Laryngopharyngeal Reflux Disease: Integrative Approaches [1st ed.] 978-3-030-12317-8;978-3-030-12318-5

Table of contents :
Front Matter ....Pages i-x
Front Matter ....Pages 1-1
Laryngopharyngeal Reflux (Michele P. Morrison, Danielle C. Anderson)....Pages 3-11
The Approach to a Patient with Suspected Laryngopharyngeal Reflux Disease (LPRD) (Lawrence Borges, Thomas L. Carroll)....Pages 13-31
Commonly Confused Conditions (Elisabeth H. Ference, Vicki Henderson, Marilene B. Wang)....Pages 33-45
Front Matter ....Pages 47-47
Lifestyle and Dietary Modifications (Suraj Kedarisetty, Ahmed M. S. Soliman)....Pages 49-57
Medical Management of LPR (Justin Field, Deena Midani, Yellowlees Douglas, Michael S. Smith)....Pages 59-73
Surgical Management of Reflux (Abbas E. Abbas, Shawn Robinson)....Pages 75-87
The Role of Voice Therapy in Treating Symptoms of Laryngopharyngeal Reflux (Barbara Ebersole, Liane McCarroll)....Pages 89-102
Probiotics and Herbal Therapies (Agnes Czibulka)....Pages 103-113
Integrative East-West Medicine for Reflux Disease (Malcolm B. Taw)....Pages 115-129
Back Matter ....Pages 131-135

Citation preview

Laryngopharyngeal Reflux Disease Integrative Approaches Nausheen Jamal Marilene B. Wang Editors

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Laryngopharyngeal Reflux Disease

Nausheen Jamal  •  Marilene B. Wang Editors

Laryngopharyngeal Reflux Disease Integrative Approaches

Editors Nausheen Jamal Division of Otolaryngology-Head & Neck Surgery University of Texas Rio Grande Valley School of Medicine Edinburg, TX USA

Marilene B. Wang Department of Head and Neck Surgery UCLA David Geffen School of Medicine Los Angeles, CA USA

ISBN 978-3-030-12317-8    ISBN 978-3-030-12318-5 (eBook) https://doi.org/10.1007/978-3-030-12318-5 © Springer Nature Switzerland AG 2019 Chapter 1 was created within the capacity of an US governmental employment. US copyright protection does not apply. This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

Laryngopharyngeal reflux (LPR) disease is a common disorder in general medical, otolaryngology, and gastroenterology practices. Anti-reflux precautions and proton-­ pump inhibitors (PPI) continue to be effective treatment strategies, but there are adverse effects associated with long-term PPI therapy, and therefore innovative and integrative approaches are desirable. We organized a panel discussion at the annual meeting of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) in 2016 and 2017 focusing on integrative treatments for LPR. Sponsored by the Complementary/Integrative Medicine Committee of the AAO-HNS, it was met with enthusiastic audience response, and the idea for this textbook was born. In this book, current evaluation methods and diagnostic testing for LPR are discussed, as well as the latest updates in medical and surgical treatments. In addition, novel treatment strategies including voice therapy, probiotics, herbal therapies, and integrative East-West medicine approaches are presented. Because of the strong mind-­ body connection in LPR, such integrative approaches offer a valuable and effective treatment option for patients. Edinburg, TX, USA  Los Angeles, CA, USA 

Nausheen Jamal Marilene B. Wang

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Contents

Part I Understanding and Recognizing LPR 1 Laryngopharyngeal Reflux ����������������������������������������������������������������������    3 Michele P. Morrison and Danielle C. Anderson 2 The Approach to a Patient with Suspected Laryngopharyngeal Reflux Disease (LPRD)������������������������������������������������������������������������������   13 Lawrence Borges and Thomas L. Carroll 3 Commonly Confused Conditions��������������������������������������������������������������   33 Elisabeth H. Ference, Vicki Henderson, and Marilene B. Wang Part II Treatment Options for LPR 4 Lifestyle and Dietary Modifications ��������������������������������������������������������   49 Suraj Kedarisetty and Ahmed M. S. Soliman 5 Medical Management of LPR ������������������������������������������������������������������   59 Justin Field, Deena Midani, Yellowlees Douglas, and Michael S. Smith 6 Surgical Management of Reflux ��������������������������������������������������������������   75 Abbas E. Abbas and Shawn Robinson 7 The Role of Voice Therapy in Treating Symptoms of Laryngopharyngeal Reflux������������������������������������������������������������������   89 Barbara Ebersole and Liane McCarroll 8 Probiotics and Herbal Therapies��������������������������������������������������������������  103 Agnes Czibulka 9 Integrative East-West Medicine for Reflux Disease��������������������������������  115 Malcolm B. Taw Index������������������������������������������������������������������������������������������������������������������  131 vii

Contributors

Abbas  E.  Abbas, MD, MS, FACS  Lewis Katz School of Medicine, Temple University Health System, Philadelphia, PA, USA Danielle C. Anderson, DO  Otolaryngology Head & Neck Surgery, Naval Medical Center Portsmouth, Portsmouth, VA, USA Lawrence  Borges, MD, MPH  Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Thomas  L.  Carroll, MD  Division of Otolaryngology, Brigham and Women’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Agnes Czibulka, MD  Yale School of Medicine, Department of Surgery, Section of Otolaryngology, ENT Medical and Surgical LLC, New Haven, CT, USA Yellowlees Douglas, PhD  Independent Researcher, Brooklyn, NY, USA Barbara Ebersole, BFA, MA, CCC-SLP  Department of Speech Pathology, Fox Chase Cancer Center, Temple Head and Neck Institute, Temple University Health System, Philadelphia, PA, USA Elisabeth  H.  Ference, MD, MPH  Rick and Tina Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA Department of Otolaryngology-Head and Neck Surgery, Children’s Hospital Los Angeles, Los Angeles, CA, USA Justin  Field, MD  Division of Gastroenterology and Hepatology, Department of Medicine, Mount Sinai Beth Israel, Mount Sinai West and Mount Sinai St. Luke’s Hospitals, New York, NY, USA

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Contributors

Vicki  Henderson, MSP  Department of Speech Pathology, St. Jude Hospital, Fullerton, CA, USA Suraj  Kedarisetty, MD  Department of Otolaryngology-Head & Neck Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA Liane McCarroll, MS, CCC-SLP  Department of Speech Pathology, Fox Chase Cancer Center, Temple Head and Neck Institute, Temple University Health System, Philadelphia, PA, USA Deena Midani, MD  Gastroenterology, Cedars-Sinai Medical Group, Los Angeles, CA, USA Michele P. Morrison, DO  Otolaryngology Head & Neck Surgery, Naval Medical Center Portsmouth, Portsmouth, VA, USA Shawn  Robinson, MD  Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA Michael  S.  Smith, MD, MBA  Division of Gastroenterology and Hepatology, Department of Medicine, Mount Sinai West and Mount Sinai St. Luke’s Hospitals, New York, NY, USA Ahmed  M.  S.  Soliman, MD  Department of Otolaryngology-Head & Neck Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA Malcolm  B.  Taw, MD, FACP  UCLA Center for East-West Medicine, UCLA Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Marilene  B.  Wang, MD  Department of Head and Neck Surgery, David Geffen School of Medicine of the University of California, Los Angeles (UCLA), Los Angeles, CA, USA

Part I

Understanding and Recognizing LPR

Chapter 1

Laryngopharyngeal Reflux Michele P. Morrison and Danielle C. Anderson

Laryngopharyngeal reflux (LPR) is a relatively common condition that has only been recently distinguished as a separate, though related, entity from gastroesophageal reflux disease (GERD). LPR is defined as irritation and inflammation of the laryngeal structures resulting from contact with gastric secretions. It can present with a myriad of symptoms, including hoarse voice, throat clearing, chronic cough, globus sensation, postnasal drip, dysphagia, and sore throat. Many of these symptoms are vague and none are pathognomonic, highlighting the importance of familiarity with this diagnosis in order to effectively recognize and manage these patients. According to the American College of Gastroenterology, the prevalence of GERD is 10–20% in Western populations [1]. Since the 1960s, several studies have identified an association between GERD and extraesophageal symptoms, including chronic cough, pharyngitis, laryngitis, and asthma [2–4]. A large case-controlled study looked at over 100,000 cases of patients with reflux esophagitis and found an increased risk of concomitant sinus, pharyngeal, laryngeal, and pulmonary diseases [3]. The evidence on causation as well as diagnosis and treatment is still evolving, but LPR is now considered a separate disease process with distinct symptoms and management recommendations [5–7]. The symptoms reported in GERD and LPR have long been described. Hippocrates described globus pharyngeus over 2500 years ago. Heartburn was first described by Galen in 200 AD after observing that diseases of the esophagus mimicked those of The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of Defense, or the US Government. We are military service members. This work was prepared as part of our official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the US Government.” Title 17 U.S.C. 101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person’s official duties. M. P. Morrison (*) · D. C. Anderson Otolaryngology Head & Neck Surgery, Naval Medical Center Portsmouth, Portsmouth, VA, USA © Springer Nature Switzerland AG 2019 N. Jamal, M. B. Wang (eds.), Laryngopharyngeal Reflux Disease, https://doi.org/10.1007/978-3-030-12318-5_1

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the heart [8]. The correlation between dietary habits and airway disease was recognized in the third to sixth centuries and first entered the medical literature in Nicholas Rosen von Rosenstein’s 1776 textbook on The Diseases of Children and Their Remedies [9]. In 1934, George W. Bray described bronchoconstriction induced by reflex-mediated vagal irritation in response to gastric distention and advised many of the same lifestyle modifications still recommended today [10]. Peptic esophagitis (now termed GERD) was first described as a new clinical entity by American gastroenterologist Asher Winkelstein in 1935 [11]. In the 1960s, several authors noted direct links between reflux and laryngeal pathology. Cherry and Margulies published a case series of three patients with laryngeal ulcers that were refractory to voice rest, voice rehabilitation, antibiotics, and steroids. He found that all three also had gastric symptoms and radiographic evidence of gastroesophageal and esophagopharyngeal reflux. Their laryngeal symptoms resolved only after intensive treatment of their peptic esophagitis, as did the ulcerations noted on indirect laryngoscopy [12]. Cherry wrote that “esophopharyngeal reflux may well be a factor in causing other laryngopharyngeal problems for the possible relationship of gastric reflux to contact ulcers of the larynx adds a new dimension in the evaluation of laryngeal pathology.” Similarly, Malcomson used barium swallow studies to evaluate patients with “globus hystericus” and noted organic lesions in 80% [13]. He wrote that “the sensation of a lump in the throat is a real symptom related to an irritative lesion in the foregut in the majority of patients” and coined the term globus pharyngeus, which is used today [14, 15]. Since then, canine models have demonstrated deleterious effects of gastric acid on laryngeal tissues. In 1968, Delahunty and Cherry induced vocal cord granulomas in dogs by painting gastric secretions over their vocal folds [16]. In 1985, Little et al. described subglottic stenosis in mucosal lesions that were painted with gastric acid [17]. Similar findings have been echoed in more recent studies as well [18]. Meanwhile, techniques to measure esophageal acid were developing, but prolonged monitoring was not readily available until 1974, when Johnson and DeMeester reported successful data collection using an external reference electrode [19]. Wiener et al. then utilized this technology in 1989 to study the relationship between gastroesophageal reflux and otolaryngologic symptoms. This study found that 78.8% of patients with chronic hoarseness and laryngeal lesions had pH evidence of severe reflux [20]. They also noted that the reflux was worse in the upright position, unlike the classic findings in peptic esophagitis. Similar results were noted by DeMeester et al. in 1990 using 24-hour pH monitoring to evaluate 77 patients with chronic respiratory symptoms for occult GERD. They found that 70% had increased esophageal acid and that in some cases, antireflux surgery led to resolution of respiratory symptoms [21]. Efforts to more clearly identify the relationship between gastroesophageal reflux and laryngeal/respiratory symptoms yielded increasing evidence that GERD and LPR are distinct pathological processes. In 1994, Perry et al. noted improvement of 16 cases of posterior laryngitis that improved while on omeprazole and return of symptoms after discontinuation of therapy. This suggested that reflux was the underlying etiology, but only three patients had esophagitis upon entrance into

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the study [22]. A 1997 prospective study evaluated 222 children with dual-probe (esophageal and pharyngeal) pH monitoring and found that 46% had pharyngeal reflux despite normal findings on the esophageal probe [23]. In 1998, Klinkenberg-­ Knol looked at otolaryngologic manifestations of gastroesophageal reflux disease and noted that endoscopic esophagitis was present in less than 25% of patients with laryngopharyngeal disorders [24]. By the mid- to late 1990s, the term laryngopharyngeal reflux started to be used [6, 25], and in 2005, Ford published a systematic review that highlighted the unique symptom complex and pathophysiology of LPR [5]. Current understanding of LPR has come a long way since the first descriptions of symptoms. This text will provide the reader with a comprehensive understanding of LPR and present a practical evidence-based approach to the diagnosis and management of patients with this condition. The anatomical structures pertinent to understanding LPR are those of the upper aerodigestive tract, grossly, the larynx, esophagus, and stomach. The larynx is located in the anterior neck and can be broken down into three subunits: the supraglottis, the glottis, and the subglottis. The structure of the larynx is formed by three unpaired cartilages, the epiglottis, thyroid, and cricoid, along with three paired cartilages: the cuneiform, corniculate, and arytenoid. The epiglottis functions to close off the larynx during swallowing to protect the lower airway. It is a teardrop-shaped structure made of elastic cartilage with edges that curl posteriorly and is draped with mucous membrane. The lingual aspect is composed of nonkeratinized stratified squamous epithelium that reflects off the walls of the pharynx to form the glossoepiglottic folds at the root and lateral aspects of the tongue base. The aryepiglottic folds form the lateral borders of the larynx. They connect the mucosa of the lateral epiglottis to the mucosa of the arytenoid and corniculate cartilages. This mucosa is ciliated pseudostratified columnar epithelium. The arytenoid cartilages are pyramid shaped and articulate with the cricoid cartilage forming the synovial cricoarytenoid joint. Superiorly, the arytenoid is capped by the corniculate cartilages. On the lateral aspect, the muscular process serves as the insertion point for the posterior cricoarytenoid muscle and the lateral cricoarytenoid muscles. The oblique and transverse arytenoid muscles attach posteriorly. The aryepiglottic folds enclose the superior margins of the quadrangular membranes, sheets of elastic tissue that function as a sphincter while swallowing. The inferior border of the quadrangular membrane is the vestibular fold, or false cord. The thyroid cartilage is formed by quadrilateral-shaped right and left lamina that fuse at an angle anteriorly forming the laryngeal prominence. In women, the anterior angle is more obtuse at about 120°, while in men it is closer to 90, making this prominence more apparent. The laminae then extend obliquely to shield each side of the trachea. Posteriorly, the laminae are open, with elongations forming the superior and inferior horns. The inferior horn articulates with the posterolateral surface of the cricoid cartilage, forming the synovial cricothyroid joint. Medially, the cricothyroid membrane connects the inferior border of the thyroid cartilage to the cricoid cartilage, and the cricothyroid muscles traverse either side.

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On the inner surface of the thyroid cartilage, the ligaments of the vocal folds extend from the angle anteriorly to the vocal process of the arytenoid cartilages posteriorly. They are composed of elastic fibers and collagenous fibers, which constitute the intermediate and deep layer of the lamina propria, respectively. They are covered with a loose fibrous matrix of gelatinous consistency (known as the superficial lamina propria) along with a top layer of stratified squamous epithelium, which together make up the vocal fold cover. Deep to the vocal ligament is the thyroarytenoid muscle complex (also known as the vocal fold body), which originates from the lower internal surface of the thyroid cartilage, runs parallel to the vocal ligament, and then inserts onto the anterior surface of the arytenoid cartilage. The cricoid cartilage is shaped like a signet ring, with a wide lamina posteriorly that narrows to form the arch anteriorly. It is made of hyaline cartilage, and it is the only complete cartilage ring in the trachea. The midline of the lamina has a ridge posteriorly that serves as an attachment point for the esophagus. On either side of this ridge are the attachment sites for the posterior cricoarytenoid muscles, which extend upward to the muscular process of the arytenoid cartilage on the same side and function to rotate the arytenoid cartilages laterally, thereby abducting the vocal cords. The inferior aspect of the cricoid cartilage sits at about the level of C6, marking the end of the larynx and beginning of the trachea anteriorly and esophagus posteriorly. Innervation to the larynx is exclusively via the vagus nerve. The vagus nerve exits the jugular foramen and travels inferiorly within the carotid sheath. It gives off the superior laryngeal nerve, which then splits into two branches: the internal and the external laryngeal nerves. The internal branch provides sensation to the mucosa from the inferior base of the tongue to the true vocal fold. The external branch is a smaller nerve that provides motor innervation primarily to the cricothyroid muscle, with some contribution to the inferior constrictor. The vagus nerve continues into the mediastinum, where it branches into the recurrent laryngeal nerve on each side. On the left, this branch wraps around the aortic arch at the ductus arteriosus and ascends along the tracheoesophageal groove to enter the larynx posterior to the cricothyroid joint. On the right, the recurrent branch passes around the right subclavian artery before following a similar path. Arterial supply to the larynx comes from the external carotid superiorly and the subclavian artery inferiorly. The superior thyroid artery branches into the superior laryngeal artery and the cricothyroid artery, while the inferior thyroid artery, off of the thyrocervical trunk, gives rise to the inferior laryngeal artery. The superior laryngeal artery courses near the internal branch of the superior laryngeal nerve, and the inferior thyroid artery lies in close association with the recurrent laryngeal nerve. Venous drainage follows the same general course. The esophagus is a fibromuscular tube that connects the oral cavity and pharynx to the stomach. It is bounded superiorly by the upper esophageal sphincter and inferiorly by the lower esophageal sphincter before transitioning into the stomach. It is composed of linear and circumferential muscles that work in coordination to propel food down its length. Innervation is via the vagus nerve, as well as the cervical and thoracic sympathetic trunk. The upper portion of the esophagus receives arterial sup-

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ply via the inferior thyroid artery, the middle via the bronchial arteries, and the lower via the left gastric artery and the inferior phrenic artery. The esophagus pierces the diaphragm at T10; however, this relationship is altered in cases of hiatal hernias. The stomach is a sac-shaped organ with concentric and longitudinal musculature that contracts rhythmically to mix food bolus with gastric secretions and prepare food for continuation into the small intestine. The pyloric sphincter marks the exit of the stomach and, in cases of pyloric hypertrophy, may contribute to delayed emptying and reflux. The cellular composition of gastric mucosa varies along the length of the stomach and is grouped into three types of glands. The cardiac glands are found in the cardia, the region where the esophagus empties into the stomach, and contain primarily mucus-secreting foveolar cells. Acid-secreting oxyntic glands are the dominant gland type and are found in the fundus and body. They contain parietal cells, enterochromaffin-like (ECL) cells, chief cells, and mucous cells. The pyloric glands, located in the antrum, contain G cells, D cells, and mucus-secreting cells. These cells interact via various feedback mechanisms to regulate the environment in the gastric lumen. Gastric acid secretion occurs in three phases and is regulated by the autonomic nervous system and several hormones. The cephalic phase comprises 30% of total gastric acid production and is mediated by cholinergic pathways activated by stimulation of the senses, thought, and swallow. The gastric phase is responsible for 60% of acid production and is mediated in large part by gastrin released in response to mechanical distention of the stomach and the chemical effects of food. The intestinal phase accounts for only 10% of secretion and is stimulated by small intestine distention when chyme passes through the pyloric sphincter [26]. Parietal cells produce and secrete gastric acid, which is a mixture of hydrochloric acid, potassium chloride, and sodium chloride. Their cell membranes infold according to secretory demand to form channels, or canaliculi, that increase their secretory surface area. Production begins in the cytoplasm with catalyzation of carbon dioxide and water by carbonic anhydrase into carbonic acid, which immediately dissociates into hydrogen and bicarbonate ions. The bicarbonate ion diffuses into venous blood in exchange for a chloride ion, which is then transported via conductance channels into the canaliculi. Hydrogen potassium ATPase actively pumps hydrogen ions from the cytoplasm into the canaliculi in a one-to-one exchange with potassium ions. There, the hydrogen ions combine with chloride to form hydrochloric acid, which is then secreted from the oxyntic gland into the stomach lumen. Acid in the canaliculi can reach a minimum pH of 0.8. This is buffered to a luminal pH of 1.5–3.5 by secretion of mucus and bicarbonate ions from foveolar cells [27]. Multiple agents act on parietal cells to stimulate acid secretion: gastrin released from G cells in the antrum, histamine released from ECL cells, and acetylcholine released from postsynaptic parasympathetic nerve fibers. Gastrin acts via the cholecystokinin B receptor by inducing the insertion of K+/H+ ATPase pumps into the apical membranes of parietal cells. It also binds to these same receptors on ECL cells to stimulate the release of histamines. Histamines are the most significant ­positive regulator of gastric acid secretion. They bind to H2 receptors on parietal cells to induce the uptake of carbon dioxide and water from the blood. Parasympathetic

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nerve endings via the vagus and the enteric nervous system secrete acetylcholine and gastrin-releasing peptide to stimulate parietal cells directly via the M3 receptor and indirectly via gastrin and histamine release. Also housed in the oxyntic glands are gastric chief cells, which secrete pepsinogen and gastric lipase mainly in response to cholinergic activity [28]. Pepsinogen is converted to pepsin upon contact with gastric acid and begins lysing peptide bonds in food proteins that have been denatured by the acidic environment. This acidity also has disinfectant properties by inhibiting the growth of many microorganisms. Pepsin is maximally active at pH 2 and deactivates at pH 6.5, but it does not denature until pH 8. Reflux of pepsin into the esophagus and laryngopharynx has been shown to cause damage even above pH 4, and the combination of acid plus pepsin has been found to be more ulcerogenic than acid alone [26, 29]. Testing for pepsin levels in throat sputum has shown to positively correlate with high reflux symptom index and reflux findings scores [30]. Thus, the presence of buffering chemicals, acid inhibition pathways, and competent anatomic barriers is imperative to prevent injury and disease. The esophageal sphincters function as anatomic barriers. The upper esophageal sphincter sits in a state of tonic contraction at 30–50 mm Hg to prevent air from entering the esophagus during respiration and prevents backflow from the esophagus into the pharynx [31, 32]. The lower esophageal sphincter sits at a resting pressure of 10–45  mm Hg to prevent food and stomach acid from refluxing into the esophagus during gastric peristalsis. In the stomach, the foveolar cells produce alkaline mucus to protect the gastric mucosa from corrosion. The production of acid itself is inhibited by somatostatin, which is released from D cells located in the pyloric antrum in response to gastrin and vasoactive intestinal peptide. Once the acidic chyme passes the pyloric sphincter, the drop in duodenal pH below 4.5 stimulates the release of secretin from S cells in the duodenal mucosa. Secretin acts on the pancreas and Brunner’s glands of the duodenum to stimulate secretion of sodium bicarbonate to neutralize gastric acid. Secretin also reduces acid secretion by stimulating the release of somatostatin, inhibiting the release of gastrin, and downregulating the secretory mechanics of parietal cells. The presence of chyme also stimulates the release of cholecystokinin, which causes the pancreas to release trypsinogen and the gallbladder to release alkaline bile. Trypsinogen is activated by enteropeptidase, forming trypsin, which breaks the peptides produced from pepsin-induced proteolysis, down further into amino acids. Like pepsin, trypsin has been implicated in GERD and LPR as a result of studies showing increased production of inflammatory mediators resulting from trypsin exposure. Naito et al. induced chronic esophageal inflammation in rats by performing esophagogastroduodenal anastomosis and successfully treating the resulting esophageal erosions with a primary trypsin inhibitor [33]. Fitzgerald et al. showed human epithelial cells had increased chemokines and prostaglandins when exposed to trypsin in vitro [34]. Bile contains bactericidal salt anions that promote ingestion of fat, neutralize microorganisms, and increase chymal pH. While these acid-neutralizing products are protective in the upper gastrointestinal tract, their prolonged presence in the esophagus and laryngopharynx also causes clinically significant damage. This is

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evident in patients with GERD and LPR whose symptoms persist despite maximal gastric acid suppression. Sasaki et al. studied the effect of bile acids at acidic and basic pH on laryngeal mucosa in rats and found statistically greater inflammation scores than saline controls that were also equal to or greater than hydrochloric acid [35]. The mechanism of damage is thought to be disorganization of cellular membrane structure or interference with cellular metabolism after the bile salt becomes trapped inside mucosal cells [26]. The symptoms of LPR may be attributable to direct or indirect mechanisms, and the physiologic differences between the larynx and the esophagus may explain why many patients with LPR do not also have esophagitis. Laryngeal mucosa does not have the same alkaline mucus-secreting cells that protect the stomach and so is susceptible to damage upon direct contact with caustic gastric secretions. The esophagus is protected by salivary bicarbonate, which is swallowed throughout the day and functions to neutralize refluxate, while peristaltic motility prevents prolonged exposure. Some authors have hypothesized that LPR symptoms occur in patients with reflux who incur laryngeal injuries from viral infection or voice abuse that render the mucosa vulnerable to further injury by gastric secretions. Alternatively, reflux into the esophagus may trigger vagally mediated laryngeal reflexes, such as cough and bronchoconstriction. Independent patient factors such as resting tones of upper and lower esophageal sphincters, anatomic distortions such as hiatal hernia, magnitude of increases in intra-abdominal pressure, diet, and eating habits can affect the propensity for these reflux mechanisms. Additionally, several authors have proposed that patients with LPR have contributing laryngeal hypersensitivity [36–38]. Psychogenic factors may also play a physiologic role, as emotional stress has been shown to increase upper esophageal sphincter tone and may explain the anecdotal correlation between globus sensation and anxiety [39]. These pathways serve as targets for therapy as the current mainstays of treatment involve lifestyle and diet modifications, antireflux medications, and voice retraining therapy. Our understanding of upper aerodigestive pathology has evolved to acknowledge laryngopharyngeal reflux as a distinct entity. The close anatomic relationship of the upper digestive tract necessitates the elegantly complex design of the larynx, which functions to protect the lower airways during deglutition, while still allowing for respiration and phonation. Irritation of laryngeal tissues disrupts these functions, producing a range of voice, swallow, and airway symptoms. The indistinct nature of many of these symptoms can be frustrating for patients and providers alike. Knowledge of the underlying mechanisms of LPR and GERD provides insight to treatment options and facilitates a logical approach to these patients.

References 1. Katz PO, Gerson LB, Vela MF.  Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108:308–28. https://doi.org/10.1038/ ajg.2012.444; published online 19 February 2013.

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2. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis. 1990;141:640–7. 3. el-Serag HB, Sonnenberg A.  Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology. 1997;113(3):755–60, ISSN 0016-5085. 4. Olson NR. Laryngopharyngeal manifestations of gastroesophageal reflux disease. Otolaryngol Clin N Am. 1991;24(5):1201–13. PubMed PMID: 1754220. 5. Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA. 2005;294(12):1534– 40. https://doi.org/10.1001/jama.294.12.1534. 6. Klinkenberg-Knol EC. Otolaryngologic manifestations of gastro-oesophageal reflux disease. Scand J Gastroenterol Suppl. 1998;225:24–8. Review. PubMed PMID: 9515748. 7. Khan AM, Hashmi SR, Elahi F, Tariq M, Ingrams DR. Laryngopharyngeal reflux: a literature review. Surgeon. 2006;4(4):221–5. Review. PubMed PMID: 16892839. 8. Modlin IM, Moss SF, Kidd M, Lye KD. Gastroesophageal reflux disease: then and now. J Clin Gastroenterol. 2004;38(5):390–402. Review. PubMed PMID: 15100517. 9. Stephen J, Sontag MD. Gastroesophageal reflux and asthma. Am J Med. 1997;103(5, Suppl 1):84S–90S, ISSN 0002-9343. 10. Bray GW. The treatment of asthma. Postgrad Med J. 1935;11(120):339–45. 11. PubMed PMID: 21312974; PubMed Central PMCID: PMC2476505. 12. Winkelstein A. Peptic esophagitis. J Am Med Assoc. 1935;104(11):906–9. 13. Cherry J, Margulies SI. Contact ulcer of the larynx. Laryngoscope. 1968;78(11):1937–40. 14. Malcomson KG. Radiological findings in globus hystericus. Br J Radiol. 1966;39(464):583–6. 15. Lee BE, Kim GH. Globus pharyngeus: a review of its etiology, diagnosis and treatment. World J Gastroenterol: WJG. 2012;18(20):2462–71. https://doi.org/10.3748/wjg.v18.i20.2462. 16. Malcomson K. Globus hystericus vel pharyngis: a reconnaissance of proximal vagal modalities. J Laryngol Otol. 1968;82(3):219–30. https://doi.org/10.1017/S0022215100068687. 17. Delahunty JE, Cherry J.  Experimentally produced vocal cord granulomas. Laryngoscope. 1968;78(11):1941–7. PubMed PMID: 5722897. 18. Little FB, Koufman JA, Kohut RI, Marshall RB.  Effect of gastric acid on the pathogenesis of subglottic stenosis. Ann Otol Rhinol Laryngol. 1985;94(5 Pt 1):516–9. PubMed PMID: 4051410. 19. Adhami T, Goldblum JR, Richter JE, Vaezi MF. The role of gastric and duodenal agents in laryngeal injury: an experimental canine model. Am J Gastroenterol. 2004;99(11):2098–106. PubMed PMID: 15554987. 20. Johnson LF, Demeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol. 1974;62(4):325–32. PubMed PMID: 4432845. 21. Wiener GJ, Koufman JA, Wu WC, Cooper JB, Richter JE, Castell DO. Chronic hoarseness secondary to gastroesophageal reflux disease: documentation with 24-h ambulatory pH monitoring. Am J Gastroenterol. 1989;84(12):1503–8. PubMed PMID: 2596451. 22. DeMeester TR, Bonavina L, Iascone C, Courtney JV, Skinner DB. Chronic respiratory symptoms and occult gastroesophageal reflux. A prospective clinical study and results of surgical therapy. Ann Surg. 1990;211(3):337–45. PubMed PMID: 2310240; PubMed Central PMCID: PMC1358440. 23. Kamel PL, Hanson D, Kahrilas PJ. Omeprazole for the treatment of posterior laryngitis. Am J Med. 1994;96(4):321–6, ISSN 0002-9343. https://doi.org/10.1016/0002-9343(94)90061-2. 24. Little JP, Matthews BL, Glock MS, Koufman JA, Reboussin DM, Loughlin CJ, McGuirt WF Jr. Extraesophageal pediatric reflux: 24-hour double-probe pH monitoring of 222 children. Ann Otol Rhinol Laryngol Suppl. 1997;169:1–16. PubMed PMID: 9228867. 25. Hawkins BL. Laryngopharyngeal reflux: a modern day “great masquerader”. J Ky Med Assoc. 1997;95(9):379–85. Review. PubMed PMID: 9322411

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26. Koufman J, Sataloff RT, Toohill R. Laryngopharyngeal reflux: consensus conference report. J Voice. 1996;10(3):215–6. PubMed PMID: 8865091. 27. Johnson J. Bailey’s head and neck surgery: otolaryngology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. 28. Marieb EN, Hoehn K. Human anatomy & physiology. San Francisco: Benjamin Cummings; 2010. ISBN 0-8053-9591-1. 29. Czinn SJ, Blanchard SS. 25  – developmental anatomy and physiology of the stomach. In: Wyllie R, Hyams JS, editors. Pediatric gastrointestinal and liver disease (fourth edition). Saint Louis: W.B.  Saunders; 2011. p.  262–268.e1. https://doi.org/10.1016/B978-1-4377-07748.10025-9. ISBN 9781437707748. 30. Samloff IM. Peptic ulcer: the many proteinases of aggression. Gastroenterology. 1989;96(2 Pt 2 Suppl):586–95. Review. PubMed PMID: 2642445. 31. Lu W, Liu X, Liu Y-l, Zeng F-f, Wu T, Yang C-l, Shen H-y, Li X-p. Correlation of pepsin-­ measured laryngopharyngeal reflux disease with symptoms and signs. Otolaryngol Head Neck Surg. 2010;143(6):765–71, ISSN 0194-5998. 32. Park D, Lee HH, Lee ST, Oh Y, Lee JC, Nam KW, Ryu JS. Normal contractile algorithm of swallowing related muscles revealed by needle EMG and its comparison to videofluoroscopic swallowing study and high resolution manometry studies: a preliminary study. J Electromyogr Kinesiol. 2017;36:81–9. https://doi.org/10.1016/j.jelekin.2017.07.007. [Epub ahead of print] PubMed PMID: 28763682. 33. Kahrilas PJ, Dodds WJ, Dent J, Haeberle B, Hogan WJ, Arndorfer RC. Effect of sleep, spontaneous gastroesophageal reflux, and a meal on upper esophageal sphincter pressure in normal human volunteers. Gastroenterology. 1987;92(2):466–71, ISSN 0016-5085. 34. Naito Y, Uchiyama K, Kuroda M, Takagi T, Kokura S, Yoshida N, Ichikawa H, Yoshikawa T. Role of pancreatic trypsin in chronic esophagitis induced bygastroduodenal reflux in rats. J Gastroenterol. 2006;41(3):198–208. PubMedPMID: 16699853. 35. Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliott M, Saeed IT, Burnham WR, Farthing MJ.  Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants. Gut. 2002;50(4):451–9. PubMed PMID: 11889061; PubMed Central PMCID: PMC1773186. 36. Sasaki CT, Marotta J, Hundal J, Chow J, Eisen RN. Bile-induced laryngitis: is there a basis in evidence? Ann Otol Rhinol Laryngol. 2005;114(3):192–7. PubMed PMID: 15825567. 37. Cobeta I, Pacheco A, Mora E. The role of the larynx in chronic cough. Acta Otorrinolaringol Esp. 2013;64:363. 38. Bucca CB, Bugiani M, Culla B, et  al. Chronic cough and irritable larynx. J Allergy Clin Immunol. 2011;127:412. 39. Cook IJ, Dent J, Shannon S, Collins SM. Measurement of upper esophageal sphincter pressure. Effect of acute emotional stress. Gastroenterology. 1987;93(3):526–32. PubMed PMID: 3609662.

Chapter 2

The Approach to a Patient with Suspected Laryngopharyngeal Reflux Disease (LPRD) Lawrence Borges and Thomas L. Carroll

Typical Symptoms and Clinical Presentation Laryngopharyngeal reflux disease (LPR) occurs due to retrograde passage of stomach contents above the level of the upper esophageal sphincter (UES). Stomach refluxate passing above the UES can come into contact with all regions of the upper airway – including the larynx, hypopharynx, oropharynx, and nasopharynx – and cause a variety of symptomatic manifestations. Symptoms of LPR generally fall into one of three categories: irritative throat symptoms, voice changes, and disordered swallowing (see Table 2.1).

Irritative Symptoms Irritative throat symptoms from LPR can take several forms, ranging from a nagging, itchy discomfort, throat clearing, and chronic cough to more chronic and severe pain, similar to that felt during a viral upper respiratory infection. Some patients will experience this discomfort intermittently, presumably following discrete laryngopharyngeal reflux events. However, many patients report a more persistent irritative symptom or constellation of symptoms in the throat. LPR can cause mucus buildup in the back of the throat, which is one reason LPR can cause a L. Borges Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA T. L. Carroll (*) Division of Otolaryngology, Brigham and Women’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 N. Jamal, M. B. Wang (eds.), Laryngopharyngeal Reflux Disease, https://doi.org/10.1007/978-3-030-12318-5_2

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14 Table 2.1 Common symptoms caused by laryngopharyngeal reflux disease (LPR)

L. Borges and T. L. Carroll Irritative throat symptoms  Dry, raw, or scratchy feeling in the throat  Throat clearing  Mucus sensation  Chronic cough  Globus sensation  Throat pain  Laryngeal-disordered breathing Voice-related changes  Hoarseness  Strained or weak voice  Vocal fatigue Disordered swallowing  Dysphagia, typically felt in the upper chest and neck  Odynophagia

frequent sensation of having to clear the throat; however, LPR often produces a sensation of mucus in the pharynx with no true or excessive mucus present. In some cases, a globus (or foreign body) sensation may be the only presenting symptom of LPR, and thus reflux is important to consider when working up patients with isolated globus.

Voice Changes Hoarseness, or more global dysphonia (vocal strain, effort, fatigue, etc.), is a common presenting symptom of LPR. In severe cases, the resulting voice change can be so significant as to disrupt a patient’s personal and professional life, particularly for those patients who have public speaking or performance responsibilities. Dysphonia is often seen in combination with throat discomfort as described above and is caused by reflux-induced irritation and edema of the vocal folds. Laryngeal-disordered breathing such as paradoxical vocal fold motion disorder (PVFM, also known as vocal cord dysfunction or VCD) can also result from LPR and cause patients to present with shortness of breath and stridor. This manifestation of LPR is often initially mistaken for asthma or another primary lung disease and, as such, can lead to delays in diagnosis and be the cause of great anxiety for patients. PVFM has been theorized to occur due to decreased laryngeal sensation (rather than the often assumed increased), leading to changes in the central feedback to the brain that alerts the respiratory and swallowing centers that the airway is not protected [1]. Thus, in an already chronically inflamed larynx, other mechanochemical stimuli such as cold air, strong chemical odors, and smoke (and not a specific reflux event) may trigger the patient’s cough or PVFM event [2].

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Disordered Swallowing Dysphagia, or difficulty swallowing, often presents as a sensation of food sticking in the neck or chest during deglutition. LPR can present with dysphagia, most commonly felt in the upper chest and neck. This is usually presumed to be due to posterior laryngeal edema caused by reflux-induced tissue irritation [3]. Pain with swallowing, or odynophagia, may also be a presenting symptom of LPR.  This may be due to hyperfunctional compensation for voice disorders, leading to strap muscle pain felt during laryngeal elevation or presence of a vocal process granuloma [4, 5]. Dysphagia in LPR patients may also be related to primary esophageal dysmotility. Weaker proximal esophageal motility has been shown to be more common in patients with LPR than those without [6]. Ineffective esophageal motility, a condition defined as 50% or more ineffective or weak swallows, has also been shown to be prevalent in patients with symptoms related to extra-esophageal reflux, such as chronic cough and laryngitis [7, 8]. It is speculated that abnormal esophageal motility may contribute to LPR both by allowing easier passage of refluxed contents above the UES, as well as impairing normal esophageal clearance, and allowing refluxed contents to linger in the esophageal column. It may also be the case that esophageal reflux leads to dysmotility or vice versa [9].

Relationship to Esophageal Reflux Symptoms By default, patients with LPR must also have esophageal reflux, as all refluxed material that passes above the UES must first traverse the length of the esophageal column. Patients with LPR may therefore also report symptoms of esophageal reflux. Heartburn is the classic symptom of esophageal reflux, which is typically described as a sensation of acid rising and burning in the chest. Esophageal reflux symptoms can also include vague central chest discomfort, regurgitation of stomach contents, and esophageal dysphagia or odynophagia. In patients with these symptoms, it is often easier to make the diagnosis of LPR because esophageal reflux is already suspected. Importantly, however, the absence of esophageal reflux symptoms does not rule out LPR as the cause of throat or voice symptoms. It has been reported that as few as 40% of patients suspected of having LPR will present with concomitant esophageal symptoms [10]. This may be explained by growing evidence that pepsin, not acid, is the primary offending agent in LPR.  Pepsinogen is a proenzyme that is created by chief cells in the stomach. When pepsinogen is acidified in the stomach  – typically by hydrochloric acid secreted by gastric parietal cells – the enzyme pepsin is created, which works to digest proteins into smaller peptides. Pepsin is most active at a pH of 1.5–2 but can remain active up to a pH of 6 and intact up to a pH of 8 [11]. Pepsin has been found in higher

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quantities in the laryngeal mucosa of LPR patients when compared with healthy controls, and the presence of pepsin has been associated with a deficiency of carbonic anhydrase, which may predispose these patients to irritation and injury of the laryngeal mucosa [12]. Given the inconsistent relationship between esophageal reflux symptoms and LPR, and the growing evidence that pepsin is to blame, it is important to approach the diagnosis and management of LPR differently than one would approach traditional reflux. LPR should be on the differential when evaluating patients with isolated throat and upper airway symptoms, but it is often necessary to first rule out various other causes that can cause similar symptoms or rule in LPR with hypopharyngeal-­esophageal impedance testing. Other etiologies of LPR-like symptoms include allergy, infection, smoking, medication side effect, and primary vocal fold pathology (that may only be identified on videostroboscopy – see Chap. 7 for more information). These alternative causes of LPR-like symptoms are discussed below.

 lternative and Contributing Causes in the Evaluation of LPR A Symptoms (Covered in More Detail in Chap. 3 as Well) Allergic disease is the most common cause of overlapping symptoms in LPR patients. This includes perennial or seasonal rhinitis, chronic rhinosinusitis, and allergic laryngitis. It is important to try to distinguish between an allergic cause of symptoms and reflux when first evaluating a patient with suspected LPR. This can be done by asking the patient whether they also suffer from itchy/watery eyes, sneezing, or a runny nose and whether they have identified any triggers that precipitate their symptoms  – for instance, pet dander or pollen. It has been shown that asking patients questions related specifically to their allergic history can help clarify whether allergic disease or LPR is to blame [13]. Postnasal drip is frequently attributed to allergic/sinus disease, and while this may be true in many cases, it is not solely a rhinologic symptom. LPR should be considered strongly when postnasal drip is reported in the absence of other allergic symptoms and with an accompanying normal endoscopic nasal exam. Asthmatic patients also frequently report symptoms consistent with LPR. One study of asthmatic patients reported an almost fourfold increase in significant LPR-­ like symptoms when compared to healthy controls [14]. While some of these patients may indeed have concomitant reflux, the frequency of similar symptoms puts these patients at risk of overdiagnosis and overtreatment for reflux. It must also be realized that the opposite phenomenon occurs in patients diagnosed with asthma: some asthma patients have underlying LPR as the cause of their breathing complaints and pulmonary disease and are treated for years to alleviate the symptoms of their “asthma,” but the true underlying cause, LPR, is not considered as contribut-

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ing. Proper testing for both LPR and asthma to rule in or rule out these pathologies may warrant attention, especially in cough and dyspnea patients who do not respond as expected to albuterol or who complain more of inspiratory rather than expiratory dyspnea [15]. Smoking is an important consideration when evaluating a patient for possible LPR. Regular inhalation of tobacco smoke irritates the upper airway structures through both thermal injury and inflammation from inhaled particulate matter. This can cause chronic sore throat, cough, and hoarseness and therefore mimic symptoms of LPR. Moreover, smoking has long been thought to worsen gastroesophageal reflux and has been associated with higher rates of Barrett’s esophagus and esophageal cancer [16–18]. By exacerbating pre-existing esophageal reflux, smoking can increase the chance that a patient will also experience LPR. Medication side effects should also be on the differential in patients with throat and voice symptoms. Angiotensin-converting enzyme (ACE) inhibitors are perhaps the most common medication in this regard, as up to 35% of patients on an ACE inhibitor may develop a chronic, nonproductive cough that can mimic LPR [19]. In addition, ACE inhibitors can cause angioedema of the structures of the mouth and upper airway, including the larynx, in almost a third of cases [20]. Anticholinergic medications have also been associated with a higher risk of developing globus sensation, possibly due to reduced salivation [21]. Narcotics can lead to decreased esophageal motility and gut motility with resultant stasis and LPR [22, 23]. PVFM is often seen in the presence of LPR. More advanced hypopharyngeal-­ esophageal impedance technology may offer insight into cases of non-acid reflux that would not have previously been implicated in the etiology of a patient’s symptoms. PVFM can cause symptoms ranging from a hoarse or weak voice to difficulty breathing and can be a source of great anxiety for patients who may suffer unexpected bouts of breathlessness. PVFM is often initially misdiagnosed as asthma, which can lead to substantial unnecessary healthcare costs [24]. Throat tightness, dysphonia, strong odors as a trigger, and the absence of wheezing have all been identified as features specific to PVFM [25]. There is a significant overlap in symptoms between patients with LPR and glottic insufficiency due to vocal fold atrophy. Common symptoms include throat clearing, mucus sensation, dysphonia, and globus. For those patients who do not have LPR, vocal fold augmentation can alleviate some or all of the symptoms [26]. In summary, there is significant symptomatic overlap between LPR and various other pathologies that afflict the upper airway. This can make it difficult to accurately diagnose LPR and underscores the importance of avoiding a “shotgun” approach to treatment before a thorough evaluation is completed. The next section discusses currently available diagnostic strategies and the benefits and limitations of each (these are summarized in Table 2.2).

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Table 2.2  The most common primary diagnostic modalities available in the evaluation of suspected LPR and where they are offered Diagnostic modality Empiric PPI trial

Appropriate setting Primary care clinic; rural care setting; specialty clinic (ENT)

Reflux symptom index (RSI) questionnaire

Primary care clinic; specialty clinic; rural care setting; specialty clinic (ENT) Specialty clinic (ENT)

Flexible laryngoscopy, the Reflux Finding Score (RFS) Esophago-gastro-­ duodenoscopy (EGD)

Procedure suite (GI)

Trans-nasal esophagoscopy (TNE)

Specialty clinic (ENT or GI)

pH-metry (single/dual pH Probes or pharyngeal pH)

Specialty clinic (ENT or GI)

Specialty clinic (ENT Multi-channel intraluminal impedance or GI) and pH (MII-pH) testing

Issues to consider PRO: Noninvasive; inexpensive for patient; may be therapeutic CON: Medication side-effects; requires 6–8 weeks for effect; cost to healthcare system PRO: Fast and easy to administer; inexpensive CON: Nonspecific; may be influenced by non-LPR pathology PRO: Office-based; no sedation required CON: Nonspecific; may be influenced by non-LPR pathology; questionable inter-rater reliability PRO: Allows for evaluation of reflux esophagitis/Barrett’s CON: Limited visualization of the hypopharynx/upper esophagus; requires sedation; if normal does not rule out LPR; cost PRO: No sedation risks CON: Limited visualization of the hypopharynx/upper esophagus; Does not typically evaluate beyond LES; If normal does not rule out LPR; cost PRO: Direct measurement of acid in the esophagus or pharynx; ease of placement of pharyngeal pH-metry CON: Misses non-acid refluxate; limited normative data for pharyngeal acid exposure; pharyngeal pH-metry does not detect true reflux but rather pharyngeal pH change; cost PRO: Current gold standard; measures acid and non-acid reflux; growing evidence for use CON: Limited normative data for pharyngeal reflux exposure; not widely available; Not yet universal adoption of full column with hypopharyngeal impedance; cost

Diagnostic Evaluation Empiric Treatment with Acid Suppression Prescribing an empiric trial of acid suppression by proton pump inhibitor (PPI) is a common approach in the initial management of suspected LPR [27]. In fact, the popularity of this approach is reported to have grown among subspecialty clinicians

2  The Approach to a Patient with Suspected Laryngopharyngeal Reflux Disease (LPRD) Table 2.3 Potential side-effects of proton pump inhibitor (PPI) therapy

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Infection, including occurrence of C. diff colitis Vitamin deficiencies (calcium, magnesium, B12) Chronic kidney disease Dementia Osteoporosis Cardiovascular disease

between 2002 and 2012, despite widespread recognition of the value of objective reflux testing [28]. One possible explanation for this trend is that clinicians perceive objective testing as more costly and time-consuming, while PPIs are felt to be inexpensive and innocuous. However, the evidence to support this approach has been mixed. A 2006 meta-analysis of five studies in adult patients found a benefit of prescribing PPI therapy for patients with chronic cough and demonstrated evidence of gastroesophageal reflux [29]. A different meta-analysis looking at patients with chronic laryngitis suspected to be from reflux found that while a modest benefit of PPI therapy may exist, it did not reach clinical significance [30]. Interestingly, the largest prospective trial examined by the authors, which looked specifically at patients suspected of having reflux laryngitis but without accompanying frequent heartburn, found that high-dose PPIs were no better than placebo in providing relief of symptoms [31]. More recent data drawn from a population of patients referred for specialty otolaryngologic evaluation have shown that, while empiric PPI therapy may be effective in up to 74% of patients with suspected LPR, the downstream costs of empiric medical therapy may actually be greater than the cost of up-front testing with multichannel impedance-pH catheter and high-resolution manometry technology [32]. PPIs are also increasingly under scrutiny for their association with a variety of adverse effects (see Table 2.3). Recent evidence has linked PPI use to C. difficile colitis [33, 34], renal disease [35], and dementia [36], among others. While these types of associations are typically only thought to be an issue with long-term PPI use, the negative media attention garnered by such studies can influence patients’ willingness to take PPIs without a clear indication. Given both the lack of consistent benefit and the potential for adverse effects, alternatives to the empiric trial approach are needed.

Reflux Symptom Index (RSI) The reflux symptom index (RSI) is a nine-item questionnaire that has previously been evaluated by Belafsky et al. for assessing symptoms in patients with confirmed laryngopharyngeal reflux (LPR) on esophageal pH probe testing [37] (see Fig. 2.1). The authors compared RSI scores recorded by patients with confirmed LPR to a control group of asymptomatic patients. RSI scores were also tracked over time in patients with confirmed LPR who received treatment with acid suppression. The

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Within the last MONTH, how did the following problems affect you? 0 = No problem

5 = Severe Problem

Hoarseness or a problem with your voice

0

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Clearing your throat

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Excess throat mucous

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Difficulty swallowing food, liquids or pills

0

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Coughing after eating or after lying down

0

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Breathing difficulties or choking episodes

0

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Troublesome or annoying cough

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Sensations of something sticking in your throat or a lump in your throat

0

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Heartburn, chest pain, indigestion, or stomach acid coming up

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Fig. 2.1  RSI- Instructions: These are statements that many people have used to describe their voices and the effects of their voices on their lives. Circle the response that indicates how frequently you have the same experience. (Belafsky et al. [37])

authors conclude that the RSI is a reliable and valid tool for documenting symptom improvement in patients undergoing treatment for LPR. They also report excellent construct validity based on a significant association observed between the RSI and the voice handicap index (VHI), a separate 30-item questionnaire designed to measure voice-specific symptoms [38]. Given its ease of administration, the RSI is now often relied upon in busy clinical settings to help make the diagnosis of LPR. However, as previously mentioned, not all patients with suspected LPR actually have reflux to explain their symptoms. In addition, the relationship between the RSI instrument and other disorders that may mimic or contribute to LPR symptomatology – for example, abnormal esophageal motility, allergies, or asthma – has also not been explored. At least one study has demonstrated that the optimal RSI cutoff may be different in patients with concomitant allergic disease. A score of 19 or higher appears to best predict the presence of LPR in this group [39].

Flexible Laryngoscopy and the Reflux Finding Score (RFS) The reflux finding score (RFS) is an eight-item rating scale that was derived by Belafsky et al. in 2001 to facilitate a standardized approach to assess findings on laryngoscopy in patients with suspected LPR [40]. The scale is primarily used by

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otolaryngologists, as it requires a rating of several different abnormal laryngeal findings as noted on in-office fiber-optic laryngoscopy, including subglottic edema, ventricular obliteration, erythema/hyperemia, vocal fold edema, diffuse laryngeal edema, and posterior commissure hypertrophy. When the RFS was first created, Belafsky and colleagues concluded that the RFS is a reliable instrument for diagnosing and following LPR, and they reported a 90% inter-rater agreement. However, this high rate of inter-rater reliability was based on comparisons of RFS scores assigned by a limited number of otolaryngologists at a single institution, raising questions about generalizability. In addition, other studies published around the same time demonstrated that the same laryngeal findings attributed to reflux may also be seen in healthy volunteers [41, 42]. More recent data has shown that the RFS may not be as reliable as once thought. In 2015, a study of ten general otolaryngologists who used the RFS to assess the same endoscopic images demonstrated only poor to fair inter-rater reliability. The authors also found that the clinicians were more likely to rate a larynx as having more findings if the patient was described as having more symptoms of reflux [43]. In addition, the RFS was first validated using dual probe (esophageal and pharyngeal) pH measurement, which was considered the gold standard for LPR diagnosis at that time [40]. More recently, the use of combined pH and impedance measurement has superseded pH measurement alone as the gold standard. While there is some evidence comparing RFS findings to combined impedance-pH testing, the data are mixed. In one study of almost 100 patients with impedance-pH-­ confirmed LPR, subglottic edema was found to be specific for non-acid reflux episodes, while the presence of granuloma or granulation tissue was specific for acid reflux episodes. Posterior commissure hypertrophy and ventricular obliteration were correlated with reflux exposure time, but not number of reflux events [44]. The RFS also performed poorly in a study of pediatric patients, with a positive predictive value of only 40% when compared to impedance parameters [45].

 rans-nasal Endoscopy (TNE) T and Esophagogastroduodenoscopy (EGD) Trans-nasal endoscopy (TNE) is a method of upper aerodigestive tract evaluation in which a thin, flexible endoscope, typically less than 6 mm in diameter, is introduced through the nose and into the esophagus (Fig. 2.2). It is a safe procedure that can be performed relatively quickly in an office setting, most often by otolaryngologists. It does not require sedation, and patients who undergo TNE with local anesthesia alone report only mild discomfort [46]. TNE is thought to have some value in the work-up of esophageal reflux symptoms, particularly for male and obese patients, but there is no clear evidence to support the use of TNE in the work-up of LPR symptoms; rather it will likely prove more useful if actual rather than suspected LPR patients are offered TNE [47]. TNE, however, is a reliable tool compared to EGD for esophageal screening in appropriate patients [48].

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b

a

c

Fig. 2.2  Transnasal esophagoscope, full view (a) and proximal view (b and c)

a

b

c

Fig. 2.3  Esophago-gastro-duodenoscope, proximal view (a and b) and distal view (c)

Esophagogastroduodenoscopy, or EGD, is usually performed by a gastroenterologist and employs a larger-caliber fiber-optic scope, typically 10 mm in diameter, to evaluate the esophagus, stomach, and proximal portion of the duodenum (Fig.  2.3). EGD is commonly performed in the evaluation of esophageal reflux symptoms in order to assess for reflux-induced injury in the esophageal column.

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Fig. 2.4  Comparison of proximal portion of transnasal esophagoscope and esophago-gastroduodenoscope

Evidence of reflux in the esophagus can include acute manifestations such as esophagitis and ulceration, as well as longer-term sequelae such as stricture formation and Barrett’s esophagus, a premalignant transformation of the mucosa that indicates a higher risk of progression to esophageal adenocarcinoma. While the role of EGD in esophageal reflux is well established, the utility of EGD for evaluation of LPR in patients without any accompanying typical esophageal reflux symptoms or other indication for endoscopy is questionable [49]. Nevertheless, given the widespread availability and low risk profile of endoscopy, many patients presenting with LPR symptoms will undergo either TNE or EGD at some point in their evaluation (Fig. 2.4). It is important to remember that a negative endoscopic exam does not rule out reflux as the cause of LPR symptoms, and other diagnostic modalities should also be pursued.

Manometry High-resolution esophageal manometry (HRM) is a catheter-based test that evaluates the coordination and strength of esophageal contractions during a swallow. It is often performed just prior to the placement of impedance-pH catheters for reflux testing and can assist in proper impedance-pH catheter placement by identifying the level of the lower and upper esophageal sphincters. HRM also helps in the evaluation of esophageal reflux by identifying the presence of hiatal hernia and revealing concomitant esophageal dysmotility that may contribute to reflux. The true utility of HRM in the work-up of suspected LPR is not well established; however, there are some data to suggest an association between HRM findings and LPR. Patients with confirmed LPR have been found to have a lower resting pressure of the UES, weaker muscular

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contractions in the proximal esophagus, and more frequent breaks in peristalsis [6]. Patients with extra-esophageal reflux symptoms – such as chronic cough and laryngitis – have also been shown to have a high prevalence of weak and ineffective swallows on HRM [7, 8]. Reduced esophageal clearance may predispose to LPR by allowing refluxed stomach contents to linger in the chest, just below the level of the UES.

Measuring Acid in the Esophagus and Pharynx Acid reflux has historically been assessed by measuring the frequency of a pH drop below 4 in the distal esophagus. This metric formed the basis for the widely adopted DeMeester score for grading esophageal reflux severity and response to anti-reflux surgery. However, a positive distal esophageal acid exposure alone does not reliably predict the treatment response of LPR symptoms [50]. There is growing recognition that measuring acid in the distal esophagus is not sufficient in the work-up of patients with suspected LPR. Dual-sensor pH probes offer the ability to simultaneously measure acid exposure in both the distal and proximal esophagus. Although it is postulated that identifying frequent reflux events or increased acid exposure time in the proximal esophagus may help to identify those patients who would benefit from acid suppression therapy, studies to date have not supported this hypothesis [51, 52]. Direct pharyngeal pH measurement is an area of ongoing study, and how exactly to interpret the findings is not yet known. Several technical limitations arise when trying to measure pH in the pharynx, including drying out of the probe and interference by food and mucus with the measurement. Traditional esophageal criteria for acid reflux also do not apply. A study of pharyngeal acid exposure in healthy volunteers using the Restech® probe calculated the optimal discriminatory cutoff to be at a pH of 5.5 in the upright position and 5.0 in the supine position, versus a pH of 4 that is considered the cutoff in the esophagus [53]. Despite recognition of these different normative criteria in subsequent studies, the Restech® probe was not able to reliably differentiate between healthy volunteers and subjects with a combination of laryngeal and reflux symptoms, nor could it predict response to PPI therapy [54, 55]. In addition, as with esophageal pH measurement alone, pharyngeal pH measurement specifically misses non-acid reflux, which is discussed further in the next section.

 ultichannel Intraluminal Impedance and pH (MII-pH) M Testing and Hypopharyngeal-Esophageal Impedance with Dual pH Testing (HEMII-PH) The latest trend in diagnostic technology for reflux has been the combination of impedance sensors with pH probes. Impedance sensors measure the resistance to an electrical flow across an area. Resistance rises when the sensor is

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surrounded by air and drops when the sensor is bathed in liquid. This allows for detection of both gaseous and liquid reflux episodes, regardless of the level of acidity. By combining impedance technology with pH measurement, these tests can now provide a detailed look at both the number and extent of acidic and non-acidic reflux episodes throughout the esophageal column and up to the level of the pharynx. Multichannel intraluminal impedance and pH (MII-pH) catheters allow for acid and non-acid reflux detection up to the proximal esophagus (15  cm above LES). There is evidence that MII-pH technology can be used to improve diagnosis in patients with suspected LPR. For example, weakly acidic and non-acidic reflux episodes detected on MII-pH have been shown to correlate with symptoms in patients with chronic cough [56]. A study of 100 subjects with unexplained chronic cough also concluded that the use of MII-pH testing showed a positive association between cough symptoms and weakly acidic reflux in a significant subgroup of patients [57]. This finding is consistent with the belief that non-acid reflux may be more important than previously thought, given the stability of pepsin at higher pH.  Such an association would not have been detected if those patients had received pH testing only. However, not all studies of MII-pH testing in LPR patients have been as encouraging. In 2017, Kim et al. found that established parameters of esophageal reflux did not reliably correlate with symptoms or QOL in a cohort of patients with confirmed LPR [58]. This may be because the threshold for pathologic reflux in the pharynx is lower than that which is tolerated in the esophagus. Normative studies using healthy controls have shown that as few as two reflux events (either acid or non-acid) reaching the pharynx in a 24-hour period may be considered abnormal [59, 60]. In contrast, it may be normal for as many as 31 reflux events (acid or non-acid) to reach the proximal esophagus in the same amount of time [61]. Based on unpublished data from our institution, established esophageal impedance reflux criteria do not appear to reliably predict the presence of pharyngeal events. As such, using esophageal MII-pH criteria to define abnormal reflux in LPR-suspect patients may miss a significant proportion of patients who suffer pathologic pharyngeal reflux, despite physiologic levels of reflux in the esophagus. Given the limitations with MII-pH discussed above, the current gold standard for evaluating LPR symptoms is considered by many to be hypopharyngealesophageal multichannel intraluminal impedance testing with dual pH (HEMII-pH). This technology allows for measurement of both acid and non-acid reflux throughout the esophageal column and into the pharynx (Fig.  2.5). The addition of pharyngeal reflux detection has shown promise in the work-up of extra-esophageal manifestations of reflux. For example, evidence suggests that pharyngeal impedance monitoring can be helpful in the diagnostic work-up of patients with both adult-onset asthma and idiopathic pulmonary fibrosis, two lung diseases in which extra-esophageal reflux is postulated to play a role [62, 63]. There is also evidence to suggest that pharyngeal impedance measurement may help identify those patients with chronic cough who would benefit from antireflux surgery [64]. However, the combination of pharyngeal and esophageal pH-

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Pharyngeal

Proximal Esophageal

Distal Esophageal

Fig. 2.5  Hypopharyngeal-esophageal multichannel intraluminal impedance (HEMII-pH) tracing demonstrating non-acid laryngopharyngeal reflux event. Note retrograde flow on impedance channels and pH remaining above 4 in both proximal and distal pH sensors (top and bottom lines of figure). (Courtesy of Walter Chan, MD)

impedance testing is far from a panacea. Another study concluded that combined esophageal and pharyngeal pH-impedance testing may have only limited utility in patients with LPR symptoms refractory to PPI therapy, as many of these patients do not exhibit abnormal pharyngeal or esophageal pH-impedance reflux at all [65]. At this time, HEMII-pH testing provides the most in-depth assessment of a patient’s reflux burden as compared to other testing modalities. Our understanding of how to interpret this information in the context of LPR symptoms is incomplete but growing.

Salivary Pepsin As mentioned previously in this chapter, the presence of pepsin in the pharynx is thought by many to be a catalyst for LPR symptoms. Rapid detection assays for pepsin in saliva are now available, but the data to support routine use are limited. There is evidence that a positive test for pepsin in the saliva is 78% sensitive and 65% specific for the diagnosis of esophageal reflux-related symptoms, and the specificity increases further when higher pepsin levels are found [66]. However, in a small study of 35 subjects, salivary pepsin measurement was not able to differentiate between healthy controls and subjects with a combination of laryngeal and reflux symptoms [54]. A 2017 systematic review examining the available literature on salivary pepsin concluded that many questions remain about the optimal timing, location, and threshold values for pepsin testing in the work-up of LPR [67]. While salivary pepsin measurement is not recommended as a stand-alone diagnostic test for LPR at this time, it may have value as an adjunct test in certain patient populations.

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Conclusion In summary, LPR is a common phenomenon that can lead to a wide variety of symptoms, including irritative throat symptoms, voice changes, and disordered swallowing. The variable presentations of LPR can make diagnosis challenging. It is important for clinicians to consider LPR in patients with consistent symptoms, even when conditions such as allergies and pulmonary disease may lead to symptomatic overlap. Empiric trial of acid suppression has historically been the most popular approach to diagnosing LPR.  However, concerns about PPI safety, emphasis on cost-effective care, and evidence that points to pepsin (not acid) as the primary cofactor in LPR have all strengthened the argument for performing reflux testing up-front in LPR-suspect patients. Multiple modalities for reflux testing in LPR exist, including pH-metry, impedance measurement, and combined hypopharyngeal-­ esophageal multichannel intraluminal impedance testing with dual pH (HEMII-pH), which is the current gold standard. Salivary pepsin measurement is also being studied and may serve as a useful adjunct. Future research will help to elucidate the understanding of LPR pathophysiology and better inform the diagnostic approach.

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28. Gooi Z, Ishman SL, Bock JM, Blumin JH, Akst LM. Changing patterns in reflux care: 10-year comparison of ABEA members. Ann Otol Rhinol Laryngol. 2015;124(12):940–6. https://doi. org/10.1177/0003489415592407. 29. Chang AB, Lasserson TJ, Kiljander TO, Connor FL, Gaffney JT, Garske LA. Systematic review and meta-analysis of randomised controlled trials of gastro-oesophageal reflux interventions for chronic cough associated with gastro-oesophageal reflux. BMJ. 2006;332(7532):11–7. https://doi.org/10.1136/bmj.38677.559005.55. 30. Qadeer MA, Phillips CO, Lopez AR, et al. Proton pump inhibitor therapy for suspected GERD-­ related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol. 2006;101(11):2646–54. https://doi.org/10.1111/j.1572-0241.2006.00844.x. 31. Vaezi MF, Richter JE, Stasney CR, et al. Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope. 2006;116(2):254–60. https://doi.org/10.1097/01.mlg.0000192173.00498. ba. 32. Carroll TL, Werner A, Nahikian K, Dezube A, Roth DF. Rethinking the laryngopharyngeal reflux treatment algorithm: evaluating an alternate empiric dosing regimen and considering up-­front, pH-impedance, and manometry testing to minimize cost in treating suspect laryngopharyngeal reflux disease. Laryngoscope. 2017;127:S1–13. https://doi.org/10.1002/lary. 26806. 33. Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 2012;107(7):1011–9. https://doi.org/10.1038/ajg.2012.108. 34. McDonald EG, Milligan J, Frenette C, Lee TC.  Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection. JAMA Intern Med. 2015;175(5):784–91. https://doi.org/10.1001/jamainternmed.2015.42. 35. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study. BMC Nephrol. 2013;14:150. https://doi.org/10.1186/1471-2369-14-150. 36. Gomm W, von Holt K, Thomé F, et  al. Association of proton pump inhibitors with risk of dementia. JAMA Neurol. 2016; https://doi.org/10.1001/jamaneurol.2015.4791. 37. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice. 2002;16(2):274–7. http://www.ncbi.nlm.nih.gov/pubmed/12150380. Accessed 21 July 2016 38. Rosen CA, Lee AS, Osborne J, Zullo T, Murry T.  Development and validation of the voice handicap index-10. Laryngoscope. 2004;114(9):1549–56. https://doi. org/10.1097/00005537-200409000-00009. 39. Brauer DL, Tse KY, Lin JC, Schatz MX, Simon RA. The utility of the reflux symptom index for diagnosis of laryngopharyngeal reflux in an allergy patient population. J Allergy Clin Immunol Pract. 2017; https://doi.org/10.1016/j.jaip.2017.04.039. 40. Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope. 2001;111(8):1313–7. https://doi.org/10.1097/00005537-200108000-00001. 41. Hicks DM, Ours TM, Abelson TI, Vaezi MF, Richter JE. The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice. 2002;16(4):564– 79. http://www.ncbi.nlm.nih.gov/pubmed/12512644. Accessed 21 July 2016. 42. Milstein CF, Charbel S, Hicks DM, Abelson TI, Richter JE, Vaezi MF. Prevalence of laryngeal irritation signs associated with reflux in asymptomatic volunteers: impact of endoscopic technique (rigid vs. flexible laryngoscope). Laryngoscope. 2005;115(12):2256–61. https://doi. org/10.1097/01.mlg.0000184325.44968.b1. 43. Chang BA, MacNeil SD, Morrison MD, Lee PK. The reliability of the reflux finding score among general otolaryngologists. J Voice. 2015;29(5):572–7. https://doi.org/10.1016/j. jvoice.2014.10.009. 44. Lee YC, Kwon OE, Park JM, Eun YG. Do laryngoscopic findings reflect the characteristics of reflux in patients with laryngopharyngeal reflux? Clin Otolaryngol. 2017; https://doi. org/10.1111/coa.12914.

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45. Rosen R, Mitchell PD, Amirault J, Amin M, Watters K, Rahbar R. The edematous and erythematous airway does not denote pathologic gastroesophageal reflux. J Pediatr. 2017;183:127–31. https://doi.org/10.1016/j.jpeds.2016.11.035. 46. Streckfuss A, Bosch N, Plinkert PK, Baumann I. Transnasal flexible esophagoscopy (TNE): an evaluation of the patient’s experience and time management. Eur Arch Otorhinolaryngol. 2014;271(2):323–8. https://doi.org/10.1007/s00405-013-2633-7. 47. Howell RJ, Pate MB, Ishman SL, et al. Prospective multi-institutional transnasal esophagoscopy: predictors of a change in management. Laryngoscope. 2016;126(12):2667–71. https:// doi.org/10.1002/lary.26171. 48. Peery AF, Hoppo T, Garman KS, et al. Feasibility, safety, acceptability, and yield of office-based, screening transnasal esophagoscopy (with video). Gastrointest Endosc. 2012;75(5):945–53. e2. https://doi.org/10.1016/j.gie.2012.01.021. 49. Madanick RD.  Extraesophageal presentations of GERD.  Gastroenterol Clin North Am. 2014;43(1):105–20. https://doi.org/10.1016/j.gtc.2013.11.007. 50. Kaufman JA, Houghland JE, Quiroga E, Cahill M, Pellegrini CA, Oelschlager BK.  Long-­ term outcomes of laparoscopic antireflux surgery for gastroesophageal reflux disease (GERD)-related airway disorder. Surg Endosc. 2006;20(12):1824–30. https://doi.org/10.1007/ s00464-005-0329-9. 51. Wo JM, Koopman J, Harrell SP, Parker K, Winstead W, Lentsch E. Double-blind, placebo-­ controlled trial with single-dose pantoprazole for laryngopharyngeal reflux. Am J Gastroenterol. 2006;101(9):1972–8; quiz 2169. https://doi.org/10.1111/j.1572-0241.2006.00693.x. 52. Cool M, Poelmans J, Feenstra L, Tack J.  Characteristics and clinical relevance of proximal esophageal pH monitoring. Am J Gastroenterol. 2004;99(12):2317–23. https://doi. org/10.1111/j.1572-0241.2004.40626.x. 53. Ayazi S, Lipham JC, Hagen JA, et al. A new technique for measurement of pharyngeal pH: normal values and discriminating pH threshold. J Gastrointest Surg. 2009;13(8):1422–9. https://doi.org/10.1007/s11605-009-0915-6. 54. Yadlapati R, Adkins C, Jaiyeola D-M, et al. Abilities of oropharyngeal pH tests and salivary pepsin analysis to discriminate between asymptomatic volunteers and subjects with symptoms of laryngeal irritation. Clin Gastroenterol Hepatol. 2016;14(4):535–42.e2. https://doi. org/10.1016/j.cgh.2015.11.017. 55. Yadlapati R, Pandolfino JE, Lidder AK, et  al. Oropharyngeal pH testing does not pre dict response to proton pump inhibitor therapy in patients with laryngeal symptoms. Am J Gastroenterol. 2016;111(11):1517–24. https://doi.org/10.1038/ajg.2016.145. 56. Sifrim D, Dupont L, Blondeau K, Zhang X, Tack J, Janssens J. Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring. Gut. 2005;54(4):449–54. https://doi.org/10.1136/gut.2004.055418. 57. Blondeau K, Dupont LJ, Mertens V, Tack J, Sifrim D.  Improved diagnosis of gastro-­ oesophageal reflux in patients with unexplained chronic cough. Aliment Pharmacol Ther. 2007;25(6):723–32. https://doi.org/10.1111/j.1365-2036.2007.03255.x. 58. Kim SI, Kwon OE, Na SY, Lee YC, Park JM, Eun YG. Association between 24-hour combined multichannel intraluminal impedance-pH monitoring and symptoms or quality of life in patients with laryngopharyngeal reflux. Clin Otolaryngol. 2017;42(3):584–91. https://doi. org/10.1111/coa.12817. 59. Hoppo T, Sanz AF, Nason KS, et al. How much pharyngeal exposure is “Normal”? normative data for laryngopharyngeal reflux events using hypopharyngeal multichannel intraluminal impedance (HMII). J Gastrointest Surg. 2012;16(1):16–25. https://doi.org/10.1007/ s11605-011-1741-1. 60. Zerbib F, Roman S, Bruley Des Varannes S, et al. Normal values of pharyngeal and esophageal 24-hour pH impedance in individuals on and off therapy and interobserver reproducibility. Clin Gastroenterol Hepatol. 2013;11(4):366–72. https://doi.org/10.1016/j.cgh.2012.10.041.

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61. Shay S, Tutuian R, Sifrim D, et  al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol. 2004;99(6):1037–43. https://doi.org/10.1111/j.1572-0241.2004.04172.x. 62. Hoppo T, Komatsu Y, Jobe BA. Gastroesophageal reflux disease and patterns of reflux in patients with idiopathic pulmonary fibrosis using hypopharyngeal multichannel intraluminal impedance. Dis Esophagus. 2014;27(6):530–7. https://doi.org/10.1111/j.1442-2050.2012.01446.x. 63. Komatsu Y, Hoppo T, Jobe BA. Proximal reflux as a cause of adult-onset asthma. JAMA Surg. 2013;148(1):50. https://doi.org/10.1001/jamasurgery.2013.404. 64. Hoppo T, Komatsu Y, Jobe BA. Antireflux surgery in patients with chronic cough and abnormal proximal exposure as measured by hypopharyngeal multichannel intraluminal impedance. JAMA Surg. 2013;148(7):608. https://doi.org/10.1001/jamasurg.2013.1376. 65. Dulery C, Lechot A, Roman S, et al. A study with pharyngeal and esophageal 24-hour pH-­ impedance monitoring in patients with laryngopharyngeal symptoms refractory to proton pump inhibitors. Neurogastroenterol Motil. 2017;29(1):e12909. https://doi.org/10.1111/ nmo.12909. 66. Hayat JO, Gabieta-Somnez S, Yazaki E, et  al. Pepsin in saliva for the diagnosis of gastro-­ oesophageal reflux disease. Gut. 2015;64(3):373–80. https://doi.org/10.1136/ gutjnl-2014-307049. 67. Calvo-Henríquez C, Ruano-Ravina A, Vaamonde P, Martínez-Capoccioni G, Martín-Martín C. Is pepsin a reliable marker of laryngopharyngeal reflux? A systematic review. Otolaryngol Head Neck Surg. 2017;157(3):385–91. https://doi.org/10.1177/0194599817709430.

Chapter 3

Commonly Confused Conditions Elisabeth H. Ference, Vicki Henderson, and Marilene B. Wang

Introduction Patients who present with globus (foreign body or “lump in the throat”) sensation, hoarseness, chronic cough, and/or chronic throat clearing have a wide differential diagnosis (Tables 3.1 and 3.2). Upper airway disorders, such as postnasal drip due to rhinitis or sinusitis, can cause similar symptoms. Hoarseness can be caused by a multitude of laryngeal disorders, including functional voice disorders, chronic laryngitis, habitual throat clearing, and excessive voice use. Swallowing disorders can also produce symptoms of globus sensation and chronic throat clearing. Neoplasms impacting the aerodigestive tract, such as pharyngeal, laryngeal, esophageal, or thyroid neoplasms, can lead to stenosis or compression, which can be misdiagnosed as laryngopharyngeal reflux (LPR). Finally, environmental irritants such as tobacco, alcohol, and temperature changes can also cause inflammation, mimicking symptoms caused by exposure to gastric contents. This chapter provides a broad overview of the workup and treatment of conditions commonly confused with LPR.

E. H. Ference Rick and Tina Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA Department of Otolaryngology-Head and Neck Surgery, Children’s Hospital Los Angeles, Los Angeles, CA, USA V. Henderson Department of Speech Pathology, St. Jude Hospital, Fullerton, CA, USA M. B. Wang (*) Department of Head and Neck Surgery, David Geffen School of Medicine of the University of California, Los Angeles (UCLA), Los Angeles, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 N. Jamal, M. B. Wang (eds.), Laryngopharyngeal Reflux Disease, https://doi.org/10.1007/978-3-030-12318-5_3

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Table 3.1  Commonly confused disorders with laryngopharyngeal reflux Differential diagnosis of laryngopharyngeal reflux Nasal Allergic rhinitis, non-allergic rhinitis (cold temperatures, spicy foods, pregnancy, hormonal changes, medication side effect), structural abnormalities (deviated septum, enlarged turbinates) Sinus Acute sinusitis, chronic sinusitis with or without nasal polyposis (Fig. 3.2), allergic fungal sinusitis, chronic fungal sinusitis Laryngeal Functional voice disorders, anxiety, infectious laryngitis, allergic laryngitis, laryngeal stenosis, habitual throat clearing, excessive voice use Dysphagia See Table 3.2 Neoplasm Esophageal, pharyngeal, laryngeal, or thyroid neoplasms Environmental Tobacco, alcohol, temperature change

Table 3.2  Swallowing disorders that may be confused with laryngopharyngeal reflux Anatomic

Vocal fold paralysis, Zenker’s diverticulum, esophageal diverticulum, esophageal or cricopharyngeal achalasia, cricopharyngeal (Fig. 3.4) or diffuse esophageal spasm, pharyngeal strictures, esophageal stenosis, esophageal webs, osteoarthritic spurs of the cervical spine Congenital Tracheoesophageal fistulas, vascular compression, congenital esophageal webs, submucosal left palate Infectious Laryngitis, pharyngitis, esophagitis Neurologic Altered mental status, degenerative diseases such as Parkinson’s or multiple sclerosis, motor neuron disease such as amyotrophic lateral sclerosis, stroke, encephalopathies, myasthenia gravis, bulbar and pseudobulbar palsy, dementia, central nervous system tumors, cranial nerve injury (especially laryngeal nerve injury), Guillain-Barre, globus pharyngeus Trauma Caustic ingestion, foreign body ingestion, post-endotracheal intubation, postsurgical or postradiation changes, Mallory-Weiss syndrome Tumor Head and neck or esophageal tumors, extrinsic compression of the esophagus Systemic Hypothyroiditis, gastroesophageal reflux disease, Plummer-Vinson syndrome, myopathies such as muscular dystrophy or polymyositis, connective tissue disorders such as scleroderma, autoimmune disorders such as rheumatoid arthritis, polyangiitis granulomatosis, and Sjogren’s syndrome

Upper Airway: Nasal and Sinus Disorders Glands in the throat and nose continually produce mucus, approximately 1 liter per day, which is usually swallowed unconsciously [1]. The sensation of mucus accumulating in the throat or dripping from the back of the nose is called postnasal drip. LPR may cause symptoms of postnasal drip, but postnasal drip may also be caused by nasal or sinus disorders such as allergic rhinitis, non-allergic rhinitis, and acute or chronic sinusitis (Figs. 3.1, 3.2 and 3.3).

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Fig. 3.1  Postnasal drip may be a symptom of LPR or may be caused by acute or chronic rhinosinusitis. This patient has combined variable immunodeficiency, and her symptoms of postnasal drip are due to chronic infection of the sinus causing mucopurulent drainage. White solid arrow, left Eustachian tube orifice; white dashed arrow, nasopharynx; black dashed arrow, septum; black arrow, inferior turbinate

Fig. 3.2  Clear and purulent postnasal drip in a patient with allergic rhinitis and acute sinusitis. White dashed arrow, nasopharynx; black dashed arrow, Eustachian tube orifice

Nasal Increased nasal secretions may be due to allergies or to non-allergic triggers such as cold temperatures, certain foods/spices, pregnancy, and other hormonal changes. Various drugs, including birth control pills and some high blood pressure medications, can increase nasal mucus production. Nasal structural abnormalities, such as deviated or irregular nasal septum or enlarged inferior nasal turbinates, can also lead to impaired anterior drainage, increased posterior drainage, and increased secretions. Figures  3.1 and 3.2 demonstrate the significant

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Fig. 3.3  Nasal polyps are a marker of chronic rhinosinusitis with nasal polyposis and are often treated with oral steroids. However, oral steroids may worsen any concomitant LPR. Black dashed arrow, septum; black arrow, inferior turbinate; grey arrow, polyp

postnasal drip that can occur in allergic and non-allergic rhinosinusitis, where symptoms can mimic those occurring LPR. Allergic rhinitis can be diagnosed by a detailed history, including questions regarding seasonality of symptoms. It is then confirmed with skin prick or blood testing for antibodies that lead to an IgE-mediated hypersensitivity reaction. Patients often report sneezing, watery rhinorrhea, and itchy watery eyes. Treatment for allergic rhinitis includes oral or topical antihistamine medications, nasal steroids, leukotriene receptor antagonists, and immunotherapy. Non-allergic rhinitis has no specific testing but can be suspected based on a detailed history of triggers. Symptoms from vasomotor or non-allergic rhinitis manifest differently than those of allergic rhinitis, in that they are not exacerbated by typical environmental triggers such as pollen, dust, smog, mold, or animal dander. Changes in temperature, eating, strong odors, stress, and certain medications can cause both anterior rhinorrhea and postnasal drip mimicking LPR. Non-allergic rhinitis symptoms, including nasal congestion, runny nose, postnasal drip, and globus sensation, are more frequent as a person ages, due to weakening of the cartilage support and subsequent nasal valve collapse, glandular atrophy leading to thicker mucous, and decreased mucociliary clearance. Paradoxically, older patients will also experience dryness in the nose as well, despite having runny nose and postnasal drip [2–5]. Treatment for non-allergic rhinitis is centered on disrupting the parasympathetic triggers of mucus production with either anticholinergic topical medications or in severe cases by surgically severing parasympathetic nerve inputs to the nasal mucosa. Despite the lack of allergic etiologies for these symptoms, some patients will respond to nasal antihistamine and steroid sprays. Saline sprays, mucolytics, humidification, and oral decongestants may also be used for symptomatic relief.

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Sinus Both acute and chronic sinusitis can cause postnasal drainage that can mimic symptoms of laryngopharyngeal reflux. Acute sinusitis is defined as the sudden onset of two or more of the following symptoms for less than 12 weeks (with symptom-free intervals if the problem is recurrent) [6]: • • • •

Nasal blockage/obstruction/congestion Nasal discharge (anterior/posterior nasal drip) Facial pain/pressure Cough (daytime and nighttime)

Chronic rhinosinusitis with or without nasal polyps in adults is defined as the presence of two or more symptoms, one of which should be either nasal blockage (including obstruction and congestion) or nasal discharge (anterior/posterior nasal drip), plus or minus facial pain/pressure or reduction/loss of smell for greater than 12 weeks. Subsets of chronic rhinosinusitis include nasal polyposis, allergic fungal sinusitis, and chronic fungal sinusitis (such as fungal mycetoma, a noninvasive fungal infection producing a clump of spores, most commonly in the maxillary sinus) [7]. Figure 3.3 demonstrates nasal endoscopy findings in a patient with nasal polyps. Workup consists of nasal endoscopy and computed tomography (CT) scan of the sinuses. Treatment for both acute and chronic sinusitis includes antibiotics, topical steroids, and saline irrigations, with oral steroids used especially for patients with chronic sinusitis with nasal polyposis [6]. LPR may play a role in a subset of patients with chronic rhinosinusitis refractory to traditional medical and surgical therapy. There is moderate evidence linking reflux to chronic rhinosinusitis, most likely through direct reflux of gastric contents into the nasopharynx and nasal cavity [8]. The strongest evidence for an association of postnasal drip and gastroesophageal reflux is provided in a randomized, controlled study by Vaezi et al., which found that twice daily proton pump inhibitor dosing significantly improved symptoms of postnasal drip after 8 and 16  weeks compared to placebo [9]. Interestingly, neither baseline presence of typical reflux symptoms nor esophageal physiologic parameters predicted response to therapy [9]. Conversely, Wise et al. found that patients who had nasopharyngeal reflux events on manometry were significantly more likely to report postnasal drip symptoms compared to patients without reflux [10]. For these patients, it is unclear if LPR led to chronic rhinosinusitis or if their chronic rhinosinusitis was worsened by coexisting LPR.  Of note, many treatments for rhinosinusitis, such as oral antibiotics and steroids, can worsen gastroesophageal reflux, thus creating an exacerbating cycle. Oral steroids can increase gastric acid secretion, reduce gastric mucus, and cause gastrin and parietal cell hyperplasia, while antibiotics such as tetracyclines can lead to esophageal irritation [11, 12].

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Laryngeal Disorders While LPR may be a primary cause of or contributing factor to voice problems, voice problems may also arise in the absence of LPR, thus leading to misdiagnosis. LPR causes inflammation of the posterior larynx, vocal fold mucosa irritation, and copious thick secretions over the vocal folds, but these symptoms can also be caused by infectious or allergic chronic laryngitis. Further complicating diagnosis, LPR can create habits that further contribute to voice problems, such as habitual throat clearing or excessive muscle tension when speaking, but these habits can also arise independently.

Chronic Laryngitis While chronic laryngitis can be caused by LPR, it can also be due to infection, allergy, or environmental irritants. Chronic laryngitis is defined as laryngeal inflammation lasting more than 3 weeks, and infectious etiologies can be fungal or bacterial. Patients with a history of inhaled steroid use are at risk for chronic laryngitis both from chemical laryngopharyngitis and from candida infection [13, 14]. A recent study in which patients with infectious bacterial chronic laryngitis underwent laryngeal culture found methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, and “normal respiratory flora” [15]. In suspected cases of infectious laryngitis, culture is recommended, via biopsy if necessary. Rare causes of infectious chronic laryngitis include tuberculosis, leprosy, syphilis, rhinoscleroma, actinomycosis, and rare fungi such as blastomycosis and histoplasmosis. Treatment consists of antifungals or antibiotics, but extended courses of antibiotics may be necessary for symptom improvement and resolution of inflammation [15]. The nasoendoscopic findings of reflux and allergy in the larynx are similar. A study at a tertiary academic center of new patients with primary voice disorders found that 20% had evidence of reflux based on reflux symptom index, while 67% had positive skin prick testing for allergies [16]. Chronic allergic reactions affecting the larynx continue to be controversial regarding whether they are an independent disease process or a secondary sequela of allergic rhinitis, sinusitis, or asthma [17]. Objective testing, such as allergy testing, CT scan of the sinuses, and pulmonary function tests should be performed to elucidate the cause of inflammation in individual patients suspected of allergic chronic laryngitis.

Muscle Tension Dysphonia and Excessive Voice Use Muscle tension dysphonia occurs as a result of increased muscle tension of the intrinsic and/or extrinsic laryngeal musculature. Altered laryngeal muscle tension can result in changes in laryngeal performance despite normal anatomy [18, 19]. It

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is sometimes considered a subset of “functional” voice disorders, wherein vocal quality deteriorates in the absence of anatomic or neurologic factors that affect either the aerodynamic configuration or the vibratory property of the vocal folds. Functional voice disorders may affect up to 40% of patients presenting to outpatient voice centers [20]. Muscle tension dysphonia may develop or persist after a chemical or irritant exposure, such as LPR, with laryngeal exam showing poor vibration and closure. Patients with habituated muscle tension dysphonia have a good response to voice therapy [19]. Vocal misuse can cause chronic inflammation in professional singers and orators as well as occasional shouters. Lesions can range from simple edema to hyperplastic masses. Systemic corticosteroid therapy can be used judiciously in professional voice patients for edema from episodic abuse, mild to moderate laryngitis, allergic vocal fold edema, and vocal fold hemorrhage – however, this issue is better addressed in a holistic manner via voice therapy, as steroids may worsen any component of LPR [21]. Use of voice therapy in this population is addressed in detail in Chap. 7.

Anxiety and Habitual Throat Clearing When nervous or under stress, throat muscles can trigger spasms that lead to sensation of globus. Frequent throat clearing can be a symptom of LPR, postnasal drip, or simply a response to stress. Habitual throat clearing can increase laryngeal irritation and lead to dysphonia. Voice therapy with a knowledgeable therapist can be extremely effective for this patient population. When all other possible causes have been eliminated, botulinum toxin injections to the laryngeal musculature can be considered for habitual throat clearing determined to be a nonorganic tic [22].

Swallowing Disorders and Dysphagia Swallowing problems may result in the accumulation of secretions, solid food residuals, or liquids in the throat. This pooling or residue can mimic the sensation of postnasal drip or globus pharyngeus and lead to symptoms of hoarseness, throat clearing, and coughing. Dysphagia, defined as the symptom of difficulty swallowing, may also be caused by LPR. Swallowing is a complex function that involves the coordination of muscles in the mouth, pharynx, and esophagus; the higher cortical centers; brainstem centers such as the tract of the nucleus solitarius and nucleus ambiguus; and cranial nerves V, VII, IX, X, and XII. It is described as occurring in three phases: oral, pharyngeal, and esophageal. The oral phase is subdivided into two phases, the first of which is referred to as the oral preparatory phase, which involves the conversion of food from the solid to semisolid state and lubrication through addition and mixing of saliva [23].

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The pharynx and larynx function as a “time share” for both respiration and deglutition [23]. The most basic function of the larynx is airway protection, and during a swallow a formed bolus must be moved completely from the mouth through the pharynx and into the esophagus, while the glottis is closed and respiration is interrupted. Swallowing is a dynamic process; therefore, individuals may not exhibit signs of dysphagia with every food texture or with every act of deglutition. Any condition that damages or weakens the muscles and nerves used for swallowing can cause dysphagia and therefore can be confused with laryngopharyngeal reflux  – which, as discussed, may also lead to dysphagia (Table 3.2). Exact measures of the incidence and prevalence of swallowing disorders are difficult to determine due to differences in accepted definitions of dysphagia and differences in measurement tools across studies [24, 25]. Aging is associated with increased incidence, and intermittent dysphagia affects approximately 22% of adults over 65 years old [24, 25]. In specific populations, dysphagia is very common. For example, a systematic review found that between 37% and 78% of patients who have had a cerebrovascular accident have dysphagia [25]. Another study estimated that 38% of patients after acute stroke have aspiration [24, 25]. The differential diagnosis of swallowing disorders and dysphagia is broad (Table 3.2). In immunocompromised patients, it is important to have a high index of suspicion for infection; for example, in HIV-infected patients, candidal esophagitis is the most common cause of new onset esophageal symptoms [26]. In patients with risk factors for head and neck cancer, it is important to rule out a mass or lesion causing obstruction. In children and infants, upper aerodigestive tract anomalies such as laryngomalacia, laryngeal clefts, tracheoesophageal fistulas, foregut malformations, vascular rings, and congenital tumors such as lymphangiomas or hemangiomas may all lead to feeding problems specific to young children. These may be misdiagnosed as reflux in patient who do not undergo a complete workup [27]. Patients with dysphagia can be referred to a speech language pathologist (SLP) for further evaluation. An SLP will initially perform a clinical swallow evaluation, which consists of an examination of head and neck musculature followed by observation of the patient eating foods and liquids of various consistencies. Based on the results and resources available, a modified barium swallow study or endoscopic evaluation may be recommended. The goal of a modified barium swallow (MBS, also referred to as videofluoroscopy or VFS) and a fiberoptic endoscopic evaluation of swallowing (FEES) is to assess the anatomy and physiology of the upper aerodigestive mechanisms used in swallowing and to determine the incidence or risk of aspiration [28]. During both evaluations, patients can be instructed in management techniques, such as chin tuck or turning the head to the side, to test for improvement in swallow using these interventions. Of the two, FEES is more useful in cases in which biofeedback is needed. Other ancillary tests can include a chest X-ray to identify pneumonia, masses, or other abnormalities; direct laryngoscopy and esophagoscopy in the operating room to evaluate for masses or anatomic abnormalities; and CT or MRI to better characterize lesions of the head and neck or brain. Manometry, which uses a catheter to measure pressures at various intervals along the length of the esophagus, is used to

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diagnose and follow elevated intraluminal esophageal pressure, as found in achalasia or diffuse esophageal spasm. Laboratory tests for malnutrition (albumin), dehydration (chemistry panel), nutritional deficiencies (iron, vitamin B levels), hypothyroidism, and infectious or autoimmune diseases can also be considered as indicated by the history and physical exam. Testing specific to LPR is discussed in detail in Chap. 2. Treatment varies greatly depending on the cause, symptoms and types of swallowing problem, and goals of care. Based on the test results, the care team can develop a plan of care consisting of medical management, swallowing rehabilitation, and/or surgical intervention. If possible, the underlying cause of dysphagia should be treated (i.e., benztropine for Parkinson’s disease, nystatin for Candida, Biotene or salivary substitutes for postradiation xerostomia). Botulinum toxin injections may be useful either into the cricopharyngeal muscle for cricopharyngeal muscle spasms (Fig. 3.4) or to the submandibular and maxillary gland to decrease saliva secretion [29]. Swallowing rehabilitation may be initiated by a SLP and can take many different forms, including food modification, modified feeding activity, positioning strategies, mechanism modification, and swallowing modifications [30]. Fig. 3.4 Cricopharyngeal bar due to prominent cricopharyngeus muscle contour on barium swallow. Cricopharyngeal bar is not always related to cricopharyngeus muscle spasm/achalasia, but this patient had significant symptomatic relief of her dysphagia with botulinum toxin injection and eventually elected to undergo cricopharyngeal myotomy with significant benefit postoperatively. Black arrow, cricopharyngeal bar

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For specific anatomic abnormalities, surgical correction may be indicated. Esophageal dilation can be useful in cases of pharyngeal or esophageal strictures or webs, postoperative or postradiation scarring, or esophageal achalasia. Cricopharyngeal myotomy may be indicated for cricopharyngeal spasm. Resection of Zenker’s or esophageal diverticulum, hiatal hernia repair, vocal fold medialization for unilateral vocal cord paralysis, or fundoplication for intractable esophageal regurgitation may all alleviate underlying causes of dysphagia.

Neoplasm The relationship between LPR and neoplasm is complex. LPR can be a misdiagnosis in the presence of neoplasm, a symptom of neoplasm [31], or potentially a risk factor for the development of certain types of cancer [32, 33]. Symptoms of hoarseness, difficulty swallowing, breathing difficulties, cough, and globus can be due to laryngeal, pharyngeal, esophageal, or thyroid cancer; treatment of LPR without further workup can delay definitive diagnosis. A study by Reavis et  al. found that symptoms of LPR were more prevalent than gastroesophageal reflux disease (GERD) symptoms in patients with esophageal adenocarcinoma and may represent the only sign of disease [31]. The well-known association between GERD and esophageal adenocarcinoma has created a hypothesis that LPR may be associated with laryngeal carcinoma [32, 33]. The exact relationship between LPR and malignant changes remains to be proved, but available data suggests that LPR may be an important cofactor to tobacco and alcohol use in the development of laryngeal carcinoma, especially in nonsmokers [33–35]. Moreover, refluxed pepsin has been shown to promote epithelial proliferation, cell migration, and carcinogenesis of the larynx and pharynx [36– 38]. Therefore, LPR may be a causal factor in tumorigenesis, as well as a symptom of certain tumors.

Environmental Irritants Environmental irritants can lead to chronic laryngitis, which may be confused with LPR, but irritants such as smoking and alcohol can also increase the risk of LPR. Inhalation injuries are most commonly related to tobacco use but can also be caused by pollution and thermal injuries [33]. Patients with chronic laryngitis should be questioned about contact with toxic substances, fumes, dusts, and rapid temperature changes. While tobacco is chronically irritating to the laryngeal mucosa, cigarette smoking is also associated with relaxation of the upper and lower esophageal sphincters, and a study of smokers with heartburn symptoms demonstrated that reflux episodes occurred during two thirds of all cigarettes smoked

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[39–41]. Similarly, alcohol can act as a laryngeal irritant but also reduces the pressure of the lower esophageal sphincter, decreases esophageal motility, and increases gastrin and acid secretion, thus leading to reflux [42].

Conclusion There are a large number of common conditions that can be confused with LPR. Clouding the diagnosis is the fact that LPR can also cause or exacerbate a large number of conditions, such as chronic sinusitis, chronic laryngitis, dysphagia, and possibly laryngeal carcinoma. In cases of chronic rhinosinusitis, laryngitis, or dysphagia unresponsive to medical or surgical management, patients should also be tested for coexistent LPR or empirically treated because response to any therapy will be suboptimal if LPR is not also adequately addressed. Conversely, patients with atypical symptoms of LPR or those who do not respond to initial LPR treatments should be further evaluated for other conditions that may mimic LPR.

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31. Reavis KM, Morris CD, Gopal DV, Hunter JG, Jobe BA.  Laryngopharyngeal reflux symptoms better predict the presence of esophageal adenocarcinoma than typical gastroesophageal reflux symptoms. Ann Surg. 2004;239(6):849–56-8. https://doi.org/10.1097/01. SLA.0000128303.05898.EE. 32. Tae K, Jin BJ, Ji YB, Jeong JH, Cho SH, Lee SH. The role of laryngopharyngeal reflux as a risk factor in laryngeal cancer: a preliminary report. Clin Exp Otorhinolaryngol. 2011;4(2):101–4. https://doi.org/10.3342/ceo.2011.4.2.101. 33. Postma GN, Halum SL. Laryngeal and pharyngeal complications of gastroesophageal reflux disease. GI Motil online, Publ online 16 May 2006; doi:https://doi.org/10.1038/gimo46. 34. Koufman JA, Burke AJ. The etiology and pathogenesis of laryngeal carcinoma. Otolaryngol Clin North Am. 1997;30(1):1–19. http://www.ncbi.nlm.nih.gov/pubmed/8995133. Accessed 9 Oct 2017. 35. Koufman JA.  The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope. 1991;101(4 Pt 2 Suppl 53):1–78. http://www.ncbi.nlm.nih.gov/ pubmed/1895864. Accessed 9 Oct 2017. 36. Johnston N, Wells CW, Samuels TL, Blumin JH. Pepsin in nonacidic refluxate can damage hypopharyngeal epithelial cells. Ann Otol Rhinol Laryngol. 2009;118(9):677–85. https://doi. org/10.1177/000348940911800913. 37. Kelly EA, Samuels TL, Johnston N. Chronic pepsin exposure promotes anchorage-­independent growth and migration of a hypopharyngeal squamous cell line. Otolaryngol Neck Surg. 2014;150(4):618–24. https://doi.org/10.1177/0194599813517862. 38. Johnston N, Yan JC, Hoekzema CR, et  al. Pepsin promotes proliferation of laryngeal and pharyngeal epithelial cells. Laryngoscope. 2012;122(6):1317–25. https://doi.org/10.1002/ lary.23307. 39. Kahrilas PJ, Gupta RR. Mechanisms of acid reflux associated with cigarette smoking. Gut. 1990;31(1):4–10. http://www.ncbi.nlm.nih.gov/pubmed/2318431. Accessed 9 Oct 2017. 40. Stanciu C, Bennett JR. Smoking and gastro-oesophageal reflux. Br Med J. 1972;3(5830):793– 5. http://www.ncbi.nlm.nih.gov/pubmed/5076250. Accessed 9 Oct 2017. 41. Kadakia SC, Kikendall JW, Maydonovitch C, Johnson LF.  Effect of cigarette smoking on gastroesophageal reflux measured by 24-h ambulatory esophageal pH monitoring. Am J Gastroenterol. 1995;90(10):1785–90. http://www.ncbi.nlm.nih.gov/pubmed/7572895. Accessed 9 Oct 2017. 42. Bujanda L.  The effects of alcohol consumption upon the gastrointestinal tract. Am J Gastroenterol. 2000;95(12):3374–82. https://doi.org/10.1111/j.1572-0241.2000.03347.x.

Part II

Treatment Options for LPR

Chapter 4

Lifestyle and Dietary Modifications Suraj Kedarisetty and Ahmed M. S. Soliman

Introduction Patients presenting with hoarseness, globus sensation, throat clearing, cough, or dysphagia are commonly evaluated by otolaryngologists and often diagnosed with laryngopharyngeal reflux (LPR). Given the lack of sensitivity of the readily available diagnostics tests for LPR, most otolaryngologists initially treat patients empirically. Consensus opinion recommends using a combination of lifestyle modifications and medications [1]. In a survey, Davids et al. determined that most otolaryngologists recommended proton pump inhibitors (PPIs) and lifestyle modifications together when LPR is suspected [2]. However, there is a lack of strong evidence available in the literature to support lifestyle modifications for LPR. Most publications simply include a statement that lifestyle and dietary changes should also be considered [3]. Steward and colleagues determined that patients treated with general counseling about lifestyle and diet modifications who were then stratified into groups, with and without PPI, improved in a few months, regardless of PPI use [4]. Thus, there is evidence to support lifestyle and dietary modifications broadly to improve LPR symptoms. Yet few studies clarify the specifics of these changes or which modifications are the most effective. In this chapter, we will review the evidence for the most common modifications recommended, including diet, weight loss, exercise, tobacco and alcohol use, sleep position, as well as some alternative therapy options currently available.

S. Kedarisetty · A. M. S. Soliman (*) Department of Otolaryngology-Head & Neck Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 N. Jamal, M. B. Wang (eds.), Laryngopharyngeal Reflux Disease, https://doi.org/10.1007/978-3-030-12318-5_4

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Table 4.1  Evidence for suggested lifestyle modifications Strong evidence Head of bed elevation 6–10 inches Meal-timing, avoid fasting Strict low-acid dieta

Equivocal evidence Exercise Alcohol reduction Smoking reduction Weight loss Fiber-rich foods

Weak evidence Avoiding individual foods Alkaline water Upper esophageal sphincter device

Foods generally recommended to avoid are caffeine, citrus, chocolate, tea, carbonated beverages, salt, mint, and spicy foods

a

Diet Most of our understanding of the role of dietary factors in LPR comes from the gastroenterology literature. Much work on the effects of fatty and calorie dense meals on reflux has been done. Most studies conclude that this diet worsens reflux symptoms. Specifically, duodenal fat is thought to cause gastric distension, lower esophageal sphincter (LES) relaxation, and increased visceral sensitivity compared to glucose-rich meals, explaining some of the classic dyspepsia symptoms [5–7]. Most of these studies employ either pH probe data or GERD-focused questionnaires and are not specific to supraesophageal or laryngeal symptoms. Targeted studies focusing on LPR and fatty meals do not exist. Hamdan and colleagues compared symptoms and exam findings in fasting and non-fasting subjects over a 12-hour period [8]. While there was no significant change in physical exam findings between the groups, the fasting group did have a significant increase in laryngeal symptoms including throat clearing, postnasal drip, and globus sensation. The authors conclude that the changes in symptoms of the fasting group may be attributed to alterations in gastric acid and pepsin secretions, which increase during the fasting state. The findings suggest that patients should eat smaller, more frequent meals and avoid long time periods with an empty stomach. This study, however, was limited by the small number of subjects, all of whom were male. Several books in the lay press advocate the benefits of a low-acid diet [9–11]. Koufman and colleagues have demonstrated the utility of a strict low-acid diet in PPI-resistant LPR patients [12]. This includes avoidance of chocolate, caffeine, citrus, and spicy and acidic foods. Their study specifically involved the avoidance of foods with pH below 4 for a 2-week period in PPI-resistant patients and noted an improvement in the reflux finding score (RFS) and the reflux symptom index (RSI) with adherence to this regimen. Yet data associating LPR or GERD to individual foods is scant and at times conflicting. Nilsson and colleagues determined by survey that increased coffee use had an inverse relationship with GERD symptoms and tea intake was unrelated. Increased salt usage was associated with increased GERD symptoms, and increased dietary fiber intake was associated with decreased GERD symptoms [13]. A review by Kaltenbach et al. of dietary modifications for GERD found no strong evidence for most of these foods [14]. Specifically, they determined that citrus fruits/juices,

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carbonated beverages, coffee, chocolate, and spicy foods may be associated with worsening GERD by pH probe or manometry, though they found no specific data demonstrating significant symptom improvement with avoidance of these foods. In addition, they found no association with mint avoidance and GERD. Newberry and Lynch in a more recent review reached similar conclusions, finding minimal strong evidence associating individual foods with reflux [15]. The lack of strong data for individual foods is likely due to the difficulty of conducting a controlled, individual food avoidance trial that is sufficiently powered. As such, avoidance of these foods, and, in particular, acidic foods, is still widely recommended. The effect of meal-timing on reflux has also been investigated. Specifically, avoiding late meals has been shown to significantly decrease gastric and esophageal acidity [16]. Additionally, late meals may further increase the chance of reflux if one lies in the supine position after the meal, such as for nighttime sleep [17]. These studies would suggest the best time to have a meal in the evening is 3–6  hours before planned nighttime sleep. While there is no specific data relating meal-timing to LPR or extraesophageal reflux, late meal avoidance is generally still recommended in patients with LPR based upon the GERD data.

Weight Loss Many diseases have an increased prevalence in populations with high obesity rates. GERD is no different and is associated with an increased body mass index (BMI). In fact, a nonlinear increase in GERD with increasing BMI has been shown based on manometric findings [18]. This is explained by an increase in intra-abdominal pressure, which decreases LES pressure [19]. While this is well understood, the effect of weight loss on reducing GERD symptoms is less clear. Kjellin et al. noted little objective or symptomatic improvement in obese patients with acid reflux despite a 10-kilogram weight loss [20]. In contrast, others have demonstrated significant reduction of GERD symptoms with weight loss [21, 22]. Despite the conflicting data and the lack of study of its effects on extraesophageal symptoms, weight loss still remains one of the first-line recommendations for the non-­ pharmacological management of GERD and LPR.

Exercise Though there are no studies directly correlating exercise and LPR, several examine its effects on gastroesophageal reflux. Physiologically, acid exposure to the esophagus increases during periods of exercise in patients with and without GERD [23]. Some have suggested that this may cause exercise-induced reflux in patients already with GERD but that the increased acid exposure is temporary and is not necessarily associated with development of a new-onset pathological level of reflux. Other

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studies have shown exercise to be protective against reflux. Nilsson et al. demonstrated a decreased association of reflux in those who exercised in a cross-sectional observational study [13]. Furthermore, even in subjects with a diagnosis of GERD, the symptoms of reflux were found to be less severe in the subset who exercise [24]. Thus, for patients who complain of temporary exercise-induced reflux, it may be prudent to counsel them to continue exercising, as the end result is likely an overall decrease in symptoms. However, these studies did not specifically evaluate laryngeal symptoms.

Smoking and Alcohol Although traditional antireflux diets include the elimination of alcohol and tobacco, their effect on reflux is not clear. Several studies fail to demonstrate a significant increase in reflux in those who smoke or consume alcohol, more commonly with difficulty in finding a correlation with the latter [24, 25]. Specifically, multiple studies fail to demonstrate improvement by pH probe and manometry with tobacco or alcohol cessation [14]. In contrast, Nilsson et al. demonstrated that people with a history of 20 or more years of smoking had a higher association with reflux symptoms by survey [13]. Pehl and colleagues demonstrated that alcoholic beverages can increase heartburn symptoms [26]. They also demonstrated that white wine is worse than red wine and that beer similarly can cause an increase in GERD [27, 28]. None of these studies specifically correlate smoking or tobacco with LPR. Despite the lack of clear-cut data regarding the effect of alcohol and smoking on GERD and LPR, their elimination is still often recommended.

Position Most patients with severe GERD complain of worse nighttime symptoms. In fact, many of them reflexively make a self-correction by sleeping upright or with their head elevated on multiple pillows. Sleep has been shown to be an independent risk factor for decreased esophageal acid clearance [29]. This most likely is due to the supine position during sleep, but there may be other physiological factors that result in decreased lower esophageal pressure, such as sphincter relaxation. The most commonly utilized strategy for positional changes to reduce LPR or GERD during sleep is head of bed elevation. Multiple studies have demonstrated that 6–8 inches of elevation at the head of the bed can decrease esophageal acid exposure and increase acid clearance. Khan et  al. demonstrated reduced reflux events by pH probe, improved acid clearance, and reduced sleep disturbance with head of bed elevation [30]. Scott et al. specifically demonstrated an improvement of

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supraesophageal symptoms, such as cough, with an elevation of 6 inches [31]. In addition, these subjects had a reduction in nasopharyngeal pH with head of bed elevation. Additionally, the lateral recumbent position has been demonstrated to increase LES relaxation by pH probe [32]. Specifically, the right lateral recumbent position is associated with a higher incidence of GERD and LES relaxation compared to the left lateral recumbent position [32, 33]. Notably, body position did not affect the acidity at the gastric cardia or body, further suggesting that differential LES relaxation is what contributes to the positional reflux. However, neither of these studies demonstrated direct correlation with symptoms. Many options are available for patients to achieve the head of bed elevation. Simple options include using more pillows or sleeping in a reclining chair. Other options include differentially raising the slats under the mattress or placing bed risers under the bedposts. Many devices are available on the market to raise the head, including wedge pillows. One specific type of wedge pillow (MedCline©) succeeds in both positioning the body in the left lateral recumbent position and raising the head [34]. Tierney and colleagues determined that the use of this device significantly improves GERD and LPR symptoms [35]. Overall, body positioning seems to be quite important in LPR patients. Head of bed elevation by 6 inches and sleeping in the left lateral recumbent position have the most robust data in improving LPR.

Age Though obviously not a modifiable risk factor, the age of a patient may play a role in symptoms and treatment. Lechien et al. have reported that patients above the age of 60 generally had lower RSI scores without a difference in RFS scores, suggesting that perhaps elderly patients were less bothered by their LPR [36]. Furthermore, older patients tended to have better subjective improvement after any treatment, though they were less likely to be responsive to PPIs [37]. This may be due to underlying presbyphonia or polypharmacy causing medication interaction (e.g., levothyroxine and PPI). While a patient’s age is not modifiable, these studies may be helpful in counseling patients as to their expected response to treatment.

Alternative Treatments There are many alternative options available for the treatment of GERD and LPR that have very little available evidence to support their efficacy. A cursory Internet search reveals a plethora of over-the-counter products for laryngopharyngeal reflux. In this section, we will review only a select few options that have some evidence.

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A current hot topic in the alternative therapy realm is alkaline water, whose proponents assert numerous positive benefits, including the treatment of GERD and LPR [38]. There have been limited studies applicable to the role of alkaline water, but their relevance hinges on the theorized physiologic difference between the laryngopharynx and cervical esophagus as compared to the distal esophagus. The currently accepted definition of an acid reflux event is an esophageal pH