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CONTENTS TRANSACTIONS AMERICAN BRONCHO-ESOPHAGOLOGICAL ASSOCIATION 2010 ≈ NINETIETH ANNUAL MEETING PARIS/BALLY’S LAS VEGAS LAS VEGAS, NEVADA APRIL 28-29, 2010 ≈ PUBLISHED BY THE ASSOCIATION CONTENTS Annual Photograph ..............................................................................................................................................................5 Officers 2009-2010 ..............................................................................................................................................................6 Executive Sessions Minutes ........................................................................................................................................................................7 Reports .........................................................................................................................................................................7 Officers 2010-2011 ............................................................................................................................................................17 Presidential Address. Andrew Blitzer, MD, DDS ........................................................................................................................................18 Presentation of Guest of Honor William Lawson, MD Andrew Blitzer, MD, DDS ........................................................................................................................................19 Presentation of Chevalier Jackson Award to Clarence T. Sasaki, MD Andrew Blitzer, MD, DDS ........................................................................................................................................20 Guests of Honor 1951-2010 ...............................................................................................................................................21 Recipients of Chevalier Jackson Award .............................................................................................................................21 Introduction of Chevalier Jackson Lecturer Marshall Strome, MD Andrew Blitzer, MD, DDS ........................................................................................................................................22 Chevalier Jackson Lectures 1964-2010 .............................................................................................................................23 Presidential Citations Honoring Anthony F. Jahn, MD, Mitchell F. Brin, MD, and Robert M. Blitzer, DDS Andrew Blitzer, MD, DDS ........................................................................................................................................24 President-Elect Address. Michael A. Rothschild, MD .......................................................................................................................................27 SCIENTIFIC SESSIONS ABEA Panel on Laryngopharyngeal Reflux Moderator: Peter Belafsky, MD, PhD Panelists: Jamie Koufman, MD; Tanya Meyer, MD; Nikki Johnston, PhD; Michael Pitman, MD ..........................28 Special Presidential Lecture Airway Clinic: Bronchoesophagology in the Twenty-First Century Marshall E. Smith, MD; Mark Elstad, MD................................................................................................................29 Arytenoid Abduction: Indications and Limitations Gayle Woodson, MD..................................................................................................................................................31 Vibratory Asymmetry in Mobile Vocal Folds: Is It Predictive of Vocal Fold Paresis? C. Blake Simpson, MD; Linda Seitan May, MD; Jill K. Green, MS; Robert L. Eller, MD; Carlayne E. Jackson, MD ........................................................................................................38 Effects of Nerve-Muscle Pedicle on Immobile Rat Vocal Folds in the Presence of Partial Innervation Takashi Aoyama, MD; Yoshihiko Kumai, MD, PhD; Eiji Yumoto, MD, PhD; Takaaki Ito, MD, PhD; Satoru Miyamaru, MD, PhD ................................................................................................42 Use of a Microdebrider for Subepithelial Excision of Benign Vocal Fold Lesions Alex Y. Cheng, MD; Ahmed M. S. Soliman, MD .....................................................................................................49 Response of Cricopharyngeus Muscle to Esophageal Stimulation by Mechanical Distension and Acid and Bile Perfusion Natalya Chernichenko, MD; Jeong-Soo Woo, MD; Jagdeep S. Hundal, MD; Clarence T. Sasaki, MD...................53 Analysis of Pepsin in Tracheoesophageal Puncture Sites Jonathan M. Bock, MD; Mary K. Brawley, MA; Nikki Johnston, PhD; Tina Samuels, MS; Becky L. Massey, MD; Bruce H. Campbell, MD; Robert J. Toohill, MD; Joel H. Blumin, MD..............................59 Low-Acid Diet for Recalcitrant Laryngopharyngeal Reflux: Therapeutic Benefits and Their Implications Jamie A. Koufman, MD .............................................................................................................................................66 Cooling the “Oven”: A Temperature Study of Air and Glottal Tissue During Laser Surgery in an Ex Vivo Calf Larynx Model James A. Burns, MD; Gerardo Lopez-Guerra, MD; James T. Heaton, PhD; James B. Kobler, PhD; Julie Kraas; Steven M. Zeitels, MD ...........................................................................................................................73 Quantity and Three-Dimensional Position of the Recurrent and Superior Laryngeal Nerve Lower Motor Neurons in a Rat Model Philip Weissbrod, MD; Michael J. Pitman, MD; Sansar Sharma, MD; Aaron Bender; Steven D. Schaefer, MD ....................................................................................................................79 2 Contents 3 Assessment of Canine Vocal Fold Function After Injection of a New Biomaterial Designed to Treat Phonatory Mucosal Scarring Sandeep S. Karajanagi, PhD; Gerardo Lopez-Guerra, MD; Hyoungshin Park, PhD; James B. Kobler, PhD; Marilyn Galindo; Jon Aanestad; Daryush D. Mehta, PhD; Yoshihiko Kumai, MD, PhD; Nicholas Giordano; Anthony d’Almeida; James T. Heaton, PhD; Robert Langer, ScD; Victoria L. M. Herrera, MD; William Faquin, MD, PhD; Robert E. Hillman, PhD; Steven M. Zeitels, MD ......................................................................................................87 Potential of Induced Pluripotent Stem Cells for the Regeneration of the Tracheal Wall Mitsuyoshi Imaizumi, MD; Yukio Nomoto, MD; Takashi Sugino, MD; Masao Miyake, PhD; Ikuo Wada, PhD; Tatsuo Nakamura, MD; Koichi Omori, MD..................................................................................97 Determination of Predictive Factors of Tracheobronchial Prosthesis Removal: Stent Brands Are Crucial Guillaume Buiret, MD; Carole Colin, MD; Guillaume Landry, MD; Marc Poupart, MD; Jean-Christian Pignat, MD ......................................................................................................104 Posterior Glottic Diastasis: Mechanically Deceptive and Often Overlooked Steven M. Zeitels, MD; Alessandro de Alarcon, MD; James A. Burns, MD; Gerardo Lopez-Guerra, MD; Robert E. Hillman, PhD ............................................................................................111 Neurologic Variant Laryngomalacia Associated With Chiari Malformation and Cervicomedullary Compression: Case Reports Rajanya S. Petersson, MD; Nicholas M. Wetjen, MD; Dana M. Thompson, MD, MS...........................................121 Systematic Review of Endoscopic Airway Findings in Children With Gastroesophageal Reflux Disease Jason Glenn May, MD; Priyanka Shah, MA; Lori Lemonnier, MD; Gaurav Bhatti, MS; Jovana Koscica, DO; James M. Coticchia, MD.......................................................................................................126 Correlation of Vocal Fold Nodule Size in Children and Perceptual Assessment of Voice Quality Roger C. Nuss, MD; Jessica Ward; Lin Huang, PhD; Mark Volk, DMD, MD; Geralyn Harvey Woodnorth, MA.............................................................................................................................133 The Management of Postintubation Phonatory Insufficiency [Abstract] Lindsey C. Arviso, MD; Adam M. Klein, MD; Michael M. Johns III, MD ............................................................138 Analysis of Vocal Fold Injection Amount: Association With Diagnosis and Outcome [Abstract] VyVy N. Young, MD; Libby J. Smith, DO ..............................................................................................................138 Glidescope-Assisted Medialization Laryngoplasty: A Novel Technique [Abstract] Roberta Lima, MD; Nazaneen Grant, MD...............................................................................................................139 Laryngeal Findings in Occluded Versus Unoccluded Ostia Model of Rhinosinusitis [Abstract] Ankona Ghosh; Marcelo B. Antunes, MD; Joel Guss, MD; Fenella Long, PhD; Noam A. Cohen, MD, PhD; Natasha Mirza, MD ....................................................................................................139 Narrowband Imaging and High-Definition Television for Detection, Definition, and Surveillance of Head and Neck Cancer: A Prospective Study [Abstract] Cesare Piazza, MD; Daniela Cocco, MD; Francesca Del Bon, MD; Stefano Mangili, MD; Luigi de Benedetto, MD; Giorgio Peretti, MD ........................................................................................................140 Optimizing the Surgical Creation of a Supraglottal Sound Source: Theory and a Case Study [Abstract] Sid Khosla, MD; Shanmugam Murugappan, PhD; Bernice Klaben, PhD...............................................................140 Primary TEP Placement in Patients With Laryngopharyngeal Free Tissue Reconstruction and Salivary Bypass Tube Placement [Abstract] Vasu Divi, MD; Derrick T. Lin, MD; Kevin Emerick, MD; Daniel G. Deschler, MD ............................................141 Development of the Dyspnea Severity Index–10 [Abstract] Jackie Gartner-Schmidt, PhD, SLP; Adrianna Shembel, BS, MA; Priya Krishna, MD; Rita Hersan, CCC-SLP; Thomas Zullo, PhD; Clark A. Rosen, MD .......................................................................141 Pepsin, at pH 7, in Nonacidic Laryngopharyngeal Refluxate, Significantly Alters the Expression of Multiple Genes Implicated in Carcinogenesis [Abstract] Nikki Johnston, PhD ................................................................................................................................................142 The Role of the Modified Barium Swallow Study and Esophagram in Patients With GERD/Globus Sensation [Abstract] Jayme R. Dowdall, MD; Tom Willis, MD; Adam J. Folbe, MD; James P. Dworkin, PhD .....................................142 Effect of Different Angiolytic Lasers Upon Resolution of Submucosal Hematoma in an Animal Model [Abstract] Daniel Novakovic, MD; Joanna D’Elia, MD; Andrew Blitzer, MD; Milton Waner, MD .......................................143 Characterization of Mesenchymal Stem Cells From Human Vocal Fold Fibroblasts [Abstract] Summer E. Hanson, MD; Jaehyup Kim, MD; Beatriz H. Quinchia Johnson, DDS, PhD; Melissa Breunig; Bridget Bradley; Peiman Hematti, MD; Susan L. Thibeault, PhD..............................................143 4 Contents Utility of Diagnostic Testing in Adults With Idiopathic Subglottic Stenosis [Abstract] Melissa McCarty Statham, MD; Yash A. Patil, MD; Allesandro de Alarcon, MD; Ravindra G. Elluru, MD, PhD; Meredith E. Tabangin, MPH; Michael W. Bowen, PAC; Thomas K. Chung, BS; Michael J. Rutter, MD, FRACS ........................................................................................144 A Challenging Case: Intubation Through a Foreign Body and Foreign Body Removal From the Larynx [Abstract] Vartan A. Mardirossian, MD; Timothy Anderson, MD; Joyce Colton-House, MD ................................................144 Calcium Oxalate Crystals Decode the Pulmonary Rhizopuzzle in a Pulmonary Abscess [Abstract] Christopher G. Tang, MD; Christina C. Goette, MD; John Lin, MD; Valerie Ng, MD, PhD; Alden H. Harken, MD .........................................................................................................145 In-Office Unsedated Transnasal Bronchoscopy for Removal of an Airway Foreign Body [Abstract] Drew Plonk, MD; S. Carter Wright, Jr, MD; J. Whit Mims, MD; Catherine J. Rees, MD .....................................145 Endoscopic Management of a Penetrating Foreign Body in the Soft Tissue of the Retropharynx [Abstract] Margaret L. Skinner, MD; Mark Volk, DMD, MD ..................................................................................................146 Delay in the Diagnosis of Laryngeal Cleft Associated With Tracheoesophageal Fistula [Abstract] Margaret L. Skinner, MD; Stacey L. Ishman, MD; Umakanth Khatwa, MD; Kenan Haver, MD; Rachel Rosen, MD; Craig Lillehei, MD; Reza Rahbar, MD....................................................146 Histopathologic Investigations of the Unphonated Human Child Vocal Fold Mucosa [Abstract] Kiminori Sato, MD; Hirohito Umeno, MD; Tadashi Nakashima, MD; Satoshi Nonaka, MD; Yasuaki Harabuchi, MD .......................................................................................................147 2010 Roster of Members Honorary ..................................................................................................................................................................148 Senior .......................................................................................................................................................................148 Active .......................................................................................................................................................................149 Associate ..................................................................................................................................................................155 Corresponding ..........................................................................................................................................................155 Officers 1917-2010 ..........................................................................................................................................................157 MEMBERS IN ATTENDANCE AT THE NINETIETH ANNUAL MEETING Row 1. Mark Courey, Clarence Sasaki, Gregory Grillone, Ellen Deutsch, Andrew Blitzer, Michael Rothschild, Gregory Postma, Milan Amin, David Eibling, J. Scott McMurray. Row 2. Michael Setzen, Gaelyn Garrett, Gayle Woodson, Stephen Conley, Ravindhra Elluru, Eiji Yanagisawa, Tadashi Nakashima, Julie Wei, Charles Ford, Ellen Friedman, Gady Har-El, Jean Abitbol, Arnold Komisar, Marvin P. Fried. Row 3. Edward Damrose, Natasha Mirza, Randal Paniello, Steven Zeitels, Mark Persky, Daniel Wohl, Alessandro de Alarcon, Frederik G. Dikkers, Lauren Holinger, James Burns, Nick Maragos, Harvey Tucker, Stanley Shapshay. Row 4. Craig Zalvan, Adam Klein, Paul Castellanos, Steffen Maune, Hirohito Umeno, Koichi Omori, Nicole Maronian, Shigeru Hirano, Joel Blumin, Rob Stachler, Jim Cuyler, Libby Smith. Row 5. Karen Zur, Ahmed Soliman, Thomas Murry, Lucian Sulica, Albert Merati, Kiminori Sato, Lee Akst, Steve Parnes, Peter Koltai, Clark Rosen. Row 6. Marshall Smith, Mario Andrea, Seth Dailey, Allan Abramson, Michael Johns. 5 OFFICERS 2009-2010 PRESIDENT PRESIDENT-ELECT ANDREW BLITZER, MD, DDS New York, New York MICHAEL A. ROTHSCHILD, MD New York, New York VICE-PRESIDENT PAST PRESIDENT ELLEN S. DEUTSCH, MD Wilmington, Delaware JAMIE A. KOUFMAN, MD New York, New York SECRETARY TREASURER GREGORY A. GRILLONE, MD Boston, Massachusetts GREGORY POSTMA, MD Augusta, Georgia EDITOR CHAIR AWARDS AND THESIS COMMITTEE J. SCOTT MCMURRAY, MD Madison, Wisconsin CLARENCE T. SASAKI, MD New Haven, Connecticut CHAIR NOMINATING COMMITTEE CHAIR FOREIGN BODY AND ACCIDENTS COMMITTEE CLARENCE T. SASAKI, MD New Haven, Connecticut DANA THOMPSON, MD Rochester, Minnesota CHAIR DIFFICULT AIRWAY COMMITTEE CHAIR PHARYNGEAL AND ESOPHAGEAL COMMITTEE IAN N. JACOBS, MD Philadelphia, Pennsylvania MILAN AMIN, MD New York, New York CHAIR INTERNATIONAL RELATIONS COMMITTEE CHAIR NEW TECHNOLOGY COMMITTEE MARC J. REMACLE, MD, PHD Yvoir, Belgium J. SCOTT MCMURRAY, MD Madison, Wisconsin CHAIR RESEARCH AND EDUCATION COMMITTEE CHAIR ONCOLOGY COMMITTEE MARK S. COUREY, MD Nashville, Tennessee JAMES A. BURNS, MD Boston, Massachusetts REPRESENTATIVES TO THE BOARD OF GOVERNORS DANA THOMPSON, MD Rochester, Minnesota GREGORY A. GRILLONE, MD Boston, Massachusetts CHAIR SCIENTIFIC PROGRAM JAMES A. BURNS, MD Boston, Massachusetts REPRESENTATIVE AMERICAN ACADEMY OF OTOLARYNGOLOGY– HEAD AND NECK SURGERY COUNCIL MEMBERS AT LARGE PETER BELAFSKY, MD Sacramento, California DAVID E. EIBLING, MD Pittsburgh, Pennsylvania IAN N. JACOBS, MD Philadelphia, Pennsylvania WEBMASTER MICHAEL A. ROTHSCHILD, MD New York, New York 6 Spring 2010 ABEA Council Meeting Minutes Attending: Milan Amin, MD Peter Belafsky, MD Andrew Blitzer, MD James Burns, MD Mark Courey, MD Ellen Deutsch, MD David Eibling, MD Gregory Grillone, MD Ian Jacobs, MD Jamie Koufman, MD Scott McMurray, MD Gregory Postma, MD Marc Remacle, MD Michael Rothschild, MD Clarence Sasaki, MD The October 3, 2009, Council Meeting minutes were approved. I. PRESIDENT’S REPORT — ANDREW BLITZER, MD 1. Hoarseness Guidelines Discussion: The controversy that followed the publication of the guidelines has raised a number of procedural and scientific issues in a public forum. Hopefully, other symptoms-based guidelines that will be published in the future will not have the same kind of problems that occurred with the hoarseness guidelines. This was in part a criticism of the guidelines on scientific grounds, but more so a criticism of the process. Evidence-based medicine is important, but as someone at the Harvard School of Public Health once said of otolaryngology, “...in your field there is no Level I evidence to show that packing the nose stops nosebleeds because no one has done that study.” The hope is that with the various responses from the ABEA and ALA there will be information that will clearly neutralize and counterbalance the effect of what originally came out in the guidelines. The hope is also that there will be enough good data out there to address any of the ill effects that may have come from the Hoarseness Guidelines. In the interim we have probably changed the process and established the ABEA in a greater way in laryngology. Dr Blitzer thanked all who have been involved in this project. Action Items: a. Dr Eibling has been working on the rebuttal representing the ABEA. The document has gone through several drafts and has been reviewed by Dr Postma (representing the ABEA), as well as Dr Fried (representing the ALA) and Dr Blitzer (representing both the ABEA and the ALA). There is a final document ready for Dr Rosenfeld, and we understand that he will publish it as-is. Hopefully, this will end up in the “white journal” with both the ABEA and the ALA as sponsors. b. Dr Lucian Sulica has spearheaded the scientific response to the guidelines, which will be published in the Laryngoscope as a joint effort of the ABEA and ALA. c. There will be a mini-seminar at the Academy meeting in Boston on “Hoarseness: Best Practices.” Hopefully, what comes out of that meeting will be published somewhere. d. Dr Koufman acquired several web sites, including hoarsenessguidelines.com, which can be used to post any rebuttal documents of position statements. When the ABEA comes up with these documents, she would like permission to put it on-line. 2. ABEA Program Discussion: Dr Blitzer thanked all the Council and said that the next 2 days will show what a strong organization we have and what a great program we have put together. Action Item: Each year, the outgoing President gives a gift to each Council member in appreciation of their support during their presidency. Dr Blitzer has decided to present a certificate of appreciation to each Council member and has made a $200 donation in the name of each Council member toward the Past President’s Advisory Committee, headed by Dr Sasaki. 7 8 Minutes & Reports 3. ABEA/ALA/ELS Combined Meeting Discussion: Dr Blitzer spoke with Dr Remacle about the combined meeting with the ABEA, ALA, and ELS meeting at COSM. The tentative footprint would be that the ABEA and ALA would each have a half-day session of their own and that on the second day both half-day sessions would be devoted to the combined ABEA/ALA/ELS meeting. Another issue that needs to be resolved is the registration process. The question is whether the ELS group could register once for both the combined meeting and the ABEA meeting. We would include ELS members on the Program Committee, panels, etc. COSM is in Chicago in 2011, in San Diego in 2012 (which would make for a much longer flight for ELS members), and in Orlando in 2013. A final decision needs to be made about which year we will hold the combined meeting. In return, the ABEA will encourage its members to attend the ELS meetings. Action Items: a. Dr Grillone will be discussing this at the COSM Secretaries Liaison Committee meeting later this week and will report back at the next ABEA Council meeting. b. Dr Remacle will be discussing the combined meeting at the next ELS Executive Council and will report back at the next ABEA Council meeting. 4. Committee Composition Discussion: The ABEA is a very vibrant organization, and we have many members, including younger members who would like to be more involved with the society. We need to make an effort to include them. To that end, Dr Grillone solicited the membership, asking for names of those interested in becoming more involved. He distributed the list, as well as a list of current Committee Chairs and members. These lists were reviewed by the Council. The Council also reviewed the progression table developed by Dr Deutsch to determine which committee chairs and members had expired terms (see also President-Elect and Vice-President reports below). Action Item: Dr Rothschild, as one of his first charges, will further review these documents and draw from the list of interested members to appoint new committee chairs and other Council positions as appropriate. 5. New Committees Discussion: In an effort to enrich the ABEA and expand representation within the Council, Dr Blitzer has proposed three new committee changes that require approval by the Council. The new committees are as follows. Resident/Fellow Committee — for those residents and/or fellows who would like to play a more active role in the ABEA. The chair would be a non-voting member of the Council. The charge of the committee would be to bring to the Council issues pertinent to residents and fellows. This would hopefully allow the infusion of new ideas from these younger members and plant the seed for other residents to become interested in the ABEA. When they finish their training, they might want to apply for active membership. The Academy has a Section for Residents and Fellows (SRF), and they actually have one non-voting member on the Academy’s board of directors. There was also discussion that resident membership should be a distinct category different from the category of candidate member. The resident membership category would allow residents at any level to become a member even before they were eligible for candidate membership. Any resident in good standing could apply as a resident member with completion of an application without formal review by the Council. They would then go on the mailing list to receive the newsletter, and when they completed residency they would be encouraged to become a candidate or active member. We could communicate with the program chairs and ask them to advise any resident in an accredited program that they could become a resident member by submitting a one-page application. Past Presidents Advisory Committee — Many of the ABEA Past Presidents have spent many years on the Council, and they still have much that they would like to and could offer to the society. This would allow those Past Presidents who are interested in staying active in the society a chance to do so. This would also help Dr Sasaki’s development efforts in the President’s Circle. The charge of Minutes & Reports 9 this committee would be to provide senior-level advice to the Council. The chair of this committee would sit on the Council as an ex officio member. The chair will communicate with the other Past Presidents prior to Council meetings and bring their comments to the meeting. They would also have the option to meet separately as a group. International Committee — When Dr Blitzer mentioned collaboration with the ELS in the last Newsletter, Dr Yanagisawa wrote him to say that when he was President they met with the Japan Laryngological Society in a collaborative effort. The International Liaison has been an integral part of the Council, but this single position allows representation from only one region of the globe. An International Committee would allow representation from other regions, such as South America, Central America, and Asia. At the Academy, outside of Canada, Brazil has the largest number of attendees. They have over 6,000 otolaryngologists, and they have almost 400 laryngologists. It would be very advantageous to reach out and have representation from countries such as Brazil on the International Committee. We encouraged the corresponding members several years ago to become active. However, the By-Laws are not clear on the requirements for active membership of international physicians. There is no distinction in the ELS, and their members just have to have the appropriate board certification. The corresponding (ie, international) membership category was originally established because of the difficulty that international members often had in traveling long distances to attend meetings in the United States. That is no longer an issue, and many “corresponding” members come to many of our meetings. There should be one representative from Asia, one from Europe, and one from South America on the committee. Dr Remacle, currently the International Liaison, would serve as the first chair of the International Committee. The charge of the committee would be to represent the interests of our international members. Action Items: a. Dr Grillone will look into clarifying the current requirements for candidate membership and determine whether additional By-Laws language is necessary for the resident membership. b. Dr Grillone and Dr Deutsch will to look into coming up with appropriate By-Laws language so that the requirements for active membership are clarified and modified appropriately, allowing international physicians to become active members. Votes: a. The council unanimously voted to 1) approve the formation of the Past President’s Advisory Committee as an ad hoc committee and 2) to appoint Dr Blitzer (immediate Past President) as the first chair of the committee. b. The council unanimously voted to approve the formation of the Residents and Fellows Committee as an ad hoc committee. The incoming president will appoint the chair of the Residents Committee. 6. ABOto Certification Exams Discussion: Dr Blitzer received a letter from Bob Miller, Executive Director of the ABOto, saying that they have recently altered the blueprints of the ABOto exam to more accurately reflect individual otolaryngology practices. One component of each exam would be a clinical fundamentals section that would test general knowledge that all otolaryngologists should have, regardless of primary focus. Examples include airway management, tracheotomy, CPR, etc. Dr Miller asked the ABEA to 1) comment on the list of topics as to their applicability to our specialty and 2) identify individuals who would be interested in writing this clinical fundamentals curriculum and possibly writing test questions. Drs Burns, Grillone, and McMurray indicated that they would be interested. Action Item: Dr Blitzer will submit Drs Burns, Grillone, and McMurray’s names to Dr Miller. 7. Senior Membership Status for Pat Bradley Discussion: Dr Pat Bradley has been a member since 1991 and wrote to Dr Blitzer to ask that he be given emeritus status, as he is fully retired from practice and can’t afford dues but would still 10 Minutes & Reports like to stay involved. Our senior member category requires that they have 20 years of membership or be age 65 and request in writing that they be placed in senior status. Vote: The Council unanimously voted to approve senior membership status for Dr Bradley. 8. Contract With the Annals Discussion: Dr Blitzer said that we need to look at our relationship with the Annals and determine whether we should continue that relationship. The ALA recently signed a new contract with the Laryngoscope, making it the official journal of the ALA, so that all papers from the ALA meeting will be published in the Laryngoscope. One of the proposals that came out of the ALA was to make either a new journal or a sub-journal, for example, a sub-journal of the Laryngoscope just on laryngology or “airway issues,” which could include bronchology, laryngology, and upper airway disorders. Creating a separate journal from scratch runs the risk that authors may not want to contribute because the impact is low. Dr Courey is on the ALA and ABEA councils and could represent the ABEA with both journals (Annals and Laryngoscope) regarding this issue. Dr McMurray said that the ABEA contract with the Annals started in 1994 and is renewed every 5 years. The current contract ends in 2014. The contract includes subscriptions to the Annals for the members. The Annals publisher, Ken Cooper, informs us that this represents 252 print subscriptions and on-line access for the past 12 years (which he quoted out as a $240 value). He said that was worth $125,000 in addition to the $7,000 a year with which we can do whatever we want. The Annals publishes the Transactions at cost and mails them to the members. The Annals also gives us free advertisement and free publicity, and they give us priority for publication of papers that have been presented. Dr McMurray asked Ken Cooper about publishing a synopsis of the panel discussions, and Ken thought that was a great idea. Dr McMurray also asked them for $2,500 to support a panel, and Ken Cooper said in these economic times they didn’t feel they could do that. Ken Cooper later sent Dr McMurray an e-mail and said that the Annals is the last independently owned journal and that down the line the ABEA may want to have their own journal and perhaps that would be a perfect fit. The amount of money they are giving us is less than what other journals are giving. Dr Rothschild was at the board meeting of the Archives last month and reported that it seems fairly clear that print publishing will go away in the not-too-distant future. Production is expensive, and there are significant environmental impacts of printing and shipping. Action Items: a. Dr McMurray will speak with the Annals (Ken Cooper) to find out whether they would be willing to provide free journal subscriptions to the new class of resident members. b. Dr Courey will investigate potential options with both publishers and report back after his meetings. II. PRESIDENT-ELECT’S REPORT — MICHAEL ROTHSCHILD, MD 1. Committee Composition Discussion: Dr Rothschild has worked with Drs Blitzer and Deutsch on the progression of the Executive Council members. In accordance with the By-Laws, committee membership is for 3 years with the option for an additional 3-year term for committee chairs. Dr Deutsch prepared a proposed progression table that shows that many of the chairs have been on for several years more than the specified terms. If people are in their second term, they will be asked whether they want to serve out their second term. Dr Deutsch said that the time limit only went into effect when the By-Laws were revised 2 years ago. She suggested that rather than make a lot of changes at once, we stagger those who have been in their position the longest and perhaps have three new chairs a year. Proposed changes to the standing committees are as follows. a. Research and Education — Dr Courey has been chair for 7 years, and he will step down. Drs Aviv and Grillone have been committee members. Dr Aviv has been President, and Dr Grillone is currently Secretary. Dr Rothschild will select both the chair spot and the committee members. Minutes & Reports 11 b. Difficult Airway — Dr Jacobs has been chair for 8 years and will step down. Dr Karen Zur will become chairman. c. New Technology — Dr McMurray has been chair for 9 years and will step down. Committee members are Drs Dana Thompson, Michael Rutter, Paul Willging, and Andy Inglis. Dr Rothschild will ask one of these committee members whether they would like to be chair. d. Foreign Body — Dr Thompson has been chair for 5 years and will stay if she wants. If not, Dr Gresham Richter would be a good choice. e. Oncology — Dr Burns has been chair for 7 years. He will stay. f. International Liaison — Dr Remacle has been in this position for 6 years. He will become chair of the newly proposed International Committee and will select other International Committee members. g. Pharyngoesophageal — Dr Amin has been chair for 3 years with no committee members. He would like to stay on and select some committee members. h. BOG Gov — Dr Grillone has been on for 6 years. i. BOG PR — Dr McMurray has been on for 9 years and will step down. j. BOG Legislative — Dr Thompson is in her second year and will stay. k. Council at Large — Drs Belafsky and Eibling are the current Councilors-at-Large. Their terms will expire in 2013. Action Item: Dr Rothschild will further review the progression table and draw from the list of interested members compiled by Dr Grillone to appoint new committee chairs and other Council positions as appropriate. 2. Online Voting/Nominations for Officer Positions Discussion: There was a discussion about the possibility of getting the slate of officers from the Nominating Committee ahead of the Annual Meeting and then allowing members to vote on the web site. We could also accept nominations from the membership prior to the announcement of the selections from the Nominating Committee. This would allow members to vote if they are unable to attend the Business Meeting. The President-Elect nominee should be selected from individuals holding the position of Secretary, Treasurer, Editor, or Vice-President; this would be the pathway to President. Committee chairs and Councilors-at-Large may move into one of the four officer positions: Secretary, Treasurer, Editor, or Vice-President. It would be best to continue this policy, as it assures continuity and institutional memory. Nominations from the membership would be for the committee chairs and Councilors-at-Large. The Nominating Committee for this year will be Dr Koufman as Past President, and the remainder of the Nominating Committee would be chosen at the first Business Meeting. Dr Deutsch reported from the By-Laws that “This will consist of four members, three of whom shall be nominated and elected the preceding year (we have been out of compliance with this requirement) by the voting members at the executive session of ABEA and the fourth member will be the immediate Past President.” We have accepted nominations at the Business Meeting, and then they meet to present the slate the following day. Dr Koufman will select three members for the Nominating Committee this year. Dr Gregory Postma will be nominated as President-Elect, and Dr Dana Thompson as Treasurer. Once we achieve compliance with the By-Laws, there will be an opportunity to bring in one new person on the Council each year. Peter Koltai was on the Council from 2001 to 2002 and served as Secretary for 4 years before moving off. The Council felt that we should consider folding him back into succession for President. Dr Koltai left the Council because of his commitment to serve as ASPO president, but he would like to return to the Council once his term as ASPO president is up. Action Item: The discussion regarding on-line voting was tabled and will be discussed further at a later date. 3. Chevalier Jackson Stamp Project Discussion: There was a discussion about the possibility of having a Chevalier Jackson postage 12 Minutes & Reports stamp. Dr Wayne Hellman provided us with a historical essay published in the Newsletter last year. The Post Office publishes stamps to honor famous Americans, and Dr Jackson would be a good choice. He not only practiced bronchoscopy, but advanced the field of public health and safety. Furthermore, he is a real American hero, because in 1916 the Europeans were still the predominant names in medicine, and he pushed back the frontiers of medicine from this side of the Atlantic. Dr Hellman would be willing to help with this project and has a lot of knowledge on the history of Dr Jackson. III. VICE-PRESIDENT’S REPORT — ELLEN DEUTSCH, MD 1. Progression Table Dr Deutsch’s progression table was discussed previously (see President-Elect’s report). 2. AAO-HNS Guidelines Clinical Practice Guidelines continue to evolve. Some suggestions have been specialty-specific guidelines. Dr Deutsch would be willing to help anyone who would like to submit a topic for consideration. Tonsillectomy may be the next Guideline. 3. Surgical Specialties Advocacy Meeting There will be a surgical specialty advocacy meeting in Washington, DC, in July. Dr Jacobs volunteered to attend on behalf of the ABEA. Action Item: Dr Jacobs will report back at the fall Council meeting. IV. TREASURER’S REPORT — GREGORY POSTMA, MD 1. Financial Report Dr Postma provided a financial report. We decided to let our investments ride through the recession. We had an increase of $1,150.32 since December 2008 in Wachovia Money Market, and an increase of $25,105.72 in the Mellon Funds during the same period. 2. The President’s Circle The President’s Circle was $15,000 as of December 31, 2009 but we are close to $25,000 now, which is very encouraging. V. EDITOR’S REPORT — SCOTT MCMURRAY, MD Transactions Discussion: Dr McMurray said the 2008 Transactions have been published and we are nearly ready for the 2009 edition; all the papers are in. There are some additions he would like to add to the 2009 edition, and he will be sending some e-mails out. There was a discussion about publishing the Transactions on the web site, which would save publication and postage costs. All papers for 2010 should have been submitted to Dr McMurray. If anyone has pictures for their presentations, please submit them to Dr McMurray. VI. SECRETARY’S REPORT — GREGORY GRILLONE, MD 1. SLC Update Discussion: Dr Grillone reported that Dr Jerry Goldstein is stepping down this year as chairman of the Secretaries Liaison Committee and that Dr Stanley Shapshay will be taking over. He will attend the meeting this year and will take over officially after the meeting. 2. COSM Convention Cancellation Insurance Discussion: Dr Grillone distributed a COSM convention cancellation insurance memo. This is something the ACS has done in the past with the societies, and they will ask about it at the SLC meeting this week. This is necessary to ensure against any forced cancellation or forced reduction in attendance at meetings. Vote: The Council voted unanimously to approve ABEA participation in the insurance plan. Minutes & Reports 13 3. Future Meetings Discussion: Dr Grillone discussed the schedule for the Annual Meeting for the coming 3 years. The footprint is as follows. a. 2011 — April 27–May 1 in Chicago. b. 2012 — April 18-22 in San Diego. c. 2013 — April 10-14 in Orlando. 4. Candidates for Membership The following candidates were presented for membership and applications reviewed. a. Fredrik Dikkers, MD. b. Nanzeen Grant, MD. c. Priya Krishna, MD. d. Jeffrey Simons, MD. e. Jean Verheyden. f. Nwanmegha Young, MD. g. Jonathan Bock, MD, has only been in practice for 2 years, so will be advised that he will be in the candidate category this year and active next year. VII. DEVELOPMENT OFFICER’S REPORT — CLARENCE SASAKI, MD The President’s Circle Discussion: Dr Sasaki prepared a letter to the membership outlining the purpose and success of the President’s Circle, which will promote the science necessary in the care of our patients. As we go into phase II of this development project, he suggested that the Council develop a succession of advisors. He would like to continue for another year and see how it goes. There was a discussion about whether these funds had been earmarked for any particular activity. Dr Sasaki said the ABEA has never had a lot of money, and his original thought was that it would be used to support the general fund. We don’t want to shackle these funds so we can’t use them, but we don’t want to make it too easy. Dr Sasaki said that phase III could be to determine whether we need to establish an endowment. VIII. PROGRAM COMMITTEE — JAMES BURNS, MD 1. Dr Burns thanked Drs Belafsky and Postma for moderating the panels. 2. The Council thanked Drs Burns and Blitzer for the program they have set up. 3. The panels will be recorded. They will give Leora a tape, which she will see that Dr Rothschild will get. IX. FOREIGN BODY COMMITTEE — DANA THOMPSON, MD Dr Amin reported for Dr Thompson that there were four very good submissions and that they chose one by Vartan A. Mardirossian, MD, of Boston, on “A Challenging Case: Intubation Through a Foreign Body and Foreign Body Removal From the Larynx.” X. AWARDS AND THESIS COMMITTEE — CLARENCE SASAKI, MD 1. Dr Sasaki reported that the Broyles-Maloney Award had been given to Sandeep Karajanagi, PhD, of Boston, for “Assessment of Canine Vocal Fold Function After Injection of a New Biomaterial Designed to Treat Phonatory Mucosal Scarring.” 2. There were no Steven Gray or Seymour Cohen awards this year. XI. PHARYNGEAL & ESOPHAGEAL COMMITTEE — MILAN AMIN, MD Nothing to report. 14 Minutes & Reports XII. NEW TECHNOLOGY — SCOTT MCMURRAY, MD Dr McMurray thanked the Council for the 9 years he has served with them. XIII. RESEARCH AND EDUCATION COMMITTEE — MARK COUREY, MD Nothing to report. XIV. INTERNATIONAL COMMITTEE — MARC REMACLE, MD ABEA/ALA/ELS combined meeting (see President’s Report). XV. BOARD OF GOVERNORS — GREGORY GRILLONE, MD Reimbursement for Endoscopic Treatment of Zenker’s Diverticulum Discussion: Dr Grillone discussed that he had been investigating reimbursement for this procedure. In Massachusetts, many payers do not reimburse for this procedure, even though it is faster and requires less recovery time than open procedures. He discussed the problem with representatives from the BOG, including Drs Schreibstein and Waguespack. The BOG indicated it might be a good idea if the ABEA came up with a position statement for endoscopic Zenker’s diverticula. Action Item: Drs Amin, Koufman, and Belafsky will work on the position statement and report at the fall meeting. XVI. ACS ADVISORY COMMITTEE — GREGORY GRILLONE, MD Nothing to report. XVII. WEBMASTER — MICHAEL ROTHSCHILD, MD 1. Dr Rothschild reported that he is able to host and maintain the ABEA web site. The site was recently overhauled so it is now Smartphone and iPhone accessible. 2. We are now sending the Newsletter out to the membership electronically, and it will be available on-line in an electronic format. Back issues will be available as PDFs, as well. 3. We have the 2005 and 2006 Foreign Body Award clips on line. We also have the audio from the 2008 and 2009 COSM. Dr Rothschild encouraged anyone who has a video clip to submit it so he can review it for placement on the site. 4. He has added Dr Sasaki’s fundraising letter, along with a downloadable form that can be used for contributing to the ABEA. XVIII. DIFFICULT AIRWAY COMMITTEE — IAN JACOBS, MD 1. Dr Jacobs said that they had their annual course with Dr Deutsch and Dr Zur, which went well. They had registrants from the Northeast, and they are looking to expand it nationally. Dr Thompson is going to do it at Mayo, and Dr Gresham Richter is interested in doing it in South Carolina. They are working on the IRBs. 2. The specialty committee (SSAC) will meet on Friday. XIX. ONCOLOGY COMMITTEE — JAMES BURNS, MD Dr Burns reported that the Oncology Committee was accepted to present an ABEA-sponsored miniseminar at the Academy. “State-of-the-Art Endoscopic Management of Larynx and Pharynx Cancer.” XX. COUNCILORS-AT LARGE — PETER BELAFSKY, MD, AND DAVID EIBLING, MD Voice-Lift Procedure Discussion: Dr Belafsky said that in ENT Today there is a reference to treatment of dysphonia as a cosmetic procedure. If we are going to have a position statement, it should emphasize the disability associated with voice disorders in the elderly. Dr Koufman said she addressed this when the term “voice lift” was originally used and that it should be abandoned. This is not a cosmetic procedure. Dr Blitzer said he was contacted at the time by a reporter from the London Times who asked him to comment on this procedure. He told them this was not a new concept. Augmentation of the vocal cord Minutes & Reports 15 has been going on for many years. The only difference is that they have some new materials, but in no way should it be suggested that when you are 60 years old you are going to have an operation and sound like you did when you were 16. There are things we can do to improve voice, but such complete rejuvenation of the voice is an unrealistic expectation. Dr Koufman wanted the record to show that she introduced bilateral medialization laryngoplasty in 1989. Before that, they weren’t doing anything bilateral except catastrophic Teflon injections. XXI. SURGICAL SUBSPECIALTIES ADVISORY COMMITTEE (SSAC) — IAN N. JACOBS, MD Nothing to report. XXII. NEW BUSINESS Leora Loy was excused from the meeting while a discussion was held regarding her stipend. The Council unanimously felt that she continues to do an outstanding job as liaison to the Secretary of the society. In recognition of her efforts, the Council voted to approve a $1,500 bonus this year. The Council meeting was adjourned at 6:30 PM. ACCOUNTANTS’ COMPILATION REPORT To the Board of Directors of the American Broncho-Esophagological Association, Inc: AMERICAN BRONCHO-ESOPHAGOLOGICAL ASSOCIATION, INC STATEMENT OF ASSETS AND UNRESTRICTED NET ASSETS CASH BASIS DECEMBER 31, 2009 We have compiled the accompanying statement of assets and unrestricted net assets-cash basis of the American Broncho-Esophagological Association, Inc (a nonprofit organization) as of December 31, 2009, and the related statement of unrestricted revenues, expenses, and other changes in unrestricted net assets-cash basis for the year then ended, in accordance with Statements on Standards for Accounting and Review Services issued by the American Institute of Certified Public Accountants. These financial statements have been prepared on the cash basis of accounting, which is a comprehensive basis of accounting other than generally accepted accounting principles. ASSETS Checking account Savings account President’s Circle account Investments — Mellon Private Capital Management Total assets TOTAL UNRESTRICTED NET ASSETS $32,908 247,506 15,250 171,181 466,845 $466,845 See Accountants’ Compilation Report. AMERICAN BRONCHO-ESOPHAGOLOGICAL ASSOCIATION, INC STATEMENT OF UNRESTRICTED REVENUES, EXPENSES, AND OTHER CHANGES IN UNRESTRICTED NET ASSETS CASH BASIS FOR THE YEAR ENDED DECEMBER 31, 2009 A compilation is limited to presenting in the form of financial statements information that is the representation of management. We have not audited or reviewed the accompanying financial statements and, accordingly, do not express an opinion or any other form of assurance on them. However, we did become aware of a departure from the cash basis of accounting that is described in the following paragraph. REVENUES Dues Registration Annals Sponsorships and donations Interest income Investment income — Mellon Bank Unrealized gain on investments — Mellon Bank Total revenues EXPENSES Meetings AAO-HNS council meeting COSM meeting Awards and grants Chevalier Jackson Broyles Maloney Seymour Cohen Secretarial support Professional services Bank service charges Trustee fees Foreign tax Office supplies Realized loss on sale of securities Total expenses CHANGE IN UNRESTRICTED NET ASSETS UNRESTRICTED NET ASSETS JANUARY 1, 2009 UNRESTRICTED NET ASSETS DECEMBER 31, 2009 Investments have been stated at market value, which is not considered a generally accepted modification of the cash basis of accounting. The effects of this departure from the cash basis of accounting on the accompanying financial statements have not been determined. Management has elected to omit substantially all of the disclosures ordinarily included in financial statements prepared on the cash basis of accounting. If the omitted disclosures were included in the financial statements, they might influence the user’s conclusions about the Organization’s financial position and changes in net assets. Accordingly, these financial statements are not designed for those who are not informed about such matters. Piccerelli, Gilstein & Company, LLC Providence, Rhode Island June 21, 2010 See Accountants’ Compilation Report. 16 $37,565 16,315 7,000 15,250 1,150 3,408 28,213 108,901 2,012 15,896 2,500 1,500 1,000 9,500 4,369 248 489 20 119 6,029 43,682 65,219 401,626 $466,845 OFFICERS 2010-2011 PRESIDENT PRESIDENT-ELECT MICHAEL A. ROTHSCHILD, MD New York, New York GREGORY POSTMA, MD Augusta, Georgia VICE-PRESIDENT PAST PRESIDENT ELLEN S. DEUTSCH, MD Wilmington, Delaware ANDREW BLITZER, MD, DDS New York, New York SECRETARY TREASURER GREGORY A. GRILLONE, MD Boston, Massachusetts DANA THOMPSON, MD Rochester, Minnesota EDITOR CHAIR AWARDS AND THESIS COMMITTEE J. SCOTT MCMURRAY, MD Madison, Wisconsin ANDREW BLITZER, MD, DDS New York, New York CHAIR NOMINATING COMMITTEE CHAIR FOREIGN BODY AND ACCIDENTS COMMITTEE JAMIE A. KOUFMAN, MD New York, New York GRESHAM RICHTER, MD Little Rock, Arkansas CHAIR DIFFICULT AIRWAY COMMITTEE CHAIR PHARYNGEAL AND ESOPHAGEAL COMMITTEE KAREN B. ZUR, MD Philadelphia, Pennsylvania MILAN AMIN, MD New York, New York CHAIR INTERNATIONAL RELATIONS COMMITTEE CHAIR NEW TECHNOLOGY COMMITTEE MARC J. REMACLE, MD, PHD Yvoir, Belgium PAUL WILLGING, MD Cincinnati, Ohio CHAIR RESEARCH AND EDUCATION COMMITTEE CHAIR ONCOLOGY COMMITTEE SETH DAILEY, MD Madison, Wisconsin JAMES A. BURNS, MD Boston, Massachusetts REPRESENTATIVES TO THE BOARD OF GOVERNORS GREGORY A. GRILLONE, MD Boston, Massachusetts J. SCOTT MCMURRAY, MD Madison, Wisconsin DANA THOMPSON, MD Rochester, Minnesota CHAIR SCIENTIFIC PROGRAM KAREN B. ZUR, MD Philadelphia, Pennsylvania COUNCIL MEMBERS AT LARGE REPRESENTATIVE AMERICAN ACADEMY OF OTOLARYNGOLOGY– HEAD AND NECK SURGERY PETER BELAFSKY, MD Sacramento, California DAVID E. EIBLING, MD Pittsburgh, Pennsylvania REZA RAHBAR, MD Boston, Massachusetts IAN N. JACOBS, MD Philadelphia, Pennsylvania WEBMASTER MICHAEL A. ROTHSCHILD, MD New York, New York 17 PRESIDENTIAL ADDRESS ANDREW BLITZER, MD, DDS I welcome you to the 90th Annual Meeting of the American Broncho-Esophagological Association, a society that was started by Chevalier Jackson. I wish to thank Dr James Burns, who worked tirelessly as Program Chairman; Leora Loy, who serves as Administrator of the ABEA; and all of the council members whose wisdom and guidance serve the society well. In the Hippocratic oath that we all have taken upon graduation from medical school, it says “...to respect the hard-won scientific gains of those physicians in whose steps I walk and gladly share such knowledge as is mine with those who follow.” Jackson says in his autobiography, “Achievement brings pleasure, but also the onerous feelings of obligation; never refuse to treat patients in need of care; the work of physicians in prevention of disease should equal their work in curing disease; always share and teach the skills you have learned to your students; and always look for ways of giving back for the honor of being a physician.” Some of the ways that all of you can give back are: –Volunteer for the committees and help make the organization better. –Join the ABEA and contribute to the meetings. –Donate money to the President’s Circle and Foundation Fund to help support the meetings, awards, and resident and fellow participation. –Present your work at our meetings and publish in our journal (the Annals). 18 PRESENTATION OF GUEST OF HONOR WILLIAM LAWSON, MD ANDREW BLITZER, MD, DDS William Lawson grew up in New York City and received his DDS and MD degrees from New York University. He did his oral surgery and otolaryngology training at the Mt Sinai Medical Center, with a brief interruption as a Captain in the US Army Medical Corps. He is a Professor of Otolaryngology, and has remained with the faculty of Mt Sinai Medical Center for 36 years, training me and many of the otolaryngologists in the audience. The breadth of his knowledge is encyclopedic. His surgical skills and teaching span much of our specialty, including head and neck cancer, trauma and reconstructive surgery, sinus and airway surgery, and facial plastic surgery. He is the director of a facial plastic surgery fellowship, director of a sinus and airway disease laboratory, and member of the multi-discipline Head and Neck Tumor Board. He is a fellow of 12 societies, including the ABEA, American Laryngological Association, Triological Society, Society of Maxillofacial Surgery, and American Rhinologic Society. He has received numerous honors and awards, including a Distinguished Candidate’s Thesis and Presidential Citation from the Triological Society. He has held many offices in these societies, including on the boards of directors of the American Academy of Facial Plastic and Reconstructive Surgery and the American Board of Facial Plastic Surgery, and as President of the New York Laryngological Society. He has taught courses and given lectures worldwide on the subjects of head and neck disease and surgery, airway evaluation and surgery, and facial plastic surgery. His basic research is comprehensive and spans results from his animal laboratory for sinus and airway disease, the comparative and paleo anthropology of airway development (for which he is a consultant to the Museum of Natural History in New York), and basic principles of head and neck tumors and reconstruction. Bill has published 186 peerreviewed articles, 65 chapters, and 3 texts, including the classics The Paraganglionic Chemoreceptor System: Physiology, Pathology, and Clinical Medicine (Zak, Lawson) and Surgery of the Paranasal Sinuses (Blitzer, Lawson, Friedman). I am honored to have Bill as my guest of honor, recognizing all the tireless efforts he made in teaching me, and as my friend for over 35 years. 19 PRESENTATION OF CHEVALIER JACKSON AWARD TO CLARENCE T. SASAKI, MD ANDREW BLITZER, MD, DDS Clarence Sasaki was born in Hawaii and attended college in California. He migrated east and received his MD from Yale University. He did general surgery at Dartmouth Medical Center, served in the military in Vietnam, and then returned to Yale for otolaryngology residency training. He has remained a loyal faculty member and major pillar of the institution. He is recognized worldwide for his contribution to the basic and clinical science of laryngology. He has given numerous named lectureships; has received numerous prizes for his contributions, including the Keese Prize from Yale, the Fowler Award from the Triologic Society, the Casselberry Award from the American Laryngological Association, the BroylesMaloney Award from the ABEA, the Chevalier Jackson Lecturer for the ABEA, and the Guest of Honor and Presidential Citation from the American Laryngological Association. He is a member of 11 editorial boards and is a research advisor or investigator to over 30 scientific projects. He is a member of over 20 professional organizations and has held various offices of 7 of them, including President of the ABEA and the Dysphagia Research Society. His scholarly contributions are acknowledged worldwide and include 214 peer-reviewed articles, 68 chapters, and 7 textbooks. He is the quintessential scholar, scientist, and teacher, and we are fortunate to have him as part of the ABEA. I am honored and privileged to call him my friend. 20 GUESTS OF HONOR 1951-2010 1951 1959 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 FERNAND EEMAN, MD LOUIS H. CLERF, MD W. LIKELY SIMPSON, MD EDWIN N. BROYLES, MD SAM E. ROBERTS, MD LYMAN RICHARDS, MD VERLING K. HART, MD JULIUS W. MCCALL, MD FRANCIS W. DAVISON, MD DEAN M. LIERLE, MD LEROY A. SCHALL, MD HERMAN J. MOERSCH, MD LOUIS H. CLERF, MD JOSEPH P. ATKINS, MD RICARDO TAPIA ACUNA, MD PAUL H. HOLINGER, MD ARTHUR M. OLSEN, MD FRANCIS E. LEJEUNE, SR, MD ALDEN H. MILLER, MD CHARLES M. NORRIS, MD CHARLES F. FERGUSON, MD EMILY LOIS VAN LOON, MD DONALD F. PROCTOR, MD FRANK D. LATHROP, MD JOHN E. BORDLEY, MD GABRIEL F. TUCKER, JR, MD STANTON A. FRIEDBERG, MD 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 F. JOHNSON PUTNEY, MD HOWARD A. ANDERSEN, MD JOHN P. FRAZER, MD PAUL H. WARD, MD D. THANE R. CODY, MD M. STUART STRONG, MD BRUCE BENJAMIN, FRACS DAVID R. SANDERSON, MD MICHAEL E. JOHNS, MD JOHN A. KIRCHNER, MD ROBERT W. CANTRELL, MD EIJI YANAGISAWA, MD LAUREN D. HOLINGER, MD WILLIAM R. HUDSON, MD ROBERT H. OSSOFF, DMD, MD TREVOR J. MCGILL, MD FLAVIO APRIGLIANO, MD STANLEY M. SHAPSHAY, MD MINORU HIRANO, MD, PHD R. ROX ANDERSON, MD HUGH F. BILLER, MD FRANK E. LUCENTE, MD MARVIN P. FRIED, MD MARSHALL STROME, MD 2009 JAMES PEPA 2010 WILLIAM LAWSON, MD RECIPIENTS OF CHEVALIER JACKSON AWARD (Established 1958) 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 LOUIS H. CLERF, MD (No award) HERMAN J. MOERSCH, MD PAUL H. HOLINGER, MD EDWIN N. BROYLES, MD LEROY A. SCHALL, MD HERBERT W. SCHMIDT, MD PAUL G. BUNKER, MD JOEL J. PRESSMAN, MD VERLING K. HART, MD JOSEPH P. ATKINS, MD ANDERSON C. HILDING, MD ROBERT M. LUKENS, MD CHARLES M. NORRIS, MD ARTHUR M. OLSEN, MD CHARLES F. FERGUSON, MD SHIGETO IKEDA, MD BLAIR FEARON, MD FRANCIS W. DAVISON, MD SEYMOUR R. COHEN, MD M. STUART STRONG, MD DEGRAAF WOODMAN, MD ALBERT H. ANDREWS, JR, MD GABRIEL F. TUCKER, JR, MD HOWARD A. ANDERSEN, MD PAUL H. WARD, MD 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 21 BRUCE BENJAMIN, FRACS LORING W. PRATT, MD ROBERT S. FONTANA, MD CHARLES W. CUMMINGS, MD BERNARD R. MARSH, MD DAVID R. SANDERSON, MD WILLIAM W. MONTGOMERY, MD JOHN A. TUCKER, MD GERALD B. HEALY, MD VINCENT J. HYAMS, MD LAUREN D. HOLINGER, MD STANLEY M. SHAPSHAY, MD ROBERT H. OSSOFF, DMD, MD JOHN M. FREDRICKSON, MD HASKINS KASHIMA, MD EIJI YANAGISAWA, MD WILLIAM W. MONTGOMERY, MD JACK L. GLUCKMAN, MD ELLEN M. FRIEDMAN, MD ROBIN T. COTTON, MD CHARLES W. VAUGHAN, MD ANDREW BLITZER, MD GAYLE E. WOODSON, MD ROBERT J. TOOHILL, MD PETER KOLTAI, MD CLARENCE T. SASAKI, MD INTRODUCTION OF CHEVALIER JACKSON LECTURER MARSHALL STROME, MD ANDREW BLITZER, MD, DDS Marshall Strome grew up in Michigan, went to school at the University of Michigan, and completed his otolaryngology residency at the University of Michigan. He served briefly on the faculty of the University of Connecticut, and then joined the faculty of the Beth Israel Hospital, Brigham and Women’s Hospital, and Harvard Medical School, where he served for over 20 years as Chief of Otolaryngology. In 1993 he was recruited to be the Professor and Chairman of the Otolaryngology Department of the Cleveland Clinic, where he served for 11 years. He is now a major part of the New York Head and Neck Institute and is a member of the faculty at the New York Center for Voice and Swallowing Disorders, teaching our fellows endoscopic surgery for cancer of the larynx and pharynx. Marshall has received countless awards and visiting professorships from around the world for his work, including the Medal of the City of Paris; Medallion of Honor from the American Academy of Facial Plastic and Reconstructive Surgery; the Sword of Saudi Arabia; and the Millenium Ogura Lecturer. He has been an officer for many of our societies, including President of the Society of Urologic Oncology and the American Laryngological Association. He serves on over a dozen editorial boards. He has published over 170 peer-reviewed papers, 50 chapters, and 4 books. His research and teaching contributions continue to stimulate so many in our field. His novel contri- butions include the first and only human laryngeal transplantation, the first robotic laser surgery for a laryngeal malignancy, and new endoscopic laryngeal preservation operations for malignancy. Most of all, Marshall has been a ski partner and dear friend for better than 25 years. 22 CHEVALIER JACKSON LECTURES 1964-2010 1964 DONALD F. N. HARRISON, MD. Esophageal Replacement in Postcricoid Cervical Esophageal Carcinoma. 1965 ERIC CARLENS, MD. Mediastinoscopy. 1966 JOHN L. POOL, MD (Moderator). Carcinoma of the Bronchus: A Panel Discussion. Presentations: ERNEST L. WYNDER, MD. The Epidemiology of Cancer of the Bronchus — Facts and Suppositions. PAUL H. HOLINGER, MD. Postsurgical Endoscopic Management of Tracheal and Bronchial Resection and Anastomosis. LESLIE BERNSTEIN, MD. Two Thousand Bronchoscopies in Search of Cancer. JOHN L. POOL, MD. Is Surgery Worthwhile in Carcinoma of the Bronchus? ROBERT H. SAGERMAN, MD. New Directions in the Radiotherapy of Lung Cancer. 1967 EELCO HUIZINGA, MD. The Tussive Squeeze and Bechic Blast of Chevalier Jackson. 1968 PAUL H. HOLINGER, MD. Management of Esophageal Lesions Caused by Chemical Burns. 1969 PLINIO DE MATTOS BARRETTO, MD. Endoscopic Surgery of the Pharyngo-esophageal Segment. 1970 JAMES R. JUDE, MD. Otolaryngological Aspects of Cardiac Arrest. 1971 JO ONO, MD. Endoscopic Microsurgery of the Larynx. 1972 G. GORDON MCHARDY, MD. Reflux Esophagitis. 1973 HERMES C. GRILLO, MD. Obstructive Lesions of the Trachea and Their Management. 1974 JOHN R. GUTELIUS, MD. Effect of Government Payment of Medical Fees on Medical Practice and Education in Canada. 1975 DONALD O. CASTELL, MD (Captain, MC USN). Physiology and Pathophysiology of the Gastroesophageal Sphincter. 1976 G. PAUL MOORE, PHD. Observations on Laryngeal Disease, Laryngeal Behavior and Voice. 1977 MARY ELLEN AVERY, MD. In Quest of the Prevention of Hyaline Membrane Disease. 1978 GEORGE BERCI, MD. Analysis of New Optical Systems in Bronchoesophagology. 1979 GABRIEL F. TUCKER, JR, MD. Pediatric Laryngobronchoesophagology. 1980 FLAVIO APRIGLIANO, MD. Esophageal Stenosis in Children. 1981 PETER STRADLING, MD. A Photographer’s View of the Tracheobronchial Tree. 1982 ARTHUR M. OLSEN, MD. Esophagology: An Update. 1983 BRUCE BENJAMIN, FRACS. Congenital Laryngeal Webs. 1984 RONAN O’RAHILLY, MD. Respiratory and Alimentary Relations in Staged Human Embryos. New Embryological Data and Congenital Anomalies. 1985 JOHN A. TUCKER, MD (Moderator). Esophageal Reflux in Children: A Panel Discussion. Participants: Samuel R. Schuster, MD; Sandra Sue Kramer, MD; Marvin Ament, MD. 1986 WILLIAM G. ANLYAN, MD. Critical Issues in Medicine Today. 1987 GUI-YI TU, MD. Stomach Pull-up and Colon Transfer in the Management of Cancer of the Hypopharynx and Cervical Esophagus. 1988 LUCIUS D. HILL III, MD. What Would Chevalier Jackson Think? 1989 BERNARD R. MARSH, MD. Teaching Bronchoesophagology in Otolaryngology–Head and Neck Surgery Residencies in the United States. 1990 DAVID R. SANDERSON, MD. Health-Care Economics in the 1990s. 1991 MICHAEL E. JOHNS, MD. If I Had to Do It Again Would I Want It to Be the Same as Before? 1992 WHITNEY A. ADDINGTON, MD. Needed: The Reorganization of Health Care, Not More Money. 1993 HENRY J. HEIMLICH, MD, SCD. The Heimlich Maneuver in Infants and Children: The Best Treatment for Saving Drowning and Choking Victims. 1994 JOHN A. KIRCHNER, MD. The Glottic Gateway. 1995 MINORU HIRANO, MD. Phonosurgery: Past, Present, and Future. 1996 HAROLD C. PILLSBURY III, MD. A Strategy for Academic Specialists in a Managed Care World. 1997 GERALD B. HEALY, MD. The Legacy of Jackson: Has It Been Lost? 1998 ROBIN T. COTTON, MD. The Story of Laryngotracheal Reconstruction in Children. 1999 JAMES A. KOUFMAN, MD. Laryngopharyngeal Reflux: A New Paradigm of Airway Disease. 2000 STANLEY M. SHAPSHAY, MD. Twenty-Five Years’ Experience With Endoscopic Laser Treatment for Vocal Cord Cancer: What Is the Standard of Care in Y2K? 2001 PAUL A. LEVINE, MD. Accurate Endoscopic and Radiologic Pretreatment Evaluation: The Jackson Legacy and Its Impact on the Evolution of Therapy for Sinonasal Malignancies. 2002 STEVEN D. GRAY, MD. Tissue Engineering the Laryngeal Components: Pushing the Edges of Biotechnology. 2003 WOLFGANG STEINER, MD. Transoral Surgical Management of Hypopharyngeal Carcinoma. 2004 JONATHAN E. AVIV, MD. Transnasal Esophagoscopy: From New Frontier to the Future of Esophagology. 2005 JOHN L. WARD, PHD. Cancer of the Vocal Folds: A Patient’s Perspective. 2006 STEVEN M. ZEITELS, MD. Concepts and Culture of Innovation. 2007 PEAK WOO, MD. Office-Based Interventional Laryngology: Our Legacy and Our Future. 2008 REZA SHAKER, MD. Reciprocal Physiology and Pathophysiology of the Upper Gut and Airway. 2009 CLARENCE T. SASAKI, MD. The Vagus Nerve: Dispelling the Animal Spirits. 2010 MARSHALL STROME, MD. Laryngeal Transplantation: The End of the Beginning. 23 PRESIDENTIAL CITATIONS HONORING ANTHONY F. JAHN, MD, MITCHELL F. BRIN, MD, AND ROBERT M. BLITZER, DDS ANDREW BLITZER, MD, DDS ANTHONY F. JAHN (L) & ANDREW BLITZER (R) Born in Budapest and schooled in Toronto, Anthony F. Jahn is the product of a University of Toronto residency. He comes from professional music family and is himself a concert pianist. I met Tony in 1979, when he joined our faculty as an otologist at Columbia. In a short time, he also worked with Jim Gould and Eugene Grabscheid in treating professional voice. He joined the staff of doctors at the Metropolitan Opera Company, and recently became the medical director of the Metropolitan Opera Company, consultant to the Juilliard School of Music, consultant laryngologist for the Royal Shakespeare Company, and Adjunct Professor of Voice Pedagogy at the Westminster Choir College in Princeton, New Jersey. Tony has served as Professor and Chairman of Otolaryngology at the University of Medicine and Dentistry of New Jersey, and now serves as Professor of Clinical Otolaryngology of the Columbia University College of Physicians and Surgeons. He teaches the care of professional voice to our fellows at the New York Center for Voice and Swallowing Disorders. He has given lectures and taught courses worldwide for greater than 30 years on otology and voice. He is a trained and certified acupuncturist and a student of Eastern medicine. He has for many years participated in mercy medical missions to southeast Asia. He has been a guest examiner of the American Board of Otolaryngology, serves as a reviewer or editorial board member for a dozen journals, and has written over 90 peer-reviewed articles, chapters, or books, including the classic Care of the Professional Voice. Most importantly, Tony has been a best friend for over 30 years. 24 Presidential Citations 25 ANDREW BLITZER (L) & MITCHELL F. BRIN (R) Mitchell F. Brin grew up in New Jersey, and went to college at the University of Pennsylvania. He returned to New York and was a student at Columbia College of Physicians and Surgeons. I first met Mitchell as a third-year student and tried to convince him to go into otolaryngology. He chose neurology because he didn’t like having to get to the operating room so early in the morning, only to find out years later that he was seeing patients at 7 AM. He did his internal medicine at Mt Sinai, neurology at Columbia, and his movement disorders neurology fellowship at Columbia. He then became part of the Stan Fahn Movement Disorders Center at Columbia, where I began working with him on head and neck dystonias and botulinum toxin therapy. Mitchell and I worked together closely in treating a variety of neurologic conditions affecting the larynx, including spasmodic dysphonia, Parkinson’s disease, and tremor. Mitchell worked at Columbia until 1994, when he moved to the Mt Sinai Medical Center in New York, where he is Bachman-Strauss Professor of Movement Disorders Neurology. He currently is also Vice-President for Development and Therapeu- tic Head, Botox Neurology Worldwide for Allergan Pharmaceutics. Among Mitchell’s many talents are his keen research analytical abilities. He has served as a scientific advisor to the Parkinson Study Group, American Association of Neurology Therapeutics subcommittee, National Spasmodic Dysphonia Association, founder of We Move, founder of the Soviet-American Neurogenetics Group, review board member of US Pharmacopeia, Associate Member of the American Academy of Otolaryngology–Head and Neck Surgery, and member of the Neurolaryngology Study Group, among many others. He has taught worldwide on evaluation and treatment of movement disorders. He serves as a reviewer for 15 journals, as well as an ad hoc reviewer for the National Institutes of Health. He has written over 100 peer-reviewed papers, 60 chapters, 116 abstracts or reviews, and 50 collaborative papers from the Parkinson Study Group, and is a coeditor for our text Neurologic Disorders of the Larynx, now in its second edition. Most of all, he has been a dear friend for over 30 years. 26 Presidential Citations ROBERT M. BLITZER (L) & ANDREW BLITZER (R) Robert M. Blitzer, whom I have known longer than all of the other award winners, was born in New York and schooled in New York. He received his DDS degree from Temple University, where he became board-certified in prosthodontics and was part of the dental faculty until 1995. During his tenure at Temple, he became an expert in the science and evolution of dental materials. His research led him to become a consultant and then in 1995 director of Clinical Research for Dentsply in Delaware. He continued the clinical practice of dentistry, as well as teaching. He is an Associate Professor of Dentistry at the University of Maryland as has served as a consultant to the Wilkes-Barre VA and the VA Medical and Regional Office Center in Wilmington, Delaware. He has expanded the evaluation and treatment of dysphagia (particularly management of oral phase deficits with prosthetic dental devices and swallowing retraining). He has lectured worldwide, and his science continues to be used in the innovation of new materials. He is the recipient of honors and invited lectureships worldwide. He has numerous publications and has received many honors as an outstanding teacher. Most of all, he is my baby brother whom I love. PRESIDENT-ELECT ADDRESS MICHAEL A. ROTHSCHILD, MD Standing on the shoulders of giants makes any job easier, and this one is no exception. In my first official communication, I have to acknowledge my predecessors in this role — from Dr Jackson to Dr Blitzer — who have done so much to make the ABEA into the renowned and scholarly association that it is today. Over the next 12 months, we will be implementing several initiatives launched during the last administration. We will be accepting applications for the new resident member class (with a representative at the board meeting). Also, we will be developing the Past Presidents council that will spearhead the development effort begun by Dr Sasaki and serve as a source of advice and perspective in the years to come. We are in the process of bringing a number of current members into leadership roles on the council, and we continue our ongoing membership drive, bringing new colleagues in the field of bronchoesophagology into our ranks. I am looking forward to a productive year, culminating in our annual spring meeting. I hope to see you all in Chicago in 2011, where I am anticipating yet another terrific forum for the presentation of new research, and the renewal of old friendships. 27 ABEA Panel on Laryngopharyngeal Reflux Moderator: Peter Belafsky, MD, PhD Panelists: Jamie Koufman, MD; Tanya Meyer, MD; Nikki Johnston, PhD; Michael Pitman, MD Case Presentation. Thirty-eight-year-old man with chief complaint of globus failing treatment with twice-daily proton pump inhibitors. Also with symptoms of mild dysphagia and excessive throatclearing (Reflux Symptom Index [RSI] = 18, Eating Assessment Tool-10 [EAT-10] = 9). Panel Recommended Subsequent Evaluation and Treatment. Balloon dilation of the upper esophageal sphincter to address the cricopharyngeal bar as a treatment of his globus and a dilation of his Schatzki ring as a treatment of his dysphagia. The question was raised about whether the Schatzki ring could be protective against reflux. The consensus from the panel was that most gastroesophageal reflux is from transient lower esophageal sphincter relaxations and that dilating the ring would not make the gastroesophageal reflux worse. Pharmaceutical History. Hypertension on Prinizide. Social History. Attorney and professional voice user. No tobacco or illicit drugs. Social alcohol use. Panel Recommended Evaluation. Comprehensive head and neck examination with flexible video laryngoscopy. Results of Dilation to 60F of Upper Esophageal Sphincter and Schatzki Ring. Improved dysphagia (EAT-10 = 4). No improvement in globus or throatclearing. Results of Initial Evaluation. Normal head and neck examination with evidence of chronic laryngitis on laryngoscopy with vocal fold edema and an early granuloma formation (Reflux Finding Score [RFS] = 9). Panel Recommended Subsequent Evaluation and Treatment. Twenty-four hour dual-probe ambulatory pH and impedance testing without proton pump inhibitors. Panel Recommended Subsequent Evaluation. Unsedated transnasal esophagoscopy. Results of pH and Impedance Testing. The patient’s symptoms of globus and throat-clearing got worse after abruptly stopping the twice-daily proton pump inhibitors. The reflux testing revealed that the pH was less than 4 for 3.6% of the time. There were 3 episodes of a pH less than 4 in the hypopharynx, 5 episodes of a pH between 4 and 5 in the hypopharynx, and 14 weakly-acid reflux episodes. Negative symptom association with throat-clearing. Results of Transnasal Esophagoscopy. Mildly constricting Schatzki B ring. No evidence of peptic esophagitis or Barrett metaplasia. It was felt by the panel that the Schatzki ring was potentially the cause of the patient’s dysphagia but unlikely the cause of his globus. Panel Recommended Subsequent Evaluation and Treatment. The patient should be offered simple reassurance vs. a further work-up with fluoroscopy and manometry. The patient remained significantly bothered by the globus and desired a more-extensive work-up. A fluoroscopic swallow study and highresolution pharyngeal and esophageal manometry was performed. Panel Recommended Subsequent Evaluation and Treatment. Because of the abnormal pH testing, the patient was placed back on proton pump inhibitors, and a strict low-acid diet, liquid alginate 30 mL after meals and before bedtime, and baclofen 20 mg 3 times per day were recommended. Because of the relationship between ACE inhibitors and cough and the potential relationship between ACE inhibitors and throat-clearing, the patient was referred back to his primary care physician to discuss replacing the ACE inhibitors with another anti-hypertensive medication. Results of Fluoroscopy. Non-obstructing cricopharyngeal bar, 2-cm hiatal hernia, and a mildly constricting Schatzki B ring. Results of Manometry. Normal pharyngeal peak pressure with slightly elevated upper esophageal sphincter residual pressure. Normal esophageal body motility. Results of Aforementioned Treatment. Globus and throat-clearing significantly improved. RSI = 7 (within normal limits). 28 SPECIAL PRESIDENTIAL LECTURE Airway Clinic: Bronchoesophagology in the Twenty-First Century Marshall E. Smith, MD; Mark Elstad, MD By nature of the anatomical overlap of the upper aerodigestive tract, diseases of these structures affect a variety of medical specialties. Team care for clinical conditions that cross specialty boundaries has become the standard of care for problems such as clefts and craniofacial disorders in pediatrics and head and neck cancer in adults. In diagnosis and treatment of diseases of the esophagus and tracheobronchial tree, the specialties of pulmonary medicine and gastroenterology have also made significant advances in diagnosis and treatment in the past 30 years. This report describes our 12-year experience with a multidisciplinary clinic for team care management of diseases of airway obstruction in adults. An update from the emerging field of interventional pulmonology is highlighted. We thank President Blitzer, Guests of Honor, and members of the ABEA for the opportunity to present our perspective on a multidisciplinary approach to bronchoesophagology. Our theme is that collaborative care wins — for patients and the caregivers. This type of model for clinical care is not totally novel. Many members of the ABEA are pediatric otolaryngologists. They know that in children’s hospitals, care teams have evolved for decades in treatment of conditions such as clefts and craniofacial disorders and spina bifida. The internet was surveyed to find pediatric hospitals that have a team for care of aerodigestive tract disorders. There are many programs now in place for managing airway, voice, and swallowing disorders in children. The teams vary in composition. They include otolaryngology, pulmonary medicine, gastroenterology, sleep medicine, pediatric surgery, speech-language pathology, respiratory therapy, and nursing. Some have scheduled care conferences, and some have immediate care coordination during the clinic visit. A key feature of collaborative care is that the patient sees more than one specialist during a clinic visit, and the specialists discuss and coordinate each patient’s care. In head and neck cancer care, team management has also become standard through collaboration between specialists in head and neck surgery, radiation oncology, medical oncology, reconstructive surgery, dentistry, prosthodontics, prosthetics, pathology, radiology, speech-language pathology, and nursing. strengths and resources in their particular institution and situation and build them up. At the University of Utah, the airway clinic’s origins can be traced to the early 1990s, when Dr Steve Gray, a prominent member of the ABEA, was working on a particularly difficult case of laryngotracheal papillomatosis. He asked Dr Elstad to help him manage the disease in the lower airway. Dr Elstad was doing rigid bronchoscopy as a self-taught interventional pulmonologist, treating mainly endobronchial tumors as he learned from a text by Dr Chevalier Jackson1 and observation of Dr Jim Harrell. Drs Gray and Elstad also collaborated in caring for some patients with airway stenosis with endotracheal stents.2 When Dr Smith came to the University of Utah in 1997, the airway patients came to the voice disorders clinic. This was inefficient for the speech pathologist, and a pulmonologist was not available for the complicated cases. Drs Smith and Elstad decided that it would be far better to have patients who required more than one specialist to be scheduled at the same time. They had enough patients that they began to run a separate clinic. In 1998, they opened the University of Utah Airway Disorders Clinic and began seeing patients together routinely. For 3 years, a gastroenterology fellow worked there, too, making for a full aerodigestive team. The clinic is currently working to recruit another interested gastroenterologist. At the Airway Clinic, there are 2 half-days each month when patients are jointly seen in dual, 30-minute appointments with both the laryngologist and the pulmonologist. Patients are seen in an outpatient Each bronchoesophagologist needs to assess the From the Division of Otolaryngology–Head and Neck Surgery (Smith) and the Division of Critical Care, Occupational, and Pulmonary Medicine, Department of Internal Medicine (Elstad), University of Utah School of Medicine, Salt Lake City, Utah. Correspondence: Marshall E. Smith, MD, Division of Otolaryngology–Head and Neck Surgery, University of Utah School of Medicine, 3C-120 SOM, 50 N Medical Dr, Salt Lake City, UT 84132. 29 30 Special Presidential Lecture otolaryngology clinic in rooms that are equipped for endoscopy. They are examined, the endoscopic examinations are recorded, and then the cases are staffed together by both doctors. The most common disorders seen are idiopathic subglottic stenosis and postintubation stenosis. The clinic sees a few adults with problems from congenital diseases. Other conditions include autoimmune diseases affecting the airway, tracheobronchomalacia, laryngeal paralysis, vocal fold paralysis and fixation, and occasionally, anastomotic stenosis from lung transplantation. For evaluation, the clinic relies heavily on the laryngotracheobronchoscopy procedure.3 This is the diagnostic procedure that makes the Airway Clinic work. It is done awake and unsedated and accomplishes the assessment in almost all patients. No separate sedated bronchoscopy is needed. It helps considerably with presurgical planning. Training and expertise in this procedure is a crucial component of the success of the Airway Clinic. This procedure can be learned through courses at the AAO-HNS annual meeting, which are generally taught by members of the ABEA. Both otolaryngologists and pulmonologists should develop skill with this procedure. Ideally, the examinations should be done jointly, so technical facility can be compared and constructively critiqued. About 60% of the bronchoscopy procedures performed at the clinic are for evaluation and diagnosis, and about 40% are for treatment. The speed of the procedure is a big advantage. Outpatient flexible bronchoscopy is performed in minutes instead of the typical 2 hours when done under sedation in the conventional pulmonologist endoscopy clinic. Thus, it is a very efficient method for evaluating the airways. The activities of the Airway Clinic also include surgical treatment and evaluation of outcomes. Examples of studies at our center include the effect of mitomycin C treatment of laryngotracheal stenosis, and the vocal consequences of cricotracheal sleeve resection.4,5 In 2009, the operative logs of the clinic included 14 open reconstructive procedures, 75 endoscopic procedures, 10 stent placements, 9 intrabronchial valve replacements, and 20 diagnostic bronchoscopies with sedation. One of the newer bronchoscopic procedures being used at the clinic is endobronchial ultrasound for diagnosis of bronchogenic carcinoma. This procedure has essentially eliminated the need for mediastinoscopy in evaluating the disease. Intrabronchial valves are a new device for treating emphysema patients. Lung volume reduction surgery has resulted in improvement in both patient quality of life and measurable gains in pulmonary function. However, it is an expensive and often morbid procedure. A trial is now under way to assess intrabronchial valves that are placed through a bronchoscope into the segmental bronchial airways. They self-expand and contract and redirect air to healthier tissue. This is a less-invasive alternative that may achieve similar results. Our clinic is participating in the device trial and looking at patient satisfaction and survival rates. In summary, the combined resources and expertise of laryngology and pulmonology in evaluation and management of airway lesions yield many positive benefits for patients and clinicians. Patients frequently come to the clinic complaining of shortness of breath, and it’s not always due to an airway lesion, even though a known airway lesion may exist. Other causes of dyspnea, related to different organ systems, are important to recognize, and the benefit of having a physician with an internal medicine perspective to help assess and manage them is invaluable. Collaboration with doctors in other specialties is as simple as going ahead and doing it. Those interested in developing a clinical practice model like this can find appropriate colleagues to develop expertise with and simply start seeing patients together. REFERENCES 1. Jackson C, Jackson CL. Bronchoesophagology. Philadelphia, Pa: WB Saunders, 1950. 2. Kurrus JA, Gray SD, Elstad MR. Use of silicone stents in the management of subglottic stenosis. Laryngoscope 1997;107: 1553-8. 3. Hogikyan ND. Transnasal endoscopic examination of the subglottis and trachea using topical anesthesia in the otolaryn- gology clinic. Laryngoscope 1999;109:1170-3. 4. Smith ME, Elstad M. Mitomycin C and the endoscopic treatment of laryngotracheal stenosis: are two applications better than one? Laryngoscope 2009;119:272-83. 5. Smith ME, Roy N, Stoddard K, Barton M. How does cricotracheal resection affect the female voice? Ann Otol Rhinol Laryngol 2008;117:85-9. Arytenoid Abduction: Indications and Limitations Gayle Woodson, MD Objectives: I report further experience with arytenoid abduction (AAb), a procedure that enlarges the glottis by external rotation of the arytenoid cartilage and thus moves the vocal process laterally and rostrally, but does not preclude adduction for phonation. Therefore, AAb has the potential to preserve voice in patients with bilateral abductor laryngeal paralysis. Methods: I performed a retrospective review of AAb in 11 patients with bilateral laryngeal paralysis and 3 patients with other neurologic causes of glottal airway compromise, ie, adductor breathing dystonia, frequent laryngospasm, and progressive laryngeal breathing dysfunction. Results: Seven of the 11 patients with bilateral paralysis had dramatic airway improvement. One patient required a tracheotomy after AAb, and 3 patients with an existing tracheotomy could not be decannulated. Arytenoid abduction relieved airway obstruction in the patient with recurrent laryngospasm and in the child with progressive laryngeal breathing dysfunction, but the patient with adductor breathing dystonia has persistent stridor. The factors associated with a poor airway outcome included prolonged tracheotomy, electromyographic evidence of inspiratory activity of adductor muscles, chronic obstructive pulmonary disease, sleep apnea, and prior cordotomy or arytenoidectomy. Conclusions: Arytenoid abduction is most effective in patients with bilateral laryngeal paralysis of less than 1 year’s duration who do not have unfavorable laryngeal adductor activity. Key Words: arytenoid cartilage, bilateral laryngeal paralysis, surgery. are temporary, and the injection must be repeated every few months. All of these approaches not only enlarge the airway, but also increase the glottal gap during phonation. As a result, the voice is weaker and breathier, and speech requires more effort. Every incremental gain in breathing is accompanied by further loss of voice. Sometimes, patients have significant aspiration and recurrent pneumonia because the glottis does not close during the swallow.9,10 The optimal result expected from these procedures is a compromise, to improve breathing without causing aspiration during swallowing or an unacceptable deterioration of voice.11,12 A better functional result could be achieved if dynamic function could be restored, with opening for breathing and closing for phonation. Through the years, much effort has focused on surgical reinnervation to restore movement to the paralyzed larynx. However, to date, only limited success has been reported.13-16 The arytenoid abduction (AAb) procedure is intended to enlarge the airway in patients with bilateral laryngeal paralysis while preserving residual or recovered motion in adductor muscles. Clinical experience and animal experiments indicate that af- INTRODUCTION Bilateral vocal fold immobility is one of the most challenging clinical problems encountered in the practice of laryngology. The primary symptom is airway obstruction, as the vocal folds do not open during inspiration. Patients also have various degrees of vocal impairment. Tracheotomy provides an adequate airway, and does not impair glottal function in phonation. However, a tracheotomy is a significant functional and cosmetic handicap. The first surgical procedures used to relieve airway obstruction in patients with bilateral laryngeal paralysis were external approaches to cordectomy, arytenoidectomy, and arytenopexy.1-3 Endoscopic approaches were also described,4 and with the advent of laser surgery, endoscopic arytenoidectomy, cordectomy, and cordotomy became technically easier.5,6 A vocal fold lateralization suture is particularly useful in patients with acute laryngeal paralysis, in whom there is a possibility that motion could be recovered.7 However, all of these procedures improve breathing by statically enlarging the glottal airway. Botulinum toxin injection into adductor muscles is another option that has been reported to improve the airway in these patients, with variable results.8 The effects of the toxin From the Division of Otolaryngology, Southern Illinois University School of Medicine, Springfield, Illinois. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Gayle Woodson, MD, Division of Otolaryngology, Southern Illinois University School of Medicine, Springfield, IL 62794-9662. 31 32 Woodson, Arytenoid Abduction Revisited A B Fig 1. (Patient 11) Direct laryngoscopic view of larynx of patient 11 demonstrates passive mobility of arytenoid cartilages. A) Vocal folds at rest. B) Vocal folds displaced by tip of laryngoscope. ter recurrent laryngeal nerve injury, the vocal fold gradually migrates to a midline position.17-19 This change in position has been attributed to preferential reinnervation of adductor muscles.19,20 With little or no reinnervation of the abductor muscles, the vocal folds remain in the adducted position. The AAb procedure was designed on the basis of 3-dimensional motion analysis research in cadaver larynges that indicated that the posterior cricoarytenoid (PCA) muscle, the only abductor muscle of the larynx, and the adductor muscles rotate the arytenoid cartilage around different axes.21 Furthermore, when an arytenoid adduction suture is in place, an AAb suture does not move the vocal process away from the midline.22 Endoscopic observations in patients undergoing arytenoid adduction surgery have confirmed that the vocal process can be medialized by an arytenoid adduction suture, even during traction on a second suture that mimics the action of the PCA muscle.22 On the basis of these observations, the AAb procedure was designed. It uses a single suture to pull the muscular process of the arytenoid cartilage inferiorly. This externally rotates the arytenoid cartilage to move the vocal process laterally and superiorly, to enlarge the glottis.23 A distinction must be made between bilateral vocal fold immobility due to mechanical fixation and paralysis due to neural impairment of laryngeal muscles. In patients with paralysis, the vocal folds can be passively displaced laterally (Fig 1); however, when there is fixation of the vocal folds or the cricoarytenoid joint by scar tissue, AAb would not be effective. Arytenoid abduction was previously reported as a promising surgical procedure that reduced airway obstruction without sacrificing vocal function in 6 patients with bilateral laryngeal paralysis.23 Further experience with this treatment for a relatively uncommon condition is presented to clarify the indications for the procedure and to review unsuccessful cases, so that factors that may have contributed to unsatisfactory results may be identified. METHODS The records of the Southern Illinois University Voice Center from June 2005 through December 2009 were reviewed to identify patients in whom AAb had been performed. Each patient had presented with airway obstruction and bilateral vocal fold immobility and had a diagnosis made by videoendoscopy in the clinic. Direct laryngoscopy was performed under general anesthesia to assess the passive mobility of the arytenoid cartilages. Lateral pressure was applied on the membranous vocal fold to displace it while the arytenoid cartilage was observed for motion. The vocal folds were also simultaneously displaced with the tip of a Holinger laryngoscope (Fig 1). If the vocal folds had a good range of motion, AAb was performed. Briefly, the posterior larynx was exposed by the same cervical approach used in arytenoid adduction. A suture was placed through the muscular process, and then inferior traction was applied. The larynx was observed endoscopically to confirm lateral displacement of the vocal process, and then the suture was secured to the inferior cornu of the thyroid cartilage. Patients without a tracheotomy were extubated in the operating room after the procedure and admitted to the hospital overnight for observation. Patients with an existing tracheotomy were discharged on the same Woodson, Arytenoid Abduction Revisited 33 PATIENTS WITH BILATERAL LARYNGEAL PARALYSIS WHO UNDERWENT ARYTENOID ABDUCTION Patient No. Sex Presenting Airway Airway Outcome Presenting Voice Voice Outcome Prior Surgery 1 2 3 4 F F F F Intubation Idiopathic Thyroidectomy Intubation Stridor, dyspnea Stridor, distress Stridor, dyspnea Tracheotomy Somewhat breathy Slightly weak Weak, breathy Weak, breathy No change Same Slightly worse Same No No Cordectomy Multiple F M Thyroidectomy Thyroidectomy Stridor, dyspnea Tracheotomy Weak, breathy Normal Weaker Same Multiple No 7 M Congenital Tracheotomy Weak Same No 8 9 10 11 F M M F Thyroidectomy Esophageal cancer Lung cancer Thyroidectomy Stridor, distress Stridor, distress Tracheotomy Tracheotomy Tracheotomy No stridor No stridor Better, still has tracheotomy Slight stridor Better, still has tracheotomy Better, still has tracheotomy No stridor No stridor Decannulated Decannulated 5 6 Normal Weak, breathy Weak Weak Normal Same Same Improved No No No No Cause day with the tracheotomy in place, and then returned to the clinic after a few days for a trial of decannulation. RESULTS BILATERAL LARYNGEAL PARALYSIS Eleven patients with bilateral paralysis underwent AAb. The cause of paralysis was thyroidectomy in 5 patients and idiopathic in 2 patients. Other causes included intubation (in 2 patients), esophageal cancer, and lung cancer. Five patients presented with a tracheotomy in place, whereas 4 had acute airway distress and had AAb performed urgently as an alternative to tracheotomy. Two other patients had significant restriction of activity due to stridor, and AAb was performed electively. Three patients had previously undergone arytenoidectomy and/or cordotomy. Patient information is detailed in the Table. Successful Airway Outcomes. Seven patients with bilateral paralysis had immediate and dramatic improvement in the airway, including 2 patients with a preexisting tracheotomy who were subsequently decannulated. Figure 2 shows views of the larynx during inspiration and during phonation before and after AAb. This patient had fairly good mobility of the left arytenoid cartilage; however, that function was obscured by the overhanging right arytenoid cartilage. After AAb, the right arytenoid cartilage was lifted out of the airway and the motion of the left arytenoid cartilage was “unmasked.” Two patients noted a slight decrease in vocal function. One patient had previously undergone endoscopic cordotomy. That procedure had resulted in immediate airway improvement, but over time the patient developed recurrent airway obstruction due to scar contracture of the glottis. Her voice was significantly breathy before AAb, and after the procedure it was noticeably more breathy. Only 1 other patient noticed a decrease in vocal function. None of the patients developed aspiration during swallowing. Failures. Three of the patients with an existing tracheotomy could not be decannulated, and patient 1, who did not originally have a tracheotomy, had persistent stridor after AAb and eventually required tracheotomy. Laryngeal electromyography performed in 2 of the patients with persisting airway obstruction after AAb detected strong inspiratory activation of the thyroarytenoid (TA) muscle. In both patients, laryngoscopy under general anesthesia had documented mobile vocal folds, and the AAb suture resulted in significant lateral displacement of the vocal fold under anesthesia. However, during awake examination, both vocal folds were in the midline. After failure of AAb, patient 1 was treated with botulinum toxin injection into her left TA muscle. However, her airway was not sufficiently improved to permit decannulation. Subsequent cordotomy and arytenoidectomy also failed to provide an accurate airway, and tracheotomy was performed. Patient 4, who presented with a tracheotomy, had a complex medical history. She developed bilateral laryngeal paralysis after intubation for sepsis that developed after a perforation during colonoscopy, followed by pulmonary fibrosis. Tracheotomy was performed. She was eventually decannulated, but sought treatment for her weak voice. She underwent left thyroplasty followed by revision thyroplasty, and tracheotomy was performed for airway management. She presented to our clinic with the hope that her airway could be restored. Her mean phonation time before surgery was only 2 seconds. Larynge- 34 Woodson, Arytenoid Abduction Revisited A B C D Fig 2. (Patient 11) Flexible laryngoscopy before and after arytenoid abduction. A) Phonation before surgery. B) Inspiration before surgery. C) Phonation after surgery. D) Inspiration after surgery. al stenosis was suspected because the problem had arisen after intubation; however, at direct laryngoscopy the vocal folds were mobile to palpation, and under anesthesia right-sided AAb significantly widened the glottis. The left thyroplasty implant was also removed. Immediately after surgery, her airway was markedly improved and the tracheotomy was removed. However, 1 month later, she presented with inspiratory stridor, and examination revealed inspiratory adduction of the left vocal fold. Left-sided AAb was then performed, but during surgery, the arytenoid cartilage fractured. Since surgery, she has remained tracheotomy-dependent. Another patient who could not be decannulated after AAb (patient 7) was a 15-year-old boy who had been tracheotomy-dependent nearly all his life. After AAb, laryngoscopy revealed an improved glottal airway, with an inspiratory glottal angle that increased from 2° to 15°. However, he became anxious when the tracheotomy was removed or capped and did not tolerate decannulation. OTHER CAUSES OF GLOTTAL AIRWAY IMPAIRMENT Arytenoid abduction was also performed in 3 patients who had glottal obstruction with a neurologic cause other than bilateral laryngeal paralysis. Patient 12. A 38-year-old man presented with episodic laryngospasm that had previously been managed with periodic injections of botulinum toxin. The episodes of laryngospasm began after a tracheal resection for acquired subglottic stenosis that had resulted from prolonged endotracheal intubation. The botulinum toxin injections suppressed the spasms, but resulted in a breathy voice and required frequent repeat injection. Arytenoid abduction was offered as an option. The procedure prevented complete obstruction during the spasm and did not impair his voice. The patient was pleased with the ability to maintain his airway without sacrificing his voice; however, 1 year later he required tracheotomy because of recurrent subglottic stenosis. He currently has a T-tube in place that is plugged, so that he breathes across the glottis. His laryngeal airway is Woodson, Arytenoid Abduction Revisited still adequate and is not occluded by spasm. Patient 13. A 10-year-old boy presented to our clinic with nocturnal airway obstruction that had made him tracheotomy-dependent since infancy. Evaluation at that time demonstrated inspiratory adduction of the vocal folds during sleep. He was managed with periodic botulinum toxin injection into his TA muscles and was successfully decannulated. Over the next 4 years, his nocturnal stridor became less responsive to botulinum toxin and he began to develop airway obstruction that persisted during wakefulness. This progressed to severe stridor, despite bilateral chemodenervation of the TA muscles. Flexible endoscopy revealed failure of inspiratory vocal fold abduction, particularly on the left side. Left-sided AAb was performed, and his airway was vastly improved. Two years later, he maintains an adequate airway without the need for botulinum toxin therapy. The cause of his progressive airway impairment is still unknown. Patient 14. A 70-year-old man presented with inspiratory stridor. Endoscopy revealed severe edema over the arytenoid cartilages that prolapsed into his airway during inspiration. His vocal folds did not abduct during quiet breathing, but opened widely during the inspiratory phase of a cough and during prephonatory inspiration. Electromyography demonstrated bilateral phasic inspiratory adduction of his TA muscles, as well as episodic myotonic discharges. An electromyogram of limb muscles did not demonstrate any evidence of systemic myopathy. He was treated with injections of as much as 30 units of botulinum toxin into the left TA muscle, and bilateral injections of 5 units. His voice was softer after each botulinum treatment, but his stridor persisted. He also underwent microlaryngoscopy with excision of redundant mucosa without further improvement. After left-sided AAb, his airway and exercise tolerance were improved, but his stridor persisted. Endoscopy demonstrated inspiratory supraglottic constriction. DISCUSSION Bilateral laryngeal paralysis has long been managed either by tracheotomy or by surgical procedures that statically enlarge the glottis with resection of glottal tissue or with lateral fixation of the arytenoid cartilage.1-7,10,11 Such glottal enlargement procedures improve the airway, but do so at the expense of the voice, because the glottis cannot close for phonation. Additionally, there is a significant incidence of aspiration during swallow, because laryngeal closure during swallow is impaired. The incidence of aspiration is higher after procedures that resect the 35 body of the arytenoid cartilage.11,12 The goal of all such procedures — arytenoidectomy, arytenopexy, and/or cordotomy — is to gain a significant static improvement in the airway, with an acceptable decrease in voice quality. The ideal treatment would restore some dynamic function, so that the larynx could open for breathing and close for speech and swallowing. There has been much interest in reinnervation of the larynx as a means of restoring normal motion, but as yet, success is rare.12,13 Both clinical experience and animal experiments indicate that residual adductor muscle activity is very common in immobile vocal folds after injury to the recurrent laryngeal nerve. This has been attributed to spontaneous regeneration of the recurrent laryngeal nerve, with a predominance of reinnervation to adductor muscles.20 Thus, paralyzed vocal folds tend to lie immobile near the midline, because there is inadequate muscle force to abduct the vocal folds. This is the most likely explanation for the classic observation that vocal folds move medially over time after recurrent laryngeal nerve injury. Preferential reinnervation of adductor muscles and inadequate reinnervation of abductor muscles can account for the predominance of airway symptoms, with fairly acceptable voice, commonly observed in patients with bilateral paralysis. Therefore, if a procedure could provide abduction without abolishing residual phonatory adduction, it could restore vocal fold motion with respiration and phonation. The AAb procedure was designed on the basis of research in cadaver larynges that indicated that abduction of the arytenoid cartilage does not abolish adductor motion. The cricoarytenoid joint is essentially a ball and socket, rather than a hinge joint. Thus, motion is not restricted to simple opening and closing. Three-dimensional motion analysis demonstrates that the force exerted by laryngeal adductor muscles rotates the arytenoid cartilage about a nearly vertical axis. In contrast, the PCA muscle pulls downward and medially on the muscular process, moving the vocal process upward and outward. The axis of rotation of the arytenoid cartilage during PCA contraction is oblique, rather than vertical.21 Thus, contraction of the PCA muscle does not preclude adduction of the arytenoid cartilage by contraction of the adductor muscles. Experiments in cadaver larynges have demonstrated that when an arytenoid adduction suture is in place, inferior traction on the muscular process does not move the vocal process away from the midline.22 Endoscopic observations in patients undergoing arytenoid adduction surgery have confirmed that the vocal process can be medialized by an arytenoid adduction suture, even during traction on a second suture that mimics the action of 36 Woodson, Arytenoid Abduction Revisited the PCA muscle. The initial experience with AAb in 6 patients resulted in excellent airway improvement with preservation of voice in 5 patients, 4 of whom had been tracheotomy-dependent.23 In this present series, AAb was only successful in 7 of 11 patients. Thus, our total experience to date is that AAb significantly improved the airway in 12 of 17 patients with bilateral laryngeal paralysis. None of the patients developed swallowing problems or aspiration. The reported success rates for other surgical procedures used to treat bilateral vocal fold motion impairment vary greatly. In a series of 69 patients treated with endoscopic subtotal arytenoidectomy, PlouinGaudon et al24 reported no problems with voice or aspiration and reported that all of their patients with tracheotomy were decannulated. Most other authors have not reported such a high rate of success. Ossoff et al4 reported sustained airway restoration in 24 of 28 patients treated with laser arytenoidectomy. Limitations were due to scar contracture and intraluminal granulation.4 In a series of 25 patients with bilateral paralysis treated with cordotomy, Laccourreye et al25 reported significant airway improvement in 9 of 15 patients who had unilateral cordotomy, and in 10 of 10 patients who had bilateral cordotomy. Of note, all of the patients in their series were reported to have severe airway obstruction, but none had a tracheotomy before surgery.25 In our combined series, AAb was successful in 7 of the 8 patients who did not have a preexisting tracheotomy. However, only 5 of the 9 patients with a preexisting tracheotomy were decannulated. Factors noted in patients with poor airway results included paradoxical vocal fold adduction, prolonged tracheotomy dependence, and poor lung function. Patients who have had prolonged tracheotomy have had long-standing vocal fold immobility and could therefore have fibrotic contracture of adductor muscles. Such contracture would prevent lateralization of the arytenoid cartilage by the abduction suture, even if the joint is not ankylosed. Paralysis of long duration has also been associated with poor outcomes for arytenoid adduction in patients with unilateral laryngeal paralysis.26 It is not surprising that paradoxical vocal fold adduction would impair results. The AAb suture does not immobilize the arytenoid cartilage in all dimensions, and active adduction is still possible. Thus, inspiratory adductor activity can significantly restrict the airway. For example, the patient with adductor breathing dystonia had persistent stridor after this procedure. A preoperative electromyogram and careful assessment by flexible endoscopy are recommended to detect possible inspiratory adductor activity so that patients can be appropriately counseled on the potential outcome. Botulinum toxin alone has been reported as a treatment for airway obstruction in patients with bilateral laryngeal paralysis by blocking the activity of adductor muscles.8 In theory, such treatment could improve the results for AAb surgery. In this series, botulinum toxin was injected into adductor muscles of 2 of our patients who did not have sufficient airway improvement after AAb. Patient 1 had persistent stridor after AAb for bilateral paralysis and did not have improvement after subsequent endoscopic cordotomy and arytenoidectomy. Botulinum toxin injection was also ineffective. An electromyogram documented strong adductor activity on the left side, and 20 units of toxin were injected into that side. The patient’s stridor was not improved, and tracheotomy was performed. It is possible that she had some contracture of adductor muscles. Patient 14 was a 70-year-old man with dystonic inspiratory adduction of the larynx. His stridor persisted after multiple treatments with various doses of botulinum toxin and also after bilateral AAb. It appeared in the latter case that his stridor persisted because of contraction of supraglottic muscles. Arytenoid abduction is clearly more technically difficult and potentially has more postoperative morbidity than endoscopic cordectomy or arytenoidectomy. Its major advantage is restoration of laryngeal motion by unmasking residual adductor activity. Theoretically, it should result in a better airway and a stronger voice than other procedures, so long as the patient does not have unfavorable laryngeal adductor activity. Furthermore, it should not result in aspiration, because it does not remove tissue from the glottis and does not preclude dynamic closure during the swallow. It provides a stable, adjustable, and potentially reversible enlargement of the airway. Finally, because there are no intraluminal raw surfaces or mucosal incisions, there is minimal risk of intraluminal scarring or granulation tissue. CONCLUSIONS Arytenoid abduction is an effective option in the management of patients with airway obstruction due to bilateral laryngeal paralysis. It significantly enlarges the airway without creating an intraluminal mucosal defect, and does not abolish residual phonatory adduction. It may be less effective in the presence of active paradoxical vocal fold adduction or prolonged tracheotomy. Further experience in a larger population could confirm the good voice outcomes and lack of glottal incompetence during swallow. Woodson, Arytenoid Abduction Revisited 37 REFERENCES 1. Jackson C. Ventriculocordectomy: a new operation for the cure of goitrous paralytic laryngeal stenosis. Arch Surg 1922;4:257-74. 2. King BT. New and function-restoring operation for bilateral abductor cord paralysis: preliminary report. JAMA 1939; 112:814-23. 3. Woodman D. A modification of the extralaryngeal approach to arytenoidectomy for bilateral abductor paralysis. Arch Otolaryngol 1946;43:63-5. 4. Ossoff RH, Duncavage JA, Shapshay SM, Krespi YP, Sisson GA Sr. Endoscopic laser arytenoidectomy revisited. Ann Otol Rhinol Laryngol 1990;99:764-71. 5. Thornell WC. Intralaryngeal approach for arytenoidectomy in bilateral abductor vocal cord paralysis. Trans Am Acad Ophthalmol Otolaryngol 1949;53:631-6. 6. Dennis DP, Kashima H. Carbon dioxide laser posterior cordectomy for treatment of bilateral vocal cord paralysis. Ann Otol Rhinol Laryngol 1989;98:930-4. 7. Lichtenberger G. Reversible lateralization of the paralyzed vocal cord without tracheostomy. Ann Otol Rhinol Laryngol 2002;111:21-6. 8. Ekbom DC, Garrett CG, Yung KC, et al. Botulinum toxin injections for new-onset bilateral vocal fold motion impairment in adults. Laryngoscope 2010;120:758-63. 9. Hillel AD, Benninger M, Blitzer A, et al. Evaluation and management of bilateral vocal cord immobility. Otolaryngol Head Neck Surg 1999;121:760-5. 10. Eckel HE, Thumfart M, Wassermann K, Vössing M, Thumfart WF. Cordectomy versus arytenoidectomy in the management of bilateral vocal cord paralysis. Ann Otol Rhinol Laryngol 1994;103:852-7. 11. Worley G, Bajaj Y, Cavalli L, Hartley B. Laser arytenoidectomy in children with bilateral vocal fold immobility. J Laryngol Otol 2007;121:25-7. 12. Al-Fattah HA, Hamza A, Gaafar A, Tantawy A. Partial laser arytenoidectomy in the management of bilateral vocal fold immobility: a modification based on functional anatomical study of the cricoarytenoid joint. Otolaryngol Head Neck Surg 2006;134:294-301. 13. Tucker HM. Human laryngeal reinnervation: long-term experience with the nerve-muscle pedicle technique. Laryngo- scope 1978;88:598-604. 14. Crumley RL. Experiments in laryngeal reinnervation. Laryngoscope 1982;92(suppl 30):1-27. 15. van Lith-Bijl JT, Stolk RJ, Tonnaer JA, Groenhout C, Konings PN, Mahieu HF. Laryngeal abductor reinnervation with a phrenic nerve transfer after a 9-month delay. Arch Otolaryngol Head Neck Surg 1998;124:393-8. 16. Marie JP, Dehesdin D, Ducastelle T, Senant J. Selective reinnervation of the abductor and adductor muscles of the canine larynx after recurrent nerve paralysis. Ann Otol Rhinol Laryngol 1989;98:530-6. 17. Faaborg-Andersen K. The position of paretic vocal cords. Acta Otolaryngol 1964;57:50-4. 18. New GB, Childrey JH. Paralysis of the vocal cords: a study of 217 medical cases. Arch Otolaryngol 1932;16:143-9. 19. Woodson GE. Configuration of the glottis in laryngeal paralysis. II: Animal experiments. Laryngoscope 1993;103:123541. 20. Woodson GE. Spontaneous laryngeal reinnervation after recurrent laryngeal or vagus nerve injury. Ann Otol Rhinol Laryngol 2007;116:57-65. 21. Bryant NJ, Woodson GE, Kaufman K, et al. Human posterior cricoarytenoid muscle compartments. Anatomy and mechanics. Arch Otolaryngol Head Neck Surg 1996;122:1331-6. 22. Woodson GE, Picerno R, Yeung D, Hengesteg A. Arytenoid adduction: controlling vertical position. Ann Otol Rhinol Laryngol 2000;109:360-4. 23. Woodson G, Weiss T. Arytenoid abduction for dynamic rehabilitation of bilateral laryngeal paralysis. Ann Otol Rhinol Laryngol 2007;116:483-90. 24. Plouin-Gaudon I, Lawson G, Jamart J, Remacle M. Subtotal carbon dioxide laser arytenoidectomy for the treatment of bilateral vocal fold immobility: long-term results. Ann Otol Rhinol Laryngol 2005;114:115-21. 25. Laccourreye O, Paz Escovar MI, Gerhardt J, Hans S, Biacabe B, Brasnu D. CO2 laser endoscopic posterior partial transverse cordotomy for bilateral paralysis of the vocal fold. Laryngoscope 1999;109:415-8. 26. Woodson GE, Murry T. Glottic configuration after arytenoid adduction. Laryngoscope 1994;104:965-9. Vibratory Asymmetry in Mobile Vocal Folds: Is It Predictive of Vocal Fold Paresis? C. Blake Simpson, MD; Linda Seitan May, MD; Jill K. Green, MS; Robert L. Eller, MD; Carlayne E. Jackson, MD Objectives: The purpose of this study was to determine whether the videostroboscopic finding of vibratory asymmetry in mobile vocal folds is a reliable predictor of vocal fold paresis. In addition, the ability of experienced reviewers to predict the distribution (left/right/bilateral) of the paresis was investigated. Methods: This is a retrospective chart review of all patients who presented to our clinic during a 3-year period with symptoms suggestive of glottal insufficiency (vocal fatigue or reduced vocal projection) accompanied by the videostroboscopic findings of bilateral normal vocal fold mobility and vibratory asymmetry. Twenty-three of these patients underwent diagnostic laryngeal electromyography of the thyroarytenoid and cricothyroid muscles to determine the presence of vocal fold paresis. Results: Nineteen of the 23 patients (82.6%) were found to have electrophysiological evidence of vocal fold paresis, either unilaterally or bilaterally, when videostroboscopic asymmetry was present in mobile vocal folds. However, the three expert reviewers’ ability to predict the distribution (left/right/bilateral) of the paresis was poor (26.3%, 36.8%, and 36.8%, respectively). Conclusions: The videostroboscopic finding of vibratory asymmetry in mobile vocal folds is a reliable predictor of vocal fold paresis in most cases. However, the ability of expert reviewers to determine the distribution (left/right/bilateral) of the paresis using videostroboscopic findings is poor. This study highlights the value of laryngeal electromyography in arriving at a correct diagnosis in this clinical situation. Key Words: electromyography, videostroboscopy, vocal fold paralysis, vocal fold paresis. nocent asymmetries [on laryngoscopy] from significant findings may present the greatest challenge in defining vocal fold paresis.”7(p159) The clinical setting of glottal insufficiency symptoms and grossly intact vocal fold mobility has previously been described. In these cases, vibratory asymmetry may be the only laryngoscopic clue to suggest VFP.7 Identification of the asymmetry may help guide the clinician toward performing LEMG and eventually confirming a diagnosis of VFP. INTRODUCTION Vocal fold paresis (VFP) is a well-established, albeit controversial, entity. Its incidence is not well established, but it is likely rare. The few reports that are available in the literature have shown a range of as many as 29 cases in a year to as few as 13 cases over 4 years in tertiary laryngology practices.1-4 Although all of these studies used laryngeal electromyography (LEMG) to confirm the diagnosis, clinicians often use subtle asymmetries on videostroboscopy as indicators that paresis is likely present. During videostroboscopic examination, reduced vocal fold movement (adduction or abduction), vocal fold bowing, incomplete glottal closure, and vibratory asymmetry can all be associated with VFP.4,5 Rubin et al6 have also described the use of repetitive phonatory tasks to induce fatigue as a means of bringing out hypomobility in paretic vocal folds. As pointed out by Sulica and Blitzer, however, “Separating in- The purpose of this study was to determine whether the videostroboscopic finding of vibratory asymmetry in mobile vocal folds was a reliable predictor of VFP. In addition, the ability of experienced reviewers to predict the distribution (left/right/bilateral) of the paresis was investigated. METHODS Institutional Review Board approval was obtained From the Departments of Otolaryngology–Head and Neck Surgery (Simpson, May, Green) and Neurology (Jackson), University of Texas Health Science Center–San Antonio, and the Department of Otolaryngology–Head and Neck Surgery, Wilford Hall Medical Center, Lackland Air Force Base (Eller), San Antonio, Texas. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: C. Blake Simpson, MD, Dept of Otolaryngology–Head and Neck Surgery, University of Texas Health Science Center, Medical Arts and Research Center, 8300 Floyd Curl Dr, San Antonio, TX 78229. 38 Simpson et al, Vibratory Asymmetry in Vocal Folds from our institution before the study period. A retrospective chart review was carried out for all patients who presented to our clinic during a 3-year period and underwent LEMG for suspected vocal fold paresis. Over the study period, 48 patients with suspected VFP underwent diagnostic LEMG. Of those, 23 patients met the study criteria with symptoms of VFP (vocal fatigue or reduced vocal projection) accompanied by the videostroboscopic findings of bilateral normal vocal fold mobility and vibratory asymmetry. The diagnostic LEMG examinations included an evaluation of the motor unit morphology and recruitment of motor unit potentials (MUPs) for the thyroarytenoid and cricothyroid muscles. Interpretation of the LEMG findings was done by a neurologist (C.E.J.) who was blinded to the findings of the laryngoscopic examination. In all cases, abnormal LEMG findings were considered to be present when there were large-amplitude polyphasic MUPs and incomplete recruitment of MUPs. All abnormal LEMG findings were then classified as left, right, or bilateral, depending on the side of involvement. We did not distinguish between recurrent laryngeal nerve (RLN) and superior laryngeal nerve (SLN) neuropathy for the purposes of this portion of the study. In other words, if the RLN, SLN, or both showed electrophysiological evidence of denervation, the findings were considered “abnormal” for that side. Our endoscopic clinical examination protocol was as follows. All of the patients underwent videostroboscopy by means of a flexible laryngoscope with a distal chip (Olympus ENF-VQ, Olympus Surgical, Orangeburg, New York) rhinolaryngoscope, and most also had rigid laryngoscopy with a 70° rigid endoscope (KayPENTAX, Lincoln Park, New Jersey). The patients were instructed to phonate /i/ at low, modal, and high frequencies. When indicated, the technique of “unloading” as described by Koufman8 was also used to help reveal more subtle vibratory asymmetry that may have been hidden under compensatory muscle tension patterns. When retrospective evaluation of the endoscopic segments was carried out, the following protocol was used. The best-quality videostroboscopic examination (either flexible or rigid) was used for each case. Of the 48 cases in which LEMG was performed for suspected paresis, 23 examinations that were considered to show isolated vibratory asymmetry were selected for the study. The other 25 cases, which showed vocal fold immobility, partial immobility, videostroboscopic evidence of incomplete closure, or vocal fold lesions, were excluded. 39 TABLE 1. VOCAL FOLD PARESIS DEMOGRAPHICS AND LEMG FINDINGS Age (y) Gender Duration LEMG Findings Cause of Paresis 62 67 30 36 28 65 36 69 35 36 44 29 58 37 51 43 76 58 54 F F M M M M F F F M F F F F F F M M F 1y 1y 9y 36 y 4 mo 6y 10 y 2 mo 1y 7y 9y 1.5 y 9 mo 1y 5y 16 mo 6 mo 14 mo 4 mo B RLN + SLN B RLN L RLN + SLN B RLN B RLN B RLN + SLN B RLN B RLN B RLN B RLN R RLN L RLN L RLN B RLN L RLN R RLN B RLN B RLN L SLN Idiopathic Idiopathic Idiopathic Congenital Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Traumatic LEMG — laryngeal electromyography; B — bilateral; RLN — recurrent laryngeal nerve paresis; SLN — superior laryngeal nerve paresis; L — left; R — right. The videos were edited to include only segments in which the vocal folds were in a fully adducted position and were engaged in vibratory activity. We decided not to show footage of vocal fold mobility, in order to help exclude any possible bias that could occur from interpreting vocal fold movement. The video segments were then randomized and were interpreted by three reviewers with extensive experience in videostroboscopic interpretation. Each video segment was reviewed, and the following questions were addressed: 1) Is asymmetry of vibration (amplitude or mucosal wave) present? 2) If vibration is asymmetric, which side has the increased amplitude and/or mucosal wave? and 3) On which side would you predict the paresis to be present? The LEMG results were used as the gold standard for the diagnosis of VFP. Interpretation of the videostroboscopic findings by our reviewers was then compared to this gold standard to determine the predictive value of subjective vibratory asymmetry on videostroboscopic examination. RESULTS Of the 19 patients with a diagnosis of LEMG-confirmed VFP (Table 1), the mean patient age was 48.5 years (range, 28 to 76 years). Twelve of the patients were female (63.2%) and had a mean age of 48.8 years, and 7 patients were male (36.8%) and had a mean age of 47 years. The mean time interval from 40 Simpson et al, Vibratory Asymmetry in Vocal Folds TABLE 2. LEMG RESULTS AND REVIEWERS’ INTERPRETATION Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Reviewer 1 L R R R R R R L L B R L R L R L R R L R R R R Reviewer 2 R R R B B R R L R B B L B B B L B L B B L B B Reviewer 3 R R R R B R R L B B B L L B R R B L B R R B L LEMG B B L Normal B Normal B B R B B B R Normal L L B Normal L R B B L L — left-sided paresis; R — right-sided paresis; B — bilateral paresis. the onset of symptoms to presentation to our clinic was 4.8 years (range, 2 months to 36 years). The cause of the paresis was idiopathic in the vast majority of cases (17 of 19 or 89.5%), and the remaining cases were congenital (1 of 19 or 5.2%) or traumatic (1 of 19 or 5.2%). In terms of neural involvement, the majority of cases involved the RLN only. Ten cases were bilateral RLN paresis, and 5 cases were unilateral RLN paresis. The remaining cases were 2 cases of bilateral combined RLN and SLN paresis, 1 case of unilateral combined RLN and SLN paresis, and 1 case of unilateral SLN paresis. Of the 23 patients with symptoms of glottal insufficiency and isolated vibratory asymmetry on videostroboscopy, 19 (82.6%) were found to have electrophysiological evidence of denervation of one or both vocal folds (Table 2). However, the individual reviewers’ ability to correctly predict the distribution of the paresis was quite poor. Given three options (bilateral, left, or right), each reviewer was unable to correctly predict the side in most cases (reviewer 1, 5 of 19 correct; reviewer 2, 7 of 19 correct; and reviewer 3, 7 of 19 correct). With all examination evaluations combined, the side of paresis was correctly predicted in only 33.3% of cases (19 of 57). DISCUSSION The idea behind this study was to answer a com- mon question that is posed in our multidisciplinary clinics. As a general rule, the voice team (which includes the senior author, speech pathologist, and resident physician) reviews the videostroboscopic examination of the patient and discusses the subjective interpretation of the vibratory parameters. In most cases of suspected VFP, the clinicians can agree that vibratory asymmetry is present, and LEMG will later confirm the diagnosis. However, the reliability of using vibratory asymmetry to correctly predict the presence of VFP has not been examined. Although we can usually agree on the presence of vibratory asymmetry, there is often a debate about the sidedness of the suspected paresis. Conventional thinking suggests that the denervated side will have an increased amplitude and/or mucosal wave due to the laxity of the paretic vocal fold. Despite this consensus, we have noted that many times the clinicians do not agree as to which side(s) is involved. Obviously, the clinical diagnosis of some cases of VFP is fairly straightforward when based on videostroboscopic findings and clinical history. In the setting of gross hypomobility and glottal insufficiency, the diagnosis is not often in question. However, when there are no readily apparent differences in vocal fold mobility, the diagnosis can be more difficult to make, or may not be suspected by the clinician at all. In these cases, vibratory asymmetry may be the only clue that VFP is present.7 This finding may help guide the clinician toward performing LEMG and establishing a correct diagnosis. Our clinical protocol for patients with symptoms suggestive of glottal insufficiency and an increased amplitude and/or mucosal wave or “chasing wave” (asymmetry of vibration) is to recommend LEMG. Obviously, not all patients with this combination of symptoms and findings agree to undergo or follow up for diagnostic LEMG, so we are not able to comment on the positive predictive value of vibratory asymmetry in these cases. Nonetheless, when vibratory asymmetry prompted LEMG testing in our series, the clinical “hunch” ended up being correct in 83% of cases. However, the ability of experienced clinicians to correctly predict which side was involved was quite poor (33.3%). This is exactly the percentage one would expect if the clinician’s determination were randomly generated; ie, there is a 1-in-3 chance of predicting the outcome correctly. The difficulty partially arises from using the subjective observation that one side demonstrates increased vibratory amplitude (often thought to be a manifestation of reduced muscular tone in a denervated vocal fold). By necessity, that determination involves using the contralateral side as a control, ie, the side with the “normal tone.” In many cas- Simpson et al, Vibratory Asymmetry in Vocal Folds es, however, this side may also be affected, making the assumption of unilaterality erroneous. Despite this problem, there were many cases in which the reviewer correctly predicted that the paresis was unilateral, but the predicted side (ie, distribution of involvement) was incorrect. Relying solely on laryngoscopic findings to predict VFP continues to be problematic. Other studies have shown that 25% to 40% of patients had LEMG findings that were not predicted by their laryngoscopic examination.2,3 Although vibratory asymmetry is fairly predictive of VFP (83% of cases in our study), determining the distribution (left/right/bilateral) of the paresis is very poorly predictive. Interpretation of videostroboscopic examinations is by nature subjective. We have observed that vibratory asymmetry can sometimes be difficult to detect on routine stroboscopy. The best method of accentuating asymmetry is to have the patient phonate 41 at a modal or low fundamental frequency at a high intensity. In addition, extinguishing any secondary supraglottic muscular tension seems to be beneficial, as this allows for the differential tension of the true vocal folds to be observed. Last, recording the examination and playing it back in slow motion, or performing frame-by-frame analysis, is yet another method to aid in the detection of vibratory asymmetry. CONCLUSIONS The videostroboscopic finding of vibratory asymmetry in mobile vocal folds is a reliable predictor of VFP in most cases. However, the ability of expert reviewers to determine the distribution (left/right/ bilateral) of the paresis using videostroboscopic findings is poor. This finding highlights the value of LEMG in arriving at a correct diagnosis in this clinical situation. REFERENCES 1. Merati AL, Shemirami N, Smith TL, Toohill RJ. Changing trends in the nature of vocal fold motion impairment. Am J Otolaryngol 2006;27:106-8. 2. Heman-Ackah YD, Barr A. Mild vocal fold paresis: understanding clinical presentation and electromyographic findings. J Voice 2006;20:269-81. 3. Koufman JA, Postma GN, Cummins MM, Blalock DP. Vocal fold paresis. Otolaryngol Head Neck Surg 2000;122:53741. 4. Simpson CB, Cheung EJ, Jackson CJ. Vocal fold paresis: clinical and electrophysiologic features in a tertiary laryngology practice. J Voice 2009;23:396-8. 5. Altman KW. Laryngeal asymmetry on indirect laryngos- copy in a symptomatic patient should be evaluated with electromyography. Arch Otolaryngol Head Neck Surg 2005;131:35660. 6. Rubin AD, Praneetvatakul V, Heman-Ackah Y, Moyer CA, Mandel S, Sataloff RT. Repetitive phonatory tasks for identifying vocal fold paresis. J Voice 2005;19:679-86. 7. Sulica L, Blitzer A. Vocal fold paresis: evidence and controversies. Curr Opin Otolaryngol Head Neck Surgery 2007;15: 159-62. 8. Koufman JA. Evaluation of laryngeal biomechanics by fiberoptic laryngoscopy. In: Rubin JA, Sataloff RT, Korovin GS, Gould WJ, eds. Diagnosis and treatment of voice disorders. New York, NY: Igaku-Shoin, 1995:122-34. Effects of Nerve-Muscle Pedicle on Immobile Rat Vocal Folds in the Presence of Partial Innervation Takashi Aoyama, MD; Yoshihiko Kumai, MD, PhD; Eiji Yumoto, MD, PhD; Takaaki Ito, MD, PhD; Satoru Miyamaru, MD, PhD Objectives: We investigated whether implantation of an ansa cervicalis nerve (ACN)–muscle pedicle into the thyroarytenoid (TA) muscle is efficacious in the presence of partial recurrent laryngeal nerve (RLN) innervation. Methods: We studied a total of 36 rats. Twelve of the rats served as positive and negative control animals. In the remaining 24 rats, the left RLN was transected, a 1-mm piece of nerve was removed, and the stumps were abutted in silicone tubes (STs), inducing partial RLN regeneration. Twelve of the ST-treated rats underwent this procedure alone, and the other 12 rats had a nerve-muscle pedicle (NMP) implanted into the left TA muscle 5 weeks after ST treatment. At 15 weeks, reinnervation was assessed by histologic evaluation of the TA muscle and by electromyography with stimulation of the RLNs and ACNs. Results: The muscle area, the number of nerve terminals, the number of acetylcholine receptors, and the ratio of nerve terminals to acetylcholine receptors were significantly greater (p < 0.05) in the NMP group than in the ST group. Electromyography elicited TA muscle compound action potentials upon stimulation of the RLNs and ACNs. Conclusions: In rats, NMP implantation is efficacious for reducing atrophic changes in the TA muscle in the presence of partial RLN innervation. Key Words: nerve-muscle pedicle, neuromuscular junction, partial denervation, recurrent laryngeal nerve paralysis. on a partially innervated TA muscle is questionable because of synkinetic RLN reinnervation, which is common clinically. Therefore, it is necessary to determine whether an NMP can innervate a TA muscle that is partially innervated by the RLN. INTRODUCTION Unlike the complete loss of recurrent laryngeal nerve (RLN) innervation, which leads to marked thyroarytenoid (TA) muscle atrophy, many RLN injuries cause partial denervation and reinnervation with various degrees of vocal fold motion impairment, accompanied by weakness, synkinesis, and partial atrophy.1 Successful clinical application of the nerve-muscle pedicle (NMP) implantation method for patients with unilateral vocal fold paralysis has been reported.2 Previously, we demonstrated that ansa cervicalis nerve (ACN) NMP flap implantation into the TA muscle prevented the denervation and atrophy associated with complete RLN denervation in rats.3,4 Therefore, the NMP procedure can enable effective motor innervation following complete denervation. In other nonlaryngeal muscles, implanted foreign nerves will partially reinnervate denervated muscles.5 MATERIALS AND METHODS Animal Preparation and Endoscopic Observation. Thirty-six 8-week-old female Wistar rats were used. The animals were housed at a constant temperature (22°C) on a 12-hour light-dark cycle and were given food and water as desired. All experiments were conducted in accordance with the guidelines of the Animal Care and Use Committee in compliance with the Animal Research Center at Kumamoto University’s Graduate School of Medicine, Kumamoto, Japan. First, the vocal folds of the animals were examined endoscopically (Nisco, Tokyo, Japan) to check for spontaneous motion of the bilateral vocal folds while anesthetized intraperitoneally with ketamine hydrochloride (50 mg/kg) and xylazine hydrochloride (10 mg/kg). Six animals without left RLN transection served as a control group. The Nevertheless, it is possible that innervated, functionally active muscle fibers will not accept further innervation.6 If so, the effect of the NMP procedure From the Departments of Otolaryngology–Head and Neck Surgery (Aoyama, Kumai, Yumoto, Miyamaru) and Pathology and Experimental Medicine (Ito), Kumamoto University School of Medicine, Kumamoto, Japan. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Yoshihiko Kumai, MD, PhD, Dept of Otolaryngology–Head and Neck Surgery, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556, Japan. 42 Aoyama et al, Nerve-Muscle Pedicle in Partially Innervated Larynx A 43 Fig 1. A) Silicone tube (ST) model. One millimeter of left recurrent laryngeal nerve (RLN) was resected at level of seventh tracheal ring, and both nerve stumps were passed into ST. Photograph is magnified view of ST. B) Nervemuscle pedicle (NMP) model. Five weeks after ST implantation, NMP flap was implanted in exposed thyroarytenoid (TA) muscle through window made in thyroid cartilage. Photograph shows rat larynx after ST procedure and NMP implantation. B other 30 animals were anesthetized as described above. The strap muscles were exposed via a vertical midline skin incision. Under an operating microscope (SN-MD2; Nagashima Medical Instruments, Tokyo), the sternohyoid muscles were divided at the midline. After exposure of the left RLN, a 1-mm length was resected at the level of the seventh tracheal ring. In 6 of the transected animals (complete denervation group), the distal end of the nerve was ligated with 4-0 nylon suture, whereas the proximal end was embedded in the sternohyoid muscle to prevent contact between the cut ends, as described previously.3 In the remaining 24 animals, both nerve stumps were placed in a silicone tube (ST) and fixed to it with 9-0 nylon suture. After the procedure, left vocal fold immobility was confirmed endoscopically and the skin incision was closed. The animals, which were allowed to recover in an approved animal care facility, were divided into 2 groups: 12 that underwent anastomosis only, with STs (ST group; Fig 1A), and 12 in which, under an operating microscope, the ACN branch was harvested with a 0.5 × 0.5 × 0.5-mm piece of sternohyoid muscle and implanted in the TA muscle through a small window made in the thyroid cartilage. An NMP flap was firmly sutured to the surface of the TA muscle by use of 9-0 nylon suture, as previously described,2,3 5 weeks after anastomosis (NMP group; Fig 1B). Each group was divided into 2 groups of 6, one for histologic analysis and the other for evoked electromyography (EMG). Evoked EMG. At 15 weeks after the ST procedure, reinnervation was assessed in the NMP group by EMG with stimulation of the right RLN, left RLN, and ACN, as described elsewhere,4,7 before and after transection of the left RLN and ACN (Fig 2). A monopolar platinum electrode, 0.08 mm in diameter and coated with silicone, was inserted into the TA muscle through the thyroid cartilage. Evoked EMG signals were recorded through a Neuropack (MEB-9102; Nihon Kohden, Tokyo) combined with an electric stimulator (SEN-3301; Nihon Kohden). A single 100-μs pulse of supramaximal intensity was applied for stimulation. Area of TA Muscle and Individual Muscle Fibers. We next examined the areas of the entire TA muscle and individual muscle fibers in the total denervation, ST, and NMP groups, as earlier described.3,4 The areas were determined on the basis of pixel numbers 44 A Aoyama et al, Nerve-Muscle Pedicle in Partially Innervated Larynx B Fig 2. A) Electrically stimulated (point α — treated RLN; point β — ansa cervicalis nerve [ACN]; point γ — untreated RLN) and transected (point a — treated RLN; point b — ACN) portions were subjected to evoked electromyography. B) Representative evoked electromyographic findings for left and right TA muscles in NMP group at 15 weeks. 1) Waveform with stimulation of point α before RLN transection. 2) Waveform with stimulation of point α after RLN transection at point a. 3) Waveform with stimulation of point β before ACN transection. 4) Waveform with stimulation of point β after ACN transection at point b. 5) Waveform with stimulation of point γ of RLN on untreated side. by tracing the outlines of the TA muscle and its individual fibers with the Image software program (National Institutes of Health, Bethesda, Maryland). Atrophic changes in the TA muscle were evaluated by comparing the areas from the treated (left, T) and untreated (right, U) sides (T/U ratio). In the control group, the areas of the complete TA muscle and its individual muscle fibers were evaluated by comparing both sides as described above. In addition, the percentage of muscle fibers containing centrally located nuclei (based on 100 muscle fibers from a single animal) was determined for the treated side in all animals, and the results for each group were averaged. Neuromuscular Junctions. The numbers of neuromuscular junctions (NMJs), nerve terminals (NTs), and acetylcholine receptors (AchRs) in the groups were determined as earlier described.3,4 Sections were incubated with polyclonal rabbit anti-human synaptophysin antibodies (Dako, Tokyo) to label NTs, and with rhodamine-conjugated α-bungarotoxin (Sigma, Tokyo) to label AchRs. We calculated the T/U ratios for the NTs and AchRs and the NT/ AchR ratio on the treated side in each group. Statistical Analysis. All data were subjected to unpaired Student’s t-tests and are presented as the mean ± SD. Differences were considered statistical- ly significant at p < 0.05. RESULTS Endoscopic Observation. Fifteen weeks after RLN transection, no spontaneous vocal fold movement was noted on the left side in any of the animals in the denervation, ST, and NMP groups. Evoked EMG. In the NMP group, when the RLN proximal to the ST was stimulated before its transection, evoked action potentials were seen in the TA muscle (Fig 2B, row 1), whereas no muscle activity was elicited when the same portion of the RLN was stimulated after the RLN was transected at point “a” (Fig 2B, row 2). Conversely, when the transplanted ACN was stimulated at point “β,” evoked action potentials were seen in the TA muscle (Fig 2B, row 3); however, no muscle activity was elicited when the distal transected ACN was stimulated at the same portion (Fig 2B, row 4). On the untreated side, evoked action potentials were seen in the TA muscle (Fig 2B, row 5). Areas of TA Muscle and Individual Muscle Fibers. In the NMP group, the total TA muscle area on the treated side (Fig 3D) was smaller than that in the control animals (Fig 3A), but larger than those in both the denervation and ST groups (Fig 3B,C). Magnified images of the TA muscle revealed that Aoyama et al, Nerve-Muscle Pedicle in Partially Innervated Larynx 45 A B C D E F G H Fig 3. Representative microscopic findings of TA muscle with hematoxylin and eosin staining. A,E) Control group. B,F) Group at 15 weeks with complete RLN denervation procedure alone. C,G) ST group at 15 weeks with ST procedure alone. D,H) NMP group at 15 weeks with ST procedure and NMP implantation at 5 weeks. Ultimately, evaluation times were same (23-week-old animals). Scale bars — 200 μm in A-D; 20 μm in E-H. the areas of individual muscle fibers on the treated side (Fig 3H) were similar to those in the control group (Fig 3E), and larger than those in the denervation and ST groups (Fig 3F,G). The T/U ratio for the entire TA muscle area in the NMP group was significantly greater than that in the ST group (p < 0.01; Fig 4A). Although the difference did not reach statistical significance, the T/U ratio for the areas of individual muscle fibers in the NMP group was slightly larger than that in the ST group (p = 0.051; Fig 4B). Centralized Nuclei in Muscle Fibers. The incidence of centralized nuclei in the fibers on the treated side in the NMP group was significantly greater than those in the control, denervation, and ST groups (p < 0.01; Fig 5). Neuromuscular Junctions. A number of synaptophysin-positive NTs (Fig 6A-D) and α-bungarotoxin–positive AchRs (Fig 6E-H) were observed in all groups. The T/U ratios of the number of NTs and AchRs, and the NT/AchR ratio for the NMP group (for the quantitative measurement of regenerated NMJs8), were significantly higher than those for the denervation and ST groups (p < 0.01; Fig 7). DISCUSSION Previously, we demonstrated that ACN NMP implantation into the TA muscle prevented the denervation atrophy associated with complete RLN den- Fig 4. Comparison of treated-untreated ratios of TA muscle area for A) entire muscle and B) individual muscle fibers between all groups (control, RLN denervation [RD], ST, and NMP groups) at 15 weeks. All data are presented as mean ± SD. Differences were considered statistically significant at p < 0.05. A B 46 Aoyama et al, Nerve-Muscle Pedicle in Partially Innervated Larynx time period. We assume that decreasing or increasing this time period might bring about a relatively low degree of variance in NMJ regeneration. Fig 5. Percentage of muscle fibers containing centrally located nuclei at 15 weeks, based on 100 fibers in TA muscle for all groups (control, RD, ST, and NMP groups). All data are presented as mean ± SD. ervation in rats.3,4 However, as was shown previously, innervated, functionally active muscle fibers may not accept further innervation.6 Thus, the effect of the NMP procedure on a TA muscle that is partially innervated because of RLN synkinetic reinnervation is questionable. This prompted us to investigate the effects of dual innervation, which imply additional effects of the foreign nerve (ACN NMP) on the reinnervation of a TA muscle partially innervated by the RLN. We examined the effect of ACN NMP implantation 15 weeks after the ST procedure, because our previous studies3,4 demonstrated that the prominent effect of the NMJ regeneration was obtained by this Injury to the RLN may cause various degrees of vocal fold motion impairment secondary to ineffective, synkinetic muscle activity, rather than chronic denervation or marked muscle atrophy1 — a finding suggesting that partial, misdirected reinnervation of the intrinsic laryngeal muscles has occurred. Nonfunctional laryngeal reinnervation following RLN injury, presenting as a completely immobile vocal fold, may be due to the loss of adductor and abductor fiber organization during regenerative growth of the RLN.9 Various experimental animal models have been used to study peripheral nerve injury and functional recovery with synkinetic muscle activity,10,11 including an animal model of RLN crush injury using aneurysm clips to simulate synkinetic muscle activity following intraoperative RLN injury.12 Tessema et al12 described this crush injury model as a valuable RLN synkinetic reinnervation model; however, in our preliminary study, endoscopy revealed the recovery of vocal fold mobility 6 or 7 weeks after the procedure (data not shown). This contradiction (a persistently immobile vocal fold following RLN injury) was the basis for our use of the ST model as an RLN synkinetic reinnervation model with an immobile vocal fold. In our preliminary study, endoscopy revealed consistent vocal fold immobility, whereas histologic examina- A B C D E F G H Fig 6. Representative microscopic findings of neuromuscular junctions in TA muscle. A,E) Control group. B,F) Denervation group at 15 weeks with complete RLN denervation alone. C,G) ST group at 15 weeks with ST procedure alone. D,H) NMP group at 15 weeks with ST treatment and NMP implantation at 5 weeks. Neuromuscular junctions were double-stained with fluorescein isothiocyanate–labeled synaptophysin (A-D) and rhodamine-labeled α-bungarotoxin (E-H). Scale bars — 20 μm. Aoyama et al, Nerve-Muscle Pedicle in Partially Innervated Larynx A B 47 C Fig 7. A,B) Temporal changes in treated-untreated ratios of number of A) nerve terminals and B) acetylcholine receptors among all groups. C) Comparison of ratio of number of nerve terminals to that of acetylcholine receptors on treated side of TA muscle between all groups (control, RD, ST, and NMP groups). Data are presented as mean ± SD. Differences were considered statistically significant at p < 0.05. tion showed nerve regeneration through the ST preventing TA muscle atrophy; these data, in addition to our electrophysiological findings, including the prolonged latency of the evoked EMG (Fig 2B, row 1) and the reappearance of NMJs, validate this as an RLN synkinetic reinnervation model with an immobile vocal fold (details to be presented in another article). We implanted the ACN NMP into the TA muscle 5 weeks after the ST procedure because of observations that demonstrate RLN synkinetic reinnervation at this very time point. However, further investigation is necessary to see whether this waiting period until implantation might be critical to the efficacy of this procedure, because a longer waiting period might bring about a lower degree of plasticity of the NMJ arrangement. In this study, using the ST model, we found that NMP implantation is efficacious (in comparison with the ST group) for reducing atrophic changes (represented by the muscle area) and increasing synapse formation (represented by the ratio of NTs to AchRs in the TA muscle), even in the presence of partial RLN innervation. In addition, EMG showed that TA compound action potentials could be elicited by stimulating the proximal sides of both the transected RLN and the transferred ACN. Thus, partially innervated TA muscle fibers can accept foreign motor nerves (ACN) in addition to reinnervation from the original RLN. A previous study demonstrated that newly fused satellite cell nuclei were initially centralized in regenerated myofibrils and later migrated to a more peripheral location.13 Although it is difficult to demonstrate a direct correlation between the presence of centralized muscle fiber nuclei and the regenerative capacity of a partially innervated TA muscle by use of our study design, we postulate that dual neural input into the partially innervated TA muscle occurred as a result of NMP implantation, on the basis of a comparison between the numbers of centralized nuclei in the ST and NMP groups (p < 0.01). It remains to be addressed to what extent reinnervation occurs by sprouting of the foreign nerve (ACN) into the partially innervated TA muscle. We postulate that the transplanted ACN sprouts so that it targets original or newly formed AchRs to form new NMJs.3,4 Axonal sprouting is the process by which fine nerve processes grow out from intact axons at NTs to give rise to terminal sprouts. This commonly occurs as a natural compensatory mechanism following motor neuron diseases or trauma, such as partial nerve injuries.14 Previous studies showed that several factors influence this process, including the amount of scar tissue that forms at the implantation neuroma, the number of motor axons in the donor nerve, and the level of neuromuscular activity in the recipient muscle.15 It was previously shown that the efficacy of the NMP method for a partially denervated muscle was critically dependent on the level of neuromuscular activity in the recipient muscle.16 Interestingly, excessive neuromuscular activity significantly reduces the bridging of perisynaptic Schwann cell processes between innervated and denervated end plates, thereby inhibiting axonal sprouting in partially denervated muscle.14 By contrast, moderate and chronic increases in muscle activity, such as synkinetic nerve regeneration or moderate exercise, promote axonal sprouting of the implanted nerve, which may facilitate functional recovery in partially innervated muscle.16 Thus, a partially innervated TA muscle due to RLN synkinetic reinnervation, which might show a long-term 48 Aoyama et al, Nerve-Muscle Pedicle in Partially Innervated Larynx increase in muscle activity, could promote sprouting from the transplanted ACN, which in turn would increase the NT/AchR ratio with positive EMG findings as a consequence of the newly formed NMJs. Further investigation is necessary to see whether the waiting period for the implantation might be critical for the efficacy of this procedure, because a longer waiting period might cause a lower degree of plasticity of the NMJ arrangement. CONCLUSIONS Histologic and electrophysiological analyses confirmed that reinnervation using the NMP procedure can reduce atrophic changes in the TA muscle, even in the presence of partial RLN innervation 5 weeks after the ST procedure in rats. Thus, the NMP method may be useful for treating patients in whom partial innervation of the TA muscle is suspected. REFERENCES 1. Crumley R. Laryngeal synkinesis revisited. Ann Otol Rhinol Laryngol 2000;109:365-71. 2. Tucker HM. Long-term results of nerve-muscle pedicle reinnervation for laryngeal paralysis. Ann Otol Rhinol Laryngol 1989;98:674-6. 3. Kumai Y, Ito T, Udaka N, Yumoto E. Effects of a nervemuscle pedicle on the denervated rat thyroarytenoid muscle. Laryngoscope 2006;116:1027-32. 4. Miyamaru S, Kumai Y, Ito T, Sanuki T, Yumoto E. Nervemuscle pedicle implantation facilitates re-innervation of longterm denervated thyroarytenoid muscle in rats. Acta Otolaryngol 2009;129:1486-92. 5. Brown MC, Ironton R. Sprouting and regression of neuromuscular synapses in partially denervated mammalian muscles. J Physiol 1978;278:325-48. 6. Mark RF. Selective innervation of muscle. Br Med Bull 1974;30:122-6. 7. Zealear D, Swelstad M, Fortune S, et al. Evoked electromyographic technique for quantitative assessment of the innervation status of laryngeal muscles. Ann Otol Rhinol Laryngol 2005;114:563-72. 8. Deschenes MR, Will KM, Booth FW, Gordon SE. Unlike myofibers, neuromuscular junctions remain stable during prolonged muscle unloading. J Neurol Sci 2003;210:5-10. 9. Gacek RR. Morphologic correlates for laryngeal reinner- vation. Laryngoscope 2001;111:1871-7. 10. Mu L, Yang S. An experimental study on the laryngeal electromyography and visual observation in varying types of surgical injuries to the unilateral recurrent laryngeal nerve in the neck. Laryngoscope 1991;101:699-708. 11. Flint PW, Downs DH, Coltrera MD. Laryngeal synkinesis following reinnervation in the rat. Neuroanatomic and physiologic study using retrograde fluorescent tracers and electromyography. Ann Otol Rhinol Laryngol 1991;100:797-806. 12. Tessema B, Roark RM, Pitman MJ, Weissbrod P, Sharma S, Schaefer SD. Observations of recurrent laryngeal nerve injury and recovery using a rat model. Laryngoscope 2009;119:164451. 13. Hawke TJ, Garry DJ. Myogenic satellite cells: physiology to molecular biology. J Appl Physiol 2001;91:534-51. [Erratum in J Appl Physiol 2001;91:2414.] 14. Tam SL, Gordon T. Neuromuscular activity impairs axonal sprouting in partially denervated muscles by inhibiting bridge formation of perisynaptic Schwann cells. J Neurobiol 2003;57:221-34. 15. Sorbie C, Porter TL. Reinnervation of paralysed muscles by direct motor nerve implantation. An experimental study in the dog. J Bone Joint Surg Br 1969;51:156-64. 16. Tam SL, Gordon T. Mechanisms controlling axonal sprouting at the neuromuscular junction. J Neurocytol 2003;32: 961-74. Use of a Microdebrider for Subepithelial Excision of Benign Vocal Fold Lesions Alex Y. Cheng, MD; Ahmed M. S. Soliman, MD Objectives: We present a series of patients who underwent excision of subepithelial lesions using a laryngeal microdebrider. Methods: A retrospective review was carried out of all patients who between June 2005 and April 2009 underwent microlaryngoscopy and excision of vocal fold lesions by the senior author using a microdebrider. The patients’ demographics, past medical history, preoperative and postoperative videostroboscopy findings, and surgical pathology findings were reviewed. Results: Eight patients were identified. All were female and had a mean age of 44 years (range, 21 to 54 years). Four patients had a unilateral pseudocyst, 2 patients had bilateral pseudocysts, 1 patient had bilateral Reinke’s edema, and 1 patient had unilateral Reinke’s edema. Through an incision made just lateral to the lesion on the superior surface, a small microdebrider blade was inserted and run at 800 to 1,000 revolutions per minute in oscillation mode with low wall suction until the lesion was completely excised, and the overlying epithelium was left intact. Postoperative videostroboscopic examination of the larynx revealed an absence of lesions and near-complete glottal closure in all patients. Seven of the 8 patients reported an improvement in voice. Conclusions: Microdebrider excision of subepithelial vocal fold lesions is feasible. The patients with Reinke’s edema had slightly more residual edema, a decreased epithelial wave, and less improvement in voice as compared to the patients with pseudocysts. Meticulous technique, low oscillation speeds, and low wall suction are necessary to avoid injury to the overlying epithelium. Key Words: benign lesion, microdebrider, surgical treatment, vocal fold lesion. Its use in the treatment of Reinke’s edema was first described in 2000,7 and very recently, functional outcomes were reported.8 INTRODUCTION The microdebrider is a powered microdissecting instrument that was originally designed for arthroscopic knee surgeries. With a small oscillating blade within a protected sheath that provides continuous suction, the microdebrider is able to remove tissues within a tight space and allow an unobstructed operative field. Further technological advances in microdebrider design have since allowed it to access the narrow confines of the upper aerodigestive tract and thus allowed its use in otolaryngology. Microdebrider use in endoscopic sinus surgery was first reported in 1996,1 and it was subsequently adapted for laryngeal applications in 1999.2 Its first use in the larynx was as an effective debulking tool for laryngeal papillomas and later for various other laryngeal disorders.3-5 More delicate laryngeal surgery using smaller blades at low rotational speeds has been briefly mentioned in the literature for epithelial lesions, including polyps and granulomas.6 Benign subepithelial disorders of the true vocal folds include Reinke’s edema, cysts, pseudocysts, and fibrous masses. Although traditional surgical excision of true cysts using microsurgical techniques is more straightforward, it is more challenging for pseudocysts, of which the wall is thinner and often adherent to the subepithelium of the elevated microflap. In Reinke’s edema, the thick gelatinous matrix is often too thick to remove with suctioning alone. In these selected situations, we have used the microdebrider to excise the lesions subepithelially. We review our experience and technique with the microdebrider in patients with benign subepithelial vocal fold lesions. METHODS After obtaining Institutional Review Board ap- From the Department of Otolaryngology–Head and Neck Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Ahmed M. S. Soliman, MD, Dept of Otolaryngology–Head and Neck Surgery, Temple University School of Medicine, 3400 N Broad St, Kresge West 102, Philadelphia, PA 19140. 49 50 Cheng & Soliman, Subepithelial Microdebrider Excision (Patient 2) Endoscopic views of endoscopic subepithelial shaver excision of pseudocyst. A) Subepithelial lesion is seen on right true vocal fold. B) After incision alongside lesion with sickle knife, microdebrider is introduced into subepithelial space and lesion is excised. C) Epithelium has been redraped, leaving smooth edge. A B proval, we carried out a retrospective review of all patients who underwent microlaryngoscopy and excision of vocal fold lesions by the senior author (A.M.S.S.) using the microdebrider from June 2005 to April 2009. The patients’ demographics, past medical history, and preoperative and postoperative laryngoscopy findings were reviewed. After the airway was secured, an operative laryngoscope was inserted and the larynx was suspended with the true vocal folds in view. Under microscopic visualization, a sickle knife was used to incise the epithelium just lateral to the lesion on the superior surface of the vocal fold. An angled blunt elevator was then used to dissect the lesion away from the underlying superficial lamina propria and vocal ligament and the overlying epithelium. In cases in which the lesion was tightly adherent to the overlying epithelium, the Xomed XPS Shaver system with a Magnum handpiece (Medtronic-Xomed, Jacksonville, Florida) was used. An angled 2.9- or 3.5-mm round window microdebrider blade (Skimmer) was inserted and then run at 800 to 1,000 revolutions per minute in oscillation mode with low wall suction until the lesion was completely excised, and the over- C lying epithelium was left intact (see Figure). Strict care was also taken to keep the underlying superficial lamina propria and vocal ligament undisturbed. The 3.5-mm blade was used initially until the availability of the 2.9-mm blade, which is now used exclusively. The 2 patients with Reinke’s edema had the excess epithelium excised sharply with an upbiting microscissors after the gelatinous matrix was removed with the microdebrider subepithelially. Rigid or flexible videostroboscopic examination of the larynx (KayPENTAX, Lincoln Park, New Jersey) was performed before and after the operation in all patients. RESULTS Twelve patients who underwent excision of vocal fold lesions using a microdebrider were identified. Four patients with airway-obstructing polyps were excluded from the study because these lesions were not excised subepithelially. The remaining 8 patients were all female and had a mean age of 44 years (range, 21 to 54 years). All patients presented with a chief complaint of hoarseness. Other symptoms included globus sensation, excessive throat Cheng & Soliman, Subepithelial Microdebrider Excision clearing, and inability to sing as usual. Three patients (38%) had a history of smoking. All patients underwent preoperative videostroboscopy, which revealed a unilateral pseudocyst in 4 patients, bilateral pseudocysts in 2 patients, bilateral Reinke’s edema in 1 patient, and unilateral Reinke’s edema in 1 patient. All patients were empirically treated with daily proton pump inhibitors started at their preoperative visit and continued after the operation. All patients underwent elective outpatient sameday surgery. They were intubated with a 6.0 endotracheal tube and underwent general anesthesia. Surgical excision was carried out as described in the surgical technique. The postoperative diagnoses concurred with the preoperative impression in all cases. The first postoperative appointment was at a mean of 16.3 days from the date of surgery. One patient did not return to the office; however, on telephone interview 2 years after her procedure, she reported her voice to be normal. Of the 7 patients who returned to the office, 6 (85.7%) reported subjective improvement in symptoms. Videostroboscopic examination of the larynx revealed an absence of lesions and near-complete glottal closure in all patients. All had a slightly decreased mucosal wave, as well as mild edema and/or erythema of the operated vocal fold. This finding was more pronounced in the 2 patients with Reinke’s edema. Postoperative videostroboscopy of the patient who reported no improvement in voice showed similar findings. Six patients had a second follow-up office visit (mean, 78.5 days). The patient who reported no early postoperative improvement continued to have similar complaints, although her videostroboscopic examination findings were normal; it was later learned that she was applying for disability benefits from her job as a telephone operator. Three patients who had pseudocysts removed reported near-normal voice quality; their videostroboscopic examinations revealed a symmetric, periodic mucosal wave with complete glottal closure and an absence of lesions. Two patients who had Reinke’s edema reported marked improvement in voice, but on videostroboscopic examination had mild edema of the affected vocal folds. DISCUSSION The microdebrider has been successfully used in the larynx, primarily for the debulking of various lesions, including papillomas, polyps, and granulo- 51 mas. However, its use for excision of subepithelial lesions other than Reinke’s edema has not been previously reported. We report its application to selected cases as a targeted approach for a surgically challenging situation. Whenever possible, every attempt was made to remove the lesions by use of traditional micro-instruments; however, when there was tight adherence to the overlying epithelium or a large amount of gelatinous matrix that could not be suctioned, the microdebrider provided a significant advantage. It is also important to emphasize that as in traditional cold microsurgical techniques, every effort is made to avoid injury to the underlying superficial lamina propria and vocal ligament, which are most important in vibratory function, as well as to avoid injury to the overlying epithelium. The use of adequate magnification and low wall suction along with the low variable oscillation is critical in achieving this goal. Unlike the original descriptions by Sant’Anna and Mauri7 of its use in a rotational mode, we found the microdebrider’s oscillation mode to be more efficient in removing the lesion while preserving the overlying epithelium. In addition, rather than setting a fixed speed as recommended by Flint,6 we found that using the variable speed controller allowed more precise control over the resection. Our oscillation speeds of 800 to 1,000 revolutions per minute were also higher than previously reported. We found that the fibrous nature of the lesions did not allow them to be easily resected at the lower speeds; however, we recommend using the lowest speed necessary to achieve resection. One reported shortcoming of the microdebrider is the inability to collect a specimen. Although the amount of tissue removed is quite small, an in-line specimen trap can be used to collect a specimen for pathological examination. Certainly, if there are suspicious epithelial changes, a sample is obtained with a small forceps and microscissors before the use of the microdebrider. Another limitation of the microdebrider blade is its size. Although introduction of the 2.9-mm blade was a major improvement, further refinement such as flattening of the tip would allow easier insertion through the epithelial incision. A case of anterior web and granuloma formation after use of the microdebrider for removal of a polyp has been reported.9 No such complications occurred in our series. In our technique, the blade remains subepithelial and the overlying surface is not violated. We do, however, agree that the highest level of care is necessary in using powered instruments in the larynx. In our opinion, they should not be used if 52 Cheng & Soliman, Subepithelial Microdebrider Excision the lesion can be easily removed by traditional cold microsurgical techniques. this technique. Although no formal voice analysis was performed, all patients reported subjective improvement in their voice after surgery; this was also evident on perceptual evaluation by the examining laryngologist. Videostroboscopic examination of the larynx in the early postoperative period showed findings typical of those seen after the same procedure done without the microdebrider; they included edema, erythema, and stiffness of the operated vocal fold. These findings were more pronounced in the patients with Reinke’s edema, as expected, given that the incision was larger and the dissection more extensive. Objective voice evaluation and comparison with traditional microsurgical techniques in a controlled study is necessary to further determine the usefulness of Microdebrider excision of subepithelial vocal fold lesions is feasible. Patients with Reinke’s edema had slightly more residual edema, a decreased mucosal wave, and less improvement in voice as compared to patients with pseudocysts. Meticulous technique, low variable oscillatory speeds, and low wall suction are necessary to avoid injury to the overlying epithelium and to the underlying superficial lamina propria and vocal ligament. Further refinements in instrument design would facilitate use through smaller incisions. A larger, controlled study with objective voice analysis and comparison with traditional microsurgical techniques is necessary to further define the role of the microdebrider in the treatment of subepithelial vocal fold disease. CONCLUSIONS REFERENCES 1. Setliff RC III. The hummer: a remedy for apprehension in functional endoscopic sinus surgery. Otolaryngol Clin North Am 1996;29:95-104. 2. Myer CM III, Willging JP, McMurray S, Cotton RT. Use of laryngeal micro resector system. Laryngoscope 1999;109: 1165-6. 3. Patel RS, Mackenzie K. Powered laryngeal shavers and laryngeal papillomatosis: a preliminary report. Clin Otolaryngol Allied Sci 2000;25:358-60. 4. Rees CJ, Tridico TI, Kirse DJ. Expanding applications for the microdebrider in pediatric endoscopic airway surgery. Otolaryngol Head Neck Surg 2005;133:509-13. 5. Nuyens M, Zbaren P, Seifert E. Endoscopic resection of laryngeal and tracheal lesions using the microdebrider. Acta Otolaryngol 2006;126:402-7. 6. Flint P. Powered surgical instruments for laryngeal surgery. Otolaryngol Head Neck Surg 2000;122:263-6. 7. Sant’Anna GD, Mauri M. Use of the microdebrider for Reinke’s edema surgery. Laryngoscope 2000;110:2214-6. 8. Honda K, Haji T, Maruyama H. Functional results of Reinke’s edema surgery using a microdebrider. Ann Otol Rhinol Laryngol 2010;119:32-6. 9. Mortensen M, Woo P. An underreported complication of laryngeal microdebrider: vocal fold web and granuloma: a case report. Laryngoscope 2009;119:1848-50. Response of Cricopharyngeus Muscle to Esophageal Stimulation by Mechanical Distension and Acid and Bile Perfusion Natalya Chernichenko, MD; Jeong-Soo Woo, MD; Jagdeep S. Hundal, MD; Clarence T. Sasaki, MD Objectives: The aim of this study was to identify the response of the cricopharyngeus muscle (CPM) to esophageal stimulation by intraluminal mechanical distension and intraluminal acid and bile perfusion. Methods: In 3 adult pigs, electromyographic (EMG) activity of the CPM was recorded at baseline and after esophageal stimulation at 3 levels: proximal, middle, and distal. The esophagus was stimulated with 20-mL balloon distension and intraluminal perfusion of 40 mL 0.1N hydrochloric acid, taurocholic acid (pH 1.5), and chenodeoxycholic acid (pH 7.4) at the rate of 40 mL/min. The EMG spike density was defined as peak-to-peak spikes greater than 10 μV averaged over 10-ms intervals. Results: In all 3 animals, the spike density at baseline was 0. The spike densities increased after proximal and middle distensions to 15.2 ± 1.5 and 5.1 ± 1.2 spikes per 10 ms, respectively. No change in CPM EMG activity occurred after distal distension. The spike density following intraluminal perfusion with hydrochloric acid at the distal level was 10.1 ± 1.1 spikes per 10 ms. No significant change in CPM EMG activity occurred after acid perfusion at the middle and proximal levels. No change in CPM EMG activity occurred after intraluminal esophageal perfusion with either taurocholic acid or chenodeoxycholic acid. Conclusions: Proximal esophageal distension, as well as distal intraluminal acid perfusion, appeared to be important mechanisms in generation of CPM activity. Bile acids, on the other hand, failed to evoke such CPM activity. The data suggest that transpyloric refluxate may not be significant enough to evoke the CPM protective sphincteric function, thereby placing supraesophageal structures at risk of bile injury. Key Words: bile acid, cricopharyngeus, gastroesophageal reflux. INTRODUCTION disease states is still incomplete. The CPM is tonically active at rest and relaxes during swallowing, belching, and vomiting. On the one hand, the sphincteric function of the CPM remains controversial, perhaps serving to prevent esophageal distension during deep inspiration as intrathoracic pressure approaches subatmospheric, while volumetrically stabilizing the vocal tract by ensuring against esophageal penetration as the vocal tract pressure rises above atmospheric during phonation.3-5 On the other hand, retrograde flow of esophageal contents has been increasingly recognized as a cause of chronic lung disease and laryngeal dysfunction.6 Therefore, it has been suggested that evoked CPM contraction in response to stimulatory events distal to it may be protective against esophageal reflux and aspiration.7 Others suggest that increased CPM tone evoked by distal events provides the basis for hypo- The upper esophageal sphincter (UES) is functionally defined as the high-pressure zone separating the pharynx from the cervical esophagus. Anatomically, the UES is a musculocartilaginous structure with its anterior wall defined by the posterior surface of the cricoid cartilage inferiorly, as well as the arytenoid and interarytenoid muscles superiorly. Posteriorly and laterally, the UES is defined by the inferior pharyngeal constrictor, the cricopharyngeus muscle (CPM), and portions of the upper esophageal circular muscle fibers.1,2 It is generally believed, however, that the CPM is the main muscle responsible for UES function. Even though the anatomy of the UES is well defined, our current understanding of its normal physiologic function and its role in the development of From the Section of Otolaryngology–Head and Neck Surgery, Yale University School of Medicine, New Haven, Connecticut. This study was performed in accordance with the PHS Policy on Humane Care and Use of Laboratory Animals, the NIH Guide for the Care and Use of Laboratory Animals, and the Animal Welfare Act (7 U.S.C. et seq.); the animal use protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Yale University. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Clarence T. Sasaki, MD, Section of Otolaryngology–Head and Neck Surgery, Yale University School of Medicine, 333 Cedar St, PO Box 208041, New Haven, CT 06520. 53 54 Chernichenko et al, Cricopharyngeus Muscle in Esophageal Stimulation pharyngeal pulsion diverticuli in susceptible populations by increasing hypopharyngeal pressure during swallowing, leading to herniation of the posterior pharyngeal wall weakness known as Killian’s triangle. Thus, of all muscle groups in the head and neck, none surpasses the CPM in capturing our clinical imagination and investigative curiosity. Although the role of the UES has been studied with the help of manometry, videofluoroscopy, videoendoscopy, and electromyographic (EMG) testing,8-10 the CPM’s contribution in terms of increased muscle action potential in response to mechanical distension, acid perfusion, and bile perfusion in the same subject has not been demonstrated. This study was designed to investigate the response of the CPM to esophageal stimulation by mechanical distension, hydrochloric acid perfusion, and bile acid perfusion. Is its major sphincteric response due to intraluminal distension? Or does acid and/or bile perfusion influence the EMG findings in the CPM? Does the location of the stimulus within the esophagus alter its response? MATERIALS AND METHODS Three adult male Yorkshire pigs were used in the study. The animals were approximately 5 to 8 months of age, and weighed from 50 to 70 kg. The porcine aerodigestive tract was selected as a model because of its anatomic and physiologic similarity to that of humans.11 Anesthesia was induced with an intramuscular injection of ketamine hydrochloride (30 mg/kg) and xylazine hydrochloride (5 mg/kg) and was maintained with isoflurane inhalation via a nose cone. By aseptic techniques, a vertical midline incision was made extending from the level of the hyoid bone to the sternal notch. A tracheotomy was performed to provide maintenance inhalational anesthesia through an endotracheal tube inserted through and secured to the tracheostoma. This surgical exposure also facilitated identification of the CPM and insertion of EMG electrodes. No pharmacologic muscle relaxation was used. Electrocardiography, respiratory rate, pulse oximetry, and core body temperature were continuously monitored and recorded every 15 minutes. A 2-cm anterior pharyngotomy was performed to allow direct visualization of the larynx and hypopharynx, as well as insertion of Foley and perfusion catheters under direct vision. Esophagoscopy was performed via the pharyngotomy to establish the total esophageal length. The esophageal length was used to determine the level of proximal, middle, and distal stimulation at 1 cm below the UES, 12 cm above the gastroesophageal junction, and 2 cm above the gastroesophageal junction, respectively. An XLTEX-Neuromax (Oakville, Canada) oscilloscope was used for EMG recording. Mechanical Distension. A 12F Foley catheter was used for mechanical distension of the esophagus. A Foley catheter balloon was rapidly inflated with 20 mL of air delivered in 5 seconds to the distal, middle, and proximal parts of the esophagus in random order. Each distension was separated in time by 5 minutes. The EMG activity was recorded at baseline and with stimulation. Intraluminal Perfusion With Hydrochloric Acid. To simulate conditions of acid reflux, we perfused the esophagus at the proximal, middle, and distal levels with 40 mL of 0.1N hydrochloric acid (pH 1.5) at a rate of 40 mL/min via a Precision Syringe Pump (Chemyx, Stafford, Texas) in random order. Saline perfusion was used as a control. All perfusions were followed by a saline wash of 30 mL and were separated by intervals of 5 minutes or until the CPM EMG findings stabilized at baseline. Intraluminal Perfusion With Bile Acids. To simulate conditions of bile reflux, we perfused the esophagus at the proximal, middle, and distal levels with taurocholic acid (more than 95% pure; Sigma-Aldrich, St Louis, Missouri) at a concentration of 5 mmol/L titrated to pH 1.5 and chenodeoxycholic acid (more than 98% pure; Sigma-Aldrich) at a concentration of 5 mmol/L titrated to a pH of 7.4 by use of a protocol identical to that of the hydrochloric acid perfusion. A total of 6 EMG measures at each site were obtained for each protocol per animal to provide sufficient power for statistical analysis. The random order of acid and bile application was intended to reduce the possibility that intraluminal migration of test solution might vertically contaminate the sitespecific level of esophageal stimulation. The EMG spike density, which was defined as peak-to-peak spikes greater than 10 μV averaged over 10-ms intervals, was calculated and compared to baseline. The mean spike density and standard error were calculated. RESULTS In all 3 animals, the spike density at baseline was 0. Importantly, the 3 animals responded similarly to stimulations. The CPM EMG activity occurred immediately after balloon distension. The spike densities following proximal and middle distensions increased and were 15.2 ± 1.5 and 5.1 ± 1.2 spikes Chernichenko et al, Cricopharyngeus Muscle in Esophageal Stimulation 55 TABLE 1. SPIKE DENSITIES Animal 1 Stimulation Animal 2 Animal 3 Total 15.1 ± 3.9 0.5 ± 0.5 0 17.5 ± 6.1 11.8 ± 4.6 0 12.8 ± 5.6 3.0 ± 1.3 0 15.2 ± 1.5 5.1 ± 1.2 0 Following intraluminal perfusion with hydrochloric acid Proximal 0 0 Middle 0 1.2 ± 0.8 Distal 0 12.8 ± 2.9 0 1.8 ± 0.7 8.2 ± 3.0 0 0.5 ± 0.2 9.2 ± 3.7 0 1.2 ± 0.4 10.1 ± 1.1 Baseline Following esophageal distension Proximal 0 Middle 0 Distal 0 Data are spikes per 10 ms (mean ± SE). per 10 ms, respectively. No change in CPM EMG activity occurred after distal distension as compared to baseline (Table 1). Representative EMG recordings of CPM at baseline and following esophageal distension at the proximal, middle, and distal levels are presented in Fig 1. The CPM EMG activity usually occurred 30 seconds after initiation of intraluminal perfusion of hydrochloric acid at the distal level (spike density, 10.1 ± 1.1 spikes per 10 ms). No significant change in Fig 1. Electromyographic (EMG) recordings of cricopharyngeus muscle (CPM) at baseline and following esophageal distension at proximal, middle, and distal levels. Amplitude calibration is 10 μV. Time calibration is 10 ms. CPM EMG activity occurred after perfusion at the proximal and middle levels as compared to baseline (Table 1). Representative EMG recordings of the CPM at baseline and following intraluminal perfusion with hydrochloric acid are presented in Fig 2. No change in CPM EMG activity occurred after intraluminal esophageal perfusion with saline solution. Notably, no change in CPM EMG activity occurred after intraluminal esophageal perfusion with either taurocholic or chenodeoxycholic acid (Table Fig 2. EMG recordings of CPM at baseline and following intraluminal perfusion with hydrochloric acid. Amplitude calibration is 10 μV. Time calibration is 10 ms. 56 Chernichenko et al, Cricopharyngeus Muscle in Esophageal Stimulation TABLE 2. SPIKE DENSITY AT BASELINE AND FOLLOWING INTRALUMINAL PERFUSION WITH TC AND CDC Proximal Middle Distal TC 0 0 0 Baseline CDC 0 0 0 Stimulation TC CDC 0 0 0 0 0 0 TC — taurocholic acid; CDC — chenodeoxycholic acid. 2). Representative EMG recordings of the CPM at baseline and following intraluminal perfusion with taurocholic and chenodeoxycholic acids are presented in Figs 3 and 4. ry importance in mediating the UES relaxation response.9,13 Furthermore, the proximal rather than the distal esophagus seems to be the stronger stimulus site for eliciting the esophageal-UES contractile reflex in humans.14 This physiologic observation finds morphological support in Neuhuber’s15 observation that in the rat model the most cranial part of the esophagus receives the greatest vagal sensory innervation and that the density of innervation decreases distally. Our functional EMG data from the pig model support these observations. Prior studies have clearly demonstrated that intraluminal esophageal balloon distension causes increased UES pressure.9,12 It has been also shown that the esophageal-UES reflexes are mediated via the brain stem by vagal afferents arising from the esophageal mucosa and muscle layers. Mechanoreceptors located in the muscular layer are primarily responsible for the contractile response of the UES, whereas mucosal mechanoreceptors are of prima- The role of intraluminal hydrochloric acid perfusion in the stimulation of CPM contraction has been controversial. Gerhardt et al16 demonstrated a significant UES pressure increase when the proximal esophagus of humans was stimulated with acid. However, further studies have called this finding into question by showing that the UES response to intraluminal infusion of hydrochloric acid in normal volunteers, although more pronounced at the proximal level, is indistinguishable from those produced by saline solution and intraluminal distension, and the investigators postulated that acidification may not by itself stimulate this reflex.17 Still others have Fig 3. EMG recordings of CPM at baseline and following intraluminal perfusion with taurocholic acid. Amplitude calibration is 10 μV. Time calibration is 10 ms. Fig 4. EMG recordings of CPM at baseline and following intraluminal perfusion with chenodeoxycholic acid. Amplitude calibration is 10 μV. Time calibration is 10 ms. DISCUSSION Chernichenko et al, Cricopharyngeus Muscle in Esophageal Stimulation observed a significant rise in UES pressure following acid infusion 5 cm proximal to the gastroesophageal sphincter.18 We have clearly shown that in a pig model hydrochloric acid stimulation of the distal esophagus induces CPM EMG activity, whereas balloon distension at the same level elicits no change in basal CPM activity. Therefore, it is reasonable to conclude that acid stimulation in itself evokes CPM activity, not merely enhancing the reflex response to intraluminal distension. It has previously been recognized that the earliest change associated with injury from acid refluxate is increased paracellular permeability due to damage to the intercellular junctions and subsequent development of “dilated intercellular spaces.”19 This event allows hydrogen ions to penetrate the intercellular spaces and reach vagal sensory nerve endings between the mucosal cells, in such a way as to trigger evoked CPM activity. One would expect hydrogen ions present in taurocholic acid solution at pH 1.5 to trigger a similar physiologic response. Interestingly, we observed no change in basal CPM activity in response to esophageal stimulation by bile acids. Requiring further inquiry, the following hypothetical explanations are offered. On the one hand, an absence of response to taurocholic acid (pKa 2) could be attributed to its preferential “intramucosal trapping” due to prevalence of its nonionized lipophilic form at pH 1.5 with subsequent entrapment in the intracellular compartment due to ionization at neutral pH.20 This “intramucosal trapping” of taurocholic acid may result in sufficient cellular edema to block paracellular permeability and therefore prevent development of vagal stimulation related to 57 dilated intercellular spaces. On the other hand, it is possible that the presence of taurocholic acid in addition to hydrogen ions could be so caustic as to either block or destroy sensory nerve endings, in such a way as to block signal detection. An absence of an evoked CPM response to esophageal stimulation by bile acids is an interesting observation in light of a growing understanding that transpyloric refluxate in gastroesophageal reflux is not uncommon. Although bile reflux may be directly injurious to esophageal and supraesophageal mucosa,21 there does not seem to be sufficient evidence of its effect on evoked CPM sphincteric function. These observations further suggest that effective antacid therapy, while neutralizing the caustic effects of acid on esophageal and supraesophageal mucosa, may also blunt the effect of proximal CPM protective function when gastroesophageal refluxate contains significant concentrations of caustic bile salts at near-neutral pH, thereby placing supraesophageal structures at added risk of bile injury. CONCLUSIONS Physiologically, the cardinal events that occur during gastroesophageal reflux are esophageal distension and reflux of acid with or without duodenal contents. Observed in our experiments, reflex CPM contraction in response to proximal balloon distension, as well as acid stimulation of the distal esophagus, may be explained as a response acting to prevent gastroesophageal refluxate from entering the pharynx. However, transpyloric refluxate does not appear a significant-enough stimulus to evoke a CPM protective sphincteric function. Acknowledgment: The authors are grateful to Dr Roy Orlando, MD, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, for his advice on acid-induced mucosal permeability. REFERENCES 1. Sivarao DV, Goyal RK. Functional anatomy and physiology of the upper esophageal sphincter. Am J Med 2000;108(suppl 4A):27S-37S. 2. Singh S, Hamdy S. The upper oesophageal sphincter. Neurogastroenterol Motil 2005;17(suppl 1):3-12. [Erratum in Neurogastroenterol Motil 2005;17:773.] 3. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991;101(suppl 53):1-78. 4. Sasaki CT, Kim YH, Sims HS, Czibulka A. Motor innervation of the human cricopharyngeus muscle. Ann Otol Rhinol Laryngol 1999;108:1132-9. 5. Perera L, Kern M, Hofmann C, et al. Manometric evidence for a phonation-induced UES contractile reflex. Am J Physiol Gastrointest Liver Physiol 2008;294:G885-G891. 6. Hunt PS, Connell AM, Smiley TB. The cricopharyngeus sphincter in gastric reflux. Gut 1970;11:303-6. 7. Belsey R. Functional disease of the esophagus. J Thorac Cardiovasc Surg 1966;52:164-88. 8. Shaker R, Ren J, Medda BK, et al. Identification and characterization of the esophagoglottal closure reflex in a feline model. Am J Physiol Gastrointest Liver Physiol 1994;266:G147G153. 9. Lang IM, Medda BK, Shaker R. Mechanism of reflexes induced by esophageal distension. Am J Physiol Gastrointest Liver Physiol 2001;281:G1246-G1263. 10. Lang IM, Dantas RO, Cook IJ, Dodds JW. Videoradiographic, manometric and electromyographic analysis of canine upper esophageal sphincter. Am J Physiol Gastrointest Liver Physiol 1991;260:G911-G919. 11. Schopf BW, Blair G, Dong S, Troger K. A porcine model of gastroesophageal reflux. J Invest Surg 1997;10:105-14. 12. Creamer B, Schlegel J. Motor responses of the esophagus to distension. J Appl Physiol 1957;10:498-504. 58 Chernichenko et al, Cricopharyngeus Muscle in Esophageal Stimulation 13. Szczesniak MM, Fuentealba SE, Burnett A, Cook IJ. Differential relaxation and contractile responses of the human upper esophageal sphincter mediated by interplay of mucosal and deep mechanoreceptor activation. Am J Physiol Gastrointest Liver Physiol 2008;294:G982-G988. 14. Enzmann DR, Harell GS, Zboralske FF. Upper esophageal responses to intraluminal distension in man. Gastroenterology 1977;72:1292-8. 15. Neuhuber WL. Sensory vagal innervation of the rat esophagus and cardia: a light and electron microscopic anterograde tracing study. J Auton Nerv Syst 1987;20:243-55. 16. Gerhardt DC, Shuck TJ, Bordeaux RA, Winship DH. Human upper esophageal sphincter. Response to volume, osmotic, and acid stimuli. Gastroenterology 1978;75:268-74. 17. Thompson DG, Andreollo NA, McIntyre AS, Earlam RJ. Studies of the oesophageal clearance responses to intraluminal acid. Gut 1988;29:881-5. 18. Wallin L, Boesby S, Madsen T. The effect of HCl infusion in the lower part of the esophagus on the pharyngo-esophageal sphincter pressure in normal subjects. Scand J Gastroenterol 1978;13:821-6. 19. Orlando RC. Current understanding of the mechanisms of gastro-oesophageal reflux disease. Drugs 2006;66(suppl 1): 1-5, 29-33. 20. Schweitzer EJ, Bass BL, Batzri S, Harmon JW. Bile acid accumulation by rabbit esophageal mucosa. Dig Dis Sci 1986; 31:1105-13. 21. Sasaki CT, Marotta J, Hundal J, Chow J, Eisen RN. Bileinduced laryngitis: is there a basis in evidence? Ann Otol Rhinol Laryngol 2005;114:192-7. Analysis of Pepsin in Tracheoesophageal Puncture Sites Jonathan M. Bock, MD; Mary K. Brawley, MA; Nikki Johnston, PhD; Tina Samuels, MS; Becky L. Massey, MD; Bruce H. Campbell, MD; Robert J. Toohill, MD; Joel H. Blumin, MD Objectives: Tracheoesophageal puncture (TEP) and prosthesis insertion is a well-established method of voice rehabilitation after laryngectomy. Maintenance of the prosthesis and tract can be challenging, and reflux to the TEP site has been proposed as a cause. The sites of TEP were evaluated for the presence of pepsin in tissue biopsy specimens and tract secretions to explore this association. Methods: Patients with TEP were interviewed for a history of symptoms related to reflux, medication use history, TEP voice quality, and incidence of TEP complications. Tissue biopsy specimens and tract secretions were obtained from TEP sites and analyzed for the presence of pepsin via sodium dodecyl sulfate–polyacrylamide gel electrophoresis Western blot analysis. Results: Twelve of 17 patients (47%) had some history of preoperative or postoperative symptoms of gastroesophageal reflux disease or laryngopharyngeal reflux. Pepsin was present within the TEP site in a total of 10 of 17 patients (58%; 7 of 17 tissue biopsy specimens and 6 of 7 secretion samples). There were no statistically significant associations between the presence of pepsin and sex, reflux history, use of acid suppressive medicine, or time since laryngectomy. Conclusions: Reflux with subsequent pepsin deposition into the TEP tract occurs in a majority of laryngectomy patients. Further studies on the effect of reflux on the health and function of the TEP tract are warranted. Key Words: head and neck cancer, laryngectomy, pepsin, reflux, tracheoesophageal puncture. method of TEP they described could be performed in minutes as part of the initial laryngectomy or as a secondary procedure. They also led efforts to develop easily replaceable prosthetic valves to facilitate adequate voice production and prevent backflow and aspiration of saliva. Over the past 30 years, many improvements in valve prosthesis design have been developed, but the problems of leakage, granulation, aspiration, debris, infection, and contamination continue to complicate prosthesis use. Required rates of prosthesis change vary widely in reported series, ranging from 2 months to 60 months.5 Over this same 30 years, information concerning laryngopharyngeal reflux (LPR) and its relationship to the development of laryngeal and pharyngeal cancers has appeared in the literature.6-11 Copper et al12 studied the prevalence of gastroesophageal reflux disease (GERD) or LPR in 24 patients with laryngeal and pharyngeal squamous cell carcinomas. In addition, 10 patients who had undergone irradiation were evaluated for reflux. Using 24-hour dual-probe pH monitoring, Copper et al12 determined that 20 of 24 cancer patients had pathological reflux, includ- INTRODUCTION Laryngectomy remains the standard of care for the treatment of many advanced-stage or recurrent laryngeal cancers. Rehabilitation of alaryngeal speech is a basic need for patients after this operation. The idea of constructing a communication between the upper trachea and pharynx for this purpose was developed in the 1960s, but initial attempts using this technique for speech rehabilitation were complicated by problems of saliva and food leakage into the trachea, as well as eventual stenosis of the tracheopharyngeal tract.1 Eventual efforts to surgically create a communication tract between the pharynx and trachea were pioneered by Asai,2 Miller,3 and Montgomery and Toohill.1 These early procedures were complicated by the need for multiple surgical stages to create a tracheopharyngeal tract, and often led to problems with tract stenosis, leakage, and aspiration. The modern version of tracheoesophageal puncture (TEP) for postlaryngectomy speech was introduced by Singer and Blom4 in 1980. The endoscopic From the Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Jonathan M. Bock, MD, Dept of Otolaryngology and Communication Sciences, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226. 59 60 Bock et al, Analysis of Pepsin in Tracheoesophageal Puncture Sites TABLE 1. PATIENT REFLUX HISTORY QUESTIONNAIRE Department of Otolaryngology and Communication Sciences Center for Communication and Swallowing Disorders Name: ___________________________________________ Date: ___________________________ Date of Laryngectomy: ______________________________ Date of TEP: _____________________ Before your laryngectomy, how did the following affect you? (0 = no problem and 5 = severe problem) 1. Clearing your throat 0 1 2 2. Excess mucus or postnasal drip 0 1 2 3. Coughing after you eat or after lying down 0 1 2 4. Breathing difficulties or choking episodes 0 1 2 5. Troublesome or annoying cough 0 1 2 6. Sensations of something sticking in your throat or a lump in your throat 0 1 2 7. Heartburn, chest pain, indigestion, or stomach acid coming up 0 1 2 After your laryngectomy, how do the following affect you? (0 = no problem and 5 = severe problem) 1. Excess mucus in your throat 0 1 2 2. Sensations of something sticking in your throat or a lump in your throat 0 1 2 3. Heartburn, chest pain, indigestion, or stomach acid coming up 0 1 2 Were you on reflux medication before your surgery? _____yes ______no Are you on reflux medication now? _____yes ______no Medication: ______________________________________ Subject number: _______ 3 3 3 3 3 3 3 4 4 4 4 4 4 4 5 5 5 5 5 5 5 3 3 3 4 4 4 5 5 5 ing 62% with LPR on testing. They concluded that LPR is a common problem in patients with head and neck cancer.12 the TEP site. Ongoing reflux into the upper esophagus after laryngectomy would not be particularly bothersome if there were no communication between the esophagus and the airway. However, when TEP has been performed for voice rehabilitation, this communication may be more vulnerable to the effects of reflux, as some of the protective mechanisms that retard reflux may be disturbed by laryngectomy. A study by Pattani et al13 confirmed that acid suppression therapy was beneficial to the majority of TEP patients as it related to voice production and TEP health. Studies have also indicated that pepsin can be injurious to the extraesophageal tissues, suggesting that acid reduction therapy using proton pump inhibitors may not be sufficient to inhibit damage to these areas, including the TEP site.14 Patients. This study was approved by the Institutional Review Board of the Medical College of Wisconsin. The study volunteers were initially identified from the TEP registry of the speech-language pathology section of the Department of Otolaryngology and Communication Sciences of the Medical College of Wisconsin. All patients used TEP prostheses from Atos Medical Inc (Hörby, Sweden). All consecutive laryngectomy patients were included in the study as they presented for routine TEP maintenance. Enrolled patients were interviewed for past evidence of LPR and/or GERD before and after laryngectomy (Table 1). Use of acid suppressive medication before and after surgery was also documented. Symptoms of LPR and GERD were judged on a scale from 0 (none) to 5 (severe) on the basis of average scores on survey analysis. Frequency of prosthesis changes and the presence of granulation, leakage, or prosthetic debris were noted. Detection of pepsin in tissues or fluid secretions is a relatively simple and noninvasive method to detect ongoing reflux events to extraesophageal structures.14 We hypothesize that many observed difficulties with TEP, such as frequent prosthesis changes or poor alaryngeal speech, may be associated with reflux of gastric contents to the TEP site. The purpose of this study was to evaluate the prevalence of reflux in patients who had undergone laryngectomy and TEP placement by analysis for pepsin in biopsy specimens from the TEP tract and secretions from METHODS Specimens. Biopsy specimens of the TEP tract were obtained along the tract with a 2-mm cup forceps (Fig 1) and placed in sterile saline solution until later analysis. Secretions were obtained by collecting fluid from around the TEP tract site into a small suction trap (No. 7419101, Medtronic Xomed, Jacksonville, Florida). Voice Analysis. Enrolled study participants had Bock et al, Analysis of Pepsin in Tracheoesophageal Puncture Sites 61 and secretion results and clinical parameters (GERD and LPR symptoms, current proton pump inhibitor therapy, gender, time since laryngectomy, history of radiotherapy) were compared by use of Fisher’s exact test. Associations between pepsin status and TEP change rate and complications were analyzed by use of Student’s t-test. Statistical significance was established at a p value of less than 0.05. RESULTS Fig 1. Tissue biopsy specimens were obtained from tracheoesophageal puncture (TEP) tract sites by use of 2-mm cup forceps at middle portion of tract. Associated secretions were collected in suction trap. their TEP voicing interpreted by an unblinded speech-language pathologist (M.K.B.), and overall voice quality was assessed by interpreting vocal fluency, mucoid wetness, strain, and breathiness to formulate an overall impression of TEP voice function (good, fair, poor). Western Blotting. Total protein was extracted from biopsy specimens and secretions from the TEP tract in urea lysis buffer,15 and protein content was measured by Bradford assay (No. 500-0006, BioRad, Hercules, California). We loaded 30 μg of total protein (less in the case of low-concentration specimens) on 10% sodium dodecyl sulfate–polyacrylamide gel electrophoresis gels according to standard protocol. Purified human pepsin 3b16 and human pepsinogen I (P1490, Sigma, St Louis, Missouri) were run alongside TEP samples as positive and negative controls, respectively. Proteins were transferred to polyvinylidene fluoride membrane (RPN2020F, GE Healthcare, Piscataway, New Jersey) and probed with rabbit antipepsin antibody (1:35014) and mouse anti-β-actin antibody (1:5000, No. CP01, EMD Chemicals, Gibbstown, New Jersey). Blots were then probed with appropriate peroxidase-conjugated secondary antibody diluted 1:5,000 (P0447/ P0448, Dako, Copenhagen, Denmark). All antibodies were diluted in phosphate-buffered saline solution, 0.1% Tween-20, and 5% nonfat dry milk. Blots were exposed to enhanced chemiluminescence reagents (sc-2048, Santa Cruz Biotechnology, Santa Cruz, California) and then submitted to radiographic exposure and development. Statistics. Associations between pepsin biopsy Seventeen patients who had undergone laryngectomy with TEP (ages 51 to 76 years; mean, 66 years; 12 male, 5 female) were enrolled in this study between September 2009 and January 2010 (Table 2). The average length of time since laryngectomy was 39 months (range, 6 to 129 months), and the length of time since TEP placement was 37.6 months (range, 6 to 121 months). The average time between prosthesis changes was 1.97 months (range, 0.5 to 4.8 months). Most patients (11 of 17, or 65%) had a TEP placed as a primary procedure, and the remainder had their TEP placed secondarily within 3 to 6 months after laryngectomy. Most patients (13 of 17, or 76%) had a history of irradiation during their cancer treatment. The most common reason for prosthesis change was leakage around the prosthesis. Voicing was judged as good in 13 patients, fair in 2 patients, and poor in 2 patients. All patients had biopsy specimens taken of tissue from the TEP tract. Seven of these biopsy specimens (41%) showed positive sodium dodecyl sulfate–polyacrylamide gel electrophoresis immunoblotting for the presence of pepsin (Fig 2A). Later in the study, we also collected a concurrent specimen of the associated secretions from the TEP tract as described above. Three patients had these secretions tested for pH, and all were found to have secretions of pH 6.5 to 7. Six of 7 TEP secretion specimens (85%) had positive immunoblot staining for the presence of pepsin (Fig 2B). One half of patients with secretions demonstrating pepsin also had biopsy specimens that were positive for pepsin. A total of 10 of 17 patients (59%) tested positive for pepsin in either the TEP tract biopsy specimen or secretions. Nine patients had prelaryngectomy symptoms suggestive of LPR (excessive mucus, globus sensation, acid taste), and these symptoms persisted in all 9 after laryngectomy, although there was a general trend toward decreased severity of LPR symptoms. Symptoms of GERD (including heartburn, chest pain, and indigestion) were present in 6 cases before laryngectomy, and all of these patients continued to note these problems after laryngectomy. Two patients who denied preoperative symptoms of 62 Bock et al, Analysis of Pepsin in Tracheoesophageal Puncture Sites TABLE 2. PATIENT DATA TL Pt Age Duration No. (y) Sex (mo) RT 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 52 F 87 – LPR Before TL Severe LPR After TL Mild GERD Before TL Average GERD PPI PPI TEP Pepsin Pepsin After Before After Change Voice in TEP in TEP TL TL TL Rate (mo) Quality Complications Biopsy Secretions Severe Severe Debris, – granulation, leakage 71 F 82 + Moderate Moderate – – + + 4.0 Poor Debris, + leakage 51 M 12 + Mild Mild – – – + 0.5 Good Debris, – + leakage 77 M 6 + Mild Moderate Mild Mild + + 1.0 Fair Leakage – 74 M 10 + Mild Moderate – – – + 0.6 Good Leakage + 51 F 11 + Severe Mild Severe Severe + + 1.2 Good Leakage + 74 F 39 + – – Severe Severe + + 1.8 Good Leakage – 73 M 31 + Severe Mild Severe Severe + + 1.6 Good Debris, – leakage 75 M 42 + – – – – – + 4.8 Poor Leakage – 66 M 85 + – – – Severe – + 1.7 Good Debris, + + leakage 76 M 129 – – – – – – + 1.0 Good None + 59 M 107 + – – – – – + 2.4 Good Debris, + + leakage 59 M 33 + – – – – – – 1.5 Good Debris, + + leakage 75 M 9 + – – – – – – 2.5 Fair Leakage – + 65 M 16 + – – – Moderate – – 1.8 Good Debris, – – leakage 67 M 42 – Mild Mild – – – – 4.2 Good Leakage – 52 F 121 – Severe Severe Severe Severe + + 1.7 Good Debris, – + granulation, leakage TL — total laryngectomy; RT — radiotherapy; LPR — laryngopharyngeal reflux; GERD — gastroesophageal reflux disease; PPI — proton pump inhibitor; TEP — tracheoesophageal puncture. GERD noted them after laryngectomy, leading to a total of 8 patients (47%) with postoperative symptoms of GERD. There was no statistical association between pepsin positivity of the tract biopsy specimen and current GERD symptoms (p = 0.18, Fisher exact test). Acid suppressive medications were commonly used in our study group, but were unrelated to + + 1.3 Good pepsin positivity of the tract biopsy (p = 0.4, Fisher exact test). No statistically significant associations between the presence of pepsin and the frequency of prosthesis changes, history of radiotherapy, or incidence of various TEP complications could be made on the basis of this limited observational patient series (p = 0.6, Student’s t-test). Fig 2. Western blotting data. Biopsy specimens and associated secretions from TEP tract were assayed for presence of pepsin by standard sodium dodecyl sulfate–polyacrylamide gel electrophoresis techniques. Proteins were separated by electrophoresis, transferred to nitrocellulose membranes, and probed for pepsin and β-actin. Purified human pepsinogen 1 and human pepsin were included as negative and positive immunoblotting controls, respectively. Representative TEP biopsy extracts are shown (TEP11 to TEP14) with range of signal strength, including one negative assay (TEP14) with strong β-actin signal. Representative TEP secretion assays are shown on right (TEP12S, TEP14S, and TEP15S), again showing range of intensity with negative sample (TEP15S). Bock et al, Analysis of Pepsin in Tracheoesophageal Puncture Sites DISCUSSION Both acidic and nonacidic elements of gastric refluxate, including pepsin, remain a therapeutic problem in many patients with reflux, and the TEP population is no exception. Current work with impedence technology is attempting to establish better normative data for reflux events in normal and pathological conditions,17 but the overall effect of digestive enzyme deposition on laryngeal tissues is still an area of active research. Pepsin is a proteolytic enzyme produced only by the mucosa of the stomach, and detection of this protein outside the stomach provides evidence of ongoing reflux of stomach contents.18 We have previously identified that esophageal mucosa does not significantly uptake pepsin, even in patients with pH-probe–proven LPR, whereas laryngeal mucosa seems much more sensitive to pepsin uptake.19 Identification of pepsin in the TEP tract and associated secretions therefore suggests the presence of reflux episodes into the upper esophagus in our study subjects, and our data support the use of pepsin analysis of TEP biopsy specimens and secretions for detection of ongoing reflux to the TEP site. It is unclear whether secretion testing alone is sufficient to predict the possible detrimental tissue effects from pepsin at this time; however, the noninvasive nature of secretion testing is favorable for clinical use. Studies to evaluate the mechanism of pepsin uptake into tissues of the larynx and esophagus are necessary to clarify the effect of pepsin in secretions on the adjacent tissues. Pepsin uptake appears to be tissue-specific, and is seen in the esophagus and larynx of patients with LPR, but is not present in nasopharyngeal or palatine tonsil biopsy specimens. Patients with LPR also often have pepsin present in nasopharyngeal secretions despite negative nasopharyngeal tissue biopsies (N. Johnston, unpublished data). Pepsin assays hold significant promise for detecting reflux, and noninvasive testing for pepsin may become more widely accepted in the future.18 There are no commercial methods for testing for the presence of pepsin in oropharyngeal or esophageal secretions at this time, but such products are in development and promise to greatly enhance the care of patients with refluxassociated disorders. The management of nonacidic reflux is incompletely addressed with currently available treatments. Antireflux surgery, including Nissen fundoplication, is likely the best option at present for total control of esophageal reflux. Studies have shown good control of extraesophageal symptoms from reflux in carefully selected patients known to have LPR20; however, the invasive nature of this intervention always requires careful consideration. Few studies have in- 63 vestigated the role of fundoplication in the control of reflux after laryngectomy. Jobe et al21 published a series of 9 patients with laryngectomy and TEP who were treated with fundoplication for known reflux, and described severe problems with bloating and hyperflatulence after fundoplication in this cohort. Given these surgical challenges, improved medical treatment protocols would be of great benefit to these patients. Liquid alginate suspension is an effective antireflux medication that is currently available in Europe (Gaviscon Advance, Reckitt Benckiser Healthcare, Kingston-Upon-Thames, England) and holds great promise as a potential treatment for both acidic and nonacidic reflux.22 It is a well-tolerated mucosal protectant with minimal side effects as compared to acid suppressive therapy.23 Other options for treatment could include gastric prokinetic agents such as metaclopramide or erythromycin, although long-term use of these agents in patients with reflux remains controversial.24 Just over half of the patients in our study had symptomatic complaints of LPR before the diagnosis of laryngeal cancer, and all of these patients continued to have pharyngeal symptoms of reflux after laryngectomy, including globus sensation, excessive mucus, and throat irritation. A third of patients had persistent symptoms of GERD after surgery. There was a mixed association between GERD and LPR symptoms and the presence of pepsin in the TEP tract. The majority of the TEP patients studied in this protocol were treated with acid suppression medications, including 8 of the 10 patients who had positive results for pepsin. The usual problems of granulation, leakage, prosthetic debris, contamination, and the need for frequent prosthesis changes were also apparent in this patient population. The majority of the patients included in this study had a frequent need for prosthetic change (average, 1.97 months), and perhaps this study was biased to those with more severe or ongoing issues related to TEP speech and a heightened risk of LPR. Nearly all patients in this study had some degree of complications from TEP placement. However, only 2 of the 17 patients in our cohort had TEP voicing problems that were significant enough to be noted by others. One of these patients was noted to have pepsin in the TEP tract with multiple associated TEP complications, but the other did not have pepsin present and had minimal complications. These data provide some further support for the recommendation that TEP patients should be routinely treated with acid suppression medications.13 The effects of laryngectomy and reflux on the overall function of the digestive tract remain unclear at this time, and many potential questions arise in 64 Bock et al, Analysis of Pepsin in Tracheoesophageal Puncture Sites considering this issue. Laryngectomy is known to cause increased esophageal transit time, decreased esophageal contraction strength, altered proximal esophageal contraction, and deranged upper esophageal sphincter opening.25 The effects of laryngectomy on the function of the lower esophageal sphincter are less clear. The direct effect of regurgitation of gastric juices into the larynx is a well-known entity, but is there an added reflex, likely via the vagus nerve or autonomic nervous system, that promotes reflux through the lower esophageal sphincter.26 Does laryngectomy alter lower esophageal sphincter function via derangement of this vagal pathway once the superior and recurrent laryngeal nerves are transected? Few studies have directly addressed these questions, but some data exist to show that function of the lower esophageal sphincter remains intact after laryngectomy or laryngeal irradiation.27,28 The ultimate alteration of the larynge- al function and physiology occurs with total laryngectomy, and evidence indicates that laryngectomy may prolong or extend the impact of preoperative reflux symptoms.21,25,29,30 The role that laryngectomy plays in altering esophageal physiology and subsequent reflux warrants continued study. In conclusion, we demonstrated in this observational study that pepsin is present in the TEP tract tissues or secretions of more than half (10 of 17, or 58%) of laryngectomy patients, suggesting that a majority of these patients have ongoing reflux. Acid suppression appears to have little impact on the presence of pepsin in the secretions and tissues of the TEP tract of laryngectomy patients. Our data suggest that further studies are warranted of the impact of pepsin and reflux on the mucosal health and function of the extraesophageal tissues in patients who have undergone TEP and laryngectomy. REFERENCES 1. Montgomery WW, Toohill RJ. Voice rehabilitation after laryngectomy. Arch Otolaryngol 1968;88:499-506. 2. Asai R. Asai’s new voice production method: a substitution for human speech. In: Proceedings of the 8th International Congress of Otorhinolaryngology, Tokyo, Japan, 1965. 3. Miller AH. First experiences with the Asai technique for vocal rehabilitation after total laryngectomy. Ann Otol Rhinol Laryngol 1967;76:829-33. 4. Singer MI, Blom ED. An endoscopic technique for restoration of voice after laryngectomy. Ann Otol Rhinol Laryngol 1980;89:529-33. 5. Ferrer Ramírez MJ, Guallart Doménech F, Brotons Durbán S, Carrasco Llatas M, Estellés Ferriol E, López Martínez R. Surgical voice restoration after total laryngectomy: long-term results. Eur Arch Otorhinolaryngol 2001;258:463-6. 6. Glanz H, Kleinsasser O. Chronic laryngitis and carcinoma [in German]. Arch Otorhinolaryngol 1976;212:57-75. 7. Ward PH, Hanson DG. Reflux as an etiological factor of carcinoma of the laryngopharynx. Laryngoscope 1988;98:11959. 8. Morrison MD. Is chronic gastroesophageal reflux a causative factor in glottic carcinoma? Otolaryngol Head Neck Surg 1988;99:370-3. 9. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991;101(suppl 53):1-78. 10. Freije JE, Beatty TW, Campbell BH, Woodson BT, Schultz CJ, Toohill RJ. Carcinoma of the larynx in patients with gastroesophageal reflux. Am J Otolaryngol 1996;17:386-90. 11. Biacabe B, Gleich LL, Laccourreye O, Hartl DM, Bouchoucha M, Brasnu D. Silent gastroesophageal reflux disease in patients with pharyngolaryngeal cancer: further results. Head Neck 1998;20:510-4. 12. Copper MP, Smit CF, Stanojcic LD, Devriese PP, Schou- wenburg PF, Mathus-Vliegen LM. High incidence of laryngopharyngeal reflux in patients with head and neck cancer. Laryngoscope 2000;110:1007-11. 13. Pattani KM, Morgan M, Nathan CO. Reflux as a cause of tracheoesophageal puncture failure. Laryngoscope 2009;119: 121-5. 14. Johnston N, Knight J, Dettmar PW, Lively MO, Koufman J. Pepsin and carbonic anhydrase isoenzyme III as diagnostic markers for laryngopharyngeal reflux disease. Laryngoscope 2004;114:2129-34. 15. Axford SE, Sharp N, Ross PE, et al. Cell biology of laryngeal epithelial defenses in health and disease: preliminary studies. Ann Otol Rhinol Laryngol 2001;110:1099-108. 16. Crapko M, Kerschner JE, Syring M, Johnston N. Role of extra-esophageal reflux in chronic otitis media with effusion. Laryngoscope 2007;117:1419-23. 17. Savarino E, Tutuian R, Zentilin P, et al. Characteristics of reflux episodes and symptom association in patients with erosive esophagitis and nonerosive reflux disease: study using combined impedance–pH off therapy. Am J Gastroenterol 2010; 105:1053-61. 18. Samuels TL, Johnston N. Pepsin as a marker of extraesophageal reflux. Ann Otol Rhinol Laryngol 2010;119:203-8. 19. Johnston N, Dettmar PW, Lively MO, et al. Effect of pepsin on laryngeal stress protein (Sep70, Sep53, and Hsp70) response: role in laryngopharyngeal reflux disease. Ann Otol Rhinol Laryngol 2006;115:47-58. 20. Catania RA, Kavic SM, Roth JS, et al. Laparoscopic Nissen fundoplication effectively relieves symptoms in patients with laryngopharyngeal reflux. J Gastrointest Surg 2007;11:157988. 21. Jobe BA, Rosenthal E, Weisberg TT, et al. Surgical management of gastroesophageal reflux and outcome after laryngectomy in patients using tracheoesophageal speech. Am J Surg 2002;183:539-43. 22. McGlashan JA, Johnstone LM, Sykes J, Strugala V, Dettmar PW. The value of a liquid alginate suspension (Gaviscon Bock et al, Analysis of Pepsin in Tracheoesophageal Puncture Sites Advance) in the management of laryngopharyngeal reflux. Eur Arch Otorhinolaryngol 2009;266:243-51. 23. Hampson FC, Jolliffe IG, Bakhtyari A, et al. Alginateantacid combinations: raft formation and gastric retention studies. Drug Dev Ind Pharm 2010;36:614-23. 24. Emerenziani S, Sifrim D. Gastroesophageal reflux and gastric emptying, revisited. Curr Gastroenterol Rep 2005;7:1905. 25. Choi EC, Hong WP, Kim CB, et al. Changes of esophageal motility after total laryngectomy. Otolaryngol Head Neck Surg 2003;128:691-9. 26. Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med 1997;336:924-32. 65 27. Dantas RO, Aguiar-Ricz LN, Oliveira EC, Mello-Filho FV, Mamede RC. Influence of esophageal motility on esophageal speech of laryngectomized patients. Dysphagia 2002;17:121-5. 28. Gaze MN, Wilson JA, Gilmour HM, MacDougall RH, Maran AG. The effect of laryngeal irradiation on pharyngoesophageal motility. Int J Radiat Oncol Biol Phys 1991;21:131520. 29. Welch RW, Luckmann K, Ricks PM, Drake ST, Gates GA. Manometry of the normal upper esophageal sphincter and its alterations in laryngectomy. J Clin Invest 1979;63:1036-41. 30. Gerwin JM, Culton GL, Gerwin KS. Hiatal hernia and reflux complicating prosthetic speech. Am J Otolaryngol 1997;18: 66-8. Low-Acid Diet for Recalcitrant Laryngopharyngeal Reflux: Therapeutic Benefits and Their Implications Jamie A. Koufman, MD Objectives: Laryngopharyngeal reflux (LPR) is an expensive, high-prevalence disease with a high rate of medical treatment failure. In the past, it was mistakenly believed that pepsin was inactive above pH 4; however, human pepsin has been reported to be active up to pH 6.5. In addition, it has been shown by Western blot analysis that laryngeal biopsy samples from patients with symptomatic LPR have tissue-bound pepsin. The clinical impact of a low-acid diet on the therapeutic outcome in LPR has not been previously reported. To provide data on the therapeutic benefit of a strict, virtually acid-free diet on patients with recalcitrant, proton pump inhibitor (PPI)–resistant LPR, I performed a prospective study of 20 patients who had persistent LPR symptoms despite use of twice-daily PPIs and an H2-receptor antagonist at bedtime. Methods: The reflux symptom index (RSI) score and the reflux finding score (RFS) were determined before and after implementation of the low-acid diet, in which all foods and beverages at less than pH 5 were eliminated for a minimum 2-week period. The subjects were individually counseled, and a printed list of acceptable foods and beverages was provided. Results: There were 12 male and 8 female study subjects with a mean age of 54.3 years (range, 24 to 72 years). The symptoms in 19 of the 20 subjects (95%) improved, and 3 subjects became completely asymptomatic. The mean pre-diet RSI score was 14.9, and the mean post-diet RSI score was 8.6 (p = 0.020). The mean pre-diet RFS was 12.0, and the mean post-diet RFS was 8.3 (p < 0.001). Conclusions: A strict low-acid diet appears to have beneficial effects on the symptoms and findings of recalcitrant (PPIresistant) LPR. Further study is needed to assess the optimal duration of dietary acid restriction and to assess the potential role of a low-acid diet as a primary treatment for LPR. This study has implications for understanding the pathogenesis, cell biology, and epidemiology of reflux disease. Key Words: acid reflux, adenocarcinoma, antireflux, Barrett’s esophagus, chronic cough, diet, esophageal cancer, gastroesophageal reflux disease, heartburn, hoarseness, laryngopharyngeal reflux, low acid, low fat, pepsin, proton pump inhibitor. jury — and it is peptic (not acid) injury.1,5,8,9,11-17 (Pepsin does, however, require some acid for activation.) We previously showed that 19 of 20 patients (95%) with clinical and pH-documented LPR had tissue-bound pepsin identifiable by Western blot analysis, as opposed to only 1 of 20 control subjects (5%).9 In addition, peptic injury is associated with depletion of key protective proteins, including carbonic anhydrase, E-cadherin, and most of the stress proteins.5,8,9,11-15 INTRODUCTION Laryngopharyngeal reflux (LPR) is a controversial, high-prevalence disease, and it differs from classic gastroesophageal reflux disease (GERD) in many ways.1-10 Typically, patients with LPR have daytime (upright) reflux without having heartburn or esophagitis.1-3 In addition, one of the most important differences between LPR and GERD is that the threshold for laryngeal tissue damage is much lower than that for the esophagus.1,5,8 As many as 50 reflux episodes (less than pH 4) per day are considered normal for the esophagus, whereas as few as 3 reflux episodes per week are too many for the larynx.1 Equally important in understanding the biology of LPR is consideration for the stability and spectrum of activity of human pepsin.14 In the past, it was mistakenly believed that pepsin was inactive above pH 4.1 The early experiments on which that result was based were performed with porcine pepsin, and not human pepsin. Indeed, pig pepsin is inactive at greater than pH 4; however, human pepsin retains some of its proteolytic activity up to pH 6.5, THERAPEUTIC IMPLICATIONS OF CELL BIOLOGY OF LPR The cell biology of LPR holds the key to understanding the susceptibility of the larynx to peptic in- From the Voice Institute of New York, New York, NY. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Jamie A. Koufman, MD, Voice Institute of New York, 200 W 57th St, Suite 1203, New York, NY 10019. 66 Koufman, Low-Acid Diet for Laryngopharyngeal Reflux 67 TABLE 1. TRADITIONAL ANTIREFLUX DIET AND LIFESTYLE MODIFICATION PROGRAM Human pepsin activity curve. (Data from Johnston et al.14) depending on the substrate.14 The pepsin activity curve is shown in the Figure.14 Peak peptic activity (100%) occurs at pH 2, but there is still some (10%) activity at pH 6.14 In other words, clinical disease (LPR) is associated with tissue-bound pepsin,9 and laryngeal damage occurs at pH 5.0 or less.8 CLINICAL CONSIDERATIONS For more than 25 years, LPR was diagnosed in my practice by the symptoms and findings of LPR and by ambulatory 24-hour (simultaneous pharyngeal and esophageal) pH monitoring.1-3,7 Treatment for moderate to severe LPR was typically twice-daily proton pump inhibitors (PPIs) with an H2-receptor antagonist at bedtime and an antireflux dietary and lifestyle modification program (Table 1). There was some customization of the conventional antireflux protocol, eg, one cup of coffee a day, no citrus, no carbonated beverages. We have long recognized that some patients who drank excessive amounts of carbonated beverages might gain control of their LPR simply by eliminating those beverages. Indeed, carbonated beverage consumption is one of the most common identifiable causes of medical treatment failure in LPR. With our 2007 study14 showing peptic activity up to pH 6.5, and having previously found (by immunohistochemical analysis) pepsin within the tissue biopsy specimens of patients with LPR,9 we recognized that tissue-bound pepsin in these patients might be activated by exogenous hydrogen ions from any source, including dietary ones. Consequently, in 2008 we began measuring the pH of common foods and beverages and restricting patients with LPR from consuming anything below pH 5 for a trial period of 2 weeks. To our surprise, this appeared to have outstanding therapeutic benefits for many patients. In the ensuing few years, we continued to refine If you use tobacco, quit, because smoking causes reflux. Do not wear clothing that is too tight, especially trousers, corsets, and belts. Avoid exercising, especially weight-lifting, swimming, jogging, and yoga, after eating. Do not lie down after eating; do not eat within 3 hours of bedtime. Elevate the head of your bed if you have nighttime reflux (hoarseness, sore throat, and/or cough in the morning). Limit your intake of red meat, butter, cheese, eggs, and anything with caffeine. Completely avoid fried food, high-fat meats, onions, tomatoes, citrus fruit or juice, carbonated beverages (soda), beer, hard liquor, wine, mints, and chocolate. this induction reflux diet to exclude all recognized reflux trigger foods, as well as anything that we identified to be acidic (below pH 5). Eggs and red apples, for example, used to be on the induction diet, but we found that those foods caused problems for some of our patients, so they were removed. Thus, the approved foods and beverages list for the induction reflux diet evolved to its present form (Table 2). MATERIALS AND METHODS All of my adult patients with pH-documented LPR on “maximum” antireflux therapy (twice-daily PPIs with an H2-receptor antagonist at night) were eligible for the study if they were failing to improve on medical treatment and did not have potentially life-threatening manifestations of LPR. Specifically excluded were patients with airway stenosis, laryngeal neoplasia, and/or pulmonary disease. Medical treatment failure was defined as no improvement in symptoms — according to a validated outcomes measure, the reflux symptom index (RSI)18,19 — on office visits at least 2 months apart. Incidentally, it has been my routine practice for the past 25 years to have all patients complete the RSI at every visit. Before inclusion in the low-acid diet study, patients were offered other alternatives such as changing their antireflux medications or evaluation for antireflux surgery. If the low-acid reflux diet was elected (Table 2), patients had to agree to be compliant with the conditions of the diet, which was very restrictive (nothing below pH 5). For example, the diet allows no fruit except bananas and melons. Patients were counseled about what they could and could not eat and were provided with a handout that explained the purpose of the diet and its scientific basis, as well as a list of foods and beverages that were allowed. Study subjects were instructed to eat only from the list of the items in Table 2 for 2 weeks 68 Koufman, Low-Acid Diet for Laryngopharyngeal Reflux TABLE 2. INDUCTION REFLUX DIET Agave Aloe vera Artificial sweetener (maximum 2 teaspoons per day) Bagels and (non-fruit) low-fat muffins Banana (great snack food) Beans (black, red, lima, lentils, etc) Bread (especially whole grain and rye) Caramel (maximum 4 tablespoons per week) Celery (great snack food) Chamomile tea (most other herbal teas are not acceptable) Chicken (grilled, broiled, baked, or steamed; no skin) Chicken stock or bouillon Coffee (maximum 1 cup per day; best with milk) Egg whites Fennel Fish (grilled, broiled, baked, or steamed) Ginger (ginger root, powdered, or preserved) Graham crackers Herbs (excluding all peppers, citrus, garlic, and mustard) Honey Melon (honeydew, cantaloupe, watermelon) Mushrooms (raw or cooked) Oatmeal (all whole-grain cereals) Olive oil (maximum 2 tablespoons per day) Parsley Pasta (with nonacidic sauce) Popcorn (plain or salted, no butter) Potatoes (all of the root vegetables except onions) Rice (healthy, especially brown rice, a staple during induction) Skim milk (alternatively, soy or Lactaid skim milk) Soups (great homemade with noodles and vegetables) Tofu Turkey breast (organic, no skin) Turnip Vegetables (raw or cooked, but no onion, tomato, or peppers) Vinaigrette (maximum 1 tablespoon per day; toss salads) Whole-grain breads, crackers, and breakfast cereals or until the first follow-up visit thereafter. I performed a laryngeal examination with each office visit, as is the routine for management of LPR. The reflux finding score (RFS)20 was calculated for each patient for each visit; however, for this study, it was not blinded, as it was anticipated that there would be no significant change in the RFS. We have previously reported that the laryngeal findings of LPR do not usually change as quickly as the symptoms.19 (I never expected the degree of improvement in the RFS that was found.) For statistical analysis I used Students’ t-test for the pre-diet and post-diet RSI and RFS data. Institutional Review Board approval was not sought for this study, as it was deemed unnecessary because 1) the strict, low-acid, induction reflux diet carried no risk of harm; 2) the diet was a logical extension of the traditional antireflux diet; 3) alternative therapeutic alternatives were neither denied nor precluded; and 4) there was no risk of violation of patient confidentiality, as no one but the author had access to the study data. RESULTS There were 12 male and 8 female subjects with a mean age of 54.3 years (range, 24 to 72 years). All of the study subjects claimed complete compliance with the prescribed diet. Nineteen of the 20 subjects (95%) improved on the low-acid diet, and 1 got worse. Three subjects became completely asymptomatic, and another went from an initial RSI score of 28 to a post-diet RSI score of 4. The mean prediet RSI score was 14.9, and the mean post-diet RSI score was 8.6 (p = 0.020); the mean RSI improvement was 6.3. The mean pre-diet RFS was 12.0, and the mean post-diet RFS was 8.3 (p < 0.001). The data are shown in Table 3. DISCUSSION In 1981, I was emergently consulted to see a patient with airway obstruction. Portable endoscope in hand, I rushed to the hospital to see a stridulous patient. She calmly pointed to her throat and gasped, “Can’t breathe…acid reflux.” After a quick bedside endoscopy, I took her to the operating room and removed the two largest obstructing vocal process granulomas that I have ever seen before or since. The patient was placed on a postoperative regimen of high-dose cimetidine, head-of-bed elevation, and a restricted diet: no fried food, no coffee, no tomatoes, onions, garlic, cheese, chocolate, or mints, as well as no late eating. Under that treatment, the patient got well. She was my introduction to LPR. In the 30 years since, reflux medications have evolved, and now many patients with LPR are started on “maximal antireflux treatment” consisting of twice-daily PPIs (before breakfast and before the evening meal) and an H2-receptor antagonist at bedtime.21 Although this regimen results in better acid suppression than did previous medical therapy, there is still a significant rate of medical treatment failure (10% to 17%).22,23 It is presumed that PPI failure is due to a “bioavailability” problem (ie, poor drug absorption).22 More than a decade ago, we recognized that carbonated beverages, particularly caffeinated cola drinks, were a major risk factor for LPR. Indeed, excessive consumption of carbonated beverages was the single most commonly identified cause of medical treatment failure among our patients with LPR. Koufman, Low-Acid Diet for Laryngopharyngeal Reflux 69 TABLE 3. RESULTS Subject Age (y) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Mean 29 70 72 53 61 41 62 57 82 33 65 52 63 60 60 59 52 24 39 52 54.3 Sex F F F M M M M M F M M F M M F M F M M F Reflux Symptom Index Score Before After Diet Diet Change 28 4 10 10 29 18 20 1 2 12 27 21 13 7 7 19 21 22 15 12 14.9 On the basis of clinical experience, we also limited our patients’ intake of citrus fruits and hot (pepper) sauces. Other than these few specifics, the antireflux diet has not changed much over the years — that is, until recently. In 2008, we began measuring the pH of common foods and beverages, and as a consequence of finding acid in almost everything we tested, we began to limit the acid intakes of our patients with LPR, with surprisingly good results. The clinical results reported herein are particularly striking and significant because “maximum antireflux therapy” was failing in the study patients. In the months since this paper was presented, many additional patients with LPR have been treated with a low-fat, low-acid diet as the cornerstone of therapy, with or without adjunctive antireflux medications. The induction reflux diet is still recommended for the first 2 to 4 weeks with a gradual reintroduction of some fatty foods and other historically “refluxogenic” foods. Cheese, eggs, meats, sauces, and condiments are allowed in moderation, but the key elements of the maintenance reflux diet are that it remains relatively low in acids and low in fat. With fatty foods in particular, we teach patients moderation, and to use tasty fats as flavorings, not as main ingredients. We also introduce the concept of pH balancing. The idea is that acidic foods may be combined with nonacidic foods. Strawberries, for example, which are not allowed to be eaten by 4 3 0 8 35 15 8 0 0 10 16 12 7 4 3 7 16 9 8 7 8.6 24 1 10 2 –6 3 12 1 2 2 11 9 6 3 4 12 5 13 7 5 6.3 Reflux Finding Score Before After Diet Diet 13 12 10 10 12 13 11 10 14 14 16 14 9 9 12 11 14 12 12 12 12.0 8 5 0 9 12 10 9 4 9 11 11 9 5 9 11 10 11 11 8 4 8.3 themselves on the reflux diet, are permitted when added to breakfast cereal with milk, preferably lowfat milk, which has a high pH. In other words, the cereal and milk buffer the acidic fruit; ie, they pHbalance the dish. It is important to recognize that these ideas and their practical applications in clinical practice have evolved over a period of many years. By reporting a series of worst-case, PPI-resistant patients who had successful outcomes with a strict low-acid diet, it is my hope to stimulate interdisciplinary research in the areas of reflux, nutrition, and the American diet. Indeed, the contemporary American diet appears to be making Americans sick. SCIENTIFIC BASIS FOR DIETARY ACID RESTRICTION IN REFLUX MANAGEMENT Despite the popular use of the term “acid reflux” among the lay public, most of the clinical manifestations of LPR and GERD are due to pepsin.1-3,5,7-9,11-17 Pepsin is responsible for tissue injury and inflammation, and the confusion stems from the fact that pepsin requires acid activation.1,14 The pepsin activity profile (see Figure), the cell biology of LPR, and clinical experience with pharyngeal pH monitoring all suggest that the threshold of the larynx for peptic injury is far less than that of the esophagus.1,8,11-17 Surprisingly little acid is needed for peptic activation, and pepsin remains mildly proteolytic up to pH 6.5.14 In addition, tissue-bound pepsin can be acti- 70 Koufman, Low-Acid Diet for Laryngopharyngeal Reflux vated by hydrogen ions from any (including a dietary) source.14 It appears that the key to the development of clinical laryngeal disease is the presence of tissue-bound pepsin,8,9 which causes depletion of protective cell proteins such as carbonic anhydrase, E-cadherin, and the stress (“heat-shock”) proteins.8,9,12,13 Johnston et al8 demonstrated (in vitro and in vivo) that peptic laryngeal damage occurs at pH 5. It was basic science that led us to consider the possibility that the contemporary reflux epidemic might be related to the contemporary American diet. INCREASING PREVALENCE OF REFLUX DISEASE AND REFLUX-RELATED ESOPHAGEAL CANCER The prevalence of acid reflux disease (GERD and LPR) has increased dramatically in our lifetimes.24,25 Using a Poisson model and an analysis of 17 prevalence studies, El-Serag24 showed that since 1976, the mean rate of increase of GERD has been a staggering 4% per year (p < 0.0001). Altman et al25 reported that office visits to otolaryngologists for LPR increased almost 500% from 1990 to 2001. Those authors hypothesized that the increase was due to obesity and a greater awareness of LPR by otolaryngologists25; however, reportedly, only 27% of the study patients were counseled about an antireflux diet.25 An even more ominous trend is the skyrocketing increase in the prevalence of esophageal cancer in the United States.26-30 The US National Cancer Institute data from 2005 reveal that esophageal cancer had increased 600% since 1975 (from 4 to 23 cases per million).26 During this same period, its mortality rate increased sevenfold, despite increased esophageal surveillance26,27; the histopathology has been trending toward more deadly, poorly differentiated adenocarcinomas.27,28 In addition, the prevalence of Barrett’s esophagus (a reflux-related precursor to esophageal cancer) is also very high.27-30 Reavis et al29 reported that patients with hoarseness, sore throat, and chronic cough (LPR symptoms) had Barrett’s esophagus just as frequently (7% to 10%) as did patients with GERD and heartburn. Thus, routine esophageal screening for both LPR and GERD was (and still is) recommended.29,30 INCREASED PREVALENCE OF REFLUX IN YOUNG PATIENTS In 2010, we estimated the prevalence of reflux (GERD and LPR) in the United States by interviewing 656 adult US citizens while they were waiting in line to purchase discount theater tickets in Times Square in New York City. (This specific location appeared to provide us with a reasonable approximation of a national sample.) The interviews were carefully conducted to elicit all reflux symptoms and medications, both over-the-counter and physician-prescribed. Respondents were considered to have a tendency to reflux if they had multiple reflux symptoms and/or took reflux medications. For the purposes of this survey, respondents with only one symptom, such as hoarseness or cough, were not considered to have reflux, as one symptom may have many different causes. The data revealed that an astonishing 40% (262 of 656) of the study group had reflux disease, with 22% (144 of 656) having classic GERD and another 18% (118 of 656) having LPR. There were no statistical differences between age groups, genders, and regions of the country. The most striking and unanticipated result was that 37% of the 21- to 30-yearold age group had reflux. In the past, reflux was primarily a disease of overweight, middle-aged people. Now, we are finding that many of our reflux patients are neither old nor obese.10 This trend toward younger and younger patients with more and more severe reflux has been noted by other experienced clinicians (J. Hunter and R. Sataloff, personal communications, 2011). CHANGES IN AMERICAN DIET IN PAST FIFTY YEARS Coincident with the reflux epidemic, the American diet has changed dramatically.31-36 Since the 1960s, there have been four parallel unhealthy dietary trends: 1) increased saturated fat; 2) increased high-fructose corn syrup; 3) increased exposure to organic pollutants (eg, DDT, PCBs, dioxins); and 4) increased acidity.33-35 The last of these trends — increased dietary acid — may hold the key to understanding the contemporary reflux epidemic and the dramatic increases in Barrett’s esophagus and esophageal cancer.29,33,34 In 1973, after an outbreak of food poisoning (botulism), the US Congress enacted Title 21, mandating that the US Food and Drug Administration (FDA) ensure the safety of processed food crossing state lines by establishing “Good Manufacturing Practices.”33,34 How was this accomplished? Through acidification of bottled and canned foods, which was intended to prevent bacterial growth and prolong shelf life. For two generations, the FDA has never wavered from this path, apparently without ever considering the possibility that the acidification of America’s food supply might have potential adverse health consequences. From the 1979 Title 21 Act34: Acidified foods should be so manufactured, processed, and packaged that a finished equilibrium pH value of 4.6 Koufman, Low-Acid Diet for Laryngopharyngeal Reflux or lower is achieved. If the finished equilibrium pH is 4.0 or below, then the measurement of acidity of the final product may be made by any suitable method. [April 1, 2002; US Government Printing Office, 21CFR114.80] In other words, the FDA actually encourages food manufacturers to reduce the pH of their products to less than 4.0, the same pH level as stomach acid.1 In addition to acetic, ascorbic, citric, and hydrochloric acids as food additives, the FDA allows more than 300 other chemicals that are “generally regarded as safe” (GRAS).33-36 Many of these GRAS food additives were approved in the 1970s without the benefit of contemporary methods of scientific testing and analysis.34,36 Furthermore, in 1997, the FDA was directed to provide specific criteria for food manufacturers to report their use of GRAS additives in their products; inexplicably, as of this writing, those criteria have still not been established.36 Thus, with regard to food additives, the food industry remains completely self-regulated.33,36 In 2010, the US Government Accountability Office, a bipartisan group of scientists, published a scathing report on the FDA’s lack of oversight of food manufacturing.36 In particular, they were critical of the FDA’s negligence in failing to monitor GRAS food additives, as referenced above.33-35 In searching the literature, it appears that neither the FDA nor the scientific community have examined the acidity question. No one, it appears, has considered the possibility that the acidification of the nation’s food might have potentially adverse health consequences; today, almost all food that is bottled or canned is below pH 4.33 It is interesting to note that the Amish, who grow and consume their own organic food, have aerodigestive tract cancer rates (eg, larynx, pharynx, esophagus) that are only 37% the rates of controls.37 In attempting to explain those findings, the authors emphasized that the Amish do not drink alcohol or smoke tobacco, but they did not discuss or consider the possible health benefits of a diet devoid of acids and other food additives.37 DIETARY ACID AS POSSIBLE MISSING LINK IN REFLUX EPIDEMIC Why are reflux disease and esophageal cancer epidemic? Many years ago, when esophageal can- 71 cer was relatively uncommon, reflux patients usually presented in middle age. Today, we are seeing comparable disease in patients in their twenties (J. Hunter and R. Sataloff, personal communications, 2011). Overacidity in the diet may be the missing link that explains the reflux epidemic, as well as increasing rates of Barrett’s esophagus and esophageal cancer. At present, even baby food is acidified. We tested the acidity of an “organic” banana baby food and found it to be pH 4.3; normally, banana is pH 5.7. The label of the so-called “organic” banana product revealed that it had had both ascorbic and citric acids added. Indeed, almost all bottled and canned foods and beverages contain ascorbic acid and/or citric acid; sometimes the packaging is less obvious and may just read “vitamin C–enriched” or “vitamin C–enhanced.”33 Knowing what we now know about the cell biology of reflux, the stability and activity of pepsin, and the contemporary American diet, it is reasonable to postulate that the acidification of America’s food supply may be responsible for the reflux epidemic. Diet may be the primary factor in the prevalence, mechanisms, manifestations (including neoplasia), and outcomes of reflux disease, particularly as it affects the laryngopharynx and esophagus. Further research is needed to investigate this question. Until now, it appears that fundamental nutritional issues related to how food has been preserved for the past two generations may have been overlooked. Dietary acid may turn out to have serious adverse health effects on the general population, and how food is preserved may soon become a perplexing public health conundrum. In the meanwhile, it seems likely that patients with LPR will benefit from a low-acid diet. CONCLUSIONS A strict low-acid (“acid-free”) diet appears to be beneficial for patients with pH-documented LPR. In this study, the diet was shown to improve both the symptoms and the laryngeal findings of patients with recalcitrant (PPI-resistant) LPR. Also raised by this study are broader public health policy issues related to FDA-mandated acidification of manufactured foods and beverages. REFERENCES 1. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991;101 (suppl 53):1-78. 2. Koufman JA. Perspective on laryngopharyngeal reflux: from silence to omnipresence. In: Branski R, Sulica L, eds. Classics in voice and laryngology. San Diego, Calif: Plural Publishing, 2009:179-266. 3. Koufman JA, Wiener GJ, Wu WC, Castell DO. Reflux 72 Koufman, Low-Acid Diet for Laryngopharyngeal Reflux laryngitis and its sequelae: the diagnostic role of 24-hour pH monitoring. J Voice 1988;2:78-9. 4. Postma GN, Tomek MS, Belafsky PC, Koufman JA. Esophageal motor function in laryngopharyngeal reflux is superior to that of classic gastroesophageal reflux disease. Ann Otol Rhinol Laryngol 2001;110:1114-6. 5. Axford SE, Sharp S, Ross PE, et al. Cell biology of laryngeal epithelial defenses in health and disease: preliminary studies. Ann Otol Rhinol Laryngol 2001;110:1099-108. 6. Amin MR, Postma GN, Johnson P, Digges N, Koufman JA. Proton pump inhibitor resistance in the treatment of laryngopharyngeal reflux. Otolaryngol Head Neck Surg 2001;125:3748. 7. Koufman JA, Belafsky PC, Bach KK, Daniel E, Postma GN. Prevalence of esophagitis in patients with pH-documented laryngopharyngeal reflux. Laryngoscope 2002;112:1606-9. 8. Johnston N, Bulmer D, Gill GA, et al. Cell biology of laryngeal epithelial defenses in health and disease: further studies. Ann Otol Rhinol Laryngol 2003;112:481-91. 9. Johnston N, Knight J, Dettmar PW, Lively MO, Koufman J. Pepsin and carbonic anhydrase isoenzyme III as diagnostic markers for laryngopharyngeal reflux disease. Laryngoscope 2004;114:2129-34. 10. Halum SL, Postma GN, Johnston C, Belafsky PC, Koufman JA. Patients with isolated laryngopharyngeal reflux are not obese. Laryngoscope 2005;115:1042-5. 11. Knight J, Lively MO, Johnston N, Dettmar PW, Koufman JA. Sensitive pepsin immunoassay for detection of laryngopharyngeal reflux. Laryngoscope 2005;115:1473-8. 12. Gill GA, Johnston N, Buda A, et al. Laryngeal epithelial defenses against laryngopharyngeal reflux: investigations of Ecadherin, carbonic anhydrase isoenzyme III, and pepsin. Ann Otol Rhinol Laryngol 2005;114:913-21. 13. Johnston N, Dettmar PW, Lively MO, et al. Effect of pepsin on laryngeal stress protein (Sep70, Sep53, and Hsp70) response: role in laryngopharyngeal reflux disease. Ann Otol Rhinol Laryngol 2006;115:47-58. 14. Johnston N, Dettmar PW, Bishwokarma B, Lively MO, Koufman JA. Activity/stability of human pepsin: implications for reflux attributed laryngeal disease. Laryngoscope 2007;117: 1036-9. 15. Samuels TL, Johnston N. Pepsin as a marker of extraesophageal reflux. Ann Otol Rhinol Laryngol 2010;119:203-8. 16. Lillemoe KD, Johnson LF, Harmon JW. Role of the components of the gastroduodenal contents in experimental acid esophagitis. Surgery 1982;92:276-84. 17. Johnson LF, Harmon JW. Experimental esophagitis in a rabbit model. Clinical relevance. J Clin Gastroenterol 1986;8 (suppl 1):26-44. 18. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice 2002;16:2747. 19. Belafsky PC, Postma GN, Koufman JA. Laryngopharyngeal reflux symptoms improve before changes in physical findings. Laryngoscope 2001;111:979-81. 20. Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope 2001;111:1313-7. 21. Koufman JA, Aviv JE, Casiano RR, Shaw GY. Laryngopharyngeal reflux: position statement of the Committee on Speech, Voice, and Swallowing Disorders of the American Academy of Otolaryngology–Head and Neck Surgery. Otolaryngol Head Neck Surg 2002;127:32-5. 22. Amin MR, Postma GN, Johnson P, Digges N, Koufman JA. Proton pump inhibitor resistance in the treatment of laryngopharyngeal reflux. Otolaryngol Head Neck Surg 2001;125:3748. 23. El-Serag H, Becher A, Jones R. Systematic review: persistent reflux symptoms on proton pump inhibitor therapy in primary care and community studies. Aliment Pharmacol Ther 2010;32:720-37. 24. El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol 2007;5: 17-26. 25. Altman KW, Stephens RM, Lyttle CS, Weiss KB. Changing impact of gastroesophageal reflux in medical and otolaryngology practice. Laryngoscope 2005;115:1145-53. 26. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97:142-6. 27. Lund O, Hasenkam JM, Aagaard MT, Kimose HH. Timerelated changes in characteristics of prognostic significance in carcinomas of the oesophagus and cardia. Br J Surg 1989;76: 1301-7. 28. Conio M, Blanchi S, Lapertosa G, et al. Long-term endoscopic surveillance of patients with Barrett’s esophagus. Incidence of dysplasia and adenocarcinoma: a prospective study. Am J Gastroenterol 2003;98:1931-9. 29. Reavis KM, Morris CD, Gopal DV, Hunter JG, Jobe BA. Laryngopharyngeal reflux symptoms better predict the presence of esophageal adenocarcinoma than typical gastroesophageal reflux symptoms. Ann Surg 2004;239:849-58. 30. Amin MR, Postma GN, Setzen M, Koufman JA. Transnasal esophagoscopy: a position statement from the American Broncho-Esophagological Association. Otolaryngol Head Neck Surg 2008;138:411-4. [Erratum in Otolaryngol Head Neck Surg 2009;140:280.] 31. Bellis M. Introduction to pop: the history of soft drinks timeline. About.com (http://inventors.about.com/od/sstartinventions/a/soft_drink.htm). Accessed March 2010. 32. Lobbying 2009: American Beverage Association. Center for Responsive Politics. (http://www.opensecrets.org/lobby/ clientlbs.php?year=2009&lname=American+Beverage+Assn &id). Accessed March 2010. 33. Koufman JA, Stern JC, Bauer MM. Dropping acid: the reflux diet cookbook and cure. Minneapolis, Minn: Reflux Cookbooks, 2010. 34. Acidified foods. Code of Federal Regulations — Title 21 — Food and Drugs Chapter I, Department of Health and Human Services Subchapter B — Food for Human Consumption Part 114. United States Food and Drug Administration. Arlington, Va: Washington Business Information, 2010. 35. Generally recognized as safe food additives: FDA database of selected GRAS substances. United States Food and Drug Administration. Springfield, Va: National Technical Information Service, 2009. 36. Food safety: FDA should strengthen its oversight of food ingredients determined to be generally recognized as safe (GRAS). GAO-10-246, United States Government Accountability Office, February 3, 2010. 37. Westman JA, Ferketich AK, Kauffman RM, et al. Low cancer incidence rates in Ohio Amish. Cancer Causes Control 2010;21:69-75. Cooling the “Oven”: A Temperature Study of Air and Glottal Tissue During Laser Surgery in an Ex Vivo Calf Larynx Model James A. Burns, MD; Gerardo Lopez-Guerra, MD; James T. Heaton, PhD; James B. Kobler, PhD; Julie Kraas; Steven M. Zeitels, MD Objectives: Endoscopic microlaryngeal laser surgery performed with general anesthesia through a laryngoscope speculum generates heat that accumulates at the distal lumen, creating an “oven” effect and potentially causing bystander thermal damage to nontarget tissue such as the contralateral vocal fold. We report the effects of cooling on air and tissue temperatures that occurred during simulated laryngeal laser surgery with KTP and thulium lasers in an ex vivo calf model. Methods: Ten fresh excised calf larynges were studied at room temperature. Laser energy was applied to one vocal fold for 2 minutes, with or without cooling, while temperatures were monitored with sensors placed within the glottal lumen or inserted superficially into the contralateral vocal fold. A pulsed KTP laser (525 mJ) was used for 5 larynges, and a thulium laser (7 W, continuous) was used for the other 5 larynges. Results: Heating was slightly greater for the KTP laser than for the thulium laser with use of these parameters. The lumen temperatures for both lasers increased an average of 13.2°C without cooling, but only 6.7°C with cooling (p < 0.05). The contralateral vocal fold (subepithelial space) temperature increased an average of 6.8°C without cooling, but only 4.2°C with cooling (p > 0.05). Conclusions: Cooling with room-temperature air during laryngeal laser surgery reduces luminal air and contralateral vocal fold temperatures. This effect is believed to be due to elimination of the plume of steam and smoke that significantly heats surrounding structures. Key Words: cooling, laser, microlaryngoscopy, thermal damage, vocal cord, vocal fold. ately adjacent to the primary target of the laser. Excessive heat can lead to epithelial sloughing, direct damage to the underlying superficial lamina propria, and excessive scarring and fibrosis.16,17 INTRODUCTION Endoscopic laryngeal laser surgery has gained broad acceptance for the treatment of various benign and malignant disorders. Since the initial clinical use of the carbon dioxide laser by Strong and Jako1,2 and Vaughan,3 the variety of available lasers has expanded to provide both cutting-ablating properties4,5 and selective photoangiolysis.6-9 All lasers commonly used in endolaryngeal surgery generate heat, and the thermal effects of lasers on laryngeal tissue are well documented both in ex vivo animal models4,10-14 and in human clinical series.3,5,7,8,15 Although the thermal effect of lasers can be favorable (such as in coagulation of small blood vessels for optimal hemostasis during extensive endolaryngeal resection5), the heat generated by lasers can also be unfavorable. Collateral thermal damage should be minimized during endoscopic laser procedures, especially when the layered microstructure of the vocal folds either is the primary target or is immedi- Endoscopic microlaryngeal laser surgery performed with general anesthesia through a rigid laryngoscope generates heat that accumulates within the confined space of the distal lumen, creating an “oven” effect. Careful intraoperative observation can reveal evidence of tissue singeing unrelated to direct application of laser energy to endolaryngeal structures. Thus, it appears that “bystander” thermal damage can occur separate from the target tissue, such as on the contralateral vocal fold (Fig 1). Although previous work has shown that precooling diminishes thermal effects at the target site,13 no prior study has examined the effects of cooling on luminal air temperature at the distal laryngoscope or on temperature within the superficial lamina propria of the contralateral vocal fold. Cooling tissue with From the Department of Surgery, Harvard Medical School, and the Center for Laryngeal Surgery and Voice Rehabilitation, Massachusetts General Hospital, Boston, Massachusetts. This work was supported in part by the Institute of Laryngology and Voice Restoration and the Eugene B. Casey Foundation. Dr Zeitels has an equity interest in Endocraft LLC, which makes the glottiscope that was used in the study. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: James A. Burns, MD, Center for Laryngeal Surgery and Voice Rehabilitation, One Bowdoin Square, 11th Floor, Boston, MA 02114. 73 74 Burns et al, Cooling During Glottal Laser Surgery Fig 1. Endoscopic surgery with use of KTP laser to treat left glottal cancer. Disease is unilateral, with laser being directed at left-sided lesion (A). During treatment, debris and singed tissue accumulate on contralateral vocal fold, as seen on medial edge (B) and on undersurface (C) of right vocal fold. Right vocal fold is being retracted laterally to show undersurface. A C B pressurized room air offers a less expensive alternative to cooling devices that generate hypothermic airflow, because most standard operating rooms are already equipped with pressurized air. This article reports the cooling effects of directed pressurized room-temperature air on lumen and glottal tissue temperatures during simulated laryngeal laser surgery with KTP (potassium-titanyl-phosphate) and thulium lasers in an ex vivo calf model. MATERIALS AND METHODS Fresh calf larynges were obtained from a meatpacker and maintained on ice until being warmed to room temperature at the time of the experiment. Standard intraoperative conditions typical of endoscopic microlaryngeal laser surgery as performed through a rigid laryngoscope were replicated as far as possible in the ex vivo benchtop model (Fig 2). These conditions included placement of a standard cuffed endotracheal tube to block the distal egress of heat and the use of suctioning during application of laser energy. A Universal Modular Glottiscope (Endocraft LLC, Providence, Rhode Island) was used to obtain exposure of the glottal surface that was the target for laser application. Endoscopic laryngeal laser surgery was simulated in 10 excised calf larynges with two commonly used lasers: the 2.01-μm thulium laser (Revolix Jr, LISA Laser, Katlenburg-Lindau, Germany; 400-μm fiber) and the 532-nm KTP laser (Aura XP with StarPulse, Laserscope Inc, San Jose, California; 400-μm fiber). The thulium laser (7 W continuous power) was used to make a controlled cut on the mid-musculomembranous and paraglottic regions of 5 calf larynges. Laser energy was evenly applied over one vocal fold surface while temperature measurements were taken from the glottal lumen and subepithelial tissue layer of the contralateral vocal fold. Cutting was performed for 2 minutes without application of a cooling airflow, and 2 minutes with cooling. The KTP laser (525 mJ, 15-ms pulse width, 2 pulses per second) was likewise used to cut and ablate one vocal fold for 2 minutes in 5 calf larynges, with and without the cooling airflow. The excised calf larynges did not contain perfusing tissue, so there was no selective uptake of laser energy from this photoangiolytic laser; rather, heat was generated by the nonspecific application of laser energy to the tissue. Temperature measurements were obtained with a 1.0-mm thermistor (Thermometrics, Edison, New Burns et al, Cooling During Glottal Laser Surgery 75 Fig 2. Procedural setup of ex vivo calf model simulating endoscopic microlaryngeal laser surgery. Inset) Typical laser wound on left vocal fold, along with thermometer probe and thermistor. Jersey) and a contact thermometer (Omega dual input HH506R, Omega Engineering Inc, Stamford, Connecticut) that were placed within the immediate subepithelial space of the vocal fold contralateral to the laser application and in the glottal lumen, respectively. The thermometer within the glottal lumen was positioned to measure luminal air temperature near the tip of the glottiscope. Temperature measurements from within the superficial lamina propria of the contralateral vocal fold were obtained by placing a thermistor into this position through a lateral puncture with an 18-gauge carrier needle and confirming its subepithelial placement visually. with cooling. For each 2-minute laser application, the average temperature of the hottest 5 consecutive seconds (Tavg) was calculated by custom software written in Matlab (MathWorks Inc, Natick, Massachusetts). Cooling was applied by directing pressurized room-temperature air through a second catheter affixed parallel to the laser catheter. The lowest rate of airflow (2 L/min) that would eliminate the visible plume of steam and smoke during lasering was chosen (Fig 3). The Tavg values were compared for the cooled versus noncooled conditions collapsed across laser type with 1-tailed Student’s t-tests (alpha level of less than 0.05 for significance). For each calf larynx and laser application, temperature measurements during lasering without cooling were obtained first, followed by lasering RESULTS A The heating effects were very similar for the KTP B Fig 3. Plume of steam obscures optimal view of calf vocal fold during simulated laser surgery using thulium laser without cooling (A). Effective cooling with application of pressurized room-temperature air through second lumen next to laser catheter creates clear view of vocal folds with no visible steam plume (B). Blue thermistor tip used to measure ambient air temperature at glottiscope tip is seen in upper left corner of each image. 76 Burns et al, Cooling During Glottal Laser Surgery peratures reached 29.0°C (KTP) and 24.9°C (thulium), which were decreased to about 23°C (slightly higher than room temperature) for both lasers with cooling. DISCUSSION Fig 4. Graphic representation of luminal air (in lumen) and contralateral vocal fold (in tissue) temperature measurements obtained for each laser with and without cooling. and thulium lasers with use of these parameters. Because both lasers showed the same trend in terms of their effect on luminal air and glottal tissue temperatures, as well as their response to cooling, the results for these two lasers were averaged. Temperature recordings with and without cooling are reported for measurements made within the luminal air at the tip of the glottiscope and within the immediate subepithelial (superficial lamina propria) space of the contralateral vocal fold. Figure 4 summarizes the temperature measurements obtained for each laser with and without cooling in the luminal air and contralateral vocal fold. Note that the ex vivo calf larynx tissue began at room temperature (approximately 20°C). Luminal Air. Without cooling, the luminal Tavg for both lasers (10 specimens) at the tip of the glottiscope increased an average of 13.2°C. With cooling, luminal Tavg was reduced nearly 50%, to only 6.7°C (degrees of freedom, 9; p < 0.05). The peak luminal temperatures without cooling reached as high as 39.7°C (KTP) and 34.7°C (thulium), having started at about 20°C, or room temperature. Lower peak temperatures for each laser were noted with cooling (29.9°C for KTP and 31.8°C for thulium). Contralateral Vocal Fold. Without cooling, the contralateral vocal fold (subepithelial space) temperature for both lasers (10 specimens) increased an average of 6.7°C. Debris in the form of charred bits of tissue accumulated on the endolaryngeal tissues during lasering without cooling. With cooling, the average increase in the contralateral vocal fold was slightly reduced to only 4.2°C, which was not significantly different than the noncooled condition (degrees of freedom, 8; p > 0.05). However, there was no accumulation of debris on the endolaryngeal tissues with cooling. Peak contralateral vocal fold tem- Prior studies evaluating the effect of cooling during laser surgery have focused on reducing thermal injury at the target site.13,14 On the basis of results obtained in those studies, we now routinely attach a cooling device when cutting-ablating laryngeal tissue with the thulium laser. Since evidence suggests that cooling the target tissue during pulsed KTP laser photoangiolysis can impede optimal vessel coagulation at standard power and pulse-width settings,14 cooling is not routinely utilized during these procedures. Although this judicious use of cooling has reduced thermal effects at the site of disease and allowed for selective vessel coagulation, intraoperative and postoperative observations have occasionally revealed evidence of tissue singeing at distant sites such as the contralateral vocal fold. Heated tissue debris produced during laser cutting and carried in the steam and smoke plume can be seen deposited throughout the endolaryngeal tissues. Additionally, epithelial sloughing has been detected after operation, consistent with a thermal injury from contact with elevated intraluminal air temperatures. Clearly, the thermal effects from heat-trapping at the distal glottiscope have the potential to impair the structure and function of otherwise normal laryngeal tissue. The results of this study help us to define the scope of the problem in terms of the magnitude of the temperature elevation and to work toward a solution to eliminate this problem. Luminal air temperatures increased an average of 13°C above baseline after 2 minutes of standard lasering technique that included the usual suction devices employed to evacuate smoke and debris from the treatment site. The average temperature of the hottest 5 consecutive seconds (Tavg) was reported in this study because of the highly variable temperature readings that were obtained throughout the 2-minute laser period. This variability seemed to be related to the amount of visible smoke and debris, with higher temperature measurements recorded when more smoke was present. Suctioning did not always immediately eliminate the smoke and debris, allowing for accumulation of heat at the distal end of the glottiscope and creation of an “oven” effect as lasering continued. This same phenomenon is occasionally seen during operation when the suction catheter is occluded from debris or from abutting tissue during retraction. Since certain common laryngeal laser procedures (both KTP and thulium) require more Burns et al, Cooling During Glottal Laser Surgery than 30 minutes of total laser time, the “oven” effect is potentially magnified beyond the effect measured in this study. In this ex vivo model, the glottal tissue started at room temperature (approximately 20°C) and the luminal air temperatures reached peak values approximately 19°C above baseline. Extrapolation of this result to actual endoscopic laryngeal laser surgery, with starting temperatures at 37°C (body temperature), predicts peak temperatures near 57°C. Temperatures in this range can cause irreversible structural changes ranging from epithelial damage and local inflammation18,19 to protein denaturation.20 Heat dissipation from blood flow through perfusing tissue is presumed to be negligible in this scenario, as the accumulation of heat over time would overwhelm the tissue’s capacity to dissipate the heat. Thus, results from the ex vivo calf larynx are expected to be similar to perfusing laryngeal tissue models in this regard. Models have been established that can be used to predict the quantitative effect of raising air temperature on the potential for injury to the surrounding tissue. For example, Leach et al19 used a guinea pig skin model to demonstrate the degree of epithelial damage from graded temperature exposures. Temperatures of 47°C for up to 6 minutes of exposure time produced no change, 1-minute exposures of 50°C to 55°C caused epithelial sloughing, and just 10 to 20 seconds of exposure at 70°C to 80°C created a severe burn injury. Exposing the phonatory layered microstructure to these temperatures for even short periods of time can possibly lead to epithelial sloughing and web formation, especially if extensive lasering is occurring near the anterior commissure. Cooling the “oven” within the luminal air at the glottal surface by directing pressurized room-temperature air through a second lumen next to the laser catheter reduced the temperature elevation by nearly 50%. In the clinical scenario of endoscopic laryngeal laser surgery, this could keep the peak temperatures below 47°C and thereby greatly reduce the risk of thermal damage to collateral structures. Our results also showed that subepithelial tissue temperatures within the contralateral vocal fold were reduced with cooling (although not statistically significant), although the average temperature increase was much less than the increase observed in luminal air temperature during lasering (6.7°C and 13.2°C, respectively). Effective cooling in this study required the continuous flow of air near the target tissue to keep debris and smoke from collecting at the distal glotti- 77 scope. Clinically, there is a natural tendency for heat to accumulate in the area between the endotracheal balloon and the glottiscope tip, because there is little circulation of air and no natural egress. Without cooling, heat will eventually be vented through the glottiscope and through the suction cannula, but not before reaching peak temperatures of approximately 19°C above baseline. Evaporative cooling of tissue and convection that blows away the steam and smoke plume are the presumed mechanisms of action of effective cooling of the “oven” that was demonstrated herein. Utilizing the ex vivo calf vocal fold is an effective and efficient way to obtain initial data regarding the thermal effects of lasers and the response to cooling. Although there are obvious limitations to this model, such as variations in soft tissue hydration, temperature, and turgor in comparison to perfusing tissue, the data are useful in calibrating optimal parameters for lasering and cooling laryngeal tissue. The temperature elevations recorded within the luminal air and subepithelial space of the contralateral vocal fold during this study support the concept that thermal damage can occur unrelated to the primary treatment of disease. Further study in a perfusing animal model, such as the rat larynx model proposed by Mallur et al,21 or by direct measurements of air and tissue temperatures during human surgery would overcome the limitations of an ex vivo model and perhaps yield further information that would directly improve surgical outcomes. Future investigations will seek to quantify the extent of tissue damage from lasering created by exposure to elevated luminal air temperatures over various durations of time. CONCLUSIONS 1. Cooling with room-temperature air during laryngeal surgery with KTP and thulium lasers decreases the average rise in luminal air temperatures by nearly 50% in this ex vivo model. 2. Laryngeal structures such as the contralateral vocal fold that are distant from the target tissue are subject to temperature increases and can be effectively cooled with pressurized room-temperature air. 3. Effective cooling is believed to be due to elimination of the steam and smoke plume that accumulates near the treatment site and heats surrounding structures. 4. Thermal damage from indirect laser-generated heat should be quantified in live-perfusing models in future studies. 78 Burns et al, Cooling During Glottal Laser Surgery REFERENCES 1. Strong MS, Jako GJ. Laser surgery in the larynx. Early clinical experience with continuous CO2 laser. Ann Otol Rhinol Laryngol 1972;81:791-8. 2. Strong MS. Laser management of premalignant lesions of the larynx. Can J Otolaryngol 1974;3:560-3. 3. Vaughan CW. Transoral laryngeal surgery using the CO2 laser: laboratory experiments and clinical experience. Laryngoscope 1978;88:1399-420. 4. Shapshay SM. Laser applications in the trachea and bronchi: a comparative study of the soft tissue effects using contact and noncontact delivery systems. Laryngoscope 1987;97(suppl 41):1-26. 5. Zeitels SM, Burns JA, Akst LM, Hillman RE, Broadhurst MS, Anderson RR. Office-based and microlaryngeal applications of a fiber-based thulium laser. Ann Otol Rhinol Laryngol 2006;115:891-6. 6. McMillan K, Shapshay SM, McGilligan JA, Wang Z, Rebeiz EE. A 585-namometer pulsed dye laser treatment of laryngeal papillomas: preliminary report. Laryngoscope 1998;108: 968-72. 7. Franco RA Jr, Zeitels SM, Farinelli WA, Anderson RR. 585-nm Pulsed-dye laser treatment of glottal papillomatosis. Ann Otol Rhinol Laryngol 2002;111:486-92. 8. Burns JA, Zeitels SM, Akst LM, Broadhurst MS, Hillman RE, Anderson RR. 523-nm Pulsed potassium-titanyl-phosphate laser treatment of laryngeal papillomatosis under general anesthesia. Laryngoscope 2007;117:1500-4. 9. Broadhurst MS, Akst LM, Burns JA, et al. Effects of 532nm pulsed-KTP laser parameters on vessel ablation in the avian chorioallantoic membrane: implications for vocal fold mucosa. Laryngoscope 2007;117:220-5. 10. Rebeiz EE, Aretz HT, Shapshay SM, Pankratov MM. Application of pulsed and continuous wave 1.32 and 1.06 microns wavelengths of the Nd:YAG laser in the canine tracheobronchial tree: a comparative study. Lasers Surg Med 1990;10:501-9. 11. April MM, Rebeiz EE, Aretz HT, Shapshay SM. Endo- scopic holmium laser laryngotracheoplasty in animal models. Ann Otol Rhinol Laryngol 1991;100:503-7. 12. Sullivan CA, Rader A, Abdul-Karim FW, Abbass H, Moher RM. Dose-related tissue effects of the CO2 and noncontact Nd:YAG lasers in the canine glottis. Laryngoscope 1998;108: 1284-90. 13. Burns JA, Kobler JB, Heaton JT, Lopez-Guerra G, Anderson RR, Zeitels SM. Thermal damage during thulium laser dissection of laryngeal soft tissue is reduced with air cooling: ex vivo calf model study. Ann Otol Rhinol Laryngol 2007;116:8537. 14. Burns JA, Kobler JB, Heaton JT, Anderson RR, Zeitels SM. Predicting clinical efficacy of photoangiolytic and cutting/ ablating lasers using the chick chorioallantoic membrane model: implications for endoscopic voice surgery. Laryngoscope 2008;118:1109-24. 15. Herdman RC, Charlton A, Hinton AE, Freemont AJ. An in vitro comparison of the erbium:YAG laser and the carbon dioxide laser in laryngeal surgery. J Laryngol Otol 1993;107:90811. 16. Stern LS, Abramson AL, Grimes GW. Qualitative and morphometric evaluation of vocal cord lesions produced by the carbon dioxide laser. Laryngoscope 1980;90:792-808. 17. Meyers A. Complications of CO2 laser surgery of the larynx. Ann Otol Rhinol Laryngol 1981;90:132-4. 18. Barbet JP, Chauveau M, Labbé S, Lockhart A. Breathing dry air causes acute epithelial damage and inflammation of the guinea pig trachea. J Appl Physiol 1988;64:1851-7. 19. Leach EH, Peters RA, Rossiter RJ. Experimental thermal burns, especially the moderate temperature burn. Exp Physiol 1943;32:67-86. 20. Clark JH. Denaturation changes in egg albumin with urea, radiation, and heat. J Gen Physiol 1943;27:101-11. 21. Mallur PS, Amin MR, Saltman BE, Branski RC. A model for 532-nanometer pulsed potassium titanyl phosphate (KTP) laser-induced injury in the rat larynx. Laryngoscope 2009;119: 2008-13. Quantity and Three-Dimensional Position of the Recurrent and Superior Laryngeal Nerve Lower Motor Neurons in a Rat Model Philip Weissbrod, MD; Michael J. Pitman, MD; Sansar Sharma, MD; Aaron Bender; Steven D. Schaefer, MD Objectives: We sought to elucidate the 3-dimensional position and quantify the lower motor neurons (LMNs) of the recurrent laryngeal nerve (RLN) and the superior laryngeal nerve (SLN) in a rat model. Quantification and mapping of these neurons will enhance the usefulness of the rat model in the study of reinnervation following trauma to these nerves. Methods: Female Sprague-Dawley rats underwent microsurgical transection of the RLN, the SLN, or both the RLN and SLN or sham surgery. After transection, either Fluoro-Ruby (FR) or Fluoro-Gold (FG) was applied to the proximal nerve stumps. The brain stems were harvested, sectioned, and examined for fluorolabeling. The LMNs were quantified, and their 3-dimensional position within the nucleus ambiguus was mapped. Results: Labeling of the RLN was consistent regardless of the labeling agent used. A mean of 243 LMNs was documented for the RLN. The SLN labeling with FR was consistent and showed a mean of 117 LMNs; however, FG proved to be highly variable in labeling the SLN. The SLN LMNs lie rostral and ventral to those of the RLN. In the sham surgical condition, FG was noted to contaminate adjacent tissues — in particular, in the region of the SLN. Conclusions: Fluorolabeling is an effective tool to locate and quantify the LMNs of the RLN and SLN. The LMN positions and counts were consistent when FR was used in labeling of either the RLN or the SLN. Fluoro-Gold, however, because of its tendency to contaminate surrounding structures, can only be used to label the RLN. Also, as previously reported, the SLN LMNs lie rostral and ventral to those of the RLN. This information results in further clarification of a rat model of RLN injury that may be used to investigate the effects of neurotrophic factors on RLN reinnervation. Key Words: animal model, Fluoro-Gold, Fluoro-Ruby, laryngeal nerve, lower motor neuron. INTRODUCTION cles. Both of these considerations require resolution at the laryngeal muscle and the laryngeal motor neuron in the brain stem. An animal model is critical to understanding the cause of synkinesis and later devising treatments to potentiate the proper regeneration of the RLN. Such a model would need to be investigated by endoscopic, electromyographic, and histologic techniques to elucidate the neurologic regenerative processes that occur at both the larynx and the lower motor neurons (LMNs) in the nucleus ambiguus (NA). In the present study, we aimed to update the rat model by elucidating the 3-dimensional organization of the LMNs of the RLN and the SLN. We provide an accurate reference for future experiments involving retrograde labeling via muscle injections and direct application of tracers to the RLN after injury. These future experiments will enhance our understanding of the mechanism of synkinesis and exploration of treatment to restore proper Iatrogenic injury to the laryngeal nerves is a relatively common complication of thyroid, cervical, or cardiothoracic surgery. The recurrent laryngeal nerve (RLN) and the superior laryngeal nerve (SLN) serve as conduits of both motor information and sensory information to and from the larynx. The RLN innervates both adductor and abductor muscles in the larynx. After transection of the RLN, the aberrant regeneration of the axons results in synkinesis that leads to vocal fold immobility. Synkinesis of laryngeal muscles may be considered in two ways. In one, a single regenerating RLN axon may innervate both adductor and abductor muscles. Conversely, regenerating axons may inappropriately innervate the adductor or abductor muscle, with abductor axons innervating adductor muscles and adductor axons innervating abductor mus- From the Department of Otolaryngology, New York Eye and Ear Infirmary, New York (Weissbrod, Pitman, Schaefer), and the Department of Cell Biology, New York Medical College, Valhalla (Sharma, Bender), New York. This study was performed in accordance with the PHS Policy on Humane Care and Use of Laboratory Animals, the NIH Guide for the Care and Use of Laboratory Animals, and the Animal Welfare Act (7 U.S.C. et seq.); the animal use protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of New York Medical College. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Michael J. Pitman, MD, 310 E 14th St, 6th Floor, New York Eye and Ear Infirmary, New York, NY 10003. 79 80 Weissbrod et al, Recurrent & Superior Laryngeal Nerve Lower Motor Neurons function via accurate reinnervation. Previous studies have examined the NA in rats by using retrograde labeling with variable results.1-6 The current study was intended to reexamine the location and quantity of LMNs within the NA, and specifically the relationship between the RLN LMNs and the SLN LMNs, through the use of more sophisticated labeling agents that enable complete visualization of neurons, dendrites, and axons. We chose Fluoro-Ruby (FR; Invitrogen, Carlsbad, California) and Fluoro-Gold (FG; Fluorochrome LLC, Denver, Colorado) because they are easily processed and allow for clear visualization of labeled cells. Via retrograde transport, these chemicals avidly label LMNs and their processes in a relatively short period of time and remain in the cell bodies for many months without transsynaptic labeling.7 METHODS Experimental Animals. Twenty female Sprague Dawley rats weighing 250 g were used in the present study. Humane care was provided for the animals, and all institutional and national guidelines were observed. The animals underwent transection of the right RLN only (4 animals), the right SLN only (4 animals), or both the RLN and SLN (8 animals) or sham surgery (4 animals). After transection, the proximal nerve stumps were soaked in labeling agent consisting of 5% FG in 0.1 mol/L phosphate-buffered saline solution (PBS) or 5% FR in PBS for a period of 5 minutes for retrograde labeling of the neurons in the brain stem. The transected nerve end was isolated from the surrounding fascia and smooth muscles. Gelfoam soaked with the fluorochrome was then packed around the transected nerve end and left in place for 5 minutes. After this procedure, the cut nerve was thoroughly washed with PBS and the area was dried with cotton swabs to minimize contamination of the dye in the surrounding tissue. This technique was an alternative to placing the nerve end in a well filled with fluorochrome. In previous experiments, the well technique appeared to result in more nerve end trauma, as well as contamination of surrounding tissue. The choice of these fluorochromes was based upon our previous work. Fluoro-Gold may penetrate intact axons and label other neurons in the brain stem. This situation was avoided by the isolation and washing of the nerve after exposure to the fluorochrome. Fluoro-Ruby, on the other hand, has a higher molecular weight, and its use in the central nervous system of the rat caused no erroneous labeling.7 Fluoro-Gold and FR labeling was performed in 4 groups of animals. In one group of 4 animals, the RLN was labeled with FG and the SLN with FR. In a second group of 4, the RLN was labeled with FR and the SLN with FG. In a third group (8 total), 4 animals had only the RLN labeled with FR and the other 4 had only the SLN labeled with FR. Sham surgery and labeling was performed on a fourth group of 4 animals. Surgical Procedures. Each animal was sedated with isoflurane and then received an intramuscular injection of 70 mg/kg of ketamine hydrochloride and 7 mg/kg xylazine hydrochloride to produce sufficient anesthesia. The anterior cervical region was injected subcutaneously with 0.2 mL of 1% lidocaine hydrochloride with epinephrine (1:100,000). Anesthesia was confirmed with a tail and foot pinch before the surgical procedure commenced. The animals were placed supine, and a vertical midline incision was made extending to the sternum. The strap muscles were separated in the midline and retracted with an eyelid retractor. With an operating microscope (Carl Zeiss AG, Oberkochen, Germany), the RLN was identified in the tracheoesophageal groove and isolated from its surrounding structures. The SLN was identified as it coursed horizontally to the cricothyroid muscle. Depending on the experimental condition, the RLN, the SLN, or both the RLN and SLN were sharply transected. The RLN was transected at the level of the seventh tracheal ring, and the SLN was transected just proximal to its entry into the larynx. After transection, fluorochrome was applied to the proximal nerve stump for a period of 5 minutes. In cases in which dual labeling was performed, cotton was placed between the labeling sites to prevent contamination. In all experiments, only the right RLN and right SLN were transected, with the contralateral side serving as a control. After nerve labeling, the area was blotted with cotton to remove excess tracer, and the incision was closed with 3-0 silk suture. To confirm injury to the RLN, we performed transoral laryngoscopy with a 0° rigid nasal endoscope (Karl Storz, Tuttlingen, Germany) to confirm absence of movement and vocal fold paralysis. For sham surgical procedures, the above process was performed, including identification and isolation of the appropriate nerves. Gelfoam soaked with fluorolabeling agent was packed around the uncut nerve at the site for a period of 5 minutes. The Gelfoam was removed, the area was blotted with cotton, and the wound was closed in the above fashion. On postoperative day 10, the animals were painlessly sacrificed by lethal inhalation of isoflurane. Immediately thereafter, the brain stems were harvested and placed for 4 hours in 4% paraformaldehyde Weissbrod et al, Recurrent & Superior Laryngeal Nerve Lower Motor Neurons 81 Fig 1. Retrograde-labeled laryngeal motor neurons (LMNs). A) Photomicrograph shows Fluoro-Gold (FG)–labeled recurrent laryngeal nerve (RLN) LMNs in nucleus ambiguus (NA). Photo was taken with 20× objective. Scale bar — 100 μm. B) Photomicrograph shows Fluoro-Ruby (FR)–labeled RLN LMNs in NA. Scale bar — 100 μm. C) Superimposed image of FGlabeled RLN and FR-labeled superior laryngeal nerve (SLN). Area imaged is caudal region of NA. Note more rostral (top of image) and lateral (right of image) orientation of SLN LMNs. Scale bar — 200 μm. A B in 0.1 mol/L pH 7.2 PBS. The isolated brain stems were then transferred into 30% sucrose in PBS and kept at 4°C until the tissue sank to the bottom of the container. The tissue was embedded in optimal cutting temperature medium (OCT). The brain stems were sectioned with a cryostat (Leica Microsystems, Wetzlar, Germany) into 40-μm-thick serial, longitudinal sections and mounted onto precoated slides. After allowing the sections to dry overnight, we irrigated sections in sterile saline solution to dissolve the OCT, mounted them with 1:1 PBS-glycerin, and cover-slipped them. The slides were kept at 4°C in a closed container to avoid light contamination until examination via fluorescent microscopy. Quantification of Fluorolabeled LMNs. The brain stem sections were examined by light microscopy (Axioskop, Zeiss) by a reviewer who was unaware of the surgical procedure performed. The slides were systematically examined to ensure that all labeled cells were appropriately counted. Only cells that had visible cell bodies and contained the nucleus were counted. The counts were confirmed by 2 other viewers in a blinded fashion. In specimens labeled with 2 fluorochromes, FR and FG interference C and absorption filters (Zeiss) were used to view and capture images. Double images were then digitally superimposed. After quantification of cells, images were processed to assess stereotactic LMN position. Individual sections were digitized, and labeled cells within each section were demarcated digitally into an x- and y-coordinate system. The perimeter of each section was outlined digitally and assigned x- and ycoordinates as well. The z-coordinate was assigned on the basis of specimen number within the serially cut sections. Each section was then aligned in the x- and y-planes in order to be centered on the preceding specimen. The x- and y-coordinates for each cell were then recorded on a spreadsheet. The coordinates were then plotted in a 3-dimensional graph with Sigmaplot (Systat Software Inc, Chicago, Illinois). RESULTS The NA in the brain stem of the rat has an unusual territorial domain. It has two subdivisions: an upper part and a lower part. The upper subdivision lies caudal to the facial nucleus, and the majority of the 82 Weissbrod et al, Recurrent & Superior Laryngeal Nerve Lower Motor Neurons A B C D Fig 2. NA distribution of FG-labeled RLN (white) and FR-labeled SLN (gray). Note rostral, lateral, and ventral orientation of SLN LMNs as compared to more dorsal, caudal, and medial position of RLN LMNs. A,B) FGlabeled LMNs are brought to front of image. C,D) FR-labeled LMNs are brought to front of image. Dashed line demarcates level of obex. SLN LMNs are located in it. The RLN LMNs are located in the ventral and caudal subdivision. We have followed the classification of Bieger and Hopkins6 to identify the subdivisions of the NA. When FR or FG was used on the transected RLN, in 3 different experimental settings (total of 12 animals), the average number of labeled LMNs in the ventral and caudal region of the NA was 243 (Fig 1A,B). When the SLN was labeled with FR, the average number of labeled LMNs in the NA was 117. In the middle region of the two subdivisions of the NA, there were labeled LMNs from the SLN and the RLN. In cases in which the SLN and RLN were labeled with separate dyes, there was overlap of labeled LMNs in the middle location of the subdivisions of the NA (Figs 1C, 2, and 3); however, we did not observe any neurons that were double-labeled with the two different fluorochromes. When the SLN was labeled with FG, the number of labeled LMNs was very high (mean, 422; 4 samples; see Table). A reasonable consistency in the number of LMNs labeled with FR was evident. It was also evident that labeling of the RLN with either FG or FR gave a consistent number of labeled LMNs. A major discrepancy in the number of labeled LMNs from the SLN when FG was used as a tracer can be attributed to the capability of FG to avidly label the LMNs of injured muscles surrounding the SLN. The findings suggest that the RLN is composed of a larger number of axons from the NA than is the SLN. Additionally, the use of FR in the present experiments provided more consistent and accurate labeling than did the use of FG. Statistical analysis using a 2-tailed t-test for cells labeled through the RLN (12 samples) shows the Weissbrod et al, Recurrent & Superior Laryngeal Nerve Lower Motor Neurons 83 Fig 3. Three-dimensional representation of relationship between RLN LMNs (white) and SLN LMNs (gray). SLN LMNs are lateral, rostral, and ventral as compared to RLN LMNs. There is also small area of overlap in medial region of NA. mean as 242.58 (SEM, 4.9; p < 0.001). In the SLN (8 samples), the mean number of labeled cells was 117 (SEM, 8.9; p < 0.001). The group in which FG was used to label the SLN was not included in the statistical analysis. In the sham surgical condition, when the intact RLN or SLN was smeared with FR or FG, no neuNUMBERS OF LABELED NEURONS IN NUCLEUS AMBIGUUS Group Fluorochrome Tracer RLN-Labeled LMNs SLN-Labeled LMNs A (n = 4) Fluoro-Ruby 230 240 260 266 Mean = 249 120 129 130 90 Mean = 117 C (n = 8) Fluoro-Gold Fluoro-Ruby 243 246 239 236 Mean = 241 238 243 244 267 Mean = 248 2 2 B (n = 4) 311 430 529 420 Mean = 422 74 158 120 116 Mean = 117 Groups A and B represent one fluorochrome used to label recurrent laryngeal nerve (RLN) and other fluorochrome used to label superior laryngeal nerve (SLN). Arrows point to dual-labeled animals. Group C represents animals singly labeled with Fluoro-Ruby. LMNs — lower motor neurons. rons within the NA were labeled — a finding confirming that neither dye labeled intact axons in the present experiments. Labeling with FG in the transected nerves (both SLN and RLN) resulted in scattered labeling of cells in the dorsal and peri-NA regions. There was increased contamination noted in FG-labeled SLN LMNs, which was likely due to labeling of nerve endings in the dissected strap muscles and nearby pharyngeal constrictor muscles. No LMNs were labeled with FR when the nerves were intact (sham experiments), likely because of the higher molecular weight resulting in less-avid uptake in surrounding muscle. Two animals were excluded from the LMN count studies after surgical transection and labeling; one animal died in the perioperative period and the other was not included because a number of sections were destroyed during sectioning. The LMNs of the SLN lie rostral, lateral, and ventral in relation to the more caudal, dorsal, and medial position of the RLN LMNs (Fig 2). The LMNs of the RLN and SLN did share a region of overlap in the more rostral portion of the RLN distribution. The fact that there was no dual labeling of any LMNs suggests that entirely separate LMN axons from the NA traverse the RLN and SLN. The majority of labeled neurons for the RLN and SLN were confined within the NA. However, in 2 animals, a few labeled neurons were encountered in the area corresponding to the contralateral NA. In 1 animal, 4 cells were noted, and 8 were noted in the 84 Weissbrod et al, Recurrent & Superior Laryngeal Nerve Lower Motor Neurons other. DISCUSSION This study was designed as a complement to prior published work from our laboratory that details techniques for studying reinnervation in rats and for following animals after crush injury.8,9 These earlier studies focused on nerve injury via an aneurysm clamp. In many of the studied conditions, the vocal folds had purposeful movement after crush injury. To ensure an experimental condition that reliably and reproducibly creates synkinesis, we transected the nerves instead of causing a crush injury. Nerve transection leads to reliable and consistent nonfunctional synkinetic reinnervation of the larynx as evaluated by kinesiologic, histologic, and electromyographic parameters.10 The present work is a part of ongoing research on rats that is aimed at creating a comprehensive model to study laryngeal reinnervation following injury. A number of contemporary groups have made attempts at studying neuroregenerative agents in rats after injury.11-13 Although some of this work holds potential promise, most of these studies are based on incomplete animal models (without functional studies and sometimes without experimental controls), leaving room for doubt about their validity. Understanding reinnervation requires examination of events at the site of injury (the nerve) and the effects on the end organ (the larynx), and also an understanding of events at the level of the motor neurons (the NA). For laryngeal nerve injury, this is a complicated proposition, given contributions to the larynx from both the SLN and the RLN, with the RLN carrying both adductory and abductory efferent fibers. Cataloging the organization of LMNs within the NA is of paramount importance in understanding the potential reorganization of abductor and adductor signals that can occur after injury leading to synkinesis. Once the adductor and abductor LMN populations are established in normal animals, one could look for inappropriate LMN labeling in the LMNs in the NA. Conversely, the possibility exists that an axon of one LMN may innervate both muscles. In these scenarios, one would see double labeling of LMN with two different dyes. For these reasons, it is critical to establish the accurate position of the LMN pool for the RLN and the SLN. Our future studies stand to unravel the varied populations of LMNs that innervate separate sets of muscles in the larynx. The study of the RLN and SLN LMNs in rats is not novel. Using horseradish peroxidase (HRP), diamidino yellow, and true blue, Portillo and Pásaro1 injected laryngeal muscle groups. For the cricothy- roid muscle, 22 to 90 LMNs were labeled, depending on the labeling agent used. The mean value for the posterior cricoarytenoid, thyroarytenoid, and lateral cricoarytenoid muscles combined was 215.1 Therefore, working under the assumptions that the cricothyroid LMNs constitute the LMNs of the SLN and that the sum of the posterior cricoarytenoid, thyroarytenoid, and lateral cricoarytenoid LMNs equal those of the RLN, the mean values of labeled LMNs in their study were lower than those in the present study. In another study, Hinrichsen and Ryan2 used HRP to label the cut nerve ends of the RLN, and they immersed the nerve endings in an HRP solution, thereby increasing cell labeling; however, significant variability in results was encountered. Both studies1,2 used labeling agents that are somewhat unreliable and are likely the source of much of the difference and confusion in the literature. Furthermore, injection of HRP into muscles as opposed to labeling transected nerve ends has the potential to label fewer LMNs. Flint et al3 undertook a similar approach to categorize the LMNs and addressed questions regarding postinjury synkinesis in animals. Horseradish peroxidase, diamidino yellow, and fast blue were used to label either specific muscle groups or nerves. The relationships of the LMN muscle groups were largely consistent with those in previous studies; however, labeling of the RLN showed fewer LMNs than in similar studies and the present study. In addition, an experimental condition was undertaken in which the posterior cricoarytenoid, thyroarytenoid, and lateral cricoarytenoid muscles were injected with HRP 15 weeks after transection and reanastomosis. These authors showed a decreased number of labeled LMNs, as well as a loss of spatial segregation in respect to the studied LMN groups, validating the importance of analyzing the LMNs when considering laryngeal nerve injury and synkinesis. The current study used FG and FR, two examples of retrograde fluorolabeling agents. Previous work in rats using biotinylated dextran amines (BDAs) as labeling agents has generated results similar to those of the current study. When BDAs were used to label the RLN, there was a range of 121 to 240 LMNs, with an average of 143.4 Again using BDAs, Pascual-Font et al5 found that the SLN had an average of 111 LMNs. In addition to SLN labeling, they noted significant labeling of the ipsilateral dorsal motor nucleus of the vagus nerve — a finding attributed to efferent preganglionic parasympathetic neurons. Additional labeling was noted in the ipsilateral solitary tract and the nucleus of the ipsilateral solitary tract, both likely representing afferent laryngeal sensory fibers carried within the SLN.5 The present Weissbrod et al, Recurrent & Superior Laryngeal Nerve Lower Motor Neurons study confirms the above LMN counts, although our labeling was more consistent. We also noted very few labeled cells outside the expected confines of the NA; however, we did not quantify these cells, as they do not represent LMNs that drive the RLN or SLN and do not contribute to postinjury synkinesis. In the present series of experiments, we found only that FR reliably labels the SLN without contamination. With FR, the mean number of labeled neurons was 116, with a range of 74 to 158. These results are consistent with those of prior studies.1,4,5 The disparity within fluorolabeling agents is consistent with a number of previous studies that have shown that FR only effectively labels damaged or cut nerves in the facial muscles of the rat,14 and that it has poor labeling capacity when injected directly into muscle.15 This tendency would make FR contamination via surrounding musculature unlikely. Conversely, in a mouse model of the tibial nerve and gastrocnemius muscles, FG showed good retrograde transport in both cut nerve labeling and muscle injection, but was found to show an increased potential for background diffusion. These findings suggest that if muscle is damaged during surgery, contamination and resultant LMN labeling with FG is more likely. In the present study, LMN labeling outside of the NA can be attributed to a number of possible scenarios. First, there are afferent sensory and parasympathetic nerves within the RLN and SLN that originate in the nucleus of the solitary tract and the dorsal motor nucleus. It is further possible that contamination of surrounding tissues takes place during the dissection of the RLN and SLN. Access to the SLN requires significantly more dissection of surrounding muscles than does access to the RLN. There are 85 fascial planes over all of the surrounding structures that can serve as natural barriers to contamination. As such, contamination with FG via injured muscle is likely the reason for the disparate SLN quantification in our study that resulted in elevated numbers of LMNs. In the present study, regardless of the agent used, the RLN LMNs were consistently labeled in number and location. In conclusion, labeling of the RLN and SLN, with FR in particular, produces consistent results that allow the quantification and confirmation of the position of the LMNs of the laryngeal nerves. FluoroRuby is optimal for this study because of its ardent ability to be taken up by transected nerves with minimal contamination of surrounding tissues. Although FG is also avidly taken up by cut nerves, we believe it also has the tendency to contaminate nearby tissues in situations in which there has been extensive muscle dissection. The position of the LMNs of the RLN and SLN in this study is consistent with the findings of prior studies: the LMNs of the SLN lie rostral, ventral, and lateral to those of the RLN, with a small area of overlap. This study also confirms the higher number of RLN LMNs that were identified in one study4 and the location of these LMNs identified in others.3,6 The present observations support the superiority of the new staining techniques and resolve the controversy and confusion that resulted from disparate LMN counts seen in studies that used other techniques. The information from this study further clarifies the use of the rat as a model for RLN injury. This study also provides baseline information for future study of specific intralaryngeal muscle LMN groups and, eventually, the study of neurotropic or other pharmacologic agents with the motive of improving postinjury function and reducing synkinesis. Acknowledgment: We thank Dr Alan Springer for his statistical analysis. REFERENCES 1. Portillo F, Pásaro R. Location of motoneurons supplying the intrinsic laryngeal muscles of rats. Horseradish peroxidase and fluorescence double-labeling study. Brain Behav Evol 1998;32:220-5. 5. Pascual-Font A, Maranillo E, Merchán A, Vázquez T, Sañudo JR, Valderrama-Canales FJ. Central projections of the rat superior laryngeal nerve [in Spanish]. Acta Otorrinolaringol Esp 2006;57:295-9. 2. Hinrichsen CFL, Ryan AT. Localization of laryngeal motoneurons in the rat: morphologic evidence for dual innervation? Exp Neurol 1981;74:341-55. 6. Bieger D, Hopkins DA. Viscerotopic representation of the upper alimentary tract in the medulla oblongata in the rat: the nucleus ambiguus. J Comp Neurol 1987;262:546-62. 3. Flint PW, Downs DH, Coltrera MD. Laryngeal synkinesis following reinnervation in the rat. Neuroanatomic and physiologic study using retrograde fluorescent tracers and electromyography. Ann Otol Rhinol Laryngol 1991;100:797-806. 7. Ahmed FAKM, Ingoglia NA, Sharma SC. Axon resealing following transection takes longer in central axons than in peripheral axons: implications for axonal regeneration. Exp Neurol 2001;167:451-5. 4. Pascual-Font A, Maranillo E, Vázquez T, Sañudo JR, Valderrama-Canales FJ. On the number and morphometrical parameters of the nucleus ambiguous neurons after the injury and regeneration of the recurrent laryngeal nerve in the rat [in Spanish]. Acta Otorrinolaringol Esp 2008;59:163-9. 8. Tessema B, Roark RM, Pitman MJ, Weissbrod P, Sharma S, Schaefer SD. Observations of recurrent laryngeal nerve injury and recovery using a rat model. Laryngoscope 2009;119:164451. 9. Tessema B, Pitman MJ, Roark RM, Berzofsky C, Sharma 86 Weissbrod et al, Recurrent & Superior Laryngeal Nerve Lower Motor Neurons S, Schaefer SD. Evaluation of functional recovery of recurrent laryngeal nerve using transoral laryngeal bipolar electromyography: a rat model. Ann Otol Rhinol Laryngol 2008;117:604-8. 10. Pitman MJ, Weissbrod P, Roark R, Sharma S, Schaefer SD. Electromyographic and histologic evolution of the recurrent laryngeal nerve from transection and anastomosis to mature reinnervation. Laryngoscope 2011;121:325-31. 11. Shiotani A, O’Malley BW Jr, Coleman ME, Flint PW. Human insulinlike growth factor 1 gene transfer into paralyzed rat larynx: single vs multiple injection. Arch Otolaryngol Head Neck Surg 1999;125:555-60. 12. Mori Y, Shiotani A, Saito K, et al. A novel drug therapy for recurrent laryngeal nerve injury using T-588. Laryngoscope 2007;117:1313-8. 13. Hydman J, Remahl S, Björck G, Svensson M, Mattsson P. Nimodipine improves reinnervation and neuromuscular function after injury to the recurrent laryngeal nerve in the rat. Ann Otol Rhinol Laryngol 2007;116:623-30. 14. Choi D, Li D, Raisman G. Fluorescent retrograde neuronal tracers that label the rat facial nucleus: a comparison of Fast Blue, Fluoro-ruby, Fluoro-emerald, Fluoro-Gold, and DiI. J Neurosci Methods 2002;117:167-72. 15. Hayashi A, Moradzadeh A, Hunter DA, et al. Retrograde labeling in peripheral nerve research: it is not all black and white. J Reconstr Microsurg 2007;23:381-9. Assessment of Canine Vocal Fold Function After Injection of a New Biomaterial Designed to Treat Phonatory Mucosal Scarring Sandeep S. Karajanagi, PhD; Gerardo Lopez-Guerra, MD; Hyoungshin Park, PhD; James B. Kobler, PhD; Marilyn Galindo; Jon Aanestad; Daryush D. Mehta, PhD; Yoshihiko Kumai, MD, PhD; Nicholas Giordano; Anthony d’Almeida; James T. Heaton, PhD; Robert Langer, ScD; Victoria L. M. Herrera, MD; William Faquin, MD, PhD; Robert E. Hillman, PhD; Steven M. Zeitels, MD Objectives: Most cases of irresolvable hoarseness are due to deficiencies in the pliability and volume of the superficial lamina propria of the phonatory mucosa. By using a US Food and Drug Administration–approved polymer, polyethylene glycol (PEG), we created a novel hydrogel (PEG30) and investigated its effects on multiple vocal fold structural and functional parameters. Methods: We injected PEG30 unilaterally into 16 normal canine vocal folds with survival times of 1 to 4 months. Highspeed videos of vocal fold vibration, induced by intratracheal airflow, and phonation threshold pressures were recorded at 4 time points per subject. Three-dimensional reconstruction analysis of 11.7 T magnetic resonance images and histologic analysis identified 3 cases wherein PEG30 injections were the most superficial, so as to maximally impact vibratory function. These cases were subjected to in-depth analyses. Results: High-speed video analysis of the 3 selected cases showed minimal to no reduction in the maximum vibratory amplitudes of vocal folds injected with PEG30 compared to the non-injected, contralateral vocal fold. All PEG30-injected vocal folds displayed mucosal wave activity with low average phonation threshold pressures. No significant inflammation was observed on microlaryngoscopic examination. Magnetic resonance imaging and histologic analyses revealed time-dependent resorption of the PEG30 hydrogel by phagocytosis with minimal tissue reaction or fibrosis. Conclusions: The PEG30 hydrogel is a promising biocompatible candidate biomaterial to restore form and function to deficient phonatory mucosa, while not mechanically impeding residual endogenous superficial lamina propria. Key Words: hoarseness, hydrogel, polyethylene glycol, scar. INTRODUCTION there has not been a reliable method to restore normal suppleness to stiff vocal folds.7,8 This capability would be highly desirable, given the large numbers of patients with benign and malignant processes who sustain diminished pliability of phonatory mucosa from phonotrauma, disease, or instrumentation. About 6.6% of the American working-age population is affected by voice-related disorders, and most of these patients present with diminished phonatory Optimal vocal function requires an aerodynamically competent glottal valve and pliable phonatory mucosa. During the past century, surgeons became adept at repairing aerodynamic incompetence by restoring glottal closure. This was achieved by augmenting the paraglottic space1-4 and/or repositioning the arytenoid5,6 to close the rima glottidis. However, From the Center for Laryngeal Surgery and Voice Rehabilitation (Karajanagi, Lopez-Guerra, Park, Kobler, Galindo, Aanestad, Mehta, Kumai, d’Almeida, Heaton, Hillman, Zeitels) and the Department of Pathology (Faquin), Massachusetts General Hospital, the Departments of Surgery (Karajanagi, Lopez-Guerra, Park, Kobler, Kumai, Heaton, Hillman, Zeitels) and Pathology (Faquin), Harvard Medical School, the Department of Medicine, Boston University School of Medicine (Herrera), the School of Engineering and Applied Sciences, Harvard University (Mehta), and the School of Engineering, Boston University (Giordano), Boston, and the Department of Chemical Engineering (Karajanagi, Park, Langer) and the Harvard-MIT Division of Health Sciences and Technology (Kobler, Heaton, Langer, Hillman), Massachusetts Institute of Technology, Cambridge, Massachusetts. This work was supported in part by the Eugene B. Casey Foundation and the Institute of Laryngology and Voice Restoration. Dr Zeitels has an equity interest in Endocraft LLC. This study was performed in accordance with the PHS Policy on Humane Care and Use of Laboratory Animals, the NIH Guide for the Care and Use of Laboratory Animals, and the Animal Welfare Act (7 U.S.C. et seq.); the animal use protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of the Massachusetts General Hospital. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Winner of the Broyles-Maloney Award. Correspondence: Sandeep S. Karajanagi, PhD, Center for Laryngeal Surgery and Voice Rehabilitation, Massachusetts General Hospital, Bartlett Hall Extension, 413, Boston, MA 02114. 87 88 Karajanagi et al, Canine Vocal Fold Function After Injection of New Biomaterial mucosal pliability of their vocal folds.9 The need for methods to restore vocal fold pliability has generated an increasing number of efforts to develop biological and/or synthetic remedies. A recent series of review articles provides an excellent overview of the wide range of treatment strategies that are under development.10-17 These proposed therapies include the use of synthetic biomaterials (some based on natural extracellular matrix components such as hyaluronic acid [HA] and collagen), cells (stem cells or fibroblasts), autologous tissue (fat or fascia), scaffolds (synthetic or tissue-based), and growth factors and other chemical agents, such as steroids and phytochemicals. All of these approaches have demonstrated some positive results in animal studies, and small-scale human trials have studied several types of treatment. Biomaterials have several potential advantages over other approaches, including availability, limited biological side-effects, control over viscoelastic material properties, immediate benefit, and procedural simplicity (eg, delivery via injection). Recently, some human subject experiments suggested that biomaterial therapy may be effective for vocal fold scar. In a 2-year study, 40 patients with vocal fold scar, vocal fold atrophy, or sulcus vocalis were injected with auto–cross-linked polysaccharide HA gel (Fidia Advanced Biopolymers, Abano Terme, Padova, Italy).18 The material was placed into the lamina propria for treating the scar and sulcus or into the thyroarytenoid muscle for closing the glottal gap. This study had a pretreatment-posttreatment design, with multivariate statistical analysis of voice and endoscopic parameters. Glottal closure, vibratory pattern, and mucosal waves were significantly improved at the first follow-up (1 to 3 months) and at 12 months after injection. In two other studies using esterified HA (MeroGel; Medtronic Xomed, Jacksonville, Florida), the placement of HA-based fibers beneath phonosurgical microflaps appeared to have a positive effect on the long-term measures of voice production.19,20 The positive vocal outcomes reported in these initial human experiments are somewhat tempered by the heterogeneity of the vocal conditions treated and by inadequate controls. However, this work, as well as a host of animal studies,13,21-23 does suggest that biomaterials may provide short- and long-term benefits for treatment of vocal fold scar, and that materials with established biocompatibility in other parts of the body can be relatively safe for use in the vocal folds. Hylan-B, auto-crosslinked polysaccharide HA gel, and MeroGel were initially designed for appli- cation in other tissues (eg, skin or dermis), and it would be serendipitous if they happened to be optimal for vocal fold applications. Ideally, substances would be designed specifically for the vocal fold on the basis of the rheological and functional properties of the normal vocal fold mucosa, as well as for their use in scar-stiffened tissue. Since the primary component of the vocal fold’s layered microstructure responsible for vibration is the superficial lamina propria (SLP),24 we created a novel hydrogel, PEG30 (patent pending), with rheological properties that lie near the lower limits of normal vocal fold stiffness. In choosing materials, an additional consideration becomes the potential regulatory hurdles for approval of novel chemical formulations. We therefore based PEG30 on polyethylene glycol (PEG) because PEG is an established biocompatible polymer widely used in numerous products approved by the US Food and Drug Administration. We investigated its effects on multiple vocal fold structural and functional parameters. MATERIALS AND METHODS Preparation of PEG30 Hydrogel. PEG30 hydrogels were prepared by photopolymerization of PEG diacrylate (PEG-DA; SunBio Inc, Orinda, California) in the presence of PEG (Aldrich, St Louis, Missouri; both with molecular weight of 10 kd). Briefly, aqueous solutions of PEG and PEG-DA (both 100 mg/mL) were made in sterile phosphate-buffered saline solution (PBS) and mixed in the volumetric ratio 3:7 of PEG-DA to PEG. This solution (1 mL) was gelled for 200 seconds with 0.05% (wt/vol) of Irgacure 2959 (Ciba, Tarrytown, New York) as the photoinitiator. An EXFO Lite lamp (Lumen Dynamics Group, Mississauga, Canada) that generated ultraviolet light of intensity 10 mW/cm2 (measured at 365 nm) was used for the gelation. The entire process was carried out in a sterile laminar flow hood. The gel disks thus formed were rinsed with 70% ethanol (3× at 1 minute per wash), rinsed in sterile PBS (3× at 5 minutes per wash), and then incubated in sterile PBS for 24 hours at 37°C. The swollen gels were progressively sheared through needles of decreasing bore size to make them injectable through a 25-gauge needle. The gels were stored at 4°C sealed in a capped syringe until further use. Mechanical Testing of Hydrogels. The viscoelastic shear properties of the hydrogels were measured at low frequencies with an AR-2000 rheometer (TA Instruments, Inc, New Castle, Delaware). A coneand-plate geometry was used to apply oscillatory shear to hydrogel samples with an acrylic cone (60mm diameter, 2° angle) and a flat metallic Peltier plate heated to 37°C. Sheared gels were placed be- Karajanagi et al, Canine Vocal Fold Function After Injection of New Biomaterial tween the heated plate and the cone so that a manufacturer-specified gap of 61 μm was maintained between the cone and the plate. The gel was subjected to an oscillatory shear at 1 Hz for 2 minutes to equilibrate the entire gel to a uniform temperature of 37°C. Strain sweep tests were done to ensure that the shear property measurements were done in the linear region of the stress-strain curve. The viscoelastic shear properties are independent of the percentage strain in the linear region. A target shear strain value was therefore identified by measuring the viscoelastic shear properties as a function of the percentage strain applied. A 0.6% strain was typically used to measure the shear properties by means of a frequency sweep. Measurements of the shear properties were then made by systematically varying the frequency from 1 to 10 Hz. The elastic shear modulus (G') at 10 Hz was used as a measure of the mechanical properties of the PEG30 hydrogel used in this study. The elastic shear modulus of PEG30 fell within or below the ranges reported in the literature for normal phonatory mucosa,25 thereby demonstrating adequate softness and/or pliability at low frequencies to justify in vivo testing. Animal Care. This study was performed in accordance with the PHS Policy on Human Care and Use of Laboratory Animals, the NIH Guide for the Care and Use of Laboratory Animals, and the Animal Welfare Act (7 U.S.C. et seq.). All experimentation followed an animal use protocol that was approved by the Committee on Animal Care and the Institutional Animal Care and Use Committee of the Massachusetts General Hospital. All surgical procedures and housing of animals took place at the Massachusetts General Hospital. Sixteen research-bred dogs (young adult male hounds, 8 months to 1 year in age) were obtained from Covance Research Products (Cumberland, Virginia). Through an arrangement with the supplier, we were able to obtain animals that had been endoscopically pre-screened for laryngeal disorders, which are not uncommon due to excessive barking. Before every procedure, the dogs were premedicated with acepromazine maleate (0.05 mg/kg), glycopyrrolate (0.01 mg/kg), and butorphanol tartrate (0.2 mg/ kg). Anesthesia was maintained throughout the surgical procedures with intravenous propofol (10 mL for induction, followed by 0.5 mg/kg per minute or more given intravenously as needed). Spontaneous respiration was maintained, medical-grade oxygen was supplied continuously through the mouth, and a heating pad was used to maintain body temperature throughout the surgery. Heart and respiratory rates were monitored continuously by a monitoring 89 device and visual observation. At the conclusion of each phonatory testing session (see below), the dogs were watched until they regained consciousness and were given the nonsteroidal anti-inflammatory drug meloxicam (0.2 mg/kg), buprenorphine hydrochloride (0.01 mg/kg), and the antibiotic Baytril (enrofloxacin; 5 mg/kg). Surgical Procedures. The dogs were placed in a supine posture on a surgical table with the head and neck supported. The vocal folds were exposed by standard endoscopic techniques and visualized with a Leica F40 surgical microscope. PEG30 was injected unilaterally in 16 normal canine vocal folds with postinjection survival periods of 1, 2, 3, and 4 months (n = 4 per time point). The contralateral fold served as a control. An average of 60 μL of PEG30 was injected in the vocal fold with a 25-gauge Zeitels Vocal-Fold Infusion Needle26 (Endocraft, Providence, Rhode Island) and a specially modified industrial viscous fluid dispenser (model HP7× by Nordson EFD, Westlake, Ohio) that was pneumatically driven and provided improved injection control compared with conventional handheld syringes or injection guns. The HP7× handpiece was modified to use a high-precision linear transducer and digital meter so that dispenser output could be measured in real time. The injection volumes for dogs 1 to 3 reported in this study were 69, 52, and 53 μL, respectively. We made periodic examinations of in vivo vocal fold appearance using standard microlaryngoscopy. Specifically, examinations were made at the following time points after injection for dogs with 1-, 2-, 3-, and 4-month survival times, respectively: 1, 2, and 4 weeks; 2, 5, and 8 weeks; 4, 8, and 12 weeks; and 4, 8, 12, and 16 weeks. High-speed videos (4,000 frames per second) of the vocal fold vibration were also recorded during these examinations by using a 16-gauge needle inserted in the trachea to create subglottic air pressure for phonation. Air delivered for phonation was warmed (37°C to 39°C) and humidified by a Conchatherm unit (high-flow model; Hudson RCI, Temecula, California). A pressure sensor (MPX2010GP; Motorola, Schaumburg, Illinois) was mounted on the air supply tube near its connection to the needle inserted into the trachea, and a condenser microphone (ECM50PSW; Sony, New York, New York) was positioned approximately 15 cm from the mouth opening. Simultaneous acoustic and pressure signals were filtered and recorded digitally (20,000-Hz sampling rate) with Axon Instruments hardware (Cyberamp 380, Digidata 1440a) and software. Phonation threshold pressures were monitored in real time during data collection in or- 90 A Karajanagi et al, Canine Vocal Fold Function After Injection of New Biomaterial B Fig 1. Example endoscopic view of vocal folds and derivation of amplitude asymmetry measure. A) High-speed video image taken during maximum abduction during phonation. B) Derivation of lateral displacement waveforms for right and left vocal folds. Images are rotated to orient glottis vertically and are cropped to optimize image processing. Digital kymogram is generated from position halfway between anterior and posterior commissures. Lateral displacement waveforms are then obtained by tracing edges of vocal folds in digital kymogram. Relative vocal fold pliability is estimated by calculating ratio between maximum amplitude of vocal fold injected with biomaterial and that of noninjected vocal fold. der to monitor and control phonation driving pressures, and were also measured from recorded signals during subsequent analyses. Our method for testing vocal function uses a tracheal needle to supply air with instrument-manipulated adduction of the vocal folds to initiate phonation. These recordings allow us to assess the pliability of the vocal folds under physiological conditions. Furthermore, this in vivo procedure allows us to test vocal function at multiple time points, which is ideal for following the progress of the effect of PEG30 injection over time and minimizes the number of animals needed. High-Speed Video Data Collection and Analysis. Imaging of canine vocal fold vibration during induced phonation was accomplished by attaching a Phantom v7.3 high-speed video camera (Vision Research, Inc, Wayne, New Jersey) to the optical adapter of the operating microscope. This enabled magnified high-quality color imaging at 12bit quantization with a complementary metal–oxide–semiconductor image sensor. High-speed video data were recorded at 4,000 images per second with maximum integration time and a spatial resolution of 448 horizontal × 424 vertical pixels to capture an approximately 2-cm2 target area. Illumination was provided by a Leica F40 surgical microscope with an integrated 300-W xenon arc light source. Each high-speed video data segment consisted of 1,000 images (250 ms). A previous report describes the digital image processing methods that were used to estimate lateral displacements of the left and right vocal folds from the recorded high-speed video segments.27 Briefly, the processing steps included correction of motion artifact; user selection of a glottal midline; rotation and cropping of images to vertically orient the midline; conversion from color to monochromatic images; user selection of an intensity threshold that optimized glottal edge detection; generation of a digital kymogram at the mid-musculomembranous glottis; and extraction of waveforms representing the amplitude of left and right vocal fold motion from the kymograms (Fig 1). To assess the impact of the injected biomaterial on the pliability of the vocal fold, we defined a measure of left-right amplitude asymmetry as the ratio between the maximum amplitude of the injected vocal fold and the maximum amplitude of the noninjected vocal fold. Magnetic Resonance Microscopy and/or Microimaging. Immediately after euthanasia, the larynges were removed, rinsed with 0.9% saline solution, and fixed in cold PBS-buffered 4% paraformaldehyde. Magnetic resonance microimaging of the excised larynges was done as described elsewhere.28 Briefly, the larynges were suspended in Fomblin and imaged with a Bruker Avance-500 nuclear magnetic resonance spectrometer (11.7 T; 500 MHz for proton). A 30-mm “birdcage” transmitter and/or receiver coil was used for imaging. Transverse and/or coronal scans were obtained throughout the length of the segment with multi-slice multi-echo sequences. Transverse and/or coronal and axial images were then obtained through regions of interest. Gradient recalled echo images were acquired according to the following parameters: slice thickness, 0.3 mm; field of view, 20 mm; MTX, 512 (pixel size, 39 μm); and the following pulse parameters: repetition time, 1,000 ms; echo time (effective), 8.3 ms; flip angle, 10°; and NEX, 32. Sixty-four transverse or coronal slices and 32 axial slices were obtained per dog larynx for all 16 dogs injected. Fat was suppressed Karajanagi et al, Canine Vocal Fold Function After Injection of New Biomaterial 91 Fig 2. Representative example of histology– magnetic resonance imaging matching (top panels) that was used for 3-dimensional reconstruction of vocal fold with Amira software (bottom panels). Arrows show location of residual PEG30 and cellular infiltrate. A — anterior; P — posterior. with a fat-presaturation pulse during imaging. Data were processed with Paravision software provided by the vendor. Histologic Analysis. Each excised larynx was bisected in the sagittal plane, and each half was then trimmed and cut in two pieces in the coronal plane near the middle of the vocal folds. The pieces were oriented appropriately and embedded in paraffin. Coronal sections, 5 μm thick, were cut and saved at fixed intervals along the anterior-posterior extent of the vocal fold. For each specimen, we used the magnetic resonance images to guide the cutting of the paraffin sections such that the injection sites were fully encompassed. Alternate slides were stained with hematoxylin and eosin and Masson’s trichrome stains and examined with brightfield microscopy. Digital photomicrographs were obtained with a Zeiss Axioskop2 microscope system. When necessary, differential interference contrast microscopy was used to improve image quality. Identification of Cases With Superficial Injections. In order to correctly attribute potential postin- jection changes in the in vivo vibration of the vocal folds to the injected biomaterial, we reasoned that it would be important that the injected biomaterial and the reaction that it caused be extremely superficial so as to maximally affect vocal fold vibration. In order to visualize and quantify the 3-dimensional (3-D) location of the residual biomaterial and the accompanying biological reaction, we used calibrated magnetic resonance images in combination with histologic imaging. Masson’s trichrome– stained histologic sections were matched with coronal magnetic resonance microimaging slices in order to delineate residual biomaterial and cellular infiltrate from the surrounding vocal fold tissue in the magnetic resonance microimages as described in detail elsewhere.28 An example of magnetic resonance imaging–histology image matching is shown in Fig 2 (top panels). Three-dimensional reconstruction of consecutive calibrated magnetic resonance microimaging slices was then done with Amira software (Visage Imaging, Inc, San Diego, California) to visualize the location and quantify the volume of the residual biomaterial and cellular infiltrate (Fig 2, 92 Karajanagi et al, Canine Vocal Fold Function After Injection of New Biomaterial Fig 3. “Vibratory zone” (shaded in blue) of vocal fold identified in magnetic resonance microimaging slice of vocal fold. Arrow shows location of residual material and cellular infiltrate. bottom panels). Data from all 16 cases were screened to identify subjects that had residual biomaterial and/or cellular infiltrate in the key “vibratory zone” of the vocal folds. The vibratory zone of the vocal fold was identified as the area in the SLP defined by points 1 mm on the superior surface and 2.5 mm on the medial surface from the free edge of the vocal fold (Fig 3). As part of the screening process, subjects that had less than 5 μL of residual biomaterial and cellular infiltrate were eliminated. For each of the remaining subjects, 3 to 4 consecutive magnetic resonance microimaging slices with the highest percentage of residual biomaterial and cellular infiltrate were identified. For each of these magnetic resonance microimaging slices, we computed the “vibratory fraction,” ie, the percentage of the vibratory zone occupied by the residual biomaterial and cellular infiltrate, and averaged it across the measured slices. The 3 animals that had the highest average vibratory fractions were identified and subjected to in-depth analyses. Representative magnetic resonance microimages and the 3-D reconstructions of vocal folds for the 3 selected cases are shown in Fig 4. One subject each with survival time points of 1 month, 2 months, and 3 months constituted the 3 subjects selected by this screening process. RESULTS Vocal Fold Function Before and After PEG30 Injection. We evaluated vocal fold function for the 3 selected animals (those with the most superfi- cial PEG30 injections; see Methods) during in vivo phonation, whereby delivery of subglottic air pressure and manual adduction of the arytenoid cartilages caused the vocal folds to valve the airstream in a manner resembling natural phonation. All vocal folds at all time points displayed clear evidence of mucosal wave activity. The average phonation threshold pressures were low (4 to 8.5 cm H2O). Analysis of symmetry in vocal fold amplitude failed to show a consistent difference in lateral tissue excursion for the injected versus noninjected (control) vocal folds (Fig 5). Statistical comparison of the relative vocal fold amplitude (injected divided by noninjected) prior to injection versus the last recording time for each animal failed to find a difference (2-tailed paired t-test, p = 0.26). Likewise, phonation threshold pressures did not differ between preinjection measures and the last recording session for each animal (2-tailed t-test, p = 0.40; Fig 6). Taken together, these two findings suggest that the injected gel and/or tissue response did not appreciably alter the pliability of the superficialmost portion of the SLP during manually elicited phonation. Biocompatibility of PEG30. Multiple in vivo examinations of the canine vocal folds with an operating microscope and gentle blunt-instrument palpation revealed no clinical evidence of inflammation such as erythema or edema. In all 3 cases, the injected vocal fold surface looked identical to the noninjected vocal fold under high magnification. Histologic analysis of the vocal fold for canine 1 (survival time of 1 month after injection) revealed the presence of PEG30 in the vocal fold, accompanied by significant macrophage infiltration at the implantation site, including and surrounding the PEG30 (Fig 7A,B). To a lesser extent, lymphocytes and plasma cells were also present. No giant cells or neutrophils were observed. Slight to mild fibrosis was seen, but no fibrotic capsule formation was observed around the PEG30. The macrophages adjacent to the implant had a foamy cytoplasm suggesting active phagocytosis of the PEG30 by the macrophages. These observations suggest that PEG30 is biodegradable by macrophage-mediated phagocytosis. Similar histopathologic findings were observed for canine 2 (survival time of 2 months after injection) and canine 3 (survival time of 3 months after injection), although with amounts of residual PEG30 and macrophages that decreased with each successive month (Fig 7C,D). No fibrosis in the vocal fold was seen for either canine 2 or canine 3. The foreign body response to PEG30 seemed to resolve over time, with no apparent damage to the surrounding vocal fold tissue and with replacement of the lost material by loose connective tissue. Karajanagi et al, Canine Vocal Fold Function After Injection of New Biomaterial 93 Fig 4. Representative magnetic resonance microimages (top panels) and respective 3-dimensional reconstructions (bottom panels) of vocal folds for 3 selected dogs. “Vibratory zone” is shaded in blue, and arrows show location of residual PEG30 and cellular infiltrate. Canine 1 received 2 injections, both at time zero. Relatively more superficial-medial injection is shown by arrow in magnetic resonance microimage and in 3-dimensional reconstruction. A — anterior; P — posterior. In all 3 animals, no signs of any long-lasting fibrosis or other tissue damage were seen. Overall, the absence of a neutrophil response, the lack of a fibrotic capsule, and the macrophage-mediated clearance of PEG30 with minimal to no fibrosis suggest that PEG30 is biocompatible and biodegradable in Fig 5. Comparison of ratios of amplitude asymmetry between injected and noninjected vocal folds for 3 selected dogs as function of time. the vocal folds. DISCUSSION Normal vocal fold vibration is manifested primarily as a wave of displaced mucosal tissue on the sur- Fig 6. Comparison of phonation threshold pressures for 3 selected dogs as function of time. 94 Karajanagi et al, Canine Vocal Fold Function After Injection of New Biomaterial A B C D face of the vocal folds, ie, the mucosal wave. The phonatory or vibratory mucosa is mostly composed of a soft and pliable layer of SLP with a thin covering of epithelium that essentially mimics the biomechanical properties of the SLP substrate. The main cause of chronic dysphonia or voice loss is permanent damage and/or scarring of the normal SLP. No proven methods currently exist for restoring normal function to vocal folds that have lost the pliability of this key vibratory layer. This report describes the results from initial testing of a new synthetic PEG30 hydrogel being developed to restore vibratory function to vocal folds that have lost some pliability of the phonatory mucosa. Polyethylene glycol was chosen as the basis for this new material because numerous PEG-based materials are already approved by the US Food and Drug Administration for implants in other parts of the body, and therefore our modification had good potential to be biocompatible. In addition, during initial low-frequency rheometric screening, the PEG30 formulation seemed soft and pliable enough to potentially mimic the biomechanical function of normal SLP, and it could be injected through the different types of 25-gauge needles currently used for vocal fold infusion during phonosurgery.26 It was Fig 7. Masson’s trichrome– stained images of PEG30-injected vocal folds of A,B) canine 1, C) canine 2, and D) canine 3. deemed necessary to first determine if the impact of PEG30 on healthy vocal fold tissue and function was acceptable prior to investigating its use in vocal fold pathology, particularly since most patients who have lost some pliability of the phonatory mucosa still retain some normal regions of SLP. The biocompatibility and impact on vocal function of PEG30 were tested longitudinally in an in vivo canine model with survival times ranging from 1 to 4 months. This report focuses on results from 3 dogs (1 each at 1, 2, and 3 months) for whom 3-dimensional reconstruction analysis of 11.7-T magnetic resonance imaging and serial-section histologic analysis of excised larynges showed that the PEG30 injections were superficial, so as to ensure maximal impact on vocal fold vibratory function. The presence of PEG30 did not negatively affect normal phonatory vibration: the injected canine vocal folds displayed clear mucosal waves at all 3 postinjection time points, vibratory amplitudes that did not differ significantly from those of the contralateral noninjected vocal folds, and no significant change in phonation threshold pressure relative to preinjection phonation. The PEG30 also appeared to elicit a minimal biological response when implanted in the SLP of ca- Karajanagi et al, Canine Vocal Fold Function After Injection of New Biomaterial nine vocal folds, with no evidence of an overt inflammatory response either in terms of the vocal fold surface or with respect to histologic findings. The biological response to PEG30 in the vocal folds of the remaining 13 dogs was similar to that seen in the 3 selected cases. In all dogs, the residual PEG30 was actively phagocytosed by macrophages, and the amount of residual PEG30 and macrophages progressively decreased with an increase in survival period. The PEG30 and the foreign body reaction were resorbed with no apparent damage to the surrounding vocal fold tissue, and the lost PEG30 was replaced by nonfibrotic loose connective tissue. An in-depth examination of the biological response to PEG30 in all 16 animals, however, is out of the scope of this report that focuses primarily on the functional evaluation of PEG30 injected in the phonatory mucosa. A future report will utilize histologic data from the entire cohort of 16 animals to evaluate the biological response to PEG30 in detail. Overall, comparative analysis of histologic results across 1- to 3-month survival end points indicates that after PEG30 is injected into the SLP of vocal folds it biodegrades within 3 to 4 months without creating damage (fibrosis) or mechanical changes (stiffness) in healthy tissue. If it is assumed that there are no residual beneficial effects after PEG30 has been resorbed (eg, stimulation of tissue remod- 95 eling), then the current formulation of PEG30 would probably have to be reinjected at approximately 3-month intervals to maintain its positive impact on vocal function. Reinjections could probably be accomplished as an outpatient procedure. This 3-month outpatient treatment interval for chronic vocal fold scarring is generally in line with the timing of the repeated Botox injections that are currently used to manage chronic laryngeal dystonias. Devising strategies to increase the residence time of PEG30 by using chemical engineering and other approaches, however, is also an important goal. In summary, the results of this initial assessment provide support for the continued development and testing of PEG30 as a potential treatment for hoarseness resulting from deficiencies in pliability and contour of the phonatory mucosa. CONCLUSIONS The PEG30 hydrogel is a promising candidate biomaterial to restore vibration to scarred or deficient phonatory mucosa, since PEG30 exhibits in vivo biocompatibility and pliability without impeding normal SLP function. These characteristics support a potential treatment paradigm for a majority of cases of irresolvable hoarseness, including vocal fold scar, since most patients have some residual pliable mucosa impeded by focal zones of stiffness. REFERENCES 1. Brunings W. Technique of autoscopic operations. Direct laryngoscopy, bronchoscopy, and esophagoscopy. London: Bailliere, Tindall, & Cox, 1912:118-20. 2. Payr E. Plastik am schildknorpel zur Behebung der Folgen einseitiger Stimmbandlahmung. Dtsch Med Wochenschr 1915;43:1265-70. 3. Arnold GE. Vocal rehabilitation of paralytic dysphonia. I. Cartilage injection into a paralyzed vocal fold. AMA Arch Otolaryngol 1955;62:1-17. 4. Isshiki N, Morita H, Okamura H, Hiramoto M. Thyroplasty as a new phonosurgical technique. Acta Otolaryngol 1974;78:451-7. 10. Allen J. Cause of vocal fold scar. Curr Opin Otolaryngol Head Neck Surg (in press). 11. Bless DM, Welham NV. Characterization of vocal fold scar formation, prophylaxis, and treatment using animal models. Curr Opin Otolaryngol Head Neck Surg (in press). 12. Chhetri DK, Mendelsohn AH. Hyaluronic acid for the treatment of vocal fold scars. Curr Opin Otolaryngol Head Neck Surg (in press). 13. Kishimoto Y, Hirano S, Kitani Y, et al. Chronic vocal fold scar restoration with hepatocyte growth factor hydrogel. Laryngoscope 2010;120:108-13. 5. Isshiki N, Tanabe M, Sawada M. Arytenoid adduction for unilateral vocal cord paralysis. Arch Otolaryngol 1978;104:5558. 14. Kishimoto Y, Welham NV, Hirano S. Implantation of atelocollagen sheet for vocal fold scar. Curr Opin Otolaryngol Head Neck Surg (in press). 6. Zeitels SM, Hochman I, Hillman RE. Adduction arytenopexy: a new procedure for paralytic dysphonia with implications for implant medialization. Ann Otol Rhinol Laryngol Suppl 1998;107(suppl 173):1-24. 15. Long JL. Tissue engineering for treatment of vocal fold scar. Curr Opin Otolaryngol Head Neck Surg (in press). 7. Zeitels SM, Healy GB. Laryngology and phonosurgery. N Engl J Med 2003;349:882-92. 8. Zeitels SM, Blitzer A, Hillman RE, Anderson RR. Foresight in laryngology and laryngeal surgery: a 2020 vision. Ann Otol Rhinol Laryngol Suppl 2007;116(suppl 198):1-16. 9. Roy N, Merrill RM, Thibeault S, Parsa RA, Gray SD, Smith EM. Prevalence of voice disorders in teachers and the general population. J Speech Lang Hear Res 2004;47:281-93. 16. Sataloff RT. Autologous fat implantation for vocal fold scar. Curr Opin Otolaryngol Head Neck Surg (in press). 17. Suehiro A, Hirano S, Kishimoto Y, Rousseau B, Nakamura T, Ito J. Treatment of acute vocal fold scar with local injection of basic fibroblast growth factor: a canine study. Acta Otolaryngol 2010;130:844-50. 18. Molteni G, Bergamini G, Ricci-Maccarini A, et al. Autocrosslinked hyaluronan gel injections in phonosurgery. Otolaryngol Head Neck Surg 2010;142:547-53. 19. Finck C, Lefebvre P. Implantation of esterified hyaluronic 96 Karajanagi et al, Canine Vocal Fold Function After Injection of New Biomaterial acid in microdissected Reinke’s space after vocal fold microsurgery: first clinical experiences. Laryngoscope 2005;115:18417. 20. Finck CL, Harmegnies B, Remacle A, Lefebvre P. Implantation of esterified hyaluronic acid in microdissected Reinke’s space after vocal fold microsurgery: short- and long-term results. J Voice 2010;24:626-35. 21. Duflo S, Thibeault SL, Li W, Shu XZ, Prestwich GD. Vocal fold tissue repair in vivo using a synthetic extracellular matrix. Tissue Eng 2006;12:2171-80. 22. Hansen JK, Thibeault SL, Walsh JF, Shu XZ, Prestwich GD. In vivo engineering of the vocal fold extracellular matrix with injectable hyaluronic acid hydrogels: early effects on tissue repair and biomechanics in a rabbit model. Ann Otol Rhinol Laryngol 2005;114:662-70. 23. Jahan-Parwar B, Chhetri DK, Ye M, Hart S, Berke GS. Hylan B gel restores structure and function to laser-ablated canine vocal folds. Ann Otol Rhinol Laryngol 2008;117:703-7. 24. Hirano M. Phonosurgery: basic and clinical investigations. Otologia (Fukuoka) 1975;21:239-442. 25. Chan RW, Titze IR. Viscoelastic shear properties of human vocal fold mucosa: measurement methodology and empirical results. J Acoust Soc Am 1999;106:2008-21. 26. Zeitels SM, Vaughan CW. A submucosal true vocal fold infusion needle. Otolaryngol Head Neck Surg 1991;105:478-9. 27. Mehta DD, Deliyski DD, Zeitels SM, Quatieri TF, Hillman RE. Voice production mechanisms following phonosurgical treatment of early glottic cancer. Ann Otol Rhinol Laryngol 2010;119:1-9. 28. Herrera VL, Viereck JC, Lopez-Guerra G, et al. 11.7 Tesla magnetic resonance microimaging of laryngeal tissue architecture. Laryngoscope 2009;119:2187-94. Potential of Induced Pluripotent Stem Cells for the Regeneration of the Tracheal Wall Mitsuyoshi Imaizumi, MD; Yukio Nomoto, MD; Takashi Sugino, MD; Masao Miyake, PhD; Ikuo Wada, PhD; Tatsuo Nakamura, MD; Koichi Omori, MD Objectives: Our previous studies focused on basic research and the clinical applications of an artificial trachea. However, the prefabricated artificial trachea cannot be utilized for pediatric airways, because the tracheal frame needs to expand as the child develops. The purpose of this study was to evaluate the potential of induced pluripotent stem (iPS) cells for the regeneration of the tracheal wall. Methods: We cultured iPS cells in a 3-dimensional (3-D) scaffold in chondrocyte differentiation medium (bioengineered scaffold model), and the results were compared with those in a 3-D scaffold without iPS cells (control scaffold model). The 3-D scaffolds were implanted into tracheal defects in 8 nude rats. After 4 weeks, the regenerated tissue was histologically examined. Results: Implanted iPS cells were confirmed to exist in all 5 rats implanted with bioengineered scaffolds. Cartilage-like tissue was observed in the regenerated tracheal wall in 2 of the 5 rats in the bioengineered scaffold model, but in none of the 3 rats in the control scaffold model. Conclusions: Implanted iPS cells were confirmed to exist in the bioengineered scaffold. Cartilage-like tissue was regenerated in the tracheal defect. This study demonstrated the potential of iPS cells in the regeneration of the tracheal wall. Key Words: bioengineered scaffold, chondrogenesis, induced pluripotent stem cell, regeneration, tracheal wall. the regeneration of tracheal tissue.3-5 This technique was used in 4 patients,6 and all cases have shown good progress without restenosis. However, the premade artificial trachea cannot be utilized for pediatric airways, because the tracheal frame needs to expand as the child develops. Even now, the treatment of pediatric laryngotracheal stenosis remains a difficult challenge, because treatment often requires multistaged procedures and successful decannulation sometimes fails after a series of operations.7,8 INTRODUCTION Reconstruction of the upper airway after the resection of malignancies or stenotic inflammatory lesions is thought to be difficult. The trachea is composed of the tracheal epithelium, a ligament comprising collagen fibers for the maintenance of elasticity, and cartilage. Ideally, both the airway framework and the endotracheal surface should be reconstructed. Several types of flaps and grafts, made from cartilage, muscle, skin, and so on, have been used in the repair of defects after the resection of tracheal lesions.1,2 However, postoperative scarring or granulation is sometimes observed, leading to airway stenosis. Therefore, reconstruction of the respiratory tract with full functionality is vital after surgical treatment for cancer or stenotic inflammatory lesions. Our group has developed and clinically applied an artificial trachea made from a collagen sponge with a polypropylene scaffold frame for If the tracheal wall could be regenerated with patient-derived cells, this problem would be solved. Previously, novel embryonic stem (ES) cell–like pluripotent cells, known as induced pluripotent stem (iPS) cells, were generated from mouse skin fibroblasts by the introduction of 4 transcription factors.9 These cells are capable of unlimited symmetric selfrenewal, thus providing an unlimited cell source for tissue engineering applications. In addition, the use From the Department of Otolaryngology (Imaizumi, Nomoto, Omori), the Department of Basic Pathology (Sugino), the First Department of Physiology (Miyake), and the Department of Cell Science, Institute of Biomedical Sciences (Wada), School of Medicine, Fukushima Medical University, Fukushima City, and the Department of Bioartificial Organs, Institute for Frontier Medical Sciences, Kyoto University, Kyoto (Nakamura), Japan. This study was supported in part by a Challenging Exploratory Research grant from the Japan Society for the Promotion of Science and in part by a Grant-in-Aid for Young Scientists (Startup) from the Japan Society for the Promotion of Science. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Mitsuyoshi Imaizumi, MD, Dept of Otolaryngology, Fukushima Medical University, School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan. 97 98 Imaizumi et al, Induced Pluripotent Stem Cells ated cells.14 For this purpose, we prepared puromycin-resistant SNL 76/7 cells. Briefly, the Streptomyces alboniger puromycin-N-acetyl-transferase gene was subcloned into a retrovirus shuttle vector, pCX4bsr,15 and introduced into SNL 76/7 cells by infecting the recombinant retrovirus vector as described previously.16 The puromycin-resistant SNL cells were selected by culturing in DMEM in the presence of 2 μmol/L puromycin. Fig 1. Green fluorescent protein–expressing undifferentiated induced pluripotent stem (iPS) cell colonies. Bar — 100 μm. of iPS cells obtained from patient-derived somatic cells can prevent transplant rejection. Recent studies have found that iPS cells could provide a new cell source for regeneration therapy.10-13 The purpose of this study was to evaluate the potential of iPS cells in the regeneration of the tracheal wall through the effective use of a bioengineered scaffold containing iPS cells. MATERIALS AND METHODS Cell Culture. Induced pluripotent stem cells from the iPS-MEF-Ng-20D-17 line (20D-17 purchased from Riken BioResource Center, Tsukuba, Japan) were routinely cultured on a feeder layer of mitomycin C–inactivated mouse embryonic fibroblasts, SNL 76/7 (DS Pharma Biomedical Co, Ltd, Osaka, Japan) in a cultivation medium consisting of Dulbecco’s modified Eagle’s medium (DMEM; Gibco, Invitrogen, Grand Island, New York) supplemented with 15% fetal bovine serum (FBS; SAFC Biosciences, Lenexa, Kansas), 2 mmol/L L-glutamine (Gibco, Invitrogen), 0.4 mL β-mercaptoethanol (Sigma-Aldrich, St Louis, Missouri), and nonessential amino acids (Gibco, Invitrogen). Induced pluripotent stem cell lines were passaged every second day with 0.25% trypsin–ethylenediaminetetraacetic acid (Gibco, Invitrogen). To maintain iPS cell pluripotency, we cultured iPS cells in the above-mentioned medium on puromycin-resistant SNL 76/7 cells containing 1.0 μg/mL puromycin (Sigma-Aldrich) during selection of undifferentiated cells, to select green fluorescent protein (GFP)–expressing undifferentiated cells (Fig 1), on a gelatin-coated dish (6 cm in diameter). The GFP expression became negative when differentiation was induced, whereas GFP expression remained in undifferenti- Morphological Examination In Vitro. Induced pluripotent stem cells were cultured on a gelatincoated dish in a chondrocyte differentiation medium (CDM; Cell Applications, Inc, San Diego, California) to confirm chondrogenic differentiation of iPS cells. As a control, iPS cells were cultured on a gelatin-coated dish in 10% FBS–DMEM. After 6 weeks of cultivation, iPS cells were stained with Alcian blue to detect acidic proteoglycans produced by chondrocytes.17 Detection of Gene Expression by Quantitative Reverse Transcription–Polymerase Chain Reaction. Total RNA was isolated with an RNeasy Mini-Kit (Qiagen, Hilden, Germany). Samples were treated with Turbo DNase-free (Ambion, Austin, Texas) to remove traces of genomic DNA contamination. Total RNA (0.4 μg) was reverse-transcribed to complementary DNA by use of Superscript III Reverse Transcriptase (Invitrogen, Carlsbad, California) and oligo-dT primer according to the manufacturer’s instructions. Real-time polymerase chain reaction was performed with master mixes (Applied Biosystems, Foster City, California) for SYBR green incorporation and an ABI Prism 7300 detector. The thermal cycling conditions were 50°C for 2 minutes and 95°C for 10 minutes, followed by 40 cycles of 95°C for 15 seconds and 60°C for 1 minute. The following premade primers purchased from TaKaRa Bio (Shiga, Japan) were used: type II collagen (Col2a1; MA067811), type I collagen (Col1a1; MA093358), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; MA050371). The primer sequence for genes encoding the matrix protein type II collagen was 5'-AGGGCAACAGCAGGTTCACATAC-3', 5'-TGTCCACACCAAATTCCTGTTCA-3'. Bone matrix protein collagen I (5'-ATGCCGCGACCTCAAGATG-3', 5'-TGAGGCACAGACGGCTGAGTA-3') and the “housekeeping gene” GAPDH (5'-TGTGTCCGTCGTGGATCTGA-3', 5'-TTGCTGTTGAAGTCGCAGGAG-3') were used as internal standards. Fabrication of Bioengineered Scaffold and Differentiation of iPS Cells. Omori et al5 and Nakamura Imaizumi et al, Induced Pluripotent Stem Cells 99 Fig 2. Fabrication of bioengineered scaffold. Three-dimensional (3-D) scaffold consists of collagenous sponge and polypropylene mesh. Control scaffold model is 3-D scaffold with gel only. Bioengineered scaffold model is 3-D scaffold with gel containing chondrogenic cells differentiated from iPS cells. CDM — chondrocyte differentiation medium. et al3 developed an artificial trachea made from a collagen sponge scaffold and polypropylene mesh based on the concept of in situ tissue engineering for tracheal regeneration. The polypropylene mesh used was a conventional material developed for clinical applications, and the collagen sponge consisted of type I and type III collagens of porcine origin. The procedure for the production of the artificial trachea was described by Nakamura et al.3 The sponge, with a pore size range of 100 to 500 μm, was made from porcine dermal atelocollagen, consisting of type I (70% to 80%) and type III collagen. The atelocollagen was dissolved in a hydrochloric acid solution, pH 3.0, at a concentration of 1.2%, stirred at 8,000 rpm for 15 minutes, freeze-dried, and heated at 140°C in a vacuum for 24 hours. In our current study, we used a 3-dimensional (3-D) scaffold (diameter, 10 mm; thickness, 3 mm) made from a piece of artificial trachea. Collagen gel containing iPS cells was prepared as follows. A type I collagen solution (Nitta Gelatin, Osaka), fivefold-concentrated DMEM/F-12, and reconstituted buffer (25 mmol/L Hepes, 0.15 mol/L sodium hydroxide) were mixed at a ratio of 7:2:1. Induced pluripotent stem cells were suspended in the reconstituted collagen solution at a density of 5.0 × 106 cells per milliliter. To cultivate the iPS cells, we used a 3-D scaffold made from the abovementioned collagen sponge scaffold with polypropylene mesh. Four hundred microliters of 0.3% collagenous solution containing the iPS cells was introduced into the 3-D scaffold (2.0 × 106 cells per scaffold) in Millicell Culture Plate inserts (Millipore Co, Billerica, Massachusetts) with a membrane filter (0.4 μm in pore size), and the collagenous solution was allowed to infiltrate the scaffold. The bioengineered scaffolds were then incubated at 37°C for at least 30 minutes, and the collagenous solution formed a gel. These bioengineered scaffolds were placed in 6-well polystyrene plates (Becton Dickinson, Franklin Lakes, New Jersey) containing 2 mL of CDM (bioengineered scaffold model). As a control, collagen gel without iPS cells (control scaffold model) infiltrated into a 3-D scaffold was cultured in 10% FBS–DMEM. After 6 weeks of cultivation in vitro, each of the scaffolds was implanted into nude mice (Fig 2). Implantation Into Tracheal Defects in Rats. This study was carried out under the control of the Animal Care and Use Committee in accordance with Guidelines for Animal Experiments of Fukushima Medical University, the Japanese Government Law Concerning the Protection and Control of Animals, and the Japanese Government Notification on Feeding and Safekeeping of Animals. A total of eight 8- to 10-week-old, male F344/ NJcl-rnu/rnu nude rats were used as implant recipients in this study. The 8 rats each received one of the two types of 3-D scaffold (bioengineered scaffold or control scaffold). Tracheostomy and implantation of one of the two types of scaffold were performed under general anesthesia induced by inhalation of isoflurane. The cervical tracheas were exposed through a vertical skin incision, and the sternohyoid and sternothyroid muscles were split along the median line. Tracheal defects, approximately 1.5 mm in width by 2.5 mm in length, were then formed. The scaffolds were laid onto the tracheal defects. In order to prevent shifting of the graft, we then replaced the sternohyoid and sternothyroid muscles over the graft and sutured them. Finally, the incised skin was sutured. At 28 days after the operation, the rats were painlessly sacrificed, and the tracheas and the sternohyoid and sternothyroid muscles were removed en bloc (Fig 2). The samples were fixed in 100 Imaizumi et al, Induced Pluripotent Stem Cells A B Fig 3. Morphological examination in vitro. Bars — 100 μm. A) Six weeks after cultivation, iPS cells cultured in CDM show Alcian blue–stained areas around iPS cell colonies. B) In contrast, iPS cells cultured in 10% fetal bovine serum–Dulbecco’s modified Eagle’s medium show no Alcian blue–stained areas. 4% paraformaldehyde, embedded in paraffin, and sliced for hematoxylin and eosin staining and immunohistochemical analysis. To detect differentiation of the tissue components, we performed immunohistochemical analysis using antibodies to cytokeratin AE1/3 (DAKO, Tokyo, Japan) for the epithelium, glial fibrillary acidic protein (DAKO) for the nervous system, and muscle-specific actin (Enzo, New York, New York) for muscles. RESULTS Morphological Examination In Vitro. Six weeks after cultivation, iPS cells cultured in CDM showed Alcian blue–stained areas around iPS cell colonies (Fig 3A). In contrast, iPS cells cultured in 10% FBS–DMEM showed no Alcian blue–stained areas (Fig 3B). Detection of Gene Expression by Quantitative RT-PCR Analysis. Messenger RNA expression of type II collagen was increased 4 weeks after cultivation with CDM. Expression of type I collagen, an osteogenic differentiation marker, was not detected in either group at any time point (Fig 4). Implantation of 3-D Scaffolds Into Tracheal Defects in Rats. Survival of the iPS cells was confirmed in the bioengineered scaffold in all 5 rats, from the formation of various tissues derived from the three germ layers of the teratoma. Glands, nerves, and muscles were identified by hematoxylin and eosin staining and immunohistochemical analysis (Fig 5). The teratomas were identified just outside the implants in all cases. In the regenerated tissue of the tracheal wall, cartilage-like tissue was observed (Fig 6) in 2 of the 5 rats in the bioengineered scaffold model. One and two cartilage-like tissue foci, respectively, were identified in the 2 rats. The cartilage-like formations identified were one tenth the size of the cartilage defect in the original trachea. On the other hand, no cartilage-like tissue was observed in any of the 3 rats in the control scaffold group (Fig 7). DISCUSSION Cartilage regeneration therapy has been applied clinically to the treatment of osteoarthritis. The first implantation of autologous cultured chondrocytes Fig 4. Polymerase chain reaction– based analysis of chondrocyte differentiation in vitro. Messenger RNA expression of type II collagen was increased 4 weeks after cultivation. Expression of type I collagen, osteogenic differentiation marker, was not detected in either group at any time point. A) Type II collagen. B) Type I collagen. A B Imaizumi et al, Induced Pluripotent Stem Cells 101 Fig 5. Histologic findings of teratoma formation in vivo. In bioengineered scaffold, tissues associated with three germ layers of teratoma, such as glands (endoderm), nerves (ectoderm), and muscles (mesoderm), were identified by B,D,F) hematoxylin and eosin staining and C,E,G) immunohistochemical analysis performed with antibodies to cytokeratin AE1/3 (C), glial fibrillary acidic protein (E), and musclespecific actin (G). A) Original ×40. Bar — 1 mm; arrows — teratoma formation in bioengineered scaffold. B,C) Glands (original ×400). D,E) Nerves (original ×400). F,G) Muscles (original ×400). A B D F C E G was performed in the treatment of knees with articular cartilage defects more than 20 years ago. To reduce surgical invasiveness and complications, the procedure for chondrocyte implantation has been improved; however, no consensus has been reached regarding this treatment.18 Further difficulties remain, in that the amount of autologous chondrocytes is limited, and invasive procedures are essential. Thus, numerous studies have focused on the differentiation of chondrogenic cells in vitro, with mesenchymal cell lines and ES cell lines used as potential cell sources.19-24 These reports show that mesenchymal stem cells and ES cells have chondrogenic potential. Although mesenchymal cell lines, such as mesenchymal stem cells from bone marrow, are relatively safe, these cells have limited ability to proliferate and differentiate, and their ability to do so is further decreased after several passages. On the other hand, ES cells are capable of unlimited proliferation and differentiation into any tissue or cell. However, teratoma formation and ethical issues have posed problems for tissue engineering applications using ES cells. This is the first demonstration of iPS-derived cells differentiating into chondrocytes in a 3-D scaffold for tracheal regeneration. Induced pluripotent stem cells have the potential to differentiate into chondrogenic cells, as shown by the appearance of Alcian blue–stained colonies and expression of a cartilage-associated gene. Normal iPS cells were slightly stained with Alcian blue, whereas iPS cell colonies cultured with CDM were strongly stained with Alcian blue. This finding suggests that proteoglycan is strongly expressed in differentiated iPS cells. This study suggests the potential for iPS cells to be used as a new cell source in tracheal regeneration therapy. Our results show that iPS cells differentiate into chondrocytes in vitro. Cartilage-like tissue was observed in vivo in the 3-D scaffold containing differ- 102 Imaizumi et al, Induced Pluripotent Stem Cells A A B B Fig 6. Histologic findings of implanted bioengineered scaffold in vivo. A) Original ×40. Bar — 1 mm. B) Original ×400. Bar — 100 μm. Cartilage-like tissue was observed in rats in bioengineered scaffold model. Fig 7. Histologic findings of implanted control scaffold in vivo. A) Original ×40. Bar — 1 mm. B) Original ×400. Bar — 100 μm. No cartilage tissue was observed in rats in control scaffold model. entiated iPS cells. In our current study, we implanted the 3-D scaffold containing differentiated iPS cells after culture for 6 weeks into in vivo tracheal defects because most of the chondrocytic cells were stained with Alcian blue in vitro. release of various factors appropriate to maintain a chondrogenic phenotype. However, the regenerated tissue was rather far from the area of the tracheal cartilage defects. In future, we intend to further investigate scaffold size, thickness, and gel volume to better match the tracheal defect area. In this study, cartilage-like tissue could be confirmed in vivo. However, similar studies using ES cells failed to observe cartilage tissue formation in vivo, although histologic and polymerase chain reaction analysis has demonstrated chondrogenic differentiation in vitro.24,25 The reason suggested for this finding was that predifferentiation in vitro was insufficient to maintain a stable chondrogenic phenotype in vivo. Grafts, in these studies, were implanted ectopically in the subcutaneous tissue of the backs of nude mice. The lack of chondrogenic signals in the ectopic implantation site suggests the dedifferentiation or cell death of the implanted cartilaginous tissue. Thus, continuous chondrogenic stimulation may need to be maintained. In our study, differentiated iPS cells were implanted in tracheal cartilage defects. The conditions in this case may induce the In the bioengineered scaffold, the survival of iPS cells was confirmed by teratoma formation. In this study, all implanted iPS cells formed teratomas. There are no previous reports on the use of iPS cells for tracheal cartilage regeneration; however, the current study has indicated that teratoma formation from iPS cells may be affected by the method used for reprogramming and differentiation, the site of transplantation, the host background, and other factors. It was also shown that there was a significant correlation between teratoma size and undifferentiated iPS cell content.26 We tried to induce the differentiation of the iPS cells to chondrocytes using bone morphogenetic protein 2. However, these iPS cells also formed teratomas (data not shown). To reduce teratoma formation, we will attempt to re- Imaizumi et al, Induced Pluripotent Stem Cells duce the number of undifferentiated cells by using more effective methods that were described previously.13,22,23 Information with regard to the ratio of differentiated to undifferentiated cells would also be useful in dealing with the problem of teratoma formation. Further studies on inducing the effective differentiation of iPS cells to chondrocytes in vitro are expected. CONCLUSIONS This is the first demonstration that iPS-derived 103 cells differentiate into chondrocytes in 3-D scaffolds implanted for tracheal regeneration. Our study demonstrated that iPS cells have the potential to differentiate into chondrogenic cells, as shown by the appearance of Alcian blue–stained colonies and expression of a cartilage-associated gene of collagen type II in vitro. Implanted iPS cells were confirmed to exist in the 3-D scaffold in vivo. Cartilage-like tissue was regenerated in tracheal defects with use of iPS cells. Our results suggest the potential of iPS cells in the regeneration of the tracheal wall. Acknowledgments: We thank Etsuko Sato and Yuka Sato for their technical assistance. REFERENCES 1. Caputo V, Consiglio V. The use of patient’s own auricular cartilage to repair deficiency of the tracheal wall. J Thorac Cardiovasc Surg 1961;41:594-6. 2. 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Arterioscler Thromb Vasc Biol 2009;29:11003. 14. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007; 448:313-7. 15. Akagi T, Sasai K, Hanafusa H. Refractory nature of normal human diploid fibroblasts with respect to oncogene-mediated transformation. Proc Natl Acad Sci U S A 2003;100:1356772. 16. Hatsuzawa K, Tamura T, Hashimoto H, et al. Involvement of syntaxin 18, an endoplasmic reticulum (ER)–localized SNARE protein, in ER-mediated phagocytosis. Mol Biol Cell 2006;17:3964-77. 17. Steedman HF. Alcian blue 8GS: a new stain for mucin. J Cell Sci 1950;1:477-9. 18. Brittberg M. Cell carriers as the next generation of cell therapy for cartilage repair: a review of the matrix-induced autologous chondrocyte implantation procedure. Am J Sports Med 2010;38:1259-71. 19. Ahrens M, Ankenbauer T, Schröder D, Hollnagel A, Mayer H, Gross G. Expression of human bone morphogenetic proteins–2 or –4 in murine mesenchymal progenitor C3H10T1/2 cells induces differentiation into distinct mesenchymal cell lineages. DNA Cell Biol 1993;12:871-80. 20. Mackay AM, Beck SC, Murphy JM, Barry FP, Chichester CO, Pittenger MF. Chondrogenic differentiation of cultured human mesenchymal stem cells from marrow. Tissue Eng 1998;4:415-28. 21. Solchaga LA, Penick K, Goldberg VM, Caplan AI, Welter JF. Fibroblast growth factor–2 enhances proliferation and delays loss of chondrogenic potential in human adult bone-marrow–derived mesenchymal stem cells. Tissue Eng Part A 2010; 16:1009-19. 22. Kramer J, Hegert C, Guan K, Wobus AM, Müller PK, Rohwedel J. Embryonic stem cell–derived chondrogenic differentiation in vitro: activation by BMP-2 and BMP-4. Mech Dev 2000;92:193-205. 23. Wakitani S, Aoki H, Harada Y, et al. Embryonic stem cells form articular cartilage, not teratomas, in osteochondral defects of rat joints. Cell Transplant 2004;13:331-6. 24. Jukes JM, Moroni L, Van Blitterswijk CA, de Boer J. Critical steps toward a tissue-engineered cartilage implant using embryonic stem cells. Tissue Eng Part A 2008;14:135-47. 25. De Bari C, Dell’accio F, Luyten FP. Failure of in vitro– differentiated mesenchymal stem cells from the synovial membrane to form ectopic stable cartilage in vivo. Arthritis Rheum 2004;50:142-50. 26. Miura K, Okada Y, Aoi T, et al. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 2009;27: 743-5. Determination of Predictive Factors of Tracheobronchial Prosthesis Removal: Stent Brands Are Crucial Guillaume Buiret, MD; Carole Colin, MD; Guillaume Landry, MD; Marc Poupart, MD; Jean-Christian Pignat, MD Objectives: We sought to describe in a retrospective study our experience in the endoscopic management of tracheobronchial stenoses over 20 years and to determine prognostic factors of stent removal. Methods: We analyzed the medical records of 166 patients (111 male and 55 female) who underwent the placement of a prosthesis for all causes of tracheobronchial stenosis between 1990 and 2009. Results: Overall, 34% of the patients had their stents removed. The incidence of complications for the first stent was 0.08 per patient-month. One hundred five patients (63%) had no complications. In univariate analysis, stent removal was significantly linked with the stent brand. In multivariate analysis, taking into account the causes of stenosis, the stent brand appeared to be the only factor that significantly influenced stent removal. Finally, stenosis with more than 1 stent replacement was most prone to repeat endoscopies. Conclusions: Even though endoscopic stent placement is a relatively safe and effective treatment for tracheobronchial stenoses, particularly in cases with malignancy, complications led to stent removal in about one third of cases. The type of stent chosen is crucial. Key Words: bronchoscopy, stent, upper airway. INTRODUCTION fore TBS placement. The complications of TBSs are frequent and often require repeated endoscopies that sometimes lead to removal of the TBS. The aim of this study was to evaluate the predictive factors for TBS removal in order to warn practitioners about the risks of TBSs. Although tracheobronchial stents (TBSs) are not recent,1 they have only been used routinely since the end of the 1990s. Their purpose is to restore the tracheobronchial patency reduced by endoluminal cellular proliferation, external compression, or both,2 often while patients are waiting for another treatment (such as chemotherapy and/or radiotherapy3,4). Placement may be preceded by a preparatory treatment.5 A formal contraindication to surgical treatment (related to the disease or the general status of the patient) leaves two indications for TBS placement: 1) malignancies (obstruction by extrinsic and/or intrinsic compression, tumoral progression in spite of frequent laser treatments, tracheoesophageal fistula [TEF], postobstructive pneumonia6); and 2) benign causes (pulmonary transplantation, prolonged intubation, tracheotomy, irradiation, polychondritis, congenital and idiopathic granulomatosis,7 loss of cartilaginous support6). However, the decision not to operate must be made in expert centers. In the series of Gaissert et al,8 for example, two thirds of the cases were considered operable be- MATERIALS AND METHODS Patient Selection. A list of the patients treated between January 1, 1990, and September 30, 2009, for TBS placement in the Otorhinolaryngology and Cervicofacial Surgery Unit of the Croix-Rousse University Hospital was provided by the hospital’s Department of Medical Information. The data were compared to the records of the endoscopy room, in which all of the results of endoscopies and interventional endoscopies are systematically indexed. The files of 166 patients were finally retained and retrospectively analyzed. Method of Treatment. The patients underwent placement of a TBS, possibly preceded by bronchial de-obstruction (with forceps and/or a laser), during From the Otorhinolaryngology and Cervicofacial Surgery Unit, Hôpital de la Croix-Rousse, Centre Hospitalier Universitaire Lyon (all authors), and the Université Claude Bernard Lyon 1 (Buiret, Colin, Landry, Pignat), Lyon, France. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Guillaume Buiret, MD, Otorhinolaryngology and Cervicofacial Surgery Unit, Hôpital de la Croix-Rousse, 104 Grande Rue de la Croix-Rousse, 69004 Lyon, France. 104 Buiret et al, Is Stent Brand Predictive Factor of Complications? 105 TABLE 1. CHARACTERISTICS OF POPULATION Sex Male Female Mean age Age range Causes of stenosis Benign Extrinsic compression Tracheoesophageal fistula Pulmonary transplantation Intubation Tracheal resection-anastomosis Tracheomalacia Tracheotomy Two or more causes Others Malignant Extrinsic compression Tracheoesophageal fistula Lung cancer Esophageal cancer Thyroid cancer Tracheal cancer Others 111 (67%) 55 (33%) 59.7 y (SE, 16.1 y) 6.6 to 90.1 y 91 (55%) 8 4 12 14 5 9 28 4 7 75 (45%) 35 19 9 2 3 3 4 tracheobronchial endoscopy with suspension laryngoscopy (method described previously9). Several brands of prostheses were used during the study period. The following nonexpandable prostheses were used: Aboulker (10 prostheses placed between 1981 and 2005), Cook (William Cook Europe, Bjaeverskov, Denmark; 8 prostheses placed between 1990 and 1996), Novatech Y (Novatech SA, La Ciotat, France; 24 prostheses placed between 2002 and 2009), and Rush Y (Boston Scientific, Natick, Massachusetts; 23 prostheses placed between 2001 and 2008). The following expandable covered prostheses were used: Wallstent (Boston Scientific; 20 prostheses placed between 1997 and 2008), Hanarostent (MI Tech Co, Pyeongtaek, South Korea; 6 prostheses placed between 2002 and 2005), Novatech Silmet (Novadis, Holy Victoret, France; 25 prostheses placed between 2007 and 2009), Novatech Y (Novadis; 1 prosthesis placed in 2009), Tracheobronxane (Novatech SA; 19 prostheses placed between 2001 and 2007), and Ultraflex (Boston Scientific; 15 prostheses placed between 1981 and 2005). The only expandable uncovered prosthesis used was the Wallstent (Boston Scientific; 10 prostheses placed between 1994 and 2005). End Point. The aim of the study was to establish Fig 1. Overall survival by cause of stenosis. predictive factors for removal of the TBS. The duration of prosthesis use was from the day of placement to the time of death or to the date of the last followup visit, limited to September 30, 2009, for the remaining patients. Data Analysis. Univariate analyses were performed, and statistical differences in the duration of the prostheses were tested by a Cox model for a risk α of 0.05. In case of significant predictive factors, multivariate analyses taking into account the principal potential confounding factors were performed. The statistical analyses were carried out with SPSS v12.0 software. RESULTS The characteristics of the population are described in Table 1, and Fig 1 presents the overall survival curve of the patients. The causes of stenosis were mainly benign (55%). Nearly 60% of the benign stenoses were caused by tracheomalacia, tracheotomy, or intubation. The 7 other benign causes (Table 1) comprised 1 tracheal burn, 1 tracheal chondroma, 1 Lortat-Jacob mucosynechiant dermatitis, 1 Riedel’s thyroiditis, 1 tracheal radionecrosis, and 2 pseudo-inflammatory tumors. Malignancies were the cause of stenosis in approximately 45% of the cases, and more than 75% of these were intrinsic or extrinsic tumoral compressions. The 4 other malignant causes (Table 1) comprised 2 non-Hodgkin’s lymphomas, 1 Hodgkin’s lymphoma, and 1 tracheal resection-anastomosis for tracheal cancer. The distribution of types of first prosthesis used is presented in Table 2. Ninety-three expandable covered prostheses (56%), 12 expandable uncovered prostheses (7%), and 61 nonexpandable prostheses (37%) were used in the first intention. More than 65% of the stenoses with benign causes were treat- 106 Buiret et al, Is Stent Brand Predictive Factor of Complications? TABLE 2. DISTRIBUTION OF TYPES OF FIRST PROSTHESIS USED BY CAUSE OF STENOSIS Prosthesis Type Cause Benign Extrinsic compression Tracheoesophageal fistula Pulmonary transplantation Intubation Tracheal resection and anastomosis Tracheomalacia Tracheotomy Two or more causes Others Malignant Extrinsic compression Tracheoesophageal fistula Lung cancer Esophageal cancer Thyroid cancer Tracheal cancer Others Total Expandable Covered Expandable Uncovered Nonexpandable 61 4 3 6 12 4 4 22 2 4 32 9 9 9 0 3 2 0 93 10 1 0 2 1 0 2 4 0 0 2 2 0 0 0 0 0 0 12 20 3 1 4 1 1 3 2 2 3 41 24 10 0 2 0 1 4 61 ed with a covered expandable prosthesis. Approximately 40% and 50% of the stenoses with malignant causes were treated with expandable covered and nonexpandable prostheses, respectively. The complication rate for the first prosthesis was 0.08 per patient-month (147 endoscopies for complications in 1,796 months of prosthesis use). One hundred five patients (63%) did not have any complications. The prostheses of 57 patients (34%) had to be removed: 3 on the day of placement, 1 on the 2nd day, 4 between the 3rd and 7th days, and 13 between the 8th and 30th days. Table 3 presents the reasons for removal according to the type of prosthesis. Other reasons for TBS removal comprised 1 failure of installation, 1 prosthesis fatigue, and 1 case of esophageal prosthesis placement, which made the TBS unbearable. Figure 2 shows the distribution of stent removal according to time. The mean duration before removal was 277 days (SE, 540 days), the median was 67 days, and the range was 0 days to 7.5 years. Forty-five prostheses had to be replaced (79% of the removed prostheses). The distribution of second prosthesis types is presented in Table 3. Generally speaking, when the first prosthesis was expandable and covered, then the replacement prosthesis was expandable and covered (66%) or nonexpandable (34%). If the first prosthesis was nonexpandable, then the replacement prosthesis usually was also nonexpandable (85%). Total 8 4 12 14 5 9 28 4 7 35 19 9 2 3 3 4 166 The analysis of the presumed predictive factors for removal is presented in Table 4. The hazard ratios represent the probability of maintenance of the prosthesis. The greater the ratio, the longer the prosthesis remained in place. Multivariate analysis made it possible to take into account the causes and potential confounding factors. The second prosthesis had to be removed in 18 patients (40%), and 17 of them had a third prosthesis. The third prosthesis had to be removed in 7 patients (39%), and 5 of them had a fourth prosthesis. The fourth prosthesis had to be removed in 4 patients (57%), and 3 of them had a fifth prosthesis. The fifth prosthesis had to be removed in 1 patient (33%), who had a sixth prosthesis. DISCUSSION Our study on a broad series with several TBS brands is the first to show that the only significant predictive factor for prosthesis removal is the prosthesis brand used. Contrary to the study of Saad et al,9 this finding was independent of the benign or malignant nature and precise cause of the stenosis and independent of the type of prosthesis (nonexpandable, expandable covered, or uncovered). In ascending order, from the least stable to the most stable, the prostheses were as follows: Ultraflex, covered Wallstent, Cook, Hanarostent, Aboulker, Tracheobronxane, Novatech Silmet, uncovered Wallstent, Novatech Y, and Rush Y. The majority of prosthesis removals were per- Buiret et al, Is Stent Brand Predictive Factor of Complications? 107 TABLE 3. REASONS FOR REMOVAL BY TYPE OF PROSTHESIS AND DISTRIBUTION OF SECOND PROSTHESIS TYPES Reason for Removal Migration Granuloma Sputum retention No. of Patients 19 13 6 Type of Prosthesis No. of Patients/ Total No. of Stents Expandable covered 13/93 Nonexpandable 6/60 Expandable covered 9/93 Expandable uncovered Nonexpandable 1/12 3/60 Expandable covered 2/93 Nonexpandable 4/60 Infection 5 Expandable covered 4/93 Extremity overgrowth 4 Nonexpandable Expandable covered 1/60 3/93 Ineffectiveness 3 Cough 2 Nonexpandable Expandable covered Expandable uncovered Nonexpandable Nonexpandable 1/60 1/93 1/12 1/60 2/60 Cure Other reasons 2 3 Expandable covered Expandable covered Nonexpandable 2/93 2/93 1/60 formed within 1 year of implantation and in a quasisuperposable way, whether the cause of stenosis was benign or malignant (Fig 2). Only 2 removals were justified by an apparent cure of the stenosis. This was a lower rate than that in the series of Martinez-Ballarin et al,10 in which 21 of 48 prosthesis removals were justified by an apparent cure. Only 3 prostheses had to be removed on day 0, and 1 on day 1, for bad tolerance or ineffectiveness, and in the literature, the rate of effectiveness of the stents on dyspnea is very high: between 80% and 97%.4,11-13 Stents also significantly improved the scores on pulmonary function tests.14-16 However, the effect of stents on survival has been studied very little. Lemaire et al3 and Xu et al17 showed that survival increased if external radiotherapy was performed after TBS placement, as compared to the survival with TBS placement alone. However, no studies comparing etiologic treatment with versus without a TBS were found in the liter- Second Prosthesis 1 no second prosthesis 7 expandable covered prostheses 1 expandable uncovered prosthesis 4 nonexpandable prostheses 1 no second prosthesis 1 expandable covered prosthesis 4 nonexpandable prostheses 2 no second prosthesis 3 expandable covered prostheses 4 nonexpandable prostheses 1 expandable covered prosthesis 1 no second prosthesis 2 nonexpandable prostheses 1 no second prosthesis 1 nonexpandable prosthesis 1 no second prosthesis 1 expandable covered prosthesis 2 nonexpandable prostheses 2 expandable covered prostheses 1 expandable uncovered prosthesis 1 nonexpandable prosthesis 1 no second prosthesis 1 expandable covered prosthesis 2 nonexpandable prostheses 1 nonexpandable prosthesis 1 no second prosthesis 1 nonexpandable prosthesis 1 expandable uncovered prosthesis 1 no second prosthesis 1 nonexpandable prosthesis 2 no second prosthesis 2 expandable covered prostheses 1 nonexpandable prosthesis ature. Relief of dyspnea in terminal palliative care was initially one of the major indications for use of a TBS, because TBSs are particularly effective in increasing short-term survival and quality of life.18 The main disadvantage of the TBS is the high incidence of complications, which in published series ranges from 13%3 to 72%.12 Dasgupta et al,19 in a series of 37 patients, reported the incidence of complications in a more relevant way: the longer a patient has a TBS, the greater the risk of complications. Dasgupta et al19 thus calculated the incidence of complications in terms of patient-months (probability of a complication in 1 patient in a month). We also used this method in our study. Another term that seems important to us is the incidence of “no complications.” Indeed, several complications often occur in 1 patient, and the incidence of complications is therefore overestimated. 108 Buiret et al, Is Stent Brand Predictive Factor of Complications? TABLE 4. ANALYSIS OF PREDICTIVE FACTORS FOR STENT REMOVAL Fig 2. Time of stent removal by cause of stenosis. The principal complications are migrations, granuloma, sputum retention, in-stent tumoral growth or overgrowth, and hemoptysis. Chhajed et al20 even showed that patients with tracheobronchial stenosis after pulmonary transplantation had reduced survival in the event of a TBS complication. Every prosthesis has advantages and disadvantages (Table 5), and no ideal prosthesis exists. Our experience in TBS use enables us to put forward a number of reasons why certain stent brands have greater rates of complications and removal than others. Rush prostheses are very effective, and can be cut to the required length for the trachea, as well as for the bronchi. They do not move easily and are not very prone to cause infection. They are not expandable and therefore are sometimes difficult to place. Some cases of granuloma at their ends, especially the lower end, occur. They are easy to remove. A problem sometimes arises in terms of the contact with the wall of the trachea, as the stent’s diameter is greater in the distal part than in the proximal part (contrary to the dimensions of the trachea). Novatech Y prostheses also can be cut to length, but once dilated, the force they exert is lower than that of the Rush prosthesis. They are sometimes difficult to place (nonexpandable prostheses); they are a little prone to cause infection, but are effective. The patented studs do nothing to prevent migration and hamper positioning after insertion. This stent is easy to remove. Novatech Silmet prostheses are generally the best for the majority of tracheal stenoses, but the release technique could be improved. They are prone to cause infections, but are quite easy to remove. Cook prostheses are very rigid and bring effec- Univariate Analysis Multivariate Analysis HR HR Female sex 0.688 Age 1 Malignancy 1.479 Causes * Type of prosthesis Nonexpandable 1 prostheses Expandable covered 0.591 prostheses Expandable uncovered 0.546 prostheses Prosthesis brand Nonexpandable prostheses Aboulker 13.152 Cook 2.573 Novatech Y 8.424 Rush Y 11.101 Expandable covered prostheses Wallstent 1.472 Hanarostent 4.152 Novatech Silmet 7.062 Tracheobronxane 5.081 Ultraflex 1 Expandable uncovered prostheses Wallstent 10.31 p 0.232 0.971 0.315 0.612 0.218 0.62 * 0.009 p 0.431 0.612 0.001 10.424 8.701 88.268 122.902 2.496 9.372 17.750 10.626 1 57.8 *Hazard ratios (HRs) are not specified, because they would crowd Table, but parameter is not significant. tive dilation and good calibration. They allow excellent drainage of secretions, and granulomas are rare. Release requires experience, because they need to be pushed forward gently. Removal is feasible but difficult. The problem is the very limited range of diameters and lengths, which reduces indications. Two prostheses should not be placed end-to-end (because of the occurrence of stenosis between them) or one inside the other (to avoid any migration of the unit). Hanarostent prostheses are no longer used, as they do not provide enough expansion. Wallstent and Ultraflex prostheses, covered or not, are rather easy to place, but cause severe mucosal reactions at their extremities, with granuloma and infections. Tracheobronxane prostheses are not very practical and do not expand sufficiently, and the patented studs have no utility; they should never be placed between the cartilages of the trachea, and contact between the prosthesis and the tracheal wall must be avoided, as there is a risk of sputum accumulation at the lower end. Buiret et al, Is Stent Brand Predictive Factor of Complications? 109 TABLE 5. ADVANTAGES AND DISADVANTAGES OF TYPES OF TRACHEOBRONCHIAL STENTS Advantages Disadvantages Expandable uncovered stents Immediate relief of dyspnea Little sputum retention Effectiveness on intrinsic and extrinsic obstructions Ease of deployment Low migration rate Possible in fibroscopy in outpatients Low thickness, good internal/external diameter ratio No interference with mucociliary clearance Improvement of quality of life Growth within stent or at ends Not usable with tracheoesophageal fistula Difficulty of removal after epithelialization Infection Hemorrhage Granuloma Fracture or crushing if external force is too great Diminution of length if increase of diameter Y stent not available Stent fatigue and fracture Expandable covered stents Treatment of extrinsic compression Treatment of tracheoesophageal fistula Less migration than nonexpandable prostheses Facility and precision of placement under video control Large choice of diameters Low thickness, good internal/external diameter ratio Good biocompatibility Less risk of tumoral ingrowth (except at ends) compared to expandable uncovered stents Easier to remove Less interference with mucociliary clearance than nonexpandable stents Less fracture than expandable uncovered stents Granulation at ends Migration Obstruction by sputum Repositioning and extraction more difficult, but remain possible Expensive Can occlude small bronchi Diminution of length if increase of diameter Exactitude of placement with fluoroscopy is clearly less than with visual installation Radial force could cause necrosis and formation of tracheoesophageal fistula High rate of minor complications (bad positioning, granulation, retention of secretions) Fracture or crushing if external force is too great Only Y stent available Nonexpandable stents Facility of placement and repositioning Facility of removal Resistance to external compression Y stents for perfect adaptation to carina Minimal granulation Resistance to tumor ingrowth or intrastent granulation Can allow hemostasis in event of perendoscopic hemorrhage Not expensive Migration Thickness of wall, reduction of internal diameter Retention or adherence of sputum General anesthesia and rigid bronchoscopy Rigid Interference with mucociliary clearance Less effective than expandable stents in case of compression mass because of lack of expansion No conformation to sinuosity of tracheobronchial tree Three techniques for TBS placement are currently used. Initially described with Dumon nonexpandable prostheses, placement during bronchoscopy under general anesthesia is the most frequently used technique. It ensures relatively safe access to the bronchial tree, allows better endoscopic visualization of the tumor, and gives more room to the operators.2 In our opinion, suspension laryngoscopy under general anesthesia provides a wider range of possibilities than does bronchoscopy21,22 (laser, electrocoagulation, dilation). Moreover, the instruments can be changed more quickly than with bronchoscopy,22 because both hands are free. Moreover, laryngoscopy makes it easier to determine the location of the stenosis compared to the carina, and to measure stenosis length and diameter compared with the trachea diameter. The disadvantages include the risk of dental avulsion injury, the risk of oropharyngeal injury,22 and the need for general anesthesia. More recently, the practice of prosthesis placement under local anesthesia, possibly without fluoroscopy,23 has spread. This technique seems sure, fast, and well tolerated, and is usable in emergencies24 and in outpatients, thus decreasing the length of hospitalization and costs.25 The main disadvantages include frequent malpositioning13,24,26 leading to immediate repositioning, frequent fluoroscopy,2 limited interventional possibilities due to the low number of working channels,22 and an inability to use a laser correctly.27 We have no experience of this technique in our center. 110 Buiret et al, Is Stent Brand Predictive Factor of Complications? Acknowledgment: The authors thank Philip Bastable, English Medical Department, University of Burgundy, Dijon, France, for the English translation. REFERENCES 1. Montgomery WW. T-tube tracheal stent. Arch Otolaryngol 1965;82:320-1. 2. Makris D, Marquette CH. Tracheobronchial stenting and central airway replacement. Curr Opin Pulm Med 2007;13:27883. 3. Lemaire A, Burfeind WR, Toloza E, et al. Outcomes of tracheobronchial stents in patients with malignant airway disease. Ann Thorac Surg 2005;80:434-8. 4. Walser EM, Robinson B, Raza SA, Ozkan OS, Ustuner E, Zwischenberger J. Clinical outcomes with airway stents for proximal versus distal malignant tracheobronchial obstructions. J Vasc Interv Radiol 2004;15:471-7. 5. Bolliger CT, Sutedja TG, Strausz J, Freitag L. Therapeutic bronchoscopy with immediate effect: laser, electrocautery, argon plasma coagulation and stents. Eur Respir J 2006;27:125871. 6. Chin CS, Litle V, Yun J, Weiser T, Swanson SJ. Airway stents. Ann Thorac Surg 2008;85:S792-S796. 7. Walser EM. Stent placement for tracheobronchial disease. Eur J Radiol 2005;55:321-30. 8. Gaissert HA, Grillo HC, Wright CD, Donahue DM, Wain JC, Mathisen DJ. Complication of benign tracheobronchial strictures by self-expanding metal stents. J Thorac Cardiovasc Surg 2003;126:744-7. 9. Saad CP, Murthy S, Krizmanich G, Mehta AC. Selfexpandable metallic airway stents and flexible bronchoscopy: long-term outcomes analysis. Chest 2003;124:1993-9. 10. Martinez-Ballarin JI, Diaz-Jimenez JP, Castro MJ, Moya JA. Silicone stents in the management of benign tracheobronchial stenoses. Tolerance and early results in 63 patients. Chest 1996;109:626-9. 11. Ryu YJ, Kim H, Yu CM, Choi JC, Kwon YS, Kwon OJ. Use of silicone stents for the management of post-tuberculosis tracheobronchial stenosis. Eur Respir J 2006;28:1029-35. 12. Kapoor BS, May B, Panu N, Kowalik K, Hunter DW. Endobronchial stent placement for the management of airway complications after lung transplantation. J Vasc Interv Radiol 2007;18:629-32. 13. Monnier P, Mudry A, Stanzel F, et al. The use of the covered Wallstent for the palliative treatment of inoperable tracheobronchial cancers. A prospective, multicenter study. Chest 1996;110:1161-8. 14. Miyazawa T, Yamakido M, Ikeda S, et al. Implantation of ultraflex nitinol stents in malignant tracheobronchial stenoses. Chest 2000;118:959-65. 15. Vergnon JM, Costes F, Bayon MC, Emonot A. Efficacy of tracheal and bronchial stent placement on respiratory functional tests. Chest 1995;107:741-6. 16. Abdullah V, Yim AP, Wormald PJ, van Hasselt CA. Dumon silicone stents in obstructive tracheobronchial lesions: the Hong Kong experience. Otolaryngol Head Neck Surg 1998;118: 256-60. 17. Xu X, Tajima H, Ishioh M, et al. Study on the treatment of tracheobronchial stenosis using expandable metallic stents. J Nippon Med Sch 2001;68:318-27. 18. Vonk-Noordegraaf A, Postmus PE, Sutedja TG. Tracheobronchial stenting in the terminal care of cancer patients with central airways obstruction. Chest 2001;120:1811-4. 19. Dasgupta A, Dolmatch BL, Abi-Saleh WJ, Mathur PN, Mehta AC. Self-expandable metallic airway stent insertion employing flexible bronchoscopy: preliminary results. Chest 1998; 114:106-9. 20. Chhajed PN, Malouf MA, Tamm M, Spratt P, Glanville AR. Interventional bronchoscopy for the management of airway complications following lung transplantation. Chest 2001;120: 1894-9. 21. Merrot O, Buiret G, Gleizal A, Poupart M, Pignat JC. Management of tracheobronchial stenoses with endoprostheses: experience with 103 patients and 11 models. Laryngoscope 2008;118:403-7. 22. Eckel HE, Berendes S, Damm M, Klussmann JP, Wassermann K. Suspension laryngoscopy for endotracheal stenting. Laryngoscope 2003;113:11-5. 23. Herth F, Becker HD, LoCicero J III, Thurer R, Ernst A. Successful bronchoscopic placement of tracheobronchial stents without fluoroscopy. Chest 2001;119:1910-2. 24. Spinelli P, Cerrai FG, Spinelli A. Palliation of tracheobronchial malignant obstruction with metal stents in emergency conditions. Minerva Chir 1998;53:373-6. 25. Yerushalmi R, Fenig E, Shitrit D, et al. Endobronchial stent for malignant airway obstructions. Isr Med Assoc J 2006; 8:615-7. 26. Shin JH, Kim SW, Shim TS, et al. Malignant tracheobronchial strictures: palliation with covered retrievable expandable nitinol stent. J Vasc Interv Radiol 2003;14:1525-34. 27. Vergnon JM. Supportive care. Endoscopic treatments for lung cancer [in French]. Rev Mal Respir 2008;25:3S1603S166. Posterior Glottic Diastasis: Mechanically Deceptive and Often Overlooked Steven M. Zeitels, MD; Alessandro de Alarcon, MD; James A. Burns, MD; Gerardo Lopez-Guerra, MD; Robert E. Hillman, PhD Dysphonia secondary to posterior glottic aerodynamic incompetence can often be recognizable acoustically, but difficult to document visually. This mechanical impairment in posterior glottic closure is the result of injury caused by airway instrumentation. The difficulty of recognition of this entity is due to posterior supraglottic soft tissue that obscures the complete view during posterior glottic adduction, the lack of a structural organization of the cricoarytenoid region injury that leads to this disorder, and the lack of nomenclature. A retrospective assessment was done on 3 patients who underwent surgical reconstruction to correct posterior phonatory incompetence subsequent to laryngotracheal intubation. All 3 had sustained an injury to the cricoarytenoid joints, and 2 of the 3 had undergone paraglottic space medialization laryngoplasty that failed to solve the posterior glottic insufficiency. New procedures were designed and performed in these patients to correct the posterior glottic incompetence and are described: laryngofissure and partial posterior cricoid resection, endoscopic pharyngoepiglottic-aryepiglottic fold advancement-rotation flap with interarytenoid interposition, and interarytenoid submucosal implant augmentation. Although the academic literature is replete with reports describing stenosis resulting from impaired cricoarytenoid joint abduction, the term glottic diastasis provides nomenclature for the inability to normally adduct the arytenoid cartilages. The initial experience with surgical reconstruction is preliminary, but encouraging. Key Words: cricoid cartilage, dysphonia, hoarseness, intubation, laryngofissure, laryngoplasty, larynx, stenosis, vocal cord, vocal fold. been elegantly described by Vijayasekaran et al3 and Benjamin and Holinger.4 To the best that we could determine, Bastian and Richardson5 provided the sole report to focus on the vocal deficits associated with inadequate phonatory adduction subsequent to endotracheal tube–induced posterior glottic injury. Benjamin and Holinger4 provided an intraoperative photograph illustrating the nature of the injury. INTRODUCTION Vocal dysfunction secondary to mechanical trauma of the posterior glottis from laryngotracheal reconstruction and/or airway stents is familiar to most laryngeal surgeons. The inadequate posterior glottal closure can be audibly perceived as breathy dysphonia. However, the diminished airway caliber appropriately supersedes vocal dysfunction as the focus of treating clinicians. Indwelling stents have long been used to reestablish an adequate laryngeal airway when posterior glottal injury has resulted in stenosis.1,2 In our experience, permanent hoarseness subsequent to laryngotracheal intubation is substantially less recognized and understood than is incompetent posterior glottic closure caused by indwelling stents used to treat stenosis, caused by laryngotracheal reconstruction with a posterior cricoid cartilage graft interposition, or caused by cancer resection.6-9 Remarkably, there is a population of patients who have permanent posterior glottic injury with a sustainable airway caliber but develop impaired cricoarytenoid adduction as a result of limited laryngotracheal intubation. The complex mechanisms of injury in the posterior glottis and cricoarytenoid joints resulting from laryngotracheal intubation have In patients who have had laryngotracheal intubation, the dysphonia secondary to posterior glottic aerodynamic incompetence can often be recognizable acoustically, but is difficult to document visu- From the Department of Surgery, Harvard Medical School (Zeitels, Burns, Lopez-Guerra, Hillman), and the Center for Laryngeal Surgery and Voice Rehabilitation, Massachusetts General Hospital (Zeitels, Burns, Lopez-Guerra, Hillman), Boston, Massachusetts, and the Department of Otolaryngology–Head and Neck Surgery, University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio (de Alarcon). This work was supported in part by the Eugene B. Casey Foundation and the Institute of Laryngology and Voice Restoration. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Steven M. Zeitels, MD, Center for Laryngeal Surgery and Voice Rehabilitation, Massachusetts General Hospital, One Bowdoin Square, 11th Floor, Boston, MA 02114. 111 112 Zeitels et al, Posterior Glottic Diastasis ally.5 Our observations revealed that patients often sound substantially more breathy than they appear on laryngoscopic examination. This is because the upper arytenoid and corniculate regions tilt forward in an attempt to close the glottic incompetence, and they obscure visualization of a posterior keyhole aperture at the vocal fold level. Identifying the submucosal posterior glottic injury can be further opacified when the patient has also sustained vocal fold denervation. Despite the commonly used term glottic stenosis for inadequate abductory opening of the glottic aperture, we could not identify an ideal term for inadequate adductory closure of the posterior glottis. Considering this scenario, we consulted with an individual skilled in the Greek language, and on the basis of that discussion and further analysis, determined that an optimal term for inadequate interarytenoid closure/apposition would be posterior glottic diastasis. Diastasis can be defined as a permanent separation of structures that should be joined, which describes arytenoid closure during phonatory glottic adduction. Koufman et al10 utilized the term arytenoid hypertelorism for the malpositioned arytenoid cartilage associated with a chondrosarcoma. This was accurate for tumor-related arytenoid displacement, which is analogous to displacement of the midface and orbit, but is not ideal for a scenario in which the cricoarytenoid joints are not displaced. In our experience, patients who present with dysphonia secondary to glottic diastasis have all sustained injury from mechanical instrumentation of the posterior glottic region. Although we have commonly observed idiopathic glottic stenosis, we have not identified idiopathic glottic diastasis. Limited recognition of posterior glottic diastasis arises from the frequent difficulty in visually identifying laryngotracheal intubation–induced posterior glottic incompetence, along with the lack of diagnostic terminology. Even when clinicians clearly recognize the harsh, breathy dysphonia, two typical strategies are utilized to treat the patient. Most commonly, the patients are deemed to have “hyperfunctional” voices, and voice therapy is administered. Not uncommonly, those who have sustained posterior glottic injury from an endotracheal tube have underlying reflux laryngitis,11 so this chronic mucosal problem is treated as well. Alternatively, but not exclusively, the presumed diminished glottic closure is deemed to be neurogenic paresis, so that a medialization of the anterior paraglottic phonatory mucosal region is performed. The arytenoid cartilage frequently retains substantial mobility, and arytenoid repositioning procedures are not done, so as not to diminish the airway caliber for the promise of some enhanced vocal function. Although we had recognized this entity with increasing frequency, we had difficulty designing the optimal procedure that would rectify the problem without placing the cricoarytenoid abductory function at risk in one or both vocal folds. Conceptually, we concluded that there were three possible reconstructive possibilities, and an example of each of these is described herein. The documentation detailed herein should provide the readership with clarity about this entity and lead to development of further-enhanced reconstructive options. MATERIALS AND METHODS An Institutional Review Board–approved retrospective assessment was done on 3 patients who underwent surgical reconstruction to correct posterior phonatory incompetence. The procedures were classified as follows: 1) laryngofissure and partial posterior cricoid resection; 2) endoscopic pharyngoepiglottic-aryepiglottic fold advancement-rotation flap with interarytenoid interposition; and 3) interarytenoid submucosal implant augmentation. All 3 patients had sustained an intubation-induced injury to the cricoarytenoid joints. Two of the 3 had undergone paraglottic space medialization laryngoplasty that failed to solve the posterior glottic insufficiency. CASE REPORTS Patient 1. This patient (Figs 1 and 2) was a 35year-old woman who developed an acute myasthenic crisis and was orotracheally intubated for 3 days in the intensive care unit. After that intubation, her voice never recovered. She had severe breathy dysphonia. Her initial treating laryngologist noted the posterior glottic incompetence and diagnosed it as bilateral paresis. She underwent paraglottic space augmentations initially, with office-based Cymetra (Micronized AlloDerm) injections, followed by bilateral silicone medialization. The patient reported that the transcervical medialization resulted in worse vocal quality. On presentation to us, there was normal and brisk symmetric abduction of both arytenoid cartilages, and there was bilateral limited adduction that did not allow for interarytenoid closure. When she presented, the expanded paraglottic space from the left implant was easily seen through the ventricular surface of the vocal fold mucosa. There was substantial loss of interarytenoid soft tissue, and the outlining of the cricoid cartilage was easily seen posteriorly; the glottis was leaking air posteriorly during phonatory adduction. In an attempt to close the keyhole aperture posteriorly, a Zeitels et al, Posterior Glottic Diastasis A B C D E F 113 Fig 1. (Patient 1) A) Office telescopic image during full abduction. Note contour swelling of left vocal fold from submucosal implant in paraglottic space. B) Office telescopic examination during adduction. Note substantial glottic incompetence. C) Microlaryngoscopic examination of pharyngoepiglottic fold. Aryepiglottic fold flap is being sutured into interarytenoid region. D) Early postoperative office telescopic examination shows fibrinous exudate in left aryepiglottic fold region. Left vocal fold is seen distantly in central aspect of left side of image. E) Office telescopic examination approximately 3 weeks after operation during full abduction. F) Office telescopic examination approximately 3 weeks after operation during full adduction. long pharyngoepiglottic and aryepiglottic fold advanced rotation flap was made. The tip of that flap, which started from the lateral oropharyngeal wall, was sutured into the interarytenoid region. This procedure was done without altering the interarytenoid muscle or the capsule of either cricoarytenoid joint. In the immediate postoperative period, the patient’s voice was dramatically better. Flexible laryngoscopic examination revealed that the posterior keyhole aperture had been closed by the flap. On the first postoperative day, the voice had deteriorated in part, and the patient reported having coughed extensively during the prior evening. Laryngoscopy revealed that the distal tip of the flap had dissociated from the interarytenoid region, presumably from the vigorous coughing and the newly established aerodynamic competency. It was elected not to reposition the flap, because only one suture had become dissociated and the voice was still 114 Zeitels et al, Posterior Glottic Diastasis A Fig 2. (Patient 1) A) Laryngofissure has been performed. Suction cannula is positioned between inferior posterior cricoid incision edges on perichondrium. Hook is being used to withdraw inferior aspect of strip of cricoid cartilage from posterior cricoid plate. B) After removal of posterior cricoid strip, Prolene sutures are used to reapproximate edges of posterior cartilage. C) Office telescopic examination during abduction, approximately 3 weeks after operation. Glottis is well healed. Remnant of anterior laryngofissure can be seen through glottic aperture. Interarytenoid region during full abduction is diminished by approximately 3 mm, which was thickness of posterior cricoid cartilage strip. D) Office telescopic examination on same day as C, now showing substantial adductory improvement. B C substantially improved over the preoperative state. Furthermore, there was no pathway to preclude the same event from occurring again. After healing, there was substantial improvement in the patient’s vocal quality, timbre, projection, and stamina, but they were certainly not ideal. After utilizing her voice for a while, she deemed it to be functional but not optimal and inquired whether anything further could be done. Subsequently, a laryngofissure was performed after a precise, microlaryngoscopically controlled separation of the anterior commissure tendon. Three millimeters of the posterior cricoid region was removed, and the cricoid cartilage was reapproximated posteriorly. A tracheotomy was performed, and the tube was left in place throughout the perioperative period with the cuff inflated so as to avoid subcutaneous emphysema. The cuff was deflated at 7 days, and the tracheotomy tube was removed at 8 days. The patient’s postoperative healing was uneventful, and her voice was dramatically improved because of the D substantially improved closure of her interarytenoid region. As was to be expected, she has 3 mm of diminished abductory airway caliber; however, it has not caused significant airway symptoms, even during moderate athletic exercise. Patient 2. This patient (Fig 3) was a 62-year-old woman who developed encephalopathy and was orotracheally intubated for 8 days. After a complete neurologic recovery from that process, she was noted to have a severely breathy voice with diminished mobility of both arytenoid cartilages and bilateral granulomas. She underwent laryngeal electromyography, of which the findings were normal, and removal of the granulomas was done. Subsequently, the patient was referred for management of bilateral cricoarytenoid joint fixation, which was approximately 7 months subsequent to the intubation. Her clinic examination revealed that both arytenoid cartilages were in a fixed and abducted position at approximately 7.0 mm. She had a very breathy phonation quality and could partially “sphincter” Zeitels et al, Posterior Glottic Diastasis A B C D 115 Fig 3. (Patient 2) A) Office flexible laryngoscopic examination at full abduction. B) Same examination as in A, during attempts at adduction, shows that larynx is “sphinctering.” However, there is minimal alteration of interarytenoid region because of cricoarytenoid fixation. C) Office flexible laryngoscopic examination at approximately 1 month. As in patient 1, interarytenoid distance at full abduction is now diminished by approximately 3 mm. D) Same examination as in C, during adduction, reveals that although patient cannot adduct arytenoid cartilages, she can “sphincter” laryngeal musculature to achieve substantial closure of phonatory mucosa. the anterior phonatory glottis so that there was limited phonatory mucosal vibration from high subglottic pressures. Because of the aerodynamic incompetence, she had a very weak voice. The patient generally had a sedentary lifestyle, even before the encephalopathy, and had limited aerodynamic exercise requirements. The glottic diastasis was unequivocal, given the normal electromyographic findings and the history of intubation. A transoral-transcervical laryngofissure with resection of 3 mm of posterior cricoid cartilage was done on this patient as well. Afterward, she maintained a 4.5-mm interarytenoid airway that was sufficient for normal activities. However, with sphincteric closure of the phonatory region, along with her extremely pliable vibratory mucosa, she had dramatic improvement in vocal function. In the 6 months after the operation, she has not had airway difficulties. She has not had symptoms of sleep apnea; however, on deep inspiration, she has mild stridor. Patient 3. The patient (Figs 4 and 5) was a 53-yearold woman who underwent lung transplantation and had laryngotracheal intubation for approximately 10 days. She also sustained left vocal fold paralysis. The initial treating laryngeal surgeon performed multiple Radiesse (calcium hydroxylapatite microspheres) injection medialization procedures in the paraglottic space with the hope of closing the glottic gap. An injection for excessive paraglottic space did not solve the posterior glottic incompetence and actually compounded the dysphonia, because the normally pliable phonatory mucosa became extremely stiff from the excessive expansion of the paraglottic space. This patient was treated in a 2-stage fashion. At the initial procedure, a microlaryngoscopic exploration was done with a Hunsaker jet-ventilation catheter. A superior-surface cordotomy was done on the left vocal fold. An excessive amount of Radiesse was immediately encountered and extracted from the paraglottic soft tissue. The superior vocal fold incision was sutured closed, and a lipoinjection12 was done to replace the volume-depleted paraglottic region. Microlaryngo- 116 Zeitels et al, Posterior Glottic Diastasis A B C D E F Fig 4. (Patient 3) A) Office telescopic examination during full abduction demonstrates paralyzed left vocal fold. B) Office telescopic examination during adduction reveals poor glottic closure and submucosal swelling of left vocal fold from prior implant of paraglottic space. C) After substantial anesthesia of corniculate region, flexible laryngoscopic examination of interarytenoid region shows significant loss of interarytenoid soft tissue caused by previous use of endotracheal tube, revealing outline of cricoid cartilage. D) Flexible laryngoscopic examination in close proximity to left vocal fold reveals submucosal Radiesse (calcium hydroxylapatite microspheres) bulging below mucosa of superior surface of vocal fold. E) Microlaryngoscopic examination shows dissection of Radiesse from paraglottic space through superior-surface epithelial cordotomy. F) Large piece of Radiesse is being removed through epithelial cordectomy. scopic examination of the interarytenoid region revealed that the endotracheal tube had caused substantial loss of soft tissue. Therefore, a mucosal incision was made at the cephalad end of the cricoid cartilage, and a cold-instrument pocket was created. Then, a portion of the Radiesse that had been extracted from the left paraglottic space was reimplanted in the interarytenoid region to diminish the posterior glottic keyhole aperture while not injuring the cricoarytenoid joint capsules. Despite some vocal improvement, there was persistent posterior glottic incompetence due to the malpositioned arytenoid cartilage, as well as the incompletely corrected extensive loss of interarytenoid soft tissue from the previous indwelling endotracheal tube. At a second procedure, an adduction arytenopexy13,14 was done with monitored intrave- Zeitels et al, Posterior Glottic Diastasis A B C D 117 Fig 5. (Patient 3) A) After removal of Radiesse, epithelial cordotomy is sutured closed. B) Microlaryngoscopic examination of interarytenoid region demonstrates submucosal pocket that has been made just inside left interarytenoid region, with piece of Radiesse in place. Mucosal incision is being sutured closed. C) Office telescopic examination during abduction, after second-stage procedure in which adduction arytenopexy was performed. D) Office telescopic examination demonstrates substantially enhanced adductory closure. nous sedation. This diminished the posterior glottic incompetence that was secondary to the abducted arytenoid cartilage in the paralyzed vocal fold. After the operation, the patient had further enhancement of her vocal function. Voice Assessment. Standard voice assessments were performed before and after surgery in 2 of the 3 patients. The third patient did not return for postsurgical voice assessment because of medical complications related to transplantation treatment. The assessments included videostroboscopy, completion of the Voice-Related Quality-of-Life Survey (V-RQL),15 and objective acoustic and aerodynamic measures of vocal function. Because of their reliance on subjective judgments, observations from videostroboscopic recording were not used as formal data and are only included in the context of discussing the results of vocal function measures. The details of the protocol for obtaining acoustic and aerodynamic measures of vocal function have previously been described.13 For the 2 patients with complete voice assessment data, postsurgical measures were compared descriptively with presurgical measures and with historical norms.13 RESULTS Despite the disparate mechanical injuries, all 3 patients reported substantial improvement in their vocal function. None have had a complication or have required airway intervention as a result of the narrowed glottic aperture. The presurgical and postsurgical voice assessment results for the 2 patients with complete data are summarized in the Table. We utilized a subset of 4 primary voice assessment measures to evaluate the impact of the surgery on vocal function. The measures included the overall V-RQL score, the average fundamental frequency (vocal pitch) during reading of a standard passage, the ratio between noise and harmonic energy during sustained vowels (noise-to-harmonics ratio [NHR]; voice quality), and the average oral airflow rate (in liters per second) during comfortable sustained vowel production as an estimate of average glottic airflow. Patient 1 displayed dramatic postsurgical improvements in V-RQL score, NHR, and airflow; the V-RQL score increased by 70 points, and the NHR and airflow rate decreased from highly abnormal values to within normal limits. The fundamental fre- 118 Zeitels et al, Posterior Glottic Diastasis PRESURGICAL AND POSTSURGICAL VOICE ASSESSMENT RESULTS FOR TWO PATIENTS WITH COMPLETE DATA V-RQL Score Patient Preop Postop 1 2 Norms 2 28 72 40 100 = best F0 (Hz) Preop Postop 183 178 Aphonic 192 180-230 NHR Preop Airflow (L/s) Postop 0.37 0.17 Aphonic 0.21 ≤0.19 Preop Postop 0.792 0.147 Aphonic 0.530 0.05-0.25 V-RQL — Voice-Related Quality-of-Life Survey; F0 — fundamental frequency; NHR — noise-to-harmonics ratio. quency for patient 1 was in the low-borderline-normal range before and after surgery. Patient 2 was actually aphonic before surgery, so it was not possible to obtain acoustic and aerodynamic measures. After surgery, patient 2 did display measurable phonation, with an improvement of 12 points in V-RQL score, a normal fundamental frequency, and abnormally high values for NHR and airflow rate. DISCUSSION Glottic stenosis, with its associated airway narrowing and breathing restriction due to diminished arytenoid abduction, has been recognized since the origin of our specialty with widespread adoption of mirror laryngoscopy.16 This was not uncommonly due to severe infectious upper respiratory tract diseases that afflicted the laryngeal airway. As necessary, tracheotomy17 was performed to bypass the obstructed laryngeal airway. In the late 19th century, O’Dwyer18 perfected the placement of tubular indwelling stents. Although the size, shape, and constituent material of these stents have changed and developed over the past 150 years, their efficacy in reestablishing airway patency is well established. O’Dwyer’s work provided a foundation for 20th-century laryngotracheal intubation.19 Laryngotracheal intubation can result in posterior glottic phonatory incompetence during arytenoid adduction, visually observed as a keyhole aperture (Fig 4C), because of a combination of one or more of three factors. These include loss of arytenoid cartilage3,5 from pressure necrosis, injury of the medial cricoarytenoid joint,3,5 and loss of normal interarytenoid mucosal soft tissue. Typically, an indwelling endotracheal tube or stent leads to pressure necrosis of the posterior glottic tissues, resulting in the aforementioned findings. A classic posterior cricoid split with cartilage interposition is actually designed to create posterior glottic diastasis to remedy the more morbid and common problem of stenotic airway obstruction. Although a submucosal loss of arytenoid cartilage and submucosal fibrosis of the medial cricoarytenoid joint are difficult to observe, loss of interarytenoid redundant mucosa that is normally present can be observed with careful office-based laryngoscopy (Fig 4C). This mucosa, which often becomes hyperplastic in patients with reflux,20 stretches thin during interarytenoid abduction and corrugates to close the extreme posterior glottis during adduction. Flexible laryngoscopy with substantial topical anesthesia for extreme posterior positioning of the distal scope shaft is often necessary to observe the posterior glottis keyhole-aperture incompetence, because the supraglottic arytenoid region and associated corniculate mucosa often tilt forward and obscure the site of glottic air leakage. In 2 of the 3 cases described herein, unsuccessful prior attempts at glottic closure were made by augmenting the paraglottic space. Patient 1 had multiple bilateral Cymetra injections followed by bilateral silicone medialization procedures. These procedures had a detrimental vocal effect, because they did not close the posterior glottic gap, yet they increased the surface tension and stiffness of the phonatory mucosa. A similar mechanical outcome occurred in patient 3, who underwent multiple injections of Radiesse into the paraglottic region. Reconstructive Options. Although there has been limited recognition of the vocal deficits characterized herein as posterior glottic diastasis, a phonosurgical solution has not been forwarded, in part because of the unavoidable concern that reconstructive efforts to enhance phonation would negatively affect the airway and possibly lead to intubation or tracheotomy. Although we had only preliminary success in this small pilot group of patients, we present this report because the clinical concepts are robust. The patient population who would benefit from repair is small and geographically widespread, so establishing optimal reconstructive techniques will require multiinstitutional incremental advancements that integrate different surgeons’ creative innovations. There are two feasible approaches for closing posterior glottic phonatory incompetence while preserving an adequate posterior glottic airway. One would be to replace the lost soft tissue in the interarytenoid region at the cephalad edge of the posterior cricoid cartilage, and the second would be to diminish the inter–cricoid facet distance and there- Zeitels et al, Posterior Glottic Diastasis by bring the arytenoid cartilages closer together. We approached the problem initially by augmenting the lost soft tissue and had limited success. Thus far, it has been more effective to remove a strip of cricoid cartilage posteriorly. This latter procedure can be understood as the inverse of a posterior cricoid split and distraction with a rib graft.6 We replaced lost soft tissue in the interarytenoid region endoscopically in 2 of the 3 cases. In the patient who underwent the pharyngoepiglottic and aryepiglottic fold flap, the voice was initially much stronger; however, a coughing episode with the newly competent posterior glottic valve partially dislodged the distal flap from the interarytenoid region. Her voice maintained some improvement over her preoperative state, but became substantially better after a second procedure with removal of a strip of posterior cricoid cartilage. The patient who underwent placement of Radiesse in a submucosal interarytenoid pocket also gained improvement; however, there was not enough redundant mucosa in that region after the intubation injury to substantially diminish the aperture of the aerodynamically incompetent posterior glottis. Because of her underlying vocal fold paralysis, she also required repositioning of her arytenoid body on the cricoid facet to optimize her voice. Thus far, our impression is that if the airway caliber is deemed to be adequate for a patient’s needs, dysphonia from glottic diastasis is best treated by a laryngofissure and removal of a vertical strip of posterior cricoid cartilage to diminish the inter– cricoid facet distance. Not surprisingly, this is the inverse of the procedure undergone by those who have a posterior cricoid cartilage interposition6,7 to splay the posterior cricoid facets to treat glottic and subglottic stenosis. In patient 2, the endotracheal tube functioned as a stent, completely fixing the cricoarytenoid joints in a widely abducted position, rather than leading to the more common scenario of stenosis. In our view, she could tolerate some nar- 119 rowing of her airway aperture, because she was relatively sedentary. With removal of a posterior 3-mm strip of cricoid cartilage, she was able to maintain a comfortable airway yet had remarkable improvement in her voice through general sphincteric closure of her phonatory glottic valve. Complete voice assessment data were available for 2 of the 3 patients. In both cases, there was clear improvement in postsurgical vocal function. One of the patients went from being aphonic to having measurable phonation that was abnormally breathy (increased airflow rate and NHR) and was associated with a surprisingly small improvement in the subject’s perception of her vocal status (V-RQL). The other patient displayed dramatic improvements in both objective (NHR and airflow rate) and self-rated (V-RQL) measures of vocal function. Taken together, the results from these preliminary cases provide evidence that the new surgical procedures described here have had a decidedly positive impact on vocal function. CONCLUSIONS Limited awareness of the physiology underlying breathy dysphonia associated with vocal fold adductory tissue injuries from laryngotracheal intubation has been compounded by difficulty in visually identifying the often-subtle submucosal trauma. This is in contrast to the glottic aerodynamic incompetence that is easily seen and heard after surgical treatment of glottic cancer, stenosis, or bilateral paralysis. The academic literature is replete with reports describing stenosis resulting from impaired cricoarytenoid joint abduction, yet we were unable to find a term for impaired posterior glottic adductory closure. We think that posterior glottic diastasis can serve as nomenclature for this disorder, and the initial experience with surgical reconstruction is encouraging. Several treatment strategies have been demonstrated herein that should catalyze further multi-institutional innovations and efforts. REFERENCES 1. Mackenzie M. Dilators of the larynx. In: Diseases of the pharynx, larynx, and trachea. New York, NY: William Wood, 1880:192-5. 5. Bastian RW, Richardson BE. Postintubation phonatory insufficiency: an elusive diagnosis. Otolaryngol Head Neck Surg 2001;124:625-33. 2. Jackson C, Jackson CL. Dilation with elastic rubber core molds. In: The larynx and its diseases. Philadelphia, Pa: WB Saunders, 1937:447-54. 6. Cotton RT. The problem of pediatric laryngotracheal stenosis: a clinical and experimental study on the efficacy of autogenous cartilaginous grafts placed between the vertically divided halves of the posterior lamina of the cricoid cartilage. Laryngoscope 1991;101(suppl 56):1-34. 3. Vijayasekaran S, Sances R, Cotton R, Elluru RG. Changes in the cricoarytenoid joint induced by intubation in neonates. Arch Otolaryngol Head Neck Surg 2006;132:1342-5. 4. Benjamin B, Holinger LD. Laryngeal complications of endotracheal intubation. Ann Otol Rhinol Laryngol Suppl 2008;117(suppl 200):1-20. 7. Rutter MJ, Cotton RT. The use of posterior cricoid grafting in managing isolated posterior glottic stenosis in children. Arch Otolaryngol Head Neck Surg 2004;130:737-9. 8. Smith ME, Marsh JH, Cotton RT, Myer CM III. Voice 120 Zeitels et al, Posterior Glottic Diastasis problems after pediatric laryngotracheal reconstruction: videolaryngostroboscopic, acoustic, and perceptual assessment. Int J Pediatr Otorhinolaryngol 1993;25:173-81. 9. Zeitels SM, Hillman RE, Franco RA, Bunting GW. Voice and treatment outcome from phonosurgical management of early glottic cancer. Ann Otol Rhinol Laryngol Suppl 2002;111(suppl 190):1-20. 10. Koufman JA, Cohen JT, Gupta S, Postma GN. Cricoid chondrosarcoma presenting as arytenoid hypertelorism. Laryngoscope 2004;114:1529-32. 11. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991;101(suppl 53):1-78. 12. Burns JA, Kobler JB, Zeitels SM. Microstereo-laryngoscopic lipoinjection: practical considerations. Laryngoscope 2004;114:1864-7. 13. Zeitels SM, Hochman I, Hillman RE. Adduction arytenopexy: a new procedure for paralytic dysphonia with implications for implant medialization. Ann Otol Rhinol Laryngol 1998;107(suppl 173):1-24. 14. Zeitels SM, Mauri M, Dailey SH. Adduction arytenopexy for vocal fold paralysis: indications and technique. J Laryngol Otol 2004;118:508-16. 15. Hogikyan ND, Wodchis WP, Terrell JE, Bradford CR, Esclamado RM. Voice-related quality of life (V-RQOL) following type 1 thyroplasty for unilateral vocal fold paralysis. J Voice 2000;14:378-86. 16. Solis-Cohen J. Diseases of the throat: a guide to diagnosis and treatment. New York, NY: William Wood, 1880:58693. 17. Louis A. Louis on bronchotomy. Presented before the Royal Academy of Surgery of France in 1784. In: Ottley D, ed. Observations on surgical diseases of the head and neck. London: The Sydenham Society, 1848:214-78. 18. O’Dwyer J. Chronic stenosis of the larynx treated by a new method. Med Rec (NY) 1886;29:641. 19. Zeitels SM, Broadhurst MS, Akst LM, Lopez-Guerra G. The history of tracheotomy and intubation. In: Myers EN, Johnson JT, eds. Tracheotomy: airway management, communication, and swallowing. San Diego, Calif: Plural Publishing, 2007:1-21. 20. Jackson C, Jackson CL. Pachydermia of the larynx. In: The larynx and its diseases. Philadelphia, Pa: WB Saunders, 1937:194-8. Neurologic Variant Laryngomalacia Associated With Chiari Malformation and Cervicomedullary Compression: Case Reports Rajanya S. Petersson, MD; Nicholas M. Wetjen, MD; Dana M. Thompson, MD, MS Two infants presented with intermittent stridor and evidence of laryngomalacia on flexible laryngoscopy. The first was a 10-month-old girl who had undergone 3 supraglottoplasty surgeries at an outside institution, without long-term resolution of symptoms. She was found during our evaluation to have a Chiari malformation. Laryngomalacia symptoms resolved after suboccipital decompression and C1 laminectomy, and the patient remained symptom-free at 6-month follow-up. The second infant was a 24-day-old boy with velocardiofacial syndrome who was found to have posterior cervicomedullary junction compression at the level of C1. He underwent C1 laminectomy for decompression of the brain stem, which resulted in immediate resolution of symptoms, and he remained symptom-free at 12-month follow-up. Neurologic abnormalities have been reported in up to 50% of infants with laryngomalacia. As such, brain stem dysfunction should be considered among the causes of laryngomalacia during evaluation, especially in patients with failure of supraglottoplasty. Both of these infants had resolution of symptoms after their neurosurgical procedures. Key Words: brain stem compression, Chiari malformation, laryngomalacia, stridor. INTRODUCTION toms resolved after decompressive surgery. Laryngomalacia is a condition of weak laryngeal tone resulting in dynamic prolapse of supraglottic tissue into the airway. This causes inspiratory stridor and airway obstruction. The diagnosis is suspected in the presence of symptoms of inspiratory stridor that worsens with agitation, supine positioning, feeding, and crying, and is confirmed by flexible laryngoscopy. Laryngoscopic findings may include prolapse into the airway of supra-arytenoid mucosa or the arytenoid cartilages themselves, foreshortened aryepiglottic folds, and/or an omega-shaped or retroflexed epiglottis. In up to 20% of infants with laryngomalacia, there have been associated neurologic abnormalities.1 Laryngeal stridor has been reported in association with Chiari II malformations (caudal displacement of the brain stem into the cervical spinal canal associated with myelomeningocele), with the stridor most often caused by vocal fold paralysis.2-9 In some of these cases, the actual laryngeal abnormality was not discovered.3,4 We present 2 cases of infants with neurologic variant laryngomalacia. One infant was found to have an underlying Chiari I malformation, and the other was found to have cervicomedullary compression by a C1 posterior arch. In both patients, laryngomalacia and associated symp- CASE REPORTS Case 1. A 10-month-old girl with intermittent inspiratory stridor, episodes of cyanosis, and aspiration throughout infancy presented to our clinic. The stridor worsened with supine positioning. She had undergone supraglottoplasty 3 times at an outside institution, with only temporary improvement in symptoms. After the first supraglottoplasty, the episodes of cyanosis resolved. She had temporary relief of other symptoms, but shortly after surgery she experienced worsening stridor and aspiration. This prompted a second supraglottoplasty 5 months later, from which she had relief of symptoms for only 2 days. Overall, the stridor was improved after her first surgery, but was still present during sleep and with agitation. A third supraglottoplasty was performed 1 month later, again with only 2 days of symptom relief. The patient presented to us 7 days after her last surgery. At presentation, she had inspiratory stridor during sleep without desaturations. The stridor was high-pitched during sleep, and the patient’s breathing sounded raspy during the daytime while she was active. She was not experiencing cyanosis or retractions. She was still aspirating thin liquids, and was From the Departments of Otorhinolaryngology (Petersson, Thompson) and Neurologic Surgery (Wetjen), Mayo Clinic, and the Division of Pediatric Otorhinolaryngology, Mayo Clinic and Mayo Eugenio Litta Children’s Hospital (Thompson), Rochester, Minnesota. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: Dana M. Thompson, MD, Division of Pediatric Otorhinolaryngology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905. 121 122 Petersson et al, Neurologic Variant Laryngomalacia A B Fig 1. (Case 1) Magnetic resonance imaging. A) Preoperative scan shows Chiari I malformation with descent of cerebellar tonsils below foramen magnum. B) Scan performed 6 months after neurosurgical decompression shows resolution. on a thickened formula diet. She was on twice-daily proton pump inhibitor and nighttime histamine 2 receptor antagonist therapy. Flexible laryngoscopy revealed a slightly omega-shaped epiglottis without significant supra-arytenoid tissue prolapse; the lowest oxygen saturation was 90% during the examination. Significant cobblestoning of the posterior pharyngeal wall was noted. A functional endoscopic evaluation of swallowing study revealed laryngeal penetration of thickened formula with resultant cough, and occasional bolus passage without penetration or aspiration; there was direct laryngeal penetration and aspiration with thin liquid. As it is unusual for an infant to continue to have symptoms of laryngomalacia after a third supraglottoplasty, a thorough evaluation was planned. Computed tomography (CT) scans of the neck and chest showed no anatomic anomalies and no signs of chronic aspiration. Magnetic resonance imaging (MRI) of the head was scheduled to look for any intracranial or skull base disorders as contributing factors and did, in fact, reveal a Chiari I malformation, with descent of the cerebellar tonsils below the level of the foramen magnum with significant compression within the foramen magnum (Fig 1A). The patient was referred to the pediatric neurosurgery department at this time, and further plans for a pH study and overnight polysomnography were put on hold. She was taken to the operating room in conjunction with our pediatric neurosurgery colleagues for microlaryngoscopy and rigid bronchoscopy and for suboccipital decompression and C1 laminectomy. Her airway examination revealed an omega-shaped epiglottis with the lateral surfaces folding into the airway and producing stridor and foreshortened aryepiglottic folds, but no arytenoid prolapse. Rigid bronchoscopy revealed mucosal edematous changes but a widely patent airway. On postoperative day (POD) 1, the patient still had her baseline level of inspiratory stridor, with some improvement on POD 2, when she was discharged from the hospital. By her 1-week follow-up appointment, her stridor had resolved. She was still taking thickened formula, but without any symptoms of aspiration. Six months after her decompressive surgery, she was completely asymptomatic; she had no stridor or signs of aspiration with thin liquids, was tolerating table foods, was in the 95th percentile for weight, and was no longer requiring proton pump inhibitors or histamine 2 receptor antagonists. Her postoperative MRI no longer showed descent of her cerebellar tonsils (Fig 1B). Case 2. A 24-day-old boy with velocardiofacial syndrome presented with intermittent biphasic stridor, nasopharyngeal regurgitation, spitting up, and brief cyanotic episodes that occurred with feeding. Flexible laryngoscopy confirmed laryngomalacia with supra-arytenoid tissue prolapse into the glottal inlet, foreshortened aryepiglottic folds, and a slightly omega-shaped epiglottis (Fig 2A); he experienced desaturations into the mid-80% range during the examination. As such, overnight oximetry was performed and revealed a mean oxygen saturation of 95% with a high of 100% but a low of 72%; Petersson et al, Neurologic Variant Laryngomalacia A 123 B Fig 2. (Case 2) Flexible laryngoscopy. A) Preoperative laryngoscopy shows supra-arytenoid tissue prolapse obscuring visualization of vocal folds, foreshortened aryepiglottic folds, and omega-shaped epiglottis on inspiration. B) One day after neurosurgical decompression, significantly decreased prolapse of supra-arytenoid tissue allows visualization of vocal folds on inspiration. an oxygen saturation of less than 90% was recorded for 3.5% of the test duration. High-kilovoltage airway films and fluoroscopy were performed because of the biphasic nature of the stridor, and the findings were normal. During a medical genetics evaluation, MRI revealed posterior cervicomedullary compression and kinking of the brain stem (Fig 3), prompting evalu- Fig 3. (Case 2) Preoperative magnetic resonance imaging demonstrates posterior cervicomedullary compression and kinking of brain stem. ation by the pediatric neurosurgery department. A CT scan performed to evaluate the bony anatomy revealed incomplete ossification of the anterior arch of C1, kinking of the upper cervical spinal cord by the C1 posterior arch, and lateral displacement of the C1 lateral masses with bony settling of the occiput onto C2. Dynamic MRI was then performed to assess the stability of his craniovertebral junction; it demonstrated clear compression of the spinal cord in neutral position and reduced compression in extension. There was no translational instability on flexion-extension plain radiographs or dynamic MRI, and no anterior compression of the brain stem. Decompression with C1 laminectomy followed by temporary cervicothoracic external orthosis stabilization until occipitocervical stability could be demonstrated was recommended by the pediatric neurosurgery department. The patient was taken to the operating room in conjunction with our pediatric neurosurgery colleagues for microlaryngoscopy and rigid bronchoscopy and for C1 laminectomy. The airway examination revealed a slightly omega-shaped epiglottis, foreshortened aryepiglottic folds, and significant supra-arytenoid prolapse into the airway; the findings on rigid bronchoscopy were unremarkable. On POD 1, his stridor at baseline had nearly resolved, feeding had improved, and flexible laryngoscopy showed significantly decreased prolapse of supraarytenoid tissues (Fig 2B), and the patient was discharged from the hospital. At his 2-week follow-up visit, he was free of stridor and was no longer spit- 124 Petersson et al, Neurologic Variant Laryngomalacia ting up with feeding. Flexible laryngoscopy revealed a normally shaped and placed epiglottis and only mild supra-arytenoid prolapse; there was no audible stridor, even with agitation. Supraglottoplasty was never required. The child remained symptom-free at the 18-month follow-up, and cervical flexion-extension radiographs demonstrated no occipital C1-2 instability. DISCUSSION Laryngeal stridor due to vocal fold paralysis associated with Chiari II malformations (also known as Arnold-Chiari malformations) has been commonly reported.2-9 There have been few reported cases of laryngomalacia associated with Chiari malformations, and no reported cases of laryngomalacia caused by C1 posterior arch compression of the cervicomedullary junction. Portier et al6 described a case of an infant with a Chiari I malformation (elongation of cerebellar tonsils through the foramen magnum) and laryngomalacia causing respiratory obstruction that resolved 10 days after posterior fossa decompression. Their study found that major abnormal laryngeal dynamics, most often vocal fold paralysis, were found in 11% of infants with Chiari II malformations and less than 1% of those with Chiari I malformations. Neither of our patients had vocal fold paralysis in addition to laryngomalacia. Neurologic disease of any type is a well-known comorbidity associated with laryngomalacia, with reported rates of 8% to 50%, and is known to contribute to supraglottoplasty failure.1,10-17 Supraglottoplasty in general carries a high success rate, and has been reported to approach 94%, even when revision is required.1,18 Thus, the fact that our first patient failed to have complete resolution of symptoms after 3 supraglottoplasty procedures led us to believe that she may have had an underlying neurologic disorder. It is important to consider potential comorbidities and additional testing in infants with failed supraglottoplasty, as it is an operation with high success rates in the absence of comorbidities. Recognizing that our second patient had MRI evidence of cervicomedullary compression that could be decompressed by a neurosurgical procedure obviated the need for supraglottoplasty. This patient might have undergone supraglottoplasty first, with potential failure, if MRI had not been performed for evaluation of anomalies associated with velocardiofacial syndrome. The pathophysiology of brain stem dysfunction associated with Chiari malformations has been attributed to either hydrocephalus or brain stem compression itself.6 Our patient with the Chiari I malformation did not have hydrocephalus, so we assume that the dysfunction was related to physical compression. Knowledge of the neurologic pathways responsible for laryngeal function and tone is important in understanding how brain stem compression may contribute to development of laryngomalacia. There is a vagal nerve–mediated reflex called the laryngeal adductor reflex,1 which is activated when mechanoreceptors and chemoreceptors of the superior laryngeal nerve are stimulated, sending sensory afferent information to the brain stem nuclei responsible for regulating respiration and swallowing. Integration between the nucleus tractus solitarius and the nucleus ambiguus occurs in the brain stem. Efferent signals are sent via the vagus nerve to the larynx, causing vocal fold adduction and a swallow. These efferent signals are also responsible for laryngeal tone.1 Thus, brain stem compression may affect efferent vagal responses, leading to decreased laryngeal tone and laryngomalacia. Both of our patients had complete resolution of symptoms associated with laryngomalacia and no evidence of laryngomalacia on flexible laryngoscopy after their brain stem decompressive procedures. This outcome may be further evidence supporting the neurologic theory of laryngomalacia causation. CONCLUSIONS Neurologic abnormalities have been reported in up to 50% of infants with laryngomalacia. As such, brain stem dysfunction should be considered among the causes of laryngomalacia prompting further evaluation, especially in patients who have failed supraglottoplasty or other underlying comorbidities (eg, genetic syndrome, congenital anomalies). Both of these infants had resolution of laryngomalaciaassociated symptoms after their brain stem decompression procedures. REFERENCES 1. Thompson DM. Abnormal sensorimotor integrative function of the larynx in congenital laryngomalacia: a new theory of etiology. Laryngoscope 2007;117(suppl 114):1-33. 2. Smith ME. The association of laryngeal stridor with meningo-myelocele. J Laryngol Otol 1959;73:188-90. 3. Fitzsimmons JS. Laryngeal stridor and respiratory obstruction associated with meningomyelocele. Arch Dis Child 1965;40:687-8. 4. Krieger AJ, Detwiler JS, Trooskin SZ. Respiratory function in infants with Arnold-Chiari malformation. Laryngoscope 1976;86:718-23. 5. Cochrane DD, Adderley R, White CP, Norman M, Steinbok P. Apnea in patients with myelomeningocele. Pediatr Neurosurg 1990-1991;16:232-9. Petersson et al, Neurologic Variant Laryngomalacia 6. Portier F, Marianowski R, Morisseau-Durand MP, Zerah M, Manac’h Y. Respiratory obstruction as a sign of brainstem dysfunction in infants with Chiari malformations. Int J Pediatr Otorhinolaryngol 2001;57:195-202. 7. Morley AR. Laryngeal stridor, Arnold-Chiari malformation and medullary haemorrhages. Dev Med Child Neurol 1969; 11:471-4. 8. Papasozomenos S, Roessmann U. Respiratory distress and Arnold-Chiari malformation. Neurology 1981;31:97-100. 9. Holinger PC, Holinger LD, Reichert TJ, Holinger PH. Respiratory obstruction and apnea in infants with bilateral abductor vocal cord paralysis, meningomyelocele, hydrocephalus, and Arnold-Chiari malformation. J Pediatr 1978;92:368-73. 10. Hoff SR, Schroeder JW Jr, Rastatter JC, Holinger LD. Supraglottoplasty outcomes in relation to age and comorbid conditions. Int J Pediatr Otorhinolaryngol 2010;74:245-9. 11. Reddy DK, Matt BH. Unilateral vs bilateral supraglottoplasty for severe laryngomalacia in children. Arch Otolaryngol Head Neck Surg 2001;127:694-9. 125 12. Olney DR, Greinwald JH Jr, Smith RJ, Bauman NM. Laryngomalacia and its treatment. Laryngoscope 1999;109:17705. 13. Toynton SC, Saunders MW, Bailey CM. Aryepiglottoplasty for laryngomalacia: 100 consecutive cases. J Laryngol Otol 2001;115:35-8. 14. Denoyelle F, Mondain M, Gresillon N, Roger G, Chaudre F, Garabedian EN. Failures and complications of supraglottoplasty in children. Arch Otolaryngol Head Neck Surg 2003;129: 1077-80. 15. Roger G, Denoyelle F, Triglia JM, Garabedian EN. Severe laryngomalacia: surgical indications and results in 115 patients. Laryngoscope 1995;105:1111-7. 16. McClurg FL, Evans DA. Laser laryngoplasty for laryngomalacia. Laryngoscope 1994;104:247-52. 17. Prescott CA. The current status of corrective surgery for laryngomalacia. Am J Otolaryngol 1991;12:230-5. 18. Richter GT, Thompson DM. The surgical management of laryngomalacia. Otolaryngol Clin North Am 2008;41:837-64, vii. Systematic Review of Endoscopic Airway Findings in Children With Gastroesophageal Reflux Disease Jason Glenn May, MD; Priyanka Shah, MA; Lori Lemonnier, MD; Gaurav Bhatti, MS; Jovana Koscica, DO; James M. Coticchia, MD Objectives: We performed a systematic review of published literature correlating findings on endoscopic evaluation of the larynx and trachea in the pediatric population with the incidence of gastroesophageal reflux disease. Methods: Eight articles were identified through a structured PubMed search of English-language literature using the key terms laryngopharyngeal reflux, extraesophageal reflux, and gastroesophageal reflux. A systematic review was performed relating the presence of reflux in the pediatric population to findings on endoscopic airway evaluation. A covariant analysis was performed, and each study was weighted according to the number of available samples in that study as a fraction of the total. Overall odds ratios and confidence intervals were computed for each endoscopic finding on the basis of the documented absence or presence of gastroesophageal reflux disease. Results: A correlation was seen between the endoscopic findings and the presence of reflux. Conclusions: Arytenoid, postglottic, and vocal fold edema and erythema, lingual tonsil hypertrophy, laryngomalacia, and subglottic stenosis are among the endoscopic findings most frequently identified in patients with gastroesophageal reflux disease. Certain findings commonly encountered on endoscopic evaluation of the larynx and trachea in children who present with respiratory symptoms do indeed demonstrate a correlation with the presence of laryngopharyngeal reflux disease and may indicate the need for antireflux therapy. Key Words: extra-esophageal reflux, gastroesophageal reflux disease, laryngopharyngeal reflux. INTRODUCTION ration pneumonia, exacerbation of asthma, apnea, stridor, croup, and laryngitis or hoarseness.2 A relationship has also been shown between GERD and chronic lung diseases such as cystic fibrosis and bronchopulmonary dysplasia.3 It has been postulated that more than 40% of children with GERD have associated respiratory manifestations.4 The anatomic proximity of the larynx and supraglottis to refluxing material from the esophagus makes associated airway findings a distinct possibility. Reflux disease has become one of the most prevalent disease entities in the United States, with an estimated 75 million people suffering from gastroesophageal reflux disease (GERD). In the pediatric population, the prevalence has been reported to be as high as 22%.1 Gastroesophageal reflux is defined as a retrograde movement of gastric contents, including pepsin, bile, and pancreatic enzymes, into the esophagus. Reflux beyond the esophagus is termed laryngopharyngeal reflux (LPR). Extraesophageal reflux disease refers to nongastrointestinal manifestations of reflux disease. There is increasing evidence that GERD, and more specifically LPR, is associated with other medical problems ranging from chronic otitis media with effusion to airway abnormalities and esophageal dysfunction. A thorough understanding of the pathophysiology involved and its possible implications has become a necessity. The classic symptoms for GERD include heartburn, regurgitation, and dyspepsia, whereas the presentation of LPR may be less predictable. In the pediatric population, airway symptoms include aspi- The most significant difference between LPR and GERD is heartburn, as the majority of children with LPR do not have esophagitis or its primary symptom, heartburn.2 Common LPR symptoms include frequent throat clearing or cough, globus or foreign body sensation, and hoarseness, among others. Endoscopic findings that are commonly associated with chronic inflammation include edema and erythema of the arytenoids, redundancy of interarytenoid mucosa or pachydermia, and inflammatory changes of the vocal folds. In contrast, GERD is associated with heartburn and can occasionally be associated with distal esophageal changes and metaplasia, such as From the Division of Pediatric Otolaryngology, Department of Otolaryngology, Wayne State University, Detroit, Michigan. Presented at the meeting of the American Broncho-Esophagological Association, Las Vegas, Nevada, April 28-29, 2010. Correspondence: James M. Coticchia, MD, 4201 St Antoine, Suite 5E, Detroit, MI 48201. 126 May et al, Review of Gastroesophageal Reflux Disease in Barrett’s esophagus. One key point in understanding these two disease entities is that both GERD and LPR can occur in synchrony. The possible connection between GERD and airway abnormalities remains a controversial topic. Recently, there has been increasing evidence supporting a link between GERD or LPR and airway disease. The difficulty in dealing with this topic is in finding a cause-and-effect relationship between GERD and airway disease. How does the clinician tell whether GERD and airway disease merely coexist? Furthermore, some studies in the literature show coexistence and possible connection, but few show convincing causality. Several retrospective and prospective studies have demonstrated airway findings characteristic of GERD- or LPR-positive pediatric patients. These findings included arytenoid, interarytenoid, and postglottic edema and erythema, laryngomalacia, subglottic stenosis, cobblestoning of the tracheal mucosa, and blunting of the carina. Yellon et al3 showed a correlation between several endoscopic airway findings and GERD, which included laryngomalacia, subglottic stenosis, and posterior glottal edema and erythema. Their study also reported a correlation between GERD and airway symptoms such as cough, stridor, asthma, and croup. Halstead5 reported a 35% reduction in the need for airway surgery for subglottic stenosis if patients received aggressive therapy for GERD. This study is important in that it points to a causality of GERD in airway disease. Aggressive treatment of a patient’s reflux resulted in decreased airway disease and thus a reduction in the need for airway surgery. Several other studies have also pointed to treating reflux as a means of improving the pediatric airway. Tashjian et al6 investigated the effects of Nissen fundoplication on reactive airway disease. They showed that effective management of GERD or LPR via Nissen fundoplication decreased airway disease in children. Common presenting symptoms for these children included cough, dyspnea, and airway congestion. The study showed that 75% of children who underwent Nissen fundoplication were off all reflux medications and, more importantly, were symptom-free. Another study, by Suskind et al,7 showed the resolution of reflux-related otolaryngology symptoms after antireflux surgery. Otolaryngology symptoms included subglottic edema, subglottic stenosis, reflex apnea, and recurrent croup. These studies showed resolution of airway symptoms after surgical management of medically refractory reflux that pointed to a cause-and-effect relationship between GERD and airway disease. Unfortunately, no studies to date have attempted to analyze and evaluate the current literature correlating common airway findings on 127 endoscopy to the presence of GERD or LPR. The purpose of this study was to perform a meta-analysis to evaluate the correlation of endoscopic findings of LPR and GERD in the pediatric population. Our hypothesis holds that there is an increasing body of literature that supports a link between GERD and endoscopic findings consistent with airway disease. METHODS A systematic review was performed of articles relating the presence of reflux disease in the pediatric population to findings on endoscopic airway evaluation. These were identified through a structured PubMed search of the English-language literature using the key terms laryngopharyngeal reflux, extraesophageal reflux, and gastroesophageal reflux, as well as subglottic stenosis and laryngomalacia. Additional articles were obtained by hand-searching the references listed in those papers identified by the above search criteria. The literature search was performed in late 2009 and represented the studies available at that time. We included all articles found by the above-mentioned literature search and hand search method. We excluded articles studying strictly endoscopic findings in the pediatric population. The result was a total of 20 articles.3-5,7-23 Each was reviewed to determine the level of evidence, subject population, methods of evaluation, results, and conclusions. Fourteen of the 20 articles were used in the study. Six could not be included in the statistical analysis because of an inability to compare them to the other articles in the study. (Two articles were based on different therapies administered to patients with symptoms. Three articles did not include the numbers of patients with GERD for each airway finding reported, and instead only discussed percentages of patients with GERD and certain airway findings. One article looked only at patients who had a diagnosis of GERD and whose airway findings were investigated.) Further, 6 additional articles were excluded because of numbers too small for comparison and unclear methodology. The result was 8 articles that were reviewed and submitted to meta-analysis.3-5,9,11,12,18,23 There are several ways in which clinicians measure GERD. The gold standard has shifted over the years and is currently a 24-hour pH probe study. Methods have included the following: evaluation of esophageal biopsies on a histopathologic examination suggestive of GERD, barium reflux into the esophagus on a barium swallow test, double and single pH probes showing a pH of less than 4 for 5% to 8% of time, and number of reflux episodes. Several studies used multiple methods. 128 May et al, Review of Gastroesophageal Reflux Disease Fig 1. Meta-analysis of arytenoid edema and erythema and gastroesophageal reflux disease.4,11 CI — confidence interval. Asterisk — p < 0.05. Fig 2. Meta-analysis of posterior glottal edema and erythema and gastroesophageal reflux disease.4,11 Asterisk — p < 0.05. The age ranges of the children used in the different studies varied tremendously. Some studies had a wide range, evaluating children in ages ranging from 10 days to 17 years. Other studies focused on a very narrow age range. sis revealed a correlation between 6 endoscopic airway findings and the presence of GERD. The airway findings that correlated to GERD in a statistically significant manner are listed below. Arytenoid edema and erythema were found to correlate with GERD with a relative risk of 2.46 (Fig 14,11). Lingual tonsil hypertrophy was found to correlate with GERD with a relative risk of 2.24. Posterior glottal edema and erythema were found to strongly correlate with GERD, with a relative risk of 3.19 (Fig 24,11). Subglottic stenosis was found to correlate with the presence of GERD in 4 studies with a relative risk of 2.5 (Fig 34,9,11,16). Tracheal edema was found to correlate with GERD with a relative risk of 1.86. Vocal fold edema and nodules was found to have the strongest correlation to GERD, with a relative risk of 12.15 (Fig 411,12). Epiglottic and supraglottic collapse were found to correlate with GERD, but not in a statistically significant manner. Moderated risk ratio analysis was performed on 4 variables as mentioned above. The variables that were studied in at least 3 articles were included in Several airway findings were observed in patients from the studies. These included lingual tonsil swelling, postglottic edema and erythema, arytenoid edema and erythema, ventricle obliteration, true vocal fold edema, laryngomalacia, tracheomalacia, vocal fold lesions, subglottic stenosis, supraglottic stenosis, hypopharyngeal cobblestoning, narrowed trachea, posterior pharyngeal wall cobblestoning, innominate artery compression, choanal atresia, posterior glottal cleft, blunt carina, general edema and erythema, and increased secretions. Some findings were echoed in multiple reports. Five reports mentioned laryngomalacia, and 4 mentioned subglottic stenosis. Fisher’s exact test was used to evaluate the significance of contingency tables obtained from individual studies. The data from individual studies with appropriate sample size were then combined, and the significance was determined similarly. Weights were assigned to a study based on its sample size relative to the total sample size. Odds ratios with the 95% confidence interval along with the weights are reported in the plots shown in Results. Moderated risk ratios were calculated. This method examines risk factors (in this case, airway findings) evaluated in 4 or more studies. The closer the value of the moderated risk ratio is to 1, the stronger the correlation between the risk factor and GERD. RESULTS A meta-analysis and a moderated risk ratio analysis evaluated the correlation between endoscopic larynx and airway findings and GERD. Meta-analy- Fig 3. Meta-analysis of subglottic stenosis and gastroesophageal reflux disease.4,9,11,16 Asterisk — p < 0.05. May et al, Review of Gastroesophageal Reflux Disease Fig 4. Meta-analysis of vocal fold edema and nodules and gastroesophageal reflux disease.11,12 Asterisk — p < 0.05. the moderated risk ratio analysis. The moderated risk ratio analysis illustrated the percentage chance that a patient had GERD in the presence of specific endoscopic airway findings. Patients with epiglottic or supraglottic collapse had a 67% chance of GERD. Patients with posterior glottal edema and erythema had a 70% chance of having GERD. Patients with subglottic stenosis had a 65% chance of having GERD. Patients with vocal fold edema and/or nodules had an 88% chance of having GERD. Patients with all 4 findings had a greater than 70% chance of having GERD (Fig 53-5,9,11,12,18,23). The reported incidence of GERD in patients presenting with respiratory symptoms within the 8 studies ranged from 31% to 86%. Laryngomalacia and subglottic stenosis have been frequently examined in the literature in association with GERD, and Fig 5. Moderated risk ratio comparing 4 variables that were compared in 3 or more of studies.3-5,9,11,12,18,23 129 were found concomitantly in 63% to 80% and 57% to 95% of patients, respectively. Importantly, a correlation was identified by Giannoni et al18 between the severity of laryngomalacia and that of GERD. Additional endoscopic laryngeal findings frequently documented in the presence of GERD included postglottic, arytenoid, and true vocal fold edema and lingual tonsil hypertrophy. Furthermore, Carr’s triad11 of postglottic edema, loss of arytenoid contour, and lingual tonsil hypertrophy was found in 61.5% of patients with GERD by Mitzner and Brodsky,4 whereas Carr et al11 concluded that each finding was pathognomonic for the disease. Last, treatment options for GERD, including behavioral changes, medical therapy, and surgical therapy, have proven to have a significant impact on the improvement of symptoms, as well as endoscopic findings, even resulting in the avoidance of airway surgery in 35% of one study population. DISCUSSION Numerous investigators have performed endoscopic evaluations on children with a variety of clinical presentations that include recurrent croup, stridor, chronic cough, and even failure to thrive. Many of these clinical studies have attempted to correlate endoscopic findings with different diagnostic tests for GERD, including vocal erythema and edema, posterior glottal edema and erythema, arytenoid edema, and even subglottic stenosis. The reflux of gastric contents into the larynx and supraglottis (laryngopharynx) has been implicated as an inflamma- 130 May et al, Review of Gastroesophageal Reflux Disease tory cofactor and a possible cause of many adult and pediatric respiratory disorders.5 The gold standard for diagnosing GERD is 24-hour pH probe monitoring. Endoscopic evaluation via direct laryngoscopy and bronchoscopy is considered the gold standard for diagnosing upper airway disease. Common findings associated with chronic inflammation include supraglottic edema and erythema, vocal fold edema and erythema, posterior glottal edema and erythema, tracheal edema and loss of tracheal rings, and, finally, subglottic stenosis. The studies reviewed in this report looked for endoscopic findings consistent with GERD and LPR. Although there is no study that shows that specific endoscopic findings are only caused by reflux disease, the literature has consistently investigated a consistent set of airway findings. One could argue that many of the same airway findings could be attributed to intubation trauma, but to do so would be to ignore a large body of evidence that points to the purported link between reflux and airway disease. Both GERD and LPR cause chronic low-grade inflammation consistent with the pathogenesis of posterior glottal edema and erythema, vocal fold edema and nodules, and even subglottic stenosis. Halstead5 sought to show a correlation between GERD and pediatric upper airway disorders. The study looked at 51 children who underwent evaluation for GERD as a possible cofactor in their upper airway disease. Forty-one of these children underwent 24-hour pH probe monitoring. Laryngoscopy was performed to evaluate the children’s airway. The study showed that all but 1 of the 41 children probed had 10 or more episodes of pharyngeal reflux. It is believed that even 1 episode of reflux is indicative of the presence of GERD. The laryngeal appearance ranged from subtle edema to alarming erythema and edema. Airway findings included true vocal fold nodules, laryngomalacia, and subglottic stenosis. The study showed that significant GERD occurs in many pediatric upper airway disorders. The study showed reductions in symptoms, in airway findings, and, most importantly, in the degree of surgical intervention. The vast majority of children (90%) with subglottic stenosis showed a partial or complete resolution of GERD symptoms with medical or surgical therapy. These children showed a reduction in stridor, and 35% avoided airway surgery altogether. This study clearly shows a likely cause-and-effect relationship between GERD and/ or LPR and airway disease. Similar studies have shown a marked decrease in airway disease and/or interventions by better controlling GERD and/or LPR. Tashjian et al6 performed a retrospective review of 24 children who underwent Nissen fundoplication. Common presenting symptoms of airway disease included cough, dyspnea, airway congestion, and weight loss, and the patients were taking multiple medications for reflux. Bronchoscopy showed lipid-laden macrophages on bronchial washings. After the Nissen fundoplication, 75% of the patients stopped taking all medications and were symptom-free. Another study, by Suskind et al,7 showed the resolution of reflux-related otolaryngological symptoms after antireflux surgery. Otolaryngological symptoms in the study were defined as subglottic edema, subglottic stenosis, reflex apnea, and recurrent croup. In all 14 patients, the otolaryngological symptoms resolved after antireflux surgery. Again, these studies point to a likely connection between GERD and airway disease. However, the study was limited by several factors. It was a retrospective study of patients who underwent evaluation for GERD. Also, there were no further delineations of which specific airway findings, such as posterior glottal edema or erythema, and vocal fold edema or erythema, correlated most strongly with GERD. Giannoni et al18 investigated the incidence of GERD in patients with laryngomalacia. A prospective study was performed of 33 consecutive infants, 27 of whom were undergoing evaluation for GERD via either esophagogram or 24-hour pH probe monitoring, with a new diagnosis of laryngomalacia. GERD was observed in 64% of patients and was associated with severe symptoms and a prolonged, complicated course. Evaluation was done via questionnaire of the child’s caregiver. Endoscopic findings were broken down by severity of laryngomalacia found on laryngoscopy. The limitation of this study is that it only examined children with a new diagnosis of laryngomalacia. Also, once again, there was no correlation done between specific endoscopic findings and the presence or severity of GERD. Yellon et al3 investigated esophageal biopsy as a means of diagnosing GERD. Also, the presence of endoscopic findings such as posterior glottal erythema and edema, laryngomalacia, and subglottic stenosis in children with GERD was investigated. A historical cohort study was done on children who underwent esophageal biopsy to investigate the presence of GERD. Esophageal biopsies were found to be an effective method of diagnosing GERD. There was also a correlation shown between GERD and posterior glottal erythema and edema, laryngomalacia, and subglottic stenosis. A limitation of the study is that it was a historical cohort study. Also, it only investigated children who underwent esophageal bi- May et al, Review of Gastroesophageal Reflux Disease opsy. Multiple methods were used to detect GERD in the 8 studies that we reviewed. These methods included single pH probe monitoring, double pH probe monitoring, and esophageal biopsy. However, it should be noted that 24-hour pH monitoring is now considered the gold standard of detecting GERD because of its 87% sensitivity, 93% specificity, and 92% accuracy. Chronic and uncontrolled inflammation is now believed to play a key role in the development of subglottic stenosis. We sought to evaluate the studies currently in the literature regarding the presence of GERD and airway disease in children. Our systematic review showed a statistically significant correlation between GERD or LPR and arytenoid edema and erythema, lingual tonsil hypertrophy, posterior glottal edema and erythema, tracheal edema, vocal fold edema and nodules, and, most importantly, subglottic stenosis. Certain endoscopic findings showed a stronger correlation with GERD. Lingual tonsil hypertrophy and tracheal edema showed a statistically significant correlation with GERD, but also showed the weakest connection with GERD. Arytenoid edema and erythema and subglottic stenosis had a relative risk of around 2.5. In other words, children with arytenoid edema and erythema were 2.5 times more likely to have GERD than is the general population. Interestingly, posterior glottal edema and erythema showed a stronger correlation with GERD, with a relative risk of greater than 3. Vocal fold edema and nodules had the strongest correlation, with a relative risk of greater than 12. The key point of this study was elicited by the moderated risk ratio analysis of all 8 studies. This analysis showed the likelihood of having GERD with respective endoscopic findings. Patients with epiglottic or supraglottic collapse had a 67% chance of having GERD. Patients with posterior glottal edema and erythema had a 70% chance of having GERD. Patients with subglottic stenosis had a 65% chance of having GERD. Patients with vocal fold edema and nodules had an 88% chance of having GERD. Finally, patients with all 4 findings had a greater than 70% chance of having GERD. This study points to a prominent role of GERD in the development and worsening of airway symptoms. If a patient is found to have vocal fold edema and nodules, then it is likely that GERD is present, as well. This is an important indicator as to how that patient is to be managed in the future. Studies have shown decreased morbidity of airway disease with aggressive management of GERD.5 This is the first study to show a statistically significant correlation between the presence of GERD and endoscopic 131 findings of arytenoid edema and erythema, lingual tonsil hypertrophy, posterior glottal edema and erythema, tracheal edema, vocal fold edema and nodules, and, most importantly, subglottic stenosis Any systematic review is limited, in that it is not a randomized, controlled trial. Also, among the different studies, it is difficult to ensure consistency in terminology among raters: what constitutes erythema, what constitutes edema, etc. Also, a metaanalysis is somewhat limited by its very design. Comparing various studies and drawing conclusions from multiple studies as a group can be difficult at best, and impossible at worst. The studies were done by multiple groups on different patient populations and using different criteria. Finally, any patient population that undergoes endoscopic evaluation is subject to bias, because those children had airway symptoms severe enough to necessitate an airway procedure. Future studies should include a randomized, controlled trial investigating endoscopic findings and their possible correlation with GERD. Also, few studies have attempted to compare the effects of aggressive treatment of GERD and its impact on the outcome and resolution of endoscopic airway findings. CONCLUSIONS This systematic review has shown endoscopic airway findings to correlate with the presence of GERD or LPR. It showed a correlation between GERD or LPR and arytenoid edema and erythema, lingual tonsil hypertrophy, posterior glottal edema and erythema, tracheal edema, vocal fold edema and nodules, and, most importantly, subglottic stenosis. Also, a moderated risk ratio analysis showed that children with arytenoid edema and erythema, posterior glottal edema and erythema, subglottic stenosis, and vocal fold edema and nodules had a more than 70% chance of having GERD. Multiple studies have shown that effectively treating GERD lessens, if not resolves, airway disease and symptoms. Certain findings commonly encountered on endoscopic evaluation of the larynx and trachea in children who present with respiratory symptoms do indeed demonstrate a correlation with the presence of GERD, and may indicate that antireflux therapy should be considered in the treatment of this population of patients. Prior studies have shown that aggressive antireflux management reduces the amount of airway surgery necessary for these patients.7 The correlation of endoscopic airway findings and GERD in the 8 articles systematically reviewed by our study points to the necessity of reflux management in children with the airway findings discussed. 132 May et al, Review of Gastroesophageal Reflux Disease REFERENCES 1. Brodsky L, Carr MM. Extraesophageal reflux in children. Curr Opin Otolaryngol Head Neck Surg 2006;14:387-92. diatric patients. Int J Pediatr Otorhinolaryngol 2005;69:110912. 2. Walner DL, Stern Y, Gerber ME, Rudolph C, Baldwin CY, Cotton RT. Gastroesophageal reflux in patients with subglottic stenosis. Arch Otolaryngol Head Neck Surg 1998;124:551-5. 3. Yellon RF, Coticchia J, Dixit S. Esophageal biopsy for the diagnosis of gastroesophageal reflux–associated otolaryngologic problems in children. Am J Med 2000;108(suppl 4a): 131S-138S. 4. Mitzner R, Brodsky L. Multilevel esophageal biopsy in children with airway manifestations of extraesophageal reflux disease. Ann Otol Rhinol Laryngol 2007;116:571-5. 5. Halstead LA. Gastroesophageal reflux: a critical factor in pediatric subglottic stenosis. Otolaryngol Head Neck Surg 1999;120:683-8. 6. Tashjian DB, Tirabassi MV, Moriarty KP, Salva PS. Laparoscopic Nissen fundoplication for reactive airway disease. J Pediatr Surg 2002;37:1021-3. 7. Suskind DL, Zeringue GP III, Kluka EA, Udall J, Liu DC. Gastroesophageal reflux and pediatric otolaryngologic disease: the role of antireflux surgery. Arch Otolaryngol Head Neck Surg 2001;127:511-4. 8. Bibi H, Khvolis E, Shoseyov D, et al. The prevalence of gastroesophageal reflux in children with tracheomalacia and laryngomalacia. Chest 2001;119:409-13. 9. Halstead LA. Role of gastroesophageal reflux in pediatric upper airway disorders. Otolaryngol Head Neck Surg 1999;120: 208-14. 10. Little JP, Matthews BL, Glock MS, et al. Extraesophageal pediatric reflux: 24-hour double-probe pH monitoring of 222 children. Ann Otol Rhinol Laryngol Suppl 1997;106(suppl 169):1-16. 11. Carr MM, Nagy ML, Pizzuto MP, Poje CP, Brodsky LS. Correlation of findings at direct laryngoscopy and bronchoscopy with gastroesophageal reflux disease in children: a prospective study. Arch Otolaryngol Head Neck Surg 2001;127:36974. 12. Carr MM, Abu-Shamma U, Brodsky LS. Predictive value of laryngeal pseudosulcus for gastroesophageal reflux in pe- 13. Matthews BL, Little JP, McGuirt WF Jr, Koufman JA. Reflux in infants with laryngomalacia: results of 24-hour double-probe pH monitoring. Otolaryngol Head Neck Surg 1999; 120:860-4. 14. Walner DL, Holinger LD. Supraglottic stenosis in infants and children. A preliminary report. Arch Otolaryngol Head Neck Surg 1997;123:337-41. 15. Walner DL, Stern Y, Gerber ME, Rudolph C, Baldwin CY, Cotton RT. Gastroesophageal reflux in patients with subglottic stenosis. Arch Otolaryngol Head Neck Surg 1998;124:551-5. 16. Stroh BC, Faust RA, Rimell FL. Results of esophageal biopsies performed during triple endoscopy in the pediatric patient. Arch Otolaryngol Head Neck Surg 1998;124:545-9. 17. Gumpert L, Kalach N, Dupont C, Contencin P. Hoarseness and gastroesophageal reflux in children. J Laryngol Otol 1998;112:49-54. 18. Giannoni C, Sulek M, Friedman EM, Duncan NO III. Gastroesophageal reflux association with laryngomalacia: a prospective study. Int J Pediatr Otorhinolaryngol 1998;43:1120. 19. Belmont JR, Grundfast K. Congenital laryngeal stridor (laryngomalacia): etiologic factors and associated disorders. Ann Otol Rhinol Laryngol 1984;93:430-7. 20. Mandell DL, Yellon RF. Synchronous airway lesions and esophagitis in young patients undergoing adenoidectomy. Arch Otolaryngol Head Neck Surg 2007;133:375-8. 21. Ungkanont K, Friedman EM, Sulek M. A retrospective analysis of airway endoscopy in patients less than 1-month old. Laryngoscope 1998;108:1724-8. 22. Block BB, Brodsky L. Hoarseness in children: the role of laryngopharyngeal reflux. Int J Pediatr Otorhinolaryngol 2007; 71:1361-9. 23. Carr MM, Nguyen A, Poje C, Pizzuto M, Nagy M, Brodsky L. Correlation of findings on direct laryngoscopy and bronchoscopy with presence of extraesophageal reflux disease. Laryngoscope 2000;110:1560-2. Correlation of Vocal Fold Nodule Size in Children and Perceptual Assessment of Voice Quality Roger C. Nuss, MD; Jessica Ward; Lin Huang, PhD; Mark Volk, DMD, MD; Geralyn Harvey Woodnorth, MA Objectives: We examined the relationship between the size of vocal fold nodules and perceptual rating of voice quality in children. Methods: We carried out an Institutional Review Board–approved retrospective study in a voice clinic within a tertiarycare pediatric medical center. We studied children seen between 2000 and 2009 with a primary diagnosis of vocal fold nodules as the cause of their voice disturbance. Pediatric vocal fold nodule size was rated with a published validated scale, and voice quality was rated on the Consensus Auditory-Perceptual Evaluation of Voice scale. Results: One hundred forty-five patients met the inclusion criteria. Small nodules were noted in 23% of patients, medium nodules in 39%, and large nodules in 37%. Univariate and multivariate analyses demonstrated a statistically significant relationship (p < 0.05) between vocal fold nodule size and rated perceptual qualities of overall severity of voice disturbance, roughness, strain, pitch, and loudness. With the exception of loudness, as vocal fold nodule size increased, the mean value of perceptual characteristics became larger. The age of the patient was a significant factor associated with the overall severity of the voice disturbance and roughness. Conclusions: The overall severity of a child’s voice disturbance and qualities of roughness, strain, pitch, and loudness have a strong correlational relationship with pediatric vocal fold nodule size, which is suggestive of causality. Key Words: CAPE-V scale, child, vocal fold nodule, voice quality. In addition, it is well recognized that some children improve with no intervention — only natural physical growth and maturity. INTRODUCTION Vocal fold nodules are widely appreciated to be the most common and important physical finding associated with dysphonia in pediatric patients. Approximately 40% of patients seen in a pediatric tertiary care voice clinic are diagnosed with vocal fold nodules1 (also Nuss et al, unpublished observations). There may be a number of underlying factors creating an environment in which nodules are more likely to develop. Such contributing causes include laryngopharyngeal reflux, vocal hyperfunction, vocal overuse and abuse, and even a genetic predisposition toward the development of nodules.2-4 One area of difficulty has been in understanding whether the size of a vocal fold nodule in a child actually matters, and whether our treatment attempts should even consider the size of nodules as an important factor. It is possible to objectively rate the size of vocal fold nodules in children by use of a validated scale.7 An experienced clinician’s perceptual assessment of a child’s voice quality can also be objectively reported with a validated scale.8 The goal of this study was to determine whether there is any relationship between vocal fold nodule size in children and perceptual assessment of their voice quality. The management of pediatric vocal nodules has not been standardized, but is generally based on the severity of the voice disorder. Many of the treatment options for children have been inferred from adult therapies, including voice rest, voice therapy, treatment of laryngopharyngeal reflux, and medical management of any associated condition that may interfere with the resolution of vocal fold nodules.5,6 METHODS The Committee on Clinical Investigation at Children’s Hospital Boston approved this retrospective study. The Voice Clinic at Children’s Hospital Boston maintains a database of children evaluated since From the Department of Otolaryngology and Communication Enhancement (Nuss, Ward, Volk, Woodnorth) and the Clinical Research Program (Huang), Children’s Hospital Boston, and the Department of Otology and Laryngology, Harvard Medical School (Nuss, Ward, Volk, Woodnorth), Boston, Massachusetts. Correspondence: Roger C. Nuss, MD, Dept of Otolaryngology and Communication Enhancement, Children’s Hospital Boston, 300 Longwood Ave, Boston, MA 02115. 133 134 Nuss et al, Vocal Nodule Size & Voice Quality Fig 1. Distribution of patient population by age and nodule size. Fig 2. Mean values of perceptual characteristics according to nodule size. 1996. The inclusion criteria for this study included ages 2 through 18 years, examinations recorded between 2000 and 2009, a recorded high-quality digital videolaryngoscopic examination confirming the presence of vocal fold nodules, and documented perceptual ratings of voice quality on the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) scale.8 95% consistency, ie, a high degree of intrarater reliability. Perceptual assessment of voice quality was performed by an experienced pediatric voice and speech pathologist using the CAPE-V scale.8 The characteristics measured included roughness, strain, pitch, loudness, breathiness, and overall severity. Transnasal videostroboscopic examination was performed in all patients. An FNL-10RP3 fiberoptic nasolaryngoscope (KayPENTAX, Lincoln Park, New Jersey) was used for transnasal examinations in children 13 years of age and above; a KayPENTAX FNL-7RP3 fiberoptic nasolaryngoscope was used in children 2 to 12 years of age. Topical anesthesia was achieved with the application of a 1:1 mixture of 0.05% oxymetazoline hydrochloride solution and 4% lidocaine hydrochloride sprayed into the nasal passage. Videostroboscopy examinations were recorded with a KayPENTAX Digital Video Stroboscopy System (Model 9295). A 1-way analysis of variance (ANOVA) was used to analyze the relationship of nodule size and perceptual voice variables (roughness, strain, pitch, loudness, breathiness and overall severity) at the univariate level. A t-test was used to see whether nodule type (sessile or discrete) was significantly related to perceptual voice measures. Age groups (2.0 to 5.9 years, 6.0 to 11.9 years, and more than 12 years of age) and gender were also tested at the univariate level by use of an ANOVA and a t-test to determine whether they were significantly associated with perceptual voice variables. Nodule size, nodule contour, age, and gender were all included for multivariate analysis using factorial ANOVA. Main effects and interaction terms were checked for statistical significance, then least square means for perceptual voice variables were computed adjusted for the significant factors. Patients were separated into three different age groups associated with the levels of development: 2.0 to 5.9 years, 6.0 to 11.9 years, and more than 12 years of age. The senior author (R.C.N.) rated vocal fold nodule size as small, moderate, or large, according to a previously validated scale.7 Additionally, nodule contours were rated as being either sessile or discrete by use of this scale. Nodule sizes and contours were later re-rated by the senior author, blinded to the original rating. There was a more than All of our tests were 2-sided and set 0.05 as a standard type I error. The statistical software package SAS 9.2 was used for analysis (SAS Institute, Cary, North Carolina). TABLE 1. MEAN SCORE OF PERCEPTUAL CHARACTERISTICS, BASED ON CAPE-V SCALE, BY NODULE SIZE Nodule Size Small Medium Large p Roughness Strain Pitch Loudness Breathiness Severity 25.32 30.74 40.31 <0.0001 31.11 35.18 48.24 <0.0001 14.62 22.32 27.22 0.0072 3.00 8.11 –4.19 0.0165 20.94 23.60 27.59 0.1847 29.68 37.21 49.04 <0.0001 CAPE-V — Consensus Auditory-Perceptual Evaluation of Voice. Nuss et al, Vocal Nodule Size & Voice Quality 135 Fig 3. Mean values of perceptual characteristics by nodule type (sessile versus discrete). RESULTS A total of 145 patients met the selection criteria. The distribution of patients in this study is displayed in Fig 1. There was an approximately 2-to-1 maleto-female ratio, with 66% male and 34% female. The preschool age group, 2 to 5.9 years of age, made up 31% of patients in this study. The school-age group, 6.0 to 11.9 years of age, included 61% of the study population. Teenagers, 12 to 18 years of age, were just 8% of the study population. Overall, small nodules were noted in 23% of patients, moderate nodules in 39%, and large nodules in 37%. Fig 4. Mean values of perceptual characteristics according to age. ated with roughness (p = 0.0286) and overall severity (p = 0.0349). The group 6 to 11.9 years of age had the smallest disturbance, and the groups 2 to 5.9 years of age and more than 12 years of age had very similar levels of disturbance, as seen in Fig 4 and Table 3. Gender was not found to be a significant factor associated with any perceptual characteristics. Univariate analysis showed a statistically significant association between nodule size and the perceptual measures of roughness, strain, pitch, loudness, and overall severity. With the exception of loudness, as vocal fold nodule size increased, the mean value of perceptual characteristics became larger. The association of each perceptual voice characteristic and vocal fold nodule size is shown in Fig 2. Table 1 lists the value of means and p values according to the F-test. In a multivariate analysis of overall severity of voice disturbance, vocal fold nodule size and patient age were found to be significant independent variables, with p values of less than 0.0001 and 0.0023, respectively. Interaction between these two variables was not significant. After adjusting for age, the difference of mean severity between nodule sizes large and small was 20.19 (p < 0.0001), that between sizes large and medium was 13.6 (p < 0.0001), and that between sizes medium and small was 6.59 (p = 0.1513). Figure 5 displays the estimated means for overall severity of voice disturbance based on multivariate analysis of the independent variables age and vocal fold nodule size. Table 4 includes numerical data of the same. Nodule type (sessile versus discrete) was also analyzed as an independent factor for perceptual characteristics. Analysis of results demonstrated that the mean value of perceptual characteristics was larger when the nodule contour was discrete rather than sessile. However, statistical significance was achieved only with the characteristic of roughness. Figure 3 and Table 2 summarize the means and p values of perceptual characteristics by nodule type. DISCUSSION The ability to assess vocal fold nodules in children has been limited in the past by the lack of a val- Age was noted to be a significant factor associ- TABLE 2. MEAN SCORE OF PERCEPTUAL CHARACTERISTICS, BASED ON CAPE-V SCALE, BY NODULE TYPE Nodule Type Sessile Discrete p Roughness Strain Pitch Loudness Breathiness Severity 31.66 38.55 0.0392 37.83 43.77 0.1638 22.01 23.60 0.6768 1.97 3.73 0.7565 23.61 27.63 0.7565 38.77 43.97 0.1653 136 Nuss et al, Vocal Nodule Size & Voice Quality TABLE 3. MEAN SCORE OF PERCEPTUAL CHARACTERISTICS, BASED ON CAPE-V SCALE, BY AGE Age Group 2-5.9 y 6-11.9 y >12 y p Roughness Strain Pitch Loudness Breathiness Severity 37.91 30.28 36.09 0.0286 44.86 36.83 41.67 0.2614 25.59 20.51 24.00 0.3151 8.52 –0.67 1.92 0.0905 25.64 22.86 31.92 0.1996 44.93 36.80 44.45 0.0349 idated scale to report the size of the nodule, as well as the absence of a validated scale to rate the perceptual characteristics of voice quality. In the absence of accepted valid scales, reports of voice quality in children with vocal fold nodules have been difficult to interpret and sometimes contradictory.9-13 Presently, there are excellent tools both to report the size of vocal fold nodules in children and to describe the perceptual characteristics of the child’s voice. A validated scale used to rate the size of pediatric vocal fold nodules has been created, and is proving useful in a clinical context, as well as in clinical research.7 The CAPE-V scale has been successfully used in the pediatric population, providing a significant improvement in our ability to describe a child’s hoarse voice quality. This study was undertaken to better understand whether there indeed is any relationship between the size of vocal fold nodules in children and the associated voice disturbance as perceived by an experienced speech and language pathologist. A previous study failed to demonstrate any significant correlation, but that study may have been flawed by the lack of a validated instrument for assessing voice quality.12 The important finding in the present study is that there is a statistically significant association between nodule size and the perceptual measures of roughness, strain, pitch, and overall severity. As vocal fold nodule size increases, the mean value of these perceptual characteristics becomes larger. In summary, size matters. The contour of the nodule (sessile or discrete) was not generally found to be a significant factor associated with voice quality. The age of the child was noted to be significant for voice qualities of roughness and overall severity; the youngest age group (2 to 5.9 years) and the oldest age group (more than 12 years) were more severely affected by the presence of nodules. Interestingly, gender was not found to be a significant independent risk factor for voice quality. The results of this study may be useful in a clinical context, as following a child’s voice quality by use of the CAPE-V scale may be a reliable guide to the size of the underlying vocal fold nodules. Improvements in a child’s voice quality would suggest a decrease in the size of the nodules. A worsening voice quality may indicate increasing size of vocal fold nodules, or the development of another factor that is contributing to the voice disturbance. Clinical observations of a child’s larynx, as obtained during fiberoptic videolaryngoscopy, will continue to be the gold standard of the health and condition of the vocal folds. However, there are frequent occasions in which we would like to reassure an anxious parent that their child’s vocal fold nodules are improving — without the need for a repeat fiberoptic examination. The present report suggests that perceptual assessment of a child’s voice quality, as performed longitudinally on several occasions, is a reliable guide to the size of previously diagnosed nodules. Perceptual assessment of voice quality is performed by an experienced speech and language pathologist, and may be used in conjunction with patient-based surveys to improve our ability to describe voice disorders and offer optimal management.14 This report indicates that perceptual assessment using the CAPE-V scale in children offers an indirect means to follow vocal fold nodule size. TABLE 4. ESTIMATED MEAN SCORE FOR OVERALL SEVERITY OF VOICE DISTURBANCE (AS RATED WITH CAPE-V SCALE) BASED ON MULTIVARIATE ANALYSIS OF AGE AND VOCAL FOLD NODULE SIZE Fig 5. Estimated means for overall severity of voice disturbance based on multivariate analysis of independent variables age and vocal fold nodule size. Nodule Size Small Medium Large Age 2-5.9 Years 36.29 42.88 56.48 Age 6-11.9 Years 26.01 32.60 46.20 Age >12 Years 34.08 40.67 54.27 Nuss et al, Vocal Nodule Size & Voice Quality Clinical research of pediatric voice disorders requires an ongoing emphasis on the use of validated instruments. The CAPE-V scale and a previously published scale of vocal fold nodule sizes7 are important tools to assist researchers in describing the effectiveness of various therapies and interventions. CONCLUSIONS The size of vocal fold nodules in children is noted 137 to have a significant statistical correlation with perceptual qualities, including overall severity of voice disturbance, roughness, strain, pitch, and loudness. With the exception of loudness, as vocal fold nodule size increases, the mean value of perceptual characteristics becomes larger. The present report indicates that the perceptual assessment of a child’s voice quality using the CAPE-V scale offers an indirect means to follow vocal fold nodule size. REFERENCES 1. Akif Kiliç M, Okur E, Yildirim I, Güzelsoy S. The prevalence of vocal fold nodules in school age children. Int J Pediatr Otorhinolaryngol 2004;68:409-12. evaluation of voice: development of a standardized clinical protocol. Am J Speech Lang Pathol 2009;18:124-32. 2. Hirschberg J, Dejonckere PH, Hirano M, Mori K, Schultz-Coulon HJ, Vrticka K. Voice disorders in children. Int J Pediatr Otorhinolaryngol 1995;32(suppl):S109-S125. 9. Lee L, Stemple JC, Glaze L, Kelchner LN. Quick screen for voice and supplementary documents for identifying pediatric voice disorders. Lang Speech Hear Serv Sch 2004;35:30819. 3. De Bodt MS, Ketelslagers K, Peeters T, et al. Evolution of vocal fold nodules from childhood to adolescence. J Voice 2007;21:151-6. 10. Niedzielska G. Acoustic analysis in the diagnosis of voice disorders in children. Int J Pediatr Otorhinolaryngol 2001;57: 189-93. 4. Gray SD, Hammond E, Hanson DF. Benign pathologic responses of the larynx. Ann Otol Rhinol Laryngol 1995;104: 13-8. 11. Niedzielska G, Glijer E, Niedzielska A. Acoustic analysis of voice in children with noduli vocales. Int J Pediatr Otorhinolaryngol 2001;60:119-22. 5. Hooper CR. Treatment of voice disorders in children. Lang Speech Hear Serv Sch 2004;35:320-6. 12. Shah RK, Engel SH, Choi SS. Relationship between voice quality and vocal nodule size. Otolaryngol Head Neck Surg 2008;139:723-6. 6. McMurray JS. Disorders of phonation in children. Pediatr Clin North Am 2003;50:363-80. 7. Shah RK, Feldman HA, Nuss RC. A grading scale for pediatric vocal fold nodules. Otolaryngol Head Neck Surg 2007; 136:193-7. 8. Kempster GB, Gerratt BR, Verdolini Abbott K, Barkmeier-Kraemer J, Hillman RE. Consensus auditory-perceptual 13. Shah RK, Woodnorth GH, Glynn A, Nuss RC. Pediatric vocal nodules: correlation with perceptual voice analysis. Int J Pediatr Otorhinolaryngol 2005;69:903-9. 14. Karnell MP, Melton SD, Childes JM, Coleman TC, Dailey SA, Hoffman HT. Reliability of clinician-based (GRBAS and CAPE-V) and patient-based (V-RQOL and IPVI) documentation of voice disorders. J Voice 2007;21:576-90. The Management of Postintubation Phonatory Insufficiency Lindsey C. Arviso, MD; Adam M. Klein, MD; Michael M. Johns III, MD Objectives: Prolonged intubation may lead to medial arytenoid cartilage erosion and cricoarytenoid joint scarring with subsequent glottic insufficiency. This has been referred to as post-intubation phonatory insufficiency (PIPI). Reports on treatment outcomes for this condition are lacking. Methods: A single institution retrospective chart review from January 2007 to the present was performed for PIPI diagnosis. Data were collected for injury, symptoms, diagnosis, interventions, and outcomes. Results: Four patients with PIPI underwent treatment to improve voice. Patient 1 underwent injection augmentation of the anatomic deficiency as well as the ipsilateral true vocal fold. Patient 2 had a revision thyroplasty and subsequently 2 injections of the posterior defect and true vocal fold. Patient 3 was treated with thyroplasty and arytenoid adduction. Patient 4 underwent thyroplasty with adduction arytenopexy. Limited to no phonatory improvement was achieved in any case. Conclusions: The management of patients with PIPI is difficult. Currently, no reliable means are available to restore cartilaginous defects in the respiratory glottis. Patients with this condition should be counseled as to the difficult nature of treatment. Analysis of Vocal Fold Injection Amount: Association With Diagnosis and Outcome VyVy N. Young, MD; Libby J. Smith, DO Objectives: We reviewed a large database of vocal fold injection (VFI) patients, to determine a correlation between amount injected, diagnosis, and outcome. Methods: Retrospective review of surgical and clinical databases was performed on all patients undergoing VFI between July 2005 and August 2009. Results: 335 patients were identified. Patients undergoing unilateral VFI for paralysis or bilateral VFI for atrophy who had pre- and post-operative Voice Handicap Index-10 (VHI) scores (n = 102) were analyzed. The average amount injected was 0.58 cc for paralysis and 0.78 cc for atrophy. The average amounts injected for paralysis patients were 0.67 cc for “great,” 0.69 cc for “good,” 0.49 cc for “fair,” and 0.56 cc for “poor” outcomes. The average amounts injected for atrophy patients were 0.8 cc for “great,” 0.63 cc for “good,” 0.88 cc for “fair,” and 0.90 cc for “poor” outcomes. Comparison was made between patients with more versus less favorable outcomes. None of these differences were statistically significant (p values > 0.168). Conclusions: Vocal fold injection is increasingly used for management of atrophy and paralysis. However, the “optimal” amount of material to inject remains undefined. Presently, there are no reports in the literature that numerically delineate this quantity, forcing surgeons to rely on their own best judgment. This is the first paper which attempts to define numerically an appropriate amount of injection material for atrophy and paralysis patients, and to try to correlate the amount of injected material with outcome. The current study demonstrates no significant difference between injected amounts based on diagnosis or outcome, suggesting that the optimal quantity is based on factors other than simply diagnosis. 138 Glidescope-Assisted Medialization Laryngoplasty: A Novel Technique Roberta Lima, MD; Nazaneen Grant, MD Objectives: Injection medialization laryngoplasty can be performed under direct laryngoscopy or local anesthesia with a flexible scope. While sufficient in most cases, these techniques are limited in certain patient populations with anatomical limitations to laryngeal exposure, including the patient whose C-spine precludes extension, the irradiated neck, and the patient who cannot tolerate an office procedure. Our objective is to describe a novel technique of injection with direct visualization under general anesthesia utilizing video-assisted blade laryngoscopy for vocal fold medialization in a select population. Methods: In a case series of three patients, the technique, laryngeal exposure, and duration of the procedure were explored. All three patients had dysphonia with glottic insufficiency and refused awake medialization under local anesthesia. Two had cervical spine abnormalities that precluded full neck extension, and one had severe radiation fibrosis of the neck. Calcium hydroxylapatite paste was injected with a flexible transoral injection needle. Results: The Glidescope, a curved laryngoscopy blade with an attached video monitor, produces a sufficient view of the larynx without the need for a direct line of vision from the examiner to the larynx. In two patients, video-assisted laryngoscopy provided excellent visualization for successful injection medialization. In one patient, the visualization of the anterior vocal folds was not adequate and a flexible bronchoscope was additionally used, resulting in a successful medialization. For two patients, the time of the procedure was less than with traditional approaches. Conclusions: Video-assisted blade laryngoscopy for vocal fold medialization in patients with difficult laryngeal exposure is a novel and effective technique. Laryngeal Findings in Occluded Versus Unoccluded Ostia Model of Rhinosinusitis Ankona Ghosh; Marcelo B. Antunes, MD; Joel Guss, MD; Fenella Long, PhD; Noam A. Cohen, MD, PhD; Natasha Mirza, MD Rhinosinusitis and laryngitis are often found to coexist. Patients with rhinosinusitis exhibit a range of laryngeal complaints, including hoarseness, persistent cough, and globus sensation. The purpose of this study was to determine if there was evidence of laryngeal inflammation in a rabbit model of sinusitis. Acute sinusitis was induced in 2 sets of rabbits. In 11 rabbits, the maxillary ostium was occluded and a bacterial inoculum was placed in the sinus to induce sinusitis. After 1 week, the sinus was unoccluded in 5 rabbits, resulting in purulent rhinorrhea that was allowed to persist for 1 week prior to sacrificing the animal (occluded). The remaining 6 rabbits were sacrificed after 1 week without unocclusion of the inoculated sinus (unoccluded). Three rabbits served as normal controls. Inflammation in each larynx (using H & E–stained slides from tissue at the levels of supraglottis, glottis, and subglottis) was scored by a blinded pathologist on a scale of 1 to 17. There was no statistically significant difference in the inflammatory score between occluded, unoccluded, and control rabbit larynges (p = 0.20). There was, however, a trend toward a higher inflammatory score in the unoccluded group. One week of acute sinusitis with or without purulent rhinorrhea is not associated with significant laryngitis in rabbits. However, higher inflammatory scores in the unoccluded group versus the occluded group may indicate that postnasal discharge has a direct irritative effect on the larynx. While the model is limited, it provides the initial steps in studying the relationship between rhinosinusitis and laryngitis. 139 Narrowband Imaging and High-Definition Television for Detection, Definition, and Surveillance of Head and Neck Cancer: A Prospective Study Cesare Piazza, MD; Daniela Cocco, MD; Francesca Del Bon, MD; Stefano Mangili, MD; Luigi de Benedetto, MD; Giorgio Peretti, MD Objectives: Narrowband imaging (NBI) is an optical technique in which a filtered light enhances the neoangiogenic pattern of neoplasms. Its accuracy is implemented by a high-definition television (HDTV) camera. The aim of the study was to evaluate the diagnostic gain in the pre-, intra-, and postoperative evaluation of head and neck cancer (HNC). Methods: 419 patients who had squamous HNC of the nasopharynx, oropharynx, hypopharynx, oral cavity, or larynx or were previously treated for it were prospectively evaluated by white light (WL) and NBI ± HDTV between April 2007 and August 2009. The patients were divided into group A (157 patients submitted to pre- and intraoperative WL and NBI endoscopy) and group B (262 subjects evaluated at least 6 months after treatment). Tumor resection was performed, taking into account NBI information. The sensitivity, specificity, positive and negative predictive values, and accuracy were calculated. Results: Overall, 104 of the 419 patients (25%) showed adjunctive findings with NBI and HDTV in comparison to standard WL endoscopy. Among them, 91 (87%) received histopathologic confirmation (false-positive rate, 13%). The sensitivity, specificity, positive and negative predictive values, and accuracy were 98%, 83%, 96%, 98%, and 91%. Conclusions: NBI and HDTV showed its value in better defining tumor extension (upstaging of 51 neoplasms), detecting 5 synchronous lesions, evaluating an incomplete response to radiotherapy before planned neck dissection in 3 cases, and identifying 2 unknown primaries. NBI in the post-treatment setting precociously detected 26 recurrences and 4 metachronous tumors. Optimizing the Surgical Creation of a Supraglottal Sound Source: Theory and a Case Study Sid Khosla, MD; Shanmugam Murugappan, PhD; Bernice Klaben, PhD Objectives: In the classic source-filter theory, the vibrating vocal folds act as the source of sound and the vocal tract acts as the filter. After reconstructive surgery for conditions such as laryngeal stenosis, trauma, or cancer, the vocal folds sometimes do not effectively vibrate. As a compensatory mechanism, vibration of supraglottal structures will be used as the primary source of sound. The resulting voice is often harsh, aperiodic, not loud enough, and difficult to understand. Methods: Our work in an animal model has shown that vortices are important for producing a loud, intelligible voice; we have also discovered some of the necessary biomechanical conditions for optimal vortex production during phonation. These biomechanical conditions will be discussed, along with a description of how these conditions were met in the laryngeal reconstruction of a patient. This patient suffered a complete crush injury of his thyroid, and two potentially vibrating structures were built on the medial surface of the arytenoids. After 2 months, endoscopic surgery was then done to create the necessary conditions mentioned above. Results: Stroboscopic and high-speed videography show relatively periodic, symmetric vibrations of the new sound source. The vocal intensity range is from 40 to 100 dB. Quality-of-life scores and jitter and shimmer are within the normal range. Conclusions: In one patient, we show how our understanding of vortex production, developed in an animal model, can be used to create an optimal supraglottal vibrating sound source. 140 Primary TEP Placement in Patients With Laryngopharyngeal Free Tissue Reconstruction and Salivary Bypass Tube Placement Vasu Divi, MD; Derrick T. Lin, MD; Kevin Emerick, MD; Daniel G. Deschler, MD Objectives: We examined the feasibility and advantages of primary tracheoesophageal puncture (TEP) with intraoperative placement of the voice prosthesis for patients undergoing laryngopharyngectomy requiring free tissue reconstruction and salivary bypass tube placement. Methods: After Institutional Review Board approval, a retrospective chart review was completed of all cases of primary tracheoesophageal prosthesis placement completed at the time of laryngopharyngectomy and free tissue reconstruction of the pharynx. Results: Six patients were identified; 4 underwent total laryngopharyngectomy and 2 underwent total laryngectomy with partial pharyngectomy. Three patients received preoperative full-dose radiotherapy to the larynx, and 1 received full-dose irradiation for an oral cavity primary. Radial forearm free flap reconstruction was performed in 5 patients, and an anterolateral thigh flap in 1. A salivary bypass tube was placed in all cases. All patients had a 20F Indwelling BlomSinger prosthesis (InHealth Technologies, Carpinteria, California) placed. No complications were noted with intraoperative prosthesis placement. No prostheses were dislodged in the postoperative period. Three of the 6 subjects had initial success with tracheoesophageal voice production. One patient required removal of the TEP postoperatively for feeding tube placement. The prosthesis was replaced 1 month later with good voice restoration. One patient died of disease before voice evaluation, and 1 patient was lost to follow-up. At 6 months, 4 patients available for evaluation had successful voice outcomes and 3 were disease-free. Conclusions: This study demonstrates the effectiveness of voice prosthesis placement at the time of primary TEP associated with free tissue reconstruction of a laryngopharyngeal defect. Development of the Dyspnea Severity Index–10 Jackie Gartner-Schmidt, PhD, SLP; Adrianna Shembel, BS, MA; Priya Krishna, MD; Rita Hersan, CCC-SLP; Thomas Zullo, PhD; Clark A. Rosen, MD Paradoxical vocal fold motion disorder (PVFMD) is a condition in which the vocal folds adduct involuntarily during inspiration and sometimes during exhalation. The purpose of this study was to develop a dyspnea severity index that can be used as a clinical tool to 1) estimate perceived severity and 2) evaluate possible treatment outcomes in patients with dyspnea related to the upper airway. A clinical consensus with laryngologists and speech-language pathologists was used to develop a list of clinically significant questions/items. Two hundred consecutive patients who either had a complaint of cough and/or dyspnea filled out the original instrument. Principal component analyses and item analyses were performed. Factor analysis was performed, confirming that the majority of the questions were related to a single factor. Another clinical consensus was held to reduce the questionnaire to 10 questions each, and it was re-run for reliability. Cronbach’s alpha coefficient demonstrated excellent internal reliability. The Dyspnea Severity Index–10 allows clinicians to quantify patients’ perception of the problems related to dyspnea and may allow for treatment results evaluation in the future. 141 Pepsin, at pH 7, in Nonacidic Laryngopharyngeal Refluxate, Significantly Alters the Expression of Multiple Genes Implicated in Carcinogenesis Nikki Johnston, PhD Objectives: The role of reflux as a causative agent in laryngeal cancer is controversial. Many clinical studies strongly support an association between reflux and laryngeal cancer; however, it is difficult to prove causality. The objective of this study was to investigate the effect of pepsin exposure on the expression of 84 genes implicated in carcinogenesis. Methods: Human hypopharyngeal epithelial FaDu cells were incubated with or without 0.1 mg/mL human pepsin at pH 7, 37°C, overnight. The expression of 84 genes implicated in carcinogenesis was analyzed via RT2 qPCR array. Results: The expression level of 27 genes implicated in carcinogenesis was significantly altered in human hypopharyngeal epithelial cells exposed to pepsin at neutral pH relative to control cells (>1.5-fold change in gene expression; p < 0.05). Genes involved in cell cycle control, DNA damage repair, apoptosis and cell senescence, signal transduction molecules and transcription factors, adhesion, angiogenesis, and invasion and metastasis were significantly affected by pepsin at pH 7 compared to pH 7 control. Conclusions: Reflux of pepsin, even at nonacidic pH, may result in neoplastic changes in the aerodigestive tract. The Role of the Modified Barium Swallow Study and Esophagram in Patients With GERD/Globus Sensation Jayme R. Dowdall, MD; Tom Willis, MD; Adam J. Folbe, MD; James P. Dworkin, PhD Objectives: Globus sensation is a common benign finding that is often associated with frequent throat clearing and is commonly a result of laryngopharyngeal reflux. We aimed to further examine the role of the modified barium swallow study (MBSS) with esophagram. We hypothesized that a radiographic swallow study does not add diagnostically significant information in the investigation of globus sensation. Methods: We performed a retrospective chart review of patients presenting to Karmanos Cancer Institute with a chief complaint of globus sensation between 2000 and 2009 who underwent both MBSS and esophagram. IRB approval was obtained. Results: Of the 380 patients who underwent MBSS, only 68 patients were eligible for this study. Over 70% of patients were on reflux medicines; 81% of the MBSS studies were completely normal; 62% of the esophagram results were completely normal; and 18% of patients were noted to have hiatal hernia, 10% with mild reflux. Esophagoscopy was performed in 45% of patients, of which the findings of 35% were normal. One patient initially had a normal EDG and then was subsequently diagnosed with gastric cancer. Hiatal hernia was noted in 45%. Fifty-nine percent of patients underwent CT scans of the neck with IV contrast, of which 67% had minor findings. Conclusions: Positive findings are often benign and can be treated with reflux medications. Esophagoscopy often showed normal findings and was most sensitive for hiatal hernia. No hypopharyngeal cancer was noted. Therefore, MBSS and esophagram for patients with globus sensation is most often negative and does not add additional diagnostic information. 142 Effect of Different Angiolytic Lasers Upon Resolution of Submucosal Hematoma in an Animal Model Daniel Novakovic, MD; Joanna D’Elia, MD; Andrew Blitzer, MD; Milton Waner, MD Objectives: Hematoma of the vocal fold is traditionally treated with a period of voice rest, on the order of weeks, to allow natural resolution. This downtime may have significant impact upon the professional voice user. A number of hemoglobinavid lasers exist on the market today. This study was designed to examine whether treatment with such lasers will accelerate resolution of submucosal hematoma. Methods: This was a prospective, blinded, controlled interventional animal study. Venous blood was drawn from 6 white rabbits and was used to create an array of 0.05 mL submucosal hematomas in the buccal cavities of each animal. Laser energy from one of three different lasers (532 nm KTP, 532 nm diode, or pulsed dye laser) was applied to each of the test hematomas at varying energy levels. Lesions were photographed before intervention and then after intervention at days 0, 2, 4, 6, 8, 10, 12, and 14. Animals were sacrificed on day 14, and the hematoma grid was assessed by a blinded pathologist for evaluation of hematoma resolution and collateral tissue damage. Photographs were assessed for color density and determination of time to resolution. Results/Conclusions: We present an animal model of submucosal hematoma and discuss our findings with respect to resolution of hematoma treated with hemoglobin-avid lasers. Characterization of Mesenchymal Stem Cells From Human Vocal Fold Fibroblasts Summer E. Hanson, MD; Jaehyup Kim, MD; Beatriz H. Quinchia Johnson, DDS, PhD; Melissa Breunig; Bridget Bradley; Peiman Hematti, MD; Susan L. Thibeault, PhD Objectives: Mesenchymal stem cells (MSCs), originally isolated from bone marrow, are fibroblast-looking cells that are now assumed to be present in the stromal component of many tissues. MSCs are characterized by a certain set of criteria, including their growth culture characteristics, a combination of cell surface markers, and the ability to differentiate along multiple mesenchymal tissue lineages. We hypothesized that human vocal fold fibroblasts (hVFF) isolated from the lamina propria meet the criteria established to define MSCs and are functionally similar to MSCs derived from bone marrow (BM) and adipose tissue (AT). Methods: hVFF were previously derived from human vocal fold tissues. MSCs were derived from BM and AT of healthy donors, based on their attachment to culture dishes and their morphology, and expanded in culture. Cells were analyzed for standard cell surface markers identified on BM-derived MSCs as well as the ability to differentiate into cells of mesenchymal lineage, ie, fat, bone, and cartilage. We investigated the immunophenotype of these cells before and after interferon-γ (INF-γ) stimulation. Results: hVFF displayed cell surface markers and multipotent differentiation capacity characteristic of MSCs. Furthermore, these cells exhibited similar patterns of expression of HLA and co-stimulatory molecules after stimulation with INF-γ compared to MSCs derived from BM and AT. Conclusions: Based on our findings, hVFF derived from lamina propria have the same cell surface markers, immunophenotypic characteristics, and differentiation potential as BM- and AT-derived MSCs. We propose that VF fibroblasts are MSCs resident in the vocal fold lamina propria. 143 Utility of Diagnostic Testing in Adults With Idiopathic Subglottic Stenosis Melissa McCarty Statham, MD; Yash A. Patil, MD; Allesandro de Alarcon, MD; Ravindra G. Elluru, MD, PhD; Meredith E. Tabangin, MPH; Michael W. Bowen, PAC; Thomas K. Chung, BS; Michael J. Rutter, MD, FRACS Objectives: We describe a cohort with idiopathic subglottic stenosis (ISGS) and examine the utility of investigative studies performed to diagnose and guide treatment of ISGS-associated airway obstruction. Methods: We performed a retrospective review. Results: A total of 36 patients with ISGS were treated from 1999 to 2009. All patients were female, with a mean age of 43.3 years (19.9 to 63). All patients exhibited focal subglottic stenotic lesions, with the average size of the subglottis accommodating a 4.5 endotracheal tube on initial evaluation and 64% (n = 23) of subjects demonstrating a Cotton-Myer grade III subglottic stenosis. Seven of the 36 patients (19.4%) reported worsening of their symptoms during the second trimester of pregnancy. The medical comorbidities examined included hypertension (27.8%), reflux (22.2%), asthma (16.7%), diabetes mellitus (8.3%), obstructive sleep apnea (8.3%), and rheumatologic disorders (none). The average body mass index (BMI) approached obesity (29.9), and only 27.8% of patients had a BMI in the normal range. The mean number of diagnostic tests performed in this cohort was 10.8 ± 3.2 (range, 4 to 18). Erythrocyte sedimentation rate or C-reactive protein was elevated in 30.6% (11/36). None of the patients demonstrated positive serology for circulating or perinuclear anti-neutrophil cytoplasmic antibodies (c-ANCA, p-ANCA). Other than subcentimeter thyroid nodules, computed tomography of the neck demonstrated focal subglottic narrowing in studied patients. Conclusions: ISGS is a diagnosis of exclusion in the evaluation of patients with subglottic stenosis. In this cohort, an extensive radiographic and serologic evaluation was not predictive in guiding treatment of ISGS in the absence of systemic comorbidities or findings suggestive of a rheumatologic process. A Challenging Case: Intubation Through a Foreign Body and Foreign Body Removal From the Larynx Vartan A. Mardirossian, MD; Timothy Anderson, MD; Joyce Colton-House, MD The patient was a 70-year-old man with chronic dysphagia and altered mental status after a fall who was seen in a tertiary care center clinic for sudden significant worsening of dysphagia, dysphonia, and drooling over the past several hours. The fiberoptic examination of the larynx showed that a complete superior denture was lodged around the epiglottis with the teeth in the valleculae and the metallic frame and hooks against the posterior wall of the hypopharynx. A single attempt was made to remove it in the clinic, but this was unsuccessful. During the visit and in the hour to follow, the patient developed signs of mild to moderate airway obstruction but maintained good oxygenation. He was brought urgently to the OR, where he was fiberoptically intubated. Given the particular position and the conformation of the foreign body, the intubation was performed through it. Subsequently, with the help of endoscopic forceps, the denture was slid upward and out along the endotracheal tube; once the denture was out of the patient’s mouth, the anesthesia circuit had to be interrupted in order to complete its removal from the end of the endotracheal tube. Despite some mild edema of the epiglottis and the aryepiglottic folds caused by the prolonged presence of the foreign body in the upper airway, the patient was successfully extubated and transferred to the postoperative care unit and then to the floor in stable condition. 144 Calcium Oxalate Crystals Decode the Pulmonary Rhizopuzzle in a Pulmonary Abscess Christopher G. Tang, MD; Christina C. Goette, MD; John Lin, MD; Valerie Ng, MD, PhD; Alden H. Harken, MD Objectives: We emphasize the calcium oxalate crystal signature of potentially devastating craniofacial and pulmonary mucormycosis. Methods: We examined a patient status post treatment of a necrotizing pulmonary abscess with microbiological and pathological follow-up. Results: The patient was a 69-year-old man admitted for pneumonia who developed a necrotizing pulmonary abscess. Tracheobronchial cultures initially grew out large septate hyphae suggestive of aspergillus. A left anterior thoracoplasty with a pectoral and intercostal muscle flap was performed. Calcium oxalate crystals were present in the abscess fluid suggestive for an infection by Aspergillus niger. However, the rib resection grew out aseptate hyphae suggestive of Rhizopus microsporus (class Zygomycetes), which was also confirmed by culture. Conclusions: Mucormycosis, a devastating fungal infection that often causes necrotizing abscesses of the sinuses and brain in rhinocerebral manifestations, can sometimes cause pulmonary infections in immunocompromised individuals. Rarely do these Zygomycetes produce calcium oxalate crystals, which are essentially pathognomonic for necrotizing aspergillosis, particularly Aspergillus niger. There have only been 3 documented cases of pulmonary mucormycosis with evidence of calcium oxalate crystals, 2 of which were in patients with concomitant oxalosis. This documented case of pulmonary mucormycosis emphasizes that calcium oxalate crystals can be found in patients with fungal infections other than aspergillus. In-Office Unsedated Transnasal Bronchoscopy for Removal of an Airway Foreign Body Drew Plonk, MD; S. Carter Wright, Jr, MD; J. Whit Mims, MD; Catherine J. Rees, MD Objectives: We describe the use of a 5.1-mm distal chip transnasal endoscope in the unsedated office setting to remove an airway foreign body. Methods: We report the single case of a 90-year-old woman with a history of severe COPD requiring home oxygen who presented to the otolaryngology clinic complaining of persistent cough that began after “choking” on a piece of corn the previous night. Results: The patient was not in distress, and her comorbidities made general anesthesia a high risk; therefore, the decision was made to proceed with unsedated, in-office bronchoscopy for diagnosis and possible intervention. After the application of topical anesthesia, the scope was advanced into the airway and a single corn kernel was identified in the right middle lobe distal bronchi. A combination of cup forceps and the suction port of the endoscope were used to withdraw the corn kernel from the right lung into the nasopharynx. The corn kernel was positioned deliberately into the pyriform sinus, and the foreign body was swallowed under direct visualization. The patient tolerated the procedure well. Conclusions: In-office unsedated bronchoscopy is an additional option when considering the removal of an airway foreign body in the appropriate patient and setting. 145 Endoscopic Management of a Penetrating Foreign Body in the Soft Tissue of the Retropharynx Margaret L. Skinner, MD; Mark Volk, DMD, MD Objectives: We review the challenges of endoscopic treatment of a foreign body embedded in the soft tissue of the retropharynx and the unique management techniques employed. Methods: A patient presented to a tertiary care children’s hospital, intubated and sedated, after unproductive endoscopic exploration for a metallic foreign body. Plain film images and intraoperative fluoroscopy confirmed an aspirated straight sewing needle to be localized to the soft tissues of the retropharyngeal and parapharyngeal space at the level of the hypopharynx. Due to concern that traditional neck exploration would expose the surgical team to high risk of needle stick injury, endoscopic neck exploration was undertaken. Specific challenges included management of the endotracheal tube (ETT), localization of the foreign body below the mucosal surface, and endoscopic dissection of the soft tissue. Results: Nontraditional instrumentation and intraoperative fluoroscopy were used to remove an aspirated straight needle from the soft tissues of the retropharyngeal and parapharyngeal space by endoscopic technique, alleviating the need for open neck exploration. Conclusions: Compared with traditional suspension laryngoscopy, the Crowe-Davis mouth gag and Draffin Rod suspension provided excellent exposure of the hypopharynx and retropharyngeal space with adequate clearance for intraoperative C-arm fluoroscopy while controlling the ETT. Intraoperative fluoroscopy localized the foreign body and was essential in the management of a submucosal metallic foreign body. The use of pediatric laparoscopic instruments enabled endoscopic guided dissection of the soft tissues of the retropharynx and minimally invasive extraction of the foreign body, and minimized the risk of injury to the operative team. Delay in the Diagnosis of Laryngeal Cleft Associated With Tracheoesophageal Fistula Margaret L. Skinner, MD; Stacey L. Ishman, MD; Umakanth Khatwa, MD; Kenan Haver, MD; Rachel Rosen, MD; Craig Lillehei, MD; Reza Rahbar, MD Objectives: We evaluated the incidence of laryngeal clefts associated with tracheoesophageal fistula (TEF) and sought to determine whether patients with TEF are more likely to have delayed diagnosis of concomitant laryngeal cleft anomalies. Methods: A retrospective chart review of consecutive children with posterior laryngeal cleft anomalies was carried out at a tertiary care children’s hospital between 2002 and 2008. Diagnosis of posterior laryngeal cleft was made by rigid laryngoscopy and bronchoscopy and classified with the Benjamin-Inglis system. Diagnosis of TEF was determined by review of the medical records. Significance was evaluated with the two-tailed Mann Whitney U-test. Results: Fifty-three patients found to have laryngeal clefts were identified. Of the 53 patients, 27 had type 1 clefts, and 26 had type 2 clefts. The overall incidence of TEF was 15.0% (N = 8). The mean age at laryngeal cleft diagnosis was 2.98 years. For patients without TEF, the mean age at diagnosis was 2.35 years (3 months to 15 years), compared with 6.84 years (1 to 17 years) for patients with TEF (p = 0.0144). Conclusions: The coincidence of TEF and laryngeal cleft in this series is consistent with that reported in the literature. Cases of TEF are diagnosed and treated for laryngeal cleft anomalies later than cases without TEF (p = 0.0144). Because of the similarity of symptoms, the diagnosis of laryngeal cleft may be delayed in patients with TEF, and screening for laryngeal clefts should be considered in children with persistent symptoms after TEF repair. 146 Histopathologic Investigations of the Unphonated Human Child Vocal Fold Mucosa Kiminori Sato, MD; Hirohito Umeno, MD; Tadashi Nakashima, MD; Satoshi Nonaka, MD; Yasuaki Harabuchi, MD Objectives: Stellate cells (SCs) in the human maculae flavae (MFe) located at both ends of the human vocal fold mucosa are inferred to be involved in the metabolism of extracellular matrices (EMs). The MFe are considered to be an important structure in the growth and development of the human vocal fold mucosa. It is also hypothesized that the tensions caused by phonation (vocal fold vibration) after birth stimulate SCs to accelerate production of EMs and form the layered structure. If the hypotheses are correct, some morphological differences should be detected between normal and unphonated vocal fold mucosae. Methods: Vocal fold mucosae, which have remained unphonated since birth, of 2 children (7 and 12 years old) with cerebral palsy were investigated by light and electron microscopy and compared with those of normal subjects. Results: The vocal fold mucosae (including MFe) were hypoplastic and rudimentary and did not have a vocal ligament, Reinke’s space, or a layered structure. The lamina propria appeared as a uniform structure. Some SCs in the MFe showed degeneration, and not many vesicles were present at the periphery of the cytoplasm. The SCs synthesized fewer EMs, such as fibrous protein and glycosaminoglycan. The SCs appeared to have decreased activity. Conclusions: The present study supports the hypothesis that the mechanotransduction caused by phonation after birth stimulates SCs in the MFe to accelerate production of EMs and form the layered structure. Vocal fold vibration after birth is an important factor in the growth and development of the human vocal fold mucosa. 147 2010 ROSTER OF MEMBERS Honorary Members 1982 (1948) 1981 (1958) (1980) James P. Dudley, 1835 Franklin St, Apt 1103, San Francisco, CA 94109-3457 Juan Carlos Arauz, Je Uriburur, 1252-3D, Buenos Aires 1114, Argentina John F. Daly, 56 Florence St, Hillsdale, NJ 07642-1034 Andres L. Delgado 1978 Mary D. Lekas, 129 Terrace Ave, Riverside, RI 02195-4726 1999 2008 Reza Shaker, Froedtert Memorial Lutheran Hosp, Div of Gastroenterology, 9200 W Wisconsin Ave, Milwaukee, WI 53226 1992 (1978) Arndt J. Duvall III, Univ Hosp, Box 396, 420 Delaware St SE, Minneapolis, MN 554550374 Peter Stradling, Apple Acre, Sampford Brett, Taunton, Somerset TA4 4LB, England 2003 (1975) L. Penfield Faber, 1725 W Harrison St, Rm 218, Chicago, IL 60612-3732 1980 (1954) J. Allan Fields, 440 Royal Plaza Dr, Fort Lauderdale, FL 33301-2516 2009 (1995) Charles N. Ford, Univ of Wisconsin Hosp & Clinics, 600 Highland Ave, K4/714 CSC, Madison, WI 53792-7375 1982 (1979) Senior Members Miguel A. Abado, J. No. 165 Vedado, Havana, Cuba 2006 (1974) Allan L. Abramson, PO Box 566, White Lake, NY 12786-0566 2002 (1978) 2008 (1980) Warren Y. Adkins, Jr, 680 Pawley Rd, Mt Pleasant, SC 29464-3566 John M. Fredrickson, 205 Dartmouth Dr, Albuquerque, NM 87106 2006 (1980) 1984 (1959) John R. Ausband, 1510 Riverside Dr, Beaufort, SC 29902-6487 William H. Friedman, 3023 N Ballas Rd, #5600, St Louis, MO 63131-2330 1990 (1976) 1985 (1956) William L. Barton, 2147 Sautee Tri, Sautee Nacoochee, GA 30571 Herman Froeb, 9834 Genessee, Ste 109, La Jolla, CA 92037-1222 2002 (1975) 1991 (1971) James D. Baxter, 1237 Northshore Blvd E, Apt 908, Burlington, ON L7S 2H8, Canada Willard A. 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Bradley, 37 Lucknow Dr, Mapperley Park, Nottingham NG3 5EU, England Kenneth M. Grundfast, Dept of Oto, Boston Med Ctr, D616, 88 E Newton St, Boston, MA 02118-2308 1996 (1978) 2003 (1974) Thomas C. Calcaterra, UCLA HSC, 10833 Le Conte Ave, Rm 62-158, Los Angeles, CA 90095 Donald B. Hawkins, 5049 El Adobe Lane, La Crescenta, CA 91214-2105 2004 (1978) Leonard L. Hays, 708 Summit Lakeshore Rd NW, Olympia, WA 98502-9482 2001 (1976) Robert W. Cantrell, 1925 Owensville Rd, Charlottesville, VA 22901 1987 (1953) Henry J. Heimlich, Heimlich Inst, 311 Straight St, Cincinnati, OH 45219 1992 (1974) Francis I. Catlin, 8580 Woodway Dr, #1124, Houston, TX 77063-2466 1996 (1974) William R. Hudson, Duke Univ Med Ctr, PO Box 3805, Durham, NC 27710-3805 1993 (1976) Paul L. Chodosh 2009 (1990) 2004 (1982) Noel L. Cohen, NYU Med Ctr, 530 First Ave, New York, NY 10016-6402 Michael E. Johns, Emory Univ, 1440 Clifton Rd NE, Ste 400, Atlanta, GA 30322 1998 (1975) Robert I. Kohut, 2620 S Riverchurch Rd, Woodleaf, NC 27054 2004 (1969) George H. Conner, Lebanon VA Med Ctr, 2 E High St, Lebanon, PA 17042-5454 2002 (1980) 2004 (1978) Charles W. Cummings, 13940 Mantna Mill Rd, Glyndon, MD 21071 2003 (1976) 1982 (1961) Timothy L. Curran, 50 Winding Lane, Avon, CT 06001-2624 1992 (1973) Paul A. Kvale, Henry Ford Hosp, 2799 W Grand Blvd, Detroit, MI 48202-2608 Louis D. Lowry, 503 Centerbridge Meadowood, Lansdale, PA 19446 George D. Lyons, 6323 West End Blvd, New Orleans, LA 70112 148 Members 149 1998 (1989) Anthony J. Maniglia, 4167 Palm Ln, Miami, FL 33137 1984 (1965) 2000 (1973) Bernard R. Marsh, 4244 Mount Carmel Rd, Upperco, MD 21155-9557 Melvin L. Samuels, 12458 Woodthorpe Ln, Houston, TX 77024-4136 2003 (1970) 2005 (1991) Kenneth F. Mattucci, Northshore Oto Assoc, 11 Nome Dr, Woodbury, NY 11797-3404 David R. Sanderson, 10676 E Bella Vista Dr, Scottsdale, AZ 85258 2003 (1990) 2003 (1979) Gregory J. Matz, 910 N Lake Shore Dr, Apt 1119, Chicago, IL 60611 Gary L. Schechter, Oto-HNS, 825 Fairfax Ave, No. 510, Norfolk, VA 23507-1912 1998 (1970) 1985 (1978) Harry W. McCurdy, 6006 Dellwood Pl, Bethesda, MD 20817-3812 Joyce Schild, 853 W George, Chicago, IL 60657 1989 (1958) 2009 (1990) W. Frederick McGuirt, Sr, Dept of Oto, Wake Forest Med Ctr, Medical Center Blvd, WinstonSalem, NC 27157 Myron J. Shapiro, 81 Sand Spring Rd, Morristown, NJ 07960-6702 2001 (1974) Harvey D. Silberman, 2401 Pennsylvania Ave, Apt 8A4, Philadelphia, PA 19130-3030 10467-2404 1991 (1959) Francis L. McNelis, 37 Baggy Wrinkle Cove, Warren, RI 02885-4114 1990 (1963) James T. Spencer, 329 Baker Ln Ridgemont, Charleston, WV 25302 1984 (1964) Harold C. Menger, 7809 Myrtle Ave, Glendale, NY 11385-7439 1991 (1978) Philip M. Sprinkle, 315 Hospital Dr, Ste 108, Martinsville, VA 24112-1927 1991 (1987) Peter J. Moloy, 607 Newcastle, Irvine, CA 92620 2006 (1980) Harvey M. Tucker, Dept of Oto, Metrohealth, 2500 Metrohealth Dr, Cleveland, OH 44109 2003 (1980) Willard B. Moran, Jr, 5914 Chestnut Ct, Edmond, OK 73003-2515 1998 (1970) 1991 (1970) Karl M. Morgenstein, 3650 N 36th Ave, Apt 70, Hollywood, FL 33019-1931 John A. Tucker, Children’s Hosp of Philadelphia, Dept of Ped Oto, 34th & Civic Ctr Blvd, 1st Fl Wood, Philadelphia, PA 19104-4399 2000 (1978) 1984 (1965) Harry R. Morse, 365 N Main St, Quail Hollow Unit A4, West Lebanon, NH 03784 Donald P. Vrabec, 2010 Snydertown Rd, Danville, PA 17821-7720 1983 (1963) 2003 (1980) Eugene N. Myers, Dept of Oto, Eye & Ear Inst, 200 Lothrop St, Ste 500, UPMC, Pittsburgh, PA 15213-2546 Duncan D. Walker, Jr, 114 Idle Hour Dr, Macon, GA 31210-4434 1993 (1969) Paul H. Ward, 32178 Atosona Dr, PO Box 250, Pauma Valley, CA 92061-0250 2006 (1978) H. Bryan Neel III, 828 SW 8th St, Rochester, MN 55902 1996 (1978) Louis W. Welsh, 2236 Deer Path Rd, Huntingdon Valley, PA 19006-5906 1996 (1970) Martin Norton, 1624 Cherokee Rd, Ann Arbor, MI 48103-4449 1980 (1960) Chester M. Weseman, 45 Oak Ridge Rd, Berkeley, CA 94705-2425 2006 (1978) Moses Nussbaum, Beth Israel Med Ctr, 10 Union Square E, Ste 4J, New York, NY 10003-3881 2009 (1981) 1989 (1971) Joan O’Brien 2001 (1979) Nels R. Olson, 2178 Overlook Ct, Ann Arbor, MI 48103-2336 Ernest A. Weymuller, Jr, Univ of Washington, Dept of Oto, BB-1165 Health Sci Bldg, 1959 NE Pacific St, Box 356515, Seattle, WA 981956515 1991 (1964) 2003 (1978) James L. Parkin, 2390 Bernadine Dr, Salt Lake City, UT 84109 John R. Williams, The Brittany, Unit 304, 4021 Gulf Shore Blvd N, Naples, FL 33940-3414 1991 (1965) M. Lee Williams, PO Box 723, Irvington, VA 22480-0723 2006 (1979) Eiji Yanagisawa, 25 Hickory Rd, Woodbridge, CT 06525 2000 (1970) C. Thomas Yarington, Jr, 2136 38th Ave E, Seattle, WA 98112-2413 2003 (1973) Anthony J. Yonkers, 508 Ridgewood Dr, Bellevue, NE 68005-4711 2002 (1984) Victor Passy, 101 The City Dr S, #29E, Orange, CA 92868-3201 1990 (1963) Claude Pennington, ENT Ctr of Central Georgia, 800 First St, PO Box 1916, Macon, GA 31202-1916 1985 (1954) Loring W. Pratt, 37 Lawrence Ave, Fairfield, ME 04937-1245 1994 (1974) Robert Priest, 1928 E River Terrace, Minneapolis, MN 55414-3672 1975 (1947) F. Johnson Putney, 991 Harbortowne Rd, Charleston, SC 29412 2003 Mona M. Abaza, 7700 E 6th Ave Pkwy, Denver, CO 80230 1983 (1959) Richard A. Rasmussen, 946 Bellclaire Ave SE, Grand Rapids, MI 49506-3104 1989 Elliott Abemayor, 12169 Greenock Lane, Los Angeles, CA 90049-2849 1993 (1969) Frank N. Ritter, 2675 Englave Dr, Ann Arbor, MI 48103-2221 2000 Jean Abitbol, 1 Rue Larguilliere, 75016 Paris, France 2008 Lee Akst, Loyola Univ Med Ctr, Dept of Oto, 2160 S First Ave, Maywood, IL 60153 1968 Bobby R. Alford, Baylor College of Med, Dept of Oto, 2003 (1974) Robert J. Ruben, Montefiore Med Ctr, Dept of Oto, 3400 Bainbridge Ave, 3rd Fl, Bronx, NY Active Members 150 Members One Baylor Plaza, NA102, Houston, TX 77030-3498 2003 Kenneth W. Altman, Mt Sinai Sch of Med, Dept of Oto, One Gustave L Levy Place, Box 1189, New York, NY 10029-6500 2003 Milan R. Amin, NYU Voice Ctr, NYU Sch of Med, 550 First Ave, NBV5, East 5, New York, NY 10016 1998 of OSU, 2351 E 22nd St, Cleveland, OH 44115-3111 1996 Orval E. Brown, Southwestern Med Ctr at Dallas, Dept of Oto, 5323 Harry Hines Blvd, Dallas, TX 75235-9035 1999 J. Dale Browne, Dept of Oto, Wake Forest Univ Sch of Med, Medical Center Blvd, Winston-Salem, NC 271570001 Vinod K. Anand, 251 Highland Meadow Rd, Flora, MS 39071 1995 Brian B. Burkey, VUMC, Dept of Oto, S-2100 Med Ctr N, Nashville, TN 37232-2559 2006 Timothy Anderson, 1 Hay Rd, Belmont, MA 02478 2005 1991 Mario Andrea, Av Elias Garcia 57-48, 1000-148 Lisbon, Portugal James A. Burns, Dept of Surg, Ctr for Laryngeal Surgery & Voice Rehab, 208 Village Ave, Dedham, MA 020264231 2000 Donald J. Annino, 47 Valley Rd, Wellesley, MA 02481 2000 1997 Max M. April, 115 Bacon Rd, Old Westbury, NY 11568 Nicholas Busaba, Mass Eye & Ear Infirmary, 243 Charles St, Boston, MA 02114 1975 1999 Ellis M. Arjmand, Cincinnati Children’s Hosp Med Ctr, 3333 Burnet Ave, ML 2018, Cincinnati, OH 45229 David D. Caldarelli, Dept of Oto, Rush-Presbyterian Hosp, 1653 W Congress Pkwy, Chicago, IL 60612-3833 1979 Rinaldo Canalis, 457 15th St, Santa Monica, CA 90402 Ricardo Carrau, Ohio State Univ, 456 W 10th Ave, Rm 4024, Columbus, OH 43210 1993 James E. Arnold, 31449 Shaker Blvd, Pepper Pike, OH 44124 2001 1996 Jonathan E. Aviv, 200 West End Ave, Apt 17C, New York, NY 10023-4801 1997 Paul F. Castellanos, Div of Oto, Univ of Maryland, 16 S Eutaw St, Ste 500, Baltimore, MD 21201-1619 2006 James Batti, Connecticut Children’s Med Ctr, 282 Washington St, Hartford, CT 06106 2007 Dinesh K. Chhetri, UCLA Sch of Med, Div of Head & Neck Surg, 62-132 CHS, Los Angeles, CA 90095 1997 Nancy Bauman, Dept of Oto, Univ of Iowa Hosp, 200 Hawkins Dr, Iowa City, IA 52242-1009 2008 Ajay E. Chitkara, 23 Driftwood Lane, East Setauket, New York, NY 11733 2009 Richard A. Beck, Advanced Oto Services, PA, 3627 University Blvd S, Ste 210, Jacksonville, FL 32216-4211 1997 1989 Stephen P. Becker, Otolaryngology Associates, 233 E Erie St, Ste 804, Chicago, IL 60611-2906 Sukgi Choi, Children’s Natl Med Ctr, Dept of Oto, 111 Michigan Ave NW, Ste 800, Washington, DC 200102970 1990 2006 Peter Belafsky, UC Davis, 2521 Stockton Blvd, #7200, Sacramento, CA 95817 Lanny G. Close, Columbia Univ, Dept of Oto, 630 W 168th St, New York, NY 10032 1993 1988 Thomas P. Belson, 1111 Delafield St, Ste 102, Waukesha, WI 53188-3402 Sharon L. Collins, 6 Timber Shadows Rd, Belleville, IL 62221 1993 1990 Gerald S. Berke, Div of Oto-HNS, UCLA, 10833 Le Conte Ave, Rm 62-132 CHS, Los Angeles, CA 90095 Stephen F. Conley, 9000 W Wisconsin Ave, PO Box 1997, Milwaukee, WI 53201 1978 1997 Robert G. Berkowitz, Dept of Oto, Royal Children’s Hosp, Flemington Rd, Parkville, Victoria 3161, Australia Robin T. Cotton, Children’s Hosp Med Ctr, Dept of Oto, 3333 Burnet Ave, OSB 3110, Cincinnati, OH 45229 1995 Mark S. Courey, UCSF Voice Ctr, 2330 Post St, 5th Fl, San Francisco, CA 94115-1809 1990 David J. Beste, Children’s Hosp of Wisconsin Office Bldg, 9000 W Wisconsin Ave, Ste 208, Milwaukee, WI 53226 1991 Dennis M. Crockett, 4650 Sunset Blvd, Los Angeles, CA 90027 1992 1999 Neil Bhattacharyya, Joint Ctr for Oto, 333 Longwood Ave, 3rd Fl, Boston, MA 02115-5711 James P. Cuyler, 1849 NW Kearney, Ste 300, Portland, OR 97209-1412 2004 2008 Martin A. Birchall, UCL Ear Institute, Royal Natl Throat, Nose & Ear Hosp, 330 Gray’s Inn Rd, London, WC1X 8DA Seth H. Dailey, Univ of Wisconsin Hosp & Clinics, K41713 CSC, 600 Highland Ave, Madison, WI 537927375 2006 1990 Jeffrey W. Birns, 5400 Balboa Blvd, Ste 126, Encino, CA 91316-1528 Edward Damrose, 260 Mosher Way, Palo Alto, CA 94304 2000 1988 Andrew Blitzer, NY Ctr for Voice and Swallowing, 425 W 59th St, 10th Fl, New York, NY 10019-1128 David H. Darrow, Eastern Virginia Med Sch, Dept of Oto, 825 Fairfax Ave, Norfolk VA 23507 1995 R. Kim Davis, 6459 S 640 E, Murray, UT 84107 2003 Joel H. Blumin, Med College of Wisconsin, 9200 W Wisconsin, Milwaukee, WI 53226 2009 Alessandro de Alarcon, Cincinnati Childrens Hosp, MLC 2018, 3333 Burnet Ave, Cincinnati, OH 45229 1987 Ronald S. Bogdasarian, Michigan Oto Surg Assoc, 5333 McAuley Dr, Ste 2017, PO Box 994, Ann Arbor, MI 48106-0994 Linda Brodsky, 65 Le Brun Circle, Amherst, NY 14226 Michael Broniatowski, Cleveland Clinic Health Sci Ctrs 2000 Bernard DeBerry, 16300 Sand Canyon, Ste 909, Irvine, CA 92618 Ziad E. Deeb, Washington Hosp Ctr, Dept of Oto, 110 Irving St NW, Washington, DC 20010 Mark D. Delacure, New York Univ Med Ctr, Dept of Oto, 1993 1998 1999 2003 Members 151 530 First Ave, Ste 7U, Skirball Bldg, New York, NY 10016 2008 Christine Gail Gourin, Med College of Georgia, 1120 16th St, BP 4109, Augusta, GA 30912 2003 Craig S. Derkay, Eastern Virginia Med Sch, Dept of Oto, 825 Fairfax Ave, Norfolk, VA 23507 2010 1998 Daniel E. Deschler, 1347 Massachusetts Ave, Lexington, MA 02420-3000 Nazaneen Grant, Georgetown Univ Hosp, Dept of Oto, 3800 Reservoir Rd NW, 1 German, Washington, DC 20007 2003 John H. Greinwald, Jr, 9067 Symmes Ridge Lane, Symmes, OH 45140 1998 Gregory A. Grillone, Dept of Oto, Boston Med Ctr, D616, 88 E Newton St, Boston, MA 02118-2308 1993 Benjamin Gruber, 111 N Wabash, Ste 1603, Chicago, IL 60602-2002 2008 Stacey Halum, Indiana Univ, Dept of Oto-HNS, 702 Barnhill Dr, Ste 860, Indianapolis, IN 46202 1997 Ellen Deutsch, Dept of Ped Oto, Alfred I. duPont Hosp for Children, 1600 Rockland Rd, POB 269, Wilmington, DE 19899 2010 Frederik G. Dikkers, Univ Med Ctr Groningen, Univ of Groningen, PO Box 30.001, 9700 RB Groningen, Netherlands 1997 Oscar Dias, Dept of Oto, Univ of Lisbon, Av Egas Moniz, Lisbon 1600, Portugal 2000 1998 Donald T. Donovan, Dept of Oto & Communication Sci, One Baylor Plaza, NA 102, Houston, TX 770303411 David J. Halvorson, 1010 First St N, Ste 301, Alabaster, AL 35007-8725 1983 Edward Doolin, Dept Ped General & Thoracic Surg, Children’s Hosp of Philadelphia, 34th & Civic Ctr Blvd, Philadelphia, PA 19104 Steven D. Handler, Children’s Hosp of Philadelphia, Richard D. Wood Ctr, 1st Fl, 34th St & Civic Center Blvd, Philadelphia, PA 19104-4343 1999 Gady Har-El, 193-38 Keno Ave, Hollis, NY 11423 Amelia F. Drake, Univ of North Carolina, Dept of OtoHNS, 170 Manning Dr CB7070, Physicians Office Bldg, Rm G-116, Chapel Hill, NC 27599-7070 1997 Earl Harley, Dept of Oto, Georgetown Univ Med Ctr, 3800 Reservoir Rd NW, Washington, DC 20007-2196 2004 1991 Michael E. Dunham, 9300 Valley Children’s Place SE18, Madera, CA 93636 Christopher J. Hartnick, Dept of Oto, Mass Eye & Ear Infirmary, 243 Charles St, Boston, MA 02114 2003 1986 Roland D. Eavey, Mass Eye & Ear Infirmary, Dept of Oto, 243 Charles St, Boston, MA 02114-3002 Bruce H. Haughey, Washington Univ Sch of Med, Dept of Oto, 517 S Euclid Ave, Box 8115, St Louis, MO 63110 1978 1995 David E. Eibling, Eye & Ear Inst, 200 Lothrop St, #500, Pittsburgh, PA 15213-2548 Gerald B. Healy, Children’s Hosp, Dept of Oto, 300 Longwood Ave, No. 5, Boston, MA 02115-5724 2002 1994 David W. Eisele, 601 N Caroline St, Ste 6210, Baltimore, MD 21287 Diane G. Heatley, Div of Oto-HNS, Univ of Wisconsin Hosp, 600 Highland Ave, K4-710, Madison, WI 537927375 2009 Ravindhra G. Elluru, Cincinnati Childrens Hosp, MLC 2018, 3333 Burnet Ave, Cincinnati, OH 45229 2004 Yolanda Heman-Ackah, Philadelphia Voice Ctr, 25 Bala Ave, Ste 200, Bala Cynwyd, PA 19004 1979 Willard E. Fee, Jr, Stanford Cancer Ctr, 875 Blake Wilburn Dr, Rm CC-2227, Stanford, CA 94306-5826 1991 Robert A. Hendrix, 105 Shannon Ct, Rocky Mount, NC 27804 2000 James W. Forsen, Jr, 621 S New Ballas Rd, Ste 622A, St Louis, MO 63141 1980 Arthur S. Hengerer, Dept of Oto, 601 Elmwood Ave, Box 629, Rochester, NY 14642-0629 1985 Marvin P. Fried, Montefiore Med Ctr, Dept of Oto, 3400 Bainbridge Ave, 3rd Fl, Bronx, NY 10467-2490 1997 Garrett D. Herzon, Cedars-Sinai Med Ctr, Ste 440E, 8631 W Third St, Los Angeles, CA 90048 1985 Ellen M. Friedman, 2521 Reba Dr, Houston, TX 77019 1997 Raymond L. Hilsinger, Jr, HNS Dept, 280 W MacArthur Blvd, Oakland, CA 94611-5642 1990 Michael Friedman, 30 N Michigan Ave, Ste 1107, Chicago, IL 60602 2003 Michael L. Hinni, Mayo Clinic Scottsdale, 5777 E Mayo Blvd, Phoenix, AZ 85054 1999 C. Gaelyn Garrett, 7302 Med Ctr E, South Tower, Nashville, TN 37212 2002 Shigeru Hirano, 51-2 Hirano-Toriimae-Cho #405, Kitaku, Kyoto 603-8321, Japan 1986 Kenneth A. Geller, c/o CHLAMS #78, 4650 Sunset Blvd, Los Angeles, CA 90027 1999 Henry T. Hoffman, Dept of Oto, Univ of Iowa Hosp, 200 Hawkins Dr, Iowa City, IA 52242-1009 2002 Eric M. Genden, Dept of Oto, Mt Sinai Med Ctr, 1 Gustave L. Levy Pl, New York, NY 10029-6574 1978 Lauren D. Holinger, Dept of Oto, Children’s Memorial Hosp, 2300 Children’s Plaza, Box 25, Chicago, IL 60614 2003 Mark E. Gerber, Ped Oto-HNS, North Shore Univ Health System, 501 Skokie Blvd, Northbrook, IL 60062 1993 Andrew J. Hotaling, 18 S Clay St, Hinsdale, IL 605213235 1984 Carol R. Gerson, 1031 Ashland Ave, River Forest, IL 60305 1991 Andrew F. Inglis, Children’s Hosp & Regional Med Ctr, PO Box 5371 1 6E-1, Seattle, WA 98105-0371 1992 W. Jarrard Goodwin, Jr, Univ of Miami, No. 4037, 1475 NW 12th Ave, Miami, FL 33136-1002 1997 2009 Joshua A. Gottschall, Kaiser Permanente Med Ctr, ORLHNS, 2800 W MacArthur Blvd, Oakland, CA 94611 Ian Jacobs, Dept of Ped Oto, Children’s Hosp of Philadelphia, 34th St & Civic Center Blvd, 1st Fl Wood, Philadelphia, PA 19104 1976 Bruce W. Jafek, Univ of Colorado, Dept of Oto B-205, 1995 2003 152 Members 4200 E Ninth Ave, Denver, CO 80262 1989 2009 Scharukh Jalisi, Boston Univ Med Ctr, ORL-HNS, 820 Harrison Ave, Ste FGH4, Boston, MA 02118 Howard L. Levine, Cleveland Nasal Sinus & Sleep Ctr, 5555 Transportation Blvd, Cleveland, OH 44125-5325 1990 2005 Michael M. Johns, 550 Peachtree St, Ste 400, Atlanta, GA 30308 Paul A. Levine, UVA, Oto-HNS, Box 800713, Charlottesville, VA 22908-0713 1989 Rodney P. Lusk, 555 N 30th St, Omaha, NE 68131 1985 Jonas T. Johnson, Eye & Ear Inst, Dept of Oto, 200 Lothrop St, Ste 500, UPMC, Pittsburgh, PA 15213-2546 2008 2000 Paul J. Jones, Rush Univ Med Ctr, Dept of Ped Oto, 1611 W Harrison, Ste 550, Chicago, IL 60612-3833 David L. Mandell, Ctr for Ped ENT, Ste B-900, Bethesda Health City, 10301 Hagen Ranch Rd, Boynton Beach, FL 33437 2009 1991 Raleigh O. Jones, Jr, Univ of Kentucky Med Ctr, Div of Oto, 800 Rose St, Rm C-236, Lexington, KY 40536-0084 Nicolas Maragos, Mayo Clinic, 200 First St SW, Rochester, MN 55905 1995 2004 David E. Karas, 14 Willard Ave, Madison, CT 06443 1999 Jan L. Kasperbauer, Mayo Clinic, Dept of Oto, 200 First St SW, Rochester, MN 55905-0002 Lynette J. Mark, Johns Hopkins UMC, Div of Anesthesia for Oto-HNS, 600 N Wolfe St, Tower 711, Baltimore, MD 21287-8711 2003 1973 Burns W. Kay, One W Hellman Ave, No. 8, Alhambra, CA 91803 Nicole C. Maronian, Univ of Cleveland, 11100 Euclid Ave, LKS 5045, Cleveland, OH 44106-5045 2005 1997 William M. Keane, 925 Chestnut St, 6th Fl, Philadelphia, PA 19107 Steffen Maune, Univ of Kiel, Dept of Oto, Arnold-Heller-Str 14, 24105 Kiel, Germany 1984 1992 Donald B. Kearns, 3030 Children’s Way, Ste 402, San Diego, CA 92123-4228 Thomas V. McCaffrey, Univ of Southern Florida, 12902 Magnolia Dr, Ste 3057, Tampa, FL 33612-9416 2008 1993 James H. Kelly, 6701 N Charles St, GBMC Rm 4202, Baltimore, MD 21204 Timothy M. McCulloch, Univ of Wisconsin Hosp & Clinics, K4/719 Clinical Sci Ctr, 600 Highland Ave, Madison, WI 53792-7375 1998 David W. Kennedy, Univ of Pennsylvania Med Ctr, Dept of Oto, 3400 Spruce St, Ravdin 5, Philadelphia, PA 19104-4264 1982 John C. McDougall, Mayo Clinic, 200 SW First St, Rochester, MN 55905 1984 Trevor J. I. McGill, Children’s Hosp, Dept of Oto, Fegan 9, 300 Longwood Ave, Boston, MA 02115-5724 1998 Kemp H. Kernstine, City of Hope Natl Med Ctr, 1500 E Duarte Rd, Warshaw MOB, Duarte, CA 91010 1998 1998 Joseph E. Kerschner, Dept of Ped Oto, Children’s Hosp of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226-4810 William Frederick McGuirt, Jr, 4308 Allstair Rd, Winston-Salem, NC 27104 2000 1984 Charles P. Kimmelman, 985 Fifth Ave, 7A, New York, NY 10021 J. Scott McMurray, Div of Oto-HNS, Univ of Wisconsin Hosp, 600 Highland Ave, K4-710, Madison, WI 537927375 2003 2008 Adam M. Klein, Emory Voice Ctr, 550 Peachtree St, MOT, Ste 9-4400, Atlanta, GA 30308 2008 1992 Peter J. Koltai, Stanford Univ Sch of Med, Div of Ped Oto, 801 Welch Rd, Stanford, CA 94305-5739 2000 1988 Arnold Komisar, 1421 Third Ave, 4th Fl, New York, NY 10028 1990 1990 Charles F. Koopmann, 2514 Hawthorne Rd, Ann Arbor, MI 48104 2005 1989 Jamie Koufman, 121 Bank St, Apt K, New York, NY 10014 1996 Dennis H. Kraus, Memorial Sloan-Kettering Cancer Ctr, 1275 York Ave, Box 285, New York, NY 10021-0032 1984 1989 Yosef P. Krespi, NYHNI, 110 E 59th St, Ste 8C, New York, NY 10022 1997 2010 Priya D. Krishna, UPMC Mercy Hosp, Dept of Oto, Ste 11500, Bldg B, 1400 Locust St, Pittsburgh, PA 15219 1993 Frederick A. Kuhn, Med College of Georgia, Div of ENT, 4750 Waters Ave, BP 4117, Ste 112, Savannah, GA 31404-6267 2008 Denis C. LaFreniere, Univ of Connecticut Health Ctr, Div of Oto-HNS, MC-6228, 263 Farmington Ave, Farmington, CT 06032-6228 1988 William Lawson, Dept of Oto, Mt Sinai Med Ctr, Five E 98th St, 8th Fl, Box 1191, New York, NY 10029 Albert L. Merati, Univ of Washington Sch of Med, 1959 NE Pacific Dr, Seattle, WA 98195-6161 Tanya K. Meyer, 10 E Lee St, #1101, Baltimore, MD 21202 Henry A. Milczuk, Dept of Oto-HNS, Oregon Health Sci Univ, PV-01, 3181 SW Sam Jackson Park Rd, Portland, OR 97201-3011 Robert P. Miller, 8780 Golf Rd, Ste 200, Niles, IL 607145611 Natasha Mirza, MD, Univ of Pennsylvania Med Ctr, Voice & Swallowing Ctr, 5 Ravdin, 3400 Spruce St, Philadelphia, PA 19104 Rose M. Mohr, Dept of Oto, Campus Med Arts Bldg #2, Ste 230, 29101 Health Campus Dr, Westlake, OH 44145 Anthony J. Mortelliti, Dept of Oto, SUNY Upstate Med Univ, 750 E Adams St, Syracuse, NY 13210 Melissa Mortensen, Univ of Virginia Health System, ORL-HNS, PO Box 800713, Charlottesville, VA 229080713 Harlan R. Muntz, Primary Children’s Med Ctr, 100 N Mario Capecchi Dr, #4500, Salt Lake City, UT 84113 Charles M. Myer III, Children’s Hosp Med Ctr, Dept of Ped Oto, 3333 Burnet Ave, ML 2018, Cincinnati, OH 45229-3026 James L. Netterville, VUMC, Dept of Oto, 7209 Med Ctr E, South Tower, 1215 21st Ave S, Nashville, TN 372325555 2009 1991 1994 1993 Members 2009 J. Pieter Noordzij, Boston Med Ctr, ORL-HNS, 715 Albany St, Boston, MA 02118 1995 Laurie A. Ohlms, Children’s Hosp, Dept of Oto, 300 Longwood Ave, Boston, MA 02115 2006 Bert O’Malley, Univ of Pennsylvania, 3400 Spruce St, 5 Ravdin, Philadelphia, PA 19104 2007 153 1986 Mark A. Richardson, Dept of Oto, Oregon Health Sci Univ, PV-01, 3181 SW Sam Jackson Park Rd, Portland, OR 97239 2009 Gresham T. Richter, Univ of Arkansas for Med Sci, Ped Oto, Arkansas Children’s Hosp, 4301 W Markham, Slot 543, Little Rock, AR 72205 Laura Orvidas, Mayo Clinic, Dept of Oto, 200 First St SW, Rochester, MN 55905 1994 William J. Richtsmeier, Bassett Healthcare, One Atwell Rd, Cooperstown, NY 13326-1301 1984 Robert H. Ossoff, VUMC, S-2100 Med Ctr N, Nashville, TN 37232-2559 1994 Marion B. Ridley, 3203 Bayshore Blvd #1802, Tampa, FL 33629 2001 Randal C. Paniello, Washington Univ Med Ctr, Dept of Oto, 660 Euclid Ave, Box 8115, St Louis, MO 631101007 1998 Frank L. Rimell, 420 Delaware St SE, MMC 396, Minneapolis, MN 55455-0374 1976 2000 Albert H. Park, Primary Children’s Med Ctr, Div of Oto, 100 N Mario Capecchi Dr, #4500, Salt Lake City, UT 84113 Eugene Rontal, 28300 Orchard Lake Rd, No. 100, Farmington Hills, MI 48334-3704 1981 Michael Rontal, 28300 Orchard Lake Rd, No. 100, Farmington Hills, MI 48334-3704 1990 Steven M. Parnes, 389 Hanley Rd, Nassau, NY 12123 2003 1998 Thomas R. Pasic, Univ of Wisconsin Hosp, 600 Highland Ave, K4-712, Madison, WI 53792-7375 Kristina W. Rosbe, Univ of California–San Francisco, Dept of Oto, Ste A730, San Francisco, CA 94143-0342 1998 1987 Mark S. Persky, Beth Israel Med Ctr, 10 Union Sq E, Ste 4J, New York, NY 10003 Clark A. Rosen, Eye & Ear Inst, 200 Lothrop St, Ste 500, Pittsburgh, PA 15213 1999 1994 Glenn Edison Peters, Univ of Alabama at Birmingham, BDR 563, 1530 3rd Ave, Birmingham, AL 35294-0012 Richard M. Rosenfeld, Dept of Oto, 339 Hicks St, Brooklyn, NY 11201 2004 1984 Harold C. Pillsbury III, 103 Turtleback Crossing Dr, Chapel Hill, NC 27516 Douglas A. Ross, St Vincent, Dept of Surg, 2800 Main St, Bridgeport, CT 06606-4201 1998 1991 Robert L. Pincus, 36A E 36th St, Ste 200, New York, NY 10016-3463 Michael Rothschild, MD, Park Ave ENT, 1175 Park Ave, Ste 1A, New York, NY 10128 2005 2009 Michael Pitman, New York Eye & Ear Infirmary, 310 E 14 St, New York, NY 10003 John S. Rubin, 15 Smith Close, London SE 165 PB, England 2004 1999 William M. Portnoy, 160 W 18th St, New York, NY 10011-5403 Michael J. Rutter, Cincinnati Children’s Hosp, Dept of Ped Oto, 3333 Burnet Ave, ML 2018, Cincinnati, OH 45229 1998 Gregory Postma, Med College of Georgia, Dept of Oto, 1120 15th St, BP-4109, Augusta, GA 30912 2003 Alain Sabri, American Univ of Beirut Med Ctr, Dept of Oto-HNS, PO Box 113-6044, Beirut, Lebanon 1997 William Potsic, Div of Oto, Children’s Hosp of Philadelphia, 34th St & Civic Center Blvd, Richard D. Wood Bldg, Philadelphia, PA 19104-4303 1989 Clarence T. Sasaki, Yale Univ Sch of Med, Section of Oto, 333 Cedar St, PO Box 208041, New Haven, CT 06520-8041 1992 Seth M. Pransky, 3030 Children’s Way, Ste 402, San Diego, CA 92123-4228 1997 Robert Sataloff, 1721 Pine St, Philadelphia, PA 191036701 2002 Reza Rahbar, Dept of Oto, Children’s Hosp, 300 Longwood Ave, Boston, MA 02115 2000 Kiminori Sato, 8-18-2-chome Kanaike-Machi, Oita-Shi 870-0026, Japan 2001 Elie E. Rebeiz, New England Med Ctr, 302 Marlborough St, Boston, MA 02116-1607 1996 Richard L. Scher, Div of Oto, Duke Univ Med Ctr, Box 3805, Durham, NC 27710 2009 Catherine J. Rees, Wake Forest Univ Health Sci, Med Ctr Blvd, Winston, NC 27157 1998 Scott R. Schoem, 245 Westmont St, West Hartford, CT 06117 2003 Mark Reichelderfer, Univ of Wisconsin Hosp, 600 Highland Ave, H6/516 CSC, Madison, WI 53792-5124 2005 John M. Schweinfurth, Univ of Mississippi, Dept of Oto, 2500 N State St, Jackson, MS 39216-4505 1980 Timothy J. Reichert, 621 S New Ballas Rd, Ste 383A, St Louis, MO 63141-8232 1983 1986 James S. Reilly, Alfred I. duPont Hosp for Children, 1600 Rockland Rd, Wilmington, DE 19899 1996 Anthony J. Reino, 175 Memorial Hwy, Ste 1-2, New Rochelle, NY 10801 1997 Marc Remacle, Service ORL, UCL Mont-Godinne, Av Therasse 1, Yvoir 5530, Belgium 1980 Dale H. Rice, USC Health Consultation Ctr, 1510 San Pablo St, Ste 201, Los Angeles, CA 90033-4586 Roy B. Sessions, Beth Israel Med Ctr, 10 Union Sq E, Ste 45, New York, NY 10003-3314 Michael Setzen, 600 Northern Blvd, Ste 310, Great Neck, NY 11021-5200 Udayan K. Shah, Alfred I duPont Hosp for Children, Div of Oto, 1600 Rockland Rd, Wilmington, DE 19803 Jo Shapiro, Div of Oto, Brigham & Women’s Hosp, 45 Francis St, Boston, MA 02115-5711 Nina Shapiro, Div of HNS, UCLA Med Ctr, 10833 Le Conte Ave, Rm 62-158 CHS, Los Angeles, CA 900953075 1988 1998 1998 1998 154 Members 1984 Stanley M. Shapshay, University ENT, 35 Haskett Blvd, Albany, NY 12208 of Med, 601 Caroline St, 6th Fl, Baltimore, MD 212870910 2006 Anat Shatz, Shaare Zedek Med Ctr, Dept of Oto, 78 Hagalil St, Ganey Tikva 55900, Israel 2010 V. Jean Verheyden, Central Oregon ENT LLC, 2450 NE Mary Rose Place, Ste 120, Bend, OR 97701 2000 Gary Y. Shaw, 11911 W 139 Terr, Overland Park, KS 66221 2000 David L. Walner, 1680 Cloverdale Ave, Highland Park, IL 60035 2006 Akihiro Shiotani, 5-3-1 Nogata Nakano, Tokyo 1650027, Japan 1980 Ko-Pen Wang, Harbor Hosp Ctr, 3001 S Hanover St, Baltimore, MD 21225 1993 William W. Shockley, Div of Oto, Univ of North Carolina, CB 7070, 610 Burnett-Womack Bldg, Chapel Hill, NC 27599-7070 1995 Robert F. Ward, Weill Cornell Med College, Dept of Oto, 1305 York Ave, 5th Floor, New York, NY 10021 1998 2000 Sally R. Shott, MD, Children’s Hosp Med Ctr, 3333 Burnet Ave, MCL 2018, Cincinnati, OH 45229-3039 Mark K. Wax, Dept of Oto, 3181 SW Sam Jackson Park Rd, PV-01, Portland, OR 97201-3098 2004 2010 Jeffrey P. Simons, Langone Med Ctr, Ped Oto-NYU, 550 First Ave, New York, NY 10016 Julie L. Wei, Univ of Kansas Med Ctr, Dept of Oto, Mailstop 3010, 3901 Rainbow Blvd, Kansas City, KS 66160 2000 C. Blake Simpson, Univ of Texas Health Sci Ctr, 7703 Floyd Curl Dr, MSC 777, San Antonio, TX 78229-3900 1996 1984 George T. Simpson II, 3495 Bailey Ave 503-C, Buffalo, NY 14215 Gregory S. Weinstein, Dept of Oto, Univ of Pennsylvania Med Ctr, 5 Ravdin, 3400 Spruce St, Philadelphia, PA 19104-4219 1984 2010 John T. Sinacori, 600 Gresham Dr, Ste 1100 RP, Norfolk, VA 23507 Robert A. Weisman, 5215 Cannito Vista Lujo, San Diego, CA 92130 1993 2003 Marshall E. Smith, Univ of Utah Med Ctr, Div of Oto, 50 N Mario Capecchi Dr, Rm 3C120 SOM, Salt Lake City, UT 84132 Mark C. Weissler, 100 Faison Rd, Chapel Hill, NC 27517 1991 Barry L. Wenig, Evanston Northwestern Hosp, Div of Oto, 1000 Central, Ste 610, Evanston, IL 60201 1980 Raymond O. Smith, 4200 W Memorial Rd, No. 606, Oklahoma City, OK 73120-8305 1995 Jay A. Werkhaven, VUMC, Dept of Oto, 7209 Med Ctr E, Nashville, TN 37232-2559 1990 Richard J. H. Smith, Dept of Oto, Univ of Iowa Hosp, 200 Hawkins Dr, Iowa City, IA 52242-1078 1999 2004 Ahmed Soliman, Temple Univ Sch of Med, Dept of Oto-HNS, 3400 N Broad St, Kresge 102, Philadelphia, PA 19140 Ralph Wetmore, Children’s Hosp of Philadelphia, Dept of Ped Oto, 34th St & Civic Center Blvd, Philadelphia, PA 19104 1997 Brian Wiatrak, Ped ENT Associates, 1940 Elmer J Bissell Rd, Birmingham, AL 35243 2007 Robert Stachler, 527 N Cranbrook Dr, Bloomfield Hills, MI 48301-2402 2000 J. Paul Willging, Children’s Hosp Med Ctr, 3333 Burnet Ave, MCL 2018, Cincinnati, OH 45229 1987 James A. Stankiewicz, Dept of Oto, Loyola Univ Med Ctr, 2160 S First Ave, Maywood, IL 60153-3304 1997 Daniel Wohl, 4114 Sunbeam Rd, Ste 403, Jacksonville, FL 32257 1981 Marshall Strome, 450 E 83rd St, Apt 23C, New York, NY 10020-6293 1993 Peak Woo, 143 Hudson Ave, Tenafly, NJ 07670 2001 W. Edward Wood, 22 Lindsey Ave, Danville, PA 17821 1978 Fred J. Stucker, Louisiana State Univ Med Ctr, Dept of Oto-HNS, 1501 Kings Hwy, Shreveport, LA 71103 2000 2004 Lucian Sulica, Weill Cornell Med College, Dept of Oto, 1305 York Ave, 5th Floor, New York, NY 10021 B. Tucker Woodson, Med College of Wisconsin, Clinic at Froedtert, 9200 W Wisconsin Ave, Milwaukee, WI 53226 2002 2007 Dana Suskind, Univ of Chicago, Oto-HNS, 5841 S Maryland Ave, M/C 1035, Chicago, IL 50537 Gayle W. Woodson, 1317 Wiggins Ave, Springfield, IL 62704 1999 2008 Thomas G. Takoudes, 46 Prince St, Ste 601, New Haven, CT 06519 Audie L. Woolley, Ped ENT Associates, 1940 Elmer J Bissell Rd, Birmingham, AL 35243 1997 2008 Ichiro Tateya, Dept of Oto-HNS, Graduate Sch of Medicine, Kyoto Univ, Sakyo-ku, Kyoto 606-8507, Japan Ken Yanagisawa, Univ Towers, 98 York St, New Haven, CT 06511-5602 2010 2000 David J. Terris, Georgia Health Sci Univ, Dept of Oto, 1120 Fifteen St, BP-4109, Augusta, GA 30912-4060 Nwanmegha Young, Yale Univ, Dept of Oto, 333 Cedar St, PO Box 208041, New Haven, CT 06520-8041 2009 2000 Dana M. Thompson, 1402 Autumn Sage Courts W, Rochester, MN 55902 Craig H. Zalvan, Institute for Voice & Swallowing Disorders, 777 N Broadway, Ste 303, Sleepy Hollow, NY 10591 1985 Jerome W. Thompson, UT Health Sci Ctr, Dept of Oto, 956 Court Ave, Rm B226, Memphis, TN 38163 1997 George Zalzal, Children’s Natl Med Ctr, Dept of Oto, 111 Michigan Ave NW, Washington, DC 20010 1976 Robert J. Toohill, Med College of Wisconsin, Clinic at Froedtert, 9200 W Wisconsin Ave, Milwaukee, WI 53226 1991 Steven M. Zeitels, 100 Bellevue St, Boston, MA 024581921 1996 David Tunkel, Dept of Oto, Johns Hopkins Univ Sch 2006 Karen Zur, Children’s Hosp of Philadelphia, Richard D. Members Wood Ctr, 1st Floor, 34th St & Civic Ctr Blvd, Philadelphia, PA 19104-4399 1992 David A. Zwillenberg, 266 Linden Lane, Merion, PA 19066 Associate Members 155 seau, 26 Ave du Dr Arnold Netter, Paris Cedex 75012, France 2008 Dana M. Hartl, Institut Gustave Roussy, Oto-HNS, 39, rue Camille Desmoulins, 94805 Villejuif, France 1982 Minoru Hirano, 242-5 Nishimachi, Kurume-shi 830, Japan 2008 Lynn Acton, Yale Univ, Communication Disord Ctr, 333 Cedar St, New Haven, CT 06520 1995 Yasuo Hisa, Dept of Oto, Kyoto Prefectural Univ of Med, Kawaramachi-Hirokoji, Kyoto 602-8566, Japan 1984 Jerome C. Goldstein, 4119 Manchester Lake Dr, Lake Worth, FL 33467-8175 2000 Katsuhide Inagi, Kitasato Inst Med Ctr, 6-100 Arai, Kitamoto, Saitama, Japan 1998 Andrew Herlich, Temple Univ, Dept of Anesthesiol, 3rd Fl, Broad & Ontario Sts, Philadelphia, PA 19104 1973 S. N. Jain, A1 F2 Poonam Apts, Abid Shopping Ctr, Chiraz Ali Lane, Hyderabad 500001 India 2009 Nikki Johnston, Med College of Wisconsin, Otol & Commun Sci, Div of Research, Froedtert West, 9200 W Wisconsin Ave, Milwaukee, WI 53226 1976 Otto Jepsen, Univ Dept of Oto, Arhus Kommunehospital, 8000 Arhus, Copenhagen, Denmark 2008 Steven B. Leder, Yale Univ Sch of Med, Dept of SurgOto, PO Box 208041, New Haven, CT 06520-8041 2005 Benjamin Y. Kim, Yonsei Univ College of Med, Dept of ENT, CPO Box 8044, Seoul, Korea 2008 Heather Lisitano, Yale Univ, Oto, 800 Howard Ave, YPB 4th Floor, New Haven, CT 06520-8041 1994 Hisayoshi Kojima, Dept of Oto, Kyoto Univ Fac of Med, Syogoinn Kawahara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan 2005 Thomas Murry, Columbia Univ, Dept of Oto, Harkness 8-812, New York, NY 10032 1979 Carl-Eric Lindholm, Dept of Oto, Orebro Med Ctr Hosp, S-701 85 Orebro, Sweden 2009 Diana Marie Orbelo, Mayo Clinic, 200 First St SW, Rochester, MN 55905 2004 2001 JoAnne Robbins, William S. Middleton VA Hosp, GRECC (11G), 2500 Overlook Terrace, Madison, WI 53705 Burkard M. Lippert, SLK-Kliniken Heilbronn GmbH, Dept of ORL, Am Gesundbrunnen 20-26, 74078 Heilbronn, Germany 1980 Salvador Magaro, R Pena 1279-10B, Buenos Aires 1021, Argentina Libby J. Smith, Eye & Ear Institute, 203 Lothrup St, Ste 519, Philadelphia, PA 15123 2002 Hans F. Mahieu, VU Med Ctr, Dept of Oto, POB 7057, 1007 MB Amsterdam, Netherlands 1992 Wolf J. Mann, Dept of Oto, Langenbeckstr, Mainz 55101, Germany 2008 Corresponding Members 1974 Bruce N. Benjamin, 19 Prince Rd, Killara, NSW 2071, Australia 1987 1993 Daniel F. Brasnu, HEGP, Dept of Oto, 20 rue Leblanc, Paris 75015, France Juan Antonio Mazzei, AV Las Heras 2321, 2nd Fl, C1425ASA C.A. Buenos Aires, Argentina 1991 1991 G. Patrick Bridger, 21 Kitchener Pl, Ste 1, Bankstown, NSW 2200, Australia Randall P. Morton, Green Lane Hosp, ORL Dept, Green Lane West, Auckland 3, New Zealand 1991 2001 Harvey L. Coates, 208 Hampden Rd, Nedlands, Perth, WA 6009, Australia Yasushi Murakami, 4-2 Goryoshita, Ryoanji, U-Kyo-Ku, Kyoto 616, Japan 2004 2006 Jacob Cohen, 119 Shderot Rothschild St, 64271 TelAviv, Israel Tadashi Nakashima, Kurume Univ Sch of Med, Dept of Oto-HNS, 67 Asahi-machi, Kurume 830-0011, Japan 1946 Emiro E. Delima, Rua Alvaro Alvin 31 130, Rio de Janeiro, Brazil 1997 Michael Nash, Dept of Oto, Soroka Univ Med Ctr, Box 151, Beer Sheva 84101, Israel 2004 Ari DeRowe, Tel-Aviv Med Ctr, Dana Children’s Hosp, 6 Weitzman St, Tel-Aviv, Israel 1976 Arnold M. Noyek, Mt Sinai Hosp, 600 University, Rm 401, Toronto, Ontario M5G 1X5, Canada 1965 J. M. DuBois de Montreynaud, Centre Hosp Univ, 45 Rue Cognacq-Jay, Reims Cedex 51090, France 2002 Koichi Omori, Dept of Oto-HNS, Grad Sch of Med, Kyoto Univ, 54 Kawahara-cho, Shogoin, Kyoto 6068507, Japan 2002 Hans E. Eckel, HNO Abteilung, Dept ORL, Landeskrankenhaus Klagenfurt, St Veiter Str 47, A-9020 Klagenfurt, Austria 1987 1988 Alfio Ferlito, Dept of Oto-HNS, Univ of Udine, Policlinico Universitario, Piazzale Solavia Maria della Misericordia, 33100 Udine, Italy Tadesz M. Orlowski, Dept of Thoracic Surg, 105 Grabiszynska Str, 53-439, Wroclaw, Poland Alexei Ovchinnikov, Surgery Clinik N1, First Moscow Medical Institute, Dovator Str 15, Moscow, Russia Panagiotis E. Pantazepoulos, 54 Homiru St, Athens 135, Greece Kishore Prasad, 1st Floor Nethravathi Bldg, Balmatta, Mangalore, Karnataka State, India, 575001 Alessandra Rinaldo, Dept of Oto-HNS, Univ of Udine, Policlinico Città di Udine, Viale Venezia 410, Udine 33100, Italy 1980 2003 2001 Rolando Fonseca, La Rioja 3920, La Lucila, Buenos Aires 1636, Argentina Gerhard Friedrich, Auenbruggerplatz 26-28, A-8036 Graz, Austria E. Noel Garabedian, Service ORL, Hosp Armand Trous- 1984 1966 2004 2000 156 1974 2005 2002 1991 2004 2005 2000 Members Marcel Savary, Rue Neuve 10, Yverdon 1400, Switzerland Christian Sittel, Oto-HNS, Klinkum Stuttgart-Katharinenhospital, Kriegsbergstraße 60, 70174 Stuttgart, Germany Conrad F. Smit, Vrije Univ Med Ctr, POB 7057, 1007 MB Amsterdam, Netherlands Gordon B. Snow, VUMC, Dept of Oto, De Boelelaan 1117, 1081 Amsterdam, 1081-HV, Netherlands Georg Mathias Sprinzl, Univ of Innsbruck, HNO Klinik Anichstr, Dept of Oto, 356020 Innsbruck, Austria Wolfgang Steiner, Univ of Goettingen, ENT Dept, RobertKoch-Str 40, Goettingen 37075, Germany Juan Manuel Tato, Lago Hess 13 110 110KM 13 1, Av Bustillo 8400 San Carlos, Rio Negro 8400, Argentina 2002 Jean M. Triglia, Hôpital d’Enfants CHU La Timone, Dept of Pediatric Oto, 13385 Marseille Cedex 5, France 2004 Hirohito Umeno, Kurume Univ, Dept of Oto-HNS, 67 Asahi-machi, Kurume 830-0011, Japan 1991 Toshiyuki Uno, Kyoto Prefectural Univ, Kawaramachi Hirokoji, Kamikyo-ku, Kyoto 602-8566, Japan 1993 Jos J. M. van Overbeek, Kosterijweg 9, 9761 GD Eelde, Netherlands 2003 Jochen Werner, Dept of Oto, Univ of Marburg, Deutschhausstr 3, 35037 Marburg, Germany 2008 Jeong-Soo Woo, 4 Maplecrest Lane, Hamden, CT 06514 OFFICERS 1917-2010 1917 1918 1919 1920 1921 1922 1923 1924 1925 1926 1927 1928 1929 1930 1931 1932 1933 1934 1935 1936 1937 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 1948 Chevalier Jackson, MD Hubert Arrowsmith, MD John W. Murphy, MD Henry L. Lynah, MD Harris P. Mosher, MD Samuel Iglauer, MD Robert C. Lynch, MD Ellen J. Patterson, MD William B. Chamberlin, MD D. Crosby Greene, MD Sidney Yankauer, MD Charles J. Imperatori, MD Thomas E. Carmody, MD Henry B. Orton, MD Louis H. Clerf, MD Richmond McKinney, MD Waitman F. Zinn, MD Henry Hall Forbes, MD H. Marshall Taylor, MD Joseph C. Beck, MD Gordan Berry, MD John Kernan, MD Lyman Richards, MD Gabriel Tucker, MD W. Likely Simpson, MD Robert L. Moorehead, MD Robert L. Moorehead, MD Carlos E. Pitkin, MD Carlos E. Pitkin, MD Robert M. Lukens, MD Millard F. Arbuckle, MD Paul H. Holinger, MD 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 PRESIDENTS LeRoy A. Schall, MD Chevalier L. Jackson, MD Herman J. Moersch, MD Fred W. Dixon, MD Edwin N. Broyles, MD Clyde A. Heatly, MD Daniel S. Cunning, MD Clarence W. Engler, MD Walter B. Hoover, MD Francis W. Davison, MD Verling K. Hart, MD F. Johnson Putney, MD Alden H. Miller, MD Joseph P. Atkins, MD Stanton A. Friedberg, MD Charles M. Norris, MD Daniel C. Baker, Jr, MD Blair Fearon, MD Francis E. LeJeune, Jr, MD Charles F. Ferguson, MD Arthur M. Olsen, MD Richard W. Hanckel, MD John R. Ausband, MD John S. Knight, MD Gabriel F. Tucker, Jr, MD Howard A. Anderson, MD Walter H. Maloney, MD Seymour R. Cohen, MD Paul H. Ward, MD James B. Snow, Jr, MD Joyce A. Schild, MD 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Loring W. Pratt, MD M. Stuart Strong, MD Bernard R. Marsh, MD John A. Tucker, MD Frank N. Ritter, MD William R. Hudson, MD David R. Sanderson, MD C. Thomas Yarington, Jr, MD Robert W. Cantrell, MD H. Bryan Neel III, MD, PhD Gerald B. Healy, MD Charles W. Cummings, MD Lauren D. Holinger, MD Haskins K. Kashima, MD Eiji Yanagisawa, MD Robert H. Ossoff, DMD, MD Stanley M. Shapshay, MD Rodney P. Lusk, MD W. Frederick McGuirt, MD Paul A. Levine, MD Ellen M. Friedman, MD Robin T. Cotton, MD Peak Woo, MD Charles N. Ford, MD Steven M. Zeitels, MD Jonathan E. Aviv, MD Gady Har-El, MD Clarence T. Sasaki, MD Jamie A. Koufman, MD Andrew Blitzer, MD, DDS Michael A. Rothschild, MD 1917 1918 1919 1920 1921 1922 1923 1924 1925 1926 1927 1928 1929 1930 1931 1932 1933 1934 1935 1936 1937 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 1948 Hubert Arrowsmith, MD John W. Murphy, MD Harris P. Mosher, MD Robert C. Lynch, MD Robert C. Lynch, MD Charles J. Imperatori, MD Fielding O. Lewis, MD Thomas E. Carmody, MD D. Crosby Greene, MD Sidney Yankauer, MD Henry B. Orton, MD W. Likely Simpson, MD H. Marshall Taylor, MD Richmond McKinney, MD Edwin McGinnis, MD D. Campbell Smyth, MD LeRoy A. Schall, MD H. Marshall Taylor, MD Gabriel Tucker, MD John Kernan, MD William F. Molt, MD Edward A. Looper, MD Dean M. Lierle, MD Carlos E. Pitkin, MD Robert L. Moorehead, MD Fletcher D. Woodward, MD Fletcher D. Woodward, MD Kenneth A. Phelps, MD Kenneth A. Phelps, MD Murdock Equen, MD Edwin N. Broyles, MD Francis W. Davison, MD 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 VICE-PRESIDENTS Sam E. Roberts, MD Murdock Equen, MD Frederick T. Hill, MD George J. Taquino, MD Walter H. Hoover, MD Daniel S. Cunning, MD Howard W. D. McCart, MD Walter P. Work, MD Walter P. Work, MD George S. McReynolds, MD Daniel C. Baker, Jr, MD Julius W. McCall, MD Herbert W. Schmidt, MD Herbert H. Harris, MD James A. Harrill, MD Paul G. Bunker, MD Joel J. Pressman, MD William A. Lell, MD Arthur M. Olsen, MD Oliver W. Suehs, MD C. E. Munoz-MacCormick, MD G. Edward Tremble, MD John S. Knight, MD Richard A. Rasmussen, MD* Seymour R. Cohen, MD Donald F. Proctor, MD John E. Rayl, MD Joyce A. Schild, MD John P. Frazer, MD James D. Baxter, MD William R. Hudson, MD 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Bernard R. Marsh, MD John E. Rayl, MD Willard A. Fry, MD Robert W. Cantrell, MD Francis I. Catlin, MD Henry J. Heimlich, MD Robin T. Cotton, MD LaVonne Bergstrom, MD Donald B. Hawkins, MD Thomas C. Calcaterra, MD Mary D. Lekas, MD Eiji Yanagisawa, MD Eiji Yanagisawa, MD Ellen M. Friedman, MD Ellen M. Friedman, MD W. Frederick McGuirt, MD W. Frederick McGuirt, MD Ellen M. Friedman, MD Ellen M. Friedman, MD Robin T. Cotton, MD Jonathan E. Aviv, MD Jonathan E. Aviv, MD Jonathan E. Aviv, MD Jonathan E. Aviv, MD Jamie A. Koufman, MD Jamie A. Koufman, MD Jamie A. Koufman, MD Ellen S. Deutsch, MD Ellen S. Deutsch, MD Ellen S. Deutsch, MD Ellen S. Deutsch, MD 157 –––– *Served as President. 158 Officers PRESIDENTS-ELECT 1969 1970 1971 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 Richard W. Hanckel, MD John R. Ausband, MD Robert E. Priest, MD (April to Sept. ’71) John S. Knight, MD (Sept. ’71) Gabriel F. Tucker, Jr, MD Howard A. Anderson, MD Walter H. Maloney, MD Seymour R. Cohen, MD Paul H. Ward, MD James B. Snow, Jr, MD Joyce A. Schild, MD Loring A. Pratt, MD M. Stuart Strong, MD 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 Bernard R. Marsh, MD John A. Tucker, MD Frank N. Ritter, MD William R. Hudson, MD David R. Sanderson, MD C. Thomas Yarington, Jr, MD Robert W. Cantrell, MD H. Bryan Neel III, MD, PhD Gerald B. Healy, MD Charles W. Cummings, MD Lauren D. Holinger, MD Haskins K. Kashima, MD Eiji Yanagisawa, MD Robert H. Ossoff, DMD, MD Stanley M. Shapshay, MD 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Rodney P. Lusk, MD W. Frederick McGuirt, MD Paul A. Levine, MD Ellen M. Friedman, MD Robin T. Cotton, MD Peak Woo, MD Charles N. Ford, MD Steven M. Zeitels, MD Jonathan E. Aviv, MD Gady Har-El, MD Clarence T. Sasaki, MD Jamie A. Koufman, MD Andrew Blitzer, MD, DDS Michael A. Rothschild, MD Gregory Postma, MD SECRETARIES 1928-1930 1931 1932 1933 1934-1939 1939-1948 1948-1953 Louis H. Clerf, MD Richmond McKinney, MD Edwin McGinnis, MD Henry Hall Forbes, MD Lyman Richards, MD Paul H. Holinger, MD Edwin N. Broyles, MD 1953-1960 1960-1965 1965-1970 1970-1974 1974-1978 1978-1984 1984-1990 F. Johnson Putney, MD Daniel C. Baker, Jr, MD John R. Ausband, MD Walter H. Maloney, MD Loring W. Pratt, MD David R. Sanderson, MD Lauren D. Holinger, MD 1990-1995 1995-1999 2000-2001 2002-2005 2005-2008 2009- Rodney P. Lusk, MD James A. Duncavage, MD Charles N. Ford, MD R. Kim Davis, MD Peter J. Koltai, MD Gregory A. Grillone, MD 1994-1999 2000-2002 2003-2005 2006-2009 2010- Paul A. Levine, MD Steven M. Zeitels, MD Clarence T. Sasaki, MD Gregory Postma, MD Dana Thompson, MD 1989-1995 1995-2000 2000-2004 2004-2008 2008- Stanley M. Shapshay, MD Peak Woo, MD Gady Har-El, MD Michael A. Rothschild, MD J. Scott McMurray, MD TREASURERS 1928-1930 1930-1933 1933-1946 1946-1954 1954-1959 1959-1964 Henry B. Orton, MD Waitman F. Zinn, MD Robert M. Lukens, MD Clyde A. Heatly, MD Verling K. Hart, MD Charles M. Norris, MD 1964-1969 1969-1977 1977-1982 1982-1985 1985-1990 1990-1994 Richard W. Hanckel, MD John P. Frazer, MD John A. Tucker, MD C. Thomas Yarington, Jr, MD Mary D. Lekas, MD Robert H. Ossoff, DMD, MD EDITORS 1928-1939 1939-1947 1947-1952 1952-1958 1958-1963 Ellen J. Patterson, MD Louis H. Clerf, MD Fred W. Dixon, MD Francis W. Davison, MD Stanton A. Friedberg, MD 1963-1968 1968-1972 1972-1977 1977-1983 1983-1989 Charles F. Ferguson, MD Gabriel F. Tucker, Jr, MD James B. Snow, Jr, MD Frank N. Ritter, MD Gerald B. Healy, MD