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Laryngopharyngeal reflux: diagnosis, treatment and latest research 11 3

SummaryAim A review of the recent changes in understand-ing of laryngopharyngeal and extra-oesophageal reflux symptoms.

Method Literature search over 7 years (2008–2015) and relevant historical cited articles.

Results Modern investigation more clearly shows a subgroup of patients with intermittent full column oesophago-gastric-reflux-causing symptoms. Multiple other sites in the lung, head and neck may also be impli-cated in the reflux disease process.

Conclusion Understanding of extra-oesophageal reflux symptomology is evolving. New equipment and techniques suggest further areas of research, and as yet effective therapy remains elusive for some.

Keywords Laryngopharyngeal reflux · Gastro-oesophageal reflux · Laparoscopic fundoplication

Aim

Review the recent changes in the evaluation of cause, investigation and therapy in the evolving area of extra-oesophageal symptoms of reflux disease.

Method

Ongoing review of the literature has been pursued by the senior author (GLF) of PubMed and the National Centre for Biotechnology Information (NCBI) at the National Library of Medicine (NLM). Search was conducted monthly using (“laryngopharyngeal reflux”[MeSH] OR LARYNGOPHARYNGEAL REFLUX[Title/Abstract]) OR ((COUGH[Title/Abstract] OR “cough”[MeSH]) AND (“gastroesophageal reflux”[MeSH] OR “GASTROESOPH-AGEAL REFLUX”[Title/Abstract] OR “GASTROOESOPH-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-GOPHARYNGEAL REFLUX[MESH] OR REFLUX) AND IMPEDANCE and (“Barrett Esophagus”[MAJR] AND DYSPLASIA) OR (“Barrett’s dysplasia”) OR (Barrett*[ti] AND DYSPLASIA[ti]).

Bibliographies of multiple articles contained further article references from earlier years and have been uti-lised selectively in discussion. The references were then utilised to elucidate the multiple topics addressed in the review. Criteria for selection were relevance, English lan-guage, and publication in reputable peer-reviewed jour-nals unless of substantial significance.

G. L. Falk, MBBS, FRACS ()Suite 29, 12-18 Tryon Rd,NSW 2070 Lindfield, Australiae-mail: sydney.heartburn@gmail.com

G. L. Falk, MBBS, FRACSUniversity of Sydney,Sydney, Australia

G. L. Falk, MBBS, FRACSMacquarie University,Sydney, Australia

S. J. Vivian, BASydney Heartburn Clinic,Lindfield, Australiae-mail: sarahjaynevivian@gmail.com

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

Eur SurgDOI 10.1007/s10353-016-0385-5

Laryngopharyngeal reflux: diagnosis, treatment and latest research

G. L. Falk1,2,3 · S. J. Vivian4

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

The spectrum of gastro-oesophageal reflux disease

Reflux disease, in its various forms, affects a large group of society. Typical gastro-oesophageal reflux disease (GORD) affects at least 10 % of individuals in Western society [1]. And it has been estimated that about 10 % of ear, nose and throat specialty (ENT) workload reflects possible atypical reflux patients [2]. While typical reflux disease has long been relatively easy to diagnose both symptomatically and on testing, extra-oesophageal dis-ease is still not adequately diagnosed, and treatment is fraught. Further, it is recognised there is a lack of a gold standard diagnostic test ([3], p.  37). There are limita-tions in the diagnostic equipment and physiological understanding of the illness, and the symptoms are non-specific. Unsurprisingly, surgery for laryngopharyngeal reflux (LPR) has been dogged by poor results in con-tradistinction to the good results obtained in refractory standard reflux disease. This review attempts to deal with some matters of standard reflux disease and surgery as well as the pathophysiology and management of LPR.

Symptoms

The Montréal criteria largely recognises GORD by cardi-nal symptoms of heartburn and fluid regurgitation, usu-ally considered more than once or twice per week [4]. The Montréal definition also recognises atypical or extra-oesophageal reflux disease where symptoms merge into the laryngopharynx, nasopharynx and lung and dental erosion. Even this distinction is not simple; water brash (the phenomenon of increased salivation) is often misin-terpreted by clinicians, and post nasal drip syndrome is confusing to patient and clinician. Severe standard reflux can be associated with LPR symptoms and pulmonary aspiration and usually reflects severe disease often in the supine position with gross flooding of the oesophagus. This is quite different from LPR disease where heartburn and regurgitation are “silent” or less prominent. Alarm symptoms such as the dysphagia or odynophagia (pain on swallowing), anaemia, haematemesis or weight loss must be identified expeditiously to exclude the onset of malignant complication.

Typical gastro-oesophageal reflux disease

This condition is largely identified by the presence of symptomatology of heartburn and regurgitation and occasional dysphagia in the presence of oesophagitis. It is recognised that 15–20 % of the adult population in Australia will suffer heartburn more than once per week [5]. This is similar to studies from the USA and one would expect throughout the Western world [1]. The burden of disease in the community is therefore quite substantial.

Pathophysiology

The anomalousness of reflux disease hinges around the abnormal frequency or duration of exposure to gastric contents within the tubular oesophagus. There is a bal-ance between mucosal attack and the mucosal defences and between clearance of the oesophagus and frequency, volume and concentration of reflux fluid. In lesser cases of reflux disease, transient lower oesophageal sphincter relaxation occurs (TLOSR) [6] and the trans-diaphrag-matic pressure gradient allows fluid to pass upwards into the oesophagus to be cleared by secondary peristalsis. Should the gradient be great, such as in chronic pulmo-nary disease or obesity, reflux may be increased. Delayed gastric emptying in the reflux patient is frequent and may exacerbate reflux exposure. Peristalsis may be deficient [7, 8] and the oesophagus not clear normally. Muco-sal resistance may be diminished such as in patients on prostaglandin inhibitors, chemotherapy, steroids or having a chronic medical illness. Loss of tight junction integrity may play a role in symptomatology [9–11]. More 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-els of reflux fluid within the oesophagus and increasing levels of oesophagitis evident at endoscopy [15].

Complications

Oesophagitis and the oesophageal ulceration are com-plications of reflux of gastric content. Continued inflam-mation may lead to the development of scarring and strictures, deep ulceration and haemorrhage, inhalation of gastric contents causing aspiration pneumonia and the development of Barrett’s oesophagus and subsequent risk of carcinoma. Barrett’s mucosa may pass through the typical metaplasia-dysplasia-carcinoma sequence. The risk of reflux causing carcinoma has been well rec-ognised especially demonstrated in a seminal article by Lagergren et al. where the duration and severity of symp-toms was positively associated with increasing rates of oesophageal adenocarcinoma (Figs. 1, 2; [16]).

Diagnosis

Historically, the diagnosis of reflux disease has largely been based on the symptoms of heartburn and regurgita-tion. The response to therapy has been measured against control of these symptoms. Symptomatic diagnosis con-tinues to be the recommendation of most gastroenter-ology societies probably due to the lack of sensitivity of endoscopy to diagnosis [17]. This recommendation con-tinues despite good study (the Diamond Study) showing a sensitivity and specificity of the symptomatic diagnosis of GORD of 62 and 67 %, respectively [18].

Objective diagnosis has hinged around performance of endoscopy or response to proton pump inhibitor

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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 diagno-sis 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 oesopha-gus is increasing in Western civilisation [20, 21].

Surveillance of patients identified with Barrett’s oesophagus is frequently recommended [5]. It is there-fore worthwhile identifying the presence of Barrett’s oesophagus for purposes of prevention of dysplasia or carcinoma development. Radiofrequency ablation man-agement by endoscopy has proven safe and effective for dysplasia in expert groups [22–24]. Guidelines for man-agement of Barrett’s dysplasia and superficial carcinoma are published (Fig. 3; [25–27]).

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 (picture of oesophageal grading). It is graded according to the Los Angeles classification, which reflects the sever-ity of reflux exposure and degree of damage and indi-rectly the healing rates of medical therapy (Figs. 4, 5, 6).

Hiatus hernia may be demonstrated but does not confirm reflux disease diagnostically. The gold standard diagnostic test for reflux disease has been a 24-h pH study [28], but more recently it has become evident that symp-toms may occur due to non-acid reflux disease [29]. The advent of impedance technology (tube study combined with pH) identifying gas and non-acidic fluid as well as acidic fluid has added to the understanding of physiol-ogy of this illness. This information may be displayed by colour plot graphic (Figs. 7, 8; [30]). Automatic reporting may help guide the clinician to relevant “episodes” which can be confirmed or deleted. Biopsy of the oesophagus showing inflammatory cell infiltrate is not diagnostic of

(PPI). Various gastroenterology societies have recom-mended a trial of PPI, enabling the practitioner to treat by medication. Endoscopy is not recommended initially for heartburn and regurgitation. Only if the patient requires ongoing therapy to control symptoms (refractory disease) is endoscopy recommended [5]. The so-called PPI test has been fashionable in the clinical diagnosis of GORD for a considerable period. Trust in this “test” is largely fallacious, having been shown in the Diamond Study that “symptomatic response to esomeprazole was neither sensitive nor specific for diagnosis of GORD” [18].

Endoscopy has been recommended for alarm symp-toms of dysphagia, odynophagia, haematemesis or weight loss and anaemia. Additionally it is recommended if the diagnosis is unclear, where symptoms persist or are refractory to treatment, and when complications are suspected [19]. However, it has been demonstrated that

Fig. 3 HALO 90 radiofrequency ablation (RFA) for endoscopic treatment, as described in the text

Fig. 2 Hemicircumferential polypoid tumour lower oesopha-gus: biopsies showed adenocarcinoma. ACE adenocarcino-ma oesophagus

Fig. 1 Columnar lined oesophagus under narrow band im-aging: biopsies showed no dysplasia. CLE columnar lined oesophagus

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

in grading of oesophagitis. The Los Angeles classification system for oesophagitis is universally recognised [32].

Medical treatment Lifestyle manoeuvres, loss of weight and antacid are commonly utilised and either single or double dose proton pump in addition (PPI). Approxi-mately 30 % of patients will have troublesome break-through symptomatology on this therapy, and 10–20 % of patients will have unhealed oesophagitis [1, 19, 33, 34]. General practice (family doctor) interview of these patients infrequently identifies breakthrough symp-toms such as atypical chest pain or nocturnal proximal regurgitation symptoms, and the lack of efficacy of PPI is frequently undetected. Sometimes the lifestyle manage-ment and dietary restrictions grossly affect the quality of life of the patient and are frequently not considered. For

reflux but can exclude eosinophilic oesophagitis as an alternative.

DeMeester and Johnson initially developed a scoring system of diagnosis of reflux [28]. This has largely become the standard for diagnosis, utilised in patients where it had been unclear or prior to surgery to reduce failure of surgical therapy. Use of 24-h pH study may enable diagno-sis in the patient group without oesophagitis, resistance to medical therapy or after commencement of therapy. A small tube is passed trans-nasally, and electrode and sensor are fixed 5 cm about the cardio-oesophageal junc-tion (COJ). Results are compared with established nor-mals. Results are recorded by a data logger over a 24-h period. More recently, the Bravo device (Given Imaging Ltd., Yoqneam 20692 Israel) has achieved similar results when placed by a remote transponder attached to the oesophageal wall [31]. Increasing levels of acid exposure, as seen by the 24-h pH study, show progressive change

Fig. 7 Oesophagitis—grade D

Fig. 6 Oesophagitis—grade C

Fig. 5 Oesophagitis—grade B

Fig. 4 Oesophagitis—grade A

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Laryngopharyngeal reflux: diagnosis, treatment and latest research 51 3

gery, LARS) and is most frequently a 360° fundoplication. The so-called tailored approach to ineffective oesopha-geal motility (IEM) has not been shown scientifically necessary [1].

Surgical outcome has been repeatedly demonstrated by meta-analysis and systematic review to exceed that of medical [40]. Despite these proven outcomes, there con-tinues to be substantial discussion amongst the medical community (non-surgical) about the potential for side effects and revision surgery. Reduced mobilisation of the fundus and some partial fundoplication techniques have improved effective outcome beyond the initial operation of Rudolf Nissen [41]. While fundoplication commonly

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 patients leaving an enormous gap in therapeutic man-agement and large numbers of patients with continued symptoms of oesophagitis. These patients would be rep-resented in the area above the curves (Figs.  9, 10). The indications for surgery generally have been failure of medical therapy for symptoms or oesophagitis.Before performing surgery, the oesophageal diagnostic advisory panel [39] recommended endoscopy and con-sidering reflux diagnostic with grade C or D oesopha-gitis or long segment Barrett’s oesophagus confirmed. Manometry and oesophageal pH monitoring were rec-ommended in patients other than those diagnosed on the criteria above. High-resolution manometry at this stage has not been considered indicated for assessment for antireflux surgery [1]. Surgery is now predominantly performed by laparoscopy (laparoscopic antireflux sur-

Fig. 9 Comparison of esomeprazole 40 mg and lansoprazole in resolution of heartburn. Maximal effective response to med-ication, 75 % [35]

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

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

by partial symptomatic outcome and incomplete, inad-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-oesopha-geal/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 pharyngeal diagnosis of reflux include a globus sensa-tion, frequent throat clearing, cough, hoarseness, throat pain and excessive mucus in the throat. Sinus symp-toms may be recognised as nasal discharge, central or lateral facial pain, earache, ear dullness and episodes of infection. Dentists now frequently describe loss of tooth enamel as being related to reflux [4, 45–49]. Gross pulmo-nary aspiration has been recognised in a small percent-age of patients for a considerable amount of time. Reflux is strongly implicated in the rejection of lung transplant grafts, and antireflux surgery makes more than a 20 % difference to graft survival [50–54]. What is not read-ily apparent however are lesser grades of pulmonary reflux disease, which are less symptomatic and perhaps are implicated in pulmonary fibrosis, bronchiectasis, occasional lung infection and an asthma-like syndrome. Reflux cough syndrome is particularly well recognised [55–58].

Many patients do not describe typical heartburn and regurgitation. This condition, because of the lack of heartburn, has been often described as “silent” reflux. The Diamond study identified 49 % of patients having

bears this eponym, it has passed through several itera-tions and in most hands is generally quite different from that originally described. Recently in this journal, Kristo et al. [42] have argued for specialised centres of excel-lence to obtain adequate improved outcomes (Figs.  11, 12).

Some endoscopic antireflux therapies are showing promise [38]; however, many other techniques while initially appearing favourable have not stood the test of time. It remains to be seen whether these new tech-niques such as Linx® (Torax Medical, St Paul MN 55126, USA), where a magnetic cuff is placed around the COJ, or trans-oral incisional fundoplication (TIF: Endogas-tric Solutions, Remond WA 98052, USA) ultimately pass the test of time. Comparison by randomised controlled trial against medical and surgical therapy has not been adequate. Multiple other endoscopic techniques were initially greeted with enthusiasm by the non-surgical gas-troenterology community and tended only to be judged

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

Fig. 11 Endoscopic retrograde view of fundoplication in cardia

Fig. 10 Comparison of esomeprazole 40 mg and pantopra-zole in resolution of heartburn. Maximal effective response, 70–76 % [34]

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Reduced cough threshold has been identified in gen-esis of symptomatology and has been demonstrated by capsaicin testing and other irritant agents; it is associated with non-acid reflux on impedance studies [84, 85].

Falk et al. (Fig.  13; [86]) reported a tight correlation demonstrated by cluster analysis suggesting possible physiological causes of proximal reflux disease. Patients with a strong clinical likelihood of LPR were investigated by two channel impedance 24-h pH study and a stan-dardised reflux scintigraphic study. Strong association was found between increasing levels of proximal acid exposure, diminished oesophageal motility, scinti-graphic pulmonary aspiration and scintigraphic pharyn-geal contamination raising the prospect of a pathway for further investigation.

Diagnosis

Atypical symptoms

Atypical symptoms are largely non-specific and may arise due to non-reflux causes from the head and neck, trachea and bronchus, pulmonary substance, medications and generalised systemic disorder. This makes it extremely difficult to identify and diagnose a homogenous patient group which is a likely cause of the difficulty in finding an adequate treatment due to lack of a diagnostic gold standard [3].

Many practitioners and studies have called into ques-tion the very existence of supra-oesophageal reflux dis-ease [87, 88]. However supra-oesophageal reflux disease has now been included in the classification of Montréal [4, 18]. Symptoms score has been widely utilised in ENT [89, 90].

Laryngoscopy

Signs of inflammation may be identified in the larynx and pharynx and have been attributed to chronic LPR disease. 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 intrao-bserver 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 intraob-server 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 that laryngoscopy as a diagnostic tool is limited to per-haps the most severe changes of laryngeal inflammation

atypical symptomatology in a community-based study [18].

Complications in all these organs may occur with onset of vocal granuloma, voice change interfering with work, excessive cough-reducing quality of life, sinus infection, dental caries, early infection often requiring surgery in children, asthma and hospital admission, gross pulmo-nary infection and pulmonary damage and is implicated in the loss of graft in the lung transplantation [4, 19, 59–64]. There is concern that some dysplasia and carcinoma of the larynx may also be reflux related [65].

Pathophysiology of atypical reflux symptoms

Potentially damaging substances are present within reflux fluids which may cause damage within the phar-ynx including acid, pepsin, bile salts, bacteria, pancreatic proteolytic agents and pepsin (remaining active pH up to 6 [66]). Pepsin has been demonstrated in the laryngeal mucosa and middle ear fluid [67, 68].

IEM and poor oesophageal clearance are strongly associated with atypical proximal symptomatology [69–75]. A recent study in our group has shown that reduction in clearance in the oesophagus measured by impedance is predictive of proximal reflux identified in scintigraphic studies [76]. Such clearance abnormally was also closely correlated with worsening peristaltic function of the oesophagus.

Additionally, an oesophago trachea neural mediated bronchial reflex mechanism has also been suggested with experimental supportive evidence from several authors [77, 78]. It has been the “Concord group” (see Appendix) experience that a significant proportion of patients with proximal reflux do not have heartburn and are so tradi-tionally designated “silent” perhaps due to medicine’s ignorance of this entity [69, 77, 79, 80]. Multiple research-ers however are aware of this “silent” phenomenon, as interestingly is the patient population, even if the illness is treated with scepticism by conventional medicine [55, 81–83].

Fig. 13 Physiological factors associated with laryngopharyn-geal reflux symptoms—a cohort study [86]

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potentially better ability to diagnose LPR due to the abil-ity 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 imped-ance pH studies [97, 104]. Normal proximal oesophageal values are in dispute with substantial difference in val-ues 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

While a response to PPI has been considered by some to indicate the presence of reflux disease in the laryngo pharynx, the Cochrane review [108] found no high-quality trials, and a systematic review and meta-analysis failed to demonstrate superiority of PPI over placebo in the LPR patient group [109–111].

Exclusion of other diseases

Exclusion of other diseases is required (pulmonary, smoking, allergies, postnasal drip, other laryngeal dis-ease, pharyngeal infection, vocal abuse, environmental irritants, alcohol abuse, viral disorder, drugs, psychoso-matic depression) to name but a few [112]. Laryngopha-ryngeal syndromes can be more confidently predicted if postnasal drip, medical cause of cough, smoking, abnor-mality on chest X-ray and stable management of asthma are excluded. In this circumstance, a multidisciplinary approach is practically found to be of value in selecting a group of patients with a higher pretest probability of reflux-caused abnormality. A multidisciplinary approach of ENT, respiratory medicine, oesophageal physiology and surgery may be clinically valuable and has certainly been the “Concord group” experience.

Experimental

Pepsin testing

Pepsin has been found in the middle ear of children with otitis media [64]. Pepsin may also be assayed from saliva and from bronchial lavage. A pepsin assay (Peptest™: RDBiomed Limited, Hull HU16 5JQ, UK) is now avail-able, but techniques of collection and sites have yet to be proven of clinical value [113–116]. Nonetheless, it con-tinues to raise the likelihood that proximal reflux disease can cause many different phenomena.

Pepsin tests and bile acids have been investigated in studies in probable reflux cough patients to identify gas-

including granuloma, subglottic stenosis and dysplasia [93].

Gastroscopy in atypical reflux disease

Reports have demonstrated that less than 30 % of patients with extra-oesophageal manifestations of reflux have oesophagitis [91, 101]. Clearly distal oesophagitis does not discriminate which individual has proximal reflux and so cannot be utilised for the presence of proximal reflux or identification of reflux in the pharynx or lung. Changes seen in passing the larynx by gastroenterology must be discounted in a similar fashion to laryngos-copy. Similarly, visualisation of oesophageal erythema has never been diagnostic of reflux. Biopsy, while it may exclude diagnosis like eosinophilic oesophagitis, is also not diagnostic of reflux disease proximally or distally. Gastroscopy therefore is of limited diagnostic use in LPR patients apart from exclusion of other diseases.

Tube-based studies

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 the value of pH recording in the proximal oesophagus. Vaezi et al. [101], Vakil et al. [4] and Koufman [102] report the sensitivity of oesophageal and pharyngeal monitoring of pH ranging from 50 to 80 % making diagnosis doubt-ful. There remains an intrinsic deficiency of pH recording reflux as it measures acid as a surrogate of reflux fluid. Acid is lacking in many episodes of reflux proximally as neutralisation occurs and a variable number of reflux episodes are non-acid at outset. Measurement of acid is therefore a poor surrogate for the detection of the pres-ence of refluxed fluid (Figs. 15, 16).

The advent of intraluminal impedance and 24-h PH monitoring was initially greeted with enthusiasm for a

Fig. 14 Laryngoscopic image of a vocal granuloma [100]

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

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

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

accumulation of reflux in the pharynx (Fig. 18) predictive of symptoms and lung disease [139].

Medical treatment

Lifestyle modification

Pearson [141] has demonstrated dietary and behaviour modification to be effective in typical reflux manage-ment and reduction of weight in the obese being demon-strated to improve gastro-oesophageal reflux symptoms [142, 143]. The effectiveness of weight loss does however remain controversial, and whether it improves objective measures is uncertain. There is little evidence that life-style change demonstrated in typical gastro-oesophageal reflux symptomatology also benefits the atypical LPR group.

PPI

While theoretically an attractive treatment, episodes of reflux high in the oesophagus are saliva and relatively non-acidic fluid by the time of passage to the upper oesophagus. Recent meta-analysis of randomised tri-als demonstrated little advantage over that of placebo in patients with suspected chronic laryngitis from reflux [111]. Similarly in a review by Reimer and Bytzer, no dif-ference was convincingly shown between the PPI therapy and placebo in randomised control study [144]. Addition of nocturnal H2

RA has not been shown effective [145, 146].

Reflux inhibition

Lesogaberan has been shown to reduce the rate of tran-sient lower oesophageal sphincter relaxation [147], but is of uncertain clinical effect and in our experience has not made a great deal of difference to LPR symptoms, although baclofen has been shown to decrease acid reflux events and acid exposure [148, 149]. However, use of baclofen has been limited by side effects in our experience. Results overall have been disappointing in association with PPI [147, 150]. Further studies require objective scores for cough to identify treatment affects more accurately [151]. Baclofen may theoretically benefit reflux cough by inhibition of the reflux and cough effect [152–155].

Prokinetic

Prokinetic agents while theoretically beneficial have not been shown to be of any value in LPR disease [141]. A recent systematic review found articles giving conflicting evidence regarding the effectiveness of prokinetic agents and were not able to make recommendations [156].

tric contents in the regions outside the stomach. Both sputum and bronchial lavage have been investigated. 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-ease. Pepsin has been identified in the middle ear aspira-tion fluid especially in neonates suggesting a cause for a subset of middle ear infection [64, 113, 114, 120]. In the future, this test may prove to be sensitive and specific for diagnosis of LPR disease [121, 122].

pH pharyngeal catheters

Standard catheters in the pharynx are considered inac-curate [123–125], but meta-analysis suggested it may be of value [126]. New devices are under development due to the inaccuracy of standard catheters placed in the pharynx due to the artefact from movement and the dry-ing of the electrode (ResTech, San Diego, CA 92127) [127]. No clinical data are available, and the usefulness of this has to be considered limited as it is apparent that much proximal reflux is non-acid and so will not be evident on acid (pH) pressure alone. Low-acid and non-acid fluids are increasingly being recognised by clinicians as being symptomatic in some patients [128–130]. Even if the new pH devices are able to accurately register acid in the pharynx, they remain intrinsically inaccurate due to the acid pressure being variable in reflux fluid [131].

Scintigraphy

Identification of fluid from the stomach above the cri-copharyngeus may select a group of patients with reflux-mediated extra-oesophageal symptoms. Isotope in gastro-oesophageal fluid has an intrinsic potential value as it can be traced and is not susceptible to arte-fact, drying or movement as are the catheter-based tests. It does not require the presence of acid as a “marker” of the presence of reflux fluid. It is a positive identifier of gastric fluid. Scintigraphy for reflux has been utilised in children for many years, and modifications of these techniques have been shown to provide good details of GORD and lung aspiration [79, 132–138]. Results vary depending upon technique [133, 135, 137, 138]. Stan-dardisation of technique therefore is vital for reproduc-ibility of this test. Results in our series [139] are similar to the study of Bestetti et al. [140]. Symptoms were also tightly correlated with pharyngeal exposure in our report [139]. Usefulness of this technique remains to be proved but may obviate invasive intrinsically misguided (testing for acid) and inaccurate tests (intraobserver variability) but requires a particular standardised technique with the rigid approach to methodology and preparation of contrast.

Scintigraphy has the ability to show pulmonary and pharyngeal reflux (Fig. 16b, 17a) and can show temporal

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Surgical treatment

Mainie et al. [163] report a group of surgical patients with selection by multichannel intraluminal imped-ance pH monitoring in a group of PPI unresponsive LPR symptoms. Patients with abnormal non-acid reflux were selected for antireflux surgery. Excellent results were obtained in a high proportion of patients. In contradis-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 patients with good results for LPR symptoms with favour-able results in excess of 90 % [80] similarly to the group of Mainie et al. [29] suggesting that adequate identification of pharyngeal reflux without recourse to acid detection may have value. It may be that accurate determination of reflux contamination proximally may allow a group of 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 con-trol, reduction in cough and throat symptoms range [60, 164–171].

Cough suppression

Short 3-day courses of prednisone 25 mg have occasion-ally given relief albeit transient, anecdotally. In a search of the literature (PubMed), dextromethorpan has shown no value, although it has been recommended [157]. Ket-amine has not proven helpful [158]. Morphine and gaba-pentin have been symptomatically useful, but limited by dependence [159, 160].

Pain modulation

Treatment of patients with sensitive oesophagus and partial response to PPI may benefit from visceral pain management [107]. Other groups have also had a favour-able experience with pain modulation in non-erosive reflux disease and LPR [161, 162].

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

Fig. 18 Scintigraphy show-ing rising levels of pharyngeal contamination

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The difficulty remains, it seems; in selection of appro-priate patient groups for surgery, rather than doubt about disease existence. Results obtained by our group are by multidisciplinary exclusion of alternative disease and a combination of standardised reflux scintigraphy and ini-tially 2 channel 24-h pH study, later evolving to 2 channel impedance studies (proximal and distal). The gold stan-dard accurate diagnostic test predictive of symptoms and therapeutic outcome, however, remains elusive. Medi-cal treatment remains empirical, and evidence suggests there is a low prospect of amelioration of symptoms of LPR. Occasional patients seem to gain some symptom reduction.

Compliance with ethical standards

Conflict of interest The authors declare no conflict of interest.

Appendix

Concord atypical reflux group

Prof. Gregory L. Falk—sydney.heartburn@gmail.comProf. Hans Van der Wall—hvanderwall@gmail.comMs. Leticia Burton—leticia.burton@gmail.comMs. SarahJayne Vivian—sarahjaynevivian@gmail.comDr. Arj Ananda—ananda@drananda.com.auDr. John Beattie—drjcbeattie@gmail.comProf. Alvin Ing—ajing@med.usyd.edu.auDr. Stephen Parsons—sparsons@bigpond.net.au

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