NORD gratefully acknowledges Alexander Gelbard MD, Associate Professor, Laryngeal Surgery, Co-director, Center for Aerodigestive Health, Department of Otolaryngology, Vanderbilt School of Medicine, for assistance in the preparation of this report.
Idiopathic subglottic stenosis (iSGS) is a narrowing (stenosis) of a specific portion of the windpipe (trachea) known as the subglottis (just below the vocal cords). Idiopathic means that the underlying cause of this narrowing is unknown. Most patients have scar tissue (fibrosis) and inflammation in the affected area. Symptoms may include shortness of breath upon exertion (dyspnea), hoarseness, and a high-pitched wheezing sound when breathing in or out (stridor). The disorder occurs almost exclusively in women. The condition often recurs despite treatment.
Stridor and dyspnea are the most common symptoms. The noisy breathing that characterizes stridor can resemble (and is often mistaken for) wheezing. These symptoms often lead affected individuals to be misdiagnosed with asthma and can result in a delay in diagnosis. Stridor can become progressively worse over time. Shortness of breath upon exertion can also be slowly progressive, worsening over a period of years so that affected individuals are gasping for breath after simple activities or even at rest.
Other symptoms that have been reported in adults with idiopathic subglottic stenosis include voice changes, increased mucus production, and persistent cough.
By definition, the exact, underlying cause of idiopathic subglottic stenosis is unknown. Inflammation and scarring of the affected area is usually present.
In the largest study to date, the investigators of the North American Airway Collaborative (NoAAC) examined 1056 iSGS patients across 40 participating institutions: they were otherwise healthy, perimenopausal (mean age 50.4 years), Caucasian (95%) and female (98%).
The remarkable consistency of the iSGS population (nearly all white females) would appear to offer support for the idea that a conserved and consistent biologic process is driving a singular disease. While the clinical similarity would suggest a sex-linked genetic abnormality, the relatively mature age of presentation argues against a purely genetic etiology (as genetic diseases most commonly arise in infancy or childhood). Within the NoAAC iSGS1000 cohort there are 15 familial pairs (i.e. mother and daughter both have iSGS, or two sisters both have iSGS). Additionally, 3 other familial cases have been reported, Dumoulin et al. 2012.
The nearly universal involvement of females, and the age of presentation (~50 years) coinciding with the hormonal alterations observed in near menopause (average age 50), would support a hormonally-mediated process. There are also more than 50 women in NoAAC iSGS1000 cohort that report their symptoms began in pregnancy (itself marked by high maternal estrogen). Yet the role of estrogen in the fibroinflammatory scarring of the airway remains to be defined. Alternative causes for iSGS have been put forward; including a subtle manifestation of collagen vascular disease, an anatomic predisposition of the smaller female subglottis, mechanical trauma from coughing, as well as gastroesophageal reflux disease. Yet these concepts have not proven applicable to the majority of patients, nor when applied therapeutically have they brought tangible benefits.
Although several theories have been proposed to address the underlying causes, no conclusive evidence for any one theory exists. It is possible that multiple factors (e.g. environmental, genetic, and immunologic) may be necessary for the development of the disorder. More research is necessary to determine the specific causes and underlying mechanisms that ultimately lead to the development of idiopathic subglottic stenosis.
Symptoms occur because of narrowing of a specific area of the windpipe known as the subglottis. The windpipe, or trachea, is the tube or passageway that connects the mouth and the nose to the lungs. The windpipe is located in the front of the neck and begins below the voice box (larynx) in the throat. The area of the larynx consisting of the vocal cords and the slit-like opening in between them is called the glottis. The subglottis is the region that runs from below the glottis to the top of the windpipe. The windpipe is made up of 15-20 C-shaped rings; the first two rings of the windpipe (tracheal rings) are often affected. The subglottic area is contained within the cricoid cartilage, the only complete ring of cartilage in the airway.
Idiopathic subglottic stenosis is a rare disorder that affects women almost exclusively. The disorder most often occurs in women between the ages of 30 and 50, but has been reported in younger women, and elderly adults as well. Idiopathic subglottic stenosis only accounts for approximately 15% of all cases of subglottic stenosis. However, the exact incidence and prevalence is unknown. Because people may go undiagnosed or misdiagnosed, determining the true frequency of idiopathic subglottic stenosis in the general population is difficult.
Diagnosis of idiopathic subglottic stenosis is basically one of exclusion, in which the known causes of subglottic scarring are ruled out. A diagnosis is obtained through identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.
Clinical Testing and Workup
A diagnosis of subglottic stenosis may be suspected based on the results of pulmonary function tests. These tests, which require an individual to breathe into a machine called a spirometry to measure how much air they can breathe out or take in, can reveal reduced airflow and reduced air volume.
The narrowed (stenotic) region can be seen with a computerized tomography (CT) scan of the neck. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Additionally, standard chest x-rays (radiographs) can provide information on the location and degree of stenosis.
Blood tests will be performed to look for antibodies that indicate the presence of certain autoimmune disorders such as Wegener’s granulomatosis known to cause subglottic stenosis.
A diagnosis of subglottic stenosis can be confirmed based on direct examination of the subglottic area of the windpipe through a procedure known as endoscopy. During this procedure, a physician runs a small tube called an endoscope down the throat. The endoscope allows a physician to view the lower recesses of the throat and the upper portion of the windpipe including the subglottic region. An endoscopic exam can reveal the narrowed portion of the subglottic area.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disorder, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific therapeutic interventions for individuals with idiopathic subglottic stenosis. Specific therapies that have been used to treat affected individuals include medications and/or surgery.
Affected individuals who have a mild case of idiopathic subglottic stenosis (e.g. no symptoms) may not require treatment. Instead they may be best treated by periodic observation to see whether symptoms develop or if the narrowing progresses (i.e. narrows further).
Several different surgical procedures have been used to treat idiopathic subglottic stenosis, but are generally categorized into: 1) endoscopic dilation of the tracheal stenosis (accomplished with rigid instruments or inflatable balloons); 2) endoscopic resection of the stenosis (with prolonged medical therapy after surgery); or 3) open neck surgery with resection of the affected tracheal segment with end-to-end anastomosis. All approaches have unique benefits and drawbacks which can significantly impact the patient’s quality of life and day-to-day existence. Comparative data on the success of each approach or the drawbacks have never been systematically evaluated.
In endoscopic dilation the patient undergoes exposure of the tracheal scar with endoscopes through the mouth in the operating room. Dilation of the scar is accomplished by either rigid instrument, or inflatable balloon. Laser surgery, in which a laser in used to cut away the narrowed portion of the windpipe, has also been used in conjunction with endoscopic dilation. Endoscopic dilation is a minimally invasive procedure that is often done as an outpatient procedure. However, this procedure often only provides temporary relief and reports in the medical literature suggest a high recurrence rate, meaning the affected area with become narrow again and additional dilations (or another treatment) will be required.
Somewhat similarly, in endoscopic resection the patient undergoes exposure of the tracheal scar with endoscopes through the mouth, however a CO2 laser is then utilized to resect a significant portion of the scar, followed by long-term adjuvant medical therapy (Anti-reflux, antibacterial, and inhaled corticosteroid).
In individuals who do not respond to less invasive surgical options, open airway surgery may be performed. In open surgery (also called cricotracheal resection or laryngotracheoplasty), the trachea is approached via an external incision (or cut) on the front of the neck. During this procedure the narrowed area of tissue is cut away (resected) and the affected areas of the larynx and windpipe are surgically reconstructed.
In cricotracheal resection a portion of the cricoid cartilage is taken with the scar and the ends of the airway are sewn back together. If the narrowed portion extends to the vocal cords, this surgery risks significant voice changes post-operatively.
Laryngotracheoplasty in another form of open surgery that has been used to treat affected individuals. During this procedure, the cricoid is split open and some of the narrowed tissue is removed. Then, a piece of cartilage, usually taken from a rib, is molded into an elliptical shape and grafted into the affected area to widen the area and provide support. This surgery may require the temporary placement of a T-tube (a special type of stent) and a breathing tube (tracheostomy).
Tracheal resection and laryngotracheoplasty are forms of open surgery and generally have been reserved for individuals with severe narrowing (a long and scarred area of narrowing) who haven’t responded to other therapeutic options. These procedures require hospitalization and carry greater risk than the less invasive options, but reports suggest excellent long-term results. One main concern of this surgery is the proximity of the scar to the vocal cords and the potential for post-operative voice changes (lowering the pitch of the voice). Despite the greater risk, some physicians believe that tracheal resection and laryngotracheoplasty should be considered earlier as treatment options because of the may provide greater long-term results rather than requiring affected individuals to undergo repeated balloon dilations or laser therapy.
Rarely, affected individuals may require the insertion of a tube into the windpipe through an incision in the neck (tracheostomy). This procedure has been used to help secure the airway for subsequent endoscopic or open surgical procedures. In patients with acute airway distress, tracheostomy may be the initial treatment option.
Additional Medical Therapies
A medication known as mitomycin-C has been used at the time of surgery. Mitomycin-C was thought to slow the process of scarring in the windpipe and was believed to delay the recurrence of stenosis following surgery. However, most studies have not shown that mitomycin-C resulted in a significant delay of disease recurrence.
Some individuals may respond to corticosteroid therapy to treat the inflammation associated with idiopathic subglottic stenosis. These steroids can be delivered via an inhaler, injected directly thru the skin, or taken orally. No studies have defined which patients respond best to steroids or if there is a difference in effectiveness between the different routes of delivery.
Affected individuals may also be treated with medications that treat gastroesophageal reflux (GERD). Case reports in the medical literature indicate improvement in certain individuals who received anti-reflux therapy (such as individuals who have a history of GERD). This therapy is usually combined with dietary and lifestyle changes (such as avoiding foods/drinks that worsen reflux).
The North American Airway Collaborative is conducting a prospective multi-institutional study on treatment outcomes in iSGS. This study is aimed at answering the questions: (1) How well do the most commonly used treatments in iSGS work? and (2) What quality-of-life trade-offs are associated with each approach? With the results of this trial, the investigators hope to provide information to iSGS patients: (1) “Given my personal characteristics, conditions, and preferences, what should I expect will happen to me?” and (2) “What are my options, and what are the potential benefits and harms of these options?” Patients must be 18 years of age or older at screening, and fulfill other eligibility criteria. For more information, please go to https://clinicaltrials.gov/ct2/show/study/NCT02481817
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