4, T|e Roya| Co||ees ol 3ureors ol Ed|rour| ard lre|ard
221 C||r|ca| Rev|eW Laryngopharyngeal reux: A literature review A. Y. Khen 1
3. R. heshmi 2 F. Elehi 1 Y. 7eriq J
0. R. /ngrems 1 1 0earrmenr ol EhT, Poya| Suenr los|ra|, heuorr, $ourn wa|es 2 0earrmenr ol /naesrnes|a, wexnam Park los|ra|, $|ougn ur J 0earrmenr ol EhT, Vayo los|ra|, Lanore, Pak|sran 0orresonoenoe ro. /. V. rnan 4 0|os Y Suaoo, Tnornn|||, 0aro|ll 0F14 90Z Ema||. anuar_mo|nQyanoo.oom Laryngopharyngea| reux (LPR} |s a common cond|t|on encountered |n oto|aryngo|og|ca| pract|ce |n the Un|ted K|ngdom. |t |s one of the most |mportant aet|o|og|ca| factors for many |nammatory d|sorders of the upper aerod|gest|ve tract. The presentat|ons are d|verse and |nc|ude chron|c hoarse- ness, sensat|on of a fore|gn body |n the throat, sore throat, dysphag|a, postnasa| dr|p, excess|ve throat mucous, chron|c cough and throat c|ear|ng. LPR pat|ents may not comp|a|n of heartburn. A|though LPR |s common, |ts d|agnos|s may not be easy, as |ts symptoms are non spec|c and the |aryngea| nd|ngs are not a|ways assoc|ated w|th symptom sever|ty. Th|s art|c|e d|scusses an overa|| v|ew of LPR |n terms of pathophys|o|ogy, c||n|ca| presentat|on, d|agnos|s and treatment Keywords: Laryngopharyngeal reux, voice disorders, upper aerodigestive tract, heartburn Surgeon, 1 August 2 221-225 |NTR00U6T|0N Laryngopharyngeal reux (LPR) is a common condition seen in otolaryngological practice in the United Kingdom. While many names have been advocated Ior reux induced laryngeal disorders (Table 1), LPR is the term accepted by the American Academy oI Otolaryngology: Head and Neck surgery. 1 TALE 1. TERH8 U8E0 T0 EXPRE88 REFLUX- |N0U6E0 LARYNCEAL 0|80R0ER8 Laryrop|aryrea| reux Posler|or |aryr|l|s 0aslro-oesop|aea| reux Reux |aryr|l|s 0aslro-oesop|aea|-|aryrea| reux 3upra oesop|aea| reux Exlra oesop|aea| reux The term reux comes Irom a Greek word that means back ow`` and in LPR reIers to the back ow oI stomach contents above the upper oesophageal sphincter, causing symp- toms related to the pharynx and larynx. 2 LPR is one oI the Ioremost recognised aetiological Iactors behind the development oI various in- ammatory disorders oI the upper aerodiges- tive tract. 3 Although heartburn (pain caused by oesophagitis) is one oI the key symptoms oI gastroesophageal reux disease (GORD), it is oIten absent in patients with LPR. 3-5 This is be- cause most individuals with LPR have normal oesophageal acid clearance, which is a useIul marker oI oesophageal motor Iunction. Conse- quently in many oI the individuals with LPR, the quantity oI acid Iound in the oesophagus is below the level required Ior the diagnosis oI GORD to be made. This 'physiological or 'silent reux does not produce symptoms such as heartburn. However, in contrast to the oesophagus, the mucosa oI the larynx is thin, Iragile, and poorly tailored to protect itselI against acid and activated pepsin and hence is less able to respond well to chemi- cal trauma. The larynx and pharynx are also devoid oI the acid clearance mechanism Iound in the oesophagus and thus is Iar more liable to peptic injury. 3,6,7 Hence the chemical trauma to the larynx and pharynx creates a local mucosal lesion. There is another proposed theory that acid stimulates vagally-mediated reexes in the distal oesophagus, leading to laryngopha- ryngeal changes and presents with chronic cough and throat clearing sensation. 8 Lewin HW DO (2003) Iound no signicant association between the occurrence oI heartburn and LPR in their patients. 9 Their results support other authors` ndings that heartburn may not be a dependable marker oI LPR. 3,4,10 There is no agreement to clearly describe the diIIerence between physiological events and 221-225 T|e Roya| Co||ees ol 3ureors ol Ed|rour| ard lre|ard 222 @ 2006 $urgeon 4. 4, pathological episodes. 11 The number oI reux episodes and acid exposure times are important in diIIerentiating normal in- dividuals Irom patients with LPR. 12 It is believed to be normal Ior the oesophagus to experience as many as 50 reux episodes a day. 3,13 For the larynx, as little as three reux incidents a week have been considered to be linked with the development oI notable disease. 3,6 This is because oI weakness in protection oI the laryngeal epithelium as compared with that Iound in the oesophagus, as discussed above. 6,14
LPR occurs most Irequently while the patient is in the erect posture and is thereIore Iound most commonly in the daytime. This diIIers Irom GORD where reux occurs more regularly when the patient is supine, usually during night time. 1,3,15,16
This relationship between reux and body position has been Iurther analysed by Lewin HW DO (2003) in their study, where the Irequency oI reux occurrence was higher in the erect than the supine position in 91 oI 34 patients. Their study supported a contrast between the presentation oI LPR and that oI GORD. 9
The occurrence oI reux in patients with voice disorders may reach up to 50. 17 Physical evidence oI LPR was present in 64 oI the cohort described by Reulbach HW DO (2001) in their study oI 100 volunteers over the age oI 40 with no history oI voice disorders. 18 Some authors think that LPR is a common condition in patients with head and neck cancer, and suggest that LPR has a role in the carcinogenesis process oI the squamous cell car- cinoma oI the head and neck. 19-21 However, the precise method responsible Ior the development oI cancer by LPR remains uni- dentied. The increased incidence oI squamous cell carcinoma oI the larynx and the oesophagus in heavy smokers and drink- ers and the high association between tobacco and alcohol con- sumption with GORD raises the possibility that GORD may be related to the development oI upper aerodigestive carcinoma, especially laryngeal carcinoma. 3 Lewin HW DO (2003), in their study oI 40 patients with histologically conrmed moderate to severe dysplasia or early carcinoma oI the larynx, established objective evidence oI LPR in 85 oI patients. This strength- ens the ndings Iurther that LPR is a Irequent event among patients diagnosed with carcinoma oI the larynx. However, it is important to note that others do not accept this hypothesis and Ieel that there is neither any consensus on whether LPR is linked with squamous cell carcinoma oI the larynx, nor is there suIcient data ascertaining LPR as an ultimate risk Iactor Ior cancer. 9
6L|N|6AL FEATURE8 Patients with LPR commonly present to general practitioners (or other primary care doctors) and otolaryngologists with symptoms oI dysphonia, a sensation oI a lump in the throat, cough, chronic throat clearing, dysphagia, postnasal drip, ex- cessive throat mucus and a strange taste in the mouth, but oIten do not complain oI heartburn. 1,3,22 As noted above, this contrasts with GORD where heartburn is a common symptom. 1,3,15,22-26 Previous work by Delahunty and Cherry (1968) established that inammation, ulceration and the development oI granu- lation tissue on the vocal Iold mucosa occurred aIter exces- sive contact with gastric contents. 27 A more recent study has shown that patients with chronic reux present with increased interarytenoid or posterior glottic inammation or erythema, hypertrophy oI the posterior commissure (cobblestoning), and granulation tissue Iormation in severe cases. 28 KouIman HW DO (1988) have proposed that laryngeal oedema (not erythema) is the most regular laryngeal nding connected with reux. 26
0|ACN08|8 Although LPR is common, its diagnosis may not be easy be- cause its symptoms are indistinct and the laryngeal ndings are not always correlated with symptom severity. 29 Until recently, there has been no agreement about the suit- able methodology to identiIy or measure LPR, and there is still little consensus concerning the indications Ior treatment and the most Iavourable evaluation oI treatment response. 3,7,30 Even though 24-hour ambulatory pH monitoring (use oI a single probe in the oesophagus) is a well recognized technique Ior assessing GORD, it has not achieved the same level oI endorse- ment Ior LPR. The level oI normal reux into the laryngophar- ynx remains debatable. 7,10 ThereIore, the data explaining the occurrence and pattern oI LPR are scarce and the signs and symptoms oI LPR that may diIIerentiate it Irom GORD have not been well dened. 9 Wiener HW DO (1986) were the rst to use concurrent oesophageal and pharyngeal pH monitoring Ior diagnostic evaluation oI patients with LPR symptoms. 22 In this technique, two pH probe devices (pharyngeal and oesophageal) monitor the acid reux. The pharyngeal probe is placed proximally at the upper oesophageal sphincter and the oesophageal probe is placed distally above the gastroesophageal junction. This en- hanced technique precisely detects acid reux episodes above the upper oesophageal sphincter. When guided by manometry, double probe pH monitoring can now be considered the gold standard Ior the diagnosis oI LPR. 7,16,31,32 BelaIsky HW DO (2001) developed an eight-item reux nding score (RFS) (Table 2). 29 This score is based on objective nd- ings observed during beroptic nasoendoscopy oI the larynx. This aims to Iacilitate the standardisation oI the clinical nd- ings oI LPR so that clinicians may improve on diagnosis, quan- tiIy symptom severity, and measure therapeutic eIIectiveness oI patients with this disorder. The score ranges Irom a minimum oI zero (no abnormal ndings) to a maximum oI 26 (worst score possible). It is essential to note that the RFS is simply a clinical scale oI laryngeal inammation. The independent items on RFS are not designed to individually Iorecast the presence or absence oI LPR. 33 Other Iactors such as inIection, allergy, neoplasia, auto-immune disorders and environmental toxins may add to the inammation and hence contribute to an abnor- mal RFS. 34 In a study oI 40 patients with LPR and 40 normal control individuals, it was Iound that mean RFS Ior the normal individual was 5.2, while the mean RFS Ior patients with con- rmed LPR was 11.5. The authors concluded that RFS oI six should be considered normal and RFS oI greater than seven is statistically associated with LPR in 95 oI individuals. 33 A strong relationship between erythema and LPR has been noted by some investigators. 35 In Iact, laryngeal erythema is a rather non-specic nding that is considerably dependent on the examination technique. However, laryngeal erythema can be classied as isolated when limited to the mucosa overly- ing the arytenoid and corniculate cartilages and diIIuse when it extends over the entire larynx. In contrast with localised erythema, diIIuse erythema is more expected to be associated with LPR. 34 BelaIsky HW DO (2001) in their study oI 40 patients with LPR, conrmed by dual probe (simultaneous oesophageal and 221-225 @ 2006 $urgeon 4. 4, T|e Roya| Co||ees ol 3ureors ol Ed|rour| ard lre|ard 223 pharyngeal) pH monitoring, Iound the most common signs in persons with LPR was posterior laryngeal hypertrophy, which was recognised in 85 oI all patients beIore the start oI any treatment. 29 Partial or total obliteration oI laryngeal ventricle (the space between true and Ialse vocal cords) as a result oI swelling oI the true and Ialse cords is another important discov- ery in 80 oI patients with pH documented LPR. 33 TALE 2. REFLUX F|N0|NC 860RE 6ond|t|on RF8 3uo|oll|c oedera 0= aoserl 2= preserl verlr|cu|ar oo||leral|or 0= rore 2= parl|a| 1= corp|ele Eryl|era/|yperaer|a 0= rore 2= arylero|ds or|y 1= d|lluse voca| cord oedera 0= rore 1= r||d 2= roderale 3= severe 1= po|ypo|d 0|lluse |aryrea| oedera 0= rore 1= r||d 2= roderale 3= severe 1= ooslrucl|r Posl corr|ssure |yperlrop|y 0= rore 1= r||d 2= roderale Vocal Iold granulomas are recurrent benign lesions which were once believed to occur as a result oI undue mechanical trauma (endotracheal intubation, chronic cough and excessive throat clearing) on the vocal process oI the arytenoid, but are now being considered a consequence oI LPR. 36-38 Pseudo sul- cus vocalis, also known as inIra-glottic oedema, is a pattern oI oedema on the ventral surIace oI the vocal Iold that extends Irom the anterior commissure to the posterior larynx. The presence oI pseudo sulcus alone is suggestive oI a diagnosis oI LPR. 39-41 Recently, it has been suggested that there is an association between hypertrophy oI Waldeyer`s ring (palatine tonsils, pha- ryngeal tonsils, lingual tonsil and intervening lymphoid tissue) lymphatics and LPR. 42 Endoscopic ndings oI excessive throat mucus may be related to LPR. This is named as 'water brash and is dened as the abrupt lling oI the mouth with clear mu- cous. Water brash is linked with the LPR. There is a release oI salivary bicarbonate during an event oI acid reux. The bicarbonate here acts as an endogenous antacid that provides a protective response to neutralise stomach acid. 43 Galli HW DO (2003) in their study oI 33 patients with clinical symptoms and signs oI LPR gave their patients a 60-day course oI acid suppression therapy (20mg Omeprazole twice daily), at the same time achieving a reasonable response in symptoma- tology, as set out in the guidelines which came Iorward Irom the 1997 Consensus ConIerence Report on LPR. Seventy three per cent oI the patients were Iound to have a complete sympto- matic improvement to acid suppression test, while partial im- provement in 12 and no response in 15 was documented. In spite oI the known resistance oI proton pump inhibitors in some individuals, the 'Omeprazole test is possible in the initial as- sessment oI LPR in outpatients, especially when double probe pH monitoring study is not possible. 44-46
TREATHENT The neutralisation oI the acidity oI the reux has been the Ioundation oI the treatment oI LPR. 2 Generally, there are sev- eral treatments Ior LPR such as changing liIestyle and dietary modication to reduce reux, medicines to minimise stomach acid and surgery to prevent reux in a Iew resistant cases. 47
L|festy|e Hod|cat|ons Most people with LPR need to modiIy how and when they eat as well as other day-to-day activities (Table 3). 48 TALE 3. L|FE8TYLE AN0 0|ETARY H00|F|6AT|0N8 3lop sro||r Appropr|ale spac|r oelWeer rea|s Avo|d eal|r W|l||r l|ree |ours ol oedl|re LoW lal d|el Reduce |rla|e ol collee, c|lrus ju|ces ard zzy dr|r|s Reduce We||l |l ooese L|r|l a|co|o| |rla|e Avo|d ca|c|ur c|arre| o|oc|ers, l|eop|y|||re, arl|c|o||rer|cs, oela- o|oc|ers, ard sore ca|c|ur supp|ererls |l poss|o|e, W||c| are l|ou|l lo |rcrease aslr|c ac|d Hed|ca| Treatment Along with advice on liIestyle and dietary modications, most oI the patients will require some Iorm oI medical therapy. The aim oI the medical management oI LPR is neutralisation oI the gastric juice acidity and the enhancement oI gastrointestinal tract motility. 2 Treatment with proton pump inhibitors (PPI) is required Ior the resolution oI laryngeal symptoms and physical ndings oI patients with LPR. Symptom resolution oI straightIorward LPR usually takes place within two months oI therapy with PPI. Nonetheless, the objective ndings oI LPR recover more slowly and continue to get better Ior the period oI six months oI treatment. Voice disorders may have numerous causes. ThereIore, the lack oI ability oI proton pump inhibitors to entirely resolve the symp- toms or physical ndings is likely. Treatment oI LPR oI more 221-225 T|e Roya| Co||ees ol 3ureors ol Ed|rour| ard lre|ard 221 @ 2006 $urgeon 4. 4, than six months may be indicated to attain a Iull resolution oI physical ndings and to reduce the risk oI the return oI symp- toms. Termination oI treatment based on the presumption that LPR symptoms are getting better alone may be premature. This conclusion concurs with the view oI the Consensus ConIerence Report on LPR (1997) that the suggested twice daily PPI treat- ment be continued Ior a minimum period oI six months. 33 Besides the nature oI treatment, the dosage and duration oI treatment is also oI great interest. A considerable number oI patients on twice daily PPIs do not have satisIactory acid suppression Ior curing the LPR. 49 As a consequence, this group oI patients may need a higher dosage oI PPI or replacement by H 2 receptor antagonists. LiIelong treatment with PPI in some patients may be inevitable. 33
Ant|-Reux 8urgery Fundoplication augments treatment oI LPR in Iew patients with severe LPR or those who are intolerant to anti-reux medicine or resistant to PPI. 33,50,51 This surgical treatment provides relieI oI LPR symptoms Ior many years. 60N6LU8|0N Although LPR is a common condition presenting in ENT set- tings, the symptoms and signs may be complex. Most clinicians rely on their clinical judgment Ior diagnosing this condition. Proton pump inhibitors remain the standard treatment and should be continued Ior a minimum oI six months. 6opyr|ght 8 June 200 REFEREN6E8 1. KouIman JA, Aviv JE, Casiano RR, Shaw GY. Laryngopharyngeal reux: position statement oI the committee on speech, voice, and swallowing disorders oI the American Academy oI Otolaryngology-Head and Neck Surgery. 2WRODU\QJRO +HDG 1HFN 6XUJ 2002;127(1):32-35. 2. Sung MW, Roh JL, Park BJ, Park SW, Kwon TKm Lee SJ HW DO. 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Prevalence oI reux in 113 consecutive patients with laryngeal and voice disorders. 2WRODU\QJRO +HDG 1HFN 6XUJ 2000;123(4):385-8. 18. Reulbach TR, BelaIsky PC, Blalock PD, KouIman JA, Postma GN. Occult laryngeal pathology in a community-based cohort. 2WRODU\QJRO +HDG 1HFN 6XUJ 2001;124(4):448-50. 19. Copper MP, Smit CF, Stanojcic LD, Devriese PP, Schouwenburg PF, Mathus-Vliegen LM. High incidence oI laryngopharyngeal reux in patients with head and neck cancer. /DU\QJRVFRSH 2000;110(6):1007-11. 20. Freije JE, Beatty TW, Campbell BH, Schultz CJ, Toohill RJ. Carcinoma oI larynx in patients with gastroesophageal reux. $P - 2WRODU\QJRO 1996;17:386-90. 21. Dagli S, Dagli U, Kurtaran H, Alkim C, Sahin B. Laryngopharyngeal reux in laryngeal cancer. 7XUN - *DVWURHQWHURO 2004;15(2):77-81. 22. Wiener GJ, Cooper JB, Wu WC, KouIman JA, Richter JE, D.O. C. Is hoarseness an atypical maniIestation oI gastroesophageal reux (GER) ? An Ambulatory 24 hour pH study. *DVWURHQWHURORJ\ 1986;90:A1691. 23. Wiener GJ, KouIman JA, Wu W, Cooper WJ, Richter JE, Castell DO. Chronic hoarseness secondary to gastro-esophageal reux disease: documentation with 24 hour ambulatory pH monitoring. $P - *DVWURHQWHURO 1989;84:1503-8. 221-225 @ 2006 $urgeon 4. 4, T|e Roya| Co||ees ol 3ureors ol Ed|rour| ard lre|ard 225 24. Olson NR. EIIects oI stomach acid on larynx. 3URF $P /DU\QJRO $VVRF 1983;104:108-12. 25. Wiener GJ, KouIman JA, Wu WC, Cooper JB, Richter JE, Castell DO. The pharyngoesophageal dual ambulatory pH probe Ior evaluation oI atypical maniIestation oI gastroesophageal reux (GER). *DVWURHQWHURORJ\ 1987;92: A1694. 26. KouIman JA, Wiener GJ, Wu WC, Richter JE, Castell DO. Reux larynx and its sequelae: the diagnostic role oI ambulatory 24-hour pH monitoring. - 9RLFH 1988;2:78-89. 27. Delahunty JE, Cherry J. Experimentally produced vocal cord granulomas. /DU\QJRVFRSH 1968;78:1941-47. 28. Ulualp SO, Toohill RJ. Laryngopharyngeal reux: state oI the art diagnosis and treatment. 2WRODU\QJRO &OLQ 1RUWK $P 2000;33(4):785-802. 29. BelaIsky PC, Postma GN, KouIman JA. Laryngopharyngeal reux symptoms improve beIore changes in physical ndings. /DU\QJRVFRSH 2001;111(6):979-81. 30. Walner DL, Stem Y, Gerber ME, Rudolph C, Baldwin CY, Cotton RT. Gastroesophageal reux in patients with subglottic stenosis. $UFK 2WRODU\QJRO +HDG 1HFN 6XUJ 1998;124:551- 55. 31. Johnson PE, KouIman JA, Nowak LJ, BelaIsky PC, Postma GN. Ambulatory 24-hour double-probe pH monitoring: the importance oI manometry. /DU\QJRVFRSH 2001;111:1970-75. 32. Vaezi ME, Shroeder PL, Richter JE. Reproducibility oI proximal probe pH parameters in 24-hour ambulatory esophageal monitoring. $P - *DVURHQWHURO 1997;92:825-29. 33. BelaIsky PC, Postma GN, KouIman JA. The validity and reliability oI the reux nding score (RFS). /DU\QJRVFRSH 2001;111(8):1313-17. 34. BelaIsky PC. Abnormal endoscopic pharyngeal and laryngeal ndings attributable to reux. $P - 0HG 2003;115 Suppl 3A: 90S-96S. 35. Hanson DG, Jiang J, Chi W. Quantitative color analysis oI laryngeal erythema in chronic posterior laryngitis. - 9RLFH 1998;12:78-83. 36. Milko TL. Peptic (Contact ulcer) granuloma oI the larynx. - &OLQ 3DWKRO 1989;42:800-804. 37. Svensson G, Schelen L, Fex S. Pathogenesis oI idiopathic contact granuloma oI the larynx: results oI a prospective clinical study. $FWD 2WRODU\QJRO 1988;449:123-25. 38. Ylitalo R, Ramel S. Extraesophageal reux in patients with contact granuloma: a prospective controlled study. $QQ 2WRO 5KLQRO /DU\QJRO 2002;111:441-46. 39. Hickson C, Simpson CB, Falcon R. Laryngeal pseudosulcus as a predictor oI laryngopharyngeal reux. /DU\QJRVFRSH 2001;111(10):1742-45. 40. Heman-Ackah YD, Kelleher K, SataloII RT. InIerior glottic ridges that prevent vocal Iold closure. (DU 1RVH 7KURDW - 2002;81:207-9. 41. BelaIsky PC, Postma GN, KouIman JA. The association between laryngeal pseudosulcus and laryngopharyngeal reux. 2WRODU\QJRO +HDG 1HFN 6XUJ 2002;126(6):649-52. 42. Mamede RC, De Mello-Filho FV, Vigario LC, Dantas RO. EIIect oI gastroesophageal reux on hypertrophy oI the base oI the tongue. 2WRODU\QJRO +HDG 1HFN 6XUJ 2000;122:607-10. 43. Helen JF, Dodds WJ, Hogan WJ. Salivary response to esophageal acid in normal subjects and patients with reux esophagitis. *DVWURHQWHURORJ\ 1987;93:1393-97. 44. Kamel PL, Hanson D, Kahrilas PJ. Omeprazole Ior the treatment oI posterior laryngitis. $P - 0HG 1994;96:321-26. 45. Noordzij JP, Khidr A, Evans BA, Desper E, Mittal RK, Reibel JF HW DO. Evaluation oI omeprazole in the treatment oI reux laryngitis: a prospective, placebo-controlled, randomized, double-blind study. /DU\QJRVFRSH 2001;111(12):2147-51. 46. Galli J, Scarano S, Agostino S, Quaranta N, Cammarota G, Ottaviani F. Pharyngolaryngeal reux in outpatient clinical practice: personal experience. $FWD 2WRUKLQRODU\QJRO ,WDO 2003;23(1):38-42. 47. BelaIsky PC, Postma GN, KouIman JA. Validity and reliability oI the reux symptom index (RSI). - 9RLFH 2002;16(2):274- 77. 48. Maceri DR, Zim S. Laryngospasm: an atypical maniIestation oI severe gastroeophageal reux disease. /DU\JRVFRSH 2001;111:1976-79. 49. Amin MR, Postma GN, Johnson P, Digges N, KouIman JA. Proton pump inhibitor resistance in the treatment oI laryngopharyngeal reux. 2WRODU\QJRO +HDG 1HFN 6XUJ 2001;125(4):374-78. 50. Westcott CJ, Hopkins MB, Bach K, Postma GN, BelaIsky PC, KouIman JA. Fundoplication Ior laryngopharyngeal reux disease. - $P &ROO 6XUJ 2004;199(1):23-30. 51. Toohill RJ. Fundoplication Ior laryngopharyngeal reux disease. - $P &ROO 6XUJ 2004;199(5):837; author reply 838. TRUE 0R FAL8E 0UE8T|0N8 (Answers at end of |ssue} LPR occurs most commonly in the following: 3up|re poslure Erecl poslure 0ayl|re N||l l|re Pal|erls W|l| vo|ce d|sorders For the treetment of LPR: Ved|ca| lrealrerl |s rol reeded C|ares |r ||lesly|e ard d|el car |e|p |r r|r|r|z|r l|e syrplors PPls do rol |ave ary ro|e Neulra||sal|or ol l|e aslr|c ac|d |s rol recesssary 3ur|ca| |rlerverl|ors |||e lurdop||cal|or ray |ave lo oe carr|ed oul |r pal|erls res|slarl lo arl|-reux red|c|re l|erapy 221-225