Since the late 1960s, gastroesophageal acid reflux has been implicated in the pathogenesis of several extraesophageal disorders, including laryngitis.[1] Although the cause-effect relationship has been strengthened by more recent evidence, the body of evidence on causation, diagnosis, and treatment of these increasingly diagnosed disorders is still evolving.
Barium esophagography and laryngoscopy are among the procedures used in determining the presence of reflux, with proton pump inhibitors (PPIs) being the mainstay of treatment for laryngopharyngeal reflux (LPR).
Signs and symptoms of reflux
Various symptoms, functional and structural abnormalities that involve the larynx, and other contiguous structures positioned proximal to the esophagus constitute the spectrum of these disorders. Patients presenting with extraesophageal reflux–related signs and symptoms may account for up to 10% of an otolaryngologist's practice.[2] A large amount of gastroesophageal reflux disease (GERD)–associated and laryngopharyngeal reflux (LPR)–associated processes are treated primarily by otolaryngologists. This list includes the following:
Chronic laryngitis
Hoarseness
Globus sensation
Chronic cough or throat clearing
Dysphagia
Halitosis
Chronic rhinosinusitis
Laryngeal malacia
Laryngeal stenosis
Laryngeal carcinoma
Various terms such as laryngopharyngeal reflux (LPR), supraesophageal GERD, atypical GERD, and extraesophageal complications of GERD have been used to describe this group of symptoms and signs. Although addressed by various terms, these basically represent supraesophageal complications due to reflux of gastric acid content through the esophageal/pharyngeal/laryngeal/pulmonary axis. Although these symptoms were previously thought to constitute the spectrum of GERD, laryngopharyngeal reflux (LPR) is today thought to be a distinct entity and should be managed differently.[3] Laryngopharyngeal reflux (LPR) is the term used in this article to discuss the pathogenesis of reflux laryngitis.
Workup
Laryngoscopy is the primary procedure for diagnosing laryngopharyngeal reflux (LPR). The more commonly used flexible laryngoscopy is more sensitive but less specific than rigid laryngoscopy in revealing laryngeal tissue irritation in suspected laryngopharyngeal reflux (LPR).[4]
Failing to recognize laryngopharyngeal reflux (LPR) is dangerous, while overdiagnosis of laryngopharyngeal reflux (LPR) can lead to unnecessary costs and missed diagnosis. Inflamed laryngeal tissue affected by laryngopharyngeal reflux (LPR) is more easily damaged from intubation, has a high risk of progressing to contact granulomas, and may evolve to symptomatic subglottic stenosis.[5]
In a report, laryngopharyngeal reflux (LPR) symptoms were found to be more prevalent in patients with esophageal adenocarcinoma than were typical GERD symptoms, and they often represented the only sign of disease.[6] On the other hand, increased awareness may lead to overdiagnosis of the condition because typical laryngopharyngeal reflux (LPR) symptoms are nonspecific and can occur in processes such as infection, vocal abuse, allergy, smoking, inhaled irritants, and alcohol abuse.[3]
Caution must also be taken to rule out serious processes that may present with similar symptoms, such as laryngeal cancer, before proceeding with conservative management.
Management
Four categories of drugs are used in treating laryngopharyngeal reflux (LPR): PPIs,[7] H2-receptor agonists, prokinetic agents, and mucosal cryoprotectants. However, PPIs are the mainstay of treatment.
The apparent advantage of operative therapy is that it corrects the antireflux barrier at the gastroesophageal junction and prevents the reflux of most stomach contents, thus preventing acid and nonacidic material from coming in contact with the pharyngolaryngeal mucosa. Candidates for antireflux surgery are often patients who require continuous or increasing doses of medication to maintain their response to acid suppressive therapy.
The management of patients with suspected laryngeal manifestations of GERD continues to be controversial.[8] Issues are whether laryngopharyngeal reflux is a real disease, whether laryngeal physical exam in patients with symptoms of GERD is useful as a marker for response to treatment, how to differentiate and treat patients with chronic laryngitis with and without reflux symptoms, and the benefits of PPIs in patients with different symptoms. Continued acid suppression is unlikely to provide dramatic symptom improvement for patients whose conditions are completely unresponsive after 1-2 months of treatment with twice-daily PPI. Vaezi et al state "Any suggestions that reflux still may be playing a role in patients refractory to therapy, especially if suggested by nonspecific laryngeal findings, is a less than optimal use of resources and should be discouraged."[8]
The image below is a scoring system for presence and degree of symptoms.
View Image
The RSI documents the presence and degree of nine laryngopharyngeal reflux (LPR) symptoms both before and after treatment; maximum score: 45.
Major factors that have led clinicians to associate chronic supraesophageal disorders with reflux of gastric acid include the frequent lack of an etiology for some chronic laryngeal symptoms and findings, the recurrent or persistent nature of these disorders, and the benefit of empiric antireflux treatment as reported by multiple observational studies. However, the cause-effect relationship has been difficult to establish for several reasons, including the following:
GERD is a prevalent disorder, but only a small proportion of these patients have supraesophageal problems.
Although a significant subset of these patients may have abnormal esophageal acid exposure, in most patients, esophageal symptoms or esophagitis is absent.
Ascertaining whether supraesophageal disorders result from neurally mediated cough and chronic throat clearing or from direct injury from mucosal contact with substances in the refluxate has been difficult. However, most believe that the mucosa of the pharyngolarynx is not designed to handle the direct injury of acid or pepsin found in the refluxate.
Response to agents that inhibit gastric acid secretion has not been as clear as response for esophageal signs and symptoms of reflux disease.
Unfortunately, a direct relationship between refluxed gastric acid and most of these suspected supraesophageal complications have been difficult to conclusively establish to date. This dilemma is further complicated by the fact that patients with suspected pharyngeal and laryngeal complications of reflux disease frequently lack the characteristic features of GERD, including its symptom of heartburn, and some patients may have suspected reflux-induced supraesophageal and esophageal peptic injuries, which are independent of each other.
Two hypotheses exist about how gastric acid precipitates extraesophageal pathologic response. The first purports direct acid-pepsin injury to the larynx and surrounding tissues. The second hypothesis suggests that acid in the distal esophagus stimulates vagal-mediated reflexes that result in bronchoconstriction and chronic throat clearing and coughing, eventually leading to mucosal lesions. These 2 mechanisms may act in combination to produce the pathologic changes seen in laryngopharyngeal reflux (LPR).[9]
The following 4 physiological barriers protect the upper aerodigestive tract from reflux injury:
The lower esophageal sphincter
Esophageal motor function with acid clearance
Esophageal mucosal tissue resistance
The upper esophageal sphincter
The delicate ciliated epithelium of the respiratory tract is sensitive to damage when these mechanisms fail. Dysfunction in the cilia leads to mucus stasis. The accumulation of mucus produces sensations that provoke chronic throat clearing. Direct irritation of the upper airway by gastric refluxate can cause laryngospasm, producing symptoms of chronic coughing and choking.
The combination of direct injury by refluxate and symptoms such as chronic laryngospasm and throat clearing can lead to vocal cord edema, contact ulcers, and granulomas that cause other LPR-associated symptoms such as hoarseness, globus pharyngeus, and sore throat.
Evidence suggests that in both healthy and patient populations the refluxed gastric acid may come into contact with structures as high as the pharynx. Furthermore, several signs of laryngeal irritation, which are generally considered to be signs of laryngopharyngeal reflux (LPR), were found to be present in a high percentage of asymptomatic individuals on laryngoscopic examination.[4]
These findings suggest the existence of interindividual variability in terms of mucosal resistance to acid exposure, both in the esophagus and pharyngolarynx. Currently, the understanding of the pharyngolaryngeal defense mechanisms against refluxed acid is limited, and the natural history of the disease is unknown. This problem is further magnified by the fact that pharyngolaryngeal lesions may have multiple etiologies with similar appearance and presentation.
More recent investigation into defense mechanisms against refluxed acid in the larynx and surrounding tissues suggests a possible mechanism of increased susceptibility in some patient populations. Defense mechanisms in the epithelium of the esophagus and larynx are known to differ. Active bicarbonate production is pumped into the extracellular space in the esophagus but not into the larynx. Recent investigations suggest that laryngeal tissues are protected from reflux damage by a carbonic anhydrase in the mucosa of the posterior larynx. The carbonic anhydrase enzyme catalyzes hydration of carbon dioxide to produce bicarbonate, which neutralizes the acid in refluxate. Carbonic anhydrase isoenzyme III, expressed at high levels in normal laryngeal epithelium, was shown to be absent in 64% of biopsy specimens from laryngeal tissues of laryngopharyngeal reflux (LPR) patients.[10]
A study by Eckley et al indicated that persons with reflex laryngitis have lower concentrations of salivary epidermal growth factor (EGF) than do healthy controls, even after treatment, suggesting a lack of protective mechanisms in these individuals against GERD.[11]
Despite the common understating that reflux of acid causes respiratory symptoms, a recent prospective study from Sweden found that a 10-year follow-up of individuals with esophageal and pharyngeal acid exposure did not correlate with increase risk of airway symptoms or laryngeal abnormalities.[12]
GERD is one of the most common disorders; US population surveys, for example, suggest that as many as 50% of adults (or 60 million people) have symptoms of heartburn at least once a month. More than one quarter of adult Americans use antacids 3 or more times per month. Although nearly half of the US population experiences occasional heartburn, only 4-7% report daily symptoms. This group of patients most likely represents those with significant esophageal complications of reflux disease.
The true incidence of GERD might be underestimated because of the relatively low proportion of individuals who seek medical attention for reflux symptoms. One report found that only 5% of patients with symptoms of heartburn and regurgitation had visited a physician because of this problem within the preceding year. An estimated 4-10% of chronic nonspecific laryngeal disorders in otolaryngology clinics are associated with reflux disease.
A retrospective review showed a significant increase in US ambulatory care visits for GERD, from a rate of 1.7 per 100 to 4.7 per 100 over 12 years. Otolaryngologists appeared to have an increasingly prominent role in management of this disease.[13]
International
In a Brazilian study of children and adults with dysphonia, Martins et al found that among 1305 adults aged 19-60 years, reflux laryngitis was the second most prominent cause of the problem (164 patients, 12.6%), behind functional dysphonia (268 patients, 20.5%).[14]
Mortality/Morbidity
Symptoms of laryngopharyngeal reflux are more prevalent in patients with esophageal adenocarcinoma (EAC) than typical GERD symptoms and may represent the only sign of disease. Chronic cough is an independent risk factor associated with the presence of EAC.[6] Therefore, laryngopharyngeal reflux (LPR) symptoms should be assessed in the screening for esophageal cancers and Barrett esophagus. Laryngopharyngeal reflux (LPR) may be a significant risk factor for the development of EAC.
Chronic laryngopharyngeal reflux (LPR) is a risk factor for symptomatic subglottic stenosis, laryngeal malacia, laryngeal stenosis, and laryngeal carcinoma.
Race
No particular racial predilection reported.
Sex
A slightly higher prevalence in males than females may exist (55% vs 45%).
Age
The percentage of patients with GERD who are older than 44 years appears to be slowly growing.
The most common symptoms used by ENT physicians to diagnose GERD-related laryngitis or laryngopharyngeal reflux (LPR) included globus, throat clearing, cough, and hoarseness; sore throat and dysphagia were considered less useful.[15]
The typical symptoms of laryngopharyngeal reflux (LPR), as listed above, can be caused by chronic irritation of the vocal cords due to overuse, smoking, alcohol, infection, and allergies and other environmental irritants.
Furthermore, history alone is often insufficient to elicit clues that suggest acid reflux as a cause of these symptoms. Most patients with suspected laryngeal complications of GERD may have no esophageal symptoms.
Most ENT physicians reported that they relied significantly more on symptoms, rather than on laryngoscopic signs, in diagnosing laryngopharyngeal reflux (LPR).
Belfasky et al (2002) published the self-administered 9-item reflux symptom index (RSI) to assist clinicians in documenting the presence and degree of laryngopharyngeal reflux (LPR) symptoms, both before and after treatment.[16] The reflux symptom index is depicted in the image below.
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The RSI documents the presence and degree of nine laryngopharyngeal reflux (LPR) symptoms both before and after treatment; maximum score: 45.
See the list below:
Supraesophageal
Globus (This was the primary symptom in 4% of visits and was unrelated to the severity of reflux symptoms in a large cohort of more than 4000 general otolaryngology clinic patients. Globus was not associated with any specific psychometric parameters in 88 gastroenterology clinic patients.)
A history of persistent throat clearing
Chronic cough
Halitosis
Recurrent or persistent hoarseness, especially in the morning
Esophageal symptoms associated with laryngopharyngeal reflux (LPR)
Regurgitation: A history of regurgitation, particularly at nighttime, associated with cough or with symptoms suggesting aspiration is the most significant clue to the possibility of supraesophageal complications of GERD. Unfortunately, this symptom complex occurs in a minority of patients.
Heartburn: The presence of heartburn symptoms can be a significant indication, but it should be defined appropriately in terms of the specific location and description of these symptoms. In a study of a large number of patients with suspected otolaryngologic complications of GERD, only 43% had classic symptoms of heartburn, regurgitation, or dysphagia. Heartburn was reported by 72% of 50 patients with idiopathic hoarseness and normal laryngoscopic findings who were refractory to speech therapy. Overall, GERD was demonstrable in 40% of patients by either esophagraphy or a 24-hour ambulatory pH study.
Other classic GERD-related history findings: These include patient symptoms related to the intake of tomato-based and/or spicy foods. These types of questions are important screening tools. Patients should also be asked about the frequency of using over-the-counter antacids. Often, patients deny having heartburn but then respond positively to questioning regarding problems with specific food types and/or frequent use of antacids.
Visualization of the larynx and vocal cords for signs of laryngopharyngeal reflux (LPR) requires a laryngoscopic examination. The most useful signs of GERD-related laryngitis or laryngopharyngeal reflux (LPR) were reported to be erythema, edema, presence of posterior commissure bar, and cobblestoning, while pseudosulcus vocalis; ulcers; and ventricular obliteration, nodules, polyps, and leukoplakia were reported to be less useful.[15]
Pseudosulcus vocalis (see below) was shown to be reported in as many as 90% of laryngopharyngeal reflux (LPR) cases. In a separate study, pseudosulcus was show to have a 70% sensitivity and 77% specificity in patients with laryngopharyngeal reflux (LPR). This further supports that the presence of pseudosulcus vocalis is suggestive of laryngopharyngeal reflux (LPR).[16]
Helicobacter pylori bacteria could enter and colonize the nasopharyngeal cavity by gastroesophageal reflux and may elicit otitis, sinusitis, pharyngitis, or laryngitis.
Belfasky et al (2002) developed an 8-item clinical severity scale to document laryngopharyngeal reflux (LPR) findings during fiberoptic laryngoscopy, which are quantified as the reflux finding score (RFS; as seen in the image below). The following 8 items are assessed to aid in the diagnosis of laryngopharyngeal reflux (LPR):
Pseudosulcus vocalis
Ventricular obliteration
Erythema/hyperemia
Vocal fold edema
Diffuse laryngeal edema
Posterior commissure hypertrophy
Granuloma/granulation
Thick endolaryngeal mucus
The image below describes the reflux finding score in more detail.
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The reflux finding score (RFS) documents the presence and degree of eight laryngopharyngeal reflux (LPR) findings during fiberoptic laryngoscopy; maxi....
See the list below:
Posterior laryngitis: The classic laryngeal physical findings of laryngopharyngeal reflux (LPR) reported in the otolaryngology literature are edema and erythema of the posterior commissure.
Pseudosulcus vocalis: The medial edge of the vocal cord appears to have a linear indentation due to diffuse infraglottic edema.
Vocal cord granuloma
Subglottic stenosis - Subglottic stenosis is a significant complication associated with chronic pharyngeal acid exposure.
Contact ulcer of larynx
Additional signs related to laryngopharyngeal reflux
Recurrent or refractory sinusitis: A recent study on the long-term outcome of adult patients who underwent functional endoscopic sinus surgery indicated that GERD predicted poor symptom relief.
Dental erosions: Patients have a smooth, glazed, dished-out appearance of the dentin on the lingual surfaces of the teeth. The deleterious effect of regurgitated gastric acid on the teeth has been suggested in reports dating back to the early 1970s. These include association of dental erosions with hiatal hernia, chronic vomiting, rumination, alcoholic gastritis, and regurgitation, as well as anorexia nervosa and bulimia. Dental erosions are defined as the loss of tooth substance by a chemical process that does not involve bacteria. Dental erosions are hard dished-out areas with a smooth and glistening base as opposed to the soft, dark, and jagged-edge lesions of dental caries. The prevalence of dental erosions in patients with GERD was reportedly 20-55%, in contrast to 2-18% in the general population.
Sandifer syndrome: The unique neck posture in Sandifer syndrome is a clue to acid reflux disease in infants or young children. This posture is an anatomic defense mechanism against repetitive acid reflux.
Retrograde reflux of gastric acid or other contents (ie, pepsin) or both into the supraesophageal aerodigestive tract with mucosal injury from direct contact
Damage to cilia from refluxate that leads to mucous stasis and chronic throat clearing and cough, with consequent symptoms of laryngeal inflammation and irritation
Gastroesophageal reflux that leads to neurally mediated chronic cough and throat clearing with consequent symptoms with or without tissue injury
A defect in carbonic anhydrase isoenzyme III
Deglutitive pharyngolaryngeal abnormalities that lead to abnormal laryngeal exposure to contents transported in antegrade direction (possible role of defective airway protective defense mechanisms)
A demonstration of a structural abnormality on barium contrast esophagraphy may supply useful clues to the presence of GERD (eg, the presence of hiatal hernia or distal esophageal narrowing or stricture). The former finding may be a clue; the latter is evidence of damage secondary to GERD.
Although reflux of gastric barium into the esophagus during fluoroscopy is not specific for diagnosing reflux disease, spontaneous frequent barium reflux to the aortic arch correlates well, in the authors' experience, with patients who have extensive esophageal acid exposure revealed by pH monitoring. Overall barium esophagography has a sensitivity of only 33% in diagnosing reflux.[9]
Pharyngeal reflux was noted in 25% of patients with globus who were evaluated with esophagraphy. However, the diagnostic yield of this technique in regard to pharyngolaryngeal complications of reflux disease is unacceptably low. Furthermore, the technique does not reveal intermittent reflux or provide assessment of the status of the fine mucosa.
The laryngoscopic examination is the primary procedure for diagnosing laryngopharyngeal reflux (LPR). As stated above, several signs of posterior laryngeal irritation are usually seen, with edema and erythema being the most useful for diagnosis. Pseudosulcus vocalis is also thought to be somewhat specific for laryngopharyngeal reflux (LPR).
Several signs suggestive of laryngopharyngeal reflux (LPR) have been shown to be present in a high percentage of asymptomatic individuals, raising questions about the diagnostic specificity of the laryngoscopic examination. Furthermore, pseudosulcus vocalis was found in up to 37% of asymptomatic individuals. One criticism of the following study was the inclusion of subclinical reflux disease.[4]
Laryngeal examination with the more commonly used flexible laryngoscopy is more sensitive but less specific than rigid laryngoscopy in revealing laryngeal tissue irritation in suspected laryngopharyngeal reflux (LPR).[4]
Endoscopic examination of the esophagus
Demonstrating signs of esophageal inflammation at endoscopic examination does not incriminate GERD as the possible etiology in a supraesophageal disorder. However, it does help to build a possible scenario for the role of acid reflux and alerts the clinician to a possible explanation for the patient's problems. Unfortunately, the presence of esophagitis revealed during endoscopic examination is not a constant finding in patients with suspected supraesophageal complications of GERD and has rarely been documented in patients with reflux laryngitis. Prior reports have shown that less than 30% of patients with extraesophageal manifestations of reflux show endoscopic evidence of esophagitis.
Although the absence of physical damage to the esophagus in most patients with suspected supraesophageal complications of GERD appears at first glance to be a paradox, most investigators in this field have come to accept this fact based on the assumption that the magnitude of acid reflux that reaches the pharynx may be adequate for causing pharyngolaryngeal lesions but inadequate for inducing esophageal damage. This is possibly caused by differences in tolerance to acid exposure between esophageal and pharyngeal mucosa.
Often, patients with suspected supraesophageal complications of GERD have been treated with antacids at doses acceptable for healing esophagitis but inadequate for treating the suspected supraesophageal complications. In these situations, the macroscopic peptic lesion of the esophageal lining may have disappeared. Subtle distal esophageal scars or pitting above the gastroesophageal junction is a hallmark of gastroesophageal reflux. Obviously, the presence of Barrett columnar lining, with or without associated esophageal inflammation, indicates the presence of acid reflux disease.
Ambulatory pharyngoesophageal pH monitoring was once considered the criterion standard for diagnosing reflux. However, this diagnostic modality is less sensitive in those with extraesophageal manifestations of GERD such as reflux laryngitis. Studies have shown that the distal proximal and hypopharyngeal pH monitoring are only 70%, 50%, and 40% sensitive in detecting reflux.[15] Furthermore, recent data suggest that abnormal findings of pH monitoring do not predict response to therapy.
In esophageal pH monitoring, a distal pH probe is located 5 cm above the lower esophageal sphincter (LES) by tradition, and the proximal pH probe is usually placed 20 cm above the LES, just below the upper esophageal sphincter. A third pH probe is placed in the pharynx to simultaneously record changes associated with acid escape into the pharynx. The pH readings are recorded for 24 hours while the patient indicates onset and end of meals, sleep, and symptoms events. Information provided by this test includes the frequency, duration, and site of reflux events.
The reference range of total acid exposure when the pH probe is positioned beneath the upper esophageal sphincter is approximately 0-1% over a 24-hour period. However, a significantly greater percentage of distal reflux episodes reached the proximal esophagus in a group of patients with laryngitis compared with control groups, and the number of pharyngeal reflux episodes and acid exposure time were also significantly greater in the laryngitis group.
Overall proximal esophageal and pharyngeal reflux events are short-duration events. Given the sensitivity of the supraesophageal regions to acid exposure, comparable acid exposure time to the esophagus may not be necessary for the development of lesions. Consequently, the number of reflux events may be a better diagnostic clue than acid exposure time.
The most meaningful computed values are those that indicate the total time of esophageal exposure to a pH level of less than 4.0 and a differentiation of total acid exposure in the upright versus the supine position. Laryngopharyngeal reflux (LPR) is confirmed if the total time of exposure is greater than 1% over 24 hours.
The reference range of values for the proximal probe varies between various centers and currently lacks standardization. Such lack of standardization remains a significant concern with regard to the diagnostic accuracy of this modality.
Intraluminal combined pH monitoring and impedance testing may be used to detect nonacid or gas causes of reflux in patients with atypical symptoms that have not responded to proton pump inhibitors.[17]
Posterior laryngitis is characterized by hyperplasia of the squamous epithelium with a chronic inflammatory infiltrate in the submucosa. Disease progression leads to the epithelium becoming atrophic and ulcerated with deposits of fibrin, granulation tissue, and fibrosis in the submucosa.
Because of reservations regarding specificity of the laryngoscopic examination, many physicians have opted to begin a trial of empiric therapy.
Four categories of drugs are used in treating laryngopharyngeal reflux (LPR): proton pump inhibitors (PPIs),[7] H2-receptor agonists, prokinetic agents, and mucosal cryoprotectants.
PPIs are the mainstay of treatment. PPIs are the most effective drugs in treating GERD that involves the esophagus. Acid reflux events are decreased by greater than 80%, and healing of esophagitis is reported in 80-90% of patients. The response to medical therapy in patients with suspected supraesophageal complications of GERD is not as efficacious as that noted in esophageal complications of GERD. Although PPIs appear to be effective, higher doses for a longer duration are necessary as compared with esophageal GERD disease.
Based on these clinical experiences, a similar approach for the treatment of suspected supraesophageal complications of GERD was recommended by the Working Party at the First Multidisciplinary Symposium on Supraesophageal Complications of Reflux Disease. The recommendation calls for a double standard dose of PPI therapy initially for patients with suspected supraesophageal complications of GERD and a duration of therapy for at least 3, and possibly 6, months.
At the completion of this initial trial, assessment of the patient's symptoms and the response to therapy should be critically evaluated. Before medical therapy can be considered unsuccessful, adequate esophageal and gastric acid suppression should be documented. Recently, a noncontrolled study reported the results of PPI therapy in 16 patients with persistent posterior laryngitis for whom H2 receptor therapy was unsuccessful. Omeprazole treatment ranged from 6-24 weeks with a dosage of 40 mg of omeprazole at nighttime. (This dose was increased to 40 mg bid for 6 wk in 4 patients with continuing symptoms.) At the conclusion of the study, both the laryngoscopy scores and the esophageal symptom indices improved significantly. However, symptoms recurred after the discontinuation of acid suppressant therapy, suggesting that acid reflux was indeed the underling etiology.
In cases of unsuccessful medical therapy, consideration needs to be given to nonacidic refluxate. Multichannel intraluminal impedance testing may be indicated to look for nonacid, as well as gaseous, events as a possible cause.
The importance of long-term treatment for laryngeal complications of reflux disease is stressed because the injury to the epithelium is a chemical burn and takes weeks to months to resolve. For most patients, an 8-week course of antisecretory treatment, used for esophageal reflux injury, is inadequate. Recurrence of symptoms is common in patients who require PPI therapy for initial treatment.
Table 2. shows key features of the 7 studies that evaluated efficacy of antireflux medical treatment. These studies were published from 1991-1997 and reported on 346 adult patients with otherwise unexplained posterior laryngitis suspected to be caused by GERD who received antireflux medical treatment in an uncontrolled nonblinded clinical trial. Outcomes Reported by Trials of Antireflux Medical Treatment of Reflux Laryngitis
View Table
See Table
Intervention generally consists of standard antireflux nonpharmacologic measures and acid suppression with a variable dose of omeprazole and in one trial with H2 receptor antagonists (H2RA). The duration of intervention varied from 6-24 weeks, and postintervention follow-up varied considerably.
Outcome was generally assessed by change in symptom score and laryngoscopic severity score. One study reported only acoustic parameters as the outcome, and another study evaluated only patient-reported overall improvement. Except for one study, others performed ambulatory pH monitoring in only selected patients with refractory symptoms. Most studies reported recurrent symptoms off treatment after an initial favorable response maintained while on treatment.
However, at present, difficulties exist with the interpretation of trials using PPIs for treatment of patients with suspected supraesophageal complications of GERD. This is because studies contain small groups of patients, treatment duration is very short, and no control groups have been included.
Future studies using PPIs in patients with suspected supraesophageal complications of GERD require properly designed controlled protocols to fully evaluate treatment efficacy. H2RA and prokinetic medications have not, for the most part, found an effective role in treating patients with suspected supraesophageal GERD complications. Because the efficacy of diagnostic testing is not 100% in substantiating the role of acid reflux in supraesophageal disorders, at times a therapeutic trial may be the only recourse. In this situation, attempts at maximal acid suppression are critical and require potent PPI therapy.
A study by Zalvan et al reported that a diet-based approach to the treatment of laryngopharyngeal reflux (LPR) compared favorably with the use of PPIs. The study found that in patients who followed a treatment regimen consisting of alkaline water (pH >8.0) and a 90% plant-based, Mediterranean-style diet, along with standard reflux precautions, the percentage who experienced a clinically meaningful reduction in the Reflux Symptom Index (RSI) was greater than it was for those who underwent PPI therapy in combination with standard reflux precautions (62.6% vs 54.1%, respectively). There was also a greater mean RSI reduction in the Mediterranean-diet group than in the PPI patients (39.8% vs 27.2%, respectively). The investigators cautioned, however, that the clinical significance of these results needs further research.[18]
A study by Lechien et al indicated that gender-related variation exists with regard to voice quality changes following proton pump inhibitor and dietary therapy for laryngopharyngeal reflux (LPR). While both males and females who underwent treatment showed significant improvement in the reflux finding score and reflux symptom index, a number of acoustic measurements (such as percent jitter, percent shimmer, phonatory fundamental frequency range, fundamental frequency variation, peak-to-peak amplitude variation) improved significantly in males but not in females.[19]
The apparent advantage of operative therapy is that it corrects the antireflux barrier at the gastroesophageal junction and prevents the reflux of most stomach contents, thus preventing acid and nonacidic material from coming in contact with the pharyngolaryngeal mucosa. The candidates for antireflux surgery are often patients who require continuous or increasing doses of medication to maintain their response to acid suppressive therapy. The case has been made for young patients, noncompliant patients, and those who choose to have this type of therapy. Often, financial concerns of the patient have been a reason for a fundoplication operation.
Except for 2 studies reporting the result of Nissen fundoplication in patients with pharyngolaryngeal complications of reflux disease, the published reports generally deal with efficacy and long-term outcomes of the operation in patients with esophageal complications of reflux disease. Although the long-term efficacy of laparoscopic fundoplication is not available, 80-90% of patients are reported to be asymptomatic or have minimal symptoms following a conventional open fundoplication operation. In a 10-year follow-up after open fundoplication surgery, 91% of patients continued to have control of their symptoms. Short-term outcome results following laparoscopic fundoplication indicate symptom control in 85-90% of patients with acceptable low morbidity rates.
Two prospective uncontrolled clinical trials evaluated the efficacy of Nissen fundoplication for patients with GERD–related laryngeal disorders. In 1993, Deveney et al studied 13 consecutive patients with symptomatic laryngitis and objective evidence of GERD who were refractory to treatment with H2RA and included those with previous laryngeal carcinoma (38%) and leucoplakia (46%). Symptoms resolved and laryngoscopic abnormalities disappeared in 73% of patients who were monitored for 11 months.
In 1998, So et al evaluated improvement in symptom score over an average of 22 months in 35 patients with cervical or thoracic symptoms, most of whom had pharyngeal acid reflux by a 24-hour pH study.[20] Heartburn requiring antacids was reported by 86% of patients, and 37% had evidence of esophagitis. Although 93% of patients were relieved of heartburn, only 58% of them showed an improved supraesophageal symptom score. Symptom response to preoperative acid suppression was a significant predictor of postoperative improvement.
The recent introduction of minimally invasive laparoscopic fundoplication for the most part has replaced conventional open fundoplication operation. Subsequently, an increasing number of patients are undergoing laparoscopic fundoplication encouraged by this new technology and a greater acceptance on the part of the treating physician. Because many surgeons with little experience in esophageal physiology or traditional fundoplication operation have begun to perform this procedure, not unexpectedly, the number and severity of complications resulting from laparoscopic fundoplication have increased. For that reason, this operation should not be first-line therapy for patients with suspected supraesophageal complications of GERD. Exceptions to this approach would be dramatic situations such as obvious regurgitation and aspiration or laryngospasm.
In fact, demonstration of the effectiveness of acid suppression therapy should be the major criteria for predicting successful outcome of fundoplication operation. The morbidity associated with fundoplication operations varies but may be significant. The frequency of postoperative dysphagia ranges from 0-17% in large reported series.
Fundoplication surgery is championed as the treatment of choice, particularly for the young patient with significant GERD who faces a lifetime of medical treatment with a potentially negative impact on lifestyle.
In a recent long-term Finnish study,[21] evidence showed that laparoscopic Nissen fundoplication did provide long-term satisfactory results in patients suffering from reflux-induced laryngitis.
A multidisciplinary approach involving an otolaryngologist, gastroenterologist, speech therapist, and pulmonologist optimizes the diagnostic evaluation and management.
ENT physicians consider symptoms such as throat clearing and chronic cough most useful in the diagnosis of laryngopharyngeal reflux (LPR), along with findings on laryngoscopic examination. Many gastroenterologists perform pretherapy testing, which has low sensitivity in laryngopharyngeal reflux (LPR). Furthermore, a dichotomy can be found in treatment dose, duration, and perceived patient response to therapy between the 2 specialties. Cross-communication education between gastroenterology and otolaryngology is needed in understanding and treating LPR- and GERD-related laryngitis better.[15]
Meals should be eaten 2-3 hours before lying down.
Avoid food and beverages that affect the LES muscle action (eg, fried or fatty foods, chocolate, peppermint, alcohol, coffee, carbonated beverages, citrus fruits or juices, tomato sauce, ketchup, mustard, vinegar).
Eat at a slower pace to reduce aerophagy.
Patients with concurrent deglutitive abnormalities benefit from specifically targeted interventions (eg, swallowing therapy by a speech-language pathologist).
A variety of pharmacologic agents are available for suppressing gastric acid secretion. These include H2RAs such as famotidine, ranitidine, nizatidine, and cimetidine; proton pump inhibitors (PPIs) such as omeprazole; prokinetic agents such as cisapride and tegaserod; and mucosal cytoprotectants such as sucralfate. Evidence that supports the efficacy of the H2RAs is questionable. PPIs are significantly more potent and reliably achieve a greater magnitude of gastric acid inhibition. In addition, compared with esophageal symptoms, significantly greater acid inhibition is required to relieve supraesophageal symptoms and, especially, to achieve mucosal healing. Hence, the choice of PPIs over H2RAs is clear as a first-line pharmacologic intervention.
Omeprazole has been studied most extensively and is the only agent used in the clinical trials evaluating efficacy of PPIs in supraesophageal disorders. However, experience with lansoprazole is increasing, and newer agents (rabeprazole, pantoprazole[22] ) promising sustained and more potent gastric acid suppression with once daily dosing have recently arrived.
Prokinetic agents accelerate esophageal clearance and increase lower esophageal sphincter (LES) tone. The prokinetic agent cisapride has been discontinued because of serious adverse effects or ventricular arrhythmia. Tegaserod decreases reflux and LES relaxation events and is useful for treating laryngopharyngeal reflux (LPR) associated with esophageal dyskinesia.
Tegaserod was temporarily withdrawn from the US market in March 2007; however, as of July 27, 2007, restricted use of tegaserod is now permitted via a treatment IND protocol. The treatment IND will allow tegaserod treatment of irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) in women younger than 55 years who meet specific guidelines. Its use is further restricted to those in critical need who have no known or preexisting heart disease.
Earlier this year, tegaserod marketing was suspended because of a meta-analysis of safety data pooled from 29 clinical trials that involved more than 18,000 patients. The results showed an excess number of serious cardiovascular adverse events, including angina, myocardial infarction, and stroke, in those taking tegaserod compared with placebo. In each study, patients were assigned at random to either tegaserod or placebo. Tegaserod was taken by 11,614 patients, and placebo was taken by 7,031 patients. The average age of patients in these studies was 43 years, and most patients (ie, 88%) were women. Serious and life-threatening cardiovascular adverse effects occurred in 13 patients (0.1%) treated with tegaserod; among these, 4 patients had a heart attack (1 died), 6 had unstable angina, and 3 had a stroke. Among the patients taking placebo, only 1 (0.01%) had symptoms suggesting the beginning of a stroke that went away without complication. For more information, see the FDA MedWatch Product Safety Alert.
Sucralfate is a polysulfated salt of sucrose that may be helpful as an adjunct in protecting injured mucosa from the harmful effects of acid and pepsin.
Clinical Context:
Specifically suppress gastric acid secretion by potent inhibition of the H+/K+ -ATPase enzyme system at secretory surface of gastric parietal cell. This blocks the final step in gastric acid production. Effect is dose related and inhibits both basal and meal-stimulated acid secretion. Omeprazole has been studied most extensively and is the only agent used in the clinical trials evaluating efficacy in supraesophageal disorders.
Clinical Context:
Suppresses gastric acid secretion by specific inhibition of the H+/K+ -ATPase enzyme system (ie, proton pump) at the secretory surface of the gastric parietal cell. It blocks the final step of acid production. The effect is dose related and inhibits both basal and stimulated gastric acid secretion, thus increasing gastric pH levels.
Clinical Context:
Suppresses gastric acid secretion by specifically inhibiting H+/K+ -ATPase enzyme system at the secretory surface of gastric parietal cells. Use of the IV preparation has only been studied for short-term use (ie, 7-10 d).
Clinical Context:
Available in US by restricted treatment IND for irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) in women younger than 55 years who meet specific guidelines. Used for the short-term treatment of women with irritable bowel syndrome in whom constipation is the predominant symptom. Serotonin type 4 receptor partial agonist with no affinity for 5-HT3 receptors. May trigger peristaltic reflex via 5-HT4 activation, which enhances basal motor activity and normalizes impaired GI motility. Research studies have shown inhibitory activity of the drug on visceral activity in the GI tract.
Clinical Context:
Binds to positively charged proteins in exudates and forms a viscous, adhesive substance that protects GI lining against pepsin, peptic acid, and bile salts. Used for short-term ulcer management.
Continued monitoring of response to treatment and need for dose adjustment is essential. The primary tools include degree of symptom reduction, laryngoscopic improvement, ambulatory 24-hour pH monitoring to assess the degree of acid suppression, and physiologic correlation with symptoms prior to modifying treatment measures.
Educating patients on physiologic abnormalities and events is essential to ensure their full participation to realize the maximum treatment benefits. Emphasize the need for continued pharmacological treatment, lifestyle, and dietary modifications and relation with possible esophageal symptoms.
For patient education resources, see the Heartburn/GERD/Reflux Center, as well as Gastroesophageal Reflux Disease (GERD) FAQs, Reflux Disease (GERD), and Laryngitis.
Pamela A Mudd, MD, MBA, Attending Physician in Pediatric Otolaryngology, Children's National Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Bardia Amirlak, MD, Assistant Professor of Plastic Surgery, Director of Residency Cosmetic Clinic, Director of Plastic Surgery Global Health Program, University of Texas Southwestern Medical Center at Dallas; Chief of Hand and Peripheral Nerve Surgery, Dallas Veterans Affairs Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Robert M Kellman, MD, Professor and Chair, Department of Otolaryngology and Communication Sciences, State University of New York Upstate Medical University
Disclosure: Nothing to disclose.
Chief Editor
Arlen D Meyers, MD, MBA, Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;The Physicians Edge;Sync-n-Scale;mCharts<br/>Received income in an amount equal to or greater than $250 from: The Physicians Edge, Cliexa<br/> Received stock from RxRevu; Received ownership interest from Cerescan for consulting; .
Additional Contributors
Clark A Rosen, MD, Director, University of Pittsburgh Voice Center; Professor, Department of Otolaryngology and Communication Science and Disorders, University of Pittsburgh School of Medicine
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Merz North America Inc<br/>Received consulting fee from Merz North America Inc for consulting; Received consulting fee from Merz North America Inc for speaking and teaching.
Ramin Soraya, MD, Chair, Department of Science, West Coast University, Dallas
Disclosure: Nothing to disclose.
Reza Shaker, MD,
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Ann L Edmunds, MD, PharmD, to the development and writing of this article.
The RSI documents the presence and degree of nine laryngopharyngeal reflux (LPR) symptoms both before and after treatment; maximum score: 45.
The RSI documents the presence and degree of nine laryngopharyngeal reflux (LPR) symptoms both before and after treatment; maximum score: 45.
The reflux finding score (RFS) documents the presence and degree of eight laryngopharyngeal reflux (LPR) findings during fiberoptic laryngoscopy; maximum score: 26.
The RSI documents the presence and degree of nine laryngopharyngeal reflux (LPR) symptoms both before and after treatment; maximum score: 45.
The reflux finding score (RFS) documents the presence and degree of eight laryngopharyngeal reflux (LPR) findings during fiberoptic laryngoscopy; maximum score: 26.
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