestive tract depends on appropriate migration of mesenchyme from the fourth and sixth branchial arches, and from the endoderm of the foregut, respectively. As the foregut develops in a caudal to cranial direction, during the fourth and fifth weeks of gestation, the lateral tracheoesophageal folds move medially to fuse and form the tracheoesophageal septum, thus separating the primordial esophagus from the laryngotracheal tube.[5]

There are multiple theories proposed to explain the development of LC:

• Increased intraembryonic pressure due to lordotic curvature of the spine during heart development, causing strain and displacement of the developing esophagus
• Incomplete or anomalous re-canalization of the esophagus
• Persistence of an abnormal vessel leading to vascular insufficiency in the foregut, resulting in growth anomalies
• Abnormal stem cell differentiation leading to failure of septation [6]

Embryological models in rats have demonstrated a relationship between doxorubicin exposure, tracheoesophageal fistula, and VACTERL syndrome (vertebral anomalies, anal atresia [imperforate anus], cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal anomalies, limb abnormalities [especially radial limb defects]). Still, LC was not observed in these experiments.[7]

Epidemiology

The overall incidence of LC is estimated to be between 1:10,000 and 1:20,000 live births.[8][9] This is very likely an underestimate, since small clefts are often asymptomatic. LC is uncommon, accounting for approximately 1.5% of pediatric laryngeal pathologies.[10] A 2006 study used endoscopy to evaluate 264 consecutive pediatric patients with chronic cough or aspiration and identified 20 cases of type I LC, which accounted for only 7.6% of the cases in their patient pool.[11] Studying the epidemiology of LC in detail is challenging due to its low prevalence; however, the limited data available have shown a higher incidence in males than females (a ratio of 5:3), and there is no evidence to suggest a racial predilection.[2][12][13] Most cases of LC are sporadic, and although the condition can occur in the context of several different syndromes, no specific genetic sequence has been identified that causes isolated LC.

Pathophysiology

LC presents on a continuum with mild stridor at one end and respiratory distress at the other. The most common symptoms are coughing and stridor, which worsen with feeding, as well as recurrent aspiration-induced upper respiratory infections. The severity of presentation depends primarily on the depth of the cleft, which is most often described using the 4-tiered Benjamin-Inglis classification, developed in 1989.[14] Type I clefts can be treated conservatively with watchful waiting, but types II through IV require either endoscopic or open surgical intervention. Post-intervention outcomes are variable, and patients may continue to aspirate due to other comorbidities, even with full closure of the cleft.

History and Physical

Most patients with LC present with frequent coughing, difficulty feeding, and recurrent respiratory tract infections. The differential diagnosis for these complaints is broad; therefore, the initial encounter should include a thorough history and physical examination that evaluates for more common problems before focusing on potential rare congenital laryngeal anomalies. Taking a comprehensive history of the patient is the first step in the diagnosis process. This should begin with a discussion of the pregnancy, including prenatal care, maternal and fetal complications during gestation, duration of the pregnancy, type of delivery, need for any neonatal resuscitation or intensive care unit admission, and results of newborn screening blood and hearing tests. Specific inquiries into feeding habits, frequency of regurgitation, frequency of upper respiratory infections, weight gain, aspiration, coughing, choking, or other respiratory compromise should also be pursued.

As LC can be associated with various syndromes, the parents should be asked about the presence of similar symptoms in other family members. Direct questions about surgeries on the digestive or respiratory system early in life may provide helpful information that more open-ended queries may not. The physical examination should comprehensively evaluate the body systems that may be involved with syndromes that can include LC.[15] Important symptoms and findings within those systems are highlighted below.

• Neurological: Evaluation of muscle tone and reflexes
• Craniofacial: Malformation of external and middle ears, cleft lip or palate, hypertelorism
• Respiratory: Stridor, retractions, desaturations
  • Determining if these symptoms are positional is especially important. Worsening symptoms in a supine position may indicate laryngomalacia.
• Gastrointestinal: Anal atresia
• Genitourinary: Hypospadias and other anatomical malformations
• Extremities: Polydactyly or syndactyly

Evaluation

The timing and sequence of evaluation for upper respiratory tract disorders, such as LC, vary from practice to practice but should generally be initiated as soon as possible to limit respiratory complications, particularly in higher-grade (types III and IV) clefting. Noninvasive tests can be considered first for patients presenting with mild symptoms. A chest x-ray may be used to screen for active pneumonia in patients who are acutely symptomatic, but it is not routinely necessary. The most common study performed before invasive testing is the modified barium swallow study (MBSS), also known as the video-fluoroscopic swallow study.[16] This test evaluates the swallow dynamically, providing information on the oral, pharyngeal, and upper esophageal phases of deglutition. Laryngeal penetration and aspiration are easily identified with MBSS, but attention to the entire swallow is also important, as other associated dysfunctions can indicate underlying neurological issues or additional anatomical defects.[17] 

The presence of swallowing deficits has been shown to predict worse functional outcomes.[18] Fiberoptic endoscopic evaluation of swallowing (FEES) is another test that can be performed outside the operating room to help diagnose LC. The examination consists of using a flexible transnasal endoscope to observe the patient swallowing dyed materials. The most common finding described in LC is a posterior-anterior penetration pattern through the cleft.[19] This contrasts with the more common lateral-to-medial pattern seen in other swallowing disorders, such as neuromuscular dyscoordination. Endoscopic swallowing evaluation is less commonly pursued in infants, as obtaining patient cooperation is challenging, and the degree of penetration or aspiration cannot be graded quantitatively. Remember that although useful, these studies provide only a single snapshot of the patient’s swallow. Patients with intermittent aspiration and frequent upper respiratory infections but a normal MBSS or FEES should still be considered for surgical evaluation.

Microlaryngoscopy and bronchoscopy (MLB) with palpation of the interarytenoid space is the gold standard for LC diagnosis. This procedure is performed under general anesthesia, with the patient breathing spontaneously in the absence of positive pressure ventilation, which might otherwise mask the airway collapse associated with tracheobronchomalacia, a common comorbidity of LC.[20][21] The patient is positioned supine, and direct laryngoscopy is performed with the topical application of a weight-based 4% lidocaine solution to the larynx to reduce the risk of laryngospasm. After suspension, a surgical microscope or Hopkins rod telescope is used to visualize the larynx in greater detail. A right-angle probe or a similar instrument is subsequently used to palpate the interarytenoid space (see Image. Diagnostic Laryngoscopy of a Type I Laryngeal Cleft and Image. Diagnostic Laryngoscopy of a Type I Laryngeal Cleft Before Palpation). Type I clefts are typically not detectable without palpation, as redundant mucosa in the area usually prolapses into the defect, mimicking the appearance of normal anatomy.[22] Palpation should be continued along the entire length of the defect to assess its anatomical extent and inform management accordingly. Recording photos or videos of the examination is crucial for treatment planning and counseling patients or their parents.

Once examination under anesthesia is complete, the cleft can be classified using the Benjamin-Inglis system, which describes clefts based on their depth in relation to key anatomical landmarks.[14] Type I is purely interarytenoid, and type II extends into the posterior cricoid plate but not completely through it. Type III fully splits the posterior cricoid plate but does not extend past the thoracic inlet, and type IV extends beyond the thoracic inlet (see Image. Benjamin-Inglis Grading System for Laryngeal Clefts). Other classification systems have also been published but have not been widely adopted.[2][9][23][24][25] In 2006, Sandu and Monnier further refined the Benjamin-Inglis classification system by subdividing types III and IV.[26] Type IIIa is a full division of the posterior cricoid plate, but no further, and IIIb extends beyond the posterior cricoid plate but not to the thoracic inlet. Type IVa extends distal to the thoracic inlet but proximal to the bronchi, and type IVb reaches down into the bronchi. The surgeon must be alert for comorbidities during evaluation, especially during MLB. Findings characteristic of gastroesophageal reflux disease (GERD) and laryngomalacia are the most common.[27][28] Tracheobronchomalacia, tracheoesophageal fistula, and tracheobronchial dyskinesia may also be seen alongside type III and IV clefts.[29]

Once the diagnosis of LC is established, clinical judgement should guide investigation for further defects. LC is associated with CHARGE (coloboma, heart malformations, choanal atresia, growth and mental retardation, genitourinary malformations, ear malformations) syndrome, VACTERL association, 22q11.2 microdeletion (DiGeorge syndrome/velocardiofacial syndrome), Pallister-Hall syndrome (polydactyly, cutaneous syndactyly, hypothalamic hamartoma, imperforate anus, renal anomalies, and bifid uvula), and Opitz-Frias syndrome (hypertelorism, hypospadias, brain defects, intellectual disability, cleft lip/palate, and imperforate anus) among other, rarer conditions.[3][15] Suspicion for these syndromes should trigger evaluation of the neurological, cardiac, pulmonary, gastrointestinal, and genitourinary systems.

Treatment / Management

Conservative Management 

There is a general consensus that patients with symptomatic type I LC should undergo a trial of conservative management with swallowing therapy, thickened feeds, and aggressive management of GERD. Authors estimate that anywhere from 19% to 66% of patients with type I LC experience full improvement with this approach.[30][31] Some debate remains regarding the duration of this trial, with recommendations ranging from 1 month to 1 year before considering operative intervention. Conservative management should be discontinued, however, if there is worsening aspiration, recurrent respiratory infections, or poor weight gain. Some clinicians forgo conservative management in patients with comorbidities that increase the risk of aspiration, such as neurological issues affecting swallowing coordination.[32] Typically, conservative measures do not play a role in the management of cleft types II through IV.

Interarytenoid Injection Augmentation

Interarytenoid injection augmentation (IIa) is a procedure in which temporary filler material, usually sodium carboxymethylcellulose, is injected into the opposing medial surfaces of the LC to obturate the cleft in the short term (~3 months). This technique is often used as an intermediate measure in type I clefts that have not responded to conservative management or as a first intervention in some type II clefts, and is not used in types III or IV clefts, as they require more aggressive surgical solutions. Few patients' symptoms fully resolve after IIa; it is more commonly used as a type of diagnostic or prognostic intervention to estimate the chance of improvement after formal surgical repair.[33] Approximately 60% of patients experience a significant improvement in radiological and swallowing function following IIa.[33] Depending on the injectate, results can last anywhere from one to three months. Gelfoam is reported to have the shortest duration, with calcium hydroxyapatite having the longest (6–12 months).[34]

Endoscopic Repair With Suture Closure

This technique is suitable for all types I and II clefts, as well as most type III clefts. There have been reports of repairing type IV clefts in this manner, but this is not a common practice. During this procedure, the patient is suspended using a laryngoscope that provides visualization of the most distal portion of the cleft. A carbon dioxide laser, thulium fiber laser, or standard laryngeal surgical instruments are used to denude the opposing mucosal surfaces of the cleft (see Image. Type I Laryngeal Cleft Undergoing Repair).[35] The defect is then closed with sutures up to the level of the arytenoid cartilages, either in a single or double layered fashion (see Image. Type I Laryngeal Cleft After Endoscopic Repair With Sutures). Surgeons often reinforce the suture closure with a surgical glue, such as fibrin.

Throughout the procedure, the patient is oxygenated intermittently as dictated by pulse oximetry via a ventilation port on the laryngoscope, an endotracheal tube in the oropharynx, jet ventilation, or intermittent intubation. Close coordination with the anesthesiologist is paramount, especially given the increased risk of airway fire associated with the laser. Outcomes of endoscopic intervention are generally good, especially in lower-grade clefts. Approximately 90% of patients demonstrate improvement in their presenting symptoms 12 months postoperatively.[30] More recently, a variation of the endoscopic approach has been described, using a surgical robot for improved access and visualization to decrease operative times for type I LC repairs.[36]

Open Surgical Repair

This technique is the most invasive and is only used in complicated type III LCs, most type IV LCs, and those that have failed endoscopic repair. There are 3 approaches to large clefts:

• Lateral pharyngotomy approach: This is most often performed if the LC has less than 2 cm of tracheal extension. The main risk is injury to the recurrent laryngeal nerves.[8]
• Anterior laryngofissure: This is the most common approach to the cervical portion of severe clefts. A transverse cervical incision is made at the level of the cricothyroid membrane, the isthmus of the thyroid is divided, and the strap muscles are separated to expose the thyroid cartilage.[15] This approach poses no risk to the recurrent laryngeal nerves and is a simpler dissection overall; however, there is a reportedly increased risk of laryngeal instability or growth disturbance postoperatively.[9][17][37]
• Transthoracic approach: This access is mandatory for type IV clefts that, by definition, extend beyond the thoracic inlet. Many experts combine thoracotomy and anterior laryngofissure to approach the intra- and extra-thoracic aspects of the defect.[38][39][40] This approach requires assistance from pediatric thoracic surgery, pediatric cardiac anesthesia, and in many cases, the extracorporeal membrane oxygenation or cardiopulmonary bypass teams to eliminate the obstruction that an endotracheal tube would place in the operating field.

Once the defect is fully exposed via the chosen approach, the sequence and technique of the repair vary from surgeon to surgeon. The method described by Geller et al is summarized here.[40] The esophageal and tracheal aspects of the defect are separated to permit independent closure. The esophageal defect is sutured closed first, typically using interrupted absorbable 4-0 to 6-0 polyglactin or nonabsorbable 6-0 polypropylene sutures, along with a knot pusher.[16][41] Next, the tracheal edges are incised to promote scar formation between the opposing raw edges, then sutured closed end to end. It may not be possible to close the cleft in separate esophageal and tracheal layers; however, every effort should be made to do so to facilitate the placement of an interposition graft, thereby decreasing the risk of suture line dehiscence.

At the level of the cricoid, a carved costal cartilage graft is placed to reinforce the laryngeal closure and prevent the development of postoperative stenosis. One or both sternohyoid muscles may be separated from the sternal or hyoid insertions and interposed between the laryngotracheal and esophageal repairs with sutures securing them to the deep cervical fascia on the contralateral side of the neck. There are reports of many other materials being used as interposition grafts, including, but not limited to, pericardium, sternocleidomastoid flaps, pleura, jejunum, and tibial periosteum.[42] Regardless of the material used, an interposition graft is essential to decrease the risk of repair dehiscence, tracheoesophageal fistula, or other severe complications, even if the tracheal and esophageal suture lines are carefully positioned to avoid overlap. The best outcomes appear to result from vascularized interpositions.[4] Once the interposition graft is in place, the cartilaginous incisions made during the approach are closed along with the overlying soft tissue.

The patient is typically left intubated for anywhere from 1 to 10 days, depending on the clinical course. Tracheostomy is usually avoided because of the risk the tube poses to the newly-sewn repair. Serial MLBs are performed, often beginning around postoperative days 10 to 14, with minor procedures, such as granulation tissue debridement, performed as needed. Strict medical control of GERD must be maintained throughout the recovery period to optimize healing. If the patient’s comorbidities permit, trials of oral intake can be initiated 14 days or more after the operation. A post-treatment MBSS is usually obtained 2 to 3 months after surgery.

Differential Diagnosis

The wide range of presenting symptoms associated with the different types of LC requires a broad differential diagnosis. Patients with minor symptoms from a low-grade LC, such as coughing, positional stridor, and minor feeding difficulties, should have conditions like GERD, laryngomalacia, and eosinophilic esophagitis ruled out before investigating the possibility of a congenital anomaly. More severe symptoms like recurrent aspiration pneumonia, choking episodes, and weight loss may be caused by tracheoesophageal fistula, vocal cord paresis, and severe laryngomalacia in addition to LC.

Prognosis

LC prognosis depends upon the severity of the presenting symptoms.

• Type I and II LC have very good prognoses. Some authors have found that more than half of patients with type I LC resolve their symptoms with medical management alone. A successful IIa with recurrence of symptoms as the injectate absorbs predicts successful endoscopic repair with a greater than 90% success rate.[43]
• The prognosis of type III and IV LC has improved as the development of endoscopic techniques has decreased morbidity, and a better understanding of postoperative management has reduced mortality from 40% to 90% in the 1980s to as low as 6% in the 2010s.[29][44] Higher grade clefts, however, are often associated with other serious congenital anomalies that may substantially increase the risk of morbidity and mortality. In 1990, Myer et al reported that 60% of deaths after LC repair occurred in patients with other comorbidities.[12]

Complications

Complications vary depending on the severity of the LC. Small type I LCs may produce no symptoms or complications and resolve as the patient grows. With larger defects, the risk for systemic complications increases, particularly of the pulmonary and gastrointestinal systems. The most common complications of untreated LCs are recurrent pneumonias, choking spells, aspiration, and malnutrition.

Each type of intervention has its unique set of complications as well:

• IIa: Recurrence of symptoms will necessarily occur with this approach; due to the bioresorbable nature of the injectate materials, the effects will wear off with time. True complications associated with this procedure are rare, with some study results reporting no complications at all.[34][45] Results from one study reported post-injection laryngeal swelling that resolved with systemic steroids.[46] Care must be taken to avoid injection into the subglottis, which would present as worsening biphasic stridor or even respiratory distress.
• Endoscopic repair: Complication rates with this procedure depend on the type of defect being repaired. Repairs of type I and II clefts are generally well tolerated, but reported complications include postoperative dehydration, laryngeal or supraglottic scarring, and oral lacerations from incautious instrumentation. Postoperative dehiscence is rare with these smaller defects.[45] Type III defects have a much higher risk of postoperative dehiscence, tracheoesophageal fistula formation, and persistent aspiration. Complication rates are estimated to be 25% to 43%.[47][48]
• Open repair: In addition to the hazards of endoscopic repair, open repair of type III and IV LCs also poses the risk of recurrent laryngeal nerve injury and tracheomalacia, correcting the latter of which may require subsequent resection of the affected segment or aortopexy. The rates of repair breakdown, tracheoesophageal fistula, and persistent symptoms are also higher after repair of high-grade LCs, with revision required in up to 50% of cases.[4][35][4][49][50][51][52]