Laryngopharyngeal Reflux: Diagnosis, Treatment and Latest Research

Review

Eur Surg DOI 10.1007/s10353-016-0385-5

Laryngopharyngeal reflux: diagnosis, treatment and latest research

G. L. Falk1,2,3 · S. J. Vivian4

Received: 13 December 2015 / Accepted: 13 January 2016 © Springer-Verlag Wien 2016

Summary Aim Aim A review of the recent changes in understanding of laryngopharyngeal and extra-oesophageal reflux Review the recent changes in the evaluation of cause, symptoms. investigation and therapy in the evolving area of extra- Method Literature search over 7 years (2008–2015) oesophageal symptoms of reflux disease. and relevant historical cited articles. Results Modern investigation more clearly shows a subgroup of patients with intermittent full column Method oesophago-gastric-reflux-causing symptoms. Multiple other sites in the lung, head and neck may also be impli- Ongoing review of the literature has been pursued by the cated in the reflux disease process. senior author (GLF) of PubMed and the National Centre Conclusion Understanding of extra-oesophageal for Biotechnology Information (NCBI) at the National reflux symptomology is evolving. New equipment and Library of Medicine (NLM). Search was conducted techniques suggest further areas of research, and as yet monthly using (“laryngopharyngeal reflux”[MeSH] OR effective therapy remains elusive for some. LARYNGOPHARYNGEAL REFLUX[Title/Abstract]) OR ((COUGH[Title/Abstract] OR “cough”[MeSH]) AND Keywords Laryngopharyngeal reflux · (“gastroesophageal reflux”[MeSH] OR “GASTROESOPH- Gastro-oesophageal reflux · AGEAL REFLUX”[Title/Abstract] OR “GASTROOESOPH- Laparoscopic fundoplication AGEAL REFLUX”[Title/Abstract] OR “gastroesophageal reflux”[MeSH Terms] OR REFLUX[Title/Abstract])) for the years 2008–2015. Relevant articles were extracted pro- gressively and topics searched on PubMed as required from 2008 onward. Further searches were conducted for (GASTROESOPHAGEAL REFLUX[MESH] OR LARYN- G. L. Falk, MBBS, FRACS () GOPHARYNGEAL REFLUX[MESH] OR REFLUX) AND Suite 29, 12-18 Tryon Rd, IMPEDANCE and (“Barrett Esophagus”[MAJR] AND NSW 2070 Lindfield, Australia DYSPLASIA) OR (“Barrett’s dysplasia”) OR (Barrett*[ti] e-mail: sydney.heartburn@gmail.com AND DYSPLASIA[ti]). G. L. Falk, MBBS, FRACS Bibliographies of multiple articles contained further University of Sydney, article references from earlier years and have been uti- Sydney, Australia lised selectively in discussion. The references were then G. L. Falk, MBBS, FRACS utilised to elucidate the multiple topics addressed in the Macquarie University, review. Criteria for selection were relevance, English lan- Sydney, Australia guage, and publication in reputable peer-reviewed jour- nals unless of substantial significance. S. J. Vivian, BA Sydney Heartburn Clinic, Lindfield, Australia e-mail: [email protected]

1 3 Laryngopharyngeal reflux: diagnosis, treatment and latest research 1 Review

The spectrum of gastro-oesophageal reflux Pathophysiology disease The anomalousness of reflux disease hinges around the Reflux disease, in its various forms, affects a large group abnormal frequency or duration of exposure to gastric of society. Typical gastro-oesophageal reflux disease contents within the tubular oesophagus. There is a bal- (GORD) affects at least 10 % of individuals in Western ance between mucosal attack and the mucosal defences society [1]. And it has been estimated that about 10 % of and between clearance of the oesophagus and frequency, ear, nose and throat specialty (ENT) workload reflects volume and concentration of reflux fluid. In lesser cases possible atypical reflux patients [2]. While typical reflux of reflux disease, transient lower oesophageal sphincter disease has long been relatively easy to diagnose both relaxation occurs (TLOSR) [6] and the trans-diaphrag- symptomatically and on testing, extra-oesophageal dis- matic pressure gradient allows fluid to pass upwards into ease is still not adequately diagnosed, and treatment is the oesophagus to be cleared by secondary peristalsis. fraught. Further, it is recognised there is a lack of a gold Should the gradient be great, such as in chronic pulmo- standard diagnostic test ([3], p. 37). There are limita- nary disease or obesity, reflux may be increased. Delayed tions in the diagnostic equipment and physiological gastric emptying in the reflux patient is frequent and may understanding of the illness, and the symptoms are non- exacerbate reflux exposure. Peristalsis may be deficient specific. Unsurprisingly, surgery for laryngopharyngeal [7, 8] and the oesophagus not clear normally. Muco- reflux (LPR) has been dogged by poor results in con- sal resistance may be diminished such as in patients tradistinction to the good results obtained in refractory on prostaglandin inhibitors, chemotherapy, steroids or standard reflux disease. This review attempts to deal with having a chronic medical illness. Loss of tight junction some matters of standard reflux disease and surgery as integrity may play a role in symptomatology [9–11]. More well as the pathophysiology and management of LPR. severe disease may become evident with the presence of a hiatus hernia [12] and absolute reduction in the lower oesophageal sphincter tone [13, 14] with increasing lev- Symptoms els of reflux fluid within the oesophagus and increasing levels of oesophagitis evident at endoscopy [15]. The Montréal criteria largely recognises GORD by cardi- nal symptoms of heartburn and fluid regurgitation, usually considered more than once or twice per week [4]. Complications The Montréal definition also recognises atypical or extra- oesophageal reflux disease where symptoms merge into Oesophagitis and the oesophageal ulceration are com- the laryngopharynx, nasopharynx and lung and dental plications of reflux of gastric content. Continued inflam- erosion. Even this distinction is not simple; water brash mation may lead to the development of scarring and (the phenomenon of increased salivation) is often misin- strictures, deep ulceration and haemorrhage, inhalation terpreted by clinicians, and post nasal drip syndrome is of gastric contents causing aspiration pneumonia and the confusing to patient and clinician. Severe standard reflux development of Barrett’s oesophagus and subsequent can be associated with LPR symptoms and pulmonary risk of carcinoma. Barrett’s mucosa may pass through aspiration and usually reflects severe disease often in the the typical metaplasia-dysplasia-carcinoma sequence. supine position with gross flooding of the oesophagus. The risk of reflux causing carcinoma has been well rec- This is quite different from LPR disease where heartburn ognised especially demonstrated in a seminal article by and regurgitation are “silent” or less prominent. Alarm Lagergren et al. where the duration and severity of symp- symptoms such as the dysphagia or odynophagia (pain toms was positively associated with increasing rates of on swallowing), anaemia, haematemesis or weight loss oesophageal adenocarcinoma (Figs. 1, 2; [16]). must be identified expeditiously to exclude the onset of malignant complication. Diagnosis

Typical gastro-oesophageal reflux disease Historically, the diagnosis of reflux disease has largely been based on the symptoms of heartburn and regurgita- This condition is largely identified by the presence of tion. The response to therapy has been measured against symptomatology of heartburn and regurgitation and control of these symptoms. Symptomatic diagnosis con- occasional dysphagia in the presence of oesophagitis. tinues to be the recommendation of most gastroenter- It is recognised that 15–20 % of the adult population in ology societies probably due to the lack of sensitivity of Australia will suffer heartburn more than once per week endoscopy to diagnosis [17]. This recommendation con- [5]. This is similar to studies from the USA and one would tinues despite good study (the Diamond Study) showing expect throughout the Western world [1]. The burden of a sensitivity and specificity of the symptomatic diagnosis disease in the community is therefore quite substantial. of GORD of 62 and 67 %, respectively [18]. Objective diagnosis has hinged around performance of endoscopy or response to proton pump inhibitor

2 Laryngopharyngeal reflux: diagnosis, treatment and latest research 1 3 Review

Fig. 1 Columnar lined oesophagus under narrow band im- Fig. 3 HALO 90 radiofrequency ablation (RFA) for endoscopic aging: biopsies showed no dysplasia. CLE columnar lined treatment, as described in the text oesophagus only about 9 % of patients are diagnosable by endoscopy

once PPI is commenced. Its use is therefore largely for the exclusion of alternative diagnosis. A positive diagnosis of reflux can be made before treatment in up to 50 % of patients by mucosal change. To these indications for endoscopy, one could add male sex, age over 40, change in symptomatology and length and severity of symptoms possibly predictive of the development of carcinoma [16]. The rate of adenocarcinoma of the lower oesophagus is increasing in Western civilisation [20, 21]. Surveillance of patients identified with Barrett’s oesophagus is frequently recommended [5]. It is therefore worthwhile identifying the presence of Barrett’s oesophagus for purposes of prevention of dysplasia or carcinoma development. Radiofrequency ablation management by endoscopy has proven safe and effective for dysplasia in expert groups [22–24]. Guidelines for management of Barrett’s dysplasia and superficial carcinoma Fig. 2 Hemicircumferential polypoid tumour lower oesopha- are published (Fig. 3; [25–27]). gus: biopsies showed adenocarcinoma. ACE adenocarcinoma oesophagus Oesophagitis has been the mainstay of the diagnosis of reflux, but only 50 % of patients with heartburn and regurgitation will demonstrate any such acute change (PPI). Various gastroenterology societies have recom- (picture of oesophageal grading). It is graded according mended a trial of PPI, enabling the practitioner to treat by to the Los Angeles classification, which reflects the sever- medication. Endoscopy is not recommended initially for ity of reflux exposure and degree of damage and indi- heartburn and regurgitation. Only if the patient requires rectly the healing rates of medical therapy (Figs. 4, 5, 6). ongoing therapy to control symptoms (refractory disease) Hiatus hernia may be demonstrated but does not is endoscopy recommended [5]. The so-called PPI test confirm reflux disease diagnostically. The gold standard has been fashionable in the clinical diagnosis of GORD diagnostic test for reflux disease has been a 24-h pH study for a considerable period. Trust in this “test” is largely [28], but more recently it has become evident that symp- fallacious, having been shown in the Diamond Study that toms may occur due to non-acid reflux disease [29]. The “symptomatic response to esomeprazole was neither advent of impedance technology (tube study combined sensitive nor specific for diagnosis of GORD” [18]. with pH) identifying gas and non-acidic fluid as well as Endoscopy has been recommended for alarm symp- acidic fluid has added to the understanding of physiol- toms of dysphagia, odynophagia, haematemesis or ogy of this illness. This information may be displayed by weight loss and anaemia. Additionally it is recommended colour plot graphic (Figs. 7, 8; [30]). Automatic reporting if the diagnosis is unclear, where symptoms persist or may help guide the clinician to relevant “episodes” which are refractory to treatment, and when complications are can be confirmed or deleted. Biopsy of the oesophagus suspected [19]. However, it has been demonstrated that showing inflammatory cell infiltrate is not diagnostic of

1 3 Laryngopharyngeal reflux: diagnosis, treatment and latest research 3 Review

Fig. 6 Oesophagitis—grade C Fig. 4 Oesophagitis—grade A

Fig. 5 Oesophagitis—grade B Fig. 7 Oesophagitis—grade D reflux but can exclude eosinophilic oesophagitis as an alternative. DeMeester and Johnson initially developed a scoring in grading of oesophagitis. The Los Angeles classification system of diagnosis of reflux [28]. This has largely become system for oesophagitis is universally recognised [32]. the standard for diagnosis, utilised in patients where it had been unclear or prior to surgery to reduce failure of Medical treatment Lifestyle manoeuvres, loss of weight surgical therapy. Use of 24-h pH study may enable diagno- and antacid are commonly utilised and either single or sis in the patient group without oesophagitis, resistance double dose proton pump in addition (PPI). Approxi- to medical therapy or after commencement of therapy. mately 30 % of patients will have troublesome break- A small tube is passed trans-nasally, and electrode and through symptomatology on this therapy, and 10–20 % sensor are fixed 5 cm about the cardio-oesophageal junc- of patients will have unhealed oesophagitis [1, 19, 33, tion (COJ). Results are compared with established nor- 34]. General practice (family doctor) interview of these mals. Results are recorded by a data logger over a 24-h patients infrequently identifies breakthrough symp- period. More recently, the Bravo device (Given Imaging toms such as atypical chest pain or nocturnal proximal Ltd., Yoqneam 20692 Israel) has achieved similar results regurgitation symptoms, and the lack of efficacy of PPI is when placed by a remote transponder attached to the frequently undetected. Sometimes the lifestyle manage- oesophageal wall [31]. Increasing levels of acid exposure, ment and dietary restrictions grossly affect the quality of as seen by the 24-h pH study, show progressive change life of the patient and are frequently not considered. For

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Fig. 8 Graphic representation of impedance study. The yellow area indicates reflux, and the tracings indicate change in impedance across electrodes. The simplicity of the Klaus graph (Figs. 16, 17) is highlighted

patients failing PPI, nocturnal H2 antagonists have been recommended, but data now indicate the duration of efficacy is measured only in weeks [29]. Despite generally perceived safety of PPI therapy, it is emerging that there may be side effects at double dose and real rates of adverse events, including osteoporotic fracture, increased pneumonia and bowel infection [19, 36], and a recent report shows possible association with myocardial infarction, with or without clopidogrel use [37].

Surgical treatment It has been calculated by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) organisation in the USA that approximately 30 % of reflux patients experience inadequate medical therapy and are therefore candidates for surgery [38]. Surgery is however only pursued in approximately 3 % of those Fig. 9 Comparison of esomeprazole 40 mg and lansoprazole patients leaving an enormous gap in therapeutic man- in resolution of heartburn. Maximal effective response to med- agement and large numbers of patients with continued ication, 75 % [35] symptoms of oesophagitis. These patients would be rep- resented in the area above the curves (Figs. 9, 10). The gery, LARS) and is most frequently a 360° fundoplication. indications for surgery generally have been failure of The so-called tailored approach to ineffective oesopha- medical therapy for symptoms or oesophagitis. geal motility (IEM) has not been shown scientifically Before performing surgery, the oesophageal diagnostic necessary [1]. advisory panel [39] recommended endoscopy and con- Surgical outcome has been repeatedly demonstrated sidering reflux diagnostic with grade C or D oesopha- by meta-analysis and systematic review to exceed that of gitis or long segment Barrett’s oesophagus confirmed. medical [40]. Despite these proven outcomes, there con- Manometry and oesophageal pH monitoring were rec- tinues to be substantial discussion amongst the medical ommended in patients other than those diagnosed on community (non-surgical) about the potential for side the criteria above. High-resolution manometry at this effects and revision surgery. Reduced mobilisation of the stage has not been considered indicated for assessment fundus and some partial fundoplication techniques have for antireflux surgery [1]. Surgery is now predominantly improved effective outcome beyond the initial operation performed by laparoscopy (laparoscopic antireflux sur- of Rudolf Nissen [41]. While fundoplication commonly

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Fig. 12 Laparoscopic view of fundoplication under construc- tion. IVC inferior vena cava

Fig. 10 Comparison of esomeprazole 40 mg and pantoprazole in resolution of heartburn. Maximal effective response, by partial symptomatic outcome and incomplete, inad- 70–76 % [34] equate objective study and rapidly disappeared from use (EndoCinch: Bard, Murray Hill NJ, USA; Enteryx: Boston Scientific, Malborough Mass, USA; Enteryx injectable

polymer). Stretta® (Mederi Therapeutics Inc, Greenwich CT 06830 USW) continues under some investigation.

Atypical reflux disease

(Alternative terms: extra-oesophageal/supra-oesophageal/laryngopharyngeal reflux disease, LPR) There are several recognised atypical reflux syndromes described by the Montréal classification as laryngeal, cough, asthma and dental [4]. We would propose that some sinus disease and middle ear infection may well be also become recognised as separate syndromes. Naso- pharyngeal reflux was demonstrated by DelGaudio [43]. Improvement in chronic sinusitis has been noted with reflux therapy [44]. Symptoms frequently associated with a laryngeal and Fig. 11 Endoscopic retrograde view of fundoplication in pharyngeal diagnosis of reflux include a globus sensa- cardia tion, frequent throat clearing, cough, hoarseness, throat pain and excessive mucus in the throat. Sinus symp- bears this eponym, it has passed through several itera- toms may be recognised as nasal discharge, central or tions and in most hands is generally quite different from lateral facial pain, earache, ear dullness and episodes of that originally described. Recently in this journal, Kristo infection. Dentists now frequently describe loss of tooth et al. [42] have argued for specialised centres of excel- enamel as being related to reflux [4, 45–49]. Gross pulmo- lence to obtain adequate improved outcomes (Figs. 11, nary aspiration has been recognised in a small percent- 12). age of patients for a considerable amount of time. Reflux Some endoscopic antireflux therapies are showing is strongly implicated in the rejection of lung transplant promise [38]; however, many other techniques while grafts, and antireflux surgery makes more than a 20 % initially appearing favourable have not stood the test difference to graft survival [50–54]. What is not read- of time. It remains to be seen whether these new tech- ily apparent however are lesser grades of pulmonary niques such as Linx® (Torax Medical, St Paul MN 55126, reflux disease, which are less symptomatic and perhaps USA), where a magnetic cuff is placed around the COJ, are implicated in pulmonary fibrosis, bronchiectasis, or trans-oral incisional fundoplication (TIF: Endogas- occasional lung infection and an asthma-like syndrome. tric Solutions, Remond WA 98052, USA) ultimately pass Reflux cough syndrome is particularly well recognised the test of time. Comparison by randomised controlled [55–58]. trial against medical and surgical therapy has not been Many patients do not describe typical heartburn and adequate. Multiple other endoscopic techniques were regurgitation. This condition, because of the lack of initially greeted with enthusiasm by the non-surgical gas- heartburn, has been often described as “silent” reflux. troenterology community and tended only to be judged The Diamond study identified 49 % of patients having

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atypical symptomatology in a community-based study Reduced cough threshold has been identified in gen- [18]. esis of symptomatology and has been demonstrated by Complications in all these organs may occur with onset capsaicin testing and other irritant agents; it is associated of vocal granuloma, voice change interfering with work, with non-acid reflux on impedance studies [84, 85]. excessive cough-reducing quality of life, sinus infection, Falk et al. (Fig. 13; [86]) reported a tight correlation dental caries, early infection often requiring surgery in demonstrated by cluster analysis suggesting possible children, asthma and hospital admission, gross pulmo- physiological causes of proximal reflux disease. Patients nary infection and pulmonary damage and is implicated with a strong clinical likelihood of LPR were investigated in the loss of graft in the lung transplantation [4, 19, 59– by two channel impedance 24-h pH study and a stan- 64]. There is concern that some dysplasia and carcinoma dardised reflux scintigraphic study. Strong association of the larynx may also be reflux related [65]. was found between increasing levels of proximal acid exposure, diminished oesophageal motility, scintigraphic pulmonary aspiration and scintigraphic pharyn- Pathophysiology of atypical reflux symptoms geal contamination raising the prospect of a pathway for further investigation. Potentially damaging substances are present within reflux fluids which may cause damage within the pharynx including acid, pepsin, bile salts, bacteria, pancreatic Diagnosis proteolytic agents and pepsin (remaining active pH up to 6 [66]). Pepsin has been demonstrated in the laryngeal Atypical symptoms mucosa and middle ear fluid [67, 68]. IEM and poor oesophageal clearance are strongly Atypical symptoms are largely non-specific and may arise associated with atypical proximal symptomatology [69– due to non-reflux causes from the head and neck, trachea 75]. A recent study in our group has shown that reduction and bronchus, pulmonary substance, medications and in clearance in the oesophagus measured by impedance generalised systemic disorder. This makes it extremely is predictive of proximal reflux identified in scintigraphic difficult to identify and diagnose a homogenous patient studies [76]. Such clearance abnormally was also closely group which is a likely cause of the difficulty in finding correlated with worsening peristaltic function of the an adequate treatment due to lack of a diagnostic gold oesophagus. standard [3]. Additionally, an oesophago trachea neural mediated Many practitioners and studies have called into ques- bronchial reflex mechanism has also been suggested with tion the very existence of supra-oesophageal reflux dis- experimental supportive evidence from several authors ease [87, 88]. However supra-oesophageal reflux disease [77, 78]. It has been the “Concord group” (see Appendix) has now been included in the classification of Montréal experience that a significant proportion of patients with [4, 18]. Symptoms score has been widely utilised in ENT proximal reflux do not have heartburn and are so tradi- [89, 90]. tionally designated “silent” perhaps due to medicine’s ignorance of this entity [69, 77, 79, 80]. Multiple research- Laryngoscopy ers however are aware of this “silent” phenomenon, as interestingly is the patient population, even if the illness Signs of inflammation may be identified in the larynx and is treated with scepticism by conventional medicine [55, pharynx and have been attributed to chronic LPR disease. 81–83]. Consistent guidelines and consensus for the diagnosis of LPR is lacking [91]. Laryngeal signs for LPR considered by ENT surgeons as suggestive of diagnosis are posterior

laryngeal erythema, intra-arytenoid bar and cobbleston- ing, oedema and granuloma [91]. However, high intraobserver error rates have been identified in this area [92], and these changes have been observed in many normal volunteers [93, 94]. Laryngoscopy findings therefore have largely been demonstrated not accurate due to intraobserver variability [92, 95, 96] and lack of sensitivity [97]. A 2007 study by Vavricka showed no difference between normals and the atypical reflux group [98]. However, Habermann et al. [90] have seen substantial clinical value in a blinded cohort study using ENT symptoms and examination. Belafsky et al. [99] have demonstrated some reliability of a scoring system of examination (Fig. 14). This uncertainty has largely lead to the recognition Fig. 13 Physiological factors associated with laryngopharyn- that laryngoscopy as a diagnostic tool is limited to per- geal reflux symptoms—a cohort study [86] haps the most severe changes of laryngeal inflammation

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potentially better ability to diagnose LPR due to the ability to identify both acid and non-acid reflux events [103]. Poor correlation however has been shown between laryngeal changes thought to be due to reflux and impedance pH studies [97, 104]. Normal proximal oesophageal values are in dispute with substantial difference in values in different series [39, 105, 106]. The situation is not definitive, and a diagnostic test for proximal reflux and laryngopharyngeal symptoms remains elusive. Use of a pharyngeal recording site is being trialled but is defec- tive on a number of counts including a lack of identifiable normal values, substantial intraobserver variability [107] and difficulty placing the catheter accurately. Further study will be required to determine the predictive value of results obtained by this technique. Nasal secretions can be acidic.

PPI test Fig. 14 Laryngoscopic image of a vocal granuloma [100] While a response to PPI has been considered by some to indicate the presence of reflux disease in the laryngo including granuloma, subglottic stenosis and dysplasia pharynx, the Cochrane review [108] found no high- [93]. quality trials, and a systematic review and meta-analysis failed to demonstrate superiority of PPI over placebo in Gastroscopy in atypical reflux disease the LPR patient group [109–111].

Reports have demonstrated that less than 30 % of patients Exclusion of other diseases with extra-oesophageal manifestations of reflux have oesophagitis [91, 101]. Clearly distal oesophagitis does Exclusion of other diseases is required (pulmonary, not discriminate which individual has proximal reflux smoking, allergies, postnasal drip, other laryngeal dis- and so cannot be utilised for the presence of proximal ease, pharyngeal infection, vocal abuse, environmental reflux or identification of reflux in the pharynx or lung. irritants, alcohol abuse, viral disorder, drugs, psychoso- Changes seen in passing the larynx by gastroenterology matic depression) to name but a few [112]. Laryngopha- must be discounted in a similar fashion to laryngos- ryngeal syndromes can be more confidently predicted if copy. Similarly, visualisation of oesophageal erythema postnasal drip, medical cause of cough, smoking, abnor- has never been diagnostic of reflux. Biopsy, while it may mality on chest X-ray and stable management of asthma exclude diagnosis like eosinophilic oesophagitis, is also are excluded. In this circumstance, a multidisciplinary not diagnostic of reflux disease proximally or distally. approach is practically found to be of value in selecting Gastroscopy therefore is of limited diagnostic use in LPR a group of patients with a higher pretest probability of patients apart from exclusion of other diseases. reflux-caused abnormality. A multidisciplinary approach of ENT, respiratory medicine, oesophageal physiology Tube-based studies and surgery may be clinically valuable and has certainly been the “Concord group” experience. The 24-h PH study may be considered to have been the gold standard for diagnosis of typical reflux disease in the past; however, there continues to be controversy about Experimental the value of pH recording in the proximal oesophagus. Vaezi et al. [101], Vakil et al. [4] and Koufman [102] report Pepsin testing the sensitivity of oesophageal and pharyngeal monitoring of pH ranging from 50 to 80 % making diagnosis doubt- Pepsin has been found in the middle ear of children with ful. There remains an intrinsic deficiency of pH recording otitis media [64]. Pepsin may also be assayed from saliva reflux as it measures acid as a surrogate of reflux fluid. and from bronchial lavage. A pepsin assay (Peptest™: Acid is lacking in many episodes of reflux proximally as RDBiomed Limited, Hull HU16 5JQ, UK) is now avail- neutralisation occurs and a variable number of reflux able, but techniques of collection and sites have yet to be episodes are non-acid at outset. Measurement of acid is proven of clinical value [113–116]. Nonetheless, it con- therefore a poor surrogate for the detection of the pres- tinues to raise the likelihood that proximal reflux disease ence of refluxed fluid (Figs. 15, 16). can cause many different phenomena. The advent of intraluminal impedance and 24-h PH Pepsin tests and bile acids have been investigated in monitoring was initially greeted with enthusiasm for a studies in probable reflux cough patients to identify gas-

8 Laryngopharyngeal reflux: diagnosis, treatment and latest research 1 3 Review

Fig. 15 Colour plot graphic of impedance tracing; delayed clearance of fluid in the mid-oesophagus

Fig. 16 Colour plot graphic of belch followed by poor reflux clearance 30 s. Blue vertical is belch followed by reflux of fluid

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tric contents in the regions outside the stomach. Both accumulation of reflux in the pharynx (Fig. 18) predictive sputum and bronchial lavage have been investigated. of symptoms and lung disease [139]. Studies have not demonstrated a difference between healthy controls as yet [50, 117–119]. The usefulness of this test remains uncertain in cough and pulmonary dis- Medical treatment ease. Pepsin has been identified in the middle ear aspiration fluid especially in neonates suggesting a cause for a Lifestyle modification subset of middle ear infection [64, 113, 114, 120]. In the future, this test may prove to be sensitive and specific for Pearson [141] has demonstrated dietary and behaviour diagnosis of LPR disease [121, 122]. modification to be effective in typical reflux management and reduction of weight in the obese being demonstrated to improve gastro-oesophageal reflux symptoms pH pharyngeal catheters [142, 143]. The effectiveness of weight loss does however remain controversial, and whether it improves objective Standard catheters in the pharynx are considered inac- measures is uncertain. There is little evidence that life- curate [123–125], but meta-analysis suggested it may be style change demonstrated in typical gastro-oesophageal of value [126]. New devices are under development due reflux symptomatology also benefits the atypical LPR to the inaccuracy of standard catheters placed in the group. pharynx due to the artefact from movement and the drying of the electrode (ResTech, San Diego, CA 92127) [127]. No clinical data are available, and the usefulness of this PPI has to be considered limited as it is apparent that much proximal reflux is non-acid and so will not be evident on While theoretically an attractive treatment, episodes of acid (pH) pressure alone. Low-acid and non-acid fluids reflux high in the oesophagus are saliva and relatively are increasingly being recognised by clinicians as being non-acidic fluid by the time of passage to the upper symptomatic in some patients [128–130]. Even if the new oesophagus. Recent meta-analysis of randomised tri- pH devices are able to accurately register acid in the als demonstrated little advantage over that of placebo pharynx, they remain intrinsically inaccurate due to the in patients with suspected chronic laryngitis from reflux acid pressure being variable in reflux fluid [131]. [111]. Similarly in a review by Reimer and Bytzer, no difference was convincingly shown between the PPI therapy and placebo in randomised control study [144]. Addition

Scintigraphy of nocturnal H2RA has not been shown effective [145, 146]. Identification of fluid from the stomach above the cri- copharyngeus may select a group of patients with reflux-mediated extra-oesophageal symptoms. Isotope Reflux inhibition in gastro-oesophageal fluid has an intrinsic potential value as it can be traced and is not susceptible to arte- Lesogaberan has been shown to reduce the rate of tran- fact, drying or movement as are the catheter-based tests. sient lower oesophageal sphincter relaxation [147], but It does not require the presence of acid as a “marker” is of uncertain clinical effect and in our experience has of the presence of reflux fluid. It is a positive identifier not made a great deal of difference to LPR symptoms, of gastric fluid. Scintigraphy for reflux has been utilised although baclofen has been shown to decrease acid in children for many years, and modifications of these reflux events and acid exposure [148, 149]. However, techniques have been shown to provide good details of use of baclofen has been limited by side effects in our GORD and lung aspiration [79, 132–138]. Results vary experience. Results overall have been disappointing in depending upon technique [133, 135, 137, 138]. Stan- association with PPI [147, 150]. Further studies require dardisation of technique therefore is vital for reproduc- objective scores for cough to identify treatment affects ibility of this test. Results in our series [139] are similar more accurately [151]. Baclofen may theoretically benefit to the study of Bestetti et al. [140]. Symptoms were also reflux cough by inhibition of the reflux and cough effect tightly correlated with pharyngeal exposure in our report [152–155]. [139]. Usefulness of this technique remains to be proved but may obviate invasive intrinsically misguided (testing for acid) and inaccurate tests (intraobserver variability) Prokinetic but requires a particular standardised technique with the rigid approach to methodology and preparation of Prokinetic agents while theoretically beneficial have not contrast. been shown to be of any value in LPR disease [141]. A Scintigraphy has the ability to show pulmonary and recent systematic review found articles giving conflicting pharyngeal reflux (Fig. 16b, 17a) and can show temporal evidence regarding the effectiveness of prokinetic agents and were not able to make recommendations [156].

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Fig. 17 Scintigraphy. a Scintigraphic images of reflux and pulmonary aspiration. b Scintigraphic counts at line of interrogation

Fig. 18 Scintigraphy showing rising levels of pharyngeal contamination

Cough suppression Surgical treatment

Short 3-day courses of prednisone 25 mg have occasion- Mainie et al. [163] report a group of surgical patients ally given relief albeit transient, anecdotally. In a search with selection by multichannel intraluminal imped- of the literature (PubMed), dextromethorpan has shown ance pH monitoring in a group of PPI unresponsive LPR no value, although it has been recommended [157]. Ket- symptoms. Patients with abnormal non-acid reflux were amine has not proven helpful [158]. Morphine and gaba- selected for antireflux surgery. Excellent results were pentin have been symptomatically useful, but limited by obtained in a high proportion of patients. In contradis- dependence [159, 160]. tinction however, results of surgery have been generally disappointing, adequate results being reported in the 60 % range [60, 164–171]. We have reported a group of Pain modulation patients with good results for LPR symptoms with favourable results in excess of 90 % [80] similarly to the group of Treatment of patients with sensitive oesophagus and Mainie et al. [29] suggesting that adequate identification partial response to PPI may benefit from visceral pain of pharyngeal reflux without recourse to acid detection management [107]. Other groups have also had a favour- may have value. It may be that accurate determination able experience with pain modulation in non-erosive of reflux contamination proximally may allow a group of reflux disease and LPR [161, 162]. patients to be adequately selected for surgery. Multiple studies of surgical therapy while having less than uni- form results have substantial response rates in 60–80 % of selected patients, with improvements in asthma control, reduction in cough and throat symptoms range [60, 164–171].

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The difficulty remains, it seems; in selection of appro- 8. Patti MG, Goldberg HI, Arcerito M, Bortolasi L, Tong J, Way priate patient groups for surgery, rather than doubt about LW. Hiatal hernia size affects lower esophageal sphincter function, esophageal acid exposure, and the degree of disease existence. Results obtained by our group are by mucosal injury. Am J Surg. 1996;171(1):182–6. http://www. multidisciplinary exclusion of alternative disease and a ncbi.nlm.nih.gov/pubmed/8554137. combination of standardised reflux scintigraphy and ini- 9. Weijenborg PW, Smout AJPM, Verseijden C, van Veen tially 2 channel 24-h pH study, later evolving to 2 channel HA, Verheij J, de Jonge WJ, et al. Hypersensitivity to acid impedance studies (proximal and distal). The gold stan- is associated with impaired esophageal mucosal integ- dard accurate diagnostic test predictive of symptoms and rity in patients with gastroesophageal reflux disease with therapeutic outcome, however, remains elusive. Medi- and without esophagitis. AJP Gastrointest Liver Physiol. 2014;307(3):G323–9. http://ajpgi.physiology.org/cgi/ cal treatment remains empirical, and evidence suggests doi/10.1152/ajpgi.00345.2013. there is a low prospect of amelioration of symptoms of 10. Björkman EVC, Edebo A, Oltean M, Casselbrant A. Esoph- LPR. Occasional patients seem to gain some symptom ageal barrier function and tight junction expression in reduction. healthy subjects and patients with gastroesophageal reflux disease: functionality of esophageal mucosa exposed Compliance with ethical standards to bile salt and trypsin in vitro. Scand J Gastroenterol. 2013;48(10):1118–26. http://www.tandfonline.com/doi/ful l/10.3109/00365521.2013.828772. Conflict of interest 11. Mönkemüller K, Wex T, Kuester D, Fry LC, Kandulski A, The authors declare no conflict of interest. Kropf S, et al. Role of tight junction proteins in gastroesophageal reflux disease. 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