Laryngopharyngeal Reflux and Voice

Claudia Eckley, MD

Gastroesophageal Reflux has been studied by the scientific community for over a century, and seemed to be a well known disease affecting individuals with anatomical or functional abnormalities of the lower digestive tract until otolaryngologists started reporting cases of atypical laryngitis and pharyngitis thought to be associated to the retrograde assent of gastroesophageal content into the upper respiratory tract, namely the pharynx and the larynx.  The first known report of such an association in the English literature was that of Cherry and Margulies in 1968, who documented two patients with contact ulcers and granulomas and observed  that the lesions could have been caused by reflux of the gastric contents into the hypopharynx ¹. Interestingly, after this novel report, a few more decades elapsed until a consistent literature on the topic emerged. It was only in the 80`s that the medical community, namely otolaryngologists, thanks to the wider use of fibreoptic laryngoscopy in clinical practice, could document the chronic changes in the laryngopharyngeal tissue thought to be associated to direct or indirect injury caused by the gastroduodenal contents. As one may expect, the scientific community was very resistant to this change in paradigm regarding the well accepted knowledge of GERD, its diagnostic methods and treatment at the time.

Since a significant number of patients with extraesophageal manifestations of GERD do not present with the classical symptoms of the disease (epigastric pain, heartburn, digestive problems) ^2,3, and the leading diagnostic tools at the time, namely esophagogastroduodenoscopy (EGD), barium swallows and single probe prolonged esophageal pH monitoring, presented a low sensitivity, the scientific community was clearly divided between believers and non-believers ^{2, 4-6}.

The development of technology capable off establishing an objective association between the laryngopharyngeal symptoms, the mucosal abnormalities associated to LPR, and the presence of gastroesophageal contents in the upper airway has increased the number of believers, and has also changed the understanding of GERD and reflux-related diseases in the digestive tract, such as non-erosive reflux esophagitis and other respiratory disorders associated to reflux. However the sensitivity and specificity of the current existing diagnostic tools for LPR are still less than optimal, whereas the majority of the tests are invasive and costly, making the diagnosis of this highly prevalent disease still essentially clinical, especially in developing countries. One can imagine how questionable it may be, in the current age of high tech medicine, to establish the diagnosis of a disease that causes chronic pharyngitis and laryngitis based solely on suggestive symptoms and laryngoscopic signs of inflammation ^3,7, since many of these signs have been reported in healthy individuals ^{8, 9}. As much as the quality of laryngoscopes has evolved ¹⁰, inflammation and mucosal changes can be caused by an infinite number of intrinsic and extrinsic factors, many of them as prevalent as reflux. In fact, a number of studies on asthma and allergic laryngitis have shown that the laryngoscopic findings in such patients are quite similar to those of patients with LPR ^{3, 11,12}. It is also expected that chronic alcohol and tobacco use will cause changes to the laryngopharyngeal mucosa, as well as vocal habits and even snoring ^8,12-16. In an ideal world patients would present with only one of these risk factors. However, in the majority of patients an association of many of these causes of chronic laryngitis are found and it is the medical team`s task to diligently try to sort out base line structural or functional abnormalities, risk factors and habits to establish appropriate treatment strategies^17,18. Medical treatment of LPR is also a challenge, since there is no available drug that effectively bars reflux of the gastric contents into the esophagus and the upper airway. Antiacids, H2 antagonists, proton pump inhibitors, alginates, and prokinectcs, most commonly used, may all provide temporary relief, but at best they only change the chemical properties of the refluxate or improve somewhat peristalsis and accelerate stomach transit ^2,3 . Surgery can also be a strategy for treating refractory patients, those with complications, to avoid prolonged drug use, with drug resistance/intolerance, but short and especially long-term results of fundoplication in patients with LPR are not always optimal ^3,19. The controversies on the diagnosis and treatment of this highly prevalent disease make GERD and LPR a continuous topic of medical and health related research.

The objective of the current review was to compile the significant literature published in the Journal of Voice on the topic of GERD-related head and neck disease, and specifically on Laryngopharyngeal Reflux (LPR) in the past 30 years.

MATERIAL AND METHODS

The current review aimed to systematically study scientific articles on the topic of GERD and its extraesophageal manifestations published in the Journal of voice from March, 1987 to December, 2017. Initially a general search for articles that covered the topic was carried out using the specific terms GERD, laryngopharyngeal reflux, chronic reflux laryngitis, extraesophageal reflux, supraesophageal reflux and reflux. All the articles that contained any of these terms in the title or as key words were reviewed. Further, articles that contained reference to these terms were also reviewed. Because of the known association between certain laryngeal disease and LPR, additional search was carried out using the possible “reflux related” terms: muscle tension dysphonia, chronic cough, paroxysmal vocal fold movement, irritable larynx, contact ulcers and granulomas, laryngomalacia, laryngeal stenosis, leukoplakia, cancer.

A total of 615 articles were initially identified and after review 119 articles were selected, 8 reviews, 57 retrospective studies, 52 prospective studies and 02 case reports.  

CLINICAL PRESENTATION

The chemical and enzymatic properties of the refluxate cause inflammation and mucosal abnormalities in the pharynx and larynx. The resulting symptoms and behavioral changes can have a significant impact on voice production ²⁰.

Common symptoms related to LPR are throat pain or discomfort, foreign body sensation, globus, throat clearing, cough, dysphonia, layngospasm ^2,7,21. These non-specific laryngopharyngeal symptoms were already associated to GERD in the first issues of J Voice. A Panel Discussion on medical management of voice disorders was published in the first issue of volume 1 of J Voice in 1987. Five clinical cases were presented, at least three of them with symptoms that today would likely be attributed to LPR, but only one case was suspected and worked up by a gastroenterolosist, who ordered a barium swallow (which was negative); the patient was treated with H2 antagonists and cimetidine nonetheless, and improved of the laryngeal irritation ^13-15. However, the first article to specifically address GERD-related laryngitis was published in 1988 and reported on 32 patients with chronic laryngitis, investigated with manometry and prolonged double probe esophageal pH monitoring, finding that although 75% of patients had pathological reflux the majority (69%) referred no digestive complaints. The authors called attention to the importance of the silent character of atypical reflux ⁴. The first publication to use the term laryngopharyneal reflux reported on a multidisciplinary consensus about the topic in 1996 ².

Fibreoptic laryngoscopy, both flexible and rigid, reveals the suggestive inflammatory signs of posterior laryngitis, characteristically erythema and edema of the arytenoids, interarytenoid mucosa, and posterior pharyngitis ². Although inflammation tends to be more severe in the posterior laryngopharynx and larynx, it may commonly be diffuse and described as varied degrees of edema, erythema and mucosal abnormalities, ranging from metaplasia of the interaritenoid mucosa (so called “coble-stoning”), to leukoplakia, displasia and rarely cancer ^22-24. Posterior glottis lesions are believed to be a result of an association of intrinsic and/or extrinsic irritants (LPR, tobacco and alcohol use, trauma) associated with negative behavioral patterns, such as throat clearing and cough ^23,25-27_.  Vocal process granulomas have also been associated to compensatory mechanisms due to glottic insufficiency ^27-31. A retrospective cohort study conducted by Haggit et al in 2014 found that the majority of patients with spontaneous posterior glottic lesions were smokers and presented clinical signs of significant psychological stress; only 1.5% of the series had malignancy ²³.

Dysphonia is a highly prevalent symptom in LPR, reported in 10 up to 91% of patients ^{18, 32-40}, and especially in professional voice users ^{36, 41-47}.  Chronic laryngeal inflammation associated to abusive vocal habits and inadequate lifestyle frequently result in disturbed vocal production ^{44, 48}. According to a systematic review conducted by Lechien at al on the etiology and pathophysiology of voice problems in patients with LPR, dysphonia can be caused by both microscopic and macroscopic histopathologic changes in the mucosa of the vibratory margin of the vocal folds, such as epithelial cell dehiscence, microtraumas, inflammatory infiltrates, Reinke space dryness, mucosal drying, and epithelial thickening ³⁹. A number of epidemiological studies have reported a high incidence of LPR in dysphonic patients. Spantideas studied 340 randomly selected adults finding a positive answer to the question “hoarseness or a problem with your voice” in 38.5% in the general Greek population and in 90.6% of patients with LPR ¹⁸. Martins et al reviewed 2019 medical records of a voice clinic at a tertiary center and found LPR-related voice problems in 12.5% of children and 26.5% of adults ³⁸. Myint et al in 2016 reviewed the charts and videolaryngoscopies of 51 opera student-singers comparing initial evaluation to follow-up after acute voice problems, finding a significant increase in LPR at follow-up visits suggesting that physical and behavioral aspects associated to singing predispose to the development or worsening of the disease ⁴⁶.

A questionnaire that aimed to understand the opinion of three voice-related professional groups about factors influencing vocal fold nodules in singers reported that GERD was found to be very important or extremely important by all three professional groups and the treatment had a positive impact on voice⁴⁹.

Houtte et al in 2011 published a review on muscle tension dysphonia (MTD) defining it as a clinical and diagnostic term which describes a spectrum of disturbed vocal fold behavior caused by increased tension of the (para)laryngeal musculature ⁵⁰. Current knowledge seems to view MTD as a bridge between functional and organic disorders, caused by a possible combination between psychological and/or personality factors, vocal misuse and abuse, and compensation for underlying disease, such as LPR ^50-52.

In fact, the phsychological distress caused by chronic disease, such as LPR and GERD, may significantly impact quality of life (QOL), especially in professional voice users ^53,54. Connor et al surveyed 1845 adults in a community using VHI, SF-12, and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaires reporting significant reductions in perceived quality of general health, digestive health, and voice-related quality of life in subjects with both GERD and laryngeal symptoms, in comparison with subjects manifesting each symptom group alone, or in subjects with no symptoms ⁵³. Lee et al used SF-36 to prospectively study 138 adults with LPR before and after treatment with lansoprazole for 12 weeks finding a significant improvement, not only in clinical symptoms and signs of the disease, but in overall quality of life ⁵⁵. Moore et al, however, did not find a correlation between reflux related dysphonia and QOL in 15/80 patients studied with VHI and SF-12 short study after 6 months of follow-up ⁵⁶_.

Chronic cough has also been linked to LPR, whereas it is unknown if the cough mechanism is caused by chemical irritation of the upper respiratory tract of reflex vagal neuropathy, or most likely, a combination of both⁴². In patients with chronic cough there seems to be a two-way negative feedback, where cough causes reflux and the increased intraabdominal pressures during cough may also trigger reflux. Other neurological pathways will also be discussed further. Patients with chronic cough are frequently treated for reflux regardless of a positive objective diagnostic test establishing a direct correlation between the cough symptom and a reflux episode ⁵⁷.

Patients with LPR may or may not have associated GERD. Rouev et al prospectively studied 46 adults with laryngopharyngeal symptoms suggestive of LPR with EGD and prolonged pH monitoring, finding that 72% had LPR and 51% had GERD as well. They concluded that GERD may cause laryngopharyngeal symptoms and that laryngopharyngeal symptoms can be predictors of GERD ⁵⁸. A large community based survey found more than 66% of subjects reported either GERD or laryngeal symptoms, and 26% reported both GERD and laryngeal symptoms ⁵³.

DIAGNOSIS

The diagnosis of LPR is controversial. Clinical symtoms and videolaryngoscopic signs may be non-specific and objective methods of assessing reflux are invasive, costly and not sufficiently sensitive to warrant their use in daily clinical practice, especially in developing countries ^18,59.

In order to reduce subjectivity of diagnosis based on symptoms, a number of clinical scores has been proposed over the years. The most widely used score is the Reflux Symptom Index (RSI), a nine-domain questionnaire on laryngopharyngeal and digestive symptoms related to reflux, proposed by Belafsky et al in 2002 ³⁴. Several translations and adaptations of the RSI into other languages have been published in the journal, such as, Italian⁶⁰, Arabic ⁶¹, Greek ¹⁸, Chinese⁵⁹, French ⁶², and Pilipino ⁶³ showing high psychometric properties and proving a reliable, reproducible clinical method of diagnosing and following clinical outcome in patients with LPR ^18,34,59-63.

Videolaryngoscopic signs of inflammation, which depend on the subjective assessment of the naked human eye, seem to be less reliable for clinical diagnsosis. A cross section survey applied to one thousand general otolaryngologists found that half were concerned about overdiagnosing LPR based on laryngeal findings ⁶⁴. Belasfsy et al also proposed The Reflux Finding Score (RFS), a 13-domain instrument that addresses endolaryngeal signs and severity of inflammation ⁶⁵. However, this instrument seems to be less reliable than the RSI for diagnosis of LPR ⁶⁶. A study conducted in a group of general otolaryngologists showed that these professionals did not show reliable, reproducible results on RFS scores, and that symptoms influenced the final scores⁶⁶. Another study comparing RFS ratings between speech-language pathologists and otolaryngologists found significant discrepancies in the level of rater agreement regarding the presence and the severity of physical findings attributed to LPR ⁶⁷.

However, when careful exclusion of other possible causes or even associated causes of chronic laryngitis are addressed, RSI and RFS combined have proven to be widely used in clinical practice for the diagnosis of LPR and seem to offer a more cost effective, less invasive means of diagnosis ^{18,60,62,63,68}.

Other technologies have been proposed to assess laryngeal and pharyngeal signs of inflammation^69-71. Improvements in the subjectivity of the analysis of endoscopic images have been suggested over the years, but none have been widely used in clinical practice. Jiang et al in 1998 used computer image analysis software to quantify the average color values, hue, saturation, and brightness from digitized color images obtained from videolaryngoscopies of patients with LPR and healthy controls finding significantly greater average color value ratings of redness of the vocal folds in patients with chronic laryngitis than normal subjects, and also a significant reduction in redness of the vocal folds after treatment of LPR⁷². Witt et al in 2014 used pattern recognition of a combination of hue and textural parameters to identify signs of chronic laryngitis comparing the laryngoscopic images of 20 patients with LPR diagnosed by a positive RFS to 42 controls, finding a high diagnostic accuracy when both parameters were combined ⁷¹_. Based on the knowledge that colors in nature are produced by a combination of the three primary colors red, green, and blue (RGB) and that RGB measurements provide an objective numeric value,  the degree of pathology of a tissue can be interpreted according to RGB values. This technology was used by Ozturan et al in 2017 in a case-control study comparing 72 patients with LPR and 35 healthy individuals⁷³. The authors found significant RGB differences between the laryngoscopic images of patients and controls, as well as those of patients before and after treatment ⁷³.

Narrow band imaging (NBI), an endoscopic technique using filtered wavelengths in order to enhance microvascular abnormalities offering optimal visualization of the subtle neoangiogenic changes associated with precancerous and neoplastic diseases, has not successfully aided in the diagnosis of LPR ⁶⁹_.

EGD and barium swallow with water siphonage have proven a very low sensitivity in the diagnosis of LPR, mostly because a great number of patients with this supraesophageal form of the disease do not have anatomical or functional abnormalities to the digestive tract ^3,7,74,75. In 2002 Rubin et al tried to establish a correlation between the inflammatory signs found in patients with non-malignant laryngeal disorders associated to LPR and H. pylori ¹⁷.Although a trend toward greater infection in older patients when compared to healthy matched controls was found, no significant correlation between this pathologic agent, well known to contribute to erosive digestive tract disease and cancer, could be established ¹⁷.

Objective methods of monitoring reflux to the upper airway, such as wired or wire-less prolonged esophageal-pH monitoring, esophageal pH-impedance (MII-pH) and oropharyngeal pH monitoring (Restech ^DX), have greatly expanded our knowledge of the physiology of esophageal reflux ^3,75,76. The challenge in these tests has been to establish normative data for the upper (pharyngeal or crycopharyngeal) sensor, as not only acid but also weakly acid reflux is known to cause damage to the laryngeal mucosa ^4,75-78. Laryngopharyngeal reflux episodes are few in number and very brief in duration. For this reason, the parameters used to quantify lower esophageal reflux do not apply for the upper probe⁷⁶. A great number of otolaryngologists seem to consider positivity for the upper sensor in double probe prolonged esophageal pH monitoring as any single drop below pH 4 regardless of its duration ^4,77. However, studies showing that weakly acidic pH can also cause damage to the laryngeal tissue have taken a few authors to accept a pH cut-off at 5 for the proximal sensor ^2,79. Vincent et al in 2000 used the Reflux Area Index (RAI), a ratio which incorporates not only the number and duration of episodes with pH < 4 but also the degree to which those events drop below pH 4, to try to establish normative data to the proximal probe during prolonged esophageal pH monitoring, observing that normal subjects display physiologic reflux above the upper esophageal sphincter mostly in the upright position, and that RAI appears to be a useful indicator of proximal reflux severity ⁷⁶. Musser compared RAI scores to RSI and RFS finding a low intra and inter-rater agreement for all three scores, and especially for RFS⁷⁹. 

Vailati et al conducted a study using oropharyngeal pH monitoring for diagnosis and control of treatment outcome in patients with clinical and laryngoscopic sings of LPR finding a sensitivity of 69% and a specificity of 100%. All patients with a positive oralpharyngeal pH test and none of those with a negative test responded to clinical treatment with full dose PPI. Responsive patients showed both a higher oropharyngeal acid exposure in orthostatic position and a higher Ryan score, compared with nonresponders 80.

Kavitt et al in 2017 reported on a novel esophageal impedance testing performed during EGD and that does not require prolonged use of catheters. They prospectively studied 41 patients with symptoms suggesting LPR through EGD (with esophageal surface impedance tested at 2, 5 and 10 cm above the sqamouscolumnar junction-SCJ) and 48-hour wireless pH monitoring comparing the presence or absence of erosive esophagitis to the presence of distal pathological reflux and finally to mucosal impedance (MI). They found that patients with LPR and evidence of acid reflux (with or without erosive esophagitis) had a lower MI than those without at 2 cm above the SCJ, with a trend at 5 cm and 10 cm as well. In those with nonerosive disease who had abnormal reflux by pH monitoring, MI values were similar to those with erosive esophagitis. The authors concluded that their findings pointing to the fact that MI can differentiate those with abnormal reflux pattern from those with normal reflux parameters in patients with normal EGD findings ⁷⁵.

On the promising front of diagnostic tests for LPR is salivary pepsin dosage ⁸¹. Pepsinogen is a proenzyme secreted by gastric chief cells that is converted into pepsin in acidic conditions. Accordingly, several studies have suggested that pepsin is direct evidence of reflux, and can be considered a reliable diagnostic marker of LPR. Salivary pepsin detection is a convenient, non-invasive, and inexpensive way to diagnose LPR ⁸¹. Commercial ELISA kits using one or two recombinant pepsin 3b antibodies have shown moderate sensitivity and specificity for the diagnosis of LPR, comparable to those of more invasive methods, such as prolonged esophageal pH-metry and impedance-pH ⁸¹. Jung et al conducted a prospective study on 50 patients diagnosed with LPR by RSI, RFS and 24-hour multichannel intraluminal impedance pH monitoring. They reported that 41 of the 50 patients had positive saliva pepsin ELISA tests, but found no correlation between pepsin levels and RSI, RFS, MII-pH   ⁸². Another recent study conducted by Gong et al used immunohistochemistry to detect pepsin in 26 biopsies from patients with vocal fold leukoplakia comparing them with 20 vocal fold biopsies from control subjects observing that 64.4% of the leukoplakia patients were pepsin positive compared to only 20% of the controls. The authors suggest that pepsin immunohistochemical staining could be a biomarker of LPR and that LPR may be a risk factor for the development of vocal fold leukoplakia⁸³.

Studies comparing the sensitivity of clinical diagnostic methods, such as RSI and RFS, to objective methods have also been conducted ⁵_. In 2014 Wan et al compared two groups of patients with LPR before and after treatment, one diagnosed clinically with RSI and RFS and the other with MII-pH, concluding that both methods were similar in diagnostic and prognostic capacity ⁵_.

DIAGNOSIS OF VOICE PROBLEMS RELATED TO LPR

Acoustic Analysis has also been carried out trying to establish the vocal characteristics of patients with LPR ^20,84-87. The pioneer study to use acoustic analysis as an outcome measure in 68 patients with reflux laryngitis found no significant difference in voice parameters after 12-week course of omeprazole 20 mg b.i.d. ⁸⁸.  A prospective study of 41 dysphonic patients with LPR designed to  explore the impact of the selection of the analyzed time interval on the significance of acoustic measurements used to investigate laryngopharyngeal reflux (LPR) treatment efficacy observed that acoustic voice parameters, such as jitter, jitter percent, relative average perturbation, pitch perturbation quotient, shimmer, shimmer percent, amplitude perturbation quotient, and smoothed amplitude perturbation quotient were the indices most sensitive to medical treatment efficacy ²⁰. Another study by Lopes et al observed that isolated acoustic measures were not able to discriminate patients with and without laryngeal alteration, but combined acoustic measures such as jitter, shimmer, fundamental frequency and glottal to noise excitation  discriminated between the presence and the absence of laryngeal alteration and was able to differentiate laryngeal alterations  like vocal fold nodules, paralysis and LPR ⁸⁶.

ASSOCIATION WITH OTHER CONDITIONS AND DISEASES

GERD and LPR have been associated with a number of other diseases over the years and especially with those affecting the respiratory and digestive systems. Mechanical changes in the intraabdominal pressure and in the pressure of the upper (UES) and especially the lower esophageal sphincters (LES) during coughing, snoring or during laryngospasm have been associated to GERD and LPR ⁸⁹.

LPR has also been shown to negatively influence the outcome of non-invasive and invasive procedures to the larynx ^90-92. Wang et al observed that LPR was a significant negative prognostic factor on voice in patients  with vocal fold polyps treated with intralesional steroid injection ⁹¹. In a retrospective study of the success rate of speech rehabilitation in patients undergoing laryngectomies and radiation therapy conducted by Cocuzza et al,  a higher rate of failure of speech rehabilitation in laryngectomy patients with gastroesphageal reflux was observed ⁹⁰.

Pregnancy is a physiological state that characterizes some of the above mechanical changes. Some of the voice changes reported in pregnant women may be associated to chronic reflux laryngitis, although this condition presents with a number of associated hormonal changes that notoriously influence fluid balance and edema. A study of 50 pregnant women in the first, second and third  trimesters and 15 non-pregnant women using acoustic voice parameters, VHI-10 and RFS scores found that RFS was higher in the first and third trimesters than the second trimester and control groups. VHI-10 scores were significantly higher in the third trimester ^93,94.   

Changes in body weight and eating disorders may also predispose to LPR and voice problems ^95,96. Rothstein in 1989 published a series of eight patients with bulimia and hoarseness. Reflux was diagnosed through esophagograms in four patients and double-probe 24-hour pH-metry (proximal positivity considered as any single drop in pH<4) in another four. Treatment with omeprazole improved symptoms in only half of the patients ⁹⁷. Morrison et al in 1990 were the first to report on laryngoscopy findings associated with vomiting laryngeal injury in bulimic patients ⁹⁵. They reported 13 females with eating disorders (3 bulemic with voice complaints) finding superficial telangiectasia of the glottic mucosa and subepithelial vocal fold hemorrhages with scaring even in those patients without voice complaints. Although forceful vomiting and passive reflux may cause very different strain to the larynx, many of the findings reported above can also be observed in patients with LPR and voice abuse ³.

On the other end of eating disorders is morbid obesity. Despite the known influence of increased intraabdominal pressure and decreased LES tone found in obese and morbidly obese patients on GERD/LPR, a study published by Hamden et al in 2014 failed to find and changes in laryngeal findings and voice quality in morbidly obese patients before and after significant weight loss following bariatric surgery ⁹⁶.

A recent review of literature on episodic laryngeal breathing disorders (ELBD) defined it as a spectrum of respiratory disorders, with no known etiology ⁹⁸. Included in this spectrum are the so-called paradoxical vocal fold motion/ movement disorder (PVFMD), vocal cord dysfunction (VCD), irritable larynx syndrome (ILS), exercise-induced laryngeal obstruction, laryngospasm, Munchausen stridor, and many additional terms implying functional laryngeal respiratory pathology ⁹⁸. Based on their literature review, Shembel et al proposed a novel theoretical paradigm and algorithm for identifying trigger patterns and clinical presentation of distinct forms of ELBD and suggested that the diagnosis of any of these disorders should be made by systematic exclusion ⁹⁸. Paradoxical vocal fold movement disorder (PVFMD) has thus been described as a laryngeal-based respiratory disorder characterized by the inappropriate, involuntary closure of the true vocal folds usually during inspiration ^89,99-102. This may result in recurrent episodes of stridor, dyspnea, a choking sensation, and dysphonia has been associated with many triggers, including voice use, exercise, psychological conditions, environmental and occupational irritants, rhinosinusitis, gastroesophageal reflux disease, and neuroleptic drugs resulting in a poor quality of life ^98,103-106. In children and adolescents it is most commonly seen in those who are high achievers academically and athletically ¹⁰⁶. These _symptoms frequently mimic those of asthma ¹¹. The management of PVFMD and the other confounding Laryngeal Breathing Disorders involves treating underlying comorbid conditions, such as gastroesophageal or laryngopharyngeal reflux disease, in addition to behavioral breathing therapy ^98,105,106.

Like ELBD neurogenic chronic cough is currently a diagnosis of exclusion. Vertigan examined cough triggers in individuals with chronic cough (CC) identifying sensory symptoms consistent with central reflex sensitization (paresthesia and allotussia), which in their opinion supports that chronic cough may be cough a sensory neuropathic disorder ¹⁰⁷. A link between chronic cough and paradoxical vocal cord movement was also suggested ¹⁰⁴. In a later study the authors treated cough-related voice problems with two specifically designed voice therapy programs finding improvement in subjective voice parameters and electroglottographic outcomes¹⁰⁸. Bock et al compared the laryngeal electromyographic (LEMG) surface-evoked laryngeal sensory action potentials (SELSAP) from 30 patients with chronic cough to a control population without significant laryngeal symptoms, finding significantly lowered median SELSAP peak amplitude in patients also suggesting laryngeal sensory neuropathy ¹⁰⁹.

 Rheumatoid arthritis (RA) may cause dysphonia due to inflammatory crycoarytenoid anchyloses, central neuropathy and or GERD/ LPR secondary to chronic use of non-steroidal and steroidal inflammatory drugs, and immunosupressors ¹¹⁰. In 2016 Roy et al studied QOL and voice related complaints in 100 patients with RA to determine the frequency, severity, risks associated with, and quality of life burden of voice disorders. Although 35% of the patients interviewed reported chronic voice problems, only a small number had sought medical attention and the authors were unable to establish a correlation between vocal complaints and GERD-related symptoms or diagnosis ¹¹⁰.

Matsumaki et al studied the prevalence of LPR in patients with lumbar kyphosis comparing the RSI scores of a group of 20 patients with this spinal deformity to 31 healthy controls. The authors found that patients with lumbar kyphosis scored higher on the RSI sub-domains heartburn, hoarseness, and problem with swallowing and concluded that the prevalence of laryngopharyngeal reflux disease and gastroesophageal reflux disease was significantly higher in patients with lumbar kyphosis than in controls ¹¹¹.

A case-control study of 100 patients with type-II Diabettes Mellitus (DM) and 30 controls was carried out to establish the correlation between LPR and glycemic control, duration of the disease, and presence of neuropathy. The authors found a correlation between LPR and neuropathy, but could not establish a significant association between DM and LPR ¹¹².

TREATMENT

Lifestyle changes and Voice Therapy

The increasing incidence of GERD and LPR and the unsustainable results after discontinuing medical treatment point to the essential role of unhealthy, reflux promoting diet and lifestyle. Addressing these behavioral issues is key to treatment ⁷. Treatment compliance is poor, as many patients do not understand the correlation between their laryngopharyngeal symptoms and reflux, especially those that do not present significant digestive complaints. Pisegna et al studied patients` reflux-related symptoms and treatment compliance finding that PPI compliance was poor, and the reasons for poor compliance could have been prevented with patient education ¹¹³. Even when PPI compliance was adequate, symptoms like globus, mucous, voice dysfunction, and dysphagia persisted. They concluded that other interventions such as evidence-based diet and behavioral changes should be a part of voice/dysphagia/reflux therapy ¹¹³.

Selby et al in 2003 proposed that the hyperfunctional voice patterns observed in a group of patients with LPR was due to laryngeal inflammation and not vocal abuse ³⁵. Patients underwent 8 weeks of speech therapy encouraging easy onset of phonation, decreasing muscular tension, decreasing vocal intensity, improving respiratory support, and improving coordination between respiration and articulation ³⁵.

Clinical Treatment

Proton pump inhibitors (PPIs) are the mainstay of current medical management for LPR but may be insufficient in managing some patients' symptoms ³. The dose and duration of treatment varies widely amongst studies varying from a full therapeutic dosage twice daily ^20,68,80 to a lower dose twice daily ^{5,20,55,59,63}  for no less than 8 weeks duration. Despite their effectiveness, about 20-30% of patients report an inadequate response and alternative drugs are required. High dose PPI have been suggested for patients who have refractory disease or develop drug resistance ¹¹⁴. However, in a prospective study of the effect of super high dose of PPI (120 mg daily) on patients with refractory LPR conducted by Portnoy et al in 2014, no statistically significant decrease in acid reflux episodes was observed during 24-hour pH impedance monitoring ¹¹⁵.

Antireflux medications are also widely used before and after phonomicrosurgery based on the premise that reflux episodes occurring during the perioperative period could negatively impact healing. In 2014 Amin et al conducted a retrospective chart review to determine the influence of these medications on operative outcomes in 51 patients who underwent surgical treatment for benign vocal fold lesions finding no significant difference in Voice Handicap Index (VHI)-10 and RSI scores between those patients on antireflux therapy and those that did not receive this medication ¹¹⁶_.

Caution must be exercised when prescribing these drugs for prolonged periods of time. The long-term adverse effects of PPI use have not been studied extensively, but several analyses have demonstrated epidemiological links between PPI use and adverse outcomes. These include altered mineral and vitamin absorption, orthopedic injury, acute coronary syndromes (ACS), and infectious risks, likely more prevalent in post-menopausal women, who are also frequently affected by GERD and LPR ¹¹⁷.  Mc Kinnon, Hawkshaw and Sataloff made sensible considerations on the mortality associated to chronic PPI use in an editorial published in 2017 concluding that “medication prescribing should be based on an appropriate clinical indication, and the patient needs to be re-evaluated to ensure that the indications for medication use still exist, that the course of therapy is impacting the clinical condition positively, and that no significant complications have developed” ¹¹⁸.

Surgical Treatment

Laparoscopic Nissen fundoplication (LNF) is well established for treatment of gastroesophageal reflux disease with a high success rate, but its role in the treatment of LPR remains uncertain ¹⁹. In a pilot study conducted by Weber et al in 2014, 25 professional voice users refractory to standard or super-high-dose medical management were followed after Laparoscopic Nissen fundoplication (LNF). Despite no significant changes in laryngoscopic findings, 86% of patients referred improvement of LPR symptoms, 60% did not require any anti-reflux medication postoperatively and an additional 24% were on less medication ¹⁹.

An interesting article by Jiang et al noticed an improvement in the RSI scores and dysphagia when reviewing the outcome of 41 patients with dysphagia who underwent partial or complete crycopharyngeal myotomy. Contrary to the common concept that a lowered UES tone would facilitate reflux, the opposite was observed in their study ¹¹⁹.

FINAL CONSIDERATIONS

GERD is currently considered the most prevalent disease of the digestive tract, affecting between 12-40% of the population. LPR is reported as a cause of 10 up to 60% of visits to the otolaryngologist ⁸⁷. The incidence of this disease started to soar in the past 3 or 4 decades and is mostly associated to the drastic changes in behavioral and dietary habits. This must be considered with great caution by the health care professional seeking to treat patients with any form of the disease, and especially LPR, since patients many times do not have detectable anatomical or functional abnormalities in the digestive tract.  Dispensing medication that interferes with the production of acid or the activation of gastric enzymes, or even with peristalsis, will not sustainably change the progress of the disease unless behavioral and eating habits are addressed.  That remains our greatest challenge. In post-modern society of fast everything and overachieving goals, of processed foods and acidic tap water, it seems that such time-consuming conscious effort in controlling diet and habits, is a daunting task for the patients and even more daunting for the health professional trying to propose such. A multidisciplinary and knowledgeable approach is essential to achieve adequate diagnosis and treatment and to enable long lasting disease remission.

Our understanding of laryngopharyngeal reflux has significantly improved over the past 3 decades, but there still remain many challenges in its diagnosis and long-term treatment.