Bluestone and Stool’s Pediatric Otolaryngology [Volume 1, 5 ed.] 9781607950189, 1607950189, 9781607952589, 1607952580, 2014000079

Table of contents :
Volume 1
Dedications
Table of Contents
Section Editors
Author Listing
Foreword
Preface
Acknowledgments
Encomium
Section 1 Basic Science/General Pediatric Otolaryngology
Evolution of Pediatric Otolaryngology
Phylogenetic Aspects and Embryology
Genetics, Syndromology, and Craniofacial Anomalies
Outcomes and Evidence-Based Medicine in Pediatric Otolaryngology
Ethical Issues in Pediatric Otolaryngology
Professionalism, Communication, and Teamwork in Surgery
Pediatric Otolaryngology: A Psychosocial Perspective
Psychiatric Disorders in Pediatric Otolaryngology
Munchausen Syndrome by Proxy
Pediatric Anesthesiology
Allergy and Immunology
Pediatric Neurology
Pediatric Ophthalmology
Pediatric Hematology: The Coagulation System and Associated Disorders
Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections
The Role of Biofilms in Pediatric Otolaryngologic Diseases
Pediatric Gastroenterology
Pediatric Pulmonology
Pediatric Oral and Maxillofacial Surgery: Craniofacial Growth and Interdisciplinary Surgical Care
Section 2 Ear and Related Structures
Embryology and Developmental Anatomy of the Ear
Physical and Physiological Bases of Hearing
Methods of Clinical Examination: Ear and Related Structures
The Assessment of Hearing and Middle-Ear Function in Children
Methods of Examination: Radiologic Aspects
Vestibular Evaluation
Otorrhea
Tinnitus in Children
Balance Disorders
Genetic Hearing Loss and Inner Ear Diseases
Nongenetic Hearing Loss
Congenital Inner Ear Anomalies
Cochlear Implants in Children
Congenital Anomalies of the External and Middle Ears
Surgical Management of Microtia and Congenital Aural Atresia
Diseases of the External Ear
Otitis Media and Eustachian Tube Dysfunction
Complications and Sequelae of Otitis Media
Facial Paralysis in Children
Diseases of the Labyrinthine Capsule
Injuries of the Ear and Temporal Bone
Tumors of the Ear and Temporal Bone
Section 3 The Nose, Paranasal Sinuses, Face, and Orbit
Embryology and Anatomy of the Paranasal Sinuses
Nasal Physiology
Methods of Examination of the Nose, Paranasal Sinuses, Face, and Orbit
Imaging of the Paranasal Sinuses in Pediatric Patients With Special Considerations for Endoscopic Sinus Surgery
Nasal Obstruction and Rhinorrhea
Epistaxis
Pediatric Headaches
Oral and Facial Neuropathic Pain in Children
Orbital Swellings
Congenital Malformations of the Nose and Paranasal Sinuses
Rhinitis and Acute and Chronic Sinusitis
Surgical Management of Chronic Rhinosinusitis
Complications of Rhinosinusitis
Allergic Rhinitis
Foreign Bodies of the Nose
Injuries of the Nose, Facial Bones, and Paranasal Sinuses
Tumors of the Nose, Paranasal Sinuses, and Nasopharynx
1-Index
Volume 2
Table of Contents
Section Editors
Author Listing
Section 4 The Mouth, Pharynx, and Esophagus
Embryology and Anatomy of the Mouth, Pharynx, and Esophagus
Physiology of the Mouth, Pharynx, and Esophagus
Methods of Examination of the Mouth, Pharynx, and Esophagus
Congenital Malformations of the Mouth and Pharynx: Orofacial Clefts and Related Syndromes
Inflammatory Disease of the Mouth and Pharynx
Tonsillectomy and Adenoidectomy
Pediatric Sleep Disorders
Dental and Gingival Disorders
Orthodontic Problems in Children
Idiopathic Conditions of the Mouth and Pharynx
Oral Cavity and Oropharyngeal Manifestations of Systemic Disease
Diseases of the Salivary Glands
The Management of Drooling (Sialorrhea)
Tumors of the Mouth and Pharynx
Pediatric Dysphagia
Functional Abnormalities of the Esophagus
Eosinophilic Esophagitis
Foreign Bodies of the Pharynx and Esophagus
Trauma to the Mouth, Pharynx, and Esophagus in Children
Caustic Injuries and Acquired Strictures of the Esophagus
Neurologic Disorders of the Mouth, Pharynx, and Esophagus
Section 5 The Airway
Developmental Anatomy and Physiology of the Larynx, Trachea, Esophagus, and Lungs
Physiology of the Larynx, Airways, and Lungs
Methods of Examination of the Pediatric Airway
Radiologic Evaluation of the Pediatric Airway
Cough
Stridor: Presentation and Evaluation
Aspiration: Etiology and Management
Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease
Congenital Laryngeal Anomalies
Congenital Malformations of the Trachea and Bronchi
Pediatric Upper Airway Infections
Acquired Disorders of the Larynx and Trachea
Pediatric Tracheotomy
Pediatric Airway Stenosis: Minimally Invasive Approaches
Airway Surgery: Open Approach
Foreign Bodies of the Larynx, Trachea, and Bronchi
Diagnosis and Management of Pediatric Laryngotracheal Trauma
Tumors of the Larynx, Trachea, and Bronchi
Section 6 The Head and Neck
Laser Surgery
The Neck: Embryology and Anatomy
Methods of Examination of the Head and Neck
Imaging of Pediatric Neck Masses
Neck Masses
Congenital Cysts and Sinuses of the Head and Neck
Cervical Adenopathy
Head and Neck Space Infections
Benign Tumors of the Head and Neck
Malignant Tumors of the Head and Neck
Thyroid
Injuries of the Neck
Craniofacial Development and Congenital Anomaly: A Contemporary Review of Processes and Pathogenesis
Primary Care of Infants and Children With Cleft Palate
Pediatric Plastic Surgery of the Head and Neck
Hemangiomas and Vascular Malformations
Pediatric Skull Base Surgery
Section 7 Communication Disorders
Disorders of Language, Phonology, Fluency, and Voice in Children: Indicators for Referral
Velopharyngeal Insufficiency
Pediatric Voice Disorders: Evaluation and Treatment
Early Identification and Early Intervention for Hearing Loss
Amplification Selection for Children with Hearing Impairment
Behavioral Intervention and Education of Children With Hearing Loss
Auditory Access to Language Resulting from Cochlear Implant Technology
2-Index

Citation preview

About the pagination of this eBook This eBook contains a multi-volume set. To navigate this eBook by page number, you will need to use the volume number and the page number, separated by a hyphen. For example, to go to page 5 of volume 1, type “1-5” in the Go box at the bottom of the screen and click "Go." To go to page 5 of volume 2, type “2-5”… and so forth.

Bluestone and Stool’s

Pediatric Otolaryngology 5th Edition, Volume 1 Editors-in-Chief

Charles D. Bluestone, MD, FACS, FAAP Distinguished Professor of Otolaryngology University of Pittsburgh School of Medicine Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Jeffrey P. Simons, MD, FACS, FAAP Associate Professor of Otolaryngology University of Pittsburgh School of Medicine Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Gerald B. Healy, MD, FACS, FRCS(Eng), FRCS (Ire) Professor of Otology & Laryngology, Harvard Medical School Emeritus Healy Chair in Otolaryngology, Boston Children’s Hospital Emeritus Surgeon-in-Chief, Boston Children’s Hospital Boston, Massachusetts Past President, American College of Surgeons

2014 People’s Medical Publishing House—USA Shelton, Connecticut

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People’s Medical Publishing House-USA 2 Enterprise Drive, Suite 509 Shelton, CT 06484 Tel: 203-402-0646 Fax: 203-402-0854 E-mail: [email protected] © 2014 PMPH-USA, LTD All rights reserved. Without limiting the rights under copyright reserved above, no part of this publication may be reproduced, stored in or introduced into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise), without the prior written permission of the publisher. 14 15 16 17/King/9 8 7 6 5 4 3 2 1 ISBN-13 ISBN-10 eISBN-13 ISBN-10

(2 volume set) 978-1-60795-018-9 (2 volume set) 1-60795-018-9 978-1-60795-258-9 1-60795-258-0

Printed in the United States of America by King Printing Company, Inc. Editors: Carole Wonsiewicz & Linda Mehta Copyeditor/Typesetter: diacriTech; Cover designer: Mary McKeon Library of Congress Cataloging-in-Publication Data Bluestone and Stool’s pediatric otolaryngology / editors-in-chief, Charles D. Bluestone, Jeffrey P. Simons, Gerald B. Healy. — 5th edition. p. ; cm. Preceded by: Pediatric otolaryngology / [edited by] Charles D. Bluestone ... [et al.]. 4th ed. c2003. Includes bibliographical references. ISBN-13: 978-1-60795-018-9 (2 volume set) ISBN-10: 1-60795-018-9 (2 volume set) ISBN-13: 978-1-60795-258-9 (eISBN) ISBN-10: 1-60795-258-0 (eISBN) [etc.] I. Bluestone, Charles D., 1932- editor of compilation. II. Simons, Jeffrey P., editor of compilation. III. Healy, Gerald B., 1942- editor of compilation. [DNLM: 1. Otorhinolaryngologic Diseases. 2. Adolescent. 3. Child. 4. Infant. WV 140] RF47.C4 618.92’09751—dc23 2014000079 Sales and Distribution Canada Login Canada 300 Saulteaux Cr., Winnipeg, MB R3J 3T2 Phone: 1.800.665.1148 Fax: 1.800.665.0103 www.lb.ca

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Dedications

To my wife, Patsy, for 58 years of a wonderful and loving marriage, for her support and patience over the past 30 years during the countless hours of organizing, writing, and editing these five editions; and to our son Jim, his wife Maria (for her expert editing of the otitis media chapters), and our delightful granddaughters, Dane and Elyse. And lastly, to my late colleague and friend Sylvan E. Stool, coeditor for the first four editions, who collaborated with me for a year to develop the initial table of contents as we tried to codify the practice of the new subspeciality of Pediatric Otolaryngology that we had been practicing for many years. CHARLES D. BLUESTONE, MD, FACS, FAAP

To my wife, Kate, for her love, support, and encouragement; and to my daughters, Ellie and Lily, who are a constant source of joy and inspiration; and to my parents, Dora and Howard, who have provided me with opportunities for a fine education, instilled in me a love of learning, and influenced me to strive for excellence. JEFFREY P. SIMONS, MD, FACS, FAAP

To my loving wife, Anne, and dear children, Lisa and Laurie. Without their support, love, and wisdom, my life would be empty. Also to my teachers and mentors and the countless patients, students, residents, fellows, and colleagues who allowed me to realize my dream of caregiver and teacher. GERALD BURKE HEALY, MD, FACS

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Table of Contents

Section Editors

xiii

Author Listing

xv

Foreword by Eugene N. Myers

xxix

Preface

xxxi

Acknowledgments Encomium to Sylvan E. Stool

xxxiii xxxv

SECTION 1: BASIC SCIENCE/GENERAL PEDIATRIC OTOLARYNGOLOGY Michael J. Cunningham and Joseph E. Dohar

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1.

Evolution of Pediatric Otolaryngology................................................................................................................................ 3 Robert J. Ruben

2.

Phylogenetic Aspects and Embryology ............................................................................................................................. 13 Anne Chun-Hui Tsai and Carol Walton

3.

Genetics, Syndromology, and Craniofacial Anomalies ..................................................................................................... 27 Anne Chun-Hui Tsai and Carol S. Walton

4.

Outcomes and Evidence-Based Medicine in Pediatric Otolaryngology ........................................................................... 59 Jennifer J. Shin and Christopher J. Hartnick

5.

Ethical Issues in Pediatric Otolaryngology ....................................................................................................................... 69 David B. Waisel and Laurie A. Ohlms

6.

Professionalism, Communication, and Teamwork in Surgery .......................................................................................... 81 Rahul K. Shah

7.

Pediatric Otolaryngology: A Psychosocial Perspective ..................................................................................................... 89 Edward J. Goldson and Kenny H. Chan

8.

Psychiatric Disorders in Pediatric Otolaryngology ........................................................................................................... 99 Abigail L. Donovan and Bruce J. Masek

9.

Munchausen Syndrome by Proxy .................................................................................................................................... 107 Basil J. Zitelli

10.

Pediatric Anesthesiology ................................................................................................................................................. 113 Lynne R. Ferrari

11.

Allergy and Immunology ................................................................................................................................................ 127 Deborah A. Gentile and David P. Skoner

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vi Table of Contents 12.

Pediatric Neurology ......................................................................................................................................................... 133 Amy C. Goldstein

13.

Pediatric Ophthalmology ................................................................................................................................................. 143 Melanie Kazlas

14.

Pediatric Hematology: The Coagulation System and Associated Disorders ................................................................... 155 James D. Cooper and A. Kim Ritchey

15.

Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections ............................................................ 171 Stephen I. Pelton

16.

The Role of Biofilms in Pediatric Otolaryngologic Diseases .......................................................................................... 191 J. Christopher Post and Garth D. Ehrlich

17.

Pediatric Gastroenterology .............................................................................................................................................. 199 Philip E. Putnam

18.

Pediatric Pulmonology .................................................................................................................................................... 217 Jonathan E. Spahr

19.

Pediatric Oral and Maxillofacial Surgery: Craniofacial Growth and Interdisciplinary Surgical Care............................ 233 Bernard J. Costello and Ramon L. Ruiz

SECTION 2: EAR AND RELATED STRUCTURES Margaretha L. Casselbrant, David H. Chi, and Margaret A. Kenna 20.

Embryology and Developmental Anatomy of the Ear ..................................................................................................... 253 Nathan Page and Keiko Hirose

21.

Physical and Physiological Bases of Hearing.................................................................................................................. 271 John D. Durrant

22.

Methods of Clinical Examination: Ear and Related Structures....................................................................................... 301 Charles D. Bluestone and Jerome O. Klein

23.

The Assessment of Hearing and Middle-Ear Function in Children ................................................................................ 317 Brian Fligor

24.

Methods of Examination: Radiologic Aspects ............................................................................................................... 355 Hisham M. Dahmoush, Arastoo Vossough, and Avrum N. Pollock

25.

Vestibular Evaluation ...................................................................................................................................................... 409 Joseph M. Furman, Margaretha L. Casselbrant, and Susan L. Whitney

26.

Otalgia ............................................................................................................................................................................. 423 Frank W. Virgin and Greg Licameli

27.

Otorrhea........................................................................................................................................................................... 431 Joseph E. Dohar

28.

Tinnitus in Children......................................................................................................................................................... 447 Samantha Anne and Anne F. Hseu

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Table of Contents

vii

29.

Balance Disorders............................................................................................................................................................ 453 Margaretha L. Casselbrant and Joseph M. Furman

30.

Genetic Hearing Loss and Inner Ear Diseases ................................................................................................................ 465 Michael S. Hildebrand, A. Eliot Shearer, Murad Husein, and Richard J.H. Smith

31.

Nongenetic Hearing Loss ................................................................................................................................................ 513 Margaret A. Kenna

32.

Congenital Inner Ear Anomalies ..................................................................................................................................... 531 David H. Chi and Ellis M. Arjmand

33.

Cochlear Implants in Children ........................................................................................................................................ 547 Richard T. Miyamoto, R. Christopher Miyamoto, and Karen Iler Kirk

34.

Congenital Anomalies of the External and Middle Ears ................................................................................................. 561 Makoto Miura and Isamu Sando

35.

Surgical Management of Microtia and Congenital Aural Atresia ................................................................................... 595 Robert F. Yellon

36.

Diseases of the External Ear............................................................................................................................................ 621 Barry E. Hirsch and Noriko Yoshikawa

37.

Otitis Media and Eustachian Tube Dysfunction .............................................................................................................. 633 Charles D. Bluestone and Jerome O. Klein

38.

Complications and Sequelae of Otitis Media .................................................................................................................. 761 Charles D. Bluestone, David H. Chi, and Jerome O. Klein

39.

Facial Paralysis in Children ............................................................................................................................................. 849 Barry M. Schaitkin

40.

Diseases of the Labyrinthine Capsule ............................................................................................................................. 869 Diego Preciado, Gilbert Vezina, and Rahul Shah

41.

Injuries of the Ear and Temporal Bone ............................................................................................................................ 879 Ana H. Kim, Clare Dean, and Simon C. Parisier

42.

Tumors of the Ear and Temporal Bone ............................................................................................................................ 895 Pamela A. Mudd and Stephen P. Cass

SECTION 3: THE NOSE, PARANASAL SINUSES, FACE, AND ORBIT Todd D. Otteson and Raymond C. Maguire

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43.

Embryology and Anatomy of the Paranasal Sinuses ....................................................................................................... 913 Michael Rontal, Todd D. Otteson, Jack B. Anon, and S. James Zinreich

44.

Nasal Physiology ............................................................................................................................................................. 927 Asli Sahin-Yilmaz and Robert M. Naclerio

45.

Methods of Examination of the Nose, Paranasal Sinuses, Face, and Orbit ..................................................................... 943 Gi Soo Lee, Reza Rahbar, and Gerald B. Healy

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viii Table of Contents 46.

Imaging of the Paranasal Sinuses in Pediatric Patients With Special Considerations for Endoscopic Sinus Surgery ............................................................................................................................................... 951 Ken Kazahaya

47.

Nasal Obstruction and Rhinorrhea .................................................................................................................................. 963 Walter M. Belenky, David N. Madgy, Michael S. Haupert, and Sonal Saraiya

48.

Epistaxis .......................................................................................................................................................................... 981 Scott C. Manning, Prabhat Bhama, and Marvin C. Culbertson III

49.

Pediatric Headaches......................................................................................................................................................... 989 Belinda A. Mantle

50.

Oral and Facial Neuropathic Pain in Children................................................................................................................. 993 Navil F. Sethna

51.

Orbital Swellings ........................................................................................................................................................... 1003 Jeffrey D. Suh and Nina L. Shapiro

52.

Congenital Malformations of the Nose and Paranasal Sinuses ..................................................................................... 1017 Todd D. Otteson

53.

Rhinitis and Acute and Chronic Sinusitis ...................................................................................................................... 1037 Ellen R. Wald

54.

Surgical Management of Chronic Rhinosinusitis .......................................................................................................... 1057 Rodney P. Lusk

55.

Complications of Rhinosinusitis ................................................................................................................................... 1065 Natalie E. Edmondson and Sanjay R. Parikh

56.

Allergic Rhinitis ............................................................................................................................................................ 1075 Andrew MacGinnitie

57.

Foreign Bodies of the Nose ........................................................................................................................................... 1089 Desiderio Passali and Raymond C. Maguire

58.

Injuries of the Nose, Facial Bones, and Paranasal Sinuses ........................................................................................... 1095 Andrew M. Shapiro and Fred Fedok

59.

Tumors of the Nose, Paranasal Sinuses, and Nasopharynx ........................................................................................... 1109 Anthony E. Magit

SECTION 4: THE MOUTH, PHARYNX, AND ESOPHAGUS Dennis J. Kitsko and Deepak K. Mehta 60.

Embryology and Anatomy of the Mouth, Pharynx, and Esophagus ............................................................................. 1123 Nira A. Goldstein and Sharon Marie Tomaski

61.

Physiology of the Mouth, Pharynx, and Esophagus ...................................................................................................... 1145 John Sinacori and Craig S. Derkay

62.

Methods of Examination of the Mouth, Pharynx, and Esophagus ................................................................................ 1151 Karen B. Zur, Lawrence W.C. Tom, William P. Potsic, and Steven D. Handler

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Table of Contents

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ix

63.

Congenital Malformations of the Mouth and Pharynx: Orofacial Clefts and Related Syndromes............................... 1161 Frederic W. B. Deleyiannis and Raymond C. Maguire

64.

Inflammatory Disease of the Mouth and Pharynx......................................................................................................... 1175 Karen F. Watters, Naishadh Patil, and John Russell

65.

Tonsillectomy and Adenoidectomy .............................................................................................................................. 1189 David H. Darrow, Craig S. Derkay, and Ron Mitchell

66.

Pediatric Sleep Disorders .............................................................................................................................................. 1223 Sangeeta Chakravorty, Dennis Kitsko, and Deepak Mehta

67.

Dental and Gingival Disorders ...................................................................................................................................... 1231 Brian S. Martin, Yasser Armanazi, J. E. Bouquot, and M. M. Nazif

68.

Orthodontic Problems in Children ................................................................................................................................ 1243 Sylvia A. Frazier-Bowers and L’Tanya J. Bailey

69.

Idiopathic Conditions of the Mouth and Pharynx ......................................................................................................... 1259 George H. Conner and Kay W. Chang

70.

Oral Cavity and Oropharyngeal Manifestations of Systemic Disease .......................................................................... 1269 Rodrigo C. Silva, Paul Rosen, and Jeffrey P. Simons

71.

Diseases of the Salivary Glands .................................................................................................................................... 1279 Deepak Mehta and David L. Mandell

72.

The Management of Drooling (Sialorrhea) ................................................................................................................... 1289 Dennis J. Kitsko and Deepak Mehta

73.

Tumors of the Mouth and Pharynx ................................................................................................................................ 1297 Carlos Gonzalez

74.

Pediatric Dysphagia ....................................................................................................................................................... 1311 Matthew Bromwich, Aliza P. Cohen, Claire K. Miller, and J. Paul Willging

75.

Functional Abnormalities of the Esophagus.................................................................................................................. 1323 Andrew J. Hotaling and Carl W. Moeller

76.

Eosinophilic Esophagitis ............................................................................................................................................... 1337 Todd D. Otteson and Alka Goyal

77.

Foreign Bodies of the Pharynx and Esophagus ............................................................................................................. 1347 Scott C. Manning

78.

Trauma to the Mouth, Pharynx, and Esophagus in Children ........................................................................................ 1355 Michael S. Cohen, David L. Mandell, and Jeffrey P. Simons

79.

Caustic Injuries and Acquired Strictures of the Esophagus .......................................................................................... 1365 Kathryn L. Colman, Jeffrey P. Simons, and Cuneyt M. Alper

80.

Neurologic Disorders of the Mouth, Pharynx, and Esophagus ..................................................................................... 1381 Ingrid Loma-Miller and Michael J. Painter

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x Table of Contents

SECTION 5: THE AIRWAY David L. Mandell and Reza Rahbar 81.

Developmental Anatomy and Physiology of the Larynx, Trachea, Esophagus, and Lungs .......................................... 1397 Glenn Isaacson

82.

Physiology of the Larynx, Airways, and Lungs ............................................................................................................ 1407 Robert E. Wood

83.

Methods of Examination of the Pediatric Airway ......................................................................................................... 1415 David Albert and Peter Bull

84.

Radiologic Evaluation of the Pediatric Airway ............................................................................................................. 1425 Ammie White, Tamara Feygin, and Avrum N. Pollock

85.

Cough ............................................................................................................................................................................ 1459 Andrew J. Hotaling and James J. Jaber

86.

Stridor: Presentation and Evaluation ............................................................................................................................. 1473 Peter J. Koltai, Aaron C. Lin, and Jenő Hirschberg

87.

Aspiration: Etiology and Management.......................................................................................................................... 1485 Carine Fuchsmann, Sonia Ayari, and Patrick Froehlich

88.

Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease ..................................................... 1495 Dana Mara Thompson

89.

Congenital Laryngeal Anomalies .................................................................................................................................. 1517 Mark E. Gerber and Judy L. Chen

90.

Congenital Malformations of the Trachea and Bronchi ................................................................................................ 1533 Luv R. Javia, Brian P. Dunham, and Ian N. Jacobs

91.

Pediatric Upper Airway Infections ................................................................................................................................ 1547 David L. Mandell

92.

Acquired Disorders of the Larynx and Trachea ............................................................................................................ 1555 Nicolas Leboulanger and Eréa Noël Garabedian

93.

Pediatric Tracheotomy ................................................................................................................................................... 1565 Ralph F. Wetmore

94.

Pediatric Airway Stenosis: Minimally Invasive Approaches ......................................................................................... 1581 Samuel T. Ostrower and Reza Rahbar

95.

Airway Surgery: Open Approach .................................................................................................................................. 1593 Michael J. Rutter, Evan J. Propst, Aliza P. Cohen, and Alessandro de Alarcon

96.

Foreign Bodies of the Larynx, Trachea, and Bronchi.................................................................................................... 1609 David H. Darrow and Michael A. DeMarcantonio

97.

Diagnosis and Management of Pediatric Laryngotracheal Trauma .............................................................................. 1627 Robert J. Tibesar, Susan E. Pearson, Frank L. Rimell, and James D. Sidman

98.

Tumors of the Larynx, Trachea, and Bronchi ................................................................................................................ 1635 Dale A. Tylor and Seth M. Pransky

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xi

SECTION 6: THE HEAD AND NECK Trevor J. McGill and Robert F. Yellon

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99.

Laser Surgery............................................................................................................................................................... 1655 Jay Werkhaven

100.

The Neck: Embryology and Anatomy ......................................................................................................................... 1665 Mark A. Richardson and Kathleen C. Y. Sie

101.

Methods of Examination of the Head and Neck ......................................................................................................... 1681 Joseph Haddad Jr., Sarah E. Keesecker, and David T. Kent

102.

Imaging of Pediatric Neck Masses .............................................................................................................................. 1691 Kalliopi Petropoulou and Barton F. Branstetter IV

103.

Neck Masses ................................................................................................................................................................ 1717 Paul W. Bauer and Rodney P. Lusk

104.

Congenital Cysts and Sinuses of the Head and Neck .................................................................................................. 1737 Robert F. Yellon and David H. Chi

105.

Cervical Adenopathy ................................................................................................................................................... 1747 Ari J. Goldsmith and Richard M. Rosenfeld

106.

Head and Neck Space Infections ................................................................................................................................. 1767 Robert F. Yellon, Todd Falcone, and David W. Roberson

107.

Benign Tumors of the Head and Neck ......................................................................................................................... 1791 Karen F. Watters, Reza Rahbar, and Trevor J. McGill

108.

Malignant Tumors of the Head and Neck .................................................................................................................... 1803 Kenneth R. Whittemore Jr. and Michael J. Cunningham

109.

Thyroid ......................................... .............................................................................................................................. 1841 Jeffrey C. Rastatter, Sivi Bakthavachalam, and John Maddalozzo

110.

Injuries of the Neck ..................................................................................................................................................... 1851 Peggy E. Kelley

111.

Craniofacial Development and Congenital Anomaly: A Contemporary Review of Processes and Pathogenesis ................................................................................................................................................................ 1861 Adel Y. Fattah, John G. Meara, and Jonathan A. Britto

112.

Primary Care of Infants and Children With Cleft Palate ............................................................................................. 1879 Margaret L. Skinner and David E. Tunkel

113.

Pediatric Plastic Surgery of the Head and Neck .......................................................................................................... 1885 Lorelei J. Grunwaldt and Joseph E. Losee

114.

Hemangiomas and Vascular Malformations ................................................................................................................ 1901 Ravindhra G. Elluru, Matthew Bromwich, and Aliza P. Cohen

115.

Pediatric Skull Base Surgery ....................................................................................................................................... 1919 Harshita Pant, Carl H. Snyderman, Elizabeth C. Tyler-Kabara, Carlos D. Pinheiro-Neto, Maria Koutourousiou, Juan C. Fernandez-Miranda, Eric W. Wang, and Paul A. Gardner

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xii Table of Contents

SECTION 7: COMMUNICATION DISORDERS Howard C. Shane 116.

Disorders of Language, Phonology, Fluency, and Voice in Children: Indicators for Referral .................................... 1945 Thomas F. Campbell, Christine A. Dollaghan, and J. Scott Yaruss

117.

Velopharyngeal Insufficiency ...................................................................................................................................... 1961 Jeremy D. Prager, Aliza P. Cohen, and J. Paul Willging

118.

Pediatric Voice Disorders: Evaluation and Treatment ................................................................................................. 1971 Roger C. Nuss and Geralyn Harvey Woodnorth

119.

Early Identification and Early Intervention for Hearing Loss ..................................................................................... 1987 Terrell A. Clark

120.

Amplification Selection for Children With Hearing Impairment ................................................................................ 1995 Todd A. Ricketts, Erin M. Picou, and Anne Marie Tharpe

121.

Behavioral Intervention and Education of Children With Hearing Loss ..................................................................... 2019 Sheila Pratt

122.

Auditory Access to Language Resulting From Cochlear Implant Technology ........................................................... 2033 Marilyn W. Neault

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Section Editors

Margaretha L. Casselbrant, MD, PhD

Dennis J. Kitsko, DO, FACS, FAOCO

Todd D. Otteson, MD, MPH

Professor of Otolaryngology University of Pittsburgh School of Medicine Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 25: Vestibular Evaluation 29: Balance Disorders

Assistant Professor of Otolaryngology University of Pittsburgh School of Medicine Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 66: Pediatric Sleep Disorders 72: Management of Drooling (Sialorrhea)

David H. Chi, MD

Raymond C. Maguire, DO

Associate Professor of Otolaryngology–Head and Neck Surgery University Hospitals Case Western Reserve Medical Center Chief, Pediatric Otolaryngology Rainbow Babies and Children’s Hospital Cleveland, OH 43: Embryology and Anatomy of the Paranasal Sinuses 52: Congenital Malformations of the Nose and Paranasal Sinuses 76: Eosinophilic Esophagitis

Associate Professor of Otolaryngology University of Pittsburgh School of Medicine Director, Hearing Center Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 32: Congenital Inner Ear Anomalies 38: Complications and Sequelae of Otitis Media 104: Congenital Cysts and Sinuses of the Head and Neck

Assistant Professor of Otolaryngology University of Pittsburgh School of Medicine Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 57: Foreign Bodies of the Nose 63: Congenital Malformations of the Mouth and Pharynx: Orofacial Clefts and Related Syndromes

Michael J. Cunningham, MD, FACS

Center for Pediatric Otolaryngology–Head/Neck Surgery, Boynton Beach, FL Clinical Associate Professor, NOVA Southeastern University College of Osteopathic Medicine, Division of Otolaryngology, Department of Surgery Voluntary Associate Professor, Miller School of Medicine, University of Miami Affiliate Clinical Assistant Professor of Biomedical Science, Charles E. Schmidt College of Biomedical Science Florida Atlantic University Boca Raton, FL 71: Diseases of the Salivary Glands 78: Trauma to the Mouth, Pharynx, and Esophagus in Children 91: Pediatric Upper Airway Infections

Otolaryngologist-in-Chief Gerald B. Healy Chair in Pediatric Otolaryngology, Boston Children’s Hospital Professor of Otology and Laryngology Harvard Medical School Boston, MA 108: Malignant Tumors of the Head and Neck

Joseph  E.  Dohar,  MD, MS, FAAP, FACS Professor of Otolaryngology University of Pittsburgh School of Medicine Professor, Department of Communication Science and Disorders University of Pittsburgh School of Health and Rehabilitation Sciences Medical Director, Pediatric Voice, Resonance and Swallowing Center Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 27: Otorrhea

Margaret A. Kenna, MD, MPH, FACS, FAAP Director of Clinical Research Department of Otolaryngology and Communication Enhancement Boston Children’s Hospital Professor of Otology and Laryngology Harvard Medical School Boston, MA 31: Nongenetic Hearing Loss

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David L. Mandell, MD, FAAP, FACS

Trevor J. McGill, MD Professor of Otology and Laryngology Associate in Otolaryngology and Communication Enhancement Boston Children’s Hospital Harvard Medical School Boston, MA 107: Benign Tumors of the Head and Neck

Deepak K. Mehta, MD Associate Professor of Otolaryngology University of Pittsburgh School of Medicine Director, Pediatric Aerodigestive Center Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 66: Pediatric Sleep Disorders 71: Diseases of the Salivary Glands 72: Management of Drooling (Sialorrhea)

Reza Rahbar, DMD, MD Associate Otolaryngologist-in-Chief McGill Chair in Pediatric Otolaryngology Department of Otolaryngology and Communication Enhancement Boston Children’s Hospital Harvard Medical School Boston, MA 45: Methods of Examination of the Nose, Paranasal Sinuses, Face, and Orbit 94: Pediatric Airway Stenosis: Minimally Invasive Approaches 107: Benign Tumors of the Head and Neck

Howard C. Shane, PhD, CCC-SLP Professor, Department of Communication Sciences and Disorders Associate Professor, Department of Otology and Laryngology Director of the Center for Communication Enhancement and the Autism Language Program, MGH Institute of Health Professions Boston Children’s Hospital Harvard Medical School Boston, MA

Robert F. Yellon, MD, FACS Professor of Otolaryngology University of Pittsburgh School of Medicine Director of Clinical Services and Co-Director Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 35: Surgical Management of Microtia and Congenital Aural Atresia 104: Congenital Cysts and Sinuses of the Head and Neck 106: Head and Neck Space Infections

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Author Listing

Alessandro de Alarcon, MD, MPH

L’tanya J. Bailey, DDS, MS

Director, Center for Pediatric Voice Disorders Cincinnati Children’s Hospital Medical Center Assistant Professor, Department of Pediatrics Assistant Professor, Otolaryngology–Head and Neck Surgery University of Cincinnati College of Medicine Cincinnati, OH 95: Airway Surgery: Open Approach

Department of Orthodontics and Dentofacial Orthopedics University of North Carolina at Chapel Hill Chapel Hill, NC 68: Orthodontic Problems in Children

David Albert, MD, FRCS Senior ENT Surgeon Great Ormond Street Hospital London, England 83: Methods of Examination of the Pediatric Airway

Cuneyt M. Alper, MD Professor of Otolaryngology, Division of Pediatric Otolaryngology Director, Pediatric Otolaryngology Fellowship Program Children’s Hospital of Pittsburgh Pittsburgh, PA 79: Caustic Injuries and Acquired Strictures of the Esophagus

Samantha Anne, MD, MS Assistant Professor of Otolaryngology Cleveland Clinic Children’s Hospital Head and Neck Institute Cleveland, OH 28: Tinnitus in Children

Jack B. Anon, MD Otolaryngologist Erie, PA 43: Embryology and Anatomy of the Paranasal Sinuses

Ellis M. Arjmand, MD, PhD Director of the Ear and Hearing Center Cincinnati Children’s Hospital Medical Center Director, Pediatric Cochlear Implant Program Medical Director, Liberty Campus Professor, Otolaryngology–Head & Neck Surgery University of Cincinnati College of Medicine Cincinnati, OH 32: Congenital Inner Ear Anomalies

Yasser Armanazi, DMD Clinical Assistant Professor Case Western Reserve School of Dentistry Cleveland, Ohio 67: Dental and Gingival Disorders

Sonia Ayari, MD Department of ENT–Head and Neck Surgery Hospital Edouard Heriot Lyon, France 87: Aspiration: Etiology and Management

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Sivi Bakthavachalam, MD, FACS Pediatric Ear, Nose, and Throat of Atlanta Atlanta, GA 109: Thyroid

Paul W. Bauer, MD Surgical Director Cook Children’s Medical Center Cochlear Implant Program Fort Worth, TX 103: Neck Masses

Walter M. Belenky, MD Otolaryngology Children’s Hospital of Michigan Detroit, MI 47: Nasal Obstruction and Rhinorrhea

Prabhat Bhama, MD Clinical Fellow Department of Otolaryngology Division of Facial Plastic and Reconstructive Surgery Harvard Medical School/Massachusetts Eye and Ear Infirmary Boston, MA 48: Epistaxis

Charles D. Bluestone, MD, FACS, FAAP Distinguished Professor of Otolaryngology University of Pittsburgh School of Medicine Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 22: Methods of Clinical Examination: Ear and Related Structures 37: Otitis Media and Eustachian Tube Dysfunction 38: Complications and Sequelae of Otitis Media

J. E. Bouquot, DDS, MS Adjunct Professor and Past Chair (retired) Department of Diagnostic & Biomedical Sciences University of Texas School of Dentistry, Houston, TX Adjunct Professor, Department of Rural Health & Community Dentistry Past Chair Department of Oral & Maxillofacial Pathology West Virginia University School of Dentistry Director of Research, The Maxillofacial Center for Education and Research Morgantown, WV 67: Dental and Gingival Disorders

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Author Listing

Barton F. Branstetter IV, MD

Kay W. Chang, MD

Director, Head and Neck Imaging Clinical Director, Neuroradiology Associate Professor of Radiology, Otolaryngology, and Biomedical Informatics UPMC Presbyterian Radiology Department Pittsburgh, PA 102: Imaging of Pediatric of Neck Masses

Associate Professor of Otolaryngology Stanford University Stanford, CA 69: Idiopathic Conditions of the Mouth and Pharynx

Jonathan A. Britto, BSc(hons), MB, MD, FRCS(Plast) Consultant Plastic and Craniofacial Surgeon The Craniofacial Unit Great Ormond Street Hospital for Children NHS Trust London, England 111: Craniofacial Development and Congenital Anomaly: A Contemporary Review of Processes and Pathogenesis

Matthew Bromwich, MD,FRCS Assistant Professor, Pediatric ENT University of Ottawa Division of Otolaryngology–Head & Neck Surgery Children’s Hospital of Eastern Ontario Principal Investigator, Division of Oncology, CHEO Research Institute Ottawa, Ontario, Canada 74: Pediatric Dysphagia 114: Hemangiomas and Vascular Malformations

Peter Bull, FRCS Great Ormond Street Hospital London, England 83: Methods of Examination of the Pediatric Airway

Thomas F. Campbell, PhD Professor and Executive Director of the Callier Center for Communication Disorders School of Behavioral and Brain Sciences Department of Communication Sciences and Disorders University of Texas at Dallas Dallas, TX 116: Disorders of Language, Phonology, Fluency, and Voice in Children: Indicators for Referral

Judy L. Chen, MD Clinician Educator Pediatric Otolaryngology, Cochlear Implants, Head & Neck Surgery NorthShore University Health System Northbrook, IL 89: Congenital Laryngeal Anomalies

Terrell A. Clark, PhD Director, Deaf and Hard of Hearing Program, Department of Otolaryngology & Communication Enhancement and Senior Associate in Psychiatry Associate Scientific Medical Staff Boston Children’s Hospital Assistant Professor of Psychiatry, Harvard Medical School Boston, MA 119: Early Identification and Early Intervention for Hearing Loss

Aliza P. Cohen, MA Division of Pediatric Otolaryngology–Head and Neck Surgery Cincinnati Children’s Hospital Medical Center Cincinnati, OH 74: Pediatric Dysphagia 95: Airway Surgery: Open Approach 114: Hemangiomas and Vascular Malformations 117: Velopharyngeal Insufficiency

Michael S. Cohen, MD, FACS Massachusetts Eye and Ear Hospital Instructor of Otolaryngology Harvard School of Medicine Boston, MA 78: Trauma to the Mouth, Pharynx, and Esophagus in Children

Kathryn L. Colman, MD

Professor Department of Otolaryngology University of Colorado Aurora, CO 42: Tumors of the Ear and Temporal Bone

Visiting Instructor Division of Otolaryngology-Head and Neck Surgery University of Utah School of Medicine Pediatric Otolaryngologist Primary Children’s Hospital University of Utah Health Care Salt Lake City, UT 79: Caustic Injuries and Acquired Strictures of the Esophagus

Sangeeta Chakravorty, MD, Dip. ABSM

George Conner, MD

Stephen P. Cass, MD, MPH

Assistant Professor, Pediatrics University of Pittsburgh School of Medicine Pittsburgh, PA 66: Pediatric Sleep Disorders

Emeritus Professor of Surgery Penn State University State College, PA 69: Idiopathic Conditions of the Mouth and Pharynx

Kenny H. Chan, MD

James D. Cooper, MD

Chairman, Department of Pediatric Otolaryngology Children’s Hospital Colorado Professor of Otolaryngology University of Colorado School of Medicine Aurora, CO 7: Pediatric Otolaryngology: A Psychosocial Perspective

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Assistant Professor of Pediatrics Division of Pediatric Hematology and Oncology University of Pittsburgh School of Medicine Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 14: Pediatric Hematology: The Coagulation System and Associated Disorders

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Author Listing Bernard J. Costello, DMD, MD, FACS

Christine A. Dollaghan, PhD

Professor and Program Director Chief, Pediatric Oral and Maxillofacial Surgery Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 19: Pediatric Oral and Maxillofacial Surgery: Craniofacial Growth and Interdisciplinary Surgical Care

Professor, Child Language Development and Disorders School of Behavioral and Brain Sciences University of Texas at Dallas Dallas, TX 116: Disorders of Language, Phonology, Fluency, and Voice in Children: Indicators for Referral

Marvin C. Culbertson III, MD

Abigail L. Donovan, MD

Staff Physician, Emergency Department Connecticut Children’s Medical Center Hartford, CT 48: Epistaxis

Assistant Professor of Psychiatry, Harvard Medical School Assistant Psychiatrist, Massachusetts General Hospital Boston, MA 8: Psychiatric Disorders in Pediatric Otolaryngology

Hisham M. Dahmoush, MBBCh, FRCR

Brian P. Dunham, MD

Pediatric Radiology Fellow Department of Radiology Children’s Hospital of Philadelphia University of Pennsylvania Philadelphia, PA 24: Methods of Examination: Radiologic Aspects

Attending, The Children’s Hospital of Philadelphia Division of Otolaryngology Assistant Professor, Otorhinolaryngology: Head and Neck Surgery University of Pennsylvania School of Medicine Philadelphia, PA 90: Congenital Malformations of the Trachea and Bronchi

David H. Darrow, MD, DDS Departments of Otolaryngology and Pediatrics Eastern Virginia Medical School Department of Otolaryngology Children’s Hospital of The King’s Daughters Norfolk, VA 65: Tonsillectomy and Adenoidectomy 97: Diagnosis and Management of Pediatric Laryngotracheal Trauma

John D. Durrant, PhD

Clare Dean, MD

Natalie E. Edmondson, MD, FACS

New York Eye and Ear Infirmary New York, NY 41: Injuries of the Ear and Temporal Bone

Otolaryngology UCLA Medical Center Los Angeles, CA 55: Complications of Nasal and Sinus Infections

Frederic W.B. Deleyiannis, MD, MPhil, MPH, FACS Chief, Department of Pediatric Plastic Surgery Director, Cleft Lip and Palate Clinic Director, Craniofacial Microsurgery & Trauma Departments of Surgery and Otolaryngology Children’s Hospital Colorado Professor, University of Colorado School of Medicine Denver, Colorado 63: Congenital Malformations of the Mouth and Pharynx: Orofacial Clefts and Related Syndromes

Michael A. DeMarcantonio, MD Departments of Otolaryngology and Pediatrics Eastern Virginia Medical School Norfolk, VA 96: Foreign Bodies of the Larynx, Trachea, and Bronchi

Craig S. Derkay, MD, FAAP, FACS Professor and Vice-Chairman Department of Otolaryngology–Head & Neck Surgery Eastern Virginia Medical School Director, Pediatric Otolaryngology Children’s Hospital of the King’s Daughters Norfolk, VA 61: Physiology of the Mouth, Pharynx, and Esophagus 65: Tonsillectomy and Adenoidectomy

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Professor Emeritus, Department of Communication Science & Disorders School of Health and Rehabilitation Sciences University of Pittsburgh Pittsburgh, PA 21: Physical and Physiologic Bases of Hearing

Garth D. Ehrlich, PhD Professor of Microbiology and Immunology Professor of Otolaryngology-Head and Neck Surgery Executive Director, Center for Advanced Microbial Processing (CAMP) Institute of Molecular Medicine and Infectious Disease Executive Director, Center for Genomic Sciences Institute of Molecular Medicine and Infectious Disease Executive Director, Genomics Core Facility Clinical and Translational Research Institute Drexel College of Medicine Philadelphia, PA 16: The Role of Biofilms in Pediatric Otolaryngologic Diseases

Ravindhra G. Elluru, MD, PHD Division of Pediatric Otolaryngology–Head and Neck Surgery Cincinnati Children’s Hospital Medical Center Cincinnati, OH 114: Hemangiomas and Vascular Malformations

Todd E. Falcone, MD Department of Otolaryngology Boston University Medical Center Boston, MA 106: Head and Neck Space Infections

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Author Listing

Adel Fattah, BSc(hons), PhD, MB, BChir, FRCS(Plast)

Carine Fuchsmann, MD

Specialist Registrar in Plastic Surgery The Craniofacial Unit Great Ormond Street Hospital for Children London, England 111: Craniofacial Development and Congenital Anomaly: A Contemporary Review of Processes and Pathogenesis

Department of ENT–Head and Neck Surgery Hospital Edouard Heriot Lyon, France 87: Aspiration: Etiology and Management

Fred Fedok, MD, FACS Professor and Chief Section of Otolaryngology Department of Surgery Pennsylvania State University College of Medicine Hershey, PA 58. Injuries of the Nose, Facial Bones, and Paranasal Sinuses

Juan C. Fernandez-Miranda, MD

Joseph M. Furman, MD, PhD Director, Division of Balance Disorders UPMC Center for Hearing and Balance Professor, Departments of Otolaryngology, Neurology, Bioengineering and Physical Therapy University of Pittsburgh School of Medicine Pittsburgh, PA 25: Vestibular Evaluation 29: Balance Disorders

Assistant Professor of Neurological Surgery Director, Surgical Neuroanatomy Lab University of Pittsburgh School of Medicine Pittsburgh, PA 115: Pediatric Skull Base Surgery

Eréa Noël Garabedian, MD

Lynne R. Ferrari, MD

Associate Professor, Neurological Surgery Co-Director, Center for Skull Base Surgery Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh, PA 115: Pediatric Skull Base Surgery

Robert M. Smith Professor of Pediatric Anesthesiology Harvard Medical School Chief, Perioperative Anesthesia Medical Director, Operating Rooms and Perioperative Programs Boston Children’s Hospital Boston, MA 10: Pediatric Anesthesiology

Armand Trousseau Children Hospital Paris, France 92: Acquired Disorders of the Larynx and Trachea

Paul A. Gardner, MD

Deborah A. Gentile, MD

Department of Radiology Children’s Hospital of Philadelphia University of Pennsylvania Philadelphia, PA 84: Radiologic Evaluation of the Pediatric Airway

Director of Research, Division of Allergy, Asthma and Immunology Allegheny General Hospital, Pittsburgh, PA Associate Professor of Pediatrics Drexel University School of Medicine Philadelphia, PA 11: Allergy and Immunology

Brian Fligor, ScD

Mark E. Gerber, MD

Director of Diagnostic Audiology Instructor of Otology and Laryngology Department Audiology/Otolaryngology and Communication Enhancement Harvard Medical School Boston, MA 23: The Assessment of Hearing and Middle-Ear Function in Children

Director, Pediatric Otolaryngology- Head/Neck Surgery NorthShore University Health System Clinical Associate Professor The University of Chicago Pritzker School of Medicine NorthShore University Health System Northbrook, IL 89: Congenital Laryngeal Anomalies

Sylvia A. Frazier-Bowers, DDS, PhD

Pediatric Otolaryngology Division of Otolaryngology/Ear, Nose and Throat Maimonides Infants & Children’s Hospital Associate Professor, State University of New York (Downstate) Brooklyn, New York 105: Cervical Adenopathy

Tamara Feygin, MD

Associate Professor Department of Orthodontics School of Dentistry University of North Carolina at Chapel Hill Chapel Hill, NC 68: Orthodontic Problems in Children

Patrick Froehlich, MD Sainte-Justine Hospital Service d’ORL Montreal, Quebec Canada 87: Aspiration: Etiology and Management

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Ari J. Goldsmith, MD

Edward J. Goldson, MD Professor, Department of Pediatrics University of Colorado Medical School Children’s Hospital Colorado Aurora, CO 7: Pediatric Otolaryngology: A Psychosocial Perspective

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Author Listing Amy C. Goldstein, MD

Michael S. Haupert, DO, MBA

Assistant Professor of Pediatrics University of Pittsburgh School of Medicine Director, Neurogenetics and Metabolism Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 12: Pediatric Neurology

Chief, Otolaryngology Associate Clinical Professor, Wayne State University Children’s Hospital of Michigan Detroit, MI 47: Nasal Obstruction and Rhinorrhea

Nira A. Goldstein, MD

Professor of Otology & Laryngology Harvard Medical School Emeritus Healy Chair in Otolaryngology Boston Children’s Hospital Emeritus Surgeon-in-Chief Boston Children’s Hospital Boston, MA Past President, American College of Surgeons 45: Methods of Examination of the Nose, Paranasal Sinuses, Face, and Orbit

Associate Professor, Division of Pediaric Otolaryngology State University of New York Downstate Medical Center Brooklyn, NY 60: The Mouth, Pharynx, and Esophagus

Carlos Gonzalez, MD, FACS Professor and Chairman, Otolaryngology Head and Neck Surgery University of Puerto Rico School of Medicine Chief of Surgery, San Jorge Children’s Hospital San Juan, Puerto Rico 73: Tumors of the Mouth and Pharynx

Alka Goyal, MD Department of Gastroenterology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 76: Eosinophilic Esophagitis

Lorelei J. Grunwaldt, MD Director, Vascular Anomalies Center Director, Brachial Plexus Clinic Division of Pediatric Plastic Surgery Children’s Hospital of Pittsburgh of UPMC Assistant Professor of Surgery Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 113: Pediatric Plastic Surgery of the Head and Neck

Joseph Haddad Jr., MD Professor and Howard W. Smith Interim Chairman Department of Otorhinolaryngology – Head/Neck Surgery Columbia University Medical Center Children’s Hospital of New York New York, NY 101: Methods of Examination of the Head and Neck

Steven D. Handler, MD, MBE Professor of Otorhinolaryngology: Head and Neck Surgery The Children’s Hospital of Philadelphia Philadelphia, PA 62: Methods of Examination of the Mouth, Pharynx, and Esophagus

Christopher J. Hartnick, MD, MSEpi Professor of Otology and Laryngology Harvard Medical School Division Director, Pediatric Otolaryngology Director, Pediatric Airway, Voice and Swallowing Center Chief Quality Officer for Otolaryngology Massachusetts Eye and Ear Infirmary Boston, MA 4: Outcomes and Evidence-Based Medicine in Pediatric Otolaryngology

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Gerald B. Healy, MD, FACS, FRCS (Eng), FRCS (Ire)

Michael S. Hildebrand, PhD NHMRC CJ Martin Fellow, Epilepsy Research Center Department of Medicine University of Melbourne Melbourne, Australia 30: Genetic Hearing Loss and Inner Ear Diseases

Keiko Hirose, MD Associate Professor, Otolaryngology–Head and Neck Surgery Division Director, Pediatric Otolaryngology Washington University School of Medicine St. Louis, MO 20: Embryology and Developmental Anatomy of the Ear

Barry E. Hirsch, MD, FACS Professor, Departments of Otolaryngology, Neurologic Surgery, and Communication Science & Disorders Director, Division of Otology & Neurotology University of Pittsburgh School of Medicine Pittsburgh, PA 36: Diseases of the External Ear

Jenő Hirschberg, MD, PhD, DSc Professor, Division of Pediatric Otorhinolaryngology and Bronchology Saint John’s Hospital Budapest, Hungary 86: Stridor: Presentation and Evaluation

Andrew J. Hotaling, MD Chief, Section of Pediatric Otolaryngology Professor, Departments of Pediatrics and Otolaryngology–Head and Neck Surgery Loyola University Medical Center Maywood, IL 75: Functional Abnormalities of the Esophagus 85: Cough

Anne F. Hseu, MD Department of Otolaryngology Cleveland Clinic Children’s Hospital Head and Neck Institute Cleveland, OH 28: Tinnitus in Children

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Author Listing

Murad Husein, MD

Sarah E. Keesecker, MD

Associate Professor and Undergraduate Director Department of Otolaryngology–Head and Neck Surgery London Health Sciences Centre–Victoria Hospital London, Ontario, Canada 30: Genetic Hearing Loss and Inner Ear Diseases

Columbia University Medical Center New York, NY 101: Methods of Examination of the Head and Neck

Glenn Isaacson, MD, FACS, FAAP Professor, Otolaryngology–Head and Neck Surgery Assistant Professor, Pediatrics Director, Pediatric Otolaryngology Temple University School of Medicine Philadelphia, PA 81: Developmental Anatomy and Physiology of the Larynx, Trachea, Esophagus, and Lungs

James J. Jaber, MD, PhD Assistant Professor, Department of Otolaryngology–Head & Neck Surgery Head and Neck Surgical Oncology Loyola University Medical Center Maywood, IL 85: Cough

Ian N. Jacobs, MD Director, The Center for Pediatric Airway Disorders The Children’s Hospital of Philadelphia Associate Professor, Otorhinolaryngology: Head and Neck Surgery University of Pennsylvania School of Medicine Philadelphia, PA 90: Congenital Malformations of the Trachea and Bronchi

Luv R. Javia, MD Cochlear Implant Program Center for Pediatric Airway Disorders, Children’s Hospital of Philadelphia Assistant Professor of Clinical Otorhinolaryngology/Head & Neck Surgery University of Pennsylvania Perelman School of Medicine Philadelphia, PA 90: Congenital Malformations of the Trachea and Bronchi

Ken Kazahaya, MD, MBA, FACS Associate Director, Division of Pediatric Otolarynology Director, Pediatric Skull Base Surgery Medical Director, Cochlear Implant Program Co-Lead Surgeon, Pediatric Thyroid Center Children’s Hospital of Philadelphia Associate Professor of Clinical Otolaryngology Department of Otorhinolaryngology/Head &Neck Surgery University of Pennsylvania Perelman School of Medicine Philadelphia, PA 46: Imaging of the Paranasal Sinuses in Pediatric Patients With Special Considerations for Endoscopic Sinus Surgery

Melanie A. Kazlas, MD Director, Pediatric Ophthalmology & Strabismus Service Massachusetts Eye and Ear Infirmary Instructor, Harvard Medical School Boston, MA 13: Pediatric Ophthalmology

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Peggy E. Kelley, MD, FACS, FAAP Associate Professor University of Colorado at Denver Health Science Center Department of Pediatric Otolaryngology Children’s Hospital Colorado Aurora, CO 110: Injuries of the Neck

David T. Kent, MD Resident, Department of Otolaryngology–Head & Neck Surgery University of Pittsburgh Medical Center Pittsburgh, PA 101: Methods of Examination of the Head and Neck

Ana H. Kim, MD Associate Professor, New York Medical College Director of Otologic Research Otology, Neurotology, Skull Base New York Eye and Ear Infirmary New York, NY 41: Injuries of the Ear and Temporal Bone

Karen Iler Kirk, PhD, CC-SLP, ASHA Fellow Shahid and Ann Carlson Khan Professor Head, Department of Speech and Hearing Science University of Illinois Champaign-Urbana Champaign, IL 33: Cochlear Implants in Children

Jerome O. Klein, MD Professor of Pediatrics Department Pediatric Infectious Disease Boston University School of Medicine Boston, MA 22: Methods of Clinical Examination: Ear and Related Structures 37: Otitis Media and Eustachian Tube Dysfunction 38: Complications and Sequelae of Otitis Media

Peter J. Koltai MD, FACS, FAAP Professor and Chief Division of Pediatric Otolaryngology Stanford University School of Medicine Lucile Packard Children’s Hospital Stanford, CA 86: Stridor: Presentation and Evaluation

Maria Koutourousiou, MD Clinical Instructor Department of Neurosurgery University of Pittsburgh School of Medicine Pittsburgh, PA 115: Pediatric Skull Base Surgery

Nicolas Leboulanger, MD Pediatric Otolaryngology–Head and Neck Surgery Department Armand Trousseau Children Hospital Paris, France 92: Acquired Disorders of the Larynx and Trachea

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Author Listing Gi Soo Lee, MD, EdM

David N. Madgy, DO

Clinical Instructor Department of Otology and Laryngology Harvard Medical School Boston Children’s Hospital Boston, MA 45: Methods of Examination of the Nose, Paranasal Sinuses, Face, and Orbit

Chief of Otolaryngology Children’s Hospital of Michigan–Detroit Associate Clinical Professor, Pediatrics Wayne State University Detroit, MI 47: Nasal Obstruction and Rhinorrhea

Greg Licameli, MD, MHCM

Professor, Department of Surgery University of California, San Diego San Diego, CA 59: Tumors of the Nose, Paranasal Sinuses, and Nasopharynx

Associate in Otolaryngology Director, Cochlear Implant Team Boston Children’s Hospital Assistant Professor of Otology and Laryngology Harvard Medical School Boston, MA 26: Otalgia

Aaron C. Lin, MD Assistant Professor Division of Pediatric Otolaryngology University of Southern California Keck School of Medicine Children’s Hospital of Los Angeles Los Angeles, CA 86: Stridor: Presentation and Evaluation

Ingrid Loma-Miller, MD Assistant Professor of Pediatrics Eastern Virginia Medical Center Pediatric Neurology Children’s Hospital of the King’s Daughters Norfolk, VA 80: Neurologic Disorders of the Mouth, Pharynx, and Esophagus

Joseph E. Losee, MD, FAAP, FACS Professor of Surgery and Pediatrics Chief, Pediatric Plastic Surgery Director, Pittsburgh Cleft-Craniofacial Center Program Director, Plastic Surgery Residency Division of Pediatric Plastic Surgery Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 113: Pediatric Plastic Surgery of the Head and Neck

Rodney P. Lusk, MD, FACS Director ENT Institute Boys Town National Research Hospital Omaha, NE 54: Surgical Management of Chronic Rhinosinusitis 103: Neck Masses

Andrew MacGinnitie, MD, PhD Division of Immunology, Boston Children’s Hospital Department of Pediatrics Harvard Medical School Boston, MA 56: Allergic Rhinitis

John Maddalozzo, MD, FACS Professor of Otolaryngology–Head and Neck Surgery Children’s Hospital of Chicago Research Center Northwestern University Feinberg School of Medicine Chicago, IL 109: Thyroid

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Anthony E. Magit, MD, MPH

Scott C. Manning, MD Division Chief, Otolaryngology Head and Neck Surgery Program Director, Otolaryngology Education Professor, Pediatric Otolaryngology Head and Neck Surgery Seattle Children’s Hospital Seattle, Washington, DC 48: Epistaxis 77: Foreign Bodies of the Pharynx and Esophagus

Belinda A. Mantle, MD Director, Pediatric Otolaryngology Osborne Head and Neck Institute Los Angeles, CA 49: Pediatric Headaches

Brian S. Martin, DMD, MS Chief, Division of Pediatric Dentistry Children’s Hospital of Pittsburgh of UPMC Clinical Assistant Professor University of Pittsburgh School of Dental Medicine Pittsburgh, PA 67: Dental and Gingival Disorders

Bruce J. Masek, PhD, ABPP Clinical Director Emeritus, Outpatient Child and Adolescent Psychiatry Massachusetts General Hospital Associate Professor of Psychology (Psychiatry) Harvard Medical School Boston, MA 8: Psychiatric Disorders in Pediatric Otolaryngology

John G. Meara, MD, DMD, MBA Plastic Surgeon-in-Chief Department of Plastic and Oral Surgery Boston Children’s Hospital Boston, MA 111: Craniofacial Development and Congenital Anomaly: A Contemporary Review of Processes and Pathogenesis

Claire Kane Miller, PhD Program Director, Division of Speech-Language Pathology University of Cincinnati College of Medicine Cincinnati, OH 74: Pediatric Dysphagia

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xxii

Author Listing

Ron Mitchell, MD

Roger C. Nuss, MD, FACS

Professor of Otolaryngology and Pediatrics University of Texas Southwestern Medical Center William Beckner Distinguished Chair in Otolaryngology Children’s Medical Center Dallas, TX 65: Tonsillectomy and Adenoidectomy

Assistant Professor, Department of Otology & Laryngology Harvard Medical School Director, Pediatric Voice & Airway Disorders Boston Children’s Hospital Boston, MA 118: Pediatric Voice Disorders: Evaluation and Treatment

Makoto Miura, MD, DMSc

Laurie A. Ohlms, MD

Director, Department of Otolaryngology Japanese Red Cross Society Wakayama Medical Center Wakayama-city, Japan 34: Congenital Anomalies of the External and Middle Ears

Boston Children’s Hospital Department of Otolaryngology Boston, MA 5: Ethical Issues in Pediatric Otolaryngology

Richard T. Miyamoto, MD

Samuel T. Ostrower, MD, FAAP

Arilla Spence DeVault Professor and Chairman Department of Otolaryngology–Head and Neck Surgery Indiana University School of Medicine Indianapolis, IN 33: Cochlear Implants in Children

R. Christopher Miyamoto, MD, FACS, FAAP Pediatric Otolaryngology Peyton Manning Children’s Hospital Assistant Professor of Clinical Pediatrics and Otolaryngology–Head & Neck Surgery Indiana University School of Medicine Indianapolis, IN 33: Cochlear Implants in Children

Carl W. Moeller, MD Private Practice, Otorhinolaryngology Hartford, CT 75: Functional Abnormalities of the Esophagus

Pamela Anne Mudd, MD Pediatric Otolaryngology Fellow University of Colorado Hospital Denver, CO 42: Tumors of the Ear and Temporal Bone

Robert M. Naclerio, MD Professor and Chief Otolaryngology–Head and Neck Surgery University of Chicago Chicago, IL 44: Nasal Physiology

M. M. Nazif, DDS, MDS Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 67: Dental and Gingival Disorders

Marilyn W. Neault, PhD, PASC, CISC Director, Habilitative Audiology Program Boston Children’s Hospital Assistant Professor of Otology and Laryngology Harvard Medical School Boston, MA 122: Auditory Access to Language Resulting from Cochlear Implant Technology

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Medical Director Department of Pediatric Otolaryngology–Head & Neck Surgery Joe DiMaggio Children’s Hospital, Hollywood, Florida Affiliate Assistant Professor Florida Atlantic University Charles E. Schmidt College of Medicine Boca Raton, Florida 94: Pediatric Airway Stenosis: Minimally Invasive Approaches

Nathan Page, MD Arizona Otolaryngology Consultants Phoenix, AZ 20: Embryology and Developmental Anatomy of the Ear

Michael Painter, MD, ABPN Professor of Neurology and Pediatrics University of Pittsburgh School of Medicine Director of Neurodevelopment Disabilities Program Division of Neurology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 80: Neurologic Disorders of the Mouth, Pharynx, and Esophagus

Harshita Pant, BMBS, PhD Departments of Otolaryngology and Medicine The University of Adelaide Adelaide, Australia 115: Pediatric Skull Base Surgery

Sanjay R. Parikh, MD, FAAP, FACS Medical Director, Surgical Specialties Bellevue Clinic and Surgery Center Seattle Children’s Hospital Associate Professor Department of Otolaryngology–Head and Neck Surgery University of Washington Seattle, Washington 55: Complications of Nasal and Sinus Infections

Simon C. Parisier, MD Professor Emeritus, Department of Otolaryngology New York Eye and Ear Infirmary New York, NY 41: Injuries of the Ear and Temporal Bone

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Author Listing Desiderio Passali, MD

J. Christopher Post, MD, PhD, FACS

Chair of Ear, Nose and Throat University of Siena Siena, Italy 57: Foreign Bodies of the Nose ENT Consultant/Honorary Senior Lecturer Sligo General Hospital Sligo, Ireland 64: Inflammatory Disease of the Mouth and Pharynx

President and Chief Scientific Officer Allegheny-Singer Research Institute Medical Director, Center for Genomic Sciences Director Pediatric Otolaryngology Allegheny General Hospital Pittsburgh, PA Professor of Otolaryngology and Microbiology at Drexel College of Medicine and Temple University School of Medicine Philadelphia, PA 16: The Role of Biofilms in Pediatric Otolaryngologic Diseases

Susan E. Pearson, MD, FAAP, FACS

William P. Potsic, MD, MMM

Naishadh Patil, FRCS

Pediatric Otolaryngology Consultant, Mayo Clinic Health System Clinical Assistant Professor University of Minnesota School of Medicine Mankato, MN 97: Diagnosis and Management of Pediatric Laryngotracheal Trauma

Stephen I. Pelton, MD Professor of Pediatrics and Epidemiology Director, Section of Pediatric Infectious Disease Boston University School of Medicine Boston, MA 15: Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections

Kalliopi Petropoulou, MD Assistant Professor Diagnostic Radiology and Neuroradiology University of Pittsburgh Pittsburgh, PA 102: Imaging of Pediatric Neck Masses

Erin M. Picou, PhD Associate Professor and Director of Graduate Studies Department of Speech and Hearing Sciences Vanderbilt University Medical Center Nashville, TN 120: Amplification Selection for Children With Hearing Impairment

Carlos D. Pinheiro-Neto, MD, PhD Department of Otolaryngology Albany Medical Center Assistant Professor of Surgery, Albany Medical College Albany, NY 115: Pediatric Skull Base Surgery

Avrum N. Pollock, MD, FRCPC Pediatric Neuroradiologist and Pediatric Radiologist The Children’s Hospital of Philadelphia Associate Professor of Clinical Radiology Perelman School of Medicine University of Pennsylvania Philadelphia, PA 24: Methods of Examination: Radiologic Aspects 84: Radiologic Evaluation of the Pediatric Airway

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Emeritus Professor CE of Otorhinolaryngology: Head and Neck Surgery Attending Otolaryngologist and Vice Chairman for Clinical Affairs, Department of Surgery Senior Surgeon, Division of Otolaryngology The Children’s Hospital of Philadelphia Philadelphia, PA 62: Methods of Examination of the Mouth, Pharynx, and Esophagus

Jeremy D. Prager, MD, FACS Co-Director, Aero-digestive Program Department of Pediatric Otolaryngology Children’s Hospital Colorado Assistant Professor, Colorado University School of Medicine Aurora, CO 117: Velopharyngeal Insufficiency

Seth M. Pransky, MD Director, Pediatric Otolaryngology Rady Children’s Specialist Medical Foundation Clinical Professor of Surgery Division of Otolaryngology, University of California School of Medicine San Diego, CA 98: Tumors of the Larynx, Trachea, and Bronchi

Sheila Pratt, PhD Department of Communication Science & Disorders University of Pittsburgh Geriatric Research and Education Clinical Center VA Pittsburgh Healthcare System Pittsburgh, PA 121: Behavorial Intervention and Education of Children With Hearing Loss

Diego Preciado, MD, PhD Associate Professor Departments of Pediatrics and Surgery George Washington University School of Medicine and Health Sciences Children’s National Medical Center Center for Genetic Medicine Research (CGMR) Washington, DC 40: Diseases of the Labyrinthine Capsule

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Author Listing

Evan J. Propst, MD, MSc, FRCSC

Michael Rontal, MD

Assistant Professor Department of Otolaryngology–Head and Neck Surgery University of Toronto and Hospital for Sick Children Toronto, Ontario, Canada 95: Airway Surgery: Open Approach

Otolaryngologist Rontal-Akervall Clinic Farmington Hills, Michigan 43: Embryology and Anatomy of the Paranasal Sinuses

Philip E. Putnam, MD, FAAP

Division of Pediatric Rheumatology, Department of Pediatrics Nemours/Alfred I. duPont Hospital for Children Wilmington, DE 70: Oral Cavity and Oropharyngeal Manifestations of Systemic Disease

Professor of Pediatrics Division of Gastroenterology, Hepatology, and Nutrition Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine Cincinnati, OH 17: Pediatric Gastroenterology

Jeff C. Rastatter, MD Assistant Professor in Otolaryngology–Head & Neck Surgery Children’s Memorial Hospital Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, IL 109: Thyroid

Mark A. Richardson, MD, FACS Department of Otolaryngology Oregon Health & Science School of Medicine Portland, OR 100: The Neck: Embryology and Anatomy

Todd A. Ricketts, PhD Associate Professor and Director of Graduate Studies Department of Speech and Hearing Sciences Vanderbilt University Medical Center Nashville, TN 120: Amplification Selection for Children With Hearing Impairment

Frank L. Rimell, MD Associate Professor, Pediatric Otolaryngology University of Minnesota Pediatric Otolaryngologist Children’s Hospital and Clinics of Minnesota Minneapolis, MN 97: Diagnosis and Management of Pediatric Laryngotracheal Trauma

A. Kim Ritchey, MD Vice Chairman for Clinical Affairs and Professor Department of Pediatrics Division of Hematology/Oncology University of Pittsburgh School of Medicine Pittsburgh, PA 14: Pediatric Hematology: The Coagulation System and Associated Disorders

David W. Roberson, MD, FACS Associate Professor of Otology and Laryngology Harvard Medical School Boston Children’s Hospital Boston, MA 106: Head and Neck Space Infections

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Paul Rosen, MD

Richard M. Rosenfeld, MD, MPH Professor and Chairman of Otolaryngology State University of New York (Downstate) Brooklyn, NY 105: Cervical Adenopathy

Robert J. Ruben, MD, FAAP, FACS Distinguished University Professor Departments of Otorhinolaryngology–Head and Neck Surgery and Pediatrics Albert Einstein College of Medicine Montefiore Medical Center New York, NY 1: Evolution of Pediatric Otolaryngology

Ramon L. Ruiz, DMD, MD Director, Craniofacial and Pediatric Oral and Maxillofacial Surgery Arnold Palmer Children’s Hospital Orlando, FL 19: Pediatric Oral and Maxillofacial Surgery: Craniofacial Growth and Interdisciplinary Surgical Care

John Russell, MCh Surgery, FRCSI, FRCS (ORL) Pediatric Otolaryngology Our Lady’s Children Hospital, Crumlin Dublin, Ireland 64: Inflammatory Disease of the Mouth and Pharynx

Michael J. Rutter, MD Pediatric Otolaryngologist and Director of Clinical Research Cincinnati Children’s Hospital Medical Center Professor, Department of Pediatrics Professor, Otolaryngology–Head and Neck Surgery University of Cincinnati College of Medicine Cincinnati, OH 95: Airway Surgery: Open Approach

Asli Sahin-Yilmaz, MD Associate Professor, Otolaryngology Clinic Umraniye Education and Research Hospital Istanbul, Turkey 44: Nasal Physiology

Isamu Sando, MD, DMSc Emeritus Professor, Department of Otolaryngology University of Pittsburgh Pittsburgh, PA 34: Congenital Anomalies of the External and Middle Ears

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Author Listing Sonal Saraiya, MD

James D. Sidman, MD

Pediatric–Otolaryngology Children’s Hospital of Michigan Detroit, MI 47: Nasal Obstruction and Rhinorrhea

Professor of Otolaryngology and Pediatrics University of Minnesota Children’s Hospitals and Clinics of Minnesota Minneapolis, MN 97: Diagnosis and Management of Pediatric Laryngotracheal Trauma

Barry M. Schaitkin, MD, FACS Professor of Otolaryngology University of Pittsburgh School of Medicine Residency Program Director Department of Otolaryngology Eye and Ear Institute of Pittsburgh Pittsburgh, PA 39: Facial Paralysis in Children

Navil F. Sethna, MD, FAAP Associate Professor of Anesthesiology, Harvard Medical School Senior Anesthesiologist, Perioperative and Pain Medicine Clinical Director, Mayo Family Pediatric Pain Rehabilitation Center Boston Children’s Hospital Boston, MA 50: Oral and Facial Neuropathic Pain in Children

Rahul K. Shah, MD, FACS, FAAP Associate Professor, Departments of Pediatrics and Surgery George Washington University School of Medicine and Health Sciences Children’s National Medical Center Washington, DC 6: Professionalism, Communication, and Teamwork in Surgery 40: Diseases of the Labyrinthine Capsule

Nina L. Shapiro, MD Professor, Department of Otolaryngology Head & Neck Surgery David Geffen School of Medicine at UCLA Los Angeles, CA 51: Orbital Swellings

Andrew M. Shapiro, MD Clinical Associate Professor Departments of Surgery & Pediatrics Pennsylvania State University College of Medicine Hershey, PA 58: Injuries of the Nose, Facial Bones and Paransal Sinuses

A. Eliot Shearer, MD, PhD Department of Otolaryngology–Head & Neck Surgery University of Iowa Carver College of Medicine University of Iowa Iowa City, IA 30: Genetic Hearing Loss and Inner Ear Diseases

Jennifer J. Shin, MD, SM Massachusetts Eye and Ear Infirmary Boston, MA 4: Outcomes and Evidence-Based Medicine in Pediatric Otolaryngology

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Kathleen C.Y. Sie, MD Professor, Otolaryngology/Head & Neck Surgery University of Washington School of Medicine Richard and Francine Endowed Chair in Childhood Communication Research Seattle Children’s Hospital Seattle, Washington, DC 100: The Neck: Embryology and Anatomy

Rodrigo C. Silva, MD University of Florida College of Medicine Department of Otolaryngology UF Health Shands Children’s Hospital Gainesville, FL 70: Oral Cavity and Oropharyngeal Manifestations of Systemic Disease

Jeffrey P. Simons, MD, FACS, FAAP Associate Professor of Otolaryngology University of Pittsburgh School of Medicine Division of Pediatric Otolaryngology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 70: Oral Cavity and Oropharyngeal Manifestations of Systemic Disease 78: Trauma to the Mouth, Pharynx, and Esophagus in Children 79: Caustic Injuries and Acquired Strictures of the Esophagus

John T. Sinacori, MD, FACS Assistant Professor, Department of Otolaryngology Director, Voice and Swallowing Center Eastern Virginia Medical School Norfolk, VA 61: Physiology of the Mouth, Pharynx, and Esophagus

Margaret L. Skinner, MD Division of Pediatric Otolaryngology–Head and Neck Surgery Johns Hopkins Medical Institutions Baltimore, MD 112: Primary Care of Infants and Children With Cleft Palate

David P. Skoner, MD Director, Division of Allergy, Asthma and Immunology Professor of Medicine Temple University School of Medicine Pittsburgh, PA 11: Allergy and Immunology

Richard J.H. Smith, MD Professor of Otolaryngology, Pediatrics, Internal Medicine, Molecular Physiology, and Biophysics University of Iowa Carver College of Medicine Iowa City, IA 30: Genetic Hearing Loss and Inner Ear Diseases

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Author Listing

Carl H. Snyderman, MD, MBA

Anne Chun-Hui Tsai, MD, MSc, FAAP, FACMG

Department of Otolaryngology Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh, PA 115: Pediatric Skull Base Surgery

Director, CDRC Genetics Chief of Pediatric Genetics Oregon Health and Sciences University Portland, OR 2: Phylogenetic Aspects and Embryology 3: Genetics, Syndromology, and Craniofacial Anomalies

Jonathan E. Spahr, MD Associate Professor of Pediatrics University of Pittsburgh School of Medicine Clinical Director, Pediatric Pulmonology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 18: Pediatric Pulmonology

David E. Tunkel, MD

Jeffrey D. Suh, MD

Assistant Professor of Neurological Surgery and Bioengineering University of Pittsburgh School of Medicine Children’s Hospital of Pittsburgh of UPMC Pittsburgh, PA 115: Pediatric Skull Base Surgery

Assistant Professor, Rhinology and Skull Base Surgery David Geffen School of Medicine at UCLA Los Angeles, CA 51: Orbital Swellings

Anne Marie Tharpe, PhD Associate Professor and Director of Graduate Studies Department of Speech and Hearing Sciences Vanderbilt University Medical Center Nashville, TN 120: Amplification Selection for Children With Hearing Impairment

Dana Mara Thompson, MD, MS, FACS

Division of Pediatric Otolaryngology–Head and Neck Surgery Johns Hopkins University School of Medicine Baltimore, MD 112: Primary Care of Infants and Children With Cleft Palate

Elizabeth C. Tyler-Kabara, MD, PhD

Dale Amanda Tylor, MD, MPH Assistant Professor of Otolaryngology Vanderbilt University Medical Center Division of Otolaryngology Washington Township Medical Foundation Fremont, CA 98: Tumors of the Larynx, Trachea, and Bronchi

Division Head, Pediatric Otolaryngology, Ann & Robert H. Lurie Children’s Hospital of Chicago Professor of Otolaryngology Northwestern University Feinberg School of Medicine Chicago, IL 88: Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease

Gilbert Vézina, MD

Robert J. Tibesar, MD

Frank W. Virgin, MD

Pediatric ENT and Facial Plastic Surgery Children’s Hospital of Minnesota Assistant Professor, Department of Otolaryngology-Head and Neck Surgery University of Minnesota Medical School Minneapolis, MN 97: Diagnosis and Management of Pediatric Laryngotracheal Trauma

Assistant Professor, Division of Pediatric Otolaryngology Vanderbilt University School of Medicine Pediatric Otolaryngology Monroe Carell Jr. Children’s Hospital Nashville, TN 26: Otalgia

Associate Professor of Radiology and Pediatrics The George Washington University School of Medicine and Health Sciences Children’s National Medical Center Washington, DC 40: Diseases of the Labyrinthine Capsule

Arastoo Vossough, MD, PhD

Attending Surgeon The Children’s Hospital of Philadelphia Philadelphia, PA 62: Methods of Examination of the Mouth, Pharynx, and Esophagus

Adult and Pediatric Neuroradiologist Children’s Hospital of Philadelphia Assistant Professor of Radiology Perelman School of Medicine at University of Pennsylvania Philadelphia, PA 24: Methods of Examination: Radiologic Aspects

Sharon Marie Tomaski, MD

David B. Waisel, MD

Division of Pediatric Otolaryngology–Head & Neck Surgery Marietta Memorial Hospital Marietta, Ohio 60: Embryology and Anatomy of the Mouth, Pharynx, and Esophagus

Chairman, Fellow Selection Committee MOR Program Director Boston Children’s Hospital Boston, MA 5: Ethical Issues in Pediatric Otolaryngology

Lawrence W.C. Tom, MD, FACS

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Author Listing Ellen R. Wald, MD

J. Paul Willging, MD

Department of Pediatrics University of Wisconsin School of Medicine and Public Health Madison, WI 53: Rhinitis and Acute and Chronic Sinusitis

Director, Interdisciplinary Feeding Team FEES Clinic and the Velopharyngeal Insufficiency Clinic Cincinnati Children’s Hospital Medical Center Professor, Department of Pediatrics Professor, Otolaryngology–Head and Neck Surgery University of Cincinnati School of Medicine Cincinnati, OH 74: Pediatric Dysphagia 117: Velopharyngeal Insufficiency

Carol Walton, MS, CGC Director, Graduate Program in Genetic Counseling Associate Professor, Pediatrics University of Colorado–Anschutz Medical Campus Aurora Children’s Hospital Colorado Aurora, CO 2: Phylogenetic Aspects and Embryology 3: Genetics, Syndromology, and Craniofacial Anomalies

Eric W. Wang, MD Assistant Professor Department of Otolaryngology University of Pittsburgh School of Medicine Pittsburgh, PA 115: Pediatric Skull Base Surgery

Karen F. Watters, MB, BCh, MPH Instructor, Otology & Laryngology Harvard Medical School Attending, Department of Otolaryngology and Communication Enhancement Boston Children’s Hospital Boston, MA 107: Benign Tumors of the Head and Neck

Jay A. Werkhaven, MD Associate Professor and Director of Analytics Department of Otolaryngology Vanderbilt University Medical Center Nashville, TN 99: Laser Surgery

Ralph F. Wetmore, MD Chief, Division of Otolaryngology The Children’s Hospital of Philadelphia E. Mortimer Newlin Professor of Pediatric Otolaryngology Director, Pediatric Otolaryngology Fellowship Program Professor of Otorhinolaryngology–Head and Neck Surgery Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA 93: Pediatric Tracheotomy

Susan L. Whitney, PhD, PT, ATC Associate Professor Departments of Otolaryngology and Physical Therapy Director of Vestibular Rehabilitation Program Centers for Rehab Services, Eye & Ear Institute Pittsburgh, PA 25: Vestibular Evaluation

Kenneth R. Whittemore Jr., MD, MS Associate in Otolaryngology Department of Otolaryngology & Communication Enhancement Boston Children’s Hospital Boston, MA 108: Malignant Tumors of the Head and Neck

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Robert E. Wood, MD, PhD Professor, Pediatrics and Otolaryngology Director, Pulmonary Bronchology Division of Pulmonary Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, OH 82: Physiology of the Larynx, Airways, and Lungs

Geralyn Harvey Woodnorth, MA, CCC-SLP Director, Speech-Language Pathology Program Department of Otolaryngology and Communication Enhancement Boston Children’s Hospital Boston, MA 118: Pediatric Voice Disorders: Evaluation and Treatment

J. Scott Yaruss, PhD Associate Professor Director, MA/MS Programs in Speech-Language Pathology University of Pittsburgh Pittsburgh, PA 116: Disorders of Language, Phonology, Fluency, and Voice in Children: Indicators for Referral

Noriko Yoshikawa, MD Otolaryngology Head and Neck Surgery Oakland Medical Center Oakland, CA 36: Diseases of the External Ear

S. James Zinreich, MD Professor of Radiology Division of Neuroradiology Johns Hopkins Hospital Baltimore, MD 43: Embryology and Anatomy of the Paranasal Sinuses

Basil J. Zitelli, MD Edmund R. McCluskey Professor of Pediatric Medical Education University of Pittsburgh School of Medicine Chief, The Paul C. Gaffney Diagnostic Referral Service Children’s Hospital of Pittsburgh Pittsburgh, PA 9: Munchausen Syndrome by Proxy

Karen B. Zur, MD Assistant Professor Department of Otolaryngology–Head & Neck Surgery Perelman School of Medicine University of Pennsylvania Director, Pediatric Voice Clinic Associate Director, Center for Pediatric Airway Disorders Children’s Hospital of Philadelphia Philadelphia, PA 62: Methods of Examination of the Mouth, Pharynx, and Esophagus

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Foreword

In 1972, I accepted the position of first academic chairman of the Department of Otolaryngology at the University of Pittsburgh. I realized that the two greatest regional assets that could contribute to developing the most outstanding otolaryngology department in the country were the Eye and Ear Hospital of Pittsburgh and the Children’s Hospital of Pittsburgh next door. I was determined to create a Department of Pediatric Otolaryngology, although at that time Children’s Hospital in Boston had the only such department. My training at the Massachusetts Eye and Ear Infirmary and rotations at Children’s Hospital Boston had shown me the enormous value of developing professionals dedicated to caring for children with diseases of the ear, nose, and throat. One of the first doctors I recruited to the faculty was Charles D. Bluestone, whose passion and enthusiasm for pediatric otolaryngology was boundless. He promised to make the Department of Otolaryngology at Children’s Hospital of Pittsburgh the best in the world. Shortly after his arrival, we recruited Sylvan Stool to join us, and the team of Bluestone and Stool became recognized as the founding fathers of the specialty of pediatric otolaryngology. Our Department of Pediatric Otolaryngology offers a full range of expertise in the field, but there is a special emphasis on Bluestone’s particular area of research and interest—the problems of otitis media and middle-ear effusion. He founded the Otitis Media Research Center (generously funded by the National Institutes of Health since 1978), which has a multidisciplinary research team combining the efforts of both basic and clinical scientists to develop new hypotheses which have resulted in improved patient care methods for children with diseases of the middle ear. The first edition of Pediatric Otolaryngology by Bluestone and Stool, published exactly 30 years ago in 1983, was the first book dedicated specifically to pediatric otolaryngology. It was a single-volume text oriented to diseases in this specialty and emphasizing concepts rather than techniques. The authors were the “all-star” team of otolaryngology, since pediatric otolaryngology was not yet recognized as a subspecialty. Colleagues from other specialties wrote outstanding chapters in related fields. The 5th edition of the book has doubled in size and is now a two-volume text, including a new section devoted to basic science, general pediatric otolaryngology and other pediatric subspecialty areas. Unfortunately, many of the original authors have retired or are in the “big operating room in the sky,” but an impressive group of new authors has contributed chapters. Many of these authors are graduates of the two-year Fellowship Training Program established by Bluestone and Stool. They now serve as chiefs of divisions of pediatric otolaryngology and as department chairs. Diagnostic imaging chapters in each subspecialty section present hundreds of new diagnostic CTs and MRIs. Such chapters were nonexistent in the 1st edition, because CT scans and other imaging techniques had not yet come into general use. Dr. Charles Ferguson, senior otolaryngologist at Children’s Hospital in Boston, wrote the foreword to the first edition in 1983. He was a pioneer in the field of otolaryngic care of children, and I had the good fortune to meet him during my residency at Massachusetts Eye and Ear Infirmary. We became good friends and colleagues. In that first foreword, he wrote: “The evolution of Pediatric Otolaryngology as a true subspecialty is a lifetime dream fulfilled. It is most exciting and also gratifying to know that there are now over a score of otolaryngologists who devote over 80% of their professional time to this specialty.” It has been extraordinary to witness the tremendous growth of our specialty with thousands of pediatric otolaryngologists around the world and the growth of knowledge that has greatly improved the care of children with pediatric otolaryngic disorders. This 5th edition reflects the accumulated knowledge and clinical skill acquired over the past 30 years. I congratulate Dr. Bluestone and his team for persevering and producing another outstanding edition of this extraordinary text. Eugene N. Myers, MD, FACS, FRCS Edin (Hon) Distinguished Professor and Emeritus Chair Department of Otolarygnology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

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Preface

It is with great pride and excitement that we publish this fifth edition of Pediatric Otolaryngology three decades after the first edition in 1983. This edition reflects the current state of knowledge and practice in pediatric otolaryngology, a subspecialty that has dramatically grown along with our textbook. This edition includes 29 new chapters and 141 new authors (217 total authors), a new section on Basic Science and General Pediatric Otolaryngology, and new addition of color. All authors and the 14 section editors (names listed on the front cover and title page) are authorities in their respective fields. Without the hard work and devotion of these section editors, this fifth edition would not have become a reality. They devoted countless hours recruiting new authors and peer-reviewing and editing each chapter. We sadly regret that the late Sylvan E. Stool, coeditor of the first four editions, could not witness the amazing maturation of Pediatric Otolaryngology and the publication of this edition. In his honor, we have included his Encomium to remind those who knew him of his tremendous accomplishments and contributions to our subspecialty and to enlighten those too young to have benefitted from his ever-present warm friendship and intellect. We give special thanks to Eugene N. Myers who graciously wrote the Foreword as he is uniquely qualified to reflect not only on the progress in the field of pediatric otolaryngology over the past 40 years but also the growth and development of this textbook. We thank our editors at PMPH-USA, Carole Wonsiewicz and Linda Mehta, whose expertise and attention to detail was invaluable. We are indebted to Deborah Buza, administrative assistant, for her dedication and persistence over the past three years tracking all chapters, keeping authors informed, and the production schedule going, and also to Maria B. Bluestone who provided expert and invaluable editorial aid for several chapters. As editors, we hope the health care of infants and children will be improved by those healthcare professionals who use this textbook as a reference in this 21st century.

Charles D. Bluestone, MD, FACS, FAAP Jeffrey P. Simons, MD, FACS, FAAP Gerald B. Healy, MD, FACS

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Acknowledgments

I personally want to thank and acknowledge the work and dedication of my two new editors, Gerald Healy and Jeffrey Simons, who accepted my invitation to join in preparing this fifth edition and carry on the role of Sylvan Stool in the first four editions. I consider Gerry a dear friend and colleague and believe I might have some minor influence in his choosing pediatric otolaryngology as a career path as I suggested that to him back in the early 1970s while we were in Boston. He followed me as Chief of Otolaryngology at Boston City Hospital but went on to develop the prestigious Department of Pediatric Otolaryngology at Boston Children’s Hospital, become a professor at Harvard, and the only otolaryngologist to serve as President of the American College of Surgeons in its 100-year history. Many of the new authors in this edition are from his former department at Harvard. Jeffrey I consider to be a rising star in the new generation of pediatric otolaryngologists and without his painstaking efforts to organize and recruit section editors and authors, and edit chapters, this edition would never have become a reality. My sincere hope is that he will carry the textbook to new and better editions in the future.

Charles D. Bluestone We wish to acknowledge the chapter contributions of the distinguished and dedicated authors (217) and the 14 section editors who made this fifth edition possible. Thank you to Eugene N. Myers for his gracious Foreword. We give special thanks to Deborah Buza for her dedication and commitment to the coordination and collation of manuscripts and for her kind and compassionate but persistent reminders to authors and section editors to adhere to our publisher’s production schedule. A special thanks also goes to Carole Wonsiewicz, Development Editor at our publisher, PMPH-USA, and Maria B. Bluestone who provided her expert and invaluable editorial expertise for several chapters. Finally, we thank our mentors and our patients and families who allow us to learn from them and pass the knowledge on to our colleagues and students.

Charles D. Bluestone Gerald B. Healy Jeffrey P. Simons

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Encomium Sylvan E. Stool, MD (1925–2004)

It is my honor to dedicate this fifth edition of Pediatric Otolaryngology to the memory of the late Sylvan E. Stool, MD, pioneer in Pediatric Otolaryngology and my coeditor of the first four editions. Sylvan not only dedicated his career to providing health care to infants and children with ear, nose, and throat diseases and disorders but also was committed to teaching students, residents, and fellows, many of whom are now leaders in our field. He was board-certified in both pediatrics and otolaryngology, a distinction that was, and still is, rare in Pediatric Otolaryngology. He was born on November 7, 1925, in San Angelo, Texas, where his parents were in the dry goods business and grew up on the dusty plains of west Texas. Sylvan attended high school in Abilene, which was then the University of Texas in Austin. He was accepted into an accelerated program at Southwestern Medical College designed to fill the shortage of physicians during and after World War II and graduated with an MD on June 3, 1947, at the age of 20. This was the first year that the Hippocratic Oath was administered at medical school graduations (UT Southwestern Medical Center: Commemorating the First Fifty Years, p.11). After completing a two-year rotating internship and residency in general practice in Dallas and Ft. Worth, Sylvan completed a one-year fellowship in Pediatric Surgery at the Children’s Orthopedic Hospital in Seattle. After he could obtain no further training in surgery, he decided to pursue a residency in pediatrics at the University of Utah. He was a captain in the United States Air Force during the Korean War and stationed in hospitals in Guam and Japan. After the war, he received an appointment as a Fellow in

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Boston Children’s Medical Center. It was there that Sylvan had his first exposure to otolaryngology while filling in for a sick colleague. This position allowed him to work closely with Drs. Charles Ferguson and Carlyle Flake, two of the few early otolaryngologists who worked in Children’s Hospital. He was able to live in the house officers’ quarters and, as he described it, was allowed “to eat two free meals a day.” After his experience in Boston, Sylvan practiced pediatrics at Denver General Hospital in 1955 during which time he noticed the prevalence of ear and hearing problems in his patients and initiated an informal ENT clinic. He then realized that he needed further formal instruction in otolaryngology. When Dr. Victor Hillyard was appointed Chief of Otolaryngology at the University of Colorado Hospital, Sylvan inquired about training in otolaryngology, and Dr. Hillyard immediately offered him a residency position. (Dr. Hillyard and Sylvan received a grant from NIH and Fitzsimmons Army Hospital to fund his training.) Sylvan and I first met in 1961 while we were both residents in otolaryngology; he at the University of Colorado and I at the University of Illinois. We met while attending the national meeting of the American Medical Association in Denver, and he expressed such a keen interest in my exhibit on tracheobronchial mechanics that we immediately became life-long friends (Fig. 1). The late Dr. C. Everett Koop, a pioneer in pediatric surgery and later the celebrated US Surgeon General, was appointed Chief of Surgery and was charged with staffing

FIGURE 1. Sylvan and Charley in Pittsburgh.

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Encomium

Children’s Hospital of Philadelphia (CHP) with specialists in pediatrics. Following Sylvan’s residency in 1963, he received an inquiry from CHP to help Mary Ames establish a rehabilitation center to serve children with multiple defects. For Sylvan, Philadelphia was a much different environment from the West. He found the East Coast medical community more set in its ways and resistant to changing established medical fields, for example, only the Jackson-trained bronchoesophagologists performed endoscopy and many had difficulty accepting the concept of age-related specialist in otolaryngology. After a few years, the otolaryngology training programs in Philadelphia recognized opportunities in pediatric otolaryngology, and their residents requested rotations with Sylvan at the Children’s Hospital where he was the Director of Otolaryngology for 12 years. Sylvan then realized that unless Pediatric Otolaryngology, similar to Pediatric Surgery as led by Dr. Koop, achieved academic recognition and the ability to train fellows, it could never be established as a true subspecialty. It was then that Sylvan and I discussed the possibility of initiating a Fellowship in Pediatric Otolaryngology in Pittsburgh, since at that time it seemed impossible to achieve such a fellowship in Philadelphia. In 1975, Sylvan accepted an offer from Dr. Eugene N. Myers, the first Academic Chairman of the Department of Otolaryngology at the University of Pittsburgh School Medicine, to join me at the Children’s Hospital of Pittsburgh. Sylvan was a tenured Professor of Otolaryngology and Pediatrics at the Medical School and Director of Education in the Division at Children’s Hospital of Pittsburgh and remained until 1994. The first Fellow in Otolaryngology was recruited in 1975, funded by Children’s Hospital for one year. In 1985, Sylvan became Principal Investigator for a training grant from the National Institutes of Health to fund a research fellowship year in Pediatric Otolaryngology, and this research year combined with the clinical year initiated our two-year Fellowship in Pediatric Otolaryngology. While Sylvan was in our Department, 40 Fellows were trained in Pittsburgh. Most of the graduates are now in academic medicine, many are Directors of Divisions of Pediatric Otolaryngology, and some chairs of departments. During Sylvan’s years in Pittsburgh we invited the only 20 Pediatric Otolaryngologists we knew in the United States and Canada to form the Study Club (Fig. 2). In 1994, Sylvan returned to Denver invited by one of his Fellows, Kenny Chan to join him at The Children’s Hospital where he held the title of Senior Lecturer at the University of Colorado School of Medicine. He worked part-time in the clinic and the operating room and occasionally on-call duties to help out. He continued to engage residents in various research projects with a focus on toy safety. His “Otitis Media Workshop” became well-known all over the Rocky Mountain region and beyond. His Colorado years afforded many opportunities to reacquaint with former pediatric colleagues and friends from the 1960s. One of his memorable presentations, entitled “The Golden Years of Otolaryngology,” was delivered

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FIGURE 2. Initial 1977 meeting of 20 pediatric otolaryngologists in Pittsburgh. The outcome of this meeting was the formation of the Otolaryngology and Bronchoesophagologic Section of the American Academy of Pediatrics.

in 2002 at the Western Society of Pediatric Otolaryngology Meeting, where there were few dry eyes in the audience. His primary clinical interest was in management of the pediatric airway, and during the last few years of his illustrious career focused on the prevention of obstruction of the airway from foreign objects, primarily potentially dangerous toys. In 1968, Sylvan made his most important and lasting contribution to the health and well-being of children when he introduced the life-saving stay sutures to the tracheotomy procedure that is now the standard of care for children. Sylvan suffered a fatal heart attack in 2004 and “died with his boots on” placing a set of tympanostomy tubes in a cleft palate patient on the day he died. He was the first to report that almost all infants with unrepaired cleft palates had chronic middle-ear effusion. His accomplishments and contributions to medicine are numerous. He published more than 150 peer-reviewed articles and 70 publications. Sylvan was past president of the Society for Ear, Nose and Throat Advances in Children (SENTAC), and in 1995, the Society established the Sylvan E. Stool Lectureship. Also in 1995, the Department of Otolaryngology established the Sylvan E. Stool Lectureship in the Carol F. Reynolds History of Medicine Society at the University of Pittsburgh School of Medicine in honor of his contributions to the history of medicine. Sylvan received the Humanitarian Award (2000) from the American Academy of Otolaryngology–Head & Neck Surgery for his commitment to teaching pneumatic otoscopy, as part of Otitis Media Workshops, not only in the United States but in many other countries, primarily those in Latin America. He made more than 30 trips to teach about otitis media with didactic and “hands-on” teaching styles. The Latin American efforts were recognized by both the World Health Organization and the Pan American Health Organization as the model of how to train local care providers.1 Just in Mexico alone these efforts

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Encomium led to (1) placement of otoscopes in all public health clinics in the country, (2) making otitis media a reportable disease in Mexico, and (3) focusing on national vaccination policy that included ear disease. This work also led to the creation of the vibrant educational organization—the Inter-American Association of Pediatric Otolaryngology—of which Sylvan was the first President. His personal life was dynamic and full as well. His eldest daughter, Evelyn, described her father’s interests as very diverse and extending well beyond medicine but always tangentially associated with it. He became fascinated in Western art through an unexpected discovery of an old book, Shut Your Mouth and Save Your Life by George Catlin. Catlin was a painter who had observed the breathing habits of the Plains Indians while traveling with them and painting their portraits. Sylvan became an expert on George Catlin's own health issues and well respected in the Western art community as one of few Catlin experts. Much of Sylvan’s joy and passion resulted from teaching, whether in the clinic, the operating room, an airstrip in the south Pacific or a hospital in South America. He traveled all over the world teaching doctors how

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to diagnose otitis media and practice airway safety. His wife, June Keil, traveled the world with him. They met in 1955 at a music appreciation class and married later that year. They had a wonderful marriage of 48 years produced four children, Evelyn, Daniel, Laura, and Karen, two grandsons, Lloyd and Sander, and much happiness and lots and lots of music. Charles D. Bluestone April 5, 2013 1. Eavey RD, Santos JI, Arriaga MA, et al. An educational model for otitis media field-tested in Latin America. Otolaryngol Head Neck Surg 1993;109:895-898.

Acknowledgments I am indebted to Evelyn Stool Waldren, for her contribution to this, her father’s, biography, Kenny Chan for his memory of Sylvan’s 10 years in Denver, Roland Eavey’s remembrances of his teaching in Latin America, Eugene N. Myers for his important additions and editing, and to Sylvan’s own reflections in the fourth edition of Pediatric Otolaryngology (pp. 62–63).

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1

S E C T I O N

Michael J. Cunningham and Joseph E. Dohar

1

Evolution of Pediatric Otolaryngology

11

Allergy and Immunology

2

Phylogenetic Aspects and Embryology

12

Pediatric Neurology

3

Genetics, Syndromology, and Craniofacial Anomalies

13

Pediatric Ophthalmology

4

Outcomes and Evidence-Based Medicine in Pediatric Otolaryngology

14

Pediatric Hematology: The Coagulation System and Associated Disorders

5

Ethical Issues in Pediatric Otolaryngology

15

6

Professionalism, Communication, and Teamwork in Surgery

Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections

7

Pediatric Otolaryngology: A Psychosocial Perspective

8

Psychiatric Disorders in Pediatric Otolaryngology

9

Munchausen Syndrome by Proxy

10

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Basic Science/General Pediatric Otolaryngology

Pediatric Anesthesiology

16 The Role of Biofilms in Pediatric Otolaryngologic Diseases 17

Pediatric Gastroenterology

18

Pediatric Pulmonology

19

Pediatric Oral and Maxillofacial Surgery: Craniofacial Growth and Interdisciplinary Surgical Care

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1

C H A P T E R

Evolution of Pediatric Otolaryngology Robert J. Ruben

P

ediatric otolaryngology (ORL) evolved through a synergy of perceived societal needs and availability of acceptable interventions, relating to the economic, social, and philosophical concept of childhood.1,2 The history and conceptualization of childhood can be usefully divided into four overlapping but distinct ideological periods.3 The first, from 1600 to the 1750s, is the end of the Reformation and the period of the Counter-Reformation; the second, from the 1750s to the 1850s, is the Enlightenment; the third, from the 1860s to the 1920s, is the Romantic period; and the last from the 1920s to the present is the period of Entitlement.

REFORMATION The Reformation and Counter-Reformation are characterized by concern with the child’s soul, exemplified in the later writings of John Locke,4 which was considered as either sinful (Reformation) or pure (Counter-Reformation). As this was a period of great economic disparities, the limited medical knowledge available was applied for the benefit of only a very few. The child, at this time and until the end of the Romantic period, was viewed economically as a producer, not as a consumer; that is, in all classes, the child was expected to augment the family economically. For this reason, boys were favored over girls. If the male child was high born, then he was trained to be a ruler and/ or a warrior. A female was valued in terms of her potential economic benefit to the family through marriage and was trained to optimize “her chances” and her usefulness to the family after her marriage. When born to peasant, males and females soon became productive workers and ultimately served as the old-age security for parent(s). In this context, most infants with otolaryngic diseases and disorders died or were abandoned.5 Two instances during the 17th century, each involving a child of a family of substantial wealth and political power, are illuminating. The first concerns the infant Dauphin of France, who became Louis XIII.6 Dr. Jean Héroard, his physician, kept a daily diary concerning the care of this very special patient, slated to rule. In 1601, at 1 day of age, his condition was noted: September 28th. His nurse was demoiselle Marguerite Hotman and as he seemed to have some difficulty in sucking his mouth was examined and it was found that he was tongue-tie; so at five o’clock in the evening M. Guillemeau, the Kings surgeon, cut the tendon three times.6

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Two weeks later, there is an outcome report to this surgical procedure for questionable pathology: when he sucks it is in great gulps so that he swallows as much in one gulp as other babies in three. His nurse never has enough for him.6

The second case, published in 1620,7 concerns the education of Luis, the congenitally deaf son of the Captain of Castile, in whose interbred family there were numerous deaf relatives. A significant motivation for pursuing the child’s education was the need for Luis to take communion, so that he could be a “legal person; then his mother, Doña Juana de Córdoba, Duchess of Frias, could be regent until Luis came of age and thereby control the patrimony. The treatment of Luis, described in Bonet’s 1620 publication, was based on an earlier lost manuscript, Doctrina para los mudos sordo, attributed to the Benedictine, Pedro Ponce de León (d. 1584), who had educated a number of the deaf Spanish nobility. These 17th-century pediatric otolaryngic interventions, one surgical and the other habilitative, reflect the status of the child. First, both had been baptized so as to be a full member of the Church. Then, and foremost, the young child was an economic producer. It was important for these highborn children to survive—for the Dauphin, to rule, and for the Spanish Luis, to keep the fortune in the family. They are characteristic of the times in that these interventions were confined to the very wealthy. For most children of the 17th century, there were neither surgeons nor deaf educators.8

ENLIGHTENMENT The Enlightenment saw a radical change in the concept of childhood, from one that considered the child as a little adult with either a sinful or a pure soul to one in which the child was essentially different from the adult in that each child was thought to come into this world with the mind as a blank slate, the famous “tabula rasa.” In a sense, “the child” was born during the period of the Enlightenment. Rousseau comments on the residual old view, and points the way to the new one, in his preface to Émile9: The wisest writers devote themselves to what a man ought to know, without asking what a child is capable of learning. They are always looking for the man in the child without considering what he is before he becomes a man.

Childhood in the Enlightenment is seen as a unique condition of life, and the child’s own “natural” course of

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development should be the basis for education. This new view leads to a new invention, the children’s book, one of the first being published by John Newberry in 1744.10 Economically, however, this conceptual change did not alter the child’s fundamental role as a producer, a role that becomes even more onerous with the advent of the industrial revolution. On the contrary, the view that the value of a child rests on his or her productivity was somewhat mitigated by the political and social revolutions at the end of the 18th century, and at this time, otolaryngic care of children became available to a somewhat larger segment of the population. Important changes in the otolaryngic care of the child began with the Abbé Charles Michel de L’Épée who undertook the teaching of two middle-class deaf sisters by means of signs to enable them to take communion.11 He expanded his teaching, at his own expense, to include a number of poor, possibly abandoned, deaf Parisian children. In 1791, Louis the XVI, the descendent of the possibly tongue-tied Dauphin, established the first state school for the deaf, open to all12 (Fig. 1-1). Its development was furthered by the Abbé Sicard who persuaded the revolutionary National Assembly that aid for the handicapped was part of the “natural duties” encompassed by the “rights of man.”13 It is interesting to consider the way this view was congruent with those of Danton and Robespierre, who believed that children belonged to the state before they belonged to their families.3 The responsibility of the state to care for the deaf rapidly spread throughout Europe and North America. Deaf children, by the end of the Enlightenment, were cared for, normatively if not in all cases, regardless of their social status. The Connecticut Asylum for the Education of Deaf and Dumb Persons—now the American School for the Deaf in Hartford, CT—was opened on April 15, 1817, the first such institution in the United States. The second was the New York Institution for the Instruction of the Deaf and Dumb; this free school for all deaf children of the state over five years old was

FIGURE 1-1. Loi Relative à M. l’Abbé de l’Épée, & à son établissement en faveur des Sours & Muets, passed by the National Assembly, Paris, July 29, 1791. Département du Varennes. Original document of the enacted legislation authorizing the establishment of a school for the deaf and appropriating 12,700 livres for expenses. This was dedicated to L’Épée, who died in 1789, and sanctioned by Louis XVI, at the time a constitutional monarch and a virtual prisoner in the Tuilleries. This was the first state-sponsored school for the deaf and was open to all.

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incorporated on April 15, 1817, and opened on May 20, 1818, in a room in an almshouse. Before opening such a school in New York, the organizing committee needed to determine the number of deaf children in the city and chose Dr. Samuel Mitchell to assess this. His pamphlet14,15 showed the current number of deaf children as 63 in New York City with 8 more in the vicinity and provided a reasonable prediction for the near future of more than 100. In part of this basis, the committee then obtained funding from the government and philanthropists and enrolled the first four pupils in 1818. Conversely, the industrial revolution, taking hold in the later years of the Enlightenment, increased the need for economic productivity for many children. It is in this period that 18th-century ideas, rooted in John Locke, were instituted as noted by Jonas Hanway as early as 1766: That poor children should be put to work at age 3 with daily bread and in cold weather, if thought to be needed, a little warm gruel. (p. 138)3

The importance of child labor in economic development can be seen, for example, in the employment records of the Manchester cotton mills in the 1830s; 76% of females working in these mills were girls under 14 years, and 61% of males were boys under 14 years.3 These children did not have access to medical, let alone otolaryngic, care.

ROMANTIC During the Romantic period of the 19th and early 20th centuries, both negative and positive experiences of childhood moved hand in hand. Some societal forces were working to better the child’s lot; for the first time, many children become in part consumers, while also maintaining their role as economic providers in most families. A great advance witnessed by this period was that orphan asylums were supplanted by children’s hospitals.3 In 1802, for example, the Hôpital des Enfants-Malades opened in Paris in the former Maison de l'Enfant-Jésus that had been founded in 1724 as an orphan asylum for abandoned girls. The middle of the 19th century saw an increased pace in the establishment of children’s hospitals, such as Great Ormond Street Hospital for Children opened in 1852 and the Children’s Hospital of Philadelphia opened in 1854, and subsequently several other major North American institutions were established including Boston Children’s Hospital in 1869, The Hospital for Sick Children, Toronto, in 1875, and the Children’s Hospital Los Angeles that was incorporated as the Children’s Hospital Society of Los Angeles in 1901.16 John Snow of London demonstrated that anesthesia could be used in children; by 1857, he had anesthetized 186 children under the age of 1 year with chloroform.17 Wilhelm Meyer discovered the disease process of the adenoid18 in 1868 and its relationship not only to otitis but also to mouth breathing, sleep disturbance, sluggish facial expression, and fatigue. Meyer’s work provided a rationale for innovations directed at improving and optimizing

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CHAPTER 1 ❖ Evolution of Pediatric Otolaryngology 5 the health and appearance of the child; these ameliorations are described often in pediatric and otolaryngic literature from the end of the 19th century into the first half of the 20th century. Hypertrophy of the tonsils and adenoid with incomplete and faulty ventilation, or acid secretions of the tonsil and adenoid as a cause of decreased appetite and subsequent malnutrition, were standard diagnoses during the first decades of the 20th century. Malnutrition, which is a very unusual indication today, was a common rationale for tonsillectomy and adenoidectomy up to the end of the 1920s. The perfectionist ideology that was to an extent a result of the romantic mind-set played a significant role in the quest for “normalcy.” Deviance was disparaged, and the normal was thought to be ultimately achievable through eugenics. One of the more benign examples of this attitude was the state-sponsored “better baby contests” held in the midwestern United States from 1920 to 1935 (Fig. 1-2).19,20 It became incumbent for the parent to do all that could be done for their child to be as normal as possible, and tonsillectomy and adenoidectomy were recommended by health providers, physicians, and public health workers to encourage full physical and mental development. Consequently, any child whose growth and development was not at “normal” became a potential candidate for this operation. A significant and efficacious advance in the ORL care of children in North America came about from the need for intervention for children with diphtheria, the most deadly pediatric otolaryngic condition of the 19th and early 20th centuries. The diphtheritic child would either suffocate or undergo myocarditis with cardiac arrest until Joseph O’Dwyer published his method of intubation in “Two cases of croup treated by tubage of the glottis”21 in 1885; he followed up this landmark description with the publication of an additional 50 cases22 in 1888. O’Dwyer’s work facilitated the acceptance of peroral endoscopy. The North American leader in this respect was Chevalier Jackson, whose attention was drawn to numerous laryngeal, tracheal, bronchial, and esophageal foreign bodies in children, culminated in the publication of his monograph on foreign bodies23 in 1936. Jackson’s work with peroral endoscopy exposed him to a large number of esophageal strictures from lye (sodium hydroxide) ingestion. He became a children’s advocate and was instrumental in the passage

of correct product labeling for containers with lye and other poisons24—the Federal Caustic Labeling Act of 1927 (Fig. 1-3). Although concern for the hearing of schoolchildren existed from the beginning of the 20th century, there was no accurate method for hearing assessment. The major advance in the diagnosis and care of children’s hearing was the development of the first commercial vacuum tube audiometer, the Western Electric 1A, by Harvey Flecther25 and introduced as a clinical tool by E. P. Fowler Jr. and R. L. Wengel26,27 in 1922. The use of this device to objectively test the hearing of school children resulted in the 1928 Fowler article entitled “Three million deafened school children.”28 This article was a major factor in the establishment of childhood hearing screening programs in the public school system (Fig. 1-4A and B).

ENTITLEMENT The political and philosophical ideals and aspirations of the mid-19th century, unsuccessfully expressed in the revolutions of 1848, but sustained and refined up to the present, have resulted in our present day principle of entitlement. The view

FIGURE 1-3. “From a photographic of a child fatally burned by swallowing Red Star Lye. The lower part of the illustration shows the inadequacy of the warning common to all labels of lye containers sold in groceries and used in kitchens. Parents are not aware of the danger of leaving the lye-preparations in the reach of children. This label is removed to get at the directions on the back, and removal usually destroys or removes the tiny, inconspicuous vertical cautionary wording.”24

A FIGURE 1-2. Spectators watching the various testing and measurement tables at the 1930 contest. (Photo courtesy of the Indiana State Archives, Indiana Commission on Public Records.19)

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B

FIGURE 1-4. A, America’s first commercially produced audiometer of the vacuum tube type. The I-A audiometer of the Western Eclectic Company.63 B, School testing with the Western Electric 4-A audiometer.63

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has been generalized that all children are entitled to life and to the fulfillment of their potential. Otolaryngic care is accessible to all children throughout much of the industrialized and postindustrialized world through various private and public state plans. From the early role as producer, the child has now become a consumer. For a glimpse of this trend beyond medicine, Disney products sold $10 million in 1933 and $3 billion in 1990 representing a 40-fold increase when corrected for inflation.3 In matters of health, there is a tension between parental control and state control, often resolved in favor of the state. A consequence of entitlement in synergy with medical advance can be found in the care of the premature infant.20,29 The first reported use of an incubator to care for a premature infant was by Carl Credé in Germany in 1837. This use was rediscovered in 1880 by Stéphane Tarnier3 who, observing chicken incubators in the Paris Zoo, applied the process tothe premature infants in the Paris Maternity hospital (Fig. 1-5). These first incubators held, like those for the chickens, multiple infants. The mortality of prematurity, despite the use of warmth, still remained quite high. The highest cause of mortality occurring in infants born before the seventh month of gestation was found by Avery in 1959 to be lack of surfactant resulting in hyaline membrane disease.30 The solution was to increase either ventilation by mechanical means or the amount of oxygen available. The latter resulted in the ophthalmologic condition retrolental fibroplasia and its associated blindness, furthering the need for a localized delivery system. In the 1940s and the 1950s, most assisted

ventilation was delivered by tank-type negative pressure ventilators such as the drinker respirator used for polio victims. The European polio epidemic of 1952 overwhelmed the supply of the iron lung-type negative respirators. To meet this problem, the physicians of Copenhagen performed tracheotomies, and the medical students hand ventilated the patients with positive pressure. This was successful, leading to the development of positive pressure respirators for the intubated premature infant.29 The infants survived but could not be extubated as they had acquired subglottic stenosis and required tracheostomies that had their own associated morbidity and mortality. This new morbidity—acquired subglottic stenosis of infancy—required and received an effective intervention, laryngotracheal reconstruction, pioneered by two pediatric otolaryngologists Blair Fearon and Robin Cotton.31,32 Thus, the entitlement of the premature baby created demand for specialized care of the infant airway; this was a salient factor that resulted in the formation of the specialty of pediatric ORL throughout the world,33 because while there may have been a need heretofore, there was little or no demand.

NORTH AMERICA In the late 1940s, three of the pioneering children’s hospitals had physicians who concentrated their practices in pediatric ORL. Drs. Charles Ferguson and Carlyle Flake worked full time at Boston’s Children’s, with their wards dedicated to the

FIGURE 1-5. Trainer’s incubators in use at the Maternité Hospital, Paris, 1884. (From the Illustrated London News, March 8, 1885: 228.)

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CHAPTER 1 ❖ Evolution of Pediatric Otolaryngology 7 treatment of croup and operating rooms on the same floor as their offices.34 Dr. Seymour Cohen, whose major interest was pediatric endoscopy, practiced at the Los Angeles Children’s Hospital. Dr. Blair Fearon, at Toronto’s Sick Children’s Hospital, practiced pediatric ORL and also, critically, undertook basic research with Dr. Robin Cotton in the reconstruction and repair of the infant airway. Their research resulted in the landmark paper entitled “Surgical correction of subglottic stenosis of the larynx: Preliminary report of an experimental surgical technique”31 in 1972. More North American physicians began to concentrate their practice to children, and there was a need to bring attention of this development to the otolaryngic community. Sylvan Stool (Fig. 1-6)35 posted a notice at the 1971 meeting of the American Academy of Ophthalmology and Otolaryngology (AAOO) for all those interested in pediatric ORL to meet informally. Approximately 20 physicians attended this initial meeting, and it was decided to convene again at the AAOO 1972 meeting in Dallas. A decision was made at the1972 meeting to form a new society focused on pediatric ORL, and a small group was formed to write a set of bylaws and incorporate this new venture. The new society was called The Society for Ear, Nose and Throat Advances in Children, Inc. (SENTAC) and was founded in 1973 as a nonprofit interdisciplinary professional organization. Its members were and continue to be otolaryngologists, pediatricians, surgeons, pediatric otolaryngologists, speech pathologists, audiologists, nurses, and basic scientists, all of whom are interested in enhancing the care of children with acquired or congenital disorders of the ear, nose, and throat. Dr. Robert Ruben was its first president. SENTAC continues to be an interdisciplinary forum for new ideas; it is one of the few medical societies in which membership is determined solely by interest, not by professional association, facilitating the successful interchange of information between many different professional and lay groups. One year later in 1975, Dr. Basharat Jazbi organized the “First International Symposium on Pediatric Otorhinolaryngology,” held in Kansas City, Missouri.36,37 Following this was a course

FIGURE 1-6. Sylvan Stool, 1925–2004.

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given at the Armed Forces of Institute Pathology in Washington, DC, in 1976 entitled “Pediatric Otolaryngic Pathology” organized by Captain Vincent J. Hyams, MC, USN. This, so far as can be determined, was the first such course ever given that systematically reviewed all that was known about the cellular pathology concerning pediatric otorhinolaryngology.38 The Pediatric Otolaryngic Study Group began in 1977 with a meeting at the Pittsburgh Children’s Hospital39 hosted by Dr. Charles Bluestone and Sylvan Stool. There were 22 attendees at this meeting, and it was decided to organize a session on Pediatric Otolaryngology and Bronchoesophagology of the American Academy of Pediatrics, which resulted in the writing of a set of bylaws. This new organization would increase the recognition of ORL and bronchoesophagology by the pediatric medical community and provide a platform for the education of both pediatricians and otolaryngologists. The study group continued to meet at different medical centers for the next few years. These meetings were informal and provided opportunities for participants to learn from their colleagues, which accelerated the dissemination of knowledge of advances in surgical techniques, instrumentation, diagnostic procedures, and effective interventions. It also allowed participants to see various clinical and administrative arrangements. Some examples of these meetings were as follows: Boston Children’s Hospital,40 hosted by Dr. Gerald Healy, in 1978 where new laser techniques were explored; Children’s Memorial Hospital, Chicago,41 hosted by Dr. Gabriel Tucker, Jr., in 1978 where pediatric endoscopy was demonstrated; Children’s Hospital of Cincinnati,42 hosted by Dr. Robin Cotton, in 1979; Children’s Hospital of Philadelphia, hosted by Dr. William Potsic, in 198043; and at the Albert Einstein College of Medicine (AECOM),44 in the Bronx, New York, hosted by Dr. Robert Ruben, in 1981, where there was an emphasis on both communication disorders, including language, and cell biology. At the AECOM meeting, there was a special session to discuss the design of a cooperative study of medical therapy for respiratory papilloma. This resulted in the 1988 article “Treatment of recurrent respiratory papillomatosis with human leukocyte interferon. Results of a multicenter randomized clinical trial.”45 A number of the members of the American Academy of Pediatrics Section of Otolaryngology and Bronchoesophagology perceived the need for a society that would be limited to those otolaryngologists who predominately practiced pediatric ORL and who demonstrated proficiency in this area. Their conception was a society modeled after the traditional ORL specialty societies such as the American Otological Society and the American Laryngological Society. At the 1979 San Francisco business meeting of the AAP Section of Otolaryngology and Bronchoesophagology, a committee was formed, chaired by Dr. Mark Richardson, to further explore this idea, formulate a set of bylaws, and incorporate the entity.46 The new society was called the American Society of Pediatric Otolaryngology and held its first meeting in Bermuda in 1985 with Dr. Seymour Cohen as its first president (Fig. 1-7).

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EUROPE

FIGURE 1-7. American Society of Pediatric Otolaryngology first meeting in Bermuda, 1985.

As pediatric ORL developed in North America, there was the desire and need to properly train physicians to become competent pediatric otolaryngologists. In 1975, Dr. Charles Bluestone, the first full-time director of the Department of Pediatric Otolaryngology at Children’s Hospital of Pittsburgh, with Dr. Sylvan Stool, created the first pediatric ORL training fellowship program; this fellowship program has been funded by the National Institutes of Health since 1985. Several other programs were initiated, including that by Dr. Gerald Healy at the Boston Children’s Hospital and by Dr. Robin Cotton at the Cincinnati Children’s Hospital Medical Center. As more fellowships were established, there was a need for quality control and also a need for certification. This initially resulted in petitioning the American Council for Medical Education (ACGME) to standardize criteria for the training of a pediatric otolaryngologist and a process of accreditation of the training program by the ACGME. Currently, there are seven ACGME-accredited fellowship programs in pediatric ORL, including those at the University of Colorado in Denver, the George Washington University/Children’s National Medical Center Program in Washington, DC, the Pediatric University of Iowa Hospitals and Clinics Program in Iowa City, the Cincinnati Children’s Hospital Medical Center/University of Cincinnati College of Medicine Program, the Children’s Hospital of Philadelphia Program in Philadelphia, the University of Pittsburgh Medical Center Medical Education Program in Pittsburgh, and the Baylor College of Medicine Program.47 There are an additional 22 fellowship programs in North America.48 As the number of applicants and fellowships increased, there was a need for a matching program. This was established in 1999. In 2000, there were 14 positions offered to 31 applicants, and in 2008, there were 35 positions offered to 48 applicants.49 This more than twofold increase in positions is consistent with the overall shifting of physicians to specialization in American medicine.50 Pediatric ORL has evolved during the past three decades as a major medical discipline in North America. Almost every major pediatric hospital is now staffed by otolaryngologists well trained and experienced in the ear, nose, throat, head, and neck diseases and disorders of children.

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Poland was the leader in the development of pediatric ORL in Europe, with the formation of specialty beginning there in the late 1940s, after the end of World War II.51,52 Associate Professor Jan Danielewicz (Fig. 1-8), the father of pediatric ORL in Poland and one of its cofounders in Europe, established the first modern Department of Pediatric Laryngology at the hospital of Mother and Child in 1947, followed in 1956 at the Warsaw University Hospital. Danielewicz created both a training program and a specialty examination in and for pediatric ORL. The first pediatric ORL examination was held in 1961. An initial “Days of Pediatric Laryngology” was held in 1958 in Zakopane, Poland, and has continued to be given every two years. Profs. Ewa Kossowska and Danielewicz went on to organize jointly the First European Congress of Pediatric Laryngologists in Warsaw in 1979. On Prof. Danielewicz’s retirement in 1973, Prof. Kossowska succeeded him. Under her leadership, the department focused on endoscopic surgery of the trachea and esophagus, laryngeal reconstructive surgery, sinonasal surgery, and the physiopathology of the upper respiratory tract and tonsillar infections. Prof. Kossowska retired in 1993 and was succeeded by Prof. Mieczyslaw Chmielik. Currently, Poland has four established clinical pediatric ORL departments: in Łódź, Poznań, Lublin, Białystok, and one that is in formation at Śląsk. The Polish Society of Pediatric Otorhinolaryngology is a registered organization. Specialized pediatric ORL training is open to all doctors who have completed their education in laryngology for two years and who pass an examination in pediatric ORL.51 In the context of the growing awareness of pediatric ORL as a significant specialty, Dr. Carlo Gatti Manacini, head of the Pediatric ORL Department in Brescia, initiated the idea of holding a World Pediatric Otolaryngology Congress,53 and the concept was a great success from the start. He, together with Drs. Renato Fior and Giulioand Giulio Pestalozza, organized the landmark First World Congress of Pediatric Otolaryngology in 1977 in Sirmione, Italy. There were round tables, instructional courses, and 150 free papers from 29 countries in 5 continents, with an attendance of more than

FIGURE 1-8. Jan Danielewicz, 1903–1982.

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CHAPTER 1 ❖ Evolution of Pediatric Otolaryngology 9 400 delegates. This Congress was a major catalyst for the initiation of focused pediatric ORL in many countries and its advancement worldwide by bringing together physicians from throughout the world for the first time, including many from Eastern Europe in the period of the “Iron Curtain,” who met for the first time as individuals on a social basis and exchanged information. Among the fruitful outcomes of this first Congress were plans for a second Congress, which was subsequently held in Bath, Great Britain, in 1982 under the organizational leadership of Mr. Robert Pracy (Fig. 1-9). The First World Congress also led to the establishment of a European Working Group in Pediatric ORL that later became the European Society of Pediatric Otolaryngology (ESPO) and to the initial planning for the creation of The International Journal of Pediatric Otorhinolaryngology.54 Renato Fior, head of the Department of Otorhinolaryngology at the Istituto Per L’Infanzia in Trieste, organized the first European Course of Pediatric Otorhinolaryngology in Trieste in 1978.55 Dr. Manacini, president of the Società Italiana di Otorinolaringologia Pediatrica, opened the meeting with the history of pediatric otorhinolaryngology in Italy. There were 20 lectures covering all the major areas of pediatric ORL. At this meeting, the bylaws for the newly formed European Working Group of Pediatric Otolaryngology (EWGPO) were established. These bylaws, which follow, demonstrate the successful cooperation of physicians coming together from many nations and exemplify the ideals of pediatric ORL: a. To foster clinical and research work in the field of medicine, functional and plastic surgery, and rehabilitation of diseases of the ear, nose, throat, and bronchoesophagology in infants and children. b. To coordinate cooperative work on a national and international basis between otolaryngologists, pediatricians, audiologists, and speech pathologists. c. To promote and maintain cooperation with other societies International Federation of Oto-Rhino-Laryngological Societies (IFOS), agencies, health departments, and organizations having a role in health planning within the countries and generally in Europe with the aim of carrying out the purposes of this working group. d. To organize an information service to provide the public and the national and international health organizations with relevant data or significant events and research findings

FIGURE 1-9. Second World Congress of Pediatric Otolaryngology held in Bath, 1982.

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in the field of pediatric ORL and on the availability of health services, preventive measures, and means for early detections of disease and of rehabilitation. e. To maintain this working group as a nonprofit organization whose activity shall be strictly scientific and charitable. Subsequent EWGPO conferences were held in Warsaw (Poland), Bath (United Kingdom), Sèvres (France), Eger (Hungary), Nijmegen (The Netherlands), and Ghent (Belgium). After the second EWGPO Congress in Sirmione in 1992 and a pediatric ORL conference in Jerusalem (1993), the VIth International Congress of Pediatric Otorhinolaryngology was held in 1994 in Rotterdam under the leadership of Profs. Carl Verwoerd and Jetty Verwoerd-Verhoef, where the Board of the EWGPO founded the ESPO; this organization gained official legal status in 1997 with a set of bylaws, signed by Renato Fior, Paul van Cauwenberge, Pekka Karma, Cor Cremers, Carel Verwoerd, and Jetty Verwoerd-Verhoef. The International Congresses have continued to be organized every four years (1998 Helsinki, Finland; 2002 Oxford, United Kingdom; and 2006 Paris, France), with the ESPO Conferences being held at the intervening two-year periods (1996 Siena, Italy; 2001 Graz, Austria; 2004 Athens, Greece; and 2008 Budapest, Hungary). Several European countries have established national societies for pediatric ORL. These include the Association Française d’Otorhinolaryngologie Pédiatrique, the British Association for Paediatric Otorhinolaryngology, the Dutch/ Flemish Working Group for Pediatric Otorhinolaryngology, the Hungarian Society of Otorhinolaryngologists Section on Pediatric Otorhinolaryngology, the Italian Society of Pediatric Otorhinolaryngology, and the Polish Society of Pediatric Otolaryngology.

ASIA AND AUSTRALASIA The Japan Society for Pediatric Otorhinolaryngology was founded in 1979. In composition, it is similar to SENTAC in that the society members consist of both otolaryngologists (approximately 80%) and pediatricians (approximately 20%).56 The society was initiated by Prof. Junichi Suzuki of Teikyo University and Dr. Keijiro Koga of The National Children’s Hospital, both in Tokyo, for the purpose of developing education, practice, and science in pediatric otorhinolaryngology. Conferences were held twice a year in July and December from 1980 to 2005 with the July conference in Osaka and the December conference in Tokyo; each conference focused on a particular theme of pediatric ORL, and presented papers were published twice a year in the Pediatric Otorhinolaryngology Japan. In 2006, the Japan Society for Pediatric Otorhinolaryngology changed the organization from holding two conferences a year to an annual meeting and to publish three issues of the society’s journal each year. Prof. Shinsaku Horiuchi of the Tokyo Medical and Dental University was the first president of the society, serving from 1979 until 1990, and Dr. Yoshiharu Niino was the first editor-in-chief of the

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Pediatric Otorhinolaryngology Japan, from 1980 until 1992. Currently, the society has approximately 600 members. Australia and New Zealand have established the Australasian Society of Paediatric Otorhinolaryngology,57 which was formed with the purpose of enabling pediatric ear, nose, and throat—head and neck surgical specialists to engage in meaningful discussion and clinical information sharing. The society promotes research in pediatric ORL and has an annual discussion forum. Membership is for ear, nose, and throat— head and neck surgical specialists who devote a substantial portion of their clinical work to pediatric care. Membership in the society, by application, is open to Australian and New Zealand surgeons.

SOUTH AMERICA58 Alexandre Médicis da Silveira in 1960 established a pediatric ORL service at the Hospital Infantil Meñino Jesus in São Paulo, Brazil. Several clinically focused conferences were held subsequently, and by 1977, these became more frequent, aided by the University of São Paulo Medical School together with that at the University of Rio Grande do Sul. Dr. Tania Sih of University of São Paulo Medical School published the first book on pediatric ORL written in Portuguese in 1998,59 followed by an edition in Spanish60 in 1999. Dr. Alberto Chinski founded the Asociación Argentina de Otorrinolaringologia y Fonoaudiologia Pediátrica, which has organized several meetings in Argentina. In 1994, Drs. Sih from Sao Palo, Brazil, Chinski from Buenos Aires, Argentina, and Roland Eavey from Boston, United States, initiated the formation of a pan-Latin American organization devoted to pediatric ORL to promote diffusion of knowledge in this area. A year later, the Interamerican Association of Pediatric Otorhinolaryngology (IAPO) was established officially in Argentina. One hundred and fifty practitioners in ORL joined the organization at that time, and Dr. Sylvan Stool became its first president. Since 1996, IAPO has promoted several Congresses held in Brazil, Ecuador, United States, Chile, Colombia, Argentina, and Panama and an international symposium every other year in São Paulo, Brazil. Thus, the organization has indeed succeeded in bringing together practitioners from much of Latin America. While focused on Latin America, its geographical inclusiveness has brought in physicians from well beyond that region, and it has enjoyed great growth in membership. Today, IAPO has over 6000 members from 85 countries across 5 continents.

CONCLUSION Pediatric otolaryngic care developed from 1600 to 2000 as a result of medical advances related to evolving conceptions of the philosophical, sociological, and economic status of the child. In the earlier periods, while from our current perspective, there was need for pediatric otolaryngic care, the demand, the economic resources, and the knowledge to effect it were not existent. Today the story is quite different:

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the needs are better understood, knowledge has advanced greatly, and almost all children in the developed nations can receive effective pediatric otolaryngic care. A substantial need remains for the effective care of children in the developing nations of the world.61 This need must be fulfilled with the deployment of appropriately educated health care providers and the fiscal resources to enable timely, effective, and efficacious prevention and care of otolaryngologic pathologies in children. This is more essential than ever because in the 21st century, the world’s economy is based fundamentally on communication, the diseases and disorders of which are the province of pediatric otorhinolaryngology.62

References 1. Ariès P. Centuries of Childhood: A Social History of Family Life, English translation by Baldick R, ed. New York, NY: Vintage Books; 1962:1–447. 2. Ruben RJ. Development of otorhinological care of the child. Acta Otolaryngol. 2004;124(4):536–539. 3. Cunningham H. Children and Childhood in Western Society since 1500. Harlow, UK: Longman; 1995:1–213. 4. Locke J. Some Thoughts Concerning Education. 4th ed. London, UK: A. and J. Churchill; 1699:1–380. 5. Marvick EW. Nature versus nurture: patterns and trends in seventeenth-century French child rearing. In: de Mause L, ed. 301. Paper ed. North Vale, NJ: Jason Aronson; 1974:259. 6. Crump L. Nursery Life 300 Years Ago. London, UK: George Routledge & Sons, LTD; 1929:1–251. 7. Bonet JP. Reduction of Letters and Art to Teach the Dumb to Speak. Madrid, Spain: Abarca de Angulo; 1620. 8. Plann S. A Silent Minority: Deaf Education in Spain, 1550–1835. Berkeley, CA: University of California Press; 1997:1–323. 9. Rousseau JJ. Emile, or On Education. (Emile, or On Education). Paris, France: A La Haye; 1762. 10. Newberry J. A Little Pretty Pocket-Book, Intended for the Amusement of Little Master Tommy and Pretty Miss Polly with Two Letters from Jack the Giant Killer. London, UK: Bible and Crown without Temple-Bar; 1744. 11. de L’Épée CM. Institution for the Deaf and Dumb, or, Collection of Exercises Supported by the Deaf & Dumb for Years 1771, 1772, 1773, & 1774 with the Letters that Accompanied the Programs of each of these Exercises. Paris, France: l’Imprimerie de Butard; 1774. 12. Loi Relative à M. Act Relative to the Abbe de l’Epee, and Its Establishment in Favor of Deaf & Dumb, Passed by the National Assembly, Paris, July 29, 1791. Department of Varennes. 1791. Département du Varennes. 1791. 13. Schama S. Citizens: A Chronicle of the French Revolution. New York, NY: Knopf; 1989. 14. Mitchell, SL. A Discourse Pronounced by Request of the Society for the Instructing of the Deaf and Dumb at the City Hall in the City of New York. New York, NY: E. Conrad; 1818:1–58. 15. Ruben RJ. Otorhinolaryngology: history in state of New York. N Y State J Med. 1978;78(11):1793–1796. 16. Ruben RJ. Development of pediatric otolaryngology in North America. Int J Pediatr Otorhinolaryngol. 2009;73:541–546. 17. Downes JJ. Historic origins and role of pediatric anesthesiology in child health care. Pediatr Clin North Am. 1994; 41(1):1–14.

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CHAPTER 1 ❖ Evolution of Pediatric Otolaryngology 18. Meyer HW. About adenoid vegetations. Hospitalstidende. 1868;11:177–181. 19. Stern AM. Better babies contests at the Indiana state fair. In: Stern AM, Markel H, eds. Formative Years: Children’s Health in the United States 1880–2000. Ann Arbor, MI: University of Michigan Press; 2001:121–152. 20. Stern AM. Making better babies: public health and race betterment in Indiana, 1920–1935. Am J Public Health. 2002;92(5):742–752. 21. O’Dwyer JP. Two cases of croup treated by tubage of the glottis. NY Med J. 1885;42:145–147. 22. O’Dwyer JP. Analysis of fifty cases of croup treated by intubation of the larynx. NY Med J. 1888;47:1841–1898. 23. Jackson C, Jackson CL. Diseases of the Air and Food Passages of Foreign-Body Origin. Philadelphia, PA: W.B. Saunders Company; 1936:1–635. 24. Jackson C, Lewis FO, Mackenzie GW. Report of the committee on lye legislation. JAMA. 1922;79:1843–1846. 25. Flecther H, Wengel RL. The frequency sensitivity of normal ears. Physiol Rev. 1922;19:553. 26. Fowler EP, Wengel RL. Presentation of a new instrument for determining the amount and character of auditory sensation. Trans Am Otol Soc. 1922;16:105–103. 27. Fowler EP, Wengel RL. Audiometric methods and their applications. Trans Am Laryngol Rhinol Otol Soc. 1922;28: 98–132. 28. Fowler EP, Flecther H. Three million deafened school children. Arch Otolaryngol. 1928;87:1877–1882. 29. Baker JP. Technology in the nursery: incubators. In: Stern AM, Markel H, eds. Ventilators and the Rescue of Premature Infants. Ann Arbor, MI: University of Michigan Press; 2002:66–90. 30. Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. Am J Dis Child. 1959;97: 518–523. 31. Fearon B, Cotton R. Surgical correction of subglottic stenosis of the larynx. Preliminary report of an experimental surgical technique, Ann Otol Rhinol Laryngol. 1972;81(4):508–513. 32. Fearon B, Cotton R. Surgical correction of subglottic stenosis of the larynx in infants and children. Progress report. Ann Otol Rhinol Laryngol. 1974;83(4):428–431. 33. Fior R. A historic profile of pediatric otorhinolaryngology. Int J Pediatr Otorhinolaryngol. 1992;23(3):253–259. 34. Stool SE. Evolution of pediatric otolaryngology. Pediatr Clin North Am. 1989;36(6):1363–1369. 35. Stool SE. Reflections. 2000. Personal communication. 36. Jazbi B. Advances in Oto-Rhino-Laryngology, Vol. 23. Pediatric Otorhinolaryngology. Eds: Jazbi B. and S. Krager; 1978;23:VIII–208. 37. Ruben RJ. Diary entry. November 9, 1975:218–252. 38. Ruben RJ. Diary entry. June 12, 1978:685–701. 39. Ruben RJ. Diary entry. April 3, 1977:765–783. 40. Ruben RJ. Diary entry. April 6, 1978:1173–1196.

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41. 42. 43. 44. 45.

46. 47. 48. 49. 50. 51.

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Ruben RJ. Diary entry. April 23, 1978:1438–1445. Ruben RJ. Diary entry. March 15, 1979:1554–1565. Ruben RJ. Diary entry. March 21, 1980:1867–1874. Ruben RJ. Diary entry. April 2, 1981:2205–2211. Healy GB, Gelber RD, Trowbridge AL, Grundfast KM, Ruben RJ, Price KN. Treatment of recurrent respiratory papillomatosis with human leukocyte interferon. Results of a multicenter randomized clinical trial. N Engl J Med. 1988;319(7):401–407. Ruben RJ. Diary entry. October 13, 1979:1806–1811. ACGME. http://www.acgme.org/adspublic/. Accessed November 5, 2008. Pediatric ORL Fellowships. http://aspo.us/fellowship-listing/. Accessed April 1, 2009. PED ORL Match. http://aspo.us/fellowship-listing/. Accessed April 1, 2009. Stevens R. American Medicine and the Public Interest. Berkeley, CA: University of California Press; 1998. Chmielik M, Kossowska E, Brożek-Mądry E. The history of pediatric otorhinolaryngology in Poland. Int J Pediatr Otorhinolaryngol. 2009. Chmielik M, Bielicka A, Ranocha C, Chmielik L. History and present situation of paediatric ENT surgery in Poland and in other central east European countries. Elsevier Int Congr Ser. 2003;1240:1371–1374. Fior R. About the 1977 world congress of pediatric otorhinolaryngology in Sirmione. Int J Pediatr Otorhinolaryngol. 2009. Ruben RJ. The origins of the international journal of pediatric otorhinolaryngology. Int J Pediatr Otorhinolaryngol. 2009. Pirsig W. The first European course of pediatric otorhinolaryngology in Trieste in October 1978. Int J Pediatr Otorhinolaryngol. 2009. Kaga K. Activities of 30 years of Japan Society for pediatric otorhinolaryngology. Int J Pediatr Otorhinolaryngol. 2009; 73:535-536. The Australian Society of Paediatric Otorhinolaryngology. http://www.asporl.org/. Accessed March 7, 2009. Sih T, Lubianca JF, Godinho R. History and evolution of pediatric otolaryngology (PED ENT) in Latin America. Int J Pediatr Otorhinolaryngol. 2009. Sih T. Otorrinolaringologia Pediátrica. Rio de Janeiro, Brazil: Revinter; 1998. Sih T. II Manual de Otorrinolaringologia Pediátrica da IAPO. Barcelona, Spain: Springer-Verlag Ibérica; 1999. Olusanya BO, Ruben RJ, Parving A. Reducing the burden of communication disorders in the developing world: an opportunity for the millennium development project. JAMA. 2006;296(4):441–444. Ruben RJ. Redefining the survival of the fittest: communication disorders in the 21st century. Laryngoscope. 2000;110 (2 Pt 1):241–245. Bunch CC. Clinical Audiometry. St. Louis, MO: C.V. Mosby Co; 1943.

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2

C H A P T E R

K

Phylogenetic Aspects and Embryology Anne Chun-Hui Tsai and Carol Walton

nowledge of the embryology, growth, and development of the face and craniofacial complex, and of the various factors involved in normal variations and anomalies of this region, facilitates understanding of the many otorhinolaryngologic disorders affecting infants and children. The face is the first region that the clinician and, indeed, the layperson inspect on encountering another person. An evaluation of facial type and facial expression are usually made instantly; thereafter, the general body type and posture are noted. This immediate composite impression provides important nonverbal clues to feelings, affect, and communication. Any observer can appreciate that there is great variation in the appearance of the normal face. In addition, there are certain characteristics that we associate with facial types almost on an instinctive basis. These variations and expectations in facial types can be appreciated by examining Fig. 2-1, which is a sketch of a group of children of different ethnic backgrounds. The variations in facial configuration are obvious: there are round, oval, long, and triangular faces. Individual characteristics of the eyes and the nose also show tremendous variation. The diagnosis of certain conditions based on facial configuration may be difficult to make unless the observer knows the hereditary background of the individual. For example, although the craniofacial features of Down syndrome are readily recognizable, an Asian newborn with a flat nasal bridge and bilateral single palmar creases could be mistaken as having Down syndrome if one is not keeping the ethnic background in mind. Increased intercanthal distance and epicanthic folds are relatively common in the general population among some Asian population.2 Thus, although we recognize great variations in facial type as being normal, we also instinctively recognize other features as being abnormal in a particular individual on the basis of our ability to assess facial patterns in the context of age, race, and ancestry. It is notable that the structures of the human craniofacial complex, which required 500 million years of natural selection to evolve, take shape embryologically in incredibly rapid sequence. The embryogenesis of the craniofacial complex is indeed an amazing phenomenon; form and function must relate to each other with an almost unbelievable precision and at exactly the right points in time. Any interference with this process, particularly in the early embryonic stages, may have catastrophic consequences. An abbreviated review of the normal embryogenesis of the human craniofacial complex follows in order for the pediatric otolaryngologist to appreciate why the anatomical and physiological development of the ears, nose, and throat structures occasionally goes awry.

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Cellular and molecular advances that have contributed to a better understanding of the embryology of facial configuration and the occurrence of craniofacial anomalies of interest to the physician are also discussed. This method of presentation parallels the way in which the clinician usually views patients with anomalies of this region.

PRENATAL DEVELOPMENT OF THE FACE The development of the face from midembryologic through midfetal life is illustrated in Fig. 2-2. At approximately 3–4 weeks of age (Fig. 2-2A), the embryo does not have a face, the head is composed of a brain covered with a membrane, and the anterior neuropore is still present. The eyes, which are represented by optic vesicles, are on the lateral aspects of the head, as in fish, and the future mouth is represented by a stomodeum. The nasal pits develop only in the latter part of this period of embryonic growth. At the embryonic age of 5–6 weeks (Fig. 2-2B), the general shape of the face has begun to develop. The frontonasal process is prominent; the nasal pits are forming laterally; and with the increase in size of the first and second branchial arches, there is the suggestion of a mouth. In the subsequent weeks of embryonic life (Fig. 2-2C), the structures that we associate with the human face—jaws, nose, eyes, ears, and mouth—take on human form.3 During this period of rapid growth and expansion, there is also tremendous differential growth. Thus, the development of a human baby is not merely the enlargement or rearrangement of a previous form but, by differential growth, the development of a new configuration. This is a concept that has been difficult for students to comprehend, perhaps because of the tendency for different stages of embryonic development to be illustrated with drawings of equal size. These illustrating techniques have been used because minute structures are difficult to demonstrate without magnification. It is important, however, to view human embryologic development in both spatial and temporal perspectives to appreciate both its similarities to phylogenetic development and its unique course in humans. The embryonic period ends at about eight weeks, at which time the embryo has achieved sufficient size and form so that facial characteristics can be recognized and photographed at actual size (Fig. 2-2D). At this stage of late embryonic or early fetal development, the facial features are characterized by the appearance of hypertelorism. During subsequent growth, it will appear as though the eyes are moving closer together. This is, however, not the case; the eyes actually continue to move farther apart, but the remainder of the face is growing at a much more rapid rate, and thus it appears that the eyes are moving closer together. These observations may

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FIGURE 2-1. Children from a sixth-grade class. Note the variation of facial types, even though all the children are the same age and race.

FIGURE 2-2. Prenatal facial development. A, An embryo of 3–4 weeks. A.N., anterior neuropore; S., stomodeum. B, An embryo of 5–6 weeks. N.P., nasal pit; 1st B.A., first branchial arch; 2nd B.A., second branchial arch. C, An embryo of 7–8 weeks. D, A fetus of 8–9 weeks. E, A fetus of 3–4 months. Fetal specimens are from the Krause Collection, the Cleft Palate Center, University of Pittsburgh.

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CHAPTER 2 ❖ Phylogenetic Aspects and Embryology be of importance in understanding some of the craniofacial syndromes in which hypertelorism is a prominent feature. The rapid growth and change in configuration, not only of the face, but also of the extremities and body, continue during the next few months (Fig. 2-2E). The fetus now has facial features that are easily recognized and construed as human. The ears, nares, and lips are well developed, and the head constitutes a large portion of the body mass, a relationship that exists at birth and gradually changes during postnatal life. This concept of differential growth is vital to the comprehension of both prenatal and postnatal development. Although this concept is difficult to grasp when the student must view development of structures of different ages magnified to the same size and when illustrations are in two dimensions, it is important to visualize the process in three dimensions as well as in the fourth dimension of time.

FORMATION OF THE CRANIOFACIAL COMPLEX The factors that influence the formation of the craniofacial complex have been the subject of investigation by embryologists for many years. Among the most interesting studies has been the research of Johnston4 into the development and migration of cells in the neural crest. These cells of ectodermal origin are found around the anterior neuropore, as demonstrated in Fig. 2-3A, whereas in most of the body, the embryonic tissue is derived from mesoderm. In the craniofacial complex, it is these neural crest cells that give rise to a

15

large variety of the connective and neural tissue structures of the skull, face, and branchial arches. Therefore such ectodermal tissue constitutes the majority of the pluripotent tissue of the face. The sequence of events after the initial formation of the neural crest cells is illustrated in Fig. 2-3B. The differentiation, proliferation, and migration of these cells are critical in the formation of the face. Neural crest cell migration occurs at different rates. For instance, the cells that form the frontonasal process are derived from the forebrain fold, and their migration is over a relatively short distance as they pass into the nasal region. However, the cells that form the mesenchyme of the maxillary processes have a considerably longer distance to migrate, because they must move into the branchial arches, where they surround the core-like mesodermal muscle plates.5 In Fig. 2-3C, the ultimate distribution of neural crest cells from the frontonasal process and from the branchial arches is illustrated. Because this mesenchymal tissue contributes to the majority of the soft tissues and bones of the face, failure of neural crest cell proliferation or migration may be responsible for a number of craniofacial abnormalities such as orofacial clefting.6 An example of a severe facial abnormality due to failure of neural crest cell migration is illustrated in Fig. 2-3D. Several recognizable craniofacial phenotypes and syndromes result from errors during such embryologic formation of the key structures of the craniofacial complex. Many of these syndromes can now be explained based on recent molecular advances that have contributed to the understanding of the genes involved (Table 2-1).

Neural crest cells A

Stom deum

rontonas

C

ranch

c

FIGURE 2-3. Formation of the craniofacial complex. A, An embryo of 3–4 weeks showing development and beginning migration of neural crest cells. B, Migration of neural crest cells to the forebrain and the branchial arches. C, Contributions to the face of the frontonasal process and branchial arches. D, Deformity caused by failure of neural crest cell migration.

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TABLE 2-1. Molecular Basis of Representative Phenotypes Resulting from Malformation of the Craniofacial Complex Key Facial Feature

Representative Syndrome(s)

Hypotelorism

Holoprosencephaly (Several genetic forms)

Other Features

Gene Symbol

Midline clefts, single/fused central incisor

SHH TGIF SIX 2 SIX 3

Hypertelorism

Midface hypoplasia

Robinow syndrome

“Fetal face” appearance, frontal ROR2 bossing, skeletal dysplasia, genital anomalies

Receptor Tyrosine Kinase-like Orphan Receptor 2 (OMIM 602337)

MID1 n/a

Midline 1 (OMIM 300552) [X-linked form] Deletion of 22q11.2 locus [AD form]

Aarskog syndrome

Hypertelorism, ptosis, anteverted nares, short stature, shawl scrotum (males)

FDG1

FYVE, RhoGEF, and PH Domain-containing Protein 1 (OMIM 300546)

Craniofrontonasal dysplasia

Hypertelorism, brachycephaly, frontal bossing, craniosynostosis (females), bifid nasal tip

EFNB1

Ephrin B1 (OMIM 300035)

Frontonasal dysplasia [aka median cleft face syndrome] (genetic form)

Ocular hypertelorism, broad nasal bridge, bifid nasal tip, median cleft lip

ALX3

Aristaless-like Homeobox 3 (OMIM 606014)

Chondrodysplasia punctata

Punctiform calcification of the bones, epiphyseal stippling, rhizomelic shortening of long bones (some types)

EBP

Emopamil-binding protein (OMIM 300205) [Conradi-Hunerman syndrome] Peroxisome biogenesis factor 7 (OMIM 601757) [Rhizomelic CDP, type 1] Glyceronephosphate O-Acyltransferase (602744) [Rhizomelic CDP, type 2] Alkylglycerone-phosphate synthase (OMIM 603051) [Rhizomelic CDP, type 3] Arylsulfatase E (OMIM 300180) [Brachytelephangic CD]

PEX7

AGPS ARSE Treacher Collins syndrome

Cleft palate, downward slanting eyes, microtia

TCOF1 TCOF2 TCOF3

DIVISIONS OF THE HUMAN FACE From the foregoing discussion, it can be seen that the human face may be divided embryologically (Fig. 2-3C). The median facial structures arise from the frontonasal processes and the lateral structures arise from the branchial arches.

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Sonic Hedgehog Transforming Growth Factor b-Induced Factor (OMIM 602630) Sine Oculis Homeobox, Drosophila, Homolog of, 2 (OMIM 604994) Sine Oculis Homeobox, Drosophila, Homolog of, 2 (OMIM 603714)

Opitz G/BBB syndrome Broad nasal bridge, anteverted nares, cleft lip/palate, laryngotracheal cleft, TE fistula, genital anomalies

GNPAT

Hypoplastic zygomatic arches

Gene Name

TCOF1/TREACLE (OMIM 606847) TOOF2/TSC2 (POLR1D) OMIM 613717 (AD) TCOF3/TSC3 (AR) OMIM 248390 PPOLR1C

This dual embryonic origin provides a basis for dividing the face into three vertical segments. The central segment, primarily the frontonasal process, includes the nose and the central portion of the upper lip. The two lateral segments that arise from the branchial arches may be called the otomaxillomandibular segments. For convenience of description, the

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CHAPTER 2 ❖ Phylogenetic Aspects and Embryology face can also be divided into three almost equal horizontal planes. The upper or frontal horizontal segment derives solely from the frontonasal process. The middle or maxillary segment derives from the maxillary process of the first branchial arch and the prolabium originates from the frontonasal process. The third horizontal segment, the lower or mandibular segment, comes from the mandibular process of the first branchial arch.

PRENATAL CRANIOFACIAL SKELETAL COMPONENTS The craniofacial skeleton provides support and protection for our most vital functions. Conceptually, it is a region with two divisions as follows: that which is involved with the central nervous system, the neurocranium, and that which is involved with respiration and mastication, the visceral cranium. It consists of the following four components: cranial base, cranial vault, nasomaxillary complex, and mandible. The skeletal structures originate spontaneously from two types of bone. One type of bone is first formed in cartilage and the other is derived from membrane. In general, the bones of the skull that represent the earliest phylogenetic structures are first formed as cartilage, which subsequently ossifies; the more recently developed craniofacial structures are derived from membranous bone. The components and structures of the fetal craniofacial complex are illustrated in Fig. 2-4–2-6. Fig. 2-4A and B shows the cartilaginous continuity of the cranial base and nasal septum as well as the arrangement of the fetal facial bones and teeth around the cartilaginous nasal capsule. The nasal septum is attached to the cranial base and the palate and

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thus constitutes a large portion of the skeletal structure in the fetal midface. Although there is much difference of opinion on this subject, growth of craniofacial cartilage is considered by some to be of prime importance in facial development. Fig. 2-4C is a parasagittal section through the cranial base and the facial structures. The cranial base is cartilaginous and provides a floor for the calvaria and a roof for the face.7 The nasal space and nasopharynx are part of the airway system. Although the airway is not functional in the fetus, alterations of the cranial base during fetal life may affect its subsequent development. As mentioned, the craniofacial skeletal complex is composed of bones of different embryonic origins. Fig. 2-5 shows the bones of cartilaginous origin (dark stipple) and those of membranous origin (light stipple); cartilage that is of branchial arch origin is indicated by solid black. In general, the base of the skull and the sphenoid, petrosal, and ethmoid bones are of cartilaginous origin. Growth of the cartilage of the cranial base occurs primarily at the cartilaginous synchondroses until cartilage is replaced by bone; thereafter, growth is at the periosteal margins. Most of the cranial and facial bones are membranous and growth takes place primarily at the margins of these bones. The major facial bones are formed from numerous ossification centers, which subsequently produce single bone in later fetal life. The importance of understanding the dual embryonic origin of the skeleton is that many diseases that affect the craniofacial complex may be manifested because of their influence on particular types of bone. For example, achondroplasia, which affects bones of cartilaginous origin, usually results in a characteristic alteration of facial configuration. The sequential development of the fetal skeleton has been studied extensively by radiographic methods. However, it is

FIGURE 2-4. Photomicrograph of a 15-week-old fetal head. A, Coronal section. B, Sagittal section. dt, deciduous tooth germ; m, maxillary bone center; np, nasopharynx; s, nasal septum. C, parasagittal section. bo, basiocciput, bs, basisphenoid cartilage; np, nasopharynx; so, spheno-occipital synchondrosis. (Adapted from the Krause Collection, the Cleft Palate Center, University of Pittsburgh.)

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Cartilaginous bone Membranous bone

FIGURE 2-5. Schematic illustration of the components of the fetal craniofacial complex of membranous origin (light stipple) and cartilaginous origin (dark stipple). The cartilage of branchial arch origin is indicated in black. (Redrawn from Stewart [1976].)

anticipated that newer imaging techniques, such as magnetic resonance imaging, will provide better visualization of the relationship of the various tissues and improve our understanding of craniofacial morphogenesis. Fig. 2-6 illustrates the definition of the structures that may be obtained by this technique. In addition, ultrasonography is a method of in vivo study that has achieved wide clinical use. This technique permits prenatal study not only of structure but also of function. Fig. 2-7 illustrates some of the information that may be obtained.

DEVELOPMENT OF CRANIOFACIAL ARTERIES, MUSCLES, AND NERVES Fig. 2-8 illustrates the development of the cranium, arteries, nerves, and muscles during embryonic and early fetal life. The characteristics of these structures are discussed in their respective sections because their growth and development are interrelated.

Arteries Fig. 2-8A shows that the early arterial supply to the head consists primarily of the dorsal aorta and an arch with a small branch coming from it, which is the primitive internal carotid artery. The future musculature consists of mesenchymal tissue in the first and second branchial arches, which are just beginning to form. As the head begins to grow and the embryo starts to develop a face, the internal carotid artery increases in both size and length and the aortic arches begin to develop. Each of the branchial arches contains not only an artery but also a nerve and a core of mesodermal tissue. Fig. 2-8B shows an embryo of about six weeks, when the first and second aortic arches

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FIGURE 2-6. A, Transverse magnetic resonance image (T2-weighted) of a 24-week-old aborted fetus at the level of the orbital floors and inner and middle ears. B, Transverse section through the fetal head at the level of the orbits (28 weeks of gestation). C, Sagittal magnetic resonance image of the fetal head (T2-weighted). D, Sagittal section of the fetal head (24 weeks of gestation). (B from Isaacson G, Mintz MC, Crelin ES. Atlas of Fetal Sectional Anatomy. New York, Springer-Verlag, 1986. C from Isaacson G, Mintz MC. Magnetic resonance image of the fetal temporal bone. Laryngoscope 96:1343, 1986. D reprinted with permission from Prenatal visualization of the inner ear, by G Isaacson and MC Mintz. Journal of Ultrasound in Medicine, Vol 5, pp. 409–410. Copyright 1986 by the American Institute of Ultrasound in Medicine.)

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CHAPTER 2 ❖ Phylogenetic Aspects and Embryology

FIGURE 2-7. Ultrasound demonstration of the profile of a fetal face and a fetal ear at 31 to 32 weeks of gestation. (Courtesy of Dr. D.L. Shea, Lady Minto Gulf Island Hospital, B.C., Canada, and Mr. Sander Keil.)

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and their arteries have formed. As the face continues to develop, these vessels ultimately disappear. The internal carotid artery at this stage has increased in size and the facial muscles are beginning to develop. The cranial nerves begin to develop as outgrowths of the central nervous system. As the skull base forms, foramina exist where bone forms around any preexisting soft tissue (blood vessels or nerves). The fifth cranial nerve (trigeminal), which ultimately supplies sensation to the face, is really a combination of three sensory nerves (the ophthalmic, mandibular, and maxillary divisions) as well as a motor nerve to the muscles of mastication. The seventh cranial nerve, which is the nerve supply to the second branchial arch, has also begun its development. By the time the embryo has facial characteristics that appear more human (Fig. 2-8C), the blood supply to the face and cranium has developed the pattern that persists into fetal and postnatal life. The third aortic arch is connected to the embryonic dorsal aorta. This arch becomes the common carotid artery, from which the external carotid artery develops to provide the major blood supply for the face. In general, these vessels have a recognizable pattern, but there is tremendous variation in their sites of origin and in the anastomoses between the internal and external carotid arteries. Fig. 2-8D illustrates the formation of the arterial supply. Note the disappearance of the first and second aortic arches; the persistence of the third arch, which becomes the common carotid; and the disappearance of the dorsal aorta between the third and fourth arches, which on the left will become the aorta. Disruptions of blood flow or angiogenesis anomalies of genetic and nongenetic nature represent important mechanisms producing craniofacial anomalies.

Muscles By the end of embryonic life, the facial musculature has become well developed and has migrated extensively superiorly into the craniofacial region. Fig. 2-8E shows the muscles contributed by the various laminae. The first branchial arch contributes the muscles that lie beneath the musculature of the second branchial arch and, in general, these have a different orientation. These muscles include the temporal, masseter, pterygoid, mylohyoid, and anterior belly of the digastric as well as the tensor muscle of the velum palatinum and the tensor muscle of the tympanum. FIGURE 2-8. Development of the craniofacial arteries, muscles, and nerves. A, A 3- to 4- week-old embryo. B, A 5- to 6-week-old embryo. C, A 7- to 8-week-old embryo. D, The fate of the aortic arches (shaded vessels persist). (Adapted from Avery.3) E, Distribution of the facial musculature in the 15-week- old fetus. (Adapted from Gasser.9)

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Nerves The nerve supply to the muscles of the face has been described by Gasser9 with further detailed discussion of the facial nerve by May.10

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MOLECULAR CONTROL OF CRANIOFACIAL DEVELOPMENT

and control of patterning data are complex and the signal transduction system is modulated at all points.

The subject of embryology is complex, running the gamut from a descriptive chronology of events that transpire during prenatal life to details of genetic types and mutations and how they affect the individual proteins and nucleic acids that are part of the molecular biology of the embryo. The transformation of a fertilized egg into a baby requires remarkable orchestration of cell migration, cell differentiation, programmed cell death, and differential growth. The information that controls this incredibly complex process is encoded in the DNA. Since each cell in the body contains the entire genome, the control of the expression of the different genes in the DNA is crucial to the differentiation of the developing organism. Many diverse organisms use essentially the same genes to control development. Genetic mechanisms that determine the anteroposterior axis, the dorsoventral axis, and left–right symmetry operate early in embryonic development. Establishment of the three layers (ectoderm, mesoderm, and endoderm) and the subsequent subdivision of the layers and tissue differentiation are also under genetic and epigenetic control. The transmission

Developmental Gene Clusters

Conserved amino terminus

Variable region

The molecular control of embryogenesis is achieved by a complex series of genes that are expressed in distinct spatial and temporal patterns in the developing embryo. These molecules can be classified into several groups as follows: transcription factors, signaling molecules, and receptors. Transcription factors The transcription factor genes act as master switches, turning other genes on and off, and thus provide genetic control of morphologic development. These genes are activated in an orderly sequence and encode nuclear DNA binding proteins that exert either positive or negative transcriptional control on other genes. These proteins act by high-affinity, site-specific binding to cognate DNA binding sites. One of the most important types of transcription factors is represented by the homeodomain proteins. These proteins contain a highly conserved homeodomain of 60 amino acids, which is a type of helix-loop-helix region (Fig. 2-9A).

Hinge region

Acidic tail Homeodomain

H2N

COOH

60 amino acids

Homeodomain α-helices 1

2

3

4

DNA-binding helix

Hexapeptide

Drosophila Hox cluster

Hexapeptide: Hox Paired domain

Ancestral Hox cluster

Paired: Pax POU-specific domain

HOXA

POU Human

LIM motif LIM

ZF

(C2–H2 Zinc fingers) 9–17

(Homeobox)

1–4

HOXB

Lab pb

bcd zen Dfd Scr

Ubx abd-A Abd-B

Hox1Hox2 Hox3Hox4Hox5 Hox6 (central)

A1

A2

A3

A4

A5

A6

A7

B1

B2

B3

B4

B5

B6

B7

C4

C5 C6

HOXC HOXD

Chromosome ftz Antp

D1

D3

D4

3

Hox 7 (posterior)

A9 A10 A11 B8 B9

A13 B13

C8 C9 C10 C11 C12 C13 D8 D9 D10 D11 D12 D13

7 17 12 2

FIGURE 2-9. A, Structure of a typical homeodomain protein, B, schematic representation of classes of homeobox-containing genes also possessing conserved motifs outside the homeodomain. Names of the different classes of genes are listed on the left. The red boxes represent the homeobox within each gene class. The other boxes represent conserved motifs specific to each class of genes. (Modified from Duboule.25) C, Comparison of mouse and human homeobox complexes to Drosophlia. (Modified from Veraksa et al.13)

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CHAPTER 2 ❖ Phylogenetic Aspects and Embryology The 180 nucleotides in the gene that encode the homeodomain are collectively called a homeobox. Homeobox regions were first discovered in the homeotic genes of Drosophila. Many other gene families contain not only a homeobox, but also other conserved sequences such as in the Zinc finger gene family (Fig. 2-9B). Examples of human homeobox genes include HOX, PAX, POU, DLX, MLX, and Zinc finger genes. Complete classification and nomenclature of all human homeobox genes are summarized by Holland et al.13 Signaling molecules Signaling molecules leave the cells that produce them and exert their effects on other cells, which may be neighboring cells or cells located at greater distances. Many signaling molecules are peptide growth factors that mediate interactions such as inductions between groups of cells in embryogenesis. When the signaling molecules form complexes with the receptors, they set off a cascade of events in a signal transduction pathway that transmits the molecular signals to the nucleus of the responding cells. The transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), and hedgehog gene families are important examples of this group. The TGF-β superfamily consists of a large number of molecules coded for by up to 30 genes and can be grouped into general classes (Fig. 2-10). Table 2-2 demonstrates some examples of BMP-2 BMP-4 dpp BMP-5 BMP-6/Vgr1 BMP-7/OP1 BMP-8/OP2 60A GDF-5 GDF-6 GDF-7 Vg1 GDF-1 GDF-3/Vgr2 Dorsalin BMP-3/Ost’n GDF-10 Nodal Inh-βΑ Inh-βΒ TGF-β1 TGF-β5 TGF-β2 TGF-β3 MIS GDF-9 FIGURE 2-10. TGF-β family comprises distinct factors that can Inhibin-α be arranged into clusters (boxes) of related isoforms. GDNF BMP-3 is

also called osteogenin. (Modified from Massagé.15)

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TABLE 2-2. Examples of Members of the TGF-b Superfamily and Their Functions

Member

Representative Functions

TGF-b1 to TGF-b5

Mesodermal induction Myoblast proliferation Invasion of cardiac jelly by atrioventricular endothelial cells

Activin

Granulosa cell proliferation Mesodermal induction

Inhibin

Inhibition of gonadotropin secretion by hypophysis

Mullerian inhibiting substance

Regression of paramesonephric ducts

Decapentaplegic

Signaling in limb development

Vg1

Mesodermal and primitive streak induction

BMP-1 to BMP-15

Induction of neural plate, induction of skeletal differentiation, and other inductions

Nodal

Formation of mesoderm and primitive streak, left–right axial fixation

Glial cell linederived neurotrophic factor

Induction of outgrowth of ureteric bud, neural colonization of gut

Source: Modified from Carlson.

members and their specific functions. TGF-β has an important role in cranial suture regulation, that is, maintaining the patency and closure of sutures at the proper time through interactions with other molecules, and it is said to have a secondary role in premature craniosynostosis. Members of the FGF family (FGF-1 to FGF-9) similarly fulfill various functions in embryogenesis. Sonic hedgehog (SHH), one of the three hedgehog proteins described in mammals, is a chief secretory product produced by various organizing centers in the embryo, stimulating target cells to produce new gene products or to undergo new pathways of differentiation. FGF and SHH participate in morphogenetic organization and stimulation of mesenchymal outgrowth of the facial primordia, resulting in outgrowth of the frontonasal, maxillary, and mandibular processes. Other examples of signaling molecules include JAGGED1, patched, CREBbinding protein, GLI3, FGFR1, CASK, treacle, FGFR2, and Wnts (pronounced wints). Receptors The signaling molecules must interact with receptors to exert an effect on responding cells. Most receptors are located on the cell surface whereas some are intracellular, such as those for lipid-soluble molecules, for example, steroids, retinoids, and thyroid hormone. Cell surface receptors

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are composed of three domains as follows: extracellular, transmembrane, and cytoplasmic. Extracellular domains contain a binding site for the ligand, which when bound effects a conformational change in the cytoplasmic domain of the receptor molecule. Cell surface receptors are of two main types as follows: those with intrinsic protein kinase activity and those that use a second-messenger system to activate cytoplasmic protein kinases. Examples of the first type include the receptors for the various fibroblastic growth factors (FGFRs). Mutations in these FGFRs can result in craniofacial malformations and many skeletal dysplasias (see later). In the second type of cell receptors, the receptors are activated by being bound with a ligand such as a neurotransmitter, peptide hormone, or growth factor, but a series of intermediate steps is required to activate cytoplasmic protein kinase (CPK). Noonan syndrome and similar syndromes are examples of mutation disruptions of this CPK activation pathway.

THE MOLECULAR BASIS OF SELECTED CRANIOFACIAL SYNDROMES Advances in molecular genetics and understanding of genetic regulation of development in humans and other organisms increasingly inform our knowledge of embryological processes underlying well-recognized clinical syndromes and phenotypes. The following selected examples illustrate how complex interactions between genetic and developmental processes produce syndromes and phenotypes of interest to clinicians seeing patients with craniofacial disorders. Refer also to Table 3-15 for discussion of clinical and genetic aspects of other important syndromes with craniofacial anomalies.

Waardenburg Syndrome Waardenburg syndrome is an autosomal dominant disorder characterized by sensorineural hearing loss, dystopia canthorum, and pigmentary disturbances such as heterochromia iridis and white forelock. Waardenburg syndrome is divided into type I (WS1) with dystopia canthorum and type II (WS2) without dystopia canthorum. Type III (WS3), with dystopia canthorum and limb abnormalities, also known as Klein–Waardenburg syndrome, and type IV (WS4), with Hirschsprung disease, also known as Waardenburg–Shah syndrome, have also been described. WS1 and WS3 are due to mutations in the PAX3 gene on 2q35. Some WS2 cases (WS2A) are associated with mutations in the microphthalmia-associated transcription factor (MITF) gene on 3p14.1-p12, whereas other WS2 families (WS2B) were mapped to 1p21-p13.3. The WS4 phenotype can result from mutations in the endothelin-B receptor gene (EDNRB) on 13q22.3, in the gene for its ligand, endothelin-3 (EDN3) on 20q13.2–13.3, or in the SOX10 gene on 22q13. The mouse model of WS1 is splotch. The splotch mouse was shown to have mutations in Pax3. PAX3 is expressed in

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the dorsal neuroepithelium, the craniofacial mesectoderm, and the limb mesenchyme, which are the precursors of the tissues defective in Waardenburg syndrome. Waardenburg syndrome is an example of genetic heterogeneity, in which mutations in different genes can produce a similar phenotype. An interaction among SOX10, PAX3, and MITF has been demonstrated. A cascade reaction was also proposed among PAX3, MITF, SOX10, EDNRB, and EDB3. Such an epistatic relationship might explain why when these genes are altered, a variable range of auditory-pigmentaryneural crest changes results, as seen in different types of Waardenburg syndrome.

Craniosynostosis Syndromes Fibroblast growth factor receptors (fgfrs) mutations FGFR2 Mutations in CRouzon and otheR syndRoMes The FGFR genes are a family of four tyrosine kinase receptors that rest on cell surfaces and function to bind FGFs, family signaling molecules that function to regulate cell proliferation, differentiation, and migration through various complex pathways. They are important in angiogenesis, wound healing, limb development, and malignant transformation. FGFs binds to FGFRs in a nonspecific manner, as any FGF can bind to the FGFR. FGFR mutations are hypermorphic, causing the gene product to perform its normal function excessively. Research has suggested that the exact mechanism of the hypermorphic effect is different for different types of mutations that have been reported in the FGFR craniosynostosis syndromes. Crouzon syndrome (CS) is an autosomal dominant condition characterized by premature craniosynostosis, hypoplastic maxilla, shallow orbits with proptosis, and external auditory canal atresia. As many as 50% of patients with CS have hearing loss, both conductive and sensorineural. Otitis media with effusion is prevalent due to eustachian tube dysfunction and malformation; thus, myringotomy and tube placement may be necessary to optimize hearing. Patients with CS may have various communication disorders related to hearing loss and the dysmorphogenesis of oral and pharyngeal structures. Language development, acquisition of voice, and articulation skills can be impacted. CS has been mapped to the long arm of chromosome 10. This mapping work was quickly followed by the discovery that mutations in the FGFR2 gene were associated with some cases of CS. Two lines of reasoning led to this discovery. FGFR2 had been shown to map to 10q25, and FGFR2 gene products were expressed in murine embryogenesis, particularly in the frontal bones, maxilla, and mandible. Several of the identified point mutations substituted a tyrosine for a cysteine within the third immunoglobulin domain, presumably affecting the ability of FGFR2 to bind its ligands. Ligand binding is necessary for dimerization of the receptor, which in turn activates the intracellular tyrosine kinase domains.

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CHAPTER 2 ❖ Phylogenetic Aspects and Embryology Mutations in FGFR2 have also been associated with three other craniosynostosis syndromes as follows: Jackson–Weiss, Apert, and Pfeiffer. Although the hands and feet are normal in patients with CS, various malformations of the hands and feet are seen in each of these syndromes. Of great interest is the fact that identical mutations in the FGFR2 gene can cause both Pfeiffer syndrome and CS. Mutations in FGFR1 have also been associated with Pfeiffer syndrome. Thus, investigations to date have shown that mutations in the same gene can cause four different clinical syndromes, mutations in different genes can cause the same syndrome, and identical mutations in the same gene can cause separate syndromes. The last observation implies that other genetic factors must be involved. The roles of the FGF receptors and ligands in human craniofacial development and overall skeletal morphogenesis have become the subject of intense investigation. FGFR3 and CRaniosynostosis FGFR3 mutations were initially described in dwarfism syndromes—achondroplasia, hypochondroplasia, and thanatophoric dysplasia. However, Meyers et al.16 found a mutation in which alanine was substituted for glutamic acid at amino acid position 391 in patients with a crouzonoid phenotype, acanthosis nigricans, and cementomas of the jaws. The FGFR3 coronal synostosis syndrome (Muenke-type craniosynostosis) is one of the most common human mutations known. It is frequently familial, often with a markedly variable phenotype, even within a single family. The mutation was first identified in a series of individuals and families with syndromic coronal craniosynostosis, including some who had previously been labeled as having Pfeiffer, Jackson–Weiss, and Saethre–Chotzen syndromes (SCSs). This mutation (Pro252Arg) is analogous to the one that was described in FGFR1 (Pfeiffer syndrome) and FGFR2 (Apert syndrome). Subsequent studies have shown that this mutation can be found in patients with isolated unicoronal or bicoronal synostosis, isolated macrocephaly, and isolated sensorineural hearing loss.

SCS SCS is an autosomal dominant acrocraniosynostotic syndrome characterized by craniosynostosis, low frontal hairline, facial asymmetry, brachydactyly, clinodactyly, and syndactyly. It has been mapped to chromosome 7p21. The gene, called TWIST (OMIM 601622), contains a basic helixloop-helix domain, a motif commonly seen in DNA binding proteins, suggesting that TWIST functions as a transcription factor. Studies have shown that TWIST is required for normal cranial neural tube closure in mice, but its exact role in suture biology is yet to be defined. TWIST may be involved upstream in the same pathway as the FGFRs, possibly regulating their expression. TWIST mutations in patients with SCS cause premature termination of the protein, suggesting that Saethre–Chotzen is caused by haploinsufficiency of TWIST.

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A significant proportion of patients with Saethre– Chotzen syndrome had deletions in 7p21.1 that encompass the TWIST gene; these could be detected by fluorescent in situ hybridization. Studies on stability, dimerization capacities, and subcellular distribution of three types of TWIST mutant revealed that at least two distinct mechanisms account for loss of TWIST protein function in patients with SCS—namely, protein degradation and subcellular mislocalization. A subset of patients with SCS phenotype can be caused by very specific FGFR3 mutation, namely, P250R, as seen in Muenke syndrome (see earlier in the text).17 In addition, at least one individual with a phenotype of SCS has been described with a mutation in the FGFR2 gene.18

Treacher Collins Syndrome Treacher Collins syndrome is an autosomal dominant craniofacial disorder characterized by malar and mandibular bone hypoplasia, abnormal pinnae and ossicles, downward-slanting palpebral fissures with notching of the lower eyelids, and cleft palate. The gene TCOF1 has been cloned and localized to 5q32-33 and its product, TREACLE, identified. The gene is widely expressed in various embryonic and adult tissues of the mouse. Peak levels of expression in the developing embryo were observed at the edges of the neural folds immediately before fusion and in the developing branchial arches at the time of critical morphogenetic events. The exact role for this gene in the development of the craniofacial complex is not completely understood. However, TREACLE is believed to be involved in nucleolar-cytoplasmic transport. One hypothesis is that the defective protein impairs the nucleolar trafficking that is critically required during craniofacial development, but others emphasize a nuclear phosphoration role for TREACLE because appropriate kinase activity in branchial arches I and II coincides with peak expression of TREACLE. It has been suggested that mandibulofacial dysostosis is a heterogeneous entity and that evaluation and counseling of affected persons should be undertaken with caution. Recently, more genes have been found. Treacher Collins syndrome type 2 (TCS2; 613717) is caused by heterozygous mutation in the POLR1D gene on chromosome 13q12.2. Treacher Collins syndrome type 3 (TCS3; 248390) is caused by compound heterozygous mutation in the POLR1C gene on chromosome 6.

Cleft Lip and Palate Congenital clefting anomalies of the lip and/or palate affect approximately 1 in 1000 live births. Their frequent occurrence and the extensive psychologic, surgical, speech, and dental involvement emphasize the importance of understanding the underlying causes. The clefting appears to result from failure of mesenchymal cell migration or mesenchymal cell transformation at the point of fusion. It can present as a component of many congenital anomaly syndromes or as a single gene disorder and may have teratogenic origins. The nonsyndromic

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forms are the most common and are likely due to secondary gene-environment interactions. Advances in both molecular and quantitative approaches have begun to identify the genes responsible for the rare syndromic forms of clefting and have also identified both candidate genes and loci for the more common and complex nonsyndromic variants. Specific alleles of TGF-α have been shown to be associated with nonsyndromic cleft palate. Related environmental factors include nutritional deprivation; phenytoin, valproic acid, thalidomide, alcohol, and dioxin are recognized teratogens that cause clefts. The exposures may disrupt the metabolic pathway that has a role in the development of cleft lip and palate. MSX1, TGFB3, RARA, ARNT2, BMP4, BMP2, FGF10, and SHOX219,20,21,22 were proposed to be contributing genes for causing cleft lip and palate. Van der Woude syndrome, the most common clefting syndrome, is a Mendelian condition with cleft lip and palate in association with pits and/or sinuses of the lower lip. Most reported cases of VWS have been attributed to mutations in the IRF6 gene mapped to chromosome 1q32-q41 (VWS1), but a second VWS locus (VWS2) has been mapped to 1p34.23 IRF-6 V274I polymorphism (rs2235371) was found to be associated in patients with nonsyndromic cleft lip and palate,24 but was not considered causal given its multifactorial inheritance. Identification of loci for this disease is likely to make great contributions to the understanding of other genes and pathways that play a part in the development of cleft lip and palate.

CONCLUSION Progress in identifying the mechanisms of control of human facial development has been accelerated by advances in molecular genetics. Identification of the genes responsible is a crucial step toward the ultimate understanding of the development of the face. Mapping and identification of the genes associated with craniofacial abnormalities will eventually elucidate the biochemical and molecular mechanisms that control the development of the human face. Knowledge of the molecular mechanisms of human craniofacial anomalies may suggest approaches for their amelioration, correction, and ultimate prevention.

Acknowledgments We would like to thank Dr. J. Christopher Post and late Dr. Sylvan Stool for their invaluable foundation and contribution to this chapter.

Selected Readings Ayala F. The mechanisms of evolution. Sci Am. 1978;239:56. This well-illustrated article explains the concepts of molecular biology as related to evolution. The entire issue is devoted to evolution. Burdi A. Biological forces which shape the human mid-face before birth. In: McNamara J, ed. Craniofacial Growth Series,

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Monograph 6. Ann Arbor, MI: Center for Human Growth and Development, University of Michigan; 1976. This comprehensive article relates molecular biology to embryonic and fetal growth. Carlson MB. Human Embryology and Developmental Biology, 4th ed. Mosby: Elsevier; 2009, p. 73. This book offers good general molecular embryology and excellent visual aide in understanding embryogenesis. Cohen MM Jr, Maclean RE. Craniosynostosis Diagnosis, Evaluation and Management, 2nd ed. Oxford, NY: Oxford University Press; 2000. Enlow D. Essentials of Facial Growth. Philadelphia, PA: WB Saunders; 1996. These books are written primarily in atlas style and illustrates craniofacial growth from embryonic to adult life. Holland PWH, Booth HA, Bruford EA. Classification and nomenclature of all human homeobox genes. BMC Biology. 2007;5(1):47. This article offers comprehensive functional classification and review of homeobox genes including pseudo genes in the human genome, describing many new loci and revisiting the nomenclature of homeobox genes. Isaacson G. Atlas of Fetal Sectional Anatomy. New York, NY: Springer-Verlag; 1986. An excellent atlas of fetal sectional anatomy, this book correlates gross, magnetic resonance imaging, and ultrasound findings. Massagué J. A very private TGF-beta receptor embrace. Mol Cell. 1, 2008;29(2):149–150. A good overview on the crystal structure of a six-element TGFb:receptor complex, addressing long-standing questions about the restrictive nature of this vital receptor Interaction. May M. The Facial Nerve. 2nd ed. New York, NY: Thieme Medical Publishers; 2000. An outstanding review of the anatomy, physiology, and disease states of the facial nerve. Moore KL, Persaud TVN. Before We Are Born: Essentials of Embryology and Birth Defects. 7th ed. Philadelphia, PA: WB Saunders; 2007. A clinically oriented embryology text that is well illustrated. Online Mendelian Inheritance in Man (OMIM). http://www.ncbi .nlm.nih.gov/entrez A complete online catalog of all human genes with a phenotype or a function. OMIM was kept as a documentary of human gene discoveries; therefore, historical facts were maintained as new comments were added instead of being revised and deleted. Robin NH. Molecular genetic advances in understanding craniosynostosis. Plast Reconstr Surg. 1999;103:1060. A good review of the common craniosynostosis syndromes. Stewart R. Genetic factors in craniofacial morphogenesis. In: Stewart R, Prescott G, eds. Oral Facial Genetics. St Louis, MO: CV Mosby; 1976. This comprehensive text with extensive references describes the genetic aspects of craniofacial abnormalities and gives other extensive descriptions of oral abnormalities. Wehr R, Gruss P. Pax and vertebrate development. Int J Dev Biol. 1996;40:369–377; and Epstein JC. Trends Card Med. 1996;6:255–260. This article gives a comprehensive review of Pax genes and their roles in vertebrate development.

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References 1. DeMyer W. Median facial malformations and their implications for brain malformations. In: Bergsma D, ed. Morphogenesis and Malformation of Face and Brain. New York, NY: Alan R Liss; 1975:155–181. 2. Fok TF. Craniofacial anthropometry of Hong Kong Chinese babies: the eye. Orthod Craniofac Res. 2003;6(1):48–53. 3. Avery T. Developmental Anatomy. 7th ed. Philadelphia, PA: WB Saunders; 1974. 4. Johnston MC. The neural crest in abnormalities of the face and brain. Birth Defects. 1975;11:1. 5. Krogman W. Craniofacial growth and development: an appraisal. Yearb Phys Anthropol. 1974;18:31. 6. Stark R. Embryology of cleft palate. In: Converse J, ed. Reconstructive Plastic Surgery. Philadelphia, PA: WB Saunders; 1977:1941–1949. 7. Burdi AR. Early development of the human basicranium: morphogenic basicranium: morphogenic controls, growth patterns and relations. In: Bosma JF, ed. NIH Symposium on Development of the Basicranium. Washington, DC: U.S. Government Printing Office; 1977:81–92. 8. Samdani AF, Williams RC, Danish S, Betz R. Torticollis manifest after a minor fall with underlying bony anomalies and a hypoplastic vertebral artery. J Pediatr Orthop B. 2009;18(5):271–274. 9. Gasser R. The development of the facial nerve in man. Ann Otol Rhinol Laryngol. 1961;76:37. 10. May M. The Facial Nerve. New York, NY: Thieme Medical Publishers; 1986. 11. Welsh IC, O’Brien TP. Signaling integration in the rugae growth zone directs sequential SHH signaling center formation during the rostral outgrowth of the palate. Dev Biol. 1, 2009;336(1):53–67. Epub 2009 September 25. 12. Darnell J, Lodish H, Baltimore D. Molecular Cell Biology. New York, NY: Scientific American Books; 1986:985–1033. 13. Holland PWH, Stewart R. Classification and nomenclature of all human homeobox genes. BMC Biol. 2007;5(47)1–28.

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14. Veraksa A, Del Campo M, McGinnis W. Developmental patterning genes and their conserved functions: from model organisms to humans. Mol Genet Metab. 2000;69:85. 15. Massagé J. TGF-β signal transduction. Annu Rev Biochem. 1994;67:753. 16. Meyers GA, Orlow SJ, Munro IR, Przylepa KA, Jabs EW. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet. 1995;11:462. 17. Chun K, Teebi AS, Jung JH, et al. Genetic analysis of patients with the Saethre-Chotzen phenotype. Am J Med Genet. 2002;110(2):136–143. 18. Paznekas WA, Cunningham ML, Howard TD, et al. Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. Am J Hum Genet. 1998;62:1370–1380. 19. Jain S, Maltepe E, Lu MM, Simon C, Bradfield CA. Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse. Mech Dev. 1998;73:117. 20. Shiang R, Lidral AC, Ardinger HH, et al. Association of transforming growth factor alpha gene polymorphisms with nonsyndromic cleft palate only (CPO). Am J Hum Genet. 1993;53:836. 21. Lidral AC, Romitti PA, Basart AM, et al. Association of MSX1 and TGFB3 with nonsyndromic clefting in human. Am J Hum Genet. 1998;63:557. 22. Yu W, Serrano M, Miguel SS, Ruest LB, Svoboda KK. Cleft lip and palate genetics and application in early embryological development. Indian J Plast Surg. 2009;42:35–50. 23. Koillinen H, Wong FK, Rautio J, et al. Mapping of the second locus for the Van der Woude syndrome to chromosome 1p34. Europ. J. Hum. Genet. 2001;9:747–752. 24. Zucchero TM, Cooper ME, Maher BS, et al. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. New Eng. J. Med. 2004;351:769–780. 25. Duboule D, ed. Guidebook to the Homeobox Genes, Oxford, United Kingdom, 1994, Oxford University Press.

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3

C H A P T E R

Genetics, Syndromology, and Craniofacial Anomalies Anne Chun-Hui Tsai and Carol S. Walton

U

nderstanding the role of genetics in the diagnosis of craniofacial anomalies requires knowledge of several topics in human genetics. This chapter reviews those topics such as chromosomes, genes, inheritance patterns and pedigree terminology fundamental to human medical genetics. Furthermore, the chapter provides an approach to genetic syndromology with illustrative examples of the more common genetic diagnoses. As such, this chapter should provide a foundation for exploring the otolaryngologic literature regarding genetics and craniofacial anomalies.

GENETICS The word genetic is derived from the Greek root gen—“to become or grow into something”. Two related terms, congenital and familial, usually arise when discussing characteristics or traits of an individual. Congenital refers to a trait that is present at birth, while familial indicates that the trait appears in more than one family member. However, neither term clearly defines a trait as genetic. Intrauterine infection is congenital, but not genetic; horizontal transmission of the hepatitis B virus is familial, but not genetic. One can have a genetic disorder, such as phenylketonuria, without a family history of this disorder. More precisely, genetic disease should be defined as a disease resulting from a change or variation in genetic material. This change may be inherited or result from a new mutation in an affected person. Genetic disorders can be categorized into the following classic groups: chromosomal anomalies, single-gene disorders, and multifactorial disorders.

CHROMOSOMAL ANOMALIES All humans typically have 46 chromosomes, present in 23 pairs. One member of each chromosome pair is inherited from each parent at the time of conception. The first 22 pairs of chromosomes are called autosomes, which are the same in males and females. The last pair of chromosomes is the sex chromosomes, so named for their involvement in gender determination. Typically, males have one X and one Y chromosome while females have two X chromosomes. The centromere separates the chromosome into two arms. The short arm of the chromosome, called the p arm (petite), and the long arm, or q arm (named because q is the next alphabetical letter) are used in describing chromosomal locations. Each arm is further subdivided into

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numbered bands that are visible using different staining techniques. The use of named chromosome arms and bands allows for universal communication of chromosome description. Consensus guidelines and standards known as the International System for Human Cytogenetic Nomenclature (ICSN) are revised periodically to reflect expanding knowledge and new cytogenetic technologies. Details of the banding system and nomenclature can be found in ISCN 2009. Fig. 3-1 demonstrates normal karyotypes for males and females. Chromosome anomalies occur in 0.4% of all live births. They are a prevalent cause of mental retardation and congenital anomalies or birth defects. Chromosome anomalies are present in a much higher frequency among spontaneous abortions and stillbirths. Abnormalities of the chromosome number and structure, fragile sites, increased chromosome breakage, and mosaicism are some examples of chromosomal anomalies.

Abnormalities of Chromosomal Number When a human cell has 23 chromosomes, such as human ovum or sperm, it is in the haploid state (n). After conception, in cells other than the reproductive cells, 46 chromosomes are present in the diploid state (2n). Any number that is an exact multiple of the haploid number such as 46 (2n), 69 (3n), and 92 (4n) is called euploid. Polyploid cells are those that contain any multiple of the haploid number other than the usual diploid number of chromosomes. Polyploid conceptions are usually not viable except in the mosaic state, with the presence of more than one cell line in the body (mosaicism is discussed later). Cells deviating from a multiple of the haploid number are called aneuploid, meaning not euploid and indicating an extra or missing chromosome. Trisomy, an example of aneuploidy, is the presence of three of a particular chromosome rather than two. Trisomy is the most common numerical chromosome anomaly in humans. Table 3-1 summarizes the most common autosomal trisomies. Monosomies, the presence of only one member of a chromosome pair, may be complete or partial. Complete monosomies may result from nondisjunction or anaphase lag. All complete autosomal monosomies appear to be lethal early in development and only survive in mosaic forms. Sex chromosome monosomy (i.e., 45,X) can be viable.

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FIGURE 3-1. Normal human karotypes for males and females.

TABLE 3-1. Common Autosomal Trisomies Feature

Trisomy 21

Trisomy 18

Trisomy 13

Eponym

Down syndrome

Edward syndrome

Patau syndrome

Liveborn incidence

1:800

1:8000

1:15,000

Tone

Hypotonia

Hypertonia

Hypo- or hypertonia

Variable

Cranium/ brain

Mild microcephaly, flat occiput, three fontanels

Microcephaly, prominent occiput

Microcephaly, sloping forehead, occipital scalp defects, holoprosencephaly

High prominent forehead

Eyes

Up-slanting, epicanthal folds; speckled iris (Brushfield spots)

Small palpebral fissures, corneal opacity

Microphthalmia, hypotelorism, iris coloboma, retinal dysplasia

Ears

Small, low-set, overfolded upper helices

Low-set, malformed

Low-set, malformed

Low-set

Facial features Protruding tongue, large cheeks, low flat nasal bridge

Small mouth, micrognathia

Cleft lip and palate

Long face, wide upturned nose, thick everted lowerlip microretrognathia, high arched/cleft palate

Skeletal

Clenched hand, absent 5th finger distal crease, hypoplastic nails, short stature, thin ribs

Postaxial polydactyly, hypoconvex fingernails, clenched hand

Absent patella or osteoarticular anomalies

Cardiac defect 40%

60%

80%

Survival

90% die within first year

80% die within first year

Rocker-bottom feet, polycystic kidneys, dermatoglyphic arch pattern

Genital anomalies, polycystic kidneys, increased nuclear projections in neutrophils

Clinodactyly 5th digit, gap between toes 1 and 2, excess nuchal skin, short stature Long-term

Other features Large fontanel, thick nuchal folds, single palmar creases

Trisomy 8 Mosaicism

Myelodysplasia

Source: Modified from Jones KL, ed. Pediatric Secrets. 2nd ed. Philadelphia, PA: Hanley & Belfus; 1997.

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Abnormalities of Chromosomal Structure There are many different types of structural chromosome anomalies. Fig.3-2 provides an ideogram of these chromosomal anomalies. Deletions (del) (see Fig. 3-2A). A deletion is the absence of a copy of a chromosomal segment; deletions can be terminal (removing an end of a chromosome) or interstitial (within a chromosome). The missing part is described using the code del, followed by the number of the involved chromosome in parentheses, followed by a description of the missing region of that chromosome, also in parentheses: for example, 46,XX,del(1)(p36.3). This nomenclature describes the loss of genetic material of band 36.3 of the short arm of chromosome 1. Fig. 3-3 shows a child with 1p36.3 deletion. Other deletions may result in clinically recognizable conditions associated with cognitive deficits, developmental delays, malformations, and characteristic facial features; for example, Wolf-Hirschhorn syndrome, del(4p) produces an unusual face with “Greek helmet” appearance of the brow ridges and nose, and cri-du-chat syndrome, del(5p), causes the infant to produce an unusual high-pitched cry.

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Duplication (dup) (see Fig. 3-2B). A duplication is the presence of an extra copy of a chromosomal segment, which can be tandem (extra genetic material present in the original direction) or inverted (extra genetic material present in the opposite direction). A duplication of chromosome 22q11 causes cat-eye syndrome, resulting in iris coloboma and anal or ear anomalies, or both. Inversions (inv) (see Fig. 3-2C). An inversion is an intrachromosomal rearrangement such that a section of the chromosome breaks and reattaches in the opposite direction. Inversions can be paracentric (not involving the centromere) or pericentric (involving the centromere). Inversions may be benign or may produce symptoms if the breakpoints or the new position of the segment disrupt normal expression of important genes. Ring chromosomes (r) (see Fig. 3-2D). A ring chromosome is a deletion of the normal telomeres and possibly other subtelomeric sequences with subsequent fusion of both ends to form a circular chromosome. Ring chromosome anomalies often cause growth retardation and cognitive deficits.

FIGURE 3-2. Ideogram of chromosomal anomalies.

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FIGURE 3-3. Child with 1p36.3 deletion syndrome, 8 months and 21 months.

Translocations (trans) (see Fig. 3-2E.). A translocation is an interchromosomal rearrangement of genetic material. These may be balanced (the cell has a normal content of genetic material arranged in a structurally abnormal way) or unbalanced (the cell has gained or lost genetic material because of unequal chromosomal interchange). Translocations may further be described as reciprocal (exchange of genetic material between two nonhomologous chromosomes) or robertsonian (fusion of two acrocentric chromosomes). Insertions (ins). An insertion is breakage at two points within a chromosome into which another piece of chromosomal material is incorporated. This requires three breakpoints and may occur between two chromosomes or within the same chromosome. The phenotype depends on the origin of the inserted materials. Microdeletion. Microdeletion may result in a contiguous gene syndrome. Microdeletions arise through the loss of genes that are adjacent to each other on a chromosome. Table 3-2 summarizes some common microdeletion syndromes. This type of deletion is too small to be detected by traditional cytogenetic methods, including high-resolution karyotyping,

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and usually requires a specialized molecular cytogenetic detection method called fluorescence in situ hybridization or FISH. A normal state is indicated by the presence of two visible fluorescent signals that represents binding of the FISH probe to both copies of chromosomal region 22q11. When only one fluorescent signal is visualized, this is diagnostic of a microdeletion at this chromosomal locus. Velo-cardiofacial syndrome or 22q11 deletion syndrome is an example of a microdeletion. Microarray-based comparative genomic hybridization or array comparative genomic hybridization (CGH) has revolutionized clinical cytogenetics. This technique provides a relatively quick method to scan the genome for gains and losses of chromosomal material with significantly higher resolution and greater clinical yield than was previously possible. A number of different array CGH platforms or “microarray chips” have emerged and are being used successfully in the diagnostic setting. In the past few years, these new methodologies have led to the identification of novel genomic disorders in patients with developmental delay/mental retardation and multiple congenital anomalies including

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TABLE 3-2. Common Human Microdeletion Syndromes Disorder

Clinical Features

Microdeletion

Williams syndrome

Unusual face, aortic stenosis, joint laxity, mental disability, cocktail party personality

7q11 (elastin gene)

Langer-Giedion syndrome

Unusual face, cartilaginous exostoses, mental disability

8q23-q24

Beckwith-Wiedemann syndrome

Large size, omphalocele, hypoglycemia

11p11-p15 Dup (p15) also

Wilms tumor-aniridia-genital defects retardation (WAGR) syndrome

Iris, genital defects, Wilms tumor, mental disability

11p13 (WT-1 Wilms tumor gene)

Prader-Willi syndrome

Unusual face, early hypotonia, feeding difficulty, later morbid obesity

15q11 pat; (some are point mutation)

Angelman syndrome

Unusual face with prominent jaw, seizures, mental disability

15q11 mat

Rubinstein-Taybi syndrome

Unusual face with broad thumbs, mental disability

16p13.3

Smith-Magenis syndrome

Unusual face, aberrant behaviors, mental disability, sleep difficulty

17p11

Hereditary neuropathy with predisposition to pressure palsies

Peripheral nerve dysfunction

17p11 (PMP 22 gene) Dup (17p11) causes CMT disease

Miller-Dicker syndrome

Hypotonia, lissencephaly (smooth brain), mental disability

17p13 (LIS-1 gene)

Alagille syndrome

Unusual face, pulmonary artery stenosis, vertebral anomalies, cholestatic liver disease

20p11-p12 (some have point mutation of JAG gene)

Shprintzen/DiGeorge syndrome

Unusually long face with palatal and speech defects, immune or genital defects

22q11

Duchenne muscular dystrophy, CGD, RP, McLeod phenotype

Muscle weakness, immune dysfunction vision problems

XP21 (dystrophin gene, others)

CGD, chronic granulomatous disease; CMT, Charcot-Marie-Tooth; JAG, jagged Alagille gene; LIS, lissencephaly; PMP, peripheral myelin protein; RP, retinitis pigmentosa.

craniofacial anomalies. Array CGH basically allows detection of all microdeletion syndromes that could previously be detected by FISH. The resolution of each technique is defined by the size of the region of genomic loss or gain that it can detect. One megabase (Mb) of DNA represents a linear sequence of one million nucleotide bases (Adenine, Thymine, Cytosine, Guanine) in the genetic code, while one kilobase (kb) of DNA represents a linear sequence of one thousand nucleotide bases. While high resolution karyotyping can detect rearrangement greater than 3–5 Mb, most platforms of microarray can detect 300–500 Kb regions of gain or loss and interpret them reliably at the clinical level. Smaller anomalies can be detected by many high-resolution arrays. However, parental studies are frequently required to determine if a small anomaly is a normal variant or a true cause of pathology. Although array CGH was initially used as an adjunct test to standard karyotype analysis, and many insurance companies considered it investigational, it has now been recommended as the first line screening genetic test in lieu of traditional

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karyotype in children with unexplained intellectual deficits and dysmorphic craniofacial features (Fig. 3-4A and B).

Sex Chromosomal Anomalies Abnormalities involving sex chromosomes, including aneuploidy and mosaicism, are relatively common in the general population. Table 3-3 summarizes the most common sex chromosome anomalies and their clinical features.

FRAGILE SITES Fragile sites are defined as regions of chromosomes that show a tendency toward separation, breakage, or attenuation under particular growth conditions. Examples are 2q13, 6p23, 9q32, 12q13, 20p11, and Xq27. Some fragile sites are related to syndromic malformations and others to cancer predisposition. The classic example is the fragile X chromosome site, Xq27, now known to be due to allelic expansion of a CGG

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FIGURE 3-4. Mendel’s principles demonstrating the two alleles, A1 and A2, segregating into two separate gametes. (Adapted from Dylsworth AS Genetics Review Course, ACMG, 1999.)

TABLE 3-3. Most Common Sex Chromosome Disorders 47,XXY (Klinefelter Syndrome)

47,XXY

47,XXX

45,X (Turner Syndrome)

1/2000

1/2000

1/2000

1/8000

Maternal age association Yes

No

Yes

No

Phenotype

Tall, eunuchoid habitus underdeveloped secondary sexual characteristics, gynecomastia

Tall, severe acne, Tall, indistinguishable indistinguishable from from normal females normal males

Short stature, web neck, shield chest, pedal edema at birth, coarctation of aorta

IQ and behavior

80–100, behavioral problems

90–110: behavioral problems, aggressive behavior

90–110: behavioral problems

Mildly deficient to normal intelligence, spatial-perceptual difficulties

Reproductive function

Extremely rare

Common

Common

Extremely rare

Gonads

Hypoplastic testes. Leydig cell hyperplasia. Sertoli cell hypoplasia, seminiferous tubule dysgenesis, few spermatogenic precursors

Normal-sized testes, normal testicular histology

Normal-sized ovaries, normal ovarian histology

Streak ovaries with deficient follicles, 5%–10% have Y-chromosomal material and are at risk for gonadoblastoma; a careful screening for Y chromosome should be performed

Frequency of live births

Source: Modified from Donnenfeld et al. 7

trinucleotide repeat of the FMR1 gene. Fragile X syndrome is characterized by a long face, prominent jaw, prominent ears, autistic tendency, mental retardation, and speech delay. It is the most common single-gene disorder causing mental retardation in males. Female heterozygotes may show some of the facial

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features with a cognitive spectrum ranging from normal intellect to learning disabilities or mental retardation. In 50% of patients with fragile X syndrome, a fragile site on the X chromosome can be induced by growing the cells in a medium depleted of folic acid. While identification of a fragile site at Xq27 was

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CHAPTER 3 ❖ Genetics, Syndromology, and Craniofacial Anomalies previously the diagnostic standard for fragile X syndrome, this form of clinical testing has been replaced by the molecular study of the number of CGG repeats of the FMR1 gene.

CHROMOSOMAL BREAKAGE (INSTABILITY) SYNDROMES Several recessive disorders are associated with increased breakage and rearrangement of chromosomes. The breaks may be spontaneous or they can be induced by a variety of mitogens and radiation. Examples include some types of Fanconi pancytopenia syndrome, Bloom syndrome, Werner syndrome, and ataxia telangiectasia (Table 3-4). Some clinical features of these syndromes, such as photosensitivity and increased predisposition to cancer, can be explained by cumulative effects of errors in DNA synthesis or repair in cells. Genes have been identified for many of these syndromes and genetic testing is available for some of them.

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gestation. A zygote may start out as a viable or nonviable trisomy, but “chromosome rescue” may result in the additional chromosome being lost during mitosis. If a normal cell line develops, the fetus may survive and the original trisomic cell line may present in some percentage or it may be lost. Mosaicism can be difficult to document through routine clinical cytogenetic analysis. While peripheral cell lines are the most obtainable tissues, they represent only one type of tissue that may be affected by mosaicism. Mosaicism may be present in some tissues but not in others. Clinical presentations associated with mosaicism can vary widely. Mosaicism for an identified syndrome (i.e., mosaic Down syndrome) may result in any of the clinical features within the spectrum of the nonmosaic phenotype. Body asymmetry, linear patchy skin, and hyper- and hypopigmentation are nonspecific indicators of chromosomal mosaicism (e.g., hypomelanosis of Ito).

SINGLE-GENE DISORDERS Mendelian Principles

MOSAICISM Mosaicism refers to the presence of two different cell lines in one individual. These varying cell lines are derived from a single fertilized egg. Studies of tissue obtained through chorionic villus sampling show that at least 2% of all conceptions are mosaic for chromosomal anomalies at or before 10 weeks’

Traditionally autosomal single gene disorders follow the principles explained by Mendel's observations, summarized in Fig. 3-4. The inheritance of genetic traits through generations relies on segregation and independent assortment. Segregation is the process through which our gene pairs are separated during gamete formation. Each gamete

TABLE 3-4. Common Chromosomal Breakage Syndromes Syndrome

Clinical Features

Gen

Cytogenetic

Cancers

Ataxia telangiectasia

Progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency

AR

Gaps, breaks, pseudo-diploid clones with rearrangements of chromosomes 7 and 14

Lymphomas, lymphocytic leukemia

Bloom syndrome

Gestational dwarfism, photosensitive telangiectatic erythroderma, long face, malar hypoplasia

AR

Excessive sister chromatid exchanges, breaks and rearrangements

Nonlymphocytic leukemias

Fanconi anemia

Radial malformations, progressive pancytopenia, hyperpigmentation, poor growth

AR

Chromatid breaks and gaps, mitomycin sensitivity

Leukemia, hepatocellular carcinoma, squamous cell carcinoma

Incontinentia pigmenti

Marbled skin pigmentation, XL eye malformations, heart, teeth, and skeleton defects

Gaps, rearrangements in lymphocytes

Acute myelogenous leukemia, pheochromocytoma

Werner syndrome

Premature again, scleropoikiloderma, juvenile cataracts, short stature with thin limbs and stocky trunk

AR

Variegated translocation mosaicism

Sarcomas, meningiomas

Xeroderma pigmentosum

Photosensitivity, neurologic deficits

AR

UV and UV mimetic sensitivity, no spontaneous chromosome instability

Basal cell carcinoma, squamous cell carcinoma

AR, autosomal recessive; XL, X-linked. Source: Adapted from Thurmon24.

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receives only one copy of each of our genes (alleles). Fig. 3-5 shows the two alleles, A1 and A2, segregating into two separate gametes. Independent assortment refers to the idea that the segregation of different alleles occurs independently. The diagram shows two separate genes, A and B, and their respective alleles segregating independently of one another. This assumes that the genes are distant from one another on the same chromosome or are located on two different chromosomes. Neighboring genes may not segregate independently.

Mendelian Disorders Victor McKusick’s catalog, Mendelian Inheritance in Man, and its successor, the OMIM-Online Mendelian Inheritance in Man database, list more than 12,000 disorders and traits for which the mode of inheritance is presumed to be autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, or Y-linked. Single genes at specific loci on one or a pair of chromosomes cause these disorders. Understanding the terminology of inheritance is helpful in approaching Mendelian

FIGURE 3-5. A. Construction of family tree or pedigree. B. Common pedigree symbols, definition, and abbreviation. (From Bennett RJ, Steinhaus KA, Uhrich SB et al: Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of National Society of Genetic Counselors. Am J Hum Genet 56:745,1995)

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CHAPTER 3 ❖ Genetics, Syndromology, and Craniofacial Anomalies disorders. Inheritance patterns can usually be explained by analysis of the pedigree and the pattern of transmission in the family, identification of a specific condition, and knowledge of that condition’s mode of inheritance.

Terminology Several terms are important in understanding inheritance patterns. These are listed below: Dominant and recessive. As defined by Mendel, concepts for dominant and recessive refer to the phenotypic expression of alleles and are not intrinsic characteristics of gene loci. Therefore, it is inappropriate to discuss “a dominant locus,” for example. Genotype. A genotype is the genetic status, that is, the alleles that an individual carries. Phenotype. A phenotype is the expression of an individual’s genotype and may be modified by environment, that is, the structural or functional nature of an individual (appearance, physical features, organ structure, biochemical, and physiologic nature) Pleiotropy. Pleiotropy is the phenomenon of a single mutant allele having widespread effects or expression in different tissues or organ systems throughout the body. In other words, pleiotropy is the quality of an allele producing more than one effect on the phenotype. For example, Marfan syndrome presents with clinical findings in different organ systems (e.g., skeletal, cardiac, ophthalmologic) due to the pleiotrophic effects of a single mutation within the fibrillin 1 gene. Penetrance. Penetrance is the proportion of individuals with a particular genotype who express the same phenotype. Penetrance is a proportion that ranges between 0 and 1.0 (or 0% and 100%). When 100% of mutant individuals express the phenotype, penetrance is complete. If some mutant individuals do not express the phenotype, penetrance is said to be incomplete or reduced. Pedigrees of dominant conditions with incomplete penetrance, therefore, are characterized by “skipped” generations with unaffected, obligate gene carriers. Expressivity. Expressivity is the variability in degree of phenotypic expression (severity) among different individuals with the same mutant genotype. Expressivity may vary extremely or be fairly consistent, both within and among families. Intrafamilial variability of expression may be due to factors such as epistasis (interaction between genes), environment, true anticipation, the presence of phenocopies, mosaicism, and chance (stochastic factors). Interfamilial variability of expression may be due to the above factors, but also may be due to allelic or locus genetic heterogeneity. Genetic heterogeneity. A number of different genetic mutations may produce phenotypes that are identical or similar enough to have been traditionally considered as one diagnosis. Examples are “anemia,” “mental retardation,” and “dwarfism.” There are two types of genetic heterogeneity: locus heterogeneity and allelic heterogeneity. Locus heterogeneity. Locus heterogeneity is a phenotype caused by mutations at more than one genetic locus, that is, mutations

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in genes at different loci causing the same phenotype or a group of phenotypes that appear similar enough to have been previously classified as a single disease, clinical entity or diagnostic spectrum. An example is Sanfilippo syndrome (mucopolysaccharidosis III A, B, C, and D) wherein the same phenotype is produced by four different enzyme deficiencies. Allelic heterogeneity. Allelic heterogeneity is a phenotype caused by more than one genetic mutation at the same gene locus, that is, different mutations in each allele at a single gene locus. For example, cystic fibrosis may be caused by many different genetic changes, such as homozygosity for the common 2206F508 mutation or the combination of ∆F508 and the R117H mutation. The latter example represents compound heterozygosity. Phenotypic or clinical heterogeneity. This term describes the situation wherein more than one phenotype is caused by different allelic mutations at a single locus. An example of phenotypic heterogeneity is different mutations within the collagen I gene causing hypochondrogenesis, Kniest dysplasia, spondyloepiphyseal dysplasia congenita and some cases of Stickler syndrome. Furthermore, different mutations in the fibroblast growth factor receptor 2 (FGFR2) gene can cause Crouzon syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome, and Apert syndrome. In both examples, the syndromes are clinically distinguishable and are due to a variety of genetic mutations within a single gene. Homozygous. Homozygous refers to a cell or organism that has identical alleles at a particular locus. For example, in an autosomal recessive disorder, the disease may manifest in an offspring because both parents transmit an identical mutation that inactivates the gene. Heterozygous. Heterozygous refers to a cell or organism that has nonidentical alleles at a genetic locus. In autosomal dominant conditions, one copy of the gene pair is inactivated while the other is functional, resulting in a disease state. A person who is heterozygous or a “carrier” for a recessive disorder does not manifest symptoms. Compound heterozygosity, described earlier, is the presence of different genetic changes at the same locus that, combined, may result in recessive disease.

PEDIGREE CONSTRUCTION AND ANALYSIS The first step in the collection of information regarding the genetics of a syndromic diagnosis is the construction of a family tree or pedigree. Underused by most medical personnel, the pedigree is a valuable record of genetic and medical information that is much more useful in visual form than in list form. The use of uniform symbols is helpful (Fig. 3-5). Tips for pedigree preparation include the following: Give simple instructions to the patient regarding desired information. Use clearly defined symbols with a key for interpretation. Identify the informant, the historian, and the date of the interview. Start in the middle of the page to allow enough room for expansion.

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Start with the proband and proceed with his or her siblings and parents. Always ask about consanguinity; sometimes the question “Are you (the parents) related by blood?” results in laughter but yields potentially useful clues suggesting autosomal recessive inheritance. Ask for details such as place of birth and size of towns, and clarify whether suspected instances of relatedness are through blood or marriage. Ask about ethnicity and countries of origin of ancestors; this information helps to define recessive conditions and may increase suspicion of certain diseases, especially with particular ethnic backgrounds. Obtain the maiden names of women in the family; this is particularly helpful for X-linked conditions. Obtain data from both sides of the family. Ask about spontaneous abortions, stillbirths, infertility, children relinquished for adoption, and deceased persons, including infant deaths. Such details are essential for understanding conditions that are lethal or are associated with reproductive losses. Even if the disease in question appears to be coming from one side of the family, always get the basic facts about the other side of the family as well. Sometimes, apparently unrelated data are very important in interpreting the family’s overall situation. In addition, obtaining data from both sides may avoid an inference of blame being placed on one family member. In the course of taking the family history, one may find information that is not relevant to the problem in question but may indicate a risk for other important health concerns. Such information should be appropriately documented and addressed. Examples of conditions that may arise are an overwhelming family history of early-onset breast and ovarian cancer, multiple pregnancy losses necessitating chromosome analyses, or symptoms of hereditary hemochromatosis, a common treatable disorder of iron metabolism.

HEREDITARY PATTERNS Autosomal Dominant Inheritance Disorders showing autosomal dominant inheritance are generally expressed when only one gene of a gene pair is altered (i.e., the individual is heterozygous). Homozygous states of autosomal dominant disorders are rare and are usually severe or lethal (e.g., homozygous achondroplasia). Dominant disorders typically result from genetic mutations within structural genes. Rarely, homozygosity may be clinically indistinguishable from heterozygosity, as in the case of Huntington disease. See Fig. 3-6 for a pedigree representative of typical autosomal dominant inheritance. Note that males and females are equally affected and that male-to-male transmission occurs. The risk for an affected person’s offspring to be affected is 50%, regardless of sex. However, risks alone do not tell the whole story in autosomal dominant disorders. Several factors may modify the clinical

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FIGURE 3-6. Pedigree representation of typical autosomal dominant inheritance.

presentation such as age of onset, decreased penetrance, and variable expressivity. In the absence of a family history with a known autosomal dominant diagnosis, the proband may represent a new mutation not carried by either parent. However, because of the risk of germline mosaicism in a parent, the risk for other siblings is low but not zero. Some clinical features of common autosomal dominantly inherited conditions are listed in Table 3-5.

Autosomal Recessive Inheritance Autosomal recessive phenotypes account for approximately one third of Mendelian disorders. These phenotypes occur when both parents are unaffected heterozygous carriers. Each parent passes either the normal or an altered gene to each of their children. Therefore, the risk to each pregnancy of two carriers is 25%. Consanguinity increases the risk of autosomal recessive disorders, as does reproduction within genetically isolated populations. With an isolated case of an undiagnosed syndrome, it may be difficult to determine whether a condition is autosomal recessive or a new dominant mutation because of the lack of informative family history. Fig. 3-7 demonstrates a typical pedigree illustrating autosomal recessive inheritance. Both male and female siblings are equally affected. Recurrence risks for other relatives are very low. When an individual is affected with an autosomal recessive disorder, the risk of an unaffected sibling to be a carrier is two-thirds. In contrast with autosomal dominant disorders, many recessive disorders involve aberrant enzyme activities that block pathways crucial

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TABLE 3-5. Clinical Features in Several Common

Malformation Syndromes With Autosomal Dominant Inheritance Causative Gene/ Locus

Syndrome

Primary Features

Stickler syndrome

Marfanoid habitus, myopia, cleft palate, arthritis

Collagen II, collagen IX

Noonan syndrome (some cases)

Short statures, ptosis, pulmonary valve stenosis, learning disabilities

Clin 12q, Clin 14q

Treacher-Collins syndrome

Down-slanting palpebral fissures, ear malformations, malar hypoplasia, lid colobomas

TCOF1,2,3

Holt-Oram syndrome

Cardiac defects, radial defects

TBX5, SALL4

Waardenburg syndrome, type I

PAX6 Increased inner canthal distance, heterochromia, white forelock, congenital hearing loss

Van der Woude syndrome

Cleft lip ± cleft palate: lip pits

IRF6

BranchioOto-Renal syndrome

Branchial cyst, hearing loss, ear malformations and kidney abnormality

EYA1

FIGURE 3-7. Typical pedigree of autosomal recessive inheritance. A. with history of consanguinity, B. with no history of consanquity.

Crouzon syndrome

Proptosis, midface hypoplasia, beaked nose

FGFR2, FGFR3

however, female carriers of X-linked disorders may exhibit skewed X inactivation. By chance, a female carrier may have more normal X chromosomes inactivated and display some symptoms of an X-linked disorder, either clinically or biochemically. A male affected with an X-linked recessive disorder transmits the nonworking gene to all of his daughters, who receive his only X chromosome, and to none of his sons, who receive his Y chromosome. Affected men in a family are related through women in the family; male-tomale transmission never occurs. A typical pedigree of an X-linked recessive condition is shown in Fig. 3-8A, and common examples of X-linked recessive syndromes are listed in Table 3-7. X-linked dominant disorders may be equally expressed in females and males since only one genetic change is needed to cause the condition. The presence of a second functioning copy of the gene on a female’s other X chromosome does not affect the severity of the condition. As our ability to detect manifestations in female carriers of X-linked recessive conditions improves, the distinction between X-linked dominant and recessive blurs. Pedigrees of X-linked dominant disorders demonstrate that affected women have affected children of both sexes while affected men have affected daughters and no affected sons.

to normal metabolic function. Important autosomal recessive disorders are presented in Table 3-6.

X-Linked Inheritance—Dominant and Recessive X-linked recessive mutations are fully expressed in males since they have only one copy of the X chromosome. On the other hand, female carriers of X-linked disorders are usually functionally mosaic. Because most females have two X chromosomes, they can have two cell populations— one carrying the normal X chromosome gene and the other carrying the altered gene. X inactivation, a process through which one X chromosome is “turned off ” during early embryologic development, is completed for dosage compensation, a regulatory mechanism to help ensure that the phenotypic expression of genes on the X chromosome is equal in the XY male and the XX female. As a result of X inactivation, females have only one X chromosome active in each cell, as do males. This process is typically random;

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TABLE 3-6. Clinical Features in Selected Malformation Syndromes With Autosomal Recessive Inheritance Syndrome

Clinical Findings

Clinical Outcome

Zellweger syndrome

Deficiency of peroxisomes, hypotonia, hepatomegaly, stippled epiphyses, hydrocephalus

Lethal by 1–4 mo

Meckel-Gruber syndrome

Encephalocele, polycystic kidneys, congenital heart disease

Lethal soon after birth

Ellis-van Creveld syndrome

Short limbs, natal teeth, congenital heart disease, polydactyly

About 50% die in infancy

Smith–Lemli-Opitz syndrome

Mental retardation, two-three toe syndactyly genital abnormalities, polydactyly, cleft palate

Some neonatal deaths; some longterm survivors

Seckel syndrome

“Bird-headed” dwarfism, primordial short stature, severe microcephaly

Survival

Ataxia-telangiectasia

Ataxia immune deficiency, elevated risk of lymphoreticular malignancy, chromosome breakage

Death in 20s–30s, usually secondary to malignancy

TABLE 3-7. Clinical Features in Selected Examples of X-Linked Disorders Disease

Gene Localization

Incidence

Clinical Findings

Hemophilia A

Xq28 (large gene; many mutations)

1:10,000

Prolonged bleeding; bruising; joint and muscle hemorrhage; deficiency of factor VIII

Alport syndrome

Xq21.3-q22

1:10,000

Renal failure, sensorineural hearing loss

Norrie disease

Xp11.4

Rare

Pseudoglioma, hypogonadism, mental retardation, microcephaly

Fragile X syndrome

Xq27.3

1 in 2000

Mental retardation, long face, prominent jaw and ears, autistic tendencies, macroorchidism

DMD

Xp21.2

1 in 3500

Progressive muscle weakness, calf pseudohypertrophy, mild mental retardation, onset > 6 years, cardiomyopathy

X-ALD

Xq28

Rare

Peroxisomal disorder resulting in accumulation of very-long-chain fatty acids in white matter and adrenal gland, eventual neurologic symptoms and Addison disease

Otopalatodigital syndrome, type 1

Xq28

1:10,000

Hearing loss, digital anomalies, cleft palate

Some X-linked dominant disorders appear to be lethal to males and are only found in females. Examples are Rett syndrome (early normal development followed by regression to severe mental retardation and seizures), Aicardi syndrome (agenesis of the corpus callosum, severe seizures, hemivertebrae, and chorioretinal abnormalities), Goltz syndrome (focal dermal hypoplasia, finger and hand anomalies, hypodontia, and colobomas), and incontinentia pigmenti (abnormalities of the hair, teeth, nails, and skin, including several stages of cutaneous changes: perinatal inflammatory vesicles, verrucous patches, distinctive hyperpigmentation, and dermal scarring). Male conceptuses with the disease mutation may spontaneously abort and appear as a history of

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multiple miscarriages to affected females. A typical pedigree is presented in Fig. 3-8B.

Y-Linked Inheritance Also known as holandric inheritance, conditions attributable to Y-linked inheritance are caused by genes on the Y chromosome. These conditions are relatively rare, with only about 40 entries listed in McKusick’s catalog. Male-to-male transmission occurs in this category, with all sons of affected males being affected and no daughters or females being affected. Fig. 3-9 shows a typical Y-linked inheritance pedigree. Table 3-8 shows several

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FIGURE 3-8. Typical pedigree of X-linked recessive condition. A. X-linked recessive B. X-linked dominant.

FIGURE 3-9. Typical Y-linked inheritance pedigree.

examples of genes and conditions caused by genes on the Y chromosome.

VARIATIONS AND EXCEPTIONS TO TRADITIONAL MENDELIAN INHERITANCE PATTERNS

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clinical examples, see Table 3-9. Please note that mitochondrial diseases are not equivalent to mitochondrial inheritance. Some of the enzymes in mitochondria, or that are required in mitochondria to produce energy, are made by the nuclear genes. Examples of the nuclear genes include the individual subunits of the OXPHOS enzyme, complex I and PDH E1-α.

Mitochondrial Inheritance

Imprinting

Mitochondria, the energy producers in cells, have their own genetic material separate from the DNA in the cell’s nucleus. These organelles are located in the ovum at the time of conception. Sperm cells do not contribute mitochondria to zygotes. All mitochondrial genes are therefore inherited only from the mother. These genes are passed down from mothers to all of their children, and conditions caused by mutations within the mitochondrial genome are commonly described as following a maternal inheritance pattern. For a classic pedigree representing mitochondrial inheritance, see Fig. 3-10 and, for

Imprinting describes the process in which genetic material is expressed differently, depending on the parent of origin. Conditions affected by imprinting may involve either a maternal or a paternal imprinting effect, in which individuals express only their paternal or maternal copy of specific genes, respectively. Maternal imprinting implies that the maternal copy of the gene is not expressed, and paternal imprinting results in no expression of the paternal copy of the gene. Mutations in these genes may have no effect if inherited from the parent whose gene is imprinted, or turned off. Table 3-10 shows the common diseases

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TABLE 3-8. Y-Linked Genes/Phenotypes (Male-to-Male Transmission Only) Gene

Gene Name

Clinical Features

AZF2

Azoospermia factor 2

Azoospermia, oligospermia

Unknown

N/A

Retinitis pigmentosa

AZF1

Azoospermia factor 1

Non-obstructive azoospermia/oligospermia

GBY

Gonadoblastoma

Phenotypic females with dysgenetic gonads, gonadoblastoma risk

Unknown

N/A

Long hairs on ear helix

GCY

Y-chromosome—influenced growth control

Involved in determination of stature

SRY

Sex-determining region, Y

Involved in sex determination in mammals

TSPY

Testis-specific protein, Y-encoded

Possibly related to spermatogonial proliferations, found in cytoplasm of spermatogonia found in early forms of seminomatous testicular tumors

TABLE 3-9. Common Disorders of Mitochondrial Inheritance Disorder

Clinical Features

Kearns-Sayre syndrome

External ophthalmoplegia, retinal degeneration, elevated cerebrospinal fluid protein, cardiac conduction defect

Leber hereditary optic neuropathy

Early-onset progressive optic atrophy

Mitochondrial encephalopathy, lactic acidosis, stroke

Short stature, sensorineural deafness, encephalomyopathy, lactic acidosis, strokelike episodes

Myoclonic epilepsy and ragged red fibers

Myoclonic epilepsy, myopathy, ragged red muscle fibers, lipomas

Neuropathy, ataxia, retinitis pigmentosa

Neuropathy, ataxia, retinitis pigmentosa

FIGURE 3-10. Classic pedigree of mitochondrial inheritance.

with the imprinting mechanism, and Fig. 3-11 shows classic clinical examples of maternal genomic imprinting. Although both are associated with a critical region on chromosome 15q, Prader-Willi syndrome, which is maternally imprinted, results when the mother’s allele is inactive, while Angelman syndrome results when the paternal allele is turned off.

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Uniparental Disomy Uniparental disomy (UPD), literally meaning “one parent, two chromosomes,” describes a situation in which both copies of one chromosome or chromosomal region are derived from a single parent, rather than typical biparental inheritance.

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CHAPTER 3 ❖ Genetics, Syndromology, and Craniofacial Anomalies UPD may be isodisomic if two copies of the same homolog are present or heterodisomic when one copy of each parental homolog is present. This phenomenon occurs in a number of ways. An originally trisomic pregnancy may “rescue” itself by removing one copy of the extra chromosome; if the embryo is left with two chromosomes from the same parent, UPD of that chromosome results. UPD can also arise after the conception of a monosomic pregnancy following nondisjunction. A monosomic cell may become disomic through UPD if the monosomic chromosome replicates itself. Table 3-10 lists the relationship of imprinting and UPD in several genetic syndromes. Referring to the conditions highlighted in Table 3-10, UPD plays a role in disorders with imprinting. Prader-Willi syndrome can be the result of UPD of the maternal chromosome 15, Angelman syndrome the result of UPD of the paternal chromosome 15, and Beckwith-Wiedemann the result of UPD of the paternal allele on chromosome 11.

Dynamic Mutations and Anticipation Expression of some autosomal dominant disorders appears to become more severe, to have an earlier age of onset

41

with each succeeding generation, or both. Historically this phenomenon called anticipation was attributed to biased ascertainment of patients. It is easy to see that in studying conditions with a wide range of intrafamilial expressivity, one is much more likely to ascertain families in whom symptoms are more severe (or started earlier) in current generations than families in which the condition was much more severe in ancestors and milder in the current generation. Fig. 3-12 demonstrates the historical observation of anticipation in several genetic diseases. While bias of ascertainment may be a correct explanation for apparent anticipation in many dominant conditions, some conditions have been identified in which the feature has a molecular basis. In these conditions, the phenotype actually can become more severe or have earlier onset with succeeding generations, or both. In these disorders showing “true anticipation,” a region of the gene is unstable because of a region of repeated trinucleotides. Normally, small numbers of such repeats are stable while a moderate number of repeats (the critical number varies with the disorder) lead to instability of the sequence, causing expansion to a large number of repeats and disrupted

TABLE 3-10. Common Syndromes Associated With Imprinting Syndrome

Clinical Features

Comment

Prader-Willi syndrome

Neonatal hypotonia, feeding difficulties, failure to thrive; eventual hyperphagia, central obesity; almond-shaped eyes, hypogonadism, mild to moderate mental retardation

Two thirds of cases are caused by deletion of paternal 15q11q13 and one fifth of cases by uniparental disomy of maternal chromosome 15

Angelman syndrome

Seizure disorder, gait ataxia/tremulous limbs, microcephaly, mental retardation, severe speech impairment, inappropriate laughter

Most cases are caused by deletion of maternal 15q11q13, with only 3% caused by uniparental disomy of paternal chromosome 15

Beckwith-Wiedemann syndrome

Overgrowth disorder, umbilical hernia/omphalocele, macroglossia, hemihypertrophy, earlobe creases, Wilms tumor

Half of cases are caused by paternal duplication of 11p15, and one fourth are caused by uniparental disomy paternal allele

FIGURE 3-11. Classic examples of maternal genomic imprinting.

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FIGURE 3-12. Anticipation in several genetic diseases. (Adapted from Aylsworth AAS. Genetics Review Course, ACMG, 1999).

gene function in subsequent generations. Examples are given in Table 3-11.

Phenocopy Phenocopy is defined as an environmentally produced phenotype that mimics a genetic phenotype. Children with intrauterine exposure to retinoids can present with ear anomalies, heart defects, and third and fourth pharyngeal pouch involvement, as occurs in DiGeorge syndrome. In such a scenario, prenatal exposure to retinoids can produce a phenocopy of DiGeorge syndrome, which usually results from microdeletion of the 22q11.2 chromosomal region. Apparent dominant transmission of a multiple congenital anomaly/ mental retardation syndrome due to familial alcoholism in multiple affected generations may also have this effect. Additionally, sporadic or environmentally caused asthma, cancer, obesity, hypertension, and psychosis in families may appear to represent a monogenic predisposing gene.

Multifactorial Disorders Multifactorial disorders are those caused by multiple factors, both genetic and environmental. These disorders may recur in families but do not show particular inheritance patterns in the pedigree. Because these conditions are more common, epidemiologic studies have allowed estimation of empirical recurrence risks for individual defects. Some multifactorial traits, such as tall and short stature, are merely variations of normal; others, such as neural tube

defects, isolated cleft lip with or without cleft palate, and congenital heart disease, are thought to exhibit a threshold effect. This threshold may vary by the sex of the affected individual, the severity of the defect, the number of family members affected, and other factors. Another group of multifactorial disorders includes those diseases common to adult life, such as diabetes mellitus, hypertension, common psychiatric disorders, and many forms of cancer and coronary artery disease. Major genetic factors are undeniable in several of these diseases, but environmental risk factors are also important and contributory. Common multifactorial birth defects are listed in Table 3-12 along with the approximate recurrence risks for first-degree relatives (siblings, additional children). Many of these traits show a strong predilection for one sex, that is, a lower genetic threshold may be necessary to cause a defect in a particular sex. Therefore, when a child with a particular disorder is of the sex that is less often affected, more genetic factors are presumed to be present. Recurrence risks for first-degree relatives of this child are higher. For example, boys are five times as likely as girls to have pyloric stenosis. When a female is affected, her parents’ risk of having another affected child is much higher than when a male child has been affected. The severity of the defect also affects recurrence risks. For example, the recurrence risk is less when a child has unilateral rather than bilateral cleft lip. Pertinent information on important multifactorial birth defects is discussed later.

Syndromology Syndromology spans almost all fields of medicine. In syndromes, individual anomalies are nonspecific. Each may occur as an isolated defect or as a component of various syndromes. Birth defects that can cause or contribute to neonatal death and disability occur in 3% to 5% of live born infants and 15% to 20% of stillborn babies. Birth defects, also called congenital anomalies or major congenital malformations, are structural defects present at birth and result from abnormal tissue differentiation or abnormal tissue and organ interaction during embryonic and fetal development. For example, congenital hearing loss, whether conductive, sensorineural, or mixed, may occur alone or together with various other abnormalities, making up a large number of different syndromes.

TABLE 3-11. Common Syndromes Associated With Trinucleotide Repeats

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Disease

STR

Gene

Locus

Normal No. Repeats

Affected Range

Dentatorubral-pallidoluysian atrophy

CAG

DRPLA

12p13.31

7–23

49–75

Friedreich ataxia

GAA

FRDA

9q13

7–38

66–1700

Huntington disease

CAG

Huntington

4p16.3

9–29

36–121

Machado-Joseph disease

CAG

SCA3/MJD

14q21

12–43

56–86

Myotonic dystrophy

CTG

DMPK

19q13

5–35

50–2000

Spinocerebellar ataxia, type 1

CAG

SCA1

6p22-p23

6–44

39–81

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CHAPTER 3 ❖ Genetics, Syndromology, and Craniofacial Anomalies TABLE 3-12. Common Multifactorial Birth Defects and

Recurrence Risks in First-Degree Relatives

Birth Defect

Recurrence Sex Ration (M:F) Risks (%)

Pyloric stenosis

5:1

Male affected: 2–5 Female affected: 7–20

Cleft lip ± cleft palate

1.6:1

Unilateral lip: 4 Unilateral lip + P: 4.9 Bilateral lip: 6.7 Bilateral lip + palate: 8

Cleft palate

1:1.14

3.5

Anencephaly/spina bifida

1:1.5

2–3

Congenital heart disease

1:1

Terminology is discussed later. Understanding such terms is helpful in approaching clinical dysmorphology.

Major Versus Minor/Isolated Versus Multiple Classified by severity, congenital anomalies can be described as major or minor. Minor anomalies occur in less than 4% of the normal population and are defined as having no major functional or cosmetic significance, such as an abnormally shaped ear or birth mark. Major anomalies are of major significance and include heart defects, abnormal brain formation, and cleft lip and palate. While isolated minor anomalies are not usually clinically significant, the chance of a major malformation increases as the number of minor malformations increases. Table 3-13 correlates the number of minor anomalies with the chance of major anomalies. Table 3-14 shows the importance TABLE 3-13. Incidence and Association of Major and Minor Anomalies

Ventricular septal defect

3

Patent ductus arteriosus

3

Hypoplastic left heart syndrome

2

Congenital Anomalies Dysmorphology is a term coined by Dr. David W. Smith in 1966 to describe the study of human congenital defects. The term refers to the study of altered (“dys”) form (“morph”) of organs or body parts that originate before birth. Dysmorphic anomalies can occur in any part of the body, and most arise during the first three months of intrauterine life. The term dysmorphic feature is generally used to indicate a change that has little or no direct functional impact but that may indicate increased risk of problems with growth, development, and health that can be predicted and managed. The presence of dysmorphic features may also have significant implications for recurrence risks of similar problems in other family members. The diagnostic tools needed for the assessment of a child with birth defects or dysmorphic features are familiar to those used by practicing pediatricians: a complete history, a meticulous physical examination, and discrimination between the normal (in all its variability) and the truly abnormal. Birth defects or dysmorphic features can be classified in different ways. By severity and the degree of involvement, they may be categorized as major or minor anomalies (roughly corresponding to the terms birth defect and dysmorphic feature) and isolated or multiple anomalies. Based on the cause of the anomalies, defects can be classified as environmental (teratogenic), chromosomal, single-gene, or multifactorial. Based on pathogenesis, they may be categorized as malformation, deformation, disruption, or dysplasia. Based on the pattern of anomalies, multiple birth defects may be identified as a sequence, syndrome, or association.

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43

Number of Minor Malformations

Incidence in the General Population

0

Chance of Major Malformation 1.4%

1

Up to 13%

3%

2

1%

11%

3

1/2000

90%

Source: Adapted from Leppig et al.17

TABLE 3-14. Examples of Minor Anomalies and Common Associated Craniofacial Syndromes

Minor Anomaly

Common Associated Syndrome

Scalp defect

Trisomy 13, 4p deletion

Confluent eyebrow (synophrys)

Cornelia de Lange syndrome

Ptosis

Saethre–Chotzen syndrome, Noonan syndrome

Preauricular tags

Goldenhar syndrome, Townes-Brocks syndrome

Cleft uvula

22q deletion syndrome

Broad thumb and great toe

Pfeiffer syndrome, Crouzon syndrome

Syndactyly

Apert syndrome

Tapering fingers

Velo-cardio-facial syndrome, Cohen syndrome

5th finger clinodactyly

Down, fetal alcohol, and Russell-Silver syndromes

Fingernail hyperconvexity

Turner syndrome

Interdigital webbing

Aarskog syndrome

Lacy/stellate irides

Williams syndrome

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of recognizing minor anomalies in diagnosing genetic diseases. While some of the features listed in the table can be normal variants, the association of other elemental findings may result in a syndromic diagnosis. Several techniques are used to help investigate major anomalies. Imaging studies such as ultrasonography, computed tomography, or magnetic resonance imaging of different organ systems can detect other birth defects. Radiographs of the skeletal structure and bone maturation may also be indicated.

Etiology The cause of multiple congenital anomalies can be classified as environmental, teratogenic, chromosomal, defects of single genes, and multifactorial.

Pathogenesis The pathogenesis of anomalies can be classified as malformation, deformation, disruption, and dysplasia. Malformations usually result from an intrinsically abnormal process of development such as an inborn error of morphogenesis. Examples are cleft lip, congenital heart disease, anencephaly, and polydactyly. Deformations usually result from extrinsic mechanical forces not related to genetic information. Examples are fetal positioning, torticollis, and plagiocephaly. Intrinsic forces such as fetal edema may result in deformation of overlying tissues. Disruptions result from extrinsic processes that interfere on a cellular level (drugs) or mechanically change the process of development. Classic examples include amniotic bands, jejunal atresia, and some forms of unilateral limb reduction. Dysplasia results from an abnormal organization of cells into tissue that may cause widespread involvement. Examples include achondroplasia and all other skeletal dysplasias.

Patterns Sequences, syndromes, and associations are terms used to describe patterns of congenital anomalies. Sequence. A sequence is defined as a pattern of multiple defects that result from a single primary malformation. Pierre Robin sequence usually starts from a primary micrognathia that subsequently causes an abnormal position of the tongue during fetal development, resulting in a cleft palate. Syndromes. A syndrome is defined as a pattern of multiple abnormalities in which all the components are pathologically related. Examples are Down syndrome in which the features are due to trisomy 21, and fetal alcohol syndrome in which all features are due to excessive maternal consumption of alcohol during gestation. Association. An association is a pattern of anomalies that occur together more frequently than expected but that are not identified as a sequence or syndrome. A classic example of this type of nonrandom occurrence of congenital anomalies is the VATER/VACTERL association (vertebral defects, anal

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atresia, cardiac anomalies, tracheoesophageal fistula, radial dysplasia, renal anomalies, limb anomalies). Discovery of a common underlying pathology for a pattern of associated anomalies may result in reclassification; for example, the CHARGE association (coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies) was recently reclassified as a syndrome following discovery of causal mutations in the CHD7 gene.

Syndrome Delineation Syndromology requires a decision as to whether a similar pattern of features in patients has an identical cause or if etiologically separate disorders with similar manifestations are present. Two basic principles for making this distinction are heterogeneity and pleiotropy as previously described. Nostalgically speaking, there are “splitters” and “lumpers” in syndromology. Splitting occurs when there is genetic heterogeneity; lumping occurs when there is pleiotropy. Identifying a syndrome is not equivalent to identifying an underlying mechanism. For example, trisomy 21 is the most common cause of Down syndrome, but a Robertsonian translocation and chromosomal mosaicism can also produce the same phenotype. These may be lumped together as the group understood to be Down syndrome and can be split apart to most accurately describe the underlying etiology of the condition with which a person is affected, which is important for provision of accurate recurrence risks. Pfeiffer syndrome also can result from both FGFR1 and FGFR2 gene mutations. Splitting these based on molecular genetic findings allows more accurate description of the condition; lumping all patients with Pfeiffer syndrome together allows for general understanding. Clinical, genetic, and molecular methods are used to recognize genetic heterogeneity. The process of syndrome delineation can lead to the establishment of separate etiologic entities that were once thought to constitute a single disorder. Fig. 3-13 summarizes the approach to syndrome delineation for multiple anomalies. Generally, a diagnosis can be placed into one of the categories discussed. Occasionally, a syndrome may be delineated in a one-step fashion; for example, when a new chromosomal abnormality is discovered during laboratory investigation of a patient clinically defined as having a provisional unique-pattern syndrome. For certain genetic disorders, the variability of the clinical expression awaits the discovery of more patients. A 22q11 deletion was historically identified in an individual with DiGeorge syndrome. With the advancement of molecular cytogenetic methods and better recognition of the phenotype, velocardio-facial (Shprintzen) syndrome, Cayler craniofacial syndrome, a subset of Opitz G/BBB syndrome, and isolated conotruncal cardiac anomalies can all result from the same chromosomal deletion. Craniosynostosis syndromes with digital anomalies were classified into specific syndromes such as Crouzon, Apert, Pfeiffer, and Jackson-Weiss before the FGFR gene family was identified. Since then, molecular

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FIGURE 3-13. Approch to syndrome delineation for multiple anomalies.

delineation has identified overlapping mutations producing these syndromes. Confusion between clinical and molecular diagnoses prompts the notion of using different axes in describing genetic conditions.

Significance of Syndrome Delineation The significance of syndrome delineation cannot be overestimated. As an unknown syndrome becomes delineated, its phenotypic spectrum, natural history, inheritance pattern, and risk of recurrence become known. This allows for better care of patients and for accurate genetic counseling. The medical implications and natural history of the syndrome can be provided and specific health supervision guidelines can be followed, as in the case of establishment of Wilms tumor protocol in patients with Beckwith-Wiedemann syndrome. Upon diagnosis, the clinician is forewarned to closely monitor the patient for development of this neoplasm. Finally, if the recurrence risk is known, the parents can receive genetic counseling about future pregnancies. This aspect of patient care is important, particularly when the recurrence risk is high and the disorder is disabling or disfiguring, has cognitive deficits as a component, or leads to a short life span. For example, cleft palate or the Pierre Robin sequence is a common feature of the Stickler syndrome, an autosomal dominant disorder with a 50% risk of recurrence when one parent is affected. If this syndrome is not identified in the proband, the parents will not appreciate the high recurrence risk if one of them is also affected and could be inappropriately counseled about multifactorial inheritance. Thus, syndrome delineation fosters good patient care and may contribute to a comprehensive treatment program. In contrast, with a provisional unique-pattern syndrome, the treatment program and overall management are relatively nonspecific.

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Importance of Syndrome Recognition in Otolaryngology Recognizing common genetic syndromes can be very helpful to otolaryngologists to ensure appropriate patient management and surgical approach. An accurate genetic diagnosis can help to avoid surgical complications that can be associated with certain genetic syndromes, prepare the family for the outcome of surgeries and avoid harmful procedures. Awareness by the otolaryngologist that a syndrome may be present in a patient, even if a specific diagnosis is not recognized, should prompt a recommendation to the primary care physician or a direct referral for evaluation of the patient by a clinical geneticist who can further assist in making the diagnosis. Surgery should not be scheduled until a syndrome that may confer increased surgical risks is excluded through clinical genetic examination and testing.

COMMON SYNDROMES WITH CRANIOFACIAL ANOMALIES In addition to the most common recognizable syndromes involving dysmorphic facial features, such as Down syndrome and fragile X syndrome, many conditions present with varied characteristic craniofacial anomalies. Accurate diagnosis allows for appropriate management and genetic counseling. Table 3-15 summarizes some recognizable conditions, along with their specific craniofacial findings, other physical findings, and current understanding of etiology and genetic testing. While many features of these varied conditions overlap, syndrome recognition is determined by the overall picture. New genetic tests for specific syndromes are being developed on an ongoing basis; a useful resource for locating current information about available tests is the Genetic Testing Registry (/www.ncbi.nlm.nih.gov/gtr/).

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Facies/HEENT findings Rounded facies; small nose with anteverted nares; broad philtrum; maxillary hypoplasia; widow’s peak; orthodontic concerns Deep-set eyes; broad forehead long straight nose with flattened tip; prominent chin; small, lowset, malformed ears; posterior embryotoxon

Branchial cleft sinuses; lacrimal duct obstruction; conductive hearing loss; abnormal upper lip with pseudocleft; low-set and malformed ears

Branchial arch anomalies including preauricular pits and branchial fistulas/cysts; abnormal pinnae; malformed inner or middle ear (or both); lacrimal duct stenosis; hearing loss

Condition

Aarskog Syndrome

Alagille Syndrome

Branchio-Oculo-Facial Syndrome

Branchio-Oto-Renal (Melnick-Fraser) Syndrome

TABLE 3-15. Syndromes with Craniofacial Anomalies

Yes/Molecular analysis of JAG1, and FISH for deletion 20p12

TFAP2A

• Autosomal dominant inheritance documented • Genetic mutations within the JAG1 gene identified in most affected individuals • specific JAG1 mutation implicated as the cause for isolated congenital heart defect • Submicroscopic deletions of the region 20p12 can be identified by FISH in a small percentage • Autosomal dominant inheritance documented • Causal mutations found in the TFAP2A gene • Transcription factor AP2-alpha is a 52-kD retinoic acid-inducible and developmentally regulated activator of transcription that binds to a consensus DNA-binding sequence CCCCAGGC promoter region of specific genes • Autosomal dominant inheritance with high penetrance and variable expression • At least three forms exist • BOR1 is caused by mutation in the EYA1 gene. EYA1 gene plays important role in the development of components of the inner ear and kidney • BOR2 is caused by mutation in the SIX5 gene. BOR3 caused by mutation in the SIX1 gene. • SIX gene family shown to play roles in vertebrate and insect development and implicated in maintenance of the differentiated state of tissues

Growth retardation, intrahepatic cholestasis, peripheral pulmonic stenosis, butterfly-like vertebral arch defects

Low birth weight, growth retardation, aplasia cutis congenita, mild mental retardation to normal intelligence

Renal dysplasia

Yes/Molecular analysis of EYA1 (BOR1); genetic testing for other forms is not currently available

Yes/Molecular analysis of FGD1

Testing Clinically Available Method

• X-linked recessive inheritance; some carrier females exhibiting mild features • faciogenital dysplasia gene (FGD1) at Xp11.21 implicated

Inheritance/Mechanism/Molecular Basis (If Known)

Mildly short stature, cognitive deficits, brachydactyly, ligamentous laxity, mild interdigital webbing, shawl scrotum

Other Findings

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(Continues)

Yes/Molecular analysis of RSK2 • X-linked dominant inheritance due to mutations in the RSK2 gene on Xp22.2 • RSK2 part of a gene family implicated in cell-cycle regulation through mitogenactivated protein kinase cascade

Mild to moderate postnatal Coarse facial features, downgrowth deficiency, severe slanting palpebral fissures, mental retardation, pectus maxillary hypoplasia, mild deformities, vertebral defects, hypertelorism, prominent brow, large hands, tapering fingers, short and broad nose with thick ligamentous laxity alae nasi and septum, anteverted nares, large mouth with thick everted lower lip, prominent ears, hypodontia, malocclusion

Coffin-Lowry Syndrome

Yes/Molecular analysis of CHD7

• CHARGE recently confirmed as syndrome • Diagnosis based on clinical findings and temporal bone imaging; genetic testing (when informative) useful to confirm diagnosis • Autosomal dominant inheritance • CHD7, encoding the chromodomain helicase DNA binding protein is only gene currently known associated with CHARGE • Sequence analysis/mutation scanning of the CHD7 coding region detects mutations in approximately 60%–65%

Cardiovascular malformations Unilateral or bilateral coloboma (75%–85%); growth deficiency of the iris, retina-choroid, (70%–80%); cryptorchidism and/or disc with or without in males; hypogonadotrophic microphthalmos (80%–90% hypogonadism in both males of individuals); unilateral or and females; developmental bilateral choanal atresia or delay; stenosis (50%–60%); cranial Neonates with multiple lifenerve dysfunction resulting in threatening medical conditions; hyposomia or anosmia, unilateral feeding difficulties are major or bilateral facial palsy (40%); cause of morbidity in all age impaired hearing, feeding groups and/or swallowing problems (70%–90%); abnormal outer ears; ossicular malformations; Mondini defect of the cochlea, and absent or hypoplastic semicircular canals; orofacial clefts (15%– 20%); tracheoesophageal fistula (15%–20%)

CHARGE Syndrome (coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, ear anaomalies)

No

• Genetic cause unknown

Klippel-Feil anomaly, Sprengel deformity, mental retardation

Facial asymmetry with short neck and low hairline; preauricular skin tags and pits; Duane anomaly; sensorineural/ conductive/mixed hearing loss

Cervico-Oculo-Acoustic Syndrome (Wildervanck Syndrome)

No

• X-linked inheritance presumed • No specific gene confirmed

Postnatal growth deficiency, hyperphalangy of the index finger, cardiac septal defects

Cleft palate; micrognathia; malformed ears

Catel-Manzke Syndrome

Yes/High-resolution karyotype with FISH for 22q11, or array CGH (microarray)

• Chromosomal: extra derivative chromosome resulting in partial tetrasomy of chromosome 22 or less frequently, duplication of 22q11 resulting in trisomy of this region • Found on cytogenetic analysis and can be confirmed using FISH or microarray

Congenital cardiac defects, anal Inferior coloboma of iris, choroid atresia, urogenital anomalies, and/or retina; mild hypertelorism mild mental retardation or with downslanting palpebral normal cognition fissures; preauricular pits or tags; micrognathia

Cat Eye Syndrome

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Bilateral cryptophthalmos, unusual eyebrows, hypoplastic notched nares, ear anomalies with atresia of the external auditory canal, cupped ears

Partial cutaneous syndactyly, incompletely developed genitalia, laryngeal stenosis/ atresia, renal hypoplasia/ agenesis, mental retardation in 50% of patients

Small for gestational age with Triangular facies, broad, bulbous dramatic postnatal growth nose with prominent nasal deficiency and delayed bone bridge and wide columella, short age, brachydactyly, clinodactyly, smooth philtrum, wide mouth mild mental retardation with with thin lips, prominent eyes in significant speech delay and infancy, deep-set appearing eyes normal motor development later, posteriorly rotated ears, short neck, low posterior hairline

Floating Harbor  Syndrome

Fraser Syndrome (Cryptophthalmos)

Yes/Molecular analysis • Autosomal dominant inheritance with of p63 gene (EEC3); variable expressivity implied no testing is • At least two forms of the disorder exist currently available • EEC1 shows linkage to 7q11.2-q21.3. for other forms of gene not yet identified EEC syndrome • Another form, EEC3, is caused by mutation in TP73L (aka. p63 gene) which shows strong homology to tumor suppressor p53 • P63 gene mutation can also cause splithand/foot malformation and RappHodgkin syndrome

Fair, thin skin with mild hyperkeratosis, hypotrichosis, hypohidrosis, hypoplastic nipples, variable defects in the midportion of the hands and feet from syndactyly to ectrodactyly, genitourinary defects in about 50% of patients

Blue irides, blepharophimosis, defects of the lacrimal duct system, cleft lip with or without cleft palate, partial anodontia, light-colored, sparse, thin, wiry hair

Ectrodactyly-Ectodermal DysplasiaClefting Syndrome (EEC Syndrome)

SRCAP

Yes/Limited molecular analysis of FREM2 gene is clinically available outside of the United States

• All cases sporadic • New mutation in autosomal dominant gene is presumed, but no causal gene identified

• Autosomal recessive inheritance documented • Fraser syndrome can be caused by mutation in the FRAS1 gene or in the FREM2 gene

Yes/Molecular analysis of NIPBL and SMC1L1

• Autosomal dominant inheritance, most representing new mutations in the family • NIPBL and SMC1L1 (SMC1A) only genes currently known to be associated with CdLS • Mutations in NIPBL identified in 50% of individuals with CdLS • Mutations in SMC1L1 identified in a small percentage of those with clinical diagnosis of CdLS

Upper limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly, cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, cryptorchidism or hypoplastic genitalia; IQ ranges from below 30 to 102 with an average of 53; autistic and  self-destructive tendencies are  frequent.

Testing Clinically Available Method

Hirsutism, synophrys, arched eyebrows, long eyelashes, small upturned nose, small widely spaced teeth, cupid’s bow mouth, microcephaly. Diagnosis of CdLS is clinically based on the presence of characteristic craniofacial features, growth failure (prenatal onset; less than fifth centile throughout life), mental retardation, limb abnormalities, and hirsutism

Inheritance/Mechanism/Molecular Basis (If Known)

Cornelia de Lange Syndrome (CdLS)

Other Findings

Facies/HEENT findings

Condition

TABLE 3-15. Syndromes with Craniofacial Anomalies (continued)

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Ocular hypertelorism, lateral displacement of inner canthi, widow’s peak, anterior cranium bifidum occultum defect, varied nasal defects, ranging from notched broad nasal tip to completely divided nostrils with median cleft lip Long palpebral fissures with everted lateral lower eyelids, ptosis, arched eyebrows, epicanthic folds, large protuberant ears, cleft palate

Microcephaly, large protruding ears, heavy eyebrows, deep-set eyes, large bulbous nose with thickened alae nasi and septum, simple philtrum, thin upper lip, sparse scalp hair Flat facies, depressed nasal bridge, prominent forehead, hypertelorism, cleft palate

Frontonasal Dysplasia Sequence

Kabuki Syndrome

Langer-Giedion Syndrome (Tricho-Rhino-Phalangeal Syndrome, Type II)

Larsen Syndrome

Yes/High-resolution karyotype with FISH for deletion of EXT1, or array CGH (microarray)

• Chromosomal microdeletion (contiguous gene deletion syndrome) due to loss of TRPS1 and EXT1 genes at 8q24.11-q24.13

Postnatal mild growth deficiency, loose skin in infancy, coneshaped epiphyses, multiple exostoses of the long bones, mild to severe mental retardation

(Continues)

Yes/Molecular analysis • Autosomal dominant inheritance of FLNB documented in most cases due to mutation in the filamin B (FLNB) gene at 3p14.3 • FLNB expressed in human growth plate chondrocytes and in developing vertebral bodies in the mouse. FLNB plays a role in vertebral segmentation, joint formation, and endochondral ossification. FLNB gene mutations also found in three other human skeletal disorders: spondylocarpotarsal syndrome, type I atelosteogenesis (AOI), and type III atelosteogenesis (AOIII) • An autosomal recessive form of Larsen syndrome may also exist

MLL2 and KDM6A

• Reportedly sporadic with new dominant mutations possible • Some families follow X-linked inheritance pattern • 8p22 rearrangement identified in some cases, but large-scale study excluded this finding

Cardiac defects in up to 50% of patients, postnatal growth deficiency, mild to moderate mental retardation, clinodactyly, persistent fetal finger pads

Multiple congenital joint dislocations, long nontapering fingers, short fingernails, dysraphism

ALX3

• Condition occurs sporadically • Primary defect in midface development due to a genetic or mechanical defect • In most cases, mechanical defect postulated

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Facies/HEENT findings Short depressed nose with flat nasal bridge and anteverted nares, large-appearing eyes, cataracts, myopia, flat midface, and prominent, protruding upper incisors Malar hypoplasia, sometimes with vertical bony cleft, down-slanting palpebral fissures, colobomata of the eyelids, ectropion, micrognathia, cleft lip or palate, or both, hypoplastic cup-shaped ears. Miller syndrome presents with Treacher Collins-like facial features but is associated with postaxial limb anomalies. Congenital facial palsy with impairment of ocular abduction; the facial nerve (cranial nerve VII) and abducens nerve (CN VI) are most frequently involved, but other cranial nerves may be involved as well

Malar hypoplasia; down-slanting palpebral fissures; high nasal bridge; partial to total absence of lower eyelashes; low-set posteriorly rotated ears; atresia of external auditory canal; cleft palate. presentation with Treacher Collins-like facial features but associated with preaxial limb deficiency

Condition

Marshall Syndrome

Miller Syndrome (Postaxial Acrofacial Dysostosis)

Moebius Syndrome

Nager Syndrome (Nager Acrofacial Dysostosis)

Testing available through exome sequencing

• Most cases are sporadic, but familial occurrence reported • Hereditary congenital facial paresis (HCFP) is isolated dysfunction of the facial nerve (CN VII) • One locus for HCFP (HCFP1) mapped to chromosome 3q. Another locus identified on chromosome 10q (HCFP2). • HCFP is sometimes considered distinct from Moebius syndrome, which shares some of the same clinical features • New autosomal dominant mutations likely responsible • Localization to chromosomal locus 9q32 accomplished through correlation with structural chromosome abnormalities • Gene is identified, SF3B4

Variable features include: orofacial dysmorphism and limb malformations; mental retardation reported in a subset of patients

Radial limb hypoplasia; conductive hearing loss; normal development and cognition

Testing available through exome sequencing

Yes, molecular testing is available

• Autosomal recessive inheritance likely because of recurrences within sibships • DHODH

Absence of fifth digit on all limbs, accessory nipples

Yes/Molecular analysis of COL11A1

Testing Clinically Available Method

• Autosomal dominant inheritance • Mutations in the COL11A1 gene at 1p21 identified

Inheritance/Mechanism/Molecular Basis (If Known)

Short stature, sensorineural deafness, calvarial thickening, spondyloepiphyseal abnormalities

Other Findings

TABLE 3-15. Syndromes with Craniofacial Anomalies (continued)

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(Continues)

Yes/Molecular analysis of FLNA • X-linked inheritance • Syndrome results from gain-of-function mutations in the gene encoding filamin A (FLNA) at Xq28 • FLNA gene is responsible for OPD1, OPD2, and frontometaphyseal dysplasia

Moderate conductive deafness; Cleft palate, frontal and occipital broad distal digits with short prominence, thick frontal bone, nails; small trunk; pectus thick base of skull, hypertelorism, excavatum; small stature; small nose and mouth cognitive deficits

Oto-Palatal-Digital Syndrome, Type I

No

• Autosomal recessive inheritance reported • No candidate locus identified

Conductive hearing loss; partial reduplication of the hallux and first metatarsal; bilateral postaxial polydactyly of hands; bilateral polysyndactyly of feet

Cleft tongue, low nasal bridge with lateral displacement of the inner canthi, broad nasal tip, midline partial cleft palate

Oral-Facial-Digital Syndrome, Type II (Mohr Syndrome)

• X-linked dominant inheritance with male Yes/Molecular analysis of OFD1 lethality • CXORF5 gene (OFD1) at Xp22.3-p22.2 is the only gene implicated

Digital asymmetry, adult polycystic kidney disease, variable mental retardation. Diagnosis established at birth in some infants on the basis of characteristic oral, facial, and digital anomalies; in others diagnosis suspected only after polycystic kidney disease identified in later childhood or adulthood

Oral frenula and clefts, hypoplastic nasal alae, lateral displacement of inner canthi, median cleft lip, cleft palate, bifid tongue

Oral-Facial-Digital Syndrome, Type I

Yes/Molecular analysis of MID1 for the X-linked form is available outside of the United States, and FISH analysis is widely available for detection of deletion of 22q11

• X-linked recessive and autosomal dominant inheritance identified • X-linked cases associated with mutation in the gene MID1 • Female heterozygotes may exhibit some clinical features of the syndrome • Autosomal dominant cases result from deletions in chromosome region 22q11

hypospadias, cryptorchidism, hernias, other midline defects (including swallowing/feeding and breathing problems), mild to moderate mental retardation

Hypertelorism; broad flat nasal bridge with anteverted nostrils; cleft lip with or without cleft palate; posteriorly rotated ears; micrognathia

Opitz G/BBB Syndrome

Yes, molecular testing is available

• Autosomal dominant inheritance with variable expression and many new mutations • Genetic linkage analysis mapped candidate locus to 6q22-q24 • Various mutations in the connexin 43 gene (GJA1) documented

Syndactyly of 4th and 5th fingers and 3rd and 4th toes, broad tubular bones

Microphthalmos; short palpebral fissures; epicanthic folds; tooth enamel hypoplasia; thin, hypoplastic alae nasi with small nares; poor-growing, sparse hair; mandible with wide alveolar ridge

Oculodentodigital Syndrome

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Prominent forehead; late closure of fontanelles; microcephaly; low-set malformed ears; downslanting palpebral fissures; flat nasal bridge; small mouth; micrognathia; cleft palate

Oto-Palatal-Digital Syndrome, Type II

Flexed overlapping fingers; short broad thumbs and great toes; small thorax; bowing of radius, ulna, femur, and tibia; flattened vertebral bodies; conductive hearing loss

Other Findings • X-linked semidominant inheritance described based on the presence of some clinical features in female heterozygotes • Otopalatodigital syndrome type II, like OPD type I caused by mutations in the gene encoding filamin A (FLNA) at Xq28

Inheritance/Mechanism/Molecular Basis (If Known) Yes/Molecular analysis of FLNA

Testing Clinically Available Method

Noonan Syndrome

Webbing of the neck, downslanting palpebral fissures, ptosis, hypertelorism, low-set ears, low posterior hairline

Short stature, shield chest, pectus excavatum, cryptorchidism, pulmonic stenosis; one-third of patients have bleeding diatheses

Yes/Molecular analysis • Autosomal dominant inheritance is available for all demonstrating genetic heterogeneity known genes and pleiomorphic phenotype • Currently mutations in four genes implicated • In nearly 50%, Missense mutations in PTPN11 identified; PTPN11 gene encodes SHP-2, a protein tyrosine kinase that plays diverse roles in signal transduction including signaling through the RAS-mitogen activated protein kinase (MAPK) pathway; Noonan syndrome-associated PTPN11 mutations are gain-of-function, with most disrupting SHP-2’s activationinactivation mechanism • Mutations in SOS1 identified in 10%–13% SOS1 may help mediate coupling of receptor tyrosine kinases to RAS signaling • Mutations in RAF1 implicated in 3%–17% Gain-of-function RAF1 mutations are associated with increased kinase and extracellular signalregulated kinase (ERK) activity • Mutations in KRAS account for fewer than 5% • Genotype-phenotype correlations continue to be defined

The RAS proteins and their downstream pathways play pivotal roles in cell proliferation, differentiation, survival and cell death, but their physiological roles in human development had remained unknown until recently. Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant multiple congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities, and mental retardation. As the genes now implicated in these syndromes encode proteins relevant for RAS-MAPK signal transduction, all of these syndromes are now understood to constitute a class of disorders caused by dysregulated RAS-MAPK signaling.

Facies/HEENT findings

Condition

TABLE 3-15. Syndromes with Craniofacial Anomalies (continued)

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Broad thumbs and toes, speech Microcephaly; frontal bossing; difficulties, unsteady gait, delayed fontanelle closure; cryptorchidism, hirsutism, down-slanting palpebral fissures; mental retardation hypoplastic maxilla with narrow palate; small mouth, beaked nose; low-set malformed ears; heavy high-arched eyebrows; long eyelashes

Rubinstein-Taybi Syndrome

(Continues)

Yes/FISH testing for • Genetic heterogeneity exists 16p13.3 deletion, • In minority of cases, this contiguous and molecular gene deletion syndrome can be analysis for point confirmed by FISH testing for 16p13.3. mutations in CREBBP FISH testing can detect fewer than 10% of cases EP300 molecular • In 50% of cases, point mutations within testing is also the cAMP-regulated enhancer-binding available protein (CREBBP) gene localized to 16p13.3 detected • Second locus at 22q13 implicated in fewer than 5%; these cases due to mutation in the E1A-binding protein, 300kD (EP300) gene that encodes p300, a histone acetyltransferase that regulates transcription through chromatin remodeling and is important in the processes of cell proliferation and differentiation

Yes/Molecular analysis of ROR2 for autosomal recessive form is available

• Genetic heterogeneity exists; both autosomal dominant and autosomal recessive forms described • Autosomal recessive form is caused by mutations in the ROR2 gene • Cause of the autosomal dominant form remains unknown

Short forearms; small hands, clinodactyly, hemivertebrae of thoracic spine, genital hypoplasia, moderately short stature

Hypertelorism; prominent eyes; frontal bossing; down-slanting palpebral fissures; small upturned nose; long philtrum; triangular mouth with downturned angles; crowded teeth; posteriorly rotated ears

Robinow (Fetal Face) Syndrome

Yes/Molecular analysis of HRAS

• Autosomal dominant new mutations with germline mosaicism accounting for the few reported cases of sibling recurrence proposed • Diagnosis based on clinical findings and confirmed by molecular genetic testing • Sequence analysis of HRAS, the only gene currently known to be associated with this syndrome detects missense mutations in 80%–90% with the clinical diagnosis

Postnatal growth deficiency; thin and deep-set nails; dark skin pigmentation; deep plantar and palmar creases; short neck; tight Achilles tendons; papillomas in the perioral, nasal, and anal regions; hypertrophic cardiomyopathy; mental retardation

Macrocephaly; coarse facial features; low-set ears with thick lobes; epicanthic folds; strabismus; thick lips, depressed nasal bridge; curly hair

Yes/Molecular analysis is available for all known genes

• Autosomal dominant inheritance speculated • Diagnosis based on clinical findings and molecular genetic testing • Four genes known to be associated with CFC syndrome: BRAF (~75%–80%), MAP2K1 and MAP2K2 (~10%–15%), and KRAS (less than 5%).

Postnatal growth deficiency; Relative macrocephaly; sparse, atrial septal defects; pulmonic curly, and poor-growing hair; stenosis and other congenital lack of eyebrows and lashes; heart defects; abnormal skin large prominent forehead; (including hyperkeratosis and bitemporal narrowing, shallow ichthyotic-type lesions), mild to orbits, hypertelorism, short moderate mental retardation upturned nose, prominent philtrum, posteriorly rotated ears

Costello Syndrome

Cardio-Facial-Cutaneous Syndrome

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Testing available through exome sequencing

Yes/FISH for deletion 22q11.2

• Autosomal recessive inheritance with genetic heterogeneity • Seckel syndrome type 1 (SCKL1) caused by mutation in the gene encoding ataxia-telangiectasia and RAD3related protein (ATR), which maps to chromosome 3q22.1-q24 • Other loci mapped to chromosomes 18p11-q11 (SCKL2) and 14q (SCKL3) • Chromosomal microdeletion (contiguous gene deletion syndrome) caused by deletion of 22q11.2 that can be confirmed by FISH in most cases. Inheritance of the deletion is autosomal dominant, although 93% of cases result from new mutations • Up to 8% of individuals with isolated palatal cleft may have deletion 22q11.2; this deletion syndrome represents the most common genetic cause of velopharyngeal incompetence • Syndrome has inter- and intrafamilial phenotypic variability. TBX1 gene maps within the 22q11.2 region proposed as the single gene cause, as many individuals with TBX1 mutation reported to have typical 22q deletion syndrome phenotype

Yes/Plasma assay • Autosomal recessive inheritance of 7-dehydro• A disorder of cholesterol metabolism cholesterol levels, • Diagnosis may be made based on clinical and molecular findings and decreased 7-dehydro analysis of DHCR7 cholesterol levels in plasma • Genetic testing of the sterol ∆D-7reductase gene (DHCR7, chromosomal locus 11q12-q13) may be done to identify causal mutations

Marked pre- and postnatal growth deficiency, mental retardation

Postnatal onset short stature; conductive hearing loss; slender hands and fingers; up to 85% have cardiac defects; increased incidence of adult psychiatric diagnoses; mild cognitive impairment

Syndactyly of the second and third toes; hypospadias, cryptorchidism; failure to thrive; moderate to severe mental retardation

High-arched/cleft palate; velopharyngeal incompetence; prominent nose with square nasal root; retrognathia, microcephaly

Microcephaly with narrow frontal area; low-set, rotated ears; ptosis; epicanthic folds; broad nasal tip with anteverted nares; micrognathia

Shprintzen Syndrome (22q11 Deletion Syndrome, Velo-cardiofacial Syndrome)

Smith-Lemli-Opitz Syndrome

Testing Clinically Available Method

Severe microcephaly; prominent nose; receding forehead; lowset malformed ears; relatively large eyes with down-slanting palpebral fissures

Inheritance/Mechanism/Molecular Basis (If Known)

Seckel Syndrome

Other Findings

Facies/HEENT findings

Condition

TABLE 3-15. Syndromes with Craniofacial Anomalies (continued)

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Auricular anomalies including overfolded ears, preauricular skin tags, some evidence of hemifacial microsomia Lower-lip pits (fistulae); cleft lip or cleft palate or both; missing central/lateral incisors, canines, bicuspids, or any combination thereof; small mounds with a sinus tract leading from a mucous gland of the lip may be present

Van der Woude Syndrome

• Autosomal dominant inheritance due to Yes/Molecular analysis of IRF6 mutations in the interferon regulatory factor 6 (IRF6) gene on chromosome 1q. IRF6-related disorders span a phenotypic spectrum from isolated cleft lip and palate and Van der Woude syndrome at the milder end to popliteal pterygium syndrome (cleft lip, cleft palate, lower lip pits, filiform synechiae of jaws and/ or eyelids, popliteal web, pyramidal skin fold on great toe, genital anomalies) at the more severe end

Growth and intelligence are normal

(Continues)

• Autosomal dominant inheritance with highly variable phenotype • Caused by mutations in the sal-like 1 (SALL1) gene. In approximately 70%, mutations in SALL1 identified

Thumb anomalies, anal defects, renal anomalies

Yes/Molecular analysis of SALL1

Yes/FISH testing for deletion of 8q24.12

• Autosomal dominant inheritance • Deletion of 8q24.12 (EXT1 gene locus) documented by FISH in fewer than 30% of cases

Mild growth deficiency; thin Pear-shaped bulbous nose; nails; epiphyseal coning; short prominent long philtrum; narrow fourth and fifth metacarpals and palate; large prominent ears; metatarsals small carious teeth; sparse, thin hair; relative hypopigmentation

Tricho-Rhino-Phalangeal Syndrome, Type I

Townes-Brocks Syndrome

Yes/Molecular analysis is available for all known genes

• Autosomal dominant inheritance with genetic heterogeneity • Mutations identified in the COL2A1, COL11A1, and COL11A2 collagen genes

Spondyloepiphyseal dysplasia, hyperextensibility, arthropathy, hypotonia, mitral valve prolapse

Flat facies, depressed nasal bridge; midface hypoplasia; clefts of hard/soft palate; bifid uvula; sensorineural and conductive deafness; dental anomalies; myopia; retinal detachments; cataracts

Stickler Syndrome

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Facies/HEENT findings

Prominent lips with open mouth; hoarse voice; medial eyebrow flare; periorbital fullness; blue eyes with stellate irides; anteverted nares; long philtrum

Condition

Williams Syndrome

Cardiovascular anomalies; growth deficiency; mild to moderate mental retardation; friendly, cocktail-party personality; renal anomalies; colic; hypercalcemia

Other Findings

TABLE 3-15. Syndromes with Craniofacial Anomalies (continued)

• Chromosomal microdeletion (contiguous gene deletion syndrome) involving the elastin (ELN) gene and other neighboring genes at 7q11.2 • FISH testing for this microdeletion is widely available. As an alternative, microarray assay can detect and further characterize the size of the deletion present in the critical region

• Diagnosis based on clinical findings. • Sequence analysis of IRF6 coding region (exons 1–9) detects mutations in approximately 70% with Van der Woude syndrome phenotype and approximately 97% with popliteal pterygium syndrome phenotype

Inheritance/Mechanism/Molecular Basis (If Known)

Yes/FISH for deletion of ELN at 7q11.2, and array CGH (microarray)

Testing Clinically Available Method

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CHAPTER 3 ❖ Genetics, Syndromology, and Craniofacial Anomalies

Next Generation Sequencing Genetic testing for single gene disorders has traditionally relied upon recognizing the clinical phenotype of a suspected syndrome and then ordering a test for sequencing or targeted mutation analysis of an individual gene associated with that syndrome. While this approach remains appropriate when only one gene or a small number of genes is responsible for the disorder, newer technologies involving “next-generation” sequencing methods have recently emerged. Exome sequencing (also known as targeted exome capture) is an efficient strategy to selectively sequence the coding regions of the genome. Exons are short, functionally important sequences of DNA which represent the coding regions in genes that are translated into protein. The exome is comprised of the approximately 180,000 exons in the human genome. The exome represents about 1% of the human genome and collectively is about 30 megabases (Mb) in length. It is estimated that about 85% of disease-causing mutations occur in the exome. Although the process is more complex than traditional sequencing approaches, exome sequencing entails certain key steps. Once a subject’s DNA sample is collected, exons are isolated or captured, amplified and sequenced. Bioinformatic approaches are then used to filter and compare the massive amounts of raw sequence data that are generated to genomic databases containing information about known normal sequences and common, likely benign polymorphisms. This technology has been used in research settings for several years to study disease pathways and to discover many causative or major contributing genes for syndromes. Recently, exome sequencing has been used more widely for clinical diagnosis. One approach involves the development of testing panels based on this “next-generation sequencing” technology that are able to simultaneously analyze dozens of genes contributing to a particular disease or phenotype to look for a causal mutation in a patient. This is a more affordable and rapid method of testing than sequencing numerous genes individually when a particular disorder is genetically heterogeneous. The whole exome sequencing (WES) approach is also beginning to be used clinically to look for causal mutations across a patient’s entire exome. This is particularly useful when initial tiers of genetic testing typically considered most appropriate for the patient’s phenotype have yielded negative results. However, the application of next-generation sequencing approaches to clinical diagnosis raises challenges. These include the technical aspects of the genomic assay itself, the complex bioinformatic analyses of massive amounts of data, and the clinicians’ expertise and ability to appropriately correlate and interpret the results in light of each patient’s unique clinical presentation. The potential for discovering variants of uncertain clinical significance or unanticipated incidental findings highlights the importance of thorough patient education about potential benefits and limitations of the technology, and careful conduct of the informed

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consent process. Currently, the diagnostic yield of WES in a clinical laboratory setting for unselected patients with a broad range of phenotypes is only around 25%. Still, WES represents both an important advance in clinical diagnostics and an effective alternative to whole genome sequencing, a potentially more powerful but exponentially more challenging technology that remains primarily a tool for genomics research at this time.

Selected References Aase JM. Diagnostic Dysmorphology. New York, NY: Plenum; 1990. Aase JM. Dysmorphologic diagnosis for the pediatric practitioner. Pediatr Clin North Am. 1992;39:135. Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y. The RAS/MAPK syndromes: novel roles of the pathway in human genetic disorders. Hum Mut. August 2008;29(8):992–1006. Arthur S. Aylsworth genetics review course. ACMG. 1999. Bennett RL, Steinhaus French K, Resta RG, Lochner Doyle D. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. J Genet Counsel. 2008;17:424–433. Curry CM. An approach to clinical genetics. In: Rudolph’s Fundamentals of Pediatrics. 2nd ed. Norwalk, CT: Appleton & Lange; 1999:147–180. Donnenfeld AE, Dunn LK. Common chromosome disorders detected prenatally. Postgrad Obstet Gynecol. 1986;6:5. Gelb BD, Tartaglia M. Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. Hum Mol Genet. October 15, 2006;15 Spec No 2:R220–R226. Gorlin RJ, Cohen MM Jr, Hennekam RCM. Syndromes of the Head and Neck. 4th ed. New York, NY: Oxford University Press; 2001. Graham JM. Clinical approach to human structural defects. Semin Perinatol. 1991;15:2. Graham JM, ed. Smith’'s Recognizable Patterns of Human Deformation. 3rd ed. Philadelphia, PA: WB Saunders; 2007. Hall JG, Allanson J, Gripp K, Slavotinek A. Handbook of Physical Measurements. 2nd ed. Oxford; New York, NY: Oxford University Press; 2007. Harper PS. Practical Genetic Counseling. 6th ed. London: Edward Arnold Ltd.; 2004. Hoffman JD, Zhang Y, Greshock J, et al. Array based CGH and FISH fail to confirm duplication of 8p22-p23.1 in association with Kabuki syndrome. J Med Genet. January, 2005;42(1):49–53. Jones KL, ed. Smith's Recognizable Patterns of Human Malformation. 6th ed. Philadelphia, PA: Elsevier Saunders; 2006. Lai JP, Lo LJ, Wong HF, Wang SR, Yun C. Vascular abnormalities in the head and neck area in velocardiofacial syndrome. Chang Gung Med J. August 2004;27(8):586–593. Leppig KA, Werler MM, Cann CI, Cook CA, Holmes LB. Predictive value of minor anomalies: I. Association with major malformations. J Pediatr. 1987;110:531. McKusick VA. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim. Mehendale FV, Sommerlad BC. Surgical significance of abnormal internal carotid arteries in velocardiofacial syndrome in 43

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consecutive hynes pharyngoplasties. Cleft Palate Craniofac J. July 2004;41(4):368–374. Mitnick RJ, Bello JA, Golding-Kushner KJ, Argamaso RV, Shprintzen RJ. The use of magnetic resonance angiography prior to pharyngeal flap surgery in patients with velocardiofacial syndrome. Plast Reconstr Surg. April 1996;97(5):908–919. Saul RA, Skinner SA, Stevenson RE, Rogers RC, Prouty LA, Flannery DB. Growth References from Conception to Adulthood. In: Proceedings of the Greenwood Genetic Center. Greenwood, SC, Greenwood Genetic Center, 1998. Shaffer LG, Slovak ML, Campbell LJ, eds. An International System for Human Cytogenetic Nomenclature (2009). Basel, Switzerland: Karger; 2009.

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Stankiewicz P, Beaudet AL. Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev. June 2007;17(3):182–192. Epub 2007 Apr 30. Review. Thurmon TF. A Comprehensive Primer on Medical Genetics. New York, NY: Parthenon; 1999:112. Zackai EH, et al. In: Polin RA, Ditmar MF, eds. Pediatric Secrets. 5th ed. Philadelphia, PA: Hanley & Belfus; 2005.

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4

C H A P T E R

C

Outcomes and Evidence-Based Medicine in Pediatric Otolaryngology Jennifer J. Shin and Christopher J. Hartnick

linical research is designed to evaluate patient-based results, particularly the accuracy of diagnostic testing and effectiveness of treatment options in clinical practice. The results of such clinical research have been in increasing demand, due to their many practical applications. First, clinical data have been proved useful in guiding management decisions, and clinicians often prefer to provide care through proven methods. In accordance with this, clinical practice guidelines based on the best available evidence have been implemented in academic institutions and private practices around the globe.1–3 Second, third-party payers regularly demand relevant evidence prior to reimbursing for treatments.4 Health care insurers consistently review and cite the published literature when evaluating new or even currently covered interventions. Furthermore, as of 2002, 42 states provided a process through which consumers could appeal denials of coverage by their health care plan to independent reviewers of the relevant clinical evidence.5 These practical applications have prompted one otolaryngologist to say that evidence-based practice “has become a necessity for practitioner autonomy and economic survival.”6 In addition to these practical applications, the academic community has developed a concerted effort to push medical education toward an evidence-based approach. Medical residency programs have incorporated these concepts into their training programs, and academic institutions have actively recruited physicians who are facile with evidence-based practice into teaching roles in their hospitals.7 The Journal of the American Medical Association, a periodical with 365,000 subscribers, has featured a series of articles specifically designed to educate physicians on the principles underlying rigorous clinical research.7 Also, through an initiative of the US Department of Human and Health Services Agency for Healthcare Research and Quality, 12 Evidence-based Practice Centers have been established in the United States. These centers serve to educate current and emerging clinicians through evidence-based practice and research. Likewise, Centers for Evidence-Based Medicine have been founded in the United Kingdom and Canada. This growing commitment of the medical field to an evidence-based approach predicts a continued need to conduct our practices on the basis of firm knowledge of the results of clinical trials. This need places an onus on physicians to base their management decisions on an understanding of the meaning and strength of the results of clinical trials. Evidence-based practice is defined as “the conscientious, explicit and judicious use of current best evidence in making

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clinical decisions about the care of individual patients.”8 It requires the discretion of the clinician’s judgment, an appreciation of individualized patient needs, and understanding of the relevant clinical research data. Evidence-based medicine is not authoritative, cookbook, or impractical. In fact, evidence-based practice ultimately stands on three legs: clinical data, clinician judgment, and patient preference.8 For most physicians, the most daunting aspect of evidencebased medicine centers around the leg that is the clinical data. Thus, this chapter delineates six concepts that will enhance the understanding of that clinical data, specifically (1) diagnostic test evaluation, (2) evaluation of management options, (3) potential errors in clinical data, (4) validity, (5) levels of evidence, and (6) systematic reviews. Then, this chapter concludes with a discussion of two practical applications of clinical data: clinical practice guidelines and pay for performance.

DIAGNOSTIC TEST EVALUATION Four key concepts define the utility of a diagnostic test: positive predictive value, negative predictive value, sensitivity, and specificity. The positive predictive value is a measure of how often a positive test result is truly correct. For example, the positive predictive value of a coagulation test for posttonsillectomy bleeding is 0.02 or 2%.9 This value means that 2% of children who have a positive test result (i.e., abnormal coagulation test) will actually bleed. This value essentially defines how much a positive test result can be trusted, with a 100% positive predictive value meaning that a positive test result is completely trustworthy. Conversely, the negative predictive value is a measure of the truth in a negative test result and defines how often a negative test result is correct. Of values that test negative, it is the proportion of values that is actually truly negative. For example, the negative predictive value of preoperative coagulation testing for posttonsillectomy bleeding is 0.92 or 92%.9 This means that 92% of children who have a negative (normal) test will not bleed postoperatively. The positive and negative predictive values are also influenced by the prevalence of disease, according to Bayes theorem. The concept underlying this theorem is that if a disease is more prevalent, then the positive predictive value is higher. Consider the following example: The test of looking at hairs on the floor is used to determine the hair color of the person who lives in a house. For example, black hairs on

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the floor mean that the person who lives there has black hair. This particular test result (black hairs on the floor) is very likely to be true positive (the person who lives there actually has black hair) in China, where the majority of people have black hair (high prevalence). However, the exact same test result (black hairs on the floor) is more likely to be wrong (the person who lives there does not have black hair) in Scandinavia, where fewer people have black hair (low prevalence). Thus, the prevalence (pretest probability) affects the predictive value of a test. Sensitivity and specificity are additional ways to measure the performance of a diagnostic test. Sensitivity is defined by the proportion of patients who truly have a disease that test positive for that disease. A high sensitivity means that a negative test result rules out the diagnosis. In other words, the false negative rate is low. To better understand this meaning, consider how sensitivity is calculated: sensitivity = true positives/(true positives + false negatives). If the number of false negatives is 0, sensitivity is 100%. Also, because all patients who truly have disease must test as either a true positive or a false negative, if the number of false negatives is 0, then all patients who have disease must be true positives. Thus, in general, a high sensitivity also means that the screening test is a good predictor of those with disease. For example, the sensitivity of laboratory coagulation screening in identifying children who will develop posttonsillectomy bleeding is 0.09, according to one study.9 This means that 9% of patients who will truly develop posttonsillectomy bleeding will have an abnormal coagulation panel (positive test). The sensitivity is low, which suggests that a positive test may not be a good predictor of postoperative bleeding. Specificity is the proportion of patients who are truly disease free that test negative for that disease. A high specificity means that a positive result rules in the diagnosis. In other words, the false positive rate is low. To better understand this meaning, consider how specificity is calculated: specificity = true negatives/(true negatives + false positives). Thus, if the number of false positives is 0, then specificity is 100%. Also, because all patients who truly do not have disease must test as either true negatives or false positives, then if the number of false positives is 0, then all patients who do not have disease must be true negatives. Thus, in general, a high specificity also means that the screening test is a good predictor of those without disease. For example, the specificity of laboratory coagulation screening in identifying children who will develop posttonsillectomy bleeding is 0.98 according to one study.9 This means that 98% of patients who will not develop postoperative hemorrhage will have a normal coagulation panel (negative test). The specificity is high, which suggests that a normal panel is associated with no bleeding. A 2 × 2 table helps further illustrate these four key concepts of positive and negative predictive values, sensitivity, and specificity.

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Positive for Disease

Negative for Disease

Positive test result

True positives

False positives

Negative test result

False negatives

True negatives

Positive predictive value = true positives/(false positives + true positives) (also influenced by pretest probability, i.e., prevalence). Negative predictive value = true negatives/(false negatives + true negatives) (also influenced by pretest probability, i.e., prevalence). Sensitivity = true positives/(true positives + false negatives). Specificity = true negatives/(true negatives + false positives).

MANAGEMENT OUTCOMES The Clinical Value of Data The clinical value of data is determined by how directly relevant the outcome measure is to a clinically meaningful issue. Some results can be measured very directly, such as decannulation after tracheotomy. However, some results are much harder to measure directly (i.e., improvement in nocturnal breathing after uvulopalatopharyngoplasty), and a surrogate endpoint or representative parameter must be chosen in its place (i.e., respiratory distress index). Such surrogate endpoints should be directly related to patientoriented outcomes to maximize the clinical value of the results.10 The exactness of results also contributes to their clinical value. Some outcomes are very clearly delineated, with minimal room for error in interpretation (i.e., survival). However, other outcomes are less obviously delineated (i.e., throat infections). In a well-designed study, any potentially ambiguous outcome measures are rigorously defined (i.e., each throat infection was documented and had at least one of the following: oral temperature >38.3°C, tender or > 2 cm lymphadenopathy, tonsil/pharyngeal exudates, group A b-hemolytic streptococcus culture positive, treatment with antibiotics for proved/suspected streptococcal infection11). Precisely defining an outcome measure permits the study results to be interpreted with greater certainty, maximizing their utility for a clinician attempting to apply them to her practice.

Measuring Subjective Results: Quality of Life In some cases, additional tools are needed to provide exact and accurate measurement of subjective results. Such tools are necessary when measuring less concrete outcomes, such as quality of life. Quality of life is a broadly defined concept that encompasses how patients feel and function

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CHAPTER 4 ❖ Outcomes and Evidence-Based Medicine in Pediatric Otolaryngology on multiple levels. Overall quality of life is affected by economic, emotional, spiritual, physical, mental, and other factors. A person’s health status or personal condition because of bodily afflictions or lack thereof is a key issue that affects people’s well-being. As physicians, we are interested in and focus on that aspect of personal welfare that is affected by health status, so-called health-related quality of life. When measuring health-related quality of life, investigators will ideally use a rigorously tested questionnaire, usually referred to as an instrument. A validated instrument has been tested to ensure that the following are true: (1) it measures what it is intended to measure (convergent validity, i.e., scores on a valid test of arithmetic skills correlate with scores on other math tests); (2) it does not inadvertently measure irrelevant changes (discriminant validity, i.e., scores on a valid test of arithmetic do not correlate with scores on tests of verbal ability)12,13; (3) its scores are stable (reliability, i.e., a patient with the same disease impact will continue to have the same response); and (4) it is sensitive to change (responsiveness, i.e., a patient with a change in disease impact will have a changed score). Overall, this means that the validated instrument does in fact measure what it is meant to measure when it is administered to the correct population. Instruments related to quality of life can be global or disease specific.10 A global instrument measures overall quality of life and may be used to determine the impact of many different diseases. One is example is the Child Health Questionnaire,14–18 which assesses a child’s physical, emotional, and social well-being from the perspective of a parent or guardian. There is a long form (50 questions) and a short form (28 questions). A disease-specific instrument, in contrast, is explicitly intended to measure the impact of one disease only. An example is the Otitis Media 6,19,20 which is validated for completion by caregivers in children aged 6 months to 12 years with chronic otitis media or recurrent acute otitis media. Caregivers rate the impact of otitis during the previous four weeks in six domains of physical suffering, hearing loss, speech impairment, emotional distress, activity limitations, and caregiver concerns. Each domain is scored on a scale of 1 (no problem) to 7 (extreme problem). In addition, a global quality of life score from 0 (worst possible) to 10 (best possible) is obtained using a visual analog scale. Often, both global and disease-specific instruments are used in the same study to provide complementary data. By using such validated instruments, investigators rigorously study more subjective outcomes.

POTENTIAL ERRORS IN CLINICAL DATA Potential Errors in Study Design The credibility of clinical data is determined by the number and magnitude of potential errors in the design of the study that produced them. Ideally, a study design ensures that only a truthful answer to the posed clinical question is

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obtained. A perfect study would show that an intervention (i.e., intravenous steroids) unequivocally caused an effect (i.e., decreased nausea and emesis) in a specified patient population (i.e., children undergoing tonsillectomy).9 A perfect study is flawless and, as such, is defined in terms of the flaws it lacks, just as a perfect test score is defined by the errors it lacks.21 Study flaws can occur because of unwanted interference from ancillary factors (i.e., confounding and bias), as well as from chance (i.e., statistical probability). Confounding A potential confounder is a factor that can cause the same outcome as the intervention of interest. It is sometimes referred to as “the third variable.” A factor is said to be confounded with another factor if it is impossible to discern which of the two is responsible for the observed effect.22 With confounding, a measure of the effect of the cause under investigation is distorted because of the presence of other potential causes of the same effect.23 In addition, the confounding variable may be associated with the intervention of interest, further complicating matters.24 Consider studying the impact of antibiotics on posttonsillectomy pain. Other factors besides antibiotics—such as surgical technique, anesthetic regimen, and use of steroids—may also influence postoperative pain and could confound the results. When confounders are present, a singular cause and effect cannot be demonstrated. Therefore, a high-quality study will try to eliminate confounders or at least carefully account for them. Randomization is one way of carefully accounting for confounders, by ensuring that they are at least balanced in the two groups being compared. In fact, the first table in the Results section of a well-reported randomized controlled trial (RCT) usually details potential confounders and demonstrates that they were distributed similarly in all of the groups that were compared. If such confounders are not managed properly, then no cause and effect can be demonstrated; the study’s conclusions must then be limited to drawing correlations between the intervention and outcome. These correlations cannot be used as proof of the intervention’s effects, although they may be used as just cause for further higher level study in which confounders will be carefully controlled.21 Bias Bias is simply an error in the technique of selecting subjects, performing procedures, measuring a characteristic, or analyzing and reporting data.22 In clinical research, bias does not imply stubbornness or willful deceit as in colloquial speech. Study techniques can artificially push the outcome in one direction, preventing a neutral demonstration of cause and effect. This artificial push constitutes bias, and many varieties of research bias have been described.23,25,26 Selection bias occurs when study subjects are improperly chosen. For example, in a study of the impact of antibiotics on adult pain after postoperative tonsillectomy, choosing only stoic patients to receive antibiotics would bias results. Worse, if

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you were comparing this group with a control group that did not receive antibiotics, and only put histrionic patients in that control group, selection bias would be even more egregious. Another type of bias is performance bias. Performance bias is introduced when there are inconsistencies in the care that is provided or exposure to other factors apart from the intervention of interest. Performing tonsillectomy with electrocautery in the group receiving antibiotics while performing cold tonsillectomy in the control group, for example, can bias results. Detection bias may also be present, where there is a partiality when assessing the outcomes. Perhaps the bestknown form of detection bias is expectation bias, where expecting a certain result can influence the result itself. Continuing with the antibiotics for tonsillectomy example, those in the antibiotic group might expect to have less pain than the control group. This expectation alone can actually result in less pain. This expectation bias can be eliminated by administering a placebo to the control group and blinding both patients and physicians.21 Other types of bias may occur during the analysis, interpretation, and even publication of results. The compilation of data may be plagued by attrition bias, which results from an excess amount (>20%) of patients lost to follow-up. Using our ongoing example, if only 1% of the patients return to report their postoperative pain, the results from the other 99% patients could have easily outweighed the results from the returning 1%, so the real result remains unknown. In addition, bias may result from not including data from patients who withdrew from the study because of treatment failure. To counteract such bias, an intention-to-treat analysis is ideally performed. In an intention-to-treat analysis, results are reported in terms of the original treatment groups regardless of whatever happened to subjects subsequent to their enrollment in the trial. For example, in a trial in which patients undergo radiation therapy versus surgical resection for laryngeal carcinoma, the survival outcome for a patient who was originally treated with radiation should be included with the data for the radiation therapy group, even if that patient subsequently required surgical resection. When results are being interpreted, a correlation bias may occur when correlation is equated with causation. For example, in a retrospective study of survival rates in patients treated with or without chemotherapy, it may be that chemotherapy is correlated with worse survival rates. However, this does not mean that chemotherapy causes death. It may simply be that chemotherapy was recommended in more advanced cases. Finally, bias may even occur in the publication stage. Publication bias in the otolaryngology literature has favored the acceptance and publication of reports of studies showing a difference in outcome in two groups, making it less likely that reports showing no difference between two groups will be distributed. Overall, bias can occur at multiple crucial junctures and may be seen not only while performing the study but also when its results are compiled and reported.21 The use of a control group can be an effective way to thwart many of these biases. A control group is used to provide a measure of what happens without the intervention.

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This control measure allows comparison of the intervention group to a group that is ideally similar in every other way. Confounders that cannot be eliminated are at least balanced in each group. Likewise patient selection, performance, outcome measurements, and analysis can be implemented in the same way in both groups to minimize bias. Ideally, then a comparative group of control subjects represents a cohort of patients that is the same as the test group with the exception of the intervention. In this ideal case, the intervention is the only difference that can account for a difference in their outcomes. If the intervention is truly the only difference between the two groups, then a true cause and effect is most likely to be demonstrated. Therefore, the presence of a control is better than none. Also, in controlled studies, the strength of the work is contingent on how well confounders and bias are accounted for and balanced between the two groups.21 Managing all these factors poses quite a challenge, however, and can be nearly impossible when the intervention has already been performed. It is because of this very reason that retrospective studies have inherent flaws; with retrospective studies, it is impossible to remove biases in selection, expectation, and detection, among others. In a prospective study, investigators can at least plan ahead to account for potential confounders and bias. They can arrange to use methods that minimize bias in selecting patients or collecting data. However, even then there may be potential biases or confounders that lie beyond the imagination of study coordinator or anyone else for that matter. With this concern in mind, the randomized controlled study was conceptualized. Because patients are randomly assigned, confounders that are known or even unknown are likely to be balanced between the intervention and control group. Therefore, the management of confounders and bias is heavily dependent on the study design, which ultimately determines the level of evidence that a study provides.21

Potential Errors From Chance A study may prove that a hypothesis is wrong, when in reality that hypothesis is right. Even if a study design is truly flawless, sometimes an error can still occur purely as a result of chance! There may be no human vice or inadvertent mistake involved; it can be just bad luck. There are two main types of bad luck that can occur. First, there is the potential for a type 1 error from chance. A type 1 error (the alpha level) is the probability that a study finds a difference when in reality no difference exists (i.e., the probability of rejecting the null hypothesis when in actuality the null hypothesis is true). For example, in truth, whether mothers have blue eyes versus brown eyes may have no impact on the height of their children. If a type 1 error occurs, however, a study may show that mothers with blue eyes have taller children; it shows an effect when in reality no true effect exists. The alpha level that is typically accepted is 5% or less, meaning that if a study demonstrates a difference, it is considered significant if there is a 5% or less chance that the study showed a difference when in fact no difference

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CHAPTER 4 ❖ Outcomes and Evidence-Based Medicine in Pediatric Otolaryngology truly exists. Acceptance of a 5% or less probability for a type 1 error as convention results in the significance-associated “P £ 0.05.” The second kind of potential error from chance is a type 2 error (the beta level), which is the probability that the study finds that there is no difference when in reality a difference exists (i.e., the probability of accepting the null hypothesis as true when in actuality the null hypothesis is false). For example, consider a coin with head on one side and tail on the other. If that coin is flipped 20 times and only tails are obtained, it may lead to the conclusion that there is no difference between the two sides of the coin, meaning that both sides have tails. But in reality a difference truly exists, meaning that there are both heads and tails present, the 20 flips resulted in data leading to a type 2 error. The beta level is generally accepted to be 10% or 20% in some scenarios. The power of a study is defined as (1 – beta), meaning the probability that a study will find a difference if a difference actually exists, so an acceptable power is 90% or 80% in some scenarios. Researchers performing clinical trials often begin with a consideration of power and sample size calculations. This is of great importance to avoid the pitfall of recruiting an inadequate number of patients, such that a study result showing no difference between groups cannot convincingly show that there is truly no such difference. Power is influenced by multiple factors, beginning with the sample size. A total of 1000 coin flips that show tails are more likely to mean that the coin actually has tail on both sides, compared with three coin flips that show tails. Therefore, a study’s susceptibility to error from chance is partially controlled by the investigators. Power is also influenced by the alpha level (see above), which is by convention set at 0.05 or a 5% probability of inaccurately rejecting the null hypothesis because of chance alone. In addition, power depends on the magnitude of difference deemed clinically significant (the delta level); as the delta level increases, the power increases. Therefore, the same study may have a high power for finding a large difference in two populations but a low power for detecting a small difference. In addition, power depends on the final outcome measurements and a calculation of their variance. Because some of these measurements will not be apparent until the study is completed, investigators must rely on estimates when attempting to ensure that a planned study is adequately powered. Here, preliminary data from previous studies prove invaluable in providing those estimates. Although investigators cannot control some factors, they need to estimate them to predict the number of patients necessary to achieve an acceptable power (90%) to detect a clinically significant outcome. In doing so, they increase the probability that their study will identify any difference that truly exists.21

VALIDITY Internal validity is determined by the purity of the measure of cause and effect within a particular study. Internal validity is highest when there is elimination of confounding factors

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and bias and represents the ability of the study design to purely test the impact of the intervention of interest.27–30 For example, if the intent is to determine the impact of putting red socks in the load of white laundry, then the test result (pink laundry) has high internal validity if purely the effect of red socks is evaluated. However, if yellow socks are also added, then the test result (orange laundry) has lower internal validity because the effect of the red socks was mixed with the confounding effect of the yellow socks. Internal validity could also be compromised if the person performing this illfated sock study is color blind, because potential bias would be introduced to the test results (laundry that is potentially interpreted as being green). Internal validity is a key concept, as it represents the purity of the cause-and-effect evaluation within a study. However, internal validity also represents the impact of an intervention under ideal circumstances, so the actual results may not practically translate into the real-world applications. External validity, in contrast, represents an evaluation of the generalizability of the study results to nonideal, more practical circumstances. External validity is the evaluation of whether study results still apply outside the context of the well-controlled study.27,28 For example, a study may evaluate an intervention and attempt to control for any confounding by ethnicity by including only Caucasian enrollees. If the intervention proves beneficial, then it may not be clear whether that same intervention would also be beneficial in African American or Hispanic patients. Thus, the study results have limited generalizability and limited external validity. As in this example, there is often a trade-off of internal validity for external validity and vice versa when conducting studies.30 A more pure, more tightly controlled study provides greater internal validity but makes it harder to extrapolate results to other circumstances. A study that accepts the presence of more potential external influences has less internal validity, but may provide more generalizable results.

LEVELS OF EVIDENCE One of the challenges in reviewing the literature lies in bringing order to the assortment of articles that are relevant to each clinical query; in other words, the approaches and results among articles may be similar or conflicting. The use of previously established levels of evidence for ranking published data helps readers understand the reliability of different reports. Using these levels also has the added benefit of providing guidance regarding the conclusions that can be drawn and the strength of recommendations made based on the reported data.31–33 These levels and their implications are as follows: Level 1 evidence is composed of RCTs or meta-analyses of RCTs. RCTs are the gold standard in study design, with randomization ideally removing unintended differences in the intervention and control groups prior to treatment. By using randomization to preventing bias in allocating patients to one group or the other, different results in the two

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groups may be attributed solely to either the intervention or lack thereof in the control group. Bias may be further minimized with this study type by blinding patients and caregivers to the type of intervention whenever possible. RCTs provide the strongest evidence for a direct cause and effect, and it is the best design to test the efficacy of the treatment in question. Recommendations based on RCTs are considered Grade A.21 Level 2 consists of prospective studies with an internal control group or a meta-analysis of prospective controlled trials. In this type of study, plans are made before patient care begins. A predetermined research protocol is used to assign patients to an intervention group or a control group. Usually, this internal control group parallels the group that receives the intervention of interest in every way except for lacking that intervention. A premeditated standardized method of data collection is used to gather results. Without randomization, the investigator is responsible for regulating potentially confounding variables that may produce misleading results. In addition, conclusions of the study must be tempered based on potential confounders that could not be regulated. Recommendations based on prospective controlled studies are appraised as Grade B.21 Level 3 includes retrospective studies with an internal control group or a meta-analysis of retrospective controlled studies. In this study design, the analysis is planned after patient care is already complete. For example, in a retrospective “case control study,” records are reviewed to find subjects who had an outcome of interest (i.e., survival); these subjects constitute the “case” group. Then records are reviewed to find patients who did not have the outcome of interest (i.e., did not survive); these subjects constitute the “control” group. Ideally, this “control” group is matched to the “case” group as closely as possible except for the outcome (i.e., similar stage N0 oral cavity carcinoma with primary surgical treatment in both groups). The proportion of each group that was exposed to a certain intervention is then compared (i.e., neck dissection as part of initial therapy). This study design is prone to selection bias, so the investigator must minimize potentially confounding differences between the “case” and “control” groups to optimize the validity of the results. In general, retrospective studies providing comparative data for a surgical intervention, either versus a nonsurgical control or versus another type of surgery, are considered level 3. Recommendations based on retrospective controlled studies are also ranked as Grade B.21 Level 4 studies are case series with no internal control group. With this type of study, the results of an intervention are reported in one group of patients without a comparison group; there is no report of a group that received either no intervention or a different intervention to place the results in context. It is purely a descriptive account and, as such, can suggest only correlations between the intervention and outcome. Alone, a study of this level cannot

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prove cause and effect, but it can document the potential for good outcome with a particular intervention. The most prudent use for this study design is to suggest hypotheses for higher level study. Recommendations based on level 4 studies are considered Grade C.21 Level 5 includes reports of expert opinions without explicit critical appraisal or on the basis of physiology or bench research alone. This designation is not meant to demean scientific research or the wisdom that follows from years of education and experience. In fact, it is because of the richness of these resources that many medical advancements are initially conceived. With this potential, expert opinions provide hypotheses that are worthy of higher level study. Recommendations based on level 5 reports are deemed Grade D.21 Although it might appear on first glance that only level 1 evidence should be considered acceptable, this idealized notion is not always practical, especially for a surgical subspecialty. Patients may hesitate to accept randomization to surgical treatment, and we frequently treat less prevalent diseases, making it difficult to attain the sizable patient pool necessary to perform a RCT of adequate power. The truth is that not all otolaryngologic interventions can be realistically evaluated by level 1 studies.21 Therefore, if level 1 studies cannot be made available, level 2 studies must suffice. Likewise, if level 1 and 2 evidence cannot be achieved, then level 3 evidence is the best choice, and so forth. As one author summarized it, “Any grade of evidence is a valid platform on which to base decisions, but only to the extent that higher grades of evidence are unavailable.”33

SYSTEMATIC REVIEWS According to Sackett, one of the foremost leaders in evidencebased medicine, “the systematic review of the effects of health care is the most powerful and useful evidence available.”31 The goal of a systematic review is to assess the literature critically to see whether a particular clinical question can be answered through rigorous analysis of the available data. This type of review includes not only the detailed results of relevant clinical trials but also an analysis of the validity of those results. A well-designed systematic review renders transparent the methodology of each of the studies included by focusing on the critical issues described above: the choice of outcome parameter, the chance of statistical errors, and the potential for confounding and bias. It also uses clearly defined inclusion and exclusion criteria to ensure that the incorporated studies, and data are chosen without predetermined bias. These inclusion/exclusion criteria are determined a priori, without knowledge of the associated study results, again to minimize any potential for bias. A systematic review differs in several key ways from a traditional narrative review. First, traditional narrative reviews often vary depending on the author. In contrast, a systematic

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CHAPTER 4 ❖ Outcomes and Evidence-Based Medicine in Pediatric Otolaryngology review is designed to minimize personal predispositions. Reproducible methods are used to produce reproducible results, and at least two authors participate in each review to corroborate findings and minimize inadvertent bias. Second, in a traditional narrative review, any variety of published articles may be cited—so in a worst-case scenario, five lowquality studies that support a point may be showcased, leaving the reader unaware of 100 high-quality studies with opposing results. A systematic review, on the other hand, gives a guarantee of thoroughness: methodical searching techniques ensure that all potentially relevant data are considered, and the article selection process is explained in detail so that any skeptical reader can verify the thoroughness for themselves. Third, a traditional narrative review typically reports results of relevant trials and whether they were statistically significant. In addition to these two features, a systematic review also gives an assessment of how credible any touted differences are, with emphasis placed on the most credible results. Finally, a traditional narrative review provides a summary of the practice considerations of the author. A systematic review provides a summary of the published data, and more so than a traditional narrative review, it empowers readers to make their own decisions based on knowledge of the strength of the data. In some systematic reviews, the outcome measures are similar enough, even in different studies, to allow pooling of the data. This statistical pooling of data can provide an estimate of the main effect of the intervention being reviewed. This pooling process is called meta-analysis and usually incorporates the results of RCTs, yielding data that are representative of all of the included study populations.34–37 A metaanalysis often includes a sensitivity analysis, which shows how or if results change under varying data-related criteria. In addition, any potential effect of publication bias (a bias that usually favors publication of positive studies, i.e., reports showing a significant difference between an intervention and control) is addressed by determining the hypothetical impact of a number of unpublished negative studies.

APPLICATIONS OF CLINICAL DATA ANALYSIS Clinical Practice Guidelines Clinical data are used as the cornerstone for the development of clinical practice guidelines, which are systematically developed documents that are meant to help guide evidence-based practice. They typically contain action statements based on the data from systematic reviews; those statements are developed to promote directed behavior and evaluate results.38 As Dr. Richard Rosenfeld described so well, “Guidelines begin where a systematic review ends by considering the role of values, diversity, patient preference, and risk-harm assessment in the decision-making process, and by using expert experience to fill gaps in the knowledge base.”39 These collective characteristics give guidelines their clout and applicability. Guidelines do not purport to dictate patient care in

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an authoritative way. They are neither recipes for cookbook generic care nor are they legal documents. Guidelines are typically developed by the relevant specialty organizations, and there have been multiple relevant publications in American Academy of Otolaryngology-Head and Neck Surgery’s journal as such.40–43 Guideline development occurs through to the following steps: (1) definition of the disease, patient population, and provider types that the guideline is meant to address, (2) establishment of leadership, stakeholders, and working group members, (3) evidence collection, rating, distribution, and synthesis, (4) action statement and guideline draft development, internal and external review, and (5) finalization by the board of directors or sponsoring organization.38 Guidelines have the benefits of providing physicians with a balanced, systematically developed pathway toward evidence-based care. They also establish solidarity and clout for the sponsoring organization. These guidelines are based on the cornerstone of clinical data, typically using the results of systematic reviews as the basis for their action statements.

Pay for Performance Pay for performance refers to the process in which providers’ reimbursement is linked to their patient outcomes.44,45 Traditionally, payment has been based on the type and quantity of care, rather than a measure of the quality of the results. Although there would ostensibly be an inherent impetus for all providers to prioritize optimization of results for their patients, reports by the Institute of Medicine and other organizations have brought such assumptions into question.46 Under a pay for performance model, physicians are rewarded for either achieving a certain threshold of patient outcomes (i.e., Surgeons achieving a less than 2% posttonsillectomy bleed rate will receive a bonus) or a certain ranking in the level of performance (i.e., The surgeon with the lowest postoperative bleeding rate will receive a bonus). Leading medical organizations have supported and helped shape this process. The American Medical Association has developed a set of principles to ensure that pay for performance programs adhere to the following: (1) prioritize quality of care, (2) promote the patient–physician relationship, (3) use voluntary physician participation, (4) incorporate accurate and fair reporting, and (5) provide fair and equitable incentives.47,48 The American College of Surgeons has developed a National Surgical Quality Improvement Program to help track surgical outcomes (i.e., What percent of patients develop postoperative infections?). They also participate in the Surgical Care Improvement Project, which focuses on process measures (i.e., How often were time outs actually performed?).49,50 Pay for performance measures create another motivation for data tracking and another application for collected data. To determine who has earned the relevant incentives, data must be collected, tracked, and analyzed at regular intervals. Thus, this evolving process has further increased the need to understand and critically appraise patient outcomes.

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References 1. Farquhar CM, Kofa EW, Slutsky JR. Clinicians’ attitudes to clinical practice guidelines: a systematic review. Med J Aust. 2002;177(9):502–506. 2. Hoyt DB. Clinical practice guidelines. Am J Surg. 1997;173(1): 32–34; discussion 35–36. 3. Weingarten S. Translating practice guidelines into patient care: guidelines at the bedside. Chest. 2000;118(2 suppl):4S–7S. 4. Piccirillo JF, Stewart MG, Gliklich RE, Yueh B. Outcomes research primer. Otolaryngol Head Neck Surg. 1997;117: 380–387. 5. Sabin JE, Granoff K, Daniels N. Strengthening the consumer voice in managed care: VI. Initial lessons from independent external review. Psychiatr Serv. 2003;54(1):24–25. 6. Bentsianov B, Boruk M, Rosenfeld R. Evidence based medicine in otolaryngology journals. Otolaryngol Head Neck Surg. 2002;126:371–376. 7. Guyatt G, Rennie D. User’s Guide to Medical Literature: Essentials of Evidence Based Clinical Practice. Chicago, IL: American Medical Association; 2002. 8. Sackett D, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence-based medicine: what it is and what it isn’t. BMJ. 1996;312:71–72. 9. Shin JJ, Hartnick CJ. Pediatric tonsillectomy. In: Shin JJ, Hartnick CJ, Randolph GW, eds. Evidence-Based Otolaryngology. New York, NY: Springer; 2008. 10. Stewart MG. Outcomes research: an overview. ORL J Otorhinolaryngol Relat Spec. 2004;66:163–166. American Academy of Otolaryngology Clinical Scholars Program. 11. Paradise JL, Bluestone CD, Bachman RZ, et al. Efficacy of tonsillectomy for recurrent throat infection in severely affected children. Results of parallel randomized and nonrandomized clinical trials. N Engl J Med. 1984;310(11):674–683. 12. Campbell DT, Fiske DW. Convergent and discriminant validation by the multitrait-multimethod matrix. Psychol Bull. 1959;56:81–105. 13. Trochim WM. Research Methods Knowledge Base 2000 http:// www.socialresearchmethods.net/kb/. 14. Broder HL, McGrath C, Cisneros GJ. Questionnaire development: face validity and item impact testing of the Child Oral Health Impact Profile. Community Dent Oral Epidemiol. 2007;35(suppl 1):8–19. 15. Raat H, Mangunkusumo RT, Landgraf JM, Kloek G, Brug J. Feasibility, reliability, and validity of adolescent health status measurement by the Child Health Questionnaire Child Form (CHQ-CF): internet administration compared with the standard paper version. Qual Life Res. 2007;16(4):675–685. 16. Drotar D, Schwartz L, Palermo TM, Burant C. Factor structure of the child health questionnaire-parent form in pediatric populations. J Pediatr Psychol. 2006;31(2):127–138. 17. Ruperto N, Ravelli A, Pistorio A, et al. Cross-cultural adaptation and psychometric evaluation of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ) in 32 countries. Review of the general methodology. Clin Exp Rheumatol. 2001;19(4 suppl 23):S1–S9. 18. Waters E, Salmon L, Wake M, Hesketh K, Wright M. The Child Health Questionnaire in Australia: reliability, validity and population means. Aust N Z J Public Health. 2000;24(2):207–210.

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19. Rosenfeld RM, Bhaya MH, Bower CM, et al. Impact of tympanostomy tubes on child quality of life. Arch Otolaryngol Head Neck Surg. 2000;126(5):585–592. 20. Rosenfeld RM, Goldsmith AJ, Tetlus L, Balzano A. Quality of life for children with otitis media. Arch Otolaryngol Head Neck Surg. 1997;123(10):1049–1054. 21. Shin JJ, Hartnick CJ. Introduction to evidence based medicine. In: Shin JJ, Hartnick CJ, Randolph GW, eds. Evidence-Based Otolaryngology. New York, NY: Springer; 2008. 22. Dawson B, Trapp RG. Basic and Clinical Biostatistics. 3rd ed. New York, NY: Lange Medical Books/McGraw Hill; 2001. 23. The Cochrane Collaboration. Cochrane Reviewers Handbook. 2001. http://www.thecochranelibrary.com 24. Hulley SB, Cummings SR, Browner WS, Grady D, Hearst N, Newman TB. Designing Clinical Research: An Epidemiological Approach. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001. 25. Sackett D. Bias in analytical research. J Chronic Dis. 1979;32 (1–2):51–63. 26. Hartmann JM, Forsen JW Jr, Wallace MS, Neely JG. Tutorials in clinical research: part IV: recognizing and controlling bias. Laryngoscope. 2002;112:23–31. 27. Crosby RA, DiClemente RJ, Green LW, Salazar LF. Research Methods in Health Promotion. John Wiley and Sons; 2006. 28. Miller SA. Developmental Research Methods. 3rd ed. Thousand Oaks, CA: Sage Publications; 2007. 29. Gliner JA. Internal and external validity in two studies that compared treatment methods. Am J Occup Ther. 1989;43(6): 403–407. 30. Godwin M, Ruhland L, Casson I, et al. Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity. BMC Med Res Methodol. 2003;3:28. 31. Sackett D, Richardson WS, Rosenberg W, Haynes RB. Evidence Based Medicine: How to Practice and Teach EBM. 2nd ed. London, UK: Churchill Livingstone; 2000:261. 32. Ball C, Sackett D, Phillips B, Straus S, Haynes B. Levels of evidence and grades of recommendations. Oxford, England. Center for Evidence-based Medicine. http://www.cebm.net/ levels_of_evidence.asp. Last revised 17 September 1998. 33. Rosenfeld R. Evidence, outcomes, and common sense. Otolaryngol Head Neck Surg. 2001;124(2):123–124. 34. Egger M, Smith GD, Phillips AN. Meta-analysis: principles and procedures. BMJ. 1997;315(7121):1533–1537. 35. Egger M, Smith GD. Meta-analysis. Potentials and promise. BMJ. 1997;315(7119):1371–1374. 36. Smith GD, Egger M. Meta-analyses of observational data should be done with due care. BMJ. 1999;318(7175):56. 37. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000;53(11):1119–1129. 38. Rosenfeld RM, Shiffman RN. Clinical practice guidelines: a manual for developing evidence-based guidelines to facilitate performance measurement and quality improvement. Otolaryngol Head Neck Surg. 2006;135(4 suppl):S1–S28. 39. Rosenfeld RM. Commentary: guidelines and otolaryngology. Otolaryngol Head Neck Surg. 2006;134(4 suppl):S1–S3. 40. Bhattacharyya N, Baugh RF, Orvidas L, et al. Clinical practice guideline: benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg. 2008;139(5 suppl 4):S47–S81.

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CHAPTER 4 ❖ Outcomes and Evidence-Based Medicine in Pediatric Otolaryngology 41. Roland PS, Smith TL, Schwartz SR, et al. Clinical practice guideline: cerumen impaction. Otolaryngol Head Neck Surg. 2008;139(3 suppl 2):S1–S21. 42. Rosenfeld RM, Andes D, Bhattacharyya N, et al. Clinical practice guideline: adult sinusitis. Otolaryngol Head Neck Surg. 2007;137(3 suppl):S1–S31. 43. Rosenfeld RM, Brown L, Cannon CR, et al. Clinical practice guideline: acute otitis externa. Otolaryngol Head Neck Surg. 2006;134(4 suppl):S4–S23. 44. Aleali SH. Pay for performance: a primer for physicians. Conn Med. 2006;70(1):33–38. 45. Lee KJ. Pay for performance (P4P). Bull Am Coll Surg. 2006;91(1):62. 46. Cognetti DM, Reiter D. The implications of “pay-forperformance” reimbursement for Otolaryngology-Head and Neck Surgery. Otolaryngol Head Neck Surg. 2006;134(6): 1036–1042. 47. AMA Trustees adopt pay for performance principles. Qual Lett Healthc Lead. 2005;17(8):15–16.

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48. Romano M. AMA sets some ground rules. Detailed conditions outlined for pay-for-performance. Mod Healthc. 2005; 35(26):17. 49. Jones RS, Brown C, Opelka F. Surgeon compensation: “Pay for performance,” the American College of Surgeons National Surgical Quality Improvement Program, the Surgical Care Improvement Program, and other considerations. Surgery. 2005;138(5):829–836. 50. Opelka FG, Brown CA. Understanding pay for performance. Bull Am Coll Surg. 2005;90(9):12–17. Portions of this chapter have been adapted from Shin JJ, Hartnick CJ. “Introduction to Evidence Based Medicine, Systematic Reviews, and Levels of Evidence,” Evidence-Based Otolaryngology. Shin JJ, Hartnick CJ, Randolph GW, Eds. Springer-Verlag International, 2008, with kind permission of Springer Science and Business Media.

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5

C H A P T E R

Ethical Issues in Pediatric Otolaryngology David B. Waisel and Laurie A. Ohlms

T

he discipline of medical ethics enables clinicians to recognize, analyze, and manage ethical dilemmas through crystallizing clinical information, clarifying moral dilemmas, and then identifying alternative solutions. Medical ethics does not replace law. Law delineates boundaries, whereas medical ethics helps physicians navigate issues unaddressed by law. It is said that law defines what “must” be done, whereas medical ethics seeks to define what “ought” to be done. The goal of this chapter is to inform otolaryngologists about medical ethics related to pediatric otolaryngology. Readers are advised to seek out one of the many other sources for a more complete review of general ethical issues relevant to otolaryngologists.

DOCTRINE OF INFORMED CONSENT Patients have a right to self-determination. Adult patients are considered to be competent to make decisions unless ruled otherwise by a judge. Decision-making capacity refers to the ability to participate in health-care decisions, and it depends on the patient’s age, the situation (such as the level of sedation), and the degree of risk in the decision. For example, sedation and the subsequent decline in decision-making capacity may leave the patient capable of making decisions involving lesser risks but not greater risks. Otolaryngologists evaluate decision making by assessing a patient’s ability to understand the situation, proposed procedure and alternatives, and the ability of the patient to communicate a decision based on internally coherent reasoning. The information that must be disclosed to a patient is illdefined. In the United States, the reasonable person standard requires that the information disclosed satisfy the hypothetical reasonable person. Unfortunately, although this provides a standard that can be used in law, it neither defines the precise information that should be given nor does provide the ability to tailor the informed consent process to the patient. Patients vary in their desire for information and desire to participate in decision making.1 Less than 20% of this variability is related to the extent of illness or sociodemographic issues, thus making prediction based on characteristics untenable.2 Otolaryngologists should ideally seek to satisfy the patient by meeting their information and decision-making needs. Satisfying the patient decreases the likelihood of being sued, although the ambiguity of “satisfy the patient” makes it difficult to use as a legal standard.3 Although the informed consent process concludes with a voluntary choice of the patient to have a specific procedure, the goal of a voluntary choice does not disqualify

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otolaryngologists from offering suggestions. As experts, otolaryngologists are obligated to offer their opinion and explain the benefits and risks of viable options.

Modifications to the Informed Consent Process for Pediatric Patients Informed Permission and the Best Interests Standard Parents or other surrogate decision-makers make medical decisions for children. Because informed consent implies that the individual affected is giving consent, the American Academy of Pediatrics suggests using the term informed permission when surrogate decision-makers authorize care.4 Although informed permission has the same requirements as informed consent, the distinction emphasizes the limits of surrogate decision making, particularly what is in the best interests of a child and in the limits of surrogate decision making for adolescents. In this chapter, the term “parent” is used for all surrogates who provide informed permission for the child. Children younger than 7 years generally do not have sufficient decision-making capacity to express informed assent. Parents, therefore, use the best interests standard to select the objectively best care. Although there is rarely one best option, there are often multiple acceptable choices. Parents have broad latitude to determine what is in their child’s best interest, in part to respect the different values in a multicultural society and in part because of the centrality of family in society. We also defer to families because parents have to “live” with their choices, and parental values are a reasonable first approximation of a child’s future values.5 Criteria to determine when a choice falls outside the range of acceptable decision making include the overall risk-to-benefit ratio based in large part on the likelihood of success and the extent of harm of the presence or absence of the intervention. For example, Baby Doe was born with Down syndrome and duodenal atresia and was permitted to die without intervention.6 Following public discussion, the consensus was that not repairing a correctable lesion was outside the bounds of acceptable undertreatment. In an example of how statute law is often a crude solution to subtle clinical decision making, subsequent “Baby Doe regulations” defined required treatment to avoid unacceptable undertreatment, leading to unacceptable overtreatment of patients.7–9 The continuum between unacceptable and acceptable treatment in the practice of otolaryngology is clear on the edges but murky in the middle. For example, it is nearly always considered unacceptable undertreatment

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for Jehovah’s Witnesses to refuse a life-sustaining blood transfusion for their child. On the contrary, even though the otolaryngologist may prefer to use stronger narcotics for posttonsillectomy pain, parents may choose to try weaker narcotics as long as the weaker narcotics do not expose the child to unacceptable pain or morbidity. Defining the point at which pain or increased risk of morbidity become unacceptable is complex. When otolaryngologists feel that parents are making decisions that fall outside the boundaries of acceptable options, they need to challenge the rights of the parents to make this decision for the child.10 Otolaryngologists may first wish to consult with colleagues regarding the appropriateness of the parent’s decisions. Otolaryngologists should seek to resolve the issues through consultations with colleagues in social work, ethics consultation, and legal medicine. Reporting the situation to child welfare authorities for possible legal intervention has significant consequences and should only be done after thorough pursuit of other mechanisms of resolution. Assent Children older than age 7 should participate in medical decision making consistent with their emotional and cognitive maturation and the implications of the decision (Table 5-1).11 For example, an 11-year-old child should participate in the

TABLE 5-1. Elements of Consent and Assent as Defined by the American Academy of Pediatrics Committee on Bioethics4

1. Adequate provision of information including the nature of the ailment or condition; the nature of the proposed diagnostic steps or treatment and the probability of their success; the existence and nature of the risks involved; and the existence, potential benefits, and risks of recommended alternative treatments (including the choice of no treatment) 2. Assessment of the patient’s understanding of the above information 3. Assessment, if only tacit, of the capacity of the patient or surrogate to make the necessary decisions 4. Assurance, insofar as it is possible, that the patient has the freedom to choose among the medial alternatives without coercion or manipulation Assent 1. Helping the patient achieve a developmentally appropriate awareness of the nature of his or her condition 2. Telling the patient what he or she can expect with tests and treatment 3. Making a clinical assessment of the patient’s understanding of the situation and the factors influencing how he or she is responding (including whether there is inappropriate pressure to accept testing or therapy) 4. Soliciting an expression of the patient’s willingness to accept the proposed care

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decision whether to have an ear tube removed in the office or in the operating room. Otolaryngologists should be aware that younger children in this age group are rigid about promises and rules and may react poorly to changes in plan. Children older than 10 years of age are more capable of understanding and cooperating with changes in plans. Otolaryngologists should assume that patients of age 14 years or older have decision-making capacity and should routinely seek to fulfill the ethical obligation for consent. Although, at age 14, many adolescents have developed their ability to reason, think abstractly, anticipate outcomes, and simultaneously consider multiple options, they do not have the maturity to fully consider long-term consequences. This emotional impulsiveness and immaturity can hamper decision making. For example, a 15-year-old who recently became quadriplegic may wish to forgo tracheotomy and die because of his physical limitations. A year later, a better perspective will permit a more thoughtful decision. Otolaryngologists should avoid pro forma solicitations of adolescents’ opinions. The American Academy of Pediatrics emphasizes that “no one should solicit a patient’s views without intending to weigh them seriously. In situations in which the patient has to receive medical care despite his or her objection, the patient should be told that fact and should not be deceived.”4 Informed Refusal Informed refusal can occur when parents decline an otolaryngologist’s recommendation, when a child refuses nonemergent care, or when parents and child prefer different options. As described previously, otolaryngologists may use the best interests standards to challenge inappropriate parental decisions for children. Decision-makers should understand the risks, benefits, and alternatives before declining a recommended therapy. Otolaryngologists should honor the right of children with significant decision-making capacity (generally about 10 years of age) to refuse nonemergent care.12 For example, consider a 13-year-old who, while moving from the stretcher to the operating room bed, declares that she does not want a tonsillectomy and adenoidectomy. She has not received any sedation. She had given informed assent to surgery in the preoperative holding area. As the otolaryngologist talks with her, she starts crying uncontrollably and continues to refuse surgery. Rather than asking the anesthesiologist to furtively induce anesthesia through her intravenous catheter, the otolaryngologist should continue talking with her. If fruitful discussion is impossible or if she continues to refuse surgery, it may make sense to leave the operating room and involve her parents. Simple interventions often resolve these situations. If she continues to refuse, it is wholly reasonable to postpone the procedure, because postponement does not increase morbidity or mortality. Forcing the child, however, may lead her to mistrust the medical profession and reject future necessary care.13 Otolaryngologists may benefit from assistance from hospital personnel experienced in conflict

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CHAPTER 5 ❖ Ethical Issues in Pediatric Otolaryngology 71 resolution, such as social workers, clinical ethicists, attorneys, and other resources. Parents and adolescents may prefer different treatment options. As children get older, they can make decisions that involve progressively greater risks, particularly if they can articulate evidence of thoughtful maturity and decision making. For example, an adolescent who can express her rational desires coherently may be permitted to forgo treatments that otherwise would decrease her risk of morbidity and mortality. Clinicians faced with these dilemmas may want to determine whether an option is unacceptable or whether it is less desirable but still acceptable.

Special Situations in Pediatric Informed Consent What Would You Do If This Was Your Child? Otolaryngologists should seek to understand what the parents are asking with this question.14,15 For example, parents may be seeking help to make a rational decision. Physicians should respond by explaining the reasons and values of their personal choices. Parents may also be asking for reassurance that they are making a good decision. Otolaryngologists who agree with the decision should offer reassurance. Otolaryngologists who believe that the decision is reasonable but not optimal should support parents through comments such as “others in the same situation have made the same choice” or by acknowledging that it is normal to feel uncertain.14 If pressed for a more direct answer, otolaryngologists who acknowledge that they would have chosen differently should emphasize that the decisions need to reflect the more relevant values of the parents. At times, particularly with complex life-changing decisions, the otolaryngologist may not know what she would do for her child. In these cases, otolaryngologists may want to offer parents an approach to address the dilemma, such as “I would gather my family to have a discussion.” Parents faced with “impossible” decisions may be reassured to know that the “expert” is similarly flummoxed. Emancipated Minor Status and Mature Minor Doctrine Emancipated minors are adolescents under the age of 18 who by statute have the right to make their own health-care decisions. The requirements to be an emancipated minor vary by state, but in general include adolescents who are married, parents, in the military, or economically independent. Mature minors are adolescents who are authorized by the court to give informed consent in specific situations. The granting of mature minor status is often based on the age and maturity of the adolescent and the level of risk of the decision.16,17 Children of Jehovah’s Witnesses Jehovah’s Witnesses interpret biblical scripture to prohibit blood transfusions because those who take blood will be “cut off from his people” and not earn eternal salvation.18,19 Courts

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have not permitted parents to refuse transfusion therapy on their child’s behalf because of the obligation of the state to protect the interests of incompetent patients, known as the legal doctrine of parens patriae.20,21 Otolaryngologist should directly address concerns about transfusion when caring for a child of Jehovah’s Witnesses.22,23 The child and family should be informed that although all attempts will be made to avoid transfusion therapy, the otolaryngologist will seek a court order authorizing the administration of life-sustaining blood if clinically necessary. Depending on the likelihood of blood loss, otolaryngologists may wish to contact hospital counsel to obtain a court order before the operation. Consider a healthy 5-year-old child of Jehovah’s Witnesses returning to the operating room for control of posttonsillectomy hemorrhage. The parents had been told before the first surgery that the need for transfusion was unlikely and that a court order would be sought if transfusion becomes necessary. During surgery for control of the hemorrhage, the child unexpectedly needs a transfusion. On the basis of the obligation to protect the interests of children, the child should be transfused blood without waiting for a court order. Waiting for the court order may permanently harm the child. Decision-makers may want to consider postponing procedures until the child is legally able to decide about transfusion therapy. Of course, delay may increase the risk or decrease the likelihood of a good outcome. Relevant considerations center on relevant quantitative and qualitative changes in risk or benefit. When otolaryngologists want to honor a mature minor’s desire to refuse transfusion therapy, it is important to ensure the fidelity of the promise by verifying that all clinicians who may provide intraoperative or postoperative care will likewise honor the mature minor’s wishes. Ideally, other clinicians should not be put in the untenable position of having to choose between their values and the promised care in an urgent or emergent situation. Confidentiality for Adolescents Otolaryngologists are required to protect patient information from unauthorized and unnecessary disclosure. Confidentiality improves the flow of information and concerns. Breaching confidentiality often leads to adolescents eschewing future medical care.24 Although maintaining confidentiality will not lead to significant harm, otolaryngologists should encourage adolescents to be forthright with parents but should respect their decision not to be. Otolaryngologists may be ethically justified in notifying the parents if maintaining confidentiality may result in harm to the adolescent.24 Standard exceptions to maintaining confidentiality include statutes requiring parental notification or when an adolescent credibly threatens harm to another person. Emancipated and mature minors have a right to complete confidentiality. Many states have statutes prohibiting physicians from notifying parents about a positive pregnancy test. In nearly all situations, it is ethically appropriate to inform only

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the adolescent of a positive presurgical pregnancy test.25 Because most otolaryngologists are not expert in the psychosocial issues of adolescent pregnancy, otolaryngologists should seek consultation with experts such as pediatricians, gynecologists, and social workers. If the otolaryngologist, anesthesiologist, adolescent, and other advisors wish to postpone the case and the adolescent does not want to inform her parents, clinicians must be careful not to inadvertently inform the parents when discussing the postponement. Emergency Care When a minor needs emergency surgery, and there is no parent available to give legal consent or informed permission, necessary therapy should be performed without obtaining consent.26 It is less clear when an adolescent refuses emergency care that the parent desires. Honoring the adolescent’s preferences depends on the extent of harm of forgoing therapy and the adolescent’s rationale. When the risk is great and the adolescent’s rationale insubstantial, the adolescent may not have sufficient decision-making capacity for this emergency decision. At this point, it may make sense to use the best interests standard. For example, following a car accident, a 17-year-old needs emergency stabilization of his spine and repair of facial fractures. He cannot move his legs. He refuses surgery, because he does not want to live if he is paraplegic. This response suggests a scared emotional response to an abrupt event. He does not have full decision-making capacity, and therefore, he cannot meet the hurdle necessary for a minor to refuse intervention. Months later, however, if he was continuing to refuse interventions, greater consideration should be given to his requests to refuse therapy. The Impaired Parent Parents with impaired judgment due to substance abuse or other reasons may be disruptive, dangerous, and unable to fulfill surrogate responsibilities. The primary focus should be the safety of the child, the impaired parent, other families, and employees.27 Clinicians should attempt to protect patient and parent confidentiality, but not at significant risk to others.27 Clinicians should use the least restrictive means to decrease risk from the impaired parent’s behavior. Although it may be desirable to postpone routine treatment until an unimpaired parent is available, otolaryngologists have to weigh the benefits of waiting with the risk that impaired parents may be less reliable and may not return for future visits. In this case, it may be wise to consider what is in the best interest of the child. Depending on the importance of the intervention, if it is in the child’s best interest, otolaryngologists may wish to proceed even if the impaired parent is unable to give legal consent. In these situations, otolaryngologists may wish to consult legal and risk management colleagues for guidance.

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FORGOING LIFE-SUSTAINING TREATMENT Do-Not-Resuscitate Orders in the Operating Room Do-not-resuscitate (DNR) orders permit patients to avoid burdens related to the resuscitation attempt or the possible loss of capacity that would follow a successful resuscitation. The American Academy of Pediatrics, the American Society of Anesthesiologists, and the American College of Surgeons recommend mandatory reevaluation of the DNR order before going to the operating room.28–30 Patients, parents, and clinicians should be involved in determining the relevant benefits and burdens of surgery and resuscitation during surgery for the child with a DNR status. The American Academy of Pediatrics guidelines include as benefits an improved quality and enjoyment of life and, in certain circumstances, a prolongation of life.31 Burdens include disability, increasing pain and suffering, decreased enjoyment of life, and a decrease in the quality of life as determined by the child and parents.31 Parents often need to be educated about the differences between resuscitation on the ward and in the operating room. The process of anesthesiology and surgery routinely causes respiratory and hemodynamic disturbances that require intervention. Parents should also know that surgical interventions increase the likelihood for resuscitation and that prognosis from witnessed arrests is better than unwitnessed arrests. Perioperative reevaluation of the resuscitation status is based on the goal-directed approach, which permits patients and clinicians to define desirable goals (instead of permissible procedures). This allows clinicians to determine whether specific interventions will achieve those goals.32 When determining goal-directed orders, the burdens that patients accept, the benefits they want, and the likelihood of specific outcomes should be discussed. For example, some may choose to accept only a minor burden in exchange for only a high likelihood of returning to preoperative function. Indeed, most patients prefer either (1) to receive full resuscitation or (2) to receive resuscitation if the interventions and burdens are temporary and reversible. Table 5-2 lists information useful in advising children and parents about perioperative resuscitation.30 Postoperative plans should be determined as part of the resuscitation discussion. It is reasonable for patients to permit a short trial of a burdensome therapy, such as mechanical ventilation, to see if they may benefit from it, but to limit the exposure to that burdensome therapy. Although some physicians are not comfortable withdrawing therapies, it is widely accepted that withdrawing and withholding life-sustaining therapies are ethically equivalent. Clinicians should consider mechanical ventilation to be a trial of therapy. In fact, to do a trial and then to withdraw a therapy is more convincing evidence of ineffectiveness than not attempting a trial of therapy.

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CHAPTER 5 ❖ Ethical Issues in Pediatric Otolaryngology 73 TABLE 5-2. Components of a Pediatric DNR Discussion30 • Planned procedure and anticipated benefit to child

TABLE 5-3. Suggested Approach for Resolving Disputes About Appropriate Care5

Parents Prefer to Accept Treatment

Parents Prefer to Forgo Treatment

Physicians consider treatment clearly beneficial

Treat

Provide treatment during review process

Physicians consider treatment to be of ambiguous or uncertain benefit

Treat

Forgo

Physicians consider treatment to be inadvisable

Provide treatment during review process

Forgo

Physicians consider treatment to be futile

Review

Forgo

• Likelihood of requiring resuscitation • Reversibility of likely causes resuscitation • Description of potential interventions and their consequences • Chances of success • Ranges of outcomes with and without resuscitation • Intended and possible venues and types of postoperative care • Establishment of an agreement through either a goaldirected approach or a revocation of the DNR order for the perioperative period • Documentation

In pediatrics, there is less importance placed on preoperative determination of postoperative plans, because usually parents are available in the postoperative period to make decisions regarding therapy. In that case, it is not unreasonable to favor a trial of therapy. Physicians underestimate the value patients place on functional status and activities of daily living and overestimate the value patients place on life expectancy.33–35 The American Academy of Pediatrics suggests that legitimate procedures for a child with a DNR order include procedures that decrease pain, provide vascular access, enable the child to be able to be discharged from hospital, treat an urgent problem unrelated to the primary problem, or treat a problem that may be related to, but is not considered, a terminal event. Physicians are more likely to resuscitate a patient against their declared preferences if the cause of the arrest is iatrogenic.36,37 To patients, what matters is the physical and mental status following resuscitation, not the cause of the arrest.38 Many states have statutes that provide explicit immunity for clinicians who honor an appropriately documented refusal of resuscitation.33 The risk of liability of not honoring a DNR order is likely to be greater than the nearly nonexistent risk of honoring a documented order.33 Readers should not misinterpret the focus of this discussion on maintaining some form of perioperative DNR to mean that it is inappropriate to revoke the DNR order. In many cases, perioperative revocation is likely to be preferred. Children and families do not have to worry if a certain intervention is considered to be resuscitative, and they do not have to worry about limiting potentially therapeutic anesthetic or surgical interventions.

Inadvisable Care Otolaryngologists may have to address conflicts about using treatments with low likelihoods of accomplishing their

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goals.39 Treatments with low likelihoods of success may be inadvisable because of burden to the child, cost, uncertain benefit, or unacceptable quality of life resulting from the therapy.40 Discussions about inadvisable treatment should include relevant stakeholders and should define the goals of the treatment, the likelihood of achieving a defined result, and the levels of evidence being used.39 Most ethicists use the approach proposed by the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research when negotiating conflicts about inadvisable care in pediatrics (Table 5-3).5 In short, clinicians may override parental preferences only if the therapy is clearly beneficial. Adopting a different approach, Texas enacted controversial legislation for resolving conflicts about inadvisable care. This approach permits physicians to unilaterally make decisions regarding inadvisable treatment provided the hospital ethics committee concurs.41–43

PEDIATRIC ISSUES IN OTOLARYNGOLOGY PRACTICE Special Requirements for Pediatric Research In the United States, federal guidelines define four categories of risk. Increased risks require a commensurate increase in potential benefits (Table 5.4).44 Guidelines are centered on the concept of minimal risk.45 Minimal risks are those risks ordinarily encountered in daily life. Some interpret minimal risk to mean risks encountered by healthy children, such as playing sports, riding in the

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TABLE 5-4. Federal Classifications for Pediatric Research44 (1) Research not involving greater than minimal risk (a) IRB determines minimal risk (b) IRB finds and documents that adequate provisions are made for soliciting assent from children and permission from their parents or guardians (2) Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (a) IRB justifies the risk by the anticipated benefit to the subjects (b) The relation of the anticipated benefit to the risk is at least as favorable as that presented by available alternative approaches (c) Adequate provisions for assent and permission (3) Research involving greater than minimal risk and no prospect of direct benefit to individual subjects but likely to yield generalizable knowledge about the subject’s disorder or condition (a) IRB determines the risk representing a minor increase over minimal risk (b) The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations (c) The intervention or procedure is likely to yield generalizable knowledge … which is of vital importance for the understanding or amelioration of subject’s disorder or condition (d) Adequate provisions for assent and permission (4) Research not otherwise approvable, which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children

car, or having a routine physical exam.45,46 A less favored relative interpretation bases minimal risk on the daily risks experienced by the research subjects who may be receiving medical treatment, such as radiologic surveillance for cancer. Regardless of the standard used, institutional review boards are overly influenced by the familiarity of an activity and may misunderstand the extent of risk in daily life and of studies, prohibiting relatively low-risk studies and permitting higher-risk studies. In general, using the cumulative risks of a round-trip car travel, bathing, and playing, a child under the age of 15 has a daily risk of mortality of 1 in 666,666.45 Similarly, otolaryngologists need to understand the interpretation of the rather ambiguous category of “research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition.” “Greater than minimal risk” has been defined to mean a “minor increase over minimal risk,” which is interpreted as those risks in which the pain, discomfort, and

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stress is transient, reversible, and not severe.46 Condition is interpreted as a set of characteristics “that an established body of scientific or clinical evidence has shown to negatively affect children’s health and well-being or to increase the risk of developing a health problem in the future.”46 A critical feature of this category is that some interpret condition to include the potential for a condition, which permits healthy children to be subjects for studies about conditions they may develop, such as cellulitis. Institutional review boards may request that pediatric studies be initially performed in less vulnerable populations, such as in older children or adults. In the context of research, it is critical to obtain assent of the child when possible, along with the informed permission of the parents. Assent can be waived when it involves no more than minimal risk to the subjects, will not adversely affect the rights of the subjects, or could not practicably be carried out without the waiver.44 Parental permission may be waived when it would be unreasonable, such as in matters of child abuse.47 For studies involving neonates, particularly around birth, it is preferable to obtain prenatal consent if possible because the immediate postnatal period is a suboptimal setting for obtaining research consent.48 An emergency exception for consent is available for short therapeutic windows, and this exception assumes consent is being sought. For school-age children and adolescents, token gifts may be given to thank the child for participation. The gift should not be so substantial as to encourage participation in the study. However, what is a token gift in one family may be a substantial or even coercive gift in another family.49 Parents may also be coerced, creating a potential conflict of interest between parents and children.49 Socioeconomically disadvantaged children are more likely to be research subjects.49 Academic hospitals located in large urban centers tend to care for socioeconomically disadvantaged children more prone to diseases affected by environment, poor nutrition, and lack of healthcare, such as asthma, trauma, obesity, and prematurity. It may be ethically acceptable for socioeconomically disadvantaged children to bear a disproportionate extent of risk necessary for scientific advances, because they may be more likely to benefit. Many, however, believe that socioeconomically advantaged patients are gaining the benefit of the research without incurring proportionate risk.

Cochlear Implantation A full discussion about the primary ethical considerations for cochlear implantation is beyond the scope of this chapter, but otolaryngologists should be familiar with the outlines of the discussion.50 We have attempted to write this section in a value neutral way, but being hearing, we suspect that we are influenced by inherent bias or by an overcorrection of that bias. This discussion focuses on the most common situation of a deaf infant of hearing parents.

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CHAPTER 5 ❖ Ethical Issues in Pediatric Otolaryngology 75 Members of the Deaf-World (the term by which deaf people call their community and culture) argue that being deaf is a culturally defining characteristic. To quote Lane, “once acculturated to the Deaf-World, Deaf people know the language, customs, attitudes, values and the like of that culture, and they self-identify as Deaf.”51 To seek to disenfranchise or eliminate the Deaf-World by “pushing” technology is tantamount to ethnocide. Even if inserting cochlear implants always resulted in perfect hearing, this child should not receive a cochlear implant, because that would lead to the destruction of Deaf-World.52 “Pushing” cochlear implants will eventually make implants the standard of care. The countervailing argument is that physical characteristics do not define membership in a culture, and therefore, there is no deaf culture.53 In fact, a child’s culture is primarily influenced by the parents, and these parents would want to bring the child up in their culture, which likely considers hearing to be a positive attribute. The second argument centers on what is in the best interests of the child. For this discussion, we assume that cochlear implants work to varying degrees. Hearing people argue that the ability to hear increases opportunities and improves the quality of life. Hearing people also argue that some hearing is better than no hearing. The chance to obtain some hearing is worth the risks of surgery and the tremendous time and energy needed to engage in postsurgical therapy, even if the investment in optimizing use of the cochlear implant hinders learning sign language. Members of the Deaf-World argue that the costs of not being immersed in the Deaf-World early in life dramatically limit opportunities and quality of life. The Deaf-World blames the assumption that “deafness is a disability” on a complete lack of understanding of the Deaf-World and of the experience of being deaf. Furthermore, by seeking to be part of the hearing world, patients are more likely to view being deaf as a negative instead of a positive. Both sides of this discussion engage in inflammatory rhetoric. Cochlear implant advocates need to understand the reasoning used by members of the Deaf-World and give credence to their belief that deafness is a central part of an individual’s personhood. To classify deafness as a disability is demeaning. On the contrary, members of the Deaf-World need to understand the reasoning and give credence to the hearing world’s presumption that any hearing is better than no hearing. Members of both the Deaf-World and cochlear implant advocates have an obligation to commit to open communication and to work fairly with families as they make their decisions. To do otherwise is unfair to the children and their families.54

Safety and Quality Care, Disclosure, and Apology Another obligation of physicians is to actively participate in quality improvement activities by following policies designed to reduce medical errors, such as universal standards of patient identification.59–61 If policies are harmful or unnecessary, physicians are obligated to question these policies through appropriate channels. Circumventing policies may harm patients, prevent improvement, and weaken the fidelity of the entire system by encouraging others to ignore policies. In one survey, 99% of parents wanted to be informed if there was potential or actual harm; 77% wanted to be informed even if there were no potential or actual harm.62 Most parents also wanted their child informed if there was the potential for harm. Physicians, however, do not routinely honor this desire.63 In one study, slightly more than half of pediatricians would disclose a serious error, and only 24% would apologize for such an error.63 An apology is an expression of regret or sorrow. More than half the states have laws prohibiting the admission of apology or sympathy as evidence of wrongdoing.64 Physicians should prepare themselves for the apology to be coolly received. TABLE 5-5. Examples of Advocacy and Participation57,58 • Raising public awareness about health or social issue • Writing a letter, signing a petition, or participating in another form of public advocacy and lobbying • Working informally with others to solve a health problem in the community • Encourage a medical society to act on an issue that concerns the public health • Serving in a local organization, political interest group, or political organization • Topics of particular relevance to pediatric otolaryngologist • Health care access • Child abuse

Advocacy and Good Citizenship

• Communication enhancement

One of the obligations of pediatric clinicians is advocacy. There is an implicit social contract between physicians and society. Society has supported the development of physicians through money, opportunities to train, and patients with and 55–57

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from whom to learn.56 Society, therefore, expects physicians to use their skills to benefit society through more than just patient care. An implicit obligation is for clinicians to “directly influence individuals’ health” in their community by participating in activities consistent with the individual’s “expertise, interests and situations.”57 In this context, a community may mean individuals in the same physical location, or it may mean patients for whom the physician has a special obligation toward such as children. Table 5-5 lists potential areas of advocacy for pediatric otolaryngologists.

• Role of subspecialty training in improving care for children • Eco-conservation in the clinic, operating room, and hospital

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Parents may be less likely to accept apologies about events that affect their children than they would about events that affect themselves. A disclosure tells what happened. Thoughtful full disclosure is gaining favor.65 On realization of the problem, the goal is to give as much information as is known, but not to speculate about what is not known, particularly about fault. Physicians should care for the patient by explaining the medical implications of the event and any necessary treatment. The patient should be informed who will provide them with further nonmedical information about the event. After a thorough investigation, the patient and family should be informed about the results, including how similar events will be prevented.

Suspicion of Child Abuse Otolaryngologists are well-positioned to recognize child abuse. Approximately 75% of child abuse is in the head, face, mouth, and neck area.66–68 Children who have physical or mental handicaps are particularly prone to abuse.69 Child abuse may occur during diagnostic or therapeutic care.70 Physicians are legally required to report the suspicion of child abuse or neglect to appropriate authorities and can be criminally prosecuted if found liable for failing to

report suspected child abuse.71 Otolaryngologists should be cognizant of injuries that are developmentally inappropriate, do not occur naturally, and are not explained by the offered history.72–74

Fetal Care Otolaryngologists need to be prepared to negotiate the ethical complexities of the maternal–fetal dyad.75 It is helpful to understand the differences between the positions of the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (Table 5-6).76–78 The differences center on when the interests of the mother and fetus diverge, such as when the mother wants to refuse a treatment for the fetus. In general, the American Academy of Pediatrics advocates for the fetus, particularly when an effective intervention to an irreversible harm poses only a small risk to the mother. The American College of Obstetricians and Gynecologists focuses on the complex issues of overriding maternal autonomy.

Complementary and Alternative Medicine Complementary and alternative medicine approaches include acupuncture, manual therapies, herbal therapies, nutritional supplements, and mind/body therapies.79 Parents may use

TABLE 5-6. Positions of the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists Regarding Ethical Considerations and Maternal Choices in Fetal Therapy76–78

American Academy of Pediatrics

American College of Obstetricians and Gynecologists

• Respect for principle of maternal autonomy

• Respect for principle of maternal autonomy

• Fetal concerns may trump maternal autonomy

• Fetal concerns may not trump maternal autonomy

• The intervention has been demonstrated to be effective

• There is a high probability of significant benefit to the fetus

• Nonintervention will lead to significant and irreversible harm

• Nonintervention will lead to a high probability of significant harm to the fetus

• There is minimal maternal risk from the intervention

• There is a relatively small risk to the pregnant woman.

Use of physical intervention

• Physical intervention may be justified and judicial authorization has been obtained

• Physical intervention is never justified

Psychosocial aspects

• Psychosocial aspects of overriding a woman’s autonomy is not addressed

Significant concerns about overriding maternal autonomy, including

Priority

Type of medical treatment worthy of judicial or physical intervention

• No comparably effective less invasive options are available

• Criminalizing noncompliance of medical recommendations • Loss of trust in the health-care system • Social costs of compromising liberty Conflict resolution

• Does not ask physicians to consider subordinating their view

• Physicians should make reasonable attempts to explain recommended treatments and to persuade the woman to comply

• Does not suggest it is reasonable to transfer the patient’s care

• Physicians should subordinate their values if necessary, because it is the woman’s decision • Suggests it may be reasonable to transfer care

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CHAPTER 5 ❖ Ethical Issues in Pediatric Otolaryngology 77 complementary and alternative medicine in part to feel like they are actively helping their child fight illness. Otolaryngologists should ensure that children are harmed by neither the addition of potentially dangerous therapies nor the forgoing of useful mainstream therapies.80

Molecular Genetic Testing On the one hand, genetic testing may help confirm a diagnosis, permitting initiation of appropriate care.81 On the other hand, genetic testing may force undesired knowledge upon others and may create economic ramifications, such as limitations in job opportunities or the ability to obtain health insurance. The American Academy of Pediatrics recommends offering testing only when there are immediate medical benefits to the child or when there is a benefit to another family member and no expected harm to the child. Otherwise, testing should be deferred until the child understands the potential ramifications of genetic testing.81

The Ethics Consultation Service Ethics committees and their consulting services act in an advisory role to help clinicians, patients, and families amicably resolve ethical dilemmas.82 Most consultations are performed by a small group of ethics committee members (typically around three people), although variations include consultations being performed by either the entire committee or one person.83 In general, all members of the hospital community may serve on an ethics committee. Most ethics consultation services permit anyone to request a consultation, require notification (not permission) of the patient, parents, and attending physician before initiating the consult, and emphasize that the choice to follow the recommendations is wholly voluntary.84 Otolaryngologists may find ethics consultation helpful with questions about informed consent, decision-making capacity, and disagreement resolution among patients, families, and clinicians.85–87 For example, consultations can help otolaryngologists determine whether parents are choosing an unacceptable option or an acceptable albeit less preferable option. Consultations can help restore functional communication between stressed clinicians and scared, exhausted parents, particularly in the settings of difficult decisions or clinical setbacks. Ethics consultations are frequently used to help assess whether an adolescent has sufficient maturity to make a decision. Consultations regarding the legitimacy of performing or forgoing a treatment permit clinicians to feel more comfortable honoring adolescent preferences. Following consultations, clinicians have an increased knowledge and comfort in dealing with ethical issues as well as a heightened awareness of the expert consulting services available. Hospitals also use ethics committees to perform organizational consultations, policy development, and educational programs. For example, an organizational consultation may be performed to determine whether and how a hospital

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should care for adolescents who wish to refuse potentially life-sustaining transfusion therapy. After a proposed policy for management of these adolescents is sanctioned, the ethics committee may take primary responsibility for educating the hospital community about the underlying rationale of new policy. Otolaryngology departments may seek help from ethics committees to optimize relationships with members of the Deaf-World. Improved professional relationships between the Deaf-World and cochlear implant advocates and formal policies delineating rights and responsibilities of the parties may help patients and families receive fair and balanced presentations of options.

References 1. Guadagnoli E, Ward P. Patient participation in decision-making. Soc Sci Med. 1998;47:329–339. 2. Benbassat J, Pilpel D, Tidhar M. Patients’ preferences for participation in clinical decision making: a review of published surveys. Behav Med. 1998;24:81–88. 3. Stelfox HT, Gandhi TK, Orav EJ, Gustafson ML. The relation of patient satisfaction with complaints against physicians and malpractice lawsuits. Am J Med. 2005;118:1126–1133. 4. Committee on Bioethics, American Academy of Pediatrics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics. 1995;95:314–317. 5. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Deciding to Forgo Life-Sustaining Treatment: Ethical, Medical and Legal Issues in Treatment Decisions. Washington, DC: U.S. Government Printing Office; 1983. 6. Pless JE. The story of Baby Doe (letter). N Engl J Med. 1983;309:664. 7. Kopelman LM, Irons TG, Kopelman AE. Neonatologists judge the ‘Baby Doe’ regulations. N Engl J Med. 1988;318:677–683. 8. Kopelman LM. Are the 21-year-old Baby Doe rules misunderstood or mistaken? Pediatrics. 2005;115:797–802. 9. Sayeed SA. Baby Doe redux? The Department of Health and Human Services and the Born-Alive Infants Protection Act of 2002: a cautionary note on normative neonatal practice. Pediatrics. 2005;116:e576–e585. 10. Kon AA. When parents refuse treatment for their child. JONAS Healthc Law Ethics Regul. 2006;8:5–9, quiz 10–1. 11. In re Green, 292 A.2d. 387 (1972). 12. Boldt v. Boldt, 544 US 929 (2005). 13. Dickens BM, Cook RJ. Adolescents and consent to treatment. Int J Gynaecol Obstet. 2005;89:179–184. 14. Kon AA. Answering the question: “Doctor, if this were your child, what would you do?” Pediatrics. 2006;118:393–397. 15. Truog RD. Doctor, if this were your child, what would you do? Pediatrics. 1999;103:153–154. 16. Will JF. My God my choice: the mature minor doctrine and adolescent refusal of life-saving or sustaining medical treatment based upon religious beliefs. J Contemp Health Law Policy. 2006;22:233–300. 17. Ariga T. Refusal of blood by Jehovah’s Witnesses and the patient’s right to self-determination. Leg Med (Tokyo). 2009;11(suppl 1):S138–S140. 18. Leviticus 7:27.

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19. Watch Tower Bible and Tract Society of Pennsylvania. How can blood save your life? Brooklyn, NY: Watchtower Bible and Tract Society of New York, Inc; 1990. 20. In re Sampson, 278 N.E.2d. 918 (N.Y. 1972). 21. Wallace v. Labrenz, 104 N.E.2d. 769 (1952). 22. Woolley SL, Smith DR. ENT surgery, blood and Jehovah’s Witnesses. J Laryngol Otol. 2007;121:409–414. 23. Adelola OA, Ahmed I, Fenton JE. Management of Jehovah’s Witnesses in otolaryngology, head and neck surgery. Am J Otolaryngol. 2008;29:270–278. 24. Council on Scientific Affairs, American Medical Association. Confidential health services for adolescents. JAMA. 1993;269: 1420–1424. 25. Committee on Adolescence, American Academy of Pediatrics. Counseling the adolescent about pregnancy options. Pediatrics. 1998;101:938–940. 26. Committee on Pediatric Emergency Medicine. Consent for emergency medical services for children and adolescents. Pediatrics. 2003;111:703–706. 27. Fraser JJ Jr, McAbee GN. Dealing with the parent whose judgment is impaired by alcohol or drugs: legal and ethical considerations. Pediatrics. 2004;114:869–873. 28. American College of Surgeons. Statement of the American College of Surgeons on Advance Directives by Patients: “Do not resuscitate” in the operating room. American College of Surgeons Bulletin. 1994;79(9):29. 29. American Society of Anesthesiologists. Ethical guidelines for the anesthesia care of patients with do-not-resuscitate orders or other directives that limit care. In: ASA Standards, Guidelines and Statements. Park Ridge, IL: American Society of Anesthesiologists. 30. Fallat ME, Deshpande JK. Do-not-resuscitate orders for pediatric patients who require anesthesia and surgery. Pediatrics. 2004;114:1686–1692. 31. Committee on Bioethics, American Academy of Pediatrics. Guidelines on forgoing life-sustaining medical treatment. Pediatrics. 1994;93:532–536. 32. Truog RD, Waisel DB, Burns JP. DNR in the OR: a goaldirected approach. Anesthesiology. 1999;90:289–295. 33. Waisel DB, Burns JP, Johnson JA, Hardart GE, Truog RD. Guidelines for perioperative do-not-resuscitate policies. J Clin Anesth. 2002;14:467–473. 34. Wenger NS, Pearson MJ, Desmond KA, et al. Epidemiology of do-not-resuscitate orders: disparity by age, diagnosis, gender, race, and functional impairment. Arch Intern Med. 1995;155:2056–2062. 35. Eliasson AH, Parker JM, Shorr AF, et al. Impediments to writing do-not-resuscitate orders. Arch Intern Med. 1999;159:2213–2218. 36. Richter J, Eisemann MR. The compliance of doctors and nurses with do-not-resuscitate orders in Germany and Sweden. Resuscitation. 1999;42:203–209. 37. Casarett DJ, Stocking CB, Siegler M. Would physicians override a do-not-resuscitate order when a cardiac arrest is iatrogenic? J Gen Intern Med. 1999;14:35–38. 38. Clemency MV, Thompson NJ. Do not resuscitate orders in the perioperative period: patient perspectives. Anesth Analg. 1997;84:859–864. 39. Consensus statement of the Society of Critical Care Medicine’s Ethics Committee regarding futile and other possibly inadvisable treatments. Crit Care Med. 1997;25:887–891.

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40. Keenan HT, Diekema DS, O’Rourke PP, Cummings P, Woodrum DE. Attitudes toward limitation of support in a pediatric intensive care unit. Crit Care Med. 2000;28:1590–1594. 41. Jacobs HC. The Texas Advance Directives Act—is it a good model? Semin Perinatol. 2009;33:384–390. 42. Truog RD. Counterpoint: The Texas Advance Directives Act is ethically flawed: medical futility disputes must be resolved by a fair process. Chest. 2009;136:968–971; discussion 971–973. 43. Fine RL. Point: The Texas Advance Directives Act effectively and ethically resolves disputes about medical futility. Chest. 2009;136:963–967. 44. Keenan HT, Diekema DS, O’Rourke PP, Cummings P, Woodrum DE. Attitudes toward limitation of support in a pediatric intensive care unit. Crit Care Med. 2000;28:1590–1594. 45. U.S. Department of Health and Human Services (45 CFR 46 subpart D). Additional protection for children involved as subjects in research. 2009. 46. Wendler D, Belsky L, Thompson KM, Emanuel EJ. Quantifying the federal minimal risk standard: implications for pediatric research without a prospect of direct benefit. JAMA. 2005;294:826–832. 47. Fisher CB, Kornetsky SZ, Prentice ED. Determining risk in pediatric research with no prospect of direct benefit: time for a national consensus on the interpretation of federal regulations. Am J Bioeth. 2007;7:5–10. 48. U.S. Department of Health and Human Services (21 CFR 50 subpart D). Additional safeguards for children in clinical investigations. 2009. 49. Mason SA, Allmark PJ. Obtaining informed consent to neonatal randomised controlled trials: interviews with parents and clinicians in the Euricon study. Lancet. 2000;356:2045–2051. 50. Coleman DL. The legal ethics of pediatric research. Duke Law J. 2007;57:517–624. 51. Levy N. Reconsidering cochlear implants: the lessons of Martha’s Vineyard. Bioethics. 2002;16:134–153. 52. Lane H, Grodin M. Ethical issues in cochlear implant surgery: an exploration into disease, disability, and the best interests of the child. Kennedy Inst Ethics J. 1997;7:231–251. 53. Lane H, Bahan B. Ethics of cochlear implantation in young children: a review and reply from a Deaf-World perspective. Otolaryngol Head Neck Surg. 1998;119:297–313. 54. Davis DS. Cochlear implants and the claims of culture? A response to Lane and Grodin. Kennedy Inst Ethics J. 1997;7:253–258. 55. Gonsoulin TP. Cochlear implant/Deaf-World dispute: different bottom elephants. Otolaryngol Head Neck Surg. 2001;125:552–556. 56. Gruen RL, Campbell EG, Blumenthal D. Public roles of US physicians: community participation, political involvement, and collective advocacy. JAMA. 2006;296:2467–2475. 57. Waisel DB. Nonpatient care obligations of anesthesiologists. Anesthesiology. 1999;91:1152–1158. 58. Gruen RL, Pearson SD, Brennan TA. Physician-citizens-public roles and professional obligations. JAMA. 2004;291:94–98. 59. Cotton RT, Cohen AP. Eco-conservation and healthcare ethics: a call to action. Laryngoscope. 2010;120:4–8. 60. Zirkle M, Roberson DW. Striving for imperfection: facing up to human error in medicine. Arch Otolaryngol Head Neck Surg. 2004;130:1149–1151. 61. Committee on Drugs and Committee on Hospital Care, American Academy of Pediatrics. Prevention of medication errors in the pediatric inpatient setting. Pediatrics. 1998;102:428–430.

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CHAPTER 5 ❖ Ethical Issues in Pediatric Otolaryngology 79 62. Waisel DB. Developing social capital in the operating room: the use of population-based techniques. Anesthesiology. 2005;103:1305–1310. 63. Matlow AG, Moody L, Laxer R, Stevens P, Goia C, Friedman J. Disclosure of medical error to parents and paediatric patients. Arch Dis Child. 2010;95:286–90. 64. Loren DJ, Klein EJ, Garbutt J, et al. Medical error disclosure among pediatricians: choosing carefully what we might say to parents. Arch Pediatr Adolesc Med. 2008;162:922–927. 65. Mehlman MJ. The shame of medical malpractice. J Leg Med. 2006;27:17–32. 66. Wojcieszak D, Saxton JW, Finkelstein MM. Sorry Works! Disclosure, Apology and Relationships Prevent Medical Malpractice Claims. Bloomington, IN: AuthorHouse; 2007. 67. Crouse CD, Faust RA. Child abuse and the otolaryngologist: part II. Otolaryngol Head Neck Surg. 2003;128:311–317. 68. Crouse CD, Faust RA. Child abuse and the otolaryngologist: part I. Otolaryngol Head Neck Surg. 2003;128:305–310. 69. Wissow LS. Child abuse and neglect. N Engl J Med. 1995;332: 1425–1431. 70. Hussey JM, Chang JJ, Kotch JB. Child maltreatment in the United States: prevalence, risk factors, and adolescent health consequences. Pediatrics. 2006;118:933–942. 71. Southall DP, Plunkett MC, Banks MW, Falkov AF, Samuels MP. Covert video recordings of life-threatening child abuse: lessons for child protection. Pediatrics. 1997;100:735–760. 72. Johnson CF. Inflicted injury versus accidental injury. Pediatr Clin North Am. 1990;37:791–814. 73. Ramnarayan P, Qayyum A, Tolley N, Nadel S. Subcutaneous emphysema of the neck in infancy: under-recognized presentation of child abuse. J Laryngol Otol. 2004;118:468–470. 74. Lin HW, Wieland AM, Ostrower ST. Child abuse presenting as oral cavity bruising. Otolaryngol Head Neck Surg. 2009;141:290–291. 75. When inflicted skin injuries constitute child abuse. Pediatrics. 2002;110:644–645. 76. Chervenak FA, McCullough LB. Ethics of fetal surgery. Clin Perinatol. 2009;36:237–246.

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77. Brown SD, Truog RD, Johnson JA, Ecker JL. Do differences in the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists positions on the ethics of maternal-fetal interventions reflect subtly divergent professional sensitivities to pregnant women and fetuses? Pediatrics. 2006;117:1382–1387. 78. Committee on Bioethics, American Academy of Pediatrics. Fetal therapy-ethical considerations. Pediatrics. 1999;103:1061–1063. 79. Committee on Ethics, American College of Obstetricians and Gynecologists Committee. Patient choice in the maternal-fetal relationship. 2004. 80. Committee on Children with Disabilities, American Academy of Pediatrics. Counseling families who choose complementary and alternative medicine for their child with chronic illness or disability. Pediatrics. 2001;107:598–601. 81. Cohen MH, Kemper KJ. Complementary therapies in pediatrics: a legal perspective. Pediatrics. 2005;115:774–780. 82. Committee on Genetics. Molecular genetic testing in pediatric practice: A subject review. Pediatrics. 2000;106:1494–1497. 83. Aulisio MP, Arnold RM, Youngner SJ. Health care ethics consultation: nature, goals, and competencies. A position paper from the Society for Health and Human Values-Society for Bioethics Consultation Task Force on Standards for Bioethics Consultation. Ann Intern Med. 2000;133:59–69. 84. Fox E, Myers S, Pearlman RA. Ethics consultation in United States hospitals: a national survey. Am J Bioeth. 2007;7:13–25. 85. Vaszar LT, Raffin TA, Kuschner WG. Hospital ethics case consultations: practical guidelines. Compr Ther. 2005;31:279–283. 86. La Puma J, Stocking CB, Silverstein MD, DiMartini A, Siegler M. Evaluation and utilization of an ethics consult service. JAMA. 1988;260:808–811. 87. Simpson KH. The development of a clinical ethics consultation service in a community hospital. J Clin Ethics. 1992;3:124–130. 88. Institutional ethics committees. Committee on Bioethics. Pediatrics. 2001;107:205–209.

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6

C H A P T E R

Professionalism, Communication, and Teamwork in Surgery Rahul K. Shah

T

he influence of the American College of Graduate Medical Education (ACGME) core competencies in transforming the educational paradigm of surgical residency and fellowship programs cannot be underestimated. The direction taken by the ACGME has resulted in the re-emergence of the core values of medicine into the forefront of education. Further, novel concepts have been introduced that have begun to effect surgical education, patient safety, and the quality of care that is delivered. Specifically, this renewed vigor and emphasis on professionalism and the newer concepts of communication and teamwork constitute the basis of this chapter with discussion centering on the surgical trainee–teacher relationship.

PROFESSIONALISM The main organizational bodies of medicine have realized that forces “largely beyond our control have brought us to circumstances that require a restatement of professional responsibility.”1,2 The surgical profession itself has raised concern that there has been a historically skewed focus on procedural aptitude and knowledge, while the humanistic qualities of medicine have taken a secondary seat in the education of current and rising trainees. When discussing the potential to educate trainees about professionalism, there is the implicit understanding that professionalism is and can be a learned behavior. Rather than relying on one’s innate characteristics to expect professional behavior, surgical educators should lead by example and show trainees how to act in a professional manner. Practical examples include learning the difficulty of maneuvering industry– physician relations and balancing duty hour restrictions with service obligations.3 In 1999, the American Board of Internal Medicine Foundation collaborated with the European Federation of Internal Medicine (IM) and the American College of Physicians-American Society of Internal Medicine Foundation and launched the Medical Professional Project. In a landmark document, simultaneously published in two prominent medical journals, this group outlined a physician charter for medical professionalism.1,2 In doing so, they discussed 3 fundamental principles of professionalism and 10 commitments or professional responsibilities that physicians should be aware of and attempt to follow. The three principles of medical professionalism are primacy of patient welfare, patient autonomy, and social justice.1,2 The primacy of patient welfare is self-evident and a value espoused by most surgeons as it has been the major focus of surgical education and mentorship for centuries.

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Protection of the primacy of patient welfare can be traced to earlier than the Hippocratic oath; essentially this principle entails serving the interest of the patient. Indeed, this is a core concept of a surgeon’s dedication and focus. The principle of patient welfare indicates that above all, the physician will act in such a manner in that the welfare of the patient is put ahead of all other interests.1,2 Although this principle may sound overly simplistic, the modern era poses threats to this value. The potential to mitigate a patient’s welfare can include instances where a surgeon is pressured by industry to try a new device during a procedure, or when a surgeon is attempting to recruit patients for a study that they want to publish in hopes of obtaining external gain in terms of promotions, prestige, grant funding, and so forth. Maintaining the primacy of patient welfare is a cornerstone principle of professionalism. The principle of patient autonomy is a relatively newer concept and challenges the older generational model of the patriarchal physician–patient relationship, which has dominated medicine in prior generations. In the prior patient–physician model, the physician would tell the patient what the treatment plan was going to be and then inform the patient about the risks and expected outcomes of such course of action. With the principle of patient autonomy, the patient and their support group become the center of the patient–physician relationship. The result is a paradigm shift in which the patient is presented with various management options and then the patient, the patient’s family, support group, and physician make a decision in which the physician then is involved in implementing. As a result of the Internet and the resultant technology explosion, the lay public’s medical educational has increased in that the relationship between the patient and the physician has become slightly altered by the patient’s convenient access to medical information. Certainly this does not mitigate the extensive training and education of physicians, but it does imply that patients have more resources available at their fingertips than in prior generations and will need help in deciphering fact from fiction. Patients are now more than ever knowledgeable about myriad treatment options for their disease, and some patients want to work in tandem with the physician to best determine the treatment or management course for their conditions. The importance of presenting medical information and research findings in a balanced manner to patients and families is expected. For example, when suggesting a patient enter a treatment study, it is imperative that

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the patient know the surgeons’ conflicts of interests and alternative treatment options and not fear recrimination or abandonment by the surgeon if they choose to opt out of a potential treatment study, which is being coordinated by the surgeon. The principle of social justice is based on the premise that all patients should have equal access to scarce finite resources. For surgical trainees, the most obvious example of this principle is the slow disappearance of the “resident clinic,” which previously cared for indigent and uninsured patients with occasional faculty supervision. Across many of our institutions, these clinics have been replaced by attendingsurgeon clinics that accommodate all patients regardless of insurance or ability to pay. The resident education is derived from understanding the pathology of each patient and spread more evenly through the attending surgeon’s case load. This principle also invokes the need to have fair distribution of finite health care resources. Such an example would be that all potential candidates for a study of a specific treatment option for their disease process be offered inclusion in the trial after a thorough explanation of the risks and benefits of the study. Individual patients decide whether to enroll or not; the physician practices this principle of professionalism by treating all patients the same and proportioning the resources of the study in a just manner without relying on preconceived notions on whom would most likely participate in the study and who would not. In addition to the 3 principles outlined above, the Medical Professionalism Project also included 10 professional responsibilities or commitments that each physician should follow.1,2 ■ ■ ■ ■

■ ■ ■ ■ ■

■

Commitment to professional competence Commitment to honesty with patients Commitment to patient confidentiality Commitment to maintaining appropriate relations with patients Commitment to improving quality of care Commitment to improving access to care Commitment to a just distribution of finite resources Commitment to scientific knowledge Commitment to maintaining trust by managing conflicts of interest Commitment to professional responsibilities

Examples of professional competence include the American Board of Otolaryngology’s maintenance of certification and the American College of Surgeons emphasis on lifelong learning. The commitment to communicating honestly with patients includes items such as the difficult topic of disclosure regarding medical errors and the consequences of such disclosure.4 Patient confidentiality should be maintained at all times, including in e-mail communications and discussions about patients in public places of the hospitals, while on cell phones, and so on. Recent technological advances have made attention to the principle of confidentiality important.

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Unfortunately, a very small minority of physicians have abused the patient–physician relationship, and as such, the commitment to maintain appropriate relations with patients can be underscored enough. Since the Institute of Medicine’s landmark publication, To Err is Human Building a Safer Health System,5 the commitment to improve the quality of care and access to care has become a core component of professionalism to ensure that our practices, skills, and research continue to evolve to provide our patients with the most up-to-date, highest, and availability of care. The commitment of a just distribution of finite resources is crucial in our era of cost containment juxtaposed with quality improvement. It is difficult to continue to augment care and the standard of healthcare within a confinement of finite resources; however, this is the reality of the current American medical system. It is the burden of the surgeon, on an individual level, to apply the principles of professionalism to ensure that patients receive equal care with proper distribution of such resources. A present day example of such a commitment is organ transplantation; sophisticated algorithms exist to assign organs with a significant effort to value a commitment of just distribution of finite resources. The commitment to scientific knowledge extends from our professional responsibility to continue with professional activities and seek out the most recent information and treatment options for our patients. To not continually seek out scientific knowledge results is a loss of the core professional characteristic of a physician. The commitment to maintaining trust by managing conflicts of interest is especially pertinent in a surgical specialty where we are accustomed to and depend on close industry–physician relations to deliver innovative treatments to our patients.6 Indeed, we value the role of industry in helping our patients obtain the most up-to-date care, and we rely on them as sources of information and guidance on use of novel technologies. However, the caveat, as underlined in the commitment, is that it is the burden of the individual surgeon to manage potential conflicts of interest. This does not come easy to surgeons. Otolaryngology literature exists to provide such guidance in hope of helping surgeons navigate the fine line between optimizing patient care and exposing oneself to injustice.6 The commitment to professional responsibility includes the very difficult task of regulating ourselves and our peers and providing remediation as needed.7 Professional discipline is a task of this commitment. Surgical specialties unfortunately are not well known for adherence to this commitment. The American College of Surgeons has a professional code of conduct, and this viewpoint and position statement are especially helpful for surgeons due to the unique needs and characteristics of our patient population.8 There are several instances where physicians know what professionalism demands from them and do not follow such course.9 For example, although 96% of respondents agreed that physicians

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CHAPTER 6 ❖ Professionalism, Communication, and Teamwork in Surgery should report impaired or incompetent colleagues to relevant authorities, only 45% of respondents who encountered such colleagues had reported them.9 The previous surgical model of the one-to-one relationship between a surgeon and a patient has now evolved to include a team approach with many involved caregivers and an extended support network.10 Surgical trainees in the current and future eras of medicine need to learn how to operationalize the Charter on Medical Professionalism to teach future generations of surgeons. This will perhaps include, in addition to knowledge-based teachings, a surgical ethics curriculum with examples and discussion of ethical dilemmas via a case study approach in hopes of teaching professionalism by example.11

COMMUNICATION To try and separate the concepts of surgical communication and teamwork does a disservice to each. Communication and teamwork are not more intertwined in any other facet of medicine than in surgery, specifically the operating room. The operating room should be the medical model for communication and teamwork and hopefully will emerge as such in the coming years. The Joint Commission’s Universal Protocol is an attempt to meld communication and teamwork into a policy position. Joint Commission data have shown that in cases of wrong site surgery, deviation from the Universal Protocol best practices occurred approximately two-thirds of the time12; the corollary would be that adherence to the Universal Protocol would be able to catch or prevent the same percentage of wrong site surgeries studied.12 Further data from the Joint Commission indicate that poor communication was a factor in 70% of serious safety events.13 Despite the obvious interdependence between communication and teamwork, for the sake of clarity in this chapter, each will be discussed distinctly. Communication is essentially the effective and efficient transfer of critical information. The transfer of information within the context of a medical hierarchy is either horizontal (peer to peer) or vertical (escalation, presenting information to a superior, etc.). Much of our educational initiatives for our trainees are geared toward attaining knowledge and technical competencies in surgery, but only recently with the introduction of the ACGME core competencies has communication become a targeted, distinct focus and an evaluated metric. The prior conceptual model of surgical risk for a patient was understandably based on the patient’s underlying disease, the prognosis of that disease, the overall health of the patient, and the treatment modality chosen to ameliorate the disease process. For myriad reasons, not much regard was given to the system of care that would affect the patient’s surgical risk.13 The previous model focused on the disease process; however, with the paradigm shift of recent years and the realization of the multidisciplinary nature of surgical care and the role of systems-based practices, the patient and

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their support network have emerged as the central focus. Thus communication between the patient and physician and between physicians and other physicians becomes imperative to optimize the patient’s outcome. When examining errors and adverse events in surgical specialties, it has been shown that communication breakdowns are frequent reasons for adverse events in the surgical domain resulting in serious injury to surgical patients.13 The concern is not trivial as life-threatening communication breakdowns occur and sometimes in retrospect, in the most simplistic of cases; many times simple communication would have averted serious patient injury.14 Analysis of surgical errors and resultant morbidity and mortality has demonstrated that communication errors occur in almost a quarter of surgical errors, following second only to errors with technical or proficiency issues.15 Hence, the return on investment for teaching proper communication techniques would most certainly be a beneficial effect on surgical errors and adverse outcomes; indeed, the hopeful outcome would be similar to the effect that proper training for technical and knowledge-based aspects presumptively achieves. In a study of closed surgical malpractice claims, the majority of communication breakdowns occurred as a result of problems with handoffs, personnel changes, and with ambiguity regarding responsibility.15 Resident physician participation increased the probability of a communication error resulting in injury when compared with a surgeon operating without a trainee. This is obviously concerning as most of the more complicated and high-risk otolaryngology procedures often involve trainees. Furthermore, when looking at the communication errors between resident and attending surgeons, the main issues were failure to convey complete information to the attending and ambiguity of responsibility following the communication encounter. These findings seem to indicate that at least minimal training in basic communication skills with clear communication expectations for residents and attending as well would ameliorate error. Underlying the need for proper vertical transfer of information (in both directions), some have suggested communication strategies that have been shown in other industries to be successful. One of the more common communication strategies that are currently being used for escalation of an issue is the SBAR method—(s)ituation, (b)ackground, (a)ssessment, and (r)ecommendation. The SBAR method comes from naval submarines and is used to facilitate accurate, rapid, and effective, vertical transfer of information. This methodology was adapted to medicine by a physician working at a major group healthcare insurance system. The SBAR method was the first of its kind to assist physicians to uniformly communication in an accurate and expeditious manner. It is important to reiterate that the SBAR method is best used for escalation of a problem to a higher authority and may not be the best communication method for horizontal transfer of information. Common examples of horizontal transfers of information include resident sign-outs or nurse–nurse shift change sign-outs. As expected, there are

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countless communication strategies that many different individuals and organizations are purporting to be the panacea for communication errors. However, we should be cautious about simply adopting what others proclaim to be successful for them; it is best that any new methodology that is introduced be properly evaluated. Stratification between technical (defined as an error when performing a procedure) and nontechnical errors also demonstrates the prevalence of communication errors—one-third of the time nontechnical errors included communication breakdowns.15 Resident work hour restrictions are germane to this discussion. The merits of the 80-hour work week in reducing fatigue and eliminating fatigue-related errors may have inadvertently increased and compounded a latent defect in the healthcare system—that of the horizontal transfer of information via handoffs.15 The 80-hour work week has resulted in many surgical and medical services implementing a night-float system with the result that many rotating trainees take responsibility for the care of complicated patients. Transfer of information from physician to physician when their “shift” ends is a ripe period for a communication breakdown and subsequent errors and adverse events. Fortunately, well-developed sign-out strategies can mitigate potential communication errors.15 In addition, some health care systems have integrated electronic medical records and computer technology to assist house staff with sign-out from a systems standpoint. Many incorrectly assume that with regards to surgery, communication breakdowns most often have an impact intraoperatively. This is not the case. Review of breakdowns in surgical communication reveal that the proportions were more or less equally divided between preoperative, intraoperative, and postoperative care.13 Furthermore, the great majority, approximately 80% of communication breakdowns, was within a single department.13 This is contrary to our preconceived notion that the majority of communication breakdowns would be interdisciplinary. This finding does present a unique opportunity for surgeons, as “control” or the ability to effectuate change in the culture of communication within a specific department (surgery, anesthesia, postanesthesia care unit, etc.) should be theoretically easier to achieve. When looking at individuals most at risk and vulnerable to communication errors, it was shown that attending surgeons were most often involved with errors involving the transmitting and receiving of communication.13 Most of the breakdowns were high-level handoffs, between attending to attending and resident to attending, and involved ambiguity about roles and responsbilities.13 Such handoffs are high-risk zones for communication breakdowns.13 The Joint Commission recognized this zone of risk and established as a National Patient Safety Goal in 2006: the requirement for institutions to have a standardized handoff in place.13 Such standardized handoffs, read backs, and automated triggers that mandate communication are expected to reduce patient injury from communication breakdowns

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within the realm of surgical care. In addition to standardized handoffs within organizations, other standardized communication protocols and the need for a “standardized lexicon”16 for medical, especially surgical communication, is imperative. Standardized communications include handoff and transfer protocols and read-backs that are consistent and expected to be followed within an organization.13,15,16 The result is to reduce ambiguity and set expectations for all to follow. Much of the culture change in medicine attempts to borrow or emulate the successfully amazing transformation of other organizations into high reliability organizations such as aviation, steel manufacturing, and nuclear medicine. One of the characteristics that crosses between these disciplines are the presence of clear communication processes that link interdisciplinary players.16 American health care has historically not had a sophisticated, organized, and consistent communication processes.16,17 However, since the Institute of Medicine report in 1999, hospitals and the governing bodies of organized medicine such as the Joint Commission have been very active in helping to initiate such changes. Medicine has unique challenges and characteristics that make information transfer challenging. Shift changes and patient location changes, in particular, are two issues that introduce additional and, at times, unanticipated handoffs.18 In such circumstances, the receiving team needs to relatively quickly learn about and take care of a critically ill patient. For any given patient, such handoffs can occur multiple times daily depending on patient acuity and stability. As the paradigm of medicine has shifted10 from the old country doctor taking a horse drawn carriage to care for a patient in their place of residence to our current state of having a dozen health care providers and many different levels of acuity in a hospital where records are computerized and medications are distributed and administered in an automated fashion, the resulting demands, especially for proper and formalized communication protocols and the need to teach surgeons and medical professionals the concepts of teamwork, are at the core of a successful and safe paradigm shift from medicine in the 20th century to modern-day medicine.10,18 A new physician role has been created, that of a hospitalist, whose function is to manage and coordinate the care of inpatients and provide a high level of transfer of information between services and on discharge so that the patient can be optimally managed by their primary physician once discharged. There are no compelling data on the effect of hospitalists on reducing errors and adverse events, but their role undoubtedly fills an important void in providing for seamless care.19

TEAMWORK The need for teamwork in the operating room cannot be overemphasized. The operating room is a good example of the ongoing change in American surgical culture from a previous model of the surgeon dictating the course of action

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CHAPTER 6 ❖ Professionalism, Communication, and Teamwork in Surgery for a patient and dominating operating room discourse, to the current model where all members of operating room team are in charge of taking care of the patient and all team members have a shared responsibility to ensure the patient’s safety and success. The modern operating room is a model of shared responsibility. However, this concept is much easier to theorize than to implement and realize. The operating room is an extremely complex social arena in which there are individuals with varied education and experience levels, different priorities and schedules, different mindsets, and different skill sets. Errors and adverse outcomes have been attributed, in part, to poor interpersonal skills, in other words, the inability to properly participate in their role on the team.20 The complexity and high risk of the operating room is demonstrated by the fact that approximately half of the adverse events affecting surgical patients occur in the operating room.20 The study and concept of teamwork in medicine has been extrapolated from successful industries that have, out of necessity, morphed into high reliability organizations to prevent catastrophic injuries. The aviation industry is a prime example. The aviation industry has a strong culture surrounding pilot and team training, simulation, establishing safe systems, and ensuring accountability and implementing change rapidly as needed to ensure safety and quality of the industry. The aviation industry and the operating room share very similar analogues.17 However, there are stark differences in the culture and teamwork of these two industries. It is well known in aviation that there is a “sterile cockpit” rule that prohibits any nonessential activities such as idle chatter or discussion in the cockpit other than flight-related information under a ceiling of 10,000 feet. It is ironic that in operating rooms, no such “sterile” or protected period exists. The closest analog is during the time-out—the 30-second exercise intended ensure the veracity of the patient, procedure, and presence of needed equipment and materials. It would be of interest to identify high-risk portions of the surgical procedure and perhaps consider similar rules to the “sterile cockpit” possibly during these periods. Current data to support such a practice are lacking. The concept of situational awareness is central to any discussion pertaining to surgical teamwork. Situational awareness is “the ability of the surgeon to observe, understand, and predict events in the operating room.”20 High situational awareness results in better teamwork and fewer errors.20 As the importance of situational awareness emerges, it is imperative that the culture in operating rooms reflect this and that surgical trainees are taught about situational awareness. An example of situation awareness is the surgeon anticipating key parts of a surgery and ensuring that the most skilled assistants are present for that part of the case. For example, it is not ideal for the scrub technician to have a lunch break during a laryngotracheal reconstruction when the surgeons are making the critical laryngeal and tracheal incisions. Using situational awareness, the surgeon should be

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able to secure buy-in of all stakeholders in the room and then clearly communicate the operative pathway or key points in a case so that the team members are aware of such and can anticipate when they will be need for the surgery to progress at the highest level. Novel team-based paradigms for the operating room using intraoperative pathways to break down complex surgical cases into constituent parts with clear assignment of expectations and responsibilities at each of the steps have resulted in a reduction in operative time and cost with improved staff satisfaction and quality metrics.21 Such paradigms should be considered landmark contributions as they are successful demonstrations of the possible role of standardizing the art of medicine, while still allowing customization for complex surgical procedures.21 It has been shown that increased team performance in the operating room leads to fewer technical errors and intraoperative problems.20 When considering areas of risk, one study of operating room teamwork examined the different roles of the team and revealed that different stakeholders emphasized different zones of risk—for example surgeons and nurses focus on different issues of team safety and efficiency. The end result is that “all the bases” were covered, each by different individuals. It was noted that errors outside the operative field (nontechnical errors) are more common than those in the operative field (technical errors), and improved team skills result in speedier completion of operations. Hence, it is advantageous that all team members do not focus on the same issues. The three main players in the operating room—the surgeons, anesthesiologists, and nurses—can use and have different team skills that come together to optimize the patient care outcome; the caveat is that all these different players must be able to work within a team model.20 This raises the question of whether “small” errors predict or serve as indicators for or lead to more serious errors and adverse events.20 This was suggested in a study of errors and adverse events for otolaryngology inpatients; there was a trend that small errors could portend more significant errors; however, this did not reach statistical significance. Although prevailing thought in the patient safety and quality improvement literature is that all errors, regardless of apparent triviality, are crucial to ameliorate as they could compound and lead to larger issues.22 High reliability organizations (or high-performance systems) are those that deal with crucial processes or decisions, at times with life-threatening potential, in such a manner that optimizes efficiency while reducing or almost making nil potential for harm.10 With regards to teaching about teamwork in medicine, we have again borrowed from high reliability organizations. Many of us have seen our own institutions embark on some variation of crew resource management to teach all staff members on the virtues of becoming a high reliability organization and how to make this happen. It is imperative to realize that on a fundamental level, health care crew resource management

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is distinctly different than crew resource management in other industries. This was shown by the adoption of crew resource management training techniques in a large academic medical center where despite training and attempts at teamwork, the outcomes were not what they had predicted.23 Further, in this study, surgeon-led domains such as the universal protocol and the postoperative team debriefing received the lowest team compliance scores. In such circumstances, there is opportunity for change. Clearly whatever team or communication model is adopted in the operating room needs to incorporate the surgeon as the leader.16 It becomes readily apparent that it is difficult to extrapolate paradigms from aviation and other high reliability industries to medicine without consideration of the nuances between the industries. The unfortunate reality is that medicine and surgery need to come up with their own iterations of crew resource management. Simulators are excellent to demonstrate individual strengths and weaknesses and get all players “on the same page.” The role of simulation training in medicine overall and in otolaryngology specifically continues to increase. Team training with anesthesiologists, surgeons, nurses, and other team providers has been shown to be highly successful when developed and implemented properly. The advantage of simulators for team training is that they permit participants to experience infrequent events in a setting equivalent to that under which team members usually work. A surgical simulation curriculum has been developed, and all members of a pediatric otolaryngology service (the fellows, residents, and medical students) participated in this curriculum.24 Despite having worked with the team for many months before the simulation, participants were was surprised to learn new things about the manner in which their colleagues handled stressful situations. Further, subsequent real airway emergencies that were managed by the team were highly successful and subjectively appeared to run smoothly—most likely attributable to the team training curriculum that all members had received. On a macro scale, when looking at evaluations by the attendees, the simulator course was noted to “[fill] an important void in their education.”24 It is perhaps not plausible that all training programs have such a simulation, but it can be possible that all medical centers can have at least one simulation laboratory where different services can rotate and practice their team building skills. Interestingly, despite large amounts of anecdotal and obvious examples of the role of teamwork in reducing errors and adverse events in surgery, there is a lack of objective scientific data. In one study, a Safety Attitudes Questionnaire was developed to assess perceptions of teamwork according to various caregiver roles. Surprisingly, the study found that although attending surgeons felt that the teamwork was high much of the time, nurses in the same cases felt nearly the opposite, that the teamwork could have been better. This study does not dispute the role of teamwork as being advantageous in the operating room

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interactions; however, it does underscore the difficulty in assessing teamwork and affecting change in the operating room.17 Furthermore, it suggests that each team member has their own biases relative to perceptions and expectations of teamwork. Technical surgical expertise and results attributed to physician skill have essentially peaked in recent years, and improvement in patient’s outcomes due to advancements in these skills is very difficult and infrequently encountered. The most significant contributors to surgical results and outcomes in the coming decades will rest on targeting the low hanging fruit—improving communication and teamwork. This will require out of the box thinking, such as the novel concept of the intraoperative pathway21 for compartmentalizing myriad tasks in a complicated surgery to perhaps instituting mandatory team training using simulators24 for infrequent though life-threatening scenarios. Initiatives such as these undoubtedly will lead to increased patient safety and improved outcomes in the future.

References 1. ABIM Foundation. American Board of Internal Medicine; ACPASIM Foundation. American College of Physicians-American Society of Internal Medicine; European Federation of Internal Medicine. Medical professionalism in the new millennium: a physician charter. Ann Intern Med. 2002;136(3):243–246. 2. Medical Professionalism Project. Medical professionalism in the new millennium: a physicians' charter. Lancet. 2002;359(9305):520–522. 3. Welling RE, Boberg JT. Professionalism lifelong commitment for surgeons. Arch Surg. 2003;138:262–264. 4. Lander LI, Connor JA, Shah RK, Kentala E, Healy GB, Roberson DW. Otolaryngologists’ responses to errors and adverse events. Laryngoscope. 2006;116(7):1114–1120. 5. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is Human Building a Safer Health System. Washington, DC: National Academy Press; 1999. 6. Shah UK, Johnston DR, Smith GM, Ziv BE, Reilly JS. Penalties for health care fraud and abuse: January 2007–March 2008. Otolaryngol Head Neck Surg. 2009;140(5):625–628. 7. Healy GB. Unprofessional behavior: enough is enough. Laryngoscope. 2006;116:357–358. 8. Gruen RL, Arya J, Cosgrove EM. Professionalism in surgery. J Am Coll Surg. 2003;197(4):605–608. 9. Cambell EG, Regan S, Gruen RL, et al. Professionalism in medicine: results of a national survey of physicians. Ann Intern Med. 2007;147:795–802. 10. Roberson DW, Kentala E, Healy GB. Quality and safety in a complex world: why systems science matters to otolaryngologists. Laryngoscope. 2004;114:1810–1814. 11. McCulloch P. Surgical professionalism in the 21st century. Lancet. 2006;367:177–181. 12. Wrong Site Surgery Summit II, The Joint Commission, Chicago, IL, February 23, 2007. 13. Greenberg CC, Regenbogen SE, Studdert DM, et al. Patterns of communication breakdowns resulting in injury to surgical patients. J Am Coll Surg. 2007;204:533–540.

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CHAPTER 6 ❖ Professionalism, Communication, and Teamwork in Surgery 14. Sullivan R, Ferriter A. Preventing life-threatening communication breakdowns. Nursing. 2008;38(2):17. 15. Rogers SO, Gawande AA, Kwaan M, et al. Analysis of surgical errors in closed malpractice claims at 4 liability insurers. Surgery. 2006;140:25–33. 16. Moorman DW. Communication, teams, and medical mistakes. Ann Surg. 2007;245:173–175. 17. Makary MA, Sexton BJ, Freischlag JA. Operating room teamwork among physicians and nurses: teamwork in the eye of the beholder. J Am Coll Surg. 2006;202:746–752. 18. Williams RG, Silverman R, Schwind C. Surgeon information transfer and communication factors affecting quality and efficiency of inpatient care. Ann Surg. 2007;245:159–169. 19. Lindenauer PK, Rothberg MB, Pekow PS, Kenwood C, Benjamin EM, Auerbach AD. Outcomes of care by hospitalists, general internists, and family physicians. N Engl J Med. 2007;357(25):2589–2600.

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20. Catchpole K, Mishra A, Handa A. Teamwork and error in the operating room analysis of skills and roles. Ann Surg. 2008;247:699–706. 21. Lee BT, Tobias AM, Yueh JH. Design and impact of an intraoperative pathway: a new operating room model for team-based practice. J Am Coll Surg. 2008;207:865–873. 22. Shah RK, Lander L, Forbes P, Jenkins K, Healy GB, Roberson DW. Safety on an inpatient pediatric Otolaryngology service: many small errors, few adverse events. Laryngoscope. 2009; 119(5):871–879. 23. France DJ, Leming-Lee S, Jackson T. An observational analysis of surgical team compliance with perioperative safety practices after crew resource management training. Am J Surg. 2008;195:546–553. 24. Zirkle M, Blum R, Raemer DB, Healy G, Roberson DW. Teaching emergency airway management using medical simulation: a pilot program. Laryngoscope. 2005;115(3):495–500.

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7

C H A P T E R

Pediatric Otolaryngology: A Psychosocial Perspective Edward J. Goldson and Kenny H. Chan

PEDIATRIC OTOLARYNGOLOGY AS A SUBSPECIALTY Pediatric otolaryngology has evolved into a distinct entity as the natural maturational process of a specialty.1 Indeed, it has been a marriage of two specialties, pediatrics and otolaryngology. The uniqueness of this field extends beyond the diseases and surgical procedures encountered in that it rests in the willingness of clinicians to embrace pediatrics. Consequently, the pediatric otolaryngologist needs to be both interested and knowledgeable in the child’s growth and development, which entails more than physical dimensions and encompasses areas such as neurodevelopmental maturation, cognitive processes, and psychosocial development. This chapter explores the psychosocial impact of pediatrics on otolaryngologic diseases.

UNIQUENESS OF PEDIATRICS Children cannot be viewed as “miniature adults.” Therefore, the delivery of pediatric health care is significantly different from that of adult health care. Trad2 underscored the complexity of pediatric health care with the following observations: (1) psychological aspects of disease assume greater significance in the pediatric population because of a child’s immature cognitive and affective responses; (2) children experience a perpetual state of flux as a result of rapid developmental changes; and (3) the physician is challenged to form a relationship not only with the patient but also with the caregiver as well. As a result, pediatric health care can be complicated by the child’s psychological and developmental state and the unique physician–patient–caregiver triad.

CHILD DEVELOPMENT When one considers the psychosocial aspects of any pediatric disease, it is essential to have some understanding of child development. How children respond to and cope with both acute and chronic illnesses is strongly influenced not only by their environmental circumstances but also by their developmental level. Children go through a number of developmental stages, including how they conceive of their illness and the world in general. They have a series of developmental and psychological tasks to accomplish. The work of Piaget3 and Erikson4 establishes a framework for conceptualizing these processes.

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During the first 12–18 months of life, infants are engaged in the process of establishing a trusting relationship with their environment. There is little cognitive representation and awareness of the environment outside of themselves, although there is movement toward simple problem solving and a coherent organization of sensorimotor activities. With stability and reliability, the child builds a secure world. The presence of illness, be it acute or chronic, interrupts and perturbs this developmental trajectory. Under conditions of illness, the parental role can be compromised and the child comes to see the world as an unsafe and unpleasant place. From the ages of 12–30 or 36 months, the child, after establishing trust in his or her environment, engages in the process of developing autonomy and some sense of self-concept. Motor and communication skills are at a level such that children have achieved a degree of competence in their ability to interact with the environment, but they still do not understand causality through logical processes. When a child is ill at this age, restrictions and prohibitions in the forms of medical procedures and prescribed medications are the rule. As a result, rather than becoming independent and assertive, the child continues in the role of dependency, has difficulty separating from familiar persons, may have an emerging poor self-image, and may be fearful of interactions with peers and adults. When children reach preschool age (3–6 years), a much broader repertoire of skills is available to them. There is a major cognitive jump in that the child enters what Piaget calls the preoperational period, during which the child is able to think about things that are not present. Although children still reason about the world from their own viewpoint, they begin to understand that events have causes, but that spatial and temporal contiguity explain these events rather than rules and principles. For the preschoolage child, the presence of an illness limits the ability to achieve motor and social competence. There are physical restrictions with resulting enforced passivity and limitations on many of the child’s goal-directed behaviors. This is a time when the child is seeking to achieve mastery over his or her world and is taking the initiative in these activities. Illness often limits the child’s success and may result in a child who is passive, fearful, and excessively dependent on adults. Children in the school-age years (6–12 years) are engaged in dealing with industry and mastery versus a sense of inferiority. Peer relationships are developing even

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further and gender identity is beginning to crystallize. They now are learning and must respond to both internal and external demands and criteria established in the school and among their peers. From a cognitive viewpoint, they are now capable of concrete operations, that is, they are able to think more abstractly. They are able to consider two aspects of a problem simultaneously. They begin to consider not only their own needs but also those of others. This is in contrast to the more immature, egocentric, and animistic thinking of the preoperational child. The school-age child has an understanding of time and causality, the way the body works, and the meaning of death. Illness in schoolage children takes on a new dimension. The sense of being different from peers and the interference of illness with their peer group interactions becomes an issue, which is not the case for the younger child. The school-age youngster may become embarrassed and uncomfortable in peer relationships and tend to withdraw. On the other hand, children with a chronic illness may be avoided or ostracized by their peers because they are different. Furthermore, psychological factors, such as feelings of inadequacy; poor self-concept; worthlessness; and being different from others, may result in withdrawing from the school environment and not actively engaging in the learning process. The teen-age years (13–18 years) bring into greater focus the issues of the school-age years and present new dimensions. The psychological tasks include the establishment of a personal identity as opposed to identity diffusion. There is a struggle to achieve independence while at the same time needing to rely on parents. The maturation in cognitive processing is characterized by the ability to abstract, to evaluate critically and deductively, to generate and test hypotheses, and to evaluate one self. The individual can understand the physiologic basis for disease and the multiple causes of disease. Characteristic of this age is an increasing need to be accepted, liked, included, and valued as the young person stumbles toward adulthood. The presence of an illness, deformity, or disability adds another crisis and more stress to an individual already under stress. It is during this age that the appearance of the condition rather than the severity of disease will influence how the young person adapts. A relatively insignificant anatomic deformity can be more devastating than a major metabolic disorder. On the other hand, the need for cooperation with medical regimens may be compromised as teenagers battle for acceptance and to establish their autonomy and identity while still being somewhat dependent on their families and medical personnel.

Significance of Psychosocial Issues and Family Function The developmental level of a child and the influence of a caregiver can have an impact on pediatric health care in many distinct ways. The significance of psychosocial disturbances in pediatrics is illustrated by the finding that 30% of

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patients in primary care settings have a diagnosable psychiatric disorder and about 20% have somatic complaints.5 The most prevalent presentation of somatization overall is recurrent abdominal pain. Although there are numerous contributing biologic factors, psychosocial development is greatly influenced by the family. Basic tasks for a family, such as protection; food; housing; and health care, can be so compromised in a dysfunctional family setting as to affect the immediate welfare of the child or alter the child’s future psychosocial maturation. Moreover, outcomes of family dysfunction, aside from inadequate medical care, include nonaccidental trauma, emotional abuse, failure to thrive, medical neglect, and Munchausen syndrome by proxy. Although the prevalence of these issues in otolaryngology has never been studied, their existence in the practice of pediatric otolaryngology is well documented.6–11

BIOPSYCHOSOCIAL MODEL OF ILLNESS Traditionally, the interaction of organic disease and psychosocial factors has been viewed dichotomously. Although the clinician is interested in the effects of disease, the psychosocial contribution to illness is left to behavioral medicine. This rigid model of illness is contrary to the reality that most diseases are not exclusively organic or psychogenic in origin. The concept of illness has changed since 1980 to accommodate a “multifactorial” approach to its understanding. The term “psychosomatic” in the classic sense is infrequently used today, and psychosomatic disorders are now classified under a group of specific psychiatric diagnostic entities.

Definition The emergence of multifactorial model of illness was fostered by Engel.12 He placed importance on considering the etiology of disease along the following four continua: disease diagnosis, characteristics of the patient, psychological stressors, and developmental issues. The first two factors are of course central to diagnosis and treatment. However, the last two factors are also of great importance, especially in considering children and adolescents. The biopsychosocial model of illness was further advanced by Molina.13 He viewed a physiologic disorder as a dynamic process that is an outgrowth of the interaction between biologic, psychological, and sociocultural factors. Vulnerability in each of these factors contributes to the disease process. Therefore, most diseases, including otolaryngologic diseases, should be analyzed taking into consideration this model of illness. The next few sections explore each of these factors and specifically attempt to examine the common childhood illness otitis media from the viewpoint of this model (Fig. 7-1).

Biologic Factors Biologic factors are primarily concerned with the genetic makeup of an individual and the propensity for development of any given disease. Although some diseases can be defined

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Biologic factors

Age Gender Race Genetic

Psychological factors

Temperament Stage of development

Crowding Cost of medical care

Social factors

FIGURE 7-1. Pathogenesis of otitis media as viewed in the biopsychosocial model of illness.

in terms of specific causes and explained at the molecular level, other diseases and mechanisms, including the inheritance of behavior traits, are more difficult to clearly define. If one considers otitis media, it becomes obvious that the current understanding of this disease cannot be reduced to the molecular/genetic level. The pathogenesis of otitis media is the result of the interactions of anatomic variations, the individual’s response to infectious agents or other antigens, environmental factors, and the individual’s capacity to mount a response to these agents and conditions. Epidemiologic studies have identified a variety of risk factors that may alert the clinician to a child who is at risk for development of otitis media. These risk factors include age, sex, race, and siblings with significant history of otitis.

Psychological Factors There is no question that there are psychological factors that contribute to the appearance and persistence of a variety of disease processes. The literature is extensive on the impact of stress on the immune system and on subsequent infectious disease and on its possible impact on oncologic disorders and perhaps on disorders of the cardiovascular system.4 Furthermore, there is ample evidence to suggest that stress has an effect on the neuroendocrine system, which can influence biologic function, often leading to disease and even death. Moreover, there are links between the immune and neuroendocrine systems that can influence the emergence of disease.

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With respect to pediatric otolaryngology, one could argue that the psychologically stressed child is more vulnerable to disease than the well-functioning, developmentally, and emotionally secure child. At present, there appear to be no specific psychological factors that contribute to otitis media, compared with the biologic factors identified earlier. However, there are psychological, temperamental, developmental, and psychosocial factors that influence how the child responds to the illness and treatment and how the child recovers. How children respond to acute illness is partially influenced by the child’s previous experience with illness. Was the child treated in a sensitive, unhurried manner by the health-care provider? Was the child supported, comforted, and nurtured by the parents? Were the caretakers and parents honest with the child? Did the caretaker relate to the child in a developmentally age-appropriate manner without being patronizing and condescending? By and large, the child who has been treated in a caring, personal manner will have less difficulty with illness, at least vis-à-vis the health-care provider, than the child who was treated cavalierly, impersonally, and in haste. The child’s psychological characteristics and temperamental traits are a second group of factors to be considered. Children who are mild mannered, trusting, and have secure and trusting relationships with their parents are at a greater advantage in dealing with illness than are those children who are not so characterized. Lavigne and Faier-Routman5 reported that the factors contributing

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most to the psychological adjustment of children to illness included characteristics of the parent/family, characteristics of the child, and, to a lesser degree, disease/disability risk factors. That is, children who are part of disorganized families where there is marital stress and parental disengagement have more difficulty adjusting to illness. Children who are emotionally stable and self-confident do better than those with difficult temperaments, cognitive impairments, increased distractibility, and poor self-concept. In the Lavigne and Faier-Routman study, socioeconomic status and stressors did not play significant roles in how the child adjusted to the illness.

Social Factors Social factors can have significant influences on how children respond to illness and to treatment. In disorganized families where there is poor compliance and an inadequate commitment to treatment, the child will do poorly. If the parents do not administer the medicine and monitor and support the child, the outcome will be less than optimal. If there is no money to purchase medication or provide other therapies, the outcome will also be less than optimal. When there is parental neglect, maltreatment, and indifference, the child will have difficulty coping with the disease and will probably not respond as promptly to treatment as do children who are in more organized, nurturing environments.

SELECTED PEDIATRIC OTOLARYNGOLOGY TOPICS The premise of a biopsychosocial model of illness as applied to pediatric otolaryngology is to establish a fundamental view that few diseases are solely biologic or psychological in origin but that most diseases are multifactorial, as illustrated in the previous model of otitis media. More important, the psychosocial impact of an illness and the result of psychosocial dysfunction as they relate to pediatric otolaryngology must be addressed. Specifically, the following discussion centers on three topics as follows: chronic illness, sensorineural hearing loss, and child abuse.

Children With Special Health-Care Needs (CSHCN) This is a group of children who represent a significant portion of the pediatric population (15%–18% of 10–13 million children)14,15,15a and will present themselves to the pediatric otolaryngologist. “Children with special health care needs are those who have or are at increased risk for a chronic physical, developmental, behavioral, or emotional condition and who also require health and related services of a type or amount beyond that required by children generally.”16(p138) This is a very broad definition and includes children with chronic illness (see below) as well as children with genetic disorders such as Down syndrome and Fragile X syndrome, those falling on the autism spectrum, and those with cerebral palsy, seizure disorders, and intellectual impairment, among others.

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Therapeutic intervention and management of children with CSHCN can be extremely challenging and difficult. Frequently these children are intellectually impaired and do not understand what is going on. Some of these children, such as those falling on the autism spectrum, can be so behaviorally and cognitively compromised that the usual strategies in working with typical children do not work. CSHCN children can be extremely frightened, aggressive, and very difficult to control, yet with patience and some different approaches can be cared for successfully. Several approaches can be tried depending on the nature of the procedure, the family, and the child. One aggressive approach would be to sedate the child and do whatever needs to be done under anesthesia. For some children, this may be the only way to safely accomplish the task. Alternative approaches involve behavioral strategies that may take a little longer but are not so invasive. One approach is to have the child come to the clinic as a “dry run” to see the setting and meet the people including the surgeon. Another strategy would be to provide the family with a picture story and/or video demonstrating what the child could expect and share this with the child prior to the visit. In addition, rewards can be offered to the child as she/he is able to cooperate and participate in the visit. This is certainly not an exhaustive list. However, the approach of addressing the unique needs of CSHCN is the central message. One needs to always remember that these children can be significantly compromised and so will need patience and tenderness if the task(s) at hand are to be accomplished.17 Chronic illness A chronic illness is defined as a chronic health condition having a severe physiologic impact with restriction of activities and the need for treatment on a regular basis. It is estimated that 1%–2% of children fall into this category. Chronic illnesses of childhood have an impact on the child’s development and behavior as well as on the family. Chronic illness can affect development directly or indirectly through restricting a child’s participation in developmentally appropriate activities. Chronic illness affects children of different ages in different ways, and this is related to both the developmental stage of the child and, in turn, the child’s understanding of the illness. The greatest impact of chronic illness on infants may lie in the direct impact on linear growth and poor weight gain. A more indirect effect of chronic illness is that toddlers and school-age children with such illnesses may be ostracized or teased by peers. Thus, the opportunity to acquire social skills and the chance to practice those skills may be curtailed. Frequent school absences not only interfere with normal socialization but also affect school performance and in turn self-worth and self-image. As mentioned previously, adolescents are preoccupied with autonomy, self-esteem, and identity. Chronic illnesses during adolescence can result in dependence on others, which may negatively affect the development of appropriate autonomy and individual identity. At first glance, there are a host of “chronic illnesses” in pediatric otolaryngology. However, few realistically meet the definition of chronic illness by virtue of either not being a debilitating illness or not requiring regular and periodic

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CHAPTER 7 ❖ Pediatric Otolaryngology: A Psychosocial Perspective treatment. One exception is severe recurrent respiratory papillomas. Although not satisfying the classic definition of “chronic illness,” several otolaryngologic diseases have been found to have significant quality of life alterations comparable to other chronic pediatric diseases. They include chronic rhinosinusitis,18 voice disorder,19 obstructive sleep disorder,20 and recurrent laryngeal papillomas.21 Tracheotomy and sensorineural hearing loss are discussed separately in the following section of this chapter as having important psychosocial impact.

Tracheotomy One of the most appropriate examples of chronic illness in pediatric otolaryngology is the tracheotomized child. The underlying pathologic processes for a tracheotomy may be diverse, but the impact on a “normal” functioning child and especially the family is relatively predictable. The most apparent effects of a tracheotomy for a child are in the areas of speech and language development. Tracheotomy in many instances results in aphonia or severe dysphonia. Its longterm impact on speech and language has been found to be related to whether a child is prelingual or postlingual at the time of decannulation.22 Children decannulated during the prelinguistic stage attained speech and language skills commensurate with intellectual functioning. On the contrary, children decannulated in the postlinguistic stage exhibit spoken language delays, including phonologic impairment at the time of decannulation. In the majority of these children, both the language and phonologic delays are correctable over time with appropriate therapy. The addition of a chronic illness to a family brings a number of challenges, demands, and sources of anxiety. The impact of a tracheotomized child on the family has been described by Wills23 who classified maternal concerns into biologic and psychological. The biologic concerns were principally related to the maintenance of a patent airway. The psychosocial concerns were as follows: (1) need for home, clinical, and group support services, (2) isolation and limitations on time, (3) economic impact, (4) altered family interaction, and (5) provision of medical care. Furthermore, the provider has to be cognizant of expectations from the family. Recent investigation in this area dealing with the Robin sequence population requiring tracheotomy has found that preintervention counseling regarding length of tracheotomy tube dependence, as well as a discussion about potential complications and hospitalization, improves parental expectations.24 The role of the pediatric otolaryngologist is to actively assist the child and the family in identifying delays in speech and language development and in making appropriate referrals. Furthermore, the clinician can help alleviate some of the biologic and psychosocial concerns. Home tracheotomy care could go a long way in resolving some of the issues. Most pediatric centers have established nursing and respiratory home care protocols or manuals that can assist in alleviating home care concerns of the care providers.

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Sensorineural Hearing Loss The psychosocial concerns relating to sensorineural hearing loss lie in its frequency, which is estimated to be 1–2 per 1000 children. The impact of hearing loss on development is as complex as the causes and types of hearing loss itself. However, factors that determine developmental outcome have been categorized by Meadow.25 They include the degree, the etiology, the age at onset of hearing loss, the family climate, and the appropriateness of educational interventions. The developmental profile of a deaf child generally shows alterations in the areas of language, cognitive development, and social and emotional development. In terms of language, profoundly deaf children are greatly impeded in the development of spoken language. In prelingual children, auditory memory, imaging, and associations are all compromised. Although it is generally accepted that the intellectual abilities of hearing-impaired children are similar to those of the hearing child except where verbal factors have a part to play, distinct differences in many cognitive skills including memory, temporal processing, semantics, and higher-level thinking exist between these two groups.26 In the area of social and emotional development, recognizable differences are found between the two groups in terms of peer interaction and aggression, with the hearing-impaired child having significant difficulties. Hearing-impaired children have a profound impact on their families. This impact begins at the time of diagnosis.27 Initially the parents undergo a grieving process, which is not unlike grieving over a loss or a death. A great deal of concern has been expressed in the area of parent–child interaction. Numerous studies have addressed the detrimental effects of a child’s hearing handicap on the mother’s communication style with her child. The success of habilitation for hearing-impaired children is greatly influenced by parental participation and counseling. A perspective on the influence of parenting and family dynamics on a hearing-impaired child can be gleaned from studies indicating that positive family practices and child-rearing attitudes promote positive academic achievements and are predictors of the development of the child’s healthy self-concept. The first task of the pediatric otolaryngologist is to assist in early detection of sensorineural hearing loss. Once hearing loss is identified, the clinician’s role is to assist the child and the family in securing appropriate referrals to speech, language, and educational specialists.

CHILD ABUSE For many practitioners, the suspicion that child maltreatment has led the parents to bring the child for help is distasteful and unpleasant, and many feel that involvement in such cases is outside of their realm of expertise. However, otolaryngologists are frequently the first to be involved in the child’s medical care. Thus, they are in a unique position to recognize when an injury to the head and neck may be the result of nonaccidental trauma or neglect.

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Child maltreatment continues to be a major public health issue in the United States and has a profound effect on the child’s psychosocial development.28 The term child maltreatment serves as an umbrella under which are included nonaccidental trauma, neglect (which can also lead to a failure to gain weight), sexual molestation, and emotional abuse. Both nonaccidental trauma and neglect have been reported in the otolaryngology literature.6–10 Nonaccidental trauma to the head and neck can take many forms that can be confused with accidental injuries unless a comprehensive history is obtained and a complete physical examination is performed. Child maltreatment must always be suspected when the injury does not “match” the history that is provided or when the caretaker claims no knowledge of how the injury occurred. Common presentations include a combination of lip bruising, torn frenulum, and pharyngeal lacerations from forced feeding; petechiae or hematoma of the pinnae can occur in isolation or in association with more severe bodily injuries. Not infrequently, one can encounter bloody otorrhea secondary to canal laceration and tympanic membrane perforation. Sometimes the presentation can be obvious as the “tin ear syndrome,” a characteristic triad of ear bruising, hemorrhagic retinopathy, and ipsilateral cerebral edema with obliteration of the basilar cisterns. Alternatively, the presentation can be insidious as anogenital recovery of human papilloma virus (HPV) in child sexual abuse cases even though otolaryngologic HPV infections generally occur in the perinatal period.29 The authors concluded that there is a substantial role for perinatal transmission of HPV among children with laryngeal papillomatosis. However, consideration of potential abuse for children with laryngeal papillomas, especially older children, and possibly for those with oropharyngeal lesions has to be included. Another aspect of maltreatment one needs to consider is neglect. Such cases may involve parents’ failing to provide medical treatments suggested by the practitioner. Neglect can occur in common illnesses, such as otitis media, and in lifethreatening illnesses, such as neoplasms. In all of these circumstances, the otolaryngologist plays an important role in differentiating what is abusive from what is not abusive and in initiating appropriate protective interventions and subsequent management of the otolaryngologic problem. It is the practitioner’s dual responsibility to report suspected maltreatment and to work with the child protection team in the care and management of the child and the family.

lacks the “instant gratification” expectation so ingrained in the training of surgeons. In reality, there is not enough time and it is not financially worthwhile to deal with psychosocial problems during a busy surgical practice. Nevertheless, to provide more comprehensive, effective, and long-lasting care, it is important that the practitioner change some approaches and expectations to come to understand, appreciate, and accept the biopsychosocial model of illness. These include the following: (1) giving up the need to always be in control, (2) being able to tolerate and letting others tolerate the unknown, (3) overcoming excessive expectations of oneself and patients, and (4) acknowledging that there may be different, equally acceptable, approaches to the management of a given disorder. After the initial step of accepting the biopsychosocial model of illness, the clinician can then concentrate on recognizing the important psychosocial issues. The diagnosis of psychosocial dysfunction is no different from that of any other clinical disorder. The physician must be a good listener and observer. Effort should be focused on identifying the following three factors: (1) recent important stressful events, (2) dysfunctional family structure, and (3) pathologic parental traits.

Childhood Stressors Rutter30 has recognized a variety of childhood stressors that the clinician should take into consideration when evaluating the child (Table 7-1). Obviously, the clinician should use caution when interviewing the parent or caregiver in the presence of a sensitive or stressed child. Sometimes it is beneficial to interview the parent or caregiver separately. In the presence of a dysfunctional family structure, it may become difficult to identify and separate childhood stressors from other dysfunctional family traits.

Family Dysfunction Parenting has never been an easy task, but changes away from traditional patterns of family organization, as reflected by an increasing prevalence of single-parent and two-wage earner families, have increased the risk for dysfunction. Changes in the contemporary family system increase the likelihood that the family will have difficulty coping with stress, including physical illness. Families that have a history of psychiatric disorder, divorce or separation, low socioeconomic status, previous traumatic experience, drug and alcohol abuse, and TABLE 7-1. Important Childhood Stressors Disruption of attachment relationship

DIAGNOSIS OF PSYCHOSOCIAL DYSFUNCTION Clinicians generally find it difficult to work within the biopsychosocial model of illness. Most are uncomfortable with the model itself. Surgeons are particularly influenced by their training to hold on to the binary (surgical versus nonsurgical) approach to medicine. In addition, the biopsychosocial model

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Persistent rejection, lack of affection, neglect, or abuse Parental ill health Chronically disturbed family relationship (e.g., parental divorce) Major life events (e.g., birth of a sibling, change of school, or hospitalization) Major trauma (e.g., major illness or injury) Source: Adapted from Rutter.30

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CHAPTER 7 ❖ Pediatric Otolaryngology: A Psychosocial Perspective family turmoil are at greater risk for poor psychological adjustment.31 Single-parent households, for example, are more likely to have limited financial resources and social supports, and they are often run by adults with little education who are forced to spend time away from the child to support the family. The assessment of an ill child from such an environment requires not only a complete medical evaluation, but also an understanding of how psychosocial factors may influence the child’s and family’s ability to cope with illness. When a family unit disintegrates and becomes dysfunctional, it occurs along a continuum. Beavers32 viewed this dysfunctional process using the following three indices: power, communication, and development (Table 7-2). In an intact and functional family unit, power is well defined, communication is candid and expresses flexibility and respect, and the child is viewed as an autonomous individual with his or her own identity. In contrast, in a dysfunctional family, power is ill defined, communication is truncated, and the child loses his or her identity. The diagnostic acumen regarding family dysfunction will be improved if the clinician concentrates on the three indices listed earlier. Therefore, all communication cues between the physician, the caregiver, and the child become important. These include body language, verbalization, and tone of voice, all of which are useful in the evaluation of family structure.

Pathologic Parental Traits The addition of a caregiver figure to the traditional physician–patient dyad complicates health-care delivery, although that person is essential to the child. Under some circumstances, this addition can potentiate the development of psychosocial dysfunction. Factors contributing to dysfunction can involve events covering a child’s life span. Early exposure to chronic illness and parents’ overconcern with their own body functions are influential factors leading to a child’s distorted concept about illness.33 One may also want to consider the pathologic personality traits of the caregiver and how they may influence the child. During the interview, the clinician should become aware of the presence of difficult parental traits. Beresin et al.34 have identified pathologic parental traits and their associated characteristics (Table 7-3). All too often the clinician becomes offended or disinterested TABLE 7-2. Family Functioning Typology Index

Optimal

Midrange

Dysfunctional

Power

Delineated

Power struggle

Difficult to define

Communication

Candor and flexibility

Intimidation and Chronically manipulation ineffective

Developmental

Autonomous

Limited identity

Source: Adapted from Beavers.32

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Loss of identity

95

TABLE 7-3. Pathologic Traits and Characteristics of Difficult Parents

Personality Traits

Associated Characteristics

Obsessive

Rigid, perfectionistic, dogmatic

Hysterical

Overemotional, oversensitive, impressionistic

Denying

Inattention to instructions, noncompliant

Dependent

Unending need for contact and support

Demanding

Egocentric and grandiose, litigious

Help rejecting

Pessimistic, distrusting

Source: Adapted from Beresin et al.34

when such parents are encountered. The likely outcome is the termination of communication, potential delay in the diagnosis of psychosocial dysfunction, and compromise of the child’s care.

MANAGEMENT OF PSYCHOSOCIAL DISORDERS Several important steps must be considered in addressing problems of psychosocial dysfunction. The most important step is for the physician to consider that there can be psychosocial causes for illness. One must consider this as an option at the outset rather than as an afterthought. This appreciation of a potentially difficult situation conveys a firm message to the patient that the caregiver has a comprehensive differential diagnosis and that psychosocial factors can contribute to physical dysfunction. It then sets the stage for the next difficult step of convincing the caretaker of the need for psychosocial evaluation and possible treatment. When therapy is recommended, it is for the purpose of helping the child and the family. Through psychosocial interventions, more adaptive methods of coping can be encouraged, more positive patterns of interaction can be developed, and social supports can be explored to help the family become a more adaptive system in its mode of functioning. The next step is, likewise, crucial to a favorable outcome. A surgeon is neither trained in family dynamics and psychiatry, nor have the time to become an expert in these fields. The involvement of other disciplines is necessary. At our institution, a team approach to psychosocial dysfunction is used. When a problem is suspected, the surgeon may make a referral to a social worker, who may be able to manage the case or make a referral to a child psychiatrist or psychologist or to a developmental pediatrician. It is helpful to have a social worker who is primarily assigned to the otolaryngology service and thereby is familiar with specialty-specific diseases and disorders. Behavioral science assessment and treatment are also designed to identify those psychosocial factors contributing

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to the physical disorder and to prevent unnecessary medical assessments and interventions. Furthermore, the behavioral science intervention can often facilitate the process of recovery. Most important, this kind of collaborative approach to the management of disease—behavioral science, medical, and surgical—acknowledges the contributions that all of these factors can have in the etiology and course of the disease. The issue in treatment should not be whether the patient is experiencing purely organic or functional problems, but rather what the relationship is between the two and what kind of strategies can be developed to effectively treat the patient. The approaches and skills of behavioral scientists need to be respected and enlisted. Their participation in the care of the patient is an important key to successful treatment. When the physical disorder is well understood by the staff, a psychopathologic process, when present, should also be clearly recognized. Moreover, when psychosocial disturbances are apparent in the child, the entire family must be considered in the therapeutic plan. As previously noted, parental and family dysfunction can have significant adverse effects on how the child copes with illness and responds to treatment. It becomes critical, under such complex and stressful circumstances, that the patient not be perceived as a burden or a malingerer. Instead, it should be recognized that the patient and the family have many complex needs, all of which need to be addressed if there is to be a successful resolution of the problem, which is possible if a multidisciplinary broad-based view of disease is considered. The treatment plan for a child with disorders that include not only physical disturbances but also psychosocial problems includes coordination of services with the primary care physician, mental health professional, surgeon, and school or other educational institution when appropriate. In addition to what has been noted earlier, one might incorporate the concept of a Medical Home, which is defined as the setting “where health care services are accessible, family centered, continuous, comprehensive, coordinated, and compassionate.” This may be located, for example, in a practitioner’s office or a school-based clinic. It is important to articulate the concept that health care is accessible and integrated and that the otolaryngologist networks with the primary care provider to address psychosocial issues that usually will devolve to the care and involvement of the primary care provider.35,36 What is most important is that all of these professionals communicate with one another and then with the family. The family needs to be included in the planning if they are to follow through with the recommendations. All too often plans are made, but they fail because the family has not been included in the process. Parents need to be considered as active and valued participants in the care of their child. This is particularly important when surgical procedures are involved that require some technical skills on the part of the parent. Parents need to know

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why things are being done and what they can expect with respect to the disease and from their child’s caretakers and what is expected of them, the parents.

CONCLUSION An understanding and acceptance of the biopsychosocial model of illness can have far-reaching positive implications for children with otolaryngologic disorders. With the use of this approach, psychosocial disorders can be promptly diagnosed and appropriately managed. To practice pediatric otolaryngology is not only to accept the challenge of becoming conversant in the physical growth and development of a child, but also to be willing to address the psychosocial aspects of the child’s and family’s life. This can be facilitated by accepting and using a more holistic approach to medical and surgical care.

Selected References Allmond BW Jr, Tanner JL. The Family is the Patient. 2nd ed. Baltimore, MD: Williams and Wilkins; 1999. Goldson E. The behavioral aspects of chronic illness. In: Geydamus DE, Wolraich ML, eds. Behavioral Pediatrics. New York, NY: Springer-Verlag; 1992. Goldson E. Behavioral issues in the care of children with special health care needs. In: Greydanus DE, Patel DR, Pratt HD, eds. Behavioral Pediatrics. 2nd ed. New York, NY, Lincoln, Shanghai: iUniverse, Inc; 2006:182–205. Helfer ME, Kempe RS, Krugman RD, eds. The Battered Child. 5th ed. Chicago and London: The University of Chicago Press; 1997. Hubbs N, Perrin JM, eds. Issues in the Care of Children with Chronic Illness. San Francisco, CA: Jossey-Bass; 1985. Hubbs N, Perrin JM, Ireys HT, eds. Chronically Ill Children and Their Families. San Francisco, CA: Jossey-Bass; 1985. Jessop DJ, Stein PEK. Essential concepts in the care of children with chronic illness. Pediatrician. 1988;15:5.

References 1. Stool SE. Evolution of pediatric otolaryngology. Pediatr Clin North Am. 1989;36:1363. 2. Trad PV. Psychosocial Scenarios for Pediatrics. New York, NY: Springer-Verlag; 1988:28–30. 3. Piaget J, Imhelder B. The Psychology of the Child. New York, NY: Basic Books; 1969. 4. Erikson E. Childhood and Society. New York, NY: Norton; 1964. 5. Lavigne JV, Faier-Routman J. Psychological adjustment to pediatric physical illness: a meta-analytic review. J Pediatr Psychol. 1992;17:133. 6. Grace A, Grace S. Child abuse within the ear, nose and throat. J Otolarynol. 1987;16:108. 7. Manning SC, Casselbrant M, Lammers D. Otolaryngologic manifestations of child abuse. Int J Pediatr Otorhinolaryngol. 1990;20:7.

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CHAPTER 7 ❖ Pediatric Otolaryngology: A Psychosocial Perspective 8. Leavitt EB, Pincus RL, Bukachevsky R. Otolaryngologic manifestations of child abuse. Arch Otolaryngol Head Neck Surg. 1992;118:629. 9. Willner A, Ledereich PS, de Vries EJ. Auricular injury as a presentation of child abuse. Arch Otolaryngol Head Neck Surg. 1992;118:634. 10. Smith ME, Darby KP, Kirchner K, Blager F. Simultaneous functional laryngeal stridor and functional aphonia in an adolescent. Am J Otolaryngol. 1993;5:366. 11. Chan KH, Martini R, Bradley WF, Stool SE. Pediatric otolaryngology: a psychosocial perspective. Int J Pediatr Otorhinolaryngol. 1995;32:159. 12. Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1977;196:129. 13. Molina JA. Understanding the biopsychosocial model. Int J Psychiatry Med. 1983;13:29. 14. Stein REK, Silver EJ. Operationalizing a conceptual-based noncategorical definition: a first look at U.S children with chronic conditions. Arch Pediatr Adolesc Med. 1999;153:68–74. 15. Newacheck PW, Strickland B, Shonkoff JP. An epidemiologic profile of children with special health care needs. Pediatrics. 1998;102:117–123. 15a. Perrin JM. Health care services for children with disabilities. Millbank Q. 2002;80:303–324. 16. McPherson M, Arango P, Fox H, et al. A new definition of children with special health care needs. Pediatrics. 1998;102:137–140. 17. Goldson E, Bauman M. Medical health assessment and treatment issues in autism. In: Gabriels RL, Hill DE, eds. Growing Up with Autism: Working with School-Age Children and Adolescents. New York, NY, London, UK: Guildford Press; 2007:39–57. 18. Cunningham JM, Chiu EJ, Landgraf JM, Gliklich RE. The health impact of chronic recurrent rhinosinusitis in children. Arch Otolaryngol Head Neck Surg. 2000;126(11):1363–1368. 19. Merati AL, Keppel K, Braun NM, Blumin JH, Kerschner JE. Pediatric voice-related quality of life: findings in healthy children and in common laryngeal disorders. Ann Otol Rhinol Laryngol. 2008;117(4):259–262. 20. Baldassari CM, Mitchell RB, Schubert C, Rudnick EF. Pediatric obstructive sleep apnea and quality of life: a metaanalysis. Otolaryngol Head Neck Surg. 2008;138(3):265–273. 21. Lindman JP, Lewis LS, Accortt N, Wiatrak BJ. Use of the pediatric quality of life inventory to assess the health-related quality of life in children with recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol. 2005;114(7):499–503.

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22. Simon BM, Fowler SM, Handler SD. Communication development in young children with long-term tracheostomies: preliminary report. Int J Pediatr Otorhinolaryngol. 1983;13:37. 23. Wills JM. Concerns and needs of mothers providing home care for children with tracheostomies. Matern Child Nurs J. 1983;12:89. 24. Demke J, Bassim M, Patel MR, et al. Parental perceptions and morbidity: tracheostomy and Pierre Robin sequence. Int J Pediatr Otorhinolaryngol. 2008;72(10):1509–1516. Epub 2008 August 20. 25. Meadow KP. Deafness and Child Development. Berkeley, CA: University of California Press; 1980. 26. Bench RJ. Communication Skills in Hearing-Impaired Children. San Diego, CA: Singular Publishing Group; 1992. 27. Kricos PB. The counseling process: children and parents. In: Alpiner JG, McCarthy PA, eds. Rehabilitative Audiology: Children and Adults. Baltimore, MD: Williams & Wilkins; 1993:211–233. 28. Goldson E. The affective and cognitive sequelae of child maltreatment. Pediatr Clin North Am. 1991;38:1481. 29. Sinclair KA, Woods CR, Kirse DJ, Sinal SH. Anogenital and respiratory tract human papillomavirus infections among children: age, gender, and potential transmission through sexual abuse. Pediatrics. 2005;116(4):815–825. 30. Rutter M. Childhood experiences and adult psychosocial functioning. Ciba Found Symp. 1991;156:189. 31. Gortmaker SL, Walker DK, Weitzman M, Sobol AM. Chronic conditions, socioeconomic risks, and behavioral problems in children and adolescents. Pediatrics. 1990;85:267. 32. Beavers WR. Healthy, midrange, and severely dysfunctional families. In: Walsh F, ed. Normal Family Processes. New York, NY: Guilford Press; 1982. 33. Engel GL. A reconsideration of the role of conversion in somatic disease. Compr Psychiatry. 1968;9:316. 34. Beresin EV, Jellinek MS, Herzog DB. The difficult parent: office assessment and management. Curr Probl Pediatr. 1990;20:620. 35. American academy of pediatrics, Ad Hoc task force on definition of the medical home: the medical home. Pediatrics. 1992;90:774. 36. American Academy of Pediatrics, Medical Home Initiatives for Children with Special Needs Project Advisory Committee. The medical home. Pediatrics. 2002;110:184–186.

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8

C H A P T E R

Psychiatric Disorders in Pediatric Otolaryngology Abigail L. Donovan and Bruce J. Masek

S

ymptoms of psychosocial stress and psychiatric disorders can manifest in any organ system in the human body. Furthermore, within any disease, organic illness and psychological illness can be present simultaneously and extraordinarily interactive. The pediatric otolaryngologist most frequently encounters these types of illnesses presenting as airway disorders, characterized by physical symptoms involving the upper airway and vocal cords, which are heavily influenced by psychological factors. These psychological factors contribute to physical symptoms, and, concurrently, the physical symptoms create a psychological response. The two most common functional airway disorders are paradoxical vocal fold movement (PVFM) and habit cough. Psychological factors may be one driving force behind the onset, exacerbation, or maintenance of these disease entities. PVFM and habit cough engender diagnostic and treatment challenges for both otolaryngologists and mental health clinicians. They are easily misdiagnosed, and patients may go through numerous doctor appointments, emergency room visits, medical tests, and medication trials in search of accurate diagnosis and symptom relief.

PARADOXICAL VOCAL FOLD MOVEMENT PVFM has been known by many different names—paradoxical vocal fold dysfunction, vocal cord dysfunction (VCD), psychogenic stridor, factitious asthma, episodic laryngeal dyskinesia, and Munchausen’s stridor. All these names refer to the same clinical entity: paradoxic adduction of the vocal cords causing upper airway obstruction. Most commonly, adduction occurs in the anterior two-thirds of the vocal folds, leaving a posterior opening or “chink.” The passage of air over the adducted folds produces symptoms from mild wheezing to severe stridor. The adduction of the vocal cords usually occurs in inspiration, but can also occur in expiration. Episodes start and stop abruptly, sometimes without any apparent trigger, and patients are asymptomatic between episodes. Episodes occur most frequently during the day and are usually absent with distraction and sleep; however, one case series has identified a small group of patients who also experienced nocturnal attacks; hence, the timing of attacks cannot be used for diagnostic exclusion.1 During episodes, patients may report feelings of throat tightness and shortness of breath. In addition, the acute onset of symptoms, and their very nature, may elicit panic and anxiety in the patient, as well as in those around them. The exact incidence of PVFM in the general population is unclear. The incidence of PVFM among patients presenting

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with asthma is reported to range from 2% (Jain et al.2) to 14% in patients with severe asthma.3 Moreover, asthma and PVFM are not mutually exclusive, further complicating this diagnostic picture. In one group of patients hospitalized for PVFM, 56% were found to have comorbid asthma.4 Cases are reported in both the adult and the pediatric literature, although, in clinical practice, teenagers are most commonly affected. Females appear to be more frequently affected than males, with an estimated ratio of 2:1 (Morris et al.5) to 3:1 (Brugman6). Female athletes may be particularly vulnerable: one study reported a 5% prevalence in elite athletes, and 95% of those affected were female.7 In addition, it has also been noted in clinical practice that many patients tend to be highly academically competitive as well. The exact etiology of PVFM is not definitively known, although there are several hypotheses. Upper airway hyperresponsiveness, triggered by infection, inflammation, allergy, gastroesophageal reflux, or toxic inhalation, has been proposed as an underlying pathology. Upper airway hyperresponsiveness then triggers the glottic closure reflex and adduction of the vocal folds. Once activated, the reflex is perpetuated, leading to PVFM.8 It has also been proposed that an inflammatory process triggers autonomic dysfunction such that subsequent stimuli induce an autonomic reflex, which results in narrowing of the upper airway and adduction of the vocal folds.9 Psychological factors are also known to play a critical role in the development and exacerbation of PVFM. It has been reported that approximately 20% of attacks are directly triggered by stress10 and that 44% of patients with PVFM have a major social stressor in their lives.11 Psychiatric disorders may also be more common in patients with PVFM, even before the onset of illness, as it has been reported in one study that 56% of patients have a current or prior psychiatric illness.12 Even when compared to other patients with respiratory disorders, such as asthma, patients with PVFM have higher levels of anxiety symptoms, higher rates of anxiety disorders (67% vs. 17%), and higher rates of all psychiatric diagnoses (67% vs. 33%).3 In addition, it is reasonable to hypothesize that as the illness progresses, as medical testing yields negative results, and as medical treatments fail, the patient’s stress and anxiety may increase, which then exacerbates the symptoms even further. Although PVFM may be heavily influenced by psychological factors, it is important to note that the disease is not manufactured on purpose by the patient, that is, it is not a factitious disorder and is not under the conscious control of the patient; rather, the psychological factors influence the symptoms on an unconscious level.

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HABIT COUGH Habit cough, also known as psychogenic cough, is one type of chronic cough that may present to the otolaryngologist. Habit cough typically begins after an upper respiratory infection, and the cough persists after the other respiratory symptoms resolve. It is frequently described as “honking” or “barking,” and the patient may exhibit a “chin-on-chest” posture while coughing. The cough can occur many times a minute,13 and it is usually less frequent with distraction and absent in sleep. The cough may also become more frequent in association with certain activities, such as school or sporting events. The patient may exhibit a lack of concern about the symptom, but other patients do present with distress. The cough does not respond to antitussives, bronchodilators, or anti-inflammatories. It is disruptive to normal activities, including school, social, and home life, and some children may even miss weeks of school and social events due to the cough. Habit cough is diagnosed in 3%–10% of children with a cough lasting longer than one month.14 It occurs most commonly in children and adolescents; up to 90% of cases are reported in patients younger than 19 years,15 and it affects males and females equally.16 Although influenced by psychological factors, habit cough may also be exacerbated by comorbid organic illness, such as gastroesophageal reflux disease (GERD) and asthma.17 Like with PVFM, the exact etiology of habit cough is unknown. However, one hypothesis is that habit cough represents a cycle where an initial irritant, such as infection, triggers a cough, which then leads to more irritation and a perpetuation of the cough cycle. Another hypothesis is that an organic illness, such as an infection, causes the cough, which then persists for psychological reasons, even after the organic illness has resolved. Various psychological stressors have been associated with habit cough, including family, academic, and social stressors. However, although habit cough can be mediated by psychological stressors, it is not considered a consciously manufactured factitious disorder; the psychological influence is unconscious and not usually recognized by the patient. A related airway disorder is habit sneezing, also known as paroxysmal sneezing. Little is known about this clinical entity, and most information is limited to the less than 50 case reports available in the literature.18 Given the rarity of this disorder and the clinical characteristics it shares with habit cough, it may be best conceptualized as a variant of habit cough. Paroxysmal sneezing is characterized by an abbreviated inspiratory phase, followed by a short nasal grunting sound, and limited aerosolization of mucosal secretions. The sneezes can occur between 30 and 100 times a minute and may last for hours. Patients typically keep their eyes open while sneezing, which is unusual with physiological sneezing. Similar to habit cough, the sneezing is absent in sleep and with distraction. Paroxysmal sneezing does not

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respond to steroids, antihistamines, or decongestants. It is hypothesized to occur more frequently in female adolescents, and most cases are associated with psychological stressors.16

ASSESSMENT AND DIAGNOSIS The diagnosis of functional airway disorders requires a medical evaluation to assess for any organic etiology that may be either directly causing the symptom or contributing to its perpetuation. Although medical evaluation is necessary, the extent of diagnostic testing should be thoughtfully considered by the otolaryngologist to avoid prolonged time to diagnosis, iatrogenic morbidity, and inadvertent secondary gain for the patient. In the case of PVFM, several organic etiologies may present with similar symptomatology. Specifically, foreign body aspiration can present with inspiratory stridor, and both clinical history and X-ray may be helpful to distinguish between the two. Laryngomalacia and tracheomalacia can also present with inspiratory stridor, although more frequently in very young children. Subglottic stenosis and adenotonsillitis also deserve consideration and evaluation. Perhaps the most common mimicker of PVFM is asthma. In particular, symptoms of asthma such as episodic shortness of breath, wheezing, and stridor are also present in PVFM. However, several differences do exist, which can aid appropriate diagnosis. In contrast to asthma, an arterial blood gas (ABG) measured during an episode of PVFM is usually within normal limits.19 Pulse oximetry is also usually normal in PVFM,8 and greater than 75% of patients with PVFM will have a normal ABG or pulse oximeter oxygen saturation.6 In addition, the onset and cessation of stridor with PVFM is acute, without the refractory period typically observed in asthma. PVFM also does not respond to beta-2 agonists, which are highly effective in asthma. Patients with PVFM also subjectively report “throat tightness,” in comparison with “chest tightness” typically reported with asthma.8 In addition, wheezing and stridor in PVFM are heard over the larynx and the upper chest, as opposed to throughout the lung fields. Pulmonary function testing (PFT) may also aid diagnosis. In PVFM presenting with inspiratory stridor, a blunting or plateau of the inspiratory flow loops is observed, in contrast to the blunting in expiratory loops observed with asthma.16 It should also be noted that these disorders are not mutually exclusive; given the high degree of comorbidity, even these factors may not be sufficient to reliably diagnose PVFM, particularly in patients with concomitant asthma. The gold standard for diagnosis remains laryngoscopy. Laryngoscopy performed during an acute attack will reveal the clearly adducted vocal folds producing stridor. However, this examination performed when the patient is asymptomatic is frequently normal and cannot be used to exclude the diagnosis. It is possible to provoke the symptoms of PVFM with methacholine, histamine, or exercise challenge20,21 or even by hypnosis.22 However, this type of provocation is not without

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CHAPTER 8 ❖ Psychiatric Disorders in Pediatric Otolaryngology risk and should only be undertaken in a setting equipped to handle patients with respiratory distress. Other organic etiologies may also contribute to the frequency and severity of PVFM. For example, PVFM may be associated with GERD. In one study, a high proportion of patients with PVFM also had glottic changes that had been previously associated with GERD.23 In another study, patients whose PFVM was triggered by reflux (as demonstrated by pH probe) had a complete resolution of their symptoms with acid suppression, diet, and lifestyle modification.24 Postnasal drip may also exacerbate or trigger PVFM.25 Although it is not clear whether these disorders are causative, they do deserve consideration as exacerbating factors. Similar to PVFM, habit cough also requires a thorough medical evaluation to diagnose and exclude organic illnesses. Cough variant asthma should be considered and assessed with PFT or even a trial of beta-agonists. Patients with habit cough have been demonstrated to produce normal PFTs, whereas asthmatic patients do not.17 Pertussis can be excluded with serum antibody testing. Chronic bronchitis, sinusitis, and croup deserve consideration, as does postnasal drip causing ongoing throat irritation. Pneumonia, particularly mycoplasma pneumonia, can also cause chronic cough. A chest X-ray may be helpful as a diagnostic test; chest X-rays in habit cough are normal17 and do not reveal signs of acute or chronic inflammation, which can be seen in other disorders. It is also important to consider the diagnosis of a tic disorder or Tourette’s syndrome, and the clinician should observe for any other potential tics, such as eye blinking, shoulder jerking, and facial grimacing. In contrast to airway disorder patients, patients with tic disorders have a younger age of onset (6–7 years) and are more frequently male (male:female ratio = 2:1). In further contrast, tic patients typically describe the ability to suppress the tics for a variable period of time and also describe a premonitory urge before the tic, followed by a feeling of relief after the tic. Habit cough may also be exacerbated by, or comorbid with, other organic disorders. Specifically, 20% of patients with habit cough have also been found to have asthma, and 16% have been diagnosed with GERD.17 The causal relationship between these disorders remains unclear, but their correlation is worth considering during diagnostic work up. Unlike PVFM, there is no definitive test for habit cough. The diagnosis remains one that is largely based on history and clinical presentation. Habit cough should be considered with a presentation of chronic cough absent or decreased in sleep, without other active symptoms of infection or inflammation. A negative medical evaluation and lack of response to standard medical treatments, including antitussives, should also prompt the consideration of habit cough. Although only limited case reports exist on the assessment and diagnosis of paroxysmal sneezing, as with other functional airway disorders, diagnosis can be made only after a thorough medical evaluation to assess for other causes of repetitive sneezing. The otolaryngologist may wish to consider allergy testing, sinus radiography, and rhinoscopy to

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rule out organic pathology. In addition, consideration can be given to neurology consultation to assess for any central or peripheral neurologic causes for the intractable sneezing.

MANAGEMENT Treatment of functional airway disorders begins with reassurance. Patients and families need to know that these symptoms are not life threatening and that the patient will not become apneic or develop irreversible respiratory distress. The very nature of these symptoms is anxiety provoking, and, at times, repeated negative medical testing, rather than calming anxieties, leads to increased anxiety and frustration, as well as a feeling that “something was missed.” Reassurance from medical doctors that all diagnostic possibilities have been investigated and that these symptoms are not life threatening is crucial for the patient to engage in further treatment and may even be therapeutic itself. In addition to reassurance, all comorbid and contributing organic disorders, such as asthma, GERD, and respiratory infections, should be aggressively treated. Ongoing inflammation and irritation can perpetuate voice disorders. A combination of treating any contributing disorders with active reassurance that the symptoms will improve can be a very successful first-line treatment regimen. In addition, speech and language pathologists can provide effective therapy for both PVFM and habit cough. Speech and language pathologists can teach a number of techniques to decrease laryngeal tone and overall symptoms, including relaxed throat breathing and abdominal breathing.26 Speech pathologists can also teach techniques to terminate an acute episode of PVFM, including panting and nasal inhalation with pursed lips exhalation, which both serve to open the airway. Specialized breathing and swallowing techniques can also be used to assist patients in overcoming the cough reflex. Respiratory retraining and breathing techniques also offer promise for symptom relief. Routine referral of all functional airway disordered patients to a mental health clinician is neither necessary nor practical given the limited numbers of these clinicians; however, there are patients for whom reassurance, treatment of comorbid symptoms, and speech therapy will not be sufficient treatment. These patients will require referral to a pediatric mental health clinician for more intensive psychological and behavioral assessment and treatment. In addition, there is a subset of patients who initially present with clear psychiatric symptoms or disorders that will also benefit from immediate referral to a mental health clinician. Patients who present with marked functional impairment, including many days or weeks of missed school, social isolation, or family conflict, will also benefit from prompt referral for psychological evaluation and treatment. Prompt referral is important, as these subsets of patients are unlikely to achieve remission of their symptoms without such treatment. Finally, patients for whom a definitive diagnosis of PVFM or habit cough is unclear may also benefit

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from a mental health examination to aid in diagnosis and eventual treatment. Many patients, particularly those with PVFM, may not display symptoms during an otolaryngology examination, making definitive diagnosis difficult. For those patients in whom the diagnosis is particularly unclear, the otolaryngologist may chose to attempt precipitating an attack to aid in diagnosis; however, for those patients in which the diagnosis can be strongly considered, despite a lack of observable symptoms, or for those who do not respond to provocation tests, a mental health examination may be of benefit. Although mental health clinicians may also be challenged by making a precise diagnosis, they may be able to uncover psychological aspects of the patient’s presentation, which could suggest or confirm the presence of a functional airway disorder. However, mental health services, particularly for children, may be scarce outside of large medical centers; therefore, many otolaryngologists may not have rapid access to mental health clinicians, and even early referral may be complicated by challenges in finding available clinicians. For the otolaryngologist who sees many such cases, it is advisable to cultivate a relationship with a child psychiatrist and child clinical psychologist to facilitate timely entry into adjunctive treatment.

PSYCHOLOGICAL AND BEHAVIORAL ASSESSMENT AND TREATMENTS Psychological Assessment Before beginning a behavioral treatment, the mental health clinician will perform a thorough psychological assessment, which includes a functional behavioral assessment (FBA), an assessment of psychosocial stressors, and a diagnostic assessment for the presence of psychiatric disorders. The FBA is an analysis of the role that the symptom plays in the patient’s environment. Every aspect of the patient’s environment at the time the symptoms occur is analyzed. Environmental issues such as parental attention, excuse from school or gym, and avoiding unpleasant activities are carefully considered. This type of assessment provides information about the aspects of the environment that may be triggering or reinforcing the symptoms. An understanding of the role that the symptom plays allows for identification of therapeutic interventions. The patient frequently does not have a conscious understanding of why the symptom has arisen and may benefit from learning the clinician’s hypothesis, presented in nonjudgmental language. Then, the patient and the clinician can explore alternative ways to meet the patient’s needs. For example, in the case of a patient who is missing school, the motivating factors for school absence must be explored. These may include an undiagnosed learning disability or bullying. This type of patient may then benefit from increased academic or social support. The child whose symptom brings attention from a parent will benefit from a set schedule of one-on-one parent time that is not dependent on the symptom. With interventions aimed at meeting

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the patient’s unconscious needs, the medical symptoms will likely improve. The mental health clinician will then evaluate for the presence of psychosocial stressors in the patient’s life that co-occurred with the onset of symptoms. Examples of stressors from clinical practice include divorce and remarriage of parents, major illness in a parent or sibling, adoption or birth of new siblings, or the loss of a relative or friend. Some stressors are not immediately obvious, and a careful interview, using open-ended and nonjudgmental questions, is important. Adolescents may not want to reveal that they are the target of bullies or that they have mixed feelings about the adoption of a new sibling. Furthermore, sometimes adolescents become so accustomed to the presence of a stressor that they no longer even recognize it as stressful. Some adolescents are unable to express their distress or conflicts in words, and so, unconsciously, the symptom speaks for them. Identifying these stressors will then allow for appropriate support and treatment. Finally, patients will also undergo a diagnostic interview to evaluate for psychopathology. The mental health clinician will assess for symptoms of mood, anxiety, and thought disorders. Not all patients with airway disorders will have major mental illness; rather, this group is a subset of the total population. However, resolution of their symptom will likely require appropriate treatment of any underlying psychopathology. In clinical practice, patients with airway disorders have been diagnosed with major depressive disorder, generalized anxiety disorder, separation anxiety disorder, and panic disorder. The assessment for psychiatric illness may be particularly important for patients with PVFM, as they are known to have higher levels of anxiety disorders. Furthermore, the symptoms of a tic disorder or Tourette’s disorder may mimic habit cough; hence, these potential diagnoses will also need to be assessed by the mental health clinician.

Psychological and Behavioral Treatments A thorough psychological assessment will allow the clinician to tailor the next phase of treatment to the individual patient. Several different treatment modalities including biofeedback, hypnosis, and psychotherapy have been successful in the treatment of airway disorders. No randomized controlled clinical studies have been completed; hence, the relative efficacy of each treatment is not well characterized. The selection of a treatment modality, or the progression through subsequent treatment modalities if the first fails, is, therefore, based on the clinical judgment of the clinician. Some patients and families may initially be reluctant to accept referral to a mental health clinician, believing that “medical” symptoms cannot be cured by a therapist or that referral to mental health means that the patient is mentally ill or that the symptoms are “all in their head.” These patients and families may be more open to psychological treatment when it is framed as support in coping with the stress of an ongoing illness. In addition, referral to a mental health

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CHAPTER 8 ❖ Psychiatric Disorders in Pediatric Otolaryngology clinician does not signify that the patient is being deserted by his or her medical doctors. In fact, all patients will benefit from regular follow-up visits with their otolaryngologist, to allow for objective assessments of symptoms severity and ongoing reassurance that either no organic illness is present or it is being treated appropriately.

Biofeedback Biofeedback training combines relaxation techniques with computer technology to increase coping skills and improve stress management. In this treatment, the patient’s biological parameters such as pulse, body temperature, respiration, skin conductance, and muscle tension are measured by using noninvasive sensors and displayed on a computer screen in a digital, real-time format. The patient then learns relaxation techniques that decrease sympathetic arousal and skeletal muscle activity. The hypothesis is that when the skeletal muscles and the autonomic nervous system are fully relaxed, it is more difficult for the symptoms of cough and stridor to occur. Successful relaxation leads to changes in the measured biological parameters, and these changes are then easily viewed and can be summarized session to session for review. Thus, the biological information is directly fed back to the patient. The direct observation of these changes, coupled with the suggestion that the patient is learning how to reproduce the effect without the need for technology, promotes a sense of mastery and control. Biofeedback has been demonstrated to be an effective treatment for both PVFM27,28 and habit cough.15,29

Hypnosis Hypnosis as used in clinical treatment bears little resemblance to that seen on television or in stage entertainment. In clinical practice, hypnosis is more accurately described as self-hypnosis, as the patient is the active agent. Self-hypnosis is the process of entering a natural state characterized by deep relaxation. Children may be particularly skilled at selfhypnosis, given their active imaginations and willingness to believe. The mechanism of hypnosis is not fully understood, but its efficacy likely relates to the promotion of increased relaxation, co-occurring with positive suggestions by the therapist, and in the case of habit cough, an alteration in the perception of the cough trigger.17 Furthermore, self-hypnosis increases both patient autonomy and self-reliance, thereby returning the locus of control to the patient. Self-hypnosis has been demonstrated as a successful, and rapid, treatment for both PVFM and habit cough. One study reported that after a single session, 38% of patients with PVFM had complete resolution of their symptoms and an additional 31% had significant improvement. Overall, 91% of patients were successfully treated with self-hypnosis.30 Similarly, it has been reported that after a single session, 78% of patients with habit cough had complete resolution of their symptoms, and an additional 12% had resolution within the next month.17 In addition, paroxysmal sneezing has also been reported to respond to hypnosis.31

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Psychotherapy Patients with more severe psychological symptoms or those with refractory airway disorders may require longer term treatment in the form of psychotherapy. Psychotherapy is used to explore both recognized and as yet unrecognized stressors and psychological conflicts. Processing these issues with a therapist can lead to insight and improved coping. For example, a highly intelligent and academically successful teenager attending a competitive school may not initially recognize the stress and pressure inherent in academically competitive institutions. The situation becomes even more complex as the teenager’s self-esteem and identity begin to be dependent on academic success, and parental pressure may also play a role in a perceived need to maintain a certain level of performance. Competitive athletes may experience similar dynamics. Another example from clinical practice is the adolescent who has mixed feelings about the adoption of a sibling; the adolescent may feel reluctant to express negative feelings, due to guilt or fear of being thought of as selfish. These feelings may be even deeply repressed and tied to more complex emotions of needing to be close to, and yet needing to grow apart from, parents. Psychotherapy can assist in exploring and elucidating some of these dynamics. In addition, psychotherapy can also be used to increase coping strategies. Concrete coping strategies such as positive self-talk, deep breathing, and distraction may be helpful for some patients. Others may find that utilizing social supports, such as teachers, parents, and friends, more frequently and effectively brings relief. Even the psychotherapy itself, providing a safe place to discuss struggles, can be an effective coping mechanism. Moreover, the therapist can advocate for the patient with parents or schools to decrease some of the external pressures on the patient and relieve sources of stress. Finally, psychotherapy provides a medium to focus on and discuss psychosocial stresses, thus obviating the need for an external symptom as a sign of distress.

Psychopharmacology There are no clear guidelines for the use of medication in airway disorders, and there is no single FDA-approved medication for the treatment of PVFM or habit cough. There have been no randomized clinical controlled trials, and, given these factors, the use of psychoactive medication in this population deserves especially careful consideration. Research indicates that patients with PVFM are more likely to have anxiety disorders.3 Indeed, benzodiazepines, used in the general treatment of anxiety disorders, may also be useful for terminating an acute episode of PVFM.5,32 However, it has been reported that ongoing treatment with benzodiazepines does not routinely result in long-term control of symptoms for patients with PVFM.33 Therefore, chronic treatment with medication should be reserved for the subset of PVFM patients who also meet full criteria for an anxiety disorder. In addition to anxiety disorders, depressive disorders may be present in these patients, either preceding the onset of the

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airway disorder or after its initiation, perhaps even as a result of the airway disorder. There are several pharmacologic options for the treatment of depression and anxiety in this population, including benzodiazepines and selective serotonin reuptake inhibitors (SSRIs). Anxiety disorders can be effectively treated with short-term use of benzodiazepines, such as lorazepam (Ativan) and clonazepam (Klonopin). These medications have the benefit of offering rapid relief; however, the physiologic dependence and the potential for abuse associated with these medications make them less ideal for long-term therapy, particularly in adolescent populations. SSRIs including fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), or escitalopram (Lexapro) have a more favorable side-effect profile for longterm therapy for anxiety disorders, although they can take up to 6–8 weeks to show efficacy. SSRIs are also effective for the treatment of depression. Although these medications are generally well tolerated, they do have the potential for serious side effects, particularly in adolescent populations. The administration, and subsequent monitoring, of these medications should be overseen by a physician with experience in their application to adolescent populations. Many patients have symptoms of anxiety, depression, or other disorders that fall below the diagnostic threshold. In these cases, the use of medication has not been carefully researched and falls to the discretion of the prescribing practitioner.

ADDITIONAL THERAPIES Various other therapies have been used to treat the pediatric airway disorders. For example, both inhaled heliox34 and nebulized lidocaine35 have been found to stop acute episodes of PFVM. Habit cough has also been successfully treated with suggestion therapy. As described, this therapy involves informing the patient that they can break the cycle of coughing by drinking water when they have the urge to cough and giving positive reinforcement and encouragement as the symptom becomes less frequent.36 Paroxysmal sneezing has also been successfully treated with suggestion therapy.18 The “bed sheet” method, which involved wrapping a bed sheet around the patient’s chest until he or she stopped coughing, is also known to be effective for habit cough.37 Injection of botulinum toxin to the thyroarytenoid muscle has also been used to stop the cough for 6–8 weeks and quickly restore full social function, whereas patients are learning behavioral techniques to control the cough should it return.38

CONCLUSION Pediatric airway disorders represent illnesses that present with physical symptoms that are heavily influenced by psychological stressors or psychiatric disease. Given the nature of the symptoms, these patients frequently present to the pediatric otolaryngologist. Many patients will respond to reassurance

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and speech therapy; however, for those who do not and for those who present with clear psychiatric illness or severe functional impairment, assessment and treatment by a mental health clinician are necessary. The diagnosis and management of these patients benefit greatly from well-coordinated care, utilizing both medical and psychological perspectives, provided jointly by the pediatric otolaryngologist and mental health clinician.

References 1. Reisner C, Nelson H. Vocal cord dysfunction with nocturnal awakening. J Allergy Clin Immunol. 1997;99:843–846. 2. Jain S, Bain V, Officer T, et al. Incidence of vocal cord dysfunction in patients presenting to emergency room with acute asthma exacerbation. Chest. 1999;116:243S. 3. Gavin LA, Wamboldt M, Brugman S, et al. Psychological and family characteristics of adolescents with vocal cord dysfunction. J Asthma. 1998;35:409–417. 4. Newman KB, Mason UG, Schmaling KB. Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med. 1995;152:1382–1386. 5. Morris MJ, Allan PF, Perkins PJ. Vocal cord dysfunction, aetiologies and treatment. Clin Pulm Med. 2006;13:73–86. 6. Brugman SM. The many faces of vocal cord dysfunction. Am J Resp Crit Care Med. 2003;167:A588. 7. Rundell KW, Spiering BA. Inspiratory stridor in elite athletes. Chest. 2003;123:468–474. 8. Hicks M, Brugman SM, Katial R. Vocal cord dysfunction/ paradoxical vocal fold motion. Prim Care Clin Office Pract. 2008;35:81–103. 9. Ayers JG, Gabbott PLA. Vocal cord dysfunction and laryngeal hyperresponsiveness; a function of altered autonomic balance? Thorax. 2002;57:284–285. 10. Lacy TJ, McManis SE. Psychogenic stridor. Gen Hosp Psychiatry. 1994;16:213–223. 11. Rogers JH. Functional Inspiratory stridor in children. J Laryngol Otol. 1980;94:669–670. 12. Ramirez RJ, Leon I, Rivera LM. Episodic laryngeal dyskinesia. Chest. 1986;90:716–721. 13. Lokshin B, Lindgren S, Weinberger M, Koviach J. Outcome of habit cough in children treated with brief suggestion therapy. Ann Allergy. 1991;67:579–582. 14. Irwin RS, Glomb WB, Chang, AB. Habit cough, tic cough and psychogenic cough in adult and pediatric populations: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(suppl 1):174S–179S. 15. Riegel B, Warmoth JE, Middaugh SJ, et al. Psychogenic cough treated with biofeedback and psychotherapy. A review and case report. Am J Phys Med Rehabil. 1995;74:155–158. 16. Butani L, O’Connell EJ. Functional respiratory disorders. Ann Allergy Asthma Immunol. 1997;79:91–99. 17. Anbar RD, Hall HR. Childhood habit cough treated with selfhypnosis. J Pediatr. 2004;144:213–217. 18. Lin TJ, Maccia CA, Turnier CG. Psychogenic intractable sneezing: case reports and a review of treatment options. Ann Allergy Asthma Immunol. 2003;91:575–578. 19. Goldman J, Muers M. Vocal cord dysfunction and wheezing. Thorax. 1991;46:401–404.

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CHAPTER 8 ❖ Psychiatric Disorders in Pediatric Otolaryngology 20. Wood RP II, Milgrom H. Vocal cord dysfunction. J Allergy Clin Immunol. 1996;98:481–485. 21. Selner JC, Staudenmayer H, Koepke JW, et al. Vocal cord dysfunction: the importance of psychological factors and provocation challenge testing. J Allergy Clin Immunol. 1987;79:726–733. 22. Anbar RD, Hehir DA. Hypnosis as a diagnostic modality for vocal cord dysfunction. Pediatrics. 2000;106:E81. 23. Powell DM, Karanfilov BI, Beechler KB, et al. Paradoxical vocal cord dysfunction in juveniles. Arch Otolaryngol Head Neck Surg. 2000;126:29–34. 24. Koufman JA. The differential diagnosis of paradoxical vocal cord movement. Visible Voice. 1994;3:49–53,70–71. 25. Balkissoon R. Vocal cord dysfunction, gastroesophageal reflux disease, and nonallergic rhinitis. Clin Allergy Immunol. 2007;19:411–426. 26. Blager FB, Gay ML, Wood RP. Voice therapy techniques adapted to treatment of habit cough: a pilot study. J Commun Disord. 1988;21:393–400. 27. Earles J, Kerr B, Kellar M. Psychophysiologic treatment of vocal cord dysfunction. Ann Allergy Asthma Immunol. 2003;90:669–71. 28. Warnes TS, Allen KD. Biofeedback treatment of paradoxical vocal fold motion and respiratory distress in an adolescent girl. J Applied Behavior Analysis. 2005;38:529–532.

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29. Labbe EE. Biofeedback and cognitive coping in the treatment of pediatric habit cough. Appl Psychophysiol Biofeed. 2006;31:167–172. 30. Anbar RD. Hypnosis in pediatrics: applications at a pediatric pulmonary center. BMC Pediatrics. 2002;2:11. 31. Elkins M, Milstein JJ. Hypnotherapy of pseudo-sneezing: a case report. Am J Clin Hypnosis. 1962;4:273–275. 32. Brown TM, Merrit WD, Evans DL. Psychoenic vocal cord dysfunction masquerading as asthma. J Nerv Ment Dis. 1988;176:308–310. 33. Kuppersmith R, Rosen DS, Wiatrak BJ. Functional stridor in adolescents. J Adolesc Health. 1993;14:166–171. 34. Weir M. Vocal cord dysfunction mimics asthma and may respond to heliox. Clin Pediatr. 2002;41:37–41. 35. Diamond ED, Kane C, Dugan G. Presentation and evaluation of vocal cord dysfunction. Chest. 2000;118;1995. 36. Weinberger M, Abu-Hasan M. Pseudo-asthma: when cough, wheezing and dyspnea are not asthma. Pediatrics. 2007;120:855–864. 37. Cohlan SQ, Stone SM. The cough and the bedsheet. Pediatrics. 1984;74:11–15. 38. Sipp JA, Haver KE, Masek BJ, et al. Botulinum toxin A: a novel, adjunct treatment of debilitating habit cough in children. Ear Nose Throat J. 2007;86:570–572.

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9

C H A P T E R

M

Munchausen Syndrome by Proxy Basil J. Zitelli

unchausen syndrome by proxy (MSP) is a disorder in which a perpetrator feigns an illness in another person by claiming certain symptoms exist or by inducing symptoms, causing unnecessary and repeated medical evaluations. It is unfortunate that the good name of Hieronymus Karl Friedreich Freiherr von Munchausen has been associated with this particularly malignant form of abuse. von Munchausen, born in 1720 to an aristocratic family, distinguished himself in the Prussian army. On retirement, he regaled friends and colleagues with fantastical tales of his travels.1 The often-fantastical tales of MSP have caused his name to be linked to this disorder. Richard Asher originally “respectfully” coined the term Munchausen syndrome, describing patients who willfully claimed or induced symptoms of factitious illness.2 These factitious claims led physicians to undertake repeated unnecessary diagnostic evaluations, prescribe dangerous therapies, or even proceed with surgery. In 1977, Meadow extended the Munchausen concept to induced factitious illness imposed on a child by a caregiver.3 He reported a 6-year-old girl with recurrent hematuria, thought to be due to the mother mixing blood with the patient’s urine. A second child at 14 months of age had recurrent episodes of hypernatremia due to salt poisoning by the mother. Meadow’s report opened the floodgates of similar experiences by many other physicians in the United Kingdom. MSP itself is an umbrella diagnosis comprised two components, the child victim and the perpetrator.4 The pediatric component is termed pediatric condition falsification (PCF). An adult falsifies signs and/or symptoms in a child victim causing them to be regarded as ill. Falsification may include: (1) directly causing conditions, (2) over- or underreporting signs or symptoms, (3) creating false appearance of signs and symptoms, and (4) coaching the victim or others to misrepresent the victim as ill. Importantly, the presence of a valid illness does not preclude falsification and often complicates diagnosis.5 If emphasis is on the perpetrator, the second component of MSP is factitious disorder by proxy, which is included in the Diagnostic and Statistical Manual IV (DSM-IV). It states that the motivation of the perpetrator is to assume the sick role by proxy and that external incentives such as economic gain are absent.6 The adult perpetrator with factitious disorder by proxy intentionally falsifies history, signs, or symptoms to meet their own psychological needs. Motivation is an important component to determine factitious disorder by proxy, which is often difficult to ascertain. For example, parents who falsify a report of sexual abuse to gain custody or to harm the spouse are engaging in PCF but do not have

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factitious disorder by proxy because the motivation is not for satisfaction of their own psychological needs. Hence, many pediatric caretakers eschew a diagnosis of MSP and emphasize the pediatric aspect of child abuse, thereby avoiding issues of the perpetrator’s motivations.

EPIDEMIOLOGY The incidence of MSP is difficult to determine because of the difficulty in making the diagnosis. McClure et al. reported an incidence in 0.5 of 100,000 children younger than 16 years and 2.8 of 100,000 in children younger than 1 year.7 MSP most likely is grossly underreported. Schreier and Libow surveyed nephrologists and gastroenterologists about their experiences with MSP. Of 316 responses to the questionnaire, 210 reported a case contact and 465 cases were confirmed or were seriously suspicious.8 It is unclear where MSP falls in incidence among the types of child abuse in the United States. Length of time from onset of symptoms to diagnosis averages from 14.9 to 21.8 months.5,9 Young children of either gender appear to be at a greatest risk. Mean age of onset ranges from 20 to 39.8 months, and generally both genders are equally victimized.5,7 Perpetrators are overwhelmingly mothers or women acting in the role of the mother, ranging from 85% to 98% of abusers.5,7 Female guardians, adoptive mothers, and nurses have been perpetrators. Most female perpetrators are married and living with their spouses.10,11 Mothers generally are beyond adolescence with a mean age of 29, married, and articulate.10 Many perpetrators have had exposure to the medical field through employment, allowing the perpetrator to gather believable evidence in the fabrication.5,12 Currently, access to the World Wide Web gives similar access to medically accurate and detailed information. Twenty-five to sixty percent of mothers have a history of possible Munchausen syndrome themselves, often exhibiting similar symptoms to their child victim.5,11 In general, perpetrator mothers have many desirable traits that throw suspicion of abuse away from them.10 They spend a large amount of time on medical units, become friends with and are respected by medical and nursing staff, participate in their child’s care, or offer to help with the care of other patients. They remain calm despite their child’s serious illness and often compliment the staff for their care and console frustrated doctors. They are often overly attentive, refusing even brief separation from their child. The motivation of mothers in factitious disorder by proxy is unclear, although the DSM-IV text revision suggests that they need to assume the sick role by proxy to gain attention and acceptance.6 Their actions dehumanize the child, and

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they use the child as an object for self-fulfillment. As a result, they enter into a perverse relationship with the medical staff. Actions of the perpetrators are conscious and planned, and at times mothers are gleeful in their duping of authority figures. Many perpetrators have coincident psychiatric disorders such as depression or personality disorders. There is also an element of compulsive behavior to repeat acts of abuse with high rates of recidivism.13 Fathers as perpetrators are much less common, accounting for about 1%–5% of perpetrators or co-conspirators.5,7,13 Perpetrator fathers generally do not develop close relationships with staff, lose their tempers easily, often have had

Case 1 A 3-year-old boy presented to the emergency room in septic shock. He had a long history of multiple episodes of otitis media leading to tympanostomy tubes and recurrent otorrhea. He required multiple courses of intravenous antibiotics, removal of a cholesteatoma, and bilateral mastoidectomies. A central venous catheter was placed two days before admission. Previous complete immunological evaluation was normal. On arrival in the emergency department, he required intubation, fluid resuscitation, and pressor support. Blood culture grew Escherichia coli and Enterobacter pseudoavium. Appropriate antibiotics were administered in the intensive care unit (ICU) where he rapidly improved. He subsequently had recurrent fevers with multiple blood cultures positive for Candida tropicalis. Extensive investigation for a site of infection was unfruitful. By day 15, he had five different bacterial pathogens and Candida species grow from multiple blood cultures. On day 18, an ICU nurse filed a report when she witnessed the mother with an intracatheter in her hand, and the following day the nurses documented the mother to place an object in her pocket when her hands had been under the child’s blanket. The nurse noted brown particulate matter in the femoral line. It was cleared and sent for culture. The patient developed polymicrobial septic shock again and was treated appropriately. The pathology report of the removed specimen grew mixed bacterial flora with yeast forms with golden brown pigment consistent with fecal material. The mother was confronted with the evidence. She did not admit or deny her actions. A court-ordered separation occurred and the patient improved. The mother had been actively involved in her son’s care and had gained the respect of the medical staff before this incident. The child was placed in foster care and thrived without further infections or otorrhea. This case illustrates the relationship the perpetrators develop with the medical staff and the depths to which they plan their abusive actions as well as the difficulty and delay in diagnosis.22

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prior psychiatric encounters, and may have had Munchausen syndrome themselves. They often falsify stories of themselves, create untrue impressive life achievements, tell stories casting themselves in a factitious hero role, or actually cause potential catastrophes to create hero situations for themselves. Histories as presented by the perpetrator are genuinely impressive in medical detail and realistic, often using medical knowledge or even medical terminology.11 Victims are seen by many physicians from different subspecialty services with a wide variety of diagnoses. The nature of the fabricated illnesses take on virtually any medical presentation including bleeding, seizures, obtundation or coma, apnea, diarrhea,

Case 2 An 8-week-old boy was referred from another institution because of recurrent bleeding from the upper respiratory tract. Episodes of bleeding were occasionally accompanied by apnea. The mother would find the child in a pool of blood apparently originating from the mouth and nose. During a previous hospitalization, the patient had 14 episodes of bleeding, 4 of which were accompanied by respiratory arrests requiring resuscitation. The mother stayed in the hospital gaining the respect and friendship of the hospital staff. Evaluations included serum chemistries, hematologic and coagulation studies, multiple X-rays, barium studies, Meckel’s scan, cardiac catheterization, pulmonary angiography, lumbar puncture, electroencephalography, esophagoscopy, gastroscopy, nasopharyngoscopy, and two bronchoscopies. A week before transfer, the patient was transfused with51 Cr-labeled erythrocytes. Nuclear scanning failed to reveal any site of bleeding. At the receiving hospital, the physical examination was normal. Shortly after admission, the mother ran out of the room stating that another episode of bleeding had occurred. Nurses found the child sleeping quietly with normal vital signs but with blood on his mouth and on the pillowcase. Blood samples from the child and pillowcase were taken for analysis. Blood from the pillowcase had no radioactivity, whereas the child’s capillary blood had significant radioactive counts from the labeled red cells. In addition, the blood type on the pillowcase was A cc, similar to the mother’s blood type, whereas the patient’s blood type was A Cc. The results were given to the parents, no accusations were made, and no further episodes occurred. The patient was transferred back to the original hospital with social service and psychiatric follow-up for the mother. The child was placed in the custody of the paternal grandmother. Psychiatric evaluations were unrevealing, and the infant was returned to the custody of the parents. The psychiatrist was a family friend. At 2 years of age, the child suddenly died. The autopsy was inconclusive, and the final diagnosis was sudden infant death.23

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CHAPTER 9 ❖ Munchausen Syndrome by Proxy vomiting, fever, rash, hematuria, glycosuria, cystic fibrosis, biochemical aberrations, recurrent infections, polymicrobial sepsis, mitochondrial disease, intestinal pseudo-obstruction, weakness, renal calculi, and even abuse itself.14 Examples of child abuse in the otolaryngology experience are well documented.15–18 Defined examples of MSP are less well documented.19–21 Two examples are summarized here. Siblings may be at significant risk for fabricated illness as well.24–27 Thirty-nine percent of siblings may suffer effects of feigned or induced disease.24 Failure to thrive, nonaccidental injury, neglect, inappropriate administration of medications, or suspicious deaths have been found in siblings of children with PCF. McClure et al. reported a two-year prospective survey of nonaccidental suffocation or poisoning.7 Eighty-three of 128 index children had siblings. Of the 83 patients with siblings, 34 were known to have had a sibling who suffered previous abuse. Fifteen of the 83 patients had a sibling who died previously (18 deaths, 5 of whom were classified as sudden infant death). The professional staff is unwittingly drawn into the perpetrator’s web of deceit. The mother often combines firmness and intensity seeking more tests and interventions with adulatory support for physicians.2,28 She preys on the physician’s self-doubt and concern of missing a diagnosis leading to a never-ending evaluation. The patient then suffers at the hand of the physician because of unnecessary and often invasive tests and treatments, leading to the term “medical child abuse.”29,30 All children suffer short-term morbidity with 75% at the hands of both the mother and the medical staff and 25% attributable to the medical staff alone.5

OUTCOME Long-term morbidity of victims of PCF is staggering. Bools et al. reported results of 54 children followed up from 1 to 14 years. Thirty children were living with the biological mother, whereas the remaining 24 lived with substitute families. Ten of the 30 children had further fabricated illnesses, whereas another 8 had other unspecified concerns. Thirteen of 30 and 14 of 24 had conduct and emotional difficulties; school performance was poor with difficulties with attention and concentration as well as truancy.31 Reactions to the abuse follow developmentally appropriate patterns. Infants may have feeding difficulties, whereas preschool children may withdraw and experience hyperactive behavior. Children may demonstrate fear of parents. Even with protection from physical injury, psychological trauma remains likely with continued inappropriate contact with the perpetrator.32 Long-term follow-up of adult victims reveal lasting emotional scars.33 Libow found that in 10 adults who were childhood victims of PCF feelings of being unloved or unsafe in childhood, and as adults, they expressed feelings of insecurity, difficulty in reality testing, avoidance of medical treatment, or posttraumatic stress symptoms. Some victims

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continued fabricating illnesses or harassing adult children with factitious illnesses even decades later.

MANAGEMENT Management of PCF is challenging.34 Diagnosis rests on recognizing warning signs such as unexplained, prolonged, or extraordinary illness; signs and symptoms that are incongruous or present only when the mother is present; ineffective or poorly tolerated treatments that are expected to prove beneficial; inappropriate maternal affect concerning the child’s illness; or family history of sudden infant death or poorly explained death of a sibling. Once PCF is suspected, all unnecessary testing must be suspended. The physician must become a medical detective. By history, the physician must define the fabricated illness and true illness and confirm events by independent eyewitnesses. Examination for a temporal association between events and presence of the mother is crucial, and confirmation of the mother’s history of the child, as well as confirming the mother’s own history, may be revealing. This may require interviews with other family members or other healthcare workers. Examine body fluids if necessary for toxins or type and match blood samples with the child and parents. If a temporal relationship exists between episodes and the mother, separating the parents from the child may be necessary. This may require a court order. Notification of child protection agencies is required in 50 states if child abuse is suspected. Covert video surveillance (CVS) has been used effectively to document abusive behavior as well as in exonerating families of abuse. Southall et al. investigated 39 children strongly suspected of being abused.35 Thirty-three of 39 videos recorded abuses to the child including poisoning, suffocation, fracture, and emotional and physical abuse. Hall et al. used CVS with 41 patients suspected of fabricated or induced disease.12 Of 23 patients documented to be victims of PCF, CVS was required to make the diagnosis in 13 of them. CVS was supportive in making the diagnosis in five children and not required to make the diagnosis in another five patients. Importantly, CVS exonerated four families. Use of CVS is controversial.36,37 Objections to CVS range from being a deceptive practice to parental expectations of privacy, possible need of a warrant, lack of consent, bordering on being a police function, and erosion of trust in medicine. Arguments in favor of CVS include parents voluntarily bringing their children to the hospital for physicians to use appropriate diagnostic measures for the child; physicians are the child’s advocate even if it is at odds with parental rights; CVS may exonerate families; if abuse is documented, appropriate intervention can be taken to habilitate and reunite the family and child as well as to help the perpetrator; video without sound does not violate statutes of reasonable privacy especially in non-government hospitals where patients are to be observed.38,39 CVS is not a police tool but rather a diagnostic tool; consent for a noninvasive diagnostic test defeats the purpose of the tool.

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Once the diagnosis of PCF is made, the medical team, led by the physician, must confront the perpetrator. Discussions may begin by summarizing evidence against disorders in the differential diagnosis and evidence for a factitious illness. The physician should assume a nonaccusatory posture and inform the family about the involvement of child protective services. Recommendations for disposition of the child will be according to protective services, but generally separation of the child and perpetrator is recommended. Placement of the child with other family members may still put the child at risk if the mother manipulates family members or is in unsupervised contact with the child. Children in contact with the mother have continued fabricated illness and poorer outcomes.40 Treatment recommendations for the perpetrator fall under factitious disorder by proxy interventions. In general, psychotherapy for mothers has been difficult. At times, only 15% of mothers admit their actions, making them recalcitrant to therapy.5 Lack of commitment to therapy or refusal to submit to counseling complicates the need for long-term therapy. Berg and Jones reported on psychiatric intervention outcomes of 13 highly selected perpetrators.41 After over seven weeks of intensive inpatient therapy, 10 of 13 mothers were reunited with their children. One of the reunited children continued with fabricated illnesses, whereas another child had ongoing parent–child conflicts. Motivated, intelligent mothers with family support may have better outcomes with psychotherapy.42

CONCLUSION MSP consists of two separate intertwined disorders, PCF, which is a malignant form of child abuse, and factitious disorder by proxy representing the disorder of the perpetrator. Diagnosis of PCF demands a high index of suspicion along with medical signs and symptoms that are incongruous with known disorders and expected pathophysiology. Once the diagnosis of PCF is made, physicians should refrain from continuing medical child abuse by ceasing all unnecessary testing. Involvement of child protective services, protecting the child, and habilitation of the family become the primary goals of medical intervention.

References 1. Raspe RE. (1785). Singular Travels, Campaigns and Adventures of Baron Munchausen. London, UK: Crosset Press; 1948. 2. Asher R. Munchausen’s syndrome. Lancet. 1951;1:339–341. 3. Meadow R. Munchausen syndrome by proxy. The hinterland of child abuse. Lancet. 1977;2:343–345. 4. Ayoub CC, Alexander R, Beck D, et al. Positional paper: definitional issues in Munchausen by proxy. Child Maltreat. 2002;7:105–111. 5. Rosenberg DA. Web of deceit: a literature review of Munchausen syndrome by proxy. Child Abuse Negl. 1987;11:547–563.

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6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:725–727. 7. McClure RJ, Davis PM, Meadow SR, Sibert JR. Epidemiology of Munchausen syndrome by proxy, non-accidental poisoning, and non-accidental suffocation. Arch Dis Child. 1996;75: 57–61. 8. Schreier HA, Libow JA. Hurting for Love: Munchausen by Proxy Syndrome. New York, NY: The Guildford Press; 1993. 9. Sheridan M. The deceit continues: an updated literature review of Munchausen syndrome by proxy. Child Abuse Negl. 2003;27:431–451. 10. Zitelli BJ, Seltman MF, Shannon RM. Munchausen’s syndrome by proxy and its professional participants. Am J Dis Child. 1987;141:1099–1102. 11. Meadow R. Munchausen syndrome by proxy. Arch Dis Child. 1982;57:92–98. 12. Hall, DE, Eubanks L, Meyyazhagen S, et al. Evaluation of covert video surveillance in the diagnosis of Munchausen syndrome by proxy: lessons from 41 cases. Pediatrics. 2000;105:1305–1312. 13. Schreier H. Munchausen syndrome by proxy. Curr Prob Pediatr Adolesc Health Care. 2004;34:126–143. 14. Meadow R. Munchausen by proxy abuse perpetrated by men. Arch Dis Child. 1998;78:3217–3221. 15. Meadow R. False allegations of abuse and Munchausen syndrome by proxy. Arch Dis Child. 1993;68:444–447. 16. Crouse CD, Faust RA. Child abuse and the otolaryngologist: part I. Otolaryngol – Head Neck Surg. 2003;123:305–310. 17. Crouse CD, Faust RA. Child abuse and the otolaryngologist: part II. Otolaryngol – Head Neck Surg. 2003;123:311–317. 18. Willging JP, Bower CM, Cotton RT. Physical abuse of children. A retrospective review and an otolaryngology perspective. Arch Otolaryngol Head Neck Surg. 1987;97:361–368. 19. Manning SC, Casselbrant M, Lammers D. Otolaryngologic manifestations of child abuse. Int J Pediatr Otorhinolaryngol. 1990;20:7–16. 20. Mra Z, MacCormick JA, Pooje CP. Persistent cerebrospinal fluid otorrhea: a case of Munchausen’s syndrome by proxy. Int J Pediatr Otorhinolaryngol. 1997;41:59–63. 21. Kravitz RM, Wilmott RW. Munchausen syndrome by proxy presenting as fictitious apnea. Clin Pediatr. 1990;29:587–592. 22. Light MJ, Sheridan MS. Munchausen syndrome by proxy and apnea (MBPA): a survey of apnea programs. Clin Pediatr. 1990;29:162–168. 23. Gartner JC, Zitelli BJ. Munchausen syndrome by proxy: a potential problem for otolaryngologists. In: Myers EN, Bluestone CD, Brackmann DE, Krause CJ, eds. Advances in Otolaryngology—Head and Neck Surgery. Vol II. St. Louis, MO: Mosby-Year Book, Inc.; 1997:75–88. 24. Kurlandsky L, Lukoff JY, Zinkham W, et al. Munchausen syndrome by proxy: definition of factitious bleeding in an infant by 51Cr labeling of erythrocytes. Pediatrics. 1979;63: 228–231. 25. Bools CN, Neale BA, Meadow R. Co-morbidity associated with fabricated illness (Munchausen syndrome by proxy). Arch Dis Child. 1992;67:77–79. 26. Lee DA. Munchausen syndrome by proxy in twins. Arch Dis Child. 1979;54:646–647.

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CHAPTER 9 ❖ Munchausen Syndrome by Proxy 27. Alexander R, Smith W, Stevenson R. Serial Munchausen syndrome by proxy. Pediatrics. 1990;86:581–585. 28. Rosen CL, Frost JD, Bricker T, et al. Two siblings with recurrent cardiorespiratory arrest: Munchausen syndrome by proxy. Pediatrics. 1983;71:715–720. 29. Schreier HA, Libow JA. Munchausen by proxy syndrome: a modern pediatric challenge. J Pediatr. 1994;125: S110–S115. 30. Bryk M, Siegel PT. My mother caused my illness: the story of a survivor of Münchausen by proxy syndrome. Pediatrics. 1997;100:1–7. 31. Roesler TA, Jenny C. Medical Child Abuse: Beyond Munchausen Syndrome by Proxy. Elk Grove Village, IL: American Academy of Pediatrics; 2008. 32. Bools CN, Neale BA, Meadow R. Follow-up victims of fabricated illness (Munchausen syndrome by proxy). Arch Dis Child. 1993;69:625–630. 33. McGuire TL, Feldman KW. Psychological morbidity of children subjected to Munchausen syndrome by proxy. Pediatrics. 1989;83:289–292. 34. Libow JA. Munchausen by proxy victims in adulthood: a first look. Child Abuse & Neglect. 1995;19:1131–1142. 35. Meadow R. Management of Munchausen syndrome by proxy. Arch Dis Child. 1985;60:385–393.

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36. Southall DP, Plunkett MCB, Banks MW, Falkov AF, Samuels MP. Covert video recordings of life-threatening child abuse: lessons for child protection. Pediatrics. 1997;100:735–760. 37. Epstein MA, Markowitz RL, Gallo DM, Holmes JW, Gryboski JD. Munchausen syndrome by proxy: considerations in diagnosis and confirmation by video surveillance. Pediatrics. 1987;80:220–224. 38. Connelly R. Ethical issues in the use of covert video surveillance in the diagnosis of Munchausen syndrome by proxy. The Atlanta study—an ethical challenge for medicine. HEC Forum. 2001;15:21–41. 39. Morrison CA. Camera in hospital rooms: the fourth amendment to the constitution and Munchausen syndrome by proxy. Crit Care Nurs Q. 1999;22:65–68. 40. Flannery MT. Munchausen syndrome by proxy: broadening the scope of child abuse. University of Richmond Law Review. 1994;28:1175–1233. 41. Berg B, Jones D. Outcome of psychiatric intervention in factitious illness by proxy (Munchausen’s syndrome by proxy). Arch Dis Child. 1999;81:465–472. 42. Nicol AR, Eccles M. Psychotherapy for Munchausen syndrome by proxy. Arch Dis Child. 1985;60:344–348.

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10

C H A P T E R

Pediatric Anesthesiology Lynne R. Ferrari

A

nesthesiologists care for children undergoing a wide variety of otolaryngology procedures. These procedures may be the most crucial for good anesthesiologist and surgeon communication to insure an optimal outcome for the patient. These are truly shared airway cases where physiologic and anatomic considerations must be fully understood and discussed to provide safe anesthetic management and ideal conditions for both patients and surgeons.

PSYCHOLOGICAL PREPARATION The objective of the preoperative evaluation of the pediatric surgical patient is to gather medical information and alleviate the fear and anxiety that exist for the patient and family. Parents are often more concerned with the risks and administration of anesthesia for their children than for themselves. The preoperative visit is an opportunity for the anesthesiologist to evaluate the child’s psychological status and family interactions. Diseases carry with them a psychosocial aspect that is different in children than in adults. For many healthy children undergoing elective surgery, the emotional disruption may surpass the medical issues.1,2 Children respond to the prospect of surgery in a varied and age-dependent manner, and the anesthesiologist must address this during the preoperative interview. The understanding of and response to illness is affected by a child’s maturity. The medical practitioner should anticipate the child’s needs and concerns and be able to interpret nonverbal expressions and actions when communication skills are not highly developed. The toddler’s greatest fear is the loss of control of actions and choices. The preschooler fears injury, the unknown, and abandonment. The preschooler interprets words literally and is unable to differentiate between what is heard and what is actually being implied. The school-aged child fears inability to meet the expectations set by adults, and death. Between the ages of 6 and 12, children begin to think more logically; they may nod with understanding and listen intently, when in fact they do not fully grasp the explanation. Adolescents fear loss of control, an altered body image, and segregation from peers. They are usually convinced that the anesthesiologist will not be able to put them to sleep and that if the anesthesiologist does succeed, they will never wake up.3 This age group interestingly requires the greatest amount of reassurance.

RISKS OF ANESTHESIA Parents may ask about the risks of anesthesia for their child. This must be evaluated on an individual basis considering the child’s age, type of surgery, and other confounding factors.4

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Parents are most concerned with the risk of death, which occurs at a rate of 1 in 185,000 healthy children. Most deaths that are due entirely to anesthesia occur in the first week of life. Other perioperative risks that are considered minor include laryngospasm that occurs at a rate of 17:1000 in children under 9 years of age but increases to 96:1000 in a child with a concomitant upper respiratory infection (URI). Bronchospasm occurs at a rate of 4:1000 but increases to 41:1000 during anesthesia in the child with URI. Children with an American Society of Anesthesiology Risk Stratification score of 3 or higher have a risk of any complication under anesthesia at a rate of 24:10005–8 (Table 10-1). The preoperative evaluation is the ideal opportunity for a calm and unhurried discussion of these risks.

HISTORY AND REVIEW OF SYSTEMS The medical history for pediatric patients begins with a description of the prenatal period, because events during pregnancy and delivery may influence the current perioperative state of health. If the child has been admitted to the neonatal intensive care unit (ICU) after birth, specific conditions should be ruled out.9 Surgical experiences or medical admissions to the hospital should be noted.10 A review of systems should be completed in addition to a description of the child’s prior anesthetic experience. Noting techniques that were successful or those should be avoided are helpful in planning a successful and positive experience. The need for premedication should be assessed, and if chosen, the effects on the airway should be considered. The child’s reaction to previous anesthetics may reveal those that should be avoided. Families should be asked about any history of unexpected death, sudden infant death syndrome, genetic defects, or familial conditions such as muscular dystrophy, cystic fibrosis, sickle-cell disease, bleeding tendencies, or human immunodeficiency virus infection. Queries specifically directed to the identification of malignant hyperthermia and pseudocholinesterase deficiency in families should be made. Malignant hyperthermia is a hypermetabolic disorder of skeletal muscle with varying presentations. It is generally accepted that the inheritance in humans is as an autosomal dominant trait with variable penetrance. When there is a history of or a strong risk of malignant hyperthermia, the volatile anesthetic agents must be avoided, because they are the most potent triggers of this disorder. Therefore, even young children must not undergo an inhalation induction of anesthesia, and intravenous access must be secured before induction and the anesthetic planned with intravenous agents.11

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TABLE 10-1. American Society of Anesthesiologists Physical Status Classification

ASA 1

A normal healthy patient

ASA 2

A patient with mild systemic disease

ASA 3

A patient with a severe systemic disease that limits activity but is not incapacitating

ASA 4

A patient with an incapacitating systemic disease that is a constant threat to life

ASA 5

A moribund patient not expected to survive 24 h with or without an operation

+E

In the event of emergency operation the physical status is preceded by an “E”

Inherited variants of pseudocholinesterase are significant, because the administration of succinylcholine and esterlinked anesthetic agents will have a prolonged effect as a result of abnormal metabolism. Cocaine toxicity may also be enhanced in these patients. As this is also an inherited disorder, it may be elicited by history and confirmed by laboratory examination (plasma cholinesterase level and dibucaine number). A positive history should result in planning for alternate drugs in the event that succinylcholine might be indicated.

MEDICATIONS AND ALLERGIES Currently, prescribed medications can have significant effects on the outcome of general anesthesia. Queries should be made regarding the use and frequency of nonprescription cold remedies that contain aspirin or aspirin-like compounds that interfere with platelet function and coagulation. Nonsteroidal anti-inflammatory drugs should be stopped at least three days before surgery, because the effect is reversible after three to five half-lives, and these drugs have half-lives of 2–12 hours. In children who have been treated for a malignancy, specific chemotherapeutic regimens should be documented. Those that cause myocardial dysfunction (anthracyclines) may require further preoperative investigation by echocardiogram. Use of mitomycin and bleomycin sulfate may result in pulmonary dysfunction, which may require further evaluation. Adjunct therapies such as the use of herbal remedies should be documented. The use of herbal substances may produce altered physiology, which may complicate the course of a general anesthetic. Exposure to tobacco smoke should be queried during the preoperative interview and should be documented, because children with long-term exposure to tobacco smoke may experience an increased incidence of airway complications under general anesthesia.12 The use of herbal and adjunct therapy is becoming more widespread. Some studies showed that up to 30% of families administer nonpharmacologic therapies to their children.13 As part of the preoperative process, inquiry about herbal and other therapies should be included, because many of these substances can interfere with normal physiologic functions. The Physician Desk Reference (PDR) publishes an herbal reference guide for this purpose.

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PHYSICAL EXAMINATION One of the key features of the physical examination in children is simple observation. Abnormal facies may be an indication of a syndrome or constellation of congenital abnormalities. One congenital anomaly is often associated with others. The rate, depth, and quality of respirations should be evaluated. Nasal or upper respiratory obstruction is indicated by noisy or labored breathing. The color, viscosity, and quantity of nasal discharge should be documented. If the child is coughing, the upper or lower airway origin of the cough, and its dry or wet quality, can be often evaluated even before auscultation of the lungs. The presence of wheezing, stridor, and retractions should be determined. The airway should be evaluated for ease of intubation. In the child who will cooperate with mouth opening, the Mallampati Classification (classes I–IV) may be used (Table 10-2). It is based on the structures visualized with maximal mouth opening and tongue protrusion in the sitting position.14 Intubation through direct laryngoscopy should be easily accomplished in class I and II airways; however, there may be difficulty in visualizing the vocal cord in class III and IV airways. If the child will not open his or her mouth, a manual estimation of the thyrohyoid distance should be made. Children with micrognathia, as in Pierre Robin syndrome or Goldenhar’s syndrome, may be especially difficult to intubate. Documentation of loose teeth should be made. In the event that a child is determined to be a “difficult intubation,” maneuvers other than direct laryngoscopy should be planned. These include awake or anesthetized fiberoptic bronchoscopy, the use of a laryngeal mask airway (LMA), and the use of a light wand or sedated awake intubation15 (Fig. 10-1). The choice must be determined by the individual skill of both the anesthesiologist and the surgeon. In any case of a possible difficult intubation, a tracheostomy set must be available in the operating room (OR).

DIAGNOSTIC TESTING Few, if any, diagnostic laboratory tests are routinely necessary in the pediatric population. Diagnostic studies should be individualized to the patient’s medical condition and the surgical procedure being performed. Serum chemistry measurements are indicated only to confirm a suspected abnormality. Serum medication levels are measured when specifically indicated. Determination of hemoglobin level before elective surgery is unnecessary for most healthy children. The routine TABLE 10-2. Mallampati Classification Class I

The soft palate, fauces, uvula, and pillars are visualized

Class II

The soft palate, fauces, and portion of the uvula but no pillars are visualized

Class III

The soft palate and base of uvula are visualized

Class IV

The hard palate is visualized

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115

DIFFICULT AIRWAY ALGORITHM 1. Assess the likelihood and clinical impact of basic management problems: A. Difficult Ventilation B. Difficult Intubation C. Difficult with Patient Cooperation or Consent D. Difficult Tracheostomy 2. Actively pursue opportunities to deliver supplemental oxygen throughout the process of difficult airway management 3. Consider the relative merits and feasibility of basic management choices: A.

Awake Intubation

vs.

Intubation Attempts After Induction of General Anesthesia

B.

Non-Invasive Technique for Initial Approach to Intubation

vs.

Invasive Technique for Initial Approach to Intubation

C.

Preservation of Spontaneous Ventilation

vs.

Ablation of Spontaneous Ventilation

4. Develop primary and alternative strategies: A.

Invasive Airway Access(b)*

Airway Approached by Non-Invasive Intubation Succeed* Cancel Case

INTUBATION ATTEMPTS AFTER INDUCTION OF GENERAL ANESTHESIA

B.

AWAKE INTUBATION

Initial Intubation Attempts Successful*

Initial Intubation Attempts UNSUCCESSFUL FROM THIS POINT ONWARDS CONSIDER: 1. Calling for Help 2. Returning to Spontaneous Ventilation 3. Awakening the Patient

FAIL Consider Feasibility of Other Options(a)

Invasive Airway Access(b)*

FACE MASK VENTILATION NOT ADEQUATE

FACE MASK VENTILATION ADEQUATE

CONSIDER / ATTEMPT LMA LMA NOT ADEQUATE OR NOT FEASIBLE EMERGENCY PATHWAY Ventilation Not Adequate, Intubation Unsuccessful

LMA ADEQUATE* NON-EMERGENCY PATHWAY

Ventilation Adequate, Intubation Unsuccessful Alternative Approaches to Intubation(c) Successful Intubation*

FAIL After Multiple Attempts Invasive Airway Access(b)*

IF BOTH FACE MASK AND LMA VENTILATION BECOME INADEQUATE

Call for Help Emergency Non-Invasive Airway Ventilation(e) Successful Ventilation*

Consider Feasibility of Other Options(a)

Awaken Patient(d)

FAIL Emergency Invasive Airway Access(b)*

* Confirm ventilation, tracheal intubation, or LMA placement with exhaled CO2

a. Other options include (but are not limited to): surgery utilizing face mask or LMA anesthesia, local anesthesia infiltration or regional nerve blockade. Pursuit of these options usually implies that mask ventilation will not be problematic. Therefore, these options may be of limited value if this step in the algorithm has been reached via the Emergency Pathway. b. Invasive airway access includes surgical or percutaneous tracheostomy or cricothyrotomy.

c. Alternative non-invasive approaches to difficult intubation include (but are not limited to): use of different laryngoscope blades, LMA as an intubation conduit (with or without fiberoptic guidance), fiberoptic intubation, intubating stylet or tube changer, light wand, retrograde intubation, and blind oral or nasal intubation. d. Consider re-preparation of the patient for awake intubation or canceling surgery. e. Options for emergency non-invasive airway ventilation include (but are not limited to): rigid bronchoscope, esophageal-tracheal combitube ventilation, or transtracheal jet ventilation.

FIGURE 10-1. American Society of Anesthesiologists’ difficult airway algorithm. (Reprinted with permission from American Society of Anesthesiologists Task Force on Management of the Difficult Airway.15 A copy of the full text can be obtained from ASA, 520 Northwest Highway, Park Ridge, IL 60068-2573. Courtesy of the American Society of Anesthesiologists.)

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measurement of coagulation parameters is controversial. A family history of abnormal coagulation, or an individual history of prolonged epistaxis, bleeding from a circumcision or a tooth extraction, or the presence of hematomas, and large bruises are better predictors of abnormal coagulation. If an otherwise healthy child has a negative history relative to the above questions, no further testing is required, because commonly used screening tests such as bleeding time, activated partial thromboplastin time, prothrombin time, and platelet count do not reliably predict surgical bleeding in procedures in which adequate hemostasis is essential such as tonsillectomy.16

SPECIAL CIRCUMSTANCES Upper Respiratory Infection The child with a recent URI poses a clinical dilemma for the anesthesiologist. Because most children can have up to 6 URIs each year, this is a common problem for which no absolute rules exist. Several potential risks are encountered in the perioperative period in the child who has an active cold or is recovering from a recent one. Cough is a sign of lower respiratory involvement and should be evaluated for upper or lower airway origin and wet or dry quality. Most children have clear breath sounds during quiet respirations. Crackles are best detected during coughing and crying. Adverse perioperative events occur more frequently in children with URIs. These include atelectasis, oxygen desaturation, bronchospasm, croup, and laryngospasm.17,18 Most of these children may be anesthetized for short procedures; however, the decision to perform a lengthy or invasive procedure must be made with caution. Decisions to cancel or postpone surgery should be made jointly by the surgeon and anesthesiologist and should be based on the type of procedure, the urgency of the procedure, and the child’s overall medical condition. Bronchial hyperreactivity may exist for up to 7 weeks after the resolution of URI symptoms, and delaying surgery for this length of time is often impractical. Most practitioners would agree that surgery may be scheduled after the acute symptoms have resolved and no sooner than two weeks after the initial evaluation.

Premature Birth Former premature infants present for various surgical procedures, some seemingly minor. The anesthetic management can be challenging, however. The extent of chronic lung disease and the possibility of postoperative apnea are of concern and require planning for appropriate monitoring. Documentation of coexisting conditions such as gastroesophageal reflux, patent ductus arteriosus, and hydrocephalus is important. The degree of respiratory compromise in former premature infants may range from no residual lung disease to serious bronchopulmonary dysplasia. The presentation of bronchopulmonary dysplasia is variable and ranges from mild radiographic changes in an asymptomatic patient to pulmonary fibrosis, emphysema, reactive airway disease, chronic hypoxemia and

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hypercarbia, tracheomalacia or bronchomalacia, and increased pulmonary vascular resistance with cor pulmonale. If pulmonary hypertension and cor pulmonale are suspected, an electrocardiogram (ECG) and occasionally echocardiogram are useful to confirm the diagnosis and guide medical therapy. Diuretics, bronchodilators, and corticosteroids should be continued up to and including the day of surgery. A hematocrit and CXR are useful in evaluating these infants. Administration of pharmacologic “stress doses” of steroids should be considered in infants receiving steroid treatment. Postoperative apnea after anesthesia has been reported in preterm and fullterm infants. No agreement exists on which infants are at risk. Reports are not consistent in identifying the postconceptual age or gestational age of at-risk patients, the methods used to detect apnea or periodic breathing, the surgical procedure, other confounding medical conditions, or even the definition of apnea.19 Apnea is central in 70% of cases, obstructive in 10%, and mixed in 20% of premature infants. Premature infants who have a gestational age of 35 weeks or more should be monitored in the hospital for postanesthetic apnea until they reach 48 weeks postconceptual age. Infants under 35 weeks gestational should be similarly monitored until they are 50 weeks postconceptual age. Monitoring consists of pulse oximetry and an apnea monitor for 24 hours after the conclusion of anesthesia. Postanesthetic apnea has been reported in full-term infants less than 4 weeks of age; therefore, monitoring is recommended in all neonates. Alternatively, non–life-threatening surgery may be postponed beyond 48-50 weeks postconceptual age to avoid the need for postanesthetic admission.19 Infants with anemia defined by hematocrit less than 30 mg/dL, apnea at home (as measured with home apnea-monitoring equipment), and a prior history of apnea and bradycardia are at increased risk. Any child considered to be at risk for postoperative apnea should be admitted for overnight observation and monitoring.19,20 A recent hematocrit or hemoglobin determination is required for the former preterm infant because anemia defined as a hematocrit less than 30 mg/dL is associated with an increased incidence of postanesthetic apnea that is unaffected by postconception age.

Asthma Children with asthma should have their medical management optimized. All medications, both oral and inhaled, should be continued up to and including the day of surgery. Oral medications may be taken with clear fluids up to two hours before the induction of anesthesia. Patients with particularly severe asthma may benefit from short-term corticosteroid therapy for several days before surgery. Therapy should be planned with the pulmonologist. Surgery should generally be postponed for children with an acute exacerbation of asthma or those who have an acute URI superimposed on chronic asthma. Asthmatic children are at increased risk of bronchospasm during general endotracheal anesthesia. The incidence of bronchospasm in asthmatic patients during anesthesia is between 8.4 and 71.0 per 1000, compared with 0.2 and 8.0 per 1000 in the general population.21 This incidence is further increased during acute

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CHAPTER 10 ❖ Pediatric Anesthesiology exacerbations. Any child who has reactive airway disease is at increased risk of bronchospasm under anesthesia even in the absence of wheezing. For this reason, children who take inhalers on an as needed or occasional basis should implement prophylactic therapy 48 hours in advance of the surgery or procedure date. If there has not been an adverse airway event, treatment with a bronchodilator is not necessary.

Cystic Fibrosis Children with cystic fibrosis have a multisystem disease, and each of these systems should be addressed during the preoperative period. Pulmonary function should be optimized through the use of antibiotic and bronchodilator therapy and vigorous chest physical therapy to clear secretions and enhance airflow. Many children have some degree of malnutrition and may need parenteral or supplemental enteral nutrition before undergoing general anesthesia and surgery. Many cystic fibrosis patients should be admitted to the hospital for medical management before their surgical procedures. All medications should be continued up to and including the day of surgery.

Cardiac Disease The child with a heart murmur or a history of a murmur warrants special consideration. The murmur should be categorized as innocent or pathologic, and the presence of hemodynamic compromise should be determined. The need for subacute bacterial endocarditis prophylaxis should be established.22 The child with significant or active cardiac disease might require an evaluation by a cardiologist before general anesthesia. Cardiac catheterization data and recommendations should be included in the preoperative evaluation. Children with cardiac disease can be divided into two categories: those who have structural congenital heart disease (corrected and uncorrected) and those who have a heart murmur (previously diagnosed or new). The child who is followed up regularly by a cardiologist should be evaluated in the preoperative period to detect and document any interval change. The child with a heart murmur or a history of a murmur warrants special consideration. The murmur should be determined to be innocent or pathologic, with or without hemodynamic compromise apparent. Innocent or nonpathologic heart murmurs may be present in up to 50% of healthy children at one point in their lives. These can be identified by four characteristics: the murmur is early systolic to midsystolic; it is softer than grade III of VI; the pitch is low to medium; and the sound has a musical, not harsh, quality.10 Children with communicating lesions between the right and left sides of the heart may be at risk for paradoxical air embolus. These considerations are best evaluated by a cardiologist if there is anything other than the presence of an innocent murmur. The need for subacute bacterial endocarditis prophylaxis should also be determined in advance of the surgical procedure.22 When the child has had a surgical repair of congenital heart disease, a description of the repair and current anatomy should be made available to the anesthesia

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team. If a defect still exists, management recommendations should be requested from the cardiologist. All current cardiac catheterization data should be reviewed.

Neurologic Disorders Neurologic status should be assessed by noting associated congenital syndromes, neurologic deficits, metabolic disorders, or seizure disorders. The physical examination should include an evaluation of the level of consciousness, ability to swallow, intactness of the gag reflex, and an adequate cervical spine range of motion, hypotonia, spasticity, and flaccidity. A description of the type, frequency, and characteristics of seizure activity should be part of the preoperative evaluation. Current medications and, if applicable, serum levels of anticonvulsant medications should be noted. Information regarding medications that were ineffective in controlling seizure activity should be included. All seizure medications should be taken up to and including the day of surgery. Oral antiseizure medications may be taken with clear fluids up to two hours before the time of surgery.

Cervical Spine Instability Several groups of pediatric patients are at risk for cervical spine instability. Children with mucopolysaccharidoses and other syndromes may have abnormalities of the odontoid process, which may result in cervical spine instability. Atlantoaxial instability and superior migration of the odontoid process can occur in patients with rheumatoid arthritis. Approximately 15% of children with Down syndrome are likewise affected. Although no uniform guidelines exist regarding the preoperative testing of such children, the suggestion has been made that children who are symptomatic (e.g., have gait disturbances, incontinence problems) should undergo flexion– extension radiography of the cervical spine and should have a neurologic consultation.23 If cervical abnormalities are noted, intubation in a neutral head position or somatosensory evoked potential monitoring of the upper extremities may be required.24

Hematologic Disorders Heterozygous sickle-cell trait does not affect anesthetic management or perioperative outcome, but homozygous sickle-cell disease, sickle cell hemoglobin C disease, and hemoglobin S-thalassemia disease carry implications for anesthetic management. Acute chest syndrome, stroke, myocardial infarction, and sickle-cell crises are of concern to the anesthesiologist. To minimize these risks, patients are vigorously hydrated preoperatively and the OR temperature is kept elevated to optimize vascular flow. In severe cases, partial exchange transfusion is performed in an attempt to decrease the level of hemoglobin S to less than 40% or transfusion to a hemoglobin value of 10 g/dL is performed. Consultation with a hematologist for the management of these patients is recommended. Coordination of care among the anesthesiologist, surgeon, pediatrician, and hematologist is essential and must begin in the preoperative period.

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Diabetes Mellitus The incidence of diabetes mellitus in the pediatric population is approximately 1.9 in 1000 school-aged children. Consultation with the pediatrician and pediatric endocrinologist is advisable. Information regarding the typical range of serum glucose control and medication regimen should be included in the preoperative evaluation. Patients with diabetes mellitus should be scheduled for surgery early in the morning, and a fasting serum glucose measurement should be obtained in the immediate preoperative period before insulin or glucose administration.25

Oncologic Disease Children with malignant disease either active, in remission, or cured may have received radiation or chemotherapy that will directly affect the anesthetic outcome. Information regarding the course of the disease, prior surgery, and a list of chemotherapeutic agents and doses should be included in the preoperative evaluation. Children suspected of having an anterior mediastinal mass require flow volume loop examination in the supine and upright positions before anesthetic induction. Specifically asking about positional changes in symptoms (orthopnea, cough while supine) or looking for signs of superior vena cava syndrome on physical examination. Clinical findings should dictate the need for other laboratory examinations such as an ECG, hemoglobin measurement, and platelet count.26,27

FASTING GUIDELINES AND INDUCTION CHOICES Fasting Guidelines Fasting guidelines for children before general anesthesia have been modified to recommend that restricting children to fasting after midnight is no longer common practice. Liberalization of oral intake results in a less anxious child, calmer parents, better maintenance of hemodynamic parameters, and less risk of intraoperative hypoglycemia. In general, most institutions allow the ingestion of clear fluids until two to three hours before the time of surgery (Table 10-3). These include water, electrolyte solutions (Pedialyte), glucose water, apple juice, white grape juice, frozen pops without fruit pulp, and gelatin. Clear fluids are defined as any fluid through which a newspaper can be read. No evidence exists that volume has an impact on gastric emptying time or residual volume; therefore, the quantity of clear fluids is not limited. Formula and breast milk are not clear fluids. Breast milk is considered to be intermediate between clear fluids and TABLE 10-3. American Society of Anesthesiologists Fasting Guidelines

2 h—clear fluids 4 h—breast milk 6 h—formula/solids 8 h—fat-containing meal

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formula. Clear policies regarding formula, breast milk, and solids should be established for each institution.

Induction Choices There are several options that are available for the induction of general anesthesia. It must be made clear that the choice is the ultimate responsibility of the attending anesthesiologist and that the input of the child and family members will be considered. For children younger than 8 years, anesthesia is best induced with a volatile anesthetic agent administered by mask. Children older than 8 years occasionally are anesthetized by mask induction, and cooperative children may choose a single-breath induction technique. The choices are based on the most appropriate method for each child and situation. Anesthesia is usually induced in older children in the same manner as in adult patients, through the intravenous route. Frequently topical anesthetic cream (EMLA or Synera) is applied to intact skin providing analgesia, thus allowing an intravenous line to be inserted without pain. Explaining the procedure to children in advance so that they are prepared is important. For developmentally challenged children who are uncooperative and difficult to reason with, anesthesia may be induced with an intramuscular injection of ketamine hydrochloride, midazolam hydrochloride, or a combination of the two. This is a fast and effective means of bringing these children into the OR, and discussion of this option is reassuring to parents who are concerned about an uncooperative or combative child. The presence of the parents is often the most effective premedication for a young child, especially a toddler, because the anxiety as a result of separation from parents is eliminated. A parent may accompany the child into the OR, and this should be an accepted practice.28–30 Parents are most effective if they have been well prepared and usually are not helpful when the child is younger than 8 months of age. The parents should be told that they may remain with the child until he or she is unaware of their presence. When a parent-present induction is unsuccessful, the cause often is inadequate preparation of parents. Parents may express their desire not to accompany their child into the OR, and this sentiment should be respected. Alternatives to parent-present induction should be explored in this situation.

SPECIAL SURGICAL SITUATIONS Tonsillectomy and Adenoidectomy The anesthetic goals are to provide a smooth atraumatic induction; to provide the surgeon with optimal operating conditions; the establishment of intravenous access to provide a route for volume expansion and medications should they be necessary; and to provide rapid emergence so that the patient is awake and able to protect the recently instrumented airway. Anesthesia is usually induced with sevoflurane, oxygen, and nitrous oxide by mask. Endotracheal intubation is accomplished under deep inhalation anesthesia or aided by a short-acting nondepolarizing muscle relaxant. An antisialagogue may be administered to minimize secretions in the operative field. An uncuffed endotracheal tube is usually used in young children; however, a

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CHAPTER 10 ❖ Pediatric Anesthesiology cuffed endotracheal tube may be an alternative provided there is a leak around the cuff between 15 and 25 cm H2O peak inflation pressure. Monitoring consists of a precordial stethoscope, ECG, temperature probe, automated blood pressure cuff, pulse oximeter, inspired oxygen, and end-tidal CO2 measurement. The use of the LMA for adenotonsillectomy was described in 1990; the widespread availability of a model with a flexible spiro-metallic reinforced shaft has increased its utilization.31,32 The flexible model has a soft, reinforced shaft that easily fits under the mouth gag without becoming dislodged or compressed. Adequate surgical access can be achieved, and the lower airway is protected from exposure to blood during the procedure.33,34 Tonsil enlargement can make LMA insertion difficult; hence, care in placement is essential. Dislodgment of the device does not occur during extreme head extension, assuming that good position and ventilation were obtained before changes in head position.35 Advantages of the LMA over traditional endotracheal intubation are a decrease in the incidence of postoperative stridor and laryngospasm and an increase in immediate postoperative oxygen saturation. Recovery is improved overall, and fewer episodes of airway obstruction have been noted. If the child is breathing spontaneously at a regular rate and depth, the LMA may be removed before emergence from anesthesia. It is often distressing for young children to awaken with the LMA still in place and although the device is an appropriate substitute for oral airway in the adult population, the same is not so in children. It is preferable to wait for the child to be “awake” and able to clear blood and secretions as efficiently as possible before removing the LMA.

ANESTHETIC CONSIDERATIONS OF POSTOPERATIVE COMPLICATIONS The most serious complication of tonsillectomy is postoperative hemorrhage, which occurs at a frequency of 0.1%– 8.1%.36 With the advent of new, more potent antiemetics, the vomiting that occurs when blood enters the stomach may be suppressed or masked. It is therefore prudent to note whether an antiemetic was given during the initial anesthetic, as there may have been more bleeding than noted by observation of hematemesis alone.31 Large volumes of blood that are not appreciated by the patient, parent, or surgeon may originate from the tonsil bed and be swallowed. Patients thus affected must be considered to have a full stomach, and anesthetic precautions addressing this problem must be taken. A rapidsequence induction accompanied by cricoid pressure and intubation with a styletted endotracheal tube is essential. Before induction, it is important that the blood pressure be checked in both the erect and supine positions (“tilt test”), looking for orthostatic changes resulting from decreases in intravascular volume, because the amount of blood swallowed is often unknown and can be considerable. Intravenous access must be established and volume replacement initiated. Acute postoperative pulmonary edema is an infrequent but potentially life-threatening complication seen when chronic

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airway obstruction is suddenly relieved. One proposed mechanism is that during inspiration in the chronically obstructed child before adenotonsillectomy, the negative intrapleural pressure that is generated causes an increase in venous return, enhancing pulmonary blood volume. During exhalation, a positive intrapleural and alveolar pressure is generated, which decreases pulmonary blood volume. The rapid relief of obstruction during the postoperative period results in a decreased airway pressure, an increase in venous return, an increase in pulmonary hydrostatic pressure, hyperemia, and finally edema.37 The prevention of this situation may be attempted during induction of anesthesia by applying moderate amounts of continuous positive pressure to the airway, thus allowing time for circulatory adaptation to take place.38 This physiologic sequence is similar to that seen in patients with severe acute airway obstruction during epiglottitis and laryngospasm.39 Nausea and vomiting may occur in up to 60% of tonsillectomy patients. It is unclear whether the cause is irritation due to blood in the stomach, interference with the gag reflex by inflammation and edema at the surgical site, or administration of opioids. The presence of blood in the stomach is a potent stimulus to vomiting, as are swelling and inflammation of the posterior pharynx and uvula. The incidence of emesis after tonsillectomy can be as great as 60%.40 There is some evidence to suggest that certain analgesic agents might increase the probability of post tonsillectomy emesis.41–43 There have been many reports of the successful use of ondansetron in controlling postoperative nausea and vomiting by antagonism of serotonin receptors. The incidence is reduced from 40% to 10% when 0.1 mg/kg is administered intravenously before incision or orally during the immediate preoperative period.44–47 An intravenous dose of 0.1 mg/kg has been shown to be a superior rescue medication administered once vomiting has begun. The optimal antiemetic may prove to be a combination of several medications, each having a unique pharmacologic effect. Metoclopramide either alone or in combination with ondansetron and dexamethasone has shown significant decrease in post tonsillectomy vomiting in children when administered in a dose of 0.5–0.15 mg/kg.48–50 There is a clinically important reduction in the incidence of nausea and vomiting following the administration of dexamethasone (0.5 mg/kg) to tonsillectomy patients. Dexamethasone significantly decreases the incidence of postoperative vomiting during the first 24 hours, shortened the time to first oral intake and the need for intravenous hydration.41,44,50,51 Posttonsillectomy dehydration secondary to poor oral intake as a result of nausea, vomiting, or pain occurs in 1.1% of cases. Vigorous intravenous hydration during surgery can offset the physiologic effects of postoperative decreases in fluid intake. Many children undergoing tonsillectomy may be safely discharged to home the same day after recovering from anesthesia. There are situations, however, in which a longer duration of postoperative monitoring is desirable. The American Academy of Otolaryngology–Head and Neck Surgery has identified specific clinical situations which increase the risk of posttonsillectomy complications52 (Table 10-4).

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TABLE 10-4. The American Academy of Otolaryngology— Head and Neck Surgery Risk Factors for Post-tonsillectomy Complications

Age under 3 years Abnormal measurement of coagulation, with or without an identifiable bleeding disorder Obstructive sleep apnea Systemic medical disorders that render the patient an increased anesthetic and surgical risk Craniofacial abnormality Acute peritonsillar abscess Geographic or social conditions that prevent easy and rapid return to the medical facility in the event of a complication

Sleep Disordered Breathing and Obstructive Sleep Apnea In children who suffer from sleep disordered breathing (SDB) repetitive arousal from sleep to restore airway patency is a common feature. Also frequently observed are episodic sleepassociated oxygen desaturation, hypercarbia, and cardiac dysfunction as a result of airway obstruction.53 These children are at significant risk for untoward events during anesthesia both from an airway perspective and as a result of associated comorbidities.54,55 Those children with SBD and obstructive sleep apnea syndrome (OSAS) who have craniofacial abnormalities such as a small maxilla and mandible, a relatively large tongue or a thick neck are at significant additional risk.56 The long-term effects of OSAS are not limited to the airway. These children have other systemic comorbidities. Increased body mass index and obesity may lead to increased cognitive vulnerability as illustrated by the increased frequency of hyperactivity and increased levels of C-reactive protein. Associated metabolic abnormalities include insulin resistance, dyslipidemia, and hypertension. Cardiovascular and hemodynamic comorbidities are more common in OSAS patients. These consist of altered regulation of blood pressure as well as alterations in sympathetic activity and reactivity. Systemic hypertension, changes in left ventricular geometry, and intermittent hypoxia leading to pulmonary artery hypertension are well described in patients with severe OSAS. The physical examination should include observation of audible respiration, mouth breathing, nasal quality to speech, chest retractions, long facies, retrognathic mandible, and inspection of tonsillar size. Auscultation should be specifically directed to detect wheezing and stridor. Polysomnography (PSG) is the gold standard for diagnosis of OSAS. Despite this, most patients do not have this examination before surgery. When planning the anesthetic technique, consideration should be given to the risks and benefits of local or regional techniques compared to general anesthesia or a combination of both.57 When sedation without a secured airway is planned, it is imperative that the level of consciousness, adequacy of ventilation, and oxygenation be continuously monitored and the risk

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of apnea be evaluated. Patients exposed to recurrent hypoxia exhibit an altered response to narcotics, which is manifested by decreases in minute ventilation, respiratory frequency, and tidal volume. It is therefore suggested that no sedative premedication be administered to OSAS patients before a general anesthetic and narcotics be administered in incremental doses beginning with one-half the recommended dose, until adequacy of ventilation and respiration is determined. Patients with OSAS who are given the same dose of narcotic as non-OSAS patients have a very high risk of serious respiratory compromise.58,59 Similarly, patients should not be extubated until fully awake and breathing at a baseline rate and depth. Decreased hypopharyngeal muscle tone may contribute to supraglottic obstruction. This may result in desaturation and breath holding on resulting in longer time to emergence from anesthesia. Children who have increased severity of OSAS, low weight, and age under 3 years exhibit a higher rate of postoperative complications. They are more likely to require supplemental oxygen, the use of an oral airway, and require assisted ventilation. Slow return of upper airway tone may lead to desaturation and laryngospasm on emergence, especially in those patients who are known to have a respiratory disturbance index (number of apneic episodes per hour) greater than 30. There is no agreement on the specific criteria that preselect elective OSAS patient for admission to the ICU postoperatively.60 Inclusive characteristics may include the following: PSG proven OSAS with a respiratory disturbance index >40, respiratory disturbance index >20 combined with either desaturation G mutation11 and patients with aminoglycosiderelated deafness due to the m.1555A>G mutation.14,15

Management In most patients, the primary deficit is cochlear and responds well to single or binaural amplification. A poor response to amplification could be due to additional central auditory involvement (such as the brainstem and connections) or coincidental middle ear disease. Patients with a severe binaural defect that does not respond well to amplification should be considered for cochlear implantation. This has been successful in many patients with isolated and syndromic deafness due to mitochondrial disease, with approximately two or three of them able to converse on the telephone following the surgery. Although complications are rare, the cochlear implantation should only be undertaken with caution. Close involvement of a mitochondrial physician is essential to identify systemic features of mitochondrial disease before, during, and after surgery, which could compromise the outcome. Cognitive impairment, hidden by severe deafness, may limit the auditory rehabilitation after successful surgery. It may not be prudent to invest in a cochlear implant in a patient with a very poor prognosis from the outset.14,15

NEUROGENETIC DISORDERS: NEUROFIBROMATOSIS Neurofibromatosis type 1 (von Recklinghausen Disease) is an autosomal dominant disorder located on chromosome 17q11.2. The clinical criteria include two or more of the following: a positive family history, six or more café au lait lesions, cutaneous neurofibromas, plexiform neurofibromas, axillary and/or inguinal freckling, optic glioma, Lisch nodules (iris hamartomas), and dysplastic bony lesions (i.e., tibial dysplasia, dysplastic vertebral bodies).16,17 The neurofibromas may involve the head and neck area, and the plexiform neurofibromas can cause compressive changes of the anatomy and require surgical debulking. Those that cannot be surgically resected and continue to grow may be amenable to specific chemotherapy treatment trials (current trials include pegylated interferon). Many patients with NF1 will develop neurofibromas along peripheral nerves that can be seen on neuroimaging, but may remain asymptomatic. If these develop in the neck or inguinal area, they may be easily palpated and confused with lymphadenopathy.18–20 Despite NF1 being autosomal dominant in nature, about 50% of the time, children will present without a positive family history having a de novo mutation. Mutational analysis is available on a commercial basis and can detect 95% of pathogenic mutations in patients who fulfill the clinical criteria.21 It is most helpful to test patients who do not fulfill the NIH diagnostic criteria, but in whom establishing the diagnosis would alter management (i.e., certain brain tumors). In some cases,

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when the NF1 gene is negative, testing for SPRED1 reveals a mutation leading to a diagnosis of Legius syndrome,22 a disorder that has similar manifestations. Even when several family members present with the same mutation, the clinical phenotype can vary in severity, thus, making prognostic counseling challenging.23 Children are followed yearly by a physician familiar with neurofibromatosis (or more closely when indicated) and an ophthalmologist and screened for comorbid symptomatology including short stature, developmental delay/learning disabilities, hypertension, and scoliosis (Table 12-5).24 With respect to pediatric otolaryngologist involvement, NF1 can lead to complicated plexiform neurofibromas of the head and neck. Management depends greatly on clinical symptoms, which are influenced by size and location of tumor. Complete resection is possible in patients with small tumors that are accessible. Not every patient with complex plexiform neurofibromas benefits from surgical resection. Benefits of surgical resection include excluding malignant transformation in a rapidly growing tumor, providing improvement in neurologic symptoms of pain or weakness, improving airway compression symptoms, and improving physical appearance of the disfiguring area.25–28 Fig. 12-1 and 12-2 demonstrate a pediatric patient’s MRI findings of NF1. Within the face, the plexiform neurofibroma involves the subcutaneous soft tissues, the parotid space, carotid space, retropharyngeal space, and masticator space on the right. Neurofibromatosis type 2 is also an autosomal dominant, located on chromosome 22q11.1–13.1, and seen in much less frequency compared with NF1. The clinical findings include central or peripheral nervous system tumors: neurofibromas,

TABLE 12-5. The National Institutes of Health (NIH)

Diagnostic Criteria for Neurofibromatosis Type 1 (NF1)

Two or more features must be present Six or more café au lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals Two or more neurofibromas of any type or 1 plexiform neurofibroma Freckling in the axillary or inguinal regions (Crowe’s sign) Optic glioma Two or more Lisch nodules (iris hamartomas) A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis A first-degree relative (parent, sibling, or offspring) with NF1 by the above criteria

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FIGURE 12-1. Coronal STIR imaging demonstrates a large rightsided plexiform neurofibroma.

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FIGURE 12-3. A patient with bilateral acoustic neuroma satisfies the criteria for NF2.

TABLE 12-6. Diagnostic Criteria for Neurofibromatosis Type 2 (NF2)

Must have either criteria 1 or 2 Bilateral masses of the eighth cranial nerve seen with appropriate imaging techniques (e.g., CT or MRI) A first-degree with NF2 and either (a) Unilateral mass of the eighth cranial nerve or (b) Two of the following characteristics •  Neurofibroma •  Meningioma •  Glioma •  Schwannoma FIGURE 12-2. Axial STIR imaging reveals same patient as in Figure 12-1 with NF1.

meningiomas, schwannomas, and bilateral acoustic neuromas.29 Patients should receive treatment for the acoustic neuromas in consultation with an experienced neurosurgeon. There are several treatment options including observation, surgical resection, stereotactic radiosurgery, and fractionated radiotherapy. For large tumors causing compression and neurological deficits, surgical resection is indicated. Smaller tumors can be managed with stereotactic radiosurgery, which preserves neurological function and prevents tumor growth. The Gamma Knife technique has been very effective in managing acoustic neuromas.30 The main concern in management is preservation of hearing and close observation including regular hearing tests

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•  Juvenile posterior subcapsular lenticular opacity

to monitor for hearing loss. In retrospective review, following a population of patients with NF2 over short term (two years) and long term (four years), acoustic neuromas increased in size (at least 5 mm) in 8% of patients during short-term follow-up and 13% of patients in long-term follow-up.31 Fig. 12-3 demonstrates a patient with NF2. In pediatric patients, the occurrence of an isolated unilateral acoustic neuroma is not a risk factor for developing NF2. However, if neurogenic tumors are found in addition to a unilateral acoustic neuroma, the risk of NF2 is high, as is the risk for developing a contralateral acoustic neuroma, and these patients should be imaged routinely and considered for NF2 genetic testing (Table 12-6).32,33

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FACIAL WEAKNESS: LOWER BRAINSTEM AND CRANIAL NERVE DYSFUNCTION Facial nerve (VII) disorders cause ipsilateral facial weakness; for the most part, it is purely motor and not sensory. Exceptions include the chorda tympani that conveys taste to the anterior two-third of the tongue and the tensor tympani that can affect hearing. The sensory supply to the face is served by the trigeminal nerve (V), which also supplies the muscles of mastication. Lesions along the facial nerve cause symptoms based on the location of the abnormality. Another distinguishing feature of examination of the facial nerve is determining whether the lesion is central or upper motor neuron (causing an isolated lower facial muscle weakness) or whether the lesion is peripheral or lower motor neuron (causing weakness of all muscles on the affected side). The most common cause of unilateral facial weakness in children (lower motor neuron) is Bell’s palsy. The Scottish anatomist and surgeon Sir Charles Bell first described Bell’s

Examination of the facial nerve should be performed as follows: (1) Observe the patient’s face at rest, looking for asymmetry of the palpebral fissures and the nasolabial fold. The weak side will have the affected eye gaping open and the fold will be flatter than the other side. (2) Ask the patient to wrinkle the forehead (tests frontalis muscle). Inability to wrinkle the forehead on one side indicates a peripheral/lower motor neuron lesion on that side. (3) Ask the patient to close the eyes tightly. Bell’s phenomenon can be seen on the weak side with the eye seen rolling up in an exposed eye. (4) Ask the patient to flare nostrils, smile, and bare teeth. A lower motor neuron lesion will show weakness in all these muscles. An upper motor neuron lesion is not as obvious and may be more noticeable with a spontaneous, emotional response (the unforced smile). The upper motor neuron lesion is on the side opposite the lower facial weakness. (5) Ask the patient to clench the neck or pull down their lower lip. This tests the platysma muscle, and weakness is evident on the same side in a lower motor neuron lesion. (6) Taste of the anterior two-third of the tongue can be done with a sugar solution, and then a salt solution on both sides with the tongue pulled out of the mouth. The tongue may be pulled back in as the patient tries to assess normal taste, but should not swallow.

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palsy in 1821, but there is still much controversy regarding its etiology and management.36 Weakness may be preceded by facial or ear pain, but the weakness is acute and usually progresses over a few hours. Many times, patients will awaken with Bell’s palsy. The palsy may be complete (involving all the facial muscle, taste, lacrimation, and hyperacusis) or incomplete. Children usually have a near full recovery within several weeks.34 Earlier testing and treatment included consideration for HSV/VZV (herpes simplex virus/varicella zoster virus) infection, including Ramsey Hunt syndrome, but has recently been found in higher association with Lyme disease.35 Evaluation should include Lyme titers and Western blot for confirmation. Earlier treatment included a short course of steroids and antiviral therapy, which is now being replaced with antibiotics. Other etiologies for Bell’s palsy include tumors, diabetes, sarcoidosis, and AIDS. The incidence of Bell’s palsy in the United States is approximately 25 cases per 100,000.36 Bell’s palsy can be recurrent in 7% of cases. Bilateral Bell’s palsy is extremely rare, occurring less than 1% of the time, and should increase the index of suspicion for a noninfectious underlying etiology.36–38 It is important to remember that the facial nerve is a peripheral nerve that can be involved in polyneuropathy caused by a systemic disease and the evaluation may be extensive; for example, in the cause of sarcoidosis, the evaluation includes a chest X-ray or CT of the chest, serum angiotensin-converting enzyme (ACE) level, and possibly CSF ACE level to document neurosarcoidosis.

Case 3 A previously healthy 16-year-old African American boy presents to the emergency room with acute onset rightsided peripheral facial palsy. He has no previous illness but recalls feeling tingling or pain over his right face the day before. He was treated with corticosteroids, Valtrex and doxycycline, and Lacrilube for eye care. Approximately 5 days later, he presented to the emergency room with left-sided facial palsy and at that time had minimal improvement in the right-sided weakness. An MRI of the brain was obtained at that time, showing enhancement of the right-side facial nerve (Fig. 12-4). His CSF revealed a lymphocytic pleocytosis and elevated protein, with negative PCR testing of HSV, VZV, Mycoplasma pneumoniae, and Bartonella henselae. His serum and CSF ACE levels were normal. CSF cytology was negative. ESR, ANA, pANCA, and cANCA were negative. His Lyme titers continued to be negative. Several days later, he began having bilateral lower extremity paresthesias and absent ankle reflexes were found on neurological examination. A chest CT was done, revealing perihilar lymphadenopathy. He was subsequently diagnosed with sarcoidosis.

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FIGURE 12-4. Magnetic resonance imaging of Bell’s palsy shows smooth enhancement involving the internal auditory canal, labyrinthine, and geniculate ganglion portions of bilateral seventh cranial nerves, right greater than the left. There is no evidence of abnormal enhancement involving any other cranial nerve.

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9. Prezant TR, Agapian JV, Bohlman MC, et al. Mitochondrial ribosomal RNA mutations associated with both antibiotic-induced and non-sydromic deafness. Nat Genet. 1993;4:289–294. 10. Chinnery PF, Elliot C, Green GR, et al. The spectrum of hearing loss due to mitochondrial DNA defects. Brain. 2000;123: 74–81. 11. Sue CM, Lipsett LJ, Crimmins DS, et al. Cochlear origin of hearing loss in MELAS syndrome. Ann Neurol. 1998;43:350– 359. 12. Chinnery PF, Griffiths TD. Mitochondrial otology. In: DiMauro S, Hirano M, Schon EA, eds. Mitochondrial Medicine. London, UK: Parthenon; 2006:chap 8, 161–178. 13. Koehler CM, Leuenberger D, Merchant S, Renold A, Junne T, Schatz G. Human deafness dystonia syndrome is a mitochondrial disease. Proc. Natl. Acad. Sci. USA. 1999;96:2141–2146. 14. Sinnathuray AR, Raut V, Awa A, Magee A, Toner JG. A review of cochlear implantation in mitochondrial sensorineural hearing loss. Otol Neurotol. 2003;24:418–426. 15. Tono T, Ushisako Y, Kiyomizu K, et al. Cochlear implantation in a patient with profound hearing loss with the A1555G mitochondrial mutation. Am J Otol. 1998;19:754–757. 16. DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000;105:608–614. 17. National Institutes of Health Consensus Development Conference Statement: Neurofibromatosis. July 13–15, 1987, Bethesda, MD. Neurofibromatosis. 1988;1:172–178. 18. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with Neurofibromatosis 1 (NF1). J Med Genet. 2007;44:81–88. 19. Friedman JM, Birch PH. Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients. Am J Med Genet. 1997;70:138–143. PMID:9128932. 20. Friedman JM, Riccardi VM. Clinical epidemiological features. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, eds. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. Baltimore, MD: Johns Hopkins University Press; 1999:29–86. 21. Messiaen LM, Callens T, Mortier G, et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15:541–555. 22. Brems H, Chmara M, Sahbatou M, et al. Germline lossof-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007;39:1120–1126. 23. Szudek J, Joe H, Friedman JM. Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1). Genet Epidemiol. 2002;23:150–164. 24. Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis type 1 revisited. Pediatrics. 2009;123:124–133. 25. Mautner VF, Hartmann M, Kluwe L, Friedrich RE, Fünsterer C. MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1. Neuroradiology. 2006;48: 160–165. 26. Serletis D, Parkin P, Bouffet E, Shroff M, Drake JM, Rutka JT. Massive plexiform neurofibromas in childhood: natural history and management issues. Neurosurg. 2007;106:363–367.

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27. Tucker T, Friedman JM, Friedrich RE, Wenzel R, Fünsterer C, Mautner VF. Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas. J Med Genet. 2009;46:81–85. 28. Wise JB, Cryer JE, Belasco JB, Jacobs I, Elden L. Management of head and neck plexiform neurofibromas in pediatric patients with neurofibromatosis type 1. Arch Otolaryngol Head Neck Surg. 2005;131:712–718. 29. Evans DG, Baser ME, O’Reilly B, et al. Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg. 2005;19:5–12. 30. Rowe JG, Radatz MW, Walton L, Soanes T, Rodgers J, Kemeny AA. Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis. J Neurol Neurosurg Psychiatry. 2003;74:1288–1293. 31. Slattery WH 3rd, Fisher LM, Iqbal Z, Oppenhiemer M. Vestibular schwannoma growth rates in neurofibromatosis type 2 natural history consortium subjects. Otol Neurotol. 2004;25:811–817. 32. Evans DG, Ramsden RT, Gokhale C, Bowers N, Huson SM, Wallace A. Should NF2 mutation screening be undertaken in

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patients with an apparently isolated vestibular schwannoma? Clin Genet. 2007;71:354–358. Evans DG, Ramsden RT, Shenton A, et al. What are the implications in individuals with unilateral vestibular schwannoma and other neurogenic tumors? J Neurosurg. 2008;108: 92–96. Peitersen E. Bell’s palsy: the spontaneous course of 2,500 peripheral facial nerve palsies of different etiologies. Acta Otolaryngol Suppl. 2002;(549):4–30. Smouha EE, Coyle PK, Shukri S. Facial nerve palsy in Lyme disease: evaluation of clinical diagnostic criteria. Am J Otol. 1997;18(2):257–261. Katusic SK, Beard CM, Wiederholt WC, Bergstralh EJ, Kurland LT. Incidence, clinical features, and prognosis in Bell’s palsy, Rochester, Minnesota, 1968–1982. Ann Neurol. 1986;20(5):622–627. Kim YH, Choi IJ, Kim HM, Ban JH, Cho CH, Ahn JH. Bilateral simultaneous facial nerve palsy: clinical analysis in seven cases. Otol Neurotol. 2008;29(3):397–400. Keane JR. Bilateral seventh nerve palsy: analysis of 43 cases and review of the literature. Neurology. 1994;44(7):1198–1202.

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C H A P T E R

Pediatric Ophthalmology Melanie Kazlas

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our of the five senses—vision, hearing, smell, and taste— are localized to the face and head. Although the pediatric otolaryngologist specializes in disorders affecting hearing, smell, and taste, familiarity with vision and the maladies that involve the eyes is also crucial to accurately diagnose and treat the ailments that afflict the child’s sensory perception. At the conclusion of this chapter, the pediatric otolaryngologist should understand how to assess vision in a neonate and a child and understand the concept of amblyopia. Clinical pearls are provided on how to perform an eye examination in a child and how to recognize diseases that affect both vision and hearing. Orbital anatomy is reviewed to assist the sinus surgeon in recognizing important landmarks during sinus surgery.

PEDIATRIC OPHTHALMOLOGIC ASSESSMENT Visual Development Vision is unique among the senses in that the ability to see is contingent upon the visual system receiving and processing high-grade visual input early in life. Any impediment to vision during the critical period of visual development can have permanent, deleterious effects on vision. Understanding this critical period of visual development, which begins at birth and is complete by about age 10, is based on the work of David H. Hubel and Torsten N. Wiesel, who shared the Nobel prize in Medicine in 1981. Using a kitten model, these scientists simulated eye misalignment, or strabismus, and blurred vision in one or both eyes. Single-cell electrode recordings from the visual cortex revealed attenuated responses from the visual cortex that received input from the misaligned or blurred eye.1 Examination of the lateral geniculate nucleus and visual cortex of these animals postmortem revealed cell death of neurons that received input from the misaligned or blurred eye. These findings were extrapolated to humans and underscore the urgency of detecting and treating any eye condition that could affect the visually immature child.

Amblyopia Amblyopia is a significant public health problem. Decreased vision, usually in one eye, from disuse during the critical period of visual development affects approximately 3% of children in the United States.2 The word amblyopia is derived from the Greek, ambly or “dull” and ops or “eye.” Strabismus

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and anisometropia are the most common causes of amblyopia. Strabismus is defined as eye misalignment such as esotropia or exotropia, also known as crossed eyes or wandering eyes. Anisometropia refers to a difference in the refractive power between the two eyes. For example, if one eye is emmetropic, requiring no corrective lens to see well, and the other eye is farsighted, then this difference establishes a competition at the cortical level that may result in amblyopia. A child with a congenital defect of the eye, such as a cataract or macular scar, will have superimposed amblyopia. This leads to worse vision than just having the anatomic defect alone. However, most children with amblyopia have structurally normal eyes. Appropriate methods of vision screening are important to detect this serious, but treatable, eye condition. Ambylopia, if detected at this age, is readily treatable. Amblyopia management includes treating any significant refractive error, that is, to prescribe glasses. If there is a structural abnormality such as a congenital cataract interfering with visual input, then it should be surgically corrected. However, prescribing glasses or improving a structural defect is insufficient to guarantee good vision. Cortical changes have become entrenched. The brain must relearn how to see well. To do this, patch the better-seeing eye part-time or full-time depending on the age of the child and the severity of the visual deficit. In noncompliant patients, atropine penalization is sometimes useful to improve the vision in the amblyopic eye. The rationale behind atropine penalization is to blur the vision in the better-seeing eye. Atropine is a long-acting anticholinergic agent administered in the form of an eyedrop, usually given daily.3

Visual Assessment A full-term infant, by age 8–12 weeks, should be able to fixate on a small toy and follow it as the examiner moves the object around. This visual milestone should be adjusted accordingly if the infant was born prematurely. Each eye should be tested separately. Do not assume that the vision is normal in the child who is tracking a target with both eyes. The visual behavior of each eye needs to be determined separately to identify possible unilateral visual loss. An adhesive eye patch is an indispensable tool (Fig. 13-1). One can simulate an adhesive eye patch by taping a child’s eye with Transpore® or paper tape. Make sure that there is no gap, especially near the medial canthal angle, for a child to inadvertently peak. An infant with good vision in each eye will not object to have either eye patched and will track a toy equally well. However, in the infant with poor vision in one eye, patching

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SECTION 1 ❖ Basic Science/General Pediatric Otolaryngology The card is divided into a gray background and an area of black and white stripes of varying frequencies, measured in cycles/degree. A child who consistently orients by moving the eyes toward, or orienting the head toward, stripes of increasing spatial frequencies correspond to better visual acuity. The most useful application of PLTs is in determining comparative acuities between the eyes, especially as a means of determining a response to amblyopia treatment in the preverbal child. The acuity measured with this test is resolution acuity, not recognition acuity. Studies have demonstrated a falsely higher measure of acuity with this technique.4 Recognition acuity is tested when a patient names an object or letter. Resolution acuity is tested when a threshold is determined by the response of the patient with an eye or head movement toward a grating pattern of increasing frequencies of black and white stripes.

FIGURE 13-1. A, Use of occluder to check vision may allow child to peek, and therefore, examiner may not detect amblyopia. B, Proper placement of adhesive eye patch to check vision.

the better-seeing eye will likely result in vigorous crying! If the child objects to either eye being patched, then the examination is inconclusive and the visit should be rescheduled. Another way to determine whether an infant is capable of looking at a target is to spin the infant at arm’s length to induce a vestibulo-ocular nystagmus. A sighted infant will have a few beats of horizontal nystagmus that will quickly be abolished by the fixation reflex. A child with poor vision will continue to have horizontal nystagmus upon cessation of spinning. Preferential Looking Technique A quantitative measure of vision can be obtained in the preverbal child with a preferential looking technique (PLT), such as with the commercially available Teller Acuity Cards®. Researchers discovered that an infant would preferentially look at black and white stripes rather than at a gray background. The infant is held by a caregiver and the examiner is positioned behind the card and views the infant through a small peephole.

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Visual Evoked Potentials Visual evoked potentials (VEP) are a specialized form of an electroencephalogram (EEG) and are useful in assessing the integrity of the visual pathways, especially. A pattern VEP will present grating or checkerboard stimuli to a child with electrodes attached to the occipital area that record electrical responses from that area. A specific visual acuity, such as a Snellen equivalent, should not be inferred with certainty from this modality. A flash VEP may be useful in predicting recovery of vision in the setting of hypoxic damage to the brain.5 The VEP may also be used with other electrophysical data such as that gathered from an electroretinogram (ERG) to determine where the defect is along the retino–geniculo–cortical pathway. An ERG is a device that records electrical activity from the retina in response to visual stimuli, usually a flash of light. The recording is obtained by electrodes placed on contact lenses that sit on the front surface of the eye. The waveforms generated give the clinician information about which groups of retinal cells or which layers of the retina may have abnormalities. Vision Screening The ideal time frame to conduct vision screening is between age 3 and 5 when the child’s visual acuity can be subjectively assessed using an age-appropriate test.6 In older children, a more precise determination of vision can be made.

EXAMINATION OF THE EYE Much can be learned from a child simply by observing the patient entering the examination room. Is the child developmentally appropriate for his or her age? For example, does a 2-year-old walk into the examination room or is the child still carried by a parent? Does a 6-month old sit up on a parent’s lap without assistance or is the baby “floppy” or hypotonic? Does a child have a head posture that could suggest torticollis? Is there facial asymmetry such as a droopy eyelid that suggests ptosis? As one establishes a therapeutic relationship with the child, the examination can proceed in greater detail.

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External Examination: Lids, Lashes, and Lacrimal System

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During embryogenesis, the epithelium of the eyelids is derived from surface ectoderm. The connective tissue of the lids, including the orbicularis oculi and levator palbebrae muscles, derives from neural crest cells. Separation of the eyelids begins in the sixth month of gestation. Variations of eyelid contour include epicanthal folds. These crescent-shaped folds of skin most often represent a normal variant. Prominent epicanthal folds can give the impression that there is esotropia or crossed eyes. Examination of the light reflex from the cornea of each eye can help distinguish true esotropia from pseudostrabismus (Fig. 13-2). Telecanthus is defined as an increased distance between medial canthi relative to age-corrected norms. Hypertelorism is defined as an increased distance between medial orbital walls as determined on X-ray. All patients with hypertelorism will have telecanthus, but not all with telecanthus will have hypertelorism. Telecanthus is seen in children

with fetal alcohol syndrome and Waardenburg syndrome. In Down syndrome, the height of the lateral canthal angle may be higher than normal relative to the medial canthal angle. Conversely, downward slanting lateral canthi are typical of Treacher-Collins syndrome or mandibulofacial dysostosis.7 There are several categories of ptosis in childhood including myogenic, neurogenic, and mechanical. Most congenital ptosis is of myogenic origin, a sporadic condition that is usually unilateral (Fig. 13-3). In myogenic ptosis, there is maldevelopment of the levator palpebrae muscle, with much of the muscle replaced with fibrous tissue and fat. Neurogenic causes of ptosis include the Marcus Gunn Jaw Wink syndrome, third nerve palsy, Horner’s syndrome, and myasthenia gravis. Mechanical causes include lid masses such as neurofibromas, hemangiomas, dermoid cyst, and chalazion. The assessment of ptosis includes determining the height of the interpalpebral fissure, margin reflex distance, which is the distance from the upper lid to the corneal light reflex, and levator function. Not all congenital ptosis constitutes a surgical indication. However, if vision

FIGURE 13-2. A, Left esotropia. Temporally displaced light reflex. B, Twin on left orthotropic by light reflex. Twin on right with left exotropia. See nasal displacement corneal light reflex left eye.

FIGURE 13-3. A, Congenital ptosis right upper eyelid. B, Bilateral congenital ptosis.

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is threatened, surgical repair is indicated. Mechanisms of visual loss in the setting of ptosis include occlusion of the visual axis and induced astigmatism, which may cause refractive amblyopia. One way to determine whether there is proptosis is to observe the eyes from behind and above the child’s head looking down at the globes to see whether one protrudes anteriorly relative to the other eye. Hertel exophthalmometry is the gold standard for determining proptosis or exophthalmos. Intact lateral rims are a prerequisite. A difference of 2 mm or more between the eyes is significant. Significant proptosis is an indication for orbital imaging to exclude an orbital mass or vascular malformation. A space-occupying lesion may cause resistance to retropulsion. Such is assessed by firmly balloting the eye in the orbit to appreciate any tightness. During the first trimester, the nasolacrimal system originates from ectoderm found between the maxillary and the lateral nasal processes. A sulcus forms, known as the nasal optic fissure. Around the sixth week of gestation, the cord of cells that lies between the nascent medical canthus and the nasal cavity detaches from surface ectoderm. Canalization of this solid core of cells occurs around 12 weeks and is typically completed by 28 weeks. An imperforate membrane, consisting of a fusion of the mucosal linings of the nasal fossa and the distal end of the nasolacrimal duct, occurs in up to 70% of newborns; most open by 4 weeks of life.8 Five percent of newborns will have clinical signs of congenital nasolacrimal duct obstruction (CNLDO). The onset of excess tearing, known as epiphora, occurs approximately 2–4 months of age and is attributed to reflex tearing (Fig. 13-4). Tear production consists of basal secretion, present at birth, and reflex tearing that develops later in response to noxious stimuli. Basal secretion of tears is produced by the accessory lacrimal glands of Krause and Wolfring located in the forniceal conjunctiva. Reflex tearing in response to emotion or noxious stimuli arises from the lacrimal gland located in the superotemporal anterior orbit. There is a deep orbital portion and superficial palpebral portion that is innervated by a branch of the facial nerve (CN 7). Afferent input is carried to the lacrimal gland along a branch of the trigeminal nerve (CN 5). Epiphora is almost always the result of an obstruction of the nasolacrimal system rather than an overproduction of tears by the lacrimal glands. Fifty percent of congenital CNLDO resolves without intervention by age 6 months of life and 95% by age 1 year.9 Conjunctivitis is one of the common complications of CNLDO. Caution must be exercised, however, not to overtreat epiphora alone with topical antibiotics. If the conjunctiva is not injected and if there is no purulent discharge on palpation of the lacrimal sac, topical antibiotics will not eradicate the condition. If there is expressible mucopurulent discharge, aerobic culture with sensitivities is indicated. In a study of 238 eyes of 187 patients with CNLDO, culture was positive for growth in 83%. In the positive cultures, 57% grew gram-positive bacteria, most commonly Streptococcus pneumonia, and 43% grew gramnegative bacteria, most commonly Hemophilus influenza.10

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FIGURE 13-4. Toddler with epiphora (fluorescein-stained tears) secondary to left-sided congenital nasolacrimal duct obstruction.

A topical third or fourth generation fluoroquinolone, such as ofloxacin 0.3% eye drops, is effective against this bacterial spectrum. Another complication that is seen related to CNLDO is irritated, macerated periocular skin. The chronic tears and secondary rubbing may lead to breakdown of the skin around the affected eye. Vigilance is needed to ensure that a secondary bacterial skin infection does not occur. To make the diagnosis of CNLDO, instill fluorescein dye into the cul-de-sac of each eye and use a cobalt blue light to monitor the egress of the dye from the tear film. A child with a patent nasolacrimal system will demonstrate absence of dye in the tear film by 5 minutes after instillation. Persistence of dye after this time is indicative of an obstruction. Most obstructions are from an imperforate membrane over the valve of Hasner, but occasionally other anomalies of the nasolacrimal system such as stenotic or atretic puncta produce epiphora. Treatment of persistent CNLDO includes probing and irrigating (P & I) with or without silicone intubation of the duct. Success rates for initial P & I are as high as 95% in children less than 1 year of age. Occasionally, the surgeon must infracture the inferior turbinate if patency is not confirmed at the time of the procedure. The Lacricath® is a device that dilates the nasolacrimal canal by applying high hydrostatic pressure from an inflatable balloon that is threaded into the nasolacrimal canal. A more rare presentation of a congenitally obstructed tear duct is a neonatal dacryocele. Dacryoceles or dacryocystoceles result from dual obstructions, one a proximal “ball valve” type of obstruction at the valve of Rosenmuller near the common canaliculus, and the other a more distal obstruction at the valve at Hasner near the inferior turbinate (Fig. 13-5). The scenario is that tears can flow into the lacrimal sac but are trapped because of the proximal and distal obstructions. A bluish swelling arises in the lacrimal sac presenting as a nodule below the medial canthal tendon in a newborn (Fig. 13-6). Before understanding the pathophysiology of this rare form of tear duct obstruction, clinicians referred to

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FIGURE 13-6. Uninfected congenital dacryocele right nasolacrimal duct. FIGURE 13-5. A, Proximal obstruction at valve of Rosenmuller. B, Distal obstruction at valve of Hasner. (Courtesy of Michael Cunningham, MD.)

this entity as an amniotecele, postulating that amniotic fluid was being trapped in the lacrimal sac and the vast majority of dacryocystoceles become infected (Fig. 13-7). An infected dacryocele in a neonate can be a serious problem because infections of the face can rapidly spread to the cavernous sinus. The immediate institution of systemic antimicrobial therapy is necessary, with consideration of hospital admission for intravenous antibiotics in consultation with a pediatric infectious disease specialist. Attempted decompression of the dacryocele digitally by pressing against the lacrimal sac is recommended. Probing and irrigating the tear duct is often necessary and a high incidence of associated intranasal cysts should be anticipated.11 An accessory lacrimal canal may present with a dimple adjacent to the lacrimal sac or anywhere along the lateral aspect of the nose below the medial canthal tendon. It may or may not be connected to the main nasolacrimal system; hence, tears from the accessory canal may or may not be present. Usually the accessory canal can be easily marsupialized. One additional observation to be made on the external examination is head posture. The differential diagnosis of torticollis or anomalous head posture is broad. Ophthalmologic etiologies include incomitant strabismus, which is defined as eye misalignment that varies in different directions of gaze (Fig. 13-8). For example, a child with a right sixth nerve palsy may adopt a head posture to the right, keeping his eyes in left gaze where motility is normal. Another entity in which a patient would adopt a head posture to compensate for incomitant strabismus is Duane’s syndrome. Duane’s syndrome represents a congenital aplasia of the sixth nerve nucleus with aberrant innervation of the lateral rectus with a branch of the third cranial nerve. The abnormal innervation of the lateral rectus results in retraction of the globe and

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FIGURE 13-7. Infected dacryocele. Erythema, induration, and purulence from rupturing abscess.

narrowing of the interpalpebral fissure on adduction. Duane’s syndrome can exist as an isolated entity or in association with Goldenhar’s oculo-acoustic vertebral syndrome. Uncorrected high refractive error, nystagmus, congenital ptosis, and congenital hemianopias are other ocular causes of torticollis. Nonocular causes include unilateral hearing loss and primary torticollis from a fibrotic sternocleidomastoid muscle.

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SECTION 1 ❖ Basic Science/General Pediatric Otolaryngology Swing the light source from one pupil to the other. Normal pupils will constrict equally as the iris sphincter muscle is activated. If the pupil dilates on performing this maneuver, a relative afferent pupillary defect is present and an evaluation for a defect in the anterior visual pathways, specifically an optic neuropathy or anterior visual pathway lesion, needs to be sought. An exception to this rule is if the optic nerves are equally damaged. For example, in bilateral optic atrophy, there will be no “relative” afferent pupillary defect, just sluggishly reacting pupils. Anisocoria is a difference in the size of the pupils (Fig. 13-9). Up to 10% of the population has physiologic anisocoria. Anisocoria is assessed by comparing the difference in pupil size in dim and ambient light. If the difference in pupil size is the same under these two conditions, the anisocoria is likely physiologic and no further work-up is necessary. If pathology is suspected, the next question to answer is which is the abnormal pupil, the smaller or the larger one. If the difference in pupil size is greater in dim illumination, then the smaller pupil is the involved pupil and Horner’s syndrome should be considered. If the anisocoria is greater in bright light, then the larger pupil is the involved pupil and a problem with the cholinergic pathway innervating the iris sphincter should be investigated. The latter differential includes a third nerve palsy or an iatrogenic etiology such as from an anticholinergic medicine like accidental instillation of atropine drops into the affected eye.12

Motility

Pupils

The assessment of ocular motility in a young child requires the parent to hold the child’s head steady. Children will typically move their head to follow an object, making assessment of motility difficult. Binocular eye movements in which each eye moves in the same direction are termed versions. Dextroversion, looking right; levoversion, looking left; supraversion, looking up;, and infraversion, looking down; should be assessed. If there is lack of full excursion into any of these

The pupils may be examined with a penlight or with a direct ophthalmoscope. With an apprehensive toddler, coming too close with the bright light of a Finoff transilluminator may result in tears and an incomplete examination. From afar, one can ascertain the red reflex and even check for a direct and consensual response of the pupils. Make a note of the shape, size, and reactivity of the pupils to light. Photons of light constitute input and travel along the afferent pathway of the pupillary reflex. Light travels along the optic nerve to synapse in the Edinger–Westphal subnucleus of the third cranial nerve. The Edinger–Westphal nucleus is stimulated to send bilateral efferent output to its end organ, the iris sphincter muscle; this is a cholinergic or parasympathetic pathway. Shining a light in one pupil will cause constriction of the ipsilateral pupil, known as the direct response, and of the contralateral pupil, known as the consensual response. To determine whether there is a relative afferent pupillary defect, also known as a Marcus Gunn pupil, perform a “swinging flashlight” test.

FIGURE 13-9. Anisocoria. Left pupil larger than right pupil.

FIGURE 13-8. A, Right head tilt secondary to left superior oblique palsy. B, Improved right head tilt after left inferior oblique myectomy.

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CHAPTER 13 ❖ Pediatric Ophthalmology directions, then monocular eye movements, also known as ductions, should also be assessed. These include supraduction, looking up; infraduction, looking down; abduction, looking laterally; and adduction, looking medially. If there is a duction deficit, there may be a causative cranial nerve palsy or a restrictive process impairing movement in a certain direction. Failure to abduct an eye fully may be the result of a sixth nerve palsy. Difficulty with adducting, depressing and/ or elevating an eye may be seen in a third nerve palsy. In a child with an acquired eye misalignment, diplopia or double vision may not be verbalized. This is because depending on the duration of the misalignment and the age of the child, there is a cortically based mechanism to suppress one image in the setting of eye misalignment. The older the child and the more recent the insult, the more likely a patient would verbalize double vision. Forced duction and force generation testing may be performed to distinguish between a paretic and restrictive strabismus. A typical example is the child with a blowout fracture of the orbit in whom Computed Tomography (CT) scanning suggests an entrapped inferior rectus muscle. The patient may exhibit limited supraduction on the affected side. Forced duction testing performed with the eye topically anesthetized with proparacaine will confirm an entrapped muscle (Fig. 13-10).

Anterior Segment The anterior segment of the eye includes the structures of the anterior one-third of the globe, specifically the cornea, anterior chamber, iris, ciliary body, and lens. During any surgery requiring general anesthesia, the eyes, and particularly the cornea, require protection. In a retrospective review of over 60,000 anesthetics, an incidence of 0.05% of eye injuries was recorded, most commonly corneal abrasion; the length of the procedure and head and neck cases were specifically identified risk factors.13 Close the lids and apply adhesive tape to ensure they remain closed throughout the

FIGURE 13-10. A toothed forceps is used to grasp topically anesthetized conjunctiva to perform forced duction test.

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surgery and are protected from inadvertent intraoperative trauma. If a corneal abrasion is suspected, the instillation of fluorescein dye into the eye and examination with a cobalt blue light are necessary; absent epithelium will stain green. A documented corneal abrasion requires the application of antibiotic ointment such as erythromycin or bacitracin ophthalmic ointment and follow up with an ophthalmologist within approximately 24 hours. Corneal abrasions usually heal quickly without scar in 24–72 hours. Until the epithelium is healed, however, the child is at risk for the development of a sight-threatening corneal ulcer. Congenital opacities of the lens, technically known as a cataract, occur in 1 in 250 live births. Most congenital lens opacities are not vision threatening, but they do interrupt the red reflex. Congenital cataracts can be seen in certain syndromes that also involve the ear, nose, or throat. Alport syndrome is an X-linked disorder characterized by sensorineural hearing loss, renal dysfunction, and anterior lenticonus, which is a bowing of the anterior capsule, the basement membrane surrounding the anterior surface of the lens. The lens may become cataractous as a result of the predisposing anterior lenticonus configuration. Neurofibromatosis type 2, one of the neurocutaneous syndromes, is characterized by a posterior subcapsular or cortical wedge type of cataract in addition to acoustic neuroma.14 The congenital rubella syndrome is characterized by the triad of sensorineural hearing loss, cataracts, and cardiomyopathy; this is thankfully exceedingly rare in the United States as a result of widespread vaccination with the measles, mumps, rubella vaccine.

Posterior Segment The posterior segment of the eye includes the vitreous, optic nerve, retina, and retinal blood vessels. Examination of the posterior segment or fundus is facilitated by use of the direct ophthalmoscope. The construction of the first direct ophthalmoscope is attributed to Helmholtz in 1851. Light emanates from the instrument and is coincident with reflected light from the posterior segment. The rich vasculature of the choroid produces the red reflex that is initially seen with the direct ophthalmoscope. The intensity of the red reflex depends, in part, on the pigmentation of the individual. Darkly pigmented individuals have more melanin in the retinal pigment epithelium that acts as a filter to the light reflected from the underlying choroidal vasculature; the red reflex from such individuals will appear darker. A set of lenses that the physician can dial eliminates the refractive error of the physician and patient and brings the structures of the posterior segment into focus. One obtains a direct magnified view of the optic nerve, blood vessels, and retina with a field of view of approximately 10 degrees in the undilated pupil. If no red reflex is seen with the direct ophthalmoscope, a wide differential diagnosis applies. A cataract or vitreous hemorrhage can impair the red reflex. More ominously, a total retinal detachment or an intraocular tumor such as retinoblastoma can produce leukocoria or white pupil.

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Optic disc swelling can be observed with the direct ophthalmoscope. The signs of optic disc swelling include blurred disc margins, nerve fiber layer edema, obscuration of the peripapillary retinal vessels, elevated optic disc, hyperemia, papillary and peripapillary splinter hemorrhages, and occasionally discrete white hard exudates on the disc and nerve fiber layer infarcts known as cotton wool spots (Fig. 13-11). Bilateral optic disc swelling in association with increased intracranial pressure (ICP) is called papilledema. Such optic nerve edema is the result of interruption of axonal transport in the anterograde and retrograde directions. The subarachnoid space is continuous with the sheath enveloping the optic nerve. Compression of the optic nerve from increased ICP is one mechanism of axonal transport disruption. The symptoms of papilledema include transient visual obscurations in which the child notes a few seconds of dimming or absent vision especially upon rising from a recumbent position. Occasionally diplopia from a nonlocalizing sixth nerve palsy will be an accompanying sign. Headache, typically worse in the morning or worse in the recumbent position, is often reported. Complaints of ear pressure or tinnitus may accompany increased ICP. Severe increased ICP

may be accompanied by nausea and vomiting. Prompt neuroimaging is needed to exclude an intracranial mass. This is particularly true in children in whom a posterior fossa tumor interrupts the flow of cerebrospinal fluid (CSF) leading to an obstructive hydrocephalus. Rarely increased ICP is associated with unilateral optic disc edema. In such circumstances, both computed tomography and magnetic resonance venography are useful to determine whether a dural sinus thrombosis is present. The superior sagittal sinus may thrombose in cases of bacterial meningitis, the lateral sinus may be involved in cases of mastoiditis, and cavernous sinus thrombosis is a potential severe orbital complication of sinusitis. The thrombosed sinus is causative of the increased ICP seen in these cases of papilledema. Head trauma can also cause a dural sinus thrombosis. Hypercoaguable states and obstructive sleep apnea have also been associated with papilledema.15 Thrombolytic therapy may then be indicated. Papilledema in the presence of a normal neuroimaging and a lumbar puncture with high opening pressure but normal CSF composition is termed pseudotumor cerebri or idiopathic intracranial hypertension.16 This condition is more common in postpubescent females and has been associated

FIGURE 13-11. Papilledema with obscured disc margins, hemorrhage, and tortuous, dilated peripapillary vessels.

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CHAPTER 13 ❖ Pediatric Ophthalmology with obesity, use of tetracycline, nalidixic acid, vitamin A, oral contraceptives, and steroids (usually withdrawal). A vision-threatening complication of chronic papilledema is irreversible visual field loss. Optic nerve sheath fenestration has been helpful in preserving vision and arresting visual field loss by relieving pressure around the optic nerve.17 Ventriculo peritoneal or ventriculo lumbar shunts have been helpful in ameliorating the debilitating headaches and visual loss associated with this condition. Usher syndrome is a heterogeneous group of autosomally recessive inherited disorders that account for 50% of deafblind patients. Usher syndrome is divided into three main phenotypes, characterized by varying degrees of sensorineural hearing loss, vestibular dysfunction, and later onset visual loss from retinitis pigmentosa.18 In one recent study, up to 10% of children with congenital severe to profound sensorineural hearing loss had Usher syndrome.19 The implications of dual sensory deficits make it imperative to identify children with Usher syndrome as soon as possible. Bilateral cochlear implants are indicated in Usher 1 (USH1) patients before 2 years of age. USH1 patients present with congenital severe to profound sensorineural hearing loss and abnormal vestibular function. Children may exhibit delayed sitting and walking. Clinical signs of pigmentary retinopathy are usually absent in the first year of life, but the ERG may reveal abnormalities. Usher 2 (USH2) patients demonstrate mild to severe sensorineural hearing loss with preserved vestibular function. Visual function can remain good through the first decade of life with a normal funduscopic appearance. However, ERG changes may be detected in asymptomatic young children. This subtype accounts for most cases of Usher syndrome. Usher 3 (USH3) patients have progressive hearing loss and progressive deterioration of vestibular function. Visual symptoms are rare in the first decade of life and the initial ERG may be normal. USH3 is rare except in Finland and in Ashkenazi Jews. The retinal degeneration reflects deterioration in the function of the photoreceptors. Photoreceptors are the light-sensing sensory cells of the outer layer of the retina. They are analogous to the cochlear hair cells of the inner ear. Both types of cells share nonmotile cilia and ribbon synapses. Molecular research has found 11 loci in 9 genes that are implicated in the pathogenesis of Usher syndrome. Different mutations in several of these genes are responsible for nonsyndromic sensorineural hearing loss (SNHL), and others give rise to autosomal recessive retinitis pigmentosa without hearing loss. Visual symptoms include difficulty with vision at night also known as nyctalopia. Peripheral vision is reduced as the disease progresses. A study of visual acuity and visual field suggested that the visual loss in USH1 patients is more severe than in USH2 patients. This will be helpful in counseling patients and families about the rate of progression of visual loss. Blindness results in most by the third to fourth decade of life. Before visible changes in the fundus, an ERG can detect abnormalities that are suggestive of retinitis pigmentosa.

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Clinically, the optic nerve develops a waxy pallor, retinal arterioles become attenuated, and there is initial pigmentary mottling of the retina, followed by pigment clumping adjacent to the blood vessels known as “bone spicules.” Microarray analysis will become readily available to sequence a patient’s DNA to look for disease-causing mutations in the gene loci known to be associated with Usher syndrome. Identification rates reached 45% for patients with USH1 (Asper Ophthalmics). This technology will be critical to identify patients who may benefit from gene therapy directed to the diseased photoreceptors.20

Craniofacial Disorders With Orbital Involvement An array of significant disease can affect the orbit. All commonly manifest a triad of “orbital signs” including proptosis, a relative afferent pupillary defect, and restricted ocular motility. Rhabdomyosarcoma (RMS) is the most common primary orbital malignancy of childhood, and the orbit is the primary site in 10% of all childhood RMS cases.21 Within the orbit, the superior temporal and superior nasal areas near the superior rectus and superior oblique muscles are the most common presenting locations. Ninety percent of RMS cases present before 16 years of age with an average age of onset of 7 years; earlier age onset portends a worse prognosis. Although previously thought to arise from primitive muscle cells, an undifferentiated mesenchymal origin is suspected. Several histopathologic subtypes are recognized, of which the most common in the orbit, is embryonal; other types include alveolar, poorly differentiated, botryoid (grapelike), or welldifferentiated pleomorphic tumors, the latter rarely found in the orbit. Common presenting signs and symptoms of orbital RMS include proptosis, ptosis, pain, and a palpable mass either in the lid or visible subconjunctivally. Ophthalmologic manifestations of parameningeal RMS include strabismus and/or corneal anesthesia secondary to cranial nerve involvement. Associated inflammatory signs can initially lead to an incorrect diagnosis of orbital cellulitis. Symptoms and signs can progress rapidly. Neuroimaging will demonstrate a well circumscribed but irregular mass that is homogenous. The Intergroup Rhabdomyosarcoma Study Group treatment protocols incorporate a combination of surgery, chemotherapy, and radiation therapy. Group I is localized disease that is completely resected; Group II is microscopic disease present after biopsy; Group III is gross residual disease after biopsy; and Group IV is distant metastasis present at the time of diagnosis. Survival is group and pathology dependent. Patients with embryonal cell-type rhabdomyosarcoma arising in the orbit have a 94% 5-year survival rate, whereas those with the alveolar cell-type rhabdomyosarcoma arising in the orbit have a 74% 5-year survival rate. External beam radiation treatment had been the mainstay of radiation treatment for this tumor, but some centers do offer proton beam treatment protocols that decrease ocular morbidity. Vigilance is needed in monitoring vision, treating amblyopia as needed, and providing

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protective eyewear with polycarbonate lenses for protection in children who are monocular. The classification of vascular lesions that arise in childhood and may affect the orbit has recently been revised.22 Vascular anomalies can be categorized into vascular tumors and vascular malformations. Hemangioma, an endothelial neoplasm, is the most common tumor of childhood with an incidence of up to 10% in Caucasian infants. There is a female preponderance and most are solitary tumors. Sixty percent are found in the craniofacial region, including the eyelid and orbit (Fig. 13-12). There is an increased incidence of hemangiomas in premature infants with a birth weight of less than 1200 g. These histologically benign vascular tumors present shortly after birth and have a rapid growth phase in the first year of life. During this proliferative phase, orbital and periorbital lesions can be disfiguring and sight threatening. The two mechanisms by which a hemangioma can threaten sight are by occlusion of the visual axis and induced astigmatism. Hemangiomas of the lid can be superficial with a bright red color with a raised excrescence or deeper involvement into the dermis is suggested with a tumor that has a bluish hue with limited changes of the overlying skin. If treatment is indicated, steroids are first-line agents to slow the proliferative phase and hasten involution. Both topical and/or intralesional steroids can be used. Great care needs to be taken with intralesional steroid injections of the eyelid or orbit as cases of subsequent blindness and eyelid necrosis have been reported. Systemic treatment with steroids may be helpful. Prednisone or prednisolone at a dose of 2–4 mg/kg/d tapered slowly over several weeks is typically utilized. Steroid treatment does have significant risks, especially in the infant population. Adrenal suppression and growth retardation have been seen with topical, intralesional, and systemic steroid use. Propanolol, given systemically, is being studied as an agent that causes involution of eyelid hemangiomas and with less serious side effects

compared with steroids.23 Tunable pulsed-dye laser is useful in treating ulcerated hemangiomas. Surgical resection of periorbital hemangiomas is often successful. Dermatomal hemangiomatous involvement of facial regions served by branches of the trigeminal nerve should raise concern of PHACES syndrome (posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities, and sternal defects in some children). The associated eye abnormalities include microphthalmia, congenital cataract, and optic nerve hypoplasia. Sinusitis in older child is the principal cause of preseptal and orbital cellulitis.24 Alternative differential diagnose include angiogenic edema secondary to allergic reaction or contact dermatitis, an inflammatory response to a bug bite, and severe viral or bacterial conjunctivitis (Fig. 13-13). The following triad distinguishes postseptal from preseptal involvement: proptosis, limited motility, and a relative afferent pupillary defect. When present, this warrants sino-orbital imaging. Contrast-enhanced CT scanning of the orbits and sinuses will help define the extent of disease. Stranding of the orbital fat may be seen with orbital cellulitis, whereas a subperiosteal abscess (SPA) will appear as a well-defined almond-shaped excrescence from one of the orbital walls. SPA and orbital abscess often require surgical intervention. Close ophthalmologic monitoring with serial CTs may be considered in SPA patients whose vision and ocular motility are not compromised. Most sino-orbital infections are polymicrobial with both aerobic and anaerobic pathogens; methicillin-sensitive and resistant Staphylococcus aureus species are also becoming increasingly common. Initial empiric antibiotic therapy must take this bacteriologic spectrum into account, and surgical drainage may be necessary for definitive culture-defined therapy. Facial trauma may result in orbital fractures. Smith and Reagan conducted primate experiments that led to a theory

FIGURE 13-12. Large hemangioma abutting left lower eyelid.

FIGURE 13-13. Conjunctivitis with periorbital edema left eyelid with mild erythema of lids OU can mimic preseptal or postseptal (orbital) cellulitis.

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CHAPTER 13 ❖ Pediatric Ophthalmology about the pathogenesis of orbital blow-out fractures. Blunt impact injuries to the orbital vault cause buckling of the weakest structures in the orbit, such as the area of the orbital floor medial to the infraorbital neurovascular bundle and also the lamina paprycea. Common symptoms of orbital blow-out fractures include pain, hypoesthesia in the area of the maxillary division of the fifth cranial nerve, and double vision if there is injury to the inferior or medial rectus muscles. The nature of the injury could be a compartment syndrome with a pattern of dysmotility suggestive of paresis or a restrictive dysmotility if there is entrapment of the muscle in the fracture. The following criteria dictate the need to repair an orbital fracture: if the orbital floor fracture occupies more than the posterior two-thirds of the orbital floor, if there is significant enophthalmos, or if there is persistent diplopia.25 A transconjunctival or subciliary approach may be used to access the orbital floor and the defect repaired with Supramid (generic) or titanium mini plates. Orbital contents that have herniated into the maxillary sinus are carefully reposited before placement of the implant. Persistent diplopia may be seen after more severe orbital fractures, such as a combined medial and orbital floor fracture and treatment with prism and even eye muscle surgery may be indicated. A devastating complication of endoscopic sinus surgery is inadvertent transection of the medial rectus muscle. Patient will awaken immediately postoperatively with a large exotropia and inability to adduct the eye. Prompt referral to a strabismus specialist is important for evaluation and timely repair. Meticulous operative technique and hemostasis, together with the careful use of the microdebrider particularly in the region of the lamina paprycea, should prevent this complication.

CONCLUSION The eyes occupy a prominent place on the face, and all otolaryngologists should be familiar with the unique sense of vision. Care of the pediatric patient who visits the pediatric otolaryngologist will be enhanced by knowledge of the interaction of the eyes with other face and head disorders.

References 1. Wiesel TN, Hubel DH. Single-cell responses in striate cortex of kittens deprived of vision in one eye. J Neurophysiol. 1963;26:1003–1017. 2. Simons K. Amblyopia characterization, treatment and prophylaxis. Surv Ophthalmol. 2005;50(2):123–166. 3. Pediatric Eye Disease Investigative Group. Two-year followup of a six-month randomized trial of atropine versus patching for treatment of moderate amblyopia in children. Arch Ophthalmol. 2005;123:149–157. 4. Kushner GJ, Lucchese, NJ, Morton GV. Grating acuity with Teller cards compared to Snellen acuity in literate patients. Arch Ophthalmol. 1995;113:485. 5. Taylor MJ, McCulloch DL. Visual evoked potentials in infants and children. J Clin Neurophysiol. 1992;9(3):357–372.

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6. Committee on Practice and Ambulatory Medicine of American Academy of Pediatrics, Section on Ophthalmology, American Academy of Pediatrics, American Association of Certified Orthoptists, American Association for Pediatric Ophthalmology and Strabismus, American Academy of Ophthalmology. Eye examination in infants, children, and young adults by pediatricians. Pediatrics. 2003;111:902–907. 7. Fries PD, Katowitz JA. Congenital craniofacial anomalies of ophthalmic importance. Surv Ophthalmol. 1990;35:87–119. 8. Guerry D, Kendig EL. Congenital impatency of the nasolacrimal duct. Arch Ophthalmol. 1948;39:193–204. 9. Petersen RA, Robb RM. The natural course of congenital obstruction of the nasolacrimal duct. J Pediatr Ophthalmol Strabismus. 1978;15:246. 10. Usha K, Smitha S, Shah N, Lalitha P, Kelkar R. Spectrum and susceptibilities of microbial isolates in cases of congenital nasolacrimal duct obstruction. JAAPOS. 2006;10(5):469–72. 11. Cunningham MJ. Endoscopic management of pediatric nasolacrimal anomalies. Otolaryngol Clin North Am. 2006;39(5):1059–1074. 12. Wilhelm H. Neuro-ophthalmology of pupillary function— practical guidelines. J Neurol. 1998;245:573–583. 13. Roth S, Thisted, RA. Eye injuries after non-ocular surgery: a study of 60,965 anesthetics from 1988–1992. Anesthesiology. 1996;85(5):1020–1027. 14. Kaiser-Kupfer MI, Freidlin V, Datiles MB, et al. The association of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2. Arch Ophthalmol. 1989;107:541–544. 15. Purvin VA, Kawasaki A, Yee RD. Papilledema and obstructive sleep apnea syndrome. Arch Ophthalmol. 2000;118(12): 1626–1630. 16. Acheson JF. Idiopathic intracranial hypertension and visual function. Br Med Bull. 2006;79–80:233–244. [Epub January 22, 2007]. 17. Corbett JJ, Nerad JA, Tse DT, Anderson RL. Results of optic nerve sheath fenestration for pseudotumor cerebri. The lateral orbitotomy approach. Arch. Ophthalmol. 1988;106(10): 1391–1397. 18. Usher CH. On the inheritance of retinitis pigmentosa, with notes of cases. R London Ophthalmol Hosp Rep. 1914;19: 130–236. 19. Mets MB, Young NM, Pass A, Lasky JB. Early diagnosis of Usher syndrome in children. Trans Am Ophthalmol Soc. 2000;98:237–242. 20. Maguire AM, Bennett J. Gene therapy for pediatric retinal diseases. In: Hartnett ME ed. Pediatric Retina. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:189–203. 21. Shields JA, Shields CL. Rhabdomyosarcoma: review for the ophthalmologist. Surv Ophthalmol. 2003;48:39–57. 22. Marler JJ, Mulliken JB. Current management of hemangiomas and vascular malformations. Clin Plastic Surg. 2005;32: 99–116. 23. Nguyen J, Fay A. Pharmacologic therapy for periocular infantile hemangiomas: a review of the literature. Semin Ophthalmol. 2009;24(3):178–184. 24. Weiss A, Friendly D, Eglin K, Chang M, Gold B. Bacterial periorbital and orbital cellulitis in childhood. Ophthalmology. 1983;90:195–203. 25. Hatton MP, Watkins LM, Rubin PA. Orbital fractures in children. Ophthal Plast Reconstr Surg. 2001;17(3):174–179.

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14

C H A P T E R

Pediatric Hematology: The Coagulation System and Associated Disorders James D. Cooper and A. Kim Ritchey

B

lood dyscrasias in children have the potential to impact the operative courses of children undergoing otolaryn­ gology procedures. This discussion is limited primarily to hemostasis and thrombosis, as these issues are most relevant to perioperative management. Textbooks of adult and pediatric hematology, oncology, bone marrow transplant, and transfusion medicine are available for a complete review of the subject.1–6

THE COAGULATION SYSTEM Vascular and Endothelial Activity When an endothelial cell is damaged, tissue factor is expre­ ssed, marking the initial step in the eventual formation of thrombin.7 Below the endothelial layer, smooth muscle and the extracellular matrix provide the vessel the abilities to constrict and dilate in response to injury.3,7 Basement membrane proteins function as binding sites for platelets and white cells.7

The Platelet Plug Platelets mature from megakaryocytes and have a life span of approximately 7–10 days. Under the conditions of shear stress, circulating platelets come into contact with exposed vascular endothelial molecules. Platelets become adherent to the site of injury through an interaction between their GP Ib­V­IX membrane receptor and exposed von Willebrand factor (VWF) on the vessel basement membrane.7 Subsequently, prothrombotic agonists increase platelet activity by triggering intracellular signaling pathways that release pooled granules.7 Concurrently, fibrinogen binding to the GP­IIb/IIIa surface marker acts as a stimulus for aggregating other platelets. Once platelets have gathered at the site of injury, phospholipids on the platelet surface interact with calcium to enable the hemostatic activity of activated factors V and X (Va and Xa).

The Clotting Cascade The coagulation cascade consists of a series of enzymes and cofactors, interacting on phospholipid surfaces to produce a fibrin clot (Fig. 14­1). The extrinsic pathway is activated when exposed tissue factor is contacted by circulating factor VIIa. With the assistance of calcium ions, factor VIIa is able to convert factors IX and X into their activated forms. Factor IXa joins with circulating factor VIIIa, calcium, and phospholipids to accelerate the conversion of factor X into its activated form. Factor Xa then forms a similar complex with factor Va, which has the ability to convert prothrombin into thrombin in a rapid fashion. Once factors IX and X are activated, they also accelerate coagulation by converting

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FIGURE 14-1. Overview of the coagulation system. Red and white boxes represent factors in the clotting cascade. The extrinsic pathway is composed of tissue factor and factor VIIa, whereas the intrinsic pathway features high-molecular-weight kininogen (HMWK) and factors XII, Xia, IXa, and VIIIa. Both pathways contribute to the conversion of factor X into its activated form, leading to thrombin generation. Thrombin not only cleaves fibrinogen into fibrin, but it also upregulates the cascade in several areas to contribute to clot propagation (represented by grey arrows).

more factor VII into VIIa by a positive feedback mecha­ nism.7 Simultaneously, thrombin triggers more activation of factors V, VIII, and XI. The primary roles of thrombin are to cleave fibrinogen into fibrin and to stimulate factor XIII into forming cross­links for clot stability.7 The extrinsic pathway may be more important to the initiation of coagulation, but the intrinsic pathway contributes more to clot propagation.7

Anticoagulant and Fibrinolytic Pathways Anticoagulant molecules help control thrombus formation. Through irreversible binding, antithrombin is able to inactivate thrombin and factors VIIa, IXa, Xa, XIa, and XIIa. This reaction is normally quite slow; however, in the presence of exogenous heparin or vascular heparan sulfate, antithrombin under­ goes a structural change and is able to act extremely rapidly.7 Other inhibitors of thrombin, including heparin cofactor II, α2­macroglobulin, and protein Z, are supplementary enzymes. Alternatively, the protein C pathway is initiated by the binding of thrombin and thrombomodulin.7 Activated protein C (APC), with assistance from protein S, proteolytically inactivates

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factors Va and VIIIa. Despites its high activity level, APC is controlled by its very short half­life, approximately 15 minutes.7 The fibrinolytic pathway produces plasmin and eventually degrades fibrin. Mediated by tissue­type plasminogen acti­ vator (t­PA), plasminogen activator inhibitor (PAI­1), α2­ macroglobulin, and α2­antiplasmin, the fibrinolytic system also plays important roles in tissue repair, macrophage function, angiogenesis, and tumor invasion.8 When fibrin is formed, plasminogen is incorporated into the thrombus mass. Fibrin­bound t­PA then converts plasminogen into plasmin.8 The half­life of t­PA is approximately only five minutes because of its regulation by PAI­1. Overall activity of the fibrinolytic system depends on the relative concentrations of plasminogen and the antiplasmins.

COAGULATION TESTING The questions of how, when, and whether to test for bleeding disorders are controversial. In many cases, a dental or otolaryngology procedure may be the first challenge of a child’s ability to form clots appropriately. A child’s personal bleeding history, as well as the bleeding history of the child’s family, is notoriously unreliable as predictors of bleeding disorders. Published rates of posttonsillectomy/adenoidec­ tomy bleeding vary from approximately 1% to 25%, although a 2001 meta­analysis narrowed the range to 2%–7%9–12 (Table 14­1). Whereas acute bleeding is often thought to be due to surgical technique and/or the opening of small blood vessels after surgery,12,13 delayed bleeding commonly relates to dislodgement of the primary eschar. Notably the prevalence

of postoperative hemorrhage is higher than the prevalence of bleeding disorders. The American Academy of Otolaryngology—Head and Neck Surgery recommends that a preoperative coagulation work­up be performed only “if an abnormality is suspected by history or if genetic information is not available.”14 Likewise, the 2008 British Committee for Standards in Haematology recommended against universal screening but did suggest that a structured bleeding history be obtained before surgeries or invasive procedures.15 A recent cost­ utility study found that the strategy of not testing children before surgery incurred a lower cost and yielded more quality­adjusted life years than testing all children or testing only those with a positive bleeding history.16 Given the risk of hemorrhage, however, many practitioners are hesitant to limit their screening practices. With such practical realities, it is imperative that pediatric otolaryngologists and hematologists collaborate to establish local standards; a potential example is shown in Fig 14­2. Normal values for laboratory studies of coagulation change during each phase of life, and pediatric laboratory values may fall outside of normal adult ranges. The coag­ ulation system is not fully mature in the first 6 months of life.17 Many of the coagulation factors have reduced levels in infants and gradually increase over the first year of life. However, factors V and VIII and VWF levels are comparable to adult levels from birth.18 Most anticoagulants are also reduced, specifically antithrombin­III and proteins C and S. Components of the fibrinolytic system start production in utero, at approximately 10 weeks gestation, but have

TABLE 14-1. Postadenotonsillectomy Hemorrhage and Bleeding Disorder Rates Positive Screening Test(s)

True Bleeding Disorder

Overall Episodes of Bleeding

#

#

%

Study

Year

Total Patients

#

Shaw

2008

842

23

2001

416

237

Gabriel

2000

1463

57

3.90

Eisert81

2006

148

27

Smith82

1990

250

44

Kang11

1994

1069

27

Close

1994

96

84

Tami

1987

Burk

85

%

%

2.73

6

0.71

—

—

56.97

0

0

105

25.2

13

0.89

151

10.3

18.24

7

4.73

9

6.1

17.6

2

0.8

8

3.2

2.53

8

0.75

64

6.0

20

20.83

3

3.13

6

6.3

775

74

9.55

—

21

2.7

1992

1603

31

1.93

2

37

2.3

1997

4370

—

—

—

—

38

0.87

Howells13

1997

339

39

11.50

0

0

10

2.9

Handler

1986

1445

—

—

—

—

38

2.6

Bolger

87

1990

52

14

26.92

6

11.5

4

7.7

Thomas

1970

206

0

0

0

0

23

11.2

Manning89

1987

994

58

5.84

—

—

36

3.6

21

Asaf

10 80

83

Zwack9

86

88

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— 0.12

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CHAPTER 14 ❖ Pediatric Hematology: The Coagulation System and Associated Disorders History/Physical Exam CBC with Platelet Count PT/PTT Closure Time Results all normal

Platelet Count, PT, PTT, or CT abnormal REPEAT

Results normal

Proceed with surgery

Results abnormal Cancel surgery and refer to hematology for evaluation

FIGURE 14-2. An example of a preoperative coagulation screening algorithm.This algorithm is one possible schema for preoperative screening. Individual institutions may have their own protocols. It can also be used as the initial approach for postoperative hemorrhages. When postoperative bleeding is present, an examination for physical or surgical causes should also be performed. Hematology should be consulted for follow-up testing of abnormal results or when the evaluation is negative and the etiology of bleeding remains unclear. CBC, complete blood count; PT, prothrombin time; PTT. activated partial thromboplastin time; CT, closure time; H/H, hemoglobin/ hematocrit.

variable levels at birth.8 Unlike plasminogen and t­PA, α2­macroglobulin and PAI­1 are increased at birth and then fall over time.17 As a result, care should be taken when evalu­ ating coagulation studies in pediatric patients. The correct diagnosis of postoperative bleeding can be very demanding. Although stabilization and resuscita­ tion are paramount when required, it is important to appre­ ciate that there may be a narrow window for diagnosis. If a specific disorder is suggested by a child’s presentation, then testing should be targeted toward the most likely diagnosis. Otherwise, screening laboratory tests (CBC with platelet count, prothrombin time [PT], partial thromboplastin time [PTT], and closure time) can be ordered while the acute event is managed (Fig. 14­2). An evaluation of surgical or physical causes should also be performed. Consultation with a pedi­ atric hematologist should be obtained to discuss special­ ized testing following an abnormal screening result or if the etiology remains unclear after a normal evaluation. If the administration of blood products or other hemostatic treat­ ments is not emergently indicated, the performance of perti­ nent diagnostic tests should be considered first. Transfusions may delay an accurate laboratory diagnosis for days to weeks.

Platelet Count and Size The number and size of circulating platelets can be deter­ mined by automated or manual methods. Thrombocytopenia is defined as a platelet count less than 150,000 cells/μL. Pseudothrombocytopenia occurs when a normal in vivo platelet count is reported erroneously low in vitro. This can occur when platelets agglutinate and are bypassed by the automated counter

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or when very large platelets are misinterpreted as leukocytes. A manual inspection of the peripheral smear appropriately prepared with a Wright–Giemsa stain will be able to clarify these situations. Platelet size is reported as mean platelet volume in femtoliters (fL). The presence of large platelets (>7 fL) may be helpful in distinguishing between various platelet disorders.

Prothrombin Time (PT), International Normalized Ratio (INR), and Activated Partial Thromboplastin Time (aPTT) The PT first was demonstrated in 1935.19 Thromboplastin and calcium are added to citrated plasma, and the time until coagulation occurs is recorded in seconds. The PT is a surrogate measure of the coagulation factors involved in the extrinsic and common pathways: VII, X, V, II, and fibrinogen. Generally, factor levels must be diminished to less than 30% before the PT will be prolonged.20 Fibrinogen levels, on the contrary, usually affect only the PT when at a concentra­ tion of less than 100 mg/dL.19 Commonly, the PT is used to monitor the effects of warfarin therapy or to evaluate for liver disease and vitamin K deficiency. The international normal­ ized ratio (INR) was developed to provide standardization of the PT when used for warfarin monitoring at different labo­ ratories. Each thromboplastin reagent and instrument has an assigned international sensitivity index (ISI). The INR is then calculated: (patient PT/control PT)ISI. The activated PTT (aPTT) reflects factors in the intrinsic and common pathways: XII, XI, X, IX, VIII, V, II, and fibrin­ ogen. Additionally, the aPTT is affected by prekallikrein and high­molecular­weight kininogen. The partial thromboplastin reagent is added to citrated plasma, a surface reacting agent, and calcium; the time to coagulation is then measured.20 The aPTT can be prolonged by deficiencies of factors if levels are less than 30%–35%. Patients who are deficient in factor XII, prekallikrein, or high­molecular­weight kininogen may have very prolonged aPTT values though without any evidence of bleeding.20 The aPTT is less reflective of variations in vitamin K–dependent factors than is the PT; however, it is much more sensitive to the effects of heparin and circulating inhibitors. The most common cause of a prolonged aPTT in chil­ dren before T&A is a nonspecific inhibitor.21 The term “inhibitor” can be defined broadly to include anticoagulants, autoantibodies, and lupus anticoagulants (LAs). To discern if a prolonged aPTT is due to factor deficiencies or the presence of an inhibitor, a mixing study (adding normal control plasma to a patient sample and then repeating the test) can be performed. An abnormal test that corrects is due to deficiencies, whereas those that remain abnormal suggest the presence of an inhibitor. A nonspecific inhibitor, meaning an abnormal mixing study without other hemato­ logic explanation, is a very benign and common finding in pediatrics.21 In this setting, an inhibitor prolongs in vitro clot­ ting times but does not represent a risk factor for bleeding. In children with hemophilia, on the contrary, inhibitors carry different and much more significant implications, as will be discussed later.

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The Bleeding Time and the Closure Time The bleeding time is a surrogate measure of both platelet number and function. To perform, a tourniquet is applied to a patient’s arm and a 1–2­mm linear incision is made on the forearm.20 Bleeding from this small cut is blotted with filter paper until it stops. The time required to do so is recorded. Currently, this test is not recommended for pediatric patients. It is very difficult to standardize across laboratories, and, in some patients, it can lead to permanent scars. Many hema­ tologists now prefer the closure time. The Platelet Function Analyzer 100 (PFA­100) is a device with two cartridges: one with a collagen/ADP membrane and another with a collagen/epinephrine membrane. A sample of patient blood is put into a citrated reservoir. The blood is aspirated through a small capillary tube onto a cartridge membrane and then through a small aperture. Platelets adhere and aggregate at the aperture and the blood flow ceases. The duration of this process is recorded as the closure time. The test is sensitive to platelet function and VWF levels and function.20 The collagen/epinephrine cartridge time can be prolonged by aspirin and certain nonsteroidal anti­inflammatory drugs. With the collagen/ADP cartridge, prolongations can be caused by von Willebrand disease (VWD) or by Glanzmann’s thrombasthenia. It is important to note that thrombocytopenia and severe anemia will prolong the closure time with both cartridges, making accurate meas­ urements impossible. Although the closure time is more convenient than the bleeding time, its utility as a screening test for coagulation disorders or postoperative bleeding has been poor.22,23

Activated Clotting Time and Thromboelastography The activated clotting time (ACT) has been used to monitor heparin in cardiac surgery, extracorporeal membrane support, and dialysis circuits. To perform the ACT, 2 mL of whole blood is put into a test tube with a surface activator, a plastic baffle, and a small magnet.24 The tube is rotated and a timer is started. As the blood clots, the magnetic field is inter­ rupted and the timer stops.24 Use of the ACT has led to more successful anticoagulation in critical care situations. Despite its simplicity, however, the ACT is subject to great inter­ and intrapatient variability. The relationship between ACT value and heparin dose is unpredictable, both due to the potential for heparin resistance and due to patients’ variable levels of antithrombin­III.24 Similarly, thromboelastography (TEG) is also a whole­blood test that can be performed at the bedside. Although it has shown some utility in limiting transfusions in liver transplantation and cardiac surgery, TEG largely remains a research tool.

Platelet Function Tests The most common test of platelet function is aggregometry. A sample of patient whole blood or platelet­rich plasma is

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combined with one of a number of platelet agonist molecules: ristocetin, epinephrine, collagen, ADP, and arachidonic acid.20,25,26 The degree and rate of platelet agglutination are recorded graphically. Different platelet disorders will have unique response patterns to each agonist. Many drugs can affect platelet function temporarily and will make tests of platelet function abnormal. These tests should not be run within 10 days of using such a drug, as the diagnosis of a true disorder could be missed.

Clotting and Von Willebrand Factor Assays Factors of the intrinsic and extrinsic pathways can be measured directly. In one­stage techniques, a mixture of diluted patient plasma and a reference sample of plasma (pooled from at least 25 donors) containing all factors except the one of interest have their clotting times measured.20 A standard curve is constructed from serial dilutions of the patient sample, from which the concentration of the factor under investigation is calculated.20 Other quantitative methods of determining factor levels include immunologic techniques such as ELISA. Factor XIII levels can be determined only with one of these techniques, as the PT and PTT measure coagulation to a point before which factor XIII plays a role. Fibrinogen levels can be measured through similar techniques. The diagnosis of all types of VWD begins with three studies. First, the ristocetin cofactor activity measures the function of available VWF in plasma. Ristocetin was initially developed as an antibiotic but was discontinued due to its tendency to cause thrombocytopenia by causing VWF to bind to platelets.27 There are several methods for this test, and interlaboratory variation is common. Second, the von Willebrand antigen level (VWF:Ag) measures the amount of VWF in the plasma. It is also advisable to ascertain the patient’s ABO blood type simultaneously. Patients with type O blood have VWF:Ag levels that can be 25% lower than the population average.27 Third, the factor VIII level is measured. Specific testing can be done subsequently to confirm the type of VWD (Table 14­2).

DISORDERS THAT PREDISPOSE TO BLEEDING Bleeding in Children “Bleeding disorders” produce an inadequate hemostatic response to tissue injury. The amount of bleeding depends on the site and degree of tissue injury as well as the severity of the defect in the hemostatic system. Epistaxis serves as a worthwhile example. It has been reported that the lifetime incidence of epistaxis approaches 60%, far above the most conservative estimates of the prevalence of bleeding disor­ ders.28 The nose receives blood from multiple areas and has a rich vascular network. Local physical injury and dryness are the most common causes of bleeding from the anterior nares.28 Likewise, infectious or allergic disease can trigger episodes of epistaxis. Whatever the inciting event, a child

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TABLE 14-2. Laboratory Differences in von Willebrand Disease Types Type 1

Type 2A

Type 2B

Type 2M

Type 2N

Type 3

vWF Ag

↓ or ↓↓

↓

↓

↓ or nL

↓ or nL

Absent

RCoF

↓ or ↓↓

↓↓ or ↓↓↓

↓↓

↓↓

↓ or nL

Absent

FVIII

nL or ↓

nL or ↓

nL or ↓

↓ or nL

↓↓

↓↓↓

RIPA

nL

↓

nL

↓

nL

Absent

vWF multimers

nL

nL

nL

Absent

Closure time

nL or ↑

↑

↑

↑

nL

↑↑↑

Bleeding time

nL or ↑

↑

↑

↑

nL

↑↑↑

Platelet count

nL

nL

↓ or nL

nL

nL

nL

Abnormal

Abnormal

Abbreviation: vWF Ag, von Willebrand antigen level; RCoF, ristocetin cofactor activity; FVIII, factor VIII level; RIPA, ristocetin-induced platelet aggregation; nL, levels are in the normal range; ↑, levels are increased (by relative amount); ↓, levels are decreased (by relative amount). Source: Adapted from Montgomery.90

with an intact hemostatic system should be able to control an episode of epistaxis with direct pressure, cauteriza­ tion, or packing. When such conservative measures fail or similar such episodes continue in a recurrent fashion, clini­ cians should be suspicious that a bleeding disorder may exist. Initial laboratory evaluation of a child with recurrent epistaxis should follow the same algorithm as that used for preoperative coagulation screening (Fig. 14­2).

Idiopathic Thrombocytopenic Purpura Idiopathic thrombocytopenic purpura (ITP) is an autoim­ mune phenomenon characterized by a low circulating platelet count. Most commonly seen in young children, there is a peak incidence between ages 2 and 4 years. Although the precipi­ tating cause may be unknown, ITP is often preceded by a mild viral illness. It can also be a secondary disease process, especially in systemic lupus erythematosis, common variable immunodeficiency, HIV, and hepatitis C.29 The pathophysi­ ology is complex, but both humoral and cellular immune processes are involved with the generation and then propaga­ tion of antiplatelet autoantibodies.29 Once platelets become coated with IgG, they are then cleared aggressively by tissue macrophages, especially in the spleen. In general, children with ITP are well appearing. Symptoms may be limited to petechiae, epistaxis, and ecchy­ moses. Alternatively, children may present with significant mucosal bleeding (approximately 3% of cases).29 In over half of the cases of childhood ITP, the presenting platelet count will be less than 20,000 cells/μL.29 Review of the blood smear generally reveals larger than normal platelets but in signifi­ cantly diminished numbers. Other cellular abnormalities should alert the clinician to diagnoses other than ITP. Any signs or symptoms that suggest an alternative diagnosis (such as prolonged fever or splenomegaly) should be investigated thoroughly. In the setting of typical ITP, a bone marrow aspi­ ration is not universally indicated, and there is no evidence to suggest that other diagnostic studies are required.29

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In most children, the disease is self­limited, and outcomes are excellent. Observation alone is a well­accepted treatment option. However, there is a small risk of intracranial hemorrhage, esti­ mated at 0.1%–0.9% of cases.29,30 Corticosteroids are typically used as ITP treatment. One common regimen is oral prednisone 2 mg/kg/dose twice daily for 4 days29; other regimens include intravenous methylprednisolone 30 mg/kg (maximum 1 g) daily for 3 days or oral dexamethasone 25 mg/m2 (maximum 40 mg) daily for 4 days. Alternatively, intravenous immunoglobulin (IVIG) can be utilized at 800–1000 mg/kg/dose (once or twice), or anti­D immunoglobulin (WinRho) can be administered as 50–75 mcg/kg/dose once (only in Rh­positive patients); these latter two medications not only require intravenous access but may have adverse events or toxicities related to their infusions. All the therapies described are likely to raise the platelet count above 20,000 in a short period of time. However, a randomized controlled trial that compares the three treatments has not been performed. Platelet transfusions are of minimal benefit, unless a severe and life­threatening hemorrhage occurs and will require two to three times the normal volume. Regardless of the modality of management, a pediatric hematologist should be directing the care of all patients with ITP.

Neonatal Thrombocytopenia Thrombocytopenia is the most common hematologic abnor­ mality of neonates. Most commonly, thrombocytopenia in this age group will be secondary to other illnesses, such as sepsis, congenital infections, or necrotizing enterocolitis. In these settings, the low platelet count is often a manifesta­ tion of disseminated intravascular coagulation. However, thrombocytopenia can be a primary process. Neonatal alloimmune thrombocytopenia (NAIT) is caused by the transpla­ cental passage of maternal antibodies directed against the paternal antigens on an infant’s platelets. Incompatibility occurs as commonly as 1 in every 350 pregnancies (50% will be first pregnancies), although thrombocytopenia develops in far fewer (1/1000–1500). The thrombocytopenia can be

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severe and difficult to treat. IVIG may be helpful, but the best treatment is the transfusion of maternally donated plate­ lets. Autoimmune thrombocytopenia, on the contrary, results from the passage of maternal autoantibodies. These are far less specific and less likely to cause severe thrombocyto­ penia. IVIG or corticosteroids have been used as effective treatment.

Aplastic Anemia and Bone Marrow Failure Aplastic anemia is marked by peripheral blood pancytopenia associated with bone marrow hypocellularity or acellularity. In the Western hemisphere, aplastic anemia occurs with an incidence of approximately two per million persons.31 Acquired aplastic anemia is an immune­mediated disease, although genetic risk factors and environmental exposures likely contribute. Recent work has shown a much deeper understanding of the role that activated T lymphocytes play in presenting hematopoietic cell antigens for destruction.32 In children, the acuity of presentation in aplastic anemia relates to the degree of pancytopenia. Severe aplastic anemia is clas­ sified as a bone marrow sample that demonstrates less than 25% cellularity, in association with peripheral cytopenias in two of the three lineages.31 The treatment for severe aplastic anemia is either hematopoietic stem cell transplantation (HSCT) or primary immunosuppression. Although it is most common for inherited bone marrow failure syndromes to be first diagnosed in children, vari­ able phenotypes are possible, and diagnosis in adulthood does occur.33 Pancytopenia is a common presentation for both Fanconi anemia (a chromosomal breakage syndrome) and dyskeratosis congenita (a telomere length disorder).33,34 Thrombocytopenia alone is a common first sign of amegakaryocytic thrombocytopenia and thrombocytopeniaabsent radii syndrome. Supportive care with transfusions is an important mainstay for all these diseases. Although the hematologic complications of some, especially thrombocytopenia­absent radii syndrome, may resolve over the first year of life, a matched­sibling HSCT is the treatment of choice for symptomatic children with other bone marrow failure syndromes.33

Leukemia Acute lymphoblastic leukemia is the most common cancer of childhood, although acute and chronic myelogenous leukemia are also seen. Symptomatic thrombocytopenia may be the reason a child with leukemia is brought to medical attention. A diminished peripheral count of one or more cell lineages is a common sign at the diagnosis of leukemia. With the initiation of chemotherapy, however, a patient’s tumor burden regresses and normal hematopoiesis have an opportunity to resume. Platelet transfusions may be required during episodes of bleeding but are not routinely given as prophylaxis unless the peripheral count is less than 10,000 cells/μL.

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Drug-Induced Thrombocytopenia Chemotherapy is a frequent etiology of drug­induced throm­ bocytopenia. Alkylating agents (such as cyclophosphamide, ifosfamide, cisplatin, and busulfan), methotrexate, thiopu­ rines, cytarabine, and the antitumor antibiotics (doxoru­ bicin, daunorubicin, and dactinomycin) are well known to cause myelosuppression with thrombocytopenia. Among the vinca alkaloid class of chemotherapy, vinblastine is known to cause myelosuppression, whereas vincristine is not. Other plant­based agents also lead to similar cytopenias, especially etoposide, topotecan, and irinotecan. However, the effects of these chemotherapeutic drugs are generally short lived and time dependent. Nitrosurea­based agents such as lomustine (CCNU) and carmustine (BCNU) can cause delayed and severe myelosuppression with nadirs up to four to five weeks after administration. Heparin­induced thrombocytopenia (HIT) occurs in up to 5% of adult patients who are exposed to heparin, although the incidence in children is significantly less.35 An initial episode of thrombocytopenia usually occurs approximately 5–10 days after exposure to heparin, although repeat episodes can occur within hours. HIT is caused by heparin­dependent antibodies against the platelet factor 4 (PF4) antigen.36 These IgG antibodies activate platelets that then stimulate coagu­ lation reactions and can lead to a transiently increased risk of thrombosis. Tests for PF4 antibodies are commercially available, although their positive predictive value is low.37 Serotonin release assays are superior diagnostic tests but difficult to obtain. Treatment of HIT involves the discontin­ uation of all heparin (including line flushes), the initiation of alternative anticoagulation, and the avoidance of platelet transfusions. Other drugs may also lead to thrombocytopenia by forming haptens or antibodies that lead to immune­mediated platelet destruction. In these situations, the decreased platelet counts usually resolve when the offending drug is discon­ tinued. Common agents include antiepileptics, quinine, and, less commonly, penicillin.

Inherited Thrombocytopenias Most of the inherited thrombocytopenias result in moderately depressed platelet counts (50,000–100,000 cells/μL) and do not require daily management.38 However, traumatic injuries, illnesses, or surgical procedures can place these children at risk for bleeding. May–Hegglin anomaly is characterized by macrothrombocytopenia and white blood cell inclusions known as Döhle bodies. Other macrothrombocytopenias are due to autosomally dominant inherited mutations in the MYH9 gene, which codes for cytoskeleton proteins.39 Wiskott– Aldrich syndrome, on the contrary, is characterized by micro­ thrombocytopenia. This disorder is caused by the X­linked inheritance of mutations in the WASP gene and is associated with decreased platelet survival, eczema, and recurrent infec­ tions.38 Treatment of bleeding in inherited thrombocytopenias

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CHAPTER 14 ❖ Pediatric Hematology: The Coagulation System and Associated Disorders consists of DDAVP (desmopressin acetate), aminocaproic acid, and platelet transfusions when necessary.

Platelet Function Disorders There are several well­known inherited conditions that result in poorly functioning platelets. Glanzmann’s thrombasthenia was first described in 1918 in a group of patients with normal platelet counts but abnormal clot retraction.39 Subsequently, this abnormality was explained by the inability of platelets to bind fibrinogen and properly aggregate due to abnormali­ ties of the αIIbß3 platelet membrane receptor.39 It is character­ ized by mucocutaneous bleeding that may begin very early in childhood. Pronounced epistaxis and menorrhagia are particularly common. Aggregation studies in these patients will show no response to epinephrine, ADP, or collagen but a normal response to ristocetin.39 Treatment of bleeding usually is accomplished with platelet transfusions; however, repeated transfusions create the risk of antiplatelet antibodies. Bernard–Soulier syndrome is characterized by recurrent mucocutaneous bleeding resulting from a defective platelet glycoprotein Ib/IX complex. This membrane molecule is responsible for the binding of VWF to damaged endothe­ lium. Patients can also have a variable amount of thrombocy­ topenia, sometimes made difficult to ascertain by automated count, as platelets tend to be very large (anywhere from 3 to 20 times larger than normal).39 A diagnosis can be confirmed by review of the peripheral smear and by platelet function studies that show abnormal response to ristocetin but normal results with ADP, collagen, and epinephrine.26,38 Treatment can be provided with DDAVP or platelet transfusions. Storage pool defects are a related group of platelet func­ tion disorders caused by various deficiencies in intracel­ lular granules. Dense granules contain ADP, ATP, serotonin, and calcium; α­granules contain VWF, thrombospondin, PF4, and other proteins.39 Patients with these disorders will demonstrate a mild bleeding tendency and impaired platelet aggregation in laboratory studies. Storage pool disorders may be associated with Hermansky–Pudlak or Chédiak–Higashi syndromes.39 Electron microscopy (EM) is the definitive method of diagnosis but is essentially unavailable. Without EM, characterization of storage pool defects can be difficult. Evaluation of the storage and/or release of ADP and ATP nucleotides can be helpful in some cases.26 Drugs and certain disease states can cause temporary impairment of platelet function. Aspirin interferes with the production of thromboxane A2 by irreversibly acetylating the active site of cyclooxygenase.40 Other nonsteroidal anti­inflammatory drugs reversibly inhibit this enzyme. An increased bleeding tendency usually is seen only in patients with an underlying coagulation abnormality, but some patients may be “hyper­responsive” to the platelet inhibiting effects.40 Antibiotics, antiepileptics, and psychotropic drugs may also lead to transient inhibitions of platelet function. In addition to medications, systemic illnesses can create an environment

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161

in which platelets lose some of their procoagulant abilities. Uremia leads to poor platelet function through various mech­ anisms. It has been shown that the degree of renal failure is correlated with prolongation of the bleeding time, though not with clinical bleeding.40

Hemophilia Hemophilia A is an X­linked bleeding disorder in which patients have a deficiency of factor VIII. Hemophilia B is a similar illness, though with a deficiency of factor IX. Hemophilia A occurs in roughly 1/5000 live male births, whereas hemophilia B affects 1 in 30,000.41,42 Despite the well­known pattern of inherited mutations in the factor VIII gene, approximately 20%–30% of patients with severe hemophilia A will not have any affected relatives.3,41,43,44 Severe hemophilia is usually diagnosed early in the first year of life, especially when a family history is known. Children with mild or moderate degrees of disease may not have bleeding episodes until early childhood. The diagnosis can be suggested by a prolonged aPTT and then confirmed by specific assays for either factor VIII or IX. The hemophilias are classified by baseline factor level: 50 mg/dL -Will have very low fibrinogen levels

Dysfibrinogenemia

Cryoprecipitate or FFP

-Diagnosed by abnormal reptilase and thrombin times with normal fibrinogen levels -Usually autosomal dominant inheritance patterns91

Factor II (prothrombin) deficiency

FFP or prothrombin complex concentrate

-Half-life: 3–4 days -Target level: >30% -Bleeding usually mild unless after trauma

Factor V deficiency

FFP

-Half-life: 36 hours -Target level: >20% -Bleeding is usually mild to moderate -Rarely can be combined with factor VIII deficiency91

Factor VII deficiency

Recombinant VIIa

-Half-life: 4–6 hours -Target level: >20% -Very rare: 1/500,000 in general population91 -Very low levels can lead to severe bleeding -Not helped by vitamin K infusions91

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CHAPTER 14 ❖ Pediatric Hematology: The Coagulation System and Associated Disorders Disorder

Treatment

Notes

Factor X deficiency

FFP or prothrombin complex concentrate

-Half-life: 40 hours -Target level: >20% -Usually features mild to moderate mucocutaneous and posttraumatic bleeding

Factor XI deficiency

FFP

-Half-life: 40–70 hours -Target level: >20% -Autosomal recessive inheritance; most frequently encountered in Ashkenazi Jewish populations91 -Bleeding most common after trauma or surgery91

Factor XIII deficiency

Cryoprecipitate or FFP

-Half-life: 11–14 days -Target level: >5% -Associated with delayed umbilical cord separation and intracranial hemorrhage with minimal trauma -Characterized by delayed hemorrhage91

PAI-1 deficiency

Antifibrinolytic agents

-Bleeding most common after trauma or surgery91 -Euglobulin lysis time will be shortened

Antiplasmin deficiency

Antifibrinolytic agents

-Mucocutaneous bleeding and hemarthroses91 -Symptoms can be similar to those in mild hemophilia -Euglobulin lysis time will be shortened

procedure. Typically, 10–20 mL/kg are transfused in chil­ dren. FFP is not indicated for volume replacement.

Cryoprecipitate Cryoprecipitate is derived from plasma by thawing FFP and removing the supernatant. The remaining product can be stored for six hours or frozen again and stored for up to one year.47 This contains concentrated amounts of factors VIII and XIII, VWF, and fibrinogen in volumes that average only 15 mL.47 The development and general availability of recombinant and/or viral­inactivated factor concentrates have made the use of cryoprecipitate for routine treatment of the hemophilias or VWD inadvisable. However, in emergency situations or in patients with dysfibrinogenemia or hypofi­ brinogenemia, cryoprecipitate is warranted. One unit for every 10 kg of patient body weight is an appropriate dose in children.

Platelets Platelets may be obtained in one of two ways: random­ donor platelets (those pooled from whole blood donations) or apheresis units (single­donor platelets). A unit of platelets centrifuged from whole blood contains between 5.5 × 1010 and 7 × 1010 in a volume of 50–75 mL of plasma.47,48 They can be stored for five days at room temperature when in a state of constant agitation. One unit for every 10 kg of body weight should increase the platelet count by 30,000–50,000.48 The maximum platelet order is six units. Children weighing less than 10 kg may receive 10 mL/kg. A single­donor unit

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163

contains approximately 3 × 1011 cells in 250 mL of plasma.47 This reduces the amount of antigenic exposure for a transfu­ sion recipient and can be dosed with 10 mL/kg up to the full volume of the unit. The primary indication for platelet transfusion is bleeding secondary to thrombocytopenia due to impaired production or a platelet function defect. Antibody­mediated or destructive thrombocytopenias (e.g., ITP) are not usually responsive to platelet transfusion; in such circumstances, platelet transfu­ sion is indicated only if there is life­threatening bleeding. Bleeding from productive thrombocytopenia responds well when a patient is transfused to a platelet count of at least 50,000. Similarly, prophylaxis during surgical or other inva­ sive procedures is successful if the platelet count can be elevated to a similar threshold.48 On the contrary, a patient with thrombocytopenia who is not bleeding and is not sched­ uled for a procedure may not need to be treated. Patients can have counts as low as 10,000 before a prophylactic transfu­ sion needs to be considered.48

Packed Red Blood Cells (PRBCs) A unit of PRBCs contains a volume of approximately 300–350 mL. This volume also contains small amounts of plasma and a preservative.47,48 The hematocrit of a unit aver­ ages between 50% and 60%. Traditionally, 10 mL/kg of PRBCs will result in a rise in 3 g/dL of hemoglobin, although newer information suggests that 12.5 mL/kg may be required for units preserved with ADSOL.47 Depending on patient size and the desire to limit the number of donors to which a

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patient is exposed, more or less can be transfused to match the volume of a unit. PRBC transfusions are indicated to improve oxygen­carrying capacity in symptomatically anemic patients or in patients experiencing acute blood loss with hemody­ namic instability.48 Red cell transfusions are not indicated for improved wound healing or in asymptomatic patients with adequate oxygen carrying capacity.

Recombinant Factor Concentrates For the treatment of hemophilia, recombinant factor prod­ ucts are dosed in terms of units of activity. For hemophilia A, 1 unit of administered factor VIII will raise the plasma concentration by 2%. For hemophilia B, 1 unit of factor IX will raise the plasma level by only 0.8%–1%. Plasma concen­ trations of 30%–50% should be suitable to control minor bleeding episodes, whereas levels of 50%–100% will be required to prevent postsurgical hemorrhage or to treat life­ threatening hemorrhages.41,42 For surgical procedures, the patient’s primary hematologist should formulate a plan of pre­ and postprocedure dosing. One significant complication of the treatment of hemo­ philia is inhibitor development. Inhibitors are antibodies that develop against factor VIII or IX molecules. Such inhibitors develop in approximately 30% of patients with severe hemo­ philia A but in only 3% of those with hemophilia B.45 Other factors, such as patient race, may affect this risk. These IgG inhibitor antibodies generally emerge within the first 50 treat­ ment days. Patients with low­titer inhibitors may be treated with higher doses of their usual factor product. However, those with high­titers require a bypassing agent, either recombinant activated factor VII (rFVIIa) or a prothrombin complex concentrate such as “Factor Eight Inhibitor Bypass Activity.” rFVIIa is licensed in the United States to treat and provide prophylaxis against bleeding in hemophilia patients with inhibitors and in patients with congenital factor VII defi­ ciency.49–52 Recommended dosages are 90 mcg/kg for hemo­ philia patients and 15–30 mcg/kg for factor VII deficiency patients. Reports of off­label use of rFVIIa in pediatric patients are now common.53–56 Most document favorable success rates in controlling nonhemophilia bleeding with rFVIIa. Despite these reports, there are no clinical trials to guide use in nonapproved settings. Adverse events, notably thrombosis, have been seen with increasing frequency.57 Consequently, off­label use of rFVIIa is not recommended outside of life­threatening situations.

Desmopressin Acetate (DDAVP) and Von Willebrand Factor (VWF) Concentrates DDAVP is a synthetic derivative of antidiuretic hormone and has been studied extensively in the treatment of VWD. Administration of DDAVP will increase plasma concen­ trations of VWF and factor VIII from endothelial cells by twofold to eightfold.27,46 An intranasal preparation with a high concentration of DDAVP is available and may be suitable for

Ch14.indd 164

the treatment of minor bleeding, but more serious bleeding will require 0.3 mcg/kg intravenously. VWF and factor VIII levels will reach peak concentrations 30–90 minutes after administration.27 The majority of patients with type I VWD will respond to DDAVP, but each individual should have their response tested before treatment. DDAVP is not useful in type III patients, and its use in type 2B has been controversial due to a transient thrombocytopenia that can develop after its administration.27 Patients with hemophilia A and factor levels greater than 5%–10% may also get a clinically significant rise in the factor level. The use of DDAVP, however, is not without toxicities. Headache, nausea, and flushing are common but generally mild.27 Tachyphylaxis can also occur, requiring that DDAVP usually be used for a maximum of no more than three to four days. Hyponatremic seizures have also been reported following DDAVP use, particularly in children younger than 2 years of age and comparatively less commonly in adults.58–60 Excessive fluid intake has been implicated commonly in these events. Why children are more susceptible remains theoret­ ical, although some have suggested that it relates to the differ­ ences in the plasma volumes and glomerular filtration rates of children and adults.58 To help prevent such possibilities, prac­ titioners should avoid prescribing hypotonic fluids, should restrict patient intake to maintenance amounts (or slightly less), and should monitor urine output closely.46,59 There are no evidence­based protocols for post­DDAVP sodium monitoring in patients not receiving IV fluids, although it is reasonable to obtain a serum level 1 hour after the infusion in children less than 15 kg. Most pediatric hematologists now recommend against the use of DDAVP in children younger than 2 years altogether.27 For patients with VWD who do not respond to DDAVP or who are faced with major surgery, trauma, or life­ threatening bleeding, plasma­derived concentrates are the treatment of choice. In the United States, Humate­P® and Alphanate SD/HT® are commercially available, although they have different VWF:factor VIII ratios.27 Dosing is based on units of VWF:RCo and patient body weight.46 For major surgery or bleeding, a loading dose of 40–60 units/ kg followed by maintenance dosing of 20–40 units/kg every 8–24 hours is recommended.27 Minor bleeding can be treated with lower doses. The patient’s plasma levels of VWF and factor VIII should be monitored both for thera­ peutic response and for adverse events, as elevated factor VIII levels may create a hypercoagulable state. (Fig 14­3) shows a proposed algorithm for perioperative management of a child with VWD.

Antifibrinolytics Antifibrinolytic agents can improve clot stability. They may be used to control either local or systemic fibrinolysis. Three agents are used commonly: aminocaproic acid, tranexamic acid, and aprotinin. Aminocaproic acid and tranexamic acid act by inhibiting t­PA and plasmin at sites of lysine binding, whereas aprotinin inhibits plasmin, trypsin, and kallikrein at

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Diagnosis of type I von Willebrand Disease in a child

DDAVP challenge test GOOD RESPONSE? NO

YES

30–60 MINUTES BEFORE SURGERY: - vWF Concentrate 40–60 units/kg IV - Aminocaproic acid 50 mg/kg PO or IV

30–60 MINUTES BEFORE SURGERY: - DDAVP 0.3 mcg/kg IV - Aminocaproic acid 50 mg/kg PO or IV

POST-OPERATIVELY

POST-OPERATIVELY

20–40 units/kg IV q 8–24 hours for 3–5 days

Aminocaproic acid 50 mg/kg/dose q 6 hours PO for 10 days

If bleeding occurs, repeat DDAVP 0.3 mcg/kg IV in 24 and 48 hours

Aminocaproic acid 50 mg/kg/dose q 6 hours PO for 10 days

FIGURE 14-3. Perioperative management of a child with von Willebrand disease. This algorithm is a proposed method of managing children with type I von Willebrand disease requiring tonsillectomy and adenoidectomy during the perioperative period. Individual institutions may have their own protocols, and a pediatric hematologist should be consulted before a final treatment strategy is put into practice. (Units refers to dosing in vWF:RCo International units/deciliter.)

serine sites.61 Aminocaproic and tranexamic acids can be used intravenously, topically, and orally. Tranexamic acid has slow renal clearance; hence, lower doses and larger intervals are used. Aminocaproic acid, on the contrary, leads to urinary levels that are up to 100 times higher than plasma amounts, requiring caution when hematuria is present.61 Aprotinin is not orally absorbed and must be administered intravenously. Control of bleeding (and not laboratory studies) is the best manner to monitor their effects. Although these agents can be used safely in most situations, patients with thrombophilia or those who face long periods of immobility are at higher risk for thrombosis. Because saliva and the oral cavity have relatively increased concentrations of plasminogen and its activa­ tors, use of antifibrinolytics has been an appealing choice following oropharyngeal surgeries.62 Although studies on the use of drugs such as aminocaproic acid in hemo­ philia have been performed, there exists few data on their use in patients with VWD. There have been no studies that have shown added benefit from the combination of preoperative prophylaxis and postoperative antifibrino­ lytics when compared to preoperative treatment alone in patients with VWD.63 Use of such drugs cannot be argued for or against with any certainty given the current lack of conclusive studies. However, recent guidelines from the

Ch14.indd 165

National Institutes of Health state that the combination is safe and generally effective for oral surgery (grade B, level IIb evidence).27 One regimen that has been used success­ fully is aminocaproic acid 50 mg/kg/dose, administered 1 hour before surgery and then every 6 hours for 10 days. Reviewing the package insert before prescription to review the full side effect profile and other information is advised.

Topical Agents As with any surgical procedure, adequate local control with cautery or suturing offers the best protection against post­ operative bleeding. However, for selected indications, the application of a topical hemostatic agent may be beneficial. As mentioned, aminocaproic acid can be applied topically with either intravenous or oral forms. This can be especially helpful for oropharyngeal bleeding, given the increased fibrinolytic factors in salivary secretions. Other agents, such as topical thrombin or fibrin glue, can also prove beneficial for surgical bleeding. Currently, most topical thrombin is a bovine­derived chemical. Using it to excess, more common in spinal fusion surgeries than in otolaryngology proce­ dures, may lead to the development of factor V inhibitors. Recombinant human thrombin is in development and will be available for topical use in the near future.

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DISORDERS THAT PREDISPOSE TO THROMBOSIS Registries and epidemiologic studies have shown that in the United States, the overall incidence of venous thromboembo­ lism (VTE) is approximately 0.49/10,000 children.64 There is a bimodal distribution, with a large peak in the newborn period and another in late adolescence.64 When evaluating a child with a thrombosis, a stepwise approach to diag­ nosis, in conjunction with anticoagulation, is recommended (Fig. 14­4). Anticoagulation is usually initiated with unfrac­ tionated heparin intravenously or low­molecular­weight heparin subcutaneously. Both should be performed with the guidance of a pediatric hematologist. Lemierre’s syndrome is an example of a thromboembolic disorder often encountered by pediatric otolaryngologists. This condition is characterized by jugular vein thrombosis and anaerobic infections in the head and neck region. The occurrence of these thromboses is likely due to a combina­ tion of venous stasis, endothelial damage from local inflam­ mation, and an underlying hypercoagulable state (acquired or inherited).65 Although the syndrome has classically been associated with Fusobacterium necrophorum, polymicrobial infections are common in children.65 Tonsillitis, pharyngitis, mastoiditis, or tooth infections that spread to the pharyngeal spaces can all lead to Lemierre’s syndrome. Anterior neck disease may present with pain, swelling, and tenderness, but

posterior compartment disease may be harder to detect until late in its course. Treatment involves targeted antimicrobial therapy and anticoagulation. In severe cases with systemic compromise from septic pulmonary emboli, a thrombectomy of the primary clot may be required.

Central Venous Catheters The greatest risk factor for VTE in children is the presence of an indwelling central venous catheter (CVC). Although the availability of CVCs has improved the care of children with various illnesses, they also provide a large occlusive surface on which thromboses can begin. It has been reported that approximately 50% of pediatric and 80% of neonatal deep vein thromboses are related to CVC placement.64 In general, larger catheters and smaller vessels increase the thrombotic risk. Additionally, CVCs placed in the left subclavian vein or with distal tips that are high in the superior vena cava may be more likely to develop a thrombosis.66 The underlying disease for which a catheter was placed often magnifies the risk. Currently, there is no recommended anticoagulation prophylaxis regimen for children with central lines, although heparin flushes are commonly used empirically.66

Oral Contraceptive Pills First­generation oral contraceptive pills (OCPs) that contain estrogen carry approximately four times the risk of

1. Antithrombin III 2. Protein C 3. Protein S

4. Prothrombin gene variant 5. Fasting homocysteine level [ideally 12 hour fasting] 6. Lupus anticoagulant panel with anticardiolipin Ab and Factor VIII 7. D-Dimer 8. Fibrinogen

VENOUS: TIER 2

1. 2. 3. 4.

1. 2. ARTERIAL: 3. TIER 1 4. 5.

9. Activated protein C resistance ratio If abnormal - Factor V Cambridge mutation Factor V Leiden If neg - HR2 haplotype mutation

Lipoprotein a PAI-1 polymorphism PNH screen (CD59) - especially patient with abdominal or cerebral thromboses Antiphosphatidylserine, Β2 glycoprotein I, and antiphospholipid antibodies Prothrombin gene variant Fasting homocysteine level Lupus anticoagulant panel APC resistance Sticky Platelet Syndrome

TIER 2

1. 2. 3. 4. 5. 6. 7.

Protein Z Extended LAC PAI-1 polymorphism PL A1/A2 polymorphism Lipoprotein a Random homocysteine level Glycoprotein Ia C807T

FIGURE 14-4. Evaluation after a thrombosis has been diagnosed. Venous thrombosis tier 1: Indication—any thromboembolic event in a pediatric patient. In the NICU population, testing should be performed for neonates with stroke, renal thrombosis, unusual location, or severity of thrombus. Venous thrombosis tier 2: Indication—patient with a negative tier 1 screen and idiopathic thromboembolic event or strong family history, or specific medical condition as described. Arterial thrombosis tier 1: Indication—arterial thromboembolic event. Arterial thrombosis tier 2: Indication—negative tier 1 screen in a patient with idiopathic arterial thromboembolic event or strong family history.

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CHAPTER 14 ❖ Pediatric Hematology: The Coagulation System and Associated Disorders thrombosis as does placebo.64 Second­generation combina­ tion OCPs with decreased estrogen components have less risk of VTE; however, third­generation OCPs have more risk.3,67,68 The mechanism is multifactorial, but OCPs are felt to produce a state of APC resistance, as well as transiently increasing levels of factor VIII, VWF, and prothrombin.64,68 Although screening all patients beginning OCP therapy is not required, a thorough medical and family history should be obtained. Those patients who have a suggestion of an inherited thrombophilic state should undergo a formal evalu­ ation. The presence of another thrombophilic state increases the risk of VTE dramatically. For example, the combination of OCP use and heterozygous factor V Leiden increases the risk of VTE 35 times higher than baseline.64

Lupus Anticoagulants and Antiphospholipid Antibodies LAs are circulating antibodies that act as inhibitors against coagulation complexes that prolong in vitro clotting reactions, commonly the aPTT.69 In general, LAs can develop in response to many medications and illnesses, even minor infections. Most LAs in children are short­lived and will not lead to thrombosis. The pathophysiology of how thromboses can develop in the setting of LAs is not fully understood, although it is likely multifactorial. Antiphospholipid anti­ bodies can be temporary or much more challenging to manage. Anticardiolipin, antiphosphatidylcholine, antiphosphatidyl­ serine, and anti­ß2­glycoprotein are among the more common antibodies detected. The antiphospholipid antibody syndrome is characterized by the presence of a persistent antiphospholipid antibody and a thrombosis.70 It can develop with or without an associated autoimmune disease and can predispose to both venous and arterial thrombosis. Extended or life­long antico­ agulation therapy may be required. Life­threatening thrombosis with dysfunction in at least three organ systems is referred to as the catastrophic antiphospholipid syndrome.

APC Resistance and Factor V Mutations Factor V Leiden was discovered in a group of patients whose plasma was resistant to the effects of APC.71 It is part of a group of disorders that are characterized by point muta­ tions that make factor Va resistant to proteolysis.64 Factor V Leiden makes up 90% of the cases of APC resistance.71 Factor V Cambridge is a similar, though less well­known, variant. Potentially, up to 8% of Caucasians are heterozy­ gous for factor V Leiden, and approximately 1 in 1000 will be homozygous.71,72 Heterozygotes have 2–7 times the baseline risk of developing VTE, whereas homozygotes may have up to 70 times the risk.64

Prothrombin Gene Variants In 1996, a mutation in the prothrombin gene (G20210A) was discovered and found to confer an increased risk of VTE.71 The effect of this mutation is the persistence of circulating

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167

prothrombin, leading to increased generation of thrombin. Two to three percent of Caucasians are heterozygotes, whereas homozygosity for this defect has been reported very rarely.71 Heterozygous individuals have approximately a three times greater risk of VTE than do unaffected persons.64

Protein C and Protein S Deficiencies The prevalence of heterozygous protein C deficiency is approximately 1/300, although most patients will not expe­ rience a thrombotic event.73,74 Heterozygous deficiencies have multiple subtypes. Type I features diminished function and amounts of the molecule, whereas type II shows normal amounts but impaired function. Neither category is likely to present with thromboses before puberty, and the popula­ tion incidence of VTE due to heterozygous deficiencies is 1/16,000 persons.75 Patients with compound heterozygous or homozygous deficiency may have variable levels of severity. Patients with severe deficiencies (concentrations of less than 0.01 units/mL) may present in the neonatal period with purpura fulminans, characterized by small vessel thromboses, massive organ damage, skin necrosis, and loss of limb and life unless treated promptly. The incidence of this is fairly low, reported as 1/500,000 live births.75 Moderately affected individuals (with levels between 0.05 and 0.25 units/mL) may have recurrent thromboembolic disease later in life.73,74 Protein S deficiency may act very similarly to protein C deficiency. Heterozygous deficiency is found with a preva­ lence of 1/33,000, although homozygous mutations leading to neonatal purpura fulminans are less common, 1/1,000,000 live births.75 Lifetime risk of VTE is increased sevenfold.76

Antithrombin-III Deficiency Located on chromosome 1, the gene for antithrombin III has over 250 mutations resulting in qualitative or quantita­ tive disorders.77 The odds ratio of VTE is increased 10–20 times over baseline in individuals who are heterozygotes for a mutation; probably, homozygosity is not compatible with life.77 This increased risk, however, is age­dependent and affects adults more frequently than children. The incidence of ATIII deficiency has been estimated to be 1 in 2000–5000, although some believe the incidence of isolated mutations in the heparin­binding site is much higher, nearly 1 in 350.77

MTHFR Mutations and Homocysteinemia Homocysteine is methylated to form methionine by the enzyme methylene tetrahydrofolate reductase (MTHFR). Mutations in the enzyme’s gene at nucleotides 677 (G–T) or 1298 (A–C) cause thermolability and a loss of function.78 In a diet deficient in folate, vitamin B6, or vitamin B12, hyper­ homocysteinemia can develop. Elevated levels can damage endothelial cells and cause the vasculature to develop a prothrombotic environment, with increased expression of factor Va and tissue factor.78 Hyperhomocysteinemia can lead to 2.5 times the baseline risk of thrombosis for

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SECTION 1 ❖ Basic Science/General Pediatric Otolaryngology

patients.64 However, heterozygous MTHFR mutations (found in approximately 35% of the population) are not associated with an increased risk of thrombosis. Homozygous mutations are associated with thromboses only if homocysteine levels are elevated.72

Thrombocytosis Thrombocytosis is defined as a platelet count more than two standard deviations above the population mean.35 Essential thrombocythemia is seldom seen in pediatric patients. It is characterized by a clonal proliferation of megakaryocyte­ derived cells with abnormal platelet function. Progression to acute myelogenous leukemia can occur but is exceed­ ingly rare. There are different diagnostic criteria depending on whether or not the JAK2 V617F mutation is present.79 Elevated platelet counts in children are usually secondary to other illnesses. Kawasaki syndrome is an inflammatory condition that frequently features platelet counts greater than 1,000,000 cells/μL; other processes such as rheuma­ toid arthritis, inflammatory bowel disease, and sarcoidosis also can be associated with elevated platelet counts. Iron deficiency anemia can shift hematopoietic ratios when red cell production is limited to produce more platelets. Additionally, because up to a third of a patient’s platelets may be sequestered in the spleen, splenectomy can lead to mark­ edly elevated circulating platelet counts.

8. 9.

10.

11.

12. 13.

14.

15.

16.

SUMMARY Hematologic conditions have various presentations and can impact multiple aspects of health. In surgical settings, an understanding of coagulation physiology will aid the accurate diagnosis and treatment of bleeding disorders and complications. Although postoperative hemorrhages may be of the highest concern to otolaryngologists, an understanding of all aspects of coagulation will prove to be most beneficial.

17.

18.

19.

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63. Mannucci PM. How I treat patients with von Willebrand disease. Blood. 2001;97:1915–1919. 64. Goldenberg NA, Bernard TJ. Venous thromboembolism in children. Pediatr Clin North Am. 2008;55:305–322. 65. Goldenberg NA, Knapp­Clevenger R, Hayes T, Manco­Johnson MJ. Lemierre’s and Lemierre’s­like syndromes in children: survival and thromboembolic outcomes. Pediatrics. 2005;116:e543–e548. 66. Journeycake JM, Buchanan GR. Thrombotic complications of central venous catheters in children. Curr Opin Hematol. 2003;10:369–374. 67. Goodnight SH, Hathaway WE. Thrombosis and pregnancy. In: Goodnight SH, Hathaway WE, eds. Disorders of Hemostasis and Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw­Hill; 2001. 68. Battaglioli T, Martinelli I. Hormone therapy and thromboem­ bolic disease. Curr Opin Hematol. 2007;14:188–493. 69. Briones M, Abshire T. Lupus anticoagulants in children. Curr Opin Hematol. 2003;10:375–379. 70. Hunt BJ. Pediatric antiphospholipid antibodies and antiphos­ pholipid syndrome. Semin Thromb Hemost. 2008;34:274–281. 71. Goodnight SH, Hathaway WE. Factor V Leiden, prothrombin gene mutation, and elevated factor VIII. In: Goodnight SH, Hathaway WE, eds. Disorders of Hemostasis and Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw­Hill; 2001. 72. Bauer KA. Inherited disorders of thrombosis and fibrinolysis. In: Orkin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux SE IV, eds. Nathan and Oski’s Hematology of Infancy and Childhood. 7th ed. Philadelphia, PA: Saunders Elsevier; 2009. 73. Bovill EG. Protein C deficiency. In: Goodnight SH, Hathaway WE, eds. Disorders of Hemostasis and Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw­Hill; 2001. 74. Triplett DA. Protein S deficiency. In: Goodnight SH, Hathaway WE, eds. Disorders of Hemostasis and Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw­Hill; 2001. 75. Petaja J, Manco­Johnson MJ. Protein C pathway in infants and children. Semin Thromb Hemost. 2003;29:349–361. 76. Bauer KA. Hypercoagulable states. In: Hoffman R, Furie Jr B, Benz EJ, McGlave P, Silberstein LE, Shattil SJ, eds. Hematology: Basic Principles and Practices. 5th ed. New York, NY: Churchill Livingstone; 2008. 77. Triplett DA. Antithrombin deficiency. In: Goodnight SH, Hathaway WE, eds. Disorders of Hemostasis and Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw­Hill; 2001.

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78. Goodnight SH, Hathaway WE. Homocysteinemia. In: Goodnight SH, Hathaway WE, eds. Disorders of Hemostasis and Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw­Hill; 2001. 79. Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med. 2006;355:2452–2466. 80. Gabriel P, Mazoit X, Ecoffey C. Relationship between clinical history, coagulation tests, and perioperative bleeding during tonsillectomies in pediatrics. J Clin Anesth. 2000;12:288–291. 81. Eisert S, Hovermann M, Bier H, Gobel U. Preoperative screening for coagulation disorders in children undergoing adenoidectomy (AT) and tonsillectomy (TE): does it prevent bleeding complications? Klin Pädiatr. 2006;218:334–339. 82. Smith PS, Orchard PJ, Lekas MD. Predicting bleeding in common ear, nose, and throat procedures: a prospective study. R I Med J. 1990;73:103–106. 83. Close HL, Kryzer TC, Nowlin JH, Alving BM. Hemostatic assessment of patients before tonsillectomy: a prospective study. Otolaryngol Head Neck Surg. 1994;111:733–738. 84. Tami TA, Parker GS, Taylor RE. Post­tonsillectomy bleeding: an evaluation of risk factors. Laryngoscope. 1987;97:1307–1311. 85. Burk CD, Miller L, Handler SD, Cohen AR. Preoperative history and coagulation screening in children undergoing tonsillectomy. Pediatrics. 1992;89:691–695. 86. Handler SD, Miller L, Richmond KH, Baranak CC. Post­ tonsillectomy hemorrhage: incidence, prevention and manage­ ment. Laryngoscope. 1986;96:1243–1247. 87. Bolger WE, Parsons DS, Potempa L. Preoperative hemostatic assessment of the adenotonsillectomy patient. Otolaryngol Head Neck Surg. 1990;103:396–405. 88. Thomas GK, Arbon RA. Preoperative screening for potential T&A bleeding. Arch Otolaryngol. 1970;91:453–456. 89. Manning SC, Beste D, McBride T, Goldberg A. An assessment of preoperative coagulation screening for tonsillectomy and adenoid­ ectomy. Int J Pediatr Otorhinolaryngol. 1987;13:237–244. 90. Montgomery RR. von Willebrand disease. In: Goodnight SH, Hathaway WE, eds. Disorders of Hemostasis and Thrombosis: A Clinical Guide. New York, NY: McGraw­Hill; 2001. 91. Bauer KA. Rare hereditary coagulation factor abnormalities. In: Orkin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux SE IV, eds. Nathan and Oski’s Hematology of Infancy and Childhood. 7th ed. Philadelphia, PA: Saunders Elsevier; 2009.

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15

C H A P T E R

Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections Stephen I. Pelton

I

nfectious complications of respiratory tract infections are commonplace. Acute otitis media is reported in 37% of children less than 3 years of age following viral upper respiratory tract infection and sinusitis in up to 9% of the children.1 Deep space infections of the submandibular, lateral pharyngeal, and retropharyngeal compartments and bacterial complications of sinus and middle ear disease, such as orbital cellulitis or mastoiditis, are less common but potentially serious infections due to their associated morbidity. The otolaryngologist must have knowledge of both the likely underlying microbiology and the appropriate antimicrobial therapy, as often empiric treatment is necessary until microbiologic specimens can be obtained. This chapter focuses on the antimicrobial agents currently available for the treatment of pediatric otolaryngologic infections.

THE β-LACTAM ANTIMICROBIAL AGENTS: PENICILLINS AND CEPHALOSPORINS β-Lactam antimicrobial agents include those with a shared structural feature, the β-lactam ring. Penicillin was the first of the β-lactams, and subsequently broader spectrum members often referred to as second-generation (ampicillin and amoxicillin), third-generation (carbenicillin and ticarcillin), and fourth-generation (piperacillin) drugs were introduced along with cephalosporins and antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin, and dicloxacillin).

The Penicillins

Penicillin G [Potassium–Pfizerpen®] and Penicillin V [Pen-Veek®, Beepen-VK®, Beepen-VK®, Ledercillin VK®, Robicillin VK®, and V-Cillin K®] Oral preparations of buffered penicillin G and phenoxymethyl penicillin (penicillin V) are absorbed well from the gastrointestinal tract (Table 15-1). Penicillin V achieves approximately 40% of the serum concentration and buffered penicillin G achieves approximately 20% of that achieved by the equivalent dose of aqueous penicillin G administered intramuscularly. Oral penicillins are satisfactory for the treatment of mild to moderately severe infections due to susceptible organisms. They are particularly effective for the treatment of streptococcal pharyngitis, as all group A streptococci remain uniformly susceptible to all penicillins and cephalosporins. Penicillin V and penicillin G demonstrate approximately equivalent in vitro activity against grampositive cocci, but the minimal inhibitory concentration for penicillin V is significantly greater than penicillin G against Haemophilus influenzae. Similarly the in vitro activity of

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penicillin G is approximately half that of amoxicillin for H. influenzae. Therefore, penicillin G or penicillin V is not appropriate for infections due to H. influenzae. Penicillin alone is no longer suitable as an empiric therapy for head and neck infections where anaerobic bacteria are suspected due to the increasing frequency of polymicrobial etiologies including penicillin-resistant bacteroides and fusobacterium. Parenteral penicillin G preparations include the potassium or sodium salts of aqueous penicillin [Pfizerpen], procaine ® ® [Wycellin ], and benzathine penicillin G [Bicillin L-A ], which modify absorption and thereby produce different patterns of peak serum concentration as well as duration of antibacterial activity both in serum and in tissues. Aqueous penicillin G produces high peak levels of antibacterial activity in serum within 30 minutes of intramuscular administration but is rapidly excreted; thus, the concentration in serum falls rapidly and is low after two to four hours after administration. When aqueous penicillin G is given by the intravenous route (compared to the intramuscular route), the peak is higher and earlier and the duration of antibacterial activity in serum is even shorter (approximately 2 hours), requiring frequent dosing (usually every four hours; six times daily). Aqueous penicillin G, given intramuscularly or intravenously, is used for severe disease due to susceptible pathogens, including suspected sepsis and meningitis. Procaine penicillin G given intramuscularly produces lower levels of serum antibacterial activity (approximately 10%–30% of the peak level) than does the same dose of the aqueous form, but activity persists in serum for as long as 12 hours. Intramuscular administration of procaine penicillin G should be reserved for patients with mild to moderate disease who cannot tolerate oral penicillins (patients who are vomiting or have diarrhea or those with altered levels of consciousness) or for patients who require the reliability of parenteral administration, but whose disease is not severe enough to warrant hospitalization and the frequent intramuscular or intravenous administration of aqueous penicillin G. Benzathine penicillin G given intramuscularly is a repository preparation providing low levels of serum activity (approximately 1%–2% of the peak level achieved by the same dose of the aqueous form). After administration of this drug, low concentrations of penicillin activity are measurable in serum for up to or longer than 14 days and in urine for several months. Significant pain at the site of injection is the major deterrent to widespread usage of this unique antibiotic formulation. Combination of the benzathine and procaine salts ® (900,000 and 300,000 units, respectively) [Bicillin C-R )] is less painful and is comparable in efficacy to benzathine alone

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TABLE 15-1. Penicillins: Antimicrobial Spectrum, Recommended Dosages, and Potential Adverse Effects Usual Pediatric Dosage

Serious Adverse Events

Susceptible pneumococci, susceptible staphylococci, N. meningitidis, Clostridium species, anaerobic streptococci

IV

25,000–400,000 units/kg/d; every 4–6 hours

Anaphylaxis, seizures at high doses, interstitial nephritis, drug fever

Penicillin VK

Susceptible pneumococci, N. meningitidis, anaerobic streptococci, group A streptococci, Clostridium species

po

25–50 mg/kg/d

Same as penicillin

Penicillin (benzathine)

Group A streptococci, Treponema pallidum

IM

25,000–50,000 units/ kg/d; 600,000 units total for less than 60 pounds; 900,000 units total for more than 60 pounds

Same as penicillin

Ampicillin

Gram + cocci, shigella, salmonella, E. coli, H. influenza, N. meningitides, P mirabilis

po or IV

50–300 mg/kg/d

Same as penicillin and diarrhea, rash (especially with EBV infection), candidal diaper rash

Amoxicillin

Similar to ampicillin

po

Up to 90 mg/kg/d administered bid

Same as ampicillin

Carbenicillin

Pseudomonas, E. coli, P. mirabilis, Enterobacter

IV

25–100 mg/kg/d every 4–6 h

Platelet dysfunction

Ticarcillin

Same as carbenicillin

IV

50–300 mg/kg/d every 4–6 h

Same as carbenicillin

Piperacillin

Similar to carbenicillin; greater gramnegative and anaerobic activity

IV

200–300 mg/kg/d every 6–8 h

Same as carbenicillin

Drug

Antibacterial Activity

Route

Penicillins

Abbreviations: IM, intramuscular; IV, intravenous po, orally. Source: Bradley JS, Nelson JD, eds. Nelson’s Pocket Book of Pediatric Antimicrobial Therapy. 18th ed. AAP; 2010–2011.

(1,200,000 units) for treatment of streptococcal pharyngitis.2 Benzathine penicillin G is appropriate only for highly sensitive organisms present in well-vascularized tissues. The primary use of intramuscular benzathine penicillin G is the prevention of recurrent group A streptococcal pharyngitis in children with earlier rheumatic fever administered every three to four weeks.3

Broad-Spectrum Penicillins

Ampicillin [Omnipen®] and Amoxicillin [Amoxil®] Ampicillin and amoxicillin are effective against a broader spectrum of bacteria than penicillin V and penicillin G because of their ability to penetrate the cell wall of gramnegative bacteria. This spectrum includes gram-positive cocci (Streptococcus pneumoniae, group A streptococci, nonpenicillinase-producing strains of Staphylococcus aureus, and oropharyngeal strains of anaerobic bacteria), gram-negative cocci (Moraxella catarrhalis), gram-negative coccobacilli

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(non-β-lactamase-producing strains of H. influenzae), and some gram-negative enteric bacilli (Escherichia coli and Proteus mirabilis). Both drugs are susceptible to cleavage of the β-lactam ring by β-lactamase-producing organisms, rendering the drugs inactive. Both drugs are available for oral administration; ampicillin alone is available in a parenteral form. Oral amoxicillin provides levels of activity in serum that are higher and more prolonged than those achieved with equivalent doses of oral ampicillin. An additional advantage of amoxicillin is that its absorption is not altered when the antibiotic is administered with food, whereas ampicillin absorption is decreased significantly under such circumstances. Because of its long record of safety and efficacy, guidelines for the treatment of acute otitis media4 recommend amoxicillin for the treatment of uncomplicated acute otitis media, specifically in those children who have not had prior treatment with β-lactam antibiotics. The major mechanism of resistance to

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CHAPTER 15 ❖ Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections penicillins among isolates of S. pneumoniae is the alteration of penicillin-binding proteins (PBP) and the resulting change in affinity for β-lactam antibiotics. This mechanism increases the minimum inhibitory concentration (MIC), but bactericidal activity can be achieved for isolates with MIC < 8 μg/mL with higher doses (70–90 mg/kg/d in 2 or 3 doses daily).5 The routine administration of higher doses has now become standard in the United States. It is important to recognize that not all sites [e.g., cerebrospinal fluid (CSF) and middle ear] achieve equivalent drug concentrations, and site-specific differences should be understood for the selection of appropriate antimicrobial therapy. Studies of middle ear concentration following higher dosing regimens (35–45 mg/kg/dose) demonstrate increased concentrations of amoxicillin in middle ear fluid,6,7 and clinical “double tap” studies have demonstrated efficacy for isolates of S. pneumoniae with MIC < 4 μg/mL.8,9 Amoxicillin–Clavulanate [Augmentin®] Amoxicillin in combination with clavulanate potassium was introduced in 1984 for oral administration. Clavulanate (potassium) is a potent inhibitor of plasmid-mediated β-lactamase enzymes preventing the destruction of amoxicillin. Therefore, amoxicillin–clavulanate is active against β-lactam-producing strains of H. influenzae, M. catarrhalis, Neisseria gonorrhoeae, E. coli, Proteus species, and anaerobic bacteria, including Bacteroides fragilis. The pharmacokinetics of amoxicillin and clavulanic acid are similar; both are rapidly absorbed and are not affected when taken with food. Diarrhea, abdominal pain, and nausea are more frequent with the combination than with amoxicillin alone, but in most studies, the number of children discontinuing treatment due to such adverse events is small. The combination of amoxicillin with the enzyme-binding clavulanate is considered to be the best oral option for children with acute otitis media or sinusitis who fail initial therapy or have been treated within the prior 30 days with amoxicillin.10 New formulations with a higher amoxicillin– clavulanate ratio have been developed and licensed, permitting the administration of high dosing regimens (70–90 mg/ kg/d amoxicillin) without unacceptable rates of intolerance due to diarrhea.11 Seventy to 90 mg/kg/d of the amoxicillin component should be used to achieve effective serum and middle ear concentrations against nonsusceptible S. pneumoniae (MIC < 4 μg/mL) and β-lactamase-producing M. catarrhalis and H. influenzae. Amoxicillin–clavulanate is an appropriate therapy when β-lactamase-producing strains of H. influenzae or M. catarrhalis are known or suspected to be the cause of otitis media, sinusitis, or conjunctivitis. Currently, virtually all strains of M. catarrhalis and 40% of nontypable H. influenzae (NTHi) are β-lactamase-producing strains.12 β-lactamase negative ampicillin-resistant strains of NTHi have also been reported; these strains have alterations in PBP that reduce affinity for B-lactams. Such strains comprise less than 5% of all NTHi isolates in the United States, but have become frequent in Japan and are increasing in France.

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173

Emerging strains of nontypable H. influenza with both altered PBP and plasmid-mediated β-lactamase-production that are resistant to amoxicillin–clavulanate even when administered at higher doses have also been reported. Ampicillin–Sulbactam [Unasyn®] Sulbactam is an irreversible inhibitor of various β-lactamases. When combined with ampicillin, sulbactam efficiently protects ampicillin from degradation by β-lactamases, permitting it to retain its inherent activity against H. influenzae, S. aureus [not including methicillin-resistant S. aureus (MRSA)], and N. gonorrhoeae. Ampicillin–sulbactam at a 2:1 ratio is approved by the US Food and Drug Administration (FDA) for parenteral use only in patients 12 years of age or older. The antimicrobial activity, pharmacokinetics, and clinical efficacy and safety are discussed in the proceedings of a symposium held in 1985.13 Ampicillin–sulbactam is also active against anaerobes including β-lactamase-producing Bacteroides species and fusobacterium; as a result, it is frequently used for head and neck infections, particularly when MRSA is unlikely to be a pathogen. Carbenicillin [Pyopen®, Geogen®, and Geocillin®], Ticarcillin [Ticar®], and Ticarcillin–Clavulanate [Timentin®] These third- and fourth-generation penicillins have a broader spectrum of activity, inclusive of P. aeruginosa, than previously available penicillins. The drugs are also effective against gram-positive cocci, H. influenzae, anaerobic bacteria including Bacteroides species, and gram-negative enteric bacilli including Enterobacter species and Proteus species. High concentrations are required to inhibit gram-negative organisms, but this disadvantage is overcome in part by the low toxicity of these drugs, even when they are given in large intravenous doses. Combination of carbenicillin or ticarcillin with an aminoglycoside such as gentamicin or tobramycin produces synergistic activity against many gram-negative enteric bacilli, and such a combination has been used effectively in the initial therapy of sepsis of unknown origin or sepsis suspected to be due to gram-negative enteric bacilli in patients with malignancy or immunosuppressive disease.14 Ticarcillin is similar to carbenicillin, but it is more active on a weight basis against some strains of P. aeruginosa and less active against gram-positive cocci. Because of the increased activity, smaller dosages of ticarcillin rather than carbenicillin may be used for treatment of disease due to gram-negative organisms.15 Ticarcillin in combination with potassium clavulanate extends the antibacterial activity of ticarcillin to include β-lactamase-producing strains of S. aureus, Klebsiella pneumoniae, and B. fragilis. At present, this combination drug is not approved for children younger than 12 years of age. One of the common uses of ticarcillin, carbenicillin, or ticarcillin–clavulanate is in the treatment of chronic suppurative otitis media with perforation and discharge due to P. aeruginosa or Proteus species.

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Although ticarcillin and carbenicillin have no dose-related toxicity, both drugs are disodium salts; the large amounts in which they are given include significant quantities of sodium: 1 g of carbenicillin contains 4.7 mEq or 108 mg of sodium and 1 g of ticarcillin contains 5.2 mEq or 120 mg of sodium. The amount of sodium administered may be of concern in the treatment of certain patients with renal or cardiac disease. Both have also been associated with inhibition of platelet function with increased risk of bleeding. Piperacillin [Pipracil®], Mezlocillin [Mezlin®], and Azlocillin [Azlin®] These parenteral penicillins have a spectrum of activity similar to that of carbenicillin and ticarcillin but show greater activity in vitro against some gram-negative bacilli and anaerobic bacteria. Piperacillin and azlocillin are more active than carbenicillin, ticarcillin, or mezlocillin against P. aeruginosa. Piperacillin and mezlocillin are more active in vitro than carbenicillin or ticarcillin against susceptible strains of E. coli, Klebsiella, Enterobacter, and Serratia species. Each of these penicillins is inactivated by β-lactamases. Piperacillin com® bined with tazobactam [Zozyn ], a β-lactamase inhibitor, preserves the activity of piperacillin against β-lactamaseproducing staphylococci, Enterobacteriaceae, anaerobes, H. influenzae, M. catarrhalis, and P. aeruginosa. In combination with an aminoglycoside, the combination may be synergistic against some gram-negative enteric bacilli. The available experience with children and adults indicate that these penicillins are effective against susceptible organisms, but the evidence is inadequate to demonstrate a significant advantage of any single drug (carbenicillin, ticarcillin, piperacillin, mezlocillin, or azlocillin). The last three drugs have half the sodium content per gram of carbenicillin or ticarcillin, a factor of some importance in patients who require large amounts of the penicillin and have cardiac or renal disease. Azlocillin and other antipseudomonal agents have been used for the treatment of chronic suppurative otitis media because of P. aeruginosa in the pediatric population.16

Penicillinase-Resistant Penicillins

Methicillin [Staphcillin®] Methicillin [Staphcillin] was the first penicillinase-resistant penicillin to be introduced and is available in parenteral form ® ® only (Table 15-2). Oxacillin [Prostaphilin and Bactocil ], ® ® and nafcillin [Unipen and Nafcil ] are available in both parenteral and oral preparations and have greater in vitro activity against gram-positive cocci. Cloxacillin and dicloxacillin are available in oral forms only and are absorbed efficiently from the gastrointestinal tract. Differences among these five penicillins include degree of binding to proteins, degree of degradation by β-lactamases, and in vitro susceptibility. All are effective for the treatment of disease due to Methicillin-sensitive Staphylococcus aureus (MSSA). Clinical studies have shown them to be comparable when

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used according to the appropriate dosage schedules. In addition, all but methicillin have proved to be effective against infections due to S. pneumoniae and group A streptococci. The penicillinase-resistant penicillins are the drug of choice when infection due to MSSA is suspected.

Carbapenem Antibiotics

Imipenem [Primaxin®] ® Imipenem [Primaxin ] was introduced in 1985 as the first carbapenem antibiotic. Carbapenems have the same ring structure as the penicillins, with substitution of carbon for sulfur in the five-member ring. Imipenem has the broadest antimicrobial spectrum available among β-lactam antibiotics, including gram-positive cocci, gram-negative cocci, gram-negative bacilli, and anaerobic bacteria. Its uses include single-drug therapy in immunocompromised patients with suspected sepsis, as an alternative to combination therapy for serious intra-abdominal infections and for severe hospitalacquired infections. Additional indications include skin and skin structure infection abscesses and cellulitis. The drug is not approved for use in children younger than 12 years old. Meropenem [Merrem®] ® Meropenem [Merrem ] is a carbapenem antibiotic that was approved in 1996 for intravenous therapy of complicated intraabdominal infections, skin and skin structure infections, and bacterial meningitis in children 3 months of age and older.17 The drug has a broad spectrum of antibacterial activity similar to that of imipenem, including gram-positive and gramnegative aerobes and anaerobes. Meropenem is effective for bacterial meningitis. Meropenem has demonstrated both in vitro activity and clinical efficacy against penicillin-resistant S. pneumoniae. The broad spectrum of activity of meropenem suggests a possible role in the treatment of complicated infections of the head and neck when MRSA is not a pathogen.

Toxicity and Sensitization of the Penicillins The penicillins have minimal dose-related toxicity but may produce allergic reactions. Because most allergic reactions are believed to be due to a metabolic breakdown product of the penicillin nucleus, allergy to one penicillin drug implies allergy to all. Seizures may occur under circumstances that result in extraordinarily high concentrations of penicillin in neural tissues. Nephritis has followed administration of some penicillins, most frequently methicillin. The mechanism of the nephrotoxicity is uncertain, but recent data suggest that the renal injury is probably antibody-mediated and not a direct toxic effect.18 Penicillin-induced hemolytic anemia is also reported with high and sustained levels of penicillin in the blood.19 Other uncommon adverse events include neutropenia associated with the use of any penicillin (white blood cell counts return to normal after the drug is discontinued); platelet dysfunction following use of carbenicillin and ticarcillin; and hepatic dysfunction reflected in elevated serum aspartate

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175

TABLE 15-2. Penicillinase-resistant Penicillins: Antimicrobial Spectrum, Recommended Dosages, and Potential Adverse Effects

Usual Pediatric Route Dosage

Drug

Antibacterial Activity

Serious Adverse Events

Dicloxacillin

Gram-positive cocci, including S. aureus. Not enterococci

po

50–100 mg/kg/d, administered q 6–8 h

Rash, diarrhea, eosinophilia, elevated transaminases

Methicillin

Same as dicloxacillin

IV

100–200 mg/kg/d

Interstitial nephritis, eosinophilia, leukopenia

Nafcillin

Same as methicillin

IV

50–200 mg/kg/d, q 4–6 h

Fever, transaminase elevation, anemia, leukopenia, nephrotoxicity

Imipenem

Gram-positive cocci, E. coli, H. influenzae, K. pneuomoniae, P. aeurginosa, Enterobacter species, acinobacter, and anaerobes

IV

60–100 mg/kg/d, q 6 h

Seizures (primarily in patients with renal dysfunction)

Amoxicillin + Clavulanate

Gram-positive cocci, H. influenzae, M. catarrhalis, E. coli, Klebsiella, B. fragilis, and fusobacterium

po

Up to 90 mg/kg/d administered bid (augmentin ES)

Similar to amoxicillin, greater diarrhea

Ampicillin + Sulbactam

Same as amoxicillin + clavulanate

IV

200–300 mg/kg/d administered every 6–8 h

Same as amoxicillin

Piperacillin + Tazobactam

E. coli, B. fragilis, K. pneumonia, H. influenzae, P. aeruginosa, and anaerobes

IV

200–300 mg piperacillin/kg/d administered q 6–8 h

Same as piperacillin

Abbreviations: IM, intramuscular; IV, intravenous po, orally. Source: Bradley JS, Nelson JD, eds. Nelson’s Pocket Book of Pediatric Antimicrobial Therapy. 18th ed. AAP; 2010–2011.

transaminase, which has been identified following the use of oxacillin, nafcillin, and carbenicillin. Sensitivity is also a potential issue with penicillin use. As with any drug or hapten, 1 of the 4 types of reactions may occur: immediate or anaphylactic reactions occurring within 30 minutes, accelerated reactions occurring from 1 to 72 hours after administration, late allergic reactions usually occurring after 3 days, and immune-complex reactions that include serum sickness, hemolytic anemia, and drug fever.

The Cephalosporins Cephalosporins and the closely related cephamycins and carbapenems, like the penicillins, contain a β-lactam chemical structure (Table 15-3). Eight oral cephalosporins (cefaclor, cefixime, cefuroxime axetil, cefprozil, cefpodoxime, ceftibuten, cefdinir, and loracarbef) and one

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parenteral cephalosporin (ceftriaxone) have been evaluated in clinical trials for therapy of acute otitis media and sinusitis. Parenteral ceftazidime with activity against S. aureus and P. aeruginosa is of particular importance for the treatment of chronic suppurative otitis media. Ceftriaxone offers the convenience of a single daily dosing regimen as well as effective therapy against β-lactamase-producing strains of H. influenzae, nonsusceptible isolates of S. pneumoniae with MICs up to 4 μg/mL (for ceftriaxone) and M. catarrhalis. In 2010, ceftaroline fosamil, an injectable cephalosporin antibiotic for the treatment of community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections including MRSA, was approved for use in adults.20 The cephalosporins have been categorized as first-, second-, third-, fourth-, and now fifth-generation drugs, based on time of introduction and, to a lesser extent, their in vitro activity.

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TABLE 15-3. Cephalosporins Drug

Antibacterial Activity

First Generation

Most gram-positive cocci (not enterococci, not penicillinresistant pneumococci, not listeria); penicillinaseproducing staphylococci (not MRSA); many E. coli, P. mirabilis, K. pneumonia

Cefazolin (IV) Cephalothin (IV) Cephalexin (po) Cephadroxil (po) Cephradine (po) Second Generation Cefaclor (po) Loracarbef (po) Cefprozil (po)

Usual Pediatric Dosage (mg/kg/d) 50–100

25–50 30 25–50

Two major divisions are those with activity against Haemophilus and the cephamycins with activity against Bacteroides (cefoxitin and cefotetan)

Serum sickness with cefaclor; Platelet dysfunction with cefoxitin

40 30 30 30 (po); 100–150 (IV)

Cefamandole (IV)

100–150

Cefoxitin (IV)

80–160

Cefotetan (IV)

60–100

Cefixime (po) Cefpodoxime (po) Cefdinir (po) Ceftibutin Ceftriaxone (IV) Ceftizoxime (IV) Cefotaxime (IV)

Allergic reactions similar to those caused by the penicillins, interstitial nephritis, drug fever

100

Cefuroxime (po, IV)

Third Generation

Serious Adverse Events

Highly active against E. coli, P. mirabilis, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, Citrobacter, Neisseria, and H. influenzae. Ceftriaxone and cefotaxime active against gram-positive cocci including many penicillin-resistant SP. Inactive against enterococci, Listeria, MRSA, and acinobacter. Cefoperazone and ceftaidime have antipseudomonal activity.

Biliary “gravel” seen with ceftriaxone

8 10 14 9 50–100 100–200 100–300

Cefoperazone (IV)

100–150

Ceftazidime (IV)

90–300

Fourth Generation Cefapime

Similar to ceftriaxone and cefotaxime against SP, penicillinase-producing S. aureus, P. aeruginosa

100–150

Fifth Generation

MRSA

Pediatric dosing not established

Ceftaroline

Abbreviations: IV, intravenous; po, orally. Source: Update on Cephalosporins in Pediatrics. Baker CJ (editor in chief ). Clinical updates in pediatric infectious diseases, NFID series, Updated June 2002. In: Bradley JS and Nelson JD, eds. Nelson’s Pocket Book of Pediatric Antimicrobial Therapy. 18th ed. AAP; 2010–2011.

Role of the Cephalosporins in Infants and Children Although many cephalosporins are available, there are only a few infectious diseases in children for which one of these drugs offers a unique advantage over previously available

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antimicrobial agents. Some of the cephalosporins, as well as meropenem, may be appropriate alternatives when allergy (usually type 1) prevents the use of penicillins.21,22 For the treatment of head and neck infections and their complications, selected cephalosporins may be considered in the following circumstances.

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CHAPTER 15 ❖ Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections 1. Disease caused by S. aureus, group A streptococcus, and S. pneumoniae in children with known or suspected allergy to penicillin that is not characterized as anaphylaxis, Steven–Johnson syndrome, toxic epidermal necrolysis, or angioneurotic edema and when MRSA is not suspected: oral or parenteral first-generation cephalosporin. 2. Otitis media, sinusitis, and mild lower respiratory infections including cases in children who may have failed on amoxicillin because of β-lactamase-producing strains of H. influenzae or M. catarrhalis: cefuroxime axetil and cefpodoxime.5 3. Mixed infections, including anaerobic bacteria: cefoxitin or cefotetan. 4. Orbital cellulitis: cefuroxime or ceftriaxone. 5. Severe complications due to gram-negative enteric bacilli: cefotaxime, ceftriaxone, or ceftazidime. 6. Ambulatory therapy for patients requiring high and sustained concentrations of drug in the blood and the tissues: ceftriaxone. 7. Infections due to or suspected to be due to P. aeruginosa: ceftazidime. 8. Nonlife-threatening infections due to MRSA: ceftaroline

First-Generation Cephalosporins The first-generation cephalosporins are effective against grampositive cocci, including β-lactamase-producing S. aureus, and have variable activity against gram-negative enteric bacilli. Six first-generation cephalosporins are currently available for use in infants and children. These include the ® ® parenteral agents cephalothin [Keflin and Seffin ], cefazolin ® ® ® ® [Ancef , Kefzol , and Zolicef ], and cephapirin [Cefadyl ] ® ® and the oral products cephalexin [Keflex , Keftal , and ® ® ® Cefanox ], cefadroxil [Duricef ], and cephradine [Velocef ], which is available in both oral and parenteral forms. The three oral preparations have comparable in vitro activity.23 First-generation cephalosporins are alternatives for disease caused by methicillin-susceptible S. aureus, penicillinsusceptible and intermediate S. pneumoniae (MIC < 2 μg/mL), and group A streptococcus. Activity against H. influenzae is limited and in general not efficacious. First-generation cephalosporins are also of value for children with disease due to susceptible organisms with a history of mild nonlifethreatening reactions to penicillin.24 They should be used cautiously in individuals with a history of anaphylaxis (see above), Steven–Johnson syndrome, toxic epidermal necrolysis, or angioneurotic edema associated with the administration of penicillin. Cefadroxil is of value for treatment of streptococcal pharyngitis because it can be administered once a day. Cephalexin may be used for mild to moderately severe staphylococcal infections of the skin and soft tissues due to susceptible isolates (MSSA). Cefazolin is extensively used for perioperative prophylaxis.

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Second-Generation Cephalosporins The second-generation cephalosporins consist of seven par® ® enteral drugs (cefamandole [Mandol ], cefoxitin [Mefoxin ], ® ® cefuroxime [Kefurox and Zinacef ], ceforanide (ceforan, ® Precef, Rancef, Xitus), cefonicid [Monocid ], cefotetan ® ® [Cefotan ], and cefmetazole [Zefazone ]) and 8 oral prep® ® arations (cefaclor [Ceclor ], cefuroxime axetil [Ceftin ], ® ® cefprozil [Cefzil ], cefpodoxime [Vantin ], ceftibuten ® ® ® [Cedax ], cefixime [Suprax ], cefdinir [Omnicef ], and lora® carbef [Lorabid ]). Each of the oral preparations is of value for the treatment of acute otitis media and sinusitis as serum and middle ear concentrations are greater than the pharmacokinetic/pharmacodynamic (PK/PD) breakpoints for susceptible and intermediate (MIC < 2 μg/mL) pneumococci, H. influenzae, and M. catarrhalis, including β-lactamaseproducing strains. Among the parenteral preparations, cefotetan, ceforanide, cefonicid, and cefmetazole are not approved for use in infants and children. Cefdinir, cefpodoxime, and cefuroxime have become the cephalosporins of choice for the treatment of middle ear and sinus infections.25,26 Cefuroxime is available in oral and parenteral forms and is of value in the treatment of diseases in which grampositive cocci, particularly methicillin-sensitive S. aureus and H. influenzae, are the likely pathogens. Common indications are upper and lower respiratory tract infections, including sinusitis and pneumonia, and the complications thereof such as orbital cellulitis (parenterally). The oral preparation, cefuroxime axetil, is considered an alternative for patients who fail initial therapy with amoxicillin for otitis media and sinusitis primarily because of its activity against β-lactamaseproducing hemophilus; however, a significant proportion of nonsusceptible Streptococcus pneumoniae (SP) isolates have MICs that exceed this PK/PD breakpoint. The oral suspension has a bitter taste, further limiting its use in infants and young children. Cefpodoxime proxetil is an oral preparation with in vitro activity against both gram-negative and gram-positive organisms of importance in otitis media. The drug has a half-life of 2.1–2.8 hours, which permits effective therapy with twicedaily oral dosing. The in vitro activity, pharmacokinetics, and clinical experience are provided in published symposium proceedings.27 The drug is now approved for the treatment of acute otitis media with a dosage schedule of once a day for five days. Cefdinir is active against the bacterial pathogens of importance in acute otitis media. Peak concentration achieved in serum following single doses of 14 mg/kg was 3.86 μg/mL. Mean middle ear concentrations were approximately 15% of corresponding plasma concentrations. The 14 mg/kg dosage can be administered once a day. A single randomized trial showed comparability of cefdinir in a once-a-day dosage schedule versus amoxicillin/clavulanate in a thrice-a-day dosage schedule for treatment of acute otitis media.28 A recent symposium on the role of cefdinir for pediatric infectious

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diseases provides a comprehensive review of pharmacokinetics, pharmacodynamics, and safety and clinical information from various trials, including efficacy for infants and children with acute otitis media.29 As with other oral cephalosporins, its PK/PD breakpoint is below the MIC of a significant proportion of nonsusceptible isolates of S. pneumoniae, limiting its value in children with risk factors for disease due to resistant pneumococci. Cefprozil is an oral cephalosporin with in vitro activity against gram-positive cocci, certain Enterobacteriaceae and gram-negative respiratory pathogens. Clinical trials indicate efficacy comparable to amoxicillin–clavulanate for acute otitis media. The drug is well absorbed from the gastrointestinal tract, has a twice-a-day dosing schedule, and has a paucity of side effects or dose-related toxicity. The clinical experience with cefprozil was reviewed at a recent symposium.30 Middle ear fluid concentrations and duration of time over MIC suggests microbiologic activity for organisms with MIC < 1 μg/mL. They also suggest higher clinical failure with cefprozil against otopathogens with MIC > 1 μg/mL. Cefaclor is an oral preparation that is effective in vitro against gram-positive cocci and H. influenzae, including β-lactamase-producing strains. Extensive experience from clinical trials supported efficacy in therapy of otitis media, sinusitis and mild to moderate cases of pneumonia. An unusual serum sickness reaction characterized by cutaneous rash, arthralgia/arthritis, and fever has been associated with administration of cefaclor in some patients. PK/PD parameters support limited efficacy against nonsusceptible isolates of S. pneumoniae. Levine31 compared rates of serum sickness reactions to cefaclor and amoxicillin in 2026 children who received 4871 courses of the antibiotics. Serum sickness (defined as arthritis/arthralgia plus a rash or urticaria) or erythema multiforme occurred in 11 children who received cefaclor and in no children given amoxicillin. Loracarbef is an oral preparation that is chemically identical to cefaclor, except that the sulfur atom in the dihydrothiazine ring has been replaced by a methylene group. The new drug is termed a carbacephem rather than a cephalosporin. Loracarbef is similar in antibacterial activity to cefaclor, with in vitro activity against most gram-positive cocci, H. influenza, and M. catarrhalis. The serum sickness–like reaction with rash, arthritis, and fever that has been reported with cefaclor has not been identified with loracarbef. As with cefaclor, loracarbef has limited activity against penicillin nonsusceptible pneumococci. Cefixime is an oral preparation that has been identified as a third-generation drug because of increased activity for gram-negative organisms, but is included here for comparison with the other oral cephalosporins of value for acute otitis media. Decreased activity against gram-positive pathogens, including nonsusceptible S. pneumoniae, has led to clinical failures in children with pneumococcal otitis media or pneumococcal bacteremia. S. aureus and coagulase-negative staphylococci are also relatively resistant. Currently, its use

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is primarily limited to urinary tract infections as the prevalence of nonsusceptible S. pneumoniae in acute otitis media and sinusitis, and the higher rates of treatment failure in that setting support the use of alternative cephalosporins (cefpodoxime, cefuroxime, and cefdinir). Ceftibuten is an oral preparation with a spectrum of activity similar to that of cefixime. However, it is stable to common plasmid- or chromosomal-mediated β-lactamases, including some enzymes that hydrolyze parenteral thirdgeneration cephalosporins. The half-life of two to three hours permits once-a-day dosing. Mean peak plasma and middle ear fluid concentrations are comparable; after a dose of 9 mg/kg once daily for 3 days, the peak was 14 μg/mL at 2 hours in plasma and 4 hours in the middle ear.32 Clinical trials indicate clinical efficacy comparable to amoxicillin/ clavulanate.33 Cefoxitin has excellent activity against anaerobic organisms, particularly B. fragilis, and selective activity against gram-negative enteric bacilli, and it has been effective for therapy of intra-abdominal, gynecologic, and respiratory infections due to mixed bacterial pathogens, including anaerobic bacteria. Cefotetan was introduced in 1986 with an in vitro spectrum of activity and clinical usage similar to that of cefoxitin, but it is not approved for use in children. Cefamandole is active against gram-positive cocci, including S. aureus, and was the first cephalosporin to be effective for infections due to H. influenzae (including β-lactamaseproducing strains). Reports of clinical and microbiologic failure in small number of cases of meningitis due to H. influenzae type b (presumably due to inadequate concentrations of drug in CSF) have limited its use.

Third- and Fourth-Generation Cephalosporins ®

®

Cefoperazone [Cefobid ], cefotaxime [Claforan ], ceftriax® ® one [Rocephin ], ceftizoxime [Cefizox ], and ceftazidime ® ® ® [Ceptaz , Fortaz , and Tanicef ] are parenteral products with efficacy in vitro against gram-positive cocci, gram-negative enteric bacilli, and H. influenzae. They have marked increased activity against gram-negative bacilli when compared with the activity of first- and second-generation cephalosporins, but reduced activity against selected gram-positive cocci such as S. aureus, requiring caution when serious staphylococcal infections have not been excluded. Cefoperazone has not been approved for use in children younger than 12 years of age. Ceftriaxone is effective against gram-positive cocci, including group A streptococci, S. pneumoniae, H. influenzae, and selected gram-negative enteric bacilli. Its activity against S. aureus is less than first- and second-generation cephalosporins, and in general, this agent is not used alone when staphylococci are considered to be likely pathogens. The unique quality of ceftriaxone is the long half-life resulting in prolonged therapeutic concentrations of drug in blood and tissues; the serum half-life is approximately 6.5 hours.

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CHAPTER 15 ❖ Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections Serum concentrations are significantly higher than the minimum inhibitory concentrations of the common pathogens responsible for acute otitis media and many head and neck infections for more than 24 hours. Such high middle ear concentrations persist for more than 48 hours after a single intramuscular dose.34 For diseases requiring prolonged therapy, ceftriaxone may be of value for use outside the hospital in single daily intramuscular doses or for intravenous administration in children with venous access. A single dose of intramuscular ceftriaxone is equivalent in clinical efficacy to 10 days of amoxicillin,35 trimethoprim-sulfamethoxazole (TMP-SMX)35 or amoxicillin–clavulanate in children with otitis media due to penicillin-susceptible S. pneumoniae or nontypable H. influenza.36 Such single intramuscular dosing is favored by parents when compared with the traditional 10 days of oral drug.37 For children who have failed amoxicillin and other oral therapies for acute otitis media, ceftriaxone (50 mg/kg IM) is clinically and microbiologically effective when administered in three consecutive daily intramuscular doses against disease due to penicillin-resistant S. pneumonia.38–40 An alternative regimen for children who have failed initial therapy with amoxicillin is a single dose of ceftriaxone and observation for 48 hours. If clinical signs resolve, no further therapy is necessary. If clinical signs persist, a second dose is administered, and if necessary, a third dose.41 Ceftizoxime has a spectrum of activity similar to that of cefotaxime. Clinical experience with the drug in children is limited. Although ceftizoxime has been approved for treatment of meningitis due to H. influenzae and S. pneumoniae, its role in other pediatric infectious diseases is uncertain. Ceftazidime was introduced for clinical use in the United States in 1985. The drug is highly resistant to inactivation by a broad spectrum of β-lactamases and has excellent activity in vitro against P. aeruginosa, including strains resistant to antipseudomonal penicillins. Its use in middle ear infections in children is most applicable to chronic suppurative otitis media or other infections in which P. aeruginosa plays an important role. Cefepime is a parenteral cephalosporin with excellent activity against gram-positive organisms and enhanced gram-negative activity including P. aeruginosa, and it has been demonstrated to have efficacy equivalent to other thirdgeneration cephalosporins such as cefotaxime, ceftazidime, and ceftriaxone. It is not approved for use in infants and children.

Fifth-Generation Cephalosporins Ceftaroline [TEFLARO™] is a novel fifth-generation cephalosporin that has activity against MRSA. In phase III clinical trials for complicated skin and skin structure infections, ceftaroline is comparable to vancomycin and aztreonam against MRSA infections.42,43 Ceftaroline recently received FDA approval for the treatment of community acquired bacterial pneumonia and acute bacterial skin and skin

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structure infections of MRSA etiology. The clinical studies indicated that ceftaroline was well tolerated; the most common adverse reactions occurring in more than 2% of patients are diarrhea, nausea, and rash.

Toxicity and Sensitization of the Cephalosporins The cephalosporins, like the penicillins, are safe for children and have almost no dose-related toxicity. Physicians should be alert for the uncommon adverse reactions, such as kidney problems, alcohol intolerance, serum sickness–like reactions, and bleeding. Bleeding problems due to hypoprothrombinemia, thrombocytopenia, or platelet dysfunction have been associated with several cephalosporins (cefoxitin). The cephalosporins may produce allergic reactions similar to those caused by the penicillins. There is cross-sensitization among the cephalosporins, and allergy to one drug implies (as is the case with the penicillins) allergy to all. Various degrees of immunologic cross-reaction of penicillins and cephalosporins have been demonstrated in vitro and in animal models.44 Patients with a history of penicillin allergy have shown increased reactivity to cephalosporins. Most patients who are believed to be penicillin allergic can be given cephalosporins without an adverse reaction occurring. For these reasons, a cephalosporin can be used with caution as an alternative to penicillin in children who have an ambiguous history of skin rash. However, cephalosporins should be avoided in patients with a known immediate or accelerated reaction to a penicillin.

THE MACROLIDES AND KETOLIDES The macrolides possess a many-membered lactone ring attached to one or more deoxy sugars. The first macrolide, eryth® ® ® romycin [E-mycin , Ery-tab , and Benzamycin ], was introduced in the 1950s as the drug of choice for penicillinallergic patients. Two newer oral macrolide antibiotics, ® ® azithromycin [Zithromax ] and clarithromycin [Biaxin ], were introduced for use in infants and children in the period of 1994 through 1996. Azithromycin differs from erythromycin in having a methyl-substituted nitrogen in its 15-member lactone ring. Clarithromycin has a 14-member ring structure with a methoxy group in the position C6 of the lactone ring of erythromycin. Azithromycin and clarithromycin, when compared with erythromycin, have several advantageous properties: prolonged half-lives, higher and more prolonged concentrations in cells and tissues, increased in vitro activity against selected organisms, and possibly less gastrointestinal distress. Pharmacologic and clinical data regarding these agents are available for review in the proceedings of a symposium on the macrolides and like compounds.45,46 ® Telithromycin [Ketek ] is the first member of the ketolide class of antimicrobials. It was developed for the treatment of

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respiratory tract pathogens resistant to macrolides. Several chemical alterations, such as a keto group at C3, enhance the binding of this compound to ribosomal RNA, which results in increased potency. However, concerns about hepatotoxicity and exacerbations of myasthenia gravis have limited its use. It has not been licensed for use in children in the United States. All the macrolides are effective against gram-positive cocci, group A streptococci, susceptible pneumococci, and susceptible S. aureus. Clarithromycin and azithromycin have greater activity against H. influenzae than does erythromycin. However, the PK/PD breakpoint suggests the MIC of most isolates is beyond that achieved with either the macrolides or the ketolides47 Other organisms of importance in respiratory infections that are susceptible to the macrolides include M. pneumoniae, Legionella species, Chlamydia species, Bordetella pertussis, and Corynebacterium diphtheriae. Azithromycin and clarithromycin are also active against Chlamydia pneumoniae and Mycobacterium avium complex. The macrolides have limited efficacy against moderately or highly penicillin-resistant pneumococci and are ineffective against erythromycin-resistant staphylococci and streptococci.

Clinical Pharmacology Erythromycin, azithromycin, and clarithromycin are well absorbed from the gastrointestinal tract.48 Food decreases the absorption of azithromycin, so this drug should be administered one hour before or two hours after meals. Food does not affect the bioavailability of erythromycin or clarithromycin; hence, the drugs may be given without regard to meals. Biliary excretion is the major route of elimination of the macrolides. The prolonged half-lives permit once-a-day dosage schedule for azithromycin and twice-a-day schedule for clarithromycin, in contrast to the four times a day schedule of erythromycin. Concentration in cells and tissues occurs with each macrolide, but most prominently with azithromycin and, to a lesser degree, with clarithromycin. High concentrations of drug have been identified in polymorphonuclear leukocytes, fibroblasts, alveolar macrophages, tonsils, sinus and middle ear fluids, and middle ear mucosa,49 while the serum concentration is comparatively low. This characteristic of high intracellular concentrations with low serum concentrations has made development of breakpoints challenging, and effectiveness varies with regard to whether the primary site of infection is intracellular or extracellular. For example, in acute otitis media, where the primary site of infection is thought to be extracellular, success or failure to sterilize the middle ear has correlated most closely with extracellular concentration and MIC for specific pathogens.

Clinical Efficacy In the American Academy guidelines for the treatment of acute otitis media, azithromycin and clarithromycin are considered appropriate therapy for children with type I (anaphylaxis)

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allergy to penicillins when risk factors for penicillin nonsusceptible S. pneumoniae or nontypable H. influenzae are absent.4 A fixed combination of erythromycin ethylsuccinate and sulfisoxazole (Pediazole) is available and effective for treatment of acute otitis media. Each 5 mL contains 200 mg of erythromycin activity and the equivalent of 600 mg of the sulfonamide. This combination provides activity against the pneumococcus and ampicillin-sensitive and -resistant strains of H. influenza and is of value for children who are allergic to penicillin or who fail initially when treated with amoxicillin and may have infection due to an ampicillin-resistant strain of H. influenzae. Azithromycin is approved for the treatment of acute otitis media in three dosage regimens: one dose per day over five days, three days of a single daily dose, or as a single dose. The total dose administered is comparable for all three regimens. The efficacy of azithromycin for acute otitis media due to H. influenzae is questionable based on microbiologic studies of middle ear fluid before and after therapy.50 Dagan et al. found a high incidence of bacteriologic failure in children treated with either dosing regimen of azithromycin.50 Animal studies suggest that the failure to clear H. influenzae at three to four days in the azithromycin arm may be due to a slower rate of eradication and that sterilization may occur later in the course of therapy.51 Clarithromycin has a spectrum of activity similar to erythromycin, but has increased activity against H. influenzae as a result of its active metabolite, 14-hydroxyclarithromycin.52 Clinical trials of children with acute otitis media document comparability of clarithromycin with cefaclor,53 amoxicillin,54 and amoxicillin–clavulanate.55 However, concerns similar to azithromycin regarding eradication of middle ear pathogens, primarily nontypable H. influenzae, limit its role in the treatment of acute otitis media. Clarithromycin has excellent in vitro activity against many of the nontuberculous mycobacterium. It is often used in conjunction with rifabutin for medical management. The dose is 15 mg/kg/d divided bid up to a maximum single dose of 500 mg. Severe neutropenia hearing loss has been reported with the combination. Azithromycin is also active against the nontuberculous mycobacterium. Drug intetraction between macrolides and rifabutin require monitoring to optimize therapeutic benefit and minimize toxicity.56,57

Toxicity and Side Effects The estolate of erythromycin may give rise to a cholestatic jaundice, which is believed to be due to a hypersensitivity reaction. The jaundice has been reported to occur almost exclusively in adults who receive the estolate for more than 14 days and usually resolves when administration of the drug is stopped. Few cases of jaundice in children have been reported, but physicians should consider a limit of therapy to 10 days and be alert for signs of liver toxicity. Concurrent use of erythromycin and theophylline in patients with asthma has been a concern because of the effect

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CHAPTER 15 ❖ Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections of the antibiotic on the pharmacokinetics of theophylline. Increases in serum theophylline concentrations have been demonstrated when administered concurrently with erythromycin and clarithromycin, but not azithromycin.

CLINDAMYCIN AND LINCOMYCIN ®

®

Clindamycin [Cleocin ] and lincomycin [Lincocin ] are effective in vitro against both anaerobic and aerobic gram-positive cocci. Many penicillin-resistant strains of S. pneumoniae are susceptible to clindamycin; a multihospital study of 1275 isolates of S. pneumoniae identified only 6.3% who were resistant to clindamycin.58 However, recently a multidrugresistant serotype 19A S. pneumoniae has emerged as an important cause of treatment failure in acute otitis media,59 mastoiditis, and sinusitis60,61 that is frequently resistant to clindamycin. Clindamycin is also active against a wide range of anaerobic bacteria, including penicillin-resistant Bacteroides species and fusobacterium, both important causes of head and neck infections.62 Clindamycin provides higher levels of activity in serum than does lincomycin, and, in contrast to lincomycin, oral absorption is not decreased when the drug is taken with food. Because of its limited activity against H. influenzae, clindamycin is most appropriate as initial therapy for otitis media only when the pathogen is known to be a susceptible gram-positive coccus. Alternatively, if the causative organism is not known, clindamycin can be combined with a sulfonamide or cefixime, both of which are active against Haemophilus species. Clindamycin is active against S. aureus, including many strains of MRSA. As such, it has become an important part of the therapeutic management of nonlife-threatening MRSA infections. Clindamycin is well tolerated in children. Diarrhea is a common side effect, but enterocolitis, reported in as many as 10% of adult patients after treatment with clindamycin, is fortunately rare in the pediatric population. Enterocolitis has also been associated with other antibiotics that alter intestinal flora including ampicillin,63 tetracycline, chloramphenicol, selected cephalosporins, and lincomycin. Overgrowth of toxin-producing strains of Clostridium difficile is responsible for most cases of antibiotic-associated colitis. The antibiotic suppresses the normal flora in the colon, and the C. difficile organisms proliferate and produce an enterotoxin that is responsible for the disease. Most cases have occurred in elderly patients, those with severe illness, or those receiving multiple antimicrobial agents.64 Concern for enterocolitis should not limit the use of clindamycin in children.

THE SULFONAMIDES AND TRIMETHOPRIMSULFAMETHOXAZOLE The first sulfonamide, the first drug of the modern antimicrobial era (Prontosil), was reported65 to be effective against infections due to β-hemolytic streptococci in 1935. Soon

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after their introduction, however, both streptococci and pneumococci developed resistance to these sulfonamides. Today, sulfonamides are used in the treatment of a wide variety of infections in children, including otitis media due to nontypable strains of H. influenzae, usually in combination with a penicillin or erythromycin, to provide coverage for S. pneumoniae. Sulfisoxazole is also efficacious for prophylaxis in children with recurrent episodes of acute otitis media.66 ® ® Trimethoprim-sulfamethoxazole [Bactrim , Septra , ® ® Cofatrim , and Primsol ] is an antimicrobial combination with significant activity against a broad spectrum of gram-positive cocci and gram-negative enteric pathogens. Trimethoprim is more active than the sulfonamide, but the mixture is significantly more effective than either drug alone. The drugs act in synergy by blocking the sequence of steps by which folic acid is metabolized. Sulfamethoxazole was chosen as the sulfonamide to use in combination with trimethoprim because the drugs have similar patterns of absorption and excretion. Both are well absorbed from the gastrointestinal tract, and food does not affect absorption. A parenteral preparation is commercially available and has been used extensively for the treatment of pneumocystis pneumonia. Adverse reactions to this combination include rashes similar to those previously associated with sulfonamides (maculopapular or urticarial rashes, purpura, photosensitivity reactions, and erythema multiforme bullosum) and gastrointestinal symptoms, primarily nausea and vomiting. Hematologic indices have been carefully evaluated because of the antifolate activity of trimethoprim. Leukopenia, thrombocytopenia, agranulocytosis, and aplastic anemia have been associated with administration of TMP-SMX, but the incidence of these adverse reactions is low. Hemolysis may occur in patients with erythrocyte deficiency of glucose6-phosphate dehydrogenase. The combination of TMP-SMX in children has been effective in the treatment of acute otitis media due to S. pneumoniae or H. influenzae (including β-lactamaseproducing strains). An increasing proportion of strains of S. pneumoniae are resistant to TMP-SMX; 19% of nasopharyngeal isolates obtained from nasopharyngeal cultures in Boston children in 2007 had MICs ≥ 0.5 mg/mL (trimethoprim) for the combination drug.67 The combination has been used with success for children who are allergic to penicillins or who fail after an initial course of ampicillin due to β-lactamase-producing strains of H. influenzae.68,69 The drug is not effective when group A streptococci is the pathogen; therefore, it is not recommended for pharyngitis due to group A streptococcus.

VANCOMYCIN ®

®

Vancomycin [Vancocyn and Lyphocin ] is a parenterally administered antimicrobial agent with a spectrum of activity limited to gram-positive organisms. It is usually

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administered by the intravenous route because intramuscular injection causes pain and tissue necrosis. Ototoxicity and nephrotoxicity resulted from high concentrations in serum of early preparations, but improvements in the manufacturing process have decreased this risk. The use of vancomycin in children has expanded as the role of MRSA as a major pathogen in skin and soft tissue infections and postoperative infections has increased. Vancomycin has become the treatment of choice for serious staphylococcal disease caused by S. aureus or Staphylococcus epidermidis resistant to the penicillinase-resistant penicillins (methicillin-resistant staphylococci), as well as for the treatment of sepsis caused by enterococci in patients who have a significant history of allergy to penicillin. Vancomycin is one of the few antimicrobial agents (linezolid, ceftaroline, levofloxacin, and rifampin are others) that are effective in vitro against penicillin-resistant strains of S. pneumoniae.70 The Centers for Disease Control and Prevention suggests empirical therapy with vancomycin in addition to a third-generation cephalosporin for cases of meningitis potentially caused by S. pneumoniae until results of culture and susceptibility testing are available.71 Vancomycin has also been reported effective for the treatment of mastoiditis and persistent otitis media due to multidrug resistant S. pneumoniae serotype 19A.59 Routine monitoring of vancomycin peak concentrations is no longer recommended as the correlate of efficacy is time of the MIC. However, measurement of trough levels is indicated in patients treated for more than three days before the fourth dose, especially in those likely to receive more prolonged therapy.72 A target trough concentration of 15–20 mcg/mL is recommended for serious infections including those due to MRSA.

THE OXAZOLIDINONES ®

Linezolid [Zyvox ] is a synthetic oxazolidinone with activity against a spectrum of gram-positive organisms that include coagulase-negative staphylococci, MSSA and MRSA, and streptococci and enterococci. Linezolid is bacteriostatic against most of these pathogens except S. pneumoniae. As an inhibitor of protein synthesis, it suppresses the production of bacterial toxins such as panton-valentine leukocidin and toxic shock syndrome toxin-1. Linezolid is active against multidrug-resistant serotype 19A S. pneumoniae.70,73 Systemic absorption is nearly 100% after oral administration allowing progression from parenteral to oral administration. It has low protein binding, which results in penetration to most body compartments including the CSF. The most common serious adverse event is bone marrow suppression, specifically thrombocytopenia, which occurs frequently with courses of therapy that exceeds four weeks. Other serious side effects include optic and peripheral neuropathy and lactic acidosis. In general, discontinuation of therapy results in resolution of these adverse events.

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THE TETRACYCLINES AND GLYCYLCYCLINES Tetracyclines are effective against a broad range of microorganisms, including gram-positive cocci and some gramnegative enteric bacilli. However, a significant proportion of group A streptococci and some strains of S. pneumoniae are resistant, limiting the empiric use of tetracyclines for respiratory tract infections. Seven tetracycline compounds are available for oral adminis® tration in the United States. These are tetracycline [Sumycin ], ® chlortetracycline, oxytetracycline [Terramycin ], demeclocy® ® cline [Declomycin ], methacycline [Rondomycin ], doxy® ® ® cycline [Doxy , Vibra , and Vibramycin ], and minocycline ® [Minocin ]. Tetracycline, chlortetracycline, doxycycline, and minocycline are also available for intravenous administration. With few exceptions, there are only minor differences in the in vitro activity of the different preparations. However, minocycline and doxycycline are effective against many strains of MSSA and MRSA; and doxycycline may inhibit strains of B. fragilis that are resistant to the other tetracyclines.74 Tetracyclines are deposited in the teeth during the early stages of calcification and cause dental staining. Total dose correlates with the degree of visible staining. Tetracyclines cross the placenta, and discoloration of teeth has been seen in babies of mothers who received tetracycline or its analogues after the sixth month of pregnancy. The permanent teeth are stained if the drug is administered after 6 months and before 6 years of age. Other adverse effects include phototoxicity (particularly with demeclocycline), nephrotoxicity (with tetracycline hydrochloride, oxytetracycline, and demeclocycline), and vestibular toxicity (with minocycline). There are few indications for administering a tetracycline to a young child with infection of the respiratory tract as other effective drugs are available for almost all infections. For a child 8 years of age and older, a tetracycline may be considered an alternative to erythromycin for disease due to M. pneumoniae, chlamydial infections (psittacosis, trachoma, and inclusion conjunctivitis), borrelia, and first-line therapy for rickettsial diseases, including Rocky Mountain spotted fever. ® Tigecycline [TYGACIL ] is the first clinically available drug in a new class of antibiotics called the glycylcyclines. It is structurally similar to the tetracyclines in that it contains a central 4-ring carbocyclic skeleton and is actually a derivative of minocycline. Tigecycline is bacteriostatic and inhibits protein synthesis. Tigecycline is given intravenously and has activity against various gram-positive and gramnegative bacterial pathogens, including activity against MRSA. In studies of complicated skin and soft tissue infections, it was demonstrated to be comparable to vancomycin and aztreonam.75 Recent studies have linked tigecycline to an increased risk for death in patients with certain severe infections. The cause is uncertain, but may be related to progression of the infection and the bacteriostatic nature of tigecycline.76

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CHAPTER 15 ❖ Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections

THE AMINOGLYCOSIDES Aminoglycosides provide a broad coverage against gramnegative enteric bacilli and some gram-positive organisms (such as S. aureus). They are rapidly bactericidal and are readily absorbed after administration. The major concerns regarding their use relate to nephrotoxicity, ototoxicity, and poor diffusion across biologic membranes, including passage into the CSF. The aminoglycosides of current impor® tance include streptomycin [Streptomycin ], kanamycin ® ® ® [Kantrex ], gentamicin [Garamycin ], tobramycin [Tobrex ® ® and Nebcin ], netilmicin [Netromycin ], and amikacin ® [Amikin ]. Their principal role in head and neck infections would be for chronic suppurative otitis media secondary to P. aeruginosa and other gram-negative bacilli. The aminoglycosides are also effective for suppurative and malignant otitis externa. At present, gentamicin, tobramycin, netilmicin, and amikacin are the most active of the aminoglycosides against P. aeruginosa. The spectra of activity of gentamicin, netilmicin, and tobramycin are similar, and strains resistant to one are usually resistant to the other. The major advantage of tobramycin is its activity against some strains of P. aeruginosa that are resistant to gentamicin. The spectrum of activity of amikacin is similar to that of gentamicin, netilmicin, and tobramycin, but there is little cross-resistance, and some gram-negative organisms resistant to these aminoglycosides are sensitive to amikacin. After parenteral administration, the aminoglycosides distribute rapidly in extracellular body water, with slow accumulation in tissues. Peak levels occur in serum one to two hours after administration, and significant activity persists for six to eight hours. Penetration across biologic membranes is variable, and diffusion into the CSF is limited (the concentration in CSF is approximately 10% of the peak serum concentration). Combining a penicillin and an aminoglycoside often results in more rapid killing, and lower concentration of drug is required to inhibit selected strains of gram-negative enteric bacilli and enterococci. All aminoglycosides may produce renal injury and ototoxicity. In general, gentamicin and tobramycin are more likely to affect vestibular function, and amikacin and kanamycin are more likely to damage the cochlear apparatus, but both functions may be affected by each drug. The cochlear effect may present as a high-frequency hearing loss or tinnitus; vestibular disturbances include vertigo, nystagmus, and ataxia. Some of the effects may be reversible, but permanent damage is frequent. Nephrotoxicity may present as albuminuria, the presence of white and red blood cells and casts in the urine sediment, or elevation of blood urea nitrogen or serum creatinine. Toxicity appears to be dose related, although eighth nerve damage has followed the use of relatively small doses in patients with renal failure. Toxicity has not been a significant problem in children with normal kidney function treated with aminoglycosides according to currently recommended dosage schedules. Toxicity has usually

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been associated with administration of high doses for a long time, previous therapy with other aminoglycosides, administration of drugs to patients with impaired kidney function, or concurrent administration of other agents that are potentially nephrotoxic. Concentrations of aminoglycosides in serum are variable and unpredictable. Patients who receive a prolonged course of aminoglycosides or who have impaired renal function require careful monitoring to determine safety as well as efficacy of the aminoglycoside.77 The desired peaks are 5–10 mcg/mL for the aminoglycosides gentamicin and tobramycin and 15–25 mcg/mL for kanamycin and amikacin. The trough should not exceed 2 mcg/mL for gentamicin and tobramycin or 10 mcg/mL for kanamycin and amikacin. The toxic ranges are considered to be 14 mcg/mL for gentamicin and tobramycin and 40 mcg/mL for kanamycin and amikacin. Dosage schedules should be modified if concentrations in serum are either too low, and therefore inadequate for optimal therapy, or too high and potentially toxic. The major use of aminoglycosides for head and neck infections in children include severe infection suspected to be due to gram-negative enteric bacilli. Aminoglycosides may be of value in combination with a broad-spectrum penicillin for chronic suppurative otitis media due to P. aeruginosa. Published proceedings of symposia should be consulted for more specific information about the pharmacologic actions and clinical uses of gentamicin,78 tobramycin,79 and amikacin.80

CHLORAMPHENICOL ®

Chloramphenicol [Chloromycetin ] is active against many gram-positive and gram-negative bacteria and chlamydiae. Oral preparations are well absorbed. The intravenous route is preferred for parenteral administration, because lower levels of serum activity follow intramuscular use. The drug diffuses well across biologic membranes, even in the absence of inflammatory reaction. Approximately 70% of the concentration of chloramphenicol in serum is present in the CSF of patients with meningitis, and similar high concentrations would be expected in the middle ear. Wide variability occurs in concentrations of chloramphenicol in the serum of infants and children, requiring monitoring of serum concentrations two or three times a week during therapy. Peak serum concentrations of 15–25 mcg/mL should be safe and effective.81 The major limiting factor in the use of chloramphenicol is its toxic effect on bone marrow.82 A dose-related anemia occurs in most patients receiving high-dosage schedules for more than a few days.83 Aplastic anemia is a rare (approximately 1 case per 20,000–40,000 courses of treatment) idiosyncratic reaction that is usually fatal. Most cases of aplastic anemia follow use of the oral preparation of chloramphenicol; there are few reports of aplastic anemia following parenteral administration alone.84 Because cases of aplastic anemia following parenteral

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administration are extraordinarily rare, clinicians should not avoid the use of intravenous chloramphenicol when there is a clear indication.

reported side effects were arthralgia and myalgia. Arthralgia was reported to occur in 2% of children treated with levofloxacin compared with 1% in the comparator group; myalgia was observed in 2% of both treatment groups.86

METRONIDAZOLE Although introduced in 1959 for treatment of Trichomonas ® vaginalis infections, metronidazole [Flagyl ] is now more widely used for infections due to anaerobic bacteria. The drug diffuses well into all tissues in both oral and parenteral forms. Anaerobic bacteria frequently play a role in chronic otitis media and sinusitis as well as deep space infections of the submandibular space, lateral pharyngeal space, or retropharyngeal space. Metronidazole is effective against Fusobacterium necrophorum and may be part of the treatment of Lemeirre’s syndrome and polymicrobial infections of the head and neck. Metronidazole is generally well tolerated, but a metallic taste is common. Serious side effects of metronidazole are rare and include seizures and peripheral neuropathy. Metronidazole should be stopped if these symptoms appear.

THE POLYMYXINS ®

®

Polymyxin [Aerospin ] and colistin [Coly-Mycin M & S] are highly effective in vitro against a broad spectrum of gramnegative enteric bacilli, including P. aeruginosa. These drugs do not diffuse well across biologic membranes, however, and are usually effective only when they are applied topically, as would be the case for external otitis media. Recently, colistin has seen a resurgence in use for the therapy of nosocomial infection due to multidrug-resistance P. aeruginosa or Acinetobacter baumannii.

THE FLUOROQUINOLONES The fluoroquinolones have a broad spectrum of activity, good oral absorption, and good tolerability. However, the use of quinolones in pediatrics has been limited by the FDA for children younger than 18 years of age primarily because of arthropathies in juvenile animals. Nevertheless, because the quinolones are active against P. aeruginosa, they have been extensively used in pediatric patients with pseudomonal infections, particularly children with cystic fibrosis, chronic suppurative otitis media, malignant external otitis, pseudomonal osteomyelitis, and febrile neutropenia.85 Recently, the emergence of multidrug-resistant S. pneumoniae has required off-label use of levofloxacin for the treatment of acute otitis media due to this pathogen.59 Although MRSA often demonstrates “in vitro” susceptibility to quinolones, development of resistance while on therapy is not uncommon. ® ® Levofloxacin [Levaquin and Quixin ], as with all quinolones, has high oral bioavailability and penetrates well into the central nervous system (CNS) and other body compartments. From a large phase III clinical trial, the most frequently

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OTOTOPICAL USE OF ANTIMICROBIAL AGENTS Use of ototopical preparations has been described in the literature since 1500 BC. A multitude of therapeutic options have been described, including astringents, antiseptics, alcohol, benzoin, and various powders. The use of various potions including red lead and resin, frankincense and goose grease, cream from cow’s milk, vermilion, olive oil, and many others “progressed” by the 1900s to the use of “rattlesnake oil” eardrops containing turpentine, camphor, menthol, and sassafras.87 The more formal role of antimicrobial agents for ototopical use was stimulated by trials of various sulfonamides for otorrhea and otitis externa. Currently available antimicrobial suspensions that are used extensively as ototopical drugs include isolated or combination preparations of colistin, neomycin, and hydrocortisone (Cortisporin TC Otic Suspension); polymyxin, neomycin, and hydrocortisone (Coly-Mycin S Otic); tobramycin and dexamethasone (Tobradex); gentamicin (Garamycin Ophthalmic); ciprofloxacin and hydrocortisone (Cipro HC Otic); ofloxacin (Floxin Otic); and ciprofloxacin and dexamethasone (Ciprodex Otic). The use of such ototopical agents in the treatment of otitis externa, chronic suppurative otitis media, and acute otitis media (otorrhea) in children with tympanostomy tubes has been extensively reviewed.88,89 Fluoroquinolone otic solutions have demonstrated efficacy for treatment of acute otitis media in patients with tympanostomy tubes and chronic suppurative otitis media in patients with perforated tympanic membranes. Cortisporin and Cipro HC Otic are approved only for acute otitis externa. Coly-mycin S Otic is approved for acute otitis externa and for the treatment of infections of mastoidectomy and fenestration cavities. Ofloxacin Otic is effective for the treatment of acute otitis media in children with tympanostomy tubes who presented with acute otorrhea. The efficacy of 10 days’ ofloxacin otic solution twice a day was compared with that of amoxicillin–clavulanate orally three times a day; the cure rate was 76% for ofloxacin versus 69% for amoxicillin–clavulanate. The eradication rates were similar for S. pneumoniae, H. influenzae, and M. catarrhalis, but ofloxacin had superior cure rates for S. aureus and P. aeruginosa.90 The combination of ciprofloxacin/dexamethasone has been shown to be superior to treatment with ciprofloxacin alone with regard to clinical resolution of otorrhea through a tympanostomy tube; the combination achieved a 20% reduction (1.1 day) in time to cessation of otorrhea.91 The efficacy of such topical preparations in the treatment of acute otorrhea through a tympanostomy tube indicates that high concentrations of drug reach

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CHAPTER 15 ❖ Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections the mucosa of the middle ear through the tube, resulting in high clinical and microbiologic cure rates. Aminoglycosides otic or ophthalmic preparations containing neomycin, gentamicin, and tobramycin may be ototoxic, but there is a paucity of human data to indicate adverse effects from instillation of these agents as eardrops. Nevertheless, the package inserts for coly-mycin and cortisporin carry a precautionary statement that the drug should be used with care in cases of perforated tympanic membranes and in long-standing cases of chronic otitis media because of the possibility of neomycin-induced ototoxicity. Sensitization does not appear to be an important problem with topical antibiotics, although some patients with chronic dermatoses may react to certain agents such as neomycin.

ANTIVIRAL AGENTS Antiviral agents are now established for the treatment of many specific viral infections. This section will review antiviral agents relevant to the treatment of infections of the head and neck such as herpes simplex and varicella-zoster viruses, cytomegalovirus, and influenza. HIV-related infections of the head and neck are also common; however, review of the treatment of HIV is beyond the scope of this chapter. Amantadine (Symmetrel), a 1-adamantanamine hydrochloride, was active against influenza virus A until 2003– 2004. Since then resistance has rapidly emerged, leading to the recommendation that adamantanes no longer be used for the treatment or prevention of influenza A disease.92 A syrup is available for use in infants and young children, and the drug is well absorbed. When initiated before infection with influenza A, such as to household contacts, amantadine was 70%–90% effective in preventing illness. Treatment begun within 48 hours after the onset of illness decreased the duration of fever and symptoms by 1–2 days. Amantadine has little or no activity against influenza B, and although active against rubella, parainfluenza, and respiratory syncytial virus in vitro, the required concentration exceeds those that can be safely administered to humans. Although the precise mode of action is unknown, antiviral activity appears to be due to interference with virus replication rather than direct inactivation of infectious virus. Rimantadine (Flumadine) is 4- to 10-fold more active than amantadine and has a similar mechanism of activity but, in general, it is better tolerated than amantadine. Neither rimantadine or amantadine are currently recommended for treatment of influenza disease due to the emergence of resistance among influenza A strains and lack of activity against influenza B virus. Zanamivir (Relenza) and oseltamivir (Tamiflu) are inhibitors of influenza A and B virus neuraminidases and effective for infection due to both influenza viruses. Zanamivir administered by nasal spray or inhalation was effective in shortening the duration and severity of symptoms of influenza A and B virus infections in adults if administered within 30 hours of

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onset of symptoms.93 Prophylactic usage was 84% effective in preventing febrile influenza.94 Oseltamivir was also effective in adults for both prevention and treatment of influenza A and B virus infections.95 If the drug is started within 36 hours of onset of symptoms, it can decrease the severity and duration of symptoms and the incidence of upper respiratory complications. Prophylactic administration was 87% effective in preventing culture-proven influenza virus infection. In 2007–2008, approximately 10% of influenza A H1N1 viruses, no A H3N2 viruses, and no influenza B viruses were resistant to oseltamivir. No viruses resistant to zanamivir were identified.96 Acyclovir [Zovirax] is a guanosine analog antiviral drug, used for the treatment of herpes simplex, varicella zoster (chickenpox), and herpes zoster (shingles). Acyclovir resembles a nucleotide but it has no 3´ end resulting in chain termination. Acyclovir is active against most known species in the herpesvirus family, with greatest activity against herpes simplex virus type I (HSV-1) and HSV type II, and decreasing activity against varicella zoster virus (VZV) Epstein–Barr virus (EBV), and cytomegalovirus (CMV). Acyclovir has poor oral bioavailability (15%–30%); therefore, intravenous administration is warranted when high concentrations are necessary. Valacyclovir [Valtrex], which is converted to aciclovir during hepatic first pass metabolism, may be used to increase oral bioavailability. Acyclovir is indicated for the treatment of HSV and VZV infections, such as genital HSV, HSV labialis, herpes zoster, and complications such as Ramsay Hunt syndrome and chickenpox in immunocompromised patients or with complications. Common adverse drug reactions (≥1% of patients) include nausea, vomiting, diarrhea, and/or headache. Serious common adverse effects associated with intravenous administration include encephalopathy and decreased renal function as a result of crystal formation in the kidney.

SELECTED ASPECTS OF ADMINISTRATION OF ANTIMICROBIAL AGENTS Dosage Schedules for Treatment of Acute Otitis Media in Infants and Children Dosage schedules of antimicrobial agents useful in otitis media are listed for infants (beyond the newborn period) and children in Table 15-4.

Food Interference With Absorption The absorption of some oral antimicrobial agents is significantly decreased when the drug is taken with food or near mealtime. These drugs include unbuffered penicillin G, penicillinase-resistant penicillins (nafcillin, oxacillin, cloxacillin, and dicloxacillin), ampicillin, azithromycin, and lincomycin. Milk, milk products, and other foods or medications containing calcium or magnesium salts interfere with absorption

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TABLE 15-4. Antimicrobial Agents for Treatment of Acute Otitis Media Drug (Trade Name)

Number of Doses/Days

Dosage (mg/kg/d)

Amoxicillin (Amoxil)

2–3 per day/10 d

40–90 mg

Amoxicillin–clavulanate (Augmentin; Augmentin ES)

2–3 per day/10 d

40–90 mg

Azithromycin (Zithromax)

1 per day/1, 3, or 5 d

30 mg as 1 dose 10 mg for 3 days 10 mg × 1; 5 mg for 2–5 days

Clarithromycin (Biaxin)

2 per day/10 d

40 mg

Erythromycin + Sulfisoxazole (Pediazole)

4 per day/10 d

40 mg

Ceftriaxone (Rocephin)

1 per day/1–3 d

50 mg

Ceftibuten (Cedax)

1 per day/10 d

9 mg

Loracarbef (Lorabid)

2 per day/10 d

30 mg

Cefprozil (Cefzil)

2 per day/10 d

30 mg

Cefpodoxime (Vantin)

2 per day/10 d

10 mg

Cefuroxime axetil (Ceftin)

2 per day/10 d

30 mg

Cefaclor (Ceclor)

2–3 per day/10 d

40 mg

Cefdinir (Omnicef )

1–2 per day/10 d

14 mg

Cefixime (Suprax)

1 per day/10 d

8 mg

Trimethoprim-sulfamethoxazole

2 per day/10 d

8 mg/40 mg

Source: Modified from Bluestone CD and Klein JO. Otitis Media in Infants and Children. 3rd ed. Philadelphia, PA.

of the tetracyclines. Absorption of penicillin V, buffered penicillin G, amoxicillin, oral cephalosporins currently available, chloramphenicol, erythromycin, clarithromycin, and clindamycin is only slightly affected by food. Antibiotics whose absorption is affected by concurrent administration of food should be taken one or more hours before or two or more hours after meals.

Intravenous and Intramuscular Administration After intravenous administration of most antimicrobial agents, there is a period when the concentration of drug in the serum is higher than it is following intramuscular administration. No therapeutic advantage, however, of intravenous administration over intramuscular administration has been demonstrable. Intravenous administration should be used if the patient is in shock or suffers from a bleeding diathesis. If prolonged parenteral therapy is anticipated, the pain on injection and the small muscle mass of the young child preclude the intramuscular route and make intravenous therapy preferable. Although intramuscular benzathine penicillin has been used in combination with a sulfonamide for therapy of acute otitis media, single-dose intramuscular ceftriaxone is the only parenteral agent to be evaluated in recent clinical

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trials. One-dose ceftriaxone was equivalent to 10 days of oral amoxicillin or TMP-SMX.97,98 Chloramphenicol, the tetracyclines, and erythromycin should be administered parenterally by the intravenous rather than the intramuscular route. Chloramphenicol has variable absorption from intramuscular sites. The intramuscular injection of parenteral tetracyclines and erythromycin causes local irritation and pain. The technique and complications of intramuscular injections are well described. In general, the site of injection in young infants is the upper lateral thigh, in children older than 2 years of age, it is the gluteal area, and for older children, it is the deltoid muscle. After selection of the proper site and insertion of the needle into the muscle, one applies negative pressure by pulling back on the plunger to be certain that the needle is not in a blood vessel. Thrombophlebitis may result from prolonged intravenous administration and sterile abscesses may follow intramuscular administration.

Compliance The most frequent drug-related factor in failure of antibiotic therapy is inadequate compliance. Frequency of dosing is important. If possible, administration of a dose during day care is to be avoided because of the uncertainty of compliance

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CHAPTER 15 ❖ Antimicrobial Agents for the Treatment of Pediatric Head and Neck Infections by caretakers. Once or twice a day is now the rule for new antimicrobial agents for infants and young children. Shorter schedules have an administrative advantage. A single dose of intramuscular ceftriaxone ensures compliance but may not be acceptable to all parents (or children). Current clinical trials include shorter courses of oral antimicrobial agents for the management of acute otitis media, but there is concern about shorter than recommended courses of oral drugs in infants younger than 2 years of age.99 Unacceptable taste or odor of drugs may result in poor compliance. In a blinded comparison of taste for 14 commonly prescribed pediatric suspensions, the study participants (pediatric staff and house staff and other health-care workers) compared the drugs in a manner similar to that used in wine tasting, including texture, smell, taste, and aftertaste.100 The cephalosporins including cefixime, cephalexin, and cefaclor had the highest overall scores. Dicloxacillin and penicillin V were the least acceptable. Other investigators have noted similar results. A recent study judged cefuroxime, cefpodoxime, and erythromycin plus sulfisoxazole “to be so unpalatable as to potentially jeopardize compliance.”101 Analyses of antibiotic suspensions for palatability have been further adjusted for cost, duration of therapy, and dosing intervals. Overall taste and cost ratings adjusted for duration and dosing interval identified azithromycin, cefdinir, loracarbef, and cefixime as the best choices and amoxicillin–clavulanate, cefuroxime, ciprofloxacin, and clarithromycin as the least favorable. Among other features that lead to problems with compliance are side effects such as diarrhea. Diarrhea leads to treatment discontinuation more frequently with amoxicillin/clavulanate and ampicillin than with amoxicillin or TMP-SMX.102 Of significant concern are studies suggesting that full compliance with medications prescribed for treatment of otitis media occurs in only 5 of 100 patients.103 Factors limiting compliance included incorrect dosage schedules (36%), early termination (37%), inadequate dispensing of medication at drugstores (15%), spilled medicine (7%), and a series of other errors by physician, pharmacist, and parents. Compliance improved to more than half when hospital pharmacy personnel gave patients and parents verbal and written instructions for administration of medications that were dispensed with a calibrated measuring device and a calendar to record doses taken. Single-dose intramuscular ceftriaxone would be of value for families that have difficulty maintaining multidose oral treatment regimens in infants and young children. A survey of parents indicated a preference for single dose intramuscular therapy for acute otitis media over standard 10-day oral therapy.

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79.

80. 81. 82.

83.

84.

85. 86.

87. 88. 89.

90.

91.

92.

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review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm. 2009;66:82–98. Jones RN, Jacobs MR, Sader HS. Evolving trends in Streptococcus pneumoniae resistance: implications for therapy of community-acquired bacterial pneumonia. Int J Antimicrob Agents. 2010;36(3):197–204. Neu HC. A symposium on the tetracyclines: a major appraisal: introduction. Bull N Y Acad Med. 1978;54:141. Scheinfeld N. Tigecycline: a review of a new glycylcycline antibiotic. J Dermatolog Treat. 2005;16(4):207–212. http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm. Accessed December 26, 2010. Touw DJ, Westerman EM, Sprij AJ. Therapeutic drug monitoring of aminoglycosides in neonates. Pharmacokinet. 2009;48(2):71–88. Finland M, Hewitt WL (guest eds). Second international symposium on gentamicin, an aminoglycoside antibiotic. J Infect Dis. 1971;124:S1. Finland M, Neu HC (guest eds). Tobramycin. Symposium of the Ninth International Congress of Chemotherapy in London, England. J Infect Dis. 1976;134:S1. Finland M, Brumfitt W, Kass EH. (guest eds). Advances in aminoglycoside therapy: amikacin. J Infect Dis. 1976;134:S235. Friedman CA, Lovejoy FC, Smith AL. Chloramphenicol disposition in infants and children. J Pediatr. 1979;95:1071. Restrepo MA, Zambrano F II. Late onset aplastic anemia secondary to chloramphenicol. Report of ten cases. Antioquia Med. 1968;18:593. Scott JL, Finegold SM, Belkin GA, et al. A controlled doubleblind study of the hematologic toxicity of chloramphenicol. N Engl J Med. 1965;272:1137. Wallerstein RO, Condit PK, Kasper CK, et al. Statewide study of chloramphenicol therapy and fetal aplastic anemia. JAMA. 1969;208:2045. Church DA, Echols RM. Ciprofloxacin use in pediatric and cystic fibrosis patients. Pediatr Inf Dis J. 1997;16:89. Noel GJ, Bradley JS, Kauffman RE, et al. Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders. Pediatr Infect Dis J. 2007;26(10):879–891. Myer CM III. Historical perspective on the use of otic antimicrobial agents. Pediatr Infect Dis J. 2001;20:98. Bluestone CD, Klein JO. Chronic suppurative otitis media. Pediatr Rev. 1999;20:277. Klein JO, ed. The use of topical ofloxacin for otic diseases in infants and children: summary and conclusions. Pediatr Infect Dis J. 2001;20:123. Goldblatt EL, Dohar J, Nozza RJ, et al. Topical ofloxacin versus systemic amoxicillin/clavulanate in purulent otorrhea in children with tympanostomy tubes. Int J Pediatr Otorhinolaryngol. 1998;46:91. Roland PS, Anon JB, Moe RD, et al. Topical ciprofloxacin/dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media and otorrhea through tympanostomy tubes. Laryngoscope. 2003;113(12): 2116–2122. http://www.cdc.gov/flu/professionals/antivirals/guidance/ antiviral_drug.htm#table2. Accessed July 2011.

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93. Hayden FG, Osterhaus ADME, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. N Engl J Med. 1997;337:874. 94. Monto AS, Robinson DP, Herlocher ML, et al. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA. 1999;282:31. 95. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med. 1999;341:1336. 96. http://www.cdc.gov/flu/professionals/antivirals/resistance.htm. Referenced December 26, 2010. 97. Green SM, Rothrock SG. Single-dose intramuscular ceftriaxone for acute otitis media in children. Pediatrics. 1993;91:23. 98. Barnett ED, Teele DW, Klein JO, et al. Comparison of ceftriax one and trimethoprim-sulfamethoxazole for acute otitis media. Pediatrics. 1997;99:23.

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99. Paradise JL. Short-course antimicrobial treatment for acute otitis media: not best for infants and young children. JAMA. 1997;278:1640. 100. Demers DM, Chan DS, Bass JW. Antimicrobial drug suspensions: a blinded comparison of taste of twelve common pediatric drugs including cefixime, cefpodoxime, cefprozil and loracarbef. Pediatr Infect Dis J. 1994;13:87. 101. Steele RW, Thomas MP, Begue RE, Despinasse BP. Selection of pediatric antibiotic suspensions: taste and cost factors. Infect Med. 1999;16:197. 102. Feder HM Jr. Comparative tolerability of ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole suspension in children with otitis media. Antimicrob Agents Chemother. 1982;121:426. 103. Mattar ME, Markello J, Yaffe SJ. Pharmaceutic factors affecting pediatric compliance. Pediatrics. 1975;55:101.

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16

C H A P T E R

The Role of Biofilms in Pediatric Otolaryngologic Diseases J. Christopher Post and Garth D. Ehrlich

TOWARD AN UNDERSTANDING OF BIOFILMS Since the time of Koch and Pasteur, bacteria have been thought

of as free-floating, independent, individual planktonic organisms. In fact, the reality is much more complex, as the vast majority of bacteria live in complex, integrated, sessile communities called biofilms. These sophisticated communities are found on both biotic and abiotic surfaces. Such biofilms consist of bacteria embedded in an extracellular slime matrix, or glycocalyx, which is made up of water and a variety of macromolecules including exopolysaccharides, proteins, and extracellular DNA (eDNA) collectively known as extracellular polymeric substances.1 The matrix provides the embedded bacteria with structure and protection; moreover, the matrix can be rapidly remodeled in response to environmental stressors. Once a biofilm is established, the bacteria within typically elaborate the matrix into complex three-dimensional structures producing variegated surfaces, dense lawns—some with streamers that form above the canopy or mushroom-like towers. These structures are both viscous and elastic, properties provided by the eDNA in the matrix, which enable the biofilm to undergo remodeling in times of environmental stress, thus enhancing the biofilm’s survivability. Once established, biofilms will periodically release a “shower” of planktonic (freeswimming) bacteria into the surrounding environment, which have the potential to form new biofilms distally. Biofilms are far more than an accretion of unicellular organisms. Given their collective and sessile nature, relatively impervious protective matrix, and periodic release of planktonic forms, a biofilm might be considered analogous to a coral reef, which is formed from colonial polyps that secrete a protective exoskeleton of calcium carbonate. In this state, they are resistant to predation by phagocytes. Continuing the analogy, coral populate distant locales by the release of a larva known as planula, a phenotype highly vulnerable to predation and adverse environmental conditions while in open water. The attachment of planula to a substrate and subsequent development of an exoskeleton develops a new reef and reestablishes the protective state—just as a biofilm does. A biofilm acts like a single dynamic living organism that can alter its physical properties in response to environmental factors and assimilate other bacterial or fungal species into an integrated polymicrobial community. A single biofilm is composed of multiple ecological niches that can vary in pH, cellular density, nutrient transport, and oxygen tension, with the biofilm base being markedly anoxic and acidic compared with the periphery. It is these distinct microenvironments that enable a single biofilm to be polymicrobial, composed

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of multiple species (and higher order taxa), all cooperating within a symbiotic framework and interacting at multiple levels including physical, metabolic, and genetic. Biofilms possess multiple systems for intercellular and interspecies communication; specialized bacterial phenotypes for differentiation of function within the community; and water channels with convective flow for the delivery of nutrients and removal of waste products corresponding to a primitive circulatory system. Moreover, recent evidence has demonstrated that they also possess a primitive neurological system in that gram-negative bacteria in biofilms secrete vesicles that are carried along extracellular protein conduits providing for high concentration signal delivery at a distance. Given this level of sophistication, a biofilm could be considered a multicellular organism.

BACTERIAL SURVIVAL IS ENHANCED BY BIOFILM FORMATION The biofilm phenotype has been in existence for over three billion years, clearly demonstrating that biofilms confer significant survival benefits to bacteria. In some aquatic environments, 99.99% of bacteria exist in biofilms. The matrix protects the embedded bacteria from various environmental hazards, such as mechanical stressors (e.g., shear), noxious chemical agents, phagocytosis, temperature fluctuations, and electromagnetic radiation. This protection enables a biofilm to survive in environments that would otherwise be inhospitable, thereby broadening the bacteria’s potential habitat range. Biofilms are present in some of the most inhospitable habitats on the earth, including Antarctica, deep-sea hydrothermal vents, and the acidic boiling waters of volcanic hot springs. The biofilm matrix also protects bacteria from host defenses that would be lethal to planktonic bacteria, forming a physical barrier to complement, antibody and immune cells, whereas the sheer size of a biofilm prevents engulfment by granulocytes, macrophages, and other phagocytes. Thus, the biofilm phenotype provides protection from both the humoral and the cellular arms of the host’s adaptive immune response. Biofilms can survive treatment by antimicrobial agents greater than 1000 times the level that will kill genetically equivalent planktonic bacteria. It was originally thought that this enhanced survival was due to the inability of antibiotics to penetrate the matrix, but the primary reason is that biofilm bacteria have a decreased rate of metabolism and replication, making them less susceptible to antibiotics that target the macromolecular biosyntheses. The protection afforded by the biofilm phenotype varies according to the

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location of the bacteria in the biofilm. The bacteria in the superficial layer are the most vulnerable, as their increased level of metabolic activity (secondary to increased levels of nutrients and oxygen) make them more susceptible to antimicrobial agents. Bacteria at deeper levels in the biofilm have a decreased rate of metabolism and replication, thus are less susceptible to antimicrobial treatments. This level of protection offers an explanation for the difficulties of managing infected prosthetic devices with antimicrobial agents. In addition to physical protection, a biofilm provides a persistent nidus from which bacteria can spread, shedding planktonic bacteria to seed new biofilm communities and populate new niches. This concept helps explain the cyclic nature of systemic symptoms that often accompany chronic infections. Bacterial survival is enhanced by the presence of distinct ecosystems within a single biofilm community. The microenvironments within a biofilm can result in the biofilm being inhabited by phenotypically different bacteria of the same species, caused by the triggering of different transcriptional signals. A biofilm with several strains of the same species will have greater genotypic diversity. Genetic material exchange between these strains through horizontal gene transfer, facilitated by the biofilm, increases the genetic diversity of individual bacteria, which improves the community’s chances of survival through increased opportunity for adaptive mutation. This concept of genetic exchange among bacterial strains of the same species, in response to environmental stresses, is known as the distributed genome hypothesis.2 This adaptive mutation within a biofilm can be thought of as a counterpoint to the host’s adaptive immune response, wherein the precursors of T- and B-lymphocytes rearrange their DNA. Thus, at its heart, a chronic infection is a war of genomic diversity. This diversity generating aspect of biofilms enables the continual production of novel bacterial populations, increasing the chances the population will survive multiple stresses or sequential antibiotic therapies and allowing the infection to persist. Thus, biofilms serve as a population-level virulence factor by enabling the resident bacteria to attain virulence attributes that single bacterial cells are incapable of obtaining.2 These biofilm-enabled, population-level virulence traits permit the bacteria to persist despite the host’s innate and adaptive immune systems.

Limitations of the Planktonic Bias Historically, bacterial research has centered on planktonic bacteria, either as unorganized clonal bacteria in liquid suspension or homogenous colonies grown on culture plates. Indeed, the majority of current antimicrobial strategies were developed to counter acute systemic infections caused by planktonic bacteria. Concentrating on planktonic bacteria is useful in the study of acute infectious processes, but not in the study of chronic bacterial infections secondary to

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bacterial biofilms. Such a bias in favor of planktonic bacteria has profound implications not only for understanding of infectious disease, but also for the diagnosis and treatment of such disease. Many of the discrepancies found today between in vitro test results and in vivo antibiotic response are due to the bias toward planktonic bacteria. The biofilm envirovar of a bacterium is more resistant than the planktonic envirovar of the same strain and is unlikely to succumb to the same treatment. Furthermore, current culture methods can identify only about 1% of the bacteria present in biofilms as the rest will not produce colonies by conventional culture methods, resulting in potential inaccurate or incomplete diagnoses. Treatments based on such traditional culture methods may have no effect on the unidentified, yet viable bacteria.

Limitations of Culture As Koch developed his famous postulates, he used culture methods similar to those in use today. These systems were designed for the detection and characterization of the planktonic bacteria that cause acute epidemic bacterial diseases. In this methodology, bacterial cells on the surfaces of appropriate agar plates replicate to produce colonies, which are then used to determine species identity and antibiotic resistance patterns. Although these techniques worked well to identify bacteria that cause acute infections, they do not suffice to identify bacteria in a biofilm. Thus, ironically, medicine’s success at treating and preventing acute infections has erected a barrier to gaining a modern understanding of chronic bacterial infection. Clinicians have been trained to see all live bacteria as culturable; if bacteria cannot be grown from a specimen, then pathogens must be absent. But even when a specimen produces a culture, that culture may not enumerate all species and strains of bacteria in mixed microbial communities such as chronic wounds.3 There are several reasons for the inherent inability to culture biofilm bacteria. The proteomes of biofilm and planktonic phenotypes differ profoundly, thus planktonic cells of Staphylococcus aureus produce colonies on agar, whereas biofilm microcolonies do not.4 Bacteria that are attached to a surface, such as those in a biofilm, are difficult to sample. For example, in a chinchilla model, multiple consecutive lavage sampling of infected middle ears revealed that the burden of Hemophilus influenzae was much greater than the burden indicated by a single lavage.5 Most of the bacteria in biofilms are also slow-growing and, therefore, difficult to grow in vitro. In addition, a culture from a biofilm will yield one colony per aggregate rather than one per bacterium, resulting in a severe underestimation of the number of bacteria present in the specimen.

Biofilm Formation Biofilm formation is a complex, coordinated series of developmental events: reversible attachment, irreversible attachment (adhesion), matrix formation, maturation, and dispersion.

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CHAPTER 16 ❖ The Role of Biofilms in Pediatric Otolaryngologic Diseases 193 Biofilm formation begins with the attachment of planktonic bacteria to a surface. The initial attachment is through van der Waals forces and then by adhesive structures such as pili and high molecular adhesions. Initially reversible, this attachment becomes firm and irreversible as the bacteria divide and form a monolayer. Some species then aggregate into microcolonies through twitch motility, a form of translocation over a moist surface in which the bacteria extend their fimbriae or pili, tether to the surface or other bacteria, and retract. Once the bacteria have reached a critical density, they produce a slimy matrix that encloses the bacteria. This matrix, sometimes termed a glycocalyx, is composed of water and macromolecules (polysaccharides, protein, and eDNA) that forms a protective, dynamic, and remodeling structure over the microcolony. Signaling molecules are produced that coordinate cell-to-cell communication and guide the formation of the nascent biofilm into an aggregate structure that can be hundreds of cells thickness and complex in form. This mature structure will intermittently release bacteria or bacterial microaggregates from the periphery, which detach and disperse to seed remote areas, starting the process anew. Bacterial biofilms can attach to either biotic or abiotic surfaces. Biotic surfaces are more resistant to bacteria than are abiotic surfaces. Mucosal surfaces have a number of defenses to prevent such attachment including biochemical surfactants, epithelial exfoliation, phagocytosis, innate immunity, and other immune responses. The coordinated activity of a biofilm requires communication between the individual bacteria. Biofilm bacteria accomplish this through a series of processes called quorum sensing in which the bacteria within a population secrete a signaling molecule. This molecule, acting in a concentration-dependent fashion, serves as a coordinator of the population’s activity. When the concentration of the signaling molecule increases to the point that the bacteria have a “quorum,” a wholesale switch in the transcriptional machinery of all bacteria in the biofilm occurs simultaneously. This coordinated switching activity occurs by the replacement of sigma factors—or “master switches”—that up- and down-regulate large sets of genes producing extensive physiological changes, including the coordinated production of toxins and other secreted molecules. Quorum sensing is used by a variety of bacterial species to control aspects of their developmental process, including rate of bacterial division, incorporation of foreign DNA, biofilm structure formation and maintenance, and virulence factors.

Biofilms in Human Disease Bacterial biofilms are now recognized as a major cause of human disease. The Centers for Disease Control estimates that over 60% of all bacterial infections in the United States are biofilm-related, with some studies placing this estimate as high as 80%.6 Among the first to recognize the importance

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of biofilms in human health were researchers in the oral health fields. They discovered that biofilms attach to the tooth enamel and gingival mucosal causing plaque, dental caries, gingivitis, and periodontal disease. A wealth of human diseases have now been recognized as biofilm illnesses including cystic fibrosis, chronic obstructive pulmonary disease, bronchiolitis and bronchiectasis, infective endocarditis, chronic prostatitis, chronic osteomyelitis, Legionnaires’ disease, biliary tract infections and gallstones, kidney stones, chronic wound infections, and chronic urinary tract infections.7 Table 16-1 enumerates the general characteristics of such biofilm infections.

Biofilms on Medical Devices Biofilm formation plays a large role in infected medical implants and devices including sutures and mesh, tracheostomy and endotracheal tubes, middle ear and cochlear implants, orthopedic implants, fracture fixation devices, gastronomy and nasogastric tubes, hemodialysis and peritoneal dialysis catheters, urinary and central venous catheters,

TABLE 16-1. Six Defining Characteristics of Biofilm Infections • Chronic infection with cycles of acute exacerbation. The active infection is suppressed with antibiotics, which cause symptoms to go into remission; however, the infection is not eradicated and symptoms reoccur once the antibiotic treatment is discontinued. • The chronic sessile attachment of a biofilm acting as a nidus, which is resistant to antimicrobial treatment, for example, infected tympanostomy tubes. If such a nidus is located at a surface/fluid interface, such as a central line or a ventriculoperitoneal shunt, planktonic showering can cause episodic acute systemic events. • Host defenses proving ineffective against the infection, resulting in “frustrated” phagocytes causing collateral tissue damage through cytotoxic effects, proteolytic effects, and proinflammatic effects, which can result in severe and sustained inflammation. Such collateral damage is often caused by an ineffective host response against a biofilm that is not highly pathogenic. • The diagnosis of a biofilm infection is problematic due to insufficient or inadequate culturing or sampling techniques. The limitations of culture also adversely impact therapy, in that there is a lack of sensitivity data to provide a rational basis for antibiotic selection. • The host shows chronic inflammatory response with the potential for stone formation, such as tonsilloliths, and perhaps salivary calculi. • The biofilm acting as an environment for the generation of resistant organisms or as a safe haven for bacteria to produce systemically acting substances such as endotoxins, exotoxins, enterotoxins, or superantigens.

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pacemakers and artificial heart valves, vascular grafts, biliary stents, and neurosurgical shunts and stimulators. The channels of endoscopic instruments are subject to the formation of biofilms resistant to standard cleaning practices, posing risk of nosocomial infection. Biofilm formation explains the extreme difficulty in eradicating prosthetic infections with conventional antibiotics, as well as the clinical observation that once a prosthetic device is infected, it generally must be removed or replaced to cure the infection. Such devicerelated biofilms act as a nidus for episodic planktonic bacterial showering contributing to potential hematogenous spread and sepsis.

The combination of CLSM and FISH is a state-of-the-art methodology for noninvasive three-dimensional imaging of biofilms with reliable identification of biofilm component bacteria.8 Atomic force microscopy can also be used for the study of biofilms and of the surfaces to which they adhere. Rather than producing a direct image, this method involves running an atomic tip over a surface to produce an image, which enables the study of bacterial/surface interactions at the nanoscopic level. This method is particularly useful for studying bacterial adhesion and the attractant/repellent properties of a surface relevant to bacteria.

Technologies for the Study of Biofilms

Biofilms in Pediatric Otolaryngologic Disease

Bacterial cultures are inadequate for the study of biofilms as they frequently fail to detect bacterial species within the biofilm and provide no information regarding its threedimensional structure. Culture techniques have been supplanted by nucleic acid-based detection and identification strategies, which enable the identification of all pathogens within a biofilm and their corresponding resistance markers. Systems such as the Ibis Biosensor system need only a few hours to identify any and all bacterial species present in a sample using broad-range polymerase chain reaction (PCR) primers to amplify highly conserved sequences across classes of organisms. Mass spectrometry then determines the molecular weights of the amplified regions, and through analysis of the multiple amplicons produced, the species can be determined by triangulation. The Ibis technology is complemented by the 454 genome sequencer, an ultra-high throughput system that uses a massively parallel sequencing-by-synthesis approach to provide not only for the de novo sequencing of whole bacterial genomes, but also for the 16S ribosomal DNA (rDNA) sequencing for the rapid and quantitative enumeration of all species present within a microbiome. Imaging technologies such as scanning electron microscopy (SEM) and transmission electron microscopy (TEM) have been used to study biofilms, but these have shortcomings. Both methods require specimens to be fixed for study, which results in drying of the biofilm matrix, and induces artifacts. Both also rely on morphological criteria for the identification of bacterial species, which can lead to misidentification and misdiagnosis. Confocal laser scanning microscopy (CLSM) produces a three-dimensional computerized reconstruction of the specimen, enabling the study of intact thick specimens with no need for fixing or sectioning, making it analogous to a microscopic computerized axial tomography system. CLSM can be paired with fluorescent in situ hybridization (FISH) to visualize bacteria in species-specific manner, enabling microbial mapping of clinical specimens; this provides spatial information that can be key to determine whether a given species is likely playing a pathogenic role or not. Conversely, bacteria can be engineered to produce fluorescence using molecules such as green fluorescent protein.

Biofilms play a central role in a number of pediatric otolaryngologic diseases, as well as infections related to devices and implants. It is important for clinicians to be familiar with the distinctive nature of the biofilm phenotype to understand the pathophysiology of chronic infections and the limitations of conventional treatments completely. In addition, such an understanding will help guide the selection of the most effective treatment strategies.

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Otitis Media The current interest in biofilms in pediatric otolaryngology began with studies to better understand the pathophysiology of one of the most prevalent pediatric diseases, otitis media (OM). Although acute OM has historically been accepted as a bacterial process, otitis media with effusion (OME) has often been regarded to be a nonbacterial inflammatory process. A number of observations supported this erroneous conceptualization: (1) most middle-ear effusions were sterile by culture, and “sterile cultures” was equated with “absence of bacteria”; (2) a number of inflammatory mediators were found in chronic effusions; (3) gram stains of chronic effusions frequently identified bacteria, but these bacteria did not support microbial culture and were dismissed as a curiosity; (4) clinically, OME did not readily resolve with antibiotics, despite achieving bacteriocidal antimicrobial concentrations in the middle ear. The fundamental issue here is a historical reliance on the planktonic notions of bacterial infection which, although useful in understanding acute infections, is inadequate in understanding a chronic infection such as OME. A series of investigations using nucleic amplification and advanced imaging technologies demonstrated that culture techniques were inadequate to describe the microbial population in OME, both in pediatric and animal models.9–12 Biofilms have been detected on the middle-ear mucosa of children with chronic OME using a variety of techniques including cultures, PCR, FISH, and CLSM with bacterial live/dead staining. In this study, biofilms were detected in 46 of 50 specimens from OME patients who underwent tympanostomy and tube replacement for OME or recurrent OM, although 8 controls (3 children and 5 adult cochlear implant

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CHAPTER 16 ❖ The Role of Biofilms in Pediatric Otolaryngologic Diseases 195 patients) were negative for biofilms. Biofilms were found in children with recurrent OM who were in clinical remission, demonstrating that the middle ear is not clear of bacteria between acute episodes.13 Recent work from Australia has shown that gram-positive cocci bacteria were present in a biofilm-like structure known as a “pod” within the cytoplasm of middle-ear mucosal epithelial cells of 4 of 11 (36%) children with OME.14 The authors suggested that this novel intracellular presence may be an important mechanism for bacterial persistence, contributing to chronic inflammation and mucus production. The above studies demonstrate the involvement of biofilms in middle-ear disease and serve to integrate other observations regarding the pathogenesis and treatment of OME. Such observations include (1) the role of viral infection disrupting mucosal defenses and setting the stage for a bacterial infection, (2) the importance of eustachian tube function in maintaining a healthy middle ear, (3) the presence of various inflammatory mediators in OME (a result of persistent bacterial presence and not the root cause of the disease process), and (4) the failure of antimicrobials and/ or steroids to effectively treat OME. The biofilm paradigm also explains the efficacy of tympanostomy tubes in the treatment of OME as this procedure (1) reventilates the middle ear, thereby increasing oxygen tension, promoting regrowth of the ciliated epithelium and reducing the number of secretory cells, (2) mechanically disrupts and debulks the biofilm, and (3) enables restoration of the host’s middle-ear mucosal defenses such as neutrophil function, which requires a highly oxygenated environment for production of their oxidative burst antibacterial defenses. These physiological changes promote biofilm clearance. The biofilm paradigm further explains the efficacy of adenoidectomy in the treatment of chronic OME. Although it has long been clinically accepted that adenoidectomy can be efficacious in reducing the recurrence of OME, the utility of the adenoidectomy was variously attributed to the improvement of eustachian tube function versus the removal of a reservoir of bacteria. There is a growing body of evidence that adenoid harbors pathogenic bacteria in the form of biofilms.15 Cholesteatoma Cholesteatomas are masses of expansive keratinizing squamous epithelium in the middle-ear space. Left untreated (surgical extirpation is the only effective treatment), cholesteatoma can expand into the mastoid process or intracranially. In ground-breaking work, Chole and Faddis have shown that microbial biofilms occur within the keratin matrix of infected cholesteatomas, both in humans and in the gerbiline model of cholesteatoma.16 In addition, they have shown that strains of Pseudomonas aeruginosa isolated from cholesteatomas are strongly adherent to keratinocytes, express quorum-sensing genes, and form biofilms in vitro. They hypothesize that the presence of bacterial biofilms in cholesteatomas explains the persistence and recurrence of

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infection, which are hallmarks of the clinical presentation of this disease. Tonsillitis and Chronic Upper Respiratory Infection Biofilms have also been implicated in tonsillitis and chronic upper respiratory infections. The seminal report used light microscopy and TEM to demonstrate the presence of amorphous polysaccharide biofilm matrices and bacteria within the tonsillar crypts of 11 of 15 infected tonsils and smaller clusters of bacteria in 3 tonsils removed for hypertrophy.17 CLSM in conjunction with fluorescent staining found biofilms in 17 of 24 tonsils removed from children with a history of chronic or recurrent tonsillitis.18 Streptococcus pyrogenes infections that fail to respond to antibiotic therapy may be related to biofilm formation.19 Culture and SEM were used to examine 32 surgical specimens from the upper respiratory tract (tonsils, adenoid, and mucosa of the ethmoid and maxillary sinuses) of 20 adults and 8 children who had upper respiratory infections that failed to respond to antibiotic treatment despite demonstrated efficacy in vitro; bacterial biofilms were found in 65.5% of specimens.20 In another study, the surfaces of adenoid and tonsils from 76 children who underwent adenotonsillectomy due to infection, obstruction, or both were examined. Of these, 22 of 26 (85%) of those with infection had adherent biofilm formation, whereas 18 of 44 (41%) of those with only obstruction had adherent biofilm formation.21 Chronic Rhinosinusitis Rhinosinusitis is a multifaceted disease involving inflammation of the nasal mucosa and paranasal sinuses. The mechanisms that drive the inflammation of chronic rhinosinusitis (CRS) are controversial, and several theories that have been put forward include allergy, aberrant reaction to fungi, disorders of the innate immune system, and superantigens from S. aureus. Parallels certainly exist with chronic OM in that both are diseases of mucosa-lined cavities connected to the nasopharynx, with chronic clinical courses punctuated by acute exacerbations, and a general refractoriness to antimicrobial therapy. Recent work indicates that bacterial biofilms may indeed play some role in the pathophysiology of CRS. Mucosal-based biofilms have been identified in experimental models of sinusitis22 and in patients with clinical rhinosinusitis.23 There is a positive correlation between in vitro biofilm-producing capacity and unfavorable outcome after functional endoscopic sinus surgery for CRS.24 Biofilm formation may represent a late phase of the inflammatory process that leads to complete destruction of the epithelium in CRS.25 The nasopharyngeal lymphoid tissue removed from children with CRS has also been reported to have a much greater biofilm load when compared with adenoid removed from children with obstructive sleep apnea. Using SEM, biofilms covered 94.9% of the mucosal surface of adenoid from children with CRS, compared with only 1.9% of adenoid from children with obstructive sleep apnea. The authors hypothesized that such adenoid biofilm in children with CRS

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acts as a bacterial reservoir and may explain why pediatric patients with CRS improve after adenoidectomy.26 Chronic Wounds Although chronic wounds of the head and neck are not common in the pediatric population, recent work has found biofilms present in diabetic foot ulcers, pressure ulcers, and venous leg ulcers, as well as in the temporal bone in the case of temporal bone osteoradionecrosis.27 Biofilms in chronic wounds can be found well beneath the surface of the wound,28 hence sampling using swabs may be inadequate for detection. Directed management of biofilms has been shown to be the most effective treatment method for chronic wounds, utilizing debridement to remove biofilms and antimicrobial treatment to prevent biofilms from reforming.29 Endotracheal Tubes and Tracheostomy Tubes Biofilms are commonly found on biomedical devices, and ENT (ear, nose, and throat) devices are no exception. Biofilms are often found on the inner surface of endotracheal tubes and can lead to ventilator-associated pneumonia.30 Biofilms are found on both the inner and the outer surfaces of endotracheal tubes in neonates even though these tubes show sterile culture results often.31 Studies have shown promise in biofilm prevention using endotracheal tubes coated with an antibacterial surface, including silver sulfadiazine in polyurethane and elemental silver. Biofilms are known to form on tracheostomy tubes as well. A variety of tube materials (e.g., polyvinyl chloride, silicone, stainless steel, sterling silver) have been tested for biofilm resistance and no difference was found among them regarding susceptibility to P. aeruginosa or Staphylococcus epidermidis biofilms.32 Tympanostomy Tubes Tympanostomy tubes removed from children with refractory post-tympanostomy otorrhea have demonstrated extensive biofilm growth. The removal of these biofilm-infected tubes often results in clinical resolution of the otorrhea. A number of strategies involving a resistant tube surface have been tested, including changing the surface morphology or energy to reduce bacterial attachment/adhesion and incorporating antimicrobial agents into the tube material. This work has shown differences in biofilm formation on the different surfaces, but no strategy has yet proven to be ideal. Recent work has also shown that exposure of the tympanostomy tube to blood enhances the formation of P. aeruginosa biofilms, a finding that has implications for tube placement procedures.33 Cochlear Implants Cochlear implants have also been shown to be susceptible to biofilm formation. In an examination of cochlear implants removed from patients due to either infection or mechanical failure, biofilms were demonstrated on all formerly implanted devices and none on the devices that had never been implanted. Bacteria were also found on never-implanted devices, suggesting that improved sterilization procedures might reduce the infection rate.34 More recent studies found differences in biofilm growth dependent upon implant surface features, including greater biofilm formation in a model with

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a surface depression,35 greater biofilm thickness in a surface depression,36 and higher bacterial counts in models with widely fenestrated drug delivery ports.37 These findings have profound implications for the treatment of cochlear implant infections and cochlear implant design.

Prevention of Biofilms Biofilm bacteria exhibit highly adaptable phenotypes, making the development of successful prevention strategies quite difficult. Most efforts in biofilm prevention fall under two general strategies: (1) the development and use of biofilmresistant surfaces or (2) acting against the bacteria and/or the matrix directly. The development of biofilm-resistant surfaces is a major focus of current materials engineering. A variety of surfaces with differing physiochemical properties have been developed, as have numerous biosurfactants. Much work has been done on the binding of antimicrobial agents to a surface, but this strategy has the potential to result in the development of resistant bacterial strains. The application of energy to a surface to disrupt biofilms has been studied as well, including the use of ultraviolet and bioelectric energies. Strategies that reduce shear forces on implants and other medical devices have the potential to reduce breakage of adhering biofilms and their subsequent dissemination, thus reducing infectious complications. Bacteria-centric strategies include preventing initial bacterial attachment, interfering with quorum sensing, or inducing bacteria to return to the planktonic state. Efforts are being made to develop targeted antimicrobial peptides and phages capable of killing quiescent biofilm bacteria. Although longterm use of antibiotics can result in the selection of resistant bacterial strains, prophylactic antibiotic use in selected surgical procedures can kill planktonic bacteria before they can adhere. Lactoferrin, an iron-chelating protein that is a component of the innate immune system, is known to stimulate bacterial motility in P. aeruginosa, which inhibits biofilm formation. Gentian violet has been shown to be effective in disrupting pseudomonas biofilms in vitro,38 although the effect of ferric ammonium citrate on pseudomonal biofilms is strain dependent. Strain differences in response to increasing iron concentration and biofilm morphology stress the importance of studying real-world clinically isolated strains in evaluating the efficacy of antibiofilm agents. Disrupting the biofilm matrix would result in the release of planktonic bacteria that will likely be more susceptible to antibiotics. An example in this respect is the use of recombinant human DNAase, an enzyme that selectively cleaves DNA, to disrupt the matrices of biofilms in cystic fibrosis patients.

Treatment of Biofilms The long-term use of low-dose macrolide antibiotics has been effective in some patients who have diffuse bronchiolitis and cystic fibrosis. The clinical effect of this treatment is nonribosomal, as the dosage is well below the microbiocidal level for Pseudomonas. The clinical effect is thought to be achieved

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CHAPTER 16 ❖ The Role of Biofilms in Pediatric Otolaryngologic Diseases 197 through two mechanisms: (1) paralysis of host neutrophils, which decreases bystander damage from oxidative burst, and (2) suppression of quorum-sensing associated genes and inhibition of twitch motility.39 In recent work, sublethal concentrations of the macrolide antibiotic azithromycin has been shown to be effective in inhibiting established biofilms and preventing the formation of new in vitro biofilms of nontypable H. influenzae.40 Other potential therapies include synthetic antimicrobial peptides, which have shown promise in the treatment of staphylococcal biofilms.41 Other promising potential future treatments include the use of ultrasound to kill bacteria in biofilms,42 and Q-switched Nd:YAG laser pulses to disrupt biofilms on inorganic surfaces.43 Concomitant therapies that focus on killing biofilm bacteria, as well as disrupting their matrices and community communications, may prove more effective than single or sequential antibiotic therapy. Other areas of medicine already employ such simultaneous multimodality approaches to diminish the likelihood of mutagenic resistance. Topical antibiotics might be useful in the treatment of biofilms because topical application can increase the dose well beyond that, which can be safely administered systemically. A topical antibiotic used at a 1000-fold concentration has been shown to produce a 2–2.5-fold log reduction in the number of viable bacteria in S. aureus biofilms, indicating a possible role for topical antibiotics in the treatment of CRS. However, work in a rabbit model showed persistent mucosal pseudomonas biofilms after treatment with a high concentration of topical tobramycin, although the authors acknowledged that SEM could not quantify treatment efficacy.44

Probiotics Not all biofilms and all bacteria are detrimental to their hosts. Humans have a symbiotic relationship with their various microbiomes, many of which exist as biofilms. Mucosal bacteria are found in the nasopharynx of healthy people, and biofilms are an integral part of the human oral cavity, gut, and vagina. Indeed the average human has 1013 cells and is the host to 1014 bacteria. These normal human bacterial flora serve as a barrier against pathogenic bacteria. Given this intimate relationship between humans and their microbiomes, our therapeutic outcomes should not be predicated on the eradication of biofilms, but rather ensuring that our patients are populated with beneficent biofilms. Beneficent biofilms could be used to prevent the formation of pathogenic biofilms or to disrupt already formed pathogenic biofilms. Beneficent biofilms could prevent the formation of pathogenic biofilms by several mechanisms including competition for adherence sites on host cells, the production of hydrogen peroxide, competition for nutrients, and production of specific growth inhibiting factors such as bacteriocins. Although efforts in the otolaryngology arena are nascent, examples include attempts to prevent recurrences of OM and streptococcal pharyngitis using hemolytic streptococcus and

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preventing recurrence of upper respiratory tract infections using “interfering” microorganisms. Work must continue to determine which biofilms are commensal and which are pathogenic so that the former may be used to help patients.

CONCLUSION Virtually, all microbes live in biofilm communities that allow bacteria to survive in the most hostile of environments and which facilitate the development of new strains in response to environmental pressure through inducible mutagenic mechanisms. The biofilm paradigm offers a much richer and more complex view of bacteria, both commensal and pathogenic. A growing body of investigative work has implicated biofilm formation in many chronic diseases of interest to pediatric otolaryngologists including chronic OM, adenoiditis and tonsillitis, CRS, and cholesteatoma and device infections. Although a focus on the planktonic phenotype of bacteria has informed treatment strategies for acute infections, this focus has failed to understand the pathophysiology of chronic infections. Understanding the biofilm phenotype offers a pathway to develop better treatments for our patients.

References 1. Whitchurch CB, Tolker-Nielsen T, Ragas PC, Mattick JS. Extracellular DNA required for bacterial biofilm formation. Science. 22, 2002;295(5559):1487. 2. Hu FZ, Ehrlich GD. Population-level virulence factors amongst pathogenic bacteria: relation to infection outcome. Future Microbiol. 2008;3(1):31–42. 3. Dowd SE, Wolcott RD, Sun Y, McKeehan T, Smith E, Rhoads D. Polymicrobial nature of chronic diabetic foot ulcers using bacterial Tag encoded amplicon pyro-sequencing (bTEFAD). PLoS One. 2008;3:e3326. 4. Brady RA, Leid JG, Camper AK, Costerton JW, Shirtliff ME. Identification of Staphylococcus aureus proteins recognized by the antibody-mediated immune response to a biofilm infection. Infect. Immun. 2006;74:3415–3426. 5. Leroy M, Cabral H, Figueira M, et al. Multiple consecutive lavage samplings reveal greater burden of disease and provide direct access to the nontypable Haemophilus influenzae biofilm in experimental otitis media. Infect Immun. 2007;75(8): 4158–4172. 6. Lewis K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol. 2007;5(1):48–56. 7. Costerton W, Veeh R, Shirtliff M, Pasmore M, Post C, Ehrlich G. The application of biofilm science to the study and control of chronic bacterial infections. J Clin Invest. 2003;112: 1466–1477. 8. Nistico L, Gieseke A, Stoodley P, Hall-Stoodley L, Kerschner JE, Ehrlich GD. Fluorescence “in situ” hybridization for the detection of biofilm in the middle ear and upper respiratory tract mucosa. Methods Mol Biol. 2009;493:191–213. 9. Post JC, Preston RA, Aul JJ, et al. Molecular analysis of bacterial pathogens in otitis media with effusion. JAMA. 1995;273:1598–1604.

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10. Rayner MG, Zhang Y, Gorry MC, Chen Y, Post JC, Ehrlich GD. Evidence of bacterial metabolic activity in culture-negative otitis media with effusion. JAMA. 1998;279:296–299. 11. Dingman JR, Rayner MG, Mishra S, et al. Correlation between presence of viable bacteria and presence of endotoxin in middle-ear effusions. J. Clin. Microbiol. 1998;36(11):3417–3419. 12. Ehrlich GD, Veeh R, Wang X, et al. Mucosal biofilm formation on middle-ear mucosa in the chinchilla model of otitis media. JAMA. 2002;287:1710–1715. 13. Hall-Stoodley L, Hu FZ, Stoodley P, et al. Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA. 2006;296:202–211. 14. Coates H, Thornton R, Langlands J, et al. The role of chronic infection in children with otitis media with effusion: evidence for intracellular persistence of bacteria. Otolaryngol Head Neck Surg. 2008;138(6):778–781. 15. Zuliani G, Carlisle M, Duberstein A, et al. Biofilm density in the pediatric nasopharynx: recurrent acute otitis media versus obstructive sleep apnea. Ann Otol Rhinol Laryngol. 2009;118(7):519–524. 16. Chole RA, Faddis BT. Evidence for microbial biofilms in cholesteatomas. Arch Otolaryngol Head Neck Surg. 2002;128(10):1129–1133. 17. Chole RA, Faddis BT. Anatomical evidence of microbial biofilms in tonsillar tissues: a possible mechanism to explain chronicity. Arch Otolaryngol Head Neck Surg. 2003;129(6):634–636. 18. Kania RE, Lamers GE, Vonk MJ, et al. Demonstration of bacterial cells and glycocalyx in biofilms on human tonsils. Arch Otolaryngol Head Neck Surg. 2007;133(2):115–121. 19. Baldassarri L, Creti R, Recchia S, et al. Therapeutic failures of antibiotics used to treat macrolide-susceptible Streptococcus pyogenes infections may be due to biofilm formation. J Clin Microbiol. 2006;44(8):2721–2727. 20. Galli J, Ardito F, Calo L, et al. Recurrent upper airway infections and bacterial biofilms. J Laryngol Otol. 2007;121(4):341–344. 21. Al-Mazrou KA, Al-Khattaf AS. Adherent biofilms in adenotonsillar diseases in children. Arch Otolaryngol Head Neck Surg. 2008;134(1):20–23. 22. Perloff JR, Palmer JN. Evidence of bacterial biofilms in a rabbit model of sinusitis. Am J Rhinol. 2005;19(1):1–6. 23. Ramadan HH, Sanclement JA, Thomas JG. Chronic rhinosinusitis and biofilms. Otolaryngol Head Neck Surg. 2005;132(3):414–417. 24. Bendouah Z, Barbeau J, Hamad WA, Desrosiers M. Biofilm formation by Staphylococcus aureus and Pseudomonas aeruginosa is associated with an unfavorable evolution after surgery for chronic sinusitis and nasal polyposis. Otolaryngol Head Neck Surg. 2006;134(6):991–996. 25. Galli J, Calò L, Ardito F, et al. Damage to ciliated epithelium in chronic rhinosinusitis: what is the role of bacterial biofilms? Ann Otol Rhinol Laryngol. 2008;117(12):902–908. 26. Coticchia J, Zuliani G, Coleman C, et al. Biofilm surface area in the pediatric nasopharynx: chronic rhinosinusitis vs obstructive sleep apnea. Arch Otolaryngol Head Neck Surg. 2007;133(2):110–114. 27. Nason R, Chole RA. Bacterial biofilms may explain chronicity in osteoradionecrosis of the temporal bone. Otol Neurotol. 2007;28(8):1026–1028.

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28. James GA, Swogger E, Wolcott R, et al. Biofilms in chronic wounds. Wound Repair Regen. 2008;16(1):37–44. 29. Panuncialman J, Falanga V. The science of wound bed preparation. Clin Plast Surg. 2007;34(4):621–632. 30. Pneumatikos IA, Dragoumanis CK, Bouros DE. Ventilatorassociated pneumonia or endotracheal tube-associated pneumonia? An approach to the pathogenesis and preventive strategies emphasizing the importance of endotracheal tube. Anesthesiology. 2009;110(3):673–80. 31. Zur KB, Mandell DL, Gordon RE, Holzman I, Rothschild MA. Electron microscopic analysis of biofilm on endotracheal tubes removed from intubated neonates. Otolaryngol Head Neck Surg. 2004;130(4):407–414. 32. Jarrett WA, Ribes J, Manaligod JM. Biofilm formation on tracheostomy tubes. Ear Nose Throat J. 2002;81(9):659–661. 33. Malaty J, Antonelli PJ. Effect of blood and mucus on tympanostomy tube biofilm formation. Laryngoscope. 2008;118(5): 867–870. 34. Antonelli PJ, Lee JC, Burne RA. Bacterial biofilms may contribute to persistent cochlear implant infection. Otol Neurotol. 2004;25(6):953–957. 35. Loeffler KA, Johnson TA, Burne RA, Antonelli PJ. Biofilm formation in an in vitro model of cochlear implants with removable magnets. Otolaryngol Head Neck Surg. 2007;136(4):583–588. 36. Pawlowski KS, Wawro D, Roland PS. Bacterial biofilm formation on a human cochlear implant. Otol Neurotol. 2005;26(5):972–975. 37. Johnson TA, Loeffler KA, Burne RA, Jolly CN, Antonelli PJ. Biofilm formation in cochlear implants with cochlear drug delivery channels in an in vitro model. Otolaryngol Head Neck Surg. 2007;136(4):577–582. 38. Wang EW, Agostini G, Olomu O, Runco D, Jung JY, Chole RA. Gentian violet and ferric ammonium citrate disrupt Pseudomonas aeruginosa biofilms. Laryngoscope. 2008;118(11):2050–2056. 39. Tateda K, Standiford TJ, Pechere JC, Yamaguchi K. Regulatory effects of macrolides on bacterial virulence: potential role as quorum-sensing inhibitors. Curr Pharm Des. 2004;10(25):3055–3065. 40. Starner TD, Shrout JD, Parsek MR, Appelbaum PC, Kim G. Subinhibitory concentrations of azithromycin decrease nontypeable Haemophilus influenzae biofilm formation and Diminish established biofilms. Antimicrob Agents Chemother. 2008;52(1):137–145. 41. Flemming K, Klingenberg C, Cavanagh JP, et al. High in vitro antimicrobial activity of synthetic antimicrobial peptidomimetics against staphylococcal biofilms. J Antimicrob Chemother. 2009;63(1):136–145. 42. Young D, Morton R, Bartley J. Therapeutic ultrasound as treatment for chronic rhinosinusitis: preliminary observations. J Laryngol Otol. 2010;124(5):495–499. 43. Krespi YP, Stoodley P, Hall-Stoodley L. Laser disruption of biofilm. Laryngoscope. 2008;118(7):1168–1173. 44. Chiu AG, Antunes MB, Palmer JN, Cohen NA. Evaluation of the in vivo efficacy of topical tobramycin against Pseudomonas sinonasal biofilms. J Antimicrob Chemother. 2007;59(6): 1130–1134.

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17

C H A P T E R

Pediatric Gastroenterology Philip E. Putnam

T

he clinical practices of otorhinolaryngology and gastroenterology necessarily overlap due to the shared anatomy and physiology at the intersection of the respiratory and gastrointestinal (GI) tracts. This chapter explores the nature and consequences of disorders of the GI tract that impact the airway in children.

GASTROESOPHAGEAL REFLUX DISEASE Gastroesophageal reflux disease (GERD) is arguably the most common, and most controversial, primary GI disorder that contributes to airway disease. The nature and pathophysiology of GERD are established in the literature, as is the relationship between GERD and airway disease.1 However, the frequency with which GERD contributes to airway disease, and a means to establish whether GERD causes, is associated with, or is an unrelated comorbidity are issues that can be difficult to sort out for an individual patient. The difficulty arises primarily from the lack of a diagnostic test that can both demonstrate reflux events and prove that they are responsible for a particular airway symptom or disease process.2 Therefore, there is no evidence-based, rational, paradigm for the evaluation of infants and children who present with airway symptoms and who might have GERD. Systematic reviews of the literature have concluded that the available studies lack consistency in definitions, assume rather than prove causal relationships, determine disease prevalence or association without determining causality, are often based on the examination of small cohorts of highly selected patients that cannot be generalized, and may afford results that conflict with the results of other studies.3–7 Much of the GERD/airway literature is retrospective case series that reflect the bias and practice of the authors or an institution rather than a prospective assessment of an issue. A comprehensive document has been published recently by an international consensus committee that summarizes the literature regarding the physiology, pathophysiology, and treatment of pediatric reflux and GERD.2

The Physiology of Reflux The concept of gastroesophageal reflux is simple despite its complex manifestations. An episode of reflux is retrograde flow of gastric contents into the esophagus and occurs consequent to relaxation of the lower esophageal sphincter (LES). Flow into the esophagus is favored during inspiration by both reduced intrathoracic pressure and increased abdominal pressure from contraction of the diaphragm, but it only occurs if the LES pressure is lower than intra-abdominal pressure and there is fluid in

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the gastric fundus. The content and volume of refluxate, its pH, and the distance it travels vary from episode to episode. The LES is a region of the distal esophagus at the level of the diaphragm that consists of intrinsic smooth muscle cell syncytium whose function is to maintain contraction except during swallowing, eructation, or vomiting. The circumferential pressure generated by the sphincter is augmented by the left crus of the diaphragm, which exerts extrinsic compression, such that the total pressure in the region should prevent gastric contents from entering the esophagus with normal respiration and with transient increases in intra-abdominal pressure. Primary hiatal herniation of stomach into the chest is uncommon in children, but it is associated with increased reflux due to the impairment of LES function resulting from loss of the normal anatomic relationships at that level. We experience all occasional episodes of reflux (GER) that are innocuous and inconsequential, but that is to be distinguished from GERD. GERD is conceptually defined as the clinically relevant sequelae of GER. Individuals with GERD have an increased number of inappropriate transient relaxations of the LES (TLESRs) that permit episodes of GER to occur. The sequelae are then related to the impact of the refluxate on those structures “north” of the diaphragm. Our understanding of the pathophysiology that permits TLESRs is evolving. Neural pathways involving the vagus nerve and neurochemical receptors, including but not limited to γ-butyrate type B (GABAB) receptors and the metabotropic glutamate type 5 receptors, play a role in LES function and maladaptive function.8,9 “Acid reflux” is a nonmedical term that is, nevertheless, popular in the community. In truth, the acidity of a given episode of GER is variable depending on the nature of and time from the last meal.10 Indeed, most episodes of GER are at best weakly acidic (by convention, pH 4–7), as they occur in the immediate period after a meal when acid has been buffered by meal constituents. Once acid production overcomes the buffering capacity of the meal, the pH of chyme does decrease such that any reflux episodes then are more acidic (by convention, pH ≤ 4 is considered acidic reflux). Gastric acid production is otherwise normal in individuals with GERD. There are several possible outcomes once gastric material has left the stomach. It may be expelled out the mouth and lost, it may be captured in the mouth and reswallowed, it may enter the hypopharynx/pharynx and encounter any of the local structures therein, or it may only travel into the esophagus and not pass the upper esophageal sphincter (UES). Swallowing and esophageal peristalsis returns refluxate to the stomach, and saliva contributes bicarbonate to

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neutralize the acid. Failure to initiate swallowing or peristalsis (e.g., during sleep or as a consequence of primary esophageal dysmotility) may prolong the contact between refluxate and the mucosa. Refluxate may come in contact with the laryngeal mucosa or be aspirated into the trachea either as it exits the esophagus (travelling orad) or during reswallowing (e.g., if the patient experiences dysphagia that risks aspiration at baseline). Unrepaired tracheoesophageal fistula or laryngeal cleft may also permit refluxed material access to the tracheobronchial tree.

Clinical Gastroesophageal Reflux Disease The manifestations of GERD are protean, although the GI symptoms are generally limited to regurgitation and heartburn. Both symptoms imply awareness of an event, either due to the unexpected appearance of gastric contents in the mouth (or pharynx) or due to pain. When studied as described below, most episodes of GER, even in individuals who have GERD, go unnoticed by the individual. The effortless regurgitation that characterizes GERD is not equivalent to vomiting, although GERD patients may report “vomiting” as a symptom, having used the term imprecisely. It is essential for the clinician to gain a clear picture from the patient as to the nature of the event: effortless regurgitation should be apparently spontaneous, not forewarned by nausea and not provoked by retching. The physiologic events that characterize true vomiting—nausea, retching, cessation of respiration, tonic contraction of chest wall and abdominal musculature as for the Valsalva maneuver, and retrograde peristalsis—are absent in GER. Although episodes of GER in infants may seem somewhat forcefully expelled, the physics and physiology of that event do not include features of vomiting, at least initially. Gagging on refluxed material may invoke the vomiting reflex that results in true vomiting, so the history may be somewhat confusing as to the primary event. Posttussive vomiting is also not reflux, although the initial cough could have been provoked by a reflux event. In pediatrics, GER and GERD are most common in infants. As a developmental phenomenon, effortless regurgitation is common (~50% of infants), tends to peak around 4 months of age, and resolve by a year.11 There is extraordinary variability among infants who regurgitate as to the frequency, amount, and consequences of their GER. The majority of infants who regurgitate are otherwise unaffected by the spit up (so-called happy spitters) and can be managed without pharmacotherapy in anticipation of resolution with maturation. Although serious complications are rare, symptoms beyond regurgitation including poor weight gain (due to poor intake or excessive calorie loss), irritability, or respiratory symptoms require additional attention and appropriate therapy. The primary symptom of GERD in infants is regurgitation, but so-called silent reflux may also occur in which non-GI complaints predominate. “Silent” is better termed “nonregurgitant,” as symptoms other than regurgitation do occur. Possible presentations of nonregurgitant reflux may include irritability, cough, laryngitis/hoarseness, feeding

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difficulty, bronchospasm, recurrent pneumonia, recurrent croup, or throat clearing. Although irritability and infant feeding problems are commonly attributed to GERD, recent studies have failed to demonstrate any benefit from empiric acid suppression compared with placebo, suggesting that the concept of acid injury promoting these otherwise nonspecific symptoms is misdirected in general.12,13 Feeding difficulty does occur in some infants who have GERD, but the “diagnosis” of GERD in the majority who are so labeled is an assumption without basis.14 It is for the astute clinician to sort out the true anatomic, physiologic, or developmental problem that leads to these symptoms. A brief trial of acid suppression may be warranted, but clinical failure to respond should suggest another diagnosis, particularly in the absence of other symptoms of GERD. Other consequences of GERD include esophagitis, which may present with nonspecific symptoms such as heartburn, dysphagia, odynophagia, nausea, or early satiety. Untreated esophagitis predisposes to serious complications including Barrett’s esophagus, peptic esophageal stricture, and even esophageal cancer. The latter phenomena are uncommon in children, but do occur.

Gastroesophageal Reflux Disease and the Airway The physiologically nonsensical term “laryngopharyngeal reflux” has nevertheless become entrenched in the medical literature to indicate the application of gastric contents onto or into the larynx or pharynx as the result of a reflux event. The term has come to broadly implicate GERD in the pathogenesis of associated airway symptoms. Supraesophageal and extraesophageal manifestations of GER are far more satisfying terms. Non-GI symptoms and signs from GERD are necessarily considered secondary manifestations and may occur singly or in combination. The bases for the secondary symptoms from GERD include tissue injury from the acid content of the refluxate (e.g., esophagitis, laryngitis, exacerbation of stridor from laryngomalacia),15–18 compensatory mechanisms that are provoked to manage the bolus of refluxate (e.g., water brash, cough, throat clearing), aspiration and failed clearance of refluxed material (recurrent pneumonia), and/or neutrally mediated manifestations of reflexes stimulated by the event (e.g., cough, bronchospasm, laryngospasm, apnea).19–25 How and whether GER influences nasal, sinus, or middle ear pathology remains under investigation and is controversial.26–28 The laryngeal mucosa may be damaged by acid exposure. Erythema, epithelial erosion, granulation tissue, or nodularity may be seen. However, these findings are not diagnostic for GERD, as all of these laryngoscopic features are nonspecific, variable, and subjectively reported with poor interobserver consistency.29–33 Patients may present with airway conditions such as hoarseness, bronchospasm, recurrent croup, and recurrent bronchopneumonia associated with GERD, but causality is difficult to prove.34 These conditions may coexist with reflux

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CHAPTER 17 ❖ Pediatric Gastroenterology such that management of the GERD alone has little impact on them,35 whereas GERD can be a significant provocative factor that, when treated, diminishes or resolves the other condition. There is a long differential diagnosis for each of the nonGI symptoms that may be associated with GERD, such that their presence does not establish the diagnosis of GERD, particularly when other characteristic features of GERD are

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absent. After thorough history and physical examination, the symptoms deserve investigation with the broader differential diagnosis in mind.36 In the final analysis, it may be possible to attribute symptoms to GERD only after the impact of antireflux therapy is observed.37 An approach to the evaluation of children who have symptoms that could be caused by or associated with GERD is presented in Fig. 17-1.

History and physical examination, review prior diagnostic studies and response to prior attempted therapy(ies)

Chronic supraesophageal symptoms without GI symptoms

Chronic supraesophageal symptoms plus GI symptoms (effortless regurgitation and/or heartburn)

Evaluation as appropriate--Chest Xray, esophagogram, direct laryngoscopy, bronchoscopy with BAL, EGD with biopsies, MII-pH

PPI trial

Persistent Symptoms (GI and airway/ respiratory) : Update history

Symptom resolution likely confirms GERD

No GER or other inflammatory changes observed-unlikely to be reflux induced symptoms. Pursue other potential etiologies

Diagnostic findings-reflux esophagitis, EoE, increased GER detected by MIIl-pH and/or strong symptom association

Evaluation as appropriate

Treat findings as appropriate. IF GERD: PPI trial Positive findings: reflux esophagitis, EoE (Eosinophilic esophagitis), abnormal MII- pH with increased GER or positive symptom association

Assure compliance, augment or change medical therapy as appropriate,

If GERD is primary diagnosis, consider fundoplication for severe symptoms and failed medical management

No abnormal findings: Update hx

Persistent GI symptoms require additional GI evaluation

Symptom resolution-establishes causal relationship with GERD, continue PPI

Persistent symptoms after 8 weeks

Consider coexisting etiologies (GERD plus other), vs persistent GERD

Repeat EGD and MIIpH on PPI, assess symptoms association

Persistent esophagitis or MII-pH shows positive symptom association: ? compliance, consider alternative therapy

Resolved esophagitis, lack of symptom assoc'n on MII-pH suggests that there is another primary airway diagnosis

FIGURE 17-1. This algorithm provides a basic process for the evaluation of children who have respiratory/airway symptoms for which GERD is included in the differential diagnosis. It assumes that common conditions (e.g., infection, foreign bodies) have already been ruled out and focuses on the evaluation of the GERD aspect of the compliant rather than the respiratory symptoms. Because there is a broad range of potential presenting complaints (e.g., hoarseness, throat clearing, cough, recurrent pneumonia), the precise nature of additional evaluation including laboratory evaluation, imaging and endoscopic assessment must be individualized and coordinated among services. Recommended PPI therapeutic trial is with 1 mg/kg/dose bid (1/2 hour before breakfast and dinner, not at bedtime) for 6–8 weeks.

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Detection of GER episodes by the means discussed next is not sufficient evidence to establish a causative role for them in the creation of non-GI symptoms. The failure of any test to prove a causal relationship between GERD and airway symptoms has continued to confound the diagnosis of GERDassociated respiratory symptoms.

Identification of Gastroesophageal Reflux Objective measures to identify and quantify episodes of GER have been available for many years, and newer technology has evolved to facilitate the characterization of many different reflux parameters. Historically, pH-metry was the mainstay of reflux detection, but suffers from a multitude of limitations, such that it has been largely replaced by multichannel intraluminal impedance monitoring that includes a pH electrode (MII-pH). pH-Metry pH-metry employs one or more pH electrodes on a catheter placed through the nose [or in a capsule that is attached to the distal esophageal mucosa (Bravo™38)]. These methods continuously sample the luminal pH and recognize reflux only when the pH decreases to four or below (by convention). The number and duration of acidic reflux episodes are determined. Additional parameters such as timing with regard to meals and body position, and association with symptoms, can be determined if the patient or observer records them precisely. The volume and proximal extent that refluxate travels cannot be determined by a single pH electrode, but catheters that employ electrodes distally and proximally can identify those episodes that travel at least to the upper electrode (without predicting the height to which it will ultimately travel). The primary (major) limitations of pH-metry are its failure to detect any reflux with pH above four and poor correlation with symptoms.39,40 There have been attempts to measure pharyngeal pH as a measure of reflux to the pharynx.41–43 The test has been difficult to perform as the standard probe tends to dry out, which interferes with accurate pH recording, and is uncomfortable if the tip of the probe is mobile in the pharynx. The refluxate may become less acidic as it travels up the esophagus and mixes with saliva, such that it may no longer meet the same pH criterion as it would in the distal esophagus for the event to be registered as reflux. It is not appropriate to extrapolate the finding of gastric contents in the pharynx to indicate aspiration or causality in any other symptom, although it is tempting to do so. Establishing normative pH standards for reflux to the pharynx has been a challenge across the age ranges. Given the significant limitations, pharyngeal pH monitoring is not a standard part of clinical evaluation of patients. Multichannel Intraluminal Impedance Plus pH-Metry (MII-pH) In contrast to pH-metry, MII-pH incorporates a pH electrode onto a catheter that also contains multiple sets of paired

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electrodes that measure intraluminal impedance.44 Impedance (resistance to flow of current between electrodes) varies by the material in contact with the electrodes. Air (swallowed or belched) has very high impedance, whereas electrolytecontaining fluids reduce the impedance. The impedance offered by tissue, as the catheter rests against it, is between the extremes of fluid and air, such that the change in impedance (induced by the movement of air or fluid through the esophagus along the catheter with swallowing, belching, reflux, or vomiting) is immediately obvious. The direction of flow is apparent by the sequential changes across several pairs of electrodes (i.e., proximal to distal vs. distal to proximal). A pH electrode near the distal end of the catheter determines the acidity of material presenting to the distal catheter, which is relevant only for fluid travelling retrograde up the esophagus. The advantage of MII-pH is that it permits detection and characterization of each reflux episode, not just those that are pH 6 weeks). Side effects are generally mild and of little consequence. Prescription formulations are available for use in infants and young children (which may be off-label, depending on the medication).65 PPIs have largely supplanted the use of H2RAs in the management of chronic GERD and include omeprazole, esomeprazole, lansoprazole, pantoprazole, and rapeprazole.66–72 They exist in the United States in multiple brands and formulations, some of which are now OTC. Their effects are more sustained due to permanent binding to and disabling of the H+-K+ ATPase molecule, allowing daily or bid dosing. Tachyphylaxis does not occur. Side effects including headache, diarrhea, nausea, and abdominal pain do occur, but are generally mild and may be amenable to change to a different compound. Raising the pH in the stomach may pose some increased risk of GI infections.73 Clinicians must be aware that some of the compounds do not have formal Food and Drug Administration (FDA) indication for use in infants or children. Prokinetics Prokinetic agents, in theory, should best address the dysmotility that underlies GERD. Medications that reduce TLESRs, increase the pressure in the LES (which is not a primary defect in the majority of patients with GERD), or improve gastric emptying (which may be prolonged in some patients who have GERD) might be expected to reduce GER symptoms by reducing the number of events. In practice, the observed benefit of this class of medication for GERD (e.g., metoclopramide) is less than might be expected, despite their readily identifiable effects on the GI tract in basic science studies.74 In the United States, metoclopramide is available but used infrequently due to the limited symptom improvement and the potential for extrapyramidal neurologic side effects and

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CHAPTER 17 ❖ Pediatric Gastroenterology even tardive dyskinesia. Medications such as cisapride that may have more definable effect on the symptoms of GERD are no longer available in the United States due to potentially serious cardiac side effects, risking arrhythmia, and even death. Short-term use of another dopamine agonist (domperidone, which is also not available in the United States) was associated with paradoxically increased GER in one study.75 Identification of the GABAB receptor involvement in the pathogenesis of TLESRs has made it a prime target for pharmacologic intervention. Baclofen is a GABAB agonist that does diminish TLESRs and reflux events, but its role in clinical management of GERD patients has been limited by the occurrence of the expected central nervous system (CNS) side effects. Clearly, LES relaxation is essential during swallowing, so targeting only inappropriate TLESRs without creating achalasia is a challenge. Nevertheless, the search for compounds that can affect GABAB and the other receptors implicated in TLESRs, but which lack CNS side effects, is ongoing and may offers some promise in controlling the primary pathophysiologic event in GERD in the future.76

Surgery for Gastroesophageal Reflux Disease The ultimate therapy for reflux is surgical fundoplication, which creates a “wrap” of gastric fundus around the intraabdominal esophagus and gastric cardia that effectively prevents retrograde flow into the esophagus while preserving esophageal emptying. There are several variations of fundoplication identifiable by the proportion of the circumference of the esophagus that is encased. Because virtually all reflux stops in response to properly performed fundoplication, all primary and secondary symptoms from GERD should cease, eliminating the need for ongoing medication. However, comorbidities that are not primary manifestations of GERD will not respond to fundoplication.77–80 Laparoscopic fundoplication has mostly replaced the open surgical procedure.81,82 Complications from fundoplication are unacceptably common (particularly in neurologically impaired individuals) and include persistent reflux (wrap that is too loose), paraesophageal herniation of the stomach (potentially requiring reoperation), dysphagia (too-tight wrap that interferes with esophageal emptying), gas bloat from the inability to eructate, and increased or decreased rate of gastric emptying. One of the most problematic side effects is persistent retching, which occurs primarily in developmentally impaired children. Some of these children were incorrectly diagnosed with GERD, having in fact true vomiting (see above) that was misidentified as GER. Although fundoplication is effective against GER, it has absolutely no role in the management of children who vomit for reasons other than GERD. Hence, the diagnostic evaluation to prove GERD and to prove the absence of any other cause of vomiting is absolutely essential prior to creation of a fundoplication. Just as it would be nonsensical to do a fundoplication for the management of

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hypertrophic pyloric stenosis, it is equally problematic to perform a fundoplication for the management of any other condition that produces vomiting rather than effortless regurgitation. The decision to proceed to fundoplication for an individual child must be made by incorporating the broader analysis of multiple factors including age, symptom complex, the likelihood of resolution of the reflux with maturation, comorbidities, and response to pharmacotherapy. In some analyses, response to fundoplication was more likely if the patient responded to acid suppression (confirming a causal relationship between reflux and the symptom).83

EOSINOPHILIC ESOPHAGITIS (EoE) Eosinophil-predominant esophagitis (EoE) has been recognized more and more commonly over the past 15 years. Prior to that, eosinophils in esophageal mucosa were associated with, and assumed to be diagnostic of, reflux esophagitis.84 However, a case series of children was reported in which presumed reflux esophagitis failed to respond to any therapy for GERD but nevertheless responded to replacement of the diet by an amino acid–based formula.85 This formed the basis for the distinction between eosinophilic esophagitis and GERD in pediatrics. Eosinophilic esophagitis is now abbreviated as EoE to distinguish it from erosive esophagitis that is traditionally abbreviated EE. EoE has undergone extensive study. As recognition of this condition as a separate entity from GERD became established and more broadly accepted, the number of children and adults diagnosed with EoE increased dramatically. Unfortunately, the absence of formal diagnostic criteria initially created inconsistencies in both the medical literature and clinical practice in identifying and treating patients. However, the medical literature has been reviewed and summarized to create an updated consensus recommendation for diagnosis and treatment of EoE.86 Although EoE and GERD are different disorders, there is considerable overlap in symptoms and histology, such that great care and compulsion are necessary during the diagnostic process before conveying a formal diagnosis to the patient. The consensus recommendations recognize that eosinophil-predominant inflammation in the esophageal mucosa is required but not sufficient for the clinical diagnosis of EoE. There are many other conditions in which eosinophils may be found in the esophageal mucosa, and none of the other histologic findings that are common in EoE are specific for it. Although a minimum number of eosinophils (per 400× high powered field, abbreviated: /hpf) is needed for a legitimate histologic diagnosis of eosinophilic esophagitis, the number in excess of 15 eos/hpf does not distinguish EoE from GERD or any other disorder for clinical purposes at any number. Only when all clinical and histologic parameters have been considered and met, the EoE clinical diagnosis can be made. It may be more appropriate to view 15 eos/hpf in an untreated patient as a threshold below which the diagnosis of EoE is

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unlikely. Because EoE may coexist with clinically relevant GERD, the diagnostic process and treatment must account for both in affected individuals. By definition, EoE is a chronic condition with immunemediated eosinophil-predominant esophageal inflammation that is present along with characteristic symptoms not responsive to treatment for GERD. The histologic characteristics of EoE are nonspecific and include an inflammatory infiltrate with eosinophils, lymphocytes, and mast cells. Basal cell layer expansion and lamina propria fibrosis may be present. Eosinophils are often layered near the luminal surface of the mucosa and may form microabscesses that are visible to the endoscopist as white specks on the surface (Fig. 17-2). These features may be patchy such that completely normal mucosa may abut remarkably inflamed tissue endoscopically and histologically. The disease tends to be more intense in the distal esophagus but can be uniform throughout the esophagus, or affect only the proximal esophagus. Endoscopic features of EoE are also characteristic but non-specific. Pallor, thickening of the epithelium leading to loss of the normally-visible vascular pattern, linear furrows, and superficial white specks of exudate are the common manifestations (Fig. 17-3). Ulceration is absent unless there is also pathologic GERD. Fragility of the epithelium may cause it to split just with passage of the endoscope against mild resistance (‘crepe paper mucosa”). Complications of chronic inflammation including a so-called ‘ringed’ esophagus, stricture formation, small caliber esophagus (long segment of narrowing) are more common in adults, but do occur in children. Early mucosal remodeling is manifest histologically as lamina propria fibrosis or deposition of a layer of dense connective tissue. This is reversible with effective therapy, resolving simultaneously with the mucosal inflammatory changes.85 Fibrosis that fails to respond to therapy is associated with the long-term sequelae and requires repeated dilatations to

FIGURE 17-2. Distal esophageal mucosa demonstrating common features of EoE in children: adherent white specks of exudate (which can be confused with fungal infection), edema, and loss of vascular markings.

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manage the resulting dysphagia. Strictures occur anywhere from just below the UES to just above the LES, but proximal strictures predominate in the author’s experience.

Symptoms from Eosinophilic Esophagitis The symptoms from EoE vary considerably by age and correlate poorly with histology.87–89 Dysphagia for solids is the predominant symptom in adults and some adolescents. Presentation in adolescents is often as a food bolus impaction requiring endoscopic removal. Many such patients will endorse a history of intermittent dysphagia of variable duration prior to the impaction, but only in response to questions directed at eliciting a history of compensatory maneuvers to avoid getting food stuck—eating slowly, chewing more, and drinking liquids with each bolus swallowed. The dysphagia is virtually always for solids only. Dysphagia for liquids, except in the presence of a food impaction, should suggest another diagnosis. Younger children (elementary school to preadolescents) may present with abdominal pain or vomiting, whereas infants and toddlers tend to present with feeding problems ranging from choking to food aversion. All these symptoms are nonspecific and require thorough investigation with the broader differential diagnosis in mind.

Eosinophilic Esophagitis and Allergy Eosinophilic Esophagitis is most commonly a manifestation of immune-mediated reaction to food antigens.90 Removal of the offending antigens permits resolution of the esophagitis, and reintroduction of the antigen provokes recurrent inflammation. Individuals who have eosinophilic esophagitis are very likely to have other allergies (food, environmental, drug), chronic rhinitis, asthma, and/or eczema. These associated phenomena have characteristic symptoms that

FIGURE 17-3. Figure 17-3 Distal esophageal mucosa demonstrating exudate as well as the typical linear furrows and thickening (that results in loss of vascular markings) that are characteristic of EoE.

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CHAPTER 17 ❖ Pediatric Gastroenterology do not necessarily respond to dietary changes and must be managed in conventional fashion along with the EoE. Patients who have EoE may present primarily with the respiratory or skin manifestations of their associated allergic disease. Subtle or intermittent GI or feeding symptoms should be sought and appropriate evaluation undertaken when present.

Eosinophilic Esophagitis and the Airway Histologic esophageal eosinophilia has been discovered in children who present with sore throat, recurrent croup, vocal nodules, hoarseness, and throat clearing.91 Although the histology may be suggestive, as in all other cases of suspected EoE, these patients must be evaluated and treated for GERD before the clinical diagnosis of EoE is appropriate. Because a substantial proportion of these children is otherwise atopic (~2/3), any given child may have multiple symptoms with overlapping pathogeneses.92,93 Allergy, GERD, and EoE may produce a similar set of symptoms, and one or more of these etiologies may indeed be present simultaneously. Nonspecific complaints such as sore throat, throat clearing, hoarseness, and cough may require therapy directed at more than one underlying etiology. For example, chronic allergic rhinitis is a particularly common symptom that is not responsive to dietary antigen elimination.

Management of Eosinophilic Esophagitis As it is a reflection of adverse immune response to food, the management of EoE is most appropriately accomplished by strict dietary antigen avoidance. Standard allergy testing by skin prick and atopy patch testing may afford insight into the foods responsible for EoE. However, if symptoms and the histologic features of EoE fail to respond to the diet predicted by allergy testing, avoidance of additional antigens may be necessary. False-positive and false-negative results from allergy testing interfere with successful implementation of an elimination diet at presentation in many children.94 Initial diet options beyond antigen elimination directed by allergy testing includes the six food elimination diet (SFED) and the elemental diet.95 SFED requires the empiric elimination of the six most common antigens that are also associated with immediate hypersensitivity reactions (i.e., milk, egg, soy, wheat, fish/shellfish, tree nut/peanut) in the US population. Resolution of esophagitis in ~70% of children who have EoE in response to this diet implies that the offending food or foods often, but not exclusively, come from this group of foods. Sequential reintroduction of the individual antigens is required to ascertain which is(are) offensive. Replacement of the diet by an elemental diet effectively restores normal esophageal histology in up to 95% of children who have been so treated, confirming that nearly all EoE is generated in response to dietary antigens.96 Speculation continues as the etiopathogenesis of EoE that fails to respond to an elemental diet.

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When any of the initial diets is successful, the actual offending food(s) from within the group is(are) not known because the antigens were eliminated simultaneously. Therefore, to determine which are safe, antigens are reintroduced sequentially. This process can be quite prolonged depending on the number of antigens that were eliminated at the outset. Frequent offenders such as milk are generally reintroduced alone, whereas antigens that are less likely to be provocative (e.g., fruits/vegetables) may be introduced in groups of two to four depending on the child. There is considerable variability among children, such that some ultimately tolerate no or very few foods, whereas others may react only to milk. Currently, it is only possible to understand an individual’s place in that spectrum in retrospect, as there are no predictive factors. Unfortunately, during the phase of food antigen reintroduction, it is quite common for the esophagitis to return without accompanying symptoms, which necessitates endoscopic evaluation to assess the esophagus before proceeding with new foods. Symptom recurrence is conceptually simpler, as it allows the food to be stopped without endoscopy, but the absence of symptoms is not a reliable predictor of the absence of inflammation.88

Pharmacotherapy for Eosinophilic Esophagitis EoE often responds to steroid therapy, although no specific medication has FDA approval for the treatment of EoE. Predictably, systemic steroids are effective but associated with all the expected side effects when used long term.85 EoE is a chronic disease that requires maintenance therapy and systemic steroids are not appropriate for that. Rarely, an acute presentation with severe dysphagia may necessitate a short course of prednisone to reduce the inflammation, but an alternative maintenance therapy must be initiated simultaneously or immediately following. Relapse of EoE is virtually universal when any therapy is discontinued. Steroids with limited absorption and extensive first-pass metabolism are effective for EoE when used topically.97,98 Both fluticasone and budesonide are formulated for use in patients who have asthma, but they reduce esophageal mucosal inflammation when delivered to the esophagus either by swallowing puffs from a metered-dose inhaler (fluticasone) or by drinking the formulation intended for nebulization (budesonide). Superficial Candida infections (oropharyngeal or esophageal) sometimes result. Systemic side effects of adrenal suppression have not been observed at the doses used for esophagitis, although the cumulative effect of multiple additional dosages for rhinitis or asthma may inhibit the hypothalamic-pituitary axis with resulting adrenal insufficiency (personal observation). The dose range for fluticasone and budesonide are wide (Fluticasone 88–1760 μg per day, budesonide 250–2000 μg per day). Generally, prospective studies have observed that

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the esophagitis resolves in 50%–80% of patients at the dose studied.95,96 Clinical observation of the nonresponders suggests that some patients fail to respond to any reasonable dose, assuming adherence (personal observation). Patients are instructed to “break the rules” to effectively use the MDI when taking these medications for this off-label purpose—no spacer is used; the patient is instructed to “hold their breath, puff and swallow”; no mouth rinse, eating, or drinking is permitted for 30 minutes postadministration to avoid diluting or removing any of the medication out of the mouth or esophagus. Retrospective analysis of the impact of fluticasone on EoE in children who are atopic (as defined by having positive skin prick tests) suggests that fewer atopic children respond than do those who have negative skin tests, such that fluticasone may not blunt the immune response to foods uniformly.99 To date, an algorithm has not been objectively established to determine which therapy a particular child who has EoE should receive. Matching therapy to the child’s phenotype makes the most sense conceptually (e.g., dietary antigen elimination for allergic patients, topical steroids for the nonatopic group), but may not be practical for some patients, as dietary antigen elimination requires considerable effort on the part of the parent and patient to maintain. The impact of dietary management on quality of life can be substantial. Eating anywhere but home (e.g., restaurant, school, friend or relative’s home) while strictly avoiding offending antigens is a challenge that some families are unable to overcome. Because life with EoE can be difficult, a multidisciplinary approach that includes gastroenterology, allergy, pathology, psychology, and dietician greatly facilitates management of the plethora of issues that arise for these patients.

DYSPHAGIA The term “dysphagia” means difficulty swallowing, implying impairment of the swallowing mechanism at any level from pharynx to stomach. There has been some dilution of the term in some centers to also encompass difficulty feeding (even if its behavioral oral aversion such as gagging on textures, for example). The latter is beyond the scope of this section, which focuses on the clinical approach to dysphagia and aspiration. True dysphagia is a manifestation of a long list of anatomic abnormalities or dysfunctions of the swallowing apparatus.100 Superficially, the normal swallow is a complex event with voluntary and involuntary components. After preparation in the mouth, the tongue delivers the food bolus to the pharynx, which contracts to push it through the relaxed UES (the cricopharyngeus muscle). Esophageal peristalsis propels the bolus to the stomach through the LES (described above). Both sphincters relax to permit bolus passage, but remain tonically contracted between swallows. The epiglottis directs liquids into the pyriform sinuses and away from the glottis as the bolus approaches the hypopharynx, while the vocal folds close to prevent tracheal aspiration.

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Disruption of any of the elements of swallowing or the attendant protective reflexes will lead to symptoms ranging from choking, gagging, gulping, coughing, food passing too slowly, food sticking (transiently or to the point of frank impaction requiring endoscopic removal), regurgitation, or vomiting.101 The broader consequence of failed swallow may be aspiration of swallowed (or refluxed) material into the trachea, contributing to lower airway disease including recurrent pneumonia. These symptoms may be present in isolation or in combination. The history of dysphagia in infants and toddlers is somewhat more difficult to obtain and comprehend as it is elicited from the guardian rather than a first-hand account of the nature of the difficulty from the child. For older children, the history should include not only review and definition of the symptom(s) but also thorough discussion of the compensatory mechanisms they use to avoid problems. Older children who have chronic dysphagia are quite successful at reducing the frequency of overt dysphagia by consciously (or unconsciously) compensating for the difficulty by avoiding certain textures of food (e.g., meat, thick bread), eating slowly, drinking liquids with each bite, and/or chewing excessively. Dysphagia for liquids has perhaps a more limited differential diagnosis than dysphagia for solids. Choking on liquids from birth is concerning for anatomic abnormalities such as laryngeal cleft, tracheoesophageal fistula (TEF), cricopharyngeal achalasia (primary or due to posterior fossa processes such as Chiari malformation), or vocal cord paralysis. Achalasia of the LES also may present with dysphagia for liquids and solids. Esophageal foreign body may induce dysphagia for liquids. Dysphagia for solids may be a manifestation of any narrowing of the esophagus [e.g., intrinsic stricture (congenital or anastomotic stricture after tracheoesophagal fistula repair, for example); extrinsic compression due to vascular anomalies such as aberrant left subclavian in combination with right aortic arch]. Dysmotility of the esophagus is more likely to cause dysphagia for solids than liquids and may result from inflammation (e.g., GERD or EoE, caustic ingestion, mucositis from chemotherapy, radiation injury), primary dysmotility (s/p esophageal atresia or TEF), and acquired dysmotility syndromes (e.g., achalasia). The possibility of a foreign body in the esophagus should be an immediate concern in an infant or toddler who experiences abrupt onset of dysphagia. Lithium ion batteries have received considerable attention recently, as they can cause local damage in the esophagus after relatively brief contact. Esophageal perforation, tracheoesophageal fistula, and aortoesophageal fistula have been reported, generating guidelines for immediate (i.e., within 2 hours) removal.102 Although coins remain the most common esophageal foreign body removed from the esophagus, all manner of small objects have been ingested by young children. Sharp objects pose hazard for both immediate perforation as well as additional injury during removal, requiring appropriate

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CHAPTER 17 ❖ Pediatric Gastroenterology equipment (e.g., overtube) and technically adept clinicians to safely get them out. The locations where foreign bodies are most likely to lodge in the normal esophagus are areas of relative extrinsic compression by the aorta, right atrium, and LES (proximal, mid, and distal, respectively) that otherwise have no impact on esophageal function. Food bolus impactions can occur anywhere and are most likely in patients who have eosinophilic esophagitis. The author’s clinical practice is to biopsy the esophagus in the majority of foreign body impactions, particularly if there is any prior history of dysphagia or endoscopic evidence for esophagitis remote from site of the impaction. It is not unusual to identify eosinophilic esophagitis in patients who ingest objects other than food that fail to pass. Unwitnessed foreign body ingestion with prolonged impaction represents a special class of foreign body that requires thoughtful, multidisciplinary care. As for more immediate complications of lithium ion battery impactions, prolonged impaction of other objects in the esophagus may result in perforation, traumatic TEF, mediastinitis or mass, stricture formation, and aortoesophageal fistula. Sequential esophagoscopy and bronchoscopy, as well as follow-up examination may be indicated depending on the location of the impaction and the local injury apparent in the esophagus after removal. Similarly, severe mucosal injury from caustic ingestion requires multidisciplinary care from initial assessment forward. Progressive structuring can occur over weeks following the ingestion, which may require repeated dilatations or surgical intervention.

Diagnostic Methods The examination employed should be directed by the nature of the complaint: solid or liquid dysphagia, age at onset (congenital vs acquired), and associated complaints (stridor, cough with feeds, recurrent pneumonia, food allergy, food impaction). Radiographic examination with barium to view the various phases of swallowing from oral preparation to esophageal emptying into the stomach is often a first step. The study may be diagnostic (esophageal stricture) or may simply describe the safety of swallowing, as determined by the presence or absence of tracheal aspiration, without deciphering the etiology. Offering barium that has been thickened may aid in prescribing the safest consistency to swallow without aspiration for those who demonstrate aspiration of thin liquids. The safety of swallowing (i.e., the likelihood of tracheal aspiration) can be investigated by fiber endoscopic evaluation of swallowing (FEES) or FEES with sensory testing.103,104 These sophisticated tests offer the additional capacity to observe laryngeal and vocal fold function during swallowing of small quantities and in response to stimulation of the local mucosa. Although it is not well suited for investigation of

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the handling of large boluses, it provides visual information in a fashion that is quite sensitive. When combined with radiographic methods, considerable information is generated regarding swallows in patients with oropharyngeal dysphagia. If esophageal empting is a concern, modified esophagram or nuclear swallowing study permit direct observation and qualitative assessment of esophageal emptying. Endoscopy may be a better choice for initial evaluation of dysphagia if there are features suggestive of inflammation (heartburn, epigastric pain, regurgitation, odynophagia) rather than obstruction. Esophagitis due to acid injury, infection (viral), caustic ingestion, or EoE are detectable grossly and/or histologically. Flexible endoscopy offers both the opportunity for diagnosis and therapy (see Esophageal Manometry section below). Foreign body retrieval, food bolus impaction removal, and through-the-scope balloon dilatation are all commonly available and employed when indicated. There is an extensive list of through-the-scope grasping devices, snares, nets, and wire baskets, such that most objects and food can be removed from the esophagus with flexible endoscopes. The timing of the examination will range from emergent (e.g., foreign bodies such as batteries or sharp objects, food bolus impaction) to urgent (caustic ingestions) to elective (i.e., within 24 hours).

Esophageal Manometry If obstruction and inflammation are absent and dysphagia persists, esophageal manometry allows description of UES and LES pressures and relaxation characteristics, as well as esophageal peristaltic wave pressure, propagation, and duration. Catheters that have multiple water-perfused channels or solid-state pressure monitors are available and can clarify the mechanics of esophageal peristalsis well. Newer sophisticated solid-state catheters provide computer-generated images of esophageal mechanics. Catheter-based pressure manometers do not define parameters of esophageal emptying, but catheters that combine manometry and impedance may provide a better sense of how well esophageal peristalsis effects emptying.

Treatment of Dysphagia The management of dysphagia is dependent on the etiology. Relief from obstruction, treatment of inflammation, and surgical management of laryngeal cleft or Chiari malformation should all result in improved swallowing. For those cases in which the potential for recovery is limited [e.g., neurogenic dysphagia as a component of encephalopathy, intrinsic dysmotility consequent to esophageal atresia or TEF, severe scarring (e.g., radiation, caustic ingestion)], patient-specific recommendations are required. The range of options is broad—some patients who consistently aspirate will benefit from being strictly NPO (nothing by mouth) and tubefed, whereas others may be rehabilitated to the limit of their

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dysfunction by modifying their feeding regimen by involving speech or occupational therapist. Many pediatric centers have multidisciplinary clinics devoted to the evaluation and treatment of feeding and swallowing disorders. Physicians, nurses, occupational therapists, speech/language pathologists, psychologists, and dieticians work together to provide comprehensive evaluation that leads to individualized treatment. Evaluation that is coordinated with radiologists familiar with swallowing and who can effectively examine swallowing in a child who lacks feeding skills or is developmentally impaired is essential.

ENDOSCOPIC THERAPY IN PEDIATRIC GASTROENTEROLOGY The practice of pediatric gastroenterology includes both diagnostic and therapeutic endoscopy. Visual inspection of the lining of the esophagus, stomach, small bowel, and colon is possible with sophisticated flexible video endoscopes that can achieve real-time high definition images. Fully functional endoscopes with a suction/biopsy channel and separate air and water channels are currently available down to 5.5 mm (outside diameter) that can be used in very small infants. Many conditions that affect the GI mucosa in children are only apparent histologically. As such, inspection of the epithelium without biopsy is not sufficient to exclude mucosal inflammation. Biopsy of esophagus, stomach, and duodenum is the standard of care in virtually every diagnostic endoscopic procedure. Advanced techniques permit advancement of a long enteroscope well into the small intestine for diagnostic and therapeutic purposes.105,106 All of the interventional techniques used in pediatric endoscopy are extrapolated from experience in adults. Virtually no large scale prospective studies have been performed in children for many techniques, although retrospective case series document safety and efficacy in the hands of the authors. These techniques add risk when compared with routine diagnostic endoscopy and therefore require thorough understanding of the generators that supply radiofrequency energy, the instruments that apply current to tissue, and experience in recognizing the lesions that are amenable to endoscopic therapy.107 Therapeutic endoscopy is commonly performed in children, including foreign body retrieval, control of bleeding, polypectomy, and stricture dilatation.108,109 Inspection of the mucosa and management of complications after caustic ingestion may be required.110 Many different specialized instruments are available to pass through the biopsy channel, including balloons, forceps, grasping tools, wire baskets, fabric nets, snares, and a variety of electrocautery tools. Most instruments are available for standard pediatric endoscopes that have a 2.8-mm biopsy channel (same as “adult” gastroscopes). Gastroscopes appropriate for use in infants have a smaller biopsy channel (2.0 mm), and some instruments are not available in that size.

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Control of bleeding from focal lesions is possible using bipolar or monopolar catheter-based instruments, as well as with injection of sclerosants or vasoactive substances (e.g., epinephrine) via through-the-scope needles.111,112 Esophageal varices may be ligated by bands that immediately tamponade and ultimately cause luminal obliteration.113–115 Argon plasma coagulation provides a noncontact method for cauterizing superficial lesions.116 In this technique, monopolar radiofrequency energy is carried by a beam of argon gas from the tip of a specialized through-the-scope catheter to an adjacent conductive tissue. The beam is “sprayed” in a sweeping motion over the area of interest and can be used to treat broader areas of affected tissue (e.g., vascular ectasia as in “watermelon” stomach) without touching it. When properly performed, the depth of injury is limited, such that perforation is uncommon. For the same reason, this procedure is not appropriate for bleeding from larger blood vessels. Tamponade of bleeding sites is possible with the scope itself (temporarily), dilating balloons (e.g., in the esophagus, with size and tension to just occlude the vessel rather than stretch the esophagus), and with endoscopically applied clips. Single or multiple clips can be deployed to manage a local source of bleeding either as definitive immediate control or to gain control before injection or cautery is applied. The biopsy channel of the endoscope permits passage of wires (with fluoroscopic guidance) that facilitate the placement of balloon dilators, Savary-Miller dilators, manometry catheters, and feeding tubes.117 Endoscopy can facilitate the passage of nasojejunal tubes and gastrojejunostomy tubes, by aiding the advancement of a wire or by grasping the tube itself. Primary placement of a feeding gastrostomy (e.g., percutaneous endoscopic gastrostomy, [PEG]) is commonly performed for a variety of indications.118 Tubes are sized to be placed even in very small infants (roughly down to 2 kg). Several brands of PEG tubes and kits containing all the components for placement are available. After tract maturity (8–12 weeks), the initial PEG tube is replaced with a skin-level “button” gastrostomy device that is more cosmetically appealing and easy for parents to replace at home. Laparoscopically assisted gastrostomy placement and special kits permit placement of a skin level device immediately.119,120 Patient needs and surgeon and gastroenterologist preference dictate which tube and technique is appropriate for initial placement. Dilatation of congenital or acquired strictures by throughthe-scope balloons is possible from 2 to 20 mm, with balloon size and tension judged on a per stricture basis.121–123 Dilatation under direct vision limits (but doesn’t supplant) the need for fluoroscopy, as the diameter of the stricture pre- and postdilatation is evident endoscopically.124 Wireguided balloons for tight strictures are available and should be passed under fluoroscopy to avoid creating a false passage or pseudodiverticulum of the wall. Contrast within the

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CHAPTER 17 ❖ Pediatric Gastroenterology balloon facilitates assessment of the completeness of dilatation at a given balloon diameter as the “waist” in the balloon is evident on X-ray. Bougienage is still performed in selected circumstances, but endoscopic balloon dilatation is preferred in most settings. Less commonly, endoscopic therapy may be possible in situations where surgical intervention would be indicated but undesirable, such as closure of recurrent tracheoesophageal fistula with cautery and fibrin glue plugs.125

COORDINATED CARE OF CHILDREN WHO HAVE AIRWAY DISEASE As a practical matter, children who present with complaints referable to the airway and who could have reflux contributing to their symptoms deserve a comprehensive, cooperative, coordinated examination. Children who have complex multisystem, genetic/congenital abnormalities pose a particular challenge for pediatric subspecialists who must work together to meet all of the child’s needs. Arguably, many children still undergo piecemeal clinical examinations, with multiple visits scattered in time and multiple procedures under separate anesthesia. Disjointed care that is poorly coordinated may be inefficient, expensive, and result in conflicting opinions and recommendations expressed to patients and their families. The opportunity exists to create a multidisciplinary service involving appropriate subspecialists and support services. In the author’s experience with such a service, experienced physicians from otorhinolaryngology, pulmonary medicine, gastroenterology, pediatric surgery, and radiology form the core. Support from nurses, speech and language pathology, occupational therapy, and dieticians are critical to the evaluation and management of complex patients. Communication among services is facilitated by combined clinic appointments and coordinated procedures under anesthesia. That practice assures that all the relevant specialists are in direct, simultaneous contact with each other and the patient/family. The patient benefits from fewer visits, fewer anesthetic to gain the same information, and more concise discussions that result in less confusion. For complex patients, this approach has been fruitful for us and our patients.

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86. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128(1):3–20. 87. Aceves SS, Newbury RO, Dohil MA, et al. A symptom scoring tool for identifying pediatric patients with eosinophilic esophagitis and correlating symptoms with inflammation. Ann Allergy Asthma Immunol. 2009;103(5):401–406. 88. Pentiuk S, Putnam PE, Collins MH, et al. Dissociation between symptoms and histological severity in pediatric eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2009;48(2):152–160. 89. Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med. 2004;351(9):940–941. 90. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, et al. 14 years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr. 2009;48(1):30–36. 91. Thompson DM, Arora AS, Romero Y, et al. Eosinophilic esophagitis: its role in aerodigestive tract disorders. Otolaryngol Clin North Am. 2006;39(1):205–221. 92. Kang SK, Kim JK, Ahn SH, et al. Relationship between silent gastroesophageal reflux and food sensitization in infants and young children with recurrent wheezing. J Korean Med Sci. 2010;25(3):425–428. 93. Arslan Z, Cipe FE, Ozmen S, et al. Evaluation of allergic sensitization and gastroesophageal reflux disease in children with recurrent croup. Pediatr Int. 2009;51(5):661–665. 94. Spergel JM, Andrews T, Brown-Whitehorn TF, et al. Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests. Ann Allergy Asthma Immunol. 2005;95(4):336–343. 95. Kagalwalla AF, Sentongo TA, Ritz S, et al. Effect of sixfood elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2006;4(9):1097–1102. 96. Markowitz JE, Spergel JM, Ruchelli E, et al. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol. 2003;98(4):777–782. 97. Konikoff MR, Noel RJ, Blanchard C, et al. A randomized double-blind placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology. 2006;131(5):1381–1391. 98. Dohil R, Newbury R, Fox L, et al. Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology. 2010;139(2):418–429. 99. Noel RJ, Putnam PE, Collins MH, et al. Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2004;2(7):568–575. 100. Lefton-Greif MA. Pediatric dysphagia. Phys Med Rehabil Clin N Am. 2008;19(4):837–851. 101. Jadcherla SR, Gupta A, Wang M, et al. Definition and implications of novel pharyngo-glottal reflex in human infants using concurrent manometry ultrasonography. Am J Gastroenterol. 2009;104(10):2572–2582. 102. Litovitz T, Whitaker N, Clark L, et al. Emerging battery-ingestion hazard: clinical implications. Pediatrics. 2010;125(6):1168–1177. 103. Willging JP, Thompson DM. Pediatric FEESST: fiberoptic endoscopic evaluation of swallowing with sensory testing. Curr Gastroenterol Rep. 2005;7(3):240–243.

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104. Link DT, Willging JP, Miller CK, et al. Pediatric laryngopharyngeal sensory testing during flexible endoscopic evaluation of swallowing: feasible and correlative. Ann Otol Rhinol Laryngol. 2000;109(10 Pt 1):899–905. 105. Barth BA, Channabasappa N. Single-balloon enteroscopy in children: initial experience at a pediatric center. J Pediatr Gastroenterol Nutr. 2010;51(5):680–684. 106. Liu W, Xu C, Zhong J. The diagnostic value of double-balloon enteroscopy in children with small bowel disease: report of 31 cases. Can J Gastroenterol. 2009;23(9):635–638. 107. Kay MH, Wyllie RJ. Therapeutic endoscopy for nonvariceal gastrointestinal bleeding. Pediatr Gastroenterol Nutr. 2007;45(2):157–171. 108. Little DC, Shah SR, St Peter SD, et al. Esophageal foreign bodies in the pediatric population: our first 500 cases. J Pediatr Surg. 2006;41(5):914–918. 109. Berggreen PJ, Harrison E, Sanowski RA, et al. Techniques and complications of esophageal foreign body extraction in children and adults. Gastrointest Endosc. 1993;39(5): 626–630. 110. Betalli P, Falchetti D, Giuliani S, et al.; Caustic Ingestion Italian Study Group. Collaborators. Caustic ingestion in children: is endoscopy always indicated? The results of an Italian multicenter observational study. Gastrointest Endosc. 2008;68(3):434–439. 111. Bhatia V, Lodha R. Upper gastrointestinal bleeding. Indian J Pediatr. 2011;78(2):227–233. 112. Arora NK, Ganguly S, Mathur P, et al. Upper gastrointestinal bleeding: etiology and management. Indian J Pediatr. 2002;69(2):155–168. 113. Poddar U, Bhatnagar S, Yachha SK. Endoscopic band ligation followed by sclerotherapy: Is it superior to sclerotherapy in children with extrahepatic portal venous obstruction? J Gastroenterol Hepatol. 2011;26(2):255–259. 114. Molleston JP. Variceal bleeding in children. J Pediatr Gastroenterol Nutr. 2003;37(5):538–545. 115. Fox VL, Carr-Locke DL, Connors PJ, et al. Endoscopic ligation of esophageal varices in children. J Pediatr Gastroenterol Nutr. 1995;20(2):202–208. 116. Khan K, Schwarzenberg SJ, Sharp H, et al. Argon plasma coagulation: Clinical experience in pediatric patients. Gastrointest Endosc. 2003;57(1):110–112. 117. Chang CF, Kuo SP, Lin HC, et al. Endoscopic balloon dilatation for esophageal strictures in children younger than 6 years: experience in a medical center. Pediatr Neonatol. 2011;52(4):196–202. 118. Fortunato JE, Troy AL, Cuffari C, et al. Outcome after percutaneous endoscopic gastrostomy in children and young adults. J Pediatr Gastroenterol Nutr. 2010;50(4):390–393. 119. Idowu O, Driggs XA, Kim S. Laparoscopically assisted antegrade percutaneous endoscopic gastrostomy. J Pediatr Surg. 2010;45(1):277–279. 120. Zamakhshary M, Jamal M, Blair GK, et al. Laparoscopic vs percutaneous endoscopic gastrostomy tube insertion: a new pediatric gold standard? J Pediatr Surg. 2005;40(5): 859–862. 121. Okada T, Sasaki F, Shimizu H, et al. Effective esophageal balloon dilation for esophageal stenosis in recessive dystrophic epidermolysis bullosa. Eur J Pediatr Surg. 2006;16(2):115–119.

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CHAPTER 17 ❖ Pediatric Gastroenterology 122. Castillo RO, Davies YK, Lin YC, et al. Management of esophageal strictures in children with recessive dystrophic epidermolysis bullosa. J Pediatr Gastroenterol Nutr. 2002;34(5):535–541. 123. Lang T, Hümmer HP, Behrens R. Balloon dilation is preferable to bougienage in children with esophageal atresia. Endoscopy. 2001;33(4):329–335.

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124. Jones DW, Kunisaki SM, Teitelbaum DH, et al. Congenital esophageal stenosis: the differential diagnosis and management. Pediatr Surg Int. 2010;26(5):547–551. 125. Richter GT, Ryckman F, Brown RL, et al. Endoscopic management of recurrent tracheoesophageal fistula. J Pediatr Surg. 2008;43(1):238–245.

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18

C H A P T E R

E

Pediatric Pulmonology Jonathan E. Spahr

arly in embryonic development, the lungs are formed as a result of the projection of the lung bud composed of epithelial tissue from the ventral foregut. By gestational week 17, all the airways have developed. From 28 weeks gestation to adolescence, the lung develops into the organ with the primary responsibility of respiration. Understanding the embryologic development of the lung is important to identify why certain disease states occur. In the case of the unified airway concept, understanding that the development of lung tissue comes from common respiratory epithelium helps explain why the upper airway and the lungs are so intimately entwined in certain disease states, especially in infants and children. The unified airway concept springs from the observation that patients with upper airway disease often have lower airway disease as well.1,2 The nose is the gateway to the lungs. It helps to protect the lower airway from inhaled foreign substances and provides a defense mechanism—both anatomic and physiologic. As the filter for the lungs, the nose and upper airway trap the foreign particles that can be later sneezed or coughed out. In addition to filtration, the nose also warms and humidifies the inhaled air to optimize its composition in preparation for gas exchange. The nasal mucosa also stimulates an inflammatory response that is more robust than, and mimicked by, the lower airways. This is particularly evident in the case of rhinitis/rhinosinusitis and asthma. Both the upper and lower airways (trachea and bronchi) are lined by pseudostratified, ciliated columnar epithelium with mucous-secreting goblet cells. Any interaction between the upper and lower airways may be because of this common origin and composition. It is because of this common respiratory epithelium that the nose and upper airway can sometimes be viewed as surrogates for what is occurring in the lower airway and lungs. One particular example that will be discussed later in this chapter is the use of nasal epithelial potential difference measurements to diagnose the chloride ion channel defect present in the airways of patients with cystic fibrosis (CF). When the airway epithelium works appropriately, it is an elegant system that serves to humidify air, protects from inhaled particles, clears foreign materials, and defends against airborne pathogens. When unified airway function is disrupted, disease may occur in both the upper and lower airways, the upper airway may affect the lower airway, or the lower airway may affect the upper airway. In the case of asthma, upper airway disease such as allergic rhinitis can trigger lower airway diseases such as inflammation and bronchoconstriction.3,4 Other clinical examples such as CF and primary ciliary dyskinesia (PCD) also illustrate the

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interrelatedness of the upper and lower airways. Certainly, in the case of PCD, where cilia are absent or dysfunctional leading to retained mucous secretions, there is a great deal of overlap pathologically and therapeutically between the upper and lower airways. Furthermore, the treatment of one, allergic rhinitis, can significantly impact the other, asthma. Therefore, the importance of pulmonologists understanding the upper airway and otolaryngologists understanding the lower airways cannot be understated.

EVALUATION OF PATIENTS WITH LUNG DISEASE A careful and focused history and physical examination can help the clinician hone in on the underlying problem and can direct further testing to confirm or exclude diagnoses of lung disease. In this section, important historical points and a focused respiratory examination will be discussed with laboratory testing to follow.

History and Physical Examination Findings As with all history taking in medicine, the chief complaint and timing, quality, character, and presentation of symptoms are important to consider with respiratory complaints. Cough is a very common complaint encountered in respiratory disease. Stratifying the duration of cough can be helpful as cough for a short duration may be due to acute illness such as infection or an inflammatory process that may remain after the acute infection (subacute cough). A chronic cough, generally defined as a cough present for more than eight weeks, is likely due to one or more of the three most common causes of chronic cough: asthma, postnasal drip, and gastroesophageal reflux (GER) disease. Wheezing is also a common symptom encountered in children with respiratory disease. Parental report of wheezing is likely to be due to asthma simply because asthma is a common entity among wheezing children. However, all that wheezes is not asthma, and the differential diagnosis for asthma is extensive (Table 18-1). When examining a child with wheezing, it is important to pay attention to the timing and quality of the wheeze. Wheezing on inhalation only, or stridor, occurs in disease states that affect the extrathoracic airway as negative pressure in the airway can lead to partial collapse of upper airway. Wheezing on exhalation only occurs in disease states that affect the intrathoracic airways as the pressure of the chest wall and lung parenchyma can cause partial collapse of lower airways. Sometimes forced

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TABLE 18-1. Differential Diagnosis of Wheezing Asthma Bronchopulmonary dysplasia Cystic fibrosis/primary ciliary dyskinesia/bronchiectasis Infection/bronchiolitis Foreign body Gastroesophageal reflux Aspiration (anterograde or retrograde) Vocal fold dysfunction Pulmonary edema Intrinsic airway obstruction Adenoma Granuloma Hamartoma Hemangioma Papilloma Extrinsic airway obstruction Congenital cysts/malformations Lymphadenopathy Tumor Vascular malformations Tracheomalacia/bronchomalacia Bronchiolitis obliterans

maneuvers by the patient are necessary to accentuate such findings. Biphasic wheezing, one that occurs on both inhalation and exhalation, can occur in asthma and bronchiolitis, but should alert the physician to the possibility of a fixed upper airway obstruction. Polyphonic wheezing has a harmonic quality that suggests airways of different sizes are being affected by bronchospasm or inflammation because the different pitches of the wheeze contribute to the polyphonic noise. Polyphonic wheezing is common in asthma and bronchiolitis. Monophonic wheezing would suggest a single, usually large, airway that is narrowed and only contributes one pitch to the sound. Monophonic wheezing is more common in foreign body aspiration and airway malacia. A double-headed stethoscope can help determine whether there is phase delay of airflow through different segments of the lung. This allows the examiner the ability to discern differential airflow that may indicate foreign bodies or focal malacia. Dyspnea is also a very common complaint encountered in patients with respiratory disease. It is both a symptom and a sign. Patients may complain of dyspnea as a sensation of difficult breathing, and clinicians can also observe dyspnea as it manifests as tachypnea and increased work of breathing. Many diseases of the respiratory system are manifested as dyspnea, and it is usually the end result of one or all of the following: compromised ventilation, compromised oxygenation, or altered respiratory mechanics leading to abnormal nervous stimuli from the respiratory system. In most instances, it is abnormalities in oxygenation and ventilation that lead to the sensation and physical findings of dyspnea. Inspection, percussion, and auscultation are important tools to employ when examining the chest. Inspection of the

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chest can help identify chest wall lesion and abnormalities such as pectus deformities, retractions, and abnormal chest and diaphragm excursion. Inspection of the chest can also be helpful in uncovering long-standing obstructive lung disease as the anterior–posterior diameter can be significantly increased and there may be a “box-like” configuration of the chest. In infants with chronic lung disease or bronchopulmonary dysplasia (BPD), subcostal retractions can occur due to highly compliant chest wall of the infant. Persistence of the appearance of subcostal retractions, or the Harrison groove, can occur in such infants. Percussion of the chest allows the physician to identify problems of the lung parenchyma and pleura. The hyperresonant chest would indicate air trapping such as in asthma or bronchiolitis or air in the pleural space as in pneumothorax. The chest that is dull to percussion would suggest fluid or mass in the lung or pleura as in pneumonia, pleural effusions, or tumor. Auscultation of the chest allows the physician to discern different disease states based on different breath sounds. Wheezing was discussed earlier. Crackles might indicate a parenchymal or airspace disease such as interstitial lung disease (ILD), congestive heart disease, or pneumonia. Rhonchi have a lower pitch than crackles and often indicate larger airway problems such as secretions or airway collapsibility. Bronchial breath sounds are normally heard over large airways in the central and upper regions of the chest. When bronchial breath sounds occur in the periphery of the lung, it suggests an alveolar filling or consolidative process like pneumonia, because the breath sounds are directly transmitted through airways to the stethoscope and not scattered among alveoli. Consolidative processes can also be detected by having the patient speak and detecting intelligible speech over the thorax or by having the patient say “E” and detecting the sound “A” (egophony). Other physical examination findings that can alert the physician to respiratory compromise include tachypnea and hypoxemia that can be either acute or chronic changes. Failure to thrive and digital clubbing may be an indicator of chronic lung disease. Tachypnea is a typical response to stress or respiratory compromise because it allows the individual to increase minute ventilation when tidal volume is compromised (minute ventilation = tidal volume × respiratory rate). Normal respiratory rates for different age groups are listed in Table 18-2. Tachypnea allows the individual to maintain adequate ventilation, but cannot be sustained for long periods of time without exhaustion of the respiratory muscles. Therefore, tachypnea, although it is an appropriate response, may be insufficient to maintain ventilation and could be a TABLE 18-2. Normal Respiratory Rates Birth–1 mo: 20–47 (33) 1 y: 15–44 (30) 4 y: 15–35 (25) 16 y: 14–30 (21) Source: Adapted from Chernick et al.5

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CHAPTER 18 ❖ Pediatric Pulmonology 219 precursor to respiratory failure. Hypoxemia can be assessed by physical examination in the form of cyanosis, but nowadays is often assessed by analyzing the hemoglobin–oxygen saturation by pulse oximetry. Probably most important in determining the level of respiratory compromise in infants and children is assessing their work of breathing. As the demand for ventilation and oxygenation increases, accessory muscles are recruited and retractions of the chest wall occur. This can be especially pronounced in the infant with a compliant chest wall and can manifest as subcostal and suprasternal retractions as well as “belly breathing.” Nasal flaring is also an indicator of significant respiratory compromise. Failure to thrive can occur in individuals with respiratory compromise due to the increased work of breathing. Digital clubbing may be a manifestation of chronic lung disease; the most common respiratory reason in children is CF. It is the result of enlargement of connective tissue in the distal phalanges of the fingers and toes due to an unknown mechanism. Probably the simplest and best known evaluation of clubbing is Schamroth’s sign in which the diamond-shaped window usually seen between the dorsum of opposed distal phalanges is obliterated, and there is a prominent angle between the distal portions of the nails (Fig. 18-1).

is airways obstruction. In pediatric pulmonary medicine, the flows during the forced exhalation may also help determine whether there is an obstructive lung disease. The forced expiratory flow between 25% and 75% (FEF25–75) of the expiratory effort is measured in liters per second. The FEF25–75 is more heavily relied upon in pediatric pulmonary medicine because it may be an early indicator of airflow obstruction even when FEV1 and FEV1:FVC may be preserved. In restrictive lung disease, one would expect that volumes would decline in concert. In other words, restriction is presumed when both FEV1 and FVC have declined, therefore preserving or even increasing FEV1:FVC. However, it is important to confirm suspicions of restrictive lung disease with measurements of lung volume and this will be discussed shortly. Equally important to the values of volume and flow are the characteristics of flow:volume curves obtained during spirometry. Fig. 18-2 illustrates the different shapes of these curves in healthy and disease states. As previously mentioned, lung volumes are important in determining whether there is a restrictive component of lung

Pulmonary Function Testing Pulmonary function testing (PFT) includes, but is not limited to, spirometry, lung volumes, diffusion capacity, respiratory muscle forces, and blood gas sampling. Spirometry is the most common and frequently used PFT as it provides valuable information about lung capacity and airflow. The purpose of spirometry is to measure the forced vital capacity (FVC), the amount of forced expired air at one second (FEV1) and airflow during a forced expiratory maneuver. By measuring these values during a forced maneuver, one can derive the maximal capacity of the lung and specifically of the airways to exchange air and identify any pathology. The FVC is the total amount of air that is exhaled during the forced maneuver. The FEV1 is the amount of air exhaled in the first second, and the ratio between the two (FEV1:FVC) can help distinguish whether there is airway obstruction. A low FEV1 with preserved FVC would indicate that there

FIGURE 18-1. Shamroth’s sign. When the dorsum of similar figures is opposed, the diamond shape between the bases of the nail bed disappears and the angle between distal portions of the nails increases (arrow). (Adapted with permission from Chernick et al.5)

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FIGURE 18-2. Flow-volume loops (FVL) obtained with spirometry demonstrating types of airflow obstruction. Flow, measured in liters per second, is recorded on the y-axis and volume, measured in liters, is recorded on the x-axis. A, Normal. B, Intrathoracic (lower airway) obstruction. Notice the characteristic “scooped” pattern of the expiratory limb of the FVL. C, Extrathoracic (upper airway) obstruction. Notice the attenuation of flow in the inspiratory limb of the FVL. D, Fixed airway obstruction. Attenuation of flow occurs in both the inspiratory and expiratory FVLs. (Adapted with permission from Mosby (Elsevier). Philadelphia. Mottram C: Manual of Pulmonary Function Testing 8th ed. 2003.)

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disease. By measuring the different capacities demonstrated in Fig. 18-3, and specifically total lung capacity (TLC), one can confirm restrictive lung disease suggested by spirometry. Lung volume testing can also determine functional residual capacity (FRC). FRC is important to understand as it is the point at which the lung and chest cavity is at equilibrium after exhalation. It is the point at which the elastic forces of the lung parenchyma recoiling inward are equal and opposite to the forces of the chest wall expanding outward. In lung disease, FRC may change depending on the type of lung disease. In restrictive lung disease, FRC is decreased, and in obstructive lung disease, FRC can be increased. In obstructive lung disease, residual volume (RV) can also help provide evidence of obstruction as it may be elevated suggesting trapped air behind obstructed airways (air trapping). An elevated RV or elevated RV:TLC is suggestive of air trapping. Another component of PFTs is the diffusing capacity for carbon monoxide (DLCO). Taking advantage of hemoglobin’s great affinity for carbon monoxide (CO), DLCO can give a good indication of diffusion because CO’s path from alveoli to hemoglobin should only be limited by diffusion across the alveolar–blood membrane. This test is not nearly as commonly used as spirometry, but can be helpful in situations where diffusion impairment is suspected. Disease states that may affect diffusion capacity include those in which the alveolar–blood interface is disrupted and include ILD,

FIGURE 18-3. Lung volumes demonstrating normal lung volumes, restrictive lung disease, and obstructive lung disease. Notice that the FRC decreases in restrictive lung disease and increases in obstructive lung disease primarily due to significant changes in the RV. TLC, total lung capacity; FRC, functional residual capacity; RV, residual volume. (Adapted with permission from Manual of Pulmonary Function Testing. 8th ed. Mosby, 2003.)

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pulmonary vascular disease, and emphysema. Because the amount of hemoglobin is important in taking up CO, anemia can decrease DLCO. Also, if CO is already present in the blood (as is the case with CO poisoning or tobacco smoke exposure), the DLCO may be decreased. Respiratory muscle forces can also be measured in the PFT laboratory and are important in situations where respiratory muscle weakness is suspected. Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) readings can be recorded during forceful inspiratory and expiratory maneuvers. Such values provide information about the strength of respiratory muscles but must be interpreted with caution as this test is most prone to bias from poor effort or air leak around the apparatus. Nevertheless, MIP and MEP testing can be useful in patients with muscle weakness as decreased pressures can predict impending respiratory compromise due to hypoventilation or submaximal cough strength. Cough strength is very important in assuring adequate clearance of respiratory secretions and avoidance of atelectasis. One of the limitations of the above testing is that it requires a cooperative subject. In the case of pediatric patients, this is not always the case. Generally, pediatric patients can perform adequate lung function testing beginning around the age of 5 years. In young children who are unable to perform the necessary maneuvers for PFT, infant PFT is an option that allows clinicians to obtain information about lung compliance, airways resistance, and response to bronchodilators. Infant PFT is available at certain pediatric pulmonary centers and does allow the interpreting physician to have data comparable with adult-type PFTs. This procedure requires the infant to be sedated, but the data obtained can be very helpful in distinguishing restrictive from obstructive lung disease and determining the severity of compromise if present. Often omitted as a PFT, the measurement of blood oxygen (PO2), carbon dioxide (PCO2), and pH are important values in determining the overall effectiveness of ventilation and oxygenation. Blood gas measurements are most reliable when obtained from an arterial blood source, but sometimes this is not feasible in the outpatient clinic. Other methods of obtaining information about PCO2 (and consequently ventilation) include venous blood gases, capillary blood gases, and measurement of end-tidal CO2. End-tidal CO2 measured at the mouth, nose, endotracheal tube, or tracheostomy tube is a noninvasive means of indirectly determining PCO2 as alveolar CO2 nearly approximates arteriolar CO2 in most cases. Measurement of oxygenation is now quite routine in many clinical areas with the use of pulse oximetry. All of the abovementioned PFTs are tests done at a steady state or rest. Challenge testing can be helpful in illustrating subtle lung function abnormalities or determining the extent of functional impairment. Challenge testing takes into consideration that not all patients will have identifiable lung function abnormalities at rest or baseline. In some individuals, there must be a stressor present to bring out abnormalities in lung function. Exercise-induced asthma

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CHAPTER 18 ❖ Pediatric Pulmonology 221 testing is an example of a challenge test that attempts to reproduce situations that would provoke an asthmatic response either by having the individual run on a treadmill or pedal on a cycle ergometer. By measuring baseline spirometry values, then having the patient exercise to a level that would reproduce the symptoms for which they are being evaluated, and then repeating spirometry after the exercise challenge, one may demonstrate exercise-induced bronchospasm. The exercise testing might also illicit other reasons for exercise intolerance such as vocal fold dysfunction (VFD) or cardiac defects. If asthma is the sole concern, then challenge testing with escalating doses of a bronchoconstrictor is possible. The most common of these tests is the methacholine challenge test, during which escalating doses of methacholine are inhaled by the patient in an attempt to elicit a drop in FEV1 and demonstrate bronchoconstriction. The test is considered positive if there is a drop of 20% or more of the FEV1 at a concentration of methacholine < 3mg/mL. This test has an excellent negative predictive value, but the positive predictive value is poor due to the fact that individuals without asthma may have a positive methacholine challenge test if recently ill with a respiratory illness. Therefore, it is recommended that patients wait at least six weeks after recovery from a respiratory illness before undergoing methacholine challenge testing. In the right clinical context, cold air challenge may also be employed to give useful information about triggers of asthma.

Radiographs Of the numerous modalities of which to image the chest, the plain chest radiograph and computed tomography (CT) are the two most often used in pediatric pulmonology. The plain chest radiograph is readily available in most clinical situations and, when interpreted carefully and correctly, can help distinguish a number of pathologic states in the chest. The CT scan of the chest significantly improves resolution of the structures in the chest cavity. Spiral CT allows detailed resolution of the airways, mediastinum, pleura, chest wall, pulmonary vasculature, and focal abnormalities in the lung. High-resolution CT allows for detailed resolution of lung architecture and is particularly helpful when evaluating interstitial or diffuse lung disease.

Flexible Bronchoscopy Certainly a comprehensive discussion of bronchoscopy by a pediatric pulmonologist would be an affront to Dr. Jackson and all otolaryngologists. Therefore, this section on bronchoscopy will be restricted to the indications, merits, and limitations of flexible bronchoscopy. There is a considerable amount of overlap when considering bronchoscopy indications by either rigid or flexible bronchoscope. Indications for flexible bronchoscopy are listed in Table 18-3. There are no absolute contraindications to flexible bronchoscopy. Relative contraindications such as bleeding diathesis and severe

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TABLE 18-3. Indications for Flexible Bronchoscopy Stridor Persistent wheeze (not responsive or poorly responsive to therapy) Atelectasis Localized hyperinflation Pneumonia Recurrent Persistent Patients unable to produce sputum Atypical or unusual circumstances (e.g., immunocompromised patients) Hemoptysis Foreign body aspiration (suspected) Suspected aspiration Evaluation of patients with tracheostomies Suspected mass or tumor Suspected airway anomalies Complications of artificial airways Source: Adapted from Chernick et al.5

hypoxemia may be correctable or acceptable if the procedure is absolutely necessary.5 The situations in which flexible bronchoscopy is superior to rigid bronchoscopy relates to the size and flexibility of the scope. Flexible bronchoscopy allows inspection of airways in patients with spine and mandibular abnormalities that make rigid bronchoscopy difficult or even dangerous to the patient. The flexible bronchoscope can enter difficult to reach areas of the bronchial tree such as apical segments and distal airways that are not readily accessible with a rigid bronchoscope. A flexible bronchoscope can also maneuver through artificial airways such as tracheostomy and endotracheal tubes if there is enough room for the scope. Generally, there should be a 1 mm difference between the inner diameter of the airway and the outer diameter of the scope. Finally, because of its smaller size and flexibility, the flexible bronchoscope can give an image of the airway without distorting contours and without need for deep sedation of the patient. This allows airway dynamics to be more optimally observed. The major limitations of the flexible bronchoscopy are its size and flexibility. In other words, removal of foreign bodies and manipulation of the airway through the flexible bronchoscope is not safe and should be done only with a rigid bronchoscope. Although suctioning of secretions and blood can be done with the flexible bronchoscope, the rigid bronchoscope has a much larger suction channel and may be more effective in certain situations (the pediatric flexible bronchoscopes have suction channels ranging from 1.2 to 2.0 mm in diameter). In many clinical scenarios, it is very helpful to have a multidisciplinary team including flexible and rigid bronchoscopists. Close collaboration between pulmonologists and otolaryngologists benefits the patient by allowing a comprehensive evaluation of the pediatric airway.

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THE ABCs OF PEDIATRIC PULMONOLOGY (ASTHMA, BRONCHOPULMONARY DYSPLASIA, AND CYSTIC FIBROSIS) Asthma The origin of asthma comes from Greek, and it means “to breathe with open mouth or pant.” Obviously, such a definition could describe a host of respiratory disorders and is probably not an accurate description of what most people identify as asthma. Asthma, as it is currently defined, is reversible airways obstruction. The reversible part, demonstrated by lung function studies, is due to contraction of smooth muscle that surrounds small- and medium-sized airways. This can be demonstrated by response to bronchodilators such as albuterol or by demonstrating bronchoconstriction due to agents such as methacholine and subsequent reversal of bronchoconstriction. With greater understanding of the disease, inflammation has been discovered to be an important factor in the pathogenesis of asthma. Despite its great complexity, this inflammatory component has been elucidated with some detail resulting in better understanding of the various components that contribute to what is clinically recognized as asthma. Furthermore, inflammation and a bronchoconstrictive response can lead to mucous secretion and plugging of mucous. Therefore, to be most accurate, asthma is a disease of bronchoconstriction, inflammation, and mucous plugging. Despite our great understanding of the disease, there is much more to be learned about asthma and it must be conceded that asthma is less of a diagnosis and more of a symptom. There are different phenotypes of asthma that exist. That is, the pathophysiology causing infantile asthma may be different from that of exercise-induced or atopic asthma. With the advancement of knowledge in the field of asthma, each different phenotype may one day have its separate diagnostic terms. This will be a significant advancement in the science and care of asthma because exacerbating factors and therapies for specific asthma phenotypes will greatly enhance patient care. What appears to be clear from epidemiologic studies is that many children will have symptoms of asthma and wheeze or cough, especially when infected with respiratory viruses. It is the children with predisposing risk factors such as allergy and a family history of asthma or allergy who are more likely to develop persistent asthma.5 Therefore, asthma should be considered in a child with recurrent wheezing or cough. However, it is often difficult to establish a diagnosis of asthma until children reach the school age of 5–6 years. There are two main reasons for this. First, determining reversible airways obstruction is greatly aided by the use of spirometry. Second, it is around the age of 5–6 years when the “early transient wheezers” can be distinguished from “persistent wheezers” or those with persistent asthma.6,7 The prevalence of childhood asthma in the United States is approximately 10%. The costs to society are quite significant as asthma is the leading cause of school absenteeism and over $3 billion is spent each year to treat children with asthma.5

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Some clinical presentations of asthma can be wheezing, chronic cough, exercise intolerance, chest pain, or dyspnea. Wheeze is a very common presenting symptom as parental report of wheeze is 81% sensitive and 85% specific for childhood asthma.8 Examination findings would include hyperresonance to percussion, polyphonic wheezing, and prolongation of the expiratory phase. Because of the reversibility of the disease, repeating the examination after treatment with bronchodilators can be helpful. Also a history of response to asthma medications can be helpful in making the diagnosis of asthma, especially in children who cannot perform diagnostic testing such as spirometry. In children who cannot perform lung function testing, history and physical examination are of paramount importance in diagnosing asthma. In this age group, consideration of risk factors for asthma (a personal history of allergy, family history, or asthma) and physical findings (polyphonic wheezing that improves with bronchodilators) can help in the diagnosis of asthma (Table 18-4).6,7 Once the diagnosis of asthma is established, attention must be focused on treatment. For those with acute and intermittent symptoms, bronchodilator therapy may be all that is needed during the occasional respiratory virus. For those with more persistent symptoms, controller therapy is needed. Controller therapy is aimed at reducing airways inflammation and preventing exacerbations. Antiinflammatory agents are the mainstay for controlling airways inflammation in asthma, and Fig. 18-4 shows the most recent guidelines from the National Asthma Education and Prevention Program published in 2007.9 Inhaled corticosteroids are potent antiinflammatory medications that, when delivered correctly, can have a significant effect on reducing exacerbations and chronic symptoms of asthma. The inhaled corticosteroids are the first-line treatment for patients with persistent asthma. Leukotriene modifiers that block either production of leukotrienes or leukotriene receptors can also be helpful in persistent asthma because leukotrienes cause airway constriction, inflammation, and mucous secretion. Most children with asthma can be maintained with inhaled corticosteroids or leukotriene modifiers, and it is up to the physician to decide what therapy best relieves asthma symptoms and prevents exacerbations, although taking into account adherence to the medical regimen. Nonadherence, inappropriate, or inadequate delivery of medications must always be considered in children who are diagnosed with asthma but not responding to therapy. TABLE 18-4. Risk Factors and Signs Predictive of Asthma in Young Children

Recurrent wheezing episodes PLUS Eczema Atopy Parental history of asthma Food allergy Peripheral blood eosinophilia Wheezing not related to infection Source: Adapted from Castro-Rodriguez et al.7

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FIGURE 18-4. National Asthma Education and Prevention Program (NAEPP) guidelines for stepwise approach to managing asthma for individuals aged 12 years and older. Continual surveillance of asthma control is needed to determine efficacy of the current asthma regimen and whether a “step up” or “step down” is needed. Notice that persistent asthma requires treatment with a daily medication. SABA, short-acting β-agonist; ICS, inhaled corticosteroid; LTRA, leukotriene receptor antagonist; LABA, long-acting β-agonist. (Adapted with permission from the NIH/National Heart, Lung, Blood Institute. Guidelines for the diagnosis and management of asthma. Bethesda, 2007.)

Exacerbating factors must be taken into consideration when evaluating the patient who does not respond to asthma therapy. Two exacerbating factors that can make asthma more difficult to control are GER and sinusitis. The role of GER in causing lower respiratory tract disease will be discussed later in this chapter. Sinus disease can have significant effects on the control of asthma and is demonstrated in Fig. 18-5.10,11 Probably the most convincing data that support the correlation between sinus disease and asthma is demonstrated when asthma control is improved after sinus disease is treated. For those who truly do not respond to asthma therapy, the diagnosis may be incorrect. Wheezing That Isn’t Asthma All that wheezes are not asthma, and there are other entities that can cause airway obstruction and symptoms that mimic asthma (Table 18-1). Perhaps the most common reason for expiratory obstruction (other than asthma) is that there is something within the airway, either completely or partially,

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impeding the airflow. Foreign bodies, aspirated particulate matter or food, GER, tumors, vascular malformations, edema, and infection can cause complete or partial obstruction of the airways. If the obstruction is in the intrathoracic airways, these intraluminal obstructions can cause expiratory obstruction. Foreign body aspiration and removal will be discussed in more detail in Chapter 96. Importantly, the treatment for foreign body aspiration is removal of the object as soon as possible to prevent complications. The most severe long-term complication of foreign body aspiration is bronchiectasis. This is a consequence of delayed removal of the object that can obstruct mucous clearance and cause chronic infection and inflammation. Bronchiectasis will be discussed later in this chapter. Expiratory obstruction from aspiration can also occur on a less acute basis as is the case with chronic aspiration of food particles, oral secretions, or stomach contents. Aspiration can occur from above the glottis as in the case of food, mucous,

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FIGURE 18-5. Hypothesized relationship between asthma and sinus disease. (Figure courtesy of Bachert et al.10)

and oral secretions, or aspiration can occur from below as in the case of GER. When a foreign material is in the airway, it not only obstructs airflow but also can irritate the airways causing inflammation and mucous secretion that can further obstruct airflow. In infants with small airways, it does not take much to cause obstruction and subsequent symptoms. Aspiration from above the glottis occurs in a number of settings. Swallowing coordination occurs at around 34 weeks gestation, and so premature infants are at risk for disorders of swallowing and consequently, aspiration. Certain conditions predispose infants and children to aspiration from above the glottis, and these include neurocognitive and neuromuscular syndromes, craniofacial abnormalities, and anomalies of the glottis and esophagus. Fatigue and intercurrent illness can acutely impact swallowing coordination as can prolonged intubation.

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GER can lead to aspiration and symptoms of airway obstruction. Apart from direct obstruction of aspirated material, silent aspiration of acidic or nonacidic gastric contents can provoke upper airway receptors leading to bronchospasm. Furthermore, GER can stimulate receptors in the lower esophagus stimulated by acid or pressure to cause bronchoconstriction and airway obstruction.5 Children at particular risk for having clinically significant reflux include those with tracheoesophageal fistulas (TEFs; even once repaired), congenital diaphragmatic hernias, chronic lung disease from prematurity, CF, asthma, hiatal hernias, and other diseases of the aerodigestive tract. Certain medications such as caffeine, b-agonists, and anticholinergics can exacerbate GER. Fatty foods, chocolate, mint, and alcohol can also exacerbate GER.

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CHAPTER 18 ❖ Pediatric Pulmonology 225 Whether aspiration is from above or below the glottis, the most common signs of aspiration are wheeze and cough, oftentimes more pronounced at night or after eating. Other signs of aspiration include gagging, stridor, hoarseness, failure to thrive, apnea, recurrent pneumonias, dental erosions, or simply colic. Older children with GER may be able to describe symptoms as “wet burps” or “hot burps.” Sometimes, reflux may be silent. Lipid-laden macrophages discovered in bronchoalveolar lavage fluid are considered to be an indicator of aspiration of fat-containing material. The lipid-laden macrophage index (LLMI) appears to be a sensitive index for aspiration, but poorly specific as other chronic lung conditions may yield high LLMIs as well.12 The LLMI may have a role as an indicator supportive of the diagnosis of chronic aspiration syndromes. Treatment involves providing therapy to improve the child’s swallowing technique and/or aggressively treating GER. In severe cases, surgical corrections such as fundoplication, tracheotomy, or tracheoesophageal separation may be needed to prevent chronic, recurrent, and debilitating aspiration. Although extrathoracic, laryngeal disorders can also present clinically similar to asthma. Specifically, VFD can present with symptoms of wheeze and shortness of breath similar to asthma, but not respond to bronchodilators or demonstrate obstruction on lung function testing. During episodes of VFD, the vocal folds paradoxically close during inspiration that may manifest as stridor and dyspnea. The vocal folds may also close significantly during exhalation and lead to a wheeze that may be difficult to distinguish from asthma. Furthermore, VFD may occur with asthma. Typically presenting during adolescence, VFD can be triggered by stressful situations or inhaled irritants. Exercise, performance anxiety, and GER are some examples. The diagnosis of VFD can be quite challenging because it is unlikely to manifest during a clinic visit, and visualization of the glottis is usually not feasible during VFD exacerbations. Spirometry measuring, both expiratory and inspiratory flows, may show attenuation flow during the inspiratory phase without flow limitation during exhalation (Fig. 18-2). Some centers offer laryngoscopy pre- and postexercise testing or methacholine challenge to evaluate patients with symptoms of VFD. Although this can help distinguish symptoms from asthma and offer a direct visualization of vocal folds during symptoms, the sensitivity and specificity of such testing have not been established. Treatment of VFD involves consultation with physicians as well as speech therapists who can teach behavioral techniques to treat and prevent symptoms. In some cases, optimizing treatment for comorbidities that may exacerbate VFD such as asthma and GER is necessary. Airway tumors are quite rare in infant and child. Bronchial adenomas are one such type of tumor that arise from mucous glands and ducts of the airways. Papillomas of the airway may occur in children exposed to human papilloma virus. These are often pedunculated, and numerous papillomas may occur throughout the airway leading to obstruction. Although

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nonmalignant, papillomas have the potential to give rise to squamous carcinoma. Even without malignant transformation, papillomas may occur in abundance and return after surgical removal leading to significant morbidity and multiple procedures throughout the child’s lifetime to treat this condition. Other benign tumors that may occur in the airways and cause obstruction include hamartomas and hemangiomas. Fortunately, the malignant airway tumors that occur in adults are rare in children, likely due to the fact that most of the adult malignancies are secondary to significant and prolonged tobacco smoke exposure. Obstruction may occur from a compressing lesion outside the lumen of the airway as well. Most times, these compressing lesions are in the mediastinum and include enlarged lymph nodes or mediastinal organs such as the thymus, cysts, tumors, or vascular structures. Bronchogenic cysts develop from bronchial walls. These congenital lesions are most commonly situated in the subcarinal region, but can occur anywhere along the bronchial tree. Cysts, such as esophageal duplication cysts, arising from the gastrointestinal tract can occur as well. Enlarged cysts can cause compression of the trachea and bronchial tree and are at risk for becoming infected. Tumors of the mediastinum include thymic tumors, teratomas, lymphomas, thyroid tumors, and neurogenic tumors. Lymph node enlargement can occur due to hematologic malignancies, sarcoidosis, and chronic inflammatory or infectious diseases. Treatment of compressing lesions is usually surgical and often necessary to prevent future complications of atelectasis, pneumonia, emphysematous changes, and the possibility of malignant degeneration. Malacia, or “softening” of the airway, is one situation in which the intrathoracic airways narrow during exhalation resulting in obstruction. Tracheobronchomalacia (TBM) is the result of compromised elastic fibers in the airway walls that are responsible for providing shape and structure. Most infants and children with TBM have some underlying or associated problem. Cardiovascular anomalies may occur in up to 60% of the cases, and half of infants with TBM have BPD and/or GER.13 Malacia of the airways can be primary (congenital) or secondary (acquired). Primary TBM is due to inadequate maturation of cartilage in the trachea or bronchi. A common cause of primary TBM is prematurity, although it may occur in full-term infants as well. Disorders associated with TBM include polychondritis, chondromalacia, Ehlers Danlos, mucopolysaccharidoses, CHARGE and VATER anomalies, trisomy 21, DiGeorge syndrome, and 22q11 deletions.13 TEF is also a cause of primary tracheomalacia that can persist long after repair of the fistula. More commonly, TBM occurs secondarily. Often this is due to an injury to the airway such as in the premature infant who is intubated for a prolonged period of time. Tracheostomy can also compromise airway structure and strength leading to tracheomalacia. External compression due to normal vascular structures, tumors, or vascular malformations may inhibit

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maturation of the airway structure. Infection can also disrupt maturation of the airway leading to TBM. Signs and symptoms of TBM are commonly wheeze or stridor, and many children will exhibit a harsh, barking cough reminiscent of croup. Recurrent episodes of croup should alert the clinician to the possibility of TBM. Other signs and symptoms of TBM include cyanotic spells, failure to thrive, chest wall retractions, and recurrent pneumonia. Because plain radiographs of the neck and chest are poorly sensitive for evaluating TBM, fluoroscopy of the neck and chest can be used to give a cinegraphic view of the airway allowing the observer to determine whether there is dynamic collapse of the airway, especially during expiratory maneuvers. Flexible bronchoscopy allows direct visualization of the airway. Although invasive, bronchoscopy can, and should, be performed with minimal sedation to observe the airway with the child breathing spontaneously. Because of the need for minimal sedation and because it does not “stent” open collapsible airways, flexible bronchoscopy may be a better alternative to rigid bronchoscopy when evaluating TBM. In some cases, the area of TBM may appear pulsatile due to vascular compression. If there is external compression of the airway, magnetic resonance imaging with magnetic resonance angiogram or CT scan with contrast may help distinguish the cause of the compression. The optimal treatment for TBM is supportive care and allowing the child to outgrow the condition. Most children with primary TBM will improve by 2–3 years of age, although those with TEF may have significant problems as they reach into their adult years.13 Chest physiotherapy can be helpful to clear retained secretions trapped by collapsible airways. Albuterol has been suggested to worsen malacia by relaxing the supporting smooth muscle around the malacic segment. This is based on clinical observations and physiologic studies in infants with TBM. Therefore, some pediatric pulmonologists will use ipratropium bromide in children who wheeze due to TBM as an alternative rescue medication to albuterol because ipratropium is believed to have less of an effect on airway smooth muscle relaxation. Because of a paucity of clinical and basic science research to support the use of any aerosolized medications for the treatment of TBM, the clinician may consider individualized trials of ipratropium and/or albuterol and monitor for any effect with the plan of stopping the medications if they are not helpful. As stated earlier, airway clearance or chest physiotherapy can be a useful treatment for children with TBM, and there are devices that produce positive expiratory pressure (PEP) and can “stent” open collapsible airways during exhalation— so-called PEP devices. Similarly, continuous positive airway pressure can “stent” open collapsible airways, promoting oxygenation and ventilation. In extreme cases of TBM, surgical treatments may be needed. Patients who have severe TBM may manifest with poor growth, frequent and recurrent respiratory exacerbations, or even death spells. Such patients will need an intervention

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to decrease their work of breathing. A tracheostomy tube may be needed in cases when positive airway pressure cannot be practically or safely administered “noninvasively” with nasal interfaces. Other surgical procedures include aortopexy, external splinting, or airway stent placement. Silicone or metallic airway stents are rarely used due to complications such as erosion, obstruction, infection, and, specifically in children, the need for replacement. Because of the invasiveness of aortopexies and external splinting, and the complication of stents, surgical treatments for TBM are reserved for infants and children with severe, life-threatening TBM. Bronchiolitis obliterans (BO) is a disorder that causes obstruction during exhalation. Like asthma, it affects smalland medium-sized airways causing expiratory obstruction and wheeze. Unlike asthma, the expiratory obstruction is not reversible with bronchodilators. BO is mostly seen in individuals with chronic rejection after lung transplantation and in individuals with graft versus host disease secondary to allogeneic bone marrow transplantation. It can occur in healthy individuals as well, although this is much less common.14 Other intrinsic causes of lower airways obstruction include BPD and bronchiectasis due to various causes. These entities will be discussed in the following sections.

Bronchopulmonary Dysplasia Infants born prematurely may have airways obstruction for other reasons than TBM. BPD is a common cause of obstruction during exhalation. Because the immature airways are smaller, compromise of the airway can be quite significant. Furthermore, prematurity and the additional insult that mechanical ventilation can incur may lead to inflammation and injury of the airways compounding obstruction. Finally, these insults can lead to scarring and fibrosis of the airways and lung parenchyma. Scarring of the airway causes restriction of airflow. Scarring of the lung parenchyma causes loss of elastic recoil and the lung architecture that helps maintain patent airways. Infants with BPD demonstrate symptoms similar to other diseases that cause obstruction during exhalation. They may wheeze, cough, and have recurrent respiratory infections. Lung function testing performed on infants and children with BPD demonstrates airflow limitation in comparison with infants born without BPD. Even infants and children born prematurely, but without evidence of BPD, may manifest signs of airflow limitation on lung function testing.15 Treatment for the infant and child with BPD is mostly supportive. Bronchodilators are usually ineffective. Despite the inflammation that can occur in BPD, inhaled corticosteroids are also ineffective.15 The most important factor in treating BPD is assuring adequate growth as this is closely tied to lung maturation. Two common complications of severe BPD include pulmonary hypertension and chronic lung disease requiring long-term respiratory support. Pulmonary hypertension is a

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CHAPTER 18 ❖ Pediatric Pulmonology 227 result of chronic lung tissue hypoxia that leads to hypoxic vasoconstriction. If left unchecked, this hypoxic vasoconstriction can lead to pulmonary hypertension. The treatment for pulmonary hypertension is oxygen supplementation. In rare instances, vasodilator agents that affect the pulmonary vasculature are needed. Even less likely, lung transplantation may be necessary. Long-term ventilatory support for chronic lung disease is another instance in which close collaboration between otolaryngologists and pulmonologists is necessary. Tracheostomy tube insertion and maintenance is frequently necessary in severe BPD to support oxygenation and ventilation while infants grow healthy lung tissue.

Cystic Fibrosis CF affects over 30,000 individuals in the United States. As an autosomal recessive genetic disorder, 1 in 25 Caucasians carry a genetic mutation for CF, and the incidence of CF among Caucasians is approximately 1 in 3000.5 The gene mutation responsible for CF encodes for the cystic fibrosis transmembrane regulator (CFTR), a protein that is trafficked to the apical portion of many epithelial cells and conducts chloride. This chloride channel defect is responsible for a multitude of problems in CF, but the most common and worrying is dried airway secretions in the lungs leading to mucous retention, chronic infection, and chronic inflammation. This triad of mucous retention, infection, and inflammation, if left untreated and even despite therapy, leads to bronchiectasis. Because the lung parenchyma is spared, the elastic forces of the lung tissue pull these damaged airways open and ektasis (Greek; stretching) of the bronchi (Greek; windpipe) occurs. Clinically, CF lung disease and bronchiectasis present as chronic cough with purulent sputum production. Examination findings may include weight loss; lung crackles, wheezes, or rhonchi; and digital clubbing. Examination of the sputum may reveal typical pathogens, with Pseudomonas aeruginosa being a common bacterium that causes chronic infection. Fig. 18-6 demonstrates the radiographic findings encountered with bronchiectasis. PFT often displays characteristic findings consistent with airways obstruction. The diagnosis of CF requires clinical suspicion plus a confirmatory test. In CF, clinical suspicion occurs when signs and symptoms are present (Table 18-5), there is a sibling with CF, or newborn screening is positive. The confirmatory testing for CF includes sweat chloride testing, nasal potential difference measurements, or genetic testing for CFTR mutations.16 The most common confirmatory test, and still considered the gold standard, is the sweat chloride test in which sweat obtained by pilocarpine iontophoresis is obtained and analyzed for the chloride content. Chloride values 60 mmol/L are diagnostic of CF in the correct clinical setting. It should be noted that newborns and infants less than 6 months of age with sweat chloride values >30 mmol/L

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should still be considered to be at risk for CF because some babies have eventually been diagnosed with CF who had sweat chloride values 30–60 mmol/L.16 Nasal potential difference testing directly evaluates chloride conductance across the respiratory epithelium at the level of the nasal turbinates. This testing takes advantage of the unified epithelium throughout the respiratory tract to measure chloride conductance at the nasal epithelium that represents chloride conductance in the lower airways. This is a highly specialized test that is offered at selected CF centers. Genetic testing for CF allows for detection of CFTR gene mutations that can lead to CF. With over 1500 CFTR gene mutations discovered to date, genetic testing has the possibility of confirming the diagnosis. The downfall of genetic testing is that not all genetic mutations of CFTR have been proven to directly contribute to the pathophysiology of CF. In fact, only 23 genetic mutations of CFTR have been directly linked with CF. However, 85% of patients with CF carry 1 of those 23 genetic mutations, and the most common CFTR mutation, by far, is the DF508 mutation.16 In 2010, nearly every child born in the United States will have newborn screening for CF. Therefore, most individuals born in the United States with CF will be identified by newborn screening as the sensitivity and specificity for newborn screening approaches 99%.16 Newborn screening for CF involves obtaining a blood sample from the newborn and measuring immunoreactive trypsinogen (IRT), which is elevated in the blood of babies with CF. Some newborn screening programs employ only IRT with a repeat test, if elevated, and then referral to a CF center for further testing (sweat chloride testing). Other programs employ a two-tiered approach that evaluates IRT and, if elevated, further evaluates for CFTR gene mutations. The result of the two-tiered approach allows for the potential diagnosis of CF if two gene mutations are discovered. Most physicians will still perform sweat chloride testing to confirm the diagnosis of CF even with newborn screening that identifies two CFTR gene mutations. The advantages of newborn screening for CF include early identification and therapy to promote growth and prevent lung disease and infection. Treatment for lung disease in CF targets the three main problems involving the lower airways: mucous retention, chronic infection, and chronic inflammation. Mucous clearance techniques with chest physiotherapy are a daily mainstay of therapy for individuals afflicted with CF because thick mucous secretions and ciliary dysfunction renders native mucous clearance ineffective. Chest physiotherapy can be done manually (chest clapping) or with a variety of devices engineered to mobilize mucous secretions to large airways for the patient to cough out. Inhaled dornase alpha, discussed later, can help to thin mucous secretions and aid in airway clearance. Likewise, inhaled hypertonic saline can help to replace sodium and chloride to the epithelial surface of lower airways and hydrate secretions to aid in mucous clearance.

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FIGURE 18-6. Radiographic findings of bronchiectasis. The chest X-ray and computed tomography scan of the chest demonstrate airway wall thickening, stretching (ectasis) of the airways, and mucous retention.

Chronic infection occurs because bacteria thrive in a mucous-rich environment such as the airways of individuals with CF. P. aeruginosa is commonly recovered from airway secretions of individuals with CF, but Staphylococcus aureus and Haemophilus influenzae chronically infect younger individuals more commonly than P. aeruginosa. Antimicrobial agents should be chosen based on results of airway secretion

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cultures. Antimicrobial therapies can be delivered orally, intravenously, and aerosolized, and all three methods are often used to fight infection in CF lung disease. Chronic infection with P. aeruginosa can be particularly harmful to the airways of individuals with CF and lead to bronchiectasis. For this reason, many pulmonologists will try to eradicate this organism when first identified. Unfortunately,

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CHAPTER 18 ❖ Pediatric Pulmonology 229 TABLE 18-5. Clinical Signs and Symptoms of CF Chronic/recurrent respiratory symptoms/disease Cough (usually productive) Wheeze/airway obstruction/hyperinflation Bronchitis/pneumonia Atelectasis Bronchiectasis Sinusitis Nasal polyps Infection with typical pathogens (Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia) Digital clubbing Gastrointestinal disease Failure to thrive Pancreatic insufficiency Pancreatitis Meconium ileus Intestinal obstruction Rectal prolapse Liver disease Fat soluble vitamin deficiency Hypochloremic metabolic alkalosis/dehydration Obstructive azoospermia Source: Adapted from Farrel et al.16

P. aeruginosa cannot always be eradicated and nearly 80% of adults with CF harbor this organism in their lungs.17 In patients chronically infected with P. aeruginosa, chronic antimicrobial therapy is often employed. Chronic use of inhaled tobramycin has been shown to decrease respiratory exacerbations and increase lung function when compared with placebo.18 Chronic use of azithromycin has also been demonstrated to decrease the likelihood of respiratory exacerbation when compared with placebo.19 Although macrolide antibiotics do not have direct killing effect on Pseudomonas species, they do appear to have an effect on P. aeruginosa that is growing in mucoid phase of growth. Azithromycin also appears to have an antiinflammatory effect beneficial in those with CF. Concern for antimicrobial resistance is a factor when deciding to implement chronic antimicrobial therapy. However, when faced with the prospect of bronchiectasis and end-stage lung disease, most choose to accept the risk of antimicrobial resistance. Finally, airways inflammation is a significant component of CF lung disease. A robust neutrophilic inflammatory response occurs in the airways of individuals with CF that can be detected even in infants with CF. As neutrophils migrate to the airway mucosa to fight chronic infection, they die and release sticky DNA from their nucleoli. Dornase alfa is a recombinant human deoxyribonuclease that hydrolyzes DNA in CF airways and makes secretions less viscous and easier to expectorate. There is likely an antiinflammatory effect of dornase alpha as well. Other antiinflammatory agents available include systemic and inhaled corticosteroids. Although chronic use of systemic

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corticosteroids appears to have beneficial effects on airways inflammation in CF, the side effect profile makes such a therapy impracticable. Inhaled corticosteroids can be used to mitigate the harmful side effects of systemic corticosteroids, but appear to be less effective and their use should be continually assessed. If there is no apparent derived benefit from inhaled corticosteroids, their continued use should be questioned. As stated earlier, CF affects many different organ systems (Table 18-5). The respiratory tract is the most commonly affected and leads mostly to morbidity and mortality with the disease. The sinuses are also often affected with chronic infection, mucous retention, and inflammation, necessitating a good working relationship between pulmonologists and otolaryngologists in the multidisciplinary care of the individual with CF. Infection of the sinuses is often with the same organisms that infect the lower airways. Therefore, recovery of P. aeruginosa from the sinuses should alert the physician to the possibility of CF. Moreover, antibiotic therapy for sinus disease in those with CF should take into consideration the organisms known to be present in the lower airways. Nasal polyposis is very common in patients with CF who suffer from sinonasal disease. Surgical resection of nasal polyps may be needed if medical therapies fail or polyps are obstructing or protruding from the nares. In contrast to asthma and sinus disease, there does not appear to be a clear correlation with sinus disease and control of lower airways disease in CF. Although there does appear to be a correlation between sinus disease and respiratory symptoms in individuals with CF, there does not appear to be a strong correlation between surgical correction of sinus disease and control of CF lung disease. Surgical treatment for sinus disease may improve symptoms and quality of life, but there does not appear to be a significant long-term improvement in lung function. The data are conflicting as to whether sinus surgery may help to prevent respiratory exacerbations of CF lung disease.20–22 Finally, sinus disease with nasal polyposis is notoriously difficult to control for long term as individuals with polyposis are likely to require repeat surgeries to take care of refractory polyposis and sinusitis. Primary Ciliary Dyskinesia Bronchiectasis is also the end result of PCD, an autosomal recessive disorder with a prevalence of 1 in 15,000–30,000.23 This prevalence is likely underestimated as individuals with this disease are often undiagnosed. Kartagener’s syndrome is the triad of bronchiectasis, sinusitis, and situs inversus. The underlying defect in PCD is an abnormal ciliary ultrastructure and function. In PCD, the cilia demonstrate abnormal beating pattern or no motility at all leading to stasis of mucous secretions. In the lower airways, recurrent and chronic infections can lead to bronchiectasis. The diagnosis of PCD is not often thought of in children who have frequent, recurrent respiratory tract infections as such infections are a commonplace in this age group. Although

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nasal congestion is a symptom common among many individuals with respiratory complaints, the child with nasal congestion from birth should alert the clinician to the possibility of PCD.23 Other factors that would alert the clinician to the diagnosis of PCD would be chronic wet cough, wheeze, bronchiectasis, and particularly severe recurrent sinusitis and otitis media. Digital clubbing and nasal polyposis, seen in CF, are not often present in PCD. Nonrespiratory issues that would raise the suspicion of PCD include situs inversus, complex congenital heart disease, polycystic kidney disease, biliary atresia and liver disease, hydrocephalus, ectopic pregnancies, male infertility, and retinal degeneration.23 Once the diagnosis is considered, there are screening and diagnostic tests to help establish a diagnosis. Screening for PCD can be performed by measuring nasal and exhaled nitric oxide. In PCD, nasal or exhaled nitric oxide is low, as opposed to the high levels that can occur in asthma. Another screening study is the saccharine test that involves placing a small amount of saccharine on the inferior turbinate and counting the time elapsed until the subject can taste the saccharine. Diagnostic tests include nuclear medicine radioisotope scans that measure mucociliary clearance from the lower airways, and biopsy of the respiratory mucosa to evaluate ultrastructure and function of the cilia. Definitive diagnosis of PCD involves electron microscopy examination of ciliary structure. Much of the treatment of PCD has been adopted from experience with CF. Enhancing mucociliary clearance with chest physiotherapy and inhaled medications such as albuterol and dornase alpha have been employed to aid in mucous clearance. As with CF, individuals with PCD can become chronically infected with organisms such as S. aureus, H. influenza, and P. aeruginosa.23 Intense monitoring and treatment by identifying and treating infections are important to maintaining lung function. Other Lung Diseases A majority of the chronic lung diseases that occur in children are airway disorders or complications that arise from airway disorders, as described earlier in this chapter. Less commonly, ILDs, primary disorders of the pulmonary vasculature, and disorders of the chest wall and pleura can present to the pediatric pulmonology clinic. With the exception of pulmonary hypertension, these lung disorders of the parenchyma, chest wall, and pleura manifest as restrictive defects of lung function. ILD is a rare disease entity to occur in infants and children. Infection from respiratory viruses is a very common cause of interstitial pneumonitis and can present as ILD. Less common causes of pediatric ILD include chronic aspiration syndromes, medication toxicity (specifically, chemotherapeutic agents), ILD secondary to connective tissue disorders, ILD specific to children only, and ILD from uncertain etiologies.24 Disorders of pulmonary vasculature are also rare in children. Primary pulmonary hypertension is much less likely to occur than pulmonary hypertension due to secondary causes

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like chronic lung disease. Pulmonary hypertension should be suspected in patients who have dyspnea and hypoxemia but few other symptoms or physical findings. It should also be suspected in individuals with severe, chronic lung disease that have a progressive unexplained decline in their respiratory status. Pulmonary hemorrhage from vasculitis or pulmonary hemosiderosis is also much less likely to occur from these primary entities of pulmonary vasculature and more likely to occur as a complication of bronchiectasis. Common chest wall disorders that occur in children can compromise respiratory mechanics leading to chronic restrictive lung disease. Scoliosis and kyphoscoliosis, if severe, can lead to a restrictive defect that compromises ventilation. Neuromuscular diseases that affect respiratory muscle strength can also limit ventilation. In disorders such as muscular dystrophy and spinal muscular atrophy, respiratory muscle weakness is progressive and life threatening. Neuromuscular diseases affect the respiratory pump and not the lung parenchyma itself. However, if left untreated, hypoventilation due to neuromuscular weakness can lead to atelectasis and pneumonia, thus worsening the restrictive defect. The treatment for restrictive lung disease due to neuromuscular weakness is ventilatory support. Oftentimes, just supporting ventilation will improve oxygenation and supplementary oxygen is not needed. In fact, supplementing oxygen without adequately supporting ventilation can mask significant hypoventilation and lead to severe complications and respiratory failure. Finally, disorders of the pleural space can occur in children, most commonly due to infection. Pneumonia can lead to an inflammatory reaction in the pleura (sympathetic effusion) or infection of the pleural space itself (empyema). Treatment for this includes treatment of the infection and, sometimes, drainage of the effusion. Hemothorax, or blood in the pleural space, can occur and is almost always secondary to trauma. Pneumothorax, or air in the pleural space, is also likely to be due to trauma. However, pneumothorax can occur as a complication of lung disease (asthma or bronchiectasis) or spontaneously. Spontaneous pneumothorax should only be entertained after lung disease is excluded. Spontaneous pneumothorax is likely to occur in tall, thin individuals, particularly in adolescents. Treatment for hemothorax and pneumothorax is drainage if they are large and causing significant respiratory compromise. Small pneumothoraces can be observed as long as the patient is not receiving positive pressure support from mechanical ventilation. Recurrent pneumothoraces or pneumothoraces refractory to chest tube drainage may require surgical or medical pleurodiesis.

References 1. Krouse JH. The unified airway—conceptual framework. Otolaryngol Clin N Am. 2008;41:257–266. 2. McDougall CM, Blaylock MG, Douglas JG, Brooker RJ, Helms PJ, Walsh GM. Nasal epithelial cells as surrogates for bronchial epithelial cells in airway inflammation studies. Am J Respir Cell Mol Biol. 2008;39:560–568.

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CHAPTER 18 ❖ Pediatric Pulmonology 231 3. Watson WT, Becker AB, Simons FE. Treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: effect on lower airway responsiveness. J Allergy Clin Immunol. 1993;91:97–101. 4. Wilson AM, Orr LC, Sims EJ, et al. Antiasthmatic effects of mediator blockade versus topical corticosteroids in allergic rhinitis and asthma. Am J Respir Crit Care Med. 2000;162: 1297–1301. 5. Chernick V, Boat TF, Wilmott RW, Bush A. Kendig’s Disorders of the Respiratory Tract in Children. 7th ed. Philadelphia, PA: Saunders Elsevier; 2006. 6. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. N Engl J Med. 1995;332:133–138. 7. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000:1403–1406. 8. Jenkins M, Clarke J, Carlin J, et al. Validation of questionnaire and bronchial hyper-responsiveness against respiratory physician assessment in the diagnosis of asthma. Int J Epidemiol. 1996;25:609–616. 9. NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. Bethesda, MD; 2002. 10. Bachert C, Patou J, Van Cauwenberge P. The role of sinus disease in asthma. Curr Opin Allergy Clin Immunol. 2006;6:29–36. 11. Rachelefsky GS, Katz RM, Siegel SC. Chronic sinusitis disease with associated reactive airway disease in children. Pediatrics. 1984;4:526–529. 12. Colombo JL, Hallberg TK. Recurrent aspiration in children: lipid-laden alveolar macrophage quantitation. Pediatr Pulmonol. 1987;3:86–89.

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13. Carden KA, Boiselle PM, Waltz DA, Ernst A. Tracheomalacia and tracheobronchomalacia in children and adults. Chest. 2005;127:984–1005. 14. Kurland G, Michelson P. Bronchiolitis obliterans in children. Pediatr Pulmonol. 2004;39:193–208. 15. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med. 2007;357:1946–1955. 16. Farrel PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation Consensus Report. J Pediatr. 2008;153:S4–S14. 17. Gibson RL, Burns JL, Ramsey BW. State of the art: pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168:918–951. 18. Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med. 1999;340:23–30. 19. Saiman L, Marshall BC, Mayer-Hamblett N. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa. JAMA. 2003;290:1749–1756. 20. Jarrett WA, Militsakh O, Anstad M, Manaligod J. Endoscopic sinus surgery in cystic fibrosis: effects on pulmonary function and ideal body weight. Ear Nose Throat J. 2004;83(2):188–121. 21. Umetsu DT, Moss RB, King VV, Lewiston NJ. Sinus disease in patients with severe cystic fibrosis: relation to pulmonary exacerbation. Lancet. 1990;335:1077–1078. 22. Madonna D, Isaacson G, Rosenfeld RM, Panitch H. Effect of sinus surgery on pulmonary function in patients with cystic fibrosis. Laryngoscope. 1997;107(3):328–331. 23. Bush A, Chodhari R, Collins N, et al. Primary ciliary dyskinesia: current state of the art. Arch Dis Child. 2007;92:1136–1140. 24. Fan LL, Deterding RR, Langston C. Pediatric interstitial lung disease revisited. Pediatr Pulmonol. 2004;38:369–378.

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Pediatric Oral and Maxillofacial Surgery: Craniofacial Growth and Interdisciplinary Surgical Care Bernard J. Costello and Ramon L. Ruiz

ral and maxillofacial surgery (OMS) involves the treatment of disorders arising within the oral cavity and from the structures of the craniofacial region. The specialty is particularly geared to be interdisciplinary as most surgeons routinely traverse the lines of dentistry and medicine to work with clinicians from a variety of areas, particularly otolaryngologists. Oral and maxillofacial surgeons who focus on pediatric patients see a wide spectrum of disorders including congenital anomalies, pathology of the head and neck, orthognathic (jaw) deformities, head and neck infections, dentoalveolar disease, craniofacial trauma, and obstructive sleep apnea (OSA). Fellowship programs in pediatric oral and maxillofacial/craniofacial surgery have become more common and are closely tied to collaborators from pediatric otolaryngology. As such, a number of cross-specialty interactions and interdisciplinary team opportunities are observed at centers around the world to provide the most comprehensive care for these disorders. When specialists work in collaboration, a high level of expertise is achieved with the end result being superior care. Craniofacial growth is an important consideration when planning interventions to complex problems in the craniofacial region. Properly staged reconstructions respect this growth potential, and a clear understanding of growth in the cranium, orbits, midface, and mandible is important when providing comprehensive care. There is a biologic consequence to early surgical intervention in growing structures of the face. Decisions regarding early surgery are carefully

made based upon functional needs and aesthetic concerns. This chapter will review some of the common disorders oral and maxillofacial surgeons treat, often in conjunction with pediatric otolaryngologists.

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GROWTH AND SURGERY IN THE CRANIOMAXILLOFACIAL REGION When treatment planning complex care for growing individuals, an important consideration when planning surgical intervention in the pediatric population is the biologic consequence of early surgery on growth potential. Dysplasias, malformations, and disruptions will usually require surgical intervention at some point. However, early surgical intervention by itself often creates a separate biologic consequence that results in growth restriction. Such growth restriction can create new problems over the growth phases of the child. A delicate balance exists between the components of the craniofacial skeleton that relies on interactions and a series of signaling events between different anatomic components (Fig. 19-1). Alterations in this process may cause imbalances that affect function or aesthetics. The predictable biologic consequence of early surgery on growth structures is significant hypoplasia or asymmetry, an imbalance that often requires secondary surgery at skeletal maturity to address the functional and aesthetic consequences. Procedures designed to address various imbalances may include cranio-orbital osteotomies, midface advancement, and mandibular advancement.

FIGURE 19-1. A, B, Multiple views of skulls from infancy through adolescence show the progression of craniofacial bone growth. The general progression is from superior to inferior with a downward and forward growth vector.

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Usually these definitive corrections are performed once the growth of these structures is complete. However, in certain instances of compelling functional concerns (e.g., OSA), or severe aesthetic problems that affect psychosocial development (e.g., exceptionally severe asymmetries or hypoplasias), early surgery may be indicated.1 This theme is a common one in craniomaxillofacial surgery. For these reasons and others outlined below, pediatric patients require long-term followup and close observation by skilled practitioners in a team setting. Representative examples of clinical challenges are briefly reviewed below to highlight interdisciplinary surgical care as well as some important concepts of craniofacial growth.

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Oculoauriculovertebral Spectrum: Treatment Planning and Growth Oculoauriculovertebral spectrum (OAVS) is a complex, three-dimensional hypoplasia that results from disruption of the development of the first and second branchial arches.2–16 OAVS is also commonly referred to as hemifacial microsomia, craniofacial microsomia, Goldenhar syndrome, and a number of other terms.16 The phenotypic variety is impressive, ranging from minimal asymmetries and simple ear anomalies to complex lateral facial clefting and disrupted development of the lateral facial and skull base structures (Figs. 19-2 and 19-3). This variable hypoplasia produces

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FIGURE 19-2. A and B, An infant female is shown with minimal features of OAVS, including external ear abnormalities. C through E, A young child with OAVS that is more significant, including external ear atresia, Kaban type IIB mandible hypoplasia, soft tissue hypoplasia, and asymmetries of the orbit, zygoma, and maxilla. She has already undergone distraction osteogenesis prior to age 5 by another surgeon but still retains significant asymmetries throughout the anatomic regions, including the mandible.

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FIGURE 19-3. A through D, This young boy with Goldenhar syndrome has a left-sided Tessier no. 7 cleft (macrostomia), left-sided hypoplasia in multiple anatomic units, and bilateral conductive hearing loss. Postoperative results show good healing of the commissure with minimal scarring.

challenging reconstructive needs. OAVS highlights a number of key treatment concepts that involve growth as well as interdisciplinary collaboration between otolaryngologists and oral and maxillofacial surgeons. Because of the multifaceted aspects of the functional and esthetic challenges faced by patients with OAVS, a number of specialists are involved in the patient’s care at multiple stages. Surgeons must understand the biologic basis for the deformity, as well as the expected esthetic and functional issues that may arise throughout the child’s stages of growth. A thoughtful, staged reconstructive approach that respects the growth of these structures is best suited to address the complex needs of patients with OAVS.15–19 The extent of the dysmorphology in OAVS is considerably variable. Although no minimal diagnostic criteria have been well described, many believe that the most basic form of this spectrum is expressed as microtia, preauricular, or auricular congenital anomalies. Patients may typically exhibit underdevelopment or lack of development of a number of structures

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associated with the first and second branchial arches, including the mandible, temporomandibular joint (TMJ), orbit, ophthalmic structures, zygoma, maxilla, external ear, internal ear, and surrounding soft tissues. Involvement is not limited to facial structures. Renal, genitourinary, cardiac, and skeletal anomalies have been reported to occur with variable frequency.4,6,7 Few patients exhibit all or even most of the reported features. Patients with multiple congenital anomalies often are classified as patients with Goldenhar syndrome. The incidence of OAVS in the general population has been estimated at 1:3,500 to 1:26,500 live births.4,8 The following sections discuss the important aspects of reconstruction for OAVS and the authors’ preferred approach. In general, those areas that have a functional concern are addressed in a standard, timely fashion to provide functional units during development when necessary. Timing of procedures is primarily based on skeletal maturity of the area of concern, such that reconstruction is provided once most growth velocity for that region is complete. However, functional issues may supersede growth concerns. For example, orthognathic surgery is typically performed during the adolescent years, when the vast majority of growth is complete, such that a stable and predictable result is achieved without the need for additional revisions. Some deformities are reconstructed in a way that is custom-tailored to the patient’s needs when necessary. Aesthetic concerns that become psychosocial problems for a child may be addressed earlier than at full maturity if the reasons are compelling. The authors’ overall approach is outlined in Table 19-1. Although considerable

TABLE 19-1. Authors’ Approach to Treatment of OAVS Deformity

Typical Age of Reconstruction

Cleft lip

3 mo or later

Cleft palate

9–14 mo Submucous cleft repaired only if speech is affected once a complete speech evaluation is performed.

Cranio-orbital asymmetry

2–5 y or later

Oribital hypoplasia/ microphthalmia

5 y or later

Zygomatic hypoplasia

5 y or later

Kaban type III TMJ (atretic TMJ/ramus)

5 y or later

Maxillomandibular asymmetry

14–16 y or later in females 16–18 y or later in males

Soft tissue deficiency, lateral face

After orthognathic procedures

External ear

5 y of age or later

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controversy surrounds the timing of these procedures, the authors prefer this approach, which respects growth potential and limits aggressive intervention when possible. One important consideration is the nature of the deformity itself and whether or not it is progressive in most patients. This is a point of contention for many practitioners, and opinions on this fundamental aspect directly affect the thought process of how clinicians approach treatment planning for OAVS. Many believe that OAVS is a stable dysmorphology, which means that the deformity does not worsen over time.17–19 Therefore, the degree of hypoplasia is similar if not identical at a young age to that seen when the patient grows to the teen years. For those who believe this to be the case, timing of orthognathic procedures is done at skeletal maturity. Thus, waiting until the adolescent years to address maxillomandibular discrepancies allows the patient to grow to maturity and permits the surgeon to provide a stable and predictable result that is not likely to require revision surgery because of additional growth. Subscribers to this philosophy accept that the deformity does not worsen over time. Therefore, there is typically no compelling reason to address asymmetries earlier for most patients.15,17 On the other side are those who believe that OAVS is a progressive deformity that should be addressed earlier to avoid additional asymmetry that might occur if one waits until skeletal maturity is reached. This is a primary argument for early distraction osteogenesis procedures aimed at lengthening the mandible at a young age to provide better symmetry early in the growth phase. Those who subscribe to this philosophy believe that leaving the deformity until the teen years will result in worsening asymmetry with time. Some data support this finding, although other data argue against it.17,19–21 Several studies have evaluated patients in a longitudinal fashion and found that the deformity is not progressive in these cohorts.15,17,22 Studies that previously had supported the idea that OAVS is a progressive deformity were not longitudinal and therefore may exhibit flaws that negate the concept of progressive deformity.17,19,20–22 Published case reports and series of both of these approaches show acceptable results.17–19 Although the early intervention approach has shown considerable merit, in the opinion of the authors, definitive operations performed in minimal stages offer the most predictable and long-lasting result with minimal intervention or chance for revision. Therefore, this approach decreases the burden on the child, family, and health care system. There are a number of anatomic regions that benefit from reconstruction in patients with OAVS. Several specific anatomic areas illustrate these growth concepts as they relate to treatment planning and are reviewed below.

EARLY MANDIBULAR LENGTHENING WITH DISTRACTION OSTEOGENESIS FOR OAVS As mentioned earlier, some surgeons believe that mandible lengthening and repositioning in the early years through

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distraction osteogenesis can improve symmetry and esthetics.18,23 If a distraction procedure or an early graft can eliminate tracheotomy dependence, value can be derived from these methods. Although initial approaches involved intervening at an early age to improve symmetry, form, occlusion, and overall function, many of these approaches were hampered by difficulty controlling vectors and the bone growth impairment that often results from early surgery. Early intervention through distraction does not improve bone growth, and there is no evidence to suggest that an improved outcome results from this approach compared with orthognathic surgery during adolescence. As a result, patients who have a deformity that is not progressive can be iatrogenically converted to a deformity that is progressive through growth restriction caused by early surgical intervention. Aesthetic issues and mild to moderate asymmetries are best addressed during the adolescent years with the use of conventional orthognathic surgical techniques with which reconstruction is as definitive as possible. This type of approach achieves the goals with minimal stress on the patient, family, and health care system (Fig. 19-4). Distraction techniques can be associated with a higher degree of infection, nonunion, and other complications that may increase the complexity of definitive reconstruction at skeletal maturity. This may produce a more difficult clinical scenario for standard orthognathic surgery approaches because bone quality and surrounding soft tissue may be affected by scarring and by hypovascularity. Thus, the benefits of distraction techniques typically do not outweigh the risks in most cases.

TEMPOROMANDIBULAR JOINT RECONSTRUCTION IN OAVS AND OTHER DISORDERS Patients with OAVS exhibit abnormalities of the TMJ, including hypoplasia and occasionally agenesis. A number of other problems may also necessitate TMJ reconstruction including tumors, trauma, or degenerative joint disease and the techniques utilized to reconstruct the area are similar. Those with mild to moderate hypoplasia from OAVS who can function well rarely have internal derangements or degenerative joint disease that affects function. These patients infrequently require significant surgical intervention regarding their TMJ. Those who have not developed a ramus/condyle/fossa unit benefit from reconstruction of the TMJ at some point. Some surgeons prefer to delay this process until growth has essentially been completed if the patient can function well (i.e., speech and mastication). It is interesting to note that most patients can function quite well when the condyle/fossa unit is not intact. For those who have psychosocial issues with the deformity or compelling functional reasons to perform a reconstruction earlier, a costochondral rib graft can provide a condyle and ramus unit.15,17,24 Patients who exhibit OSA and those with mastication difficulty may benefit from this

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FIGURE 19-4. A through E, A young boy with Goldenhar syndrome is shown with a right side that is classified as type IIA and a left side classified as type III. He has undergone a number of distraction procedures with external devices performed by another surgeon in an attempt to lengthen the right side and create a neocondyle through a transport distraction technique. Trismus may occur. Three-dimensional computed tomography scans show the postoperative anatomy. Vector control can be difficult and may alter the bone at previous distraction sites in a manner that makes conventional osteotomy or reconstructive techniques difficult.

approach at age 5 or later. Some patients will not have a fossa to accept the rib, in which case one may be reshaped and reconstructed within the skull base.15,17 Grafts placed earlier than 5 years of age may resorb and lack significant size to allow for stability and fixation. One of the main drawbacks seen with early rib grafting is the unpredictable nature of growth once the graft has been

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placed. Rib grafts may undergrow, overgrow, or theoretically grow to “perfect” size, although this is rarely the case.15,17,24 If ribs overgrow, then a significant issue may arise at the time of adolescence when a malocclusion is typically treated with orthognathic surgery. The complex asymmetry that results may be more difficult to treat than the deformity that would have resulted if the graft had not been performed. Thus, the decision of whether to perform early grafting of the TMJ must be made carefully. Costochondral grafting is not an option in all patients. This may be due to the fact that cartilage has already been harvested for ear reconstruction, because the surgical scar will be unacceptable, or because chest wall anomalies are present. In such patients, the use of a microvascular fibula reconstruction remains an option. The microvascular fibula reconstruction has the advantage of providing subcutaneous tissue and/or fascia to provide additional soft tissue volume to the lateral face. However, this requires particular expertise and significant donor site morbidity. The results for condylar replacement in the rapidly growing child can be poor as the fibula fails to grow. However, this technique is a reasonable option in the skeletally mature patient with complex hard and soft tissue deficiencies. In some instances, the option of a prosthetic TMJ replacement can be considered as a revision procedure following rib graft reconstruction or as the primary reconstruction itself. Historically, this option has not been entertained in children because of concerns that the prosthesis would not grow. Given the issues associated with unpredictable growth of a rib graft, consideration can be given to this option, particularly in the older child. A custom prosthesis usually is best suited for those patients who lack a portion of the ramus. If a large area is deficient, then grafting with autogenous materials such as costochondral rib, vascularized fibula, and/or iliac crest graft is the better choice. Transport distraction osteogenesis has been described and used to reconstruct the ramus/TMJ unit in patients with Kaban type III OAV; limited success with this technique has been reported in the literature.25–32 It is exceptionally difficult to transport a distraction disc of bone to the exact point of articulation at the base of the skull and provide the level of symmetry that can be achieved with the other aforementioned techniques. Some initial descriptions mentioned the possibility of neocondylar genesis, but no long-term outcomes of these procedures have been published.40–47 Many patients who have undergone this procedure require revision surgery with costochondral reconstruction or other techniques that are more difficult to perform after the area has developed additional scarring. Another drawback is the growth restriction that many times occurs in this area, particularly if the surgery is performed at a young age. This transforms a stable deformity into a progressive one and potentially makes later reconstructions more difficult from a technical standpoint. Even after more than a decade of experience, there are no substantiated functional outcomes of this technique have

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been reported in clinical trial or case series; therefore, this technique is not advocated by the authors. More predictable techniques such as costochondral rib grafting appear to offer better results. Current research is aimed at engineering a construct of the TMJ ex vivo and integrating a multitissue graft such that donor site morbidity can be avoided. Although these concepts are still years from clinical trials, a more custom-tailored graft that fulfills structural and functional needs much better than what surgeons currently can offer may eventually be available.33,34

Discrepancies between the maxilla and mandible may yield significant malocclusions that can be both aesthetically and functionally significant. These discrepancies are particularly evident in OAVS, and orthognathic surgery is very effective and efficient for addressing these imbalances. In addition, it is estimated that approximately 10% of the nonsyndromic population has enough of a discrepancy between the maxilla and mandible that orthognathic surgery may be helpful to effectively treat malocclusions. In most patients, these procedures are designed to coincide with the completion of facial growth to provide a stable and long-lasting correction

of the deformity. In girls, orthognathic procedures are typically performed at 14 to 16 years of age. Boys plateau their growth velocity of these structures slightly later at 16 to 18 years of life. Performing these procedures earlier typically necessitates additional corrective surgery after patients outgrow the correction with remaining growth potential. For these reasons, definitive treatment is preferable performed at skeletal maturity to avoid multiple procedures that become increasingly difficult from a technical standpoint. Orthognathic surgery is successful at addressing a variety of deformities. The procedures are designed to carefully dismantle the dysmorphic bones and reassemble them in a more normal conformation for both function and aesthetics. Significant mastication and speech issues can arise with severe discrepancies of the jaws, and these are easily addressed with these techniques. Typically, these procedures are coordinated carefully in conjunction with an orthodontist. Orthodontic mechanics (braces) are utilized to level and align the teeth primarily before, but also after, orthognathic surgery to optimize the functional occlusion and provide an aesthetic smile (Fig. 19-5) Patients and families have a high degree of satisfaction with these procedures, and many are transformative from both functional and aesthetic perspectives. In addition, these osteotomies are very successful when used to treat patients with severe sleep apnea.35–37 A variety of midface and/or

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FIGURE 19-5. This patient’s facial structures are indicative of obstructive sleep apnea exhibiting severe retrognathia and a collapsed posterior airway space in the supraglottic region. Orthognathic surgery can be utilized to improve airway dynamics and optimize the occlusion.

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cranio-orbital osteotomies can be used for more complex disorders including the craniofacial dysostosis syndromes such as Apert, Crouzon, Pfeiffer, and Saethre-Chotzen syndromes. Comprehensive care of these deformities requires a number of staged procedures over the young life of the patient and interdisciplinary care. The procedures commonly

utilized include LeFort III, monobloc, bipartition, and orbital translocation osteotomies (Fig. 19-6). For OAVS, the staged reconstruction with facial osteotomies has been discussed by many.3,15–17,19–21 The complex threedimensional deformity of OAVS usually is best approached with a Le Fort I osteotomy, bilateral sagittal split osteotomies,

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FIGURE 19-6. A Le Fort III osteotomy is utilized to advance this young adolescent’s midface and improve her aesthetics, nasal breathing, and occlusion.

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and a genioplasty when possible (Fig. 19-7). Because of the complexity of the asymmetry, the precision, control, and stability offered by orthognathic surgical techniques are almost always preferable when compared with techniques based on distraction osteogenesis. Distraction osteogenesis techniques used in the mature patient do not afford the control and precision that can be achieved with conventional orthognathic techniques and thus offer little or no advantage for the treatment of deformities associated with OAVS. It can be helpful to use both three-dimensional computed tomography images, computer planning, and stereolithographic models to plan treatment for complex three-dimensional asymmetry (Fig. 19-8).

TABLE 19-2. Staged Reconstruction of Cleft Lip and Palate Deformities

Cleft lip repair

After 10 wk

Cleft palate repair

9–18 mo

Pharyngeal flap or pharyngoplasty

3–5 y or later based upon speech development

Maxillary/alveolar reconstruction with bone grafting

6–9 y based upon dental development

Cleft orthognathic surgery

14–16 y in girls, 16–18 y in boys

Cleft rhinoplasty

After age 5, but preferably at skeletal maturity; after orthognathic surgery when possible

Cleft lip revision

Anytime once initial remodeling and scar maturation is complete, but best performed after age 5

Cleft Lip and Palate Reconstruction Comprehensive cleft care includes an interdisciplinary approach from infancy through adolescence (Table 19-2). Otolaryngologists, oral and maxillofacial surgeons, speech and language pathologists, pediatricians, geneticists, neurosurgeons, orthodontists, and a whole host of other specialists are required to provide comprehensive, contemporary care that addresses all of the needs of this population. Guidelines and principles set forth from the American Cleft Palate/ Craniofacial Association Parameters of Care provide a roadmap for surgeons interested in understanding the benefits of such an interdisciplinary team approach. It is important to consider the functional and aesthetic aspects of these anatomic areas carefully, and in an interdisciplinary fashion.39 The primary repair of clefts occurs in infancy and is well described in other countless references.39–41 Early considerations including lip and nose aesthetics, palate closure, speech development, hearing, dental health, growth, and others are key priorities throughout the first few months and years of life. Also important in the comprehensive care of patients with clefts is the rehabilitative concepts tied to maxillary

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reconstruction both at the time of mixed dentition and at skeletal maturity. Approximately 75% of patients with clefts will exhibit clefting through the primary embryologic palate that includes the dentoalveolar segment, developing teeth, piriform rim, and nasal floor.40,41 This leaves patients with the potential for a cleft-dental gap if this area is not reconstructed in a timely fashion. Most patients will benefit from a bone graft reconstruction of this area just prior to the eruption of the lateral incisor and canine teeth, which typically occurs at some point between ages 6 and 12 years of age. Dental development is considerably variable and dental radiographs are helpful to determine the exact timing of the graft. Prior

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FIGURE 19-7. A through D, A teenage girl with type IIA oculoauriculovertebral spectrum and a Tessier no. 7 cleft (repaired by another surgeon) is seen preoperatively and postoperatively. She underwent Le Fort I osteotomy, bilateral sagittal split osteotomies, and a double-stack genioplasty.

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FIGURE 19-8. A through I, A teenage girl is shown preoperatively and postoperatively after treatment for type III oculoauriculovertebral spectrum. She had a rib graft at an early age and then distraction of the rib graft site on several occasions during childhood, performed by another surgeon. During the teen years, she underwent Le Fort I osteotomy, left-sided sagittal split osteotomy, and right-sided modified sagittal osteotomy through the previous distraction site with removal of an impacted tooth, as well as asymmetric genioplasty with bone grafting. A stereolithographic model can be helpful for analyzing asymmetry in patients who have complex three-dimensional deformities.

to the surgical grafting procedure, most patients will benefit from orthodontic expansion with a palatal expansion device. A skilled orthodontist is required for this process to be effective, and the stages must be timed appropriately. Palatal expansion occurs prior to the grafting procedure; appliances help retain the expansion result in the post-operative period. Typically, iliac crest cancellous bone is utilized to reconstruct this site. A series of mucosal advancement flaps help facilitate a nasal closure, interpositional bone graft placement, and oral-side closure that must include gingival tissue at the alveolus. The design of the flaps varies with personal preference, width of the cleft, and unilateral or bilateral defects. Closure of this portion of the defect improves nasal and sinus health as well as speech.

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Orthognathic surgery is helpful for approximately 25% to 50% of patients who have cleft lip and palate reconstructive procedures. These patients have a tendency to exhibit maxillary hypoplasia with a significant Class III skeletal discrepancy. This results in a significant facial imbalance and very poor occlusion. These anatomic dysmorphologies and growth discrepancies result in a number of problems for articulation, mastication, and aesthetics. A comprehensive team approach involving speech assessments, orthodontic care, and orthognathic surgery treats these discrepancies and improves the dysmorphology. The orthodontic and orthognathic procedures should be timed carefully to coincide with the appropriate growth phases of the involved areas. Osteotomies are generally performed at

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skeletal maturity (i.e., 14–16 for girls and 16–18 for boys). Maxillary osteotomy procedures also have the added benefit of improving nasal breathing, and supporting the aesthetics of the nasal complex by improving the nasal base

position and supra-tip break (Fig. 19-9). For this reason, when orthognathic surgery is planned, the definitive nasal reconstruction should usually be delayed until after complete healing occurs.

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FIGURE 19-9. An adolescent girl born with a bilateral cleft lip and palate who exhibits severe maxillary hypoplasia. She was treated with a Le Fort I osteotomy, bilateral sagittal split osteotomies, genioplasty, septoplasty, inferior turbinectomies, and exhibits improvements in facial profile, occlusion, articulation, and overall aesthetics of the midface and nasal complex. She will still require definitive septorhinoplasty and a lip revision.

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CHAPTER 19 ❖ Pediatric Oral and Maxillofacial Surgery Prosthodontic reconstruction is also particularly important to consider. Some procedures can be performed in childhood, although full dental rehabilitation usually waits until growth maturation at approximately 16 to 18 years of age. Bone graft augmentation procedures, placement of dental implants, and comprehensive prosthodontic care are important to the complete rehabilitation of patients with clefts (Fig. 19-10). Dental implants are commonly utilized to address a variety of problems in pediatric patients. Single or multiple teeth replacements are possible and usually performed at or near skeletal maturity, however, in certain instances early placement of dental implants can be very helpful. If psychosocial or functional benefits are potentially substantial, then early placement of dental implants may be considered. Careful planning is necessary to optimize these opportunities such that treatment is efficient and long-term problems may be avoided in the adult years.

Craniomaxillofacial Pathology A large variety of pathologic entities may present in the craniofacial structures of the child. These entities also illustrate the potential for collaboration and comprehensive care. Head and neck surgeons and pathologists frequently classify lesions in this area as odontogenic, benign nonodontogenic, malignant, congenital, traumatic, or metabolic. As mentioned earlier, the required removal and treatment of such lesions at a young age is often associated with biologic consequences including growth restriction. The development and eruption

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of teeth in these areas is an important consideration, often requiring the additional skills of a pediatric dentist and orthodontist to help manage malocclusion that may be a result of excision of lesions within the dentoalveolar structures. Longterm follow-up and careful timing of the bone, soft tissue, and dental reconstruction is important when considering treatment regimens. Typically, once a pathologic entity has been identified by history, clinical examination, imaging, and/or biopsy, then a comprehensive plan involving several steps is undertaken. These may include injections, embolization, excision or resection, immediate or delayed reconstruction, adjuvant therapies, and rehabilitation. Some entities may benefit from injections or simple curettage whereas others may require composite resection. The mode of treatment is related to recurrence rate, the aggressive nature of the lesion, and the utility of adjunctive treatments such as radiation and/or chemotherapy. Negative effects on growth potential are a common concern for patients who undergo significant treatments at a young age. In addition, the level of reconstructive complexity is variable and may or may not include bone grafting, soft tissue augmentation, and/or dental implants to restore the facial support, aesthetics, and occlusion. A comprehensive interdisciplinary reconstruction in a child may have several stages and may take years to complete (Fig. 19-11). Careful team discussions of the surgical access, excision, reconstruction, and rehabilitative plans help optimize the results for complex pathology.

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FIGURE 19-10. An adolescent girl with a variant of oto-palatal digital syndrome, bilateral cleft lip and palate, and oligodontia. She had provisional restorations fabricated in childhood and multiple implants were placed in the maxilla and mandible to support fixed dental appliances for both arches. Markedly improved function and aesthetics are the result of careful planning.

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FIGURE 19-11. A 12-year-old female who initially presents with a very large central giant cell tumor that required resection due to the degree of destruction. She was reconstructed in a staged manner with a microvascular fibula, orthognathic surgery to address multiple facial disharmonies, and dental implants to replace lost teeth.

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Dentoalveolar Disease and Dental Reconstructive Surgery

Impacted Teeth Impacted and/or displaced teeth create a considerable amount of morbidity in children and young adults (Fig. 19-12). When symptomatic, their removal is indicated in a timely fashion to avoid serious infections that may become life-threatening. Pathologically positioned (impacted) third molar teeth are indicated for removal, even when asymptomatic. Impacted teeth have the potential to create a number of problems including loss of second molars due to erosion, periodontal disease, infections, and formation of destructive cysts and tumors of the jaws. Most third molar teeth extractions are performed in teenagers on an outpatient basis under a brief anesthetic with rare complications.42–46 Considerable morbidity may be endured with impacted third molars that are retained into adulthood.42–46 There are data that has shown poor outcomes for those who have wisdom teeth removed well into adult life when compared with those removed in younger years.42–46 For most patients, early removal of impacted teeth is preventative for a number of issues and will be associated with a lower complication rate.42–46 Infection The most prevalent disease in the world is dental disease (e.g., caries and periodontal disease) and can precipitate serious head and neck infections.47–50 For children, most severe infections are often the result of caries due to poor oral hygiene. Dentoalveolar infections are often mild and easily addressed with antibiotic therapy, removal of the caries or tooth in question and supportive measures. Occasionally, these multibacterial infections become severe enough to be life-threatening, particularly if there is involvement of the airway or other vital structures (Fig. 19-13). In such instances,

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FIGURE 19-12. A panoramic tomogram of an individual who has multiple impacted teeth including third molars. The expanding cyst in the right mandible has displaced the inferior alveolar nerve inferiorly.

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C FIGURE 19-13. Severe infections of the head and neck region are common and can involve vital structures such as the orbit.

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broad spectrum antibiotics with gram-negative coverage should be utilized as such infections are typically caused by Streptococcus, Bacteroides, Peptostreptococcus, Klebsiella Eikenella, and other gram-positive, gram-negative, aerobic, and anaerobic bacteria. It is important to broadly cover these infections with bacteriocidal doses of antibiotic therapy that are sensitive to the key strains typically involved in these infections. Early surgical drainage and removal of the carious dentition is the key to success. Drainage alone is usually not effective. Some progress rapidly, and if the desired response is not seen, surgical drainage and/or additional antibacterial therapy are necessary. Children are particularly susceptible to quick moving and severe deep space infections with systemic consequences. Infections of this variety can progress to the thoracic spaces, cause necrotizing fasciitis, and must be respected given their ability to create severe morbidity and mortality. In some instances, airway management including fiberoptic intubation or even tracheostomy may be necessary. Chronic infections may cause low grade symptoms and osteomyelitis affecting structural aspects of the jaws and creating deformity in the growing child (Fig. 19-14).

Craniofacial Traumatic Injuries Traumatic injuries to the facial skeleton are much less common in children than in adults.51–54 Specialized care is required to care for these injuries, and an interdisciplinary approach is helpful. As such, dedicated pediatric trauma teams are designed to provide comprehensive care to patients with the most complex injuries. Understanding principles of growth,

FIGURE 19-14. A variant of chronic mandibular osteomyelitis is seen in this child with pain, swelling, fever, and episodic chills. The computed tomography scan shows significant reactive bony changes.

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function of various components, and the unique approaches required for pediatric patients is essential to provide optimal care to these injured patients.51 A comprehensive evaluation is necessary to obtain a detailed diagnosis and formulate a comprehensive treatment plan that coordinates care of all involved injuries as well as any airway issues. Most patients with multiple facial fractures do not require tracheostomy, but careful airway management is a key to success. Detailed imaging is helpful to both appreciate the full scope of injury as well as formulate a plan for reconstruction. Panfacial injuries usually require a comprehensive approach involving a number of specialists including a pediatric neurosurgeon for transcranial approaches to the anterior skull base, frontal sinus, and cranio-orbital region (Fig. 19-15). Other instances may require the skilled followup and care of a surgeon and orthodontist because of facial growth issues. Injuries to the jaws—particularly the condyles of the mandible—require a specialized approach including attention to duration of immobilization and subsequent physical therapy. Failure to treat these injuries properly can result in poor outcomes including limited mobility or ankylosis (Fig. 19-16). Secondary reconstruction in a team fashion may be needed to address imbalances, malocclusion, airway obstruction, loss of dental structures, or other functional problems.

Craniomaxillofacial Osteotomies for OSA Another area of frequent collaboration and also illustrative of growth concerns is the comprehensive management of OSA. If nonsurgical treatments are ineffective or poorly tolerated, surgical procedures are available for refractory OSA. For many patients who are preadolescent, the surgical treatment of choice is tonsillectomy and adenoidectomy if there is obstructive adenotonsillar hypertrophy and the structures are the main component of obstruction. Less often the nasal structures may contribute to the obstruction. Another important area to consider is the tongue base and supraglottic airway. A detailed airway evaluation is necessary to comprehensively diagnose the site(s) of obstruction and help choose the most appropriate treatment regimen. Because most patients with moderate to severe OSA will have obstruction at both the palatal (retropalatal/nasopharyngeal) and tongue base (oropharyngeal/retrolingual) regions, combined procedures directed at each specific site should be considered to achieve success. It is clear that when both the base of the tongue and the soft palate are involved, procedures designed to address both sites will offer the highest success rates.35–37,38,55–59 Recently, robotic procedures have been designed to reduce the tongue base in a more aggressive manner utilizing technology to access and surgically reduce areas previously difficult to reach utilizing conventional approaches. In patients with primarily skeletal rather than soft tissue structure issues, osteotomies have a distinct advantage in addressing the true etiology of the airway collapse.

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FIGURE 19-15. This young boy was involved in a motor vehicle crash in which he was an unrestrained front seat passenger. He exhibits cranio-orbital fractures and a complex fracture of the zygoma/orbital floor/orbit roof. His physical examination reveals a significant cerebrospinal fluid leak at the anterior cranial base. The craniofacial approach is utilized to cranialize the frontal sinus and repair the fractures.

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CONCLUSIONS

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FIGURE 19-16. The result of an unrecognized condylar head fracture may be fibrosis in the TMJ, limited motion, and progressive facial asymmetry.

While adult patients often undergo osteotomies of the facial skeletal to address airway obstruction at the palatal/ tonsil and tongue base areas, pediatric patients are usually too young to consider most these procedures in the traditional manner. Early osteotomies may affect growth in a negative way and can compromise the development of teeth. In certain instances, there may be a compelling need to treat severe refractory OSA prior to skeletal maturity and technical aspects of the procedure may change based on the age and dental development. Osteotomies in the ramus of the mandible may be utilized without affecting the teeth if performed with careful planning. Interpositional bone grafts or distraction osteogenesis may be utilized to advance the mandible and improve airway dynamics.60,61 These procedures are considered in some patients with particularly severe and refractory OSA, or in patients in which airway optimization has already occurred with removal of tonsils, and adenoids.37,61 Hyoid suspension can have a role in younger children with documented prolapsed of the epiglottis.62 Elevating the hyoid bone by suspending the lateral aspects of the hyoid bone to the inferior border of the mandible can have a positive effect on airway dynamics and prevent collapse of the epiglottis in patients with obstruction at that specific level. Patients with obstruction at other levels such as the posterior pharynx or tongue base will benefit from additional procedures that address these specific points of obstruction. Segmental osteotomies of the anterior mandible are possible in those children who have already erupted the permanent dentition in the anterior mandible.35,37 The goal of these osteotomies is to advance the genioglossus and the suprahyoid musculature to optimize airway dynamics. By improving the diameter of the airway at this level, improvements can be made that reduce the severity of or cure OSA.36 Patients with more severe sleep apnea may benefit from skeletal advancement through osteotomy of the midface and/ or mandible depending upon the site of obstruction. Patients with craniofacial dysostosis syndromes (e.g., Crouzon syndrome) may have obstruction in the posterior pharynx, whereas those with Pierre–Robin sequence may have

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A wide variety of problems occur in the craniomaxillofacial region including congenital malformation, pathology, trauma, and infections. These and other complex issues are often best addressed in a team fashion. Respect for the growth potential of these areas is a key concept when considering early intervention. Treating some complex problems in the craniofacial area requires a staged treatment plan, and a balance must be achieved when the team considers functional and aesthetic concerns. These treatment plans should respect the biologic consequences of early surgery by understanding the subtleties of growth and the effect of early surgery on those structures. Those issues that are functional in nature usually take precedence, although compelling aesthetic concerns may prompt intervention early as well if psychosocial concerns are evident. Often the treatment planning includes the careful coordination of efforts from specialists trained in otolaryngology, OMS, speech pathology, orthodontics, and many others.

References 1. Adams GR. The effects of physical attractiveness on the socialization process. In: Lucker GW, Ribbens KA, McNamara JA, eds. Psychological Aspects of Facial Form Craniofacial Growth Series Monograph No. 11. Ann Arbor, MI: University of Michigan Press; 1981:25–47. 2. Goldenhar M. Associations malformatives de l’oel et de l’oreille, en particular le syndrome dermoide epimoide epibulbaire-appendices auriculaires-fistula auris congenital et ses relations avec la dysostose mandibulofaciale. J Genet Hum. 1952;1:243–282. 3. Gorlin RJ, Jue KL, Jacobsen NP, Goldschmidt E. Oculoauriculovertebral dysplasia. J Pediatr. 1963;63:991–999. 4. Gorlin RJ, Cohen MM, Hennekam RCM. Syndromes of the Head and Neck. New York, NY: Oxford Press; 2001:790-798. 5. Cohen MM, Rollnick BR, Kaye CI. Oculoauriculovertebral spectrum: an updated critique. Cleft Palate J. 1989;26: 276–286. 6. Avon SW, Shively MD. Orthopedic manifestations of Goldenhar syndrome. J Pediatr Orthop. 1988;6:683–686. 7. Rollnick BR, Kaye CI, Nagatoshi K, Hauck W, Martin AO. Oculoauriculovertebral dysplasia and variants: phenotypic characteristics of 294 patients. Am J Med Genet. 1987;26: 361–375. 8. Grabb WC. The first and second branchial arch syndrome. Plast Reconstr Surg. 1965;36:485–508. 9. Connor JM, Fernandez C. Genetic aspects of hemifacial microsomia (Letter). Hum Genet. 1984;68:349. 10. Kelberman D, Tyson J, Chandler DC, et al. Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet. 2001;109: 638–645.

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CHAPTER 19 ❖ Pediatric Oral and Maxillofacial Surgery 10a. Stromland K, Miller M, Sjogreen L, et al. Oculo-auriculovertebral spectrum: associated anomalies, functional deficits and possible developmental risk factors. Am J Med Genet. 2007;143A:1317–1325. 11. Wieczorek D, Ludwig M, Boehringer S, Jongbloet PH, Gillessen-Kaesbach G, Horsthemke B. Reproduction abnormalities and twin pregnancies in parents of sporadic patients with oculo-auriculo-vertebral spectrum/Goldenhar syndrome. Hum Genet. 2007;121:369–376. 12. Online Mendelian Inheritance of Man (OMIM). Hemifacial microsomia: gene map. Available at: http://www.ncbi.nlm.nih .gov/Omim/getmap.cgi?l164210. Accessed February 6, 2008. 13. Poswillo DE. The pathogenesis of the first and second branchial arch syndrome. Oral Surg. 1973;35:302–329. 14. Poswillo DE. Otomandibular deformity: pathogenesis as a guide to reconstruction. J Maxillofac Surg. 1974;2:64–72. 15. Posnick JC. Craniofacial and Maxillofacial Surgery in Children and Young Adults. Philadelphia, PA: WB Saunders; 2000:419–445. 16. Caccamese JF Jr, Costello BJ, Mooney MP. A novel deformity of the mandible in oculoauriculovertebral spectrum: a case report and literature review. J Oral Maxillofac Surg. 2006;64:1278–1282. 17. Posnick J. Surgical correction of mandibular hypoplasia in hemifacial microsomia: a personal perspective. J Oral Maxillofac Surg. 1998;55:811–816. 18. Kaban LB, Moses MH, Mulliken JB. Surgical correction of hemifacial microsomia in the growing child. Plast Reconstr Surg. 1988;82:9–19. 19. Kaban LB, Padwa BL, Mulliken JB. Surgical correction of mandibular hypoplasia in hemifacial microsomia: the case for treatment in early childhood. J Oral Maxillofac Surg. 1998;56:628–638. 20. Kearns GJ, Padwa BL, Mulliken JB, Kaban LB. Progression of facial asymmetry in hemifacial microsomia. Plast Reconstr Surg. 2000;105:492–498. 21. Kaban LB, Mulliken JB, Murray JE. Three-dimensional approach to analysis and treatment of hemifacial microsomia. Cleft Palate Craniofac J. 1981;18:90–99. 22. Polley JW, Figeuroa AA, Liou E, Cohen M. Longitudinal analysis of mandibular asymmetry in hemifacial microsomia. Plast Reconstr Surg. 1997;99:328. 23. Stelnicki EJ, Boyd JB, Nott RL, Barnavon Y, Uecker C, Henson T. Early treatment of severe mandibular hypoplasia with distraction mesenchymogenesis and bilateral fibula flaps. J Craniofac Surg. 2001;12:337–348. 24. Padwa BL, Mulliken JB, Maghen A, Kaban LB. Midfacial growth after costochondral graft construction of the mandibular ramus in hemifacial microsomia. J Oral Maxillofac Surg. 1998;56:122–127. 25. Zhu S, Hu J, Li J, Ying B. Reconstruction of mandibular condyle by transport distraction osteogenesis: experimental study in rhesus monkey. J Oral Maxillofac Surg. 2006;64:1487–1492. 26. Polley JW, Figueroa AA. Distraction osteogenesis: its application in severe mandibular deformities in hemifacial microsomia. J Craniofac Surg. 1997;8:422–431. 27. Stucki-McCormick S. Reconstruction of the mandibular condyle using transport distraction osteogenesis. J Craniofac Surg. 1997;8:48–52. 28. Hijiki H, Takato T, Matsumato S, Mori Y. Experimental study of reconstruction of the temporomandibular joint using a

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bone transport technique. J Oral Maxillofac Surg. 2000;58: 1270–1276. Mommaerts MY, Nagy K. Is early osteodistraction a solution for the ascending ramus compartment in hemifacial microsomia? A literature study. J Craniomaxillofac Surg. 2002;30:201–207. McCarthy JG, Hopper RA, Hollier LH, Peltomaki T, Katzen T, Grayson BH. Molding of the regenerate in mandibular distraction: clinical experience. Plast Reconstr Surg. 2003;115:1239– 1246. Huisinga-Fischer CE, Vaandrager JM, Prahl-Andersen B. Longitudinal results of mandibular distraction osteogenesis in hemifacial microsomia. J Craniofac Surg. 2003;14:934-933. Kunz C, Brauchli L, Moehle T, Rahn B, Hammer B. Theoretical considerations for the surgical correction of mandibular deformity in hemifacial microsomia patients using multifocal distraction osteogenesis. J Oral Maxillofac Surg. 2003;61:364– 368. Chu TM, Hollister SJ, Halloran JW, Feinberg SE, Orton DG. Manufacturing and characterization of 3-D hydroxyapatite bone tissue engineering scaffolds. Ann NY Acad Sci. 2000;961:114–117. Costello BJ, Sfeir C, Kumta P. Regenerative medicine for craniomaxillofacial surgery. Oral Maxillofac Surg Clin North Am. 2010. In Press. Hendler BH, Silverstein KE, Giannakopolous H, Costello BJ. Mortised genioplasty in the treatment of obstructive sleep apnea: a historical perspective and modification of design. Sleep. 2003;5:173–180. Hendler BH, Costello BJ, Silverstein KE, Yen D, Goldberg A. An analysis of uvulopalatopharyngoplasty, genioglossus advancement and maxillo-mandibular advancement for the treatment of obstructive sleep apnea. J Oral Maxillofac Surg. 2001;59(8):892–897. Costello BJ, Posnick JC. The role of maxillofacial osteotomies in the treatment of obstructive sleep apnea. Curr Opin Otolaryngol Facial Plast Surg Sec. 2003;11(4):267–274. Obwegeser HL. Correction of the skeletal anomalies of otomandibular dysostosis. J Maxillofac Surg. 1974;2:73–92. American Cleft Palate Craniofacial Association (ACPA). Parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies. http://www.acpa-cpf. org/teamcare/Parameters07rev.pdf. Accessed July 14, 2008. Campbell A, Costello BJ, Ruiz R. Outcome research for cleft lip and palate—state of the art. Oral Maxillofac Surg Clin North Am. 2010. In Press. Costello BJ, Gungor A, Ruiz R. Cleft lip and palate. In: Meyers E, ed. Otolaryngology/Head and Neck Surgery. Philadelphia, PA: W.B. Saunders; 2008. White R. Progress report on third molar clinical trials. J Oral Maxillofac Surg. 2007;65(3):377–383. Blakey GH, Marciani RD, Haug RH, et al. Periodontal pathology associated with asymptomatic third molars. J Oral Maxillofac Surg. 2002;60:1227–1233. [PubMed] Phillips C, White RP Jr, Shugars D, Zhou X. Risk factors associated with prolonged recovery and delayed clinical healing after third molar surgery. J Oral Maxillofac Surg. 2003;61:1436– 1448. [PubMed] White RP Jr, Offenbacher S, Blakey GH, et al. Chronic oral inflammation and progression of periodontal pathology in the third molar region. J Oral Maxillofac Surg. 2006;64:880–885. [PubMed]

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46. Richardson DT, Dodson TB. Risk of periodontal defects after third molar surgery: an exercise in evidence-based clinical decision-making. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;100:133–137. [PubMed] 47. Murray CJL, Salomon JA, Mathers CD, Lopez AD, eds. (2002). Summary measures of population health: concepts, ethics, measurement and applications. Geneva: WHO. Available at http://www.who.int/pub/smph/en/index.html 48. Peterson LJ. Complex odontogenic infections. In: Peterson LJ, Ellis E, Hupp JR, Tucker MR, eds. Contemporary Oral and Maxillofacial Surgery. 4th ed. St. Louis, MO: Mosby, Inc., 2003:367–379. 49. Bonapart IE, Stevens HP, Kerver AJ, Rietveld, AP. Rare complications of an odontogenic abscess: mediastinitis, thoracic empyema, and cardiac tamponade. J Oral Surg. 1995;53: 610–613. 50. Brennan MT, Runyon MS, Batts JJ, et al. Odontogenic signs and symptoms as predictors of odontogenic infection. A clinical trial. J Am Dent Assoc. 2006;137:62–66. 51. Costello BJ, Papadopoulos H, Ruiz R. Pediatric craniofacial trauma. Clin Pediatr Emerg Med. 2005;6:32–40. 52. Posnick JC, Wells M, Pron GE. Paediatric facial fractures in children: evolving patterns of treatment. J Oral Maxillofac Surg. 1993;51:836–844. 53. Kaban LB, Mulliken JB, Murray JE. Facial fractures in children: an analysis of 122 fractures in 109 patients. Plast Reconstr Surg. 1977;59:15.

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54. Haug RH, Foss J. Maxillofacial injuries in the paediatric patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:126. 55. Sher AE, Schechtman KB, Picirillo J. The efficacy of surgical modifications of the upper airway in adults with obstructive sleep apnea syndrome. Sleep. 1996;19:156–177. 56. Prinsell JR. Maxillomandibular advancement surgery in a site-specific treatment approach for obstructive sleep apnea in 50 consecutive patients. Chest. 1999;116:1519–1529. 57. Prinsell JR. Maxillomandibular advancement surgery for obstructive sleep apnea syndrome. JADA. 2002;133:1489– 1497. 58. Riley RW, Powell NB, Guilleminault C. Obstructive sleep apnea syndrome: a review of 306 consecutively treated surgical patients. Otolaryngol Head Neck Surg. 1993;108:117–125. 59. Lee NR, Givens CD, Wilson J, Robins RB. Staged surgical treatment of obstructive sleep apnea syndrome a review of 35 patients. J Oral Maxillofac Surg. 1999;57:382–385. 60. Ruiz RL, Turvey TA, Costello BJ. Mandibular distraction osteogenesis in children. Oral Maxillofac Surg Clin North Am. November 2005;17(4):475–84. 61. Bell RB, Turvey TA. Skeletal advancement for treatment of medically refractory obstructive sleep apnea in children. Cleft Palate Craniofacial J. 2001;38(2):147–154. 62. Yellon RF. Epiglottic and base-of-tongue prolapse in children: grading and management. Laryngoscope. 2006;116:194–200.

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2

S E C T I O N

Ear and Related Structures Margaretha L. Casselbrant, David H. Chi, and Margaret A. Kenna

20

Embryology and Developmental Anatomy of the Ear

32

Congenital Inner Ear Anomalies

21

Physical and Physiologic Bases of Hearing

33

Cochlear Implants in Children

22

Methods of Clinical Examination: Ear and Related Structures

34

Congenital Anomalies of the External and Middle Ears

35

Surgical Management of Microtia and Congenital Aural Atresia

36

Diseases of the External Ear

37

Otitis Media and Eustachian Tube Dysfunction

38

Complications and Sequelae of Otitis Media

39

Facial Paralysis in Children

40

Diseases of the Labyrinthine Capsule

41

Injuries of the Ear and Temporal Bone

23 The Assessment of Hearing and Middle-Ear Function in Children 24

Methods of Examination: Radiologic Aspects

25 Vestibular Evaluation 26

Otalgia

27

Otorrhea

28 Tinnitus in Children

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29

Balance Disorders

30

Genetic Hearing Loss and Inner Ear Diseases

31

Nongenetic Hearing Loss

42 Tumors of the Ear and Temporal Bone

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20

C H A P T E R

Embryology and Developmental Anatomy of the Ear Nathan Page and Keiko Hirose

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nowledge of the normal development of the ear is essential to understand congenital and acquired ear diseases in children. A basic understanding of the developmental anatomy of the otic capsule and the branchial arch system are critical components of embryology of the ear. Anatomically, the ear is divided into the external ear, the middle ear, and the inner ear. The middle ear and the inner ear develop in the lateroinferior portion of the skull called the temporal bone. There is some disagreement among authors about the exact timing of different developmental events; the timing of such events given here is an attempt to represent the most current consensus. (See also Ch 42: Tumors of the Ear and Temporal Lobe, Ch 44: Nasal Physiology, and Ch 48: Epistaxis.)

EXTERNAL EAR The external ear is divided into the pinna, or auricle, and the external auditory canal (EAC). During the fourth week of gestation, the pinna begins development from first (mandibular) and second (hyoid) branchial arch mesoderm surrounding the first branchial cleft.

During the fifth and sixth weeks, this mesoderm gives rise to six outgrowths, the hillocks of His, which condense and fuse by the third month to form the pinna. The first three hillocks derive from the mandibular arch, and the second three from the hyoid arch. There is controversy over the exact adult structures that form from these hillocks. One view asserts that the tragus is derived from the first arch consisting of the first three hillocks of His, while the rest of the pinna, with the exception of the concha, is derived from the second arch, consisting of the second three hillocks.1 A second, more widely accepted theory is that the first hillock gives rise to the tragus, the second forms the crus of the helix, the third forms the majority of the helix, the fourth becomes the antihelix, the fifth produces the antitragus, and the sixth gives rise to the lower helix and lobule.2 The concha is derived from ectoderm from the first branchial groove. Initially, the developing pinna is located caudal to the mandibular area, but by the 20th fetal week, as the mandible grows and develops, the pinna migrates cephalad to attain the adult configuration and location (Fig. 20-1A and B). In a child aged 4–5 years, the pinna is approximately 80% of the adult size; in a 9-year-old child, the pinna has attained complete adult size. In a newborn, the

FIGURE 20-1. Auricular development and anatomy. A, Fetus (5 mm); branchial arch development is evident. B, First and second branchial arches in an 11 mm fetus. Six hillocks are present; hillocks 1, 2, and 3 are from the first (mandibular) arch; hillocks 4, 5, and 6 are from the second (hyoid) arch. C, Newborn auricle: adult configuration but smaller. D, Auricle, fully developed, showing the hillocks’ relationship to anatomy. E, Auricle fully developed, showing anatomic parts. (Adapted from Anson B, Donaldson J. Surgical Anatomy of the Temporal Bone and Ear, 2nd ed. Philadelphia, PA: WB Saunders; 1973:31.)

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cartilage of the pinna is soft and pliable, with relatively more chondrocytes and an immature matrix. In a 9-year-old child, the cartilage is firmer and histologically mature. The Darwinian tubercle, which corresponds to the tip of the pinna in lower animals, appears at roughly six months of gestation.3 The postnatal anatomy of the pinna is shown in Figures 20-1C–E. Anteriorly the skin is firmly adherent to the elastic cartilage of the pinna, with an absence of subcutaneous tissue, while posteriorly the skin is separated from the cartilage by a distinct subcutaneous layer. The lobule is devoid of cartilage and contains only fibrous tissue and fat. Three extrinsic muscles (the anterior, superior, and posterior auricular muscles) attach the pinna to the scalp and the skull. These muscles, when well developed, can move the auricle as a whole. In humans, there are several intrinsic auricular muscles that are indistinguishable grossly and are functionally insignificant. The EAC develops from the first branchial groove between the mandibular and hyoid arches. At four to five weeks of gestation, a solid core of epithelial cells, derived from the ectoderm of the first groove, comes into contact with the endoderm of the first pharyngeal pouch, in the area of the tympanic ring. Then, mesoderm grows between the ectoderm and the endoderm, and the contact is disrupted. At eight weeks, the cavum conchae (first branchial groove) deepens, forming a funnel-shaped tube, the primary meatus, that becomes surrounded by cartilage and eventually becomes the fibrocartilaginous portion of the adult EAC, comprising the outer one-third of the ear canal. During the ninth week, the groove deepens, grows toward the middle ear, and comes into contact with the epithelium of the first pharyngeal pouch. A solid epidermal plug extends inward from the primary meatus to the primitive tympanic cavity, forming the meatal plate. Next, mesenchyme forms between epithelial cells of the tympanic cavity and the meatal plate to become the fibrous layer of the tympanic membrane (TM), and at nine weeks, this is surrounded by the four membrane bone ossification centers of the tympanic ring.3 Fig. 20-2 demonstrates this complicated process in the mouse embryo (in which these events occur earlier in gestation than in humans), whereas Fig. 20-3 demonstrates the anatomy at nine weeks of gestation in the human. During the 21st fetal week, the cord of epithelial cells begins to resorb, forming a canal. By the 28th week, the deepest cells of the ectodermal plug remain, forming the superficial layer of the TM. The medial two thirds of the EAC is derived from the new ectodermal tube and becomes the bony portion of the canal.2,4 If the resorption process stops prematurely, an atretic or very stenotic membranous canal may result, with a more normally developed bony ear canal, TM, and middle and inner ear. At birth, the EAC is not ossified, except for the tympanic ring, and is not of adult size. Completion of ossification occurs by the second year of life, and adult size is reached by age 9 years. After ossification, the lateral one-third of the ear canal is cartilaginous; the medial two thirds is bony. The skin

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FIGURE 20-2. Diagrammatic presentation of the development of the external auditory meatus and meatal plate in (A) 13-day old, (B) 15-day old, and (C) 19-day old mouse embryos. Initially (13th day), the epidermal histology of the adjacent, nonotic skin (ADJ) is the same as that lining the external auditory meatus (EAM) and over the presumptive pinnal tissues (PPEs). By the 15th day, the tubotympanic sulcus (TTS) has grown dorsal from the pharyngeal pouch (I); its endodermal lining approaches the presumptive meatal plate (FMP). The lumen of the latter may still be patent distally, but its epidermis, like that of the meatus, bears only a single layer of superficial peridermal cells, while that of the pinna (PPE) and the adjacent skin now have several layers of peridermal cells. By 19 days, the lumen of the external meatus and the enlarged meatal plate (MMP) have become completely occluded. The epidermis of the pinna and the adjacent skin show the first signs of cornification beneath the multilayered periderm, whereas the meatal plate appears as a simple plate but is in fact two younger epidermis lying en face. The star indicates the approximate location of the presumptive tympanic tissues, which lie between the meatal plate and the developing middle ear cavity (MEC). CPE, cornified peridermal epithelium.

FIGURE 20-3. Development of the meatus and meatal plate in relation to tympanic cavity at 9 weeks’ gestation. (Redrawn from English GM, ed. Otolaryngology, Vol. I. Diseases of the Ear and Hearing. Philadelphia, JB Lippincott, 1988, p. 12.)

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CHAPTER 20 ❖ Embryology and Developmental Anatomy of the Ear of the cartilaginous portion contains hair follicles and sebaceous and ceruminous glands. The intrinsic and extrinsic auricular muscles are innervated by the seventh cranial (facial) nerve. The nerve supply to the medial portion of the EAC is from the auriculotemporal (mandibular branch of the trigeminal) nerve. The nerve supply to the posterior ear canal and the area around the TM proceeds from Arnold’s nerve, the only cutaneous branch of the vagus (tenth cranial) nerve. Arterial supply to both the pinna and the EAC is from the superficial temporal and posterior auricular arteries.5

TYMPANIC MEMBRANE The TM develops from structures associated with both the external ear and the middle ear. At four to five weeks of gestation the primitive TM is represented by the area of contact between the ectodermal meatal forming the external auditory meatus (first branchial groove) and the lateral end of the endodermal tubotympanic recess (first pharyngeal pouch). At eight weeks, mesodermal tissue grows between the first pharyngeal pouch and the first branchial groove. The mesoderm thins out in the area of the meatal plate and becomes the fibrous layer of the TM. The fibrous layer consists of outer radial fibers and inner circular fibers. At 21 weeks, the epidermal plug (ectodermal cord) begins to resorb, forming the EAC. The most medial portion of this plug becomes the lateral layer of the TM. The completed TM has three layers: (1) an outer epithelial layer, from ectoderm of the first branchial groove; (2) a middle fibrous layer, from the mesoderm in between the first groove and the first pouch; and (3) an inner mucosal

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layer, derived from endoderm of the tympanic cavity, derived in turn from the first pharyngeal pouch. The TM inserts into the tympanic ring, which is formed during the ninth week, from four membrane ossification centers. These centers fuse and grow rapidly; the development of the tympanic ring is nearly complete by 16 weeks, with maximal growth in diameter attained in the term fetus.6 The ring is deficient at the superior cranial aspect, the notch of Rivinus. During the first postnatal year, the tympanic ring extends laterally, completing the formation of the bony EAC, the sheath of the styloid process, and the non-articular part of the glenoid fossa. By the end of the first postnatal year, two prominences found on the ventral portion of the ring have grown and fused, dividing the previous space into the adult EAC and the inferior foramen of Huschke. This foramen, except in rare instances of agenesis, closes with continuing growth of bone. At birth, the TM is almost adult sized and is nearly horizontal; however, it becomes more vertical with development of the EAC.7 The mature TM consists of two parts, the pars tensa and the pars flaccida. The pars flaccida is located superiorly, over the notch of Rivinus and the epitympanum, and is composed of only a lateral squamous and a medial mucosal layer. The pars tensa, constituting most of the TM, overlies the middle ear and is composed of all three layers: squamous, fibrous, and mucosal (Fig. 20-4). Laterally, innervation to the TM is the same as that to the EAC. Medially, innervation is supplied by the tympanic branch of the ninth nerve. Laterally, the blood supply is from the deep auricular branch of the internal maxillary artery, whereas medially it is supplied by the stylomastoid branch of the posterior auricular artery and the anterior tympanic branch of the internal maxillary artery.

FIGURE 20-4. Tympanic membrane development. A, Newborn: the tympanic membrane is almost horizontal. The lateral process of the malleus is most prominent. The pars flaccida is thicker and more vascular. B, Adult: the tympanic membrane is more vertical. The lateral process of the malleus is less prominent. The manubrium of the malleus is more vertical. The pars flaccida appears less vascular.

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MIDDLE EAR The middle ear consists of the TM, the tympanic cavity, three ossicles, two muscles, several tendons, and the eustachian tube. Connection to the mastoid bone is via the aditus ad antrum from the middle ear. The eustachian tube connects the middle ear to the nasopharynx. During the third week of gestation, expansion of the first (and, in some sources, the second) pharyngeal pouch, lined with endoderm, forms the tubotympanic recess. During weeks 4–6, there is progressive expansion; this expansion begins at the inferior aspect of the definitive tympanic cavity and progresses by invading the adjacent, loosely organized mesenchyme.3 At week 7, constriction of the midportion of the recess by the second branchial arch leads to the formation of the eustachian tube (medially) and the tympanic cavity (laterally). The terminal end of the first pharyngeal pouch divides into four sacci: anticus, posticus, superior, and medius, which progressively expand to pneumatize the middle ear and epitympanum. These four sacs become distinct anatomic areas. The saccus anticus becomes the anterior pouch of Tröltsch. The saccus medius develops into the epitympanum and petrous area. The saccus superior becomes the posterior pouch of Tröltsch, the inferior incudal space, and part of the mastoid. The saccus posterior becomes the round window, the oval window, and the sinus tympani. This expansion of the sacci also envelops the ossicles and lines the tympanomastoid compartment; the junction of two sacci gives rise to mucosal folds that transmit blood vessels. At about week 18, the epitympanum, which leads into the antrum and the mastoid, forms from an extension of the tympanic cavity. During the development of the tympanic cavity, differentiation of mesenchymal tissue above, medial to, and posterior to the tympanic cavity produces the ossicles, muscles, and tendons of the middle ear. Eventually, these structures will extend into the cavity and will be covered by the epithelial lining of the cavity, derived from the end of the first pharyngeal pouch.2

There are two middle-ear muscles. The tensor tympani and its tendon are derived from mesoderm of the first branchial arch; innervation is by the mandibular branch of the trigeminal nerve. This muscle is contained in a bony semicanal above the eustachian tube and attaches via the tendon to the manubrium of the malleus. The stapedius muscle is derived from mesoderm of the second arch and is innervated by the seventh cranial nerve. This muscle originates from the pyramidal eminence and inserts via its tendon onto the neck of the stapes. The roof of the tympanic cavity, the tegmen tympani, is formed laterally by an extension of the otic capsule and medially by fibrous tissue. This roof becomes ossified at the beginning of the 23rd week of gestation. The anterior epitympanic wall and part of the lateral tympanic cavity are formed from the tympanic process of the squamous portion of the temporal bone.7 One view holds that the main part of the floor of the middle ear is formed from an offshoot of the petrous pyramid; another view theorizes that the floor of the middle ear arises from a separate bone formed between the pyramid and the tympanic ring. During development, the tympanic cavity is filled with mucoid mesenchymal tissue. Beginning of the third month, this tissue becomes looser and vacuolated, allowing expansion of the tympanic cavity. During this expansion, the ossicles, muscles, and tendons become wrapped with tympanic cavity epithelium (Fig. 20-5). It may take one year, or even longer, for all mesenchymal tissue to resorb, and remnants of embryonic connective tissue may be evident as strands of tissue draped over the oval and round window in the adult. By the 30th week, expansion of the tympanic cavity is complete, followed 4 weeks later by that of the epitympanum. Pneumatization starts at approximately the 30th week and is nearly complete at birth. Many factors, including heredity, environment, nutrition, infection, and adequate ventilation, may play a role in the marked variability of temporal bone pneumatization.4

FIGURE 20-5. A and B, Expansion of the middle ear. (From Anson BJ, Davies J. Embryology of the ear. In: Paparella MM, Shumrick DA, eds. Otolaryngology, Vol. I, 2nd ed. Philadelphia, PA: WB Saunders; 1980:11.)

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Ossicles There are three middle-ear ossicles: the malleus, the incus, and the stapes. They are formed from the mesenchyme of the mandibular and the hyoid arches and from the otic capsule (stapes only). Specifically, the head of the malleus, and the short crus and body of the incus, arise from the mandibular arch. The manubrium of the malleus, the long process of the incus, and the head, neck, crura, and tympanic surface of the footplate of the stapes arise from the hyoid arch. The medial surface of the stapedial footplate and the annular stapedial ligament arise from the otic capsule. At 4.5 weeks, the mesenchyme of the second arch forms the blastema, which is then divided by the seventh nerve into the stapes, interhyale, and laterohyale. The stapes ring forms around the stapedial artery during weeks 5–6, and otic capsule mesenchyme appears, forming the medial footplate and the annular ligament. At 8.5 weeks, the incudostapedial joint forms. During the 10th week, the shape of the stapes changes from that of a ring to that of a stirrup. The interhyale forms the stapedius muscle and tendon, and the laterohyale becomes the posterior wall of the middle ear. The laterohyale also joins with the otic capsule to partially form the

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anterior wall of the facial canal and the bone of the stapedial pyramid. All three ossicles begin to develop during the fourth to sixth fetal weeks. During the next 3–4 weeks, the mesenchyme develops into cartilaginous models of the ossicles. The models for the incus and the malleus grow to adult size by 15 weeks; the model for the stapes reaches full size by 18 weeks. The incus and the malleus, which start as a single mass, separate, and the malleoincudal joint is formed at eight to nine weeks. Ossification of the malleus and the incus begins at 15 weeks and appears first at the long process of the incus. Remodeling of the bone of the incus and the malleus continues throughout postfetal life. Ossification of the stapes begins at week 18. There is no remodeling of the fetal bone of the stapes during postfetal life. At birth, all the ossicles are of adult size and shape. When the mesenchyme resorbs and the ossicles are free, the endodermal epithelium of the tympanic cavity connects the ossicles to the cavity wall in a mesenterylike manner. The supporting ossicular ligaments develop in these epithelial connections (Fig. 20-6)7,2,4 Fig. 20-7 shows the overall fate of the first and second branchial arches, with reference to the ossicles and surrounding structures.

FIGURE 20-6. Ossicular development. A, Fetus at 2 months: the cartilaginous ossicles are recognizable. B, Fetus at 3 months. C, Fetus at 4 months: attaining adult configuration but cartilaginous. D, Fetus at 6 months: adult configuration and size; ossification begins. E, Adult ossicles. (Adapted from Anson BJ, Davies J. Developmental anatomy of the ear. In: Paparella MM, Shumrick DA, eds. Otolaryngology, Vol. I, 2nd ed., Philadelphia, PA: WB Saunders;1980:8.)

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FIGURE 20-7. Structures derived from the branchial arch system. The diagram shows the contributions to adult anatomy of the head and neck from Meckel’s and Reichert’s cartilages: the first (mandibular) and second (hyoid) arches, respectively. These are listed with a drawing of an infant head.

Tympanic Antrum, Mastoid Air Cells, and Related Spaces The antrum is usually the largest and, in poorly pneumatized mastoids, often the only identifiable air cell in the mastoid air cell system. The antrum appears as a lateral extension of the epitympanum at 21–22 weeks. The lumen of the antrum is well developed by the 34th week, and its pneumatization is complete during the first year of life. In the adult, nearly all parts of the temporal bone are extensively pneumatized, including the zygoma, squama, petrous apex, and jugular wall areas. Air cell formation is usually completed during postfetal life but may continue into old age. Pneumatization of the petrous pyramid, which is highly variable, begins at approximately the 28th fetal week, whereas pneumatization of the mastoid air cells starts at the 33rd week. The mastoid itself is formed when the bone of the antrum and the tympanic plate expand, with air cells formed by the extension of epithelium from the antrum into the developing mastoid bone area. In the infant, the antrum is nearly adult sized, and the bulge of the lateral semicircular canal can be seen in its floor. The pattern of mastoid pneumatization is generally symmetric; however, it is highly variable among individuals. The mastoid process appears at the age of 1 year. The various forms of otitis media are often found to be associated with poorly pneumatized mastoids; however, the cause and effect relationship between these two findings

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is controversial. Currently, it is thought that mastoid air cell development can be hindered by early and repeated middleear disease.8,9 Heredity may also play a role in the extent of mastoid pneumatization.

Temporal Bone There are four parts to the adult temporal bone: petrous, squamous, tympanic, and mastoid; however, only the petrous, squamous, and tympanic parts have formed at birth. The squamous and tympanic portions form by membranous bone development. The squamous portion begins to develop at approximately week 8, and the tympanic during weeks 9–10. The petrous portion is formed from cartilage (endochondral bone) of the periotic capsule, with ossification starting in the sixth month. All portions of the temporal bone, except the petrous, continue to develop in postfetal life. The mastoid bone develops primarily after birth, with a mastoid process evident by the age of 1 year and well developed by age 3 years. Mastoid development is mainly lateral and posterior to the antrum. After birth the styloid process is formed from ossification of the mesoderm in the upper part of the second arch. At birth, the middle-ear cavity is approximately adult sized, as are the oval and round windows and the TM. The malleus, incus, and stapes reach adult size by the sixth month of gestation. At birth, the eustachian tube is about 1.7 cm

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CHAPTER 20 ❖ Embryology and Developmental Anatomy of the Ear long, about half as long as in the adult. It is fairly horizontal, with the pharyngeal opening at the level of the hard palate. With growth, the tube angles downward, with the opening at the level of the inferior nasal turbinate by the age of 6 years. During the newborn period and infancy, the lateral surface of the temporal bone differs from that in the adult. There is no bony ear canal, except superiorly, and no mastoid process. The facial nerve is very superficial as it emerges from the stylomastoid foramen behind the tympanic membrane, and can be injured by obstetric forceps or the usual posterior auricular incision used in mastoid surgery.3 The lateral surface anatomy of the temporal bone is important surgically. In postnatal life, the spine of Henle marks the posterosuperior aspect of the external ear canal, and the antrum is usually found medial to the spine. In the infant, the bone over the antrum is cribriform, allowing infection to extend subperiosteally, with posterior auricular edema, erythema, and abscess formation. The temporal line, the inferior margin of the temporal muscle, marks the approximate level of the middle fossa. There are two suture lines in the bony external canal: the tympanomastoid posteriorly and the tympanosquamous superiorly. The surgeon uses these suture lines as landmarks when making incisions in the EAC. The mandibular fossa, involved in articulation of the condyle of

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the mandible, is a concavity on the inferior surface of the squamous part of the temporal bone (Fig. 20-8).

Facial Nerve The facial nerve (seventh cranial nerve) is the nerve of the second branchial arch. At the end of the third gestational week, a collection of cells, the acousticofacial ganglion (also called the crest or primordium), can be identified as an aggregation of neural crest cells dorsolateral to the rhombencephalon and rostral to the otic placode. By the end of the fourth week, the facial and acoustic portions of the primordium have become more distinct. The facial division extends ventrally to a thickened area of surface ectoderm, the epibranchial placode, located on the upper surface of the second branchial arch. During the fifth week, the neuroblasts of the geniculate ganglion appear in the facial portion of the primordium, in the area where the placode and the neural crest cells are contiguous. Next, the distal portion of the primordium divides equally, with one portion going caudally into the second arch mesenchyme and eventually becoming the main facial nerve trunk. The other division extends rostrally into the first arch and becomes the chorda tympani nerve (at five weeks). The terminal branches of the chorda tympani end in the same

FIGURE 20-8. Lateral temporal bone development. A, Newborn: the petrous, squamous, and tympanic portions are present; the mastoid portion is not developed. The stylomastoid foramen (exit of the facial nerve) is just behind the tympanic ring. B, Infant, 1.5-years old: mastoid development is under way. The stylomastoid foramen can still be exposed and is not covered by the mastoid process. The tympanic ring is ossifying. C, Child, 5 years: the mastoid process is well developed and covers the stylomastoid foramen. The tympanic ring has completely ossified, and the entire bony EAC is osseous. D, Adult: normal anatomy.

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region that the lingual nerve (termination of a branch of the mandibular nerve) ends in; there the two nerves unite just proximal to the submandibular ganglion by the end of the seventh week.10,2,4 A 1994 study by Gasser et al. notes that the formation of the ear and associated facial nerve can be divided into three developmental time periods: (1) the blastemal phase, in which ear structures are surrounded by mesenchyme; (2) the cartilaginous phase, during which the mesenchyme transforms into the cartilaginous otic capsule; and (3) an osseous phase, with bone replacing cartilage.11These authors suggest that the course of the facial nerve is well established during the blastemal phase and is essentially set by the end of the embryonic period (57 days). The facial motor nucleus develops separately from the acousticofacial primordium and is derived from neuroblasts in the upper portion of the rhombencephalon. The motor nuclei of the sixth and seventh cranial nerves develop in close proximity in the pons, which explains the involvement of both the sixth and seventh nerves in the congenital Moëbius syndrome as well as the findings in other neoplastic, inflammatory, and vascular disorders. The sensory nervus intermedius develops from the geniculate ganglion at 7 weeks of gestation and extends to the brain stem between the motor root of the seventh and eighth nerves. The greater superficial petrosal nerve, the second branch of the seventh nerve to develop, comes from the most ventral part of the geniculate ganglion at about five weeks. The branch to the stapedius muscle develops at about eight weeks, and geniculate ganglion development is completed by week 15. This separate development of the sensory and motor parts of the seventh nerve allows patients with congenital facial paralysis to have intact sensation and taste. The seventh nerve is located in the facial canal, which develops as a sulcus on the lateral aspect of the otic capsule by the eighth fetal week. The future canal is still cartilaginous and contains the stapedius muscle, the facial nerve, and blood vessels. Closure of the canal is nearly complete by the seventh month. At birth, facial nerve development is complete. The fully developed facial nerve originates from the facial nucleus, leaving the brain stem at the inferior border of the pons between the olive and the inferior cerebellar peduncle. It enters the internal acoustic meatus (internal auditory canal) accompanied by the nervus intermedius and travels in a bony canal, the fallopian canal, laterally to the geniculate ganglion. The greater and lesser superficial petrosal nerves diverge at this point, and the remainder of the facial nerve turns posteriorly and traverses the middle ear, still in the bony canal. The facial nerve lies just above the oval window niche and, at the pyramidal eminence, turns again to take a vertical, or mastoid, course. There the nerve is located just lateral and inferior to the lateral semicircular canal, and finally exits from the stylomastoid foramen at the anterior end of the digastric groove. The chorda tympani nerve leaves the facial nerve in the vertical mastoid portion, passing in its own canal to the

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posterior iter. There it passes lateral to the long process of the incus and medial to the malleus handle to the anterior iter, entering the anterior petrotympanic fissure (canal of Huguier) to leave the middle ear.12 In as many as 55% of cases, the bony facial canal is found to be dehiscent in part of its course, most commonly in the horizontal portion.10,13 Gerhardt and Otto have suggested that the course of the facial nerve in the middle ear may influence the development of the ossicles, including malformations.14 For example, if the facial nerve overlies the footplate, the stapes may be malformed, or even atretic. There are several important spaces and landmarks in the completed, adult form of the middle ear. The canal of Huguier, already mentioned, is in the anterior middle ear and contains the chorda tympani nerve. The ponticulus is the bony ridge between the oval window and the sinus tympani; the subiculum is the bony ridge between the round window niche and the sinus tympani. The sinus tympani is bounded medially by the bony labyrinth, laterally by the pyramidal eminence, superiorly by the lateral semicircular canal and ponticulus, inferiorly by the subiculum and the jugular wall, and posteriorly by the posterior semicircular canal. The facial recess is bounded medially by the facial nerve, laterally by the bony tympanic annulus and chorda tympani, and superiorly by the short process of the incus. When middle-ear cholesteatoma is present, both the facial recess and the sinus tympani can be involved; cholesteatoma can be very difficult to detect and remove from these areas. On the anterior medial wall of the middle ear is the cochleariform process, the curved end of the tensor tympani semicanal; in revision mastoid surgery, this may be one of the few safe remaining landmarks.

INNER EAR The inner ear is in the petrous portion of the temporal bone and consists of a membranous labyrinth inside a bony labyrinth. At birth, it is adult in size and configuration except for changes in the periosteal layer of the bony labyrinth and continued postfetal growth of the endolymphatic sac and duct.

Membranous Labyrinth The adult membranous labyrinth consists of the utricle, saccule, semicircular ducts, endolymphatic sac and duct, and cochlear duct. It is housed in the bony labyrinth, contains endolymph, and is bathed by perilymph. The membranous labyrinth develops from surface ectoderm at the end of the third week of gestation. An area of plaquelike thickening appears on the lateral aspect of the neural fold dorsal to the first branchial groove and in close relation to the hindbrain (rhombencephalon). During the fourth week, the placode invaginates to become the auditory pit, and then the auditory vesicle (otocyst). During this process, it becomes surrounded by mesenchyme that will become the cartilaginous capsule of the otocyst (otic capsule).15 The auditory vesicle becomes divided into two pouches by threefolds: the

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CHAPTER 20 ❖ Embryology and Developmental Anatomy of the Ear ventral (cochlear, pars inferior) pouch will form the saccule and the cochlear duct, and the dorsal component (vestibular, pars superior) will give rise to the utricle, the semicircular ducts, and the endolymphatic duct. As differentiation of the membranous labyrinth progresses, the adult configuration is recognizable by 10 weeks of fetal life, and the membranous labyrinth without the end organ is complete by 6 months of fetal life (Fig. 20-9). However, the endolymphatic sac and duct continue to grow after birth, in conjunction with the rest of the temporal bone and with the enlargement of the posterior cranial fossa. Utricle and Saccule The utricle and the saccule are otolithic organs. The utricle is sensitive to linear acceleration, but the function of the saccule in humans is unclear. The utricle is derived from the dorsal (vestibular) pouch of the auditory vesicle, while the saccule comes from the ventral (cochlear) pouch. The utricle, saccule, and endolymphatic duct begin to develop at about week 6 of gestation and have an adult configuration by week 8. The ductus reuniens, which connects the saccule to the cochlear

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duct, forms at about seven weeks. A Y-shaped duct connects the utricle to the saccule and is composed of the utriculoendolymphatic duct and the sacculoendolymphatic duct. Neuroepithelial cells develop in the maculae of the saccule and the utricle and the cristae ampullaris of the semicircular canals (Fig. 20-10). By week 11 of gestation, development of this neuroepithelium and the supporting cells is complete. These areas of sensory epithelium secrete a gelatinous substance that becomes the otolithic membranes of the cristae. This gelatinous substance contains rhombic crystals of calcium carbonate called otoconia. The macula of the saccule lies in the vertical plane on the medial wall, whereas the macula of the utricle lies on the anterolateral wall, perpendicular to the saccular macula. The primary receptor cells in the maculae are Types I and II hair cells (Fig. 20-11). Cilia from these sensory cells extend upward into the otolithic membrane which contains the otoconia. The hair cells are surrounded by columnar supporting cells. The utricle and the saccule are both contained in the vestibule of the inner ear. The utricle is ovoid and flattened, with a rounded end that occupies the elliptic recess of the

FIGURE 20-9. Development of the membranous labyrinth. A, Fetus at 5 weeks: development of ventral (cochlear) and dorsal (vestibular) pouches. B, Fetus at 6 weeks: rapid growth. C, Fetus at 2.5 months: adult structures easily recognizable. The cochlea has attained its 2.5 turns; the semicircular canals, utricle, saccule, and endolymphatic sac and duct are well developed. D, Fetus at 6 months: membranous labyrinth development is complete, except that the endolymphatic sac and duct continue to grow during infancy. E, Adult: fully developed labyrinth. (Adapted from Anson BJ, Davies J. In: Paparella MM, Shumrick DA, eds. Otolaryngology, Vol. I, 2nd ed. Philadelphia, PA: WB Saunders;1980:14. After Bast TH, Anson BJ. The Temporal Bone and Ear. Springfield, IL: Charles C Thomas;1949.)

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FIGURE 20-10. Otolithic membrane and hair cells of utricular macula. The vestibular hair cells are mechanotransducers that convert linear acceleration and static tilt into electrical impulses carried along the eighth nerve. The stereocilia on the apical surface of the hair cells are embedded in a gelatinous matrix that contains otolithic crystals on the surface. (From Furman and Cass.37)

anteroinferior portion of the vestibule, near the oval window footplate, and connects to the cochlea via the ductus reuniens. The utricle connects posteriorly with the semicircular canals and anteriorly with the saccular and endolymphatic ducts. 5

FIGURE 20-11. Development of the otocyst. A. Cross section through the embryo during development of the otic placode as a thickening on the ectodermal membrane. B. The otic placode pinches off to form the otic vesicle (purple). C. Neuroblasts (yellow) which give rise to the statoacoustic ganglion develop from the anteroventral surface of the otocyst. D. The otocyst transforms to create the early endolymphatic ducts (ED) on the dorsal surface and the cochlear duct (CD) on the ventral side. E. The cochlea duct begins to coil and semicircular canals (SSC) begin to form. Sensory patches are drawn in green. Periotic mesenchymal cells (pink) condense around the developing membranous labyrinth to form the bony labyrinth. (From Barald and Kelley.17)

posterosuperior vestibule. The semicircular canals open into its posterior wall, and the utriculosaccular duct opens into it anteriorly. The saccule, smaller and rounded, is in the

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Endolymphatic Duct and Sac The endolymphatic duct and sac develop from the dorsal component of the otocyst at about 6 weeks of gestation, and growth continues in postfetal life. The fully developed duct lies mainly in the vestibular aqueduct, is surrounded by perilymph and periotic tissue, and is connected to the utriculosaccular duct. At its distal end lies the endolymphatic sac, in a fossa on the posterior portion of the petrous temporal bone. The duct’s two main functions are endolymph absorption and pressure equalization between the cerebrospinal fluid and the endolymphatic systems. Semicircular Canals During week 6 of gestation, the semicircular canals begin to develop from the dorsal component of the otic vesicle. The superior canal develops first, followed by the posterior and then the lateral. During week 7, a ridge-like structure, the crista ampullaris, composed of neuroepithelial cells, develops at the dilated, or ampullary, end of each semicircular duct. The ampullated end of each canal opens into the utricle, while the nonampullated end of the posterior and superior canals fuse to form the common crus, which opens into the middle portion of the utricle. The nonampullated end of the

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CHAPTER 20 ❖ Embryology and Developmental Anatomy of the Ear lateral duct opens separately into the utricle. By week 11, the neuroepithelium and supporting cells of the cristae are complete. The superior semicircular duct reaches maximal growth by week 19, followed by the posterior canal. The lateral canal reaches maximal growth by the 22nd week. Like the macula, the cristae contain both Types I and II hair cells with cilia that extend upward into the cupula. The cupula is a gelatinous mass of mucopolysaccharides within a keratin framework and forms a partition, across the ampulla (Fig. 20-12). Cochlear Duct and Organ of Corti During the sixth week of gestation, the cochlear duct develops from the ventral (saccular) pouch of the auditory vesicle. At week 7, one turn of the cochlea is formed, and by week 8, the entire 2.5–2.75 turns have been completed. The narrow tube connecting the cochlear duct to the saccule is called the ductus reuniens. The organ of Corti arises in the wall of the cochlear duct. The epithelium in the area of the future organ of Corti differentiates into two ridges of tall columnar cells that extend the entire length of the cochlear duct. The cells of these ridges secrete a gelatinous substance that becomes the tectorial membrane. The larger, inner ridge becomes the spiral limbus, and the outer, smaller ridge the organ of Corti. At the 22nd week, this

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outer ridge develops inner and outer hair cells, pillar cells, and Hensen cells. Differentiation of the inner and outer ridges begins at the basal turn of the cochlear duct and spreads to the apex. At week 8, the stria vascularis begins to develop in the external wall of the cochlear duct; it is well developed by week 20. The organ of Corti completes its development during the fifth month of gestation, with the tunnel of Corti and the spaces of Nuel being formed at the 26th week. The organ of Corti contains the sensory epithelium for hearing, which consist of hair cells and supporting cells. The afferent fibers of the auditory (eighth) nerve and the efferent fibers of the olivocochlear bundle enter the organ of Corti from beneath the basilar membrane and innervate the hair cells. The sensory cells are of two types, the inner and the outer hair cells, so named because of the cells’ relative proximity to the tunnel of Corti (located medially in the spiral cochlea). Each cell has a stereocilia bundle extending from its apical surface, and each cell surface contains a small region without the presence of a cuticular plate that indicates where a kinocilium was located during development. The supporting cells are known as Deiter, Hensen, Claudius, and Boëttcher cells, the inner border cells, the inner phalangeal cells, the inner and outer pillar cells, and the outer sulcus cells (Fig. 20-13). In the adult, the cochlear duct extends from the cochlear recess of the vestibule and ends in a blind pouch, the

FIGURE 20-12. Type I and type II hair cells. Both type I and type II hair cells are found in the vestibular organs. The type I hair cells is more flask shaped and has a cup-like contact with the afferent nerve fiber. The efferent terminals form synapses with the afferent terminals, but not directly on the type I hair cell itself. The type II hair cell is more elongated and thin and has both afferent and efferent terminals which directly contact the basolateral surface of the hair cell. (From Schwarz,39 p. 2681.)

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SECTION 2 ❖ Ear and Related Structures layers of cells are joined by tight junctions, which prevent the free mixing of perilymph and endolymph, although selective transport does occur.16 The basilar membrane is suspended between the spiral limbus and the spiral ligament. The organ of Corti overlies the basilar membrane. The establishment of the cochlear prosensory domain is the initial step in the development of the organ of Corti. Several molecules are important for formation and specification of the prosensory domain, including BMP4, Sox2, Notch, Tbx1, and the Fgf family. In addition, pRb and several cyclin kinase inhibitors (p27kip1, p21cip1, p19ink4d) regulate progenitor cell number within the prosensory domain, eliminating the need for later apoptosis of unneeded progenitors often seen in neuronal development. The prosensory cells develop into each cell type in the organ of Corti. The transcription factor Atoh1 is critical in the commitment of these progenitor cells to hair cells.17

Audiovestibular Nerve

FIGURE 20-13. Crista ampullaris, cupula, and ampullary nerve. The crista ampullaris is an enlarged portion of the end of each semicircular canal where the hair cells that encode angular acceleration are located. Within the crista of each semicircular canal, there is a cupula, or a membrane that deforms when there is acceleration in the plane of the semicircular canal. This deformation of the membrane stimulates the hair cell, and the nerve firing rate changes to account for the angular acceleration in the given plane. (From Schwarz,39 p. 2681.)

cupular cecum, at the apex. At its basal end, the small ductus reuniens communicates with the saccule. In the completed state, the cochlear duct is triangular and divides the bony cochlear canal into three separate compartments: the scala media (cochlear duct); the scala vestibuli, adjoining the Reissner membrane; and the scala tympani, adjacent to the basilar membrane. The scala media contains endolymph, and both the scala tympani and scala vestibuli contain perilymph. The floor of the cochlear duct is the basilar membrane, and the roof is the Reissner membrane, which extends from the vestibular crest of the spiral ligament to the spiral limbus and divides the scala media from the scala vestibuli. The Reissner membrane has two layers: a single layer of connective cells that faces the scala vestibuli and a single layer of epithelial cells that faces the scala media. These two

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It is currently thought that the cells that form the eighth nerve ganglion are derived from the otic vesicle. During the fourth week of gestation, these cells migrate between the epithelium and basement membrane of the otic vesicle and form the auditory ganglion. The eighth nerve ganglion then divides into a superior part (pars superior) and an inferior part (pars inferior). The pars superior gives rise to the superior (utricular) branch of the vestibular nerve, which supplies the utricular macula and the cristae ampullaris of the lateral and superior semicircular canals. The pars inferior becomes the inferior portion of the vestibular nerve supplying the saccular macula and the crista of the posterior semicircular canal, and the cochlear nerve supplying the organ of Corti. The nerve cells in the cochlear and vestibular nerve ganglia are unusual in that they remain bipolar throughout life, the central processes terminating in the brain stem, and the peripheral processes terminating in the sensory areas of the developing inner ear.2,4 The developing otocyst emits tropic and trophic factors to direct growth of axons from the statoacoustic ganglion. The specific cells responsible for these chemoattractants are not entirely known. The differentiated hair cells express BDNF and NT3, which appear to be important in guiding axonal outgrowth as developing neurons express receptors for these molecules (TrkB and TrkC). Gradients of Eph and ephrins and the Slit/Robo family of axonal repellents also appear to be involved in the development of synapses between hair cells and ganglion cells. Knockout mouse studies suggest that while hair cells are sufficient to attract appropriate axons, near normal axonal growth can be achieved without input from hair cells or the sensory primordia from which they are derived (add ref B Fekete DM, camper AM, 2007).18

Bony Labyrinth or Otic Capsule The bony labyrinth encloses the membranous labyrinth and consists of the cochlea, three semicircular canals, the vestibule, and the perilymphatic spaces. Its development occurs in three

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CHAPTER 20 ❖ Embryology and Developmental Anatomy of the Ear stages. The first stage involves condensation of mesenchyme around the developing membranous labyrinth during the fourth to sixth weeks of gestation. Areas marking the location of the internal auditory canal, the entrance of the eighth nerve, and the developing endolymphatic duct can be identified at this point. Precartilage formation begins and continues during weeks 6 and 7, when true cartilage formation begins. In the areas where the membranous semicircular duct is expanding, dedifferentiation of cartilage and precartilage allows for growth, whereas redifferentiation into cartilage is found in the trailing edge areas of membranous labyrinth growth (i.e., where expansion has stopped). The process continues until the membranous labyrinth attains adult size in midterm. The perichondrium of the otic capsule appears at week 12. The second stage in otic capsule development involves the formation of perilymphatic spaces. The vestibule, enclosing the utricle, the saccule, and part of the cochlear duct begin to develop at week 8, followed by development of the scala tympani during weeks 8–9. The scala tympani begins under the round window, and the scala vestibuli starts slightly later as an outpouching of the vestibule, near the oval window. The growth and development of the scalae closely follow that of the cochlear duct, and the scalae attain adult size by 16 weeks. The perilymphatic spaces around the semicircular ducts begin to develop after the scalae, the one around the lateral semicircular duct being the most developed. There are four projections from the perilymphatic space: the perilymphatic (periotic) duct, the fossula post fenestram, the fissula ante fenestram, and an unnamed projection around the endolymphatic duct. The fissula traverses the bony partition between the inner and the middle ear anterior to the oval window and is thought to provide an overflow channel for perilymph. The perilymphatic duct runs in a canal through the petrous bone and connects the scala tympani with the subarachnoid space. The fossula post fenestram is located posterior to the oval window and is found in only about two thirds of embryos. The third stage of otic capsule development involves ossification. This begins at about the 15th fetal week, from 14 centers, and forms the petrous part of the temporal bone. Calcification in the 14 centers precedes ossification. By the 23rd week, all the centers have fused to form a complete bony capsule. Ossification of the inner ear does not occur until each portion has attained adult size. In the adult, the bony capsule has three layers: (1) an outer layer of perichondrial (periosteal) bone, (2) a middle layer of intrachondral and endochondral bone, and (3) an inner layer of internal perichondrial bone. In the adult, the middle and inner layers can still be identified. In the region of the fissula ante fenestram, the middle layer is considered a favored site for development of otosclerosis.

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anomalies that arise. The etiologies of these variations may be multifactorial but certainly include genetic and environmental influences. Environmental factors may include prenatal infection or exposure to teratogens, as well as other poorly defined environmental effects. The definition of a normal variation versus an anomaly may be arguable, but in any case, they are uncommon and can cause severe problems for the patient and the surgeon. Some of the more common variations include persistence of the stapedial artery, a highriding jugular bulb, a dehiscent facial nerve, and congenital perilymphatic fistula. A persistent stapedial artery may tether the developing carotid artery so that it courses through the middle ear more laterally and posteriorly than it would ordinarily. In addition, incomplete pneumatization of the epitympanum may lead to fixation of the head of the malleus. (See also Ch 34: Congenital Anomalies of the External and Middle Ears.) Many congenital anomalies can occur as an isolated defect without an associated syndrome. However, over half of the commonly observed anomalies of the ear are associated with other abnormalities, often composing a recognizable syndrome.19 Some authors have extensively studied various otologic anomalies associated with other diseases and have attempted to classify them by etiology. Conditions that can be seen as isolated traits include microtia, preauricular skin tags, preauricular pits, branchial cleft sinuses, anomalies of the ossicles, aberrant facial nerve, high-riding jugular bulb, anomalous carotid artery, and absence of the round window (Table 20-1).5,20–22 A number of classification systems for anomalies of the external and middle ear has been devised in the past to account for the extent and severity of the malformation. One of these systems is described in Table 20-2. This classification was produced by Cremers and colleagues and combines features of the external ear, the ear canal, and the middle ear separating them into Type I, IIA, IIB, and III. Another classification system developed by Jahrsdoerfer is designed to predict the likelihood of success for middle-ear reconstruction and surgical hearing rehabilitation by using a scoring system TABLE 20-1. Distribution of All External Ear and Branchial Cleft Malformations

Rate per 10,000a

Malformation

Number

Preauricular sinus

446

83.74

Preauricular tags

91

17.09

Microtia

16

3.00

Other malformed pinna

61

11.45

Branchial cleft sinus

12

2.25

Based on a total population size of 53,257. Bilateral cases of any given malformation were counted as one for purposes of incidence calculations. Includes all other cases of malformed pinna. With the exception of microtia, the diagnostic labels and/or descriptions of the anomalies were not sufficiently clear to make certain the precise nosologic category. Source: From Gorlin.38 a

Variations and Anomalies During otologic surgery, the surgeon must be prepared to encounter and recognize the many possible variations and

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TABLE 20-2. Classification of External- and Middle-Ear Malformations

External canal Tympanic membrane Middle ear

Lateral bony atresia Normal Normal

Type IIA

External canal

Type IIB

External canal

Fistular, or medial bony atresia Complete atresia

Type III

Pinna

Type I

External canal Tympanic membrane Ossicles Mastoid

Severely malformed or absent Absent Small or absent Rudimentary or absent Non-pneumatize

Source: Adapted from Cremers, CWRJ, Oudenhoven JMTM, Marres EHMA. Congenital aural atresia: a new subclassification and surgical management. Clin Otolaryngol Allied Sciences 9(2);119–127, April 1984.

TABLE 20-3. Grading System of Candidacy for Surgery of Congenital Aural Atresia

Variable

Points

Stapes present

2

Oval window open

1

Facial nerve

1

Middle ear space

1

Mastoid pneumatization

1

Malleus/incus complex

1

Incudostapedial connection

1

Round window

1

External ear appearance

1

TOTAL POINTS:

10

Interpretation of rating for surgery of congenital aural atresia

for each of the following structures: stapes, oval window, middle-ear space, facial nerve, malleus and incus complex, mastoid pneumatization, incudostapedial joint, round window, and external ear appearance (Table 20-3).23 A score of 8–10 points is very favorable and below 6 is unfavorable for surgical restoration of hearing. Isolated malformations of the external ear and canal are seen in approximately 1% of newborn infants; a hearing loss can be documented in 9.3% of these children.24 Isolated anomalies of the branchial arches are much less common, with an incidence of 0.02%.25 Syndromes of the first and second branchial arches, such as Treacher-Collins or the oculo-auriculo-vertebral (OAV) syndrome, are accompanied by anomalies of these arches, including microtia, external ear canal atresia or stenosis, absent TM with an associated atresia plate, ossicular anomalies, and aberrant shape or volume of the middle ear and mastoid. The facial nerve may be hypoplastic (especially in OAV) or displaced anatomically. The branchio-oto-renal (MelnickFrasier) syndrome is characterized by preauricular sinuses, cysts or fistulas of the second branchial arch, renal anomalies, and sensorineural hearing loss as prominent features. Structural abnormalities of the inner ear have been classified in various ways. Normal anatomy of the cochlear duct is seen in (Fig. 20-14). Jackler has proposed a classification system, derived from the embryologic stage at which development was arrested. This classification incorporates various different anomalies that have been described in the past (Table 20-4 and Fig. 20-15).26 The Michel-type is the most severe and consists of complete labyrinthine aplasia. The Mondini-type results in development of a small cochlea with an incomplete or absent interscalar septum and either normal or malformed semicircular canals. This type is sometimes referred to as an incomplete partition. The Bing-Siebenmann malformation demonstrates underdevelopment of the membranous labyrinth with a well-formed bony otic capsule. The Scheibe-type of anomaly has a malformation isolated to the membranous portion of the organ of Corti and sacculus.

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Rating:

Type of candidate

10

Excellent

9

Very good

8

Good

7

Fair

6

Marginal

5

Poor

Source: With permission from Jahrsdoerfer RA, Yeakley JW, Aguilar EA et al: Am Jour Otol 13:6–12, 1992.23

Perilymphatic fistula, in some cases, is a congenital anomaly. It has been commonly associated with Mondini-type dysplasia and may be due to coexisting fistulas in the oval window and the fundus of the modiolus.27 Other anatomic areas that have been identified histopathologically with clinical signs and symptoms of perilymphatic fistula include a patent fissula ante fenestram and a patent fissure between the round window and posterior canal ampulla.28 (See Ch 35: Surgical Management of Microtia and Congenital Aural Atresia.) Large vestibular aqueduct syndrome is a relatively common congenital anomaly that is associated with progressive or fluctuating hearing loss. Hearing loss may occur spontaneously or may be associated with even mild head trauma. In those patients with large vestibular aqueducts, often hearing is normal at birth, but there is a progressive decline in hearing during the first and second decades of life. The diagnosis of large vestibular aqueduct syndrome is made on the basis of high resolution CT scan of the temporal bone. The anomaly of the vestibular aqueduct can be associated with other bony anomalies of the labyrinth such as a Mondini-type dysplasia. This condition can also be found in conjunction with congenital stapes fixation and perilymphatic gusher.

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CHAPTER 20 ❖ Embryology and Developmental Anatomy of the Ear

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FIGURE 20-14. Transverse midmodiolar view of the cochlear duct (guinea pig, basal turn). From Hawkins29.

TABLE 20-4. Classification of Congenital Cochlear Malformations

With an absent or malformed cochlea: 1. Complete labyrinthine aplasia (Michel): no inner ear development 2. Cochlear aplasia: no cochlea, semicircular canals, and vestibule normal or malformed 3. Cochlear hypoplasia: small cochlear bud, normal or malformed semicircular canals and vestibule 4. Incomplete partition of cochlea (Mondini): small cochlea with incomplete or no interscalar septum, normal or malformed vestibule and semicircular canals 5. Common cavity (Cock): cochlea and vestibule form a common cavity without internal architecture; normal or malformed semicircular canals With a normal cochlea: 1. Vestibule-lateral semicircular canal dysplasia: enlarged vestibule with a short, dilated lateral semicircular canal; remaining semicircular canals are normal 2. Enlarged vestibular aqueduct; accompanied by normal semicircular canals, normal or enlarged vestibule Source: With permission from Jackler RK, Luxford WM and House WF. Congenital malformations of the inner ear: a classification based on embryogenesis. Laryngoscope, 1987;97:2–14.26

However, in a considerable number of cases, large vestibular aqueduct syndrome may occur as an isolated anomaly.

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An attempt at hearing preservation was made by performing an endolymphatic to subarachnoid shunt.30 This technique proved to be unsuccessful and resulted in immediate postoperative hearing loss in more than half the subjects. As a result, endolymphatic shunt is not recommended for these patients. Early studies have demonstrated that endolymphatic sac obliteration may slow the progressive decline of hearing.31 However, no definitive treatment, aside from avoidance of any type of head trauma, has been established for these patients, and deafness may eventually result despite attempts to improve or stabilize the hearing. Cochlear implantation has been performed in these patients after profound hearing loss develops and has been successful in rehabilitating these patients. Congenital cholesteatoma is a well-described entity of unclear origin. The most commonly held theory invokes the role of an epidermoid formation, which normally occurs during the course of development. This epidermoid formation consists of a collection of stratified squamous cells, which occurs between 10 and 33 weeks gestation in the anterosuperior portion of the middle ear, adjacent to the tympanic membrane. Ordinarily, the epidermoid formation undergoes involution at 33 weeks gestation. However, it is thought that in cases of congenital cholesteatoma, this epidermoid formation persists and starts to create keratin.32,33

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FIGURE 20-15. Congenital malformations of the otic capsule, cochlea, and semicircular canals. A. Cochlear malformations range from mild to severe abnormalities in the cochlear partition, to a common cavity, to total cochlear aplasia. B. The abnormalities of the semicircular canals are similarly graded from isolated enlargement of the lateral semicircular canal manifested by mild dilatation to significant dysplasia in all three semicircular canals with rudimentary bud formations. LSCC, lateral semicircular canal; SSCC, superior semicircular canal. (From Jackler et al.,26 p. 42, 49.)

Although this theory is popular, epidermoid rests have been observed in postmortem temporal bones of both third trimester fetuses and children up to age 10 years without signs of keratinization or growth. Other theories for the possible embryologic origin of congenital cholesteatomas include: squamous metaplasia of cuboidal epithelium of the middle ear resulting in keratin formation in the mesotympanum; entrance of squamous epithelium into the middle ear through a marginal perforation; ectodermal implants between the first and second branchial arch fusion planes; and residual amniotic fluid squamous debris that floats into the mesotympanum and takes root.34–36

explain many congenital anomalies of the ear. Depending on the time during gestation that the abnormalities occurred, anomalies of the outer ear (pinna, EAC) and the middle ear may or may not be related to anomalies of the inner ear. Sophisticated evaluation of audiologic function (brain stem evoked responses and otoacoustic emissions) as well as radiographic evaluation of the middle and inner ear (by computed tomography and magnetic resonance imaging) make comprehensive investigation of these structures possible in young children and infants.

SUMMARY

Anson BJ, Davies J, Duckert LG. Embryology of the ear. In: Paparella MM, Shumrick DA, Gluckman JL, Meyerhoff WL, eds. Otolaryngology. 3rd ed. Philadelphia, PA: WB Saunders; 1991:3–22.

The embryology and developmental anatomy of the ear are quite complex, but an understanding of them can help

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Selected References

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CHAPTER 20 ❖ Embryology and Developmental Anatomy of the Ear Cremers CWRJ, Oudenhoven JMTM, Marres EHMA. Congenital aural atresia A new subclassification and surgical management. Clin Otolaryngol Allied Sci. 1984;9:119–127. doi:10.1111/j. 1365-2273.1984.tb01484. Gasser RF. The development of the facial nerve in man. Ann Otol Rhinol Laryngol. 1967;76:37. Pearson AA. Developmental anatomy of the ear. In: English GM, ed. Otolaryngology. New York, NY: Harper Medical; 1988:1–68. Revised ed. vol. 5. English G. Otolaryngology. New York, NY: Harper Medical; 1988.

References 1. Wood-Jones F, Wen IC. The development of the external ear. J Anat. 1934;68:525. 2. Pearson AA. Developmental anatomy of the ear. In: GM E, ed. Otolaryngology. New York, NY: Harper Medical; 1988:1-68. 3. Gulya AJ. Developmental anatomy of the ear. In: Glasscock ME III SGJ, ed. Surgery of the Ear. Philadelphia, PA: WB Saunders; 1990:5–33. 4. Schuknecht HF, Gulya AJ. Phylogeny and embryology. In: Schuknecht H, Gulya A, eds. Anatomy of the Temporal Bone with Surgical Implications. Philadelphia, PA: Lea & Febiger; 1986:235–273. 5. Donaldson JA, Duckert LG. Anatomy of the ear. In: Paparella MM, Shumrick DA, Gluckman JL, Meyerhoff WL, eds. Otolaryngology. Vol. 2. Philadelphia, PA: WB Saunders; 1991:23–58. 6. Donaldson JA, Lambert PM, Duckert LG, Rubel EW. The Ear: Developmental Anatomy. Surgical Anatomy of the Temporal Bone. New York, NY: Raven Press; 1992:19–142. 7. Anson BJ, Davies J, Duckert LG. Embryology of the ear. In: Paparella MM, Shumrick DA, Gluckman JL, Meyerhoff WL, eds. Otolaryngology. Vol. I. Philadelphia, PA: WB Saunders; 1991:3–22. 8. Palva T, Palva A. Size of the human mastoid air cell system. Acta Otolaryngol (Stockh). 1966;62:237. 9. Tos M, Stangerup SE, Hvid G. Mastoid pneumatization: evidence of the environmental theory. Arch Otolaryngol Head Neck Surg. 1984;110:502. 10. Gasser RF. The development of the facial nerve in man. Ann Otol Rhinol Laryngol. 1967;76:37. 11. Gasser RF, Shigihara S, Shimada K. Three-dimensional development of the facial nerve path through the ear region in human embryos. Ann Otol Rhinol Laryngol. 1994;103:395–403. 12. May M. Anatomy of the facial nerve for the clinician. In: May M, ed. The Facial Nerve. New York, NY: Thieme Medical; 1985:21–62, 12. 13. Baxter A. Dehiscence of the fallopian canal: an anatomical study. J Laryngol Otol. 1971;85:587–594. 14. Gerhardt JJ, Otto HD. The infratemporal course of the facial nerve and its influence on the development of the ossicular chain. Acta Otolaryngol (Stockh). 1981;91:567. 15. Li CW, McPhee J. Influences on the coiling of the cochlea. Ann Otol Rhinol Laryngol. 1979;88:280. 16. Johnson LG. Reissner’s membrane in the human cochlea. Ann Otol Rhinol Laryngol. 1971;80:425. 17. Barald KF, Kelley MW. From placode to polarization: new tunes in inner ear development. Development. 2004;131(17):4119–4130.

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18. Fekete DM, Campero AM. Axon guidance in the inner ear. Int J Dev Biol. 2007;51:549–556. 19. Bergstrom L. Assessment and consequence of malformation of the middle ear. Birth Defects. 1980;16:217–241. 20. Konigsmark BW. Pathology of hereditary deafness. N Engl J Med. 1969;281. 21. Konigsmark BW, Gorlin RJ. Genetic and Metabolic Deafness. Philadelphia, PA: WB Saunders; 1976. 22. Sando I, Shibahara Y, Wood RP. Congenital anomalies of the external and middle ear. In: Bluestone CD, Stool SE, eds. Pediatric Otolaryngology. Philadelphia, PA: WB Saunders; 1990:271–304. 23. Jahrsdoerfer RA, Yeakley JW, Aguilar EA, Cole RR, Gray LC. Grading system for the selection of patients with congenital aural atresia. Am Jour Otol. 1992;13:6–12. 24. Bodurtha J, Nance WE. Genetics of hearing loss. In: Otologic Medicine and Surgery. New York, NY: Churchill-Livingstone; 1988:831–854. 25. Melnick M. The etiology of external ear malformations and its relation to abnormalities of the middle ear, inner ear, and other organ systems. Birth Defects. 1980;16:303–332. 26. Jackler RK, Luxford WM, House WF. Congenital malformations of the inner ear: a classification based on embryogenesis. Laryngoscope. 1987;97:2–14. 27. Schuknecht HF. Mondini dysplasia: a clinical and pathological study. Ann Otol Rhinol Laryngol. 1980;89(Suppl. 65): S1–S23. 28. Kohut RI, Hinojosa R, Budetti JA. Perilymphatic fistula: a histopathological study. Ann Otol Rhinol Laryngol. 1986;95: 466–471. 29. Hawkins JE. Hearing: anatomy and acoustics. In: Best C, Taylor W, eds. Physiological Basis of Medical Practice. Baltimore, MD: Williams & Wilkins; 1966. 30. Jackler RK, Cruz ADL. The large vestibular aqueduct syndrome. Laryngoscope. 1989;99:1238–1242. 31. Wilson DF, Hodgson RS, Talbot JM. Endolymphatic sac obliteration for large vestibular aqueduct syndrome. Am J Otol. 1997;18:101–106. 32. Levenson MJ, Michaels L, Parisier SC, Juarbe C. Congenital cholesteatomas in children: an embryologic correlation. Laryngoscope. 1988;98:949–955. 33. Michaels L. Origin of congenital cholesteatomas from a normally occurring epidermoid rest in the developing middle ear. Int J Pediatr Otorhinolaryngol. 1988;15:51–65. 34. Sadé J, Babiacki A, Pinkus G. The metaplastic and congenital origin of cholesteatoma. Acta Otolaryngol (Stockh). 1983;96:119–129. 35. Rudei L. Cholesteatoma forming in the middle ear in animal experiments. Acta Otolaryngol (Stockh). 1959;50:233–242. 36. Paparella MM, Rybak L. Congenital cholesteatoma. Otolaryngol Clin North Am. 1978;11:113–120. 37. Furman JM, Cass SP. Balance Disorders: A Case Study Approach. Philadelphia, PA: FA Davis Company; 1999. 38. Gorlin RJ. Morphogenesis and malformation of the ear. Birth Defects. 1980;16:1–353. 39. Schwarz DWF. Physiology of the vestibular system. In: Cummings CW, Fredrickson JM, Harker LA, Krause CJ, Schuller DE, eds. Otolaryngology-Head and Neck Surgery. Vol. IV. St. Louis, MO: C.V. Mosby Company; 1986:2679–2721.

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C H A P T E R

Physical and Physiological Bases of Hearing John D. Durrant

THE AUDITORY RESPONSE AREA AND BASIC AUDITORY ABILITIES Sound is a form of energy created by a vibratory source, such as the vibrating prongs of a tuning fork, which causes molecules of the substance of the medium, such as air, to be displaced to and fro. Therefore, as the source vibrates, it alternately compresses and rarefies the particles of the surrounding medium, creating local alterations of pressure. These changes are minute. For instance, at sound pressures in air capable of causing pain to the ear, the steady pressure equivalent amounts to only approximately 0.1 atmospheres, whereas the minimum sound pressure detectable by the normal human ear is one ten–millionth of this value. Thus, in addition to exquisite sensitivity, the auditory system demonstrates an extraordinary dynamic range—approximately 1014: one in acoustic intensity (a power-like quantity, specifically in the vicinity of 1000 Hz). This range is all the more extraordinary when it is considered that over most of it is also an impressive frequency range—nominally 20–20,000 Hz (in humans)—this full range of detecting and encoding sounds is “online” continuously. This is unlike, for example, the visual system for which such a range is only accessible adaptively (namely, a limited dynamic range that adapts to the ambient light level from dark to bright). Listeners generally move readily from soft to loud sound environments without comparable effects to dark and light adaptation (except under conditions of sound overexposure). The physical domain of normal hearing consequently is compelling, and it is the purpose of this brief introduction to overview the relevant basic quantities of sound and corresponding basic capacities of the human auditory system. These aspects are featured here as they represent the traditional benchmarks of sensory modalities, in general, aspects incorporated ultimately in clinical hearing testing, in specific. At the same time, it is important to note that such benchmarks are considerably rarefied indices of hearing. Real-world listening, more often than not, reflects far more complex behaviors that are only variably touched upon through clinical tests of hearing, if at all. Indeed, such aspects are adequately challenging in the adult population, especially if a reliable measure is desired, such as inventories applied in hearing handicap screening or satisfaction with a hearing aid. This is particularly challenging in young pediatric patients who may lack an adequate level of sophistication of communication with the clinician, even in the most basic tests of hearing. Nevertheless, methods have been developed well to evaluate even young children, if not newborns (e.g., see Chapters 23 and 119), based essentially on metrics of the basic capacities of hearing presented herein.

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The quantification of sound itself, the physiologically appropriate stimulus of hearing, requires three measures, two having been hinted earlier. The first is its magnitude, measured in units of acoustic intensity (w/m2) or, more practically, sound pressure in units of Pascals (1 Pa = 1 N/m2). The minimal detectable sound is approximately 20 μPa (i.e., 2 × 10−5 Pa or N/m2). It is the magnitude of sound that primarily determines one’s sense of loudness. The other measure in question is frequency, the primary determinant of pitch. The unit of measure is cycles per second or hertz (Hz), the reciprocal of period—the time expended in completing one cycle of a given frequency component. It is important to realize that sounds such as those produced by the familiar tuning fork are relatively simple, because they reflect oscillations at a single frequency. Most sounds in nature or the environment are typically more complicated in their frequency composition. Nevertheless, these sounds can be analyzed and represented in terms of their frequency components and the amplitude (typically the root-mean-square magnitude) and phase (starting point within the cycle) of each. This is called spectrum analysis. Sounds of particular interest to humans, such as speech and music, not only have complex spectra, but their spectra also change rapidly over time. For the auditory system to analyze such sounds, it must be able to perform some form of spectrum analysis and to do so at rather high rates. The spectrum of the sound stimulus not only determines the loudness and pitch of a given sound, but also perceived sound qualities such as timbre. Thus, it is this ability of the auditory system to analyze complex sounds that permits distinguishing among musical instruments even when they play the same note (identical pitch). The last measure is time, which appears in various benchmarks of auditory function, starting with effects of duration of the sound. Duration of the stimulus, for example, has effects peculiar to both ends of the dynamic range. Very short stimuli prove more difficult to detect than longer duration stimuli near the limit of sound detection. This effect has to be taken into consideration when assessing hearing sensitivity. The stimulus must be presented long enough to permit the sound of least intensity to reach detection. However, intense long-lasting sounds can cause auditory fatigue (manifested as temporary decreases in hearing sensitivity) or even permanent hearing loss (such as due to occupational noise exposure or excessive recreational sound exposure). There are also issues of temporal resolution (acuity), which is of relevance to the listener’s ability to distinguish among sequentially occurring sounds, such as in speech, and to locate sounds, a two-eared function discussed later.

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The auditory response area, shown in Fig. 21-1A, is a map of the physical domain of normal hearing in amplitude-byfrequency “space.” The conventional practice is to determine and plot the magnitude measure against frequency in log–log coordinates. Consequently, frequency appears on the abscissa with logarithmic or related scaling, such as octave intervals. This places 1000 Hz approximately at the middle of the human auditory response area. The unit of measure of sound pressure is the decibel (dB), which itself is a logarithmic number. The use of decibels, rather than units of sound pressure directly, is favored by virtue of the inherent compression of the regular, linear number scale, making very small and

FIGURE 21-1. A, The auditory response area. The minimum audibility curve is based on the data of Robinson and Dadson.141 The extreme low- and high-frequency portions of the curve (broken line) have been extended based on the data of Yeowart and Evans188 and Corso,21 respectively. The curve representing the threshold-of-feeling curve is based on the data of Wegel.176 B, The critical bandwidth as a function of frequency at the center of the band. (Adapted from Zwicker et al.192)

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very large numbers more manageable. The dynamic range translates from a ratio of 1:1014 (in acoustic intensity or 1:107 in sound pressure) to a range of 0–140 dB—from about the least sound pressure normally detectable to a level physiologically inappropriate for the hearing organ. The only catch is that the decibel is equal to 20 times the log of a pressure ratio, so a reference quantity is required to maintain the actual physical value. The broadly accepted reference for sound pressure level (SPL) is 20 μPa, approximately the value at 1 kHz in Fig. 21-1A. However, for various applications, such as the gain (amplification) of a hearing aid, a relative measure may suffice. The convention of taking 20 μPa as the reference for dB SPL for its proximity to the average limit of hearing in young healthy listeners proves not to portend a singular value when the frequency of sound is varied. In fact, essentially three sides of the auditory response area (Fig. 21-1A) are defined by exploring the absolute threshold of hearing—the smallest sound pressure detectable with a specified consistency (such as 50% of the time the sound is presented)—over a wide frequency range (see the work by Robinson and Dadson141). The trough-shaped “bottom” of the area again reflects exquisite hearing sensitivity. It has been speculated that hearing sensitivity (at its best) is only limited by the “noise floor” formed by random bombardment of particles of the medium and/or fluid within the inner ear (Brownian movement, i.e., thermal noise). However, for humans, such noise appears to be some 20 dB below the limits of hearing for even the most sensitive normal-hearing individuals.60 The upper limit is no less remarkable, but for much different reasons. Sounds approaching 140 dB SPL are brutally loud and physically uncomfortable, if not painful. Permanent damage to the hearing organ is imminent at such levels, even for the briefest exposure (evidenced by acoustic trauma). Even well below 140 dB, there are warning signs that the ear’s limit of tolerance is neigh. Other signs of overstimulation include the perceptions of aural fullness, distortion, and/or tinnitus, typically experienced as ringing in the ears. Exposures to sounds of just 90 dB SPL (A-scale weighting) can cause permanent damage to the hearing organ if sustained for just 8 h/d nonstop, day after day. This is the level that the National Institute of Occupational Safety and Health has stipulated as the maximum daily dose of noise that is permissible for workers without the use of hearing protection.163 This level is likely conservative for full protection of hearing of workers and nonworkers, alike—even children. With the growth in sound power capabilities of audio systems used for public concerts of all sorts, home audio-visual systems, and personal listening devices, there is actually growing concern with leisure-related sound exposures in pediatric and young adult listeners. Young listeners have been found to demonstrate selective high-frequency decreases in hearing traditionally considered to portend occupational-noise-like hearing losses, and efforts have begun to target educating youth about the risks of such exposures(see www.dangerousdecibels .com and, e.g., Vogel et al.173).

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CHAPTER 21 ❖ Physical and Physiological Bases of Hearing The “sides” of the auditory response area formed by the minimum audibility curve (Fig. 21-1A) also effectively delimits hearing along the frequency axis. Although the auditory system is quite sensitive over the mid-range of frequencies, sensitivity suffers increasingly at the extremes above and below. What exactly are the lower and upper limits of hearing, however, is a matter of definition and is speciesdependent. For humans, the usable frequency range is fairly well centered on the spectrum of speech, although the entire hearing frequency range is not required for the reliable reception of speech. For instance, telephones or cell phones are engineered to reproduce only approximately 300–3000 Hz, clearly representing a much narrower bandwidth than the passband of the normal human auditory system. The range 20–20,000 Hz generally is accepted as the nominal useful bandwidth of human hearing, although auditory responses to sound are demonstrable significantly below (Yeowart and Evans188) and above this range (see Corso21). Still, outside of the band of 20–20,000 Hz, rather high SPLs are required to just reach threshold and may cause distortion180 or be devoid of a clear sense of pitch.22 Extraordinary sensitivity of sensory function, as reflected in the absolute threshold, is not adequate to support the sophisticated functions that are readily evident with a system that can process speech and music, or even much more basic processing in infrahuman species. Another important basic ability is that of detection of changes in the parameters of the sound or discrimination among sounds—differential sensitivity. The capacity to distinguish between complex sounds of similar spectra, such as the spoken words [bit] and [pit], is a testimonial to the superb engineering of the human auditory system. The psychophysical measure called difference limen (DL, difference or differential threshold, or commonly just noticeable difference [jnd]) provides an indication of basic differential sensitivity supporting such as speech discrimination, namely differential sensitivity apropos basic parameters of sound. For instance, the difference limen for intensity is, serendipitously, approximately 1 dB,73 which amounts to a 12% change in sound pressure and less than 1% of the dynamic range. The difference limen for frequency is approximately 0.2%,185 meaning that with some training, a listener should be able to distinguish between a tone of 1000 Hz and a tone of 1002 Hz. However, these specifications of differential sensitivity, particularly the difference limen for frequency, are valid only for the central region of the auditory response area. Decreased discrimination ability is observed at the extremes of the frequency range and/or as the limits of hearing sensitivity are approached.100 The stated difference limen for frequency also does not realistically characterize the limits of the frequency resolution of the auditory system for sounds more complex than simple tones or simultaneously occurring sounds in general. For instance, were the 1000 and 1002 Hz tones in the earlier example presented together, two tones actually would not be perceived. Rather, a single tone, yielding a singular pitch

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percept (per the average of the two frequencies) would be heard, but its loudness would wax and wane—or “beat”—two times per second (the difference frequency of 2 Hz).178 There are other perceptual attributes that reflect the inability of the auditory system to resolve closely spaced spectral components of complex sounds,133 a limit known as the critical bandwidth.151,192 Like the frequency difference limen, the critical bandwidth varies across frequency (Fig. 21-1B), and critical bands influence the loudness of complex sounds or how loudness grows as sounds are added together. Within a critical band, the loudness, for example, depends primarily upon the total sound energy, whereas the loudness of sound whose spectral components extend beyond a single critical band also depends upon how many critical bands are spanned. Beyond one critical band, loudness itself summates. For instance, speech presented at the same overall SPL as a single pure tone will sound louder than the tone. This is why patients who fake or otherwise demonstrate nonorganic losses of hearing rarely escape the attentive clinician, given their thresholds for both pure tones and speech. Hearing sensitivity for speech will be remarkably better than expected from the “alleged” tonal audiogram (apparent versus the patient’s true audiogram). Such patients tend to set an internal loudness reference, but less intensity is needed to reach this criterion for speech due to loudness summation across the critical bands. The frequency range of hearing spans over 25 critical bands. This reflects a far more course resolution than anticipated from the difference limen data (namely hundreds of bands, even if based on the most conservative DL data). It is helpful, though, that the limits of these bands are not fixed. Furthermore, more modern theory and measures present a picture of the same sort of filterbank spectral analysis but expressed in terms of the equivalent rectangular bandwidths (ERBs).55 The ERB is the bandwidth of an ideal rectangular filter of the actual auditory filter, can be estimated behaviorally using a noise interference or masking paradigm (beyond the scope here), and suggests narrower filters than the earlier critical bandwidth estimates. Nevertheless, even ERB analyses bespeak considerably less resolution power of the auditory system than would be presumed from the classical DL, also essentially at odds with the neurophysiological manifestations of cochlear “tuning” (see later in the text). Regardless, a powerful feature of the cochlear filters is that they are accessed nearly simultaneously and “on the fly,” thereby providing for efficient and continuous spectrum analysis. At the same time, ERBs are not the whole story of frequency encoding by the auditory periphery. Temporal analysis also plays a substantial role, namely within and across the filterbank (frequency) channels, which are demonstrated later in the text. Thus, limits of temporal resolution must be considered. Temporal acuity is one such benchmark, based on basic tests of listeners’ abilities to resolve two sequential events, such as distinguishing the order of occurrence of two brief impulsive sounds of different intensities. Results indicate the auditory system to be capable of resolving intervals as short

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as 1–2 ms.59,64 Even smaller time intervals may be resolved if other cues are available. A confound in trying to determine temporal acuity is the frequency makeup of the sounds employed that tend to cause spectral splatter (thus frequency cues) for extremely brief intervals/interruptions. Whatever be the exact limits of temporal resolution, what makes the auditory system such an impressive frequency encoding instrument is that it achieves a good balance of frequency and temporal resolution. It is by virtue that the auditory system is capable of carrying out spectrum analysis in real time over a broad frequency range, thereby providing for the freerunning speech communication and processing of music that is well enjoyed by the human. With these concepts of how well the auditory system functions fundamentally, how the system is built and works to support these basic capacities can now be considered. Perhaps surprisingly, many of the abilities and their limits described earlier depend greatly upon events in the auditory periphery. This is where sound energy is transduced into electrochemical events leading to neural impulses transmissible within the acoustic nerve and the brain. Also it is the peripheral system that is accessible to noninvasive medical examination and the most accessible to therapeutic and surgical treatment, including that of a true marvel of modern science and technology—the cochlear implant (see Chapter 33). Therefore, much attention is given here to the peripheral auditory system and its workings.

It is well known from physics that sound or vibratory energy transfer from one medium or vibratory system to another is optimal only when the media/systems involved are matched in terms of their impedances. Impedance is a form of opposition to vibratory motion that arises from the combined mass (or density), elasticity, and friction of a medium/system. Mathematically, impedance is a complex number, meaning that it has both magnitude and phase, requiring trigonometric analysis. It is not necessary to delve into details here. Again, the all-important concept is simply that the most efficient power transfer occurs only when impedances are matched. This is true in electrical, mechanical, and acoustical systems. For example, the output impedance of an audio amplifier (such as in a home theater sound system) must be matched to the input impedance of each loudspeaker to achieve the widest frequency response with the greatest power transfer. Not all amplifiers have output impedances that match the input impedance of a given loudspeaker or viceversa. In such cases, a transformer can be used to match the impedances. So, too, the middle ear mechanism serves as a transformer to match the impedance of air to that of the cochlear input—the oval window. The classical description of the elements of the middle ear is shown in Fig. 21-2. Here the middle ear is modeled as a system of plates or pistons and levers. The analysis of this system has been described extensively by various writers

ROUTING OF SOUND ENERGY TO THE COCHLEA—THE OUTER AND MIDDLE EAR TRANSFORMERS The overall role of the outer and middle ears in hearing are straightforward; they serve to collect sound energy and funnel it to the inner ear, constituting collectively the conduction apparatus of the ear. These are physical functions that, however, cannot be appreciated fully without considering the basic acoustical and mechanical principles underlying the functional responsibilities thereto. Considering the anatomy of the ear of various submammalian species (frogs, lizards, birds, etc.), the outer ear at first seems expendable. Indeed, it is the middle ear that makes the more substantial contribution to auditory capabilities. It is thus fitting to start more medially with this description of physiological acoustics. The contribution of the middle ear can be appreciated by considering first the simpler circumstance of transmitting sound energy from air to water. The optimal transmission will occur in this scenario when sound waves encounter a body of water at zero angle of incidence (head on), yet only 0.1% of the energy will be transmitted. This means that 99.9% will be reflected. This represents a 30-dB loss of sound energy transmission from air to water. [Note: 0.1% = 0.001, representing a ratio of 1000:1; 10 log(1000/1) = 10 log(103) = 10 × 3 = 30 dB.] Given that the organ of Corti is housed in the fluid-filled cochlea, this classical analogy makes clear that optimal hearing sensitivity is not possible through direct transmission of sound from air to cochlea.

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FIGURE 21-2. Components of the middle ear transformer, viewed as a system of two pistons connected by a folded lever. A, area; p, sound pressure; l, length. Subscripts: d, eardrum; m, manubrium of the malleus; i, long crus of the incus; s, stapes footplate. (Inspired by drawing of Zwislocki.193)

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CHAPTER 21 ❖ Physical and Physiological Bases of Hearing (see, for instance, the work by Dallos24 and Zwislocki194; Durrant and Feth,39) and is presented only conceptually here. The most obvious transformation, and indeed the largest component (numerically) of the transformation, is the large areal ratio of the tympanic membrane and the stapes footplate. Like the diaphragm of a loudspeaker, not all the surface of the eardrum is free to vibrate, but even allowing for this factor, the ratio is relatively large—approximately 13:1. Thus, the force of a sound wave acting over the eardrumpiston is funneled to the much smaller footplate area, yielding sound pressure amplification (because pressure equals force divided by area). There is an additional force amplification through the leverage of the ossicular chain system amounting to about 1.3:1. The total pressure amplification amounts to 13 × 1.3 = 17, which can be represented in decibels, equaling approximately 25 dB. At first glance, this number seems to offer the sort of match that was needed, if the air-to-water analogy were valid. However, the input impedance of the cochlea does not appear to be as great as that of water,194 thus limiting the validity of the air-to-water analogy. In addition, pressure amplification is not the only consideration. For instance, tremendous pressure might be generated by a given system. Yet, if no motion results, work (in the physical sense) has not been accomplished and no power transfer will occur. Therefore, a more comprehensive analysis requires consideration of both sound pressure and velocity transformations that, in turn, are reflected in the impedance transformation through the system. Results of such analyses have been surprisingly pessimistic, suggesting the human middle ear system to be only approximately 60% efficient or “worth” approximately 13 dB. However, although of great heuristic value, holograms of the tympanic membrane in motion suggest the classical piston model to be, at the very least, an oversimplification.169 Another aspect of the mechanics of the middle ear that has been questioned is the proper model for the impedance of the stapes footplate.89 That the middle ear transformer could be considerably more efficient, indeed, may be argued from clinical experience. The fenestration operation—predecessor of stapes mobilization surgery, wherein the eardrum is essentially connected directly to a surgically formed window in the osseous labyrinth—at times was found to yield improvements in hearing approaching 25 dB.33 Whatever the true impedance transformation of the middle ear, there is yet another value of the middle ear, one that is even less easily quantified, but conceptually easily appreciated. Were it not for the middle ear transformer, the round window would not be “protected.” Sound waves, that would otherwise reach both windows, are prevented from doing so and, in turn, phase cancellation within the cochlea is averted. Such an effect can be appreciated by a simple demonstration with a tuning fork. The fork is struck and set into vibration and then held near one ear. Rotating the vibrating fork, it is found that the intensity of the sound varies. The lowest amplitude is observed with the tuning fork broadside to the side of the head. Sound waves are excited

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by each vibrating prong but destructively interfere—cancel one another—between the prongs. Although the principle of “protection of the round window” has guided creative reconstructive surgeries in cases in which the tympanic membrane and most of the ossicular chain have been lost, total cancellation actually cannot result in the ear, at least not at all frequencies. The two windows simply do not lie in the same plane. The complete absence of the tympanic membrane and ossicular chain or simply disrupting the ossicular chain can cause hearing losses only up to approximately 60 dB. This magnitude of loss still is not as severe as it would be with total phase cancellation.126 Conductive hearing losses up to 60 dB, on the contrary, are themselves perplexing and beg the question of how, then, hearing losses due to middle ear diseases, malformations, disarticulations, or other pathologies can exceed even the most liberal estimate of the numeric worth of the middle ear. Losses of more than 25 dB indeed are common. The answer is that, as implied earlier in the text, the worth of the middle ear mechanism does not rest entirely upon the transformer ratio. Furthermore, pathological changes can cause the system to work even less efficiently than having no middle ear transformer at all. The atretic ear is a case in point. Such cases demonstrate air conduction hearing losses on the order of 50 dB. Coincidentally, when unilaterally deaf subjects are tested under earphones, transcranial conduction is observed to occur at 40–70 dB. These values largely reflect the air-toskull impedance mismatch (although in the latter example, there is some acoustic leakage under the earphone cushion that adds to the crossover). It is not difficult to imagine that as outer/middle ear pathology worsens, a specific acousticomechanical pathway into the inner ear is lost. The physical problem then is no longer the one confronting nature in the evolution of the hearing mechanism, namely the air-tocochlea mismatch. Now, energy can only reach the inner ear by bone vibration that, in turn, is governed by the air-to-skull mismatch. In the final analysis, even the most pessimistic estimates of the worth of the middle ear by physical-systems standards make it appear quite efficient overall. Yet, this efficiency is not realized without a price—its efficiency is limited across frequency. In other words, the middle ear filters sound, efficiently transferring sound energy (again) only over the midfrequency range of hearing. The middle ear mechanism becomes increasingly inefficient at the extremes of the hearing range, as was demonstrated by the minimum audibility curve (Fig. 21-1A). This point is further shown by the graphs in Fig. 21-3, wherein the sound pressure transformation between the eardrum and the cochlea yields a derived sensitivity curve remarkably similar to the minimum audibility curve. The prevailing theory for some time has been that, indeed, the overall shape of the minimum audibility curve—and thus the frequency limits of hearing—is ostensibly determined by the transfer characteristics of the middle ear.24 This view has been recently challenged,146 at least to the extent that the frequency limits are presumed to be defined by

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FIGURE 21-3. Comparison of A, sound pressure gradient across the cochlear partition and B, behavioral thresholds (minimum audibility curve) in the cat. SPL, sound pressure level; TM, tympanic membrane; CP, cochlear partition. (Based on the data of A, Nedzelnitsky122 and B, Dallos’ adaptation24 of data from Miller et al.113)

limits of the middle ear mechanism, as such. The alternative view expressed places substantially more emphasis on limits imposed by the cochlear system, previously treated uniquely as a restive load (input power absorbed independent of frequency). In any event, the foregoing consideration should not be interpreted to suggest that middle and inner ears could be freely mixed and matched across species. These portions of the peripheral auditory system have clearly evolved symbiotically, and it is the structures and mechanics of the organ of Corti that determine the overall sensitivity of the ear. The bottom line is that the mechanical efficiency of the middle ear, as terminated by the cochlea, presents a limited frequency

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range of efficient sound energy transfer to the cochlea with response-versus-frequency characteristics measured at the cochlear input strongly reflected in the minimum audibility curve (Fig. 21-3). The middle ear is truly an acousticmechanical circuit comprising equivalent stiffness (elastic), mass (inertial), and friction components. Stiffness and mass are what impart frequency-dependent behavior of such a circuit and determines its impedance. It is more complex than a simple spring mass system, which, in turn, will resonate at one frequency. Still, the middle ear does demonstrate a resonant frequency at approximately 1.2 kHz in humans. Also, in general principle, the system behaves in a manner in which frequencies below the resonant frequency are influenced more by changes in stiffness and the high frequencies by changes in mass. Middle ear (static) impedance and to some extent these components are accessible to clinical analysis using an immittance test instrument (the electroacoustic “bridge;” see Chapter 23). An emerging technology based on power reflectance at the eardrum78 provides evaluation of middle ear function across much of the audible frequency range, has already provided useful insights on the maturation of middle ear function, but has yet to receive broad adoption clinically. The middle ear impedance/power response characteristics are also not entirely static but are subject to slight changes, even under normal operation. First, there is the effect of changes in air pressure that can push or pull on the eardrum and effectively alter the stiffness of the middle ear, thus on the low-frequency side of the system. In fact, this is done purposefully in tympanometry (again see Chapter 23). These pressure changes are relieved by opening the Eustachian tube during swallowing, and so forth. Second, and more interesting from a physiological acoustics point of view, is the changes caused by the activation of the acoustic reflex (alternatively referred to as the middle ear muscle reflex or stapedius reflex, the latter term reflecting the dominance of the stapedius muscle when the reflex is elicited by sound). The acoustic reflex effects an increase in stiffness at the medial end of the ossicular chain, thus with low frequency effects although excitable over a wide range above the middle ear resonant frequency (see the work by Silman157). Consequently, this reflex can also be monitored by observing change in the input impedance of the ear, namely during relatively intense sound stimulation (largely above approximately 70 dB SPL). Clinically, acoustic reflex measurement is accomplished using the same immittance test instrument as in tympanometry. Perhaps the most commonly assumed role of the acoustic reflex is that of protecting the inner ear from overstimulation. Given that the activation of the reflex does reduce the transmission of sound through the middle ear, some protection is likely through this mechanism. However, this protection is also limited to the low frequencies, where the increased stiffening of the ossicular chain is most effective.115,116 The reflex also seems too sluggish to protect the ear from impulsive

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CHAPTER 21 ❖ Physical and Physiological Bases of Hearing sounds,158 and it probably adapts too much to offer protection against relatively constant noises.168 Furthermore, it is not clear why such a protective mechanism would have evolved in the first place, because noise pollution is a relatively modern phenomenon and is clearly man-made. Still, the acoustic reflex provides the central auditory system a means of controlling the input to the brain at the periphery, even if limited. Another role of the reflex and the most compelling role is revealed by the fact that it is activated just before and during vocalization.6 The reflex thus attenuates one’s own voice and involves to some extent both the stapedius and the tensor tympani.66 Even if limited in principle to the attenuation of low-frequency sounds, the importance of the reflex is not as vulnerable as in the “protection theory.” This is thanks to another auditory effect, spread of masking, wherein at moderate to high levels of sound, lower-frequency sounds can interfere substantially with the hearing of high-frequency sounds. The basis for this effect will become apparent upon consideration of cochlear mechanics. Clinically, the reflex offers opportunities for an additional test of normal middle ear function and neural function (given a reflex arc through the brain stem. Despite the pervasive influence of the middle ear on hearing, the outer ear is not acoustically transparent. Just as would be the case with a microphone cartridge (transducer element), the middle ear transformer cannot be placed deep in a dense pseudosphere at the end of a tube some 2.5 cm long, while feeding in sound at the opening of the tube with something like a lopsided wrinkled funnel, without acoustic consequences. Indeed, the outer ear plays a substantial role in matching the mechanics of the ear to the air medium outside, effectively amplifying sound in ways that are important to the particular species. Both the head and the auricle (or pinna) act as acoustic baffles, meaning that they will reflect some of the sound wave that will then interfere with the incident sound wave. Yet, the net effects prove to be positive, functionally overall, although the detailed story is as convoluted at the auricle itself. The short version is that, starting with these structures, shape creates nuances in the spectrum of sound ultimately reaching the eardrum that are azimuth dependent. The listener somehow learns to interpret these cues to judge the localization of sounds of different elevations, that is, above versus below as well as front to back. By virtue of its small size, however, these effects are restricted to frequencies above 4 kHz, namely for sounds whose wavelengths are short compared to the auricle’s dimensions.12,154,156 Therefore, although somewhat small and immobile in humans, the auricle is not vestigial. Although the auricle is rather a small barrier or baffle to sound, the head itself is much more substantial. It is thus acoustically important over a broader/lower frequency range. For sound waves essentially incident to the ear, it causes constructive interference. However, for an ear turned away from the sound source, the head can cast a substantial sound shadow. On the contrary, when the sound source is directly

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in front or behind the listener’s head, the acoustic differences between ears are nil, but these differences develop substantially as the head is turned, maximizing at azimuths in the vicinity of 90° azimuth (near ear) and thus placing the other (far) ear on the opposite side of the head. The binaural cues that develop from these and other relevant acoustic effects will be considered shortly. First, there is a final component of the outer ear acoustic system, the tube-like external auditory meatus that must be considered as it contributes to monaural hearing, per se. As the middle ear transformer is less than a perfect transform, and lesser was the sound frequency that deviates progressively further from the middle ear resonant frequency, the impedance at the eardrum is somewhat higher than that of air. Acoustically, as well as anatomically, the external meatus looks much like a tube with one end open and the other closed, namely reflective at the end terminated by the tympanic membrane. Such tubes at certain frequencies will form standing waves, producing resonant peaks a frequencies that are odd-integer multiples of the fundamental mode (first frequency of “resonance”). This is the same phenomenon that occurs when blowing over the mouth of an open test tube to produce a tone. The ear canal tube is approximately 2.5 cm long and has been shown to have a fundamental mode of approximately 3400 Hz.184 Standing waves create sharp resonant-like effects in perfectly rigid, simple tubes, but the ear canal effects are less strong and broader in frequency. On the contrary, its effect cannot be evaluated in isolation of the rest of the outer ear and head acoustics. The combined acoustics provides as much as 20 dB sound pressure amplification at the eardrum in the 2000– 5000 Hz region.156 Comparison of the graphs in panels A and B of Fig. 21-3, although based on data from cat, shows how there would be a progressive decrease in sensitivity above approximately 1000 Hz where sound energy fed directly to the tympanic membrane (like a free-standing microphone). Instead, hearing continues to be fairly sensitive for over two octaves above the middle ear resonant frequency. In humans, these acoustic effects are serendipitous for better hearing of upper vowel formants and consonant sounds of speech. This is important, because these sounds have much less energy than lower vowel formants and the fundamental frequency of the voice. Unfortunately, it appears that this same amplification (at least in part) predisposes the 4000 Hz region of hearing to damage from excessive noise exposure.145,168 Returning finally to the use of two ears, the placement of the ears on opposite sides of the head enhances one’s ability to locate sounds from side-to-side. In the vicinity of 90° azimuth (Fig. 21-4A) interaural differences created by combined head-baffle enhancement (near ear) and head shadow (far ear), some 15–25 dB differences between ears can be observed (depending on frequency at ≥ 2 kHz),156 thus robust interaural (sound) level differences (ILDs). Given that the jnd for intensity is on the order of a 1 dB, it is not surprising that the listener is sensitive to nearly any deviation from 0° azimuth. The minimum audible angle in fact is on the order of

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SECTION 2 ❖ Ear and Related Structures them vulnerable to location of sound sources for best hearing (and depriving them of enhancements of binaural processing, per se; see later in the text). Lastly, it should be noted that the acoustic effects of the auricle also come into play, for creating interaural difference, but for resolving what would be a “cone of confusion”114 for the auricle-less listener. Again, the contribution of the auricle is for distinguishing among sound locations at different elevations. This is ambiguous for ILDs and ITDs. The functions by which the influences of the pinna effects are expressed and which can be used to simulate virtual 3D sound localization are called head-related transfer functions , [HRTFs]).91,96

FIGURE 21-4. Simplified representation of the acoustical effects of the head on sound waves with wavelengths shorter than the diameter of the head: A, wherein the head casts a “shadow” (cross-hatched area) versus wavelengths greater than the head diameter; B, wherein diffraction dominates and “fills in” the shadow.

2° when the listener is more or less facing the sound source.114 However, such a cue is only as robust for frequencies above approximately 2 kHz, diminishing substantially below 1 kHz and negligible below 300 Hz. This is due to sound diffraction by the head, namely when the dimensions of the head (especially diameter) becomes smaller than the wavelength of sound (Fig. 21-4B). Low-frequency sounds have longer wavelengths than high-frequency sounds. This is because they have longer periods (require more time for one cycle to complete), yet sound waves of different frequencies propagate at the same speed. Crests (peaks) of the sound pressure waves occur over progressively longer intervals as frequency decreases, finally exceeding the diameter of the head. At the same time, sound diffraction becomes increasingly important and ultimately “overcome” the sound baffle and shadowing effects of the head (Fig. 21-4A). While neutralizing ILDs, there remains a difference in time of arrival of sound waves at the near versus far ear. Although relatively small (less than 1 ms; see Mills114), the auditory system is well developed to encode such a temporal feature (as hinted earlier and to be elaborated below). Thus, at lower frequencies, interaural time differences (ITDs) are available for side-to-side (lateral plane) localization of sound. To iterate, interaural intensity and time differences serve as cues for the localization of sound differing in position horizontally and develop from acoustics of the head, placement of the ears, and sound wave properties. However, the seemingly peerless localization ability of humans is not due to acoustics alone, but rather reflects substantial contributions of mechanisms more medial in the peripheral and then central systems, namely structures that can faithfully encode, preserve, and ultimately decode such acoustic cues.58 Thus, this is only the first step in sound localization in a chain of events, although a clearly critical function—the collection of sound waves. At the same time, the acoustic effects also help to account for the problems of individuals deprived of one ear. Although binaural function contributes only marginally to improved hearing sensitivity and discrimination, the sound shadow effect becomes the enemy for such patients, making

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THE ROLE AND FUNCTION OF HAIR CELLS As described in the earlier section, first, the purpose of the outer and middle ears is to efficiently transfer sound energy from air to the fluid-filled inner ear. The role of the cochlea and many of the structures of the hearing organ is, in turn, to couple this vibratory energy, delivered to the oval window by the stapes footplate, to the hair cells. These are the sensory transduction cells of hearing (and balance). In order to appreciate the mechanisms and events involved, it is worthwhile to consider just what it takes to stimulate hair cells in general, regardless of the hair cell system in question. All sensory systems employing hair cells exhibit similarities of overall design and constitute mechanoreceptors. The basic role of mechoreceptors, as their name implies, is to transduce mechanical force into electrochemical energy, leading to the point of departure of what it takes to excite such cells.

Stimulating the Generic Hair Cell Mechanoreceptor For many years, understanding of the workings of the cochlear hair cell was limited to a combination of theory, observations of the extracellularly recorded “gross” electrical potentials of the cochlea, and extra and intracellular recordings from hair cells of the lateral line organs (e.g., foundon the skin of fishes and frogs47). Observations on lateral-line hair cells were supplemented by observations on vestibular hair cells.43 The hair cells of these two systems have both stereocilia and a single kinocilium. As illustrated by Fig. 21-5A, the kinocilium provides a clear morphological “sign-post” that indicates the preferred direction of deflection of the sensory hairs for excitation of the associated sensory neuron. Back and forth deflection of the hair bundle along the axis defined by the kinocilium leads to alternating depolarization and hyperpolarization of the cell. Displacements of the hairs from side to side are ineffective. The fact that both excitation and inhibition are reflected in the pattern of discharges in the sensory neuron reflects an important aspect of neural encoding in vestibular and auditory systems alike. The vast majority of neurons in these systems exhibit some level of spontaneous activity, often 20 or more spikes/second. In the auditory system, this spontaneous activity is random over time, and, even

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FIGURE 21-5. A, Relationship of discharge rate of action potentials in the afferent neuron connected to the hair cell in response to different directions of shearing of the hairs. Adapted from Flock.47 B, Schematic representation of excitatory current flow through the hair cell (left) and [inset] mechanism of chemical transmission between the hair cell and the afferent nerve ending (right). (Adapted from Flock et al.49)

in the absence of sound stimulation, most primary auditory neurons are active.45,85 This characteristic reflects, in part, the keen mechanical sensitivity of the hair cell receptors. Indeed, higher spontaneous rate neurons tend to exhibit the greater sensitivity.45 (More on this point is discussed later in the text.) Having a relatively high spontaneous activity also substantially influences how sound stimuli are encoded and processed by the central nervous system. The model of hair cell transduction that has guided research in this area for years is that of the late Hallowel Davis.32 Davis postulated that the bending of the sensory hairs depolarizes (and alternately hyperpolarizes) the hair cell membrane by altering the membrane resistance. The hair cell membrane appears to be “leaky,” so that there is a small but constant amount of ionic current flow across the cell membrane. This leakage current is presumably the “stimulus” for the spontaneous background activity in the associated nerve fiber. Deflection of the hairs in the excitatory direction then increases the current flow and causes increased release of transmitter substance, such as glutamate, at the base of the hair cell (Fig. 21-5B).49 Only over the past couple of decades, however, have the underlying membrane biophysics begun to be understood (e.g., see Hudspeth67 and Dallos27). Suffice it to say, these details largely represent elaborations of the Davis model, the major tenant of which has reasonably withstood the test of time.167

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A pivotal component of Davis’ theory, specific to the “cochlear model” of hair cells, was the suggested role of the endolymphatic potential (EP)—the resting potential measured within scala media and generated by the stria vascularis.164 The EP is viewed as providing an extra “force” for driving current through the hair cell.32 Visualizing the EP and the resting membrane potential of the hair cells as batteries, these batteries are wired in series; this essentially doubles the transmembrane potential. The fact that the EP is found in an extracellular space that, additionally, is filled with a high concentration of potassium represents an intriguing physiologic phenomenon and gives rise to a long-standing “chicken and egg” argument. Is the EP a byproduct of the biochemical mechanisms needed to create the high potassium (and low sodium) concentration or vice versa? There is no question, nevertheless, that the presence of a normal EP is requisite for a completely normal functioning hearing organ, as reflected by EP-dependent changes in the cochlear electrical potentials discussed later in the text.65 There are additional aspects of the electroanatomy and electrical properties of the cochlea that are essential to a complete explanation of the workings of the cochlear system, although details are beyond the scope here. Nevertheless, a couple of aspects underlie an important aside apropos the treatment of profound auditory impairment, namely using a marvel of the modern age—the cochlear implant (again, see Chapter 33). This is the three-dimensional electrical circuit of the cochlea.7 This comprises circuit branches along the cochlear scalae and electrical connections to the eighth nerve. As will be seen later in the text, electrical activity of the auditory nerve is conducted back through the cochlear fluids. It follows that current delivered to the cochlear fluids (typically perilymph in scala tympani, in practice) can well get to the nerve for direct stimulation of the remaining ganglion cells. Given that the cochlear tissues look like a system of distributed resistances (i.e., current flows neither freely nor equally in all directions across and along the cochlea), the cochlear electroanatomy also provides quasi-channelized connection to the nerve. Developers, in fact, count on such more-or-less channelized access to the remaining ganglion cells in their design of the multichannel devices in common use, intended to emulate the defunct cochlear analyzer.

Stimulating Cochlear Hair Cells Cochlear hair cells have no kinocilia. Still, there are compelling anatomical signs and electrophysiological evidence that they too are directionally sensitive. A clear morphological indicator is the pattern of the stereocilia atop the outer hair cells. Maximally excitatory displacements are in the direction of the tallest hairs that, coincidentally, is toward the base of the characteristic “W” pattern of the hairs, pointing radially away from the modiolus (see Fig. 21-7A). The cochlear receptor cells thus appear to be stimulated optimally by radial deflections of their hairs (Fig. 21-6). The most interesting morphologic finding in recent years supporting this notion is

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FIGURE 21-6. Schematic representation of the organ of Corti illustrating how shearing displacements of the stereocilia can result from displacement of the basilar membrane. BM, basilar membrane; TM, tectorial membrane; IHC, inner hair cell; OHCs, outer hair cells. (Adapted from Ryan and Dallos.147)

provided by the demonstration of a system of fine linkages between successive rows of stereocilia, called “tip links.”129,130 Tip links are nearly vertically oriented (in reference to the stereocilia), but slant radially (because successive rows of hairs are taller) and are believed to be significant components in the molecular-level transduction process (Fig. 21-7A). They appear to act as ionic gates, regulating ion/ionic current flow into the hair cell (Fig. 21-7B), as predicted, in effect, by the Davis model. These molecular ionic gates thus have been localized to the tips of the stereocilia68 wherein the excitatory phase involves the influx of potassium and calcium ions. The latter influx acts as an enabler of the transduction process, whereas the “potassium current” contributes directly to the depolarization of the cell (namely, decreasing the resting cell membrane). It is also noteworthy that there are also cross or lateral links oriented horizontally (with respect to the hairbearing surface of the cell; not shown in Fig. 21-7A). These help to stiffen the hair bundle. Although the detailed mechanisms just overviewed were illustrated in reference to the outer hair cells, they serve, as well, inner-hair-cell transduction. The problem of stimulating cochlear hair cells is how to cause bending of the hairs (back-and-forth motion) through vibration of the body of the organ of Corti, a relative up-anddown motion. The solution is suggested by Fig. 21-6 and

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FIGURE 21-7. Illustrations of stereocilia atop an outer hair cell with zoomed-in view of detail to show tip links that act as ionic gates. A, and operation of the ionic gates to cause a depolarizing transmembrane current. B, inspired by Dallos25. Arrows and labels indicate excitatory direction of shearing displacement of the hairs, namely radially (rad.) away from the modiolus (mod.), displacements in that direction having an inhibitory effect. (Adapted from Durrant and Feth.39)

relies heavily on the structural relation between the effective pivot points of the tectorial membrane and the basilar membrane.147 The former pivot is effectively at the lip of the spiral

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CHAPTER 21 ❖ Physical and Physiological Bases of Hearing limbus, whereas the organ of Corti, supported by the basilar membrane, effectively rotating at or near its attachment to the osseous spiral lamina. As these two points are displaced in space, up-and-down motion of the organ creates a radial shear between its hair-bearing surface and the underbelly of the tectorial membrane. Therefore, the geometry of the hearing organ is a critical part of its design. The stereocilia have been shown to be stiff normally,48 and, as illustrated in Figure 21-6 and 21-7, the tallest hairs of the outer hair cells clearly impale the underbelly of the tectorial membrane.69 It is thus fairly clear that coupling between the tectorial membrane and the stereocilia is relatively tight for these cells101; hence, the shearing displacements created by the up-and-down motion of the basilar membrane leads directly to radial displacement of the hairs. Indeed, these structural factors apparently figure into the entire scheme of the mechanics of the cochlear partition, as well be considered further (later in the text). However, the mode of displacement of the stereocilia of the inner hair cells is less obvious. Their stereocilia appear to be virtually freestanding (Fig. 21-6) and thus not touching/impaling the underbelly of the tectorial membrane for any length of hairs.97 It is broadly held that these stereocilia are displaced by the virtual flow of fluid created in the channel between the tectorial membrane and the surface of the organ which, in turn, would be alternately compressed by the up-and-down-to-shearing-motion transformation.147 In other words, outer hair cells should be stimulated more directly by basilar membrane displacements, whereas velocity of the basilar membrane is the effective input of the inner hair cells, as in fact demonstrated experimentally,29 although there appears to be a velocity component acting to displace the hairs of outer hair cells as well.195 Nevertheless, the implicit difference in the degree of coupling

FIGURE 21-8. A, Illustration of the manner in which displacement of the stapes leads to displacement of the cochlear partition (the basilar membrane, in particular). B, Peak displacement of the traveling wave at different frequencies of the sound stimulus. C, Dependence in part upon the stiffness gradient of the basilar membrane. (Based on drawings and data of Bekesy.3)

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suggests different roles for the two types of hair cells in the mammalian hearing organ. This and other issues established even earlier in the literature make a compelling case for such dichotomous roles of the two types of hair cells—long suspected. However, the ultimate story of this dichotomy well exceeds reasonable expectations for a sensory system.

Cochlear Macro Versus Micromechanics The nature and importance of the mysterious dichotomyis better appreciated after first considering the “big-picture” or macromechanics and limits of cochlear mechanics alone. Such considerations have driven research beyond the historic work of the late Nobel laureate Georg von Bekesy. Bekesy’s work was pivotal in developing an understanding of how the organ of Corti works mechanically, simply by absorbing energy of the sound stimulus delivered to the cochlea—a passive process. That events at issue are “macro” mechanics is evident from the fact that the vibration of the hearing organ involves the entire cochlear partition. The cochlear partition, the functional name for cochlear membranous labyrinth, comprises Reisner’s membrane, sensory and supporting cells of the organ of Corti, the basilar membrane, and the fluid contained in the cochlear duct or scala media. All these move largely together in response to fluid displacement caused by motion of the stapes. The basis of this motion is illustrated in Fig. 21-8A, revealed by Bekesy’s classic experiments,3 subsequently verified ultimately using highly sophisticated measurement techniques empowered by much more modern electronics/technology (e.g., see Rhode138). Noteworthy here is the fact that stapes displacement does not lead to bulk fluid displacement through the helicotrema, except for rather lowfrequency vibrations or static displacements of the stapes.28 An inward displacement of the stapes thus displaces principally perilymph in scala vestibuli (condensation phase of the stimulus), pushes down on the cochlear partition, displaces fluid in scala tympani, and then pushes out on the round window membrane. The opposite series of events occurs in response to a pull on the stapes (the rarefaction phase, excitatory to the hair cells). In this manner, the round window membrane vibrates sympathetically with vibration of the stapes.3 In Fig. 21-8A, the cochlea is uncoiled for illustrative purposes, and the cochlear partition is represented as a single membrane, the mechanics of which are determined extensively by the properties of the basilar membrane. Interestingly, a displacement of this membrane to a push on the stapes does not lead to uniform displacement along its length. The reason that the displacement of the cochlea is regional is due to the peculiar wave motion that is excited along the basilar membrane for a given frequency of stapes vibration (initially sound). This is called the traveling wave. The most familiar example of traveling waves is that of waves observed at the seaside, coming ashore. In the cochlea, traveling waves build up from the basalward aspect of the basilar membrane and crest as they progress apicalward. The swell of up-and-down motion of the

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wave capitulates at a place specific to frequency. It is at this place that the overall maximum displacement, especially when observed for several cycles, occurs and beyond which vibration of the partition decays quickly (Fig. 21-8B). It is in this way that frequency is transformed into a place code of excitation. Whether the central auditory system uniquely uses this frequency-to-place transformation for frequency analysis is considered later in the text. In any event, this mechanism provides efficient coupling of vibratory energy delivered by the stapes to the hearing organ over a broad range of frequencies. How traveling waves occur is somewhat involved, but the most obvious anatomical change along the hearing organ contributing to their behavior is the increase in the width of the basilar membrane, as shown by Fig. 21-8C. This imparts a gradient of stiffness along the basilar membrane. This is not the complete story of the frequency-to-place transformation, as a change in mass is inevitable, as well. The buildup appears to be mediated primarily by the stiffness gradient. The resulting motion has a fairly long wavelength (takes quite a distance, even to complete just a quarter cycle of vibration). Indeed, the motion basal to the ultimate maximum of the envelope of displacement of the basilar membrane is pretty much in phase. Then a sort of resonance ensues (wherein stiffness and mass effects counter each other). The traveling wave begins to slow down, wavelength shortens, and the effects of mass rapidly shut the vibration down. This accounts, subsequently, for the sharp apicalward slope of the traveling wave envelope and the steep high-frequency slope of single-neuron frequency tuning functions (see later in the text and the work by Geisler54 for a more detailed treatment of these events). Bekesy demonstrated traveling wave motion in a working hydromechanical model. The model was constructed so as to have a single membrane separating two fluid channels (nominally, scala vestibuli and scala tympani). The model cochlear partition was a thin film, essentially rubber cement, spanning a gap of increasing width distal to the model cochlear windows. Nevertheless, the reality is that the real cochlear partition is more complex, and such complexity cannot be ignored in the final analysis. On the basis of Bekesy’s observations, it had been estimated that, at just detectable levels of sound, displacement of the basilar membrane must be on the order of the diameter of the hydrogen atom, if not less! It is difficult to conceive of such minute displacements, let alone how they could be translated into any significant movement of the stereocilia, but linearity had been assumed in the calculation. Evidence of nonlinearities in the auditory system abound in the literature, however, and the nonlinearity of basilar membrane displacement has since become firmly established.74,139 This nonlinearity is compressive—proportionally less output (displacement) occurs with increasing input (SPL at the tympanic membrane). Even more intriguing was the ultimate realization that this nonlinearity is an essential characteristic of sound transduction by the hair cells themselves and the discovery of the specific, if not peculiar, role of the outer

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hair cells. It is these cells, indeed, to which the exquisite sensitivity of hearing is now attributed (see the work by Dallos23,27). The OHCs appear to serve more as effectors— motor cells—than receptor cells, serving thus a motoric function. Actin is recognized as an essential component in muscle cells and their contractile ability, suggesting a similar role in hair cells.166 This protein is prominent in the structure of hair cells, including the fibrous-like structure of the stereocilia that makes them stiff individually, if not somewhat brittle,48 not merely stiff in bundles tied together by the lateral links (as noted earlier). Truly one of the most exciting observations in hearing science since Bekesy’s work was the demonstration and subsequent confirmation that isolated outer hair cells react—contract and extend—to an applied electric field by changing in length.8,31 This property is now attributed primarily to a specialized protein—prestin—in the outer hair cell’s membrane25 (see Fig. 21-9). Given again the tight coupling of the tectorial membrane to the stereocilia and the inherent stiffness of the latter, the OHCs appear to facilitate the vibration of the organ by actively adding energy to this motion. The general principle23 is that the driving voltage is the OHC’s own receptor potentials that, in turn, activates motor units distributed throughout the OHC’s “skin,” providing positive feedback to the motion of the basilar membrane, hence a cochlear amplifier. This is not unlike how a child being pushed in a swing at the playground can facilitate their motion by pulling/pushing on the rope and kicking out when properly timed with the motion first imparted by their playmate. The child in the swing can go higher if he/she is not “just along for the ride” (active rather than passive involvement). Thus, it is clear that OHCs are not just along for the ride. Although the foregoing discussion of the underlying mechanisms of what clearly is an active process (not merely passive use of energy already in the motion

FIGURE 21-9. Schematic representation of motile response of the outer hair cell, particularly change in state of the protein prestin. Inspired by Dallos.25 (Adapted from Durrant and Feth.39)

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from the sound stimulus), there are details beyond the scope here that still beg complete resolution. Examples include, a taunting issue form more comprehensive circuit analysis of the cochlear partition, namely including capacitance that could cause shunting of the receptor potential at high frequencies, thus less electrical drive to the “motors” with increasing frequency. Whether hair bundle motility is the actual basis or at least a contributor to the cochlear amplifier is also debated.110 However, all the engineering invested into this system by evolution was not just for exquisite sensitivity (OHC motoric response) and wide dynamic range (compressive nonlinearity). It was also dedicated to selective response to sounds of different frequencies, thereby permitting the system to more precisely represent the frequency content of even the most complex sounds (like speech) and even at low levels of stimulation. The following sections are dedicated, first, to explore fundamentally the extent to which peripheral encoding is passed along and within the central auditory system and, second, what further processing might be implicated.

NEURAL ENCODING OF THE SOUND STIMULUS AND BASIC AUDITORY INFORMATION PROCESSING Frequency The links between the hair cell receptors and the central auditory system are, naturally, the primary auditory neurons that richly innervate the organ of Corti. The response of an individual neuron can be examined using microelectrodes. Much as one can determine the minimum audibility curve, the response area of an individual primary auditory neuron can be determined.85 As illustrated in Fig. 21-10A, the SPL at which a criterion increase in spike discharge rate (above the spontaneous rate) is measured versus frequency of stimulation. This “minimum audibility curve” for neurons is called a tuning function, and as seen in Fig. 21-10A, it has a sharp minimum or “peak” of sensitivity at one frequency—the characteristic frequency (CF). The value of the CF depends on the place of origin of the neuron along the basilar membrane. In other words, nerve fibers originating from more basalward regions will have higher CFs and those from more apical regions will have lower CFs. It is evident from the tuning function that although primary auditory neurons are quite selective in their sensitivity, they are not discretely sensitive to a single frequency. Also, the roll-off in sensitivity is much steeper for frequencies above than for frequencies below CF, particularly once the SPL has been increased approximately 40 dB above which CF occurs. The question that baffled researchers for many years is whether the observed pattern of the tuning function and the degree of frequency selectivity represented by the “tip” region of the tuning function around CF is attributable

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FIGURE 21-10. A, Tuning functions illustrating the frequency response of primary auditory neurons (in this case, from cat). Based on data of Kiang and Moxon88 as presented by Zwicker.191 B, Comparison of tuning functions for the response of the basilar membrane versus a first-order neuron. The solid line is a plot of the SPL required for 3 × 10−8 cm basilar membrane displacement at the point of observation in the base of the cat cochlea. The dashed line is a single-unit tuning function (obtained in a different animal and in another laboratory by MC Liberman); the data shown are from a unit whose characteristic frequency is near that at which the minimum of the mechanical tuning function occurs. (Adapted from Khana and Leonard.84)

completely to the cochlear hydromechanical events described earlier or is additional filtering needed between the receptor and the nerve cells? The answer, as illustrated in Fig. 21-10B, is now known to be the former; the peripheral mechanical events provide all the selectivity necessary to account for the tuning curves of primary auditory neurons.84 As tuning curves derived from psychoacoustic measures191 show little increase in selectivity over the

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tuning functions of primary auditory fibers, it appears that the cochlear mechanics account much for the frequency discrimination ability of the auditory system. However, as will be discussed further (see later in the text), some central processing is required for pitch perception and, in general, the processing of complex sounds, such as those created by musical instruments and speech. This is because, for complex sounds, there are correspondingly complex patterns of motion of the basilar membrane arising from overlapping traveling waves excited by the spectral components of the given sound.80 This creates a correspondingly more complex task for the auditory system than, say, differentiating between discrete tones of different frequency, one presented after the other (i.e., as typical of the classical psychophysical paradigm for determining the frequency difference limen, discussed in the introductory section of this chapter). Nevertheless, if in fact place is the primary cue for frequency encoding, it should be possible to reconstruct the overall pattern of motion of the basilar membrane from activity recorded from neurons throughout the acoustic nerve. Through tedious and meticulous electrophysiologic experiments, such demonstrations indeed can be, and have been, made.127 As the auditory neurons leave the hearing organ in an orderly fashion, the frequency-to-place code is also expected to be reflected in the organization of the central nuclei to which the primary fibers radiate. This organizational scheme, known as tonotopic organization, has also been demonstrated for all major nuclei of the central pathways and the primary auditory cortex (e.g., see Brugge and Geisler,10 Merzenich et al.,112 and Walzl174). As illustrated schematically in Fig. 21-11,

FIGURE 21-11. Schematic illustration of tonotopical organization of a nucleus along the brainstem auditory pathway. A tonal map of the cochlea is projected effectively onto this hypothetical auditory nucleus by virtue of the orderly connection between it and the hair cells along the basilar membrane. Thus, an electrode traversing the path indicated by the arrow records activity from neurons, the characteristic frequencies (CF) of which systematically vary from low to high.

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this is demonstrated by the systematic progression in CFs of neurons encountered as a recording microelectrode is advanced along an appropriate axis. It is as if the cochlea were mapped along this axis. Because there are multiple nuclei (starting with the dorsal and ventral cochlear nuclei) or major subdivisions of nuclei (e.g., the posterior and anterior ventral cochlear nuclei), there are actually multiple maps at most, if not all, levels of the ascending of the auditory pathway. The pervasiveness of tonotopic organization in the auditory system bespeaks the importance of the place code in the encoding and processing of frequency information. Yet, it is most certainly not the only cue. The auditory neurons show considerable ability to encode temporal features of the stimulus. As expected from basic neurophysiology, however, individual neurons are capable of following each cycle of the stimulus in a one-to-one fashion for only relatively low frequencies. The putative underlying mechanism is the notion of volleying of discharge among multiple neurons per (inner) hair cell179,181 although somewhat oversimplified in its original conceptualization. A more statistical concept is necessary to describe the temporal pattern of discharges, as illustrated in Fig. 21-12. Recalling that auditory neurons typically discharge spontaneously and randomly in the absence of external sound stimulation, it is shown here that the probability of discharge at any time reflects the stimulus waveform.9,143 The “probabilistic pattern” of synchrony is nevertheless robust and presumably efficiently assessed by virtue of each inner hair cell receiving upwards of 20 afferent neurons each. Degree of synchrony of auditory neurons to the periodicity of the stimulus is efficient up to 2 kHz and significant nearly up to 5000 Hz in mammals. Not only is such temporal information available for extraction by the central system to provide, for example, a sense of fundamental pitch for complex tones (even in the absence of energy at the lowest common frequency, so-called missing fundamental), it is also available for other temporal discrimination–based

FIGURE 21-12. Periodicity in the pattern of neural discharges reflected by a histogram of the spikes occurring in each time bin over the period observed. (Based on Brugge et al.9)

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tasks. The auditory system, for example, is also impressive in its ability to follow modulations of the amplitude imparted to high frequency tones (carriers) efficiently to modulation frequencies upwards of 1 kHz.75 However, perhaps the most important function is in binaural sound localization, to which the discussion alluded earlier. For now, it is sufficient to acknowledge that the auditory system is indeed capable of impressively high frequency and “high speed” temporal encoding, as expected of any system capable of encoding and processing of such complex stimuli as speech, particularly in real time.

Intensity The intensity of the sound is important too, of course, and must be encoded for neural transmission within and for further processing by the central auditory system. At the first level of encoding, the auditory system works like most sensory systems. As illustrated in Fig. 21-13A (HR function), intensity is translated into rate of spike discharge;87 hence, the more intense the stimulus, the more vigorous the rate of discharge of the auditory neuron. There are limits, however. First, the stimulus must be sufficiently strong to cause a significant increase in discharges above the background (spontaneous) rate. A possible exception is at relatively low frequencies wherein synchronous firing of the neurons is most robust; it may be sufficient in this case for there to be only a significant increase in the degree of synchronization without a net increase in discharge rate.143 The other limit is that the discharge rate ultimately saturates. At CF for neurons responsible for the most sensitive hearing (i.e., high-spontaneous rate fibers), this typically occurs at only 20–30 dB above the spontaneous rate. Off CF, this limit moves up to 40 dB or more.148 The saturation effect raises an interesting question. If the dynamic range of the individual neuron near CF is a mere 20–40 dB, how is it that the dynamic range of the auditory system is on the order of 140 dB? The dynamic-range puzzle remains a debated issue. A workable, although not infallible solution derives from the idea of “off-frequency listening” of the neurons, as implied earlier. Therefore, as intensity of the sound increases, a spread of excitation occurs (Fig. 21-13B). Looking across many neurons, the central auditory system thus sees continued growth in the total density of neural discharges, even after neurons tuned to/near the stimulus have saturated.182,183 Indeed, the notion of spread of excitation accounts well, for example, for how one tone masks (interferes with) the detection of another.177 This is known as “spread of masking.” Listening off-frequency, on the contrary, does not appear to be necessary for intensity discrimination, because nearly the same difference limens are obtained in the presence of stop-band noise,172 that is a masker with energy above and below (but not within) the desired frequency range. The density-of-discharge code also does not necessarily address, and indeed may complicate, the problem of preservation of

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FIGURE 21-13. A, Graph conceptually of spike rate versus intensity function for a first-order neuron monitored at the characteristic frequency, high (HR) versus low spontaneous rate (LR) fibers. Based in part on data from the cat from Kiang.87 B, Hypothetical histogram of spike rate for an array of fibers. The activity of these fibers is shown at only a few sound levels. The dotted line denotes saturation of fibers whose characteristic frequencies are near that of the stimulus (i.e., originating near the peak of the traveling wave excited along the basilar membrane). (Modified after Whitfield.196)

the spectral features of speech and other complex stimuli. There are, nevertheless, low spontaneous rate fibers that tend to have very wide dynamic ranges (Fig. 21-13A, LR function). Still, it seems likely that the central system must “decompress” the input from the periphery.186 The central system perhaps can set some rules for weighting activity from different neurons (e.g., based on synchrony of discharges), thereby preserving spectral features in the neural code149,190 (see Fig. 21-14). Furthermore, there are central neurons, at least in the cortex in primates, that show sharp tuning characteristics for intensity, much as most neurons show selectivity for frequency.4,128

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SECTION 2 ❖ Ear and Related Structures various levels of the central system. A basic flow chart for the human system, on the contrary, can be described for the on-response of neurons to presentation of a simple stimulus like the acoustic click (a brief broadband sound, like that produced by the snap of the fingers) in the generation of a signal broadly used in the objective testing of pediatric patients— the auditory brain stem response (ABR) (see later in the text and Chapter 23). The major “forward” flow of information through the brain stem to produce such a basic response of the system is shown in Fig. 21-15. The pathway involving the majority of ascending neurons, as classically described, appears to be crossed (through the trapezoid body and dorsal stria) but tends to bypass the superior olivary complex. Interestingly, only the less populous uncrossed and an even less populated–crossed pathway incorporates the SOC as a “weigh station.” A peculiar feature of the human system is the complexity of the nuclei of the lateral lemnisci. On each side are actually several nuclei, although only the dorsal nucleus seems to be involved in audition. Decussation also occurs at this level. Finally, the inferior colliculi appear to be mandatory synapses for all ascending fibers in the lateral lemnisci. The inferior colliculi thus receive terminations of second-, third-, and perhaps fourth-order neurons. Consequently, the auditory system has robust representation of each ear on both sides of the brain and ample opportunities for crossover of information from one side of the brain stem to the other.

Central Monaural Processing FIGURE 21-14. A, Spectral peaks in the spectrum of the phoneme [“ah”]. B, Representation of spike rates (normalized to saturation rate) as a function of characteristics frequencies, based on data from numerous single units stimulated at increasing SPLs, 20 dB intervals starting at approximately20 dB. C, Response profiles adjusted to a “localized” synchronous rate (log units), thus a rule-based weighting of putative influence of activity, providing better preservation of representation of spectral peaks of the phoneme across SPL. Based collectively on data of Sachs and Young149 and Young and Sachs.190 (Adapted from Durrant and Feth.39)

With the entry of the acoustic nerve into the brain stem, in effect, multiplication of the primary auditory neurons begins immediately. Therefore, as noted earlier, multiple tonotopical maps of the cochlea can be found throughout the auditory system. This may seem redundant, but there also appears to be increased specialization of the response patterns of auditory neurons at the level of the cochlear nuclei and higher

OTHER ASPECTS OF CENTRAL AUDITORY PROCESSING Functional Overview of Human Central Auditory Pathways To some extent, how the central nervous system processes information is suggested by the “wiring” of the central pathways. Much of what is known about the central auditory pathways, as in other parts of the system, draws heavily upon experiments in animals, but interspecies differences can be significant. Nevertheless, the detailed wiring of the human central auditory pathways is becoming much better understood (e.g., see Moore120). It is beyond the scope of coverage here to delve into a detailed discussion of the neuroanatomy of the central auditory pathways and functions performed at

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FIGURE 21-15. Schematic representation of the human brainstem auditory pathways, for input from one ear, as presumably involved in the onset response to an acoustic click. Relative neuronal populations of the primary and secondary crossed and uncrossed pathways are signified by line density. CN, cochlear nuclei; MSO, medial superior olive; DNLL, dorsal nucleus of the lateral lemnisci; IC: inferior colliculus. (Inspired by drawings of Moore.120)

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CHAPTER 21 ❖ Physical and Physiological Bases of Hearing centers. Whereas discharge patterns are pretty much the same from one primary neuron to the next, no less than five different patterns of discharge have been identified within the cochlear nucleus complex.86 As suggested in Fig. 21-16, these different patterns may be linked to the different morphological cell types, although the association of discharge pattern with cell morphology may not be exactly as shown nor as simple. Still, the observed variations in discharge patterns represent one mechanism of feature detection by central auditory neurons. For instance, the discharge pattern of some neurons reflect selective response to stimulus onset (see cell 4 in Fig. 21-16B), whereas others demonstrate varying patterns of response and after onset (compare cells 1–3, and 5, with 1 being primary like). More centrally, neurons may be found to be more sensitive to, say, frequency modulation than to the mere onset of the stimulus. Therefore, central neurons appear to be dedicated more to the detection of particular features of the stimulus.79,162 In addition, the circuitry of the central system is elaborated, as manifested by the multiplicity of

FIGURE 21-16. A, Schematic representation of connections between the peripheral auditory system and the cochlear nuclei: AVCN, anterior and PVCN, posterior ventral cochlear nuclei; DCN, dorsal cochlear nucleus. Some of the complexity of the morphology of the second-order neurons is indicated (5 different types of neurons illustrated). B, Possible relation between cell types and discharge patterns as reflected in poststimulus time histograms. Response types are as follows: 1—primary-like, 2—“chopper,” 3—primary-like with notch, 4—“on,” and 5—“pauser.” (Adapted from Kiang.86)

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ordering of neurons in the ascending pathways, branching of ascending fibers, and the formation of feedback loops. The idea of feedback suggests the presence of a substantial descending or efferent auditory pathway,61 as is the case, although it is the lowest part of the system—the olivocochlear system—that is best known.53,175 The central system thus possesses, at the very least, some capacity for varying its input sensitivity, namely at the level of the hair cells. Fig. 21-17 presents a concept of relative strengths of activation of ascending versus descending pathways in the course of a listener processing speech in noise (assuming right ear advantage). A curiosity of the olivocochlear system is the different innervation patterns relative to inner and outer hair cell function, underscoring again the dichotomous roles of the two receptor cell types. The efferents robustly innervate the outers directly through crossed and uncrossed fibers of the medial system, whereas the afferent neurons leaving the inners receive the efferent innervation, thanks to the ipsilateral olivocochlear system, strictly uncrossed neurons. Still, the efferent endings pale in numbers compared to the afferents. However, there, again, is also the middle ear muscle reflex system (not shown), serving a similar function in principle, although on essentially opposite ends of the dynamic range and perhaps with different

FIGURE 21-17. Concept of influence of major descending auditory pathways, upon (effectively) activation during stimulation of the ascending pathways by speech noise (presuming right ear advantage, i.e., left-hemisphere dominance cortically). Emphasis is placed on the olivocochlear system and its innervation peripherally through ipsilateral and medial crossed and uncrossed pathways. LH and RH, left and right cerebral hemisphere; IC, inferior colliculus; SOC, superior olivary complex; CN, cochlear nucleus complex; LE and RE, left and right ear. (Courtesy of Dr. Thiery Morlet, Dupont Children’s Hospital. Adapted from Durrant and Feth.39)

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contributions according to frequency region (given significant attenuation of input to the cochlea in the low frequencies; see earlier in the text). The two systems have been speculated to work symbiotically to improve signal-to-noise ratio,99 and there is support for the notion of a protective role for the efferent system (e.g., see Maison and Liberman103). Although there remains much controversy about the detailed functioning of the descending system, there is no lack of experimental evidence that this system can be activated and, once activated, does something. Direct tetanic electrical stimulation of the efferents, for instance, causes substantial suppression of cochlear nerve action potentials (APs), particularly at lower levels of stimulation (see Klinke and Gallay90). This is gratifying, because this is the end of the dynamic range over which the outer hair cells operate (without saturation) and given their receiving of direct efferent innervation.175 There has long been suspicion that the efferent system could influence frequency discrimination ability, as well, through changes in peripheral frequency tuning. However, some compelling findings from a study of single-unit tuning functions in cats with surgically induced cochlear de-efferentation failed to support such expectations.98 Continued interest in the auditory efferents, nevertheless, has been stimulated by investigations of otoacoustic emissions (OAEs); as discussed later in the text, these “echoes” from the inner ear are an expression of an active micromechanical process of the cochlea, and structural aspects of the organ of Corti, attributed to the outer hair cells.82 The OAEs have been found to be suppressed at least somewhat by contralateral stimulation,20 suggesting involvement of efferent pathways. Although this effect is not nearly as robust as the effects of electrical stimulation, frequency-specific effects and equivalent decibel shifts in OAE input–output functions under contralateral suppression suggest that efferent influence may be significant. Clear experimental evidence of a substantial contribution of the efferents to auditory processing, specifically in humans and in everyday listening situations, is still lacking (e.g., see Scharf et al.152). Yet, there are potential clinical interests for tests of efferent function.171

localization is a sort of coincidence mechanism that plays on differential effects of sound source location according to different path lengths for signals arriving at the level of say the superior olivary complex, given neural conduction to be time consuming.46,72 As this (and higher levels) sees both sides on each side of the brain stem, different neurons are supposed to react according to relative position of the sound source. Interestingly, there is evidence that the cochlear nuclei may also play a role in binaural processing, namely through descending pathway connections from the superior olivary complex and/ or by virtue of inherent properties of neurons of the dorsal cochlear nucleus. This neural circuitry may help to suppress echoes that could degrade precision of sound localization in reverberant sound fields.76 Although the functional anatomy may rather be involved, the basic cues for binaural sound localization114,123 are evident, as in effect suggested earlier in this chapter. To elaborate, these cues are more easily appreciated from observations on the related phenomenon of binaural lateralization132 (see Fig. 21-18). Lateralization is generally demonstrated through presentation of a sound to the two ears individually, namely through earphones. Despite this discrete mode of stimulating the two ears, the impression is that the sounds are fused and that this fused image is located somewhere inside the head between the two ears. (In contrast, the sound image is generally externalized with sound field [loudspeaker] or virtual surround [earphone] presentation, wherein the latter effectively

Binaural Sound Processing A truly impressive aspect of central auditory processing is binaural sound localization. Although the “majority” ascending auditory pathway is crossed, the ipsilateral ascending pathway is substantial.62 With decussation of fibers at several levels of the central system, it is clear that there must be considerable interaction of information from the two ears. Nerve cell specialization and/or “wiring” is also encountered that facilitates the comparator functions underlying binaural processing.15,16,44,71,106,121,144 There are neurons at the levels of the superior olive and the inferior colliculus, for example, that receive inputs from both ears and may be excited by binaural stimuli while being inhibited by monaural stimuli. The prevalent model for neural processing of ITDs in horizontal-plane

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FIGURE 21-18. Illustration of the binaural lateralization of the sound image obtained when the same frequency tone is presented through earphones. A, At the same intensity and time/ phase. B, At different intensities (ΔI), and C, At different times/ phases (Δt) to the two ears.

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CHAPTER 21 ❖ Physical and Physiological Bases of Hearing restores information from head and pinna baffle effects lost with simple earphones.) This is essentially the same paradigm used by the physician performing the Weber test with the tuning fork—the patient is asked to determine from which side of the head the sound seems to come. Normally, the tuning fork applied somewhere to the skull at midline stimulates the two ears at the same intensity, frequency, and phase. As illustrated in Fig. 21-18, this condition leads to the perception of a single sound coming from the center of the head. With either a larger amplitude (panel B) or leading phase or earlier arrival in time (panel C) of the sound to one ear, the sound image is lateralized toward that ear. Pathology in one ear can have the same effect, hence the percept of lateralization during the Weber test. Again, the binaural system is quite sensitive to interaural time and intensity disparities. That binaural processing is so well developed for processing interaural differences and the system exhibits truly keen sensitivity to ITD can be appreciated by the fact that neural transmission and synaptic delays from the—two to three orders of neurons involved must substantially exceed even the largest ITDs possible (i.e., acoustically, as noted earlier in the text). To recap the cues for localization, listening to sounds in a sound field (as in the environment), interaural disparities are created by the separation of the two ears and acoustic effects of the outer ear and head. Time and intensity cues each serve different frequency ranges in sound localization.114 At lower frequencies, diffraction that substantially/totally fills in the head shadow is due to head diffraction, in other words, scattering sound waves around the head. Horizontal-plane localization must then rely heavily on ITDs, indeed, whereas the contribution of ILDs becomes more substantial/dominant for sounds of increasingly higher frequency (shorter wavelengths). However, binaural processing for complex high– frequency sounds, typical of environmental sounds, appears to be less cut-and-dry. Temporal cues are actually available for such sounds by virtue of interaural delays in the envelopes of amplitude modulations of these sounds.189 Such amplitude modulations again are well represented in the temporal code (e.g., see Moller117), and the hair cell synapses appear to be uncommonly efficient50 as sensory systems go, presumably serving a capacity for exquisite preservation of timing information. Finally, sounds coming from above, in front, below, or behind the listener present ambiguous interaural disparities, so, again, elevation-dependent changes in the HRTF (due ostensibly to the acoustic effects of the auricle) come into play sound localization in three-dimensional space. The emphasis here on sound localization, however, is not meant to imply that binaural processing is singularly dedicated to this function. Binaural processing also facilitates the detection and discrimination of sounds in a background of noise108 as well as selective attention.17 Indeed, one of the most common complaints of the unilaterally hearing impaired and hearing impaired individuals wearing only one hearing aid is difficulty in understanding speech in noisy places, at meetings, or in other situations in which there are “competing messages.”

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Cortical Processing Auditory processing at the cortical level is an expansive topic well beyond the purpose of this chapter, but it will be useful to briefly overview basic aspects relative to the basic auditory capacities and underlying mechanisms discussed earlier in the text. Much, if not all, of the processing discussed earlier can/ is actually likely to be accomplished at the brain stem level of the central auditory system. It has been shown, for example, that auditory decorticate animals are capable of detecting the presence of sound and changes in intensity, frequency, and location of sound.14,16,63,105,124 Hence, given that the capabilities of brain stem auditory processing are so impressive, one may wonder just what, if any, auditory abilities require cortical processing. First, there is no doubt of the necessity of cortical processing for cognition and deciphering speech information that, in turn, doubtlessly requires even more than the primary auditory cortex, per se. In addition, auditory decorticate animals (such as cats) have been found to be incapable of distinguishing between tonal patterns (wherein the same tones are included in the different patterns presented), discriminating changes in sound duration, and, in general, discriminating between stimulus conditions that involve no net change in neural activity.124 Although such animals show amazing abilities to compensate, they appear not to truly localize sound in space. This requires an internal map of auditory space92 that is apparently relegated to the cortex.5 The neuroanatomical and neurophysiological bases for cortical auditory processing are many, but the gross manifestations are tonotopical organization over the surface of the primary auditory cortex51,112,142,187 and perhaps columnar organization through different layers.1,52,70,81 The former is perhaps a mere byproduct of the orderly arrangement of neurons in the ascending pathway. Still, this system should serve to presort information according to frequency. Columnar organization, which is known better in other sensory systems, is perhaps the basis for the more advanced processing for which the cortex is responsible. At the cortex, one also expects even further specialization in the response of the neurons, and it is through the layers of the cortex that the morphological variants in the cells and the intracellular circuits are found that would be expected, intuitively, to be required for this advanced processing.

OBJECTIVE ASSESSMENT OF AUDITORY FUNCTION: PHYSIOLOGICAL-ACOUSTICAL BASES Throughout this overview of the auditory system, great reliance has been placed upon information obtained from singleunit recordings in infrahuman species, that is, bioelectrical recordings made utilizing microelectrodes capable of picking up activity from just outside or even inside single cells. However, there are also a number of gross or compound potentials

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that can be recorded in the auditory system; one of these, the EP was already mentioned. There are also various stimulusrelated potentials. Much more surprising is the appearance of weak, but readily measurable, echo-like sounds appearing in the ear canal but originating from the cochlea. These sound-evoked responses represent the activity of many cells (receptor or neural), have provided valuable indices of endorgan, eighth-nerve, and central pathway activation for basic research of auditory function. Most have proven also to be recordable, at least to some extent, in humans through noninvasive methods and to have substantial research and clinical utility. Details of such clinical applications and methods are presented in other chapters; underlying principles of the phenomena and such applications/methods are presented here.

Electrocochleography The stimulus-related electrical potentials of the organ of Corti and the acoustic nerve comprise the electric response whose recorded waveform has been called the electrocochleogram. First, there are two cochlear potentials that arise from hair cell receptor potentials—cochlear microphonics (CM)24,181 and summating potentials (SP),24 as shown in Fig. 21-19. The CM has a waveform that mimics the waveform of the sound stimulus. Therefore, if the stimulus is a tone burst, the CM will appear as a sinusoidal pulse. However, the CM waveform will often appear to be offset—the zero axis will be displaced above or below the baseline of the recording (Fig. 21-19). If the CM is “stripped” away through low-pass filtering or averaging with phase cancellation, this offset can be isolated. This is the SP—a direct current pulse in response to tone bursts. The CM and SP are products of mechanoelectrical transduction of the hair cells, with the SP being a direct manifestation of the hair cells’ characteristic nonlinearity.24 A small component of the SP may also arise from the dendrites of the primary auditory neurons, reflecting generator potentials.26 The CM and SP are recordable in the cochlear fluid spaces, on the

FIGURE 21-19. Tracings from recordings of the cochlear microphonic (CM) and summating potential (SP) along with the output of the monitoring microphone (SOUND). Insets show details of tracings through an expanded timebase. (Adapted from Durrant.34)

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round window, and at remote extracochlear sites (such as on the eardrum), hence, they are clearly extracellular manifestations of the unit receptor potentials of many stimulated cells. The unit potentials, in turn, are distributed through the elaborate electroanatomy of the cochlea. Thus, the genesis of these grossly recorded potentials is somewhat complex, yet they provide useful indices of the hydromechanical events of the cochlea and the integrity of the hair cells (e.g., see the work by Dallos24 and Durrant36). The other component of the electrocochleogram is the whole-nerve AP.24,181 This is the compound AP of the acoustic nerve in response to the onset and (to a lesser degree) offset of a sound stimulus, as shown in Fig. 21-20. Although primary auditory neurons discharge repeatedly in the presence of sound, it is at the onset of sound that they respond most vigorously (see Fig. 21-16) and to which discharges most synchronized. In general, compound nerve APs are proportional to the number of neurons activated.77 Although tone bursts and other means of stimulation can be used to derive frequency-specific information from the AP,30 the most robust responses tend to be obtained with the broad-spectrum transient known as the “click” (again, a sound similar to that produced by a snap of the fingers). Nevertheless, the AP tends to represent excitation with a bias toward the basalward fiber populations where synchronization is best.86 The AP, then, provides an indication of the pattern of excitation of the auditory neurons. Like the cochlear receptor potentials, the AP can also be recorded from inside or outside of the cochlea. Recording the AP and other components of the electrocochleogram at extracochlear sites accessible clinically requires appropriate electrodes, methods, and signal processing using computer-based signal averaging. For greatest

FIGURE 21-20. Recording of the whole-nerve action potential (AP). Inset: time-base expanded to illustrate major component waves of the AP (N1 and N2). The top trace is actually the SP-, used here to indicate exactly when the stimulus has been “turned on and off” at the level of the hair cell transducer (thus eliminating inherent time delays due to propagation of sound down the ear canal and of the traveling wave in the cochlea). (Adapted from Durrant.34)

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CHAPTER 21 ❖ Physical and Physiological Bases of Hearing sensitivity, the transtympanic method2 is preferred. A needle electrode is pushed through the eardrum with its tip resting on the promontory. However, this method generally requires local anesthesia or, in children and some adults, general anesthesia. On the contrary, with an acceptable loss of sensitivity for most purposes, it is possible to obtain electrocochleograms of reasonable quality from the surface of the tympanic membrane161 or the surface of the skin of the external auditory meatus.18 However, the farther away from the eardrum, the poorer the sensitivity and quality of the recording, because the signal diminishes systematically with distance from the cochlea, whereas the noise level is essentially independent of site. The AP is also reasonably prominent (at least in normal hearing subjects or subjects with only mild hearing loss) in surface recordings, namely from the ear lobe or mastoid, and represents the “front end” of the ABR, which is to be discussed momentarily. The choice among the various methods is a matter of what information is being sought and costbenefit considerations (i.e., the need to know) versus potential risks, should sedation or anesthesia be required. Before moving forward along the auditory pathway, it is useful to go backward for the moment, but there is another and rather startling signal of hair cell activation or more precisely complex of signals that depended on the status of the outer hair cells and generally by a combination of factors that include the inherent nonlinearity of these cells, the somewhat irregularities of their pattern in the population of the hearing organ’s surface, and cochlear mechanics. These are the OAEs.

Otoacoustic Emissions What is “startling” is that such signs of outer hair cell function, as hinted above, are acoustic signals (rather than electrical). Over a half century ago, Gold (see the work by Kemp83) suggested an active model of hair cell transduction that would lead to the feedback of sound from the inner ear. However, it is only relatively recently that OAEs were actually demonstrated supporting Gold’s theory83 (see Fig. 21-21). The OAEs have now been studied extensively (see review by Probst136) and have gained extensive clinical interest for purposes of objective assessment of peripheral sensitivity.102,140 Although not an electrophysiological response per se, OAE measurement is an evoked response method and objective test of auditory function, providing clear signs of the “reaction” of the hearing organ to sound. The OAEs are intriguing in particular as they, indeed, appear to reflect the excitation of an active micromechanical process, now recognized as the motile response of OHCs discussed earlier. That the OAEs really do come from the interior of the cochlea is suggested by several factors as follows: (1) the acoustic response has a latency and persists beyond mere reflections off the eardrum; (2) OAEs are vulnerable to adverse metabolic conditions; (3) they are absent in cases of partial or complete cochlear deafness (and in dummy/test cavities simulating the volume of the ear canal); and (4) they grow nonlinearly with stimulus level.

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FIGURE 21-21. Transient evoked otoacoustic emission recording obtained in an ear of a 7.5-year-old female with entirely normal hearing (specifically, pure-tone audiometric thresholds of 5 dB hearing level or better). A, Amplitude scale set to permit examination of the input (click) stimulus; the stimulus was 83 dB SPL (peak equivalent). B, Time window extended, sensitivity increased, and initial 4 ms of trace zeroed (blanking out input stimulus) to favor detailed inspection of the otoacoustic emission itself; there are actually two tracings overlaid, demonstrating the outstanding reproducibility of the response in this subject. (The stimulus was presented in the “nonlinear” mode, a paradigm that assures negligible contribution of stimulus artifact.). C, Spectra of the response versus background noise (black area), demonstrating the excellent signal-to-noise ratio in this case. (Data courtesy of Diane Sabo, PhD, University of Pittsburgh.)

The OAEs are measured using miniature transducers for sound generation and measurement in the ear canal, together with computer signal processing techniques similar to the measurement of evoked electric responses. Fig. 21-21 illustrates the click-evoked OAE (one of several OAE measures available). Although the click stimulus facilitates observation of the “cochlear echo” and is a useful clinical/screening test paradigm, OAEs can be elicited by brief tone bursts as well as continuous sounds (the latter being known as stimulus frequency emissions). Distortion products (DPs) in the OAE can also be recorded. Two frequency primaries are presented, f1 and f2. Another component of broad research and clinical interest currently is the cubic DP whose frequency is equal to 2f1–f2, although other order DPs are measureable. The keen interest in the cubic DP is attributable to two facts—2f1–f2 tends to be the most robust of such intermodulation products overall and is pervasive in yet other auditory measures (e.g., the easiest product that one can “hear out” in psychoacoustic experiments). The audiogram-ish “DPgram” (e.g., plot of DP SPL as a function of f2 at moderate sound levels) has natural clinical appeal and at times can present sensitive and vivid objective evidence of even punctate lesions, such as in the case who experienced a temporary borderline-mild hearing

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FIGURE 21-22. Audiogram. A, Demonstrating a mild, punctate cochlear loss and corresponding “DP-gram.” B, Demonstrating the excellent sensitivity of otoacoustic emissions to such fine hearing losses. Solid line: distortion product otoacoustic emission (2f 1–f 2); dotted line: noise floor of recording (f 2/f 1 = 1.2, P2 = P1 = 65 dB SPL).

loss “focused” around 2 kHz (Fig. 21-22). Yet, even more intriguing from a theoretical perspective, although of little apparent clinical value, is the spontaneous otoacoustic emission (SOAE). This OAE occurs in the absence of external stimulation. Many normal-hearing adults and most newborns produce measurable SOAEs, and they may appear at 1–5 or more frequencies, although typically found in the mid-range of hearing (namely where the middle ear is most efficient).

Far-field and Cortical-evoked Potentials The excitation of the whole-nerve AP by an abrupt sound actually initiates a series of electrical waves reflecting a relatively long-lasting response of the nervous system131 (see Fig. 21-23). Within the first few milliseconds or so after the onset of the stimulus, the APs of the primary auditory neurons are triggered and propagate through the nerve trunk to the cochlear nuclei. As the nerve trunk is insulated well (electrically) within the internal auditory meatus, the electrical manifestations of this initial bioelectrical activity, as seen from surface electrodes, are two waves—one essentially from the distal end and the other from the proximal end of the nerve.118 Then the second and higher order neu-

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FIGURE 21-23. Components of the auditory evoked response recorded with scalp electrodes from a human subject, elicited by an acoustic click (presented 60 dB above the subject’s behaviorally determined threshold). Tracings obtained in four different trials are overlaid to demonstrate repeatability of the responses. Top, Short-latency or “brain-stem” components. Middle, Middle latency components. Bottom, Late or long-latency (cortical) components. Major wavelets are labeled according to convention. Note: vertex positive voltages are plotted in the downward direction, for consistency between tracings here and in Fig. 21-20, in turn following the “absolute” polarity of the compound nerve response. This is opposite of the most popular convention (see Chapter 23) but is merely a matter of how the electrodes are connected to the recording amplifier. (Adapted from Picton et al.131)

rons are excited. From here, the picture gets increasingly cloudy and controversial as to which structures, specifically, are most responsible for which “bumps” in the waveform

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CHAPTER 21 ❖ Physical and Physiological Bases of Hearing of the potential. At least three, perhaps four or five, waves are presumed to arise sequentially from generators in the brain stem auditory pathways11,119 with waves III–V reflecting activity from the brain stem at levels from the cochlear nuclei to the inferior colliculus.41,120 Therefore, whereas the time difference between the occurrence of the first and the third waves reflect peripheral propagation of APs, the interval between the third and the fifth waves reflect transmission through the pontine-level pathways. The components of the electrocochleogram and the aforementioned brain stem potentials constitute the class of auditory evoked potentials (AEPs) known as short-latency potentials or the “fast components.” The whole-nerve AP and brain stem potentials thus collectively constitute the ABR that occurs approximately within the first 10 ms of stimulus onset (depending on the intensity and spectrum of the stimulus, maturation, and other factors). As more time is permitted between stimuli, still other potentials emerge (Fig. 21-23). The time window of approximately 10–50 ms contains the middlelatency response (MLR). The components of the MLR arise from higher auditory brain stem centers and primary auditory cortex.131 Finally, there are the long-latency potentials that are cortical in origin (see the work by Reneau and Hnatiow137). The P1–N2 components demarcate what has traditionally been called the AEP, but the long-latency responses include still other components, such as the mismatch negativity, cognitive potential (or P300), contingent negative variation, sustained, and steady state potentials. The long-latency potentials presumably reflect activity of much more than primary auditory cortex and appear to reflect discriminatory, cognitive, and integrative processing.134,150 All these potentials can be recorded from common electrodes placed on the surface of the scalp (e.g., one electrode on mastoid and the other at the vertex). Analysis filter and time windows, recording montage, and stimulus parameters/paradigms are varied to emphasize one class of potentials or response component over the other. The shortest latency potentials are the smallest and require the most stimulus repetitions to achieve enough signal-tonoise enhancement through signal averaging to extract them from the background noise. Here too, which potentials are recorded and the techniques used are matters of what information is desired and the need to know. In addition, because the long-latency potentials can be quite sensitive to level of arousal and even state of attention,153 the clinical application of these potentials tends to be more restricted than that of the shorter-latency potentials, which, in turn, are relatively unaffected by level of arousal (from comatose to awake and alert) or by most sedatives or anesthesia, particularly the eighth nerve and brain stem components.

audiometry. Further interest derives from their inherent value in the assessment of neurologic integrity. Now, there are various methods by which to extract synchronized signals from scalp-recorded (noninvasively recorded) brainwave activity, that is, to evoke such responses to various signals (from clicks to speech) and map responses across the scalp or deduce source locations. Some of the more modern and/ or advanced methods and applications are considered elsewhere in this book (again, see Chapter 23); the treatment here focuses on the most classical and basic responses and methods. Starting from the top and working down the auditory pathways, the long-latency or cortical AEPs have been known for decades and, indeed, have commanded interests from otologists, neurologists, audiologists, psychologists, and psychiatrists. However, interests in the long-latency responses waned considerably among otolaryngologists and audiologists during the 1970s, the period of research and development of short-latency potential measurement using surface-recording methods. Nevertheless, the P300 has attracted interest back to the long-latency time frame and, indeed, much excitement (more recently) has been developed regarding a component that occurs just before the P300, known as the mismatched negativity (MMN). Like the P300, the MMN is demonstrated by comparing averages involving epochs recorded with infrequently versus frequently occurring stimuli. The MMN however can be elicited in inattentive subjects and potentially as the basis for objective assessment of central auditory function in pediatric as well as adult subjects, particularly precognitive discrimination processing of complex stimuli-like speech.94,95 The MLRs have also grown in interest and may be used singly or in conjunction with ABR evaluations. These potentials may provide the basis for a more comprehensive analysis of auditory function (than ABR alone), because, at least, some components of the MLR appear to arise from the primary auditory cortex. The MLR is also attractive for objective audiometry, at least as an adjunct to ABR-based testing. The MLR exhibits reasonably good responsivity to low-frequency stimuli,93,111 whereas ABRs elicited by low-frequency stimuli are less robust. By far, the greatest interest in evoked potentials for otologic, neurotologic, and audiologic clinical applications, nevertheless, has been focused on the ABR (see reviews by Durrant and Wolf42 or Durrant and Ferraro38 or Goldstein and Aldrich57 for more in-depth coverage). Within a decade of the first description of the ABR in the literature, ABR evaluations became a routine offering of audiology clinics, otology and neurology practices, and electroencephalography laboratories. Evaluations of the ABR have proven valuable in several areas as follows:

Fundamentals of Clinical Utility

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Nearly all AEPs (with suitable recording and processing methods) are traceable to or near the limits of hearing, as determined by conventional audiometry (namely, using behavioral methods), making them of keen interest for objective

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determination of the integrity of the auditory nerve and brain stem to detect and distinguish between cochlear and retrocochlear lesions (“site-of-lesion” testing) screening for possible hearing defects in newborns estimating hearing thresholds in pediatric and other difficult-to-test patients

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intraoperative monitoring during otologic or neurosurgery screening/monitoring brain stem function in critically ill or comatose patients, including evaluations of brain death

The bases of clinical applications of ABR testing are summarized in Fig. 21-24. Here, key features for some common nonpathological and pathological cochlearversus-retrocochlear effects on this response from actual recordings in an intact subject (Fig. 21-24, top tracings) are shown. In brief (but see Chapter 23 for in-depth treatment of this topic), stimulus level normally has substantial effects on ABR wave morphology (waveform and number of peaks) and latencies (time from stimulus onset to a given peak). It is the features of these responses that permits hearing sensitivity and/or type of hearing impairment to be deduced, namely that empowers electric response audiometry. The pure conductive lesion (here simulated from the “normal” traces) acts as if the stimulus level has simply been decreased. Initially, pure cochlear sensorineural losses (also simulated in Fig. 21-24) have the same effect, but a neural recruitment effect then takes over at higher levels of stimulation. This is akin to loudness recruitment—ability to experience nearly normal loudness at high SPLs in the face of elevated hearing thresholds. Such effect works only if there is adequate residual sensorineural function in the face of the particular end-organ lesion (as in cases of mild to moderate high-frequency hearing losses, upwards of severe in some cases, but not severe to profound losses). Finally, a pure retrocochlear lesion will cause various effects, depending on its etiology and location along the nerve or pontine auditory pathway. The results in Fig. 21-24 from an acoustic tumor case, for example, demonstrate primarily reduced neural conduction efficiency

FIGURE 21-24. A, Normal ABR recorded at click-stimulus hearing levels indicated just at and above hearing threshold of the acoustic click stimulus—full sequence of wave components as normally evoked at 70–90 dB hearing levels. In subsequent tracings, characteristics of lesions, as indicated, are simulated from these recordings, as follows: B, Flat conductive loss; C, High-frequency sensory loss. D, Actual responses from a case of acoustic tumor, expressed in this case predominantly as a wave I–III latency prolongation (see text). DNT: did not test. (Adapted from Durrant.197)

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between the organ of Corti and the cochlear nucleus complex. The bottom two sets of tracings thus demonstrate differential diagnostic applications of the ABR. Although the ABR is a sensitive indicator of end-organ, auditory nerve, and brain stem pathology (see the work by Starr and Achor,159 Selters and Brackmann,155 and Glattke56) and it indeed can be used to estimate hearing sensitivity,109 ABR evaluations are not tests of hearing, per se. Thus, objective audiometry should not be viewed as equivalent to or a replacement for behavioral audiometry. The stimuli used are often brief transients, such as clicks and tone pips (perhaps 3 ms duration or less) unlike the relative long-duration tone bursts used in audiometry, although alternative approaches are available to close this gap between methods (such as auditory steady-state responses). More importantly, here is the simple point that normal ABR findings do not guarantee hearing/normal hearing. The ABR certainly reflects some aspect(s) of auditory processing but is not necessarily dependent on the same neural events that are essential for perception or the auditory capabilities discussed earlier.57 Indeed, as a compound neural potential, the ABR merely reflects the most robust and the most redundant feature of auditory neuronal response—stimulus onset (as noted earlier). During the early development of the ABR evaluation as a clinical tool, clinical electrocochleography also was “vying” for acceptance as a routine test procedure. Although interest in electrocochleography has waxed and waned in the United States, noninvasive electrocochleography is certainly a useful supplement to the ABR evaluation, that is, to improve the pickup of the auditory nerve component.35 In addition, the SP is known to be especially sensitive to cochlear hydrops or Ménière’s disease19 and may be useful in the assessment of fistulas.13 Auditory neuropathy/dyssynchrony,160 in effect, has given electrocochleography another surge of clinical interest as it may be useful in more clearly defining this recently described etiology, by way of the observation of robust CM appearing in the surface-recorded ECochG (an inherent part of routine recording of the ABR), which in such cases is essentially absent of eighth-nerve and (consequently) brain stem components. On the contrary, combined OAE and ABR testing is particularly helpful in the evaluation of many such cases/suspects, as well as other retrocochlear lesions37 and is technically less demanding than trans- or extra-tympanic electrocochleography. It seems fitting to return once more to the organ of Corti in this overview of clinical applications of basic auditory phenomena, as the OAE (again) is quite sensitive to pathology of the hearing organ, as well as yet another evoked response traceable to the limits of hearing. Hence, the level of clinical interest that OAEs command is well justified. All methods of OAE measurement are viable candidates for applications in newborn screening, but current interests remain focused upon transient and distortion-product OAE testing. The evoked OAE methods also permit the acquisition of frequencyspecific information, suggesting audiometric-like applications. This is a perceived strength of DPOAE assessment, in

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CHAPTER 21 ❖ Physical and Physiological Bases of Hearing particular. Again, the analysis of DPOAEs naturally produces an audiometric-like graph, commonly called DP-gram (see Fig. 21-22). The major limitation of OAE measurement for purposes of objective audiometry lies in the fundamental fact that OHCs are directly implicated in the generation of OAEs170; OHCs account for only the first 40 dB or so of the dynamic range of hearing, as alluded to earlier. Consequently, for the quantitative assessment of cochlear impairment, the test is inherently limited to hearing losses of merely subclinical and mild degrees, although mere detection of more severe losses is clearly possible. Therefore, for hearing screening, this limitation is not a problem. A global problem, however, is the limited usable frequency range. This limitation is due, first, to the noise floor of the analysis that rises systematically with decreasing frequency, typically obscuring the response starting somewhere below 1 kHz (Fig. 21-22). Finally, as OAEs truly are sounds conducted out of the inner ear, the status of the middle ear is an important and potentially confounding variable.104 For purposes of screening auditory pathology, this too is not necessarily a limitation, but it is likely to account for some false positives in newborn screening, that is, relative to true incidence of congenital sensorineural hearing losses. Nevertheless, OAE assessment has received wide interest and endorsement for newborn screening and other clinical applications. Screening of OAEs is generally considered to be a more efficient test than ABR screening, an important consideration for universal newborn screening. Large-scale studies have recently been completed and are providing information by which practical programs may be implemented (e.g., see the work by Maxon et al.107 and Prieve et al.135). Screening OAEs in older children for purposes of “school screenings” is also being considered.125

A

B

Normal

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Finally, OAE testing can certainly be useful in qualitatively corroborating hearing loss, particularly in the differential diagnosis of peripheral versus central disorders, as alluded to earlier (see the work by Durrant and Collet37 for review). This is illustrated further by clinical data presented in Fig. 21-25, which also serve to summarize various points discussed in the foregoing paragraphs. Here, click-evoked transient OAEs recorded in the normal ear of a patient and in the opposite ear, presenting a 4-kHz “noise” notch audiometrically. This is most certainly a case of end-organ pathology (definite history of acoustic trauma). In contrast are the OAE findings in one ear of another patient with a similarly notched audiogram, although occurring an octave lower. This case proved to be one of retrocochlear lesion due to an acoustic tumor. The latter-most findings, however, are entirely typical of the effects of acoustic tumors that can involve concurrent end-organ and eighth-nerve pathology, because such tumors may compress both the nerve and the cochlear blood supply.40,165 Nevertheless, OAE testing paired with electrophysiological methods can be extremely valuable in teasing out the relative contributions of sensory and neural components of hearing loss.37 Here, the inherent frequency specificity of the DP-gram is particularly useful. In addition to the obvious importance of detecting/confirming central pathology, it is important to confirm the peripheral component. This is not only a matter of differential diagnosis and medical treatment or other management of a central lesion, but also medical treatment and nonmedical therapeutic approaches to an endorgan or more peripheral component of the hearing loss, such as through hearing-aid fitting. In summary, it is now technically feasible to record objective indicators of auditory function at essentially any level

SENSORY LOSS

|*

NEURAL LOSS

|**

FIGURE 21-25. Audiograms. A, Click-evoked otoacoustic emission results. B, For right (normal) and left (sensory loss) in a case of unilateral acoustic trauma and for a case of acoustic tumor of the right ear (neural loss). In the “sensory loss” case, the spectrum (“response” window) shows no measurable emission in the frequency region of the hearing loss,* in contrast to the “neural loss” case, showing robust emissions in the vicinity of the hearing loss. **“Nonlinear” click mode. (Data courtesy of Lionel Collet, MD, PhD, Claude Bernard University, Lyon, France.)

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of the auditory system using noninvasive techniques. OAEs provide yet another measure of auditory function, particularly the most sensitive side of the auditory response area. Together with immittance test methods—tests of middle ear function (see Chapter 23)—the clinician has at his/her disposal an incredible armamentarium of objective test methods. Such tests may be employed to supplement information from more traditional tests or to provide an indication of the functional status of the auditory system when more traditional methods are unsuccessful or simply not applicable. Modern technology and accompanying computer economics have made these test procedures broadly accessible, nearly foolproof, and, thus, alluring. Such methods, however, must be applied with a solid foundation of knowledge of auditory function. The goal of this chapter was to provide such background. For only with sufficient understanding of the workings of the auditory system can inappropriate test use and/or interpretation be avoided.

Acknowledgment The author expresses his appreciation to his friend and colleague, Jean H. Lovrinic, PhD, for her helpful comments and criticisms of this chapter in earlier editions and to whom this chapter is dedicated for her years of service to the audiology profession.

Selected References Durrant JD, Feth LL. Hearing Science—A Foundational Approach. Boston, MA: Pearson Education; 2013. Comprehensive introductory text providing not only more depth of coverage of physiological acoustics and psychoacoustics, as summarized herein, but also underlying fundamentals from physics/acoustics to neurophysiology, to psychoacoustics. Geisler CD. From Sound to Synapse. New York, NY: Oxford University Press; 1998. In-depth treatise on the physiology of hearing, particularly the initial stages of encoding from outer ear to brain stem, including a thorough but “user-friendly” treatment of such concepts as nonlinearity and its importance in auditory processing. Moller A. Hearing: Anatomy, Physiology, and Disorders of the Auditory System. 2nd ed. Burlington, MA: Academic Press; 2006. Extensive academic treatment of the peripheral and central auditory systems, including relevant aspects from both basic science and disordered function and substantial coverage of functional assessments, by an author who gives pervasive contributions to the basic and clinical literature in hearing science across the auditory system.

References 1. Abeles M, Goldstein MH Jr. Functional architecture in cat primary auditory cortex: columnar organization and organization according to depth. J Neurophysiol. 1970;33:172.

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2. Aran JM, Portmann M. Electrocochleography in adults and children. Electrophysiological study of the peripheral receptor. Audiology. 1972;11:77. 3. Bekesy G von. Experiments in Hearing. Wever EG, trans-ed. New York, NY: McGrawHill; 1960. 4. Bilecen D, Seifritz E, Scheffler K, Henning J, Schulte A-C. Amplitopicity of the human auditory cortex: an fMRI study. Neuroimage. 2002;17:710. 5. Benson DA, Hienz RD, Goldstein MH. Single unit activity in the auditory cortex of monkeys actively localizing sound sources: spatial tuning and behavioral dependency. Brain Res.1981;219:249. 6. Borg E, Zakrisson JE. The activity of the stapedius muscle in man during vocalization. Acta Otolaryngol (Stockh). 1975;79:325. 7. Briaire JJ, Frijns JHM. Field patterns in a 3D spiral model of the electrically stimulated cochlea. Hear Res. 2000;148:18. 8. Brownell WE, Bader CR, Bertrand D, de Ribaupierre Y. Evoked mechanical responses of isolated cochlear outer hair cells. Science. 1985;227:194. 9. Brugge JF, Anderson DJ, Hind JE, Rose JE. Time structure of discharges in single auditory nerve fibers of the squirrel monkey in response to complex periodic sounds. J Neurophysiol.1969;32:386. 10. Brugge JF, Geisler CD. Auditory mechanisms of the lower brainstem. Annu Rev Neurosci. 1978;1:363. 11. Buchwald JS, Huang CM. Farfield acoustic response: origins in the cat. Science. 1975;189:382. 12. Butler RA, Helwig CC. The spatial attributes of stimulus frequency in the median sagittal plane and their role in sound localization. Am J Otolaryngol. 1983;4:165. 13. Campbell KC, Parnes L. Electrocochleographic recordings in chronic and healed perilymphatic fistula. J Otolaryngol. 1992;21:213. 14. Canford JL. Auditory cortex lesions and interaural intensity and phase angle discrimination in cats. J Neurophysiol. 1979;42:1518. 15. Casseday JH, Covey E. Central auditory pathways in directional hearing. In: Yost WA, Gourevitch G, eds. Directional Hearing. New York, NY: Springer-Verlag; 1987:109. 16. Casseday JH, Neff WD. Auditory localization: role of auditory pathways in brain stem of the cat. J Neurophysiol.1975;38:842. 17. Cherry C. Two ears—but one world. In: Rosenblith WA, ed. Sensory Communication. Cambridge, MA: MIT Press;1959:99. 18. Coats AC. On electrocochleographic electrode design. J Acoust Soc Am.1974;56:708. 19. Coats AC. The summating potential and Meniere’s disease. Arch Otolaryngol.1981;107:199. 20. Collet L, Kemp DT, Veuillet E, Duclaux R, Moulin A, Morgon A. Effect of contralateral auditory stimuli on active cochlear micromechanical properties in human subjects. Hear Res.1990;43:251. 21. Corso JF. The Experimental Psychology of Sensory Behavior. New York, NY: Holt, Rinehart & Winston; 1967:280. 22. Corso JF, Levine M. Pitch discrimination at high frequencies by air and bone conduction. Am J Psychol. 1965;78:557. 23. Dallos P. The active cochlea. J Neurosci.1992;12:4575. 24. Dallos P. The Auditory Periphery: Biophysics and Physiology. New York, NY: Academic Press, 1973. 25. Dallos P. Cochlear amplification, outer hair cells and prestin. Curr OpinNeurobiol. 2008;18:370.

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72. Jeffress LA. Binaural signal detection: vector theory. In: Tobias JV, ed. Foundations of Modern Auditory Theory. Vol. II. New York, NY: Academic Press; 1972:351. 73. Jesteadt W, Wier CC, Green DM. Intensity discrimination as a function of frequency and sensation level. J Acoust Soc Am. 1977;61:169. 74. Johnstone BM, Patuzzi R, Yates GK. Basilar membrane measurements and the travelling wave. Hear Res. 1986;22:147. 75. Joris PX, Yin TC. Responses to amplitude-modulated tones in the auditory nerve of the cat. J Acoust Soc Am. 1992;91:215. 76. Kaltenbach JA, Meleca RJ, Falzarano PR, Myers SF, Simpson TH. Forward masking properties of neurons in the dorsal cochlear nucleus: possible role in the process of echo suppression. Hear Res. 1993;67:35. 77. Katz B. Nerve, Muscle, and Synapse. New York, NY: McGrawHill; 1966. 78. Keefe DH, Levi E. Maturation of the middle and external ears: acoustic power-based responses and reflectance tympanometry. Ear Hear. 1996;17:361. 79. Keidel WD. Information processing in higher parts of the auditory pathway. In: Zwicker E, Terhardt E, eds. Facts and Models in Hearing. New York, NY: Springer-Verlag; 1974:216. 80. Keidel WD. Neurophysiological requirements for implanted cochlear prostheses. Audiology. 1980;19:105. 81. Kelly JP, Wong D. Laminar connections of the cat’s auditory cortex. Brain Res. 1981;212:1. 82. Kemp DT. Developments in cochlear mechanics and techniques for noninvasive evaluation. Adv Audiol. 1988;5:27. 83. Kemp DT. Stimulated acoustic emissions from within the human auditory system. J Acoust Soc Am. 1978;64:1386. 84. Khanna SM, Leonard DGB. Basilar membrane tuning in the cat cochlea. Science. 1982;215:305. 85. Kiang NYS. Discharge Patterns of Single Fibers in the Cat’s Auditory Nerve. Cambridge, MA: MIT Press; 1965. 86. Kiang NYS. Stimulus representation in the discharge patterns of auditory neurons. In: Eagles EL, ed. The Nervous System, Vol 3. Human Communication and Its Disorders. New York, NY: Raven Press; 1975:81. 87. Kiang NYS. A survey of recent developments in the study of auditory physiology. Ann Otol. 1968;77:656. 88. Kiang NYS, Moxon EC. Tails of tuning curves of auditory nerve fibers. J Acoust Soc Am. 1974;55:620. 89. Killion MC, Dallos P. Impedance matching by the combined effects of the outer and middle ear. J Acoust Soc Am. 1979;66:599. 90. Klinke R, Galley N. Efferent innervation of vestibular and auditory receptors. Physiol Rev. 1974;54:316. 91. Kistler DJ, Wightman FL. A model of head-related transfer functions based on principal components analysis and minimum-phase reconstruction. J Acoust Soc Am. 1992; 91:1637. 92. Knudsen EI, Konishi M. A neural map of auditory space in the owl. Science. 1978;200:795. 93. Kraus N, McGee T. Clinical implications of primary and nonprimary pathway contributions to the middle latency response generating system. Ear Hear. 1993;14:36. 94. Kraus N, McGee T, Carrell T, Sharma A, Micco A, Nicol T. Speechevoked cortical potentials in children. J Am Acad Audiol. 1993;4:238. 95. Kraus N, McGee T, Sharma A, Carrell T, Nicol T. Mismatch negativity event-related potential elicited by speech stimuli. Ear Hear. 1992;13:158.

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96. Kuhn GF. Physical acoustics and measurements pertaining to directional hearing. In: Yost WA, Gourevitch G, eds. Directional Hearing. New York, NY: Springer-Verlag; 1987:3. 97. Lawrence M, Burgio PA. Attachment of the tectorial membrane revealed by scanning electron microscope. Ann Otol. 1980;89:325. 98. Liberman MC. Effects of chronic cochlear deefferentation on auditorynerve response. Hear Res.1990;49:209. 99. Liberman MC, Guinan JJ. Feedback control of the auditory periphery: anti-masking effects of middle ear muscles vs. olivocochlear efferents. J Commun Disord. 1998;31:471. 100. Licklider JCR. Basic correlates of the auditory stimulus. In: Stevens SS, ed. Handbook of Experimental Psychology. New York, NY: John Wiley; 1951:985. 101. Lim DJ. Cochlear micromechanics in understanding otoacoustic emission. Scand Audiol Suppl. 1986;25:17. 102. Lonsbury-Martin BL, Whitehead ML, Martin GK. Clinical applications of otoacoustic emissions. J Speech Hear Res. 1991;34:964. 103. Maison SF, Liberman MC. Predicting vulnerability to acoustic injury with a noninvasive assay of olivocochlear reflex strength. J Neurosci. 2000;20:4701. 104. Margolis RH, Trine MB. Influence of middle-ear disease on otoacoustic emissions. In: Robinette MS, Glattke TJ, eds. Otoacoustic Emissions: Clinical Applications. New York, NY: Thieme;1997:130. 105. Massopust LC, Wolin L, Frost V. Frequency discrimination thresholds following auditorycortex ablations in the monkey. J Aud Res. 1971;11:227. 106. Masterson RB, Glendenning KK, Nudo RJ. Anatomical pathways subserving the contralateral representation of a sound source. In: Gatehouse RW, ed. Localization of Sound: Theory and Applications. Groton, CT: Amphora Press; 1982:113. 107. Maxon AB, White KR, Culpepper B, Vohr BR. Maintaining acceptably low referral rates in TEOAE-based newborn hearing screening programs. J Commun Disord. 1997;30:457. 108. McFadden D. Masking level differences determined with and without interaural disparities in masker intensity. J Acoust Soc Am. 1968;44:212. 109. McGee TJ, Clemis JB. The approximation of audiometric thresholds by auditory brain stem responses. Otolaryngol Head Neck Surg. 1980;88:295. 110. Mellado Lagarde MM, Drexl M, Lukashkina VA, Lukashkin AN, Russell IJ. Outer hair cell somatic, not hair bundle, motility is the basis of the cochlear amplifier. Nat Neurosci. 2008;11(7):746–748. 111. Mendel MI, Wolf KE. Clinical applications of the middle latency responses. Audiol J Cont Educ.1983;8:141. 112. Merzenich MM, Knight PL, Roth GL. Representation of cochlea within primary auditory cortex in the cat. J Neurophysiol. 1975;38:231. 113. Miller JD, Watson CS, Covell WP. Deafening effects of noise on the cat. Acta Otolaryngol Suppl (Stockh). 1963;176:1. 114. Mills AW. Auditory localization. In: Tobias JV, ed. Foundations of Modern Auditory Theory. Vol. 1. New York, NY: Academic Press; 1972:303. 115. Moller AR. An experimental study of the acoustic impedance of the middle ear and its transmission properties. Acta Otolaryngol (Stockh). 1965;60:129. 116. Moller AR. The middle ear. In: Tobias JV, ed. Foundations of Modern Auditory Theory. Vol. 2. New York, NY: Academic Press; 1972:135.

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CHAPTER 21 ❖ Physical and Physiological Bases of Hearing 117. Moller AR. Coding of amplitude modulated sounds in the cochlear nucleus of the rat. In: Moller AR, ed. Mechanisms in Hearing. New York, NY: Academic Press; 1973:593. 118. Moller AR, Jannetta PJ. Comparison between intracranially recorded potentials from the human auditory nerve and scalp recorded auditory brainstem responses (ABR). Scand Audiol. 1982;11:33. 119. Moller AR, Jannetta PJ, Bennett M, Moller MB. Intracranially recorded responses from the human auditory nerve: new insights into the origin of brainstem evoked potentials (BSEP). Electroencephalogr Clin Neurophysiol. 1981;52:18. 120. Moore JK. The human auditory brain stem as a generator of auditory evoked potentials. Hearing Res. 1987;29:33. 121. Moushegian G, Stillman RD, Rupert AL. Characteristic delays in superior olive and inferior colliculus. In: Sachs MB, ed. Physiology of the Auditory System: A Workshop. Baltimore, MD: National Educational Consultants; 1971:245. 122. Nedzelnitsky V. Measurement of sound pressure in the cochleae of anesthetized cats. In: Zwicker E, Terhardt E, eds. Facts and Models in Hearing. New York, NY: Springer-Verlag; 1974:45. 123. Neff WD. Localization and lateralization of sound in space. In: DeReuck AVS, Knight J, eds. Hearing Mechanisms in Vertebrates. Boston, MA: Little, Brown; 1968:207. 124. Neff WD. Neural mechanisms of auditory discrimination. In: Rosenblight WA, ed. Sensory Communication. Cambridge, MA: MIT Press; 1959:259. 125. Nozza RJ, Sabo DL, Mandel EM. A role for otoacoustic emissions in screening for hearing impairment and middle ear disorders in school-age children. Ear Hear. 1997;18:227. 126. Peake WT, Rosowski JJ, Lynch TJ III. Middle ear transmission: acoustic versus ossicular coupling in cat and human. Hear Res. 1992;57:245. 127. Pfeiffer RR, Kim DO. Cochlear nerve fiber responses: distribution along the cochlear partition. J Acoust Soc Am. 1975;58:867. 128. Pfingst BE, O’Connor TA. Characteristics of neurons in auditory cortex of monkeys performing a simple auditory task. J Neurophysiol. 1981;45:16. 129. Pickles JO, Corey DP. Mechanoelectrical transduction by hair cells. Trends Neurosci. 1992;15:254. 130. Pickles JO, Comis SD, Osborne MP. Crosslinks between stereocilia in the guinea pig organ of Corti, and their possible relation to sensory transduction. Hear Res. 1984;15:103. 131. Picton TW, Hillyard SA, Krausz HI, Galambos R. Human auditory evoked potentials. I. Evaluation of components. Electroencephalogr Clin Neurophysiol.1974;36:179. 132. Plenge G. On the differences between localization and lateralization. J Acoust Soc Am.1974;56:944. 133. Plomp R. Old and new data on tone perception. In: Neff WD, ed. Contributions to Sensory Physiology. Vol 5. New York, NY: Academic Press; 1971:179. 134. Polich JM, Starr A. Middle, late, and long latency auditory evoked potentials. In: Moore EJ, ed. Bases of Auditory Brain Stem Evoked Responses. New York, NY: Grune & Stratton; 1983:345. 135. Prieve B, Dalzell L, Berg A, et al. The New York State universal newborn hearing screening demonstration project: outpatient outcome measures. Ear Hear. 2000;21:104. 136. Probst R. Otoacoustic emissions. An overview. In: Pfaltz CR, ed. New Aspects of Cochlear Mechanics and Inner Ear Pathophysiology. Basel: Karger; 1990:1.

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137. Reneau JP, Hnatiow GZ. Evoked Response Audiometry: A Topical and Historical Review. Baltimore, MD: University Park Press; 1975. 138. Rhode WS. Basilar membrane motion: results of Mössbauer measurements. Scand Audiol Suppl.1986;25:7. 139. Rhode WS. An investigation of postmortem cochlear mechanics using the Mössbauer effect. In: Moller AR, ed. Basic Mechanisms in Hearing. New York, NY: Academic Press; 1973:39. 140. Robinette MS, Glattke TJ, eds. Otoacoustic Emissions: Clinical Applications. 3rd ed. New York, NY: Thieme; 2007. 141. Robinson DW, Dadson RS. A redetermination of the equal loudness relations for pure tones. Br J Appl Phys. 1956;7:166. 142. Romani GL, Williamson SJ, Kaufman L. Tonotopic organization of the human auditory cortex. Science. 1982;216:1339. 143. Rose JE, Brugge JF, Anderson DJ, Hind JE. Phase locked response to low frequency tones in single auditory nerve fibers of the squirrel monkey. J Neurophysiol. 1967;30:769. 144. Rose JE, Gross NB, Geisler CD, Hind JE. Some neural mechanisms in the inferior colliculus of the cat which may be relevant to localization of a sound source. J Neurophysiol. 1966;29:288. 145. Rosowski JJ. The effects of external and middle ear filtering on auditory threshold and noiseinduced hearing loss. J Acoust Soc Am. 1991;90:124. 146. Ruggero MA, Temchin AN. The roles of the external, middle, and inner ears in determining the bandwidth of hearing. Proc Nat Acad of Sci USA. 2002;99:13206. 147. Ryan A, Dallos P. Physiology of the cochlea. In: Northern JL, ed. Hearing Disorders. 2nd ed. Boston, MA: Little, Brown; 1984:253. 148. Sachs MB, Abbas PJ. Rate versus level functions for auditory nerve fibers in cats: toneburst stimuli. J Acoust Soc Am. 1974;56:1835. 149. Sachs MB, Young ED. Encoding of steadystate vowels in the auditory nerve: representation in terms of discharge rate. J Acoust Soc Am. 1979;66:470. 150. Sams M, Paavilainen P, Alho K, Naatanen R. Auditory frequency discrimination and event-related potentials. EEG Clin Neurophysiol. 1985;62:437. 151. Scharf B. Critical bands. In: Tobias JV, ed. Foundations of Modern Auditory Theory. Vol 1. New York, NY: Academic Press; 1970:159. 152. Scharf B, Magnan J, Chays A. On the role of the olivocochlear bundle in hearing: 16 case studies. Hear Res. 1997; 103:101. 153. Schwent VL, Hillyard SA, Galambos R. Selective attention and the auditory vertex potential. I. Effects of stimulus delivery rate. Electroencephalogr Clin Neurophysiol. 1976; 40:604. 154. Searle CL, Braida LD, Cuddy DR, Davis MF. Binaural pinna disparity: another auditory localization cue. J Acoust Soc Am. 1975;57:448. 155. Selters WA, Brackmann DE. Acoustic tumor detection with brain stem electric response audiometry. Arch Otolaryngol. 1977;103:181. 156. Shaw EAG. The external ear. In: Keidel WD, Neff WD, eds. Handbook of Sensory Physiology, Vol V/1. Auditory System: Anatomy, Physiology (Ear). Berlin: Springer-Verlag; 1974:455. 157. Silman S. The Acoustic Reflex: Basic Principles and Clinical Applications. New York, NY: Academic Press; 1984.

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158. Solomon G, Starr A. Electromyography of middle ear muscles in man during motor activities. Acta Neurol Scand. 1963;39:161. 159. Starr A, Achor LJ. Auditory brain stem responses in neurological disease. Arch Neurol. 1975;32:761. 160. Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI. Auditory neuropathy. Brain. 1996;119:741. 161. Stypulkowski PH, Staller SJ. Clinical evaluation of a new ECocG recording electrode. Ear Hear. 1987;8:304. 162. Suga N. Feature detection in the cochlear nucleus, inferior colliculus, and auditory cortex. In: Sachs MB, ed. Physiology of the Auditory System: A Workshop. Baltimore, MD: National Educational Consultants; 1971:197. 163. Sutter AH. Hearing conservation. In: Berger EH, Ward WD, Morrill JC, Royster LH, eds. Noise and Hearing Conservation Manual. Akron, OH: American Industrial Hygiene Association; 1986:1. 164. Tasaki I, Spyropoulos CS. Stria vascularis as source of endocochlear potential. J Neurophysiol. 1959;22:149. 165. Telischi FF, Roth J, Stagner BB, Lonsbury-Martin BL, Balkany TJ. Pattern of evoked otoacoustic emissions associated with acoustic neuromas. Laryngoscope. 1995;105:675. 166. Tilney LG, Derosier DJ, Mulroy MJ. The organization of actin filaments in the stereocilia of cochlear hair cells. J Cell Biol. 1980;86:244. 167. Tonndorf J. Davis—1961 revisited: signal transmission in the cochlear hair cell-nerve junction. Arch Otolaryngol. 1975;101:528. 168. Tonndorf J. Relationship between the transmission characteristics of the conductive system and noise-induced hearing loss. In: Henderson D, Hamernik RP, Dosanjh DS, Mills JH, eds. Effects of Noise on Hearing. New York, NY: Raven Press; 1976:159. 169. Tonndorf J, Khanna SM. The role of the tympanic membrane in middle ear transmission. Ann Otolaryngol. 1970;79:743. 170. Trautwein P, Hofstetter P, Wang J, Salvi R, Nostrant A. Selective inner hair cell loss does not alter distortion product otoacoustic emissions. Hear Res. 1996;96:71. 171. Veuillet E, Khalfa S, Collet L. Clinical relevance of medial efferent auditory pathways. Scand Audiol. 1999;51:53. 172. Viemeister NF. Auditory intensity discrimination at high frequencies in the presence of noise. Science. 1983;221:1206. 173. Vogel I, Verschuure H, van der Ploeg CP, Brug J, Raat H. Estimating adolescent risk for hearing loss based on data from a large school-based survey. Am J Pub Health. 2010;100:1095. 174. Walzl EM. Representation of the cochlea in the cerebral cortex. Laryngoscope. 1947;57:778. 175. Warr WB, Guinan JJ. Efferent innervation of the organ of corti: two separate systems. Brain Res. 1979;173:152. 176. Wegel RL. Physical data and physiology of excitation of the auditory nerve. Ann Otol Rhinol Laryngol. 1932;41:740. 177. Wegel RL, Lane CE. The auditory masking of one pure tone by another and its probable relation to the dynamics of the inner ear. Phyisol Rev. 1924;23:266.

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178. Wever EG. Beats and related phenomena resulting from the simultaneous sounding of two tones. Psychol Rev. 1929;36:402. 179. Wever EG. Theory of Hearing. New York, NY: Dover Publications; 1949. 180. Wever EG, Bray CM. The perception of low tones and the resonance volley theory. J Psychol. 1937;3:101. 181. Wever EG, Lawrence M. Physiological Acoustics. Princeton, NJ: Princeton University Press; 1954. 182. Whitfield IC. The Auditory Pathway. Baltimore, MD: Williams & Wilkins; 1967. 183. Whitfield IC. Coding in the auditory nervous system. Nature. 1967;213:756. 184. Wiener FM, Ross DA. The pressure distribution in the auditory canal in a progressive sound field. J Acoust Soc Am. 1946;18:401. 185. Wier CC, Jesteadt W, Green DM. Frequency discrimination as a function of frequency and sensation level. J Acoust Soc Am. 1977;61:178. 186. Winter IM, Robertson D, Yates GK. Diversity of characteristic frequency rate–intensity functions in guinea pig auditory nerve fibres. Hear Res. 1990;45:191. 187. Woolsey CN. Tonotopic organization of the auditory cortex. In: Sachs MB, ed. Physiology of the Auditory System: A Workshop. Baltimore, MD: National Educational Consultants; 1971:271. 188. Yeowart NS, Evans MJ. Thresholds of audibility for very lowfrequency pure tones. J Acoust Soc Am.1974;55:814. 189. Yost WA, Hafter ER. Lateralization. In: Yost WA, Gourevitch G, eds. Directional Hearing. New York, NY: Springer-Verlag; 1987:49. 190. Young ED, Sachs MB. Representation of steady-state vowels in the temporal aspects of the discharge patterns of populations of auditory nerve fibers. J Acoust Soc Am. 1979;66:1381. 191. Zwicker E. On a psychoacoustical equivalent of tuning curves. In: Zwicker E, Terhardt E, eds. Facts and Models in Hearing. New York, NY: Springer-Verlag; 1974:132. 192. Zwicker E, Flottrop G, Stevens SS. Critical bandwidth in loudness summation. J Acoust Soc Am.1957;29:548. 193. Zwislocki JJ. Analysis of some auditory characteristics. In: Luce R, Bush R, Galanter E, eds. Handbook of Mathematical Psychology. Vol 3. New York, NY: John Wiley; 1965:1. 194. Zwislocki JJ. The role of the external and middle ear in sound transmission. In: Eagles EL, ed. The Nervous System, Vol 3. Human Communication and Its Disorders. New York, NY: Raven Press; 1975:45. 195. Zwislocki JJ, Sokolich WG. Velocity and displacement in auditorynerve fibers. Science.1973;182:64. 196. Whitfield IC. Electrophysiology of the central auditory pathway. Br Med Bull. 1956;12:105–109. 197. Durrant JD. Manifestations of cochlear events in the auditory brain-stem response and its clinical applications. In: Dallos P, Ortele D, eds. The Senses: A Comprehensive Reference. Vol 3. London, UK: Elsevier; 2008:359–364.

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C H A P T E R

Methods of Clinical Examination: Ear and Related Structures Charles D. Bluestone and Jerome O. Klein

D

iagnosis of middle ear disease, when inflammation is present, can usually be made by obtaining the pertinent medical history and performing a physical examination that includes pneumatic otoscopy. (Chapter 37 provides a detailed discussion of the diagnosis of middle ear disease.) Although less common than the inflammatory disorders, congenital, traumatic, and neoplastic problems are also important (Chapters 34, 41, and 42). In addition to these two important examination methods, evaluation of the child’s hearing and middle ear function (Chapter 23) and assessment of the vestibular system (Chapter 25) may also be indicated.

SIGNS AND SYMPTOMS There are nine prominent signs and symptoms that are primarily associated with diseases of the ear and temporal bone. Otalgia is most commonly associated with inflammation of the external and middle ear but may also be of nonaural origin. In most cases, otalgia not associated with otitis media can be identified as referred pain due to discomfort with swallowing (tonsillitis), nasal obstruction, or pain in the throat (pharyngitis), but any lesion in the areas of the trigeminal, facial, glossopharyngeal, vagal, great auricular, or lesser occipital nerve supply can result in earache and include lesions in the temporomandibular joint, the teeth, or the pharynx. In young infants, pulling at the ear or general irritability, especially when associated with fever, may be the only sign of ear pain (Chapter 26: Otalgia). When purulent otorrhea is present, it is a sign of otitis externa, otitis media with perforation of the tympanic membrane, or both. Bloody discharge may be associated with acute or chronic inflammation, trauma, or neoplasm. A clear drainage may be indicative of a perforation of the drum with a serous middle ear effusion or cerebrospinal fluid otorrhea draining through a defect in the external auditory canal or through the tympanic membrane from the middle ear (Chapter 27: Otorrhea). Hearing loss is a symptom that may be the result of disease or disorder of either the external or the middle ear (conductive hearing loss) or the result of a pathologic condition in the inner ear, retrocochlea, or central auditory path ways (sensorineural hearing loss) (Chapter 30: Genetic Hearing Loss and Inner Ear Diseases). (Physical abnormalities and associated syndromes related to hearing loss are described in detail in Chapter 32: Congenital Inner Ear Anomalies) Swelling about the ear is most commonly the result of inflammation (e.g., external otitis, perichondritis, or

mastoiditis), trauma (e.g., hematoma), or, on rare occasions, neoplasm. Vertigo is not a common complaint in children but is present more often than was once thought. The most common cause is Eustachian tube–middle ear–mastoid disease,1 but vertigo may also be due to labyrinthitis; perilymphatic fistula between the inner and the middle ear resulting from a congenital defect, trauma, or cholesteatoma; vestibular neuronitis; benign paroxysmal positional vertigo; Meniere disease; or disease of the central nervous system.2 Older children may describe a feeling of spinning or turning, whereas younger children may not be able to verbalize the symptom but manifest the dysequilibrium by falling, stumbling, or “clumsiness.” Unidirectional horizontal jerk nystagmus, usually associated with vertigo, is vestibular in origin (Chapter 29: Balance Disorders). Tinnitus is another symptom that children infrequently describe but is commonly present, especially in patients with Eustachian tube–middle ear disease or conductive or sensorineural hearing loss (Chapter 28: Tinnitus in Children). Facial paralysis is an infrequent but frightening condition for both child and parents. When it is due to disease within the temporal bone in children, it most commonly occurs as a complication of acute or chronic otitis media; however, facial paralysis may also be idiopathic (Bell palsy) or the result of temporal bone fracture or neoplasm; on rare occasions, it is due to herpes zoster oticus (Chapter 39: Facial Paralysis in Children). Purulent conjunctivitis can be associated with acute otitis media. The conjunctivae are infected, there is tearing or purulent discharge, and in some children, there is concurrent ear pain. Simultaneous cultures of conjunctivae and middle ear exudates reveal nontypable Haemophilus influenzae in almost all cases.5 Other signs and symptoms of conditions that may be associated with ear disease may also be present, such as symptoms of upper respiratory allergy associated with otitis media (Chapter 56: Allergic Rhinitis). Fever is a relatively poor predictor of otitis media, but when associated with other signs and symptoms, such as otalgia, it can be a good predictor.3

PHYSICAL EXAMINATION In addition to the pertinent history, the most useful method for diagnosing ear disease is a physical examination that includes pneumatic otoscopy.4 Adequate examination of the entire child, with special attention to the head and neck, can lead to the identification of a condition that may predispose to or be associated with ear disease. The appearance of the child’s face and

Otitis media now has an international advocacy society: Society for Middle-Ear Disease (SMED) www.societyformiddleeardisease.org. This website has up-to-date clinical abstracts (Resource Center, Professionals-Abstracts) related to this chapter on Diagnosis, as well as other texts (Resource Center, Books).

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the character of his or her speech may be important clues to the possibility of an abnormal middle ear. Many craniofacial anomalies, such as mandibulofacial dysostosis (Treacher Collins syndrome) and trisomy 21 (Down syndrome), are associated with an increased incidence of ear disease (Chapter 3: Genetics, Syndromology, and Craniofacial Anomalies). Mouth breathing and hyponasality may indicate intra or postnasal obstruction, whereas hypernasality is a sign of velopharyngeal incompetence. Examination of the oropharyngeal cavity may uncover an overt cleft palate or a submucous cleft (Fig. 22-1), both of which predispose the infant to otitis media with effusion.5,6 A bifid uvula may be associated with an increased incidence of middle ear disease. An examination of the child’s head and neck may also reveal posterior nasal or pharyngeal inflammation and discharge. Other pathologic conditions of the nose, such as polyposis, severe deviation of the nasal septum, or a nasopharyngeal tumor, may also be associated with otitis media (Chapter 47: Nasal Obstruction and Rhinorrhea and Chapter 59: Tumors of the Nose, Paranasal Sinuses, and Nasopharynx). Examination of the ear itself is the most critical part of the clinician’s assessment of the patient, but it must be performed systematically. The auricle, periauricular area, and external auditory meatus should be examined first; all too frequently, these areas are overlooked in the physician’s haste to make a diagnosis by otoscopic examination, but the presence or absence of signs of infection in these areas may aid later in the differential diagnosis or evaluation of complications of ear disease. For instance, external otitis may result from acute otitis media with discharge, or inflammation of the postauricular area may be indicative of periostitis or a subperiosteal abscess that has extended from the mastoid air cells (Chapter 38: Complications and Sequelae of Otitis Media). Palpation of these areas will determine whether tenderness is present; exquisite pain on palpation of the tragus would indicate acute diffuse external otitis (Chapter 36: Diseases of the External Ear).

FIGURE 22-1. Bifid uvula, widening attenuation of the median raphe of the soft palate, and a V-shaped midline notch, rather than a smooth curve, are diagnostic of a submucous cleft palate.

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After examination of the external ear and canal, the clinician may proceed to the most important part of the physical assessment, the otoscopic examination.

OTOSCOPIC EXAMINATION Positioning the Patient for Examination The position of the patient for otoscopy depends on the patient’s age and ability to cooperate, the clinical setting, and the preference of the examiner. Otoscopic evaluation of an infant is best performed on an examining table. The presence of a parent or assistant is necessary to restrain the baby, as undue movement usually prevents an adequate evaluation (Fig. 22-2). Some clinicians prefer to place infants prone on the table, whereas others prefer them to be supine. Use of the examining table is also desirable for older infants who are uncooperative or when a tympanocentesis or myringotomy is performed without general anesthesia. Fig. 22-3 shows that infants and young children

FIGURE 22-2. Methods of restraining an infant for examination and for procedures such as tympanocentesis or myringotomy.

FIGURE 22-3. Method of restraining a child for examination of the ear.

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303

who are only apprehensive and not struggling actively can be evaluated adequately while sitting on the parent’s lap. When necessary, the child may be restrained firmly on an adult’s lap if the parent holds the child’s wrists over the abdomen with one hand and holds the child’s head against the adult’s chest with the other hand. If necessary, the child’s legs can be held between the adult’s thighs. Some infants can be examined by placing their head on the parent’s knee (Fig. 22-4). Cooperative children sitting in a chair or on the edge of an examination table can usually be evaluated successfully. The examiner should hold the otoscope with the hand or finger placed firmly against the child’s head or face, so that the otoscope will move with the head rather than cause trauma (pain) to the ear canal if the child moves suddenly (Fig. 22-5). Pulling up and out on the pinna will usually straighten the ear canal enough to allow exposure of the tympanic membrane. In young infants, the tragus must be moved forward and out of the way.

Removal of Cerumen Before adequate visualization of the external canal and tympanic membrane, with a pneumatic otoscope, can be obtained, all obstructing cerumen must be removed from the canal.7 Many children with acute otitis media have moderate to large accumulations of cerumen in the ear canal. For optimal visualization of the tympanic membrane, mechanical removal was necessary in approximately one-third of 279 patients observed by Schwartz et al.8 The necessity for cerumen removal was inversely proportional to age, with more than half of cerumen removal procedures performed in infants under 1 year of age. Removal of cerumen can usually be accomplished by use of an otoscope with a surgical

FIGURE 22-5. Methods of positioning an otoscope to enhance visualization and minimize the risk that head movement will result in trauma to the ear canal. Both of the otoscopist’s hands can be used (A), or when the child is cooperative, a finger touching the child’s cheek is sufficient (B).

head and a wire loop or a blunt cerumen curette (Fig. 22-6) or by irrigating the ear canal gently with warm water delivered through a dental irrigator (Water Pik®) (Fig. 22-7). Tympanic membrane perforations and ossicular disruption have been reported after oral jet irrigation, indicating the need for caution and use only at a low-power setting.9 Instillation of hydrogen peroxide (solution) in the ear canal for 2–3 minutes softens cerumen and may facilitate removal with subsequent irrigation. Carbamide peroxide in glycerol (Debrox®) can be used in the ear canal before irrigation. But some commercial preparations such as triethanolamine polypeptide oleate-condensate (Cerumenex®) have been reported to cause dermatitis of the external canal. These materials may be of value if used infrequently and under the physician’s supervision. Recently, Casselbrant1 reported good success using a relatively new device, OtoClear Safe Irrigation system in children.

Otoscope

FIGURE 22-4. Method of positioning a baby for otoscopic examination.

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For proper assessment of the tympanic membrane and its mobility, a pneumatic otoscope in which the diagnostic head has an adequate seal should be used. The quality of the otoscopic examination is limited by deficiencies in the designs of commercially available otoscopes. The speculum employed should have the largest lumen that can comfortably fit in the child’s cartilaginous external auditory meatus. If the speculum is too small, adequate visualization may be impaired and the speculum may touch the bony canal, which can be painful. In most models, an airtight seal is usually not possible because of a leak of air within the otoscope head or between the stiff ear speculum and the external auditory

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FIGURE 22-6. Method of removing cerumen from the external ear canal, employing the surgical head attached to the otoscope, and instruments that can be used.

FIGURE 22-8. Pneumatic otoscope with a rubber tip on the end of the ear speculum to provide a better seal in the external auditory canal.

FIGURE 22-7. Irrigation of the external canal with a dental irrigator to remove cerumen.

FIGURE 22-9. Observation of eardrum mobility with the Bruening otoscope with magnifying lens. The light source is from a lamp reflected off a head mirror.

canal, although leaks at the latter location can be stopped by cutting a small section of rubber tubing and slipping it over the tip of the ear speculum (Fig. 22-8). Many otolaryngologists prefer to use a Bruening or Siegel otoscope with the magnifying lens. Both of these instruments allow for excellent assessment of drum mobility because they have an almost airtight seal. A head mirror and lamp or a headlight (Fig. 22-9) is necessary to provide light for the examination. But the use of a head mirror or even a headlight for the examination of the tympanic membrane of an infant or child is usually not feasible, unless

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the child is effectively restrained, and when strained, the traditional otoscope or more accurately the otomicroscope is preferred.

Examination of Tympanic Membrane Inspection of the tympanic membrane should include evaluation of its position, color, degree of translucency, and mobility. Assessment of the light reflex is of limited value because it does not indicate the status of the middle ear in the evaluation of tympanic membrane middle ear disorders.

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FIGURE 22-10. Otoscopic view compared with a lateral section through the tympanic membrane and middle ear to demonstrate the various positions of the drum with their respective anatomic landmarks (see text).

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Positions Of The Tympanic Membrane The positions of the tympanic membrane when the middle ear is aerated and when effusion is present are illustrated in Fig. 22-10. The normal eardrum should be in the neutral position, with the short process of the malleus visible but not prominent through the membrane. Mild retraction of the tympanic membrane usually indicates negative middle ear pressure, an effusion, or both. The short process of the malleus and the posterior mallear fold are prominent, and the manubrium of the malleus appears to be foreshortened. Severe retraction of the tympanic membrane is characterized by a prominent posterior mallear fold and short process of the malleus and a severely foreshortened manubrium. The tympanic membrane may be severely retracted, presumably owing to high negative pressure in association with a middle ear effusion. Fullness of the tympanic membrane is apparent initially in the posterosuperior portion of the pars tensa and pars flaccida, because these two areas are the most highly compliant parts of the tympanic membrane.10 The short process of the malleus is commonly obscured. The fullness is caused by increased air pressure, effusion, or both within the middle ear. When bulging of the entire tympanic membrane occurs, the malleus is usually obscured, which occurs when the middle ear\en\mastoid system is filled with an effusion. Appearance Of The Tympanic Membrane The normal tympanic membrane has a ground-glass appearance; a blue or yellow color usually indicates a middle ear effusion seen through a translucent tympanic membrane. A red tympanic membrane alone may not be indicative of a pathologic condition, because the blood vessels of the drum head may be engorged as the result of the patient’s crying, sneezing, or nose blowing. It is critical to distinguish between translucency and opacification of the eardrum to identify a middle ear effusion. The normal tympanic membrane should be translucent, and the observer should be able to look through the drum and visualize the middle ear landmarks (the incudostapedial joint promontory, the round window niche, and frequently the chorda tympani nerve) (Fig. 22-11). If a middle ear effusion is present medial to a translucent drum, an air-fluid level or bubbles of air admixed with the liquid may be visible (Fig. 22-12).

FIGURE 22-11. Diagrammatic view of the tympanic membrane depicting important landmarks that can usually be visualized with the otoscope.

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FIGURE 22-12. Three examples of otoscopic findings (right ear).

An air-fluid level or bubbles can be differentiated from scarring of the tympanic membrane by altering the position of the head while observing the drum with the otoscope (if fluid is present, the air-fluid level will shift in relation to gravity) or by seeing movement of the fluid during pneumatic otoscopy. The line frequently seen when a severely retracted membrane touches the cochlear promontory will disappear (the drum will pull away from the promontory) if sufficient negative pressure can be applied with the pneumatic otoscope. Inability to visualize the middle ear structures indicates opacification of the drum, which is usually the result of thickening of the tympanic membrane, an effusion, or both. A bright light is necessary for accurate otoscopy. Barriga et al.11 surveyed otoscopes in physicians’ offices and hospital clinics and found that many were inadequately maintained. A light output of 100 footcandles or more was optimal for clinical otoscopy. Replacement of the bulb rather than of the battery was more likely to restore adequate light to the units with poor performance.11 Otoscope batteries should be replaced frequently, so that the ability of the examiner to look “through” the tympanic membrane will not be impaired. The electric otoscope is better than the battery type. A halogen bulb with greater than or equal to 100 footcandles is currently recommended.12 Mobility Of The Tympanic Membrane Abnormalities of the tympanic membrane and the middle ear are reflected in the pattern of tympanic membrane mobility when first positive and then negative pressure is applied to the external auditory canal with the pneumatic otoscope.13 As shown in Fig. 22-13, this is achieved by first applying slight

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FIGURE 22-14. The four quadrants of a right tympanic membrane.

FIGURE 22-13. Pressure applied to the rubber bulb attached to the pneumatic otoscope will deflect the normal tympanic membrane inward with applied positive pressure and outward with applied negative pressure if the middle ear pressure is ambient. The movement of the eardrum is proportionate to the degree of pressure exerted on the bulb until the tympanic membrane has reached its limit of compliance.

pressure on the rubber bulb (positive pressure) and then, after momentarily breaking the seal, releasing the bulb (negative pressure). When the tympanic membrane and middle ear are normal, forceful application of positive and negative pressure (i.e., deeply depressing and releasing the thumb on the rubber bulb) can be painful to the child, because the tympanic membrane is overdistended. If the tympanic membrane does not move when slight pressure is applied, more pressure is applied. The presence of effusion, high negative pressure, or both within the middle ear can markedly dampen the movements of the eardrum. When the middle ear pressure is ambient, the normal tympanic membrane moves inward with slight positive pressure in the ear canal and outward toward the examiner with slight negative pressure. The motion observed is proportionate to the applied pressure and is best visualized in the posterosuperior quadrant of the tympanic membrane (Fig. 22-14). If a two-layered membrane or an atrophic scar (due to a healed perforation) is present, mobility of the tympanic membrane can also be assessed more readily by observing the movement of the flaccid area.

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The movement of the tympanic membrane to the applied pressure from the rubber bulb attached to the otoscope can determine, in general, whether there is relatively normal pressure within the middle ear, negative or positive pressure, or a possible effusion. Fig. 22-15 shows a simple relationship between the pressure applied by the pneumatic otoscope and the response of that applied positive and negative pressure to the movement medial (in) and lateral (out) of the tympanic membrane. Fig. 22-16 shows a more specific relationship between mobility of the tympanic membrane, as measured by pneumatic otoscopy, and the middle ear contents and pressure. Fig. 22-16, frame 1, shows the normal tympanic membrane when the middle ear contains only air at ambient pressure. A hypermobile eardrum (frame 2) is seen most frequently in children whose membranes are atrophic or flaccid. The mobility of the tympanic membrane is greater than normal (the drum is said to be highly compliant) if the drum moves when even slight positive or negative external canal pressure is applied; if the drum moves equally well to both applied positive and negative pressures, the middle ear pressure is approximately ambient. However, if the tympanic membrane is hypermobile to applied negative pressure but immobile when positive pressure is applied, the tympanic membrane is flaccid and negative pressure is present within the middle ear. A middle ear effusion is rarely present when the tympanic membrane is hypermobile, even though high negative middle ear pressure is present. A thickened tympanic membrane (caused by inflammation, scarring, or both) or a partly effusion-filled middle ear (in which middle ear air pressure is ambient) shows decreased mobility to applied pressures, both positive and negative (frame 3). Normal middle ear pressure is reflected by the neutral position of the tympanic membrane as well as by its response to both positive and negative pressures in each of the previous examples (frames 1–3). In other cases, the eardrum may be retracted, usually because negative middle ear pressure is

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FIGURE 22-15. Middle ear (ME) pressure as determined by the response of the tympanic membrane when positive and negative pressures are applied with the pneumatic otoscope. If the tympanic membrane moves medial (in) to applied positive pressure and lateral (out) to applied negative pressure, ME pressure is within relatively normal limits. If the eardrum moves on applied positive pressure, but not when negative pressure is applied, positive pressure is within the ME (with or without effusion). If the drum moves on applied negative pressure, but not when positive pressure is applied, negative pressure is within the ME (with or without effusion). If the tympanic membrane fails to move after application of positive and negative pressure, effusion is present in the ME, or there is very high negative ME pressure, or both are present.

FIGURE 22-16. Pneumatic otoscopic findings related to middle ear contents and pressure (see text).

present (frames 4–6). The compliant membrane is maximally retracted by even moderate negative middle ear pressure and hence cannot visibly be deflected inward further with applied positive pressure in the ear canal. However, negative pressure produced by releasing the rubber bulb of the otoscope will

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cause a return of the eardrum toward the neutral position if a negative pressure equivalent to that in the middle ear can be created by releasing the rubber bulb (frame 4), a condition that occurs when air, with or without an effusion, is present in the middle ear. When middle ear pressure is even lower,

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CHAPTER 22 ❖ Methods of Clinical Examination: Ear and Related Structures there may be only slight outward mobility of the tympanic membrane (frame 5) because of the limited negative pressure that can be exerted through the otoscopes currently available. If the eardrum is severely retracted with extremely high negative middle ear pressure, if middle ear effusion is present, or if both occur, the examiner is not able to produce significant outward movement (frame 6). The tympanic membrane that exhibits fullness (frame 7) will move to applied positive pressure but not to applied negative pressure if the pressure within the middle ear is positive and if air, with or without an effusion, is present. In such an instance, the tympanic membrane is stretched laterally to the point of maximal compliance and will not visibly move outward any farther to the applied negative pressure, but it will move inward to applied positive pressure as long as some air is present within the middle ear mastoid air cell system. When this system is filled with an effusion and little or no air is present, the mobility of the bulging tympanic membrane (frame 8) is severely decreased or absent to both applied positive and negative pressure. Gates,14 using these principles, compared the sensitivity, specificity, and predictive value of pneumatic otoscopy and tympanometry in the detection of middle ear effusion. As the skill of the otoscopist increases, the reliance on tympanometry in the diagnosis of effusion should decrease. Fig. 22-17 shows examples of common conditions of the middle ear as assessed with the otoscope, in which position, color, degree of translucency, and mobility of the tympanic membrane are diagnostic aids. Fig. 22-18 depicts the pneumotoscopic method used to determine whether a line that is visualized on the lower portion of the tympanic membrane is (1) the tympanic membrane touching the promontory, (2) an effusion level, or (3) a scar within the tympanic membrane. When the tympanic membrane is severely retracted and no middle ear effusion is present, the tympanic membrane may touch the promontory and a line can be seen through the membrane. However, if the tympanic membrane can be pulled laterally when negative pressure is applied with the pneumatic otoscope, the line will disappear, because the membrane is no longer touching the promontory (Fig. 22-18A). A line that is due to a fluid level will move (1) up when positive pressure is applied, because the middle ear cavity is made smaller and (2) down when negative pressure is applied, because the middle ear cavity is made larger (Fig. 22-18B). If the line is a scar, it will stay in the same place on the tympanic membrane when positive and negative pressures are applied (Fig. 22-18C).

Otoscopy in the Newborn Infant The tympanic membrane of the neonate is in a position different from that of the older infant and child; if this is not kept in mind, the examiner may perceive the eardrum to be smaller and retracted, because in the neonate, the tympanic membrane appears to be as wide as it is in older children but not as high (Fig. 22-19). Fig. 22-20 shows that this perception

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is due to the more horizontal position of the neonatal eardrum, which frequently makes it difficult for the examiner to distinguish the pars flaccida of the tympanic membrane from the skin of the wall of the deep superior external canal. In the first two days of life, the ear canal is filled with vernix caseosa, but this material is readily removed with a small curette or suction tube. Low-birth-weight infants (less than 1200 g) have external canals that may be so narrow as not to permit entry of the 2-mm diameter speculum. The canal walls of the young infant are pliable and tend to expand and collapse with insufflation during pneumatic otoscopy. Because of the pliability of the canal walls, it may be necessary to advance the speculum farther into the canal than would be the case in an older child. The tympanic membrane often appears thickened and opaque during the first few days. In many infants, the membrane is in an extreme oblique position, with the superior aspect proximal to the observer (see Fig. 22-19). The tympanic membrane and the superior canal wall may appear to lie almost in the same plane, so that it is often difficult to distinguish the point where the canal ends and the pars flaccida begins. The inferior canal wall bulges loosely over the inferior position of the tympanic membrane and moves with positive pressure, simulating the movement of the tympanic membrane. The examiner must distinguish between the movement of the canal walls and that of the membrane. The following should be considered to differentiate the movement of these structures: vessels are seen within the tympanic membrane but not in the skin of the ear canal; the tympanic membrane moves during crying or respiration; and, inferiorly, the wall of the external canal and the tympanic membrane lie at an acute angle. By 1 month of age, the tympanic membrane has assumed an oblique position, one with which the examiner is familiar in the older child. During the first few weeks of life, however, examination of the ear requires patience and careful appraisal of the structures of the external canal and the tympanic membrane.

Accuracy, Validation Techniques, and Interexaminer Reliability of Otoscopy Otoscopy is subjective and thus is usually an imprecise method of assessing the condition of the tympanic membrane and middle ear. Many clinicians still do not use a pneumatic otoscope, and few have been trained adequately to make a correct diagnosis. The primary reason for this lack of proper education is the method of teaching employed. Because otoscopy involves a monocular assessment of the tympanic membrane, the teacher cannot verify that the student actually visualized the anatomic features that led to the diagnosis. An otoscope with a second viewing port is available (Fig. 22-21). Teacher and student can make observations together, and student errors can be corrected immediately. One of the most effective means of education currently available is the correlation of the otoscopic findings with those obtained by an otomicroscope that has an observer tube for the student. In this manner, the instructor can point out the

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FIGURE 22-17. Common conditions of the middle ear as assessed with the otoscope.

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FIGURE 22-18. Diagnostic significance of changing relative pressure and marks on the tympanic membrane. A, Tympanic membrane touching promontory. B, Fluid level. C, Scar in tympanic membrane (see text).

FIGURE 22-20. The position of the tympanic membrane in the child is more vertical than it is in the neonate. FIGURE 22-19. Comparison of the tympanic membrane of an older infant or a child with that of a neonate. The lateral section shows the greater angulation of the neonate external canal with regard to the tympanic membrane. The appearance of the eardrums and canals on otoscopy is depicted in the lower drawings; the neonate appears to have a smaller tympanic membrane because of angulation of the eardrum.

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critical landmarks and can demonstrate tympanic mobility using the Bruening otoscope. Assessment techniques can also be improved by correlating otoscopy findings with a tympanogram taken immediately after the otoscopic examination. Lack of agreement between the otoscopic findings and tympanometry usually results in

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FIGURE 22-21. Teaching otoscope with sidearm viewer. (Adapted from Welch Allyn, New York.)

a second otoscopic examination, because tympanometry is generally accurate in distinguishing between normal and abnormal tympanic membranes and middle ears (specifically, in the identification of middle ear effusions). The presence or absence of negative pressure within the middle ear as measured by pneumatic otoscopy can be verified only by similar results on the tympanogram. Validation of the presence or absence of effusion as observed by otoscopy is best achieved by performing tympanocentesis or myringotomy immediately after the examination. When surgical opening of the tympanic membrane is indicated, preliminary otoscopy by several examiners is an effective way of teaching many students to evaluate the state of the middle ear. In most studies of otitis media, the disease has been identified by otoscopy; however, in many such studies, no information has been offered to enable the reader to evaluate the ability of the otoscopist to make the diagnosis correctly. In an attempt to classify tympanometric patterns, Paradise et al.15 validated the diagnosis of the otoscopist by performing a myringotomy shortly after the otoscopic examination. This method of validation was also used in studies of infants with cleft palates in which two otoscopists were involved.5,16 However, most other studies of otitis media have not reported validation of the diagnostic criteria, and when attempts have been made to determine interexaminer reliability in these studies, the results have been so poor as to suggest that the data reported are inaccurate. In the design of a study in which otoscopic examination is used to identify otitis media and related conditions, the diagnostic abilities of all otoscopists included in the study must be validated and interexaminer reliability must be established. If the primary ear disorder being studied is the presence or absence of middle ear effusion, each otoscopist should have a high degree of accuracy in identifying effusion. This can be achieved by performing otoscopy in a group of children

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immediately before tympanocentesis or myringotomy.17 The sensitivity (total number of otoscopic diagnoses of middle ear effusion present divided by the total myringotomy findings when middle ear effusion is aspirated) and specificity (total number of otoscopic diagnoses of middle ear effusion absent divided by the total myringotomy findings when middle ear effusion is not aspirated) should be as high as possible. Interexaminer reliability can be tested by having all the otoscopists involved in the study independently make an otoscopic diagnosis before the tympanocentesis or myringotomy. From the Children’s Hospital of Pittsburgh, Kaleida and Stool17 reported an ongoing evaluation program of 30 clinicians, between 1980 and 1990, in their ability to diagnose middle ear effusion compared with the findings at myringotomy. The arbitrary criteria for the lowest acceptable limits for sensitivity and specificity were 80% and 70%, respectively. A total of 4147 ears were assessed, and the mean sensitivity and mean specificity for the group were 87% and 74%, respectively. The investigators concluded that a formal validation program should be used to determine otoscopic accuracy. In studies such as the one by Mandel et al.,18 the diagnosis of middle ear effusion was based on a decision-tree algorithm19 that combined the findings of a validated otoscopist, as described previously, with the results of tympanometry and middle ear muscle reflex testing (Chapter 11).

VIDEO OTOSCOPY With the advent of new and improved endoscopes, many otolaryngologists are employing this advance in documenting the otoscopic findings, for educational purposes in teaching students and house staff, as well as showing the tympanic membranes to the patient (if old enough) and their families.20

OTOMICROSCOPY Many otolaryngologists use the otomicroscope to improve the accuracy of diagnosis of otitis media and related conditions. For the assessment of tympanic membrane mobility, the microscope, when used with the Bruening otoscope and nonmagnifying lens (Fig. 22-22), is superior to conventional otoscopes; this is because the microscope provides binocular vision (and therefore depth perception), a better light source, and greater magnification. Under most conditions, otomicroscopic examination is impractical and generally not necessary. However, when a diagnosis by otoscopy is in doubt, the otomicroscope is an invaluable diagnostic aid and frequently essential in arriving at the correct diagnosis (e.g., in differentiating a deep retraction pocket in the posterosuperior quadrant of the tympanic membrane from a cholesteatoma). In addition to the advantages offered by the otomicroscope for certain diagnostic problems, it is superior to the conventional otoscopes for minor surgical procedures such as tympanocentesis, because it allows for a more precise visualization of the field.

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the emitted tone and reflection from the eardrum. A recent comparison of the older, with the newest professional and consumer models found the new models to be superior to the older ones in the diagnosis of middle ear effusion.22,23

HEARING TESTS Evaluation of hearing is discussed in detail in Chapter 23, but there are other tests of hearing available, such as tuning fork tests.

Tuning Fork Tests

FIGURE 22-22. Precise assessment of tympanic membrane mobility employing the otomicroscope and a Bruening otoscope with a nonmagnifying lens.

Even though several previous studies used the otomicroscopic examination as a validator for the presence or absence of middle ear disease (otitis media with effusion), no study has reported on the sensitivity and specificity of the microscopic examination for detecting middle ear effusion. It is purported to be superior to the standard otoscopic examination, but its superiority to tympanometry with otoscopy has not yet been shown. However, as a teaching device, the otomicroscope with an observer tube attachment is preferable to the currently available otoscope. Whenever the otoscopic examination is unsatisfactory owing to inability to adequately visualize the tympanic membrane (e.g., in a narrow external canal or an uncooperative child), an examination under general anesthesia (EUA) of the ears employing the otomicroscope may be indicated in selected infants and children, such as those in whom a suppurative complication is suspected or is present.

ACOUSTIC REFLECTOMETRY Another method to diagnose middle ear effusion is acoustic reflectometry. Unlike tympanometry, a pressure seal in the external auditory meatus is not necessary to obtain a reading.21 The device determines the probability of middle ear effusion by measuring the response of the tympanic membrane to frequency sweep. The instrument emits a tone into the ear canal, and a microprocessor analyzes the sum of

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Before the widespread availability of audiometric evaluation of hearing, tuning forks were an essential part of the physical examination of patients with a suspected hearing loss. In the modern era, many otolaryngologists have not included tuning fork tests as part of their routine examination of the ear and hearing. Sheehy et al.24 advocate their continued use to validate the audiometric assessment, and Yung and Morris25 believe that tuning forks are of value in screening for hearing loss. Their usefulness in children has been questioned, and they are considered by many to be unreliable in this age group. Capper et al.26 compared the Rinne and Weber test responses to audiometric findings in 125 children and reported that about one-third of tuning fork responses were incorrect, especially in children under 6 years of age. More recently, Behn et al.27 evaluated 58 children who had otitis media with effusion and concluded the overall accuracy to predict hearing loss was poor. But, in older children and teenagers, tuning fork tests can be helpful in assessing hearing when audiometry is unavailable or unreliable or when serial evaluation of hearing is desired after an initial audiogram has been obtained. Examples of the latter situation would be following the course of otitis media or during the immediate postoperative period after middle ear surgery. The Weber test is performed by placing a tuning fork (usually 512 Hz) at the vertex or against the teeth and asking the child whether the sound lateralizes to one ear or not. The Rinne test is performed by asking the child to compare the loudness level of the tuning fork applied to the mastoid bone and opposite the external auditory canal. (An extensive description of these and other tuning fork tests is provided by Glasscock and Shambaugh.28)

Other Subjective Tests of Hearing Although not ideal, tests of a child’s ability to hear conversational and whispered speech can be helpful as an alternative to frequent periodic audiometric tests. An example of the usefulness of such testing is when the clinician wants to serially assess the hearing of a child who has a middle ear effusion and a previously documented conductive hearing loss, as an aid in management decisions (e.g., watchful waiting versus surgical intervention), because the hearing loss may fluctuate. When performing the testing, the clinician should present words that are familiar to the child, first at a conversational

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SECTION 2 ❖ Ear and Related Structures This article provides the current methods of examination for the diagnosis of otitis media, including acoustic reflectometry. Schwartz RH, Rodriguez WJ, McAveney W, Grundfast KM. Cerumen removal: how necessary is it to diagnose acute otitis media? Am J Dis Child. 1983;157:1064. In this classic article by pediatricians, the authors present their method of removing cerumen in a busy primary care clinical practice. Behn A, Westerberg BD, Zang H, Riding KH, Ludemann JP, Kozak FK. Accuracy of the Weber and Rinne tuning fork tests in evaluation of children with otitis media with effusion. J Otolaryngol. 2007;36(4):197–202. Even though the accuracy is not optimum, this is a recent description of the use of tuning forks to evaluate the hearing of children who have middle ear effusion.

References FIGURE 22-23 A Bárány noisemaker.

level and then in a whisper. The clinician should be behind the child on the side being tested, to prevent lip reading, while masking the opposite ear; gently rubbing a small sheet of paper over the ear not being tested is usually sufficient for masking. A child who fails to repeat words spoken at a conversational level will have about a 60-dB loss or greater, whereas if conversational speech is heard and whispered speech is not, the loss can be judged to be between 30 and 60 dB. These tests should not replace behavioral or nonbehavioral audiometric tests, because their reliability is questionable, especially in young children. However, these tests can be a cost-effective way of periodically assessing hearing after audiograms have been obtained. When the findings of audiometry reveal that the child has no hearing in one ear (i.e., anacusis), the use of a Bárány noisemaker (Fig. 22-23) as a masking device may be helpful to further verify the loss. When the noise maker is inserted into the hearing ear, the patient with an anacoustic ear will not be able to repeat words that are presented in a loud voice (e.g., shouted words).

Selected References Carlson LH, Carlson RD. Diagnosis. In: Rosenfeld RM, Bluestone CD, eds. Evidence-Based Otitis Media. 2nd ed. Hamilton, Canada: B.C. Decker Inc.; 2003:136–146. This article provides an up-to-date review of diagnostic techniques for diagnosis of otitis media. Kaleida PH, Stool SE. Assessment of otoscopists’ accuracy regarding middle-ear effusion. Otoscopic validation. Am J Dis Child. 1992;146:433. This excellent article describes the methods of validation of otoscopy for clinical and research use. Ruuskanen O, Ruohola A. Diagnostic methods. In: Alper C, Bluestone CD, Casselbrant ML, et al., eds. Advanced Therapy of Otitis Media. Hamilton, ON: B.C. Decker Inc.; 2004:9–13.

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1. Casselbrant ML. Balance and otitis media. In: Alper C, Bluestone CD, Casselbrant ML, et al. eds. Advanced Therapy in Otitis Media. Hamilton, ON: B.C. Decker, Inc.; 2004:337–342. 2. Balatsouras DJ, Kaberos A, Assimakopoulos D, Katotomichelakis M, Economou NC, Korres SG. Etiology of vertigo in children. Int J Pediatr Otorhinolaryngol. 2007;71(3):487–494. 3. Medellin G, Roark R, Berman S. The usefulness of symptoms to identify otitis media. Arch Pediatr Adolesc Med. 1996:150:98. 4. American Academy of Pediatrics and American Academy of Family Physicians. Clinical practice guideline: diagnosis and management of acute otitis media. Pediatrics. 2004;113: 1451–1465. 5. Paradise JL, Bluestone CD, Felder H. The universality of otitis media in fifty infants with cleft palate. Pediatrics. 1969;44: 35–42. 6. Stool SE, Randall P. Unexpected ear disease in infants with cleft palate. Cleft Palate J. 1967;4:99. 7. Legros JM, Hitoto H, Garnier F, Dagorne C, Parot-Schinkel E, Fanello S. Clinical qualitative evaluation of the diagnosis of acute otitis media in general practice. Int J Pediatr Otorhinolaryngol. 2008;72:23–30. 8. Schwartz RH, Rodriguez WJ, McAveney W, Grundfast KM. Cerumen removal: how necessary is it to diagnose acute otitis media? Am J Dis Child. 1983;137:1064. 9. Dinsdale RC, Roland PS, Manning SC, Meyerhoff WL. Catastrophic otologic injury from oral jet irrigation of the external auditory canal. Laryngoscope. 1991;101:75. 10. Khanna SM, Tonndorf J. Tympanic membrane vibrations in cats studied by time-averaged holography. J Acoust Soc Am. 1972;51:1904. 11. Barriga R, Schwartz RH, Hayden GF. Adequate illumination for otoscopy: variations due to power source, bulb, and head and speculum design. Am J Dis Child. 1986;140:1237. 12. Pelton SI. Otoscopy for the diagnosis of otitis media. Pediatr Infect Dis J. 1998;17:540. 13. Bluestone CD, Cantekin EI. Design factors in the characterization and identification of otitis media and certain related conditions. Ann Otol Rhinol Laryngol. 1979;88:13. 14. Gates GA. Differential otomanometry. Am J Otolaryngol. 1986;7:147. 15. Paradise JL, Smith CG, Bluestone CD. Tympanometric detection of middle-ear effusion in infants and young children. Pediatrics. 1976;58:198.

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CHAPTER 22 ❖ Methods of Clinical Examination: Ear and Related Structures 16. Paradise JL, Bluestone CD. Early treatment of universal otitis media of infants with cleft palate. Pediatrics. 1974;53:48. 17. Kaleida PH, Stool SE. Assessment of otoscopists’ accuracy regarding middle-ear effusion: otoscopic validation. Am J Dis Child. 1992;146:433. 18. Mandel EM, Rockette HE, Bluestone CD, Paradise JL, Nozza RJ. Efficacy of amoxicillin with and without decongestantantihistamine for otitis media with effusion in children. N Engl J Med. 1987;316:432. 19. Cantekin EI. Algorithm for diagnosis of otitis media with effusion. Ann Otol Rhinol Laryngol. 1983;92:6. 20. Jones WS. Video otoscopy: bringing otoscopy out of the “black box.” Int J Pediatr Otorhinolaryngol. 2006;70(11):1875–1883. 21. Bluestone CD, Klein JO. Diagnosis. In: Otitis Media in Infants and Children. 4th ed. Hamilton, ON: B.C. Decker Inc.; 2007:147–212. 22. Teppo H, Revonta M. Comparison of old, professional and consumer model acoustic reflectometers in the detection of

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23.

24. 25. 26. 27.

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middle-ear fluid in children with recurrent acute otitis media or glue ear. Int J Otorhinolaryngol. 2007;71(12):1865–1872. Linden H, Teppo H, Revonta M. Spectral gradient acoustic reflectometry in the diagnosis of middle-ear fluid in children. Eur Arch Otorhinolaryngol. 2007;264(5):477–481. Sheehy JL, Gardner G, Hambley WM. Tuning fork tests in modern otology. Arch Otolaryngol Head Neck Surg. 1971;94:132. Yung MW, Morris TMD. Tuning fork tests in the diagnosis of serous otitis media. Br Med J. 1981;283:1576. Capper JWR, Slack RWT, Maw AR. Tuning fork tests in children. J Laryngol Otol. 1987;101:780. Behn A, Westerberg BD, Zang H, Riding KH, Ludemann JP, Kozak FK. Accuracy of the Weber and Rinne tuning fork tests in evaluation of children with otitis media with effusion. J Otolaryngol. 2007;36(4):197–202. Gulya JA, Minor LB, Poe DS, eds. Glasscock-Shambaugh’s Surgery of the Ear. 6th ed. Shelton, CT: People’s Medical Publishing House USA; 2010.

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23

C H A P T E R

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The Assessment of Hearing and Middle-Ear Function in Children Brian Fligor

child begins interaction with the world with a fully functioning auditory periphery, tuned to the sound of a mother’s voice. Language learning begins at the moment of birth, if not before, listening to the mother’s voice in utero. Children who have normal hearing access the sounds of speech and through a miraculous process, dissect the pops, squeaks, and hums that make up language and begin producing their own approximations innately. Children who do not have normal hearing must be identified and appropriate intervention provided to have the same language-learning opportunities. When such identification and intervention are not provided, these late-identified children lag behind in language-learning, potentially lag in acquisition of literacy, and are permanently in remediation for lost time. This greatly hinders their opportunity to achieve full academic and social potential. Hearing can neither be seen nor palpated and can only be clinically assessed through carefully study of the cause-effect relationship of sound with the individual. Behavioral and physiologic test methods have a basis in scientific inquiry, and performed correctly, yield valuable information about the capacity of the child to participate in a hearing world. Results of hearing evaluations can illuminate underlying disease and direct physicians to provide medical or surgical intervention. These important results direct the audiologist in maximizing the communication development of the child with hearing loss and guiding the family via counseling not biased toward one communication modality versus another in the hope of providing each child an opportunity to become a socially, emotionally, and academically equipped adult. This chapter is intended to cover the breadth of topics in the assessment of hearing and function of the auditory system. It is intended as an overview of the most important topics in pediatric audiology and guide for better understanding of the process of obtaining information regarding hearing in children. Where important topics are given attention but only to the extent possible in a single chapter, further selected references are highlighted. Hearing assessment falls principally into two categories: behavioral audiometry and physiologic measures of the function of auditory system. Behavioral methods of assessment include behavioral observation audiometry (BOA), visual reinforcement audiometry (VRA), conditioned play audiometry (CPA), and conventional audiometry. The three most commonly used physiologic measures in pediatric audiology are acoustic immittance, otoacoustic emissions (OAEs), and auditory evoked potentials (AEPs). Such tests provide information regarding the functional

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integrity of the auditory system but do not directly assess the perceptual event that is called hearing. Regardless of the technique used, the examiner must interpret the behavioral or physiologic responses and judge whether hearing is normal or impaired. The reliability and validity of one’s judgment depends on the particular assessment technique used and the expertise of the observer, based on one’s skills and experience. For this reason, judgments made based on a single evaluation or a single technique should be regarded with caution. To arrive at a valid assessment of hearing in the very young child, a combination of several techniques and multiple evaluations over time is often necessary. The diagnosis of hearing loss is often a process, not an event. The age and developmental level of the child significantly influence the precision with which assessment information may be obtained. The nature of the auditory response is inherently gross and reflexive in the neonate and becomes more refined and voluntary as the child develops. However, the common belief that some children are too young to be evaluated properly is not valid. Reasonably precise estimates of hearing are obtainable in most cases by objective measures of physiologic responses combined with behavioral tests. The methods used and their limitations are described in detail in the following sections.

BEHAVIORAL AUDIOMETRY Behavioral audiometry is loosely classified as the consistent observation of a change in behavior in response to sound. With the exception of reflexive responses to sound, this change in behavior requires the active participation of the individual being tested. This behavior may be reinforced to extend the duration of active participation before habituation extinguishes the response. The level of sophistication of active participation is dependent on age (and developmental status), and so with decreasing age (and thus less sophisticated active participation), the test technique used requires greater sophistication. Techniques such as BOA and VRA or conditioned orientation response audiometry (COR) require the greatest level of sophistication on the part of the examiner, and least sophistication on the part of the individual being tested. It is then possible to determine hearing status of very young children and significantly developmentally delayed individuals with a degree of accuracy. CPA requires greater sophistication on the part of the patient and less on the part of the examiner. It requires the patient to have an understanding of cause–effect relationships and respect for boundaries

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established by rules, but allows for the immediate gratification offered by reinforcement through the actual act of the behavioral response (“playing”). Conventional “hand-raising” audiometry requires the most sophistication on the part of the individual being evaluated, and the least sophistication on the part of the examiner. This technique generally can be used when the individual being tested can delay gratification and can appreciate that the reward for active participation will be given following completion of the test, such as in the form of increased knowledge of hearing status and counseling for how this impacts his or her communication ability. In the case of a child capable of performing conventional audiometry, often the delayed gratification is an appreciation for his or her parents’ desire for them to complete the hearing test. Regardless of test technique used, social reinforcement strengthens the responses and provides additional motivation to maintain attention to the task.

The Audiogram The pure-tone audiogram is a fundamental component of the audiological evaluation, as it is the graphical representation of an individual’s detection threshold for frequency-specific stimuli in the conventional audiometric range (250– 8000 Hz). Considerable information is conveyed about the functional status of the conductive and sensorineural mechanisms of the ear on a graph spanning six octaves and roughly 130 decibels. The audiogram itself has a standard format, with the distance between octaves on the abscissa equal to the distance between 20 dB on the ordinate. Such standardization allows the trained clinician quick visual recognition of type, degree, and configuration of a hearing loss regardless of the size of the audiogram. As shown in Fig. 23-1A, the octave stimulus frequencies, in Hertz (Hz), are on the audiogram abscissa, and the stimulus intensity, in decibels in hearing level (dB HL) (Decibels referenced to hearing level (dB HL) is frequency-specific normalization of decibels Sound Pressure Level (dB SPL) to Hearing Level (HL) to allow “audiometric zero” to be flat, rather than a curved line. See ANSI S3.6.1), are on the audiogram ordinate. Interoctave frequencies (750, 1500, 3000, and 6000 Hz) are typically represented with dashed or dotted lines. The figure legend (Fig. 23-1B) of the audiogram indicates the method of sound presentation (air-conduction or bone-conduction), whether the threshold was obtained using contralateral masking (unmasked or masked), if testing was completed via earphones or is not ear-specific (e.g., sound field presentation or unmasked bone conduction), and if no response was obtained at the limits of the equipment (no response; denoted as an arrow added to the lower portion of the appropriate symbol). To note, historically, bone conduction could not be performed at 8000 Hz, and so sensorineural thresholds would only be charted through 4000 Hz. Newer instrumentation now allows for a limited intensity range of testing at 8000 Hz.

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A

B FIGURE 23-1. The audiogram (A) and the symbols (B) used to denote hearing thresholds in decibels of hearing level (re: ANSI S3.61.)

The purpose of charting the observed threshold of detection (“hearing threshold”) is to document the type (conductive, sensorineural, or mixed), the degree of severity, and the frequency-specific configuration of hearing thresholds. Ideally, this information will be documented for each ear, although this is not always possible for younger patients. These aspects of the hearing loss indicate both the expected impact on communication ability and on the underlying medical condition, and drive both medical and audiological intervention strategies. Air-conduction symbols charted across frequencies are typically connected by solid lines, whereas bone-conduction symbols are typically not connected (or are connected by dashed lines). It is most appropriate to connect air-conduction symbols denoting “true” hearing threshold. For instance, symbols for masked air-conduction would be connected, as this would be expected to indicate the actual threshold in that ear at that frequency. As well, air-conduction symbols that are not connected at all may be used to indicate the admitted thresholds are elevated relative to true threshold, as in the case of nonorganic hearing loss (malingering).

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DEGREE OF HEARING LOSS Normal hearing sensitivity (e.g., Fig. 23-2A) in children is considered 15 dB HL or better,2 as hearing thresholds of 25 dB HL or poorer are considered of educational significance. On occasion, and particularly for the younger and developmentally delayed patients, 20 dB HL may be considered the limit of normal hearing. It should be noted,

however, that this limit may overlook the presence of a slight conductive hearing loss in children with very good sensorineural hearing (bone-conduction thresholds of 0 dB HL or better). The degree of hearing loss is generally described according to air-conduction thresholds and classified as “Mild” when the loss is 21–40 dB HL, “Moderate” when the loss is 41–55 dB HL, “Moderately Severe” when the loss is

B

A

C

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D

FIGURE 23-2. Sample audiograms showing normal hearing and three different types of hearing loss: A, Normal hearing (bilateral); B, Conductive hearing loss (bilateral); C, Sensorineural hearing loss (bilateral); D, Mixed hearing loss (bilateral).

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56–70 dB HL, “Severe” when the loss is 71–90 dB HL, and “Profound” at 91 dB HL and greater.

TYPE OF HEARING LOSS A conductive hearing loss is evidenced by air-conduction thresholds poorer than 20 dB HL and bone-conduction thresholds that are normal (better than 20 dB HL) and the airbone gap (the difference between air-conduction and boneconduction thresholds) is 10 dB or more. See Fig. 23-2B for an example of bilateral mild conductive hearing loss. The exception to this general guideline is the child with airconduction thresholds at 20 dB HL and bone-conduction thresholds of −10 to 5 dB HL; this child has at least a 15 dB air-bone gap, and so would be considered to have a conductive impairment. The impact of conductive hearing loss is to reduce audibility of all sound in a linear fashion; that is, the perceived loudness of a more intense sound is reduced by the same amount as a less intense sound. When air-conduction and bone-conduction thresholds are poorer than 20 dB HL and within 10 dB HL, the hearing loss is considered sensorineural (e.g., Fig. 23-2C). The impact of sensorineural hearing loss (SNHL) is to reduce audibility of sound in a nonlinear fashion: sound that falls below the threshold of audibility is not detected, whereas sound that is above the threshold of audibility is audible, and typically as loud to the person with hearing loss as to a person with normal hearing, due to the phenomenon of loudness recruitment.3 When bone-conduction thresholds are poorer than 20 dB HL and air-conduction thresholds are elevated by another 10 dB or more (an air-bone gap is present), then a mixed hearing loss is present (e.g., Fig. 23-2D). The impact of a mixed hearing loss would be that of a nonlinear reduction in audibility (the sensorineural component) with an additional linear reduction in audibility (the conductive component).

Caveats to the Type of Hearing Loss Denoted by the Audiogram It is now evident that certain hearing loss etiologies result in “erroneous” results on the audiogram. Pseudoconductive hearing loss may in fact be sensorineural, where the patient’s sensitivity to bone-conducted stimuli may be heightened due to changes in the propagation of sound energy in the cochlea.4 These include some temporal bone abnormalities, such as enlarged vestibular aqueduct and superior semicircular canal dehiscence.5,6 Pseudo-sensorineural hearing loss may be seen at or around 2000 Hz in patients with congenital or acquired stapes fixation (“Carhart’s notch”) due to a reduction in added inertial energy of the ossicles that, in the normal ear, contributes to the hearing sensitivity of boneconducted stimuli. Finally, in patients with auditory neuropathy spectrum disorder (ANSD; also known as “auditory dys-synchrony”), the pure-tone audiogram can show any type, degree, or configuration of hearing loss, and not necessarily

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be indicative of hearing function, as is the audiogram when other hearing disorders are present.7 It should be noted as well that the impact of hearing loss is not explained by the audiogram, as two individuals with the same audiogram will have different levels of disability, owing in large part to age of onset and differences in environment in which the individual functions.8 Whether the hearing loss is bilateral and symmetrical or unilateral, conductive or sensorineural, the functional impact on the individual may require greater or lesser degrees of intervention to improve hearing function. Candidacy for audiologic intervention, selection, and verification and validation of that intervention is beyond the scope of the current chapter.

Instrumentation Considerations and Limitations Posed by the Child’s Ability to Participate The entirety of this chapter assumes testing is conducted in a sound attenuated audiometric testing booth using calibrated equipment conforming to current ANSI standards. The benefits and limitations of testing in the office setting with noise makers and tuning forks is not within the scope of this chapter. Conducting pure-tone audiometry in the pediatric patient may require the use of multiple transducers and types of stimuli to obtain as complete an audiometric picture as possible. Any of the pediatric behavioral testing methods described in this chapter can be performed using any of the signals and transducers for air- and bone-conduction testing. However, since many young children do not tolerate placement of earphones (at least, not well enough to actively participate in the listening task), the use of loudspeakers for presentation of air-conducted signals is often required. The resultant hearing thresholds, obtained in the sound field, then reflect the hearing of the better-hearing ear, should an ear-difference exist. In the same vein, masked hearing thresholds (air-conduction and bone-conduction) cannot always be obtained, as testing with masking requires the patient to ignore one auditory stimulus (the masking noise) while attending to another (the test signal). Although there are exceptions, the sophistication required to direct attention to the appropriate test signal, and respond appropriately, is often beyond that of a child younger than preschool, and sometimes limited in the school-aged child. Consequently, unmasked bone-conduction thresholds are obtained; these, of course, reflect the hearing sensitivity of the better-hearing cochlea, should a difference exist between the cochleae. It is necessary to understand such limitations, as a sound field audiogram of a child with bilateral middle-ear effusion showing mild hearing loss and normal unmasked bone-conduction thresholds does not rule-out a severe-to-profound SNHL in one ear. Due to the possibility of standing waves in the conventional audiometric range resulting in phase cancellation or reinforcement (thus, creating artificially higher or lower intensities at certain frequencies), narrow band noises and warbled tones are used when presenting sound via loudspeakers.

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children These signals may also be used in younger patients to assist in improving their attention to the auditory task, without significantly reducing the frequency specificity relative to the pure tone. Unless otherwise indicated by patient history, the audiologist’s role in the audiological evaluation is to document hearing sensitivity for the sake of accessing spoken language. Normal hearing thresholds in at least one ear for octave frequencies 500–4000 Hz essentially rules-out a communicatively significant hearing loss for the child under the age of 3 years. Normal hearing thresholds in both ears for frequencies 500–4000 Hz essentially rules-out an educationally significant hearing loss for children age 3 years and up. Regardless, however, the audiologist endeavors to document hearing sensitivity in both ears 250–8000 Hz, as long as responses are judged to be clear and replicable; there are important but subtle speech cues outside the range of 500–4000 Hz. When response reliability is questioned, testing typically is suspended so as to not call into question the reliability of all responses. The transducers chosen for testing depends on the child’s willingness to accept placement on the ears or head against the desire to document hearing sensitivity across the audiometric range in each ear. Insert earphones are the transducer of choice for air-conduction testing, owing to the lighter weight, avoidance of collapsing ear canals (as can happen with supra-aural earphones), and greater reliability of sound level in the high frequencies.9 One specific reason to opt for supra-aural earphones over insert earphones is testing hearing in ears with nonintact eardrums (either perforated eardrums or those with patent tympanostomy tubes). It has been shown that significant sound pressure variations (as great as 35 dB) exist in ears with patent tympanostomy tubes or perforated eardrum, resulting in an erroneous conductive hearing loss in the low frequencies.10 The pressure variation is greatly reduced when supra-aural earphones are used, and nonexistent when loudspeakers are used. For the child with nonintact eardrum who tolerates the change of transducer, the audiologist will often test air-conduction thresholds 1000–8000 Hz using insert earphones and 250–500 Hz using supra-aural earphones.

Methods of Behavioral Hearing Assessment in the Pediatric Patient A child’s ability to respond to sound changes markedly in the first few months of life and his or her ability to participate in formal testing changes according to his or her capacity to be motivated by reward, that is, operant conditioning.11 The following test methods evolved to capitalize on response capabilities of children at different stages of development. Therefore, the age and developmental level of the child dictates which assessment method yields the most meaningful information. The audiologist experienced in assessing the pediatric patient will switch between methods, according to the ability of the child, to obtain the most complete evaluation.

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BEHAVIORAL OBSERVATION AUDIOMETRY (BOA) BOA is typically used when behavioral hearing assessment is attempted on a child with developmental age of 6 months and younger.12 BOA involves the observed, consistent, change in state with the presentation of a signal. The responses are reflexive and do not incorporate conditioning. They require the examiner to be experienced in observing the natural responses to sound early in life, such as eye-widening, eye blinks, Moro reflex, leg kicks, crying, or quieting. As an example, if at baseline the child is sucking on a pacifier, the presentation of an audible acoustic signal may cause the child to stop sucking; if this observed change in behavior is repeated with the same stimulus and same level, this can be judged a true auditory response. The more complex the frequency spectrum and the greater the sound intensity, the more robust is the behavioral response.2 Speech and music, for instance, elicit a more robust response than do narrow band noises or warbled tones.13 This phenomenon is at odds with the desire to document frequency-specific hearing thresholds. As well, these involuntary responses are subject to habituation, given that there is no consequence to the repetitive stimuli (that is, no reinforcement, negative, or positive). The nature of BOA, then, can weaken the reliability of this procedure for behavioral assessment of hearing. It is unlikely that true hearing thresholds can be determined, and so BOA should be considered a subjective screening method that will detect only significant degrees of hearing loss. A cross-check with physiological testing methods is vitally necessary for children less than 6 months developmental age.

VISUAL REINFORCEMENT AUDIOMETRY AND CONDITIONED ORIENTING RESPONSE AUDIOMETRY VRA and COR use similar techniques as BOA, except that the reflexive response of orienting toward or localizing the source of the sound is reinforced through a visual reward. The visual reward used most often clinically is illuminating and/or animating a puppet in a box with a smoked-glass front panel or a short video animation (“video VRA”). Suzuki and Ogiba14 first described the technique and gave it the term conditioned orientating audiometry, which required the child to discriminate between loudspeakers located on either side of the child. Liden and Kankkonen15 described a similar method, but used a single loudspeaker, and used the term VRA. It is more commonplace now to use the term VRA to describe the method which employs reinforcing a head-turn response to an audible stimulus. VRA is most effective when testing children developmental age 6–24 months. Depending on the maturity of the child, VRA may be necessary through age 30 months, rather than using test measures requiring the child to have

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impulse control (conditioned play tasks). The typical testing arrangement for VRA involves the child sitting on a parent’s lap, with loudspeakers and visual reinforcers located at 90° to the left and right of the child. Alternatively, loudspeakers may be located at 45° to the left and right, although this requires a less pronounced head-turn response. A conditioning stimulus is presented (often speech or music, at a level expected to be easily audible), and the reinforcer is activated to reward the child for orienting to the side of the sound source. Following conditioning, stimuli may be presented at lower intensity levels and still elicit a clear response from the child, as long as the reinforcer is sufficiently rewarding.16–19 The minimum response level (MRL) of the sufficiently conditioned child often approximates true hearing threshold, as evidenced by high correlation between VRA and electrophysiologic data documenting frequency-specific hearing thresholds.20,21 In many circumstances, it is necessary to structure the young patient’s attention and level of arousal during VRA to achieve sufficient conditioning and elicit responses near true hearing threshold. As not all children spontaneously orient to the appropriate side during conditioning, the use of a tester-assist, seated in front of the infant is often helpful. The tester-assist serves to distract the patient from orienting to either side in anticipation of the reward prior to onset of the stimulus and also helps the parent remember his or her role is to provide physical and emotional support for the child, rather than interacting with the child during the evaluation (which potentially leads to the parent cueing the child to the sound). Alternatives to using a tester-assist include the use of a “centering” toy and arranging the room so that the tester (located in a separate control room, observing through a window) is visible to the patient and so visual attention can be obtained. In practical experience, a two-tester paradigm typically results in a more complete evaluation and less frustration. This two-tester paradigm is not without controversy, as pros and cons are easily identified. Two audiologists working together significantly increases the cost of providing the service, and it is not evident that test time varies significantly whether testing is conducted with a single clinician or two. Conversely, a more complete evaluation, including thresholds obtained at more frequencies and measures of separate-ear hearing status, may result in the need for only one test rather than multiple tests to obtain the necessary information, and may avoid the need for sedation or general anesthesia if physiologic testing is deemed necessary because behavioral testing was not successful. A fair trade-off used in some programs includes the use of a trained audiology assistant.

CONDITIONED PLAY AUDIOMETRY (CPA) CPA is used to take advantage of the reward experienced through the act of the response to the stimulus itself. That is, if the response is to put a peg in a pegboard when the tone

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is presented, the play-response reinforces itself and improves the likelihood of future responses. It is used most often in children with developmental age 3–5 years, although it can be modified to be used in children younger than 3 years, such as pairing the play-response with a visual reinforcer (and social reinforcement). Following a brief conditioning period, the conditioned child will respond to stimuli of varying frequency and intensity, and MRLs approaching true hearing threshold can be obtained. Successful CPA requires the child to be able to wait, listen, and then respond to the sound through the play task. If impulsivity in responding cannot be redirected through careful structuring, the clinician is best served by changing the test method to VRA, regardless of the age of the child. For the child who will tolerate placement of earphones and is readily conditioned, the examiner can use a portable audiometer, seated in the same room as the child. A typical arrangement is for the child to be seated at a table with the toy in front of him or her, with the examiner seated in front or to the side, holding the blocks, disks, or pegs that will be the child’s responses and controlling the portable audiometer. The benefit of using the portable audiometer is that the child can be structured and conditioned with the examiner beside the patient, but at the expense of not being able to use speech as a stimulus for testing. As with BOA and VRA, speech yields the most robust response, and so it is often used for conditioning the child who is not confident enough to respond to a pure- or warbled tone or narrowband noise. For the child who is tested in the sound field because he or she does not readily tolerate placement of the earphones, using speech presented via loudspeakers with a simple “put it in” task (e.g., the child puts a block in the bucket when the examiner says “put it in”) may help the patient overcome fear of the earphones. The use of speech to condition the play task also helps the child grasp the task using frequency-specific stimuli. The use of a testerassist is also beneficial in this instance, such as for modeling the listening-and-responding behavior, and allows the tester to be in a room separate from the patient.

CONVENTIONAL AUDIOMETRY Conventional “hand-raising” audiometry is traditionally reserved for children developmental age 5 years and older. As with adults, the child is instructed to listen for the test sound and respond, either by raising the hand, pressing a button, or a verbal response. The intensity of the stimuli is varied from trial to trial, and threshold is determined by the lowest intensity at which a response is given 50% of the time. Care must be taken with the child being asked to perform conventional audiometry, as hearing testing (of any method) requires the child to maintain attention to the task for an extended period of time. Social reinforcement can help reduce the number of false-positive and false-negative responses and improved the reliability and validity of responses.22 When the validity of test results is in question,

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children the experienced clinician might change to CPA to see if the immediate gratification offered by the play task might improve response reliability.

Speech Audiometry As described in BOA, VRA, and CPA, responses to speech are typically more robust than to nonspeech stimuli, and so speech is useful in conditioning to the auditory task. However, speech awareness thresholds (SATs) and speech reception thresholds (SRTs) are useful cross-checks of the pure-tone audiogram. And since the primary goal of hearing assessment is to determine the patient’s ability to understand speech, tests of word intelligibility, yielding the Word Recognition Score (WRS), are appropriate for assessing the child’s performance to suprathreshold, complex stimuli.

SPEECH AWARENESS THRESHOLD The speech awareness threshold (SAT) is the lowest level at which the child admits to detecting speech and is reported in dB HL. Since speech is broadband (acoustic energy is distributed across the audiometric frequency spectrum), the SAT should most closely corroborate the most sensitive threshold on the pure-tone audiogram. Significant discrepancies (10 dB or more) should be investigated further and may lead the clinician to discover a steeply sloping configuration on the audiogram. For instance, a child with moderately severe hearing thresholds 500–4000 Hz but SAT of 25 dB HL may have near-normal hearing at 250 Hz. Such information can be useful for fitting of amplification and explaining to families why the child responds appropriately to many environmental sounds but has delayed speech and language.

SPEECH RECEPTION THRESHOLD The speech reception threshold (SRT) is the lowest level at which a person accurately repeats familiar words 50% of the time and is reported in dB HL. As with adults, the SRT is administered by familiarizing the child with a closed-set of spondee words (two-syllable words with equal emphasis on both syllables), and varying the intensity of those same words to estimate threshold. For younger children, the closed-set may be modified to use words that are within their vocabulary. In a child whose articulation is poor or is reluctant or shy to repeat the words, a picture pointing task can be used. Although greater test-retest reliability may be achieved with recorded speech, speech audiometry with children often requires the flexibility offered by monitored live-voice. As long as the examiner carefully monitors his or her vocal intensity, the voice can still be animated and SRT agree with the pure-tone average of 500 Hz, 1000 Hz, and 2000 Hz within 7 dB. If the SRT is more than 7 dB better than the pure-tone average, it may be because the closed-set of spondees was too small (and by chance the child guessed right), or the pure-tone thresholds were elevated relative to true threshold

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(for instance, if the child was not adequately conditioned, or the child is malingering). If the SRT is more than 7 dB poorer than the pure-tone average, it is possible there is severe distortion for complex signals, such as in ANSD or other retrocochlear disorder.

WORD RECOGNITION TESTING The Word Recognition Score (WRS) is obtained typically through an open set of 25 or 50 monosyllabic words at suprathreshold levels (often 35–45 dB relative to the SRT or pure-tone average) and is reported as a percent correct. The open-set word lists are intended to be “phonetically balanced,” representing an appropriate sample of the phonemes in the language. The WRS may yield important diagnostic information as well as give some measure of anticipated benefit from audiologic interventions. It is necessary for the audiologist to select a test that is appropriate to the child’s developmental age and hearing status, considering the child’s ability to respond (verbally or through a picture-pointing task), and on what populations the tests were normed. Word recognition testing should be performed at the child’s maximum comfortable level (MCL) unless history indicates otherwise. For a typically developing child age 7 years and older, without hearing loss, the same word lists used for testing adults can be used for testing the child. For younger children and those with hearing loss, alternative word lists and response modes have been developed. For children with normal hearing ages 4–7 years, the Phonetically Balanced Kindergarten (PBK-50)23 lists are appropriate, language level permitting. The Word Intelligibility by Identification (WIPI) test was developed to allow the patient to respond by pointing to one of six pictures on a page corresponding to the word presented.24 This test was normed on children with hearing loss age 4½ years and older, and with a response of picture-pointing rather than verbal repetition, it is well suited for assessing WRS in children with hearing loss who may have distortions in their speech, causing difficulty for the examiner to score. The NU-CHIPS (Northwestern University Children’s Perception of Speech)25 is another word recognition test that uses a picture-pointing response, only with four pictures per page and is appropriate for children with receptive language as young as 3 years old. The Early Speech Perception (ESP) was developed at Central Institute for the Deaf (CID) to allow for speech recognition testing of very young, profoundly hearing-impaired children with limited vocabulary and language skills.26 The test is composed of three sections: Part I is a pattern perception subtest and two-word identification subtests. Part II is a 12-item spondee identification test with each word having a different vowel sound. Part III is a 12-item monosyllabic word identification test containing similar words. There is also a low verbal version of the test, which is four spondees represented by pictures of objects. The purpose of the

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ESP is to separate the receptive skills into five categories: (1) No pattern perception, (2) Consistent pattern perception, (3) inconsistent word identification, (4) consistent word identification, and (5) open-set word recognition. The ESP may be especially helpful in assessing benefit and/or improvement in audiologic interventions provided to young children with significant hearing loss.

(CENTRAL) AUDITORY PROCESSING Admittedly, the pure-tone audiogram and speech audiometry do not reflect nearly the full capability of the auditory mechanism. Considerable processing through excitatory and inhibitory neurons occurs in the ascending auditory pathway and auditory cortices. The ability to localize a moving sound source with fine acuity and understand a talker despite considerable background noise owes in large part to the processing of auditory information after the cochlear transduction process. On occasion, and it is controversial how often it happens, dysfunction occurs in the ascending auditory pathway, resulting in an auditory processing disorder. Although full coverage of auditory processing disorders is outside the scope of this chapter, the interested reader may consult the Handbook of (Central) Auditory Processing Disorder, Volume 1: Auditory Neuroscience and Diagnosis and Volume 2: Comprehensive Intervention.27 As defined by the American Speech-Language-Hearing Association,28 central auditory processes are the auditory system mechanisms and processes responsible for the behavioral phenomena of sound localization and lateralization, auditory discrimination, auditory pattern recognition, temporal cues, and auditory performance decrement with competing or degraded acoustic signals. An auditory processing disorder is an observed deficiency in one or more of these auditory behaviors, despite having normal intelligence and normal hearing sensitivity. It is assumed to apply to speech as well as nonspeech, and results in difficulties with language learning and the ability to integrate rapid verbal information. The difficulty is exacerbated by background noise and reverberant acoustic environments. However, there still lacks uniform consensus and definition, identification procedures, and intervention practices. Nonetheless, when a child presents with hearing difficulties (particularly in the classroom with resultant reduction in classroom performance) and cognitive and speech-language delays have been ruled-out and the audiogram is normal, psychoacoustic tests of auditory processing abilities can be conducted to elucidate an auditory processing disorder and direct audiological interventions. Typically, efforts to improve signal-to-noise ratio in the educational setting are a first-line intervention. Use of FM educational amplification systems, note-takers, one-on-one tutoring in a quiet room, and retrofitting acoustical treatments to classrooms to reduce reverberation all serve to improve signal-to-noise.

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SUMMARY OF BEHAVIORAL TESTING METHODS Creativity, flexibility, and an ability to relate at the child’s level of motivation are necessary in order to secure the child’s trust and facilitate the behavioral audiological evaluation. The experienced clinician will move from one method to another, such as using CPA to get speech awareness thresholds, and after determining the child is having difficulty with the transition of the play task for pure-tones, will use VRA to obtain the pure-tone audiogram. The information presented describes a variety of age-dependent behavioral techniques available for evaluating the hearing status of children aged 6 months and above. For children under the age of 6 months, clinicians rely more heavily on physiological measures of hearing function. For children whose hearing can be tested via behavioral test techniques, quantitative, valid measures of hearing status can be obtained. In a well-conditioned young child, response reliability and validity approach that of conventional audiometry in adults, regardless if testing is VRA, CPA, or conventional, hand-raising audiometry. Clinicians should not apply a “MRL correction factor for age” such that responses suggesting mild or greater degrees of hearing loss be dismissed as elevated relative to true threshold due to a child’s inability to respond near threshold. Such excuses risk mislabeling a child with hearing loss as having normal hearing. Unless hearing thresholds obtained via behavioral audiometry have conclusively ruled-in normal hearing, it is advisable that physiologic measures be used to confirm hearing status. Typically, in children under the age of 3 years who are identified to have SNHL, physiologic measures are recommended to confirm presence of hearing loss.

PHYSIOLOGIC ASSESSMENT OF THE EAR AND HEARING MECHANISM For a multitude of reasons, it can be difficult to obtain a reliable test of hearing in the pediatric patient when using behavioral test methods. Tests that do not require a behavioral response are helpful to the pediatric audiologist and otolaryngologist. The three physiologic assessment techniques most often used are acoustic immittance measures (admittance or impedance), OAEs, and AEPs. These tests are often considered objective because, rather than requiring a voluntary response (i.e., active participation) from the patient, they take advantage of naturally occurring physiologic “by-products” of the process of hearing. However, the information obtained by such tests must still be interpreted by a human observer and is still susceptible to artifact and error. Therefore, the objectivity of such tests should be treated with a healthy skepticism. The behavioral audiogram remains the gold standard of assessment of hearing sensitivity, so physiologic test results are taken to supplement or provide information until the audiogram can be obtained. The primary goal of

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children the ongoing audiologic assessment of a child with hearing impairment is to develop a reliable and valid audiogram.

ACOUSTIC IMMITTANCE MEASUREMENTS Immittance is a term used to describe the transfer of acoustic energy, whether measured in terms of acoustic admittance (flow of energy) or acoustic impedance (opposition to flow of energy). Admittance and impedance are reciprocals and so provide similar information in a different way. Clinical immittance measures, which are measures of either acoustic admittance or acoustic impedance at the tympanic membrane, provide information from which inferences about the integrity of the entire middle-ear system can be made. Immittance measures that are commonly used are tympanometry and the middle-ear muscle reflex (the activation of the stapedius muscle by sound). The middle-ear muscle reflex is also commonly known as the acoustic reflex. They can be used in adults as well as in children but are particularly valuable in children because they require little cooperation and no voluntary response from the patient. Also, there is a high prevalence of middle-ear disease among children, especially otitis media with effusion, that can be reliably identified and monitored using immittance measures. To fully understand and interpret acoustic immittance test results, one should first have an understanding of the basic underlying physical principles. Only a brief introduction to some of the many and complex factors involved in acoustic immittance is presented here. The interested reader should consult the references for more comprehensive information on the development of acoustic immittance instruments and the principles of acoustic immittance testing.29–31

IMPEDANCE VERSUS ADMITTANCE IMPEDANCE The opposition to the flow of acoustic energy that is attributable to mass and stiffness is called reactance. In reactance, energy is stored. The portion of reactance that is due to stiffness is called negative, or compliant, reactance; the part attributable to mass is called positive, or mass, reactance. Resistance is the portion of the impedance attributable to friction in the system, in which case energy is dissipated as heat (albeit tiny amounts of heat). If a system has stiffness and mass, the overall reactance will be the sum of the two reactances contributed. Because one component is negative (compliant) and the other is positive (mass), the absolute magnitude of the reactance is less than either one alone. The reactance and the resistance together determine the total impedance. However, because the reactance and the resistance are out of phase with each other, the combination of components requires the use of complex (real and imaginary) numbers, which, for simplicity’s sake, are not discussed in this chapter. Mass reactance is proportional to frequency, and compliant reactance is inversely propor-

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tional to frequency; thus, their relative effects depend on the frequency of the driving force (the probe tone). Compliant (stiffness-controlled) reactance increases as frequency decreases. Mass reactance increases with increases in frequency. If a system has greater compliant reactance than mass reactance, it is called a stiffness-controlled system. If a system has greater mass reactance, it is called a mass-controlled system.

ADMITTANCE The reciprocal of impedance is admittance. The terms used to describe the components of admittance are susceptance (the reciprocal of reactance) and conductance (the reciprocal of resistance). The reciprocal of negative (compliant) reactance is positive susceptance or compliance. The reciprocal of positive (mass) reactance is negative susceptance.

MIDDLE-EAR IMMITTANCE The middle-ear system has all three elements of the aforementioned mechanical systems: There is stiffness provided by the tympanic membrane, the ossicular chain, and the volume of air in the middle ear. Mass is provided primarily by the ossicles. The resistance (or conductance) component comes primarily from the cochlea. The basis for acoustic immittance testing in the auditory system is the ability to determine the input acoustic immittance of the middle-ear system at the tympanic membrane. This is done by introducing a controlled force (voltage applied to the sound transducer within the probe assembly, producing a probe tone) into the ear canal and measuring the resulting sound pressure level (SPL). The degree to which the middle ear permits the flow of acoustic energy determines how much acoustic energy is reflected from the tympanic membrane, and as a result, the SPL measured in the ear canal. The SPL of the signal in the ear canal is proportional to the immittance in the system.31 For a given force, the greater the flow of acoustic energy through the middle ear (greater admittance, less impedance), the lower is the overall SPL in the ear canal. The poorer the flow of acoustic energy through the middle ear (less admittance, greater impedance), the greater is the SPL in the ear canal. In clinical immittance-measuring systems, the probe signal is introduced into the ear canal via a probe assembly and tip made to fit snugly into the ear canal. The assembly includes a driver, or transducer, to deliver the probe signal to the ear and a microphone used in the measurement of earcanal SPL. The other important component of the delivery system is a pump that allows the tester to vary the pressure in the ear canal (manually or automatically). When the probe assembly is fit hermetically into the ear canal with the soft tip, acoustic immittance of the ear canal and middle-ear system can be measured with different amounts of air pressure in the ear canal. That is, the air pressure in the ear canal can be

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increased or decreased with the pump and changes in voltage at the earphone needed to maintain a constant SPL in the ear canal can be used to derive measures of immittance. The changes in immittance as a function of changing air pressure in the ear canal are plotted graphically as a tympanogram.

PROBE-TONE EFFECTS The normally functioning middle-ear system is a stiffnesscontrolled system (due to the properties of the tympanic membrane, the ossicular chain, and the volume of air in the middle-ear) when immittance is measured using a lowfrequency probe tone (e.g., 226 Hz). For all practical purposes, the measure is one of compliant reactance (negative), also referred to as compliance. For this reason, acoustic immittance measures using a low-frequency probe tone are often called measures of middle-ear compliance. Some instruments incorporate a higher-frequency probe tone in addition to a tone around 226 Hz. Probe tones of 678 and 1000 Hz are closer to the resonant frequency of the middle ear and are less dominated by the stiffness in the system. A change in the stiffness of the middle ear resulting from a pathologic condition causes a greater proportional change in immittance with a high-frequency probe tone than with a low-frequency probe tone, making abnormalities easier to detect with the higher-frequency probe. This is true for pathologic conditions that increase stiffness (e.g., otosclerosis) as well as those that decrease stiffness (e.g., disarticulation of the ossicles). In addition, the high-frequency probe tone is a more sensitive indicator of changes in mass, such as those that accompany cholesteatoma and adhesions.

TYMPANOMETRY Most clinical immittance instruments measure acoustic admittance rather than acoustic impedance, in large part because the measurement of admittance requires simpler circuitry and analysis. An admittance tympanogram is simply a plot of the admittance of the middle ear as a function of air pressure in the ear canal. Admittance of the middle ear is actually inferred from two measures: a measure of the admittance of the ear canal between the tip of the probe and the tympanic membrane, and a measure of the admittance of the entire system, from probe tip through the middle ear. The acoustic admittance of only the middle ear is estimated as the difference between these two measures. The admittance of the ear canal is estimated by first sealing the ear canal with the probe tip and changing the ear-canal pressure to a very high (+200 +400 daPa) pressure or to a very low (−600 daPa) pressure, thereby effectively stiffening the tympanic membrane so that it has, for all practical purposes, no compliance (i.e., zero admittance). In that case, all of the admittance measured at the probe is a result of the volume of air in the ear canal. When a probe tone around 226 Hz is used at atmospheric pressure, the acoustic admittance, in milliSiemens (mS), of the ear canal is approximately equivalent

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to the volume (mL) of air in the ear canal. The estimate of ear-canal volume has some clinical value and is discussed later. After the estimate of the ear-canal admittance, ear-canal air pressure is varied smoothly from the extreme starting pressure, toward ambient pressure (0 daPa) and then on to the opposite extreme. Most clinical tympanometric protocols start with high positive pressure, measure ear-canal admittance (i.e., equivalent ear-canal volume), and then sweep the pressure in a positive-to-negative direction while continuously measuring admittance. For example, Fig. 23-3A is a tympanogram from a normal adult ear. The ear-canal volume (1.7 mL) was estimated first and then the immittance system’s air pump swept pressure from +400 to −600 daPa as admittance was monitored. The tympanogram plot reflects compensated admittance, that is, the admittance attributed to the ear canal is deducted from the dynamic admittance estimate so that the tympanogram reflects only the admittance of the middle ear. In a normally functioning middle ear, admittance increases as ear-canal air pressure approaches ambient pressure. Peak admittance of the middle ear should occur in the vicinity of 0 daPa, although there is some range of normal values (usually +50 to −150 daPa for children). As air pressure goes further toward high negative pressure, admittance decreases and the result is the characteristic inverted V tympanogram shape. Peak compensated admittance is the middle-ear admittance at the peak of the tympanogram (1.1 mL in Fig. 23-3A). Note that for this instrument, admittance using the 226-Hz probe tone is given in equivalent volume (mL or cc) rather than in actual physical units of admittance (mS), which are equivalent for that frequency under normal atmospheric conditions. The ear-canal pressure at which peak compensated admittance occurs is called the tympanometric peak pressure (−10 daPa on the tympanogram in Fig. 23-3A). This is highly correlated with pressure in the middle ear, as the middle-ear admittance is usually greatest when the pressure difference between the ear canal and the middle ear is low or zero.32 The tympanometric peak pressure may not necessarily reflect the actual air pressure condition of the middle ear but still is of some clinical value with respect to tympanogram interpretation. Tympanometric gradient is a measure that quantifies the rate of change in admittance around the peak of the tympanogram. Several ways of quantifying gradient have been suggested.33 The method most favored at this time is known as tympanometric width; this is the horizontal distance (in daPa units) between the sides of the tympanogram at half the peak admittance. The sharper the peak of the tympanogram, the narrower (smaller) is the tympanometric width. An alternative gradient measure is a ratio of two values, a/b, derived from the tympanogram. The first (a) is the difference in admittance between the tympanogram peak and the admittance at which the tympanogram is 100 daPa wide, and the second (b) is peak admittance. When gradient is expressed as a ratio, the possible range of values is 0 to 1 and, in contrast to the tympanometric width, the sharper is

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FIGURE 23-3. Admittance tympanograms. A, Normal findings in an adult ear. Equivalent ear-canal physical volume was estimated first with air pressure at +400 daPa, then air pressure was swept positive to negative (starting at +400 daPa), and a 226-Hz probe tone was used. Tympanometric peak pressure = −10 daPa; peak admittance = 1.1 mS (or mL); and gradient (measured as the tympanometric width) = 85 daPa. B. Admittance tympanograms for a normal-hearing adult ear with low peak admittance (0.3 mL) according to norms for the instrumentation settings used but the tympanometric peak pressure and tympanometric width (gradient) is within normal limits. C. Admittance tympanograms for an 11-year old boy with mild low-frequency conductive hearing loss. Notice the peak admittance is abnormally high (1.9 mL), causing the scale on the ordinate to change from 0-to-1.5 mL to 0-to-3 mL. Tympanometric width (gradient) at 25 daPa is also abnormally small. D. Admittance tympanograms for an 11-month-old infant with otitis media with effusion. The tympanogram has a low, rounded shape, with peak admittance at 0.1 mL and tympanometric width (gradient) equal to 240 daPa. E. Admittance tympanogram for the left ear of a 12-month-old infant with otitis media with effusion. The lack of a discernable peak causes the instrument to record “NP” (no peak) for the admittance values. F. Admittance tympanogram for the right ear of the same infant with peak admittance and tympanometric width (gradient) within normal limits but with high negative peak pressure (not an unusual finding in the contralateral ear of a child with unilateral otitis media with effusion).

the peak of the tympanogram, the greater is the gradient value. Table 23-1 provides data on children 3 years old and older, with normal otoscopic examination, from several different studies. The protocols in the studies of the children differed in some ways that are known to affect the data; all three studies are presented, with information about the protocols used, so the values can be interpreted properly. Table 23-2 provides data on younger children and illustrates developmental change in the first years of life in tympanometric variables. The tympanogram in Fig. 23-3A is within the normal range for adults.34 It provides gradient in the form of tympanometric width, which for this individual is 85 daPa.

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Some characteristics of tympanograms are useful for making clinical diagnoses. In general, pathologic conditions that stiffen the middle-ear system reduce acoustic admittance and thereby produce tympanograms with low peak admittance values (Fig. 23-3B). Pathologies that loosen the middle-ear system increase acoustic admittance and thereby produce tympanograms with high peak admittance values (Fig. 23-3C). Note that the tympanogram in Fig. 23-3C does not look radically different from the one in Fig. 23-3A. However, careful attention should be paid to the y-axis (admittance), which has been rescaled to accommodate the abnormally high admittance peak (1.9 mL). This also changes the ratio of units on the x-axis to y-axis, so the

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TABLE 23-1. Mean Values and 90% Range for Normal Ears of Children Ages Approximately 3 Years Old and Older From Three Data Sets

Nozza et al180a

Koebsell and Margolis124b

Margolis and Heller142c

Ear-Canal Volume (mL) Mean SD 5th to 95th percentiles n

0.900 0.26 0.6–1.35

NA

130

0.74 NA 0.42–0.97 92

Peak Admittance (mS) Mean SD 5th to 95th percentiles n

0.78 0.31 0.4–1.39

0.67 0.22 NA

0.50 0.19 0.22–0.81

130

60

92

104 32 60–168

124 33 68–187

100 NA 59–151

130

60

92

Tympanometric Width (daPa) Mean SD 5th to 95th percentiles n

a + 400 to − 600 daPa; 3–16 years old. Equivalent volume estimated at + 400 dapa. b MAX/MIN method, + 400 to − 400 daPa; 2.8–5.8 years old. Equivalent volume estimated by using value of minimum tail of tympanogram, which was at − 400 daPa for 43 subjects and at + 400 daPa for 17 subjects.

+ 200 to − 300 daPa; 3.7–5.8 years old. Equivalent volume estimated at + 200 daPa.

c

NA, not available from report.

relationships between admittance and pressure are different from those for the normal ear in Fig. 23-3A. It is important to be aware of the potential for changes in scaling to occur and the impact that they have on the pattern of the tympanogram, even though the actual values for the immittance parameters are accurately represented in the numeric table below the tympanogram. Otitis media with effusion tends to stiffen the middleear system, so peak admittance is reduced, but the tympanometric shape (i.e., gradient) also changes, becoming more rounded or even flat (Fig. 23-3D). Tympanometric width tends to increase as a middle-ear condition worsens and, usually, as effusion develops. Eventually, the peak is no longer detectable, and a tympanogram is considered to have “no peak,” with no estimate of tympanometric peak pressure, peak admittance, or gradient (tympanometric width) provided (Fig. 23-3E). Fig. 23-3F shows the tympanogram

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of the contralateral ear of that in Fig. 23-3E and represents normal tympanometric width and peak admittance but high negative tympanometric peak pressure, a common finding in the contralateral ear of a child with unilateral otitis media with effusion. In 1987, the American National Standards Institute (ANSI) published a standard for specifications for immittance instruments: ANSI S3.39 R1996.35 The standard requires that instruments be designed to measure actual physical quantities of immittance (admittance or impedance). It also requires that for the range of admittance values commonly associated with normal adult ears, the admittance tympanogram should maintain an aspect ratio of 300 daPa (x-axis)–1.0 mS (y-axis). Therefore, admittance tympanograms recorded on different instruments that meet the ANSI standard should be comparable with each other. It is important to note that instruments designed before the new standard recorded impedance in arbitrary compliance units rather than in absolute physical quantities, and the ratio of air pressure to “compliance units” varied from subject to subject. With those earlier instruments, actual physical quantities (impedance) had to be computed on the basis of specific measurements apart from the tympanogram. The significance of this information is that great deal of the history of interpretation of tympanograms for screening and diagnosis is tied to the early impedance instruments with arbitrary compliance units.36,37 Unfortunately, there is no way to directly compare the data from currently available instruments with those using the arbitrary units, so the use of pattern classification schemes developed based on previous methods of plotting tympanograms may not apply to the admittance tympanograms obtained with instruments that meet the current ANSI standard.

TYMPANOGRAM CLASSIFICATION BY PATTERN IDENTIFICATION In the past, pattern classification schemes37,38 were used almost exclusively for tympanogram interpretation, given the arbitrary compliance units. The one most well known is that proposed by Jerger.38 Because the system was developed using impedance meters with arbitrary compliance units, it is not quantitatively described. For Jerger type A, there is a peak that is within the normal range with respect to tympanometric peak pressure. Type A was subdivided into AS (type A, shallow), which refers to a tympanogram with a peak within the normal range of tympanometric peak pressures but with low peak immittance, and type AD (type A, deep), which refers to a tympanogram with a peak within the normal range of tympanometric peak pressures but with high peak immittance. Type B is the absence of a peak (i.e., a flat tympanogram). Type C has a peak, but it has high negative (outside the normal range) tympanometric peak pressure. Type A is considered normal. Type AS is

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TABLE 23-2. Values for Peak Admittance and Tympanometric Width for Normal Ears of Children Approximately 6 Months to 3 Years Old

Age (mo) De Chicchis et al36

Roush et al208

6–11

12–23

24–35

6–12

13–18

19–24

25–30

Mean SD Tympanometric Width (daPa)

0.32 0.16

0.34 0.01

0.47 0.24

0.39 0.15

0.41 0.16

0.48 0.18

0.52 0.24

Mean SD

168 57

143 37

130 33

160 54

148 42

149 43

142 44

Peak Admittance (mS)

associated with a stiffening pathology and normal middleear pressure (e.g., otosclerosis), and type AD is associated with a loosening pathology and normal middle-ear pressure (e.g., fracture or dislocation of ossicles). Type B is associated most commonly with middle-ear effusion; Type C is associated with eustachian tube dysfunction or other conditions that cause problems in equalization of pressure in the middle ear. Some have subdivided type C into type C1 and type C2 categories by arbitrarily dividing the range of possible tympanometric peak pressures at −100 and −200 daPa, so that a peak between −100 and −200 daPa is type C1 and a peak beyond −200 daPa is type C2.39,40 The pattern classification scheme attributed to Jerger38 and its variations are used widely in clinics. However, they have never been validated adequately and given that the new instruments record tympanograms using the actual physical units rather than the arbitrary compliance units that were used for the original classifications, the validity of such schemes using current tympanograms is more uncertain. For example, different practitioners use different peak admittance values to differentiate between the subcategories of type A or use different definitions of type B (e.g., does it represent no peak at all or some arbitrarily chosen low value of peak admittance?). In addition, the Jerger classification scheme does not take into account the shape (gradient) of the tympanogram, which carries valuable diagnostic information.37,41–44

TYMPANOGRAM CLASSIFICATION BY QUANTITATIVE ANALYSIS With the absolute physical values of immittance provided by current tympanograms, there has been increased interest in using quantitative schemes for interpretation.42,45 With

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information on the normal range of values for different age groups (see Table 23-1 and 23-2), interpretation of quantitative tympanograms is facilitated. We know that high peak admittance values can be an indication of middle-ear pathology that has reduced the stiffness of the middle-ear system or is a consequence of tympanic membrane abnormality. We can quantitatively identify ears that have low peak admittance that can result from increased stiffness such as accompanies otosclerosis or other middle-ear diseases. Abnormal middle-ear pressure may indicate eustachian tube dysfunction.

IDENTIFICATION OF MIDDLE-EAR EFFUSION Tympanometry In children, the most frequent application of tympanometry is for the diagnosis of middle-ear effusion. Nozza and colleagues43,44,46 examined the relationship between the quantitative measures of admittance tympanograms and middle-ear effusion as diagnosed by surgeons at the time of myringotomy and tube placement and/or as diagnosed by a validated otoscopist. Using logistic regression analyses, the relative ability of various tympanometric measures, alone and in combination with each other, to discriminate between ears with and ears without effusion was determined. The two best immittance measures for identifying middle-ear effusion in ears of children scheduled for myringotomy and tube surgery (a chronic otitis media group) were tympanometric width and peak compensated admittance. Receiver operating characteristic (ROC) curves for the latter two measures, along with some other combined variables, indicate the relative sensitivity and specificity of the measures (Fig. 23-4). In these ears, the findings of the surgeons provided the gold standard for the presence or absence of effusion.

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FIGURE 23-4. Receiver operating characteristic space with sensitivity and 1-specificity (i.e., false-positive rate) of tympanometric width and peak admittance (Ytm) represented as curves with symbols at selected cut-off values. Also indicated are otoscopy results combined with the two tympanometric variables. (Modified from Nozza et al.44)

Depending on the population being evaluated, the criteria developed for ears of children with chronic or recurrent middle-ear disease may or may not be appropriate. For that reason, the sensitivity and specificity of criteria based on data from children more representative of the general population43,44 were also determined (Table 23-3). The specificity of the admittance variables is much lower for the group of children receiving tubes (see Fig. 23-4) than for the group representing the general population (Table 23-3). This is probably due to the greater overlap in the distributions of ears with and ears without effusion for the different admittance variables in children undergoing myringotomy and tube surgery. For example, the distributions of peak admittance for ears with effusion from the group receiving tubes, ears with no effusion from the group receiving tubes, and ears with no effusion from the group of children representing the normal population44 are shown (Fig. 23-5). It is clear that there are three different distributions. The overlap between the distributions of the two sets of ears from the surgery group is great, limiting the extent to which any criterion is able to separate them well.

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The combination of otoscopic diagnosis and tympanometric information has also been evaluated.44 In the ears undergoing myringotomy and tube surgery, diagnostic decision criteria based on both acoustic immittance measures and the otoscopist’s diagnosis could be found that improved performance a little. For example, in this study,44 the otoscopist was highly experienced and had been validated against surgical findings. However, as is often the case, although the sensitivity of otoscopy was good (85%), the specificity was low (71%). When the acoustic immittance data were taken into account, specificity could be improved with only a little sacrifice in sensitivity. For example, a decision criterion might be as follows. If the peak admittance is 0.1 or less, the ear is considered to have effusion; if the peak admittance is more than 0.6, the ear is considered to have no effusion; and if peak admittance is between 0.2 and 0.6, the otoscopic diagnosis rules. In the data set from children undergoing myringotomy and tube surgery, a group with chronic or recurrent middle-ear disease, sensitivity was 81% and specificity was 85%, a little better than either otoscopy or peak admittance alone (see Fig. 23-4).

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children TABLE 23-3. Sensitivity and Specificity of

Tympanometric Width and Peak Admittance for Identification of MiddleEar Effusion in Ears of School-Age Children Representative of the General Population

Variable

Criterion

Sensitivity (%) Specificity (%) (n = 9) (N = 135)

Tympanometric Widtha (daPa)

> 150 > 200 > 250

89 78 78

93 99 100

Peak Admittanceb (mmho)

≤ 0.1 ≤ 0.2 ≤ 0.3 ≤ 0.4

67 78 78 78

100 100 98 89

From Nozza et al., 1994ISI (measures made on tympanometric data originally reported in Nozza et al., 1992ISO).

a

From Nozza et al., 1992.ISO

b

331

(patent) tympanostomy tube. Sometimes, visual inspection does not detect a small perforation or is insufficient to determine the status of a tube, so the tympanometric findings can be helpful. However, it is not always clear that a given ear-canal volume measurement is abnormally large. It has been reported, and observed in clinical experience, that the volume of an ear with perforation in the tympanic membrane may be very near the limits of the normal range when the middle-ear mucosa is inflamed and so results are equivocal.47 When there is a question, comparison with a normal contralateral ear is sometimes useful, because ear-canal volume is highly correlated between the ears of the same individual. If there is a large difference between the ears, an opening in one tympanic membrane is suspected. Also, previous tympanograms sometimes provide comparative data of value in making a diagnosis. An abnormally small ear-canal volume can be evidence of poor probe fit in the ear canal, an obstructed probe, or cerumen impaction. Sometimes, in trying to obtain a hermetic seal, particularly with a hand-held probe, the tip may be pressed against the ear-canal wall and occlude the tip. Also, debris or cerumen from the ear canal can get into the probe. Wax in the probe may cause measurement errors of an unpredictable nature. One should always be certain that the probe assembly is free of wax or other materials, so that valid admittance measures can be obtained.

OTHER CONSIDERATIONS

FIGURE 23-5. Distributions in percentage of ears for values of peak admittance for three groups of ears: those with middleear effusion (MEE) as determined by a surgeon from a group of children undergoing myringotomy and tube surgery (MEE group); those with no MEE from the children undergoing surgery (no MEE group) and those with no MEE from a group of children representative of the general population who entered the hospital as outpatients for services unrelated to their ears (outpatient group). (Data from Nozza, et al.43)

Some points should be borne in mind in performing tympanometry and interpreting tympanometric information. First, one should understand that the immittance of the system is measured at the plane of the tympanic membrane. If there are abnormalities of the tympanic membrane that cause it to have very high admittance, such as atrophic areas, the lower admittance of the rest of the system is obscured in the measurement. The high admittance of the tympanic membrane is recorded, and the remainder of the system does not reveal its ability to transfer acoustic energy. Also, differences in instrumentation settings can cause differences in tympanometric configuration. The rate and direction of air-pressure changes, for example, can cause differences in peak pressure and amplitude from one instrument to the next.

TYMPANOMETRY WITH INFANTS A variety of such combined decision criteria are described by Nozza and associates.44

DIAGNOSTIC VALUE OF EAR-CANAL VOLUME ESTIMATES When a tympanogram is flat and has an abnormally high equivalent ear-canal volume measurement, it is often associated with a nonintact tympanic membrane. Tympanometry performed during follow-up of myringotomy and tympanostomy tube surgery often provides evidence of a functioning

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The use of tympanometry with infants younger than 6 months is controversial. Paradise and colleagues37 found that impedance testing using a 226-Hz probe tone was not sensitive for identifying ears filled with fluid in young infants. Apparently, compliance of the earcanal wall interferes with the recording of immittance at the tympanic membrane. Marchant and colleagues48 reported success in identifying otitis media with effusion in young infants, using a 660-Hz probe tone and tympanometry measuring susceptance. Peak admittance less than 0 mS correctly indicated effusion (as determined

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by myringotomy) in a high percentage of ears of young infants. On the other hand, Holte and colleagues49 in a study of multifrequency tympanometry in infants, found that infants younger than 4 months had middle-ear admittance different from that of adults. They found that the use of a 226-Hz probe tone resulted in the least variability and recommended use of the low-frequency probe tone for admittance testing in infants. The value of highfrequency probe tone tympanometry in newborns has since gained attention.50,51 Tympanograms of infants with middle-ear effusion are illustrated in Fig. 23-6. Two ears are shown: one with middle-ear effusion and one with normal middle-ear function. The 226-Hz tympanograms both exhibited peak admittance values in the normal range. However, examination of the 1000-Hz tympanograms clearly reflects the difference between the ear with middle-ear effusion and the one with the normal middle-ear function. High-frequency probe tone tympanometry can

be invaluable when performing follow-up rescreening and diagnostic evaluations of very young infants who have been screened as newborns. This is particularly important as universal newborn screening programs increase in numbers and increasing numbers of infants are referred for followup at very young ages.

SUMMARY OF TYMPANOMETRIC ASSESSMENT TECHNIQUES Tympanometry is a graphic representation of tympanic membrane immittance when air pressure and SPL is varied in the ear canal. The tympanogram provides an estimate of acoustic immittance of the middle ear, middle-ear pressure, and how admittance changes under changing ear-canal pressure. The peak compensated acoustic immittance, tympanometric width (or gradient), and, in some cases, tympanometric peak pressure can be used to infer the status of the middle ear.

FIGURE 23-6. The 1000-Hz tympanograms from two 1-month-old infants. A. Normal pattern; a normal otoacoustic emission was measured in this ear. B. Abnormal pattern reflecting presumed middle-ear disorder. No otoacoustic emission was present. C. A 226-Hz tympanogram measured at the same time in the same ear as in B. The tympanometric pattern using the low-frequency (226 Hz) probe tone suggests normal middle-ear function; this illustrates the potential false-negative finding using low-frequency probe tones in the ears of young infants.

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ACOUSTIC MIDDLE-EAR MUSCLE REFLEX Acoustic immittance instrumentation can also be used to detect the contraction of the middle-ear muscles, the stapedius and tensor tympani, to intense sound stimulation. This contraction is called the acoustic middle-ear muscle reflex or simply the acoustic reflex.52 The afferent portion of the arc, up to and including the superior olivary complex, is shared with the hearing mechanism. The efferent fibers of the acoustic reflex arc arise from brain stem neuronal connections between the olivary complex and the facial nerve nucleus for the stapedius muscle and between the olivary complex and the trigeminal nerve nucleus for the tensor tympani muscle.53 The acoustic immittance instrument indicates the status of the acoustic reflex in two ways: first, the reflex results in a stiffening of the ossicular chain and a concomitant change in immittance; second, because the reflex is bilateral to a unilateral stimulus (the muscles of both sides contract when one ear is stimulated), an intense stimulus can be delivered to one ear, and the probe tip of the immittance instrument inserted in the opposite ear can detect the change in immittance caused by the reflex. Acoustic immittance instruments have probe tips designed both to stimulate and to detect the acoustic reflex in the same ear; the reflex is elicited and its effect on immittance is detected in the same ear. Under these conditions, the response is called the ipsilateral, or uncrossed, acoustic reflex. When the immittance instrument is used to detect an acoustic reflex elicited by stimulating the opposite ear, the response is commonly called the contralateral, or crossed, acoustic reflex. For clinical purposes, three acoustic reflex parameters are commonly considered: the reflex threshold intensity, its response amplitude decay in time, and the differential response to different types of sound stimuli. These features enable the examiner to make judgments about the hearing mechanism (and inferences about hearing), such as the type of impairment and the probable site of a lesion, and even an estimation of the degree of hearing loss and an estimation of upper limits of comfort (such as for setting maximum output levels of hearing aids or maximum stimulation for cochlear implants). The threshold of the acoustic reflex is operationally defined as the minimal stimulus intensity required to produce a reliable change in monitored immittance. This minimal intensity, or acoustic reflex threshold, is typically specified in either dB HL or dB Sensation Level (SL; referenced to the individual's behavioral hearing threshold for a given stimulus frequency). For example, a reflex threshold of 85 dB HL for a 1000 Hz pure tone can also be expressed as 85 dB SL if the individual’s hearing threshold for that stimulus is 0 dB HL. If the individual’s hearing threshold for the same 1000 Hz pure tone is 30 dB HL, the reflex threshold of 85 dB HL can also be expressed as 55 dB SL. These relationships between SL and HL are important to an understanding of the acoustic reflex parameters and the estimation of hearing sensitivity and type of hearing loss.

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In adults with normal hearing, the contralateral acoustic reflex threshold for pure tones of different frequencies is approximately 85 dB poorer than behavioral hearing thresholds (i.e., 85 dB SL). The range of effective stimulus intensities is 70–95 dB SL.53,38 Approximately 20 dB less intensity is required to elicit a reflex with a broad-band noise stimulus.53,54 Ipsilateral reflex thresholds are approximately 10 dB better than contralateral thresholds.55,56 Age is an important factor that relates to the presence of the acoustic reflex and its threshold. The average acoustic reflex threshold for adults with normal hearing is about 85 dB HL53,38 In one study of school-age children (n = 1600 ears),57 13% had absent acoustic reflexes. The average acoustic reflex threshold was 92 dB HL. Furthermore, only a small percentage of neonates exhibit an acoustic reflex when a 220 Hz probe-tone was used to detect the response.58 However, some studies have shown that the acoustic reflex is measurable in infants when a high-frequency probe tone is used.59–63 Various types of hearing impairment can influence the acoustic reflex. As Jerger and associates64 point out, the influence of cochlear hearing loss on the acoustic reflex is complex, but in general, there is less difference between the threshold of hearing sensitivity and acoustic reflex thresholds. The reflex can occur at about the same absolute level as found in normal ears, but because of the elevated hearing threshold, ears with a cochlear impairment apparently require less stimulus intensity above the hearing threshold to elicit the responses. Jerger and associates65 reported that the likelihood of eliciting the acoustic reflex was significantly reduced when the degree of cochlear hearing loss exceeded 80 dB HL. The influence of middle-ear impairment and attendant conductive hearing loss on the reflex is not so straightforward, as a result of the mode of reflex stimulation. Recall that ipsilateral acoustic reflex tests stimulate and detect the response in the same ear through the immittance instrument probe-tip assembly. In an impaired middle ear, the impedance is already abnormally altered, and further changes in impedance due to middle-ear muscle contraction may not be observable; to be detectable, these changes may require elevated stimulus intensity levels. It follows that ipsilateral acoustic reflex testing in an impaired middle ear most likely yields no response; if the response is present, the threshold of the response tends to be elevated. For that reason, the ipsilateral acoustic reflex has been used in acoustic immittance schemes for diagnosing middle-ear effusion. Cantekin and associates66 incorporated the acoustic reflex into an algorithm that included tympanometric pattern classifications and otoscopy, with the reflex serving to disambiguate one pattern that was equivocal with respect to its relationship to middle-ear effusion. On the other hand, some research has shown that the acoustic reflex is often absent in ears with no middle-ear effusion and is responsible for a high false-positive rate when used as part of a diagnostic rule for middle-ear effusion.

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The other drawback to the use of the acoustic reflex for the diagnosis of a middle-ear condition is that the reflex depends not only on middle-ear function but also on hearing and on the integrity of portions of the central nervous system (CNS). Children with severe to profound hearing impairments and those with ANSD do not exhibit acoustic reflexes, and children with CNS disorders may have abnormal acoustic reflexes. The influence of middle-ear impairment on the contralateral acoustic reflex may be somewhat harder to understand. The contralateral reflex will probably be absent if the middle ear with the probe-tip assembly is impaired or if the impaired middle ear with the stimulus earphone has a moderate to moderately severe conductive hearing loss.67 The reason for the first situation is given in the previous paragraph. In the second situation, the conductive hearing loss necessitates reflex stimulus levels that may be beyond the output capabilities of the instrument. For these reasons, the contralateral acoustic reflex is generally absent in cases of bilateral middle-ear impairment. When the impairment is unilateral, the contralateral reflex will also be absent for both ears if the impaired ear has a moderate to moderately severe conductive hearing loss. The acoustic reflex is useful in diagnosing lesions beyond the cochlea (at the eighth cranial nerve or brain stem level). Such lesions can result in either an absent or an elevated reflex or in a reflex response amplitude that rapidly decays in time to a continuous stimulus.67–69 Anderson and colleagues69 first demonstrated that for tones of 500 and 1000 Hz, the acoustic reflex in patients with an eighth cranial nerve tumor tends to have a response amplitude that decays to half strength or less in less than 5 seconds of continuous pure-tone stimulation. Jerger and associates67 and Sheehy and Inzer70 reported reflex findings in a larger series of such tumor cases and substantiated the clinical significance of reflex decay. These investigators found the reflex to be absent in most of the cases reviewed. In these studies, an abnormal reflex (absent or decaying) correctly identified 80%–86% of such retrocochlear impairments. Jerger and Jerger68 demonstrated how the comparison of ipsilateral and contralateral reflexes can be used to identify eighth nerve and brain stem level impairments. It should be apparent that the presence or absence of the acoustic reflex, its threshold, and the degree of response amplitude decay can suggest a variety of underlying pathologic conditions. Consequently, the acoustic reflex alone cannot pinpoint a specific pathologic condition. Reflex findings must be viewed in the context of the tympanometric and behavioral audiometric results to infer the nature of hearing impairment and the possible location of the underlying lesion. An absent acoustic reflex or a significantly elevated acoustic reflex threshold is highly suggestive of an impairment at some level of the auditory system. If the tympanogram

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is also abnormal, the level of impairment is likely to be the middle ear. An absent or elevated reflex with a normal tympanogram usually suggests a sensorineural impairment of either cochlear or retrocochlear origin, depending on the degree of associated SNHL. The probability of retrocochlear involvement is increased when the reflex is absent or elevated, and the tympanometrically normal ear has an SNHL of less than 80 dB HL. When the associated SNHL is 80 dB HL or more, an absent or elevated reflex can suggest either severe cochlear damage or a retrocochlear lesion. If the reflex occurs at essentially normal levels (70–100 dB HL) and does not decay in a tympanometrically normal ear with less than 80 dB HL SNHL, a probable location of the lesion is the cochlea. Certain children are unable or unwilling to yield reliable behavioral hearing test results. In these, the reflex and tympanogram can provide evidence that corroborates impressions of the child’s suspected impairment. If both the reflex and the tympanogram are normal, the likelihood of an SNHL exceeding 80 dB HL is low. Although a small proportion of otherwise normal children do not have a recordable acoustic reflex, a child with absent reflexes and a normal tympanogram in both ears may have a severe SNHL. Consequently, when less-than-reliable behavioral hearing tests suggest an impairment, measurements of the reflex and a tympanogram recording can add credence to associated clinical impressions.

OTOACOUSTIC EMISSIONS (OAEs) In 1978, Kemp71 described the measurement of sounds in the ear canal that were generated within the cochlea. These sounds, cochlear emissions, are generated as a nonlinear by-product of biomechanical activity within the cochlea, probably at the level of the outer hair cells. Although it was hypothesized many years ago that such an event occurred in the normal processing of sound, the technology, mainly miniature sensitive microphones and computerized signal analysis techniques, has now reached a level that permits measurement of these small acoustic events in the ear canal. There are two major categories of OAEs: spontaneous and evoked. Evoked OAEs have the greatest potential for clinical application and are discussed in this chapter. Spontaneously occurring emissions have not yet been found to have great clinical significance and so are not discussed further here. However, the interested reader can find information on spontaneous emissions, as well as more detailed information on all types of OAEs, in Otoacoustic Emissons: Principles, Procedures, and Protocols.72 There are three types of evoked OAEs: transient, distortion product, and stimulus frequency. Stimulus frequency emissions are technically difficult to measure and have not been studied extensively for clinical applications. Because of the relative technical advantage to measurement of transient evoked and distortion product OAEs, they have been studied

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children more thoroughly with respect to clinical testing and are favored in the clinical environment.

MEASUREMENT Evoked OAEs require that a probe assembly, similar to that used for acoustic immittance tests, be fit into the ear canal.73 In the OAE system, the probe includes a microphone for recording acoustic energy in the ear canal and a port, or ports, from which either one sound stimulus (for transient evoked) or two sound stimuli (for distortion product) are delivered. Typically, the sound source is built into the probe itself, but in some systems, the sound source or sources are external earphone drivers that are connected to the probe via sound tubes. In general, the measurement of evoked OAEs requires that a stimulus be presented and that the acoustic events in the ear canal be monitored. For transient stimuli, the acoustic energy in the ear canal, including any OAEs, is measured in a time frame following the time it takes the energy produced by the transient stimulus to dissipate. For distortion product OAEs (DPOAEs), the emission is measured during the presentation of the stimuli, but it is frequency specific and is measured in a spectral region apart from the evoking stimuli. Because OAEs are very low in amplitude, the acoustic energy in the ear canal must be computer averaged to improve the SNR sufficiently to identify the response in the presence of the ambient ear-canal noise levels. With proper technique, evoked OAEs are measurable in virtually all normally functioning peripheral auditory systems.74,75 Test-retest reliability is also quite high.76,77 Evoked OAEs are simply measured, reliable, and objective and require simple patient preparation. As such, they have great potential for use as a clinical test.

TRANSIENT EVOKED OTOACOUSTIC EMISSIONS (OAEs) Transient evoked OAEs (TEOAEs) are broad-band emissions evoked using a transient stimulus such as a click or a tone burst.78 For many years, ILO OAE systems (Otodynamics Ltd, Hatfield, Herts, United Kingdom) were the only instruments available commercially for clinical testing using transient stimuli. Consequently, most of the data in the literature and virtually all clinical information on TEOAEs were obtained using ILO systems. Default settings for the ILO88 system provide a “nonlinear” click stimulus (0.08-msec rectangular pulse) presented in four-stimuli groups. It is called a nonlinear click because in each group of four stimuli, three are presented at equal amplitude (70 dB peak SPL), and the fourth is presented at 80 dB peak SPL and is inverted in polarity. With such a presentation of stimuli, the averaged response in the ear canal for each group of four is virtually free of stimulus artifact because, in a linear system (i.e., the ear canal), the inverted pulse effectively cancels the other three pulses in the averaged response. The remaining nonlinear acoustic response in the ear canal is a result of the cochlear emission.

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Because the emission occurs over some period of time after the stimulus, the acoustic response in the ear canal during the 20-msec period after each click is monitored. Responses to stimulus groups (i.e., the four-click packets) are averaged in the time domain and alternately stored in two separate buffers (designated A and B). In the ILO88 default mode, the responses to 256 of the stimulus packets, in each buffer, are required to complete the measurement. The transient stimulus has a broadband spectrum. When the probe tip is properly fixed to the probe and the probe is seated properly in the ear canal, the spectrum is flat through about 4 or 5 kHz. In a normal ear, the TEOAE has a broadband response that reflects, in general, the spectrum of the evoking stimulus. When tone bursts are used, evoked emissions are spectrally similar to the evoking stimulus (i.e., somewhat frequency specific) in ears with normal peripheral function. A great deal of information is provided in the response output display of the ILO88 system (Fig. 23-7). The display of the TEOAE measurement includes the averaged time waveforms (buffers A and B) as measured in the ear canal, a display of the stimulus spectrum, a display of the response spectrum, the ear-canal noise level, the OAE response amplitude, and other information that is useful to interpretation. Fig. 23-7 shows the TEOAE measurement for a 6-year-old girl with normal hearing and middle-ear function. A measure called wave reproducibility, which represents the correlation between the two independent measurements of the averaged waveform (A and B buffers) in the ear canal, is often used to determine the presence or absence of response. The system also provides a value of the overall emission amplitude (called response) and the estimated noise (the difference between the A and B waveforms) in the response. In addition, a Fourier analysis of the averaged waveforms is made to obtain the spectra of both the OAE and of the ear-canal noise, which can then be examined as SNR in a frequency-specific way. The software also provides frequency-specific measures of reproducibility (1–5 kHz). In normal ears of children, a strong TEOAE response is typically found when the intensity of the transient stimulus is 80 dB peak SPL or greater, but OAE amplitude tends to decrease with age.79,80 Spektor and colleagues81 reported that the average TEOAE amplitude in children 4–10 years old with normal peripheral auditory function was 13.5-dB SPL. Nozza and associates82 also reported mean TEOAE amplitude of 13.3-dB SPL for children between 5 and 10 years old with known normal hearing and healthy middle ears. It is known also that young infants have even greater response amplitude (25–30 dB SPL) to the click stimulus (Fig. 23-8). The greater the correlation (reproducibility) for the waveforms in buffers A and B, the greater confidence one has that an emission is present. Some suggest that wave reproducibility of a minimum of 50% is required before a measurement should be accepted as a true response. The frequency-specific reproducibility and SNR measures are useful for identifying

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FIGURE 23-7. Output display of the transient evoked otoacoustic emission (TEOAE) test. The display is for a normal-hearing 6-yearold child. The upper left window (“Stimulus”) displays stimulus waveform, which is helpful for assessing the fit of the probe. The top center window identifies the patient and the test ear, the date, and any other descriptive information that is added. To the right of the identification window is a window called “Response FFT,” which has the spectrum of the background noise (dark shaded region) and the spectrum of the OAE (clear outlined area). Below the “Response FFT” is the “Stim” window, with the overall peak equivalent sound pressure level (peSPL) value and the spectrum of the stimulus as it is in the ear canal. The large window in the center (“Response Waveform”) displays two separately averaged ear canal response waveforms (overlaying each other); the time window is 0 to 20 msec, with the first 2.5 msec blanked out to eliminate recording of the stimulus. The column on the right has the average noise level in the ear canal during recording and the noise level at which responses would begin to be rejected (in dB SPL and in mPa). “Quiet ∑ N 260 = 94%” shows the percentage of accepted stimulus presentations and the user set automatic test termination number. “Noisy XN 16” represents the number of stimulus presentations that occurred during times when ear canal noise was above the noise-rejection level and as a result not included in the averaged response. In this example, 276 presentations (260+16) were required to achieve the preset required 260 acceptable presentations (i.e., 94% of stimulus presentations were in a quiet enough ear canal to record a response). Also on the right is the TEOAE amplitude (“RESPONSE 14.0 dB”) and the correlation (“WAVE REPRO 96%” i.e., wave reproducibility) between the 260 averaged responses in one storage buffer (A) and the 260 in the second storage buffer (B). The wave reproducibility (%) and the signal-to-noise ratio (“SNRdB”) for narrow-band (i.e., frequency-specific) sections of the OAE are presented. “Stimulus 79 dBpk” provides the amplitude of the stimulus in dB peSPL, agreeing with that in the “Stim” window, and the measure of “Stability,” which, along with the histogram beside it, documents how well the stimulus waveform conformed, over the period of the test, to the waveform in the ear canal at the time the test was started. Finally, information is provided on the time it took to complete the test (54 seconds) and on storage and retrieval information.

frequency-specific areas of emission. Various criteria have been applied, but at least a 3-dB SNR is required to accept a response for a given frequency band in most clinical applications. The response (the light-outlined area) is prominent relative to the noise (the dark-shaded area) when a response is present. Using clicks between 80 and 86 dB peak SPL, responses in children can typically be obtained in ears with no more than a mild hearing loss (about 30–35 dB HL).75,80,83,84 As such, OAEs are very useful for discriminating between ears with and ears without hearing loss. The potential of

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evoked OAEs for estimating threshold is the object of much research, but the data are not clear regarding the relationship between OAEs and thresholds. In general, there is a reduction in emission amplitude with decreasing intensity of the click stimulus, but it is not a linear change. The TEOAE saturates at about 70 or 80 dB peak SPL in ears with normal peripheral hearing and middle-ear function. Because of the low-amplitude emission and the noise in the measuring environment (i.e., the ear canal), it is difficult to determine the lowest intensity level at which an emission can be elicited.

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FIGURE 23-8. Transient evoked otoacoustic emissions of two 2-month-old infants with presumed normal hearing. Note that the amplitude of the waveforms and the shapes of the stimulus and FFT responses differ from those of the 6-year-old girl in Figure 11-7. This greater amplitude and slightly higher frequency response is typical in infants. A. This infant was in a light and restless sleep, and to obtain 260 acceptably quiet presentations, more than 3000 stimulus presentations were made, and the test took almost 11 minutes to complete. B. This infant was also restless, but the test could be stopped after 100 stimulus presentations; with such a strong response it was not necessary to continue the test until the 260 (default) stimulus presentations were made. This test (B) took only 2 minutes, 13 seconds.

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DISTORTION PRODUCT OTOACOUSTIC EMISSIONS (OAEs) Distortion Product OAEs (DPOAEs) are frequency-specific OAEs that are a consequence of the nonlinear nature of the cochlea. When a sound signal composed of two pure tones close in frequency and intensity is presented, that signal is reliably transduced within the cochlea, but energy at frequencies not in the original signal is also produced. The frequencies of these intermodulation distortion products are predictable, coming at frequencies equivalent to mf1 − nf2, where f1 is the lower-frequency component of the two-tone stimulus, f2 is the higher-frequency component of the stimulus, and m and n are integers. The most common distortion product measured by DPOAE systems is the 2f1 − f2 distortion product, because in most cases, it has the greatest amplitude. The fact that distortion products can be measured objectively has helped provide an understanding of cochlear function as well as providing a potentially valuable clinical tool. Because the DPOAE is generated using two pure tones close in frequency, it has quite a frequency-specific origin. Most investigators consider the stimulus frequency in a DPOAE measurement as the frequency of the second primary

tone (i.e., f2) or as the geometric mean of the two primary tones, because it is believed that the area of generation along the cochlear partition of the intermodulation distortion product is at, or just apical to, the place of the second primary tone. One advantage of the DPOAE relative to the TEOAE is that it can be used to estimate cochlear function at frequencies above those that can be assessed using the transient. With DPOAEs, test frequencies as high as 10 kHz can be assessed. Several instruments are commercially available for the measurement of DPOAEs. Amplitudes of the DPOAEs are typically 40–70 dB below the levels of the primary tones. The amplitude of the DPOAEs varies with the ratio between the two primary frequencies (f2/f1) and the difference between intensity levels of the two primaries (L1/L2). A primary frequency ratio of around 1.22 has been shown to produce DPOAEs with the greatest amplitude. A level difference of about 10–15 dB is commonly used, because in most cases, it optimizes the DPOAE amplitude.74,85 DPOAEs are usually plotted as DP audiograms or “DP-grams,” with emission amplitude plotted as a function of frequency (Fig. 23-9, left panel). As many frequencies as are desired can be assessed, from one or two points per octave up to eight or more points per octave. The DP-gram typically

FIGURE 23-9. Distortion product otoacoustic emissions (DPOAEs) in the right ear of a child with normal hearing and normal middleear function. Left bottom panel: Circular symbols connected by solid lines represent DPOAEs generated using two primary tones. The noise in the ear canal around the distortion product is represented as the noise floor (NF) and is plotted in triangles. Normative data for presence vs. absence of the DPOAE74 are plotted in dashed lines. The stimulus tones were of unequal level (f1 = 65 dB SPL, f2 = 55 dB SPL) with a frequency ratio (f2/f1) = 1.22. These primary tones are indicated at the top of the graph with square and diamond symbols, respectively. The abscissa is the frequency of the second primary tone (f2) and show the DPOAE and Noise Floor for f2 = 1500 – 10,000 Hz. Right bottom panel shows the frequency domain representation of the primary tones f1 = 4125 Hz and f2 = 5016 Hz, with the distortion product = 3234 Hz. A vertical dotted line indicates the frequency (2*f1−f2) where the distortion product is expected to be observed. Here, the distortion product magnitude is 11 dB SPL. Top panels: Details related to the test conditions, showing time domain and frequency response of the primary stimulus tones.

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children includes an estimate of the noise in the ear canal in the region of the DP frequency at the time of the measurement. That is, amplitude of the response at the DP frequency is considered the DPOAE, and amplitude of the response in some frequency range surrounding the DP frequency is taken as an estimate of the noise level in the region of the DP frequency (Fig 23-9, right panel). Signal averaging techniques are used to increase the SNR in the measurement so the low-amplitude emission can be identified in the background noise. As with the TEOAE, the DPOAE changes with age79,80 and has a nonlinear growth function. However, the DPOAE may be measurable with slightly greater degrees of hearing loss than the TEOAE. Because noise is a problem for DPOAE measurement, some investigators favor the use of the SNR (i.e., DP-to-noise floor ratio) rather than the absolute amplitude of the DPOAE to determine whether a response is present. Because OAEs are detected using an averaging technique, the duration of averaging time and the level of the background noise affect the DP-to-noise floor ratio. Most agree that to consider a DPOAE as present in the response, the amplitude at the DP frequency should be greater than the mean noise level for that frequency; some favor using as much as two standard deviations (usually about 5 or 6 dB) above the mean noise floor level before accepting a measurement as a response.

CLINICAL USE OF EVOKED OTOACOUSTIC EMISSIONS (OAEs) Both TEOAE and DPOAE measurements are attractive clinical tests because they are quick, noninvasive, easy,

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reliable, and objective. The presence of an OAE within the normal range virtually ensures normal auditory function up to and including the outer hair cells in the cochlea. The absence of an OAE, in the presence of a low noise floor and a normal middle-ear, is consistent with at least a mild degree of hearing loss (Fig. 23-10). Because OAEs depend primarily on outer hair cell function and on the biomechanical properties of the cochlea, they are vulnerable to toxic and physical agents. As such, OAEs can be used to monitor the status of ears of individuals who are receiving medical therapies known to be ototoxic or are exposed to high levels of noise. It is important to note that outer- or middle-ear disorder can prevent detection of an OAE in the ear canal, even in the presence of normal cochlear function.86,87 That is, failure to see a response on an OAE test could be due to outer-, middle-, or inner-ear abnormality, or a combination. It has been shown that experimentally induced abnormal ear-canal pressures can diminish or eliminate the emission in the ear canal.88 OAEs typically cannot be measured in most ears with middle-ear effusion. Frequency-specific data available from both the TEOAE and DPOAE tests can provide information on auditory function relative to frequency.89,90 For example, Fig.23-11A–C show the DPOAEs and audiogram of a child with unilateral moderate sensorineural hearing loss rising to normal hearing. Note the normal DPOAEs in the right (normal-hearing) ear (Fig. 23-11A) and the absent low frequency DPOAEs in the left ear (Fig. 23-11B) with the upsloping sensorineural hearing loss (Fig. 23-11C).

FIGURE 23-10. Distortion product otoacoustic emissions (DPOAEs) in the left ear of a newborn with normal middle-ear function and mild to moderate sensorineural hearing loss. Left bottom panel: X symbols connected by solid lines represent the DPOAE response to the two primary tones. The noise in the ear canal around the distortion product is represented as the noise floor (NF) and is plotted in triangles. Normative data for presence vs. absence of the DPOAE74 are plotted in dashed lines. Note the low noise floor and no DP in either the left panel DP-gram or in the right frequency response panel.

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A

B

C FIGURE 23-11. DPOAEs of the right (A) and left (B) ears of a child with left-sided moderate sensorineural hearing loss with a configuration upsloping to normal hearing sensitivity (C).

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children

AUDITORY-EVOKED POTENTIALS (AEPs) Many texts have been devoted to AEPs (e.g., Hall91) and the many advances in the years since they were first used to objectively assess hearing function. For historical reference, the interested reader is directed to a monograph by Davis.92 The present chapter does not attempt to cover the entire area in depth but instead offers a brief description of component AEPs and how they are measured. Those evoked potentials that are particularly valuable in the evaluation of hearing in children are discussed more fully, as well as attention to those children for whom the procedure is most appropriate. There are several component AEPs, and each component response occurs in a different time frame after stimulus onset. These components and their general time frames, which may overlap to some extent, include (1) the “cochlear” potentials (0–4 msec poststimulus onset), (2) the “early” potentials (4–10 or 15 msec poststimulus onset), (3) the “middle” potentials (8–50 or 80 msec poststimulus onset), (4) the “long” components (50–300 msec poststimulus onset), and (5) the “late” components (300–800 msec poststimulus onset).91 In addition, there is a category of responses called auditory steady state responses (ASSR). The ASSR is a brain potential evoked by amplitude modulation of a carrier frequency, which can be chosen to match audiometric test frequencies. The steady state evoked potential has been shown to be useful for predicting thresholds in adults and children when modulation rates between approximately 70 and 110 Hz are used, particularly in those with more severe degrees of hearing loss.93–95 Each of these components reflects electric activity from different anatomic levels in the auditory system; the earlier components are from peripheral and brain stem levels, and the latter components are from midbrain and cortical levels. Typically, for a single-channel recording, three miniature electrodes are used to record these responses. An active electrode is placed either in close proximity or in a favorable orientation to the neural generators responsible for the response component of interest. The reference electrode is placed on a site that is presumably “quiet” with respect to the component being measured. The third, or ground, electrode is placed on an indifferent site, usually the forehead or contralateral mastoid process. The actual placement of active, reference, and ground electrodes varies with the component of interest. The activity from the recording electrodes is then amplified, filtered, and analyzed by the AEP system. In essence, a computer serves to “average out” background electroencephalographic and myogenic activity, thereby enhancing the response associated with multiple stimulus presentations. The computer analysis is “triggered” at the onset of each stimulus and continues to include the time frame corresponding to the response component being measured. Excessive muscle activity, as well as electric artifacts from the surrounding environment, or line current inadequacies, can obliterate an otherwise observable electric response.

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Consequently, the child must be relaxed or, preferably, asleep. In addition, the test environment must be conducive to accurate recordings; the environment must be void of nearby sources of electric artifacts, such as transformers or fluorescent light ballasts, and adequate line current grounding is essential. In general, AEPs provide perhaps the best data for physiologic assessment of the functional integrity of the auditory system in children. However, not all response components are equally useful. The validity of the long (50- to 300msec) and late (300- to 800-msec) components for evaluating infants and children is influenced by patient state of arousal,96 although these components can provide useful clinical information in an older child who is awake, cooperative, and alert (however, such a child is not often referred for such testing). Usually, the child who is a candidate for AEP testing is either unable or unwilling to cooperate with conventional hearing tests. With regard to the long component, the inherent degree of intersubject and intrasubject variability and of the variability due to the age and attentive state of the child can lead to significant clinical error.96 In addition, it has long been known that if drugs are used to induce sleep in the child, the reliability of the long components is adversely influenced.97,98 Kraus and associates (1994)96 report that middle latency responses (10–80 msec) can be used to obtain information in children on peripheral hearing, especially in the low frequencies, where the usefulness of auditory brain stem response (ABR) is challenged. Additionally, some early to middle latency responses may shed light on auditory processing disorders and learning disabilities.99 However, because sleep state is a critical variable in detecting a response, these authors recommend monitoring sleep state while recording auditory middle latency responses, so they can be interpreted properly. The cochlear potentials (0–4 msec) are measured using electrocochleography (ECochG) and can be used to differentiate certain otologic disorders that can affect children (such as Meniere’s disease), as well as during intraoperative monitoring of the peripheral auditory system. ECochG responses reflect the two cochlear responses (the cochlear microphonic and summating potential) as well as the wholenerve action potential of the auditory nerve (the eighth cranial nerve).100 ECochG can be used to estimate hearing sensitivity, although the potentials are not as robust near threshold of hearing sensitivity as the ABR, and electrode placement is not well-tolerated by children: placement of the ear canal electrode, near the tympanic membrane, is typically not accepted and so sedation or general anesthesia are necessary.

AUDITORY BRAIN STEM RESPONSE (ABR) The evoked potentials recorded in the first 10–20 msec have been referred to as brain stem evoked response, brain stem auditory evoked response, or ABR. ABR is used in this

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chapter. It consists of five to seven vertex-positive waves, labeled with Roman numerals I to VII, that occur in the first 10 msec after stimulus onset presented at suprathreshold levels (Fig. 23-12). The landmark articles describing the ABR were by Jewett and colleagues.101–104 The neural generators of the ABR have been difficult to determine precisely. Moeller and Jannetta105 discussed the complexity of establishing a relationship between ABR waves and specific regions of the ascending pathways using a far field recording method. Relating findings in animals to those in humans also is not appropriate. Nevertheless, numerous carefully conducted studies led Moeller and Jannetta to conclude the following regarding the relationship between neural generators and ABR waves. Wave I is associated with activity from the distal portion of the eighth nerve; wave II originates from the proximal portion of the eighth nerve; wave III is associated primarily with activity in neurons of the cochlear nucleus; and wave IV has its origin primarily from neurons of the superior olivary complex, although there probably are contributions from neurons at the level of the cochlear nucleus and the lateral lemniscus as well. In general, wave V receives contributions from both the lateral lemniscus and the inferior colliculus. Waves VI and VII are dominated by activity from the inferior colliculus. Moeller and Jannetta caution that there are multiple generators for each of the ABR waves beyond wave III and that each generator beyond the cochlear nucleus contributes to more than one of the ABR waves. The electrode configuration for the ABR includes the active electrode on the vertex of the skull or the high forehead at the hairline and the reference and ground electrodes on the ipsilateral and contralateral mastoid processes or earlobes,

FIGURE 23-12. The auditory brainstem response for a young adult with normal hearing. Component waves are labeled I to VII.

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respectively. The ABR is a far field recording of tiny electric discharges (on the order of microvolts as recorded at the scalp) from multiple neurons discharging synchronously. Therefore, the stimulus must be one that can cause simultaneous discharges of large numbers of the involved neurons. Stimuli with very rapid onset, such as clicks or tone bursts, must be used. It is unfortunate that the rapid onset required to create a measurable ABR also creates a spread of energy in the frequency domain (“spectral smearing”), reducing the frequency specificity of the response. The responses to 1000–2000 clicks, filtered clicks, or brief, pure-tone bursts are typically averaged for each stimulus intensity that is used. The stimuli are presented at a rapid rate (typically 10–40 per second). The length of time required for a test depends on such factors as the number of stimuli and intensity levels tested per ear, the rate of presentation, and the number of stimuli “averaged” per test. The total test duration is seldom less than 30 minutes, and if the hearing loss has a complex configuration, or bone-conduction ABR testing is needed in addition to air-conduction testing, total test duration can take 90 minutes or more. The deleterious effects of excessive muscle activity were mentioned earlier, and this factor is particularly pertinent to obtaining accurate ABR recordings. For this reason, a child must be completely relaxed, preferably asleep, for the procedure. Natural sleep can often be facilitated by feeding babies up to about 6 months of age immediately before the test, with parents instructed to bring their baby hungry and tired but not yet asleep. Often, children 7 years or older can lie quietly for the procedure. The ABR is not believed to be affected by sedation or general anesthesia. Infants and children between about 6 months and 6 or 7 years of age can be sedated to avoid problems related to muscle activity during testing. Rules for conscious sedation are recommended by associations such as the American Academy of Pediatrics, and each hospital has policies regarding sedation. Anyone undertaking sedated ABR testing should be familiar with guidelines and policies that apply. ABR testing can also be done in the operating room when a child is anesthetized for another procedure. Dornan et al.106 caution against using ABR in the operating room as a sole measure of hearing sensitivity for the sake of determining audiological interventions, particularly when testing is conducted immediately following placement of tympanostomy tubes. In their study, the average discrepancy between ABR thresholds and follow-up behavioral audiometry was +9.7 dB in children with middle-ear effusion at the time of myringotomy, and ABR thresholds elevated as great as 45 dB above behavioral audiometric thresholds were reported. Thus, attempts to complete behavioral audiometry are warranted, when possible, in children who are considered for hearing aid fitting based on ABR thresholds obtained in the operating room following tympanostomy tube placement. Investigations subsequent to early descriptions of the ABR have shown the response to be consistent between and within subjects and to be unchanged in awake and sleeping subjects. Of the five to seven waves that constitute the ABR,

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children waves I, III, and V can be obtained consistently, whereas waves II and IV appear inconsistently between and within subjects. The latency (the time of occurrence after stimulus onset) of the various waves increases and wave amplitudes decrease, with reductions in stimulus intensity; at stimulus intensities close to behavioral hearing threshold, only wave V can be discerned (Fig. 23-13). These and other ABR properties have emerged from the extensive research efforts of a number of investigators, which have been adequately reviewed.91 Although there is no accepted standard for calibration of clicks and tone-bursts for ABR testing, biologic calibration is the appropriate best-practice for establishing calibrated intensity. A jury of 20 normal-hearing ears are used to establish behavioral thresholds for each of the ABR stimuli using the stimulus parameters established for the clinic. The unit of measure for the intensity is then labeled “dB nHL” (“decibels normal Hearing Level”) rather than dB HL. Correction factors for estimating the difference between dB nHL and dB HL comparing ABR wave V threshold and behavioral audiometry thresholds are typically used for estimating behavioral audiogram from the ABR thresholds.20,21

FIGURE 23-13. The auditory brainstem response to decreasing stimulus intensity. Each trace represents the averaged response to 1500 stimuli of the same intensity with two traces completed at each stimulus level. Note the reduction in amplitude and increase in response latency (time) of wave V with decreased stimulus intensity. Here, a repeatable wave V response is observed at 10 dB but not at 0 dB.

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There are developmental changes in the response morphology, wave amplitudes, and wave latencies of the ABR. Very early in life, only waves I, III, and V are evident, with wave I having greater amplitude than that of wave V. Over time, the relationship changes, with wave V becoming much more prominent than the other waves in the normal adult ABR. For the most part, changes in latency provide the most consistent index of development of the ABR. All ABR waves decrease in latency during early life. However, the rate of maturation of the various waves varies. Wave I has the shortest developmental time course, reaching adult latency value by about 2–3 months. Wave V has the longest course, reaching adult latency value sometime in the second year of life.107,108 Wave III matures at a point in time between the ages at which waves I and V mature. Interwave latencies (I–III, III–V, and I–V) also show developmental change. It is not clear what accounts for the developmental change in ABR wave latency, but some mechanisms have been suggested, including maturation of the cochlea, increasing myelination of the central fibers, changes in transmission characteristics of the middle ear, increased synchrony, and greater synaptic efficiency.107 The ABR is commonly used in two ways in the pediatric setting: first, as an audiometric test to estimate the type, degree, and configuration of hearing loss; and second, in the differential diagnosis or monitoring of CNS pathologic conditions.91 For the purpose of estimating the pure-tone audiogram, a search is conducted for the minimum stimulus intensity yielding an observable ABR.21 ABR thresholds using click stimuli are correlated best with behavioral hearing thresholds in the higher frequencies (1000–4000 Hz) when hearing is normal, or if the hearing loss is of a flat configuration. Efforts have been made to obtain more frequency-specific information using the ABR. Stapells and Oates20 reviewed the various ways of altering the stimulus ensemble and the recording parameters to yield more frequency-specific information than is provided by using the predominantly high-frequency click stimulus. Filtering clicks and rapidly gating tones to make tone bursts are alternatives. Gorga and Thornton109 showed that very frequency-specific stimuli can be generated using proper signal gating techniques. Use of the Blackman window,110 a gating function used to minimize the spectral smear of rapid onset of a signal, provides tone bursts with rapid onset and narrow-frequency bandwidth, suitable for eliciting a more frequency-specific ABR. Although one must be cognizant of the frequencyspecificity limitations of the ABR used for audiometric purposes, it is also important to realize that the technique does not assess the perceptual event called hearing. The ABR reflects auditory neuronal electric responses that are adequately correlated to behavioral hearing thresholds, but a normal ABR suggests only that the auditory system, up to the midbrain level, is responsive to the stimulus used, and it does not guarantee the presence of normal hearing. Conversely, failure to elicit the ABR indicates an impairment of the

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system’s synchronous response, but it does not prove that a child is deaf or has profoundly impaired hearing. In the case of children with ANSD, children may have no discernable ABR waves at the limits of the equipment. Such is evident in Fig. 23-14, where a polarity-inverting cochlear microphonic is seen to increase in size with increasing stimulus intensity, but no neurogenic waves emerge. The child in whom this ABR was recorded showed a mild-to-moderate hearing loss on behavioral audiometry and received good benefit from using hearing aids fitted to his behavioral audiogram, albeit his word recognition scores were fair, even in his best aided condition. Consequently, ABR interpretation for audiometric

FIGURE 23-14. The auditory brainstem response to clicks, recorded in a child with auditory neuropathy spectrum disorder (ANSD). The click stimuli at each level (60, 70, and 90 dB nHL) are presented using rarefaction polarity for one wave trace and also 180 degrees opposite phase: condensation polarity. If responses were neurogenic, this opposite polarity would not result in changes in the waveform. The electrical activity recorded early in the wave traces is the cochlear microphonic, and it inverts with reversing the polarity. This cochlear microphonic is absent at 60 dB nHL, small but observable at 70 dB nHL, and larger at 90 dB nHL. Showing that this cochlear microphonic is, in fact, cochleogenic rather than stimulus artifact from the earphone transducer, the two waves at 90 dB nHL with “pinched tubing” were recorded with the tubephone pinched while signal was presented to the transducer. As a result, significantly less acoustic energy actually was presented in the patient’s ear canal. If the electrical activity early in the waves was due to electrical artifact from the transducer, pinching the tubephone would have no effect on the waves. The top two waves (tube not pinched) shows a large cochlear microphonic while the next two waves (tube pinched) shows no activity. There are no neurogenic potentials following this early cochlear potential for any traces, despite the patient’s pure-tone audiogram suggested a mild-to-moderate sensorineural hearing loss.

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purposes must be qualified by other clinical assessment data, either available at the time or resulting from follow-up evaluations. As an otoneurologic technique, the ABR may be used to infer the level of the auditory system—middle ear, cochlea, eighth cranial nerve, or brain stem—at which an impairment exists.91 The latency of the ABR waves is the primary consideration in these applications. For middle-ear and cochlear impairments, wave latency as a function of stimulus intensity is important. Wave latencies at a fixed stimulus intensity provide the basis for the detection of eighth cranial nerve and brain stem impairments. In cases of middle-ear impairment, the entire series of ABR waves is delayed in time by an amount commensurate with the degree of conductive hearing loss.21 Although latency of wave V can be used to differentiate between conductive versus SNHL, Vander Werff and colleagues (2009) suggested that wave I latency provides a better index of middle-ear impairment than wave V latency. The ABR in cases of cochlear impairment generally yields a steeper latency-intensity function. In other words, wave latencies are essentially normal at a high stimulus intensity but become excessively prolonged as stimulus intensity is decreased.21,91,111 Consequently, the characteristic ABR finding in cochlear impairment includes a normal I-to-V interwave latency in addition to the steep latency-intensity function. However, the problem is complicated by the fact that the slope or configuration of the hearing loss may influence results. The ABR has also long proved effective in detecting eighth cranial nerve impairment112,113 and brain stem impairment.114,115 In general, such impairments show an increased latency difference between waves I and V. The ABR, then, is a series of positive waves occurring in the first 10–15 msec after stimulus onset that apparently reflect activity in successively higher levels of the auditory tract, up to, and perhaps including, lower midbrain centers. Within limits, the response can be used audiometrically to estimate hearing sensitivity, and it also has use for inferring at which level of the auditory system impairment might exist. The consistent nature of the ABR in both newborns and older children, and in both sleeping and awake subjects, makes the test a particularly useful tool for evaluating hearing in pediatric populations. However, it is important to remember that the ABR is evidence of synchronous neural firing and that, in ANSD and in some cases of CNS dysfunction, behavioral response to sound can be much better than would be predicted by the ABR, even showing hearing in the normal range. The ABR and other electric responses are extremely complex and difficult to interpret. A number of factors, including instrumentation design and settings, environment, and patient characteristics, may influence the quality of the recording. Testing and interpretation of electrophysiologic activity must be carried out by persons who are adequately trained; otherwise, there is the risk that unreliable and perhaps erroneous conclusions may affect patient care.

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children

REFERRAL CRITERIA FOR THE AUDITORY BRAINSTEM RESPONSE As stated earlier, the ABR has great advantages for evaluating the auditory system of young or uncooperative patients. It is a very stable phenomenon that is essentially free from the effects of state. The ABR can be measured in a patient who is awake, under sedation, or under general anesthesia. Disadvantages include the fact that measurement of the ABR is not a test of hearing but rather of electric responses in the pathways of the eighth nerve and brainstem that occur as a result of auditory stimulation. In a common application using the click stimulus, it also lacks frequency specificity. Nevertheless, the ABR test has become an irreplaceable component of the audiologic test battery. It is not an assessment technique that should be applied to every patient in need of audiologic services. However, there are situations for which the ABR can provide information essential to identification, diagnosis, or management that could not be acquired in any other way. There are other situations in which the ABR supplements or corroborates other clinical evidence. Infants who should be referred for ABR testing include (1) newborns who have been referred from universal newborn hearing screening programs for diagnostic follow-up; (2) postmeningitic infants; (3) infants with recurrent acute otitis media, persistent otitis media with effusion, or both, who are not yet reliably testable via behavioral audiometry; (4) children with significant mental retardation, emotional disturbance, or both for whom ear-specific behavioral hearing testing is not possible and necessary to obtain for management of communication difficulties; (5) children with suspected eighth nerve or brainstem disorders; (6) children with sudden-onset, fluctuating, progressive, or unilateral SNHL; (7) other difficult-to-test patients; (8) patients (especially infants) for whom ear-specific auditory responses are needed; and (9) those for whom confirmation of suspected auditory or CNS dysfunction is required.2

EARLY IDENTIFICATION AND INTERVENTION OF CHILDREN WITH HEARING IMPAIRMENT The benefit of early identification and intervention of hearing impairment in infants and children is not in doubt. Clinical experience and research clearly demonstrate that the earlier a young child with hearing impairment is identified and is entered into an early intervention program, the better is the prognosis for speech and language development as well as for future academic achievement.8,117,118 This knowledge in combination with technology that makes screening for hearing loss quick, easy, and inexpensive has been instrumental in increasing support and generating initiatives for screening the hearing of all newborns. Most states (43 as of this writing) have passed legislation that mandates universal newborn hearing screening, and all states and US territories have established Early Hearing Detection and Intervention (EHDI) programs for reporting and tracking success of

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universal newborn hearing screening. Screening beyond the newborn period is also important, because some children acquire hearing loss or have late-onset or progressive hearing loss.119,120 Screening only in the newborn period should not cause clinicians to lose sight of the fact that children can have hearing impairment during childhood that would not have been present during a newborn hearing screening. That is, passing a newborn hearing screening does not “vaccinate” a child against a future hearing loss.

UNIVERSAL NEWBORN HEARING SCREENING The notion of universal newborn hearing screening has been a controversial one. The incidence of significant congenital hearing loss is low, about 3:1000 births in the general population. What has to be considered carefully is whether there is the ability to effectively screen all infants to identify a few in a cost-effective way. With the development of screening technologies such as the automated ABR (AABR) and OAEs, most have concluded that it is feasible to conduct universal newborn hearing screening efficiently and effectively. In the past, newborn screening programs were limited to identification of newborns with risk indicators such as those provided in the Joint Committee on Infant Hearing position statements121,122 and to the application of hearing screening tests such as the ABR to only such children. Some programs involved the identification of those with risk indicators, who would be invited to have a diagnostic audiologic evaluation at a later time. In either case, it was determined that an unacceptably high number of infants with hearing loss were not being identified early and as a result were not given access to early intervention services and amplification devices that could help to minimize the impact of their hearing loss. The cost to society of serving children with congenital hearing loss who are identified late is great because such children require more special education services and therapies than do children who are identified early and receive early intervention services. The future employability and personal success of children with congenital hearing loss reasonably extends from the timeliness of identification of and intervention for hearing loss. Nevertheless, JCIH120 includes risk indicators associated with permanent congenital, delayed-onset, or progressive hearing loss in childhood (Table 23-4). One of the questions of a specifically audiologic nature has been which measure of auditory function would best serve in universal newborn hearing screening applications. Many early newborn screening programs used diagnostic ABR systems, with click stimuli presented at one or two hearing levels and pass/refer criteria set based on the outcomes of those measures.123 Such programs typically were used for screening only those determined to be at risk, so the numbers of infants screened could be managed with that approach. However, universal screening programs involve numbers too great to make such a protocol practical. Instead, audiologists have turned to automated

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TABLE 23-4. Risk Indicators Associated With Permanent Congenital, Delayed-Onset, or Progressive Hearing Loss in Childhood120

Risk Factors

References

Caregiver concern regarding hearing, speech, language, or developmental delay

(Roizen, 1999).

Family history of permanent childhood hearing loss

(Cone-Wesson et al., 2000; Morton and Nance, 2006).

Neonatal intensive care of >5 days, or any of the following regardless of length of stay: ECMO,a assisted ventilation, exposure to ototoxic medications (gentamycin and tobramycin) or loop diuretics (furosemide/lasix), and hyperbilirubinemia requiring exchange transfusion

(Fligor et al., 2005; Roizen, 2003).

In-utero infections, such as CMV,a herpes, rubella, syphilis, and toxoplasmosis

(Fligor et al., 2005; Fowler et al., 1992; Madden et al., 2005; Nance et al., 2006; Pass et al., 2006; Rivera et al., 2002).

Craniofacial anomalies, including those involving the pinna, ear canal, ear tags, ear pits, and temporal bone anomalies

(Cone-Wesson et al., 2000).

a

(Cone-Wesson et al., Physical findings, such as white forelock, associated with a syndrome 2000). known to include a sensorineural or permanent conductive hearing loss Syndromes associated with hearing (Roizen, 2003). loss or progressive or late-onset hearing loss,a such as neurofibromatosis, osteopetrosis, and Usher syndrome. Other frequently identified syndromes include Waardenburg, Alport, Pendred, and Jervell and Lange-Nielson Neurodegenerative disorders,a such as (Roizen, 2003). Hunter syndrome, or sensory motor neuropathies, such as Friedreich ataxia and Charcot-Marie-Tooth syndrome Culture-positive postnatal infections (Arditi et al., 1998; Bess, associated with sensorineural 1982; Biernath et al., hearing loss,a including confirmed 2006; Roizen, 2003). bacterial and viral (especially herpes viruses and varicella) meningitis Head trauma, especially basal skull/ temporal bone fracturea requiring hospitalization

(Lew et al., 2004; Vartialnen et al., 1985; Zimmerman et al., 1993).

Chemotherapya

(Bertolini et al., 2004).

Risk indicators of greater concern for delayed-onset hearing loss.

a

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ABR (AABR) systems and to OAEs. Each comes with advantages and disadvantages, ranging from the extent of the information provided to pass/refer rates to cost. Both ABR and OAEs been the focus of much study and interest since the 1990s,120,124–126 including a federally funded consortium project that investigated the performance of ABR, TEOAEs, and DPOAEs in screening newborns. The project, comprehensively reported in a series of articles that composed the October 2000 issue of Ear and Hearing (Vol. 21), was conducted at seven centers across the country and included more than 7000 newborns.127 The recommendations of the investigators in that project were that ABR, TEOAEs, and DPOAEs all had sufficient performance characteristics to serve well in universal newborn hearing screening applications. This is consistent with data from clinical programs that used one or more of the technologies and reported acceptable performance. More recently, the Joint Commission on Infant Hearing 2007 Position Statement120 promotes a “1-3-6” goal for outcomes of universal screening programs: all infants are screened for hearing loss by 1 month of age using an appropriate physiologic measure of auditory function; those with hearing loss are diagnosed by three months of age; and family-centered intervention for maximizing the child’s communication development begin by 6 months of age. Additionally, the use of automated ABR was recommended preferentially over OAE for infants treated in the neonatal intensive care unit for five days or more, given potential increased risk for ANSD (which would be missed by OAEs). JCIH120 recommends surveillance throughout childhood, and supports parental concern for onset of hearing loss as criteria for referral for audiological evaluation. Because of the development of almost universal access to the Internet, a great deal of information on universal newborn hearing screening and related subjects is available on the Internet. For example, the Centers for Disease Control and Prevention National Center on Birth Defects and Developmental Disabilities has a Web site on their Early Hearing Detection and Intervention Program (http://www .cdc.gov/ncbddd/hearingloss/ehdi-programs.html). Websites at the National Center for Hearing Assessment and Management (NCHAM) (www.infanthearing.org) provide a wealth of information regarding statewide screening programs, instrumentation, follow-up protocols, intervention, resources and information for parents and families, and more. The American Academy of Audiology (AAA) (www. audiology.org) also has helpful information and links to relevant sites.

OTOACOUSTIC EMISSIONS (OAEs) SCREENING Despite the strong support and use of new technologies for screening, protocols from programs that use OAEs vary and pass/refer criteria seem to be determined on a

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children program-by-program basis. There is as yet no consensus on which frequencies to consider when screening and what response parameters should be considered. Some instruments that are designed specifically for screening have preset pass/ refer criteria that are not modifiable by the person screening. The test is run and the response is analyzed against the criteria. If the criteria are met, the instrument reports a “pass”; if not, it reports a “refer.” For this reason, it is critical that an audiologist with knowledge and experience in screening, in screening technologies, and in pediatric audiology be in a position of responsibility in any universal newborn hearing screening program because predetermined test criteria may or may not be appropriate for a given program. TEOAEs—Criteria vary for “pass” and “refer” across programs using TEOAEs. The Rhode Island Hearing Assessment Program128 reported that examination of the OAE-to-noise ratio in three frequency bands (1–2, 2–3, and 3–4 kHz) and declaration of a “pass” if the ratio was more than 3 dB in each of the bands resulted in good performance characteristics. Some programs use good responses in four of five or three of four frequency bands. Others might use different criteria for accepting a response depending on the frequency band. One such protocol is to use a 3-dB SNR at 1000 and 1500 Hz and a 6-dB SNR at 2000, 3000, and 4000 Hz, with good response at four of five frequencies to indicate a “pass.” It is important for any professional with responsibility for such a program to closely monitor performance of the screening protocol that is used and to clearly understand the principles of screening. An understanding of how changes in criteria can affect not only pass and refer outcomes but also sensitivity, specificity, and predictive ability of the protocol is critical. For example, a program with a referral rate that is considered too high may change criteria to reduce the referral rate. However, a simple reduction in referrals does not necessarily indicate that the protocol has been improved if it results in an unacceptable increase in false-negative outcomes. DPOAEs—It is evident from the consortium study and from the clinical information in the literature that DPOAEs also can serve well in universal newborn screening programs.120,126,127 The specific frequencies considered and the criteria for accepting a response vary from program to program with DPOAEs in the same way they do for TEOAEs. In newborn screening applications, the ability to measure an emission below 1500 Hz can be very difficult due to noise generated by the infant and the nursery environment. Many programs opt for screening only frequencies of 1500 or 2000 Hz and above because of the false-positive rates that result when lower frequencies are included.129

AUTOMATED AUDITORY BRAIN STEM RESPONSE (ABR) The AABR has been around for some time. The cost of a test using the AABR is greater than the cost for an OAE test. However, cost effectiveness is aided by the lower referral

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rates with AABR.130 The AABR screens infants using a click at 35-dB nHL. When an infant passes the AABR, all except perhaps a mild hearing loss or steeply sloping high frequency hearing loss can be ruled out. One advantage of the AABR over OAEs is that it assesses not only the peripheral auditory system but also the lower brainstem response, and so is sensitive to presence of ANSD. This is unlike OAEs, which are a cochlear phenomenon and likely generated at the level of the outer hair cells.

SCREENING PROTOCOLS Screening program protocols vary nearly as much as they vary in criteria used for “pass” and “refer.” Because of problems with vernix in the ear canal and mesenchyme in the middle ear shortly after birth, OAE screening has a fairly high referral rate within the first 24 hours after birth.130 Sometimes, infants are screened within that time period because of discharge policies of the hospital. Rescreening before discharge can considerably reduce the over-referral rate, especially if the rescreening is done with AABR rather than with a second OAE measurement.131 An infant discharged from the hospital without passing the newborn screening will be referred for screening or diagnostic follow-up at about 2–4 weeks. Follow-up may be done in the hospital or in an audiology outpatient facility. Follow-up protocols vary, but one that is favored is to rescreen using either OAEs or AABR. At the age of 2–4 weeks, the vernix or mesenchyme often is no longer present to interfere with the measurement, and a “pass” outcome is obtained. Conversely, full, frequency-specific diagnostic ABR measures may be indicated, along with performing 1000 Hz tympanometry and OAEs. It may also advisable to perform tympanometry with a high-frequency probe tone at this time. In programs with low refer rate on universal newborn hearing screening, the rate of hearing loss on initial follow-up is fairly high. In a state with roughly a 2% refer rate on newborn hearing screening, overall one in five newborns who refer on the screening have hearing loss; one in three bilateral refers have hearing loss.132

AUDITORY NEUROPATHY SPECTRUM DISORDER There has been increasing interest in a diagnostic category that has come to light with the advent of OAEs and ABR. ANSD is a disorder found in infants and older persons who exhibit behaviors or other evidence of hearing loss, fail to generate an ABR, but have cochlear function as evidenced by present cochlear microphonic on early potentials, or normal or near-normal OAEs (see Fig. 23-14). That is, at least to the level of the outer hair cells, the peripheral auditory system is functioning within a normal to near-normal range. It is presumed that the auditory deficit is at the level of the inner hair cells or in the auditory nerve and beyond. Persons with ANSD function auditorily along a continuum, from essentially no auditory awareness to functionally normal

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hearing. A common experience, however, is that persons with ANSD universally have significantly greater difficulty hearing in noise. This phenomenon was not discovered until OAEs gave clinicians a window into the cochlea, outer hair cells in particular, and allowed them to further isolate the site of the lesion. This is a phenomenon with a low incidence and may be related to specific risk criteria in the young. For example, many infants demonstrating evidence of auditory neuropathy have a history of elevated bilirubin levels during the neonatal period or extreme prematurity.120,133

SURVEILLANCE Special emphasis is placed on the value of parental/caregiver reports of abnormal auditory behavior or delayed development of speech and language in Joint Committee on Infant Hearing120,125,126 position statements. Primary care physicians need to be sensitive to the concerns of parents and to be aware themselves of signs of delayed auditory development. After the newborn period, most infants and children with hearing impairment are first identified by a parent or caretaker. Unfortunately, the concerns of parents are sometimes minimized by primary care practitioners, largely because of the wide range of variability in normal development, because of a continued belief that hearing cannot be assessed adequately in the very young, because concern for hearing loss is dismissed based on a pass result on newborn hearing screening, or because of concerns over the cost of assessments. The consequence of delayed assessment of suspected hearing loss is delayed intervention, not only for the affected child but for the family as a whole.118,134 The impact on a family of a child with a disability such as hearing impairment is great but is complicated tremendously when parents (one or both parents) are treated as being overconcerned or foolish or are put off for many months by professionals. Parents are reliable reporters of their infant’s development, and their concerns should be taken seriously. The information in this chapter is evidence that the means are available to obtain reliable, valid, ear-specific, and frequencyspecific hearing data on infants. The cost of an audiologic evaluation is far outweighed by the benefit to the family of confirming (or ruling out) a serious disability, possibly helping to diagnose associated disabilities and beginning beneficial interventions for both infant and family. As has been stressed in legislation, such as the Individuals with Disabilities Education Act (IDEA) and its reauthorizations and amendments, intervention for children with disabilities should be family centered rather than child centered. Independent of the degree to which one agrees with the success of intervention programs for particular classes of disabled individuals, families have the right and need to know as much as possible, and as soon as possible, regarding the nature and extent of their child’s disability if a successful outcome is to be achieved.

SCREENING PRESCHOOL AND SCHOOL-AGE CHILDREN Because preschool and school-age children can typically perform behavioral audiometric tasks, such as play audiometry

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or conventional audiometry, pure-tone hearing screening rather than OAE or ABR tests is usually used. AAA135 and ASHA (1997)136 guidelines for screening for hearing impairment and middle-ear disorders recommend that for children 3 years old and above, pure-tone hearing screening be done at 20-dB HL at test frequencies of 1, 2, and 4 kHz in each ear, preferentially using behavioral test methods. A screening failure occurs when a child fails to respond to any frequency in either ear. As with all audiometric tests, noise in the test environment can artificially elevate thresholds, so screening done outside sound-treated rooms must be done with an understanding of the potential pitfalls associated with poor environmental noise conditions. These guidelines136,135 also provide a suggested protocol for screening for middle-ear disease. The protocol has several components, including recent otologic history, visual inspection of the external auditory meatus and tympanic membrane, and acoustic immittance testing. The history taking is designed to learn, either from a parent/caretaker or from the child, of any recent ear pain, drainage, or other related conditions that would signal the need for immediate medical referral. The visual inspection with an otoscope is designed to identify gross obstructions or defects in the external auditory meatus or gross abnormalities of the tympanic membrane that require immediate medical referral; it is not intended to be used for diagnosis of middle-ear disease. The acoustic immittance battery is designed primarily to identify ears that are at risk for middle-ear effusion. However, one component is designed to determine whether, in the presence of a flat tympanogram, the ear-canal volume is abnormally large. If so, an opening in the tympanic membrane is suspected that warrants medical referral unless the child is known to have polyethylene tubes in place. With respect to identification of middle-ear effusion, the need for the immittance test relates to the poor sensitivity of pure-tone hearing screening for that purpose. Both AAA135 and ASHA136 guidelines include regarding screening for middle-ear disease. Both groups have recommended the use of peak admittance and tympanometric width in the decision of whether to refer. Both protocols require referral on two tympanometric screenings separated by about six to eight weeks because of the transient nature of middleear disease. With a single test, over-referral rates tend to be very high.

MONITORING FOR OTOTOXICITY OR OVEREXPOSURE TO NOISE Children with serious illnesses are sometimes placed on medications known to be ototoxic. Monitoring of the hearing of such children is an important function of the audiology service of medical centers at which they are treated.137 Sometimes, early identification of the effects of ototoxic medication can be determined by periodic hearing testing during the treatment period.138 A typical protocol requires that a child have a hearing test before initiation of the treatment, with regular follow-up as long as the treatment continues and then after completion of treatment. If evidence of SNHL is

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children observed, usually a change in hearing of 10 dB or more at one or more frequencies, the managing physician should be notified and decisions are then made regarding the possibility of alternative treatment. Hearing loss due to ototoxicity occurs in the high frequencies first, so it is important that a monitoring program examine these. A proposed minimal test battery was recently proposed by Brock et al.138 for the sake of grading the degree of ototoxicity with as few as two to three frequencies on the audiogram, when the child is otherwise not able to cooperate for extended testing. DPOAE testing, which has capability to measure cochlear function in high frequencies, can used to monitor in cases of treatment with ototoxic medications. It is possible that DPOAEs are sensitive enough to suggest changes before they become clinically evident. It should be noted that DPOAEs are not yet vetted by agencies overseeing medical protocols for potentially ototoxic treatments, and so it is not clear what change in DPOAEs would constitute an “adverse event” for the sake of changing treatment plans. Extended high-frequency audiometry is now available with clinical audiometers, so it is possible to test at frequencies as high as 16–20 kHz in some cases. Normative data for the extra-high frequencies are limited and the test-retest reliability in children is not established, so centers that use this technique should develop their own norms. Also, it is important to understand that at the very highest frequencies (e.g., above 14 kHz), there is great variability in the measurement and very little dynamic range for the measurement of hearing loss. That is, the intensity levels required to reach thresholds in individuals with normal hearing are not very far below the maximum output possible from the instrumentation, thereby limiting clinical usefulness. Theoretically, the higher the frequencies that can be tested, the earlier potential ototoxicity can be detected. Sometimes, there is resistance from personnel in oncology or pulmonology departments because there is no alternative to the ototoxic medication, and it must be administered so the child may survive. A report from the audiologist that the hearing of a patient is being damaged is disheartening and frustrating to the managing physician because there is no choice in the matter. However, it is important to understand that audiologists are equipped not only to identify and diagnose hearing loss but also to work with children and families in the management of hearing impairment. Children who lose substantial amounts of hearing while hospitalized or while undergoing treatment become frightened, and their parents are perplexed. An audiologist can help the family understand what the child is going through and provide support, amplification, and strategies for preserving communication skills during what has to be a very unpleasant experience. The administration of an ototoxic drug may be necessary, but it is not necessary to have the child and family suffer the consequences of the drug without the help that is available. Many children are exposed to loud noise. Some children shoot guns, ride loud motorbikes, listen to loud music through portable listening devices (e.g., iPods), play in bands

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(marching or garage bands), and so on. Hearing loss prevention efforts are critical so that young people do not permanently damage their hearing.139,140 Audiologic monitoring of children known to be exposed to high levels of noise is essential to prevent significant hearing loss. Professionals in the areas of otolaryngology, pediatrics, and audiology must continue educational efforts to ensure that children practice good hearing conservation in their daily activities. The National Hearing Conservation Association (www.hearingconservation.org), the National Institute on Deafness and Other Communication Disorders (www.nidcd.nih.gov/health/wise/Pages/Default .aspx), and Dangerous Decibels (www.dangerousdecibels .org) have resources available for children, parents, and educators about hearing loss prevention strategies.

TESTS FOR FUNCTIONAL (NONORGANIC) HEARING LOSS One of the problems that audiologists face in assessing hearing behaviorally is the identification of the child with functional, or nonorganic, hearing loss. Because much of the routine clinical assessment requires a voluntary behavioral response, clinicians must take precautions to make sure that a child is not exaggerating hearing loss. Children might wish to exhibit a hearing loss because of the secondary gains that accrue from added attention or because this may help explain other undesirable behaviors, such as poor performance in school or personality problems.141 The consequences of falsely labeling a child as hearing impaired may appear in the form of parental distress, inappropriate management of the child, or reinforcement of the child’s psychological difficulties, depending on the origin of the functional hearing loss. Northern and Downs116 point out that the child who exaggerates or invents hearing loss is most probably doing so for reasons that are important to him or her. The audiologist or other professional who encounters a suspected nonorganic hearing loss should consider whether the child has a psychological or emotional need that is being met by the consequences of a hearing loss. Therefore, it is necessary in such patients that the audiologist first assesses as accurately as possible the true status of the auditory system. Second, assistance in determining which needs of the child are being met by feigning hearing loss should be offered to the family. In many cases, the child with functional hearing loss is suspected from the beginning. Observations of the child outside the test room may reveal exaggerated efforts to hear. However, observation may belie any hearing loss at all. The child’s behavior may be very different once he or she is involved with the structured task of the hearing test. A competent pediatric audiologist will notice exaggerated efforts to hear the sound, inconsistencies on repeated attempts to obtain threshold for a given stimulus, widely different thresholds depending on the method used, and lack of correspondence between SRT and PTA (although the caution previously offered regarding the effect of hearing loss configuration on this relationship should be heeded when functional hearing loss is considered). Current test methods allow clinicians to virtually rule

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out hearing loss in normal-hearing individuals with so-called objective test measures. Immittance testing, especially the acoustic reflex, OAE, and ABR tests, can usually provide sufficient hard evidence to establish whether hearing is really impaired to the degree exhibited. These tests can be used to corroborate results and impressions from informal observation and behavioral testing. There are behavioral assessment techniques that can be used in adults to obtain estimates of thresholds in patients who seem to be exaggerating. The use of such complicated tests in children is not common because of the lack of sophistication on their part in performing the tasks or in providing convincing performances on traditional testing. The Stenger test, which is beneficial in identifying functional hearing loss in patients with unilateral or asymmetric hearing loss, can be used in older children. With small children, there often are large discrepancies in the results of routine tests, so the identification of nonorganicity is not difficult. Sometimes, young children can be instructed to say “yes” when they hear a tone and “no” when they do not. A youngster who is too immature to appreciate the stimulus-response contingency will respond “no” to the sounds that are heard but are below the selected minimal response level. Infants and children with unusual configurations of hearing loss can respond in atypical ways on standard tests. The trained pediatric audiologist must use experience and creativity, along with a test battery, to establish accurate and reliable estimates of hearing.

THE ROLE OF THE AUDIOLOGIST This chapter has provided a description of the various techniques available for assessing hearing in infants and children. The reader should now have a basic understanding of the techniques for such assessment and an awareness of sources where more extensive discussion of a particular technique can be found. Throughout this chapter, it was emphasized that no one method of assessment is definitive and that accurate assessment involves the consideration of information provided by several tests of hearing used in combination. Although certain techniques can be used in isolation as screening tools in certain situations (e.g., BOA in the office setting), comprehensive assessment is based on the results of a combination of these tests. The audiologist plays a multifaceted role in the assessment process; he or she must devise and implement an assessment strategy composed of procedures that are applicable to the child in question and must interpret the results in the context of the impairment that is suspected. The audiologist must also convey assessment results to the referral source and must provide suggestions that are meaningful for the management of the child. In concert with the referral source, the audiologist can also play an important role in interpreting the results to concerned family members and in counseling the family with regard to the impact an impairment may have on the child’s future interaction with the environment from a social and an educational point of view.

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The audiologist can serve as a valuable resource for the implementation of habilitative or rehabilitative plans for a hearing-impaired child. In addition, the audiologist is usually aware of the public and special school programs in the community that will play an active role in the child’s education and is often responsible for ensuring that appropriate agencies provide necessary services. The audiologist maintains contact with such programs and agencies so that the longterm follow-up of a particular child is maintained even if family resources are limited. The audiologist should be an active team member in the general pediatric assessment of every child, regardless of age. At the audiologist’s disposal are the knowledge, experience, and techniques required to make a meaningful assessment of hearing in infants and children. In view of the importance of adequate hearing in infancy through adolescence, health care professionals are obligated to give the assessment of hearing the high priority it deserves.

Acknowledgments I would like to acknowledge the significant contributions to this chapter by Robert Nozza, Ph.D., who wrote the chapter on assessment of hearing and middle-ear function in children for the previous three editions. His exhaustive knowledge of the literature is the most expansive body of work in a single chapter seen to date. He set a very high bar, and I deeply thank him for his contribution. Timely and appropriate information from Dr. Nozza’s previous chapters was incorporated in the present chapter, but the present author accepts full responsibility for the contents.

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76. Franklin D, McCoy M, Martin G, Lonsbury-Martin B. Test/ retest reliability of distortion-product and transiently evoked otoacoustic emissions. Ear Hear. 1992;13:417–429. 77. Harris FP, Probst R, Wenger R. Repeatability of transiently evoked otoacoustic emissions in normally hearing humans. Audiology. 1991;30:135–141. 78. Kemp DT, Ryan S, Bray P. A guide to the effective use of otoacoustic emission. Ear Hear. 1990;11:93–105. 79. Prieve B, Fitzgerald T, Schulte L. Basic characteristics of click- evoked otoacoustic emissions in infants and children. J Acoust Soc Am. 1997;102 (pt 1):2860–2870. 80. Widen JE. Evoked otoacoustic emissions in evaluating children. In: Robinette MS, Glattke TJ, eds. Otoacoustic Emissions: Clinical Applications. New York, NY: Thieme; 1997: 271–306. 81. Spektor Z, Leonard G, Kim DO, Jung MD, Smurzynski J. Otoacoustic emissions in normal and hearing-impaired children and normal adults. Laryngoscope. 1991;101:965–976. 82. Nozza RJ, Sabo DL, Mandel EM. A role for otoacoustic emissions in screening for hearing impairment and middle ear disorders in school age children. Ear Hear. 1997;18: 227–239. 83. Norton SJ. Application of transient evoked otoacoustic emissions to pediatric populations. Ear Hear. 1993;14:64–73. 84. Harrison W, Norton SJ. Characteristics of transient evoked otoacoustic emissions in normal-hearing and hearing-impaired children. Ear Hear. 1999;20:75–86. 85. Hauser R, Probst R. The influence of systematic primary-tone level variation L2-L1 on the DPOAE 1f1-f2 in normal human ears. J Acoust Soc Am. 1991;89:280–286. 86. Lonsbury-Martin BL, Martin GK, McCoy MJ, Whitehead ML. Otoacoustic emissions testing in young children: middle-ear influences. Am J Otol. 1994;15(suppl 1):13–20. 87. Margolis R, Trine M. Influence of middle-ear disease on otoacoustic emissions. In: Robinette M, Glattke T, eds. Otoacoustic Emissions: Clinical Applications. New York, NY: Thieme; 1997:130–150. 88. Naeve SL, Margolis RH, Levine SC, Fournier EM. Effect of ear- canal air pressure on evoked otoacoustic emissions. J Acoust Soc Am. 1992;91:2091–2095. 89. Lonsbury-Martin BL, Martin GK. The clinical utility of distortion product otoacoustic emission. Ear Hear. 1990;11: 144–154. 90. Nelson D, Kimberly B. DPOAEs and auditory sensitivity in human ears with normal hearing and cochlear hearing loss. J Speech Hear Res. 1992;35:1142–1159. 91. Hall JW. New Handbook of Auditory Evoked Responses. Boston, MA: Pearson; 2007. 92. Davis H. Principles of electric response audiometry. Ann Otol Rhinol Laryngol. 1976;85(suppl):1-96. 93. Lins OG, Picton TW, Boucher BL, et al. Frequencyspecific audiometry using steady-state responses. Ear Hear. 1996;17:81–96. 94. Picton TW, Durieux-Smith A, Champagne SC, et al. Objective evaluation of aided thresholds using auditory steady-state responses. J Am Acad Audiol. 1998;9:315–331. 95. Rance G, Roper R, Symons L, et al. Hearing threshold estimation in infants using auditory steady-state responses. J Am Acad Audiol. 2005;16:291–300. 96. Kraus N, Kileny P, McGee T. Middle latency auditory evoked potentials. In: Katz J, ed. Handbook of Clinical Audiology. 4th ed. Baltimore, MD: Williams & Wilkins; 1994:387–402.

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CHAPTER 23 ❖ The Assessment of Hearing and Middle-Ear Function in Children 97. Davis H. Sedation of young children for evoked response audiometry (ERA): summary of a symposium. Audiology. 1973;12:55–57. 98. Skinner PH, Shimota J. A comparison of the effects of sedatives on the auditory evoked cortical response. J Am Audiol Soc. 1975;1:71–78. 99. Banai K, Abrams D, Kraus N. Sensory-based learning disability: Insights from brainstem processing of speech sounds. Int J Audiol. 2007;46:524–532. 100. Ruth RA. Electrocochleography. In: Katz J, ed. Handbook of Clinical Audiology. 4th ed. Baltimore, MD: Williams & Wilkins; 1994:339–350. 101. Jewett DL. Volume-conducted potentials in response to auditory stimuli as detected by averaging in the cat. Electroencephalogr Clin Neurophysiol. 1970;28:609–618. 102. Jewett DL, Romano MN, Williston JS. Human auditory evoked potentials: possible brainstem components detected on the scalp. Science. 1970;167:1517–1518. 103. Jewett DL, Williston JS. Auditory evoked far fields averaged from the scalp of humans. Brain. 1971;94:681–696. 104. Jewett DL, Romano MN. Neonatal development of auditory system potentials averaged from the scalp of the rat and cat. Brain Research. 1972;36:101–115. 105. Moeller AR, Jannetta PJ. Neural generators of the auditory brain stem response. In: Jacobson JT, ed. The Auditory Brainstem Response. San Diego, CA: College Hill Press; 1985:13–32. 106. Dornan B, Fligor B, Whittemore K, Zhou GW. Pediatric hearing assessment by auditory brainstem response in the operating room. Int J Pediatr Otorhinolaryngol. 2011;75: 935–938. 107. Hecox K, Burkard R. Developmental dependencies of the human brainstem auditory evoked response. Ann N Y Acad Sci. 1982;388:538–556. 108. Cox LC. Infant assessment: developmental and age-related considerations. In: Jacobson JT, ed. The Auditory Brainstem Response. San Diego, CA: College Hill Press; 1985: 297–316. 109. Gorga MP, Thornton MP. The choice of stimuli for ABR measurements. Ear Hear. 1989;10:217–230. 110. Nuttal AH. Some windows with very good sidelobe behavior. IEEE Trans Acoust Speech Signal Proc. 1981;29:84–89. 111. Fria TJ, Sabo DL. Auditory brainstem responses in children with otitis media with effusion. Ann Otol Rhinol Laryngol. 1980;68:200–206. 112. Coats AC, Martin JL. Human auditory nerve action potentials and brain stem evoked responses: effects of audiogram shape and lesion location. Arch Otolaryngol. 1977;103:605–622. 113. Clemis JD, McGee T. Brain stem electric response audiometry in the differential diagnosis of acoustic tumors. Laryngoscope. 1979;89:31–42. 114. Starr A, Achor LJ. Auditory brainstem responses in neurological disease. Arch Neurol. 1975;32:761–768. 115. Stockard JJ, Rossiter US. Clinical and pathologic correlates of brainstem auditory response abnormalities. Neurology. 1977;27:316–325. 116. Northern JL, Downs MP. Hearing in Children, 5th ed. Baltimore, MD: Williams & Wilkins; 2002. 117. Yoshinaga-Itano C, Coulter D, Thomson V. The Colorado new born hearing screening project: effects on speech and language development for children with hearing loss. J Perinatol. 2000;20(8 pt 2):S132–S137.

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118. Sininger YS, Grimes A, Christensen E. Auditory development in early amplified children: factors influencing auditory-based communication outcomes in children with hearing loss. Ear Hear. 2010;31:166–185. 119. Fligor BJ, Neault MW, Mullen CH, Feldman HA, Jones DT. Factors associated with sensorineural hearing loss in survivors of extracorporeal membrane oxygenation therapy. Pediatrics. 2005;115:1519-1528. 120. Joint Committee on Infant Hearing (JCIH). Position Statement. Pediatrics. 2007;120:898–921. 121. Joint Committee on Infant Hearing (JCIH). Position statement. ASHA. 1982;24:1017–1018. 122. Joint Committee on Infant Hearing (JCIH). Position statement. ASHA. 1990;33(suppl 5):3–6, 1991. 123. Galambos R, Wilson MJ, Silva PD. Identifying hearing loss in the intensive care nursery: a 20-year summary. J Am Acad Audiol. 1994;5:151–162. 124. National Institutes of Health (NIH). Early identification of hearing impairment in infants and young children. NIH Consens Statement. 1993;11:1–24. 125. Joint Committee on Infant Hearing (JCIH). Position statement. ASHA. 1994;36:38–41. 126. Joint Committee on Infant Hearing (JCIH). Position statement. Am J Audiol. 2000;9:9–29. 127. Norton SJ, Gorga MP, Widen JE, et al. Identification of neonatal hearing impairment: evaluation of transient evoked otoacoustic emission, distortion product otoacoustic emission, and auditory brain stem response test performance. Ear Hear. 2000;21:508–528. 128. Vohr BR, Carty L, Moore P, Letourneau K. The Rhode island hearing assessment program: experience with statewide hearing screening (1993-1996). J Pediatr. 1998;133:353–357. 129. Gorga MP, Norton SJ, Sininger YS, et al. Identification of neonatal hearing impairment: distortion product otoacoustic emissions during the perinatal period. Ear Hear. 2000;21: 400–424. 130. Gorga MP, Preissler K, Simmons J, Walker L, Hoover B. Some issues relevant to establishing a universal newborn hearing screening program. J Am Acad Audiol. 2001;12:101–112. 131. Deem KC, Diaz-Ordaz EA, Shiner B. Identifying quality improvement opportunities in a universal newborn hearing screening program. Pediatrics. 2012;129:e157–e164. 132. Liu CL, Farrell J, MacNeil JR, Stone S, Barfield W. Evaluating loss to follow-up in newborn hearing screening in Massachusetts. Pediatrics. 2008;121(2):e335–e343. 133. Sininger Y, Starr A. Auditory Neuropathy: A New Perspective on Hearing Disorders. San Diego, CA: Singular; 2001. 134. Thompson M. Birth to five: the important early years. In: Bess FH, Hall JW, eds. Screening Children for Auditory Function. Nashville, TN: Bill Wilkerson Center Press; 1992:399–434. 135. American Academy of Audiology (AAA). Childhood Hearing Screening Guidelines. Reston, VA. http://www.audiology.org/ resources/documentlibrary/Documents/ChildhoodScreeningGuidelines.pdf. 2011. 136. American Speech-Language-Hearing Association (ASHA). Guidelines for Audiologic Screening. Rockville, MD. http:// www.asha.org/policy/GL1997-00199.htm. 1997. 137. Fligor BJ, Mullen CH. Audiological monitoring for ototoxicity in medically complex children. Semin Hear. 2011;32: 273-280. 138. Brock PR, Knight KR, Freyer DR, et al. Platinum-induced ototoxicity in children: a consensus review on mechanisms,

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predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J Clin Oncol. 2012;30:2408–2417. 139. Fligor BJ, Cox LC. Output levels of commercially available compact disc players and the potential risk to hearing. Ear Hear. 2004;25:513–527.

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140. Portnuff CDF, Fligor BJ, Arehart KH. Teenage use of portable listening devices: A hazard to hearing? J Am Acad Audiol. 2011;22:663–677. 141. Martin FN. Pseudohypacusis. In: Katz J, ed. Handbook of Clinical Audiology. 4th ed. Baltimore, MD: Williams & Wilkins; 1994:553–567.

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24

C H A P T E R

Methods of Examination: Radiologic Aspects Hisham M. Dahmoush, Arastoo Vossough, and Avrum N. Pollock

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ver the recent past, cross-sectional imaging technology has evolved rapidly. Today, high-resolution and threedimensional (3-D) computed tomography (CT) scans can be performed in only a few seconds, and magnetic resonance imaging (MRI) is able to produce sophisticated images of the head and neck without the potential added risk arising from the use of ionizing radiation. However, it must be noted that there is currently no proven carcinogenic risk for a single CT scan of the temporal bone region at currently used clinical diagnostic CT radiation doses. These advances have had a profound effect on imaging of the temporal bone region. Progress has at times been so rapid that textbook descriptions of imaging may be outdated by the time of, or shortly after their publication. The descriptions found in this chapter are unlikely to be an exception. It is our hope that otolaryngologists, radiologists, and other physician groups will work together in the judicious use of these diagnostic tools, to provide the optimal imaging modality for the specific problem within the individual patient. In this chapter, the imaging modalities most commonly used are described, and specific points made regarding several common clinical situations. Imaging modalities will continue to evolve in the next few years.

IMAGING MODALITIES Plain Film Radiography and Tomography In the past, radiography and complex motion tomography were the mainstays of petrous bone imaging (Fig. 24-1). Bone anatomy was well demonstrated by these techniques owing to the density differences of bone, air, and soft tissues. However, interpretive problems occur because of the superimposition of one structure on another and the lack of bony and soft tissue contrast. Consequently, CT has replaced plain film studies of the temporal bone because of the excellent anatomic detail and tissue contrast it provides. MRI has also become a diagnostic option in evaluating the membranous labyrinth, cranial nerves, and soft tissues of the head and neck. Both the techniques are discussed later in this chapter. Although mostly no longer obtained, plain film examinations remain of value in selected instances. For example, the Stenver view is used for the evaluation of cochlear implants. The metal used in implants sometimes creates artifacts on CT and can lead to a distorted image, although these artifacts are less pronounced with the newer generation multidetector CT scanners, making the evaluation of anatomic relationships less difficult. MRI is contraindicated in patients with cochlear

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implants as the metal in the device is not compatible with the strong magnetic field. When this problem arises, plain films or tomography may still be used. The high density of metal allows good visualization of the prosthetic components on plain film when needed. Oblique views may be obtained as required (Fig. 24-2).

Computed Tomography (see Appendices I and II Currently, several imaging reconstruction algorithms (soft tissue, bone) are available for producing and displaying images in CT studies. The bone algorithm is preferred for imaging the petrous bone in many cases because it best displays bone by allowing the computer to remanipulate data in order to enhance margins between tissues with high attenuation differences. This best accentuates differences among bone, air, fluid, and soft tissue in any combination. The bone algorithm is not to be confused with the bone window of CT, which represents a display of a CT scan at a wider range of density levels rather than a recalculation of the raw computed data. CT images that are obtained using the bone algorithm rival plain film tomography for spatial resolution and far surpass it in the ability to differentiate one tissue’s attenuation from another’s. Advanced computed data manipulation also makes it possible to obtain multiple projections in CT through reformatting in any desired plane without additional scan time or radiation. These reformations have improved in quality in recent times due to the advent of volumetric acquisition made possible by multidetector CT and helical techniques with submillimeter reformations, essentially obviating the need for additional direct scanning in the coronal plane. In the past, a second set of images was obtained in the direct coronal plane for assessing the middle and inner ear. It is no longer necessary to scan in two planes, as the axial images can be obtained with very thin submillimeter slices without the penalty of significant image degradation, allowing for isotropic reconstructions in any plane, most often in the coronal (and at times in the sagittal or oblique) plane. In the past, the structure of reference used to post the axial sequence was a plane parallel to the hard palate. Now with spiral/helical imaging, the axial plane may be scanned in a plane axial to the CT gantry, or parallel to the hard palate, and then reconstructed at an angle parallel to the posterior semicircular canal (SCC) (Fig. 24-3), utilizing a sagittal reformation of the bony labyrinth. With the advent of newer technologies including dual source imaging and iterative reconstruction algorithms to

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FIGURE 24-1. Bony labyrinth (plain films). Magnified frontal views of the right (A) and left (B) temporal bones on plain film in a premature infant with poor ossification due to nutritional deficiency demonstrate the dense bony labyrinths standing out in relief against the undermineralized skull.

FIGURE 24-3. Scan plane posting on computed tomography. Two magnified scout views (obtained from a sagittal reformation) of the temporal region (with the anterior portion of the skull to the left of the image) demonstrate the method of using the plane of scanning of the temporal bone in the axial (A) and coronal (B) planes, utilizing a plane parallel to the orientation of the lateral semicircular canal for the axial image (A), with subsequent coronal plane at right angles to that chosen for the axial plane (B).

allow for dose reduction, it should be possible to reduce (though not eliminate) the streak artifact in the temporal bones of patients who have undergone cochlear implantation. Tympanostomy tubes (Fig. 24-4) are readily visible on CT but not on MRI. Similarly, metallic foreign bodies are readily visible only on conventional radiographs and CT (Fig. 24-5).

Magnetic Resonance Imaging (see Appendix III)

FIGURE 24-2. Cochlear implant (intraoperative plain film). Intraoperative coned-down oblique/lateral view of the cochlear region in a patient with a cochlear implant demonstrates its tip within the spiral of the cochlea (arrow).

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An extensive description of MRI is beyond the scope of this chapter, but several terms and ideas may be useful as they recur frequently in the discussions of this modality. Almost all clinical imaging is currently done by stimulating hydrogen nuclei of water in the body. MRI takes advantage of the fact that these hydrogen atoms can be stimulated by using very specific radiofrequencies. These stimulated nuclei

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FIGURE 24-4. Tympanostomy (TM) tubes. Axial (A) and coronal (B) CT bone windows through the left temporal bone demonstrate a tympanostomy tube traversing the tympanic membrane into the middle ear cavity (arrows).

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FIGURE 24-5. Screw in external auditory canal (EAC). Lateral scout (A) and axial bone windows (B) from CT of the temporal region demonstrate a foreign body (screw) (arrows) within the EAC.

return a characteristic radiofrequency that is proportional to the strength of the magnetic field. Thus, an image can be produced by varying the magnetic field in an imaginary grid and pinpointing slightly different characteristic frequencies within that grid. Therefore, structures that lack an adequate amount of (water) hydrogen nuclei will fail to produce a sufficient MRI signal. Some tissues lack hydrogen nuclei (air); others leave the imaging grid too rapidly to return a signal (flowing blood). Finally, the hydrogen nuclei in dense fibrous

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tissue and compact bone are bound in a tight lattice work that prohibits effective signal generation and therefore do not return a signal. These areas of absent signal will appear black on MRI, are termed signal voids, and are responsible for one of the major limitations of MRI of the temporal bone. Because air and bone each result in a signal void, the margin between them will not be imaged as in CT unless the bone contains marrow. For example, air cells within the mastoid portion of the temporal bone cannot be differentiated

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from cortical bone, and the entire region normally appears as a single signal void, as does the ossicular chain within a well-aerated middle ear cavity. Obviously, this limits the evaluation of middle ear anatomy. Conversely, normally fluidfilled structures (cochlea, SCC) and soft tissue structures (facial nerve) are visualized because they are surrounded by the signal void of bone (Fig. 24-6). Abnormal soft tissue or fluid collections such as tumors or inflammatory fluid are easily detected for the same reason. Obtaining very thin high-resolution T2-weighted images (T2WI) on MRI often results in significant image noise and reduction in image quality unless very long imaging times are used, which in turn increases the chance of patient motion and resultant blurring. This is compounded by the limitation of reaching the safe limits of radiofrequency energy deposition causing increase in body temperature. However, newer advances in both MRI pulse sequences and MRI hardware design (such as high-field scanners and parallel imaging) have helped in being able to safely produce high-resolution T2WI in clinically reasonable times. For example, in the past, obtaining 3D T2WI with thin slices and high resolution were prohibitively long for clinical use in patients. For imaging of the inner ear structures and the internal auditory canal (IAC), using a fast spin echo sequence with a flip-back driven equilibrium pulse at the end to restore the brightness of fluid can be used in order to make the imaging short enough to be used in the clinical setting. These classes of MRI pulse sequences are variously named on different MRI systems and are called DRIVE (Philips, Amsterdam, Netherlands), FRFSE (General Electric, Milwaukee, USA), or RESTORE (Siemens, Erlangen, Germany). Alternatively, various balanced gradient echo imaging sequences can be performed for high-resolution depiction of the same structures in a reasonable time frame.

These sequences include constructive interference in the steady state (CISS, Siemens), fast imaging employing steadystate acquisition (FIESTA, General Electric, Milwaukee), or balanced fast field echo (FFE, Philips, Amsterdam). Finally a third method of obtaining high-resolution T2 images with safe energy deposition limits is a modified T2 sequence called sampling perfection with application optimized contrasts using different flip angle evolutions (T2 SPACE, Siemens) or (T2 Cube, General Electric). High-resolution images with submillimeter thickness can be obtained using any one of these types of T2-weighted sequences, often with near isotropic imaging voxel size, thereby allowing for reformation of images in any plane. This becomes of paramount importance when evaluating patients with sensorineural hearing loss (SNHL) who may undergo cochlear implantation in the future, as this affords the radiologist the ability to assess for the presence, absence, or hypoplasia of the cochlear nerves, as their absence would influence patient management and candidacy for this form of surgical intervention. The nerves within the IACs are well visualized in contrast to the background of the bright CSF signal on high-resolution 3D T2 FSE or CISS. This is best demonstrated on sagittal oblique reconstructed images through the IACs where the facial nerve is located anterosuperior, the cochlear division of cranial nerve (CN) 8 is in the anteroinferior quadrant, the superior vestibular division of CN 8 is posterosuperior, while the inferior vestibular division of CN 8 is posteroinferior (Fig. 24-7). For fast depiction of fluid-containing and cystic structures, other modifications to the standard T2 sequence can sometimes be performed using rapid sequences such as single shot fast spin echo (SSFSE, Philips, General Electric) or half-fourier singleshot turbo spin echo (HASTE, Siemens). These sequences can help to quickly determine whether or not a lesion is cystic and may be helpful in depiction of sinus tracts and fistulae. Use of gadolinium-based intravenous contrast material is often not required for depiction of anatomical malformations, although use of contrast can be extremely useful and often required for depiction and characterization of masses, neoplasms, inflammatory disorders, and infectious processes. Intravenous contrast media are used if tumor is suspected, since most tumors demonstrate abnormal enhancement. More advanced sequences include Magnetic Resonance Angiography (MRA) and Magnetic Resonance Venography (MRV) which are useful in assessing arterial and venous structures respectively. Diffusion Weighted Imaging (DWI) and its complementary Apparent Diffusion Coefficient (ADC) can be helpful in the imaging of cases of certain tumors, infections, and in cases where ischemia is a concern. In a comparison of CT and MRI, each has its advantages and disadvantages. The advantages of MRI over CT include

FIGURE 24-6. Black bone on MRI (coronal HASTE). Single coronal HASTE image through the level of the temporal bones demonstrates marked signal loss (black bone) (arrows) in comparison with the fluid-filled membranous labyrinth (arrowheads).

1. No ionizing radiation. 2. The soft tissue structures including posterior fossa, temporal lobe, cranial nerves, and craniocervical junction are better demonstrated.

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FIGURE 24-7. Normal CN VII and CN VIII on MRI. Sagittal T2WI through the internal auditory canal (IAC) demonstrates the normal appearance of the four nerves (four black dots seen in relief adjacent the CSF within the IAC) normally situated within the canal at this level. By convention, with this view, the anterior portion of the skull is always depicted to the left of the image (and will be so demonstrated on all subsequent similar images). The two nerves seen anteriorly are cranial nerve VII superiorly (7-up) and the cochlear nerve inferiorly (Coke down), whereas the two nerves seen posteriorly are the superior and inferior vestibular nerves, respectively.

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3. Noninvasive vascular imaging (MRA and MRV) allows evaluation of major arteries and veins (e.g., sigmoid sinus blood flow) (Fig. 24-8). Disadvantages of MRI include 1. Its inability to distinguish air from cortical bone, obscuring details of the bony anatomy. 2. Longer examination time. 3. Higher cost. Previously, the minimal slice thickness of MRI was greater than that of CT, and there was difficulty in obtaining contiguous images. This meant less imaging detail than with CT. These limitations have become less important with the use of thin-slice, high-resolution MRI and volumetric acquisitions. MRI safety is a major concern in patients that have metallic implants, devices and foreign objects in the body. For example, the presence of cardiac pacemakers and cochlear implants have been major contraindications to MRI. Although the majority of tympanostomy tubes (T-tubes) being inserted these days are nonferromagnetic and MRI-safe, it is necessary to screen all patients with a history of surgical placement of T-tubes before performing an MRI in order to evaluate their potential safety. If no record from the surgeon or operating room can be provided to the technologist screening the patient for MRI safety, the patient’s scan often needs to be postponed until such time as it can be determined that it is safe

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B FIGURE 24-8. Normal MRV. Frontal (A) and lateral (B) views from a normal MRV of the intracranial dural venous sinuses demonstrate symmetric filling bilaterally (on the frontal view) of the bilateral internal jugular veins (IJ) and transverse/sigmoid sinus regions (TS), and normal filling of the superior sagittal sinus (SSS) and straight sinus (SS) on the lateral view.

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for the patient to enter the MRI scanner. With the increasing popularity of high magnetic field MRI scanners, such as 3 Tesla systems, it must now be ensured that the particular tympanostomy tube is safe to use at this higher magnetic field as well, since traditionally the designation “MRI safe” was used to imply safety at magnetic field strength of up to 1.5 Tesla. The MRI safety profile of middle ear ossicular prostheses must also be ensured. Traditionally young patients have usually required sedation for both CT and MRI, although this is now becoming less common in CT due to the rapid scanning time afforded by modern CT scanners. Although it was somewhat commonplace in the past for many pediatric radiology departments to administer their own conscious sedation to patients unable to stay motionless for examinations, many departments are moving to a team approach that includes hospitalists, nurses and nurse practitioners when administering conscious sedation, and nurse anesthetists and anesthesiologist in more complex cases requiring the use of Propofol and other deeper sedation agents. With the advent of faster scanners, it may be

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possible to scan younger patient without conscious sedation, especially with the help of a child life specialist.

CLINICAL SITUATIONS Imaging studies of the temporal bone are most commonly ordered to evaluate acute and chronic infection, tumors, congenital anomalies, and trauma. Acute Infection Thin-section, high-resolution CT without contrast is the imaging test of choice for uncomplicated acute infection of the mastoid and middle ear (acute otomastoiditis). With CT, even small amounts of fluid in the middle ear and mastoid air cells are detectable, as the higher attenuation of fluid contrasts well with the low attenuation of air and dense bone within these structures. CT is useful in assessing the integrity of the bony septae within the mastoid and in evaluating the integrity of the overlying cortex and soft tissues (Fig. 24-9). Acute infection of the mastoid air cells complicated by demineralization and

FIGURE 24-9. Mastoid dehiscence with infection (mastoiditis). Contrast-enhanced CT of the temporal bones consisting of axial (A) and coronal (B) soft tissue and axial (C) and coronal (D) bone windows through the region of the right temporal bone demonstrate a large amount of soft tissue swelling/mass (abscess) within the superficial soft tissues of the temporal region (arrows) (A and B) and associated bony break through along the lateral mastoid region (arrowheads) (C and D) secondary to acute coalescent mastoiditis.

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 361 erosion of the mastoid bony septae and the cortex of the mastoid bone indicate the development of acute coalescent mastoiditis, which may require surgical intervention.1,2 MRI usually reveals abnormal fluid collections (demonstrated by bright signal on T2WI images, where there should be none) but is not able to detect subtle bony changes for reasons previously discussed. Thus, MRI does not play a significant role in evaluating patients with noncomplicated inflammatory disease of the temporal bone. When the middle ear and mastoid are being evaluated for acute infection, intravenous administration of contrast material is not necessary unless an extracranial soft tissue abscess or intracranial complication is suspected. Intravenous contrast is administered to detect extra-axial (epidural or subdural) abscesses or intra-axial parenchymal brain abscesses (Fig. 24-10).3 Abscesses are rim enhancing lesions with central hypodense (on CT) collection of pus. An epidural abscess is suggested when a lenticular collection is noted adjacent to the calvarium. Associated bone destruction (osteomyelitis) is occasionally present. The involved dura enhances after contrast administration. A common location of an otogenic epidural abscess is adjacent to the sigmoid sinus. The sigmoid sinus is intradural and is easily compressed and displaced medially. The blood flow may be slowed or obstructed. When occlusion occurs, the thrombus can propagate either proximally or distally. Thus, it is important to look for features

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of jugular vein or transverse sinus occlusion, which appears as high density on non enhanced CT (Fig. 24-11A) and as a filling defect on contrast enhanced CT (Fig. 24-11C). However, determination of sigmoid sinus and jugular vein patency can be difficult with routine CT.4 The obstructed sigmoid sinus may be hard to distinguish from the adjacent epidural abscess (Fig. 24-11B) as both can be lucent with rim enhancement and can be located adjacent to the petrous bone. Use of thin slice CT venography may help in this regard. MRI is often used to evaluate suspected sigmoid sinus thrombosis. As discussed earlier, flowing blood within a vessel should appear as a distinct signal void on MRI. A vascular thrombus should appear as an abnormal signal of moderate or high intensity where a signal void would be expected to be seen. A variable amount of surrounding bright signal representing a small amount of slow-flowing blood may be seen around a partially occluded vessel (Fig. 24-11D). Slow-flowing blood can cause difficulty in confidently making the diagnosis of venous sinus thrombosis on nonenhanced standard MR sequences as slow flowing blood may also return bright signal intensity that can cause false-positive results. Gradient echo flow-sensitive sequences (Fig. 24-11E), contrast-enhanced T1WI (Figs. 24-11F and G) and MR Venography (Figs. 24-11H and I) are very reliable for excluding thrombus and may be used in conjunction with one another.

FIGURE 24-10. Intracranial (IC) extension of mastoid disease. Contrast-enhanced CT of the temporal bones consisting of axial (A) and coronal (B) soft tissue and axial (C) and coronal (D) bone windows through the region of the left temporal bone demonstrate a large amount of soft tissue swelling/mass (abscess) within the superficial soft tissues of the temporal region (arrows) (A and B) and associated bony break through along the lateral mastoid region (arrowheads) (C and D) secondary to acute coalescent mastoiditis. Note the thin amount of dural enhancement along the posterior aspect of the middle cranial fossa at approximately the 5:00 position (curved arrows) (A and B). This represents intracranial extension of mastoid disease with resultant infectious epidural enhancement.

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K

FIGURE 24-11. Jugular vein (JV) and sigmoid sinus (SS) thrombosis (secondary to mastoiditis). Multiple images were obtained from both CT (A–C) and MRI/MRV (D–K) in a patient with the complication of dural venous thrombosis and epidural abscess from adjacent right-sided mastoid disease. Axial noncontrast CT soft tissue windows of the head (A) demonstrates a dense right clot in the region of the sigmoid sinus (arrow), which is seen as a filling defect on the contrast enhanced CT (C) (arrow). Of note, on the lower slices through the contrast-enhanced CT of the head (B), the filling defect seen laterally at approximately the 9:00 position is similar in attenuation to that of cerebrospinal fluid and likely represents an extra-axial collection/abscess (arrowhead). The bright signal identified on coronal FLAIR sequence (D) (arrow) likely represents stasis of blood flow, whereas the area of signal drop-off on the axial susceptibility sequence (E) (arrow) suggests the presence of clot. Axial and coronal postcontrast T1WI through the level of interest (F–G) demonstrate the epidural collection (arrowheads) in addition to poor filling of the adjacent dural sinus (arrows). Confirmation of thrombosis within the right SS and internal jugular vein (IJV) is noted on axial (H) and coronal (I) MRV in comparison with their normal counterparts on the left. DWI (J) and ADC (K) images demonstrate a focus of restricted diffusion lateral to the right cerebellum, confirming the presence of an epidural abscess (arrowheads).

If an abscess is present, MRI will also demonstrate abnormal increased signal in the epidural space or brain on T2WI, rim enhancement on postcontrast T1WI, and restricted diffusion. The dura will be abnormally enhancing on postcontrast T1WI. At times, DWI can help in assessing the presence of purulent material as it will restrict on this sequence, thereby confirming the presence of infection (Figs. 24-11J and K and 24-12A and B). However, this ability to determine purulent material will be hampered secondary to the presence of hemorrhage, which may be the case in a postoperative patient.

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Gradenigo Syndrome A now uncommon complication of suppurative otitis media in the postantibiotic era, is the clinical entity known as Gradenigo syndrome, resulting from petrous apicitis (Fig. 24-13). The classic clinical findings are that of a triad including purulent otitis, ipsilateral abducens nerve palsy (CN VI), and deep facial or retroorbital pain in the distribution of the trigeminal nerve (CN V). With adjacent dural inflammation, the cranial nerves involved can become inflamed such as is the case with the abducens nerve as it courses through the Dorello canal,

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A

B

FIGURE 24-12. Soft tissue abscess. DWI (A) and ADC (B) images demonstrate a focus of restricted diffusion within the superficial soft tissues overlying the right mastoid, confirming the presence of a superficial soft tissue abscess (arrows).

A

E

D

C

B

F

G

H

FIGURE 24-13. Petrous apicitis. Multiple images were obtained from both CT (A–D) and MRI (E–H) in a patient with right petrous apicitis. Note the opacified petrous apex (arrows) along the right (A and C) in comparison with the normal pneumatized petrous apex (arrowheads) on the left (B and D). This is confirmed on axial T2WI (E) as fluid/soft tissue signal (arrows) within the right petrous apex (E) in comparison with its normally aerated counterpart on the left (arrowheads). On axial postcontrast imaging (F), avid gadolinium enhancement is seen corresponding to the region of the right petrous apex, indicating inflammation/petrous apicitis (arrows). Note the enhancement of the CNVII/VIII complex within the right internal auditory canal (arrowheads). DWI (G) and ADC (H) images demonstrate restricted diffusion in the region of previously documented inflammation, suggesting the presence of purulent material (arrows).

under the petroclinoid ligament, or with the involvement of the Gasserian ganglion in the region of Meckel’s cave, as is the case with the trigeminal nerve.5–7

Middle Ear Cholesteatoma and Chronic Inflammatory Disease Although readily visible with the otoscope, tympanic perforations can sometimes be identified on CT (Fig. 24-14). In patients with cholesteatoma, CT is the examination of choice,

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although some authors advocate the use of DWI MRI to assess patients with suspected cholesteatoma. However, the utility of the commonly performed echoplanar diffusion imaging sequence is limited due to artifacts at the skull base and temporal bone, often limiting evaluation. Use of nonechoplanar DWI may be of benefit in detecting and differentiating cholesteatoma from other entities.8,9 However, these types of diffusion imaging are not widely available on all MRI systems. Contrast enhancement is not needed unless there is concern regarding a concurrent intracranial pathologic condition.

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Cholesteatomas occur in two varieties, acquired and congenital. Approximately 98% of middle ear cholesteatomas are acquired and they are further divided into pars flaccida and pars tensa cholesteatomas; the former being more common. Congenital cholesteatomas are discussed later in this chapter (see Fig. 24-37). Cholesteatomas are sacs that are lined by stratified squamous epithelium and filled with keratin that becomes trapped and if left continues to grow (Fig. 24-15). As a result, debris becomes trapped in the retraction pocket and forms keratin plugs. Classically, cholesteatoma manifests as a soft tissue density mass in the middle ear cavity with adjacent bone erosion (Fig. 24-16). On CT it may be difficult to differentiate a cholesteatoma from fluid or granulation tissue, as they are of the same density/attenuation. However, the radiologist may be able to identify bone erosion, such as in the scutum or ossicles, as presumptive evidence of a cholesteatoma.

A

B

A

C B FIGURE 24-14. Tympanic membrane perforation. Axial (A) and coronal (B) CT bone windows through the right temporal bone demonstrate a hole/perforation through the tympanic membrane (arrows).

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FIGURE 24-15. Cholesteatoma aquired_01. Axial (A), coronal (B), and sagittal (C) CT bone windows through the temporal bones demonstrate a soft tissue mass (M) within the region of the left middle ear and erosion of the inferior aspect of the left mastoid bone (arrowheads). The mass is seen to surrounds the ossicles (arrows). This mass represents an acquired cholesteatoma.

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A

B

C

D

FIGURE 24-16. Cholesteatoma aquired_02. Axial and coronal bone windows from CT of the temporal bone of the affected right ear (acquired cholesteatoma) (A and C) and comparison unaffected left (middle ear effusion) (B and D) demonstrate soft tissue (asterisk) (A) filling the middle ear cavity on the right with associated rarefaction of the ossicles (arrows), and erosion of the bony scutum (arrowhead) (C).

Detection of erosion of the ossicles may be less reliable; large erosions can be seen, but small erosions are difficult to exclude. MR with contrast may differentiate granulation tissue (which enhances following contrast adminstration) from cholesteatoma (which does not enhance); however, given the small size of the structures in this area, this method may not always be reliable. DWI may be helpful in further assessing the possibility of cholesteatoma (Fig. 24-17).10 Coronal imaging is excellent for evaluating the facial nerve canal, tegmen tympani, scutum, and lateral wall of the attic, as well as the lateral aspect of the horizontal SCC. In the coronal plane, the scutum can be carefully inspected for erosions along its inferior surface. If more information regarding the horizontal SCC is desired, additional axial images nicely demonstrate it in its entirety on a single slice. Dystrophic calcification, sometimes referred to as tympanosclerosis, is considered the sequela of chronic inflammation, and may be be visualized on CT (Fig. 24-18). Labyrinthitis ossificans (LO) is an entity that is radiographically identifiable both on CT and MRI (Fig. 24-19) and is thought to be caused by several etiologies, divided into three main causes: meningogenic (from the meninges), tympanogenic (from the middle ear), and hematogenic (from the blood stream), all of which are thought to lead to suppurative labyrinthitis. LO is thought to occur in three stages:

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The first stage is the acute stage, with bacteria and leukocytes being lodged within the perilymphatic spaces; this is followed by the fibrous stage, characterized by fibroblast proliferation; and finally by the ossification stage, the stage in which CT findings becomes evident. MRI may be able to detect the first and especially the second stages by either demonstrating enhancement of the labyrinth in the acute stage or obliteration of the normal fluid-filled labyrinth by dark signal fibroblastic proliferation on T2WI in the second stage.11,12

Tumors CT and MRI are both valuable for determining the extent of head and neck neoplasms. CT best documents the extent of bone destruction in tumors originating within the petrous bone and also defines the soft tissue component relatively well. MR is superior in demonstrating the soft tissue component and its anatomical extent. MRI also has the potential to differentiate tumor from fluid trapped in the mastoid air cells, whereas tumor and fluid may appear identical on CT. On T2WI MRI, the signal of the tumor is usually less than that of the retained fluid, allowing the tumor to be distinguished from the entrapped fluid. On MRI, as tumor replaces either cortical bone or air that is normally “black,” one finds signal (brightness) where there should be none. Another potential

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366

SECTION 2 ❖ Ear and Related Structures

A

D

B

C

E

F

FIGURE 24-17. Cholesteatoma aquired_03. Multiple images from MRI of the brain with and without intravenous gadolinium demonstrate findings of acquired cholesteatoma utilizing this modality. Coronal T2WI (A) and axial FLAIR (B) images demonstrate soft tissue/fluid within the region of the left middle ear/mastoid region (arrows), a nonspecific finding. Further imaging with T1WI axial images precontrast (C) and postcontrast administration (D) confirms soft tissue within this region, the brightness within the center possibly indicating inspissated fluid (arrows). However, on the DWI (E) and ADC (F) images, the above-described focus is seen to exhibit restricted diffusion (arrows), which is helpful in differentiating acquired cholesteatoma from nonspecific inflammatory disease within the middle ear/mastoid regions.

A

B

FIGURE 24-18. Tympanic Membrane Mineralization. Coronal bone algorithm images from CT of the temporal bone of the right (A) and left (B) tympanic regions demonstrate thickening and increased attenuation of the tympanic membranes, in keeping with tympanic membrane mineralization (arrows).

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B

A

E

C

D

F

G

H

FIGURE 24-19. Labyrinthitis ossificans. Multiple images are demonstrated from both CT (A–D) (A and C on the right and B and D on the left) as well as MRI (E–H) in a patient with bilateral labyrinthitis ossificans, worse on the left than on the right. Comparative axial bone windows at the level of the cochlea(A and B) and lateral semicircular canals (C and D) demonstrate increase in sclerosis/bony deposition within the region of the cochlear modiolus bilaterally, left greater than right (arrows) (A and B). Similar sclerosis is seen about the lateral semicircular canals bilaterally, slightly greater on the right than on the left (arrowheads) (C and D). Comparative reformatted coronal high-resolution T2WI through the region of the membranous labyrinth on the right (E) and left (F) as well as axial image source image for the same sequence (G) demonstrate loss of T2 signal with apparent shortening of the lateral semicircular canals bilaterally as visualized on the coronal images (arrows) as well as attenuation of the T2-fluid signal within the expected location of the vestibules bilaterally, best appreciated on the axial image (arrows). Significant loss of T2 signal is seen within the expected location of the cochlea on the left (arrowhead) in comparison with its slightly attenuated counterpart on the right (curved arrow) (G). Bilateral cochlear enhancement (arrows), left greater than right is seen, as demonstrated on the postcontrast axial T1WI (H), suggesting some degree of acuity to this inflammatory process.

way to identify tumors on MRI is by assessing the fat in the petrous apex. Normally, fat is very bright on T1WI and gray on T2WI. As tumor replaces this fat, its normal signal is replaced by the tumor, resulting in low signal on T1WI and high signal on T2WI. Intracranial extension of tumor is generally discernible by its mass effect and higher CT attenuation compared to that of the cerebrospinal fluid (CSF). MRI is often helpful in imaging tumor extent both into the neck and intracranially and is best at defining the intracranial extent of tumor. With the use of various sequences to optimize tissue contrast, mainly fat suppression sequences, tumor margins can be visualized.

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Contrast agents should be used for tumor evaluation with both CT and MRI, as many tumors will demonstrate enhancement in both modalities. This will facilitate identification and differentiation of tumor from adjacent normal tissues. Rhabdomyosarcoma (Fig. 24-20) is the most common soft tissue sarcoma affecting children, and approximately 41% of these tumors occur in the head and neck region. Of the head and neck rhabdomyosarcomas, 8% occur within the temporal bone region. Of the four cell subtypes that are observed (pleomorphic, alveolar, botryoid, and embryonal), embryonal cell is the most common subtype found in the head and neck region.13 For evaluation of acoustic neuromas (vestibulocochlear schwannomas), contrast-enhanced MRI is the examination of

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368

SECTION 2 ❖ Ear and Related Structures

A

B

C

D

FIGURE 24-20. Rhabdomyosarcoma. Axial and coronal T2WI (A and B), and axial and coronal postcontrast T1WI (C and D) of the temporal region in a patient with biopsy proven rhabdomyosarcoma, demonstrate fluid signal/soft tissue (arrowheads) within the right petrous apex/ skull base region (A and B). This area however enhances avidly (arrowheads) on the postcontrast images, and given the involvement of the right sphenoid bone (S with an arrow) as well as the region of the carotid canal (CC with an arrow) (C), is suspicious for an aggressive tumor.

choice. The tumor occurs in the cerebellopontine (CP) angle and/or within the IAC (Fig. 24-21). It typically “lights up” on contrast-enhanced T1WI and appears as a lower signal intensity mass within the high signal of the CSF on high-resolution FSE T2.14 Intralabyrinthine schwannomas may appear as a small filling defect in fluid of the cochlea or vestibule on high resolution T2WI and exhibit contrast enhancement on T1WI. Acoustic schwannomas are rare in the pediatric age group but if they occur in children, the possibility of neurofibromatosis

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type 2 (NF2) should be assessed, especially with bilateral tumors. NF2 is an autosomal dominant disorder transmitted by chromosome 22 and is associated with multiple other CNS lesions including intracranial and spinal meningiomas, spinal cord ependymomas and nerve root schwannomas.15 Other common tumors or mass-like lesions in the CP angle include meningiomas (Fig. 24-22), which enhance homogenously. Arachnoid cysts (Fig. 24-23) or epidermoid cysts (Fig. 24-24) do not enhance but can be differentiated from

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 369

A

C

B

D

FIGURE 24-21. Acoustic schwannomas (bilateral). Axial T1WI (A), axial CISS (B), and axial (C) as well as coronal (D) postcontrast T1WI from MRI through the region of the internal auditory canals in a patient with known NF2 demonstrate bilateral intracanalicular masses (A and B) on noncontrast imaging (arrows), which demonstrate avid contrast enhancement on postcontrast imaging (arrows), highly suggestive of bilateral acoustic schwannomas.

each other on fluid attenuation inversion recovery (FLAIR) and DWI MR sequences (arachnoid cysts follow the signal of CSF on all MR pulse sequences, whereas epidermoid cysts are brighter than CSF on FLAIR and show restricted diffusion on DWI/Apparent Diffusion Coefficient (ADC)).14 Langerhans cell histiocytosis (LCH), previously known as histiocytosis X (including the three entities, eosinophilic

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granuloma [EG], Letterer–Siwe disease, and Hand–Schüller– Christian disease), is known as the great mimicker in radiology because it has protean presentations and can occur within any soft tissue or bone within the body, including the temporal bone. This lesion is characterized pathologically by aggregates of proliferating histiocytes and other inflammatory cells. The temporal bone may be affected as a solitary site

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370

SECTION 2 ❖ Ear and Related Structures

A

B

FIGURE 24-22. Meningioma (CP angle). Axial T1WI precontrast (A) and axial T1WI postcontrast (B) MR images at the level of the posterior fossa in a patient with NF 2, demonstrate a slightly low signal mass at the CP angle on the right (arrows) (A), which demonstrates avid contrast enhancement on postcontrast images (arrows) (B). Given its extra-axial location and its signal characteristics, this is suggestive of a meningioma (pathologically proven).

A

C

B

D

FIGURE 24-23. Arachnoid cyst (CP angle). A single noncontrast axial CT image (A) through the posterior fossa at the level of the CP angle and three axial images from MRI of the brain at the same level consisting of axial T1WI (B), axial T2WI (C), and axial postcontrast T1WI (D) images all demonstrate a collection of fluid identical to CSF at the right CP angle (arrows), in keeping with an arachnoid cyst, of dubious clinical significance.

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B

A

C

D

E

FIGURE 24-24. Epidermoid (CP angle). Multiple MRI sequences through the posterior fossa were obtained on a patient consisting of axial T1WI (A), axial T2WI (B), axial postcontrast T1W1 (B), axial DWI (D), and ADC (E) images. Although the extra-axial prepontine collection on the right demonstrates apparent isointense signal to cerebral spinal fluid on all conventional sequences (A–C) (arrows), restricted diffusion is demonstrated on the DWI and ADC sequences (arrows), highly suspicious for an epidermoid cyst.

or as a part of multisystem disease, and may be involved in up to 60% of patients (range of 15%–60%). Radiographically, osseous involvement is demonstrated by well-defined lytic lesions with sharp punched-out borders, without surrounding reactive sclerosis and with an enhancing soft tissue mass (Fig. 24-25).16 Owing to its dense bony covering, the bony labyrinth is infrequently affected, but its involvement should

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be suspected if the patient has concomitant sensorineural hearing loss (SNHL), as opposed to conductive hearing loss (CHL), which is not unexpected with infiltrative changes in the middle ear, ossicles, or external auditory canal (EAC). Cholesterol granulomas are cystic fluid collections that occur within the petrous apex, contain blood products, are bright on both T1WI and T2WI, and may exhibit some signal

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372

SECTION 2 ❖ Ear and Related Structures

A

E

D

F

C

B

G

H

FIGURE 24-25. Langerhans cell histiocytosis (LCH). Multiple noncontrast CT (A–E) and contrast-enhanced MRI (F–H) images were obtained in a patient with a left-sided temporal/periauricular region of bogginess. Lateral scout view of the skull from CT examination (A) demonstrates lucency in the region of the orbit/superior temporal region (arrows). Soft tissue prominence/mass (arrows) is identified on the soft tissue windows on CT in the axial (B) and coronal reformatted (D) planes, with evidence of bony destruction (arrows) with a punched out appearance of the bone at the site of soft tissue mass seen on the axial (C) and coronal (E) reformatted bone windows. In addition, note an additional lesion within the occiput (arrowhead) best demonstrated on the axial bone windows (C). A soft tissue mass (M) is confirmed on the axial T2WI (F), with confirmed avid contrast enhancement (arrows) on the postcontrast axial (G) and coronal (H) T1WI. Adjacent dural enhancement is seen on the postcontrast coronal images (H) in the region of the left middle cranial fossa (curved arrows). Given the imaging appearance and the multiplicity of lesions (orbit on scout view, occiput on axial bone view, and temporal lesion on multiple views), this is highly suspicious for LCH (pathologically proven).

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 373 drop off on susceptibility scans, due to the presence of blood products (Fig. 24-26).6,7 A rare but aggressive tumor can occur in the region of the vestibular aqueduct and is known as the endolymphatic sac tumor, which is a retrolabyrinthine papillary adenomatous tumor arising from the site of the endolymphatic sac (Fig. 24-27). In the majority of cases, these patients will also have Von-Hippel Lindau disease (VHL).17

Congenital Abnormalities and Malformations CT remains the study of choice for the evaluation of congenital anomalies of the external and middle ears, while anomalies of the inner ears are best evaluated with highresolution MRI, utilizing CT as an adjunct to evaluate bony details. The main advantage of MRI over CT in the evaluation of the inner ear structures is its ability to depict the status of the nerves in the IAC. The middle and external ears share a common embryologic origin, so it is not surprising that congenital malformations tend to involve both areas. Isolated middle ear anomalies are possible, but congenital malformations of the inner ear are most often isolated because of a separate embryologic origin. Even with an obvious external ear deformity, a detailed study of the middle and inner ears may be necessary to exclude additional anomalies that may affect surgical planning. Congenital anomalies are not uncommon in children referred for hearing loss. However, imaging may still be normal in these patients if the cause lies in the neuroepithelium or sensory epithelium, since in these cases, the gross anatomy of the bony labyrinth may be normal. Auricular and EAC abnormalities are fairly common. There may be EAC stenosis or frank atresia. In EAC atresia, the tympanic membrane is replaced by an atretic plate of variable thickness, which may be bony or membranous. Associated malformations of the middle ear and ossicles are frequent (Fig. 24-28). The most common anomaly is fusion of the malleus to the atretic plate. Anterior position of the mastoid portion of the facial nerve is usually seen with external and middle ear anomalies (Fig. 24-29). Preoperative CT evaluation of EAC stenosis/atresia is necessary to exclude concomitant congenital cholesteatoma (Fig. 24-30) and demonstrate any pathologic anatomy (temporomandibular joint anomalies, etc.).18 Rarely there can be duplication of the EAC, either soft tissue (Fig. 24-31) or bony (Fig. 24-32). If an isolated middle ear anomaly is present, the stapes and incus are the more commonly involved ossicles, while the malleus is the least often involved. Ossicular anomalies may include absence (Fig. 24-33), hypoplasia (Fig. 24-34), deformity, or fixation to another middle ear structure (Figs. 24-35 and 24-36). Congenital cholesteatomas (epidermoids) are much less common than the acquired variety and are believed to arise from aberrant epithelial remnants or rests left at the time of closure of the neural groove (between the third and fifth week of fetal life). These lesions tend to occur in the anterosuperior

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middle ear, adjacent to the eustachian tube and the cochlear promontory (Fig. 24-37), and occur with an intact tympanic membrane, without history of perforation.19 Inner ear anomalies depend largely on the time of insult. Early injuries may result in complete labyrinthine aplasia (Michel deformity). Injuries in the fourth gestational week result in failure of segmentation of the inner ear structures and may result in a common featureless cystic cavity.15,20,21 To be considered normal, the cochlea must demonstrate 2½–2¾ turns with an intact modiolus (central bony structure of the cochlea) and interscalar septum (Fig. 24-38). Incomplete partitioning of the cochlea can occur with resultant cystic bulbous cochlear turns (Figs. 24-39 to 24-41). These incomplete partitioning inner ear abnormalities have been classified as type I and type II based on their severity.22 SCCs may be absent (Fig. 24-42) or demonstrate variable deformities that may be isolated or seen concomitantly with other anomalies, malformations, and genetic syndromes (Fig. 24-43). SCC anomalies include sac-like malformations, small complete canals, or segmental dilatation; the sac-like malformations are most common and are associated with a sac-like vestibule (Fig. 24-44). The lateral SCC is the most commonly affected SCC.The large endolymphatic duct and sac is the most common identifiable associated abnormality on imaging in children with SNHL. The membranous endolymphatic duct courses through the osseous vestibular aqueduct, and in cases where the endolymphatic duct is enlarged, the vestibular aqueduct diameter is also large. The vestibular aqueduct can be identified on CT and the normal vestibular aqueduct diameter should be equal to or smaller than the diameter of the posterior SCC. More recently, specific measurements have been applied to the size of these structures.23 Abnormal dilatation is best seen on axial images. MR directly shows the dilated endolymph-containing duct and sac on fluid sensitive sequences. (Fig. 24-45). Large endolymphatic sacs can be associated with anomalies of the cochlea, in particular deficiency of the modiolus (Fig. 24-46).The classic Mondini triad consists of abnormal partioning of the cochlea, large vestibular aqueduct/endolymphatic sac and enlarged vestibule (Fig. 24-47).The IAC varies in size and length depending on the patient’s size and age (Fig. 24-48). Cochlear nerve hypoplasia (Fig. 24-49) or aplasia (Fig. 24-50) result in congenital SNHL and are identified as a small or absent cochlear nerve in the anteroinferior IAC and may be associated with narrowing of IAC and the cochlear nerve aperture at the base of the modiolus (Fig. 24-51).16 Acquired cochlear nerve atrophy also demonstrates a small cochlear nerve, but the size of the IAC is normal. In addition, there is an association of an enlarged IAC with SNHL, known as X-linked SNHL, which is a chromosomal abnormality that causes perilymphatic hydrops due to fistulous connection between the IAC and the cochlea. This syndrome is seen in young men with profound SNHL or mixed hearing loss that is often progressive and may be associated with vestibular dysfunction. The imaging

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374

SECTION 2 ❖ Ear and Related Structures

A

B

D

C

E

F

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G FIGURE 24-26. Cholesterol granuloma. Multiple noncontrast CT (A–C) and MRI (D–G) images were obtained in a patient with a left petrous bone mass. Axial CT soft tissue (A) and the bone (B) with coronal bone reformations (C) demonstrate expansile opacification of the right petrous apex (arrows), with rarefaction of the superior margin and suspected bony break through best demonstrated on coronal bone reformations (C). The lesion is both bright on T1WI (D), axial T2WI (E), and coronal CISS sequences (arrows), suggesting that this is not simple fluid. The axial B0 image (G) from the DWI sequence (sometimes referred to as the “poor man’s gradient echo/ susceptibility sequence”) suggests some signal drop-off along its inferior margin (arrows), suggestive of the presence of blood products. The imaging characteristics (bright on T1WI, bright on T2WI, and dark on gradient echo sequences) is highly suggestive for a petrous apex cholesterol granuloma.

A

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B

C

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SECTION 2 ❖ Ear and Related Structures

D

E

F

J

I

H

G

FIGURE 24-27. Endolymphatic sac tumor (ELS tumor). Multiple noncontrast CT (A–G) and contrast-enhanced MRI (H–J) images were obtained in a patient with Von-Hippel Lindau (VHL) disease. Axial noncontrast CT soft tissue window (A) through the posterior fossa demonstrates a soft tissue mass (arrows) along the posterior aspect of the petrous bone with convex anterior erosion (arrowheads). Comparative axial (B–E) and coronal (F–G) bone images through the region of interest demonstrate a destructive lesion along the right petrous bone (arrows) at the level of the IAC/cochlea (B and F) with extension superiorly to involve the posterior aspect of the superior semicircular canal (arrow) on the right (D), as compared to their normal counterparts on the left (C, E, and G). The mass is confirmed on axial T1WI (H) and T2WI (I) MRI sequences (M), with avid enhancement (arrows) demonstrated on the post contrast axial T1WI sequence (J). Given the location of the tumor at the expected site of the vestibular aqueduct in a patient with VHL disease, this is highly suspicious for an ELS tumor.

A

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B

C

D

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 377

E

F

G

H

FIGURE 24-28. Aural atresia (atresia plate). Comparative axial (A–D) and coronal (E–H) CT bone windows in a patient with right-sided aural atresia demonstrate a bony atresia plate with absence of the EAC (A and E) on the right (arrows) in comparison with its normal counterpart on the left (B and F) (arrows), as well as dysplastic ossicles on the right (C and G) (arrowheads) seen enclosed in a small middle ear cavity, versus normal appearing ossicles and middle ear cavity on the left (D and H)(arrowheads).

A

Ch24.indd 377

B

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378

SECTION 2 ❖ Ear and Related Structures

C

D

FIGURE 24-29. Aural atresia (CN7 displacement anteriorly). Comparative axial (A–B) and coronal (C–D) CT bone windows in a patient with right-sided aural atresia demonstrate anterior displacement of the facial nerve/facial nerve canal as evidenced by anterior positioning at the expected location of the posterior genu on the right (arrow) (A) as visualized on the axial image, as well as anterior positioning of the descending/vertical portion of the facial nerve canal (arrowhead) (C). Note the normally positioned posterior genu (arrow) (B) and descending facial nerve canal (arrowhead) on the left (D).

A

B

C

D

FIGURE 24-30. EAC stenosis with congenital cholesteatoma. Comparative axial (A and B) and coronal (C and D) CT bone windows in a patient with right-sided EAC stenosis demonstrates a soft tissue mass (M) (A) within the medial portion of the right EAC. Note the narrowing of the EAC on the right (arrows) (C). This lesion proved to be a congenital cholesteatoma.

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A

B

C

D

E

F

G

FIGURE 24-31. EAC duplication (soft tissue). Comparative axial (A–C) and coronal (D–G) CT bone windows in a patient with rightsided EAC duplication (soft tissue) demonstrate two separate air-containing external canals (A, B, D–F), one of which is directed more superiorly (arrows) (B, D–F), and one of which is directed more inferiorly (arrowheads) (A, D–F). Note the normal appearing left EAC (asterisks) (C and G).

A

Ch24.indd 379

B

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380

SECTION 2 ❖ Ear and Related Structures

D

C

E

G

F

FIGURE 24-32. EAC duplication (bony). Sagittal right (G) and comparative coronal (A and B) and axial (C and F) CT bone windows in a patient with right-sided EAC duplication (bony) demonstrate two separate bony canals on the right (A) (superior canal illustrated by the arrow and inferior canal illustrated by the arrowhead). Owing to the downsloping nature of both EACs (A and B on the coronal images), the true axial comparative views (C on the right and F on the left) are somewhat misleading. Additional angled true axial views through the right EAC (D and E) demonstrate the true nature of the duplication of the EAC on the right, below (D) (arrowhead), and above (E) (arrow) the large bony septum (asterisk) (A, D, and E). Sagittal reformation (anterior is located to the left of the image) (G) demonstrates a small anterior canal (arrowhead) and a larger posterior canal (arrow).

A

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B

C

D

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 381

F

E

FIGURE 24-33. Ossicular absence (stapes and long process of incus). Comparative axial (A–D) and coronal (E–F) CT bone windows demonstrate absence of the long process of the incus (arrowhead) (A) and absence of the stapes (arrows) (C and E) on the right. Note the normal long process of incus (arrowhead) (B) and normal stapes (arrows) on the left (D and F).

A

B

C

D

FIGURE 24-34. Ossicular hypoplasia. Comparative axial (A and B) and coronal (C and D) CT bone windows demonstrate hypoplasia of the ossicular chains bilaterally (arrows).

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382

SECTION 2 ❖ Ear and Related Structures

A

B

C

D

FIGURE 24-35. Ossicular fixation (malleus to epitympanum). Comparative axial (A and B) and coronal (C and D) CT bone windows demonstrate ossicular fixation of the malleus to the osseous epitympanum on the right (A and C) (arrows). Note the normal air gap between the ossicles and osseous epitympanum on the left (B and D) (arrowheads).

A

B

FIGURE 24-36. Ossicular fixation (incus to scutum). Comparative coronal (A and B) CT bone windows demonstrate ossicular fixation of the incus to the scutum on the right (A) (arrow). Note the normal air gap between the incus and the scutum on the left (B) (arrowhead).

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 383

A

B FIGURE 24-37. Cholesteatoma (congenital). Axial (A) and coronal (B) bone windows from CT of the temporal bone demonstrate a small rounded mass (arrows) within the middle ear cavity situated adjacent to the eustachian tube (arrowhead on A) and cochlear promontory (arrowhead on B). The appearance and location are typical of a congenital cholesteatoma.

characteristic in X-linked SNHL is IAC enlargement with a characteristic cork-screw appearance, that is often symmetric and bilateral, associated with hypoplasia of the base of the cochlea. Other findings can include an enlarged vestibular aqueduct and a widened proximal facial nerve canal. Of greatest significance and importance in detecting this abnormality is its association with congenital stapes fixation and stapes gusher, or perilymphatic flooding. The IAC may also be wide and patulous in patients with NF 1 (Fig. 24-52). First branchial cleft cysts are classified as either type I or type II. Type I cysts (Fig. 24-53) are purely related to the EAC, whereas the type II abnormality (Fig. 24-54) occurs primarily near the angle of the mandible, with the tract extending through the parotid gland toward the EAC. These

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cysts and fistulae can be best detected with fluid-sensitive sequences including thin-section T2WI and HASTE/SSFSE. Isolated anomalies of the facial nerve do occur, but an altered course of the facial nerve canal is most often caused by incomplete formation of the temporal bone seen with middle and inner ear anomalies. If the cochlea is small or absent, there may be anterior and medial displacement of the facial nerve canal. Aberrant position is one of the two most common abnormalities of the facial nerve, in which the facial nerve is laterally and inferiorly displaced, best depicted on coronal CT imaging. The other is partial absence of the bony wall of the tympanic portion of the facial nerve canal. Rarely, the facial nerve protrudes into the tympanic cavity (Fig. 24-55), sometimes coming into contact with the stapes or obscuring the oval window. Also rarely, there is duplication of the bony facial nerve canal.Finally, the facial nerve canal is abnormally small in Möbius syndrome, a syndrome in which the patient has congenital bilateral facial nerve paralysis.15 In these cases, the facial nerve is not seen on sagittal oblique reformatted high resolution T2WI (Fig. 24-56). Lastly, it should not be forgotten that not all causes of hearing loss are reflected in findings seen within the temporal bone. Children with in utero infections of the toxoplasmosis/other infection/rubella/cytomegalovirus/ herpes simplex (TORCH) variety have associated hearing loss and typical findings on CT of the brain of periventricular (circumventricular) calcifications (Fig. 24-57). Other causes of SNHL identified in the brain are kernicterus (bilateral globus pallidus involvement) and superficial siderosis (Fig. 24-58). Dedicated brain MR imaging may sometimes be able to depict the associated abnormalities in these patients. Identification of vascular variants and malformations is of utmost importance for preoperative planning. The most important but rare anomaly is the aberrant internal carotid artery (ICA), which extends into the middle ear cavity, and on CT appears as a soft tissue mass along the cochlear promontory (Fig. 24-59). Axial contrast-enhanced CT demonstrates a vascular “mass” continuous with the transverse portion of the carotid canal. A dehiscent jugular bulb may protrude into the middle ear cavity and have soft tissue or “mass” density on CT but will be seen to be continuous with the jugular vein (Fig. 24-60).24 The appearance of vascular abnormalities is fairly characteristic on CT, as the expected course of the vessel is seen to be altered. If the diagnosis of dehiscent jugular bulb is problematic, contrast administration should be definitive. Persistence of an embryonic stapedial artery (Fig. 24-61) can be seen, associated with the thickening of the anterior horizontal tympanic segment of the facial nerve. A clue to its presence is absence of the foramen spinosum on the ipsilateral side. When a stapedial artery persists in postnatal life, the middle meningeal artery arises from it. (The foramen spinosum is absent; it normally contains the middle meningeal artery.) A persistent stapedial artery arises from the petrous internal carotid artery and enters the posterior hypotympanum and then

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384

SECTION 2 ❖ Ear and Related Structures

A

B

D

C

E

F FIGURE 24-38. Cochlea (normal). Axial (A–C) and coronal (D–F) bone windows from CT of the left temporal bone from a normal patient demonstrates a normal cochlea on the axial and coronal images through the base (A and D), midportion (B and E), and apical (C and F) regions of the cochlea.

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 385

A

B

C

D

E

F

FIGURE 24-39. Incomplete partitioning type I (IP-1). Comparative axial (A  and B) and coronal (C and D) CT bone windows as well as axial high-resolution T2WI MRI (E) with coronal reformation (F) demonstrate bilateral absence of the normal labyrinthine structures. There is a common cystic cavity (arrows) seen in the expected location of the cochlea and vestibule.

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386

SECTION 2 ❖ Ear and Related Structures

A

B

C

D

FIGURE 24-40. Incomplete partitioning type II (IP-2). Comparative axial (A and B) and coronal (C and D) CT bone windows of the temporal bones. Note the slightly globular appearance of the cochleae with absence of the normal 2½ turns bilaterally (arrows).

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 387

A

B

C

D

E

F

FIGURE 24-41. Modiolar deficiency. Comparative axial (A-D) and coronal (E and F) CT bone windows of the temporal bones in a patient with right-sided modiolar deficiency. (A, C, and E) and the normal left cochlea for comparison (B, D, and F). Note the absence of the normally appearing sclerotic modiolus on the right (arrows) (C and E) in comparison with its normal counterpart on the left (arrowheads) (D and F).

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388

SECTION 2 ❖ Ear and Related Structures

A

C

B

D

E

G

F

H

FIGURE 24-42. Vestibular dysplasia (with SCC absence). Comparative axial (A and B) and coronal (C and D) CT bone windows as well as axial high-resolution T2WI MRI (E and F) with coronal reformations (G and H) demonstrate bilateral vestibular dysplasia (arrows) (A–D, E, G, and H) and SCC absence. There is only a vestigial superior SCC seen bilaterally (arrowheads) (F). Otherwise, the lateral and posterior SCC are absent.

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 389

A

B

FIGURE 24-43. Vestibular dysplasia (with dysplastic lateral SCC and cochlea) (IP-1). T2WI axial (A) and coronal (B) MRI images to the level of the labyrinths demonstrates a bulbous right vestibule (arrow) (A) and bulbous inlet to the right lateral SCC (B) (arrowhead). Note the normal appearance of the vestibule on the left (A) (V with arrow) and the normal appearing SCC (B) (SCC with arrowheads). Note also the incompletely partitioned cochlea on the right (curved arrow), in comparison with its normal counterpart on the left (asterisk) (A).

A

C

B

D

FIGURE 24-44. Vestibular dsysplasia (with sac-like vestibule and lateral SCC). Comparative axial (A and B) and coronal (C and D) CT bone windows in a patient with an enlarged dysplastic saclike vestibule (arrows) and lateral SCC (arrowheads) on the right (A and C) with the normal appearing vestibule (V with arrow) and lateral SCC (SCC with arrowheads) on the left (B and D).

Ch24.indd 389

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390

A

SECTION 2 ❖ Ear and Related Structures

B

FIGURE 24-45. Enlarged vestibular aqueducts (endolymphatic ducts) and endolymphatic sacs (EVA and big ELS). Axial CISS MRI images at the level of the endolymphatic sac (A) and vestibular aqueduct (B) demonstrate enlargement of both of these structures bilaterally (arrowheads delineating the ELS and arrows delineating the EVA).

A

B

FIGURE 24-46. Enlarged vestibular aqueducts and cochlear anomaly. Comparative axial (A and B) CT bone windows demonstrate a unilaterally enlarged vestibular aqueduct (A) on the right (arrow) compared to its normal counterpart (B) on the left (arrowhead). Note the dysplastic right cochlea (curved arrow) and its normal counterpart of the left (asterisk). This is a classic Mondini malformation, demonstrating 2 of the findings in the triad.

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 391

A

B

FIGURE 24-47. Mondini triad. Axial high-resolution T2WI at the level of the endolymphatic sac (A) and vestibular aqueduct (B) demonstrate enlargement of both of these structures bilaterally [arrowheads delineating the ELS (A) and arrows delineating the enlarged vestibular aqueducts (B)]. In addition, the vestibules are enlarged bilaterally (curved arrows), and there is incomplete partitioning of the cochlea bilaterally (asterisks) (B). This combination of findings is indicative of the Mondini triad.

B

A

C

FIGURE 24-48. Internal auditory canal (IAC) narrowed. Axial high-resolution T2WI (A) with coronal reformations of the right (B) and left (C) IAC demonstrate a markedly narrowed right IAC (arrows) (A and B), with its normal counterpart on the left (arrowheads) (A and C).

Ch24.indd 391

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392

SECTION 2 ❖ Ear and Related Structures

B

A

C

FIGURE 24-49. Cochlear nerve hypoplasia. Axial high-resolution T2WI (A) with sagittal reformations of the left (B) and right (C) IAC demonstrate a markedly hypoplastic left cochlear nerve (arrows) (A and B), with its normal counterpart on the right (arrowheads) (A and C).

A

B

C

D

FIGURE 24-50. Cochlear nerve aplasia. Comparative coronal (A and B) and sagittal (C and D) high-resolution T2WI of the right (A&C) and left (B&D) IAC demonstrate absence of the right cochlear nerve (arrows), with its normal-appearing counterpart on the left (arrowheads).

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 393

B

A

FIGURE 24-51. IAC and cochlear aperature narrowing. Axial high-resolution T2WI at the levels of the cochlear apertures (A) and IAC (B) demonstrate a markedly narrowed cochlear aperture (arrow) and IAC (arrowhead) on the right.

A

B

FIGURE 24-52. Patulous IAC in NF1. Axial (A) and coronal (B) T2WI in a patient with NF1 demonstrate patulous IAC bilaterally (arrows).

Ch24.indd 393

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394

SECTION 2 ❖ Ear and Related Structures

A

B

FIGURE 24-53. First branchial cleft cyst (BCC) type I. Axial (A) and coronal (B) T2WI in a patient with a type I first BCC demonstrate a small ovoid bright cystic mass within the region of the left external auditory canal (EAC) (arrows).

A

B

B

FIGURE 24-54. First branchial cleft cyst (BCC) type II. Axial (A), coronal (B), sagittal (C) HASTE images through the region of the right neck in a patient with type II first BCC demonstrate a tubular cystic structure (arrows) extending from the neck inferiorly (A) in a cephalad direction toward the level of the EAC (C).

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 395

B

A

C

D

FIGURE 24-55. Facial nerve (CN VII) dehiscence/prolapse. Comparative axial (A and B) and coronal (C and D) CT bone windows in a patient with CHARGE syndrome and right-sided (A and C) facial nerve prolapse/dehiscence (arrows). Note the normal appearing facial nerve canal on the left (arrowheads) (B and D).

A

B

FIGURE 24-56. Möbius syndrome (bilateral CN VII absence). Comparative sagittal CISS images of the right (A) and left (B) IAC in a patient with Möbius syndrome demonstrating bilateral absence of the facial nerve (arrows). There is no discernible rounded dot superior to the anteriorly located cochlear nerves (arrowheads), indicative of bilateral absence of CN VII.

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396

A

SECTION 2 ❖ Ear and Related Structures

B

C

FIGURE 24-57. Cytomegalovirus (CMV) infection. Noncontrast CT head images at the level of the lateral ventricles (A) and centrum semiovale (B) as well as T2WI (C) at the level of the lateral ventricles in a patient with a documented CMV infection, demonstrate multiple bilateral periventricular and deep white matter calcifications (arrows) secondary to in utero infection. Low attenuation within the white matter on CT (arrowheads) (A and B) corresponds to increased T2 signal within the white matter on MRI (arrowheads) (C) is in keeping with damaged white matter secondary to CMV infection.

FIGURE 24-58. Siderosis. Axial gradient echo/susceptibility image through the posterior fossa in a patient with siderosis demonstrates marked loss of signal/darkening in (India ink appearance) within the cisterns (arrows) in keeping with hemosiderin deposition secondary to prior hemorrhage.

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 397

A

B

C

D

E

F

G

H

FIGURE 24-59. Aberrant internal carotid artery (ICA). Comparative axial (A–D) and coronal (E–H) CT bone windows in a patient with an aberrant course of the right ICA (A, C, E, and G) in comparison with its normal counterpart on the left (B, D, F, and H) demonstrate an anomalous course of the right ICA with medial deviation into the region of the middle ear cavity (arrow) (A), abutting the cochlear promontory (arrows) (C, E, and G), and the approaching the level of the ossicles (arrowheads) (C, E, and G). Note the normally located ICA on the left (asterisks) (B, D, F, and H).

Ch24.indd 397

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398

SECTION 2 ❖ Ear and Related Structures

A

B

FIGURE 24-60. Dehiscent jugular bulb. Axial (A) and coronal (B) CT bone windows in a patient with dehiscence of the right jugular bulb demonstrates absence of the normal bony covering of the jugular bulb on the right (A and B) (arrows) in comparison with its normal counterpart on the left (arrowheads) (A and B).

D

C

B

A

E

F

FIGURE 24-61. Persistent stapedial artery. Comparative axial (A–D) and coronal (at the level of the anterior genu) (E and F) CT bone windows in a patient with a persistent stapedial artery demonstrate absence of the right foramen spinosum (arrow) (A) and widening of the ipsilateral facial nerve canal (arrowheads) (C and E), diagnostic of this entity. Note the normal appearing foramen spinosum (arrow) (B) and facial nerve canal (arrowheads) on the left (D and F).

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 399 ascends and travels between the crura of the stapes. Then, it courses anteriorly alongside the tympanic segment of the facial nerve within its bony canal, giving the appearance of a seemingly “thickened” nerve on CT imaging. Just posterior to the geniculate ganglion, it leaves the facial canal and then travels in the extradural space of the middle cranial fossa.25

Trauma Trauma to the ear is also best evaluated by CT. Fractures are generally easily identified by direct visualization of the fracture line and associated fluid within adjacent air cells. Fractures through the septations of the mastoid are easily appreciated. Longitudinal fractures (superoinferior) are more common and may involve the ossicles, whereas horizontal fractures are less common and may involve the inner ear structures.15 Ossicular disruption can be identified, but one must be meticulous in one’s assessment, always utilizing the opposite

A

C

normal side as an internal comparison (provided bilateral injuries are not present). Use of very high-resolution CT helps in the identification of subtle ossicular disruptions that may be difficult to detect. Depending on the mechanism of injury, the fracture may just involve the EAC (Fig. 24-62), the squamous temporal bone (Fig. 24-63), or the mastoid portion of the temporal bone (see Figs. 24-64 through 24-67). More severe injuries may involve the petrous temporal bone and may be either transverse (Fig. 24-64) involving the bony labyrinth with identification of pneumocochlea (Fig. 24-67) as well as air within the vestibule/SCCs, or longitudinal (Fig. 24-65) leading to disruption of the ossicular joints (Fig. 24-66). If the fracture traverses the facial canal at any point, traumatic facial paralysis may occur (Fig. 24-67). In rare instances, if the carotid canal is traversed by the fracture line, a dissection of the carotid artery may occur (Fig. 24-68).

B

D

FIGURE 24-62. EAC fracture. Comparative axial (A and B) and coronal (C and D) CT bone windows in a patient with a fracture through the right EAC (arrows) (A and C). Note the normal appearing left EAC (arrowheads) (B and D).

Ch24.indd 399

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400

SECTION 2 ❖ Ear and Related Structures

B

A

FIGURE 24-63. Squamous temporal bone fracture. Axial (A) and coronal (B) CT bone windows in a patient with a fracture through the right squamous temporal bone demonstrate a fracture line (arrows) associated with pneumocephalus/intracranial gas (arrowheads).

A

B

FIGURE 24-64. Horizontal fracture. Axial (A) and coronal (B) CT bone windows in a patient with a horizontal fracture through the right petrous temporal bone demonstrate a fracture line traversing the region of the anterior genu of the facial nerve canal (arrow) (A) and extending inferiorly toward the level of the vestibule (arrowheads) (B).

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 401

B

A

FIGURE 24-65. Longitudinal fracture. Axial (A) and coronal (B) CT bone windows in a patient with a longitudinal fracture through the right temporal bone demonstrate a fracture line (arrows) extending medially towards the level of the ossicles (A), best appreciated on the axial view, barely discernible on the coronal view (arrowhead), due to its relative parallel orientation to the axially acquired scan.

B

A

C

Ch24.indd 401

D

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402

SECTION 2 ❖ Ear and Related Structures

F

E

FIGURE 24-66. Ossicular distraction (traumatic). Comparative axial (A and B), coronal (C and D), and sagittal (E and F) CT bone windows in a patient with posttraumatic right-sided ossicular disruption demonstrate widening of the incudomalleolar joint on the right (arrows) (A, C, and E). Note the normal appearing comparison incudomalleolar joint on the left (arrowheads) (B, D, and F).

A

F

FIGURE 24-67. Pneumocochlea (traumatic). Axial (A) and coronal (B) CT bone windows in a patient with a horizontal petrous temporal fracture on the right (arrowheads) (A), traversing the region of the genu of CN VII. Note the pneumocochlea (arrows), indicative of fracture extension into the bony labyrinth, a type of injury usually only seen with high impact/violent trauma. Incidental note is made of fluid/soft tissue within the middle ear cavity, likely posttraumatic in nature (asterisks).

A

B

FIGURE 24-68. Carotid dissection (traumatic). Axial source (A) and coronal (MIP) (B) images from a 3D time-of-flight MRA of the neck/ head in a patient who sustained severe trauma the left neck region with resultant skull base fracture, demonstrates a filling defect (arrows) (A) within the left ICA in keeping with posttraumatic carotid dissection. Note the string like narrowing of the left ICA appreciated on the coronal MIP image (arrowheads).

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 403

MISCELLANEOUS Various bony dysplasias can be diagnosed and staged with CT, especially when utilizing bone algorithms. The characteristic density/attenuation of fibrous dysplasia (FD) (Fig. 24-69) is slightly less dense than that of normal cortical bone, with the so-called ground-glass appearance. Areas similar to soft tissue density can be seen within, depending on the degree of mineralization. Osteopetrosis is a marrow disease that leads to marked sclerosis of the bone, and hence the bone in this disease will appear very dense on CT. Involvement of the skull base can lead to foraminal enchroachment (Fig. 24-70). Similarly, CT can demonstrate the demineralized bone of otospongiosis against the denser remainder of the otic capsule (Fig. 24-71). Cochlear otospongiosis (otosclerosis) has a very characteristic appearance, with a lucency

surrounding the cochlear lumen. Although early changes can be missed, demineralization in the region of the fissula ante fenestrum (just anterior to the oval window) and sometimes narrowing of the oval window can be detected.24 Some forms of osteogenesis imperfecta may have a similar appearance to bilateral cochlear otospongiosis. Although not a bone dysplasia, Chiari II malformation leads to a recognizable deformity within the temporal bone region due to the inability of the small posterior fossa to fully accommodate the cerebellar and brainstem structures. Hence there is typical scalloping of the petrous apices, well delineated on CT of the head (Fig. 24-72). Cochlear implants are an important development in the treatment of patients with SNHL. These can be visualized on CT examination (Fig. 24-73) with some degree of streak artifact, not a limitation present with conventional temporal bone radiographs.

B

A

C

D

FIGURE 24-69. Fibrous dysplasia. Axial (A) and coronal (B) CT bone windows as well as axial (C) and coronal (D) T2WI of the left temporal bone region in a patient with fibrous dysplasia demonstrate a ground glass appearance (arrows) (A and B) of the involved bone on the CT images, where as the involved bone is only slightly brighter on T2WI MRI (arrowheads) (C and D) than that of the normal comparison bone on the right, making the diagnosis more difficult on the basis of MRI alone.

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404

SECTION 2 ❖ Ear and Related Structures

B

A

FIGURE 24-70. Osteopetrosis. Sagittal scout (A) and axial bone window (B) from CT of the head, at the level of the petrous temporal bones in a patient with osteopetrosis demonstrates marked sclerosis of the bony calvarium (arrows). Given the marked bony involvement, these patients are at risk of cranial nerve dysfunction due to foraminal stenosis at the skull base. Note the poorly visualized IAC bilaterally (arrowheads) (B).

A FIGURE 24-71. Otosclerosis. Single-axial CT bone window through the level of the left cochlea demonstrates lucency (indicated by the arrow) in this patient with known otosclerosis.

FIGURE 24-72. Petrous scalloping in Chiari II malformation. Single axial CT bone window through the level of posterior fossa in a patient with Chiari II malformation demonstrates bilateral petrous bone scalloping (arrows) due to long-standing pressure remodeling secondary to posterior fossa crowding known to occur with this malformation.

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 405

B

A

FIGURE 24-73. Cochlear implants (computed tomography [CT] scan). Sagittal scout (A) and axial bone window (B) from CT of the temporal bones, at the level of the petrous temporal bones in a patient with bilateral cochlear implants demonstrate the presence of metallic leads from the cochlear implant seen entering the mastoid bones bilaterally (arrows) as well as within the cochlea on the left (arrowheads).

SUMMARY The utility of plain films is now limited primarily to evaluation of cochlear prostheses. CT is now the study of choice for evaluation of trauma, congenital anomalies, acute and chronic inflammation, and tumor. (See Box 24-1 for definitions of the

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BOX 24-1

ABBREVIATIONS

ADC BCC CHL CISS CN CMV CN VI CN VII CN VIII CNS CP Angle CSF CT DWI EAC ELD ET ELS FFE FIESTA FLAIR

Apparent Diffusion Coefficient Branchial Cleft Cyst Conductive Hearing Loss Constructive interference in steady state Cranial Nerve Cytomegalovirus Abducens Nerve Facial Nerve Vestibulocochlear Nerve Central Nervous System Cerebello-pontine angle Cerebrospinal Fluid Computed Tomography Diffusion weighted imaging External Auditory Canal Endolymphatic Duct Eustachian Tube Endolymphatic Sac Balanced Fast Field Echo Fast Imaging Employing Steady State Acquisition Fluid Attenuated Inversion Recovery

labels used in Figs. 24-1 through 24-73.) However, if vascular compromise or intracranial extension of infection or tumor is suspected, MRI is extremely useful (as it also provides excellent evaluation of nerves). MRI continues to advance rapidly, and its use in examinations of the temporal bone will no doubt continue to increase in the years to come.

GE HASTE IAC LCH LO MDCT MRA MRI MRV MIP NF 1 NF 2 SCC SNHL T1 T2 TM TMJ TORCH VHL

Gradient Echo Half-Fourier Acquisition Single-Shot Turbo Spin-echo Internal Auditory Canal Langerhans Cell Histiocytosis Labyrinthitis ossificans Multidetector CT Magnetic Resonance Angiogram Magnetic Resonance Imaging Magnetic Resonance Venogram Maximum Intensity Projection Neurofibromatosis Type I Neurofibromatosis Type II Semicircular Canal Sensorineural Hearing Loss T1 weighted image T2 weighted image Tympanic Membrane Temporomandibular Joint Toxoplasmosis, Other, Rubella, CMV, Herpes Von-Hippel Lindau

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406

SECTION 2 ❖ Ear and Related Structures

APPENDIX I

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CHAPTER 24 ❖ Methods of Examination: Radiologic Aspects 407

APPENDIX II

APPENDIX III

References 1. Lemmerling MM, De Foer B, Verbist BM, VandeVyver V. Imaging of inflammatory and infectious diseases in the temporal bone. Neuroimaging Clin N Am. 2009;19:321–337. 2. Vazquez E, Castellote A, Piqueras J, et al. Imaging of Complications of Acute Mastoiditis in Children. Radiographics. 2003;23: 359–372. 3. Hurley MC, Heran MK. Imaging studies for head and neck infections. Infect Dis Clin North Am. 2007;21:305–353. 4. Maroldi R, Farina D, Palvarini L, et al. Computed tomography and magnetic resonance imaging of pathologic conditions of the middle ear. Eur J Radiol. 2001;40:78–93.

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5. Ludwig BJ, Foster BR, Saito N, Nadgir RN, Castro-Aragon I, Sakai O. Diagnostic imaging in nontraumatic pediatric head and neck emergencies. Radiographics. 2010;30:781–799. 6. Connor SE, Leung R, Natas S. Imaging of the petrous apex: a pictorial review. Br J Radiol. 2008;81:427–435. 7. Razek AA, Huang BY. Lesions of the petrous apex: classification and findings at CT and MR imaging. Radiographics. 2012;32:151–173. 8. Yoshida T, Ito K, Adachi N, Yamasoba T, Kondo K, Kaga K. Cholesteatoma of the petrous bone: the crucial role of diffusionweighted MRI. Eur Arch Otorhinolaryngol. 2005;262:440–441. 9. De Foer B, Vercruysse JP, Bernaerts A, et al. Detection of postoperative residual cholesteatoma with non-echo-planar

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10.

11.

12.

13.

14. 15. 16.

17.

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SECTION 2 ❖ Ear and Related Structures diffusion-weighted magnetic resonance imaging. Otol Neurotol. 2008;29:513–517. Barath K, Huber AM, Stampfli P, Varga Z, Kollias S. Neuroradiology of cholesteatomas. AJNR Am J Neuroradiol. 2011;32:221–229. Kopelovich JC, Germiller JA, Laury AM, Shah SS, Pollock AN. Early prediction of postmeningitic hearing loss in children using magnetic resonance imaging. Arch Otolaryngol Head Neck Surg. 2011;137:441–447. Isaacson B, Booth T, Kutz JW, Lee KH, Roland PS. Labyrinthitis ossificans: how accurate is MRI in predicting cochlear obstruction? Otolaryngol Head Neck Surg. 2009;140:692–696. Durve DV, Kanegaonkar RG, Albert D, Levitt G. Paediatric rhabdomyosarcoma of the ear and temporal bone. Clin Otolaryngol Allied Sci. 2004;29:32–37. Lakshmi M, Glastonbury CM. Imaging of the cerebellopontine angle. Neuroimaging Clin N Am. 2009;19:393–406. Davidson HC. Imaging of the temporal bone. Neuroimaging Clin N Am. 2004;14:721–760. Fernandez-Latorre F, Menor-Serrano F, Alonso-Charterina S, Arenas-Jimenez J. Langerhans’ cell histiocytosis of the temporal bone in pediatric patients: imaging and follow-up. AJR Am J Roentgenol. 2000;174:217–221. De Foer B, Kenis C, Vercruysse JP, et al. Imaging of temporal bone tumors. Neuroimaging Clin N Am. 2009;19:339–366.

18. Kosling S, Omenzetter M, Bartel-Friedrich S. Congenital malformations of the external and middle ear. Eur J Radiol. 2009;69:269–279. 19. Park KH, Park SN, Chang KH, Jung MK, Yeo SW. Congenital middle ear cholesteatoma in children; retrospective review of 35 cases. J Korean Med Sci. 2009;24:126–131. 20. Ozgen B, Oguz KK, Atas A, Sennaroglu L. Complete labyrinthine aplasia: clinical and radiologic findings with review of the literature. AJNR Am J Neuroradiol. 2009;30:774–780. 21. Tse KS, Chu KM, Chiu LF, Fan TW, Tsang TK. Congenital inner ear malformations. Hong Kong J Radiol. 2011;14: 118–125. 22. Sennaroglu L, Saatci I. A new classification for cochleovestibular malformations. Laryngoscope. 2002;112:2230–2241. 23. Boston M, Halsted M, Meinzen-Derr J, et al. The large vestibular aqueduct: a new definition based on audiologic and computed tomography correlation. Otolaryngol Head Neck Surg. 2007;136:972–977. 24. Vattoth S, Shah R, Cure JK. A compartment-based approach for the imaging evaluation of tinnitus. AJNR Am J Neuroradiol. 2010;31:211–218. 25. Yilmaz T, Bilgen C, Savas R, Alper H. Persistent stapedial artery: MR angiographic and CT findings. AJNR Am J Neuroradiol. 2003;24:1133–1135.

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25

C H A P T E R

Vestibular Evaluation Joseph M. Furman, Margaretha L. Casselbrant, and Susan L. Whitney

V

ertigo is defined in clinical practice as a subjective sensation of movement, such as spinning, turning, or whirling, of the patient or the surroundings. Dizziness is a nonspecific term used by patients to describe sensations of altered orientation to the environment that may or may not include vertigo. Although vertigo may be a symptom of a vestibular disorder in the pediatric population, patients react to and describe dizziness in different manners in relation to their age. For instance, young children cannot accurately relate symptoms of dizziness. Preschool children rarely complain of vertigo or dizziness but may feel clumsy or be perceived as such by family or teachers. Older children and adolescents are usually able to explain their symptoms well, with their explanations differing little from explanations of adults. In any case, a vestibular abnormality should be suspected in a child who is observed to be clumsy, displays unprovoked fright, or who spontaneously clings to a parent. Sudden and recurrent bouts of unexplained nausea and vomiting are also suggestive of a vestibular abnormality. Vertigo and dizziness are symptoms, not diagnoses. However, these symptoms may not indicate a vestibular loss, since balance is maintained through visual, proprioceptive, and vestibular signals. These three systems provide the information required for “good balance.” Damage to any of these systems or an abnormality in the central nervous system (CNS) that coordinates impulses from these three sensory systems can cause symptoms. In children as well as in adults, a careful history, physical examination, and laboratory testing can establish the cause of dizziness in most patients. In certain cases, parents are the sole source of information. It is important to allocate the time to fully investigate the medical history.

PHYSIOLOGIC BASIS OF BALANCE When a hair cell is stimulated by rotation, translation, or change in orientation with respect to gravity, the firing rate in the eighth nerve fiber innervating that particular hair cell either increases or decreases. Movements that cause the stereocilia to bend toward the kinocilium result in a depolarization of the hair cell and cause the eighth nerve fiber to increase its firing rate, whereas movements that bend the stereocilia away from the kinocilium decrease the neural firing in the eighth nerve. The eighth nerve synapses in the vestibular nuclei, which consist of superior, medial, lateral, and inferior divisions. In addition to the input from the labyrinth, the vestibular nuclei receive input from other sensory systems such as vision, somatic sensation, and audition. The sensory information is integrated and the

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output from the vestibular nuclei influence eye movements, truncal stability, and spatial orientation. (For an anatomic description of the labyrinth, see Chapter 20: Embryology and Developmental Anatomy of the Ear.) The vestibulo-ocular reflex is a mechanism by which a head movement automatically results in an eye movement that is equal and opposite to the head movement so that the visual axis of the eye stays on target, that is, a leftward head movement is associated with a rightward eye movement and vice versa. The vestibulo-ocular reflex is mediated by a three-neuron arc that includes, for the horizontal system, the eighth cranial nerve, an interneuron from the vestibular nucleus to the abducens nucleus, and the motor neuron to the eye muscle. Even when the head is at rest, there are action potentials creating a “resting discharge” in each neuron in the vestibular portion of the eighth nerve. This resting discharge is unique in that it allows the neurons to sense motion in both the excitatory and the inhibitory direction by increasing and decreasing their firing rate, respectively. Another feature of the vestibulo-ocular reflex is that the two vestibular nuclear complexes on each side of the brain stem cooperate with one another in such a way that, for the horizontal system, when one nucleus is excited, the other is inhibited. This reciprocal “push-pull” effect increases the sensitivity of the vestibulo-ocular reflex. The CNS responds to differences in neural activity between the two vestibular complexes. When there is no head movement, the neural activity, that is, the resting discharge, is symmetrical in the two vestibular nuclei. The brain detects no differences in neural activity and concludes that the head is not moving (Fig. 25-1A). When the head moves, for example, to the left, endolymph flow produces an excitatory response in the labyrinth on the side toward which the head moves, for example, on the left, and an inhibitory response on the opposite side, for example, on the right. Thus, neural activity in the vestibular nerve and nuclei, for example, on the left and right, increases and decreases, respectively (see Fig. 25-1B). The brain interprets this difference in neural activity between the two vestibular complexes as a head movement and generates appropriate vestibulo-ocular and postural responses. This reciprocal push-pull balance between the two labyrinths is disrupted following labyrinthine injury. An acute loss of peripheral vestibular function unilaterally, for example, on the right, causes a loss of resting neural discharge activity in that vestibular nerve and the ipsilateral nucleus (see Fig. 25-1C). As the brain responds to differences between the two labyrinths, this will be interpreted by the brain as a rapid head movement toward the healthy labyrinth, for example, toward the left. “Corrective” eye movements are produced toward the opposite side, resulting

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in nystagmus, with the slow component moving toward the abnormal side, for example, the right, and with the quick components of nystagmus moving toward the healthy labyrinth, for example, the left. Through compensatory mechanisms, the CNS restores the resting discharge activity within the deafferented vestibular nucleus, which reduces the asymmetry of neural activity within the bilateral vestibular nuclei and thus partially restores a functional vestibulo-ocular reflex (see Fig. 25-1D). Thus, during head movements with only one functional labyrinth, although neural activity within only one vestibular nerve is modulated both up and down, this activity causes both increases and decreases in vestibular nuclei activity (see Fig. 25-1E and F). A unilateral loss of vestibular function thus results in a reduction of

sensitivity to vestibular stimuli (i.e., a reduced “gain” of the vestibulo- ocular reflex) and an asymmetric response.

OFFICE EVALUATION OF PATIENTS WITH DIZZINESS At the initial visit, in addition to the chief complaint, a complete medical history that includes associated symptoms, past medical history, family history, and medication use is mandatory. A questionnaire sent to the patient before the initial assessment can be useful because it helps the patient or the parents to think about the child’s dizziness before the assessment. The responses should be reviewed with the patient/ parent at the initial visit.

FIGURE 25-1. Schematic illustrations of the “push-pull” effect of the vestibular-ocular reflex: (A). no head movement in healthy subject; (B). head movement to the left in healthy subject; (C). right acute peripheral vestibular injury; (D). chronic right peripheral vestibular injury; (E). chronic right peripheral vestibular injury during head movement to the left; and (F). chronic right peripheral vestibular injury during head movement to the right (for details see text). (From Furman and Cass [1994].)

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CHAPTER 25 ❖ Vestibular Evaluation After the interview, a complete physical examination should be performed, including pneumatic otoscopy and, if possible, otomicroscopy; a neurologic examination, with particular emphasis on the cranial nerves; and an examination of the eyes for spontaneous nystagmus with and without fixation and positional testing by using Frenzel goggles (Fig. 25-2) or video infrared goggles.

Neurologic Symptoms

HISTORY

Past Medical History

Chief Complaint. It is important that the child explain the symptoms in his or her own vocabulary and describe associated sensations such as headache, nausea, vomiting, or motion sickness. It might be helpful to relate the patient’s symptoms to experiences such as being on a merry-go-round. It is important to establish the onset, duration, and frequency of dizziness episodes and to associate the episodes with certain activities.

In establishing past medical history, the clinician should acquire information regarding pregnancy and delivery, for example, history of birth trauma, anoxia at delivery, presence of infectious diseases, for example, measles, mumps, or syphilis, and presence of CNS infections, including meningitis. Is there a history of administration of ototoxic medications in the neonatal period? Has the patient had diabetes, hypothyroidism or other endocrine or renal disease, eye disorders, epilepsy, noise exposure, or relevant previous surgeries?

Otologic Symptoms To determine otologic symptoms, the clinician should inquire about the presence of hearing loss (sensorineural or conductive), its onset, evolution or progression, fluctuation and worsening, and improving or stable status. Does the patient have tinnitus or a feeling of fullness? Is the hearing loss bilateral or unilateral? Does the child have a history of otitis media? Is otorrhea present? Is the patient complaining of otalgia? Previous audiograms, if available, should be reviewed.

FIGURE 25-2. Frenzel glasses with magnifying lenses and builtin illumination to facilitate observation of the eye movement.

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To establish the presence of neurologic symptoms, the clinician should determine whether there have been instances of convulsions, altered mental status, weakness, numbness, disturbances of swallowing or taste, coughing, facial paralysis, or blurring and loss of vision.

Family History In establishing the family history, the clinician should inquire in particular whether there is a family history of migraine, epilepsy, hearing loss or deafness, endocrine or renal disease, or neurofibromatosis.

PHYSICAL EXAMINATION The physical examination of children requires time and patience. Gaining the child’s confidence before starting the examination may help a great deal to get the most from a physical examination. This can be accomplished by explaining, in words the child can understand, what is going to be done and how it is going to be done, sometimes by offering a book, a toy, or even a reward to the child. General physical examination should include obtaining the patient’s blood pressure with the patient sitting, standing, and lying down. Ear examination should include pneumatic otoscopy or the use of an operating microscope. The nose, throat, and neck should also be evaluated as part of a complete physical examination. As vertigo in childhood can be a symptom of a neurologic abnormality, a complete neurologic evaluation with special attention to examination of the cranial nerves is appropriate. The optic nerve is tested by standard acuity, and both eyes are tested separately. The clinician checks for visual field defects and visualizes the fundi. The oculomotor, trochlear, and abducens nerves are tested by examining the pupils and extraocular motility. The trigeminal nerve is checked by testing sensations in the three peripheral divisions by stimulation of the forehead, cheek, and mental regions. The corneal reflex should be tested as well. Mastication function is examined by asking the patient to bite and observing the action of the temporalis and masseter muscles. The facial nerve is assessed by observing voluntary motion in all areas of the face and

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by the evaluation of facial symmetry. The auditory nerve is tested by use of tuning forks. The glossopharyngeal nerve is tested by assessing sensation in the posterior third of the tongue and tonsillar pillars. The vagus nerve can be evaluated by assessing the gag reflex. The spinal accessory nerve is assessed by elevation of the shoulders and rotation of the head. The hypoglossal nerve is tested by asking the patient to protrude the tongue. The child should also be observed when walking or running for incoordination of movements, that is, ataxia. Dysmetria may be demonstrated by the finger-to-nose and heel-to-shin tests. Additional abnormalities associated with cerebellar lesions can be assessed by evaluating the patient for dysdiadochokinesia, hypotonia, and decreased deep tendon reflexes.

EVALUATION OF NYSTAGMUS The eye movement examination can best be performed in the office through observation and by use of Frenzel goggles to look for the presence or absence of spontaneous nystagmus (see Fig. 25-2). Frenzel goggles are +20 lenses with internal illumination shining into the eyes. The advantages of Frenzel goggles are that they reduce visual fixation and magnify the size of the eye. An alternative to Frenzel goggles is the infrared video system.

Spontaneous and Gaze-Evoked Nystagmus Spontaneous nystagmus is an involuntary, rhythmic movement of the eyes not induced by any external stimulation. Spontaneous nystagmus has two components: slow and fast (Fig. 25-3). Nystagmus is named by the fast component, which is easily identified. Spontaneous nystagmus is tested by having the patient look straight ahead with and without fixation. Gaze-evoked nystagmus is assessed by having the patient deviate the eyes laterally (no greater than 30 degrees)

with fixation. Nystagmus observed at the extreme limits of gaze, that is, greater than 30 degrees, is usually physiologic. Spontaneous nystagmus in the light, that is, with fixation, can be classified in terms of severity by the “degree” of nystagmus. First-degree vestibular nystagmus is present only when the eyes are looking toward the fast component. This is the weakest intensity of spontaneous nystagmus. Second-degree nystagmus is present when the eyes are looking straight ahead and on looking toward the fast component (Fig. 25-4). In third-degree nystagmus, the nystagmus is present when the eyes are looking away from the fast component and is therefore seen in all eye positions. This represents the strongest degree of spontaneous nystagmus.

Positional Nystagmus Positional testing is performed with the use of maneuvers that may produce nystagmus or vertigo. Static positional nystagmus is assessed by placing the patient in each of the following six positions: sitting, supine, supine with the head turned to the right, supine with the head turned to the left, and right and left lateral positions. Frenzel goggles should be used in conducting the test. Persistent positional nystagmus presents as soon as the patient assumes the position and persists for as long as the patient remains in the provocative position. Paroxysmal positional nystagmus, however, has a brief latency, fatigues on repeat provocations, is usually associated with vertigo, and is evaluated by the Dix–Hallpike maneuver. To perform the Dix–Hallpike maneuver, the patient is moved rapidly from the sitting position to a right or a left head-hanging position. Perilymph Fistula Test Perilymph fistula testing can be performed by pressing the tragus and thereby creating a positive pressure in the external auditory canal or by applying positive and negative pressure in the external ear canal with use of a politzer bag or a tympanometer

FIGURE 25-3. Schematic diagram illustrating slow and fast components of nystagmus. (Adapted from Jacobson et al. [1993].)

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413

FIGURE 25-4. A spontaneous nystagmus toward the right is increased by gaze toward the right and nearly abolished by gaze toward the left (second-degree nystagmus). (From Henriksson et al. [1972].)

while observing the patient’s eyes behind Frenzel goggles. The fistula test response is positive if nystagmus and a sensation of dizziness are generated (see Chapters 21 and 24). Motor Function Test A child’s motor performance changes with age and, as a result, no one motor performance tool is the gold standard across all developmental ages. Several reliable, valid tools are used to assess “balance” performance in children. The motor performance measures discussed herein include the Peabody Developmental Motor Scale (PDMS),1 the Bruiniks-Oseretsky Test of Motor Proficiency (BOTMP),2 the Pediatric Clinical Test of Sensory Interaction for Balance (P-CTSIB), and the Sensory Organization Test of computerized dynamic posturography.

The BOTMP has more difficult balance items than the PDMS. The BOTMP balance subsection includes single leg stance on a solid surface, standing on a beam, standing on a beam with eyes closed, walking forward on a line, balance beam walking, tandem walking on a solid surface and on a beam, and stepping over a stick while on a balance beam. The complete battery also includes running speed, eight items of bilateral

The Peabody develoPmenTal moTor Scale The PDMS was developed to screen, evaluate, and determine program planning for children and to identify gross and fine motor skills that are delayed or abnormal. The PDMS assesses developmental changes in children. Researchers have demonstrated the tool’s construct, predictive, and concurrent validity; furthermore, it appears to be responsive to change over time. A component of the PDMS (the gross motor scale) is commonly used to assess motor performance. The gross motor scale includes assessment of reflexes, balance, nonlocomotor skills, locomotion, and the ability to grasp and move objects in the test environment. Raw scores, percentile scores, z-scores, and a developmental quotient can be obtained for each section and from the total gross motor battery. The tool was developed for use with children aged from birth to 7 years. The gross motor battery of the PDMS provides extensive information about the child’s motor performance (Fig. 25-5), but it is time and energy intensive and requires a large, quiet space, and equipment that is not typically found in an otolaryngology office. The bruininkS-oSereTSky TeST of moTor Proficiency The BOTMP was developed for use in children from 4½ to 14½ years of age. It includes both gross and fine motor components.

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FIGURE 25-5. A 4-year-old child attempts to skip as part of the Peabody Developmental Motor Scale.

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coordination, and strength. A standard score, percentile rank, and stanine are computed for the gross motor composite, fine motor composite, and the entire battery. The BOTMP is generally the tool used after children become able to complete the PDMS gross motor items. The BOTMP takes much less time and equipment than the PDMS; it also takes considerably less space. The PediaTric clinical TeST of SenSory inTegraTion and balance The P-CTSIB was developed as a modification of Shumay-Cook and Horak’s balance test for adults.3 It has been shown to have fair to good reliability in children. Children stand on medium-density foam (Fig. 25-6A) or with a visual conflict dome (see Fig. 25-6B) for 30 seconds. Body sway under six sensory conditions is determined with the malleoli touching and in tandem stance (heels and toes touching). The six sensory conditions are listed in Table 25-1. The P-CTSIB is an inexpensive method to replicate dynamic posturography in a clinical setting. The SenSory organizaTion TeST of comPuTerized dynamic PoSTurograPhy Computerized dynamic posturography has been used with young children to assess change over time and has been shown to be reliable.4,5 Rine et al. (1998) suggested that the test could be used on children who are at least 3 years of age.6 The test is similar to the P-CTSIB but provides objective data related to vestibulospinal function. The test may need to be adapted in order for the children to maintain attention, such as placing stickers in order to maintain their attention.

TABLE 25-1. Types of Sensory Inputs during the Six

Testing Conditions Using the Clinical Test of Sensory Interaction for Balance

Testing Conditions

Sensory Inputs Vision

Somatosensory

Vestibular

1. Eyes open, hard floor

+

+

+

2. Eyes closed, hard floor

−

+

+

3. Conflict dome, − hard floor

+

+

4. Eyes open, Foam floor

+

−

+

5. Eyes closed, foam floor

−

−

+

6. Conflict dome, − foam floor

−

+

(+) sensory input present

(−) sensory input Absent/distorted

AUDIOLOGIC EVALUATION Behavioral Audiometry Behavioral testing that is appropriate for the patient’s age is performed to assess whether there is a concomitant hearing loss and to help define the side of the lesion. The audiologic evaluation should also include, if possible, speech reception threshold and word recognition score, acoustic reflex, and tone decay. A tuning fork (512 Hz) should be used to confirm the audiometric findings. Masking is mandatory, specifically when there is a difference of hearing sensitivity between ears. The Bárány box is a useful tool for implementing office masking, or a piece of paper can be rubbed in the ear not tested. Tympanometry is performed to assess middle-ear status. (For detailed description, see Chapter 23: Assessment of Hearing and Middle Ear Function.)

Auditory Brain Stem Response Audiometry

FIGURE 25-6. (A). A child standing on the medium-density foam with her eyes open (condition 4) and standing on the foam with the visual conflict dome (condition 5) (B). Both conditions are part of the Pediatric Clinical Test of Sensory Organization and Balance.

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In cases of unilateral hearing loss and asymmetric hearing loss, the auditory brain stem response is extremely useful in the diagnostic evaluation process to determine the site of the lesion. The procedure is noninvasive and excellent for testing in small children and children who cannot cooperate on behavioral testing. Auditory brain stem testing may require sedation for small children. Clicks are delivered through earphones and are monitored by signal averaging while the patient is relaxed or asleep. The waveform and latency are studied, and the waves are compared in both ears as well as with those of normal subjects. The latencies are the most sensitive indicator of disease. Tumors can result in increased latencies and prolonged waves I to V. (For detailed description, see Chapter 23: Assessment of Hearing and Middle Ear Function.)

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CHAPTER 25 ❖ Vestibular Evaluation

ADDITIONAL TESTING After the initial office visit, with the completion of the medical history and the physical examination, the physician will have a basic understanding of the problem, classifying the disorder tentatively as nonvestibular, peripheral vestibular, or central vestibular disease. The physician determines whether further work-up is necessary to document and confirm the initial impression. Further tests may include vestibular testing, laboratory testing, and imaging. Vestibular laboratory testing is recommended in any child with a history of dizziness in whom a thorough history and physical examination has not established a diagnosis, to differentiate between a peripheral or central vestibular lesion, and to identify side of lesion in a peripheral abnormality. Because children with severe sensorineural hearing loss may have vestibular abnormalities, vestibular laboratory testing is recommended.7 This is especially important in infants and young children with delayed motor development.8 Laboratory testing is indicated when a nonvestibular condition such as metabolic abnormalities or blood dyscrasia is suspected of causing the “dizziness.” Laboratory tests include complete blood count, serum glucose, thyroid function, triglyceride, and cholesterol determinations; fluorescent treponemal antibody absorption test; erythrocyte sedimentation rate; and rheumatoid factor, antinuclear antibody, and autoimmune studies when appropriate. Imaging studies include computed tomography with or without contrast enhancement for the evaluation of bony structures of the temporal bone and middle ear. Computed tomography is performed to rule out any congenital malformations or bony abnormalities caused by infectious processes or a cholesteatoma eroding the bone or a temporal bone fracture. Magnetic resonance imaging with gadolinium injection is the most important test for ruling out a CNS lesion, cerebellopontine angle mass, posterior fossa disease, and craniovertebral abnormalities. (For detailed reading, see Chapter 12: Pediatric Neurology.)

Vestibular Laboratory Evaluation Vestibular laboratory testing may be helpful in distinguishing a peripheral vestibular abnormality from a central vestibular abnormality. Also, vestibular laboratory testing may identify the side of lesion in a peripheral vestibular abnormality. In addition, it provides permanent documentation, and changes can be followed up by repeat testing. Vestibular laboratory testing includes vestibulo-ocular and vestibulospinal tests. Both types of tests provide only an indirect measure of the function of the vestibular end organs, in that they rely on measures of motor response, that is, eye movements or postural sway, resulting from vestibular sensory input.

Videonystagmography Videonystagmography (VNG) is the laboratory diagnostic tool most commonly used to study patients with complaints

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of dizziness, vertigo, or imbalance. Eye movements are recorded with infrared video goggles. VNG includes ocular motor testing, positional testing, and caloric testing and provides a permanent record of any spontaneous nystagmus or induced nystagmus (positional or caloric) with objective measurement of the response. Comfortable darkened or seethrough goggles with an infrared camera are used. The evaluation requires approximately one hour. Patients should not be allowed to take sedatives or vestibular suppressant medications that can alter the test results for two days before testing. Children and adolescents can tolerate the testing but patience, understanding, and cooperation between technician and child are the key to success. Ocular Motor Testing Ocular motor testing consists of several tests and is designed to evaluate the ocular motor system, that is, neural motor output independent of the vestibular system (Fig. 25-7). Abnormalities in the ocular motor system may affect the vestibulo-ocular reflex and misleading conclusions can be drawn. Saccade testing, which includes calibration of the equipment, is performed by having the patient look alternatively at two targets separated by 20 degrees. By convention, upward displacement of the pen indicates eye movement to the right, and downward movement represents eye movement to the left. More extensive testing of the integrity of the saccade system uses a computer-controlled sequence of target jumps. Saccade abnormalities are defined as overshooting the target (hypermetric saccades) and undershooting the target (hypometric saccades). Disorders in the saccadic system suggest a CNS abnormality. A search for nystagmus, including spontaneous nystagmus and gaze-evoked nystagmus, is recorded with fixation and without fixation (closing the eyes or darkness) (Fig. 25-8) and by asking the patient to look 30 degrees to the right and left (see Fig. 25-4). Spontaneous nystagmus that is present in darkness without fixation and decreases or resolves with fixation suggests a peripheral vestibular disorder. However, spontaneous nystagmus that is present with fixation and does not significantly decrease with loss of fixation is most likely a CNS abnormality. Sinusoidal pursuit tracking involves asking the patient to follow a moving target back and forth along a slow pendular path. Normal subjects can follow a target smoothly without interruption. Abnormalities of pursuit tracking are caused by lesions in the CNS. Optokinetic nystagmus is induced by a visual pattern (usually black and white vertical stripes) moving across the visual field. The test is performed at different speeds with the stripes moving in the clockwise and counter-clockwise directions. In children, the projection of animals or friendly figures may help them perform the same task successfully. Abnormalities include asymmetries or absence of responses. Abnormalities of the optokinetic system suggest a CNS abnormality.

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FIGURE 25-7. Examples of normal responses and abnormalities of the saccadic eye movement system, the pursuit system, and optokinetic nystagmus. (From Baloh [1984].)

Positional Testing Positional testing includes both static and paroxysmal testing. Static positional testing includes sitting, supine, head left, head right, left lateral, and right lateral positions. Static positional nystagmus, contrary to paroxysmal nystagmus, presents as soon as the patient assumes the provocative position and persists for as long as the patient stays in that position. When static positional nystagmus is observed, it is important to assess the effect of visual fixation. Failure to suppress static positional nystagmus with visual fixation is suggestive of a CNS lesion. Static positional nystagmus is otherwise a nonspecific, nonlocalizing sign. Paroxysmal positional testing includes moving rapidly from a sitting position to head-hanging right and head-hanging left positions (Dix–Hallpike maneuver). During paroxysmal positional testing, the patient looks straight ahead with the eyes open behind darkened goggles while eye movements are recorded with video-ENG. Paroxysmal positional nystagmus is associated with vertigo, has a brief latency of 5–10 seconds, fatigues on repeat provocations, and is suggestive of a peripheral lesion. Caloric Testing Caloric testing is the mainstay of vestibular laboratory testing and produces nystagmus by thermal stimulation of the

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vestibular system. The advantage of caloric stimulation is that each labyrinth can be tested separately. Furthermore, it can also be performed in infants and young children. The patient is placed in a position so that the horizontal semicircular canals lie in the vertical plane (head elevated 30 degrees).

FIGURE 25-8. Recording of spontaneous nystagmus. Note that during eyes open (with fixation) the patient had almost no nystagmus, but during eyes open in the dark (without fixation) a latent vestibular nystagmus became manifest. Upward deflections denote rightward movement. (From Furman and Cass [1994].)

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CHAPTER 25 ❖ Vestibular Evaluation Caloric stimulation is thought to be based on a convection current in the horizontal semicircular canal induced by a thermal stimulus colder or warmer than body temperature in the external auditory canal. The gradient of temperature produces a change in the specific gravity of the endolymph in the horizontal semicircular canal, which causes a cupular deflection and a change in activity of the vestibular nerve. Cold irrigation produces a utriculofugal deflection (fast nystagmus component away from the ear); warm irrigation produces a utriculopedal displacement (fast nystagmus component toward the ear) (Fig. 25-9). There are several methods of producing a caloric stimulation. Most caloric tests use direct water stimulation. This technique requires an intact eardrum and a patent and unblocked external auditory canal. In cases of eardrum perforation or tympanostomy tubes, air caloric or closed-loop water irrigation can be used to avoid contamination of the middle ear by water. Binaural bithermal caloric testing uses stimuli of 30°C and 44°C, and each canal is irrigated for 30 seconds with 250 mL water. There is a rest period of five minutes between each irrigation. If there is no response to cold and warm irrigation, ice water irrigation should be performed. In children with bilateral vestibular loss, caloric responses are reduced or absent in both ears. However, caloric responses can be reduced or even absent with normal rotational responses in the same patient. This can be explained by the fact that caloric stimulation is nonphysiologic, whereas rotational stimulation is the natural stimulus to the labyrinth. There are several different methods to measure the caloric response. These include peak slow-component velocity,

FIGURE 25-9. Mechanism of caloric stimulation of the horizontal semicircular canal (see text for details). (From Baloh and Honrubia [1990].)

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nystagmus duration, and nystagmus frequency. The most common parameter used is the peak slow-component velocity, whose magnitude reflects the intensity of the vestibular response. Many vestibular laboratories have computerized systems that incorporate software to determine slow-component velocity and calculate vestibular paresis or hypofunction and directional preponderance. To compare the responsiveness of one ear to the other ear, it is an established practice to use Jongkees’ formula to compute a percent of “reduced vestibular response” (Eq. 25-1):

Jongkees’ Formula Reduced vestibular response formula: (R30° + R44°) − (L30° + L44°) (R30° + R44° + L30° + L44°)

× 100%

Directional preponderance formula: (R30° + L44°) − (R44° + L30°) (R30° + R44° + L30° + L44°)

× 100

R = right L = left In many laboratories, normal limits are considered a reduced vestibular response of more than 24%. A reduced vestibular response, that is, a vestibular paresis, suggests a peripheral vestibular lesion. Directional preponderance, that is, more nystagmus beating in one direction than the other, is a nonlocalizing sign that is either central or peripheral. Rotational Testing Rotational stimulation, the natural stimulus to the semi circular canals, can create a nystagmic response. Bárány9 described the use of a manual rotary chair to produce an observable nystagmus after cessation of rotation. This technique has been improved by use of computers and sophisticated hardware. Rotational testing has advantages and disadvantages. Advantages are as follows: (1) the rotation test causes less nausea than caloric stimulation, (2) the rotational stimulus is physiologic, (3) precise patterns of acceleration can be delivered, and (4) infants and young children can be tested because the child can sit on the parent’s lap during testing. The main disadvantage is that rotation stimulates both labyrinths at the same time, and thus, it is impossible to identify the vestibular function of each labyrinth separately. Thus, the caloric response and the rotation test are complementary. The rotation of the chair is produced by torque motors to control the stimulus precisely. Many different trajectories of rotation can be used for rotational testing. The most common trajectories are sinusoidal harmonic acceleration. Usually, rotation is in the horizontal plane, that is, the chair is rotated about an earth vertical axis. For the semicircular canals to be brought into the horizontal plane to be maximally stimulated by the angular acceleration, the patient’s head is tilted about

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SECTION 2 ❖ Ear and Related Structures phase is obtained from sinusoidal rotation, the time constant, a similar measure, is obtained from constant velocity rotation and describes how rapidly the vestibular nystagmus decays after an abrupt stop of the rotational chair. This is also a sensitive measure, but it is nonspecific. Asymmetry of the response, that is, directional preponderance, is derived by computing the difference between the velocity of the eye movement to right and left. The significance of asymmetry is similar to that of directional preponderance in the caloric evaluation, mainly a nonspecific sign. Changes seen in gain, phase, and asymmetry do not indicate the site or the side of the lesion. However, rotational testing measures change in response to vestibular disease and can be used to monitor the patient’s progress. Rotational testing, like many other tests in the vestibular laboratory, is helpful if it is used in relation to the results of the entire neuro-otologic assessment rather than as an isolated test.

DYNAMIC PLATFORM POSTUROGRAPHY

FIGURE 25-10. Rotational testing. The chair is rotating back and forth with the head tilted forward slightly; the testing is performed in darkness to avoid visual fixation.

15–20 degrees forward (Fig. 25-10). Testing is performed in darkness to eliminate visual fixation. Video ENG recordings are made of the eye movements induced by the rotation. The slow-component eye velocity is compared with chair velocity. Three parameters are derived from rotational testing: gain, phase, and symmetry. Gain is a measure of the magnitude of the response (eye velocity) in relation to the stimulus (rotational chair velocity). Reduced gain indicates decreased vestibular sensitivity. Unilateral vestibular loss may not reduce gain less than normal. Thus, reduced gain usually indicates bilateral vestibular loss. Phase describes the timing relationship between the stimulus (rotational chair velocity) and the response (eye velocity). If the eye movement is perfectly compensatory for the head movement, then the eye movement is 180 degrees out of phase with the head movement. This, by convention, is a zero phase lead. Perfectly compensatory eye movement (zero phase lead) usually occurs at higher frequencies (i.e., greater than 0.1 Hz). Large phase leads are present at low frequency (i.e., less than 0.05 Hz). Phase is a highly sensitive but nonspecific measure of vestibular system abnormalities. Phase changes with peripheral vestibular injury, and the changes are permanent. Although

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As mentioned earlier, balance and posture are maintained by three sensory inputs: visual, proprioceptive, and vestibular. Platform posturography can be used to assess a patient’s reliance on these sensory inputs as well as the motor responses generated to maintain proper equilibrium when the floor is moved. Computerized dynamic posturography is marketed commercially under the trade name EquiTest by NeuroCom International, Inc. (Fig. 25-11). Both the platform and the background move while the anteroposterior sway of the patient standing on the platform is monitored. Six different sensory conditions are used to test the patient’s ability to use combinations of sensory inputs (Fig. 25-12). The six EquiTest conditions are comparable to the six sensory conditions described in Table 25-1. The testing software supplied by NeuroCom allows two broad categories of tests: (1) recording of responses to small, brief movements of the support surface, either translations or rotations, and (2) recording of postural sway during various combinations of sensory inputs. These two types of tests have been called the motor control tests (formerly the movement coordination tests) and sensory organization tests. The motor control tests use a total of nine forward and nine backward translations of three different magnitudes. Also, five sequential platform rotations are delivered in the toes-up and then the toes-down direction. The forces generated during these maneuvers are analyzed by computer. The patient’s responses are compared with responses from an age-appropriate group of normal subjects. The sensory organization test uses six sensory conditions described earlier. For the two conditions wherein the visual surround is moving (conditions 3 and 6) and for the three conditions wherein the platform is moving (conditions 4–6), the movement of the visual surround or the platform is coupled to the sway of the patient in an attempt to “stabilize” the visual surround or platform rotations, thereby providing a nearly null or, at best, a distorted input from that sensation, that is, vision or somatosensation, respectively.

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CHAPTER 25 ❖ Vestibular Evaluation

FIGURE 25-11. EquiTest system (NeuroCom International, Inc.) shows the child standing on the platform surrounded by a visual scene. A safety harness is attached to the child should loss of balance occur. The platform surface and visual surround are capable of moving independently or simultaneously. Pressure-sensing strain gauges beneath the platform surface detect the patient’s sway by measuring vertical and horizontal forces applied to the surface.

The sensory organization test is the portion of computerized dynamic posturography most useful in the assessment of patients with suspected vestibular disorders. By providing reduced or distorted sensory information from the visual system and somatosensory system, the sensory organization test forces patients to rely on their vestibular sensations to maintain upright balance. In this manner, conditions 5 and 6 assess how patients use vestibular information when it is the only available input providing reliable information.

POSTUROGRAPHY AND VESTIBULAR DISORDERS—RESULTS FROM THE MEDICAL LITERATURE Several authors have studied large populations of patients suspected of having vestibular disorders and noted, as would be expected from the design of the sensory organization test,

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that patients with ongoing vestibular disorders have abnormal postural sway during conditions 5 and 6. Various other patterns aside from the “5,6” pattern also have been discussed in the literature and are shown in Figure 25-13. Figure 25-13A illustrates the typical 5,6 pattern seen in patients with acute vestibular imbalance. Another pattern, the “4,5,6” pattern (see Fig. 25-13B), has been labeled surfacedependent or combined visual-vestibular deficit. Patients with the 4,5,6 pattern are unable to stand when somatosensation is distorted despite having the opportunity for normal visual and vestibular inputs. Another pattern that has been described is that of a “severe” abnormality of postural sway (see Fig. 25-13C), wherein patients have great difficulty maintaining balance in all the conditions. Figure 25-13D illustrates a nonspecific pattern. Another pattern that has been described is that of an aphysiologic response, wherein patients appear to do better on paradigms that logically should be more difficult.10 “Compensation” begins when patients are able to make use of information from a single labyrinth as adequate vestibular input to the ocular motor, spinal motor, and perceptual systems. The process of compensation depends on a patient’s age, neurologic status generally, and his or her level of physical activity, specifically, activities that include combined visual, vestibular, and somatosensory inputs. Several studies have suggested that after successful compensation, posturography test results normalize and that patients lose their 5,6 pattern and may, in fact, have normal postural sway.11 Fetter et al.12 observed the time course of recovery after unilateral peripheral vestibular injury with posturography. Some of their data suggest that 2–3 weeks after the loss of unilateral peripheral vestibular function, most patients lose their 5,6 pattern. Thus, posturography, it has been suggested, can provide valuable information regarding the status of compensation for a peripheral vestibular deficit.

VESTIBULAR EVOKED MYOGENIC POTENTIALS Vestibular evoked myogenic potentials (VEMPs) refer to electrical activity recorded from neck muscles (cVEMPs) or eye muscles (oVEMPs) in response to intense air conducted or bone conducted auditory clicks.13,14 cVEMPs reflect stimulation of the sacculus unilaterally and thus provide information about the integrity of the sacculus and the inferior vestibular nerve. There are no other tests available that are known to assess either the sacculus or the inferior vestibular nerve in isolation. A limitation of cVEMPs is the technical challenge of obtaining an electromyographic recording from a preactivated muscle that has the appropriate amount of background activity. Another limitation of VEMPs is that they rely on normal middle-ear function when performed using air-conducted stimuli. cVEMPs have been performed successfully in children.15–17 Children as young as 3 years can tolerate testing.15 Normative data for children may differ from that of the adult population.17 cVEMP magnitudes

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FIGURE 25-12. The six sensory testing conditions of the EquiTest posturography platform. (From NeuroCom International, Inc., Clackman, OR.)

FIGURE 25-13. Patterns of abnormality on computerized dynamic platform posturography. Results shown were obtained by using the EquiTest system. The six sensory conditions refer to those shown in Table 25-2. The ordinate refers to peak-to-peak sway amplitude with 100 = 12 degrees of sway and 0 = a fall. (A). Vestibular pattern. Note that the patient swayed excessively or fell on conditions 5 and 6. (B). Surface-dependent pattern. This pattern is also known as a combined visual-vestibular pattern. Note that the patient fell on conditions 4–6, all of which are characterized by inaccurate somatosensory information because of a sway-referenced support surface. (C). Severe pattern. Note the excessive sway on all conditions with a low composite score. (D). Nonspecific pattern. Because sway on condition 6 was within normal limits while all other conditions were associated with excessive sway, this patient should be suspected of having produced an aphysiologic result, possibly on the basis of poor cooperation. (From Furman [1995].)

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CHAPTER 25 ❖ Vestibular Evaluation have been found to be elevated and the thresholds reduced in semicircular canal dehiscence syndrome. However, elevated amplitudes of VEMPs can be seen in some normal children and should be interpreted with caution.16

SUMMARY The most important part of the evaluation of the patient with vertigo and dizziness is obtaining a good medical history and a complete physical and neuro-otologic examination. Gaining maximal cooperation from each child should be attempted. Once all the information is available, the findings are analyzed by placing every result in perspective. Additional work-up required to confirm the diagnosis is then planned.

Selected References Baloh RW. The Essentials of Neurotology. Philadelphia, PA: FA Davis; 1984. Baloh JM, Halmagyi GM. Disorders of the Vestibular System. New York, NY: Oxford University Press; 1996. Baloh RW, Honrubia V. Clinical Neurophysiology of the Vestibular System. 2nd ed. Philadelphia, PA: FA Davis; 1990. Barber HO, Stockwell CW. Manual of Electronystagmography. 2nd ed. St Louis, MO: CV Mosby; 1980. Fuhrman JM. The role of posturography in the management of vestibular patients. Otolaryngol Head Neck Surg. 1995;112:8–15. Furman JM, Cass SP. Evaluation of Dizzy Patients. Slide lecture series. American Academy of Otolaryngology-Head and Neck Surgery; 1994. Henriksson NG, Pfaltz CR, Torok N, Rubin W. A Synopsis of the Vestibular System: An Effort to Standardize Vestibular Conceptions, Tests, and Their Evaluation. Basel, Sandoz; 1972. Jacobson GP, Newman CW, Kartush JM. Handbook of Balance Function Testing. St Louis, MO: Mosby-Year Book; 1993. Leigh RJ, Zee DS. Neurology of Eye Movements. 3rd ed. Philadelphia, PA: FA Davis; 1998.

References 1. Folio M, Fewell R. Peabody Development Motor Scales and Activity Cards. Hingham, MA: DLM Teaching Resources; 1983. 2. Bruininks RH. Bruininks-Osere tsky Test of Motor Proficiency: Examiners Manual. Circle Pines, MN: American Guidance Services; 1978.

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3. Shumway-Cook A, Horak FB. Assessing the influence of sensory interaction of balance. Suggestion from the field. Phys Ther. 1986;66:1548. 4. Horak B, Shumway-Cook A, Crowe TK, Black, FO. Vestibular function and motor proficiency of children with impaired hearing or with learning disability and motor impairments. Dev Med Child Neurol. 1988;30:64–79. 5. Hirabayashi S, Iwasaki Y. Developmental perspective of sensory organization on postural control. Brain Dev. 1995; 17:111– 113. 6. Rine RM, Rubish K, Feeney C. Measurement of sensory system effectiveness and maturational changes in postural control in young children. Pediatr Phys Ther. 1998;10:16–22. 7. Horak FB, Shumway-Cook A, Crowe TK, Black FO. Vestibular function and motor proficiency of children with impaired hearing or with learning disability and motor impairments. Dev Med Child Neurol. 1988;30:64. 8. Tsuzuku T, Kaga K. The relation between motor function development and vestibular function tests in four children with inner ear anomaly. Acta Otolaryngol Suppl (Stockh). 1991;481:443. 9. Bárány R. Physiologie und Pathologie des Bogengangsapparates beim Menschen. Vienna: Deuticke; 1907. 10. Hamid M, Hughes G, Kinney S. Specificity and sensitivity of dynamic posturography: a retrospective analysis. Acta Otolaryngol Suppl (Stockh). 1991;481:596. 11. Furman JM. Role of posturography in the management of vestibular patients. Otolaryngol Head Neck Surg. 1995;112:8. 12. Fetter M, Diener H, Dichgans J. Recovery of postural control after an acute unilateral vestibular lesion in humans. J Vestib Res. 1991;1:373. 13. Colebatch JG, Halmagyi GM. Vestibular evoked potentials in human neck muscles before and after unilateral vestibular deafferentation. Neurology. 1992;42:1635–1636. 14. Murofushi T, Matsuzaki M, Mizuno M. Vestibular evoked myogenic potentials in patients with acoustic neuromas. Arch Otolaryngol Head Neck Surg. 1998;124:509–512. 15. Kelsch TA, Schaefer LA, Esquivel CR. Vestibular evoked myogenic potentials in young children: test parameters and normative data. Laryngoscope. 2006;116(6):895–900. 16. Brantberg K, Granath K, Schart N. Age-related changes in vestibular evoked myogenic potentials. Audiol Neurootol. 2007;12(4):247–253. 17. Valente M. Maturational effects of the vestibular system: a study of rotary chair, computerized dynamic posturography, and vestibular evoked myogenic potentials with children. J Am Acad Audiol. 2007;18(6):461–481.

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26

C H A P T E R

Otalgia Frank W. Virgin and Greg Licameli

O

talgia is one of the most common presenting symptoms that a physician caring for the pediatric patient encounters. Examination of the external auditory canal can be limited by its caliber, obstruction from cerumen or patient compliance. Accurate diagnosis of otalgia must first rule out a primary otologic source for the discomfort. If the otologic exam is not revealing, the physician must then search for a “referred” source of otalgia based on the diverse sensory innervation of the external and middle ear. When evaluating a child with otalgia, it is helpful to divide the source of this pain into two categories. The first category includes sources of pain that are otologic in origin. This group can be further divided into processes that affect the external ear and those that affect the middle and inner ear. The second category focuses on causes for pain that are generated outside of the ear, but results in “referred” otalgia (Table 26-1).

EXTERNAL EAR Otitis Externa Acute otitis externa (OE), also known as “swimmer’s ear,” is an inflammation of the external auditory canal that can also involve the auricle. It is one of the most common sources of otalgia. Bacterial infection is the most common cause of OE with Pseudomonas aeruginosa, being the most common pathogen.1 Fungal pathogens such as Aspergillus niger are also encountered. Patients with OE often experience a sensation of fullness, otalgia, tragal tenderness (especially to motion), pruritus, decreased hearing, and ear discharge. In fungal OE, also known as otomycosis, otalgia is present but is usually secondary to pruritus. In OE, otalgia can be attributed to the sensory afferents, namely the auriculotemporal, facial, glossopharyngeal, vagus, and cervical nerves.2 Ear pain in OE is often intense and disproportionate to the degree of inflammation and findings on physical examination.3 Physical examination reveals edema and erythema of the external auditory meatus and auricular skin, and in more severe infections, the auricle may be rotated forward with edema and erythema over the mastoid. Purulence, squamous debris, impacted cerumen and often serous drainage within the auditory canal may be present. In progressive cases of acute OE, the edema and erythema increase in the external auditory canal and may spread outward to the periauricular skin and medially toward the tympanic membrane. In fungal OE, there also is a characteristic coating of the external ear canal skin and cerumen with macroscopic mycelia. Treatment involves removal of

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exudative debris, cleansing of the ear canal, and ototopic acidic drops with steroidal preparation. If the infection invades the periauricular skin, then systemic antibiotics or antifungals may be required. Immediately after the treatment, the patient should avoid further water contamination until the physical examination returns to normal and the patient is asymptomatic. Malignant OE involves progressive inflammation of the temporal bone. The infection begins as OE and progresses through the bony-cartilaginous junction of the external auditory canal and may spread to the middle or inner ear, intracranial space, cranial nerves, sigmoid sinus, regional lymph nodes, and parotid gland. The causative agent is almost always Pseudomonas aeruginosa.4 Malignant OE occurs most frequently in older individuals with diabetes mellitus and those who are immunocompromised. Patients with this condition may experience a sensation of fullness, intense otalgia, otorrhea, hearing loss, and cranial nerve palsies. Mani et al. in 2007 evaluated 23 patients with the diagnosis of malignant OE. Ten of the 23 patients (43%) had cranial nerve palsies. The facial nerve was the most commonly affected 6/10 followed by lower cranial nerves (IX, X, XI, XII) 3/10 and extended nerve palsy (VI, VII, IX, X, and XI).5 Children with malignant OE often have an acute illness and tend to develop facial nerve palsies earlier in the course of the infection, due to anatomical differences (more medial location of the fissures of Santorini and the underdevelopment of the mastoid).4 Otoscopic inspection reveals edema and erythema of the external auditory canal with characteristic granulation tissue at the bony-cartilaginous junction. Diagnosis is made through patient history, otoscopy, bacterial and fungal culture, laboratory testing, including erythrocyte sedimentation rate and C26-reactive protein. Radiologic evaluation can include technetium and gallium bone scans.6 Single photon emission CT scans have also been used to identify areas of focally increased uptake. Computed tomography and magnetic resonance imaging are useful for analyzing the extent of the condition in the middle ear, mastoid, and skull base.7 Histological examination of granulation tissue is made to exclude malignancy. Treatment is with culture directed intravenous antibiotic and topical antibiotics. Surgical debridement of necrotic tissue may be necessary in some cases.

Myringitis Inflammation of the tympanic membrane without middle ear disease is referred to as myringitis. This process can be the

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TABLE 26-1. Causes of Otalgia in the Pediatric Patient External Ear Otitis externa Myringitis Herpes zoster Perichondritis Erysipelas Furunculosis Auricular burns and frostbite Neoplasia Foreign bodies Cerumen impaction Middle Ear Acute and chronic otitis media Mastoiditis Trauma Barotrauma Eustachian tube dysfunction Neoplasia Referred Otalgia Local infection Temporomandibular joint dysfunction Dental pain Oral, oropharyngeal, esophageal, and sinus disease Eagles syndrome Carotidynia Migraine headache

cause of significant otalgia. Myringitis can manifest only as inflammation of the tympanic membrane and can also result in the formation of bullae. The cause of myringitis is infectious and is typically bacterial in nature. Streptococcus pneumonia is the most commonly isolated pathogen followed by Haemophilus influenzae and Moraxella catarralis.8 Although viral infection has often been cited as the cause of myringitis, evidence for this in the form of positive viral cultures is lacking.9 Additionally, mycoplasma pneumonia has been cited as a possible pathogen in myringitis; however, evidence does not support this theory.10 Treatment is with appropriate antimicrobial therapy and in the setting of bullous myringitis, incising the bullae can result in significant pain relief.

Herpes Zoster Herpes zoster oticus occurs upon reactivation of varicella zoster virus within the sensory nerves innervating the ear. Vesicles may temporarily appear on the auricle and in the external auditory meatus. Intense otalgia, general malaise, fever, sensorineural hearing loss, tinnitus, taste disturbance, reduced tearing, and vertigo are potential symptoms of zoster oticus.11 Ramsay Hunt syndrome is a more advanced stage of this process with partial or complete facial paralysis, due to involvement of the facial nerve. Additionally, involvement in the vestibulocochlear nerve can result in hearing loss and vertigo. Otalgia in herpes zoster oticus may originate from vesicular eruption or from irritation of involved nerves, such as the glossopharyngeal, trigeminal, vagus, and abducens

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nerves.2 Neuralgia may persist following resolution of herpes zoster oticus due to lingering inflammation of the affected nerves. Physical examination and functional testing of cranial nerves are used for diagnosis. Magnetic resonance imaging may assist in diagnosis by showing enhancement of the facial nerve and labyrinth.12 Early administration of an antiviral agent in combination with corticosteroid treatment is associated with restoring facial nerve function.13 Antibiotics may be given due to a risk of secondary bacterial infection. Although herpes zoster oticus in otherwise healthy pediatric patients is generally believed to be benign, a recent study showed that associated complications such as skin infections, ophthalmic zoster, facial paralysis, and meningoencephalitis can occur in immunocompetent children.14

Perichondritis Auricular perichondritis is an infection of the skin and perichondrium, with potential spread to cartilage of the external ear and external auditory canal. The earlobe remains unaffected due to the lack of cartilage. Erythema, edema, dull pain, and tenderness are present. In advanced cases, drainage of pus and deformation of the ear may occur. The condition is caused by a bacterial infection, most often Pseudomonas aeruginosa but may also be attributed to Staphylococcus aureus or Escherichia coli. Infection is often the result of prior ear surgery, ear piercing, mechanical damage, burn, or insect bite.15 Immunocompromised individuals are at higher risk for auricular perichondritis. Diagnosis is based on appearance, history of ear trauma, and bacterial cultures. Oral or systemic antibiotics should be administered. If there is evidence of chronic infection and necrotic tissue, surgical intervention is necessary and will likely result in cartilage loss and aesthetic deformity. Insertion of polyethylene tubes into the abscess cavity and performing irrigation using antibiotic solution is an alternative to aggressive surgical debridement and may potentially results in more aesthetic results.15

Erysipelas Auricular erysipelas is caused by group A streptococcal infection through a skin breach and extension through the cutaneous lymphatics. It is most commonly seen in elderly, very young, and immunocompromised patients. The affected area appears erythematous, swollen, and firm, with advancing, sharply demarcated, raised edges. There is a sensation of heat, fullness, pruritus, and otalgia. Fever, fatigue, chills, nausea, and lymphadenopathy may also be present. Diagnosis is made based on history and physical examination findings. Treatment is with culture directed oral or intravenous antibiotics. In severe cases, resulting in necrosis or gangrene surgical debridement is necessary.

Furunculosis The outer one-third of the external auditory canal is cartilaginous and contains hair follicles, sebaceous glands, and ceruminous glands. Bacterial infection of the external

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CHAPTER 26 ❖ Otalgia 425 canal hair appendages is often secondary to microtrauma of the canal. Symptoms of moderate auricular discomfort with palpation and mastication are seen early with furunculosis. Upper neck adenopathy occurs later in the disease process. In contrast to OE, there is usually limited canal edema and no aural discharge. Relief and resolution are aided by surgically unroofing the furuncle. Cultures of the purulent discharge will often yield staphylococcal species. Treatment is antibiotic therapy directed at these organisms and analgesics for pain management.

Frostbite of the Auricle Frostbite may occur in response to prolonged exposure to the cold. At first the skin becomes blanched, numb, and inflexible due to the formation of ice crystals within the tissue, particularly at the auricular edge. Initially the affected area is numb, but eventually becomes painful, especially in response to temperature change. Pruritus may also be present. Classification of frostbite is characterized based on the degree of damage to tissues on thawing. First-degree frostbite is characterized by increased vasodilation and edema. Vesicular eruption occurs in second-degree frostbite. In third-degree frostbite, there is necrosis of tissue with risk of infection, gangrene, and amputation. Rapid rewarming should be undertaken only if there is no possibility of refreezing. Other treatments include topical aloe vera, anti-inflammatory drugs, antibiotics, and debridement of clear, but not bloody, blisters.16

Chondrodermatitis Nodularis Chronica Helicis Chondrodermatitis nodularis chronica helicis (CNH) is a firm, well-demarcated, benign papule on the auricular helix or antihelix causing pain and tenderness. Although it is most commonly found in middle-aged and older men, it may also occur in women and in children.17,18 The etiology is variable; CNH may be caused by vascular insufficiency, mechanical irritation, prolonged pressure, or a history of cold or light damage to the area. Occasionally, CNH is associated with an autoimmune or connective tissue disorder. Although location, appearance, and presence of otalgia are usually sufficient for diagnosis, a biopsy is often taken to exclude a neoplasm. Nonsurgical therapies include cryotherapy, topical antibiotics, and topical or injection corticosteroids.19 However, surgical excision is often preferred. Recurrence of CNH is possible if all areas of inflammation are not removed. A more conservative and cost-efficient approach of using a doughnutshaped pillow for sleeping reduces otalgia in some patients with CNH.20

Tumors of the External Ear Tumors of the external ear are not commonly found in the pediatric patient. Langerhans histiocytosis and sarcomas, especially rhabdomyosarcoma, are more common than carcinomas in pediatric patients. Tumors of the external ear

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often present with chronic otalgia, otorrhea, hemorrhaging, hearing loss, and loss of cranial nerve function. Malignancy should be suspected in any nonhealing lesion of the ear. A pathologic examination is required to make the diagnosis.

Foreign Bodies Foreign bodies in the external auditory canal are common in the pediatric patient. Often encountered objects include plastic beads, ear plugs used for swimming, and various vegetable matter. The symptoms can include otalgia, pruritus, aural fullness, hearing loss, and otorrhea, depending on the length of time that an object is present. The urgency of management varies depending on the object. Foreign bodies may be removed in the clinic or in the operating room depending on the cooperation of the patient. Removal of batteries placed in the ear canal is considered an otologic emergency as these can cause extensive caustic skin and bone damage in a short period of time.21,22 Otologic drops should be avoided if the object is not clearly identified because, in a moist environment, batteries can cause increased damage and vegetable matter can swell, causing increased discomfort and added difficulty in removal.

Cerumen Impaction Patients experiencing occlusion of the external auditory canal often present with aural fullness, puritis and decreasing hearing. If otalgia is present, a concurrent otitis externa may be present as well. Cerumen impaction is often the result of inappropriate use of cotton swabs, hearing aid use or swimming plug use. Although other methods for removal exist, the safest and most effective method for removal is under direct visualization using the otologic microscope.

MIDDLE EAR Otitis Media Acute otitis media (AOM), a common reason for otalgia in children, is infection of the middle ear characterized by acute onset, middle ear effusion, and middle ear inflammation. AOM occurs most commonly in pediatric patients under 3 years of age in the winter months.3 The most common pathogens involved in AOM include: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and less commonly Pseudomonas aeruginosa, and Staphylococcus aureus. The bacteriology of AOM has evolved over time due to increased antibiotic resistance and vaccine use.23 Patients with AOM present with deep-seated otalgia, fever, irritability, and conductive hearing loss. Infection is frequently in the setting of a recent or concurrent upper respiratory tract infection. Earache stems from inflammation of the middle ear mucosa and stretching of the tympanic membrane. Otorrhea may occur if there is a perforation of the tympanic membrane, often with a corresponding cessation of otalgia. The auricle and periauricular lymph nodes appear normal

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in uncomplicated, contained AOM. Classically, otoscopic inspection reveals an erythematous, bulging tympanic membrane. Pneumatic otoscopy reveals decreased mobility or immobility of the tympanic membrane. Treatment typically involves a course of antibiotics directed at the most common pathogens. Surgical treatment is typically reserved for recurrent AOM, chronic middle ear effusion, or complications of otitis media.

Mastoiditis Acute mastoiditis is the extension of the middle ear inflammation of AOM into the antrum and mastoid air cells. Symptoms of mastoiditis may include intense otalgia, progressive hearing loss, postauricular swelling and proptosis, fever, and malaise. If mastoiditis is left untreated, serious complications, including facial nerve palsy, vertigo, petrositis, labyrinthitis, meningitis, and subperiostial or intracranial abscess may occur. These complications occur most frequently in patients presenting with elevated white blood counts.24 Children with AOM, especially males between the ages of 1 and 3, are at the highest risk for mastoiditis.25 Although acute mastoiditis originates from AOM, the bacteriology in mastoiditis may be different than that in AOM. Streptococcus pneumonia and Pseudomonas aeruginosa are common causes of acute mastoiditis.25,26 Patients are placed on intravenous antibiotics. In the setting of complications, surgical intervention such as myringotomy with tube placement, drainage of abscess, or mastoidectomy may be required.

Perforations of the Tympanic Membrane Perforations of the tympanic membrane are relatively common, although the exact incidence remains unknown. A perforation may be caused by a traumatic event to the ear (e.g., a blow to the side of the head, an extreme change in pressure, self-cleaning with a cotton-tipped swab), AOM, or prior medical treatment (e.g., ventilation tubes). If the perforation occurs secondary to AOM, the individual often experiences intense otalgia at the moment of injury, purulent drainage, trace bleeding from the external auditory canal, audible whistling sounds on blowing one’s nose or sneezing, conductive hearing loss, and tinnitus. Otoscopy is typically sufficient to diagnose a perforation, although history and audiologic testing are often also considered. Acute perforations appear as rough-edged holes in the eardrum accompanied by fresh blood, purulent drainage, and sometimes a foreign body depending on the type of insult. Most perforations are temporary and spontaneously heal after a short period of time. In these cases, antibiotics may be prescribed and the patient is instructed to keep the ear canal free of contaminated water with ear plugs or vaseline-coated cotton balls. Management also includes audiometric assessment to rule out ossicular disruption, especially when trauma is the cause of the injury. Chronic perforations may require surgical intervention, such as tympanoplasty.

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Barotrauma of the Middle Ear Barotrauma of the middle ear is caused by a sizeable difference in pressure between the environment and the middle ear space. This may occur at high altitudes, during airplane descents, or underwater diving. Barotrauma results when the Eustachian tube is unable to normalize the pressure gradient between the middle ear and the external environment. Patients with eustachian tube dysfunction, either congenital or as a result of inflammation or infection, are at a greater risk for this condition. Children are at high risk to experience barotrauma due to the anatomy of the Eustachian tube, frequency of upper respiratory infections, and adenoidal tissue blocking the tube openings. During the injury, the individual may experience acute otalgia, hearing loss, tinnitus, a sensation of fullness in the ear, and vestibular impairment. Typical findings on physical examination include a retracted tympanic membrane, hemotympanum, middle ear effusion, erythema of the tympanic membrane, and tympanic perforation in advanced cases of barotrauma. Treatment includes behavioral techniques (e.g., yawning, chewing gum, and swallowing repeatedly), nasal decongestants, and rarely surgical intervention (e.g., myringotomy and ventilation tubes). Randomized prospective studies demonstrated that adults treated with oral pseudoephedrine experienced less ear pain on an airplane descent than adults treated with placebo; however, children treated with the same decongestant did not experience this reduction in otalgia.27

Eustachian Tube Dysfunction Disturbances of the eustachian tube may cause otalgia, a sensation of fullness in the ear, difficulty in “popping” the ears, conductive hearing loss, and tinnitus. Eustachian tube dysfunction may be attributed to congenital malformation, trauma to the tube or nearby structure, or inflammation due to allergy or infection. Children generally have an increased risk of this condition as the Eustachian tube has a more horizontal configuration (less drainage), decreased cartilage support, and decreased efficiency of the tensor veli palatini when compared to adults resulting in functional obstruction. Otoscopy may reveal a retracted tympanic membrane with or without middle ear effusion. However, some cases of Eustachian tube dysfunction are not apparent with otoscopic inspection. Additional adjuncts to standard diagnostic otosocopy include: pneumatic otoscopy, nasal endoscopy, computerized tomography, and impedance audiometry. Treatment is with maneuvers designed to open the eustachian tube such as yawning and valsalva. Refractory cases and in cases with complications, myringotomy with ventilation tube placement may be necessary.

Tumors Tumors of the middle ear are extremely rare, but should be considered in patients with deep seated, unrelenting otalgia. Examples of tumors that can occur in the pediatric ear

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CHAPTER 26 ❖ Otalgia 427 include: rhabdomyosarcoma, Langerhans histiocytosis, lymphoma, adenoid cystic carcinoma, adenocarcinoma, and squamous cell carcinoma. On physical examination, there is the presence of polypoid or friable middle ear tissue that may prolapse into the external auditory canal. When the diagnosis of a middle ear mass is uncertain and malignancy is considered, biopsy is indicated.

NEURALGIFORM The ear is innervated by cranial nerves V, VII, IX, X, and cervical sensory branches. Irritation, compression, or disease of these nerves in regions of the head and neck distant from the ear may cause otalgia. Neuralgiform otalgia should be considered in the setting of a normal otologic examination. Physical examination and radiologic workup are directed at identifying the source of the pain. However, diagnosis of the source of the pain and subsequent treatment may be difficult in many cases. If the pain is intermittent and mild, treatment may not be warranted and the patient can be reassured after a thorough examination. Analyzing the severity, temporal pattern, duration, and location of the otalgia may help to diagnose and treat the underlying cause of the pain.

Cranial Nerve V (Trigeminal) The fifth, or trigeminal nerve innervates parts of the pinna, tragus, superior and anterior external auditory canal, and lateral tympanic membrane via the auriculotemporal branch of the mandibular division. Common causes of otalgia via the trigeminal nerve include odontogenic causes, temporomandibular joint disorders, infections of the soft tissues of the oral cavity, oropharynx, or nasopharynx, and lesions of the anterior portion of the tongue. Otalgia mediated through the trigeminal nerve is typically superficial, lancinating, and intermittent.

Cranial Nerve VII (Facial) The seventh or facial nerve carries sensory information from the concha, lateral antihelix, and posterior wall of the external auditory canal, posterior tympanic membrane, and postauricular skin. Bell’s palsy, Ramsay Hunt syndrome, and neoplasms or infections involving the parotid gland may cause severe otalgia mediated by the facial nerve.

Cranial Nerve IX (Glossopharyngeal) The ninth, or glossopharyngeal, nerve innervates the middle ear mucosa, medial tympanic membrane, upper Eustachian tube, and mastoid air cell system via Jacobson’s nerve, a part of the tympanic plexus. Lancinating pain mediated by the glossopharyngeal nerve radiates from the pharynx to the ear with otalgia presenting deep within the ear. Pain may be stimulated by the act of swallowing. Glossopharyngeal neuralgia may result from pathologies of the posterior oropharynx, including tonsillitis, post-tonsillectomy inflammation,

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pharyngitis, peritonsillar abscess, foreign bodies imbedded in the tongue or tonsillar region, ulcers of the posterior tongue, and uncommonly, neoplasms of the base of the tongue or tonsil.

Cranial Nerve X (Vagus) The tenth or vagus nerve provides sensory innervation for the concha, the posterior and inferior walls of the external auditory canal, and the posterior and inferior tympanic membrane. Vagus neuralgia causes pain down the length of the lateral neck from the ear to the sternum. Otalgia is less severe than other neuralgias and may come in the form of isolated attacks (paroxysmal) or prolonged dull aches. The pain tends to occur at night. Vagus nerve mediated otalgia may signal disease of the larynx, esophagus, and thyroid. It also may be triggered by behavioral activities such as swallowing, coughing, or yawning.

Cervical Nerves The greater auricular nerve, a sensory nerve made up of fibers from C2 and C3, provides sensation to the posterior portion of the lateral surface of the pinna and the majority of the medial surface of the pinna. The skin overlying the mastoid region is innervated by the lesser occipital nerve, formed from fibers of C2. There is some overlap of innervation from these two nerves. In addition to direct innervation of the external ear, these nerves also provide sensation to the skin and muscles of the neck and spine. Infection of the neck resulting in cervical lymphadenitis or abscess can result in referred otalgia.

REFERRED OTALGIA Temporomandibular Joint Disorders Temporomandibular joint disorders (TMDs) encompass a group of disorders affecting the temporomandibular joint (TMJ) and the orofacial muscles. Although TMD is less common in children than in adults, it is still found in the pediatric population. TMD is caused by the disarticulation or inflammation of the TMJ or adjacent muscles. This may occur following acute trauma, repetitive trauma (e.g., bruxism, jaw clenching, and gum chewing), juvenile rheumatoid arthritis, or anxiety.3,28 TMD may also be secondary to malocclusion or dental disease.2 TMD presents as joint tenderness, pain upon mechanical stimulation, restricted movement in the jaw, and joint crepitus. Tinnitus, dizziness, aural fullness, and headache may be the associated symptoms. Sixty-four percent of patients with TMD also have otalgia mediated by the trigeminal nerve, which is typically unilateral and pronounced early in the day.3,29 Therapy is usually nonsurgical and may include a soft diet, joint rest, massage, heat, analgesics, anti-inflammatory medications, and muscle relaxants. If nonsurgical treatments are unsuccessful, surgical intervention may be necessary.

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Odontogenic Causes Dental pathology, especially involving the mandibular molars, can be the origin of pain in 50% of referred otalgia cases.28 Pain due to odontogenic conditions is mediated via the trigeminal nerve. Teething in young children is a common cause of otalgia often causing the prelingual patient to rub or pull on the ear. Dental caries and infection of the gingivae can cause severe pain in the immediate diseased region. If the tooth pulp is involved, pain may also radiate to the ear. Treatment is with analgesics, antibiotics, and possibly surgical intervention. Dental consultation is often needed for diagnosis and treatment of the underlying process.

Salivary Glands Pathology of the major salivary glands, especially the parotid glands, may cause referred otalgia via the facial nerve. Disease of the salivary glands are diagnosed by history, physical examination, radiologic evaluation, and in the case of neoplasm, biopsy. Common prior to widespread vaccination, mumps is a viral infection caused by the mumps virus which is in the family of viruses, Paramyxoviridae, which results in bilateral parotid swelling and otalgia. Referred otalgia due to mumps is usually bilateral and may arise prior to facial swelling.29 Bacterial parotitis, which can occur in children, but is most commonly encountered in elderly and immunocompromised patients, can cause referred otalgia which is typically unilateral. Bacterial infection of the salivary glands is precipitated by obstruction of the duct, poor oral hygiene, and dehydration. Treatment of bacterial parotitis involves administration of antibiotics, hydration, warm compresses, and sialagogues. Uncommon in children, malignant neoplasms of the salivary glands can result in otalgia.

MISCELLANEOUS CAUSES Eagle Syndrome Eagle syndrome is pain of the ear, face, and throat with accompanying dysphagia due to elongation of the styloid process and calcification of the stylohyloid ligament. Pain, typically unilateral, presents in conjunction with swallowing, yawning, prolonged loud speech, and mastication. Otalgia originates from the impingement of the styloid process on the trigeminal, glossopharyngeal, and facial nerves as well as pressure on the carotid vessels. Intraoral inspection is typically unremarkable. Diagnosis can usually be made by reproducing symptoms upon palpitation of the styloid process through the tonsillar fossa. CT scan confirms the diagnosis of Eagle syndrome. This condition is treated by surgical resection of the styloid process.

Migraine Headaches Migraine headache is typically characterized by throbbing pain in the frontotemporal area, photophobia, nausea, and vomiting. Anttila et al. reported that 32% children with

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migraine headaches occasionally experience concurrent otalgia.30

EVALUATION Diagnosis of otalgia in the pediatric patient can be a challenge, depending on the cause. The initial evaluation occurs with a complete history. History should be taken from the patient, when possible, and from the patient’s caregiver. Important components of the history include onset and duration of pain, location, quality, exacerbating, and alleviating factors. Additionally, the presence of other associated symptoms such as imbalance and hearing loss should be elicited. Physical examination also plays an important part in the evaluation of otalgia. A close examination of the external ear can identify the presence of erythema, vesicles, purulence, proptosis, fluctuance, recent trauma, or a foreign body. Otoscopy is important in the evaluation of the external ear canal as well as the tympanic membrane. It is extremely important to obtain a full clear view of the tympanic membrane. When the ear canal is obstructed with debris or cerumen, this must be gently removed to provide an unobstructed view of the tympanic membrane. Pneumatic otoscopy is valuable in determining the presence of a middle ear effusion when visualization alone is not sufficient. Tympanometry may also be used to help in determining the presence of middle ear effusion, but should not be the sole method of diagnosis. When there is no clear cause of the patient’s otalgia with otologic examination, a more thorough head and neck examination should be carried out. Examination of the oral cavity and oropharynx can identify lesions, infectious and odontogenic causes of otalgia. Palpation of the neck and evaluation of range of motion can give information regarding the presence of a deep neck space infection or mass. Finally, if there is still no evidence of cause fiberoptic nasopharyngoscopy and laryngoscopy should be carried out to evaluate for the presence of a lesion in the nasopharynx, hypopharynx, or larynx. Imaging studies in the form of CT or MRI can be helpful in defining the extent of otologic disease. Additionally, if there is suspicion of referred otalgia due to an infection or neoplasm of the head and neck, imaging can be very helpful. However, imaging alone should not be relied upon alone to diagnose a cause of otalgia and should not supplant a through physical examination.

CONCLUSION Otalgia is a common complaint in the pediatric patient population. Infectious causes are the most common etiology in this group; however, there are other less evident causes for otalgia. Diagnosis can be difficult in the patient group due to anatomy and cooperation of the patient. A thorough history and physical examination are essential for proper diagnosis of the source of otalgia. Where indicated imaging studies, culture, or biopsy should be utilized to aid in the diagnosis.

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References 1. Ninkovic G, Dullo V, Saunders NC. Microbiology f otitis externa in the secondary care in United Kingdom and antimicrobial sensitivity. Auris Nasus Larynx. 2008;35(4):480–484. 2. Shah RK, Blevins NH. Otalgia. Otolaryngol Clin North Am. 2003;36(6):1137–1151. 3. Leung AK, Fong JH, Leong AG. Otalgia in children. J Natl Med Assoc. 2000;92(5):254–260. 4. Rubin J, Yu VL, Stool SE. Malignant external otitis in children. J Pediatr. 1988;113(6):965–970. 5. Mani N, Sudhoff H, Rajagopal S, Moffat D, Axon PR. Cranial nerve involvement in malignant external otitis: implications for clinical outcome. Laryngoscope. 2007;117(5):907–910. 6. Handzel O, Halperin D. Necrotizing (malignant) external otitis. Am Fam Physician. 2003;68(2):309–312. 7. Weissman JL. A pain in the ear: the radiology of otalgia. AJNR Am J Neuroradiol. 1997;18(9):1641–1651. 8. Palmu AA, Kotikoski MJ, Kaijalainen TH, Puhakka HJ. Bacterial etiology of acute myringitis in children less than two years of age. Pediatr Infect Dis J. 2001;20(6):607–611. 9. Kotikoski MJ, Palmu AA, Nokso-Koivisto J, Kleemola M. Evaluation of the role of respiratory viruses in acute myringitis in children less than two years of age. Pediatr Infect Dis J. 2002;21(7):636–641. 10. Kotikoski MJ, Kleemola M, Palmu AA. No evidence of Mycoplasma pneumoniae in acute myringitis. Pediatr Infect Dis J. 2004;23(5):465–466. 11. Ely JW, Hansen MR, Clark EC. Diagnosis of ear pain. Am Fam Physician. 2008;77(5):621–628. 12. Kuo MJ, Drago PC, Proops DW, Chavda SV. Early diagnosis and treatment of Ramsay Hunt syndrome: the role of magnetic resonance imaging. J Laryngol Otol. 1995;109(8):777–780. 13. de Ru JA, van Benthem PP. Combination therapy is preferable for patients with Ramsay Hunt syndrome. Otol Neurotol. 2011;32(5):852–855. 14. Grote V, von Kries R, Rosenfeld E, Belohradsky BH, Liese J. Immunocompetent children account for the majority of complications in childhood herpes zoster. J Infect Dis. 2007;196(10):1455–1458. 15. Prasad HK, Sreedharan S, Prasad HS, Meyyappan MH, Harsha KS. Perichondritis of the auricle and its management. J Laryngol Otol. 2007;121(6):530–534. 16. Heggers JP, Robson MC, Manavalen K, et al. Experimental and clinical observations on frostbite. Ann Emerg Med. 1987;16(9): 1056–1062.

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17. Grigoryants V, Qureshi H, Patterson JW, Lin KY. Pediatric chondrodermatitis nodularis helicis. J Craniofac Surg. 2007;18(1):228–231. 18. Rogers NE, Farris PK, Wang AR. Juvenile chondrodermatitis nodularis helicis: a case report and literature review. Pediatr Dermatol. 2003;20(6):488–490. 19. Zuber TJ, Jackson E. Chondrodermatitis nodularis chronica helicis. Arch Fam Med. 1999;8(5):445–447. 20. Sanu A, Koppana R, Snow DG. Management of chondrodermatitis nodularis chronica helicis using a 'doughnut pillow'. J Laryngol Otol. 2007;121(11):1096–1098. 21. Capo JM, Lucente FE. Alkaline battery foreign bodies of the ear and nose. Arch Otolaryngol Head Neck Surg. 1986;112(5):562–563. 22. Skinner DW, Chui P. The hazards of “button-sized” batteries as foreign bodies in the nose and ear. J Laryngol Otol. 1986;100(11):1315–1318. 23. Vergison A. Microbiology of otitis media: a moving target. Vaccine. 2008;26(suppl 7):G5–G10. 24. Tarantino V, D'Agostino R, Taborelli G, Melagrana A, Porcu A, Stura M. Acute mastoiditis: a 10 year retrospective study. Int J Pediatr Otorhinolaryngol. 2002;66(2):143–148. 25. Nussinovitch M, Yoeli R, Elishkevitz K, Varsano I. Acute mastoiditis in children: epidemiologic, clinical, microbiologic, and therapeutic aspects over past years. Clin Pediatr (Phila). 2004;43(3):261–267. 26. Oestreicher-Kedem Y, Raveh E, Kornreich L, Popovtzer A, Buller N, Nageris B. Complications of mastoiditis in children at the onset of a new millennium. Ann Otol Rhinol Laryngol. 2005;114(2):147–152. 27. Mirza S, Richardson H. Otic barotrauma from air travel. J Laryngol Otol. 2005;119(5):366–370. 28. Yanagisawa K, Kveton JF. Referred otalgia. Am J Otolaryngol. 1992;13(6):323–327. 29. Charlett SD, Coatesworth AP. Referred otalgia: a structured approach to diagnosis and treatment. Int J Clin Pract. 2007;61(6):1015–1021. 30. Anttila P, Metsahonkala L, Mikkelsson M, Helenius H, Sillanpaa M. Comorbidity of other pains in schoolchildren with migraine or nonmigrainous headache. J Pediatr. 2001;138(2):176–180.

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27

C H A P T E R

Otorrhea Joseph E. Dohar

“If automobiles had followed the same development cycle as the computer, a Rolls-Royce would today cost $100, get a million miles per gallon, and explode once a year, killing everyone inside.”

Robert Cringely he Socratic irony of Mr. Cringely’s quotation not­ withstanding, I found it most apt while considering the revision of this chapter on pediatric otorrhea. Much has been contributed to the literature. One may be tempted to con­ clude based on these contributions that this field of study has “advanced.” Closer scrutiny, however, renders, instead, the conclusion that this area has really “cycled.” Although tech­ nology and certain treatments have followed the course of the Rolls­Royce in terms of perception and cost, recent informa­ tion on the actual pathophysiology and evidence­based “best practice” have followed the path of the computer and brought to bear in stunning dynamic fashion the time­honored medi­ cal acronym “K­I­S­S” or “Keep­It­Simple­Stupid.” Simple, indeed, evidence­based, minimally invasive, and cost effec­ tive; the state­of­the­art management of otorrhea as reflected by the current literature clearly resonates these “buzz words” that define the practice of medicine in the new millennium. Otorrhea refers to discharge from the ear of any etiology. Although the causes of otorrhea are legion, it is most com­ monly due to infection of one or more anatomic sites of the ear. Certain less common infectious and noninfectious etiolo­ gies of otorrhea are discussed in other chapters of this book. The three most common infectious diseases that manifest, in part, with otorrhea are acute diffuse bacterial otitis externa (OE), acute otitis media in the presence of a tympanostomy tube, also referred to as tympanostomy tube otorrhea (TTO), and chronic suppurative otitis media (CSOM) in the presence of a chronic perforation of the tympanic membrane. Of these, OE is the most common; it is usually straightforward to diag­ nose and treat and is associated with only minimal otorrhea (see Chapter 36). Refer to Chapter 37 for a comprehensive review of the middle ear infections that present with otorrhea. This chapter aims to accomplish four objectives. First, it presents a symptom­oriented approach to the differen­ tial diagnosis of otorrhea, in general, and to the treatment of infectious otorrhea deriving from a middle ear source in particular. Second, a problem­oriented algorithm and a table listing the differential diagnosis of otorrhea are included as quick references. Third, with ongoing research aimed at the development of new ototopical therapies, gen­ eral concepts and recent developments related to ototopical therapy are detailed. Finally, recent literature relevant to the concepts of the chapter, new data on the changing face of microbiology, new treatment developments, insights into the

T

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pathophysiology and mechanism of treatment failure includ­ ing biofilm theory and “bacterial substitution,” evidence­ based best practice guidelines updates, and future directions have been added.

FEATURES Character of the Discharge Although not specific, the character of the discharge may provide a clue to the etiology of otorrhea. In general, there are four types of otorrhea: sanguineous, serous, mucoid, and purulent. “Watery” or serous drainage may suggest the pres­ ence of a cerebrospinal fluid (CSF) leak, particularly if there are copious amounts of drainage. Furthermore, if an anteced­ ent history of trauma is obtained, CSF leak must be assumed until proven otherwise. The presence of a locally destructive lesion of the temporal bone also raises the index of suspicion that watery discharge may, in fact, represent CSF. Temporal bone imaging, radionucleotide scanning, or biochemical tests on the fluid itself for glucose determination or, more specifi­ cally, for b­2 transferrin should be considered. “Bloody” or sanguineous discharge is usually associated with the finding of granulation tissue on otoscopic examination and often represents an exuberant mucosal or subepithelial host inflammatory response to infection. One must remem­ ber, however, to consider noninfectious causes of otorrhea since drainage may be a harbinger of a more serious process such as tumor. If bloody otorrhea does not respond to treat­ ment within a reasonable amount of time, further diagnostic testing should be performed (Fig. 27­1). Mucoid, purulent, and mucopurulent drainage are most suggestive of infection. Although mucoid effusion is com­ monly found at the time of tympanostomy tube placement in the setting of a chronic middle ear effusion, it is rarely seen in the presence of a nonintact tympanic membrane. This also holds true for mucopurulent otorrhea but is not the case for purulent otorrhea which is commonly seen in both scenarios.

Odor Pseudomonas aeruginosa, the most common bacterial cause of otorrhea, has a characteristic “sweet” odor. A foul­smelling odor, often found in drainage present for weeks rather than days, suggests a mixed infection that includes anaerobes. Although not ultimately a critical diagnostic determination, odor may serve as an important early clue to bacteriology, and thus, to empiric antimicrobial therapy.

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SECTION 2 ❖ Ear and Related Structures Acute Otitis Media with Tympanostomy Tubes Decision Tree Patient has purulent otorrhea through a tympanostomy tube Examine ear, perform aural toilet, confirm tube patency and unblock if occluded Is patient systemically ill (T > 102°) and/or positive for other co-morbidities (excluding viral illness like rhinosinusitis?)*

YES • Obtain specimen for gram stain, culture, and sensitivity then treat as appropriate with topical and culture-directed systemic antibiotics

NO • Treat with non-ototoxic topical antibiotic and/or anti-inflammatory

Is otorrhea present after 7–10 days? YES • Assess compliance and topical drug delivery technique (tragal pumping) • Re-examine ear microscopically, perform aural toilet, obtain specimen for culture • Consider tissue biopsy if high index of suspicion for atypical pathogens, tumor, or rare underlying etiology • Look for aerobic or anaerobic bacteria, fungus, mycobacterium • Consider cultures of oropharynx, nasoparynx, external auditory canal, nasal vestibule, middle ear, and perianal skin if MRSA suspected or if recent MRSA infection has been documented

NO • Complete Rx course; keep ears dry • Review in 4 months and/or as needed

Is culture positive? YES • Treat with hydrocellulose wick, non-ototoxic topical antibiotic, and/or topical steroid • Consider culture-guided regimen of oral or IV antibiotic; may add systemic steroid

NO • Consider less common diagnoses*

Refer to appropriate specialist

Is otorrhea present after 10–21 days? YES • Consider eustachian tube function testing (forced response test)

NO • Complete Rx course; keep ears dry • Review in 4 months and/or as needed

Does forced response test reveal decreased or increased opening pressure?

INCREASED OPENING PRESSURE • Treat with hydrocellulose wick, non-ototoxic topical antibiotic, and/or topical steriod • Replace tube, debride granulation tissue, +/– adenoidectomy

DECREASED OPENING PRESSURE • Treat with hydrocellulose wick, non-ototoxic topical antibiotic, and/or topical steroid • Remove tube, debride granulation tissue, +/– adenoidectomy *Less common diagnoses/co-morbidities • Allergy (inhalant, food, neomycin, steroid) • Inflammatory disease (histiocytosis X) • Unusual pathogens • Tumor (squamous cell or adenocarcinoma, rhabdomyosarcoma) • Osteomyelitis (consider temporal bone/skull base CT/MR and/or a radionuclear T-Bone/skull base technetium medronate methylene (Tc-99m-best of initial Dx) followed by Gallium citrate (Ga 67-best to follow resolution) bone scan) • Undiagnosed systemic disease (diabetes mellitus, immunodeficiency)

Is otorrhea present after 10–21 days?

YES • Obtain temporal bone CT scan impaging and/or 3D FIESTA temporal bone MR by FLAIR and consider mastoidectomy with tympanoplasty/middle ear exploration based on imaging outcome

NO • Complete Rx course; keep ears dry • Review in 4 months and/or as needed

FIGURE 27-1. Acute otitis media with a tympanostomy tube decision tree.

Source of Drainage From a diagnostic perspective, the most critical distinc­ tion to make when faced with a patient with a “draining ear” is distinguishing the source of the otorrhea as external or middle ear. This is usually a straightforward distinction based on history and confirmed on physical examination with careful pneumatic otoscopy and aural toilet. In general,

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pain is the key distinguishing symptom. In external auditory canal (EAC) infections, pain is prominent. Tenderness elic­ ited by manipulation of the pinna is the principal sign that corroborates the history. In rare cases in which history and physical examination alone are inadequate to differentiate an outer­ from a middle ear infection, computed tomogra­ phy (CT) imaging of the temporal bone is useful. The usual

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CHAPTER 27 ❖ Otorrhea scenario for which a CT scan is obtained is in the child with an OE that has become invasive and involves the periauricu­ lar soft tissue, leading to postauricular erythema, edema, and secondary protrusion of the lobule; signs often seen in acute coalescent mastoiditis. The EAC is often too swollen and too tender to permit adequate visualization of the eardrum. CT imaging of the middle ear cleft air cell system almost always confirms the diagnosis. Gram stain findings may also provide a clue to the source of the otorrhea pathogens. The identification of white cells on Gram stain suggests that the reservoir of the bacterial pathogens causing the otorrhea is the nasopharynx (i.e., Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis). Alternatively, the absence of white cells suggests that the source of the bacterial pathogens is the EAC, most commonly, P. aeruginosa and Staphylococcus aureus. Distinguishing the reservoir of infection is not only important when prescribing treatment for the acute infection at hand but also crucial when faced with management decisions in recurrent and/or chronic dis­ ease since surgical address of the middle ear cleft or of the nasopharynx achieves very different end points. Once the middle ear is determined to be the source of the infection, the next important factor that affects treatment choice is whether the patient manifests any systemic signs of illness (see Fig. 27­1). In children who manifest no systemic signs of illness, careful aural toilet should be performed and a nonototoxic antibiotic should be empirically chosen. If, on the other hand, the patient has systemic signs of infection such as temperature greater than 101°F, then a systemic antibiotic, usu­ ally orally administered, may be added. However, it remains a common practice, mostly among primary care physicians, to treat such cases with a systemic agent only. Generally, the empirical choice of an oral antibiotic is one from the penicillin, cephalosporin, sulfa, or macrolide families indicated for otitis media with an intact eardrum. The problem with this approach is that P. aeruginosa is often the primary pathogen isolated in TTO. At present, there is no oral antibiotic indicated for chil­ dren by the US Food and Drug Administration (FDA) with adequate activity against this organism. Although as a class, the quinolone family of antibiotics is still not indicated for ear infections in children, a substantial body of safety and efficacy experience with this class of antibiotics now exists for pediat­ ric patients both in the United States and abroad. Clearly, then, especially in children, an ototopical agent should be seriously considered in most cases. The decision is whether, in addition, a systemic agent should be used.

Topical Versus Systemic Therapy There are many advantages of using topical rather than systemic antibiotic therapy. First, topical medication is deliv­ ered directly to the infected target organ. By bypassing the sys­ temic circulation, pharmacokinetic factors such as solubility, intestinal absorption, and hepatic first­pass effects do not

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433

affect ultimate tissue concentrations. Perhaps more impor­ tantly is that, unlike systemic antibiotics, topical antibiotics do not usually contribute to the development of community­ acquired resistance. This latter factor has become a focus of current best practice guideline development and, somewhat surprisingly, has also become a key safety surveillance out­ come measure for such regulatory agencies as the US FDA and the Centers for Disease Control and Prevention (CDC). Antibiotic resistance is the single most important modern day concern in the management of infectious dis­ ease. In 1982, the US FDA stated that it “is unaware of any evidence that … topical antibiotics … have led to an increase in infection in the general population by resistant organisms…. The agency believes that if resistance were a problem … it would have been known by now.”1 This tenet on resistance and topical therapy holds for short­term use in the community as long as topical drug delivery is effective. This point was corroborated by a study done in Pittsburgh. Two hundred and thirty­one consecutive children seen at the outpatient otolaryngology clinic with draining ears from which P. aeruginosa was isolated were studied.2 In these patients, the sensitivity to polymyxin B, one of the active ingredients in Cortisporin, which was commonly used in the community since the 1970s, was 99.6%. Only one strain of P. aeruginosa proved resistant to polymyxin B. The authors concluded that, despite widespread use of ototopical poly­ myxin B in their community for nearly three decades, P. aeruginosa resistance, known to readily occur in association with systemic antibiotic therapy, had not developed. The same has been observed for topical antibiotic skin creams, lotions, and ointments as well as for antimicrobial topical eye drops. A recent study found that not only was micro­ biologic eradication using topical ciprofloxacin/dexametha­ sone in children with otorrhea significantly more effective than oral amoxicillin/clavulanate (81.3% vs. 59.1%) and that time to cessation of otorrhea was 4.0 days compared to seven to nine days but also that none of the topical treatment failures rendered new pathogens whereas nearly half (4/9) of the systemically treated patients rendered new “super­ infectors or re­infectors.”3 Three factors likely account for this finding. First, the concentrations of topical antibiotics so far exceed the minimal inhibitory concentrations (MICs) at the site of infection that eradication is more rapid and complete, thus obviating the emergence of treatment­ related resistance. Second, in general, ototopical agents are used for relatively short treatment courses. Third, these infections are, by and large, community acquired in other­ wise immunocompetent hosts. It is important to note that all five pathogens most commonly isolated from draining ears—P. aeruginosa, S. pneumoniae, S. aureus, nontype­ able H. influenzae, and M. catarrhalis are of major concern to the CDC because of their propensities to develop resist­ ance. All five pathogens should be covered empirically in the absence of a confirmatory culture. They are commonly isolated from patients of all ages and from both acutely and

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chronically draining middle ears in the face of nonintact tympanic membranes. (For a detailed description of micro­ biology of OE, TTO, and CSOM, see Chapters 36 and 37.) Resistance and pharmacokinetics are not the only advan­ tages of topical therapy. The side effect profile of systemic agents far exceeds that of topical agents. The product label of any systemic antibiotic commonly includes such untoward effects as diarrhea, nausea, rash, vomiting, abdominal pain, and headache, among others. Far more severe side effects such as Stevens–Johnson syndrome, aplastic anemia, sei­ zure, and anaphylaxis may also be encountered. With topi­ cal agents, only minor local irritative and allergic effects are commonly seen. One clinical trial comparing the efficacy and safety of topical ofloxacin with those of amoxicillin/clavula­ nate found an incidence of 6% treatment­related side effects associated with the ototopical agent compared with 31% for the systemic agent.4 Last, on average, topical therapies cost anywhere from one­half to one­third that of a 10­day course of a branded, broad­spectrum oral agent. With third­party payers and the public increasingly more focused on economics, less expen­ sive topical therapies should be used in place of systemic therapies where appropriate.

FORMULATION AND PHYSICAL PROPERTIES CONSIDERATIONS pH Most traditional ototopical agents were formulated as acidic solutions and suspensions with an average pH of 3.45. Accord­ ing to the Physician’s Desk Reference, for example, Cortisporin Otic Solution® has a pH of 3.0. Although acidic concentrations were probably used in ototopical formulations to solubilize the steroid to varying degrees, two additional reasons have been offered to justify acidic pH. First, acetic acid is bactericidal to P. aeruginosa, the major pathogen isolated from otorrhea.5 For example, VoSol Otic® (Denver Chemical Company), a 2% solution of acetic acid with 3% propylene glycol, is effective in the treatment of some discharging ears. Bactericidal activity of acetic acid and Burow’s solution (glacial acetic acid and 13% aluminum acetate) has been shown against S. aureus, Proteus mirabilis, P. aeruginosa, and Staphylococcus pyogenes.5 Addi­ tion of aluminum to acetic acid to form aluminum acetate (Burow’s solution) results in even better inhibition of growth of these four organisms. An antibiotic effective in eradicating the significant pathogens at near neutral pH may theoretically be better tolerated but also may encourage secondary infections by pathogens such as yeast that are typically inhibited by the physiologic acid pH of the EAC. The antimicrobial effect of acid on P. aeruginosa extends to other pathogens as well. Some fungi are suppressed by acetic acid in vitro. The role of fungi in ear disease is debated. A more complete discussion of the role of fungi in otorrhea is included in the section “Microbiology of Otorrhea—The Old, The New, The Ugly!”

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That the physiologic pH of the EAC is acidic is an important homeostatic and protective characteristic to keep in mind. It has been hypothesized that restoring the pH of the EAC, which is often altered by otorrhea, is beneficial. No studies have exam­ ined the effect of formulation pH as a single independent vari­ able on treatment outcome. Comparisons between cure rates for preparations that are and that are not acidic reveal little to no difference in outcome. Of course, such comparisons are far from conclusive since elements in addition to pH vary in these preparations. At this time, it is reasonable to conclude that an independent contribution to treatment outcomes by ototopical pH alone in acute infections is unlikely. It is more likely that subacute and chronic otorrhea treated on a continuous basis with ear drops is affected by the pH of the ear drops prescribed. It is known that chronic OE results in an increase (i.e., more alkaline) of pH in the EAC.6 Several of the complications that arise in the setting of otorrhea are a direct result of this pH change and of other alterations of the normal physiology of the EAC (i.e., loss of the protective features of cerumen). In fact, infections such as OE are likely, themselves, complications of EAC physiologic changes rather than inciting events. The bac­ terial species known to cause OE enter the EAC regularly. They do not, however, result in clinically significant infection unless the EAC milieu has been altered. Based on this knowledge, it is not unreasonable to consider most cases of OE “opportunistic infections.” As treating clinicians, it is important to be mindful that further changes to the normal physiologic homeostasis of the EAC as a result of certain treatments may result in more harm than good. Keeping in mind the ultimate goal of restoring normal EAC physiology rather than the myopic goal of “chas­ ing” infectious pathogens is paramount in not only achieving cure but also minimizing complications and preventing the transition of acute infections into chronic infections. This con­ cept will serve as a resounding theme in other sections of this chapter, especially when the pathogens of MRSA and fungi are discussed below. Further research is needed to answer these important questions.

Viscosity Viscosity of a topical therapy is also important because of the impact viscosity may have on the ability to effectively deliver the drug to the site of infection. The term viscosity is usually applied to liquids, and means, in a qualitative sense, the resistance that a liquid offers to flow. A liquid with a high viscosity such as molasses flows slowly. Water, which has a lower viscosity, flows more quickly. The viscosity varies con­ siderably between preparations. Resistance is very rarely seen in ototopical anti­infectives (see earlier discussion). The key to optimal use of ototopical antibiotics is adequate delivery. In general, this is the case with topical skin creams, ophthal­ mic preparations, and eardrops. In contrast, treatment­related resistance involving topical anti­infectives delivered to other sites, such as the lungs, has been reported.7,8,9 Therefore, because the high surface tension at the lateral surface of the

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CHAPTER 27 ❖ Otorrhea tympanostomy tube is one of the most critical factors that determines entry of the drops into the middle ear and because viscosity of the liquid is a variable directly related to surface tension and, more importantly, to velocity of flow, viscosity is clearly an important issue to consider when choosing an ear drop. In general, suspensions are more viscous than solu­ tions. Because of pH issues, otic suspensions (which are usu­ ally less acidic) are more commonly used than their solution counterparts. Increasing the viscosity of ototopical prepara­ tions not only negatively impacts drug delivery to the middle ear via a tympanostomy tube but also compromises the use of eardrops in conjunction with otowicks. Since the principle of otowicks relies on uniform drug delivery via capillary action, solutions with all components solubilized would be expected to be absorbed and delivered most uniformly. In general, the addition of a steroid and the pH of the solu­ tion directly affect viscosity. In order to solubilize or, at least suspend the steroid, lower and more acidic pH is necessary for many formulations. Suspensions containing a steroid, therefore, are generally more viscous and less acidic. Recent research has focused on the formulation of a steroid­contain­ ing ototopical antibiotic that is relatively less viscous and less acidic. Although still in development, such an alternative may represent an advance over those commercially available at this time.

Topical Antibiotic Alone or Combined with a Steroid? The need for a steroid in combination with an ototopical antibiotic has been debated in the past. The more evidence that is published, the more convincing the positive contribu­ tion of a steroid has become. Although the data supporting the contribution of a steroid varies by the particular condition that is the source of the otorrhea, all of these conditions are related by a final common underlying pathophysiological link, inflammation. The rationale for the inclusion of a steroid in ototopical preparations is theoretically sound. Steroids have known potent anti­inflammatory activity. Since ototopicals are most commonly used in conditions of the ear in which inflammation is a prominent component (most often as a result of infection), the inclusion of a steroid makes sense. One study by Gyde et al.9 compared the treatment of otor­ rhea with gentamicin alone or with a combination of colistin, neomycin, and hydrocortisone. The researchers concluded that the steroid­antibiotic combination was more effective in relieving inflammation in a shorter period of time and that gentamicin alone appeared to be more effective in eradicat­ ing the infecting organisms. The sample size was small and the comparators were less than ideal. Combined gentamicin­ steroid therapy was compared with placebo in a study of 163 patients with chronic otitis, and more clinical cures (52% vs. 30%) resulted with the combination treatment.7 A primate study found that, in cynomolgus monkeys with CSOM, treatment with topical ciprofloxacin effectively

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eradicated P. aeruginosa from the middle ear when compared with saline. There was no difference, however, between the two groups in terms of the rate at which the otorrhea ceased.8 Failure to resolve otorrhea despite the eradication of the infecting organism may have resulted because the inflam­ matory mucositis was inadequately treated. A second study using the same animal model found that antibiotic and steroid (tobramycin plus dexamethasone) resulted in more rapid res­ olution of otorrhea compared with antibiotic alone.10 The rate of decrease in the otorrhea score was more rapid for groups given an antibiotic and, as stated, the addition of dexametha­ sone to the antibiotic hastened this decrease even more. A similar clinical trial compared ciprofloxacin alone with ciprofloxacin plus hydrocortisone in the treatment of OE. A more rapid time course to resolution of pain (0.8 days) was seen when the steroid was added to fluoroquinolone as com­ pared with treatment with fluoroquinolone alone.11 Investiga­ tors have questioned not the contribution of the steroid but the contribution of the topical antibiotic. A study of external otitis caused by infection with P. aeruginosa or Candida albicans was done in a rat model. The researchers documented “efficient” cure with a topical group III steroid alone (i.e., without an antibiotics) and concluded that “irrespective of the microbial agent, group III steroid solution cured exter­ nal otitis efficiently in a rat model. The addition of antibiotic components to steroid solutions for the treatment of external otitis is of questionable validity.”12 A similar advantage of a topical steroid added to a topical antibiotic was seen in a clin­ ical trial of TTO. One study examining the efficacy difference between an antibiotic alone (topical ofloxacin) and an anti­ biotic/steroid topical combination (ciprofloxacin/dexametha­ sone) revealed a significantly shorter time to resolution of otorrhea by two days resulting from TTO.13 This same study also revealed a faster time to cessation of otorrhea when a steroid/antibiotic combination was used with a greater than 20% advantage conferred by the steroid at treatment day 11. The effect was still significant at 18 days as manifest by a difference of nearly 15% resolution of otorrhea in the topi­ cal steroid/antibiotic group as compared to the topical antibi­ otic alone group. Overall cure rates were higher in the group that was treated with a topical steroid in addition to a topical antibiotic. The study by Emgard et al. not only supports the anti­ inflammatory contribution of a topical steroid in otorrhea caused by OE but also suggests that a steroid may also contribute to overall cure by means of an “antimicrobial” effect. A second primate study also done in Pittsburgh demonstrated improved microbiologic eradication with an antibiotic/steroid combination as compared to a topical antibiotic alone in CSOM caused by infection with P. aeruginosa.10 This ostensible “antimicrobial” effect of a topi­ cal steroid found in these animal studies was also noted in pivotal human clinical trials. When comparing microbiologic eradication in patients with TTO, those treated with cipro­ floxacin/dexamethasone achieved microbiologic eradication

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92% of the time as compared to eradication in only 81.8% of patients treated with topical ofloxacin alone. Although one may be tempted to conclude from these data that topical cip­ rofloxacin is a “better antibiotic” than topical ofloxacin, the same result was seen when microbiologic eradication with ciprofloxacin alone was compared to eradication with cip­ rofloxacin/dexamethasone in patients with TTO. In patients with TTO caused by gram­positive pathogens, a difference of almost 15% was noted with better microbiologic eradication seen in the antibiotic/steroid­treated group. This difference was even more striking in patients with gram­negative infec­ tions in that eradication was achieved in 89.2% of patients treated with ciprofloxacin/dexamethasone compared to only 70.2% in topical ofloxacin­treated patients.14 Interestingly, although beyond the scope of this chapter, this same “anti­ microbial” effect of topical steroids has been seen in sinona­ sal and cutaneous infections. Intranasal corticosteroids, for example, cut in half the bacterial recovery rate (40.0% vs. 82.6%) in rhinosinusitis patients following revision endo­ scopic sinus surgery.15 Similar reduction in the recovery of S. aureus from the skin of patients with atopic dermatitis was seen after treatment with topical steroids.16 The mechanism of this “antimicrobial” effect of topical steroids is unknown. It has been hypothesized that steroids may inhibit Th­2 cell (T­cell subtypes­IL4) driven inflammation­epithelial breaks which expose bacterial subepithelial receptors. Other pro­ posed mechanisms suggest that steroids inhibit epithelial inflammatory gene expression that results in upregulation of factors known to augment local innate immunity such as col­ lectins, acute phase proteins, and compliment. Two randomized, evaluator­blind, multi­center, prospec­ tive clinical trials were performed, one in children aged 1–11 years and a second in patients 12 years or older.17 The safety and efficacy of ototopical ofloxacin was compared with the safety and efficacy of Cortisporin® (neomycin sulfate, polymyxin B sulfate, and hydrocortisone). The investiga­ tors found no statistically significant differences in clinical or microbiological and clinical cure rates. The failure of hydrocortisone in Cortisporin® to produce better outcomes likely relates to the pro­inflammatory properties of the for­ mulation which was not developed or FDA approved for use in the middle ear. Additionally, Cortisporin® contains hydrocortisone as the anti­inflammatory agent. On a relative scale, topical hydrocortisone is a relatively weak steroid. The more favorable results supporting the addition of a topical steroid reported earlier all pertained to topical formulations containing dexamethasone, a steroid with more relative anti­ inflammatory “potency” than hydrocortisone. Many physicians erroneously believe that the addition of a steroid may help but “can’t hurt.” This is not entirely true. The 49th edition of the Physician’s Desk Reference states, in a warning for Cortisporin® regarding the steroid component, that “Since corticoids may inhibit the body’s defense mecha­ nism against infection, a concomitant antimicrobial drug may be used when this inhibition is considered to be clinically significant in a particular case.18 Furthermore, even though

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steroids are thought of as anti­inflammatory agents, the opposite can be observed, most likely as a result of a sensiti­ zation to the steroid itself. In an article by van Ginkel et al.,19 the authors said, “In spite of their intrinsic anti­inflammatory activity, topical steroids can also enhance the inflammation due to sensitization.” In their study, 6 of 34 patients (18%) with chronic otorrhea (i.e., more than three months) treated with a steroid­containing ototopical agent had positive patch tests to steroids. This finding raises the possibility that patients with CSOM refractory to treatment with a steroid­containing topical agent are refractory, not because of failure to resolve the initial infection but because of allergic inflammation per­ petuated by continued exposure to the steroid. This body of evidence supports the use of a topical steroid combined with a topical antibiotic in most cases of otorrhea. Such support derives not only from more rapid cessation of otorrhea and higher cure rates but also from better microbio­ logic eradication in cases of infection. This latter discovery was somewhat unexpected but nonetheless welcomed by oto­ laryngologists who have long suspected that topical steroids enhance treatment effect in most mucosal inflammatory con­ ditions of the upper aerodigestive tract. In the end, aggressive treatment of acute otorrhea is the best approach to preventing chronic otorrhea nationally and globally since CSOM would not exist if every case of acute otorrhea was cured. The same can be said of chronic OE.

How Many Antibiotics to Use? Cortisporin®, Pediotic®, and Coly­Mycin®, for example, are all ototopical preparations that contain more than one antibiotic. The rationale for the antibiotics combined in such preparations is not clear. Polymyxin B sulfate (10,000 units/mL), which is used in most topical ear preparations, is active against P. aeruginosa and other gram­negative bacteria, including strains of Escherichia.20 Similarly, colistin sulfate also has bactericidal activity against most gram­negative organisms, notably P. aeruginosa, Escherichia coli, and Klebsiella species.20 Neomycin sulfate is an aminoglycoside, again with primary bactericidal activity against gram­negative organisms and some activity against S. aureus as well. None of the antibiotic components of Cor­ tisporin® or Pediotic® provide adequate coverage against S. pneumoniae.21 Yet, S. pneumoniae is one of the three most common pathogens isolated in TTO.22 In a real­life situation, if a child has a draining ear, the physician is likely to treat it by empirically selecting an antibiotic. One that does not cover a primary potential pathogen would clearly be unwise. In such a setting, Cortisporin® would have to be combined with a systemic antibiotic, defeating the goal of using topical therapy alone. The US FDA has become much more stringent and less likely to approve combination preparations unless a separate and significant contribution of elements is shown. This approach is prudent because the side effect profile of combination drugs is expanded and the potential for toxicity increases, as does cost in most cases.

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CHAPTER 27 ❖ Otorrhea Furthermore, it makes little sense to run the risk of sensiti­ zation to a compound that may be of benefit to the patient later in life if there is not a significant proven benefit for its inclusion in a combination drug. The ototopical quinolones, ofloxacin and ciprofloxacin, provide excellent coverage of all five common pathogens in TTO and appear micro­ biologically superior to older alternatives both alone and in combination for this indication. The last issue is whether dual therapy is needed to treat pseudomonal infections of the ear. This has been conven­ tional teaching with other pseudomonal infections such as pneumonia, based on the rationale that the synergy result­ ing when two drugs with different modes of activity against pseudomonal species are used is crucial in preventing the emergence of treatment­induced resistance and in increasing ultimate cure rates. In part, this rationale may have led to the development of combination ototopical agents contain­ ing an aminoglycoside (e.g., neomycin) and a member of the polymyxin family (e.g., polymyxin B sulfate). The data on the treatment of pseudomonal infections of the ear have not indicated the need for dual therapy, either topically or systemically, for routine, uncomplicated cases. A study from Pittsburgh23 revealed excellent in vitro susceptibility of aural isolates of P. aeruginosa to the semisynthetic penicillins. In children with CSOM refractory to outpatient management, single­agent intravenous therapy from this class of antibiot­ ics has been the standard treatment, with excellent results. Ototopical fluoroquinolone antibiotics provide excellent coverage of all the major pathogens found in TTO. Another study22 found that microbiologic eradication by ofloxacin used topically eradicated 94% or more of P. aeruginosa, H. influenzae, S. pneumoniae, S. aureus, and M. catarrhalis, the five major pathogens isolated in TTO. In a third clinical trial studying the efficacy of ciprofloxacin in the treatment of OE, the eradication of the pathogens was equally impressive. Taking advantage of the impressive broad­spectrum cover­ age of this class of antibiotics is desirable and enables single­ agent treatment of these infections.

ADVERSE EVENTS WITH OTOTOPICAL AGENTS Allergic Sensitization The major disadvantage of products containing neomycin is its propensity to lead to sensitization. This manifests as allergic inflammation, most often of the skin of the EAC and pinna. Van Ginkel et al.19 stated that, “Because of the high risk of sensitization, topical preparations containing neomy­ cin … should not be used routinely.” “In patients with otitis that has been treated topically, neomycin is invariably the most important sensitizer.19,24–28 Neomycin sensitization is vastly underestimated. When used in the EAC, the package insert of Cortisporin®18 states that the manifestation of sensi­ tization to neomycin is usually a low­grade reddening with swelling, dry scaling, and itching. Sensitization may manifest

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as failure to heal. As in nasal allergy, mucosa responds to allergic triggers with edema and drainage. In both skin and mucosa, the inflammatory manifestations of allergy and infection are clinically similar, if not indistinguishable.

Ototoxicity Few subjects have been greeted with more controversy and debate than the subject of ototoxicity to ototopical com­ pounds. There is little question that reversible and irreversi­ ble ototoxicity and nephrotoxicity have long been recognized as complications of systemic aminoglycoside antibiotics.29 What is less certain is whether such antibiotics, delivered topically to the middle ear, are significantly injurious to the cochlea and labyrinth. This concern has recently been further heightened by the fact that the treatment of Meniere disease may include topical gentamicin. The goal of such therapy is to purposely destroy the labyrinth. In a significant percentage of cases, loss of hearing has occured.30 It is generally believed that aminoglycosides in a healthy middle ear can enter the inner ear by diffusion across the round window and the oval window.31 Conclusive evidence that ototoxicity can occur as a result of aminoglycosides used topically in an infected ear does not exist. One confounding variable making such “proof ” difficult is that sensorineural hearing loss can occur as a result of otitis media itself.32 Determining whether the toxicity results from the primary disease or from its treatment is extraordinarily difficult. Several anecdotal reports suggest the latter.33–35 Podoshin et al.36 found that, in patients with CSOM and with comparable disease duration, those who received topical steroid alone (n = 24) had a mean sensori­ neural hearing loss of only 0.9 dB, as opposed to those who received a combination of topical dexamethasone, neomycin, and polymyxin B (n = 124), who had a mean sensorineural hearing loss of 6 dB. This difference was statistically signifi­ cant (p < .025). The authors concluded that the potential for ototoxicity resulting from certain topical preparations should not be ignored. The American Academy of Otolaryngology­Head and Neck Surgery (AAO­HNS) adopted a policy statement, #1420, on July 9, 1994, and reaffirmed it on March 1, 1998, recognizing “the appropriateness of utilizing currently available topical preparations, including those contain­ ing aminoglycosides, in the treatment of external and mid­ dle ear disorders.”37 Although the incidence of ototoxicity resulting from the use of ototopical agents in the face of infection is rare, it most likely occurs. Because of this fact, two subsequent sponsored AAO­HNS consensus panels and an evidence­based set of practice guidelines ultimately supported the use of nonototoxic topical preparations when the tympanic membrane is not intact in most cases.38,39 The first AAO­HNS sponsored consensus report38 concluded that “the availability of nonototoxic ototopical antibiotics should lead to their consideration as first­line therapy for the treat­ ment of uncomplicated CSOM and TTO.” In a survey of oto­ laryngologists,34 3.4% of respondents indicated that they had

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witnessed irreversible inner ear damage following the use of anti­infective ototopical formulations. This did not include the instances of reversible toxicity or the instances of unidentified ototoxicity. A second AAO­HNS consensus report arrived at a similar conclusion by applying evidence­based methodol­ ogy.39 Finally, AAO­HNS sponsored clinical practice guide­ lines for OE echoed this same conclusion. Although, by and large, ototoxicity is not regarded as a major issue in OE since the tympanic membrane is usually intact, a guideline to “… prescribe a non­ototoxic topical preparation” in the event of a nonintact tympanic membrane was included.40 There are several reasons why clinicians may not have identified such toxicity if and when it did occur. First, it may be reversible. This is significant especially in children. Second, those chil­ dren at highest risk for TTO are either not walking or just beginning to walk. Even if a vestibular insult were to occur in the toddler, it may likely be written off to age­appropriate “clumsiness.” Only recently have the labyrinthine effects as a result of chronic otitis media with effusion been recognized in this age group.41,42 Third, the ability to centrally compensate for a unilateral vestibular insult, especially in younger indi­ viduals, probably results in missed diagnoses as well. Fourth, if vestibular symptoms were to occur in a patient undergo­ ing treatment for TTO with a topical aminoglycoside, those symptoms are often attributed to the disease and not to its treatment. Since only histopathologic examination of the temporal bones would distinguish between these two etiolo­ gies, such potential toxic effects may go misdiagnosed. Fifth, if hearing loss occurs as a result of topical aminoglycosides in the middle ear, the highest frequencies are at greatest risk. Ultra high­frequency audiometry would be needed to detect the hearing loss, a test that is not routinely done. On the basis of what is currently known from both animal studies and from clinical experience, ototoxicity likely occurs as a result of middle ear exposure to topical ototoxic antibiotics such as aminoglycosides and to certain vehicles and antiseptics. This is a rare event, especially when such agents are used in the setting of mucosal infection and inflammation for a limited duration of time and in restricted dosages. Furthermore, it is likely that the true incidence of such toxic outcomes has been underestimated and that safer alternatives should be used when possible.

Treatment Once the middle ear is positively identified as the source of infection, aggressive aural toilet must be performed. Since the microbiology is so predictable, it is reasonable to initiate empiric treatment with a nonototoxic topical preparation and to defer culture­directed systemic therapy for treatment fail­ ures. Culture­directed systemic treatment should be consid­ ered for patients with persistent otorrhea after 7–10 days of topical treatment and initially for patients with systemic signs of illness such as high fever over 101°F. Care should be taken to obtain the sample from the middle ear rather than from the EAC, because pathogens from the latter site may not repre­ sent those responsible for the middle ear infection.43

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Interpreting Culture Data When Applied to Topical Antimicrobial Therapy One must be careful when interpreting culture results. Two clinical trials highlight this point nicely. A first trial reported the overall clinical response rate and the pathogen sensitivity for ofloxacin­treated TTO to be completely independent of one another. An 88% and 50% clinical cure rates were noted in those patients with sensitive and intermediate­resistant pathogens, respectively, as compared to a cure rate of 100% in those with resistant or acquired resistant pathogens (personal communication, Mindell Seidlin, M.D., Daiichi Pharmaceu­ tical Corporation, 1999). Similarly, in patients treated for CSOM, those with valid baseline “sensitive pathogens” were cured 95% (n = 124) of the time as compared to those with intermediate, resistant, or acquired valid baseline resistant pathogens who all had cure rates of 100% (n = 14). Although the number of nonsensitive microbiologically evaluable path­ ogens in the studies was small (n = 18) relative to the overall sample sizes of 131 and 156, it was nonetheless significant enough to demonstrate a lack of correlation between in vitro susceptibilities and clinical outcomes when topical therapies were used for treatment (personal communication, Mindell Seidlin, M.D., Daiichi Pharmaceutical Corporation, 1999). So what accounts for this ostensible contradiction that cure rates were independent of pathogen susceptibility? The Clinical and Laboratory Standards Institute (CLSI), formerly known as The National Committee of Laboratory Stand­ ards (NCCLS), breakpoints used by standard microbiology laboratories are determined based on typical tissue antibiotic levels achieved with systemic administration of antibiotics. Ototopical concentrations are, on average, 1000­fold higher than that. One study revealed that, when 0.3% ofloxacin solu­ tion was administered topically in a single dose to patients with CSOM, serial sampling up to two hours afterward showed 388.8–2849.8 μg/mL at 30 minutes with the highest value being close to the concentration of the drug itself (3000 μg/ mL).44 This was in contrast to Bluestone and Klein’s findings that middle ear fluid levels of antibiotics after oral antibiotic administration only ranged from 0.2 to 8.2 μg/mL at 0.5–2.5 hours after administration.45 Since increasing concentration is one of the primary strategies used to overcome resistance (thus, the latest recommendations to use 80–95 mg/kg of amoxicillin rather than 40 mg/kg to overcome the interme­ diate­resistant pneumococcus), only in vitro data that adjusts for the substantially higher topical concentrations would be useful. At the Children’s Hospital of Pittsburgh, this point was further substantiated in a retrospectively review of 23 positive cultures for methicillin­resistant S. aureus (MRSA) in 17 children from 1992 through 1996 seen in the outpatient department.46 Follow­up by telephone contact revealed that by the third or fourth day of treatment when the culture and sen­ sitivity data were available, the majority of cases of otorrhea had resolved, even though data suggested that the organism was resistant to the topical treatment empirically prescribed. Even the most frightening resistant organisms such as MRSA can effectively be eradicated with topical treatment.

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CHAPTER 27 ❖ Otorrhea

TROUBLESHOOTING Topical Drug Delivery It is highly unlikely that a treatment failure is due to a “drug­ bug” issue when using a broad­spectrum ototopical prepara­ tion. Investigation of alternative reasons should ensue. Focus should be on ways to enhance drug delivery. Failure to deliver the drug underlies most topical treatment failures. Topical drug delivery may be improved using several strat­ egies. First, carefully perform aural toilet. Dry mopping and suctioning the EAC with or without antiseptic irrigation are both acceptable. Second, review with the caregiver and/or with the patient optimal ototopical administration technique. Be certain the caretaker is aware that the auricle must be retracted posteriorly and superiorly in order to straighten the EAC and provide a more linear path into the middle ear. Third, it is critical that, after the dose is administered, the tragus be pumped to exceed the surface tension of the tympanostomy tube. Fourth, although product labels vary regarding the rec­ ommended time that the patient should remain with the treated ear in the upright position, the longer the better, and an aver­ age of 5–10 minutes is recommended, especially in refractory cases. This is most important with a highly resistant organism. Avoiding run­off and maintaining the concentration of the antibiotic above the minimum inhibitory concentration is crit­ ical in microbiologic eradication. Finally, the use of an otow­ ick has been beneficial in refractory cases. Wicks are not only helpful in the case of OE associated with significant swelling of the EAC but also in refractory TTO. Fenestrated wicks are recommended in TTO to allow drainage while continuing to ventilate the middle ear. Furthermore, from the standpoint of patient comfort, a fenestrated wick will prevent “ear popping” with every swallow. The precise mechanism underlying the effectiveness of otowicks in TTO is unknown; however, sug­ gested mechanisms include (1) improved delivery of the med­ ication to the medial aspect of the ear canal and middle ear via capillary action, (2) “depot” delivery of the drug resulting from the retention of the medication and by the maintenance of the medication by the wick in contact with the infected area, and (3) aural toilet by absorbing the otorrhea from the middle ear. Furthermore, the colony counts of EAC bacteria are better managed with a wick in place, likely preventing reinfection of the middle ear from EAC pathogens such as P. aeruginosa that would otherwise “swim upstream” into the middle ear. Finally, solid, nonfenestrated wicks may be considered in cases that fail initial treatment with a fenestrated wick as they possess the additional advantage of increasing the middle ear pressure “cushion” and, thus, minimizing nasopharyngeal reflux of organisms via the eustachian tube. This results in a similar effect to removal of the tympanostomy tube.

Allergy An atopic constitution should be suspected in refractory cases. The mechanisms by which allergy may result in suppurative middle ear disease are many and all must be

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carefully considered. A detailed discussion of this subject is beyond the scope of this chapter, but the common poten­ tial mechanisms will be briefly mentioned for completeness sake. It is also important to keep in mind that several different immunoglobulin E (IgE)­mediated mechanisms may occur simultaneously. Hence, a comprehensive strategy of several different therapies may be necessary to optimize treatment results. In the event that a single clinician lacks such back­ ground, an interdisciplinary team should be assembled. As stated earlier, sensitization to topical agents is a cause of treatment failures and is likely more common than pre­ viously thought. Skin sensitization manifests as erythema, edema, desquamation, otalgia, and pruritus; the same symp­ toms as OE. Similarly, mucosa reacts to allergens to which it is sensitive by producing drainage; the same principal sign as infection. In short, a failure to heal in either OE or otitis media may, in fact, represent a contact sensitization of the ototopical agent, the most common of which are neomycin­ containing products. Not only can the ototopic treatment serve as an allergen but the components of a tympanostomy tube may do so as well. Dohar reported a case of a child with CSOM that was perpetuated by contact sensitivity to the pol­ ymer from which the tympanostomy tube was constructed.47 The middle ear and eustachian tube mucosa have long been suspected of being “target organs” of allergy. This direct IgE­mediated mechanism of middle ear and eustachian tube inflammation should not be forgotten. IgE­mediated mechanisms may also arise in response to certain middle ear and EAC pathogens, namely fungi. This mechanism will be more completely discussed below.

Eosinophilic Otitis Media Finally, and quite exciting, is the recently described entity of eosinophilic otitis media (EOM).48 Although classically described in the setting of an intact tympanic membrane and chronic otitis media with effusion, this entity has also been suspected in patients whose tympanic membranes are not intact. The key microscopic finding in these patients is a middle ear effusion primarily containing eosinophils. The pathogenesis is not fully understood. Interestingly, the tubal opening duration was significantly longer in patients with EOM than in patients with asthma but without OM, con­ trols with COM, and normal controls.49 Most patients respond to steroid treatment. In steroid treatment failures ramatroban, an inhibitor of the thromboxane A2 receptor (TP) and the chemoattractant receptor­homologous molecule expressed on Th2 cells (CRTH2), has been successfully employed. Epi­ demiologic clues that should trigger serious consideration of this entity include patient age in that patients with EOM are generally older than the patient population at highest risk for recurrent acute otitis media (i.e., patients between 6 months and 3 years of age) and associated bronchial asthma. A systemic agent administered orally or, in very rare cases in which infection persists beyond three to six weeks, intravenously, may be needed to supplant ototopical therapy. Since the advent and common use of topical quinolones,

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intravenous antibiotic therapy, a once common means of treatment of CSOM in children, has become extremely uncommon. Likewise, tympanomastoid surgery, adenoidec­ tomy, and removal of retained tympanostomy tubes may be considered but are also infrequently necessary as more effec­ tive medical strategies have been adopted.

Microbiology of Otorrhea—The Old, The New, The Ugly! Although seemingly misplaced in this chapter, it is fitting to discuss the most recent literature describing the microbiol­ ogy of otorrhea under the heading of “troubleshooting” since much has been published on the potential roles of resistant pathogens such as MRSA and nonbacterial pathogens such as fungus in treatment failures. The Old The five major bacterial pathogens most commonly iso­ lated from cultures of otorrhea have not changed in decades since such surveillance has been reported. These pathogens have been mentioned above and include P. aeruginosa, S. pneumoniae, S. aureus, nontypeable H. influenzae, and M. catarrhalis.50 What has changed, however, are the susceptibilities of these pathogens to various antibiotics, the relative repre­ sentation of each, and the emergence of certain resistant strains as community­acquired infections.51 There is sig­ nificant overlap between the microbiologic susceptibility changes in otorrhea and in otitis media with an intact tym­ panic membrane for S. pneumoniae, nontypeable H. influenzae, and M. catarrhalis. These changes have occurred largely due to antibiotic use and vaccination. Particular strains of resistant S. pneumoniae such as 19A have caused significant angst in the struggle to stay ahead or, at least, keep pace with emerging bacterial resistant patterns. To avoid repetition, the reader is referred to these discus­ sions elsewhere in Section II of this book. Because of its specific relationship to otorrhea and because of an alleged cause­and­effect relationship to ototopical treatment, a more complete discussion of one such resistance issue, namely MRSA, is included below. The New What is new is the identification of a far more complex population of bacteria isolated from otorrhea deriving from patients with OE and with TTO (Personal Communication, David Stroman, Alcon Laboratories Inc., 2008). As is evi­ dent in the figures summarizing these isolates, there are far more bacterial strains represented than the five most com­ mon strains already listed above. Although the precise role of each of these organisms is unknown, what is clear is that a complex microenvironment exists in these patients and that traditional infectious disease paradigms are an oversimplifi­ cation of the reality. Potential implications of such a complex

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microenvironment are discussed in the sections on biofilms and on bacterial interference. The Ugly Fungal Otitis/Fungal OtOrrhea The subjects of Fungal and MRSA otorrhea are listed under “The Ugly” because of the erroneous reports that these pathogens have emerged as sig­ nificant pathogens in children with otorrhea due to currently accepted standards of treatment. To begin with, the role of fungi in ear disease is debated. Further fueling this debate are recent claims that widespread treatment with ototopical quinolones has led to the emergence of an increased incidence of fungal oti­ tis.52 Although fungal species have been isolated from treatment failures following ototopical quinolone treatment, no evidence for a cause­and­effect relationship exists. One study found no evidence of new fungal infections as the duration of topical ofloxacin therapy was extended for as long as four weeks.53 Similar allegations have been published in the literature regard­ ing MRSA otorrhea and are discussed in greater detail below. Complicating the matter further is the questionable rela­ tionship between the isolation of a fungal species and its role in pathogenicity of otorrhea, if any. Curiously, fungi are rarely isolated from TTO. One relatively large clinical trial found that fungi were isolated from TTO in only 2% of cases.8 Although this topic could be expanded into a chapter of its own, the salient points will be summarized. What is important to understand is that the presence of fungus in a draining ear may signify any one of the following: Fungal superinfection Secondary infection Saprophytic colonization Allergic fungal otitis media Invasive nonfulminant OM Invasive fulminant OM By identifying the role that the fungus is playing, the treat­ ment becomes obvious. In cases where the fungus is merely a saprophyte supported by an ear that is dark, warm, and moist, all that is generally needed is good aural toilet to “dry” up the ear and to debride the fungal elements. In secondary superfi­ cial fungal otitis, topical fungal therapy with a solution such as clotrimazole or a powder such as tolnaftate is generally added to aural toilet. Invasive infections generally warrant systemic antifungal therapy with amphotericin B (and its lipid formulations), various azole derivatives, echinocandins, or flucytosine. Surgical debridement and/or wide­field resec­ tion may be necessary especially in the setting of an immu­ nocompromised state. Finally, if the fungus is acting as an allergen, steroids, aggressive aural toilet, and desensitization immunotherapy may be needed. One final entity that involves fungus in a draining ear is worth particular mention, a dermatophytid (termed the Id) reaction. This condition is defined as a focus of fungal infection elsewhere in the body that causes a secondary

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CHAPTER 27 ❖ Otorrhea inflammatory process in the EAC. The pathogenesis involves the hematologic spread of fungi or their allergenic products from a primary focus of fungal infection. The key elements of the Id reaction include the following: 1. A demonstrable primary focus containing the pathogenic fungi, remote from the id lesion 2. Absence of fungi in the skin lesion at the id reaction 3. Spontaneous resolution of the dermatitis when the primary focus fungal infection has been eradicated 4. A positive immediate skin test response, demonstrating a type 1, IgE­mediated reaction to an intradermal test of the fungal antigen What is evident from this brief discussion is that the isolation of fungus from a draining ear is neither trivial (in terms of pathogenic significance) nor straightforward (in terms of treatment). This is an area in both otologic and sinonasal disease that is aggressively being investigated and that prom­ ises to evolve in the future. Mrsa Like fungal otorrhea, reports in the literature have implied a cause­and­effect relationship between the emer­ gence of MRSA otorrhea in children and treatment with topical quinolone antibiotics. Unfortunately, such a relation­ ship has not been proven and is quite unlikely. In 2003, the following statement was published, “Since the introduction of ototopical quinolones (Ciprofloxacin and Ofloxacin) in 1998, a marked increase in treatment failures of AOMT due to MRSA has resulted.”54 This statement was unfounded by actual data and was a conclusion based on a mere temporal relationship. Daniel Jernigan of the CDC, Atlanta, Georgia noted that MRSA resistance began in the 1970s—a phenom­ enon of strains isolated within hospitals (HA­MRSA). By the late 1990s or certainly early 2000s, CA­MRSA had emerged and has steadily increased. It was at this same time that, coincidentally, ototopical quinolones became commercially available. Dr. Jernigan noted two risk factors in children “… daycare” and “recent antibiotic use …”55 a risk factor also found in a study done in Pittsburgh for the specific develop­ ment of MRSA otorrhea in children.46 Although the contention that MRSA has emerged as a sig­ nificant community­acquired pathogen causing otorrhea in children due to topical quinolone ear drop use is false, this pathogen has, nonetheless, posed a challenge to clinicians and must be treated thoughtfully. Because of the capacity of MRSA to persist and to colonize the ear long after otorrhea has resolved, the treatment goal of complete eradication is not only unrealistic but dangerous. Bacterial interference is described in detail below but is a concept that is critical to keep in mind when approaching a child with MRSA otorrhea. This is so because methicillin­sensitive S. aureus (MSSA) and MRSA compete for the same ecological niches in the body as has been reported in the anterior nares for example.56 Systemic strategies may, in part, fail in these patients because

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it is virtually impossible to treat a patient with a systemic antibiotic active against MRSA while at the same time able to spare its ecological competitor, MSSA. This is the justification to admonish systemic antibiotic treatment in these patients to the extent possible unless absolutely indi­ cated. As mentioned earlier, Coticchia and Dohar46 identified recent oral antibiotic exposure as the primary risk factor in children for the development of MRSA otorrhea. It is illogi­ cal to employ a treatment which is responsible for the disease in the first place. This is the single most important aspect of the management of these patients that is overlooked. It is also difficult for consultants to enforce because patients often seek out treatment from many different health­care providers. For reasons mentioned throughout this chapter, topical strategies are preferable to systemic strategies when treating MRSA otorrhea and should be considered “first­line” ther­ apy when possible. Initial treatment with ototopical ofloxacin or ciprofloxacin/dexamethasone is reasonable. Most often, however, these preparations have already been empirically prescribed and have failed. A very recent randomized and controlled study reported eradication of MRSA from the ears of 16 patients (100% microbiologic eradication rate) who presented with MRSA otorrhea and who were treated with mupirocin ointment. Mupirocin ointment at a dose of 0.6 mg was administered locally to the tympanic membrane and to the promontory around and through the perforation with its adjacent external ear canal one to four times for two or three weeks at the clinic. The control group consisted of 10 patients with MRSA otorrhea who were treated with “ofloxacin drops adminis­ tered daily by the patients at home for 2 or 3 weeks.” Only 4 of the 10 topical ofloxacin­treated patients were success­ fully treated and the difference was statistically significant p < .001.57 Despite such excellent reported efficacy, mupi­ rocin resistance has been reported and, although unlikely, one may see treatment failures in MRSA otorrhea patients due to resistance.58 Most cases of mupirocin­resistant MRSA strains have been recovered from patients with distinct clinical and epidemiological characteristics that rarely apply to children with community­acquired otorrhea. There are no reported series of children with MRSA otorrhea and significant high­ level mupirocin resistance. The absence of such case reports notwithstanding, it is certainly possible that such a case of high­level mupirocin­resistant MRSA otorrhea may present and that an alternative topical medication might be needed. Retapamulin ointment, 1% is now commercially available and represents the first of a new class of topical antibiotics— the pleuromutilins. It has a unique mechanism of action that interferes with multiple aspects of protein synthesis. Early data suggests that retapamulin may be as much as 32× more potent against S. aureus in vitro than mupirocin and that retapamulin had lower MICs than mupirocin against drug­ resistant S. aureus.59 It remains to be seen whether or not such impressive in vitro data will pass the test of time as this

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drug becomes more widely used. It is also important to note that clinical superiority has not been demonstrated in human trials. It always must be remembered that in vitro results do not necessarily correlate with clinical efficacy. At this time, however, it is a reasonable topical alternative in cases where other topical therapies have failed due to resistance. A final simple, accessible, and cost­effective strategy for the treatment of these patients as well as for the prevention of contagion is bathing in Clorox (1 tsp per gallon water for at least 15 minutes or ¼ cup to a bathtub) three times a week for 30 days. An alternative is to swim in a chlorinated pool at the same frequency for the same duration of time. Alterna­ tive antiseptics include 2% Chlorhexidine impregnated wash clothes, Phisohex®, and Hibiclens®. Although not preferred in most cases, oral or intrave­ nous systemic antibiotic therapy may be necessary in certain cases. By and large the choice of systemic antibiotic should be made based on susceptibility results. It goes without say­ ing that the most narrow spectrum agent should be chosen. A short case series of children with refractory multiple drug­resistant S. pneumoniae or MRSA otorrhea to topi­ cal quinolone drops was reported. Seven of eight children responded to treatment with oral linezolide.60 Abscesses and other complications may require surgical incision and drain­ age. In summary, the Dos and Don’ts of effective MRSA otorrhea management are: ■

■ ■

■ ■

■

Don’t chase MRSA with systemic antibiotics labeled “susceptible” in vitro—such as Bactrim, Linezolid, or Vancomycin Don’t overoperate—that is, mastoidectomy Do identify the reservoir of colonization and consider barriers to isolate the source (most often the skin on the EAC) of MRSA from the middle ear—that is, reconstruct and close perforations of the tympanic membrane Do restore physiologic EAC homeostasis Do respect the “tincture of time” as colonization and bacterial replacement is often delayed Do rely on topical antibiotics as the mainstays of treatment

FUTURE RESEARCH Because treatment­related resistance appears less likely to occur in response to ototopical agents and because safe oto­ topical quinolones are available, topical chemoprophylaxis may be a possibility for the future. Presently, no agent is indi­ cated to prevent recurrent OE, TTO, or CSOM. Such chemo­ prophylaxis may need to be delivered not only to the EAC but also to the nasopharynx via a nasal application. The topical application of chemoprophylaxis to the nose in an attempt to reduce the bacterial load of the nasopharynx may hold exciting promise as a novel means of preventing recurrent acute otitis media. Such a strategy may not only be efficacious and safe but may also not have the disadvantage of treatment­related resistance. One barrier to such research is a regulatory opposi­ tion to antibiotic chemoprophylaxis in the United States.

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Biofilms—The Case Against Are CSOM and other chronic forms of otitis media what some investigators term biofilm diseases?61 A biofilm is a complex organization of sessile bacteria that are living together in a mutualistic fashion. Biofilms can be com­ posed of multiple bacterial species (both aerobic and anaerobic) living within distinct microenvironments. These bacteria are believed to be distinct from their planktonic forms (free­floating organisms), very resistant to antibiot­ ics and host defense mechanisms, and difficult to isolate by routine culture techniques. Unfortunately, although receiving much attention in the recent literature, definitive evidence that any form of otitis is a biofilm disease in the traditional sense of the word is lacking. In fact, there are several reasons to doubt that any form of otitis is a classic biofilm disease. First, that fact that biofilms have been dem­ onstrated in the ear means relatively little when one consid­ ers that 99% of all bacteria exist in a biofilm phenotype.62 Where there are bacteria there are biofilms. Furthermore, the pathogens that are known to cause otitis media are also known to exist as common commensal/mutualist of the human airway not infrequently isolated from the airway in asymptomatic carriers. Though some studies failed to identify biofilms on otherwise healthy middle ears, at least one study did not.63 The primary issue that argues against conditions marked primarily by otorrhea as being biofilm diseases lies in the fact that they are most often not imper­ vious to antibiotic treatment. In fact, more than 90% of these infections resolve with antibiotic therapy; a natural history strikingly different from the natural history of more classic biofilm diseases such as cystic fibrosis. Similarly, traditional biofilm theory cannot account for epithelial des­ quamation in a conventional sense. The fifth stage of bio­ film development, detachment, is intuitively different and somewhat challenging to reconcile in otitis media as com­ pared to more straightforward detachment forces in dental plaque and device­associated infections, two of the more classic examples of biofilm diseases. All of these inconsistencies can be debated and many are still under investigation. Suffice is to conclude that biofilm research is exciting. It holds promise to greatly improve understanding and success in treating middle ear infections such as CSOM and in better understanding and treating several other chronic infectious diseases. Without question, biofilm research has heightened awareness of two important aspects of the pathogenesis of otorrhea. First, it has high­ lighted the importance of the pro-inflammatory potential of biofilms in the middle ear cleft. Second, and perhaps more important, is the revelation that ear infections result from a far more complex microenvironment and dynamic interplay of organisms than previously suspected. Traditional drug­bug paradigms, although easy to understand, have been exposed as oversimplifications of the reality of a delicate microbio­ logical balance that must be maintained in order to prevent inflammatory disease states.

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CHAPTER 27 ❖ Otorrhea

Alternative Explanations of Refractory Infectious Cases of Otorrhea If not biofilms exclusively, then what other research is afoot to explain current otorrhea treatment failures? Although the literature is replete with answers to this question, only those most likely to play a role in otorrhea are discussed. Bacterial Interference Bacterial interference is the dynamic antagonistic interaction between at least two organisms that affects the life cycle of each. The production of bacteriocins and other inhibitory substances that suppress some bacterial growth or the use of nutrients in the nasopharyngeal environment essential for the growth of potential pathogens may explain this phenomenon.64 The naso­ pharyngeal flora of nonotitis media­prone (N­OMP) children contains more aerobic and anaerobic organisms with interfering capability and less potential pathogens (hemolytic streptococci, nonhemolytic streptococci, Prevotella species, and Peptostreptococcus species) than that of OMP children.65 Brook and colleagues demonstrated a similar finding in sinusitis­prone66 and Group A streptococcal pharyngotonsillitis­prone patients.67 Although this is an exciting area of research with much to be contributed, two concepts are critical to remember given what is known about the current state of the art. First and foremost, physicians have been conditioned to think that “bigger is bet­ ter” in terms of empiric choices of broad­spectrum systemic antibiotics. Furthermore, clinicians have been trained to focus on which bacteria should be eradicated rather than which bacte­ ria should survive. The liability of eradicating bacteria in areas that are not normally sterile is replacement by alternative bac­ teria. This story has been told quite nicely in the modern era of universal pneumococcal vaccination. The concept of bacterial interference begs the corollary of “less is more.” The clear focus in applying this concept is to eradicate the pathogenic bacteria while at the same time spare bacteria with interfering poten­ tial. Clearly, topical strategies are far more likely to achieve this goal than systemic strategies. Second, treatment with bacterial strains that are potentially capable of interfering with coloni­ zation and infection with other more virulent organisms is an exciting strategy that requires further investigation. The concept of probiotics has been borne out of this concept and is likely the mere “tip”of the veritable iceberg that may follow. Intracellular Cocci Coates et al.68 have provided evidence for yet another mecha­ nism that may explain resistance to antibiotic therapy but that is independent of biofilm theory. In a recent study, these inves­ tigators found that gram­positive coccal bacteria were in mid­ dle ear mucosal epithelial cells of 4 of 11 (36%) children. The morphological appearance of the bacteria and the detection of pneumolysin DNA by polymerase chain reaction (PCR) in middle ear fluid suggested a possible role for persistent intracellular infection with S. pneumoniae and other gram­ positive cocci in some cases of otitis media with effusion (OME).68 It is reasonable to expect that such intracellular cocci are also present in some patients with otorrhea.

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CONCLUSION Since this chapter began with a quote and employed other quotes and clichés throughout its body, it only seems fitting that it should end in the same way. This chapter hopefully provided new paradigms and ways to view old problems, updated the information that currently constitutes the “state of the art” in otorrhea, and offered practical algorithms that can be immediately applied to children diagnosed with otorrhea. At the same time, it emphasized the importance of medical treatment over surgical treatment and to that point I remind the readers that: A chance to cut may be a chance to cure but a chance to cut is a chance to kill It takes five years to learn when to operate and twenty years to learn when not to A very bold surgeon is the one who realizes that his patient takes all the risks The lesser the indication the greater the complication And last but not least… An Otolaryngologist is a medical specialist who does surgery

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60. Isaacson G, Aronoff SC. Linezolid for tympanostomy tube otorrhea caused by methicillin­resistant S. aureus and multiple drug­resistant S. pneumonia. Int J Pediatr Otorhinolaryngol. 2008;72(5):647–651. 61. Costerson JW, Lewandowski Z, Caldwell DE, Korber DR, Lap­ pin­Scott HM. Microbial films. Ann Rev Microbiol. 1995;49:711. 62. Fergie N, Bayston R, Pearson JP, Birchall JP. Is otitis media with effusion a biofilm infection? Clin Otolaryngol Allied Sci. 2004 Feb;29(1):38–46. 63. Dohar JE, Hebda PA, Veeh R, et al. Mucosal Biofilm Forma­ tion on Middle­Ear Mucosa in a Nonhuman Primate Model of Chronic Suppurative Otitis Media. Laryngoscope. 2005;115: 1469–1472. 64. Patek M, Hochmannova J, Nesvera J, Stransky J. Glu­ tamicin CB II, a bacteriocin­like substance produced by Corynebacterium glutamicum. Antonie Van Leeuwenhoek. 1986;52:129–140. 65. Brook I, Gober AE. In vitro bacterial interference in the nasopharynx of otitis media–prone and non–otitis media– prone children. Arch Otolaryngol Head Neck Surg. 2000;126: 1011–1013. 66. Brook I, Gober AE. Bacterial interference in the nasopharynx and nasal cavity of sinusitis prone and non­sinusitis prone children. Acta Otolaryngol. 1999;119(7):832–836. 67. Brook I, Gober AE. Role of bacterial interference and beta­ lactamase­producing bacteria in the failure of penicillin to eradicate group A streptococcal pharyngotonsillitis. Arch Otolaryngol Head Neck Surg. 1995;121:1405–1409. 68. Coates H, Thornton R, Langlands J, et al. The role of chronic infection in children with otitis media with effusion: evidence for intracellular persistence of bacteria. Otolaryngol Head Neck Surg. 2008;138(6):778–781.

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C H A P T E R

Tinnitus in Children Samantha Anne and Anne F. Hseu

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innitus is the perception of sound without an obvious acoustic stimulus. Incidence in children has been reported to range from as low as 6% up to as high as 66%.1,2 An accurate estimate of true incidence is difficult in children due to challenges with interviewing this population. In addition, children rarely spontaneously report tinnitus and may only disclose presence of noises in their ears on prompting.3 Because of these challenges, there are limited research, data, and knowledge on the etiology, evaluation, and management of pediatric tinnitus. This chapter will focus on (1) discussion of diagnosis, evaluation, and management of tinnitus in children and (2) review of recent literature and advances.

IMPACT OF TINNITUS IN CHILDREN The most common age at which children report tinnitus is around 12 years in the study by Savastano.4 In this study of over 350 children with tinnitus, nearly 65% of them reported being bothered by the tinnitus and nearly half the children reported worrying about the noise. A study by Kentish et al. reviewed the effects of tinnitus on 24 children who presented to the psychology department with complaint of troublesome tinnitus.5 In this study, the authors identified that tinnitus triggers as noise in nearly half the children, stress/anxiety in 337% of the children, and other factors such as upper respiratory infections and jaw movements contributing to the rest. The most common concurrent symptoms present in nearly 60% of the patients were related to anxiety, including panic attacks, hyperventilation, dizziness, and preoccupation with tinnitus. In addition, 25% of the patients had significant behavioral problems at home. In general, the effects of tinnitus in children can be categorized into effects on hearing, scholastics and listening, overall general health, and psychological effects. Tinnitus may not be troublesome to some children but can sometimes cause significant distress in others. Associated symptoms reported by children include headache,2 dizziness and vertigo,6 and interference with sleep.5

EVALUATION OF TINNITUS IN CHILDREN Evaluation of a child who presents with tinnitus begins with obtaining a thorough history. The onset and triggers of the tinnitus, characterization of the tinnitus, exacerbating factors, and effects on behavior at home and school must be ascertained. Questions to be asked to the child include the following as recommended by Shetye and Kennedy7: (1) Do you hear noises in your ears? (2) What do the noises sound like?

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(3) What do you call the noises? (4) What do you do when you hear the noise? (5) How does the noise affect you? (6) When is it worse—at school, at home, in morning, or in evening? (7) Where is the noise—right, left, or both ears? (8) How long have you heard these noises? Characterization of the tinnitus is paramount to guide the clinician in ordering diagnostic testing and in formulating a differential diagnosis. In multiple studies, the three most common sounds that are reported by children are ringing, buzzing, and humming.4,8 Other words commonly used to describe the sounds include whistling, banging, clicking, “beep beep,” squeaking, and like machines, cars, or wind. In addition, the effects of tinnitus must be established based on the child’s report and parental interview. It is important to question how much the tinnitus is interfering with the child’s daily activities, if the child is experiencing behavioral issues at home and difficulty with concentration at school, and whether the tinnitus is causing anxiety and related symptoms. Medical history should also inquire on the use of ototoxic medications, noise exposure, otologic history including otitis media, prior surgeries and presence of hearing loss, head trauma, neurologic and cardiologic comorbidities, and dental conditions. Finally, history of perinatal risk factors for hearing loss and perinatal infections should be attained, especially history of meningitis. Physical examination must include an overall head and neck examination with a focus on the otologic examination. In general, facial dysmorphisms must be noted; it may reveal an underlying syndrome associated with inner or middle ear anomalies and hearing loss. Examination and auscultation of the neck and periauricular areas are important to detect vascular anomalies that may cause bruits. Particular attention must be directed toward detecting external and middle ear pathologies. Foreign bodies and cerumen impaction in the external auditory canal are not too infrequent in pediatric patients. Acute otitis media and chronic otitis media with effusion are also common in many children and present treatable causes of tinnitus. The pathophysiology of tinnitus in these situations is thought to be due to effusion resulting in conductive hearing loss that reduces the masking effects of environmental sounds. This is thought to result in an unpleasant detection of normal auditory and paraauditory signals that are otherwise not detectable. After obtaining a thorough history and physical examination, testing can be done audiologically with pure tone audiometry, tympanometry, and stapedial reflexes. Pure tone audiometry must be done with air and bone conduction to determine type and severity of hearing loss. Soundfield

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testing in addition to obtaining otoacoustic emissions may be necessary in younger patients in which pure tone audiometry is not possible. Tympanometry can aid the clinician in evaluating middle ear function. Finally, stapedial reflexes, if able to be done and if present, will confirm normal lower brain stem activity. Tinnitus measurements are also recommended when possible and can be done mainly in children who are able to perform pure tone audiometry. These studies include pitch and loudness match, masking level, and residual inhibition.9 Frequency or pitch matching is performed by varying a frequency of an external pure tone or a noise band until the child reports a close match to the sound of his of her tinnitus. Relative loudness is evaluated by adjusting the loudness of the external tone to the loudness that closely matches the sound of the tinnitus. Masking of tinnitus involves using a wide-frequency band noise as a masking sound and gradually increasing the sound until its presence is detected and then proceeding to increase the intensity of the sound until the tinnitus is no longer heard. Finally, a test of residual inhibition is performed by presenting the masking signal for 60 seconds and then measuring the period of time in which the tinnitus is inhibited or decreased. Imaging studies can be done to evaluate for inner and middle ear anomalies as well as intracranial pathology. Based on the index of suspicion, computed tomography (CT) scan of the temporal bones, magnetic resonance imaging (MRI) of the internal auditory canal and cerebellopontine angle, or magnetic resonance angiography/venography (MRA/MRV) might be necessary in evaluation. Sedation is often necessary in younger patients. CT temporal bones can reveal inner and middle ear bony anomalies, while MRI is better suited when there is suspicion for vestibular schwannoma or other cerebellopontine neoplasms. MRA/MRV is recommended when a bruit is auscultated or there is suspicion for a vascular cause of tinnitus such as cases of arteriovenous malformations (AVMs) and glomus tumors.

DIFFERENTIAL DIAGNOSIS Tinnitus in children can be classified as subjective or objective. In objective tinnitus, the child and examiner both observe the sound. In subjective tinnitus, only the child perceives the sound. Subjective tinnitus is more common than objective tinnitus; however, both types have multiple possible etiologies.

Subjective Tinnitus Subjective tinnitus in a child may be due to otologic, neurologic, pharmacologic, dental, metabolic, or psychological causes. The most common cause is hearing loss. The cause of the hearing loss may be unknown in some cases, but many times, there is an obvious and treatable source for the hearing loss, that is, exposure to ototoxic medications such as cisplatin in chemotherapy or middle

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ear pathologies, such as middle ear effusion, tympanic perforation, or ossicular disruption. Many times, however, no definitive etiology for subjective tinnitus can be identified, and the tinnitus is classified as idiopathic. This is always a diagnosis of exclusion. Hearing loss Tinnitus has been reported in children with both normal and impaired hearing. As previously stated, it is difficult to establish the true prevalence of tinnitus in children but it has been consistently shown to occur more frequently in children with hearing loss.10 Nodar and his coauthors were amongst the first to demonstrate this trend in their study that found tinnitus to occur in 13.3% of children with normal hearing and 58.6% of children with sensorineural hearing loss.11 Recent literature reviews have shown prevalence rates ranging from 9% to 53% in normal hearing children and 9% to 66% in hearingimpaired children.12,13 The significant variability in literature may be explained by differences in study methodology (i.e., interview techniques or definition of tinnitus). Study populations also varied widely in children’s ages, comorbidities, and environments. Of note, in a study by Savastano, only 6.5% of normal and hearing-impaired children complained spontaneously of tinnitus. The prevalence rate of tinnitus increased to 34% when the children were specifically asked.4 In the study by Savastano, the authors also noted that in the children with hearing impairment and tinnitus, no particular type or severity of hearing loss was identified. This is in contrast to Coelho’s study that found that tinnitus was more prevalent in children with minimal to mild hearing loss than in children with moderate to profound sensorineural hearing loss.14 Furthermore, in Coelho’s research, there was a correlation between hearing-impaired children and intermittent tinnitus. Normal hearing children were more likely to experience continuous sounds. Conductive hearing loss Tinnitus associated with conductive hearing loss maybe due to otitis externa, impacted cerumen, and external ear canal foreign bodies. Middle ear pathologies that cause tinnitus associated with conductive hearing loss may include acute and chronic otitis media with effusions, chronic mastoiditis, cholesteatoma, or stapes fixation. Chronic otitis media is the most common middle ear disorder in children who experience tinnitus.15 Sensorineural hearing loss Sensorineural hearing loss can be associated with tinnitus in children and can be inherited as a genetic disorder or can be due to maternal infections, congenital anomalies, known syndromes, or neurologic disorders. Meniere’s syndrome can also cause tinnitus, although the incidence in children is extremely rare in comparison with that of adults. In contrast to conductive hearing loss where the cause is more easily identifiable, the etiology of the sensorineural hearing loss and tinnitus is often undiagnosed.

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CHAPTER 28 ❖ Tinnitus in Children Mixed hearing loss Finally, pediatric tinnitus may be associated with mixed hearing loss, or children who have hearing loss with both conductive and sensorineural components. Children who are treated with cochlear implantation are a special population who may experience tinnitus. Chadha et al. looked at the prevalence of tinnitus in this group and found that tinnitus was reported by 38% of 40 children who utilized cochlear implants.12 In these children, the tinnitus occurred most commonly on the side of the implanted ear when the implants were not in use (i.e., when in bed at night). Tinnitus was also least associated with children younger than 5 years and with children who were implanted bilaterally simultaneously. Although the prevalence of tinnitus was fairly high in this population, the authors did note that quality of life was minimally affected with only a small number of patients reporting sleep disturbance. Rehabilitation for children with hearing loss and tinnitus should be a team approach with involvement of an otolaryngologist, pediatrician, audiologist, and speech language pathologist. Hearing rehabilitation options include preferential seating at school, FM systems, speech/language therapy, hearing aids, and cochlear implants. In children with hearing loss and tinnitus, hearing aids may provide benefit by providing both sound amplification and masking of tinnitus. The external sound provided by the hearing aid is thought to mask the internal sound generated and/or perceived by the patient. Oftentimes, the device can have different volume controls that can be adjusted independently to modify the input of the hearing aid and the masking noise. The success of the hearing aid, or any masking device, will depend on the loudness of the patient’s tinnitus. Central causes The prevalence of central tinnitus has not been well documented although it is generally well accepted that central nervous system disorders can contribute to auditory dysfunction and tinnitus. Central pathologies that need to be considered in pediatric tinnitus include multiple sclerosis (MS), history of meningitis, and neoplasms of the cerebellopontine angle. In adults with MS, hearing loss with or without tinnitus is usually accompanied by other neurologic deficits. However, in children with MS, there have been case reports where the child’s only symptom at initial presentation was unilateral nonpulsatile tinnitus.16 Children with a history of meningitis are also at risk for experiencing tinnitus. In a study by Aust, 1420 children who were seen for a hearing disorder were questioned regarding tinnitus.6 Of those who did report tinnitus, meningitis and subsequent inner ear damage were reported as the probable cause in 20% of the patients. Although rare in children, tumors involving cranial nerve VIII can occur and can be associated with tinnitus. Therefore, cerebellopontine angle tumors should be considered in the differential diagnosis, particularly if the child has a family history or clinical stigmata of neurofibromatosis.

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Trauma Patients who suffer head trauma frequently report tinnitus in conjunction with hearing loss.17 Trauma may include temporal bone fractures or closed head injuries. Temporal bone fractures can result in direct injury to the cochlear nerve but can also result in hemotympanum, thereby causing conductive hearing loss and associated tinnitus. Tinnitus may also result from cervical injury such as whiplash.18 Although the exact nature of this type of injury in relation to tinnitus is unknown, it has been suggested that incorrect proprioception from nerve fibers in the neck and shoulders can cause tinnitus. Other proposed theories include transient labyrinth ischemia or hemorrhage as a result of compression of the vertebral artery, direct labyrinthine or brain stem concussion, or noise of the collision causing acoustic trauma.18 Acoustic trauma has been shown to be significantly associated with tinnitus in both univariate and multivariate analyses.19 Children, especially of adolescent age, maybe at a particular risk for hearing loss induced by noise exposure as loud music, concerts, and other exposures become more frequent. It is not uncommon for patients to experience tinnitus, trouble hearing, and/or ear pain following exposure to loud noises. Studies have shown that the sources of the loud sounds that most frequently cause ear symptoms include concerts, parties, clubs, MP3 players, and stereos, in descending order.19 Coelho et al. also showed that a history of noise exposure was a risk factor for both tinnitus sensation and tinnitus suffering with an odds ratio of 1.8 and 2.9, respectively.14 Acoustic trauma may reorganize the tonotopic map in the primary auditory cortex, thereby contributing to tinnitus. Medications Ototoxicity caused by medications is well documented in literature. Tinnitus can result as a side effect of prescribed medications especially in those that are associated with hearing loss. Tinnitus has been associated with salicylates, aminoglycosides, quinines, loop diuretics, metalloid compounds, and antineoplastic drugs. Some of these medications, such as gentamycin or cisplatin, are necessary in certain clinical situations, and therefore, tinnitus may have to be an accepted side effect. In these situations, close monitoring of hearing thresholds and, in some cases, drug levels is necessary to minimize the ototoxicity and/or vestibulotoxicity. If possible, alternative therapies should be considered. Ototoxicity can also result in tinnitus in cases of drug overdose. For instance, tinnitus can result from an aspirin overdose and at times can be reversible on discontinuing the medication. Finally, tinnitus may arise following the use of recreational drugs. There are select case reports where alcohol, marijuana, and ecstasy result in tinnitus.20 Idiopathic/other Metabolic disturbances such as hyper- and hypothyroidism have also been shown to correlate with the symptom of tinnitus.21 In hyperthyroidism, increased cardiac output can result in pulsatile tinnitus. Other metabolic conditions that have

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been shown to be associated with tinnitus include vitamin deficiencies, specifically vitamins A or B. Hyperlipidemia, although less common in children than adults, has also been linked to hearing loss and tinnitus. Dental disorders such as temporomandibular joint (TMJ) disorder or bruxism may be associated with aural symptoms such as tinnitus, otic fullness, and subjective decrease of hearing acuity.22 Some studies suggest this is due to minor alterations in the conductive properties of the middle ear although a concrete pathophysiology has yet to be elucidated. TMJrelated tinnitus is often described as rough and low pitched. Although it may be difficult to completely attribute tinnitus to psychological factors, psychological stressors can often play a major role in the perception of tinnitus. Depression and anxiety can certainly exacerbate a patient’s perception of tinnitus, making the noise more severe or intrusive. Therefore, addressing these issues is paramount in tinnitus rehabilitation.

Objective Etiologies Objective tinnitus is much less common than subjective tinnitus. The differential diagnosis of objective tinnitus can be categorized into vascular, neoplastic, and myogenic causes. Vascular Tinnitus associated with vascular anomalies is often described as soft and pulsatile in nature.23 The rhythmic sound should correlate with a patient’s pulse, and therefore, the rate of the tinnitus will increase as heart rate increases. The pulsatile nature of the noise results from increased turbulence in blood flow that may be generated by decreased vessel diameter or increased flow volume. The sound of the turbulent flow is then transmitted directly to the inner ear, thereby producing the pulsatile noise. Pulsatile tinnitus can be associated with arterial or venous origins. Arterial vascular anomalies include arteriovenous shunts or AVMs, fistulas, aneurysms, or carotid atherosclerosis. In one study of 84 patients with pulsatile tinnitus, AVMs accounted for the etiology in 27% of the patients.24 AVMs may occur between branches of the occipital artery and transverse sinus, the internal carotid artery and vertebral vasculature, or middle meningeal artery and greater superficial petrosal artery. More commonly, AVMs are found in the posterior cranial fossa but the anomalies may also be found in the middle cranial fossa.23 Tinnitus from venous anomalies may involve jugular bulb abnormalities or transverse sinus stenosis. Venous pulsatile tinnitus can be differentiated from arterial tinnitus by applying pressure to the ipsilateral internal jugular vein. In patients with venous anomaly–associated tinnitus, this maneuver should diminish the sound. Other uncommon causes of pulsatile tinnitus include a persistent stapedial artery. This occurs when the artery fails to regress at approximately 10 weeks gestation. The true prevalence of this anomaly is unknown, but may be as common

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as 1 in 5000.25 Patients may complain of pulsatile tinnitus and vertigo but may also be asymptomatic. Case reports have shown resolution of symptoms following ligation of the artery. Benign intracranial hypertension may also cause pulsatile tinnitus. The pathophysiology is thought to be secondary to the transmission of systolic pulsations of cerebral spinal fluid to the dural venous sinuses.26 The resultant compression of the venous walls renders the blood flow turbulent and causes the tinnitus. Compression of the ipsilateral internal jugular vein in this situation should also mask the tinnitus. Although vascular tinnitus is classified as objective in nature, examiners may not be always able to hear or auscultate a bruit. Therefore, anomalies within the vascular system are best evaluated by imaging such as MRI or angiography. Imaging may also help in planning surgical or endovascular interventions. Neoplasms Paragangliomas such as glomus tympanicum and glomus jugulare are benign tumors that may also produce pulsatile tinnitus in children.23 Because these tumors are exceedingly rare, patients with these lesions must be evaluated for familial forms and multicentricity. Furthermore, although these tumors may be found in patients from infancy to old age, advance-stage disease and malignancy are more common in the younger patient groups.27 Patients with glomus tumors may complain of conductive hearing loss, otalgia, bloody otorrhea, dysphagia, other cranial nerve deficits, and headaches in addition to the pulsatile tinnitus.28 Because glomus tympanicum tumors usually originate on the promontory of the cochlea, these tumors usually present with pulsatile tinnitus earlier.29 Glomus jugulare tumors, which arise from the jugular fossa, present with tinnitus at a later stage. On examination, patients can have a reddish appearing bulge behind the tympanic membrane. Pneumatic otoscopy or positive pressure causes blanching of the mass, which is known as the Brown sign. The lesions are best evaluated via fine-cut CT scans of the temporal bone although contrast enhancement may be seen on MRI as well. Imaging may provide invaluable information regarding tumor extent, which is useful in planning treatment. Therapy is primarily surgical. Myogenic The most common etiology of tinnitus with a muscular origin is palatal myoclonus, or spasms of the soft palate and pharyngeal musculature.30 This may include the tensor veli palatini, levator veli palatini, salpingopharyngeus, and the superior constrictor. When these muscles contract, the mucous membranes of the Eustachian tube respond by snapping together. As a result, the tinnitus is often described as a rhythmic clicking sound. Sometimes patients are able to describe the noise as stemming from the back of the mouth or oropharynx. Examiners may be able to hear the clicking noise with a Toynbee tube. The diagnosis of palatal myoclonus can be confirmed by electromyelogram of the palatal musculature.

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CHAPTER 28 ❖ Tinnitus in Children Additional related symptoms include aural fullness and hearing distortion; it is not uncommon for these patients to also have muscle spasms elsewhere in the body. Treatment for palatal myoclonus may include medications such as muscle relaxants. Botulinum toxin injections have also been used in select patients. Surgery is less commonly recommended but has been utilized in severe cases. Another cause may be spasm of the stapedial muscle or tensor tympani. External noises may accentuate this type of tinnitus. Medications such as muscle relaxants may be utilized to treat muscle spasm but this is not always efficacious. Other treatment options include division of the stapedius and tensor tympani muscles. Finally, there is a subset of patients in which no etiology for tinnitus may be found. This is a diagnosis of exclusion only. Patients must be carefully counseled that even though no particular cause was identified, management and treatment can still be undertaken and successful.

MANAGEMENT AND TREATMENT Tinnitus in children must be regarded as a symptom and not a specific pathology. Because it is uncommon for children to spontaneous report tinnitus, any child who describes this symptom should be taken seriously. Similarly, if a parent or clinician notes any sort of objective sound emanating from the ear, appropriate evaluation and treatment should be undertaken. Work-up for tinnitus should include a thorough history, otologic examination, and audiologic testing. Tinnitus history should be obtained by asking children open-ended, nonleading questions that allow the child to characterize the tinnitus as best as possible. Medical examination should include a complete head and neck examination, with careful attention to the otologic examination. Finally, audiologic testing should include both audiometric assessment of tinnitus frequencies and otoacoustic emission testing. Results of the above should dictate further need for radiologic examinations, blood tests, and/or neurologic consultation. For instance, presence of unilateral hearing loss may require further imaging to exclude inner ear anomalies or central nervous system lesions. A high suspicion for a vascular etiology may warrant MRI or CT angiography. Or, if the child’s examination is revealing for other neurologic deficits, referral to a neurologist would be in order. Treatment for pediatric tinnitus will depend on the sound generator site or disease entity associated with the symptom. If a child has a suspected hearing loss, the child should be referred to an appropriate pediatric audiology department for full assessment and management. If there is hearing loss present, amplification should be utilized to improve hearing and to decrease the awareness of the tinnitus. Some children may also need help and support from the child’s school. This can help the child and family best cope with the hearing loss and associated symptoms. The child’s progress at school should also be carefully monitored.

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Prevention of hearing loss and limiting noise exposure should be emphasized as well. Children and adolescents need to be educated regarding acoustic trauma, hearing loss, and tinnitus and its relation to modifiable activities. Patients should be encouraged to use ear protection when possible. Both parents and clinicians should underscore this behavior. Specific etiologies warrant directed treatments. For instance, children who are diagnosed with vascular anomalies or neoplasms causing the tinnitus will often require surgery. Children with myogenic tinnitus may need medications such as muscle relaxants. Tinnitus maskers or other types of sound generators may also be used for symptom management. This may include ear or environmental devices that provide sound enrichment. For children who have bothersome tinnitus with no easily identifiable or treatable etiology, Shetye and Kennedy proposed an algorithm on how clinicians should proceed.7 The first step is to listen and provide reassurance to both the child and family that tinnitus is a nonthreatening condition. Second, clinicians should make careful attempts to identify and address specific worries. If there are associated problems provoked or caused by the tinnitus, whether at home or at school, these should also be dealt with appropriately. Medications may also be considered as a treatment for the tinnitus. Although many drugs may exacerbate or lessen tinnitus, the pharmacodynamics of medications in relation to tinnitus is not well defined. Therefore, medications prescribed in the treatment of tinnitus are more often for symptom management. For example, sometimes antianxiety or antidepressants can improve the emotional state of tinnitus patients. Other times, medications such as sleep aids are used. Alternative medications are sometimes indicated in the use of tinnitus treatment for adults, but its use in children has not been documented or tested. There is limited data on the efficacy of these medications, but the most common medications recommended are Ginkgo Biloba and St. John’s Wort. St. John’s Wort is thought to help tinnitus patients through its antidepressant effects. Acupuncture is another alternative treatment that has been suggested for treatment. Evidencebased recommendations regarding use of any of these herbal supplements or therapies, particularly in children, have yet to be elucidated. Some children may require more formal therapy to deal with their tinnitus including relaxation techniques or psychological therapy, that is, narrative techniques.7 Thought externalizing, for example, through play or drawing, the child may learn to separate himself/herself from the symptom of tinnitus. This in effect may help the child to disconnect tinnitus from negative thoughts and feelings. Finally, it should be emphasized that counseling should provide clear and simple information to the patient and his/ her parents. Any therapy should build on the patient’s coping skills at an age-appropriate level. Education should also include identification of aggravating factors and learning steps to manage these factors.

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CONCLUSION Tinnitus is not an uncommon symptom in children, and its documented prevalence is likely underestimated. Although typically not life threatening, tinnitus can have negative impact on quality of life and it can effect the child’s behavior and scholastics. Therefore, it is important to evaluate and manage tinnitus in children promptly and appropriately. Evaluation should be tailored to age level, recognizing that interviewing a child and obtaining an accurate history may be difficult. The history in combination with physical examination and audiologic testing should guide the clinician toward possible differential diagnoses. If a specific etiology is identified, the disease entity should be treated appropriately. When the sound generator site is unclear, an age appropriate tinnitus management strategy should be applied. Regardless of the treatment protocol, explanation, and reassurance continue to be the most effective techniques that physicians and clinicians can utilize to address pediatric tinnitus.

References 1. Nodar RH, Lezak MHW. Paediatric tinnitus: a thesis revised. J. Laryngology Oto. 1984;98:234–235. 2. Stouffer JL, Tyler RS, Booth JC, Buckrell B. Tinnitus in normalhearing and hearing-impaired children. In: Aran JM, Dauman R, eds. Tinnitus 91: proceedings of the Fourth International Tinnitus Seminar. Amsterdam: Kugler Publications: 1992: 255–258. 3. Graham JM. Tinnitus in hearing-impaired children. In: Hazell JWPH, ed. Tinnitus. London, UK: Churchill Livingstone; 1987:131–143. 4. Savastano M. Characteristics of tinnitus in childhood. Eur J Pediatr. 2007;166(8):797–801. 5. Kentish RC, Crocker SR, McKenna L. Children’s experience of tinnitus: a preliminary survey of children presenting to a psychology department. Br J Audiol. 2000;34:335–340. 6. Aust G. Tinnitus in childhood. Int Tinnitus J. 2002;8(1):20–26. 7. Shetye A, Kennedy V. Tinnitus in children: an uncommon symptom? Arch Dis Child. 2010;95(8):645–648. 8. Savastano M. A protocol of study for tinnitus in childhood. Int J Pediatr Otorhinolaryngol. 2002;64(1):23–27. 9. Gordts F, Decreton S. Tinnitus in children and adolescents. B-ENT. 2007;3(suppl 7):61–63. 10. Baguley DM, McFerran DJ. Tinnitus in childhood. Int J Pediatr Otorhinolaryngol. 1999;49(2):99–105. 11. Nodar RH. Tinnitus aurium in schoolage children, a survey. J Aud Res. 1972;12:133–135. 12. Chadha NK, Gordon KA, James AL, Papsin BC. Tinnitus is prevalent in children with cochlear implants. Int J Pediatr Otorhinolaryngol. 2009;73(5):671–675.

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13. Savastano M, Marioni G, de Filippis C. Tinnitus in children without hearing impairment. Int J Pediatr Otorhinolaryngol. 2009;73(suppl 1):S13–S15. 14. Coelho CB, Sanchez TG, Tyler RS. Tinnitus in children and associated risk factors. Prog Brain Res. 2007;166:179–191. 15. Mills RP, Cherry JR. Subjective tinnitus in children with otological disorders. Int J Pediatr Otorhinolaryngol. 1984; 7(1):21–27. 16. Rodriguez-Casero MV, Mandelstam S, Kornberg AJ, Berkowitz RG. Acute tinnitus and hearing loss as the initial symptom of multiple sclerosis in a child. Int J Pediatr Otorhinolaryngol. 2005;69(1):123–126. 17. Ben-David J, Podoshin L, Fradis M. Tinnitus in children—still a neglected problem. Int Tinnitus J. 1995;1(2):155–157. 18. Tranter RM, Graham JR. A review of the otological aspects of whiplash injury. J Forensic Leg Med. 2009;16(2):53–55. 19. Quintanilla-Dieck Mde L, Artunduaga MA, Eavey RD. Intentional exposure to loud music: the second MTV.com survey reveals an opportunity to educate. J Pediatr. 2009; 155(4):550–555. 20. Han B, Gfroerer JC, Colliver JD. Associations between duration of illicit drug use and health conditions: results from the 2005–2007 national surveys on drug use and health. Ann Epidemiol. 2010;20(4):289–297. 21. Schleuning AJ, Shi BY, Martin WH. Tinnitus. In: Bailey BJ, Johnson JT, Newlands SD, eds. Head & Neck Surgery— Otolaryngology. Vol 2. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. 22. Riga M, Xenellis J, Peraki E, Ferekidou E, Korres S. Aural symptoms in patients with temporomandibular joint disorders: multiple frequency tympanometry provides objective evidence of changes in middle ear impedance. Otol Neurotol. 2010;31(9):1359–1364. 23. Liyanage SH, Singh A, Savundra P, Kalan A. Pulsatile tinnitus. J Laryngol Otol. 2006;120(2):93–97. 24. Waldvogel D, Mattle HP, Sturzenegger M, Schroth G. Pulsatile tinnitus—a review of 84 patients. J Neurol. 1998;45(3): 137–142. 25. Silbergleit R, Quint DJ, Mehta BA, Patel SC, Metes JJ, Noujaim SE. The persistent stapedial artery. AJNR Am J Neuroradiol. 2000;21(3):572–577. 26. Sismanis A. Pulsatile tinnitus. A 15-year experience. Am J Otol. 1998;19(4):472–477. 27. Jackson CG, Pappas DG Jr, Manolidis S, Glasscock ME III, Von Doersten PG, Hughes CA. Pediatric neurotologic skull base surgery. Laryngoscope. 1996;106(10):1205–1209. 28. Magliulo G, Cristofari P, Terranova G. Glomus tumor in pediatric age. Int J Pediatr Otorhinolaryngol. 1996;5:38(1): 77–80. 29. Jacobs IN, Potsic WP. Glomus tympanicum in infancy. Arch Otolaryngol Head Neck Surg. 1994;120(2):203–205. 30. Fritsch MH, Wynne MK, Matt BH, Smith WL, Smith CM. Objective tinnitus in children. Otol Neurotol. 2001;22(5): 644–649.

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29

C H A P T E R

Balance Disorders Margaretha L. Casselbrant and Joseph M. Furman

B

alance disorders in children may escape recognition because of the child’s inability to describe the symptoms, the short duration of most “dizzy” episodes, overwhelming autonomic symptoms, or the mistaken idea that an episode of organic dizziness may be a manifestation of a behavioral disorder. Although dizziness can indicate a disorder of the vestibular system, it can also indicate an abnormality of other sensory systems or an abnormality in virtually any organ system. As the etiology of balance disorders in children is multifactorial, the management depends on an accurate diagnosis. Disorders associated with dizziness in children can be divided into the following three broad categories: (1) acute nonrecurring spontaneous vertigo; (2) recurrent vertigo; and

(3) nonvertiginous dizziness, dysequilibrium, and ataxia (Table 29-1).1 The assessment of a “dizzy” child including history, physical examination, and vestibular laboratory testing is discussed in Chapter 25.

PREVALENCE The prevalence of vertigo in school-age children (5–15 years), assessed using a questionnaire, was 7% in Aberdeen, Scotland.2 A similar study in Helsinki, Finland, reported that 8% of children 1–15 years had experienced at least one episode of vertigo.3 A retrospective chart review of children 17 years or younger who visited the University ENT clinic in Helsinki

TABLE 29-1. Comparison of Disorders Causing Childhood Dizziness Disorders

Duration of Symptoms/ Episodes

Hearing

Vestibular Laboratory Abnormalities

Acute nonrecurrent spontaneous vertigo Vestibular neuritis/laryrinthitis

Days

Normal/SNHL

Unilateral caloric reduction

Trauma—labyrinthine concussion

Days

Possible SNHL

Possible unilateral caloric reduction

Perilymphatic fistula

Variable

Possible SNHL

Possible unilateral caloric reduction

Meniere disease

Minutes to hours

Low-frequency SNHL

Unilateral caloric reduction

Vestibular migraine

Variable

Normal

Possible/Directional preponderance

Anxiety

Minutes

Normal

Possible/Directional preponderance

Seizure disorder

Seconds to minutes

Normal

Normal

Periodic ataxia

Hours to days

Normal

Normal

Recurrent vertigo

Nonvertiginous dizziness, dysequilibrium, and ataxia Bilateral vestibular loss

Constant

Usually normal but may be impaired hearing loss

Bilateral caloric reduction/ reduced gain on rotation

Otitis media

Constant

Conductive hearing loss

Possible abnormal posturography

Cerebellar lesions

Constant

Normal

Abnormal ocular motor testing

Abbreviation: SNHL, sensorineural hearing loss. Source: Modified from Tusa et al.1

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during a 5-year period demonstrated that only 0.7% of the children had been evaluated for complaints of vertigo.4 These studies indicate that vertigo is not uncommon in children but is often not brought to the attention of the otolaryngologist. The various balance disorders diagnosed in more than 2000 children in France with a history of vertigo and dizziness were migrainous equivalent, 25%; paroxysmal benign vertigo of childhood, 20%; head trauma, 10%; ocular disorders, 10%; inner ear malformations, 5%; vestibular neuronitis, 5%; labyrinthitis, 5%; and others [otitis media, central nervous system (CNS) disorder, and psychogenic disorder] 20%; posterior fossa tumors were diagnosed in less than 1%.5 Vestibular and balance testing in 132 children in a tertiary hospital showed that peripheral vestibulopathy (29.5%) and migraine disease (24.2%) were the most common diagnosis followed by motor/developmental delay (10.6%), traumatic brain injury (9.8%), central nervous system structural lesions (9.1%) and behavioral/psychogenic (6.1%).6

ACUTE NONRECURRING SPONTANEOUS VERTIGO Acute nonrecurring spontaneous vertigo is unusual in children. In an acute vestibular syndrome, the vertigo that is experienced by a patient is a result of the rapid loss of unilateral peripheral vestibular function, which disrupts the “push– pull” interaction of the two labyrinths (see Chapter 25). The rapid loss of peripheral vestibular function on one side causes a reduction in the normal baseline activity in the ipsilateral vestibular nerve. As the brain responds to differences in activity between the two vestibular nuclear complexes, an acute unilateral loss of peripheral vestibular function is interpreted by the CNS as a continuous head movement. Thus, the patient experiences vertigo and exhibits nystagmus, with the fast component beating toward the contralateral ear. Additionally, the child may experience autonomic symptoms including nausea and vomiting. A process called “vestibular compensation” begins immediately, and the CNS “learns” to use the signal from one labyrinth as a sole source of vestibular input. This process of compensation depends on several factors, including a normal CNS, especially brain stem and cerebellar function, a significant amount of active eye, head, and body movements, and abstinence from vestibular suppressant medications.7 Typically, children recover from an acute loss of unilateral peripheral vestibular function in a matter of days; some children may recover so quickly that it is scarcely known that they even had an acute vestibular episode at all.

Head Trauma Head trauma can cause an acute episode of vertigo by abruptly affecting the vestibular end organ directly, that is, a labyrinthine concussion as described in Case 1. Although several theories have been proposed, the mechanism of injury in labyrinthine concussion is poorly understood. Pressure waves transmitted directly to the labyrinth through the skull or

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intracranially through the cochlear aqueduct may cause rupture of the membranous labyrinth or damage to hair cells, hair bundles, or specialized structures in the ampulla or macula. The child usually recovers completely within a short period of time, but, on rare occasions, benign paroxysmal positional vertigo or delayed endolymphatic hydrops may develop. Benign paroxysmal positional vertigo is characterized by nystagmus and associated vertigo elicited by rapid changes in head position from upright to head hanging. It is thought to be caused by canalithiasis and can be treated with particle repositioning.8 Other mechanisms of vertigo after head trauma include injury of the CNS, specifically, a brain stem or cerebellar contusion or a temporal bone fracture. A temporal bone fracture may be longitudinal or transverse. A transverse fracture is the most common cause of vertigo caused by injury to the eighth nerve or the otic capsule. This type of fracture also causes a significant sensorineural hearing loss (see Chapter 31).

Perilymphatic Fistula Another diagnostic consideration for a patient with head trauma followed by vertigo or nonspecific dizziness is that of perilymphatic fistula. Perilymphatic fistula is an anomalous connection between the inner ear and middle ear spaces and has been well documented in children.9 Although perilymphatic fistula is usually associated with hearing loss, it can be associated with vertigo alone.10 A perilymphatic fistula can be acquired or congenital. The congenital fistulas are associated with abnormalities in the temporal bone, particularly in the area of the stapes, but also in the round window area. Acquired perilymphatic fistulas are generally caused by trauma. Iatrogenic trauma, barotrauma, penetrating trauma, or head trauma may or may not be associated with a temporal bone fracture. Barotrauma can be either implosive or explosive as described by Goodhill et al.11 Implosive barotrauma can occur during diving and flying or violent sneezing and coughing and is due to a sudden pressure change in the middle ear. The explosive mechanism is caused by a sudden increase in the spinal fluid pressure and, in susceptible individuals, may be induced by straining or any type of excessive exertion such as heavy lifting or sit-ups. No symptoms are pathognomonic for a perilymphatic fistula. However, several features of the history are suggestive: (1) a history of hearing loss or vertigo after physical strain or stress, exposure to sudden alterations in environmental pressure (e.g., diving or flying), or marked alteration in middle ear pressures (e.g., violent sneezing, laughing, or blowing a wind instrument), (2) a sensorineural hearing loss that is sudden or fluctuating, or both, (3) dizziness, which may be increased by postural change, or continuous poor balance or ataxia, and (4) a sensation of a “pop” in the ear followed by hearing loss or dizziness. No test is specific for perilymphatic fistula, and the diagnosis may be difficult to make. Applying positive and

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CHAPTER 29 ❖ Balance Disorders 455 negative pressures to the external ear canal may produce eye movements or nystagmus, which may indicate the presence of a fistula (“fistula test”). However, a negative response does not exclude a perilymphatic fistula. Fluctuating hearing loss may also indicate a perilymphatic fistula. An inner ear or middle ear anomaly such as a Mondini malformation or ossicular deformities demonstrated on a high-resolution computed tomography scan should heighten the clinical suspicion of a congenital perilymphatic fistula.12 The diagnosis and treatment of perilymphatic fistula consists of exploration of the middle ear and repair of the fistula by packing with temporalis fascia or muscle. At the time of surgery, fluid from the middle ear should be collected and sent for b-2 transferrin testing, which is considered to be an objective test for the diagnosis of a perilymphatic fistula.13

Vestibular Neuritis Vestibular neuritis is rarely seen in children younger than 10 years old. It should be considered when a viral syndrome is followed by symptoms suggestive of an acute unilateral peripheral vestibular loss, which is more common in children than in adults.14 It presents with acute severe vertigo, nystagmus, nausea, and vomiting. The vertigo is worsened by head movements, and patients often prefer to lie down, usually with the affected ear up. There is no hearing loss or tinnitus. Vestibular laboratory testing indicates a unilateral reduced vestibular response to bithermal caloric testing. The symptoms resolve in children within a few days. Management is supportive and symptomatic with early ambulation. Vestibular suppressants such as meclizine may be given, but only a short course as it may delay CNS compensation. Corticosteroids, such as prednisone, may shorten the duration of the illness, but no studies of its efficacy in children have been performed.

Labyrinthitis The diagnosis of acute labyrinthitis should be used to indicate an inflammatory condition that affects the labyrinth and generally leads to both vestibular and auditory symptoms and signs. The etiology of serous (toxic) labyrinthitis is unknown, but bacterial toxins or other biochemical substances in middle ear fluid are thought to be absorbed into the inner ear, usually through the round and oval windows. Symptoms may be mild with little or no sensorineural hearing loss and resolve spontaneously (see Otitis Media). In bacterial or suppurative labyrinthitis, there is an invasion of a bacterial infection into the labyrinth from the middle ear through preformed pathways that may be caused by chronic otitis media with cholesteatoma, a prior temporal bone fracture, or a congenital bony abnormality. Alternatively, in patients with bacterial meningitis, there may be invasion of bacteria through the internal auditory canal or the cochlear aqueduct. The symptoms of suppurative labyrinthitis are

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severe, and the condition often results in loss of vestibular and auditory function on the affected side. Bacterial or suppurative labyrinthitis is a serious complication that requires immediate intravenous antimicrobial therapy and surgical intervention (see Chapter 36).

RECURRENT VERTIGO Recurrent vertigo in children can be a result of disease of the peripheral or central vestibular system. However, most recurrent vertigo in children is the result of a CNS disorder rather than a peripheral vestibular disorder (see Table 29-1).

Meniere’s Disease Meniere’s disease, a syndrome presumably caused by endolymphatic hydrops, can occur spontaneously or as a delayed sequela of previous insult from trauma or viral infection. The disorder rarely occurs in children.15–17 The disease is characterized by a complex of symptoms including dizziness, unilateral hearing loss, and unilateral tinnitus, which are usually preceded by a feeling of fullness in the affected ear. Symptoms vary among patients and may vary in the same patient over time. Some patients may have only hearing loss and tinnitus, whereas others may have only vestibular symptoms. The duration of the vertiginous episode may vary from half an hour to several hours, and episodes are frequently accompanied by autonomic symptoms such as pallor, perspiration, nausea, and vomiting. Between these acute episodes, adults and rarely children may have vague symptoms of dysequilibrium. The hearing loss in Meniere’s disease is usually a low-frequency sensorineural loss that fluctuates, that is, returns to normal between the attacks, during the early stages of the disease. Later, the hearing loss may progress to a flat sensorineural hearing loss that does not fluctuate. Children are more likely to recover auditory function than adults. Meniere’s disease can be bilateral. Also, with time, a reduction in the responsiveness of the involved peripheral vestibular system occurs. Management of endolymphatic hydrops in children includes reassurance and explanations of the condition to the parents in addition to salt restriction and a diuretic. The need for surgical treatment is rare in children.

Vestibular Migraine Migraine is probably the most common cause of recurrent vertigo in children. Whereas migraine typically presents as headache in adults, other manifestations of migraine, including recurrent vertigo and dysequilibrium, are more common in children (see Case 2). The International Classification of Headache Disorders (ICHD) of the International Headache Society18 includes benign paroxysmal vertigo of childhood in the ICHD among “childhood periodic syndromes that are commonly precursors of migraine.” However, benign torticollis in infancy is not recognized by the ICHD, even though

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many of these patients may later develop benign paroxysmal vertigo of childhood or episodes of classic migraine. In addition, the ICHD does recognize basilar-type vertigo as a migrainous symptom. In addition to benign paroxysmal vertigo of childhood, as well as paroxysmal torticollis of infancy, nonvertiginous symptoms of vestibular dysfunction can also be related to migraine. Thus, the manifestations of migraine in childhood are quite varied, including episodic true vertigo, constant imbalance, movement-associated dysequilibrium, and space and motion discomfort. Because of this highly varied presentation of symptoms, the diagnosis of migraine-related vestibulopathy requires an awareness of the potential vestibular manifestations of migraine, a meticulous history with specific inquiry into the occurrence of headache and other migraine-associated symptoms, and a careful family history. Ultimately, migraine-related dizziness remains a diagnosis of exclusion. Benign paroxysmal vertigo of childhood, first described by Basser,19 is a particular variety of paroxysmal vertigo occurring in childhood with the cardinal symptom of vertigo in isolation. There are no cochlear symptoms such as tinnitus and hearing loss. The age of onset is usually within the first 3 or 4 years of life but may occur later at age 7 or 8. The spells of vertigo are brief, usually less than one minute; they may last only seconds and rarely last more than a few minutes. During an attack, the child usually remains still and is unable to move, and frequently, the child becomes limp. During a less severe attack, the child may clutch on to something. There are no known precipitating factors, and the attacks can occur in the sitting, standing, or lying position. Pallor, nausea, sweating, and occasionally vomiting occur. Consciousness is not impaired, and the child can recall the episode. There is no pain or headache associated with the attacks. Immediately after the attack, the child resumes normal activities. The interval between the attacks varies from weekly to every six months, with monthly to bimonthly episodes being the most common. The attacks usually cease spontaneously after a few years. Physical examination, including a neurologic evaluation, is normal, as is imaging of the skull and temporal bones. Basser19 reported a moderate or complete canal paresis on caloric testing. However, the response to bithermal caloric testing has been found to be highly variable.20–22 In a recent study no objective peripheral vestibular abnormalities were recorded.6 Other testing is normal. Children with benign paroxysmal vertigo of childhood often have a positive family history of migraine, and migraine headaches may develop in later years23,24 and may respond positively to antimigrainous treatment. Paroxysmal torticollis of infancy was first described by Snyder25 and consists of episodes of head tilt, which may be associated with nausea, vomiting, pallor, and agitation. The torticollis may alternate from side to side. The episodes are brief and self-limiting and may recur for several months, but they usually resolve by age 2–3 years.

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General physical examinations, otologic, neurologic, and ophthalmologic examinations are essentially normal in all children. Electroencephalograms (EEGs) as well as radiologic studies of the head and cervical spinal have also been reported to be normal. Results of audiometry and vestibular function testing are conflicting.25–27 However, imaging has been recommended to exclude a posterior fossa lesion, which can have similar symptoms of head tilting. Drigo et al.28 reported normal neurological findings during and after an episode with no significant change in muscle tone or motor development, whereas a recent study has indicated delayed gross and fine motor development.26 Resolution of the symptoms of head tilting has been accompanied by an acceleration of motor development. These authors concluded that benign paroxysmal torticollis is probably an agesensitive migraine-related disorder. With age, the child may develop benign paroxysmal vertigo of childhood or classic migraine.27,28 No treatment has been shown to be effective. Therefore, as the attack resolves spontaneously, no treatment is usually recommended. Basilar-type migraine Bickerstaff 29 was the first to associate vertiginous symptoms preceding migraine with dysfunction of the brain stem and areas within the distribution of the basilar artery. The majority of his patients were adolescent girls in whom the symptoms often occurred premenstrually, but symptoms have also been described in preadolescent children30,31 and adults.32,33 The criteria for the diagnosis set by the ICHD for basilar-type migraine include two or more fully reversible neurological symptoms/auras lasting >5 to 39°C) and purulent nasal discharge together for >3 days “Worsening” respiratory symptoms • Resolving upper respiratory symptoms • Worsen around illness day 6 or 7 with new or recurrent fever or exacerbation of nasal symptoms and/or cough

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CHAPTER 53 ❖ Rhinitis and Acute and Chronic Sinusitis painless morning eye swelling occurs occasionally. The child may not appear very ill, and usually, if fever is present, it is low grade. It is not the severity of the clinical symptoms but their persistence that calls for attention. In clinical practice, strict observance of this presentation results in a diagnosis of acute sinusitis in 6.7% of children with upper respiratory tract symptoms who visit their primary care physician.118,129 The second presentation is characterized as having severe symptoms at the onset of illness. Severity is described as a combination of high fever, a temperature of at least 38.5°C and a particular quality of nasal discharge, a purulent nasal discharge, concurrently for at least three to four consecutive days3 The presence of persistent fever for at least three to four days distinguishes this presentation from an uncomplicated viral URI (in which fever is present for less than 48 hours). The third presentation is described as worsening symptoms or presentation with a biphasic illness (in the Scandinavian literature, this is referred to as “double sickening”).77,85 This illness begins similarly to an uncomplicated viral URI from which the patient seems to be recovering. On the sixth or seventh day of illness, the patient becomes substantially worse again. The worsening symptoms may be manifested as an increase in respiratory symptoms (exacerbation of nasal discharge or nasal congestion or daytime cough) or a new onset of fever or a recurrence of fever if it had been present at the outset. Fig. 53-3 is a schematic representation of the three presentations of acute sinusitis. On physical examination, the patient with acute bacterial sinusitis can have mucopurulent discharge in the nose or posterior pharynx. The nasal mucosa is usually erythematous

1043

but can occasionally be pale and boggy; the throat can show moderate injection. Examination of the tympanic membranes can show evidence of acute otitis media or otitis media with effusion. The cervical lymph nodes are not usually significantly enlarged or tender. Occasionally, there is either tenderness, as the examiner palpates over or percusses the paranasal sinuses, or appreciable periorbital edema, with soft, nontender swelling of the upper and lower eyelid and discoloration of the overlying skin. Unfortunately, facial tenderness is neither a sensitive nor a specific sign of sinusitis. Malodorous breath (in the absence of pharyngitis, poor dental hygiene, or a nasal foreign body) can suggest bacterial sinusitis. The physical examination, however, is of limited value as none of these characteristics differentiates rhinitis from sinusitis. Clinical Presentation of Chronic Sinusitis Chronic sinusitis should be suspected in children with very protracted respiratory symptoms: nasal discharge, nasal obstruction, or cough that has lasted for more than 30 days. Some experts define chronic sinusitis as symptoms that persist for at least 90 days.124 Although the nasal discharge is most often purulent, it may be thin and clear. Occasionally nasal discharge is minimal or absent, and cough and throat clearing are more prominent due to discharge from the posterior ethmoids. Once again, the cough should be present during the daytime, although it is usually reported to be worse at night. When nasal obstruction due to nasal congestion is pronounced, sore throat is frequently present upon awakening secondary to mouth breathing. In addition, the patient may complain of facial pain, headache, or malaise. The appetite may be poor, sleep is frequently impaired, and school

Respiratory symptoms Severity

Fever 0 1 2 3 4 5 6 7 8 9 10 11 12 (days) Persistent Symptoms

Fever Fever Severity

Severity Respiratory symptoms Respiratory symptoms 0 1 2 3 4 5 6 7 8 9 10 11 12 (days)

0 1 2 3 4 5 6 7 8 9 10 11 12 (days)

Severe Symptoms

Worsening Symptoms

FIGURE 53-3. Schematic depiction of three clinical presentations of acute sinusitis.

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SECTION 3 ❖ The Nose, Paranasal Sinuses, Face, and Orbit

performance may suffer. However, unless these less specific complaints are accompanied by respiratory symptoms, they should not be attributed to sinus infection. Fever is less prominent and found less frequently than in acute sinusitis.

Diagnosis

Physical Examination In most children less than 10 years of age, the physical examination is generally not very helpful for making a specific diagnosis of acute bacterial sinusitis. On the contrary, if the mucopurulent material can be removed from the nose, and the nasal mucosa is treated with topical vasoconstrictors, pus may be seen coming from the middle meatus. The latter observation and periorbital swelling or facial tenderness (when present) are probably the most specific findings in acute bacterial sinusitis. The signs of chronic sinusitis are not specific. They include mucopurulent nasal discharge, hypertrophied nasal turbinates, and (occasionally) intranasal polyps. The last are seen principally in association with allergy or cystic fibrosis. Some authors have noted that in children with chronic sinusitis, widening of the nasal bridge develops, producing a pseudohypertelorism. Imaging The membranes that line the nose are continuous with the membranes (mucosa) that line the sinus cavities, the middle ear, the nasopharynx and the oropharynx. When an individual experiences a viral URI, there is inflammation of the nasal mucosa and often the mucosa of the middle ear and paranasal sinuses as well. The continuity of the mucosa of the upper respiratory tract is responsible for the controversy regarding the usefulness of images of the paranasal sinuses in contributing to a diagnosis of acute bacterial sinusitis. As early as the 1940s, observations were made regarding the frequency of abnormal sinus radiographs in children without signs or symptoms of current respiratory disease.82 In addition, several investigators observed in the 1970s and 1980s that children with uncomplicated viral URI had frequent abnormalities of the paranasal sinuses on plain radiographs.69,107 These abnormalities were the same as those usually interpreted as consistent with and emblematic of acute bacterial sinusitis. As technology advanced and computed tomographic (CT) scanning of the central nervous system and skull was performed, several studies reported on incidental abnormalities of the paranasal sinuses that were observed in children.35,47 Manning et al. evaluated children undergoing either CT or magnetic resonance imaging (MRI) of the head for indications other than respiratory complaints or suspected sinusitis.80 Each patient underwent rhinoscopy and otoscopy before imaging, and each patient’s parent was asked to fill out a questionnaire regarding recent symptoms of upper respiratory tract infection. Sixty-two percent of patients overall had physical findings or history consistent with an upper respiratory inflammatory process and 55% showed some abnormalities on sinus imaging; 33% showed pronounced mucosal

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thickening or an air-fluid level. Gordts et al. made similar observations in children undergoing MRI.49 Finally, Kristo et al. deliberately subjected children with uncomplicated viral URI to MRI and confirmed the high frequency (68%) of major abnormalities seen in the paranasal sinuses.70 In summary, when the paranasal sinuses are imaged, with plain X-rays, CT, or MRI in children with uncomplicated URI, the majority of studies will be significantly abnormal with the same kind of findings that have been associated with bacterial infection of the sinuses. Accordingly, although normal X-rays or CT or MRI can assure that a patient with respiratory symptoms does not have acute bacterial sinusitis, an abnormal image cannot confirm the diagnosis and is not necessary to perform in children with uncomplicated episodes of clinical sinusitis.7 Unquestionably, CT and MRI scans are superior to plain radiographs for delineation of sinus abnormalities; however, they are not necessary in children with uncomplicated acute bacterial sinusitis. On the contrary, for cases of sinusitis that are complicated by intracranial or intraorbital suppuration, CT and MRI are helpful procedures.4 Appropriate coronal and axial scans permit simultaneous evaluation of the central nervous system, orbit, and paranasal sinuses. For patients with allergy to contrast material or those with a vascular occlusion complicating sinusitis, MRI is the best. In patients with recurrent or persistent sinusitis, there may be a concern that either a congenital bony defect or a traumatic skeletal deformity is the underlying problem. For these patients, CT imaging procedures are ideal for the evaluation of skeletal structures of the paranasal sinuses. Ultrasonography Several reports have evaluated ultrasonography as an aid in diagnosing maxillary sinusitis.79,101,106 Its advantages as compared with radiography are the use of nonionizing radiation and supposedly better ability to discriminate between mucosal thickening and retained secretions. However, even when ultrasound shows the presence of fluid, it cannot discriminate between infected and noninfected fluid. Accordingly, its use is not recommended. Sinus Aspiration A diagnosis of acute bacterial sinusitis is probably best proved by a biopsy of the sinus mucosa that demonstrates acute inflammation and invasion by bacteria. In practice, confirmation of the diagnosis is more often accomplished by culturing an aspirate of sinus secretions. Nonetheless, when simultaneous mucosal biopsies and sinus aspirates are submitted for bacterial cultures, biopsies more often yield positive results. Although it is by no means a routine procedure, aspiration of the maxillary sinus (the most accessible of the sinuses) can be accomplished easily in an outpatient setting with minimal discomfort to the patient. Puncture is best performed by the transnasal route with the needle directed beneath the inferior turbinate through the lateral nasal wall (Fig. 53-4). This route for aspiration is preferred in order to avoid injury to the natural ostium and permanent dentition. If the patient

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CHAPTER 53 ❖ Rhinitis and Acute and Chronic Sinusitis

FIGURE 53-4. Preferred method of sinus aspiration.

is unusually apprehensive or too young to cooperate, a short-acting narcotic agent can be used for sedation, or the procedure may be performed in the operating room with the patient under general anesthesia. Careful sterilization of the puncture site is essential to prevent contamination by nasal flora. A 4% cocaine solution applied intranasally will achieve mucosal anesthesia and antisepsis. Lidocaine should be injected into the submucosa at the site of the actual puncture. Secretions obtained by aspiration should be submitted for Gram stain and quantitative aerobic and anaerobic cultures. Bacterial isolates should be tested for their sensitivity to various antibiotics. A high bacterial colony count assures that the culture results reflect actual sinus infection rather than contamination; counts of greater than 104 colony-forming units per milliliter give a high degree of confirmation of in situ infection. Alternatively, a Gram stain preparation of sinus secretions may be helpful, as bacteria that are present in a low colony count (likely to be contaminants) are usually not seen on a smear. Indications for sinus aspiration in patients with suspected sinusitis include clinical unresponsiveness to conventional therapy, sinus disease in an immunosuppressed patient, severe symptoms such as headache and facial pain, and lifethreatening complications such as intraorbital or intracranial suppuration at the time of clinical presentation. Microbiology A knowledge of the bacteriology of secretions obtained directly from the maxillary sinus by needle aspiration (with careful avoidance of contamination from mucosal surfaces) provides essential information for the planning of antimicrobial therapy. Whether there is a “normal” flora of the paranasal sinuses is an area of controversy.15,124,126 However, most investigators

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believe that the paranasal sinuses are, under normal conditions, sterile.56,127 It will be difficult to resolve this controversy, because the violation of normal sinus cavities can rarely be justified. The role of anaerobic bacteria as pathogens in sinusitis has been examined infrequently but with adequate attention to anaerobic transport and culture techniques.17,125 Poor drainage of the inflamed sinus results in a lower pH and a lower partial pressure of oxygen, thereby providing an excellent environment for the growth of anaerobic bacteria. However, the in vitro growth of anaerobic bacteria may be impaired in sinus secretions obtained by irrigation, because this procedure increases oxygen pressure and dilutes bacterial titers. Finally, few studies have looked for viral agents as a cause of sinus infection, despite evidence that viruses alone may produce acute sinus disease. Sinus Aspirates Acute SinuSitiS Two elegant studies performed in adults in which careful attention was given to bacteriologic technique show nontypable H. influenzae and S. pneumoniae to be the most commonly found pathogens, accounting for approximately 74% of all bacterial strains recovered.39,59 Anaerobic bacteria accounted for 9% of isolates. Other bacteria implicated include M. catarrhalis, S. pyogenes (group A streptococcus), and a-hemolytic streptococcus. Mixed infection with heavy growth of two bacterial species was occasionally found, although most cultures grew only a single organism. Viruses were recovered from 12 of the 103 positive specimens; there were seven isolates of rhinovirus, three of influenza A, and two of parainfluenza virus. Five of these specimens also had significant growth of bacteria. A study performed in 50 children with acute maxillary sinusitis showed the bacteriology of sinus secretions to be similar to that found in adults.124 The predominant organisms include S. pneumoniae, M. catarrhalis, and nontypable H. influenzae. Both H. influenzae and M. catarrhalis may produce b-lactamase and consequently may be resistant to amoxicillin. Of interest, only a single anaerobic isolate, a Pep­ tostreptococcus, was recovered from sinus secretions during this study. Staphylococcus aureus was not isolated from a maxillary sinus aspirate in this series. Several viruses, including adenovirus and parainfluenza virus, were also recovered in approximately 10% of the patients.120 This percentage might be higher if diagnostic aspirates were obtained earlier in the course of respiratory symptoms. Unfortunately, no data have been generated regarding the microbiology of acute bacterial sinusitis in children since 1986.122 However, because of the similarity of the pathogenesis and microbiology of acute otitis media and acute bacterial sinusitis, it is acceptable to regard recent data generated from cultures of middle ear fluid, obtained by tympanocentesis from children with acute otitis media, as a surrogate for cultures of the paranasal sinuses.93 Attributable in part to the near-universal use of pneumococcal conjugate vaccine in the United States, several reports in 2004 highlighted a slight decrease in isolates of S. pneumoniae and

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SECTION 3 ❖ The Nose, Paranasal Sinuses, Face, and Orbit

an increase in isolates of H. influenzae recovered from middle ear aspirates.23,74 However, soon afterward S. pneumoniae serotype 19A (a nonvaccine strain) emerged as an important and common cause of acute otitis media.90,95 This resulted in a transient increase in S. pneumoniae isolates from cases of acute otitis media. The successful licensure of PCV13, which includes serotype 19A, has brought this issue under control.24 In a very recent report from Rochester, NY, the prevalence of S. pneumoniae in middle ear aspirates was 15%.67a Summary figures for the incidence of various bacteria in children with acute, subacute, and recurrent acute bacterial sinusitis are listed in Table 53-3. Historically, S. aureus has not had a major or minor role as a cause of acute bacterial sinusitis in children, although it is isolated with some frequency in children with intracranial complications of acute sinusitis and variably from those with intraorbital infections. A recent publication has implied that S. aureus may be an important sinus pathogen in children.131 However, it should be noted that this retrospective study tracked isolates of S. aureus that were identified in an ongoing surveillance study. Most of the isolates were obtained at the time of endoscopic sinus surgery. In the majority of cases, S. aureus was accompanied by a usual sinus pathogen (H. influenzae or S. pneumoniae). The indication for sinus surgery was unknown, and the preparation of the nose before sampling (to eliminate nasal colonization with S. aureus) is also unknown. The likelihood that many of these isolates represent nasal contamination rather than actual infection is substantial.11

Chronic Sinusitis Available microbiologic data from children with chronic sinusitis are limited and confusing because of variable definitions of chronic sinusitis, frequent failure to obtain specimens aseptically, lack of quantitation of results, and concurrent use of antibiotics. Brook examined 40 patients alleged to have chronic sinusitis (symptoms longer than 3 weeks); anaerobes were isolated from 92% of patients.16 The most common were anaerobic Gram-positive cocci (staphylococci and streptococci), Bacteroides species, and fusobacteria. Aerobes, including staphylococci, streptococci, and Haemophilus species, were isolated from 38% of patients. Muntz and Lusk reported the bacterial flora of the ethmoid bullae in children with chronic sinusitis who were TABLE 53-3. Bacteriology of Acute Sinusitis Bacterial Species

Incidence (%)

Streptococcus pneumoniae

25–25

Haemophilus influenzae

40–50

Moraxella catarrhalis

10–15

Streptococcus pyogenes

2–5

Anaerobes

2–5

Sterile

20–35

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between the ages of 9 months and 17 years.86 Specimens were obtained from the mucosa of the anterior ethmoid cell in patients undergoing endoscopic ethmoidectomy. All had received at least two courses of an appropriate antimicrobial agent and were treated until the day before surgery. Although nasal decongestion was achieved with topical application of cocaine, an effective antiseptic, contamination of the mucosa of the ethmoid bullae by nasal flora may not have been completely avoidable. Furthermore, no quantitation of the bacterial isolates was performed, and the antibiotics may have eradicated or prevented growth of other bacterial flora. Coagulase-negative staphylococci, often considered a contaminant of the nasal vault, were recovered from 44% of patients. The other common bacterial species recovered were a-hemolytic streptococci and S. aureus, followed by S. pneumoniae, H. influenzae, and M. catarrhalis. Anaerobic organisms were grown from 6% of specimens. One of the best studies on children with chronic sinusitis was reported recently by Hsin et al.63 He evaluated 165 children between the age of 4 and 16 years with 12 weeks of purulent nasal drainage/nasal congestion. A maxillary sinus puncture was done after disinfection with iodine/alcohol. There were three potential limitations: (1) no test of sterility after “sterilizing” the nose, (2) no quantitation of the bacteria recovered, and (3) no restriction on the interval from antibiotic therapy to maxillary sinus puncture. The most commonly identified bacteria were a-hemolytic streptococcus (20.8%), H. influ­ enzae (19.5%), S. pneumoniae (14.0%), coagulase-negative staphylococcus (13.0%) and S. aureus (9.3%). Anaerobes were recovered from 8.0% of all isolates. The predominance of Staphylococcus epidermidis, a-hemolytic streptococci, and other normal respiratory flora indicates that many isolates obtained from patients with chronic sinusitis may represent contamination from the nasal cavity. In patients with acute exacerbations of chronic sinusitis (intermittent episodes characterized by purulent nasal discharge), the usual microorganisms associated with acute sinusitis (i.e., S. pneumoniae, M. catarrhalis, and H. influ­ enzae) are causative. In patients with chronic persistent sinusitis (nasal congestion or rhinorrhea or cough, alone or in combination), the role of bacterial agents is less clear.86 Most organisms have been recovered in low density after inadequate sterilization of the contiguous mucosa and frequently from patients receiving antibiotics to which these organisms are susceptible. The persistence of symptoms despite multiple courses of appropriate antimicrobial agents is counter to the notion that bacterial infection is a significant component of chronic sinusitis. All these observations support the hypothesis that bacterial infection has a minor role, if any, in a substantial number of patients with chronic sinusitis.63 An alternative hypothesis regarding the importance of bacterial infection in patients with chronic sinusitis relates to the potential role of biofilms. Biofilms are organized, heterogeneous bacterial communities in which bacteria are embedded in a matrix rich in polysaccharides, nucleic acids, and proteins.97 Bacteria deep within biofilms are

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CHAPTER 53 ❖ Rhinitis and Acute and Chronic Sinusitis resistant to antibiotics and host defenses that prevent their elimination. There is evidence for the presence of biofilms in several diseases of otolaryngologic interest, including chronic sinusitis. The appeal of this concept is that it might explain the chronic nature of the infection, frequent failure to respond to antibiotics and acute exacerbations when antibiotics are discontinued in patients who have responded. Although biofilms have been demonstrated on the mucosa of patients with chronic sinusitis, they have also been seen in healthy controls. Accordingly, their precise role remains to be determined.104 Surface Cultures It would be desirable to culture the nose, throat, and nasopharynx in patients with acute sinusitis if the predominant flora isolated from these surface cultures were predictive of the bacterial species recovered from the sinus secretions. It is unfortunate that the results of surface cultures have no predictive value; accordingly, nose, throat, and nasopharyngeal cultures cannot be recommended as guides to the bacteriology of and therapy for acute or chronic sinusitis.120 It is important to note that approximately 20% of pediatric patients with acute sinusitis have pharyngeal infection with group A streptococci.122 In these patients, the mucositis caused by group A streptococci results in the obstruction of the sinus ostia and a “secondary” bacterial infection of the paranasal sinuses. Cultures of the Middle Meatus In pursuit of a method to determine the microbiologic etiology of acute bacterial sinusitis that is less invasive than performance of a maxillary sinus aspirate, surface cultures of the middle meatus have been performed. Unfortunately, studies by Gordts et al. have shown that the middle meatus is frequently colonized with S. pneumoniae, H. influenzae, and M. catarrhalis even in children without respiratory symptoms.50 There are no studies of simultaneously performed maxillary sinus aspirates and meatal cultures in children with acute sinusitis. An investigation in children with chronic sinusitis showed that endoscopic sampling of the middle meatus versus maxillary sinus puncture provided a sensitivity of 75%.63 Treatment Treatment of acute maxillary sinusitis in the preantibiotic era consisted of topical decongestants and analgesics. In severe cases, sinus aspiration was performed. The current availability of numerous antimicrobial agents to which the bacteria recovered from sinus secretions are susceptible prompts consideration of antimicrobial drugs as standard treatment of acute sinusitis. The objectives of antimicrobial therapy for acute sinus infection are achievement of a rapid clinical cure, sterilization of the sinus secretions, prevention of suppurative orbital and intracranial complications, and prevention of chronic sinus disease. Conflicting reports have appeared regarding the efficacy of antimicrobial drugs in the treatment of acute sinus infection in children and adults. An array of antimicrobial agents

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and varying dosage schedules make comparisons between different studies difficult and discrepancies hard to explain. However, several points emerge: 1. Appropriate antimicrobial agents eradicate susceptible microorganisms in sinus secretions, whereas inappropriate agents fail to do so.56,57,121 2. To accomplish sterilization of the sinus secretions, a level of antimicrobial agent exceeding the minimum inhibitory concentration for the infecting microorganism must be present in the sinus secretions. 3. In some instances in which adequate antimicrobial levels within sinus secretions are reported, sterilization of secretions is still not accomplished. This points to the importance of local defense mechanisms (e.g., ciliary activity and phagocytosis) that may be impaired in the altered environment within purulent sinus secretions (decreased partial pressure of oxygen, increased carbon dioxide pressure, and decreased pH). Accordingly, irrigation and drainage of sinus secretions may rarely be required in some patients. 4. There does appear to be a decreased frequency of serious suppurative orbital and intracranial complications of paranasal sinus disease in the antibiotic era. Antimicrobial Agents Acute BActeriAl SinuSitiS Medical therapy with an antimicrobial agent is recommended for children diagnosed as having acute bacterial sinusitis.129a The challenge regarding the selection of appropriate antimicrobial agents for patients with acute bacterial sinusitis relates to the prevalence of bacterial pathogens that are resistant to amoxicillin. Resistance is found among b-lactamase-producing H. influenzae and M. catarrhalis. Isolates of S. pneumoniae may also be resistant to penicillin and cephalosporins. The mechanism of resistance for S. pneumoniae is an alteration of penicillinbinding proteins. There is substantial geographic variability in the susceptibility of all these bacterial species to antimicrobial agents. Currently, between 10% and 50% of H. influenzae and 100% of M. catarrhalis are likely to be b-lactamase positive nationwide and nonsusceptible to amoxicillin.32,60,64,67a,115 Antimicrobial susceptibility patterns for S. pneumoniae vary considerably geographically. Isolates obtained from surveillance centers nationwide indicate that 10%–15% of upper respiratory tract isolates of S. pneumoniae are nonsusceptible to penicillin;26,27 however, values as high as 50%–60% have been reported in some areas.46,60 Of the organisms that are resistant, approximately half are highly resistant to penicillin, and the remaining half are intermediate in resistance.26,27,32,60,65,115 There has been considerable controversy regarding recommendations for antibiotic management of acute bacterial sinusitis, specifically amoxicillin vs. amoxicillinclavulanate. The desire to continue to use amoxicillin as first-line therapy in patients suspected of having acute

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bacterial sinusitis relates to its general effectiveness, safety and tolerability, low cost, and narrow spectrum. For children 2 years of age and older with uncomplicated acute bacterial sinusitis that is mild in degree of severity, who do not attend day care, and who have not recently been treated with an antimicrobial drug, amoxicillin is recommended at either a usual dose of 45 mg/kg/day in two divided doses or a high dose of 90 mg/kg/day in two divided doses (Table 53-4). A dose of amoxicillin of 45 mg/kg results in middle ear fluid levels that exceed the minimum inhibitory concentration of all S. pneu­ moniae that are intermediate in resistance and most of those that are highly resistant.46,60 It is presumed that comparable concentrations of amoxicillin are found within the paranasal sinuses. In communities with a high prevalence of S. pneumoniae that are not susceptible to penicillin, treatment should be initiated at an amoxicillin dose of 80–90 mg/kg per day in two divided doses. Risk factors for the presence of bacterial species that are more likely to be resistant to amoxicillin include (1) attendance at day care, (2) recent receipt (90% of the entire event, compared with the pre-event baseline amplitude, with continued chest wall and abdominal movement, for a duration of at least two breaths.125 A hypopnea is always obstructive and is defined as a >50% drop in airflow signal amplitude compared with the pre-event baseline amplitude for at least 90% of the duration of the event; the event must last at least two missed breaths and should be associated with an arousal, awakening, or a >3% desaturation.125 Severity is generally quantified, based on the obstructive apnea hypopnea index (OAHI). The OAHI is the total number of obstructive apneas and hypopneas divided by the total duration of sleep in hours. Although there is no consensus regarding the definition of OSA in children, an OAHI of less than or equal to 1 is considered within normal limits. An OAHI of 1–5 is very mildly increased, 5–10 is mildly increased, 10–15 is moderately increased, and greater than 15 is severely abnormal.

Cardiovascular, Behavioral, and Neurocognitive Presentations in SRBD The polysomnographic thresholds for adverse cardiovascular outcomes in SRBD have not been established. Levels of C-reactive protein (CRP), felt by many to be a risk predictor for myocardial infarction, are elevated only in severely affected children,126 However, studies suggest that even

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SECTION 4 ❖ The Mouth, Pharynx, and Esophagus

children with mild OSA demonstrate a morning blood pressure surge, and those with AHI > 5 show an increased blood pressure load and 24-hour ambulatory blood pressure, leading to cardiac hypertrophy.127,128 In behavioral studies, children with SRBD have been found to show significantly higher prevalence rates of problematic behaviors, including both internalized (e.g., withdrawal, shyness, anxiety) and externalized (e.g., emotional lability, impulsivity, hyperactivity, aggressiveness, oppositional personality, somatic complaints, and social problems) behaviors, compared with controls.129–133 Unfortunately, such studies have often been compromised by problems such as a lack of objective measures of OSA and the use of nonvalidated measures of behavior outcomes. In one study controlling for these factors, Rosen et al. demonstrated that children with SRDB, ranging from primary snoring to OSA, have a higher prevalence of problem behaviors.132 The strongest, most consistent associations were for externalizing, hyperactive-type behaviors. In another study, although their mean scores were in the normal range, children with primary snoring and AHI < 5 were found to perform worse than controls on measures related to attention, social problems, and anxious/ depressive symptoms, as well as overall cognitive abilities and some language and visuospatial functions.134 As a result, the polysomnographic level at which intervention should be considered for children with SRBD and problem behaviors remains unclear. An association with enuresis has been demonstrated in up to 50% of children with SRBD.135–140 The mechanism by which this occurs is not established, but theories include alterations in normal arousal and self alerting mechanisms, hormonal changes (lower levels of antidiuretic hormone), and increased intra-abdominal pressure. In one study, the prevalence of enuresis in children with an apnea-hypopnea index (AHI) > 1 was significantly greater than that of children with an AHI 15.136 Neurocognitive impairment is also noted in children with SRBD, and appears to be more severe in children with OSA than in those with primary snoring.141,142 It has been suggested that such impairment may result from hypoxemia-induced dysfunction of the frontal lobe.143 Most studies reveal reduced IQ scores among children with SRBD, compared with controls.141–146 In these studies, children with SRBD performed in the lower normal or borderline range. However, another study failed to detect any IQ differences.147 Verbal abilities and language scores are also reduced in children with severe OSA (AHI > 15) or severe hypoxemia, but data yield conflicting results regarding the impact of less severe forms of SRBD on such skills.142,146,148 Similarly, memory performance in children with SRBD on standardized psychometric tests has varied among studies.141,144,146,149,150 Several studies have established a lower level of school performance among children with SRBD151–155 Similarly, children with poor academic performance are also more

Ch65.indd 1198

likely to demonstrate sleep disturbances.156,157 It has also been observed that children with frequent heroic snoring during early childhood are at greater risk for poor academic performance in later years, long after resolution of the snoring.158

PRESENTATION AND EVALUATION IN RECURRENT PHARYNGOTONSILLITIS Common Bacterial and Viral Infections of the Tonsils Pharyngotonsillitis is a term used to describe any inflammation of the structures of the oropharynx. Typically, the disorder will present with symptoms of odynophagia (sore throat); however, objective signs of inflammation must be present in order to make the diagnosis. Pharyngotonsillitis may be classified based on the duration of symptoms as acute, subacute, or chronic; most patients present with acute illness. The etiologic agents responsible for pharyngotonsillitis are diverse, although Group A β-hemolytic Streptococcus (GABHS), adenoviruses, influenza viruses, parainfluenza viruses, enteroviruses, EBV, and Mycoplasma account for over 90% of these infections.159 A child with acute tonsillar infection presents with throat discomfort, fever, cervical lymphadenopathy, difficulty controlling secretions, muffled voice, and general malaise. The pharyngeal and tonsillar mucosa are typically erythematous and edematous with exudates, although petechiae are more typical of viral illness. The treatment of these illnesses varies, depending on the etiology, and therefore throat culture for treatable bacterial etiologies is usually indicated. Most viral pharyngotonsillitis require no specific therapy. GABHS infection of the tonsils is the most common bacterial infection of the tonsils, and its proper diagnosis is therefore of interest to the otolaryngologist managing a recurrently infected child. Streptococcal pharyngitis cannot accurately be distinguished from nonstreptococcal pharyngitis without appropriate diagnostic testing.160 Adenopathy, fever, and pharyngeal exudate have the highest predictive value for a positive culture and rise in antistreptolysin O (ASO) titer, and the absence of these findings in the presence of cough, rhinorrhea, hoarseness, or conjunctivitis most reliably predicts a negative culture, or positive culture without rise in ASO.160 Most clinicians still advocate throat culture to determine the appropriate treatment for GABHS; however, culture results are not available for 24–48 hours. Since some studies suggest that early antibiotic treatment hastens clinical improvement,161 an earlier diagnosis is usually desirable. The rapid detection of the group-specific carbohydrate performed at the time of the office visit demonstrates a specificity of greater than 90%, although a false-positive rate as high as 15% has been reported.162 Sensitivity is in the 60%–90% range163; as a result, throat culture should still be performed when streptococcal disease is suspected and rapid strep testing is negative.

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CHAPTER 65 ❖ Tonsillectomy and Adenoidectomy Serologic tests are recognized as the definitive means for diagnosing acute streptococcal infection. A twofold dilution increase in antistreptolysin O (ASO) titer between acute and convalescent serum, or any single value above 333 Todd units in children, is considered diagnostic, and is usually demonstrable within 1 week of infection, with a peak at 3–6 weeks. The subsequent decline usually occurs within 6–8 weeks, but may not occur for months; therefore, a persistent elevation in the ASO titer is not necessarily indicative of ongoing clinical disease. Children who have been exposed to GABHS may continue to carry the organism asymptomatically even months after adequate antimicrobial therapy. Such individuals can be distinguished by positive cultures during the asymptomatic periods, and generally will not demonstrate a rise in ASO titer if cultured during illness. Carriage rates in the literature vary from 5%–40%,164 thereby complicating the distinction between bacterial and viral pharyngitis in patients with sore throat and positive cultures. As a result, the American Academy of Pediatrics165 recommends that testing for GABHS should not be performed in children with conjunctivitis, cough, hoarseness, coryza, diarrhea, oral ulcerations, or other clinical manifestations highly suggestive of viral infection. Carriers appear to be at little risk to transmit GABHS or to develop sequelae of the disease.166 The treatment of the asymptomatic carrier should be considered only in the following situations: family history of rheumatic fever, history of “ping-pong” spread among family members, personal history of glomerulonephritis, and school epidemic of GABHS. In such cases, additional antibiotics, such as clindamycin and rifampin, have demonstrated some efficacy in clearing the organism. In refractory cases, tonsillectomy may be considered.

Pathophysiology of Recurrent Tonsillitis Studies implicate a different bacteriology among patients with recurrent tonsillitis. Cultures from the deeper tissues of recurrently infected tonsils frequently reveal pathogens, including S. aureus,167–172 H, influenzae,170–174 Actinomycetes,175–177 Chlamydia,178,179 Mycoplasma,178,179 and anaerobes.180–182 However, in several studies these core cultures were similar to results at the surface,183 while in others, the flora in the two sites showed significant differences.184,185 Furthermore, Isaacson and Parikh28 have demonstrated that tonsils do not possess a true core as is described for lymph nodes, implying that these core cultures are, in fact, samples from the deep portions of the tonsil crypts, isolating facultative anaerobes and microaerophilic bacteria surviving in a low oxygen environment. As a result, the significance of bacterial tonsil cultures remains unclear, especially since most such events are still viral in etiology. Several studies suggest that the bacteria in biofilms may be more important in recurrent tonsillitis than their planktonic counterparts.186–188 Nevertheless, the tonsils yield the highest concentration of bacteria during streptococcal infection, and their role as

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1199

“processing stations” for antigens entering the body via the oral cavity certainly suggests that they play an important role in recurrent pharyngotonsillitis. When tonsils have been recurrently or chronically infected, the controlled process of antigen transport and presentation is altered due to the shedding of the transporting M cells from the tonsil epithelium.24 As a result, tonsillar lymphocytes can theoretically become overwhelmed with persistent antigenic stimulation, rendering them unable to respond to antigens or to function adequately in local protection or reinforcement of the upper respiratory secretory immune system. Furthermore, the direct influx of antigens disproportionately expands the population of mature B cell clones and, as a result, fewer early memory B cells go on to become J-chain positive IgA immunocytes.24 There would therefore appear to be a therapeutic advantage to removing recurrently or chronically diseased tonsils. The surgeon should bear in mind, however, that tonsillectomy and adenoidectomy procedures remove a source of immunocompetent cells, and some studies demonstrate minor alterations of Ig concentrations in the adjacent tissues following tonsillectomy.25,189–192

SURGICAL CONSIDERATIONS IN SRBD To date, there are few randomized studies of the efficacy of tonsillectomy and adenoidectomy for SRBD in children; most investigations have been observational studies or systematic reviews of observational studies. Most have concluded that adenotonsillectomy should be considered first line therapy for SRBD, provided the patient has at least mild adenotonsillar hyperplasia. The outcomes appear to improve, regardless of the measure used. Polysomnographic improvement may be anticipated in 20%–90% of cases, depending on the criteria used to define OSA and the patient population studied.193–197 For example, OSA can be defined as an apnea-hypopnea index (AHI) of 1, 2, or 5.193 In children whose diagnosis of OSA was based on an AHI of five or greater, resolution rates were as high as 90%; however in children with an AHI of one or greater, rates dropped to 70%.193 Among nonobese patients, older males are at the highest risk of postadenotonsillectomy sleep apnea.195 Similarly, OSA resolution with adenotonsillectomy is higher than 80% in normal weight children but lower than 30% in obese children.113,195 Children with allergies, craniofacial, neuromuscular, and genetic disorders are also known to be at high risk for persistent postoperative OSA. Tauman et al.198 reported the normalization of sleep parameters after adenotonsillectomy for OSA in only 25% of children; however, over 50% were obese children and 71% suffered from allergies. It is therefore important to interpret the results of studies in the light of the definition used for OSA and the characteristics of the studied population.

Healthcare Utilization and Quality of Life Children with SRBD, compared to controls, have a significantly higher rate of healthcare utilization and cost. In one

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SECTION 4 ❖ The Mouth, Pharynx, and Esophagus

study, children with OSA demonstrated a 215% increase in health care usage, mostly due to increased respiratory tract infections, requiring greater use of antibiotics and a 40% higher rate of hospital visits.199 In those children who subsequently underwent adenotonsillectomy, the total healthcare costs were reduced by one-third, a change not observed among untreated control patients. Children with tonsillar disease (including those with either throat infections or SRBD) have been shown to score significantly lower than their healthy counterparts in several QoL subscales, including general health, physical functioning, behavior, bodily pain, and caregiver impact.200 However, dramatic improvements in QoL scores have been achieved following adenotonsillectomy in a number of studies, with follow-up as long as 3 years after surgery.201–217 Improvement reported by caregivers in most studies occurred irrespective of the severity of OSA and without complete resolution of the OSA. As an example, Mitchell and Kelly201 evaluated QoL in children with severe OSA and found significant improvement in general and domain scores on the OSA-18 despite the lack of resolution of the OSA in the majority of subjects. Other studies by the same authors demonstrated substantial QoL improvements in both children with OSA and those with less severe SRBD, the improvements being statistically similar between the groups in one study and greater in the less severely affected children in the other.202,203 It is therefore important to consider as candidates for adenotonsillectomy even children with mild OSA, as they may also benefit from dramatic improvements in their QoL.

Behavior and Cognition Clinical improvement in patients with SRBD and problem behaviors or cognitive impairment has been reported following adenoidectomy and/or tonsillectomy. Mitchell and Kelly showed dramatic improvement in both the externalizing and internalizing behaviors in children with OSA following adenotonsillectomy, which were seen to persist up to 18 months after surgery,218 and were independent of factors such as gender, age, ethnicity, parental education, and parental income.218,219 Interestingly, the severity of the problem behaviors in children with OSA, as well as the improvements after adenotonsillectomy, appear to be similar, regardless of the severity of the sleep disorder.220 In a study of 36 children who underwent adenotonsillectomy, Goldstein et al.221 found abnormal behavior preoperatively in 28% of patients, based on the Child Behavior Checklist (CBCL), a standardized assessment tool for childhood behavior. After surgery, the behavioral disturbances resolved in all but two patients after surgery, and a significant decrease in the mean total problem score was observed. Goldstein et al.222 found a significant improvement in disease-specific QoL after surgery in a subsequent study of 64 children before and after adenotonsillectomy for clinically diagnosed SDB, based on the OSA-18 and the CBCL. A significant correlation was seen between the improvement on the QoL instrument scores and the behavior

Ch65.indd 1200

scores. Chervin et al.223 demonstrated an improvement in problem behaviors in children 1 year after AT, compared with controls, using the Conner’s Rating Scale. They also found improvements in the objective measures of attentiveness, and nearly half of children preoperatively diagnosed with attention deficit hyperactivity disorder (ADHD) no longer met the criteria for that diagnosis a year after surgery. However, PSG measures at baseline or improvements in PSG measures after surgery were poorly predictive of which children showed either baseline abnormalities or postoperative improvement in behavior or neurocognitive functioning. Similarly, Guilleminault et al.152 demonstrated that children with ADHD surgically treated for SRBD postoperatively did not require their previously prescribed medication for hyperactivity. Chervin et al.224 further suggest that the control of snoring could eliminate ADHD in a subset of children with SRBD. These results, and those of similar studies,147,215,225,226 suggest that a diagnosis of SRBD should be entertained in children with behavioral problems, and that these children may experience sustained benefits in behavior after adenotonsillectomy. The documentation of behavioral problems may affect the decision to undertake surgical therapy, especially in children with mild OSA. Studies suggest that enuresis in children with SRBD resolves or improves in the majority of children after adenotonsillectomy. One study found that 61% of children no longer had enuresis, and 23% had a decrease in bedwetting after surgical therapy for SRBD.140 Other studies, that have followed children beyond a year, have reported similar results, with the resolution rate increasing proportionally as the time following the surgery increases.138,139 Cognitive changes following adenotonsillectomy have been studied by Gozal,98 who found a 6–9-fold increase in the expected incidence of OSA among first grade children who ranked in the lowest 10th percentile of their class. A significant improvement in academic performance followed adenotonsillectomy and the resolution of OSA; however, in some children, long-term residual deficits persisted even after treatment. Montgomery-Downs et al.227 compared results in a group of 19 socioeconomically at-risk children with OSA with those in 19 controls using the Differential Abilities Scale (DAS) and the Developmental Neuropsychological Assessment (NEPSY). Preoperatively, both the DAS and the NEPSY scores were lower in the OSA subjects than in the controls; postoperatively, significant improvement in the scores of OSA patients was noted, with the final DAS scores equivalent to the controls. Friedman et al.228 examined neurocognitive function with the Kaufman Assessment Battery for Children (K-ABC) in 39 children with documented OSA and 20 controls with no symptoms of SRBD. Preoperatively, children with OSA had lower subtest scores as well as a lower score on the general mental processing composite scale. No correlation was seen between the severity of OSA and the K-ABC scores. After adenotonsillectomy, the OSA group’s neurocognitive scores reached the level seen in the control group in both the subtests and general scale. As with behavior,

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CHAPTER 65 ❖ Tonsillectomy and Adenoidectomy the caretakers of children with cognitive impairment or poor academic performance should be questioned about the symptoms of SRBD, and surgery should be considered even in those cases deemed mild, based on the PSG.

Special Populations In children with pharyngeal compromise due to structural narrowing or decreased neurologic tone, adenotonsillectomy may be an effective intervention, but is less likely to result in complete resolution in severe OSA. Patients with obesity, cerebral palsy, Down’s syndrome, Prader-Willi syndrome, achondroplasia, mucopolysaccharidoses, or hypoplasia of the mandible or midface are at high risk for residual sleep apnea after adenotonsillectomy. Such patients are also at greater risk for postoperative complications, including early respiratory embarrassment, residual airway obstruction, and velopharyngeal insufficiency among those with a cleft palate. The prevalence of obesity in children in the United States has doubled in the last two decades, and there is evidence that this trend is likely to continue. Approximately 30% of children in the United States are overweight and 50% of overweight children are considered obese.229 The prevalence of OSA in obese children is estimated to be 30%, about 10 times higher than in normal weight children.230 There is also evidence that OSA in obese children is under-recognized.230 As a result, an increasing number of obese children will present for treatment of OSA in the coming years. In obese children, a number of factors in addition to adenotonsillar hyperplasia contribute to the obstruction of the upper airway. Adipose deposition around the pharynx causes compression and increased critical airway closing pressure, exacerbating its collapsibility. At the same time, the central adiposity causes a reduction in the resting lung volume, resulting in the loss of caudal traction on the upper airway structures, altered chest wall mechanics, and abnormalities of ventilatory control.231 Unfortunately, the therapeutic options directed at weight reduction are rarely successful. Therefore, although adenotonsillectomy improves the QoL and severity of obstruction in obese children with OSA, it does not resolve the sleep disorder or the obstruction in the majority of obese children.209,232,233 Children with cerebral palsy have a higher than normal incidence of SRBD, owing to the incoordination of their upper-airway muscles.234 In such patients, obstruction may be exacerbated by a reduced ability to handle the airway secretions. In achondroplasia, midface hypoplasia results in a relative enlargement of the lymphoid tissues. Such patients still demonstrate an improvement in obstruction after adenotonsillectomy, but also have a high rate of recidivism.235 Patients with some combination of pulmonary disease, foramen magnum stenosis, hydrocephalus, jugular foramen stenosis, severe gastroesophageal reflux disease, or cor pulmonale are less likely to respond as well to surgery.236 Children with mucopolysaccharidosis commonly experience an obstruction of the upper airway, presumably due to the accumulation of

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glycosaminoglycans in the soft tissues of the pharynx and tongue.237 Prader-Willi patients have both obesity and hypotonia238,239 and those with Down’s syndrome have multifactorial obstruction involving macroglossia, hypotonia, small pharynx, and obesity.240 In children with the above disorders, adenotonsillectomy may not be an option or may not resolve the upper airway obstruction. The interventions for residual obstruction are beyond the scope of this chapter; however, continuous positive airway pressure (CPAP) is effective in most cases, when tolerated. Uvulopalatopharyngoplasty (UPPP), previously reported to be a useful adjunctive intervention in the treatment of children with Down’s syndrome,241,242 did not improve the obstruction in a controlled retrospective study.243 Similarly, UPPP for obstruction in cerebral palsy244,245 has not been studied in a controlled investigation with preoperative and postoperative PSG.

SURGICAL CONSIDERATIONS IN RECURRENT TONSILLITIS Sore throat ranks as the fifth most common symptom for which patients seek ambulatory medical care in the United States, accounting for over 13 million medical visits annually.246 Furthermore, QoL studies of children with recurrent throat infection demonstrate lower subscale scores in the areas of general health, physical functioning, behavior, bodily pain, and caregiver impact, compared with their healthy counterparts.200 As a result, many patients afflicted with recurrent throat infection refractory to conservative management may be referred to the otolaryngologist for specialized medical, and possibly surgical, intervention. The clinician referring a child for consideration for tonsillectomy for recurrent sore throat should have recorded for each event a subjective assessment of the patient’s severity of illness; physical findings including body temperature, pharyngeal and/or tonsillar erythema, tonsil size, tonsillar exudate, cervical adenopathy (presence, size and tenderness); and the results of microbiologic testing for GABHS. A summary of the documentation should be made available to the consultant to aid in the medical decision making regarding potential surgical intervention. In children with recurrent sore throat whose tests for GABHS are repeatedly positive, it may be desirable to rule out streptococcal carriage concurrent with viral infection as carriers are unlikely to transmit GABHS or to develop suppurative complications or nonsuppurative sequelae of the disease, such as acute rheumatic fever.165,166 Supportive documentation in children who meet criteria for tonsillectomy may include absence from school, spread of infection within the family, and a family history of rheumatic heart disease or glomerulonephritis. Since many caregivers choose not to visit a medical facility for every throat infection, the documentation of events may be lacking. Studies suggest that patients whose events are less severe or well-documented do not gain sufficient benefit from tonsillectomy to justify the risk and morbidity of the

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procedure; in one study of patients observed for 1 year, only 17% of patients who otherwise met the criteria for surgery actually had documentation and confirmation of their clinical course.247 In such patients, tonsillectomy should be considered only after a period of observation, during which the documentation of additional events may be made. In all randomized controlled trials of tonsillectomy for infection, sore throat with each event was a necessary entrance criterion, and in most of these trials, sore throat was the primary outcome studied. As a result, no claim can be made for tonsillectomy in children whose constellation of symptoms does not include sore throat, even when GABHS can be cultured from the throat. There are currently no randomized controlled trials investigating the efficacy of tonsillectomy for patients experiencing recurrent tonsillitis over a period of less than 12 months. Furthermore, children with recurrent throat infections observed without surgery demonstrate high rates of spontaneous resolution.247 As a result, an observation period of at least 12 months is generally recommended prior to any consideration of tonsillectomy. In rare cases, early surgery may reasonably be considered for severely affected patients, such as those with histories of hospitalization for recurrent severe infections, rheumatic heart disease in the family, or numerous repeat infections in a single household (“ping-pong spread”), or those with complications of infection, such as peritonsillar abscess or Lemierre’s syndrome (thrombophlebitis of the internal jugular vein). The observation of patients with a history of frequent pharyngotonsillitis for more than 1 year is often a reasonable alternative to surgery. In several studies, nontonsillectomized children demonstrated spontaneous improvement during the follow-up period, often with patients no longer meeting the original criteria for study entry. In a randomized controlled trial of patients who met the “Paradise criteria” (Table 65-3), children in the control group experienced an average of only 1.17 episodes of throat infection annually in the following first year, 1.03 in the second year, and 0.45 episodes in the third year.248 Similar results were found in other trials that relaxed the “Paradise criteria,” as well as systematic reviews, in which the control patients had an average of less than one sore throat episode per year.249–253 Additional information regarding the natural history of recurrent pharyngotonsillitis is found in case series describing outcomes for patients on wait lists tonsillectomy; many children who were reevaluated after months on such lists later no longer met the criteria for surgery.254–259

Efficacy and Effectiveness of Tonsillectomy for Recurrent throat Infection In the past, clinical trials investigating the efficacy of tonsillectomy have had a high risk of bias because of poorly defined entrance criteria, the nonrandom selection of operated subjects, the exclusion of severely affected patients, or the reliance on caregivers for postoperative data collection.

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TABLE 65-3. The “Paradise criteria” for Tonsillectomy in Recurrent Tonsillitis158

Criterion

Definition

Frequency of sore throat events

7 or more episodes in the preceding year, OR 5 or more episodes in each of the preceding 2 years, OR 3 or more episodes in each of the preceding 3 years

Clinical features (one required in addition to sore throat)

Temperature > 38.3°C, OR Cervical lymphadenopathy (tender lymph nodes or > 2 cm), OR Tonsillar exudate, OR Positive culture for GABHS

Treatment

Antibiotics are administered at appropriate dose for proven  or suspected episodes of GABHS

Documentation

Each episode and its qualifying characteristics are synchronously documented in the medical record, OR In cases of insufficient documentation, two subsequent episodes of throat infection are observed by the clinician with frequency and clinical features consistent with the initial history

However, studies in which these factors were minimized suggest a modest, but statistically significant, reduction in the frequency of throat infection among severely affected patients undergoing tonsillectomy.248–250 Mildly affected individuals appear less likely to gain benefits from the procedure. In the most frequently cited and meticulous trial, Paradise and colleagues248 included patients only if their episodes of throat infection met strict criteria, as outlined in Table 65-3. The key findings of the study were as follows: 1. A mean rate reduction of 1.9 episodes of sore throat per year among tonsillectomized children during the first year of follow-up compared with controls. However, the sore throat associated with performance of the surgery (which would otherwise count as one episode) was excluded from the data. In the control group, patients also improved compared with their pre-enrollment frequency of infection, experiencing a mean of only 3.1 annual events. The differences between the groups were reduced in the second year and not significant by the third year of follow-up. 2. For episodes of moderate or severe throat infection, the control group experienced 1.2 episodes, compared to 0.1 in the surgical group. The rate reductions diminished

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CHAPTER 65 ❖ Tonsillectomy and Adenoidectomy over the subsequent 2 years of follow-up and were not significant in the third year. 3. Mean days with sore throat in the first 12 months were not statistically different between the two groups, but included a predictable period of sore throat postoperatively. Some patients from the control group opted for surgery during the follow-up period, perhaps leading to an underestimation of the effect of surgery. In addition, the distribution of patients by the frequency of throat infection was statistically different between the surgical and nonsurgical groups; the effect of this factor on the final results was uncertain. In a subsequent study by the same authors,249 the entrance criteria were relaxed, with less rigorous criteria for the number of episodes, clinical features required, and documentation (i.e., 4 –6 episodes in the last year or 3 –4 episodes per year in the last 2 years). In the two arms of the study (tonsillectomy and adenotonsillectomy vs. control), patients undergoing surgery experienced rate reductions of 0.8 and 1.7 episodes/y, respectively, in the first year. For episodes of moderate or severe sore throat, control subjects in the two arms of the study combined experienced 0.3 episodes/y overall, compared with 0.1/y in the subjects undergoing surgery. Mean days with sore throat in the first 12 months were not statistically different in either arm of the study. The investigators concluded that the modest benefit conferred by tonsillectomy in children moderately affected with recurrent throat infection did not justify the inherent risks, morbidity, and cost of the surgery. A randomized controlled trial comparing tonsillectomy with watchful waiting in children aged 2–8 years, examined fever >38.0°C for at least 1 day as the primary outcome measure.250 During a mean follow-up of 22 months, children in the tonsillectomy group had 0.2 fewer episodes of fever per person year, and from 6 to 24 months, there was no difference between the groups. The surgical group also demonstrated, per person year, mild reductions in throat infections (0.2), sore throats (0.6), days with sore throat (5.9), and upper respiratory tract infections (0.5). Pooled data from these studies were also analyzed in a Cochrane systematic review.251 Patients undergoing tonsillectomy experienced 1.4 fewer episodes of sore throat in the first year compared to the control group; however, the cost of this reduction was 1.0 episode of sore throat in the immediate postoperative period. Another systematic review suggested a 43% overall reduction in sore throat events. The number needed to treat with tonsillectomy to prevent one sore throat per month for the first year after surgery was 11.252 A third systematic review that included 13 randomized controlled trials and nonrandomized controlled studies on the efficacy of tonsillectomy in children reported pooled estimated risk differences favoring tonsillectomy over the observation of 1.2 fewer episodes of sore throat, 2.8 fewer days of school absence, and 0.5 fewer episodes of upper respiratory infection per person year.253

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Despite the modest advantages conferred by tonsillectomy for sore throat, studies of QoL universally suggest a significant improvement in patients undergoing the procedure. Only two of these studies enrolled children exclusively and both reported improved scores in nearly all subscales.260,261 However, both also had numerous methodological flaws, including the enrollment of patients with chronic tonsillitis without definition, based on signs and symptoms, absence of a control group, low response rates with potential selection bias, poor follow-up, and caregiver collection of data. A recent guideline on tonsillectomy suggests that tonsillectomy for severely affected children with recurrent throat infection should be considered an option.262 The families of patients who meet the appropriate criteria for tonsillectomy as described above must weigh the modest anticipated benefits of tonsillectomy for this indication against the natural history of resolution and the risk of surgical morbidity and complications. The guideline also suggests that patients with modifying factors, such as antibiotic allergy/intolerance, or a history of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis), or recurrent peritonsillar abscess, may reasonably be considered for earlier surgical intervention.

PRESURGICAL PLANNING FOR ADENOTONSILLECTOMY Surgical Consent and Preparing the Patient for Surgery Once a decision for surgery is made, it is imperative to have an informed consent discussion with the family regarding the risks of the procedure delineated later in this section, as well as the benefits and potential alternative treatment options. The inclusion of older children and adolescents in the consent process should be considered. The content of the discussion should be documented in the patient’s medical record, and informed consent forms utilized by the facility where the procedure is to be performed should be appropriately completed, signed, and witnessed according to that facility’s protocol. Children too young or delayed to understand the consent process should be prepared specifically for the experience well in advance. Parents should describe the expected course of events in as much detail and as frankly as possible, commensurate with the child’s ability to comprehend. Children should be told that a certain amount of discomfort will occur, but also that every effort will be made by the hospital personnel to keep any pain to a minimum. Many hospitals permit advance visits so that the children can preview the facilities and equipment that will be used and become acquainted with some of the personnel. Media such as coloring books, storybooks, and videos of familiar television and cartoon characters are also commercially available as preoperative teaching aids.

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Preoperative Coagulation Studies The need for routine preoperative laboratory studies in children scheduled to undergo elective adenotonsillar surgery remains controversial. Coagulation parameters should be assessed if the patient’s history reveals a potential bleeding disorder. In such cases, coagulation tests should include an activated partial thromboplastin time (aPTT) and a platelet count. These assays are performed to screen for disorders associated with substantial hemorrhage. Tests of prothrombin time (PT) and bleeding time or PFA 100 help in screening for all inherited or acquired coagulation disorders, such as hemophilia A and B, von Willebrand disease, thrombocytopenia, and other deficiencies. Preoperative screening for bleeding disorders by means of both history and laboratory tests can occasionally identify the patients at a heightened risk of hemorrhage, and in many centers, these screening procedures are carried out routinely. In a large, single center study by Zwack et al., the use of a screening questionnaire followed by selective laboratory screening resulted in improved outcomes over universal laboratory screening alone.263 In another prospective study, the use of a questionnaire was also found to be an effective tool for identifying the patients who are at risk for postoperative bleeding.264 The combination of a positive questionnaire and an abnormal coagulation screen in that study was also associated with a higher likelihood of postoperative bleeding. However, Howells et al. found that coagulation tests produced abnormal results in 4% of 1706 children.265 The disturbing factor in this study was that the patient’s preoperative history did not help in identifying children with abnormal coagulation. It may be concluded that universally performing preoperative coagulation studies result in both low specificity (few of the abnormal histories or abnormal test results portend eventual hemorrhage) and low sensitivity (few of the children who develop hemorrhage will have had abnormal preoperative histories or laboratory values).266 As a result, hemorrhage is bound to occur in some cases.

Choosing an Appropriate Surgical Facility With the advent of ambulatory surgical centers capable of safely handling outpatient otolaryngology procedures in children has come the increased burden on the surgeon to choose the appropriate setting for his or her patient’s surgery. Most often, pediatric adenotonsillectomy is safely performed on an outpatient basis and can be considered in a free-standing ambulatory surgical center in most children over 3–4 years of age considered to be in excellent health (ASA [American Society of Anesthesiology] Class 1).267–270 Children considered ASA Class 2 can also be managed as outpatients, but may require additional preoperative or postoperative medical therapy, or have risk factors for anesthesia or surgery that require a higher level of pediatric operative and perioperative care. Individuals should not undergo tonsillectomy as outpatients if they are significantly younger

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than 3 years, have difficulty in complying with instructions, have severe obstructive sleep apnea (AHI>15), live a significant distance from the outpatient facility, or have complex medical problems such as Down’s syndrome, craniofacial disorders, bleeding disorders, obesity, or other co-morbidities that might predispose them to an airway complication, bleeding, or postoperative dehydration. The most common causes for unanticipated inpatient stays are emesis, dehydration, hemorrhage, and respiratory complications.268,271,272 The surgeon considering outpatient tonsillectomy needs to take all the factors into account and provide an avenue for predischarge evaluation and unimpeded reentry to the health care system before undertaking tonsillectomy as an outpatient procedure.268

Perioperative Management in Special Populations Presurgical planning is of particular importance among children in special populations. Such individuals frequently have anatomic, medical, or psychosocial differences that complicate their perioperative management. Appropriate consultations from medical and surgical subspecialists should be solicited, and preoperative visitation with the anesthesiologist may be helpful. Children with Down’s syndrome pose a number of challenges for the surgeon and the anesthesia team contemplating adenotonsillar surgery. Physical features such as macroglossia and obesity may complicate the endotracheal intubation and intravenous access. There is also a high incidence of congenital cardiac disease among children with trisomy 21; as a result, preoperative consultation with an anesthesiologist may be worthwhile. Children with Down’s syndrome also have a 10%–20% incidence of an unstable transverse ligament of the atlas and are prone to atlantoaxial subluxation.273 Patients with Down’s syndrome with a history of neck pain, hyperactive deep tendon reflexes, or clonus should undergo preoperative neurosurgical or orthopedic evaluation. It has been suggested that all asymptomatic patients should have preoperative flexion/extension lateral neck films.273 Those children demonstrating an atlas-dens interval of more than 4 mm should also undergo additional neurosurgical or orthopedic assessment, although the reliablity of plain radiographs in making this diagnosis has been questioned.274 A preoperative polysomnogram in this population may be helpful in postoperative management due to the higher risk of complications. Goldstein et al. compared postadenotonsillectomy results in 87 children with Down’s syndrome to those in 64 age-matched controls and found a five times higher incidence of respiratory complications and a higher rate of postoperative dehydration.275 Preparation of the child with Down’s syndrome on the day of surgery is more difficult because of the child’s lack of understanding, and presurgical administration of anxiolytics is often necessary. Additional time should be allocated to anesthesia preparation, such as intravenous access and

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CHAPTER 65 ❖ Tonsillectomy and Adenoidectomy intubation. Due to a smaller subglottis, an endotracheal tube must be chosen that is generally one size smaller than would be predicted based upon the child’s age, height, and weight.276 Antibiotic prophylaxis against subacute bacterial endocarditis should be considered for those with congenital heart disease. Postoperatively, it has been recommended that children with Down’s syndrome be admitted to the hospital overnight after undergoing tonsillectomy and adenoidectomy.275,277 In all children with a significant risk of postoperative airway obstruction, the use of narcotics should be limited. Children with cerebral palsy also benefit from adenotonsillectomy,278,279 but require management similar to those with Down’s syndrome, with a few notable exceptions. Anatomically, such children are thinner, but often have impaired mobility due to such disorders as extremity contractures and scoliosis; such issues may complicate positioning and intubating the patient in the operating room. Hypotonia and difficulty managing secretions often increase the risk of postoperative respiratory compromise. Studies suggest that these children have a higher incidence of postoperative respiratory complications and dehydration.245,280,281 Children with cerebral palsy, like those with Down’s syndrome, have a higher need for postoperative monitoring in an intensive care setting and should generally not be operated upon in an outpatient setting. Children with morbid obesity (defined as a BMI > 30 corrected for age and gender) also present challenges when undergoing adenotonsillar surgery to correct their obstructive sleep problems.281–283 Respiratory compromise in such patients is multifactorial, as described earlier in this chapter. In children with severe symptomatology and relatively small tonsil size, preoperative polysomnography performed as a “split night” study may suggest that use of home Continuous Positive Airway pressure (CPAP) is a better alternative than surgery when tolerated since it is likely CPAP will be required postoperatively anyway.113,195 In patients who are surgical candidates, preoperative polysomnography is also recommended because of the higher incidence of postobstructive pulmonary edema and other respiratory complications that may occur after their surgery. Intraoperative challenges in these children include difficulties with intravenous access and intubation, resistance to ventilation, and suspension of the surgical mouth gag. Children with sickle cell disease are also considered at high risk for postoperative difficulties. Several regimens have been proposed to avoid provoking a sickle pain crisis after surgery. Derkay et al.284 and Halvorson et al.285 have recommended an aggressive preoperative transfusion protocol to lower the hemoglobin S ratio to less than 40% or raise the hemoglobin level greater than 100g/L (10g per deciliter), along with aggressive intravenous hydration of 1.5 X normal maintenance fluids administered 24 hours prior to surgery. Vichinsky et al.286 and Waldron et al.287 have demonstrated, however, that increasing the hemoglobin level to 10g per deciliter is an adequate goal, regardless of the hemoglobin S ratio. All authors have concurred with the need to maintain

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good hydration postoperatively, in addition to operating in a warmed operating room and providing patients with adequate pain medications postoperatively. Children with other blood dyscrasias who require adenotonsillar surgery can also be difficult to manage since a raw muscular surface is left as a consequence of the removal of the lymphatic tissue. Two of the most common coagulation defects in the general population are platelet dysfunction and von Willebrand’s disease. Many commonly used medications cause platelet dysfunction and, used postoperatively, increase the risk of bleeding287,288; as a result, it stands to reason that aspirin should be discontinued at least 2 weeks prior to surgery and all other nonsteroidal inflammatory medications for at least 4 days prior. Von Willebrand’s disease affects 1% of the general population and is transmitted by autosomal dominance with variable expression. There are over 20 different types; all affect factor VIII:vWF (von Willebrand factor) necessary in platelet activation. Type 1 is the most common (80%–90%) with subnormal plasma levels of qualitatively normal vWF. Patients with this disorder will respond to desmopressin (DDAVP), a synthetic analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), which supports coagulation. Von Willebrand’s disease Type 2 results in a defect in vWF, whereas patients with Type 3 have no vWF. Neither of these types will respond to desmopressin. Elevated PTT, bleeding time, and decreased or absent vWF antigen are diagnostic for this disease. These studies, as well as rise in ristocetin cofactor and factor VIII, may be used to measure the response to desmopressin preoperatively. Perioperative management of children with von Willebrand’s Type I consists of administration of desmopressin (0.3 μg/kg) intravenously over 30 minutes prior to surgery, 12 hours postoperatively, then every morning until the eschar has completely resolved and the fossae are completely healed.289,290 Aminocaproic acid (Amicar®) 50mg/kg is also given four times a day for 5 days after surgery to counteract the high concentration of fibrinolytic enzymes in the oral cavity. Fluids should be restricted to one half maintenance for 12 hours postsurgery and after each dose of DDAVP. Children are admitted for at least a 23-hour observation period. Adverse effects of desmopressin include hyponatremia and tachyphylaxis. In these situations, desmopressin should be discontinued and substituted with cryoprecipitate or vWFcontaining antihemophilic factor.289

ADJUVANT INTERVENTIONS FOR ADENOTONSILLECTOMY On the day of their surgical procedure, children should be permitted to remain with their caregivers throughout the preoperative admissions process and as soon as is medically feasible postoperatively. Careful preparation and kind, thoughtful management of the entire process of hospitalization and surgery should virtually eliminate the risk of untoward psychological consequences in previously well-adjusted children. For children who are emotionally disturbed, the same

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general principles apply, but in addition, specialized professional advice may be appropriate to help minimize the risk that they misinterpret the operative event. Some centers have a child life specialist available who can, on the day of surgery, engage children in activities to calm them and prepare them for the event. Preoperative anxiolytics, such as midazolam, administered prior to the procedure may be useful for children who are especially anxious or demonstrate an inability to separate from their parents. Children given these medications require monitoring by qualified nursing staff until their surgical procedure. Older children for whom an intravenous induction is planned may benefit from placement of 4% topical lidocaine (ELA-Max®) over the hand or forearm prior to entering the operating room. In some circumstances, having parents accompany their children into the operating suite or the induction room may be preferable to sedation and to the anxiety provoked by the separation. Intraoperative and postoperative antibiotics have been proposed as adjuvant medical therapy to reduce pain and foul breath and return more rapidly to a normal diet.291,292 Telian performed a prospective, randomized blinded study to look at the effect of antibiotic therapy on the recovery after tonsillectomy in children and found that the antibiotic group had fewer days of bad breath and returned to normal diet about 1 day faster than controls.291 These findings were supported by Iver et al., who pooled data from similar studies and found that the antibiotic group returned to normal oral intake on average 1 day sooner and experienced less postoperative pain.293 Based on these data, up to 79% of the polled otolaryngologists in the United States report using perioperative antibiotics in patients undergoing tonsillectomy.17 The preponderance of recent evidence, however, does not support routine antimicrobial therapy in the perioperative period. In a Cochrane review of antibiotics to reduce post-tonsillectomy morbidity, little or no evidence was found for the reduction of pain, analgesic use, time to normal diet, or secondary hemorrhage with antibiotic use.294 A statistical difference was demonstrated only in the reduction of postoperative fever, and this finding was considered likely to reflect methodologic flaws among the studies included. Furthermore, antibiotic use adds cost to the procedure, contributes to bacterial resistance, and may be complicated by rash, allergy, or gastrointestinal upset or diarrhea. As a result, a recent tonsillectomy guideline does not support the use of perioperative antibiotic therapy.262 The intraoperative administration of dexamethasone has been advocated to reduce postadenotonsillectomy nausea and vomiting and inflammation. Postoperative nausea and vomiting occur in over 70% of children who do not receive prophylactic antiemetics.295–297 Overnight hospital admission is often required for hydration, resulting in decreased patient satisfaction and the increased use of resources.298–300 Dexamethasone is a potent steroid with the advantage of a long half-life. The mechanism of efficacy of dexamethasone is unknown, but

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may be related to its anti-inflammatory properties that reduce pain and swelling.301–303 Numerous studies have demonstrated that the administration of a single intraoperative dose of dexamethasone in children undergoing tonsillectomy results in a decreased PONV.304–313 A comprehensive Cochrane literature review of randomized, blinded, placebo-controlled trials, found that a single dose of dexamethasone administered intraoperatively reduced the post-tonsillectomy emesis and resulted in a more likely return to soft or solid diet on the first postoperative day, with no adverse effects.313 Most published studies used a dexamethasone dose of 0.5 mg/kg309; however, lower doses may be equally effective.314,315 There have been no reports of infection, peptic ulceration, or adrenal suppression from the use of a single intravenous dose of dexamethasone in nondiabetic patients during pediatric tonsillectomy.313 Although one study claimed an increased risk of postoperative bleeding in children who received dexamethasone intraoperatively, this was a secondary outcome that was not significant when primary hemorrhage cases were excluded from the analysis.309 An increased risk of bleeding has not been substantiated in subsequent studies.316 Local anesthetics have been evaluated for their ability to reduce postoperative pain and morbidity.317–326 Although there are many studies in literature, results vary as tonsillectomy surgical techniques and the protocol for administration of local anesthesia were not standardized. A prospective, randomized, double-blinded clinical trial of 150 patients used an intraindividual study design to avoid some of these flaws; the authors demonstrated that the postoperative wound infiltration of bupivacaine was more effective than the preincisional peritonsillar infiltration or the use of a bupivacaine swab.326 A systemic review of these studies also found a modest reduction in posttonsillectomy pain.327 However, the trials were small in size and several involved the simultaneous administration of intravenous opiates, which may have masked the effects of the local anaesthetic. A Cochrane systematic review, conversely, found no evidence that the use of perioperative local anaesthetic in patients undergoing tonsillectomy improves the postoperative pain control.328

TECHNIQUE AND INSTRUMENTATION IN TONSILLECTOMY AND ADENOIDECTOMY Despite centuries of refinement, tonsillectomy, and to a lesser extent adenoidectomy, are associated with significant morbidity and risk. Pediatric patients still suffer from prolonged painful recoveries with odynophagia, otalgia, dehydration, and poor oral intake. The recovery from tonsillar surgery is not only difficult for children, but also for their caregivers, who lose sleep and time away from work. As a result, over the last two decades, there has been renewed interest and research into different adenotonsillectomy surgical techniques and instruments designed to reduce morbidity and speed the recovery time.

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Adenotonsillectomy Techniques Once anesthesia is induced, the airway is secured with an endotracheal tube or laryngeal mask airway. A surgical “time out” or “surgical checklist” is performed, ensuring that the proper procedure is performed on the correct patient and that medications and co-morbidities are reviewed; site-marking for adenotonsillectomy is not presently required by Joint Commission guidelines.329 With the operating table rotated 90°, the patient’s head is placed on a pillow and extended using a shoulder roll. The eyes are taped closed, and a head drape is placed to protect the face and eyes. Generally, either a McIvor or a Crowe-Davis mouth gag is used for exposure and tongue retraction. The McIvor has the advantage of resting on the alveolus rather than the teeth, but is a closed loop that occasionally impedes access to the adenoid; the Crowe-Davis gag rests on the upper anterior teeth, but its open loop gives greater access to the adenoid tissue. A slotted tongue depressor of appropriate size is inserted into the gag and opened. The gag may be suspended from the Mayo stand, but great care must be taken not to move the stand while the patient is in suspension. Alternatively, especially in obese individuals, the gag may be suspended upon a roll of towels on the patient’s chest or, using specially designed rings, supported on the operating table. When adenoidectomy is being performed, latex-free catheters inserted through the nares are used to expose the adenoid by retracting the soft palate. One of these catheters may be connected to suction to evacuate smoke, saline, or secretions from the surgical field. When performing a complete (extracapsular) tonsillectomy, a curved or straight Alyss clamp or ring forceps is used to pull the tonsil medially and dissection is started in the mucosa at the margin of the superior anterior tonsillar pillar. Finding the proper plane is essential to prevent excess bleeding and the unnecessary removal of muscle. Dissection is continued along the extracapsular plane, with care taken to avoid the lingual tonsil tissue caudally. After extraction of the tonsil, the area is irrigated, the mouth gag is released for a few minutes, and the fossae are then reexamined for further bleeding. Blood and secretions that may cause inadvertent reflex laryngospasm should be suctioned prior to extubation. The decision to perform a “partial intracapsular tonsillectomy” (PIT) as opposed to a total extracapsular tonsillectomy is surgeon-dependent. As discussed previously in this chapter, tonsillectomy performed prior to the 20th century was a less than complete removal of the pharyngeal lymphoid tissues. However, concerns that residual tissue served as a source for further infection and secondary complications suggested a need to alter the surgical technique.4 With improved anatomical understanding and surgical precision, surgeons began to advocate for complete tonsil removal, performing the procedure along the tonsil capsule.37 Regardless of the instrumentation used, total tonsillectomy leaves the musculature of the pharynx exposed to heal by secondary intention.

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In PIT, the removal of tissue is near complete, leaving a rim of tonsil tissue overlying the capsule. Once the tonsil tissue has been removed, suction electrocautery controls any residual bleeding.330,331 The cauterized tissue heals as a “natural biological dressing,” theorized to speed the healing process by reducing the exposure and inflammation of the pharyngeal musculature.332 Proponents of the partial procedure believe their patients experience less pain and a lower risk of bleeding by protecting the underlying muscle with its vasculature and nerves.333 Studies have found that PIT, performed either with the microdebrider or with the coblator (see below), results in a moderate reduction in postoperative pain, a more rapid return to normal activity and diet, and perhaps fewer delayed complications.330,331,333–340 It has been suggested that the intracapsular procedure, more so than the instrument used to perform it, may be the most important determinant of a good outcome.340–342 The QoL surveys also demonstrate a greater decrease in emotional distress in children undergoing microdebrider PIT.334 However, a major concern in PIT is tonsil remnants that may continue to cause tonsillitis and have a potential for regrowth. Large retrospective case series have suggested that tonsillar regrowth occurs in about 0.5%–6% of patients, with a smaller percentage requiring completion tonsillectomy, but follow-up in these studies was brief and captured only a subset of enrolled subjects.334,335 Peritonsillar abscess and recurrent tonsillitis have been reported after PIT, necessitating a return trip to the operating room.343 For this reason, while some clinicians suggest a possible role for PIT in the management of children with recurrent tonsillitis,343,344 others limit their use of PIT to patients with SRBD only.330,333,334 Ultimately, the surgeon and patient must together decide whether the decrease in pain with PIT justifies the risk of tonsil regrowth and potential for future infection.

Adenotonsillectomy Instrumentation Since 1980, electrocautery has been the instrument of choice for tonsillectomy, as surgeons can perform a faster procedure with minimal bleeding.17 According to a 2007 survey of members of the American Academy of Otolaryngology– Head & Neck Surgery and the American Society of Pediatric Otolaryngology, 55% of otolaryngologists indicated that electrocautery was their preferred instrument for tonsillectomy.345 Coblation® tonsillectomy was the instrument of choice in 20%–25%, cold steel techniques in 10%, and other techniques, including microdebrider partial tonsillectomy, by the remaining 10%. Traditional “cold steel” techniques using a mucosal scalpel incision; scissors, Fisher knife, or blunt dissection; and a snare at the inferior pole are still utilized by many otolaryngologists. Many clinicians believe that these techniques carry a lower risk of secondary hemorrhage and pain. Indeed, the National Prospective Tonsillectomy Audit

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(NPTA), performed in the United Kingdom in 2005, found that “hot” surgical techniques for both dissection and hemostasis (diathermy or Coblation®) carried a threefold higher risk of secondary hemorrhage when compared to cold steel tonsillectomy without the use of any “hot” technique.346 The risk of secondary hemorrhage for operations using cold steel for dissection and bipolar diathermy for hemostasis was approximately 1.5 times higher than for cold steel operations using only ties/packs for hemostasis. Similar results have been noted in systematic reviews,347 randomized controlled trials,348 and large prospective cohort studies.342,349,350 In the systematic review, bipolar diathermy dissection and hemostasis was associated with statistically significant lower odds of primary hemorrhage compared to cold steel dissection with ties/packs hemostasis.347 In a systematic review of hot (monopolar electrosurgery) versus cold knife tonsillectomy, only 6 of 815 prospective trials met the necessary inclusion criteria and revealed that postoperative hemorrhage rates were not significantly different when comparing the two methods.351 Pain, however, was significantly increased among patients undergoing “hot” tonsillectomy. In electrocautery tonsillectomy, intraoperative hemorrhage is reduced by the cauterization of the vessels as the dissection is performed. Research has shown that the heat of electrocautery (400°C) results in thermal injury to the surrounding tissue, and it is speculated that this may result in more discomfort postoperatively than with cold instrumentation.332,352 The discomfort may be minimized by using a smaller cautery tip and low power settings (10–15W).334 It is important when using cautery to protect the lips from contact with any metal that could conduct the electrocautery and result in a burn.353 Inadvertent injury may also occur during cautery tonsillectomy due to manufacturing defects, the accidental use of an uninsulated tip, or direct contact with the patient’s tissues or other conductive devices within the surgical field.354 With bipolar radiofrequency ablation (Coblation® [ArthroCare, Austin, TX]) the tonsillectomy is performed by producing an ionized saline layer that disrupts the molecular bonds without using heat. As the energy is transferred to the tissue, ionic dissociation occurs. This permits the removal of tissue at a temperature of only 45°C –85°C. It has been claimed that this technique results in less pain, faster healing, and less postoperative care.355,356 Coblation® can be used in complete tonsillectomy or PIT. Glade et al.357 and a Cochrane review358 reported similar rates of primary and secondary hemorrhage, compared to electrocautery tonsillectomy and a lower incidence of dehydration. However, the Cochrane review of nine studies could not establish an improvement in pain between Coblation® and other tonsillectomy techniques.358 Disposable wands add to the expense of performing the procedure. The microdebrider is a powered rotary shaver with continuous suction. The device consists of a rotating blade housed within a cannula or tube that attaches to a handpiece. The handpiece is, in turn, connected to a motor with foot control and a suction device. The microdebrider is used only in

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PIT procedures, with the preservation of the tonsil capsule as well as the anterior and posterior tonsillar pillars. The intraoperative blood loss is greater than that in other techniques, but appears to not be clinically significant.334 The disposable microdebrider blades and increased operative time increase the cost of surgery compared to electrocautery tonsillectomy; however, patients are saved a pathology charge for examining the tonsil and adenoid tissue. The additional costs also need to be weighed against the potential savings realized with reduced patient readmissions for dehydration and bleeding.338 Although difficult to estimate, with faster patient recovery, the parents are able to return to work faster and be more productive in their jobs. The harmonic scalpel uses ultrasonic energy to dissect the tissue. Vibrating at 55khz, the blade transfers energy to the tissue, providing simultaneous cutting and coagulation at a temperature of about 80°C. The proponents of this procedure assert that the end result is precise cutting with minimal thermal damage. Clinical studies, however, have failed to demonstrate a clinically significant benefit over electrocautery techniques.359,360 Such studies further suggest that the differences in collateral thermal damage may not be the reason for diminished pain with cold and microdebrider techniques. Regarding hemorrhage in harmonic scalpel tonsillectomy compared with conventional methods, a systematic review concluded that the current evidence regarding the use of harmonic scalpel and postoperative hemorrhage is of low quality and does not support any difference in postoperative hemorrhage rates.361 Monopolar radiofrequency thermal ablation transfers radiofrequency energy to the tonsil tissue through probes inserted in the tonsil. The procedure can be performed in an office setting under light sedation or local anesthesia. After the treatment is performed, scarring occurs within the tonsil, causing it to decrease in size over a period of several weeks. The treatment can be performed several times. The advantages of this technique are minimal discomfort, ease of operations, and immediate return to work or school. Tonsillar tissue remains after the procedure, but is less prominent. This procedure is recommended for treating enlarged tonsils and not chronic or recurrent tonsillitis and is rarely used in children.

Techniques of Adenoidectomy The setup for adenoidectomy is virtually identical to that used for tonsillectomy. However, adequate visualization is critical in adenoidectomy in order to achieve the adequate removal of tissue from the nasopharynx and choanae, to avoid injury to the eustachian tube, and to preserve the tissue overlying Passavant’s ridge, thereby avoiding postoperative velopharyngeal insufficiency (VPI). Palatal retraction is best achieved using latex-free catheters inserted through the nose, retrieved in the pharynx, and clamped to themselves over a head drape. Some clinicians use a preoperative injection of local anesthetic with epinephrine to reduce bleeding; this should be done with caution to avoid intravascular administration.

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CHAPTER 65 ❖ Tonsillectomy and Adenoidectomy Traditional adenoidectomy techniques involve the use of adenoid curettes or adenotomes. The procedure is performed by seating the instrument into the tissue superiorly at the vomer and shaving off the adenoid tissue. Hemostasis is achieved with adenoid packs, topical hemostatic agents like bismuth or tannics, neosynephrine or oxymetazoline, or the use of suction electrocautery. Although the equipment for this method is relatively inexpensive and reusable, there is poor control of tissue removal. Curette dissection may leave residual adenoid tissue in the choanae or remove excessive tissue at Passavant’s ridge, resulting in VPI. In a prospective endoscopic study, Havas demonstrated residual adenoid tissue in more than a third of patients treated with curettes, with complete removal achieved after use of the microdebrider.362 In addition, the procedure may result in excessive bleeding (especially among inexperienced surgeons who place the curette too deep), and risks transmission of Creutzfeldt-Jakob or other prion diseases. The microdebrider is an ideal instrument for adenoid removal. The device is efficient and precise, allowing for the complete, but not excessive, removal of tissue from the nasopharynx. Bleeding is reduced compared to curette procedures since there is less risk of dissection in the fascial plane. The microdebrider also facilitates “superior” adenoidectomy, performed in patients with a cleft palate, in whom an inferior strip of adenoid tissue is preserved to reduce the risk of VPI. Murray has demonstrated the benefits of using the microdebrider for adenoid removal with shorter operating times, higher surgeon satisfaction, and less bleeding.363 These findings, as well as more complete removal of tissue, were also seen in Koltai’s series.364,365 Another popular technique for performing adenoidectomy involves the use of the suction electrocautery. This has been utilized at various settings ranging from 25 to 45 watts at either cautery or spray settings. In a review by Elluru et al., the success of this technique compared favorably with more expensive techniques in terms of postoperative pain and time to perform the procedure.366 In a meta-analysis of the available literature, Reed found decreased intraoperative hemorrhage and less operative time necessary when comparing adenoidectomy performed using electrocautery in comparison to the use of curettes. They also noted a lower rate of regrowth and fewer long-term complications.367 However, these studies did not compare the adequacy of tissue removal in cautery adenoidectomy with that of traditional techniques. Glade et al. found that patients undergoing Coblation® adenoidectomy had less postoperative neck pain than those having a curette procedure, but no advantage over cautery adenoidectomy.357

POSTOPERATIVE CONSIDERATIONS Controversy exists regarding the need to perform a complete pathologic evaluation of excised tonsils, given the low incidence of significant pathologic findings. A retrospective

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evaluation by Erdag et al. found no malignancies among 2743 patients. The accompanying review of the literature identified 14 articles with unexpected malignancies in 0%–0.18% of specimens. Based upon these findings, the authors recommend that after evaluation by an experienced otolaryngologist, a pathologic evaluation of all specimens may not be necessary, especially if no preoperative risk factors (rapid unilateral enlargement, transplant patient) are present.368 Randall et al. came to similar conclusions in their review of 20 studies encompassing nearly 55,000 specimens, with truly “occult” malignancies seen in 0.011% of specimens.369 Post-tonsillectomy recovery can take from 3 to 20 days, during which pain medications are typically prescribed. Pain is greater in the mornings than the evenings, independent of the dosing schedule.370 Some clinicians avoid the use of nonsteroidal anti-inflammatory drugs (NSAIDs), given the potential for excessive bleeding due to effects on the platelet function.288,371 A Cochrane review of 13 trials found that NSAIDs did not significantly alter the postoperative bleeding, compared with placebo or other analgesics.372 Among seven trials in which ketorolac was not used, NSAIDs had no effect on the postoperative bleeding. The study suggests that, with the exception of ketorolac, NSAIDs used in the postoperative treatment of post-tonsillectomy pain do not increase the risk of bleeding. Post tonsillectomy hemorrhage rates with ketorolac range from 4.4% to 18%.373,374 Studies suggest that pain management with acetaminophen is equivalent to that achieved with acetaminophen and codeine.375,376 The administration of narcotics can also induce nausea, vomiting, and constipation, and some patients have a genetic polymorphism that alters codeine metabolism, making it less effective. However, the severity of pain may still justify the selective use of narcotic medications. Scheduled dosing does not appear to be advantageous over dosing as needed.370,375,377 Most surgeons recommend a soft diet after tonsillectomy; however, there does not appear to be any increased risk associated with an unrestricted diet.378 Patients in the United States and Canada are often advised not to eat “crunchy” or “rough” food (toast, biscuits, cookies, and crackers) as these will scrape the back of the throat, increasing the risk of bleeding or infection after the operation, whereas patients in the United Kingdom are often encouraged to eat rough foods to keep the tonsillar beds clean. Some patients will find spicy and acidic foods irritating. Adequate hydration is also very important during this time, since dehydration can increase throat pain, leading to a vicious cycle of poor fluid intake. Delayed hemorrhage typically occurs when the surface coagulum begins sloughing from the surgical sites. The bleeding often ceases spontaneously and rapidly; occasionally, the application of cold substances, such as ice water or popsicles, may be helpful if bleeding is prolonged. If the bleeding does not stop with conservative measures, the surgeon may need to control the bleeding by silver nitrate cauterization in an ambulatory setting or by electrocautery in the operating room.

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PERIOPERATIVE COMPLICATIONS Any physician who recommends tonsil or adenoid surgery must weigh the possibility that harm will result. The possible adverse consequences range from death to nonfatal direct and indirect anesthetic and surgical complications, to hypothetical interference with immunologic defense mechanisms. It is unfortunate that accurate statistics regarding mortality and morbidity in large patient populations are not readily available. Postadenotonsillectomy complications are divided into perioperative, immediate postoperative, and delayed postoperative time periods (see tables). Hemorrhage; intubation trauma causing laryngeal injury, laryngospasm or laryngeal edema; respiratory compromise or cardiac arrest; aspiration; malignant hyperthermia; and trauma to the teeth, pharyngeal wall, soft palate, or lips are among perioperative complications. Hemorrhage, infections, postoperative pain, edema and hematoma of the uvula, and pulmonary complications are common immediate postoperative complications, while postoperative scarring of the soft palate or nasopharyngeal stenosis and tonsillar regrowth or remnant are delayed complications. The surgeon should maintain vigilance for potential complications as soon as intubation is achieved. The intubation of severely obstructed individuals may remove a degree of natural positive end expiratory pressure (PEEP), resulting in postobstructive pulmonary edema as the transudation of fluid occurs in the interstitial/alveolar spaces. Affected patients demonstrate decreasing oxygen saturation despite the adequate establishment of the airway, and pink, frothy secretions may be suctioned from the tube. The initial management consists of the administration of PEEP with reintubation if necessary, as well as gentle diuresis. Airway complications, including both obstructive and central apnea, are more likely to occur in children younger than 3 years of age who had had obstructive symptoms preoperatively.268–270 In children 5–7 years of age, the anterior teeth may be exfoliating, and the mouth gag must be inserted with care to avoid the inadvertent extraction of loose teeth. A postoperative chest x-ray should be ordered if any teeth are broken or missing. Local anesthetics errantly injected into major vessels may cause cardiac complications, hemiplegia, loss of vision, anaphylaxis, and even death, though these complications are exceedingly rare. Other anesthetic complications include endotracheal tube fire (electrocautery procedure), laryngospasm, kinking of the endotracheal tube, and iatrogenic extubation. The risk of fire can be minimized by reducing the oxygen content of the inhaled gas and with the use of wet sponges in the oropharynx. Draping with towels rather than paper drapes with adhesive reduces the risk of accidental extubation when drapes are removed. Burns of the oral commissure are the most common complication for which litigation occurs after tonsillectomy.379

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These injuries may be prevented by using an insulated electrocautery spatula blade, and by inserting a finger or moist sponge between any metal retractors and the lips when using electrocautery. Towel clips can also cause trauma to the face or eyes and should be placed with caution. Hemorrhage, either primary (within 24 hours of surgery) or secondary (more than 24 hours after surgery), is the most common serious complication of adenotonsillar surgery, and is more likely to result from tonsillectomy than from adenoidectomy. In published reports, the rate of primary hemorrhage from tonsillectomy has ranged from 0.2% to 2.2% and the rate of secondary hemorrhage from 0.1% to 3%.266,380–384 In the largest study to date, Windfuhr performed a retrospective chart review of 15,218 adult and pediatric patients who underwent adenotonsillar surgery over a 13-year time frame and found a postoperative bleeding rate of 1.5%, with older males having the highest rate of bleeding and a large cohort with immediate (first 24 hours) postoperative bleeding.384 The risk of hemorrhage can be minimized by avoiding surgery during or immediately after episodes of infection, by careful attention to surgical technique, by the avoidance of postoperative dehydration, and by avoiding the use of certain NSAIDs for the relief of postoperative pain. There is also evidence that the choice of surgical technique may play a role in the incidence of postoperative hemorrhage.338 During surgery, the bleeding risk is reduced by staying in the proper plane of dissection and by obtaining hemostasis prior to the termination of the procedure. Any amount of bright red blood coming from the mouth or the nose should be addressed before leaving the operating room. If the patient complains of intermittent bleeding postoperatively, but is not actively bleeding on presentation, he or she should be admitted for overnight observation and intravenous hydration. Coagulation testing and a complete blood count should be considered when bleeding is persistent or recurrent; if abnormal, hematology consult should be obtained. In selected cases, minor bleeding may be controllable by gargling with ice water and/or the application of oxymetazoline sponges to the oropharynx. If bleeding persists and the patient is cooperative, an attempt can be made to cauterize the bleed with silver nitrate in an ambulatory setting. Patients who are uncooperative or bleeding heavily, as well as those in whom bleeding recurs, should be taken to the operating room for exploration. The removal of clots from the tonsillar fossae should identify the responsible bleeding sites. The bleeding is then controlled with suction electrocautery or a suture ligature. Suture ligation should be performed with extreme care as the tissue is friable and the suture tends to tear through the tissue. Attempting to place the suture deeper may lead to the inadvertent laceration of a major vessel deep to the fossa and possible pseudoaneurysm. The combination of multiple bleeding episodes or uncontrollable bleeding with normal coagulation tests should raise the suspicion of a vascular abnormality that should be evaluated with angiography.

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CHAPTER 65 ❖ Tonsillectomy and Adenoidectomy Mortality from tonsillectomy is estimated at 1 per 16,000–35,000 tonsillectomies with about one-third attributable to primary bleeding and the majority related to anesthetic mishaps.346,385 When death occurred, these unfortunate outcomes have been related to bleeding, aspiration, electrolyte imbalance, or anesthetic agents.386 Windfuhr et al. reported on devastating outcomes following tonsillectomy with an eye towards improving the prevention and management. They analyzed 43 cases (32 resulting in death and 11 in permanent generalized neurological deficiencies) over 28 years and found that 31/32 deaths were attributable to delayed and repeated episodes of bleeding, with primary bleeding in only one patient. Mortality was more common in younger patients (20,000 units/mm3, deep gastric ulcers, gastric necrosis, and ingestion of a strong acid.32

Medical Management Once it is established that there is no airway obstruction, mediastinitis, or peritonitis, certain measures are taken. The aim of management is to prevent strictures forming in the esophagus. Any form of management that reduces the amount of granulation tissue, the number and activity of fibroblasts, or both contributes to this end. A dilemma is in knowing whether to treat all cases of children with a history of caustic ingestion or just those with symptoms (Fig. 79-5). It is difficult to predict which children have suffered burns, so all symptomatic patients are treated until esophagoscopy confirms the diagnosis. Most children who are asymptomatic may have either no burn or a first-degree burn, and, in most (or all) of these cases, strictures do not develop. Some physicians would opt for no treatment in these children. Analgesics Intramuscular or intravenous narcotics appropriate to age and weight may be administered. However, caution must be taken not to suppress or mask the symptoms of severe complications such as esophageal perforation, mediastinitis, and peritonitis. Antibiotics Krey showed that epithelialization occurred more quickly when animals were given antibiotics.24 By reducing the number of bacteria present in the burn tissue, granulation tissue can be reduced. There have been no prospective randomized clinical studies assessing the role of antibiotics in prevention of strictures. Most series report the use of antibiotics in pediatric patients with esophageal caustic injury, but often antibiotics were used in conjunction with corticosteroids.33 It is usual to use ampicillin or ampicillin/sulbactam intravenously, or, if the patient can swallow, amoxicillin or amoxicillin/clavulanate orally. Alimentation Most patients are restricted from po intake until the decision to proceed with esophagoscopy is made. Krey suggested that particles of food become caught up in necrotic tissue and produce more granulation tissue.24 In these cases, fluids are given intravenously. If the decision is made to allow po intake and

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if the patient is able to swallow, he or she should be allowed only clear liquids. Steroids There is no general agreement over the use, dosage, or length of steroid treatment. Some studies on mice and dogs have demonstrated reduced exudate and cellular elements in the wound as well as decreased inflammatory response and granulation tissue formation leading to decreased stricture formation. However, a meta-analysis performed in 2005 did not find a significant benefit from steroid use in preventing stricture formation.34 Spain and associates showed that when cortisone was given to a group of mice with wounds on their backs, compared with control mice, they exhibited an almost complete lack of exudate and fibrin in the wounds, together with marked diminution of cellular elements.35 However, if the steroids were given more than 48 hours after the wound occurred, there was no significant difference between the group receiving the drug and the control group.35 Johnson experimented on dogs and showed that steroid therapy, if started early, definitely inhibited the inflammatory response and granulation tissue formation, with a subsequent decrease in stricture formation.36 In human patients, Anderson and colleagues performed a controlled study, concluding that although steroids appear to decrease the stricture formation in moderate to severe burns with caustic substances and to reduce the need for esophageal replacement, the differences did not reach a statistical significance because of the small number of patients.37 Howell and co-workers, in a statistical analysis of past studies, concluded that steroids were not indicated for children with first-degree burns and that further trials were needed to evaluate their efficacy in children with second- or third-degree burns.38 Additionally, Tuncer performed a prospective controlled randomized clinical study which found that steroid administration had no effect on stricture formation.39 However, in a review of 214 cases, Hawkins and colleagues concluded that steroids were effective in preventing strictures in moderately severe burns.40 In a review of 239 cases, Mamede found that patients treated with steroids had a reduced rate of stenosis compared to those treated without steroids.41 Many patients with caustic burns of the esophagus have been given steroids combined with antibiotics. Several authors have applied treatment of a combination of antibiotics and steroids and found the incidence of stricture formation to be much lower than previously.42–49 In our practice, prednisone, 2 mg/kg/d to a maximum of 60 mg/d, is recommended to be given intravenously initially, then orally after a few days as the ability to swallow returns. To be effective, steroids must be given within the first 8 hours of the injury. The extent of the injury cannot be judged until an esophagoscopy is performed, usually 24–48 hours later, and steroids are usually stopped if no injury is found. If there is a grade 2 injury found, steroids are continued. Some physicians may therefore opt to treat all cases with steroids initially, stopping them if no burn is found during esophagoscopy.

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CHAPTER 79 ❖ Caustic Injuries and Acquired Strictures of the Esophagus

1371

CAUSTIC INGESTION

ASSESS URGENCY: Stridor Hoarseness Cough Chest pain Palpitations Fever Tachycardia

History of battery Ingestion

Chest x-ray

EMERGENT Operating Room

Progressive Stricture

OBSERVE 24-72 HOURS

ESOPHAGOSCOPY

Severe Mediastinitis Perforation

Gastric pull-up Colon Interposition

Consider NO Esophagoscopy

Antibiotics Steroids Reflux treatment

Stabilize Vitals and Airway Scope Intubate Tracheostomy

Consider Esophagectomy

Household bleach hair relaxer WITHOUT Symptoms or signs

Investigate the Caustic Agent Poison Center Sample / Bottle Manufacturing Information

CBC Metabolic panel Signs of Shock Mediastnitis and/or Airway Compromise

IMMEDIATE MANAGEMENT: Reduce the contact time DO= Irrigate contact sites Drink milk/water DON’T= Induce vomiting Gastric lavage

SEVERE BURN (Grade 2b & 3)

MODERATE BURN (Grade 2a)

Stop steroids G-tube Naso-gastric tube or Stent or Silk string loop Plan retrograde dilation

MILD BURN (Grade 1)

Barium esophagogram in 3-6 weeks

Stricture

Retrograde Dilation >3 weeks

NO BURN

Prograde or Balloon Dilation

DISCHARGE

No stricture

Food Impaction or Dysphagia

ESOPHAGOSCOPY or Barium Esophagogram Determine intervals as per ease to dilate

Discontinue when no difficulty in dilations

FIGURE 79-5. Algorithm for management of a caustic burn.

Antacids Intermittent acid and pepsin exposure on burned esophageal mucosa has been shown to delay healing in an animal model.50 Aggressive antireflux treatment with H2-receptor blockers or proton pump inhibitors should be started as soon as possible and continued all through the observation

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or treatment period with or without esophageal dilatations. There may be increased gastroesophageal reflux during or after the dilatations. Lathyrogens Use of lathyrogens in the management of esophageal burns is controversial. Lathyrogens are chemicals that inhibit the

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covalent crosslinks between collagen. These crosslinks are thought to be important in the physical characteristics of newly formed collagen. It may be possible either to prevent dense scarring or to soften well-established scarring by use of these chemicals. Butler51 and Madden52 and their associates used beta-aminopropionitrile in dogs and showed greater benefit from its use than from steroids in reducing scarring. This drug is not approved for human clinical trials, however. Penicillamine was shown by Gehanno and Guedon to have good results in rats.53 Liu and Richardson pointed out that N-acetyl-L-cysteine, another lathyrogen, is commercially available and is approved for clinical use in various bronchopulmonary disorders for its mucolytic properties, and in acetaminophen and arsenic overdosage.54 They described a study of the use of N-acetyl-L-cysteine in caustic burns of the esophagus in a few rats. Another alkaloid not yet approved in humans, halofuginone, is thought to prevent collagen type I synthesis. It was found to prevent esophageal strictures and it use correlated with increased survival in a rat caustic ingestion model.55

Assessment of Social and Mental Status Assessment of social and mental status of a child and establishment of support may be critical in continued care and prevention. Sobel studied 367 families whose children had been involved in accidental poisonings and found that the frequency of poisoning was unrelated to the accessibility of toxic substances, which, he pointed out, was contrary to common sense.4 There was also found to be no relation among the level of motor development, the intelligence of the child, birth complications, and parental accident proneness. There was, however, significant association between accidental poisoning and measures of maternal psychopathology, such as the mother’s marital dissatisfaction, mental illness, poor ego strength, and sexual dissatisfaction. This author’s data suggested that a negative role performance on the mother’s part generates a power struggle with the child, which may eventually result in the ingestion of forbidden substances by the child as an act of defiance and rebellion.4 Accidental poisoning, therefore, should always be treated as a symptom of family disturbance. It is considered that psychiatric consultation or counseling are essential for giving emotional support to mothers who are unable to cope with the stress placed on them by their maternal and marital roles. The mental trauma, both for child and family, in a severe case of poisoning also warrants psychiatric support, as does the prolonged treatment necessary if a stricture develops, with frequent and, to a young child, often unpleasant visits to the hospital. In cases in which suicide has been attempted by an older child in the form of a caustic ingestion, psychiatric consultation is mandatory.

Esophagoscopy Direct visualization is the only accurate way to diagnose esophageal burns. Cardona and Daly emphasized the poor

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correlation between oral or pharyngeal ulcerations and esophageal ulcerations.28 Gaudreault and co-workers stated that the signs or symptoms do not adequately predict the presence or severity of an esophageal lesion following a caustic ingestion.56 Crain and colleagues subsequently confirmed this concept and suggested that patients with two or more serious signs, such as drooling, vomiting, and stridor, may be more reliably predicted to have esophageal burns.57 Gorman and co-workers suggested that esophagoscopy may not be required in asymptomatic patients and agreed that patients with two or more signs of oral burns, such as dysphagia, pain, and vomiting, were more likely to have esophageal burns.58 Lamireau looked at 85 children who underwent esophagoscopy following caustic ingestion, and concluded that asymptomatic patients did not need to undergo esophagoscopy.59 In this study, the absence of symptoms correlated with minimal or no lesion on esophagoscopy. However, the utility of esophagoscopy in predicting long-term sequelae is more clear. Zargar found that stricture formation occurred only in patients with grade 2b and grade 3 injuries.29 Most authors who have agreed with this conclusion recommend esophagoscopy in symptomatic children.14,60 Also, it is possible for some children without obvious symptoms who have grade 3 esophageal injury. Suggestions concerning the appropriate timing of the initial esophagoscopy vary from within 24 hours to 36 to 72 hours later. If esophagoscopy is performed within the first 24 hours, the full extent of injury may be underestimated, since, in nearly all animal experiments, it took at least 24 hours for lesions to become visible to the naked eye. However, Wijburg and colleagues advocate flexible fiberoptic esophagoscopy within the first 24 hours.61 Esophagoscopy performed later than 72 hours after the event may result in unnecessary medical treatment and hospitalization if no burns of the esophagus are found. Most physicians advocate performing an esophagoscopy for symptomatic patients 24–72 hours after ingestion. Many also recommend avoiding esophagoscopy between 5 and 15 days after caustic ingestion to reduce the risk of perforation of the esophagus when it is most susceptible to injury.29 The esophagoscope should not be advanced beyond the first area of a severe burn, since the danger of perforation becomes greater. However, advancement of an esophagoscope with a telescope or of a fiberoptic flexible esophagoscope may be performed when a mild burn is visualized in the proximal esophagus, since a severe burn may be present in the distal esophagus. Detection of caustic esophageal injury using Technetium 99m-labeled sucralfate or technetium 99m-labeled pyrophosphate (PYP) has been proposed as an alternative to esophagoscopy. One study in a rat model found that 99m-labeled PYP to be sensitive for detection of esophageal injury in rats.62 Another study looked at technetium 99m-labeled sucralfate scanning in 22 children and compared the results with endoscopic findings.63 This study found a sensitivity of 100% and a specificity of 81%. The negative predictive value was 100%.

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CHAPTER 79 ❖ Caustic Injuries and Acquired Strictures of the Esophagus Although this technique is not widely utilized at this point, it may be helpful in situations when trying to avoid endoscopy in children.

Management after Esophagoscopy Many aspects of management of esophageal burns are controversial, particularly regarding whether to place a nasogastric tube, stent, or string; whether to continue the use of steroids and for how long; whether to prescribe antibiotics, whether to perform gastrostomy; whether to plan for prograde or retrograde dilatation; and whether to resect the esophagus and reconstruct with a gastric pull-up or a colonic interposition. If no burn is seen on esophagoscopy, medication is discontinued and the diet can be advanced. The patient can be discharged from the hospital but should be seen again in three to six weeks for a follow-up visit and possibly an esophagogram, particularly if there are any symptoms. If the results are normal and the patient is still asymptomatic, no additional follow-up is necessary. If, on the basis of the esophagoscopic results, the patient is considered to have either mild or moderate ulcerative esophagitis (grade 2a injury), the combination of antibiotic and steroid therapy should be continued for three to six weeks (see earlier discussion). The patient should also be continued on antireflux medication. The child should be maintained on clear liquids or intravenous fluids for the first few days, but then may begin a soft diet. At this stage, the child may be cared for at home. After about two weeks, the steroids can be tapered so that the total time steroids are given is three to four weeks, including the taper. An esophagogram should be obtained in three to six weeks. If the child has difficulty in swallowing or the esophagogram shows evidence of early stricture formation, dilatation may be indicated (described later). If the esophagogram does not reveal evidence of stricture formation, the patient should still be seen every three months for one year, and likely have one more repeat esophagogram in three to six months. Patients with severe burns (grade 2b and 3) are initially treated the same as less severely burned patients prior to the initial esophagoscopy, but as soon as the extent of the burn is realized by esophagoscopy, the steroids are discontinued. To continue steroid treatment could increase the danger of perforation in cases in which the whole wall of the esophagus is necrotic. There is a significant risk of stricture formation in patients with severe burns (grades 2b and 3), with rates as high as 77% for grade 2b injuries and 100% for grade 3 injuries.64 The goal is either to keep a tube or stent in place to prevent the stricture or to perform repeated dilatations until scar formation is mature. In case of a severe esophageal burn, the esophagus must be rested with a gastrostomy or jejunostomy. If a safer retrograde dilatation is preferred, a string loop is inserted that utilizes the gastrostomy. Contrary to all the aforementioned methods, nasogastric intubation is advocated by some groups as the sole method of

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treatment of caustic burns. Wijburg and co-workers inserted nasogastric tubes under endoscopic control and decided when to remove them by endoscopy.61 They intubated when deep, circular esophageal burns were encountered and stated that, of 32 patients undergoing this treatment, strictures developed in only two. Subsequently, Wijburg and co-workers advocated the passage of a special nasogastric tube after esophagoscopy, within 24 hours of the ingestion.65 Coln and Chang66 and Estrera and co-workers67 advocate passing an esophageal “stent,” creating a gastrostomy and passing a transgastric jejunal tube at the time of assessment by esophagoscopy. They emphasize leaving the stent in place until healing is complete. Weekly assessment by esophagoscopy may be needed. De Peppo and co-workers suggested that, with stent placement, esophageal replacement should rarely be necessary.68 Krey found that the best results in reducing stricture formation were obtained by resting the esophagus, which may be accomplished by performing a gastrostomy and using antibiotics.24 He advocated passing a string through the esophagus and bringing it out through the gastrostomy. The upper end of the string is brought out through the nose and tied to the lower end, so that there is a continuous loop of string through the esophagus. If possible, the patient can facilitate placement of the string by swallowing it. If not, it can be done during esophagoscopy. Retrograde bougienage may be started after three to six weeks, after the first esophagogram, when the gastrostomy stoma is mature enough and when there is less risk of perforation.

MANAGEMENT OF ACQUIRED STRICTURES An example of an esophageal stricture is shown in Fig. 79-6. Such strictures may develop from other causes apart from caustic burn damage. Attempts at surgical repair of the strictured esophagus by direct end-to-end anastomosis (after excising the stenotic segment), gastric pull-up, or esophagogastric or esophagocolic anastomosis (from colon interposition) may also lead to stricturing at the repair site. Holinger and Johnston mentioned that one of the major problems after repair of congenital esophageal atresia is stenosis at the site of anastomosis.69,70 The success rate for treatment of caustic strictures with dilatation is about 60%–80%.71 However, caustic strictures are more resistant to dilation compared with strictures from other causes such as reflux or an anastamosis.72 Dilation of esophageal strictures may be performed in several ways, including traditional retrograde or prograde dilatation or radial dilatation with balloon dilators. Such balloon dilatation in a radial direction should be less likely to tear the esophagus and lead to perforation than prograde or retrograde dilatation, which generate longitudinal shear forces.73,74 Most experts feel that dilatations should be started roughly three to four weeks after ingestion to allow time for mucosal wound healing to occur. On the other hand, one study suggested that earlier dilation may help reduce the severity of

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FIGURE 79-7. Example of a Grüntzig catheter balloon partially inflated.

is that the catheter can be passed through a narrow stricture, and the balloon, when inflated, dilates in a radial direction (Fig. 79-8). Polese et al. have suggested that balloon dilation is optimal for shorter strictures and that the procedure can be done under direct endoscopic visualization, without fluoroscopic guidance.79 Several dilatations may be necessary, depending on the return of symptoms of obstruction, which, in turn, depend on the length and density of the stricture.79

Prograde Dilatation

FIGURE 79-6. Esophagogram demonstrating an esophageal stricture due to a caustic burn.

stricture formation without increasing the risk for esophageal perforation.75 Another study indicated that beginning dilations at a very late stage after the stricture is well-established (after six weeks), can lead to an increased risk for perforation and a higher recurrence rate.6 A barium swallow should be performed just before beginning esophageal dilatations to identify the location and extent of strictures.

Dilatation by Balloon A significant change in the ability of physicians to treat esophageal strictures occurred in 1974, when a balloon dilatation catheter was described by Grüntzig and Hopff (Fig. 79-7), originally to dilate atheromatous narrowing of arteries.76 The dilatation can be performed under radiographic control, with the child under general anesthesia or local anesthesia and heavy sedation. The technique is well described by Dawson and associates.77 Balloon dilatation of the esophagus can also be performed with endoscopic visualization, which is currently the more commonly used approach. Myer and coworkers suggested balloon dilatation as the procedure of choice for the management of most esophageal strictures in children.78 Balloon dilatation catheters are available in a range of sizes: from 10 to 20 mm in diameter and from 4 to 8 cm in length. The advantage of using this form of dilatation

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Several types of dilators are used for prograde dilatation. The Jackson silk-woven bougies are passed through a rigid esophagoscope under direct vision with the patient under general anesthesia. Emerson described Teflon dilators that are used in the same way.80 Other methods require the use of a string with a gastrostomy under general anesthesia. For example, the Plummer method uses metal olives passed over a string. Hine and co-workers compared the Eder-Puestow method with that used for the Celestin Neoplex dilator.81 Both methods require passage of a guidewire first, either under fluoroscopic control or through the biopsy channel of a flexible esophagoscope. Savary-Gillard polyvinyl dilators (Wilson Cook Medical, Inc, Winston Salem, NC) can also be passed over a guidewire.79 Hurst or Maloney dilators can be used with or without a general anesthetic. In the past, dilatation was often carried out using Hurst mercury bougies without general anesthesia in very young children, who were usually wrapped in a blanket and held upright on the lap of an assistant (Fig. 79-9). A bougie of suitable size was selected at the time of esophagoscopy. The tip of the dilator was inserted into the patient’s mouth and held high above his or her head so that the weight of the mercury encouraged the passage of the tube down the esophagus. Unfortunately, in some of the smaller-sized bougies, the weight of the mercury was not great enough to carry the bougie down the esophagus, so that gentle insertion of the bougie by the operator was sometimes necessary. The size of the dilator was then increased until one size was found that would not pass down the esophagus. The intervals between dilatations were governed by how well the patient can swallow food.

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The standards and expectations for the care of children have changed over the past several decades, and awake dilatation without anesthesia is not commonly performed today in the United States. A similar prograde dilatation technique can be performed in the operating room under anesthesia. These patients will probably need dilatation for the rest of their lives, but the length of time between dilatations should increase as they grow. Periodically throughout this time, radiocontrast esophagography and esophagoscopy should be performed to follow the extent of the disease. Esophageal perforations resulting from esophageal dilatations are not uncommon. Karnak and co-workers reported a 17.4% esophageal perforation rate during dilatation of caustic esophageal strictures in children with a spectrum from a minimal periesophageal leakage to massive rupture with pneumothorax and sudden death.82

Retrograde Dilatation

FIGURE 79-8. Radiographs showing a lower esophageal stricture with a Grüntzig balloon in position, partially inflated on the left and fully inflated on the right. The indentation of the balloon on the left is the stricture. Dilatation of this stricture by the balloon is in a radial direction.

FIGURE 79-9. Prograde esophageal dilatation without general anesthesia.

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Hawkins compared antegrade with retrograde dilatation of strictures and emphasized the greater degree of safety with Tucker dilators used in a retrograde fashion.11 Retrograde bougienage may be performed while the patient is awake, even in a very young child, although the procedure is generally distressing for both child and operator and may be better performed under anesthesia (Fig. 79-10A). The technique, described by Tucker, should be such that the string is always present in the esophagus (see Fig. 79-10B).83 The loop is first cut, and two pieces of string are tied to the lower end (see Fig. 79-10C). By pulling on the upper end, two new pieces are pulled out through the nose (see Fig. 79-10D). The upper end of one of these pieces of string is tied to the lower end of the same string; this is the loop that remains in the esophagus after dilatation. The second loop is brought out through the mouth with forceps (see Fig. 79-10E). A Tucker dilator is tied to the lower end of the string, and by a combination of pulling on the upper string and pushing the dilator, it can be passed up the esophagus and into the mouth (see Fig. 79-10F). Dilators of increasing size can be tied end to end like a string of sausages, and the whole string can be pulled right out through the mouth (see Fig. 79-10G). Alternatively, the first dilator can be pulled through the gastrostomy, and the string reattached to the second dilator. Occasionally, when pulling two strings up through the esophagus, they can become tangled. Another technique for retrograde dilatation involves passing only a single string and making a single loop with the string and Tucker dilators. Fig. 79-11 demonstrates an endoscopic view of a string for retrograde dilation going into the esophagus. This retrograde dilatation procedure can be undertaken twice weekly at first; the frequency is then dictated by the ease in reaching the target size with the dilators. If it is more difficult to reach the target size, the dilatations are performed more frequently. As it becomes easier to reach the target size, the dilatations can become less frequent. After 4–12 weeks of retrograde dilatation, once the interval can be spread to

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FIGURE 79-10. Retrograde esophageal dilatation.

impaction can often undergo esophagoscopy with removal of the food impaction and prograde dilatation at the same time. If, however, the food impaction is severe and there is concern for significant recurrence of the stricture, it may be prudent to remove the food impaction and then obtain an esophagogram prior to proceeding with prograde or balloon dilatation. Mendelsohn and Maloney suggested injection of steroids into the stricture at esophagoscopy. They found this to be useful if the stricture was resistant and if progress toward increasing the lumen was slow by prograde dilatation.84 They used 1.5–2 mL hydrocortisone acetate or triamcinolone acetonide (40 mg/mL) injected through the esophagoscope with a long needle; 1 mL hyaluronidase is mixed with this steroid to act as a spreading agent. This injection is followed by immediate dilatation, using dilators 2 or 4 French sizes greater than those used in previous dilatations. Bleeding is a warning sign to stop the dilatation. The researchers had no problems with infection, abscess, or perimediastinitis. They believed that the stricture was softened and that this procedure enabled dilatation to be carried out more rapidly.84 The topical application of mitomycin C has been suggested as an adjuvant to dilation in refractory strictures due to caustic ingestion in children (Pace, 2009; Daher, 2007; Rosseneu, 2007; Uhlen, 2006).72,85–87 Mitomycin C may reduce fibroblast proliferation and decrease fibrous scar formation. However, the theoretical long-term risk of secondary malignancy with mitomycin C use has prevented it from being recommended as a standard first-line therapy for children with esophageal strictures secondary to caustic ingestion.72

Replacement of the Esophagus

FIGURE 79-11. Endoscopic view of string going into esophagus for retrograde dilation.

every two weeks, it may be possible to progress to prograde dilatation, while still keeping the string loop in place. If prograde dilatation remains successful at maintaining the target size of the esophagus, after one or two months, the string and gastrostomy tube can be removed. Prograde dilatation may continue for the rest of the patient’s life, at varying intervals, depending on how the patient is doing clinically. Periodic esophagoscopy and esophagography are necessary to follow the course of the disease. Patients with esophageal strictures that have undergone dilatation have a lifelong risk of esophageal food impaction and often present with a sensation that food is getting stuck in the throat. This complaint may be a good indication for repeat prograde dilatation. Patients presenting with food

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Acquired esophageal stricture formation from caustic ingestion is the most common indication for esophagectomy in children.88 If repeated dilatation fails, esophagectomy with esophageal replacement may be the alternative. In most cases, every effort should be made to maintain esophageal function for as long as possible. Panieri and co-workers reported only 41% success with dilatation therapy.89 They reported the early factors predictive of failure of conservative treatment as (1) delay in presentation of more than one month, (2) severe pharyngoesophageal burns requiring a tracheotomy, (3) esophageal perforation, (4) stricture longer than 5 cm, and (5) inability to pass appropriate size dilators in early bougienage. Choi and co-workers suggested that children who have hypopharyngeal scarring and obliterated esophageal inlet could undergo colonic esophageal replacement with high pharyngocolic anastomosis.90 Campbell and co-workers reported cases of colon interposition.91 They stressed that achievement of good functional results with low complication rates depends on experience and the technique employed rather than on whether stomach or colon is used. Hamza et al. reported over 850 cases of esophageal replacement for caustic injury over 30 years, in which colonic interposition was utilized for 775 cases and gastric pull-up for 75 cases.71 This group prefers colonic

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interposition for replacement of the esophagus in cases of failure of esophageal dilation.71 Burgos and colleagues also believe that colonic interposition can restore gastrointestinal continuity with low mortality and a good long-term functional outcome.92 Esophageal replacement with gastric tube conduit has also been recommended with good results.93 The use of the gastric tube pull-up for replacement of the esophagus has become more popular recently because of its relative simplicity and the quality of its blood supply.88,94 Kane and others have demonstrated that an esophagectomy and gastric pull-up for esophageal lye injury can be performed with a minimally invasive approach, using a combination of thoracoscopy and laparoscopy.88 The esophagogram in Fig. 79-12 depicts a severe long, narrow stricture from a lye ingestion. This patient underwent an esophagectomy with gastric pullup; the pathology specimen revealing a severe lye stricture is shown in Fig. 79-13.

Increased Risk of Esophageal Carcinoma There is a significantly increased risk for esophageal carcinoma after severe esophageal burns.95,96 Appelqvist and Salmo97 and Hopkins and Postlethwait98 pointed out that up to 7% of patients with esophageal carcinoma have a history of caustic ingestion in childhood. It is estimated that, after caustic ingestion, there is a 1000-fold increase in the likelihood of FIGURE 79-13. Pathology specimen of esophagus after esophagectomy revealing severe lye stricture.

development of esophageal carcinoma. The interval between injury and development of the squamous cell carcinoma varies between 13 and 71 years.96–98 Therefore, in some cases, esophagectomy with reconstruction may be a reasonable alternative to long-term stricture dilation. In addition, longterm follow up and surveillance of all patients with esophageal strictures from caustic injury is important, even if the patients are asymptomatic.

SUMMARY

FIGURE 79-12. Esophagogram demonstrating a severe long, narrow stricture from a lye ingestion. (Reprinted with permission from Kane et al.80)

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Caustic ingestion is a common cause of acute esophageal injury and late esophageal complications in children. Alkaline substances are more likely to cause serious injury to esophageal mucosa compared with acidic substances. Esophageal injury secondary to ingestion of disk batteries is becoming more prevalent. Ingestion of a disk battery requires careful recognition and emergent treatment to prevent the rapid esophageal mucosal damage associated with these injuries that can then lead to severe complications. Initial assessment includes obtaining a complete history of the ingestion including type of ingested material, amount, and timing, in addition to assessing the patient’s clinical status to determine whether acute complications of esophageal injury may be present. Initial medical management may include

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restricting oral intake, antibiotics, steroids, and antireflux therapy. When indicated, an endoscopic evaluation is usually performed 24–48 hours after the ingestion to evaluate for the degree of esophageal mucosal injury. Long-term sequelae of caustic ingestion include acquired esophageal stricture formation, as well as an increased risk of esophageal carcinoma after severe esophageal burns. Methods to help prevent stricture formation may include NG tube or stent placement, repeated esophageal dilatation, and steroid use when indicated. Management techniques for an acquired stricture include esophageal dilatation and in severe cases may require esophagectomy with esophageal replacement. Prevention of accidental caustic ingestion in children is the most important tool for avoiding the short- and long-term sequelae of esophageal injury.

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59. Lamireau T, Rebouissoux L, Denis D, Lancelin F, Vergnes P, Fayon M. Accidental caustic ingestion in children: is endoscopy always mandatory? J Pediatr Gastroenterol Nutr. 2001;33:81–84. 60. Betalli P, Falchetti D, Giuliani S, et al. Caustic ingestion in children: is endoscopy always indicated? The results of an Italian multicenter observational study. Gastrointest Endosc. 2008;68:434–439. 61. Wijburg FA, Beukers MM, Bartelsman JF, Bartelsman JF, den Hartog Jager FC. Nasogastric intubation as sole treatment of caustic esophageal lesions. Ann Otol Rhinol Laryngol. 1985;94:337. 62. Aksu B, Durmus-Altan G, Funda Ustun F, et al. A new imaging modality in detection of caustic oesophageal injury: technetium-99m pyrophosphate scintigraphy. Internat J Pediatr Otorhinolaryngol. 2009;73:409–415. 63. Millar AJW, Numanoglu A, Mann M, Marven S, Rode H. Detection of caustic oesophageal injury with technetium 99m-labelled sucralfate. J Pediatr Surg. 2001;36:262–265. 64. Elshabrawi M, A-Kader HH. Caustic ingestion in children. Expert Rev Gastroenterol Hepatol. 2011;5:637–645. 65. Wijburg FA, Heymans HSA, Urbanus NAM. Caustic esophageal lesions in childhood: prevention of stricture formation. J Pediatr Surg. 1989;24:171. 66. Coln D, Chang JHT. Experience with esophageal stenting for caustic burns in children. J Pediatr Surg. 1986;21:588. 67. Estrera A, Taylor W, Mills LJ, Platt MR. Corrosive burns of the esophagus and stomach: a recommendation for an aggressive surgical approach. Ann Thorac Surg. 1986;41:276. 68. De Peppo F, Zaccara A, Dall’Oglio L, et al. Stenting for caustic strictures: esophageal replacement replaced. J Pediatr Surg. 1998;33:54. 69. Holinger PH. Endoscopic aspects of esophagitis and esophageal hiatal hernia. JAMA. 1960;172:313. 70. Holinger PH, Johnston KC. Postsurgical endoscopic problems of congenital esophageal atresia. Ann Otol Rhinol Laryngol. 1963;72:1035. 71. Hamza AF, Abdelhay S, Sherif H, et al. Caustic esophageal strictures in children: 30-years’ experience. J Pediatr Surg. 2003;38:828–833. 72. Pace F, Antinori S, Repici A. What is new in esophageal injury (infection, drug-induced, caustic, stricture, perforation)? Curr Opin Gastroenterol. 2009;25:372–379. 73. McLean GK, LeVeen RF. Shear stress in the performance of esophageal dilation: comparison of balloon dilation and bougienage. Radiology. 1989;172:983. 74. Sandgren K, Malmfors G. Balloon dilatation of oesophageal strictures in children. European J Pediatr Surg. 1998;8:9–11. 75. Tiryaki T, Livanelioğlu Z, Atayurt H. Early bougenienage for relief of stricture formation following caustic esophageal burns. Pediatr Surg Int. 2005;21:78–80. 76. Grüntzig A, Hopff H. Perkutane Rekanalisation chronischer arterieller Verschl;auusse mit einen neuen Dilatationskatheter. Modifikation der Dotter-Technik. Dtsch Med Wochenschr. 1974;99:2502. 77. Dawson SL, Mueller PR, Ferrucci JT, et al. Severe esophageal strictures: indications for balloon catheter dilatation. Radiology. 1984;153:631. 78. Myer CM III, Ball WS Jr, Bisset GS III. Balloon dilatation of esophageal strictures in children. Arch Otolaryngol Head Neck Surg. 1991;117:529.

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79. Polese L, Angriman I, Bonello E, et al. Endoscopic dilation of benign esophageal strictures in a surgical unit: a report on 95 cases. Surg Laparosc Endosc Percutan Tech. 2007;17: 477–481. 80. Emerson EB. Teflon esophageal dilators. Arch Otolaryngol. 1965;81:213. 81. Hine KR, Hawkey CJ, Atkinson M, Holmes GKT. Comparison of the Eder-Puestow and Celestin techniques for dilating benign esophageal strictures. Gut. 1984;25:1100. 82. Karnak I, Tanyel FC, Buyukpamukcu N, Hicsonmez A. Esophageal perforations encountered during the dilation of caustic esophageal strictures. J Cardiovasc Surg. 1998;39:373. 83. Tucker G. Cicatricial stenosis of the esophagus with particular reference to treatment by continuous string, retrograde bougienage with the author’s bougie. Ann Otol Rhinol Laryngol. 1924;69:118. 84. Mendelsohn HJ, Maloney WH. The treatment of benign strictures of the esophagus with cortisone injection. Ann Otol Rhinol Laryngol. 1970;79:900. 85. Daher P, Riachy E, Georges B, Georges D, Adib M. Topical application of mitomycin C in the treatment of esophageal and trachelobronchial stricture: a report of 2 cases. J Pediat Surg. 2007;42:E2–E11. 86. Rosseneu S, Afzal N, Yerushalmi B, et al. Topical application of mitomycin C in oesophageal strictures. J Pediatr Gastroenterol Nutr. 2007;44:336–341. 87. Uhlen S, Fayoux P, Vachin F, et al. Mitomycin C: an alternative conservative treatment for refractory esophageal stricture in children? Endoscopy. 2006;38:404–407. 88. Kane TD, Nwomeh BC, Nadler EP. Thoracoscopic-assisted esophagectomy and laparoscopic gastric pull-up for lye injury. J Soc Laparoendoscopic Surgeons. 2007;11:474–480.

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89. Panieri E, Rode H, Millar AJW, Cywes S. Oesophageal replacement in the management of corrosive strictures: when is surgery indicated? Pediatr Surg Int. 1998;13:336. 90. Choi RS, Lillehei CW, Lund DP, et al. Esophageal replacement in children who have caustic pharyngoesophageal strictures. J Pediatr Surg. 1997;32:1083. 91. Campbell JR, Webber BR, Harrison MW, Campbell TJ. Esophageal replacement in infants and children by colon interposition. Am J Surg. 1982;144:29. 92. Burgos L, Barrena S, Andrés AM, et al. Colonic interposition for esophageal replacement in children remains a good choice: 33-year median follow-up of 65 patients. J Pediatr Surg. 2010;45:341–345. 93. Ein SH. Gastric tubes in children with caustic esophageal injury: a 32-year review. J Pediatr Surg. 1998;33:1363. 94. Borgnon J, Tounian P, Auber F, et al. Esophageal replacement in children by an isoperistaltic gastric tube: a 12-year experience. Pediatr Surg Int. 2004;20:829–833. 95. Kim YT, Sung SW, Kim JH. Is it necessary to resect the diseased esophagus in performing reconstruction for corrosive esophageal stricture? Eur J Cardiothoracic Surg. 2001;20:1–6. 96. Ruol A, Rampado S, Parenti A, et al. Caustic ingestion and oesophageal cancer: intra- and peri-tumora fibrosis is associated with a better prognosis. Eur J Cardio-thoracic Surg. 2010;38:669–664. 97. Appelqvist P, Salmo M. Lye corrosion carcinoma of the esophagus – a review of 63 cases. Cancer. 1980;45:2655. 98. Hopkins RA, Postlethwait RW. Caustic burns and carcinoma of the esophagus. Ann Surg. 1981;194:146.

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C H A P T E R

Neurologic Disorders of the Mouth, Pharynx, and Esophagus Ingrid Loma-Miller and Michael J. Painter

V

arious illnesses have associated nervous system involvement with manifestations in the mouth, pharynx, and esophagus. The symptoms in these areas may be directly caused by nervous system disease or can be a phenomenon coexistent with neurologic problems. This chapter should help the pediatrician, otolaryngologist, and dental specialist to associate various oral, pharyngeal, and esophageal manifestations with preexisting or coexisting nervous system disorders. Recognizing appropriate associations is crucial for proper management of these patients.

ANATOMY To correlate symptoms and examination findings, it is important to understand the innervation of the mouth, pharynx, and esophagus. Motor control of mastication and facial movement is through the fifth and seventh cranial nerves, the fifth having its motor nucleus in the midpons and the seventh in the lower pontine tegmentum (Fig. 80-1). Swallowing is performed by use of 25 pairs of muscles in the oropharynx, larynx, and esophagus. Swallowing depends on a central pattern generator or “swallowing center” located in the medulla oblongata, which involves five brain stem motor nuclei (V, VII, IX, X, and XII) and two main groups of interneurons located in the dorsal medulla and the ventrolateral medulla. These neurons are involved in triggering, shaping, and timing the rhythmic swallowing pattern.1 The somatic efferent component of the ninth cranial nerve innervates only

the stylopharyngeus muscle, and the few axons of the 11th cranial nerve coming from the nucleus ambiguus join the vagus nerve after passing through the jugular foramen; thus, the vagus with its three branches (pharyngeal, superior laryngeal, and recurrent laryngeal nerves) constitutes the major motor nerve of swallowing and phonation. The upper third to one-half of the esophagus consists of striated muscle and its neural control is similar to the pharynx. However, cortical input to the esophagomotor portion of the nucleus ambiguus and tractus solitarius is not clear.2 Subcortical structures including the hypothalamus and midbrain gray matter probably play a regulatory role. The vagus nerve innervates the striated muscle of the proximal esophagus. The smooth muscle of the distal two-thirds of the esophagus is innervated by the vagus nerve through parasympathetic branches originating in the dorsal motor nucleus of the vagus in the medulla. Afferent systems including peripheral sensory receptors, brain stem centers, and ascending pathways provide information that modifies esophageal motility to correspond with bolus-specific demands. The 12th cranial nerve exclusively supplies all the intrinsic and extrinsic muscles of the tongue except the palatoglossus muscle, which is innervated by the vagus. The hypoglossal nucleus is located in the tegmentum of the medulla. General sensation of the oral cavity (anterior two-thirds of the tongue, palate, and gums) is carried by the fifth cranial nerve. Sensation from the posterior third of the tongue and upper pharynx is conveyed by the ninth cranial nerve, the rest of the pharynx and esophagus being served by the 10th cranial nerve. Taste and salivation are controlled by the seventh and ninth cranial nerves. Of the salivary glands, the ninth cranial nerve supplies only the parotid.

EXAMINATION AND CLINICAL MANIFESTATIONS

FIGURE 80-1. Brain stem with the nuclei of the cranial nerves (dorsal view).

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On individual evaluation of the aforementioned cranial nerves, abnormalities mediated through the fifth and seventh nerves are associated with noticeable facial findings, including weakness and numbness. The ninth cranial nerve is for all practical purposes a purely sensory nerve, as the stylopharyngeus muscle cannot be examined separately. Taste from the posterior third of the tongue cannot be reliably tested, and the gag reflex is the only practical test to assess function of the ninth cranial nerve. This test should be performed by gently touching the palate on both the left and the right sides. With unilateral vagus lesions, the palate is lowered and flattened at rest and deviates to the normal side on phonation.

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The posterior pharyngeal wall is also pulled toward the intact side, resembling the drawing of a curtain, known as Vernet’s sign de rideau. Because of an overlap of innervation patterns, unilateral lesions result in variable symptoms, but with bilateral involvement, there is profound hypernasal speech, regurgitation of fluid through the nose, severe dysphagia (more pronounced for liquids than solids), and aspiration. Snoring, hoarseness, and stridor may be prominent. Stridor seen with acute bilateral lesions can be severe and life-threatening. Because of palatal weakness, the patient is not able to puff out the cheeks unless the nose is pinched. This finding is in contrast to facial weakness, in which the cheeks cannot be puffed in any circumstance.3 Soft palate paralysis in conjunction with laryngeal weakness and vocal cord paralysis should lead the physician to consider a high lesion near the brain stem or the jugular foramen. Distal vagal neuropathy, below the level of the hyoid bone, manifests solely by vocal cord dysfunction. The gag reflex may be lost in lesions of the glossopharyngeal or vagus nerves. Loss of the gag reflex has considerable localizing value if there is unilateral loss. Because there is great variability in the gag reflex, however, a bilaterally diminished response may be a variation of the normal. Despite bilateral lesions of the vagus or glossopharyngeal nerves, the gag response may be partially intact as a result of the function of the tensor veli palatini muscle innervated by the trigeminal nerve.4 Although the tensor veli palatini functions primarily as the dilator of the Eustachian tube,5 it does play a role in the gag reflex. Although the gag and swallowing reflexes involve the same sensory and motor pathways, presence or absence of a gag reflex may not reflect swallowing integrity.6 Swallowing can be divided into three phases. In the initial oral phase, food is propelled toward the pharynx with the tongue and buccal musculature. In the second or pharyngeal phase, the nasopharynx closes with elevation of the soft palate, and the larynx closes with elevation of the hyoid bone and adduction of the vocal cords. Food is propelled toward the upper esophageal sphincter (cricopharyngeal muscle) by pharyngeal constrictors. The cricopharyngeal muscle relaxes reflexively, and the third phase of swallowing is characterized by esophageal peristalsis followed by opening of the lower esophageal sphincter. Cricopharyngeal malfunction is seen in various neurologic disorders.7 Typically, central nervous system problems impair cricopharyngeal relaxation; peripheral neuromuscular abnormalities reduce sphincter pressure. In peripheral neuromuscular disorders, relaxation may nevertheless be incomplete because of impaired elevation of the hyoid bone as peripheral neuromuscular disease involves all the pharyngeal muscles nonselectively. The traction force delivered by the elevation of the hyoid is required for complete opening of the sphincter.8 Symptoms of neurogenic dysphagia include prolonged feeding, drooling, nasal regurgitation, cough, and choking during feeding, which eventually result in failure to thrive. Dysphagia for liquids precedes dysphagia for solids and is characteristic of neurologic impairment

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of swallowing. The investigation of the dysphagia should include cinefluorography and manometry to differentiate the structural abnormalities from neurogenic causes. Other diagnostic testing includes esophagogram, videofluoroscopy, flexible endoscopy, ultrasound, electromyography, scintigraphy, and 24-hour pH monitoring.9 Swallowing (deglutition) syncope is an uncommon condition that may be seen in children and adults. It is characterized by a decrease in cardiac output in response to swallowing. This phenomenon is thought to be a vasovagal reflex causing bradycardia and heart block resulting in cerebral hypoperfusion and loss of consciousness. It may be precipitated by cold drinks or a large bolus of food, among other factors.10,11 Hiccups (singultus) are a common phenomenon, but rarely, intractable hiccups can herald a serious underlying neurologic disorder. The inspiration starting with the involuntary and spasmodic contractions of the diaphragm ends abruptly with the closure of the glottis. The afferent arm of this reflex includes the vagus and the phrenic nerves. Peripheral irritation of various branches of these two nerves, or a central nervous system disease affecting the area near the respiratory center in the medulla, may cause hiccups.12 Disorders of taste, phonation/articulation, and dysphagia due to anatomic abnormalities are not addressed in this chapter. Neurologic disorders affecting the mouth, pharynx, and esophagus are discussed in two groups. Primary neurologic illnesses leading to functional impairment because of direct effects on innervation are presented first, followed by disorders in which structural abnormalities in the mouth, pharynx, and esophagus coexist with neurologic abnormalities.

PRIMARY NEUROLOGIC ILLNESSES LEADING TO FUNCTIONAL DISORDERS In light of the complex neuroanatomic connections, it is evident that neurologic disorders at different anatomic levels can be responsible for various functional problems. These abnormalities are reviewed according to their functional disorder.13

Dysphagia Table 80-1 summarizes the main causes of dysphagia by neuroanatomic localization. Impairment of cortical control on brain stem nuclei due to bilateral corticobulbar lesions is the most common upper motor neuron problem affecting the mouth, pharynx, and esophagus. Unilateral lesions uncommonly impair bulbar function because bulbar centers receive bilateral input. Among several diffuse conditions affecting the brain, perinatal hypoxic injury and prematurity-related cerebral injuries (periventricular leukomalacia and subependymal hemorrhage) are the frequent causes of poor oropharyngeal coordination (sucking and swallowing). Aspiration pneumonias are a common occurrence in patients with these lesions. Congenital malformations of the brain, such as Chiari

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TABLE 80-1. Causes of Dysphagia Secondary to Cerebral Disorders Perinatal hypoxic-ischemic injury Periventricular leukomalacia Subependymal hemorrhages Congenital malformation of the brain (microcephaly, holoprosencephaly, schizencephaly) Postinfectious leukoencephalopathy Acute disseminated encephalomyelitis Leukodystrophies Epilepsy Benzodiazepines Metabolic disorders Wilson’s disease Bilirrubin-induced neurologic dysfunction (BIND) Infantile Gaucher disease Alexander disease Hexosaminidase A deficiency (Tay–Sachs disease)

Secondary to Brain Stem Disorders Posterior fossa tumors Brain stem gliomas Ischemic lesions Vertebral dissections Poliomyelitis Progressive bulbar palsy (Fazio–Londe disease) Möbius syndrome Chiari malformation: Type I and Type II Basilar impression Platybasia Syringobulbia Klippel–Feil syndrome Spinal Muscular Atrophy

type II, microcephaly, holoprosencephaly, schizencephaly, and hydrocephalus, also lead to nutritional problems through the same mechanism. Postinfectious leukoencephalopathies, acute demyelinating encephalomyelitis (ADEM), and leukodystrophies are the principal demyelinating conditions affecting swallowing in the young. Multiple sclerosis frequently affects bulbar musculature.14 Children with epilepsy may manifest oral and pharyngeal symptoms caused by distinctly different mechanisms. Frequent seizures may be responsible for a progressive encephalopathy and poor suck-swallow function. Certain seizures may present with isolated mouth-related symptoms, such as prolonged intermittent drooling and oral motor dyspraxia.15 Chewing and lip smacking movements are typical automatisms in complex partial seizures associated with impairment in consciousness during the seizure. Anticonvulsant treatment with the benzodiazepines is known to cause excessive drooling secondary to impaired swallowing. Nitrazepam, used in intractable epilepsy, has been associated with cricopharyngeal achalasia, abnormal esophageal peristalsis, and bronchospasm. This mechanism

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Secondary to Neuropathic Disorders Autoimmune Disorders Guillain–Barré Syndrome Miller Fisher syndrome Multiple sclerosis Malignancies Leukemia Lymphoma Rhabdomyosarcoma Paragangliomas/schwannomas Jugular fossa syndrome (Vernet syndrome) Diphtheria Vitamin E deficiency Isolated hypoglossal nerve palsy

Secondary to Neuromuscular Junction Disorders Myasthenia gravis Transient neonatal myasthenia Botulism Infantile botulism Lambert–Eaton myasthenic syndrome Tetanus

Secondary to Muscle Disorders Dermatomyositis Facioscapulohumeral dystrophy Myotonic dystrophy Oculopharyngeal dystrophy Congenital muscular dystrophy Duchenne/Beckers muscular dystrophy

may be related to the propensity of nitrazepam to promote parasympathetic overactivity.16 Bruxism commonly occurs in mentally retarded children. Although it is not common, destruction of the teeth or supportive structures can occur. Treatment with interdental splints may be effective in some cases.17 Metabolic illnesses affecting the central nervous system predominantly cause supranuclear bulbar symptoms usually late in the course of the disease process, but symptoms may occasionally manifest early in the course of these diseases. Several metabolic disorders are prominent in causing supranuclear oropharyngeal symptoms. Wilson disease is an autosomal recessive disorder of copper transport metabolism causing hepatolenticular degeneration. Neurologic manifestations usually occur after the second decade but may be seen earlier and include dysarthria, apraxia, drooling, dystonic smile, and impaired swallowing. Tongue dyskinesia may be among the early manifestations of this disorder.18 Infantile Gaucher disease usually manifests before 6 months of age with hypotonia, stridor, difficulties in sucking and swallowing, and oculomotor palsies. Head retraction is an early and typical sign. Splenomegaly and early demise are the rule.19

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Alexander disease is a progressive leukoencephalopathy caused by a mutation in the glial fibrillary acid protein (GFAP) gene resulting in the formation of Rosenthal fibers, which are eosinophilic protein aggregates within astrocytes, diffusely distributed throughout the brain. The clinical presentation depends on the age of onset. The most common type presents before the age of 2 years and is characterized by motor and mental retardation, megalencephaly, seizures, and bulbar dysfunction causing significant swallowing difficulties. If the disease starts between 2 and 12 years of age, children present with significant ataxia, dysphagia, and dysarthria. The adult form is similar to the juvenile form; however, they commonly have palatal myoclonus.20 Infants with hexosaminidase A deficiency (Tay–Sachs disease) typically present with developmental regression and a characteristic retinal abnormality referred to as the cherry red spot. There is, however, a spectrum of different patterns, including dysphagia, dysarthria, intellectual impairment, and lower motor neuron disease.21 Posterior fossa tumors constitute approximately half of the brain tumors encountered in the pediatric age group, and brain tumors are the second most common tumor type in children. Brain stem gliomas manifest with early bulbar involvement in association with corticospinal and cerebellar abnormalities. Progressive multiple bulbar neuropathies may be present as the only manifestation of brain stem gliomas before cerebellar and corticospinal tract signs develop. Cerebellar astrocytomas, medulloblastomas, and ependymomas of the fourth ventricle manifest with increased intracranial pressure and cerebellar abnormalities rather than lower cranial neuropathies. Brain stem ischemic lesions in children are rare, but vertebral dissection or vascular malformations are occasionally responsible for bulbar nuclear impairment. Ischemic lesions in the dorsomedial or ventrolateral medulla where the central pattern generator is located can cause dysphagia as well as sensory changes in the contralateral extremities. Among these ischemic lesions are Avellis syndrome and Wallenberg syndrome. Patients with Avellis syndrome complain of ipsilateral palatopharyngeal paresis and contralateral hemiparesis and/or hemihypesthesia. Patients with Wallenberg syndrome present with dysphagia, dysphonia, ataxia, diplopia, and vertigo.22 Poliomyelitis causes bulbar paralysis but is now relatively rare because of the worldwide immunization efforts. Spinal muscular atrophies (SMAs) are progressive illnesses of the anterior horn cells. Typically, in SMA type 1, the hypoglossal nucleus is involved resulting in tongue fasciculations. In SMA type 2, patients have difficulty with jaw opening, chewing, and swallowing.23 Brown–Vialettovan–Laere syndrome manifests with progressive sensorineural deafness in the 1st decade of life, followed after a latent period by a progressive pontobulbar palsy, involving mostly 5th, 7th, and 12th cranial nerves. Besides dysarthria, dysphagia, and facial weakness, patients develop

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limb weakness, neck and shoulder weakness, respiratory problems, optic atrophy, autonomic dysfunction, and seizure disorder.24 Fazio–Londe disease is a rare hereditary disorder with progressive bulbar paralysis secondary to degeneration of the brain stem motor neurons in association with pyramidal system involvement. Manifestation is usually between 1 and 5 years of age with stridor, dysphagia, facial palsy, tongue wasting, and fasciculations.25 Congenital agenesis of the brain stem nuclei is known as Möbius syndrome. Typical Möbius syndrome is characterized by bilateral facial and abducens palsies, but variants with involvement of other cranial nerve nuclei are known. Chiari malformation, specifically type II but also type I, may manifest with lower cranial neuropathies. Neurogenic dysphagia may be the initial manifestation causing failure to thrive, nasal regurgitation, and tracheal aspiration before further symptoms of bulbar dysfunction develop. Chiari type II malformation includes cerebellar herniation, medullary prolongation with kink, and abnormalities of the midbrain tectum. Chiari I malformation is isolated herniation of the cerebellar tonsils. With brain stem compression, symptoms such as facial palsy, central apnea, and bilateral vocal cord paralysis may occur. Early cranial cervical decompression may be necessary to prevent irreversible brain stem injury.26 Basilar impression or invagination is characterized by upward dislocation of the margins of the foramen magnum and the odontoid process with varying degrees of compression of the medulla. Acquired forms of basilar impression are due to softening of bone and are seen in illnesses such as Paget’s disease, hyperparathyroidism, rickets, achondroplasia, rheumatoid arthritis, and Hurler syndrome. Congenital basilar impression is a developmental defect of the chondrocranium and is often associated with occipitalization of the atlas, Klippel–Feil anomaly, Chiari malformation, and syringobulbia. The term platybasia refers to an abnormally obtuse angle of the clivus with the anterior cranial fossa. Isolated platybasia is neurologically insignificant, but if it is associated with invagination,27 nuchal pain, vertigo, gait abnormalities, and lower cranial nerve palsies1 may be seen. Symptoms are usually delayed to the second to fourth decade of life, but this disorder has been reported in infancy.28 Syringobulbia is the term clinically applied to brain stem symptoms caused by central cavities in the medulla. Common symptoms include occipital headaches, vertigo, dysarthria, and dysphagia as well as palatal and glossal impairment.29 The Klippel–Feil syndrome is characterized by an abnormally short neck associated with limited neck movement due to abnormal fusion and a reduced number of cervical vertebrae (Fig. 80-2). Klippel–Feil syndrome may be associated with Chiari malformation, basilar impression, hydrocephalus, and syringomyelia.30 Not infrequently, cleft palate and bifid tongue are seen with the Klippel–Feil syndrome.31 The Miller Fisher variant of Guillain–Barré syndrome typically involves cranial nerves, causing ophthalmoplegia

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FIGURE 80-2. Cervical spine radiograph of a patient with Klippel–Feil syndrome. Note bony fusion.

and bulbar palsies. The pathophysiologic mechanism is thought to be autoimmune after viral infection. Diagnosis is confirmed by anti-ganglioside GM1 antibodies.32 Progression is gradual and may require prolonged support until spontaneous recovery begins. Treatment includes the administration of intravenous immunoglobulins and/or plasmapheresis and immunosuppresant therapy in severe cases. Nerve invasion by malignant neoplasms may also result in bulbar palsy. Meningeal infiltration of leukemias or direct invasion of bulbar cranial nerves by lymphoma or rhabdomyosarcoma may lead to various symptoms. The treatment of malignant neoplasms, in particular by vincristine, is known to cause peripheral neuropathy, but cranial neuropathy33 and orofacial pain34 have been noted rarely. Irradiation of head and neck tumors may induce mucositis, hyposalivation, trismus, caries, and osteonecrosis.35 Wegener midline granulomatosis is an inflammatory condition but acts much like a malignant neoplasm, invading the skull base and encasing the lower cranial nerves. Pneumonitis invariably accompanies Wegener disease. Jugular fossa syndrome (Vernet syndrome) is characterized by gradual or rapid loss of 9th, 10th, and 11th cranial nerve function caused by a tumor in the jugular foramen. Paragangliomas and Schwannomas are more common than the invasive nasopharyngeal carcinoma or meningioma of the elderly.36

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Diphtheria has become a rare entity, but outbreaks still occur in developing countries. A small portion of infected children will have progressive systemic polyneuropathy that may be associated with cranial neuropathies. Vitamin E deficiency, particularly in abetalipoproteinemia, biliary atresia, or cystic fibrosis, typically manifests with ataxia, visual loss, and ophthalmoplegia. Bulbar involvement, however, may be seen along with the other manifestations of these disorders.16,37 Craniofacial pain syndrome (trigeminal and glossopharyngeal neuralgia) is rarely reported in children. The pain is sharp and lancinating, triggered by certain contacts, and lasts for few seconds. Involvement of the tongue is rare despite the fact that the anterior two-thirds of tongue sensation are supplied by the trigeminal nerve. Mucolipidosis type IV may be an underlying cause of craniofacial pain in childhood. Isolated hypoglossal nerve palsy (Fig. 80-3) is rarely encountered but may manifest as a transient mononeuropathy similar to Bell’s palsy.38 Internal jugular vein puncture, radiation, internal carotid artery dissection, infectious mononucleosis, birth trauma, tonsillectomy, and third molar extractions have also been associated with isolated or bilateral hypoglossal palsies.39 Similarly, isolated unilateral paralysis of the soft palate may manifest with abrupt onset of hypernasal speech and nasal regurgitation.40 Myasthenic syndromes and botulism are the two illnesses commonly affecting the neuromuscular junction. Tetanus is less common. Several types of myasthenic illnesses are observed during childhood. The typical form of myasthenia gravis is an autoimmune disease affecting the acetylcholine receptors. Ocular, bulbar, or generalized involvement can be seen in any combination. Fatigability increases dramatically with exercise. Symptomatic treatment with pyridostigmine (Mestinon) and treatment with steroids and thymectomy, both directed against the autoimmune process, can improve the patient’s function.

FIGURE 80-3. Unilateral hypoglossal involvement with atrophy.

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Transient neonatal myasthenia is observed in newborns of myasthenic mothers, and symptoms such as poor sucking and swallowing, although temporary, may last up to several months. In some congenital myasthenic syndromes, neonates may have persistent abnormalities of the neuromuscular junction, with resultant facial weakness and feeding difficulties that may require G-tube placement.41 Botulism is acquired through improperly processed food products or from contamination of open wounds with Clostridium botulinum. Onset of symptoms is within 36 hours, producing ophthalmoplegia, bulbar paralysis, and generalized weakness. Early administration of antitoxin in association with supportive treatment is the cornerstone of management. Infantile botulism differs from botulism seen in older individuals because the toxins are acquired through germinating spores in the intestine. Contaminated honey intake has been associated with this entity. Onset may be insidious, with weakness and poor feeding. Constipation and ptosis are frequently encountered. Treatment is supportive. Dysphagia is due to the involvement of the striated pharyngeal and upper esophageal muscles, rather than the smooth muscles of the esophagus.42 Trismus and dysphagia in association with a general irritability and spasms are characteristic of tetanus; dysphagia may be a presenting manifestation. The diagnosis of tetanus is purely clinical and dependent on the observation of its varying manifestations.43 Dermatomyositis typically presents with a heliotrope rash on the face and knuckles. Painful proximal muscle weakness and, in advanced cases, dysphagia due to pharyngoesophageal involvement characterize this disorder. Facioscapulohumeral dystrophy characterized by facial weakness in association with proximal upper extremity weakness is usually associated with sensory motor deafness. Myotonic dystrophy may involve the face, but this is rarely evident in childhood; impaired pharyngeal and esophageal motility are commonly encountered in childhood. Newborns of mothers with undiagnosed myotonic dystrophy sometimes present with profound generalized and facial weakness at birth (Fig. 80-4). Prolonged nasogastric feeding with gastric tube placement may be necessary in infants who manifest severe pharyngoesophageal dysmotility. Temporomandibular joint dysfunction, occlusal alterations, and swallowing and mastication difficulties are also reported with older patients.44 Oculopharyngeal dystrophy is typically an autosomal dominant disorder described in adults of French Canadian origin but appears infrequently in teenage years. Initial symptoms are usually bilateral ptosis followed by oropharyngeal dysphagia, which may respond to cricopharyngeal myotomy. Esophageal motility is normal in this disorder.45 Duchenne muscular dystrophy is due to mutation of Xp21 gene and is the most common neuromuscular disorder in childhood. Patients have progressive muscle weakness,

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leading to paralysis, respiratory, and cardiac failure. Children primarily present with difficulty in the pre-oral phase of swallowing secondary to weakness in the muscles of mastication. Choking occurs due to incomplete pharyngeal clearance and insufficient chewing of foods secondary to weakness.46 Cricopharyngeal achalasia is another cause of dysphagia, and it is usually a manifestation of diffuse central nervous system or neuromuscular disease (Table 80-2), but isolated primary neonatal cricopharyngeal achalasia has been reported.47 Cricopharyngeal myotomy can be helpful in a select group of patients who have satisfactory pharyngeal motion and no evidence of cricopharyngeal muscle relaxation.48 A work-up with cinefluoroscopy and manometry is crucial to determine these two factors. New data has shown that botulinum toxin may be helpful in the diagnosis and management of cricopharyngeal achalasia.49

FIGURE 80-4. Myotonic dystrophy in a neonate. Note tented upper lip.

TABLE 80-2. Causes of Cricopharyngeal Achalasia Secondary to Cerebral Cortex Disorders Hypoxic-ischemic injury Chiari type II malformation Congenital malformations Microcephaly Holoprosencephaly Hydrocephalus

Secondary to Brain Stem Disorders Syringobulbia Cervical syrinx Progressive bulbar palsy (Fazio–Londe syndrome)

Secondary to Muscle Disorders Myotonic dystrophy Oculopharyngeal dystrophy Congenital muscular dystrophies

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CHAPTER 80 ❖ Neurologic Disorders of the Mouth, Pharynx, and Esophagus

NEUROLOGIC DISORDERS AFFECTING THE ESOPHAGUS Neurologic disorders affecting subcortical structures, brain stem centers, the vagus nerve, the neuromuscular junction, sensory receptors, and/or muscles may disrupt proximal esophageal function. Disorders that impair proximal esophageal function may also disrupt distal esophageal motility.2 Down syndrome is the most common chromosomal abnormality affecting humans. Patients present with problems in several organ systems such as congenital heart defects, gastrointestinal anomalies, intellectual impairment, hypotonia, and increased risk for cancer. Commonly, patients have several types of esophageal dysmotility syndromes such as achalasia, gastroesophageal reflux, and dysphagia.50 Allgrove syndrome, also known as triple A syndrome, is a rare autosomal recessive disease characterized by achalasia, adrenocorticotropin-resistant adrenal insufficiency, and alacrima. Several mutations of the AAA gene in triple A patients have been identified resulting in a wide array of clinical manifestations. Commonly, patients present first with alacrima or hypoalacrima from birth, followed by achalasia in infancy and then skin hyperpigmentation in early childhood. Other clinical features include short stature, microcephaly, scoliosis, dysmorphic facies (a long, narrow face), long philtrum, and thin upper lip.51 Patients can also present with progressive muscle wasting, predominantly in the hypothenar and calf areas, secondary to motor axonal neuropathy.

Dysarthria Articulation consists of contractions of the pharynx (cranial nerves IX and X), palate (CN V to X), tongue (CN XII), and lips (CN VII), which interrupt or alter the vocal sounds. Vowels are laryngeal in origin, and consonants are formed for the most part during articulation. The consonants m, b, and p are labial, l and t are lingual, and ne and ng are pharyngeal (throat and soft palate). Defective articulation is easily recognized by listening to the patient speak during an ordinary conversation. A quick bedside test to bring out a particular abnormality is to ask the patient to repeat sounds, for example, la-la-la-la (lingual), k-k-k-k (pharyngeal), and me-me-me-me (labial). Causes of dysarthria are summarized in Table 80-3. In neuropathic dysarthria, there is special difficulty in articulation of lingual and labial consonants due to flaccidity of the musculature. When the larynx is involved, the voice is breathy, inspiration is quite audible, and phrases are short. Dysphonia (alteration of the voice to a rasping monotone due to vocal cord paralysis) may be seen as well (Table 80-4). Spastic (cortical or bulbar) dysarthric speech is characterized as slow, low in pitch, thick, and incomprehensible due to clustering of consonant sounds.

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TABLE 80-3. Causes of Dysarthria Secondary to Neuropathic or Neuromuscular Junction Disorder Miller Fisher/Guillain–Barré syndrome Myasthenia gravis Poliomyelitis Diphtheria

Secondary to Cortical or Bulbar Disorders Hypoxic-ischemic insult Progressive bulbar palsy Demyelinating diseases Leukodystrophies Multiple sclerosis Acute disseminated encephalomyelitis Vascular (ischemic or hemorrhagic) lesions Hallervorden–Spatz disease

Secondary to Acute or Chronic Cerebellar Disorders Acute or chronic cerebellar lesions Multiple sclerosis Anoxic encephalopathy Ataxia-telangiectasia Episodic ataxia (hereditary paroxysmal cerebellar ataxia) Spinocerebellar ataxias Friedreich’s ataxia

TABLE 80-4. Causes of Dysphonia Secondary to Upper Motor Neuron Disorder Disorders of the basal ganglia Posterior fossa tumors Spasmodic dysphonia

Secondary to Lower Motor Neuron Disorder Myasthenia gravis Miller Fisher/Guillain–Barré syndrome

Speech with acute or chronic cerebellar lesions (ataxic dysarthria) is marked by two major defects: articulatory and prosodic. It is characterized by slow rate, slurring, monotony, and scanning (unnatural intervals between syllables or words) of phrases. Palatal myoclonus is discussed here because it may interfere with articulation of words. It occurs after lesions of the central tegmental pathway lead to transsynaptic degeneration and hypertrophy of the inferior olivary nucleus. The lesion usually involves the ipsilateral central tegmental tract or the contralateral dentate nucleus. The cause of these lesions is usually vascular but may be neoplastic.52 Palatal myoclonus is characterized by bilateral or unilateral oscillations of the soft palate, often in association with other muscles in the pharynx, mouth, lower face, and eyes. This disease is uncommonly seen

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in childhood.53 Presentation may be a complaint of tinnitus due to rapid clicking (10–200 per minute) secondary to rapid opening and closing of the Eustachian tube.54 Spontaneous resolution usually occurs, but treatment options include the use of antiepileptic medications.16 Isolated lingual myoclonus has been reported with good response to sodium valproate.55

STRUCTURAL CHANGES ASSOCIATED WITH NEUROLOGIC ILLNESS Ulcerative Lesions The appearance of ulcerative lesions in the mouth, in most instances, is a secondary occurrence resulting from genetic, autoimmune, infectious, and toxic/metabolic causes in association with neurologic diseases (see Table 80-5). Ataxia telangiectasia is an autosomal recessive disorder manifesting with oculocutaneous telangiectasias (Fig. 80-5), progressive ataxia, choreoathetosis, and recurrent sinopulmonary infections. Ataxia is usually noted at the time children begin to walk. Recurrent respiratory infections develop between 3 and 8 years of age, and oral inflammatory lesions are observed at this time. Mental retardation is present in 30%–50% of children with ataxia telangiectasia. Chédiak–Higashi disease is characterized by dramatic depigmented areas of the skin, hair, and irises; pancytopenia; and atopy. These children also demonstrate nystagmus, weakness, and peripheral neuropathy. Decreased resistance to infection due to impaired granulocyte function results in recurrent oral inflammatory lesions. Disease becomes evident in the first 2 years of life, and symptoms resemble those seen in familial spinocerebellar degeneration. Behçet disease is characterized by the triad of uveitis with oral and genital ulcers. Oral ulcerations may be painful, while those ulcers in the genital region are typically painless. Central nervous system involvement is characterized by combinations of increased intracranial pressure, stroke, and vasculitic lesions. Oral ulcerations are usually the first manifestations of this disorder, and esophageal ulcerations are occasionally seen.56 Over 100 viruses have been associated with central nervous system infections. Oral ulcerations are frequently seen in most of these viral infections. The most common viruses include herpes simplex virus, enterovirus (Coxsackie A and B, echovirus and enterovirus2), adenovirus, and varicella.57 Herpes encephalitis is usually a fulminant illness. Characteristic hemorrhagic lesions have a predilection for the temporal and orbital frontal regions of the brain. Multiple oral vesicular lesions frequently accompany the encephalitis. The oral lesions progress through ulcerative, hemorrhagic, crusted, and confluent stages. Among the enteroviruses causing meningoencephalitis in late summer and fall, Coxsackie viruses and echoviruses are known to produce oral lesions. The typical lesions of Coxsackie virus are on the anterior

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TABLE 80-5. Causes of Oral Lesions Ulcerative Lesions Ataxia telangiectasia Chédiak–Higashi disease Autoimmune diseases: Behcet disease Crohn’s disease Systemic lupus erythematous Sjorgen’s syndrome Infections: Herpes virus Enteroviruses Coxsackie virus Adenovirus Varicella zoster Epstein–Barr virus Histoplasmosis Actinomycosis Blastomycosis Vitamin deficiencies: Thiamine Riboflavin Pyridoxine Niacin Malabsorption syndromes: Celiac disease, pernicious anemia Toxin/heavy metals: Magnesium Bismuth Lead

Pigmentary Vascular Lesions Adrenoleukodystrophy Sturge–Weber Rendu–Osler Fabry disease Tangier disease

FIGURE 80-5. Ocular telangiectasia in ataxia telangiectasia.

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CHAPTER 80 ❖ Neurologic Disorders of the Mouth, Pharynx, and Esophagus tonsillar pillar and soft palate; those of echovirus infection are less predictable in their location. Epstein–Barr virus (EBV) is frequently associated with a gamut of central nervous system abnormalities including meningoencephalitis, myelitis, and multiple cranial neuropathies.58 EBV typically produces exudative tonsillitis associated with high fever and lymphadenopathy. Histoplasmosis, actinomycosis, and blastomycosis are significant infections in immunocompromised patients. Typical mucosal lesions appear nodular and later ulcerate. In disseminated disease, central nervous system involvement is characterized by meningoencephalitis, and multiple small abscesses develop. Vitamin deficiencies, especially of thiamine (B1), riboflavin (B2), pyridoxine (B6), and niacin (B3), are responsible for oral ulcerative lesions. The tongue and buccal mucosa are red, swollen, and fissured. Central nervous system abnormalities are protean, consisting of encephalopathy, ophthalmoparesis, and peripheral neuropathies. These deficiencies are seen in circumstances of malnutrition, which may be encountered in malignant neoplasms, malabsorptive syndromes such as Celiac and Crohn’s disease, pernicious vomiting, and, of course, starvation. A number of heavy metal intoxications are known to cause oral mucosal lesions in association with neurologic signs and symptoms.59 Mercury, bismuth, lead, thallium, and arsenic poisoning produce inflammation and discoloration of the oral mucosa. Arsenic is found in some insecticides (especially ant pastes) and may contaminate unwashed fruits and vegetables. This metal results in intense abdominal pain, bloody diarrhea, a garlic odor to the breath, and acute hemorrhagic encephalopathy that may be associated with polyneuropathy. Lead encephalopathy manifests with lethargy, vomiting, colicky abdominal pain, seizures, and coma. In a minority of children, the gingivae are stained blue-black in a linear fashion. Thallium is present in a variety of depilatory agents and certain pesticides. Ingestion produces green-black discoloration of the tongue; central nervous system manifestations include irritability, convulsions, and choreoathetosis. Alopecia is often a clue to the presence of thallium. In chronic mercury poisoning, mucosal ulceration, salivation, gingivitis, and stomatitis are frequently present in association with tremor and erethism (insomnia, shyness, emotional lability, and memory loss). Encephalopathy or a neuropathy mimicking Guillain–Barré syndrome may be present. Bismuth intoxication caused by ingestion of therapeutic preparations, such as Pepto-Bismol, in large quantities is associated with a reversible encephalopathy, stomatitis, and black punctate lesions of the oral mucosa.60

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progressive neurologic deterioration of motor and cognitive function associated with adrenal atrophy. The progressive demyelination is caused by accumulation of very long chain fatty acids in the plasma, fibroblasts, and tissues. Increased pigmentation of nonexposed body surfaces, including buccal, gingival, and lingual mucosa, is an early feature of this illness.61 The vascular nevus of Sturge–Weber disease often extends to involve the mouth. The port wine nevus, capillary in nature, is seen in the distribution of the ophthalmic division of the fifth nerve with variable combinations of involvement of the second and third divisions. The slow flow capillary angioma present in the meninges causes ischemia of the overlying cerebral cortex, resulting in cortical gliosis and calcification. Involvement of the gyri with sparing of the sulci results in the characteristic “railroad track” or “tram track” calcification pattern seen on skull films. The central nervous system calcifications, however, are most readily detected by computed tomography scan. Rendu–Osler–Weber disease or hereditary hemorrhagic telangiectasia characteristically produces small angiomas over the buccal and lingual mucosae. This autosomal dominant illness presents with recurrent epistaxis, telangiectasia, and gastrointestinal bleeding. Subarachnoid hemorrhage and hydrocephalus are seen as well as unruptured intracranial angiomas. Brain abscess secondary to pulmonary arteriovenous fistulas may be encountered (Fig. 80-6).62 Fabry disease is a sex-linked recessive storage disease caused by absence of alpha-galactosidase A. Red-purple angiokeratomas are characteristically present over the scrotum and umbilical region and may be seen in the oral mucosa. The accumulation of alpha-galactosidase A in the corneas, peripheral nerves, kidneys, brain, and spinal cord leads to a painful peripheral neuropathy, encephalopathy, seizures, myelopathy, and renal failure.

Pigmentary and Vascular Lesions Pigmentary and vascular lesions are not infrequently early manifestations of specific neurologic illnesses. Adrenoleukodystrophy is a peroxisomal disorder characterized by

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FIGURE 80-6. Sturge Weber Syndrome: facial involvement of trigeminal V1, V2, and V3 dermatomes.

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Hypoalphalipoproteinemia (Tangier disease) is characterized by a pathognomonic yellow-orange enlargement of the tonsils. Asymmetric polyneuropathy characterized by relapsing weakness and sensory loss is seen in childhood.

ABNORMALITIES OF THE TEETH AND GINGIVAE Embryologically, teeth develop from neural crest cells, and hormones play a major role in dental development. These two factors explain the association of certain central nervous system abnormalities with disturbed dentition. Delayed dentition is seen with tumors involving the hypothalamus as well as developmental disorders such as cleidocranial dysostosis. Not infrequently, delayed eruption of deciduous teeth is followed by failure to shed, resulting in crowding of primary and secondary teeth. These abnormalities may precede the more common manifestations of these disorders and present the opportunity for early recognition (see Ch 67: Dental and Gingival Disorders). Craniopharyngioma is characterized by impaired growth, visual field defects, and eventual increased intracranial pressure. Cleidocranial dysostosis is characterized by a partial or complete absence of the clavicles, presence of the Wormian bones of the skull, and relative macrocephaly (Figs. 80-7 and 80-8). Basilar impression frequently present in cleidocranial dysostosis results in lower cranial neuropathies, syringomyelia, and hydrocephalus. Impaired palatal and tongue function as well as hydrocephalus and spastic paraparesis result. Supernumerary teeth are a related dental anomaly.63 Conic defects of teeth are also seen in incontinentia pigmenti, Rieger syndrome, and Williams syndrome. Incontinentia pigmenti manifests with a papular or vesicular eruption over the trunk following a dermatomal linear pattern in the newborn period (Fig. 80-9). These lesions evolve into a pigmented, whorled spidery pattern later in childhood. Dystrophic nails are frequently noted, and patients may demonstrate mental retardation and seizures. One-third of these patients have hypodontia, delayed eruption, or malformation of the teeth (Fig. 80-10). Rieger syndrome consists of dysplasia of the iris, hypodontia, and partial adontia. A variable number

FIGURE 80-7. Cleidocranial dysostosis: partial clavicular agenesis.

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of patients with this syndrome have associated myotonic dystrophy. Williams syndrome is characterized by neonatal hypercalcemia, elfin facies with a fish-shaped mouth, supravalvular aortic stenosis, and mental retardation. There is a high prevalence of tooth agenesis in patients with Williams syndrome with more than six teeth missing. Besides hypodontia, patients also have small tooth size, especially in the mesiodistal and labiolingual areas and commonly the incisors have a peg shape or screwdriver shape.64

FIGURE 80-8. Cleidocranial dysostosis: Wormian bones of the skull.

FIGURE 80-9. Bullous eruption on the neonate with incontinentia pigmenti.

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CHAPTER 80 ❖ Neurologic Disorders of the Mouth, Pharynx, and Esophagus Tuberous sclerosis typically consists of hypopigmented skin lesions, seizures, adenoma sebaceum, and mental retardation. Neurologic manifestations of tuberous sclerosis may be subtle, and recognizing oral manifestations such as hypoplasia and hypocalcification of the teeth, angiomas in the mouth, gingival fibromas, and pits in the enamel is important. Gingival fibromas cause malocclusion and abnormal eruption.65,66 Neurofibromatosis type 1 is also associated with hypodontia and occasional oral neurofibromas with cutaneous neurofibromas and cafe au lait spots.67 Macroglossia is a common manifestation (Fig. 80-11). Lesch–Nyhan syndrome is characterized by choreoathetosis, mental retardation, seizures, and self-mutilation. The self-mutilation characteristically involves chewing of the lip and buccal mucosa. Dental dysplasia is seen in this syndrome. Bilirubin-induced neurologic dysfunction (Kernicterus) secondary to neonatal hyperbilirubinemia is frequently associated

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with abnormal pigmentation and abnormalities of formation of the teeth. Other neurological symptoms include dysphagia, dysarthria, and dysphonia.68 Both pseudohypoparathyroidism and hypoparathyroidism are characterized by seizures, tetany, and muscle cramps. These disorders may be mistaken for epilepsy, but dental abnormalities are often a clue to the correct underlying diagnosis. In pseudohypothyroidism, patients are short and stout with round facies. Characteristically, the fourth metacarpal bones are unusually short. Central nervous system calcifications are frequently seen. Teeth are frequently hypoplastic but erupt in the normal sequence of tooth development. Mucopolysaccharidoses and mucolipidoses are genetically distinct metabolic abnormalities but phenotypically share the characteristics of coarse features, variable mental retardation, and ocular and bony abnormalities. Dental abnormalities including gingival hyperplasia and tooth structure are frequently observed.

STRUCTURAL CHANGES IN THE TONGUE

FIGURE 80-10. Incontinentia pigmenti. Note conic bicuspid defects and partial adontia.

Melkersson–Rosenthal syndrome is characterized by recurrent facial palsy and edema of the lips and face. Facial palsy may be unilateral or bilateral. Prominent furrowing of the tongue (lingua plicata) is frequently associated with this syndrome but is not pathognomonic. Swelling, erythema, and painful erosions affecting the gingiva, buccal mucosa, and palate are seen.69 There are five different types of hereditary sensory and autonomic neuropathies (HSAN) that differ by their mode of inheritance, pathology, natural history, biochemical, neurophysiological, and autonomic abnormalities. In HSAN type II, symptoms start during infancy. Patients have hypotonia, swallowing difficulties, constipation, apnea, and episodic fever. HSAN type III, previously known as familial dysautonomia (Riley–Day syndrome), is an autosomal recessive disease affecting mostly the Ashkenazi Jews. Patients also present during infancy with dysregulation of body temperature, blotchy discoloration of the skin, hyporeflexia or areflexia, sensory deficits, lacrimation, and mental retardation. Mental retardation becomes prominent with age. The tongue shows a striking absence of fungiform papillae, which are the clearly visible red projections among the more numerous gray filiform papillae. The red coloration is due to high vascularity. Patients with Riley–Day syndrome typically cannot distinguish between acidic and sweet solutions. Neuropathy and autonomic dysfunction result in dysphagia due to pharyngeal dyscoordination and delay in cricopharyngeal opening.70

STRUCTURAL CHANGES IN THE PALATE

FIGURE 80-11. Neurofibroma of the tongue.

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Cleft palate and lip are frequent developmental abnormalities seen in the mouth and face. The location of the cleft relative to the incisive foramen separates anterior clefts involving the lip and primary palate (including the alveolar

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ridge) from posterior clefts of the secondary palate (posterior portion of the hard palate and soft palate). Anterior and posterior clefts are embryologically distinct, but the combination of these two abnormalities is not rare. Inheritance is multifactorial.71 A number of chromosomal abnormalities are reported with clefts. Trisomy 13 and trisomy 18 are the most common ones and most frequently are associated with profound mental retardation. Two percent of cleft palate patients also have Klippel–Feil anomaly. Occipital or frontal encephaloceles may be associated with cleft palate (Fig. 80-12). The cyst may extend to the oral cavity and should not be mistaken for a nasal polyp or adenoidal mass. Median clefts rather than bilateral clefts are more commonly associated with midline central nervous system anomalies. A midline cleft of the upper lip and tongue is characteristic of Mohr syndrome (oral-facial-digital syndrome, type II), associated with conductive hearing loss and normal intelligence. Type II is in contrast to oral-facial-digital syndrome type I, which includes irregular clefts, hypoplastic nasal cartilages, asymmetrically short digits, and mental retardation.72 Duane syndrome, characterized by fibrosis of the lateral rectus muscle of the eye causing impaired ocular abduction, may occasionally be seen in association with cleft palate. Awareness of the variety of neurologic illnesses associated with oral, pharyngeal, and esophageal lesions will, it is hoped, alert specialists to specific diagnoses and allow them to undertake appropriate investigations, genetic counseling, and treatment.

FIGURE 80-12. Child with cleft palate and a nasofrontal encephalocele.

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64. Axelsson S, Bjornland T, Kjaer I, Heiberg A, Storhaug K. Dental characteristics in Williams syndrome: a clinical and radiographic evaluation. Acta Odontol Scand. 2003;61:129–136. 65. Franz DN. Non-neurologic manifestations of tuberous sclerosis complex. J Child Neurol. 2004;19:690–698. 66. Tillman JJ, DeCaro F. Tuberous sclerosis. Oral Surg Oral Med Oral Pathol. 1991;71:301. 67. Holt GR. Von Recklinghausen’s neurofibromatosis. Otolaryngol Clin North Am. 1987;20:179. 68. Shapiro SM. Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND). J Perinatol. 2005;25:54–59.

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69. Zimmer WM, Rogers RS, Reeve CM, Sheridan PJ. Orofacial manifestations of Melkersson Rosenthal syndrome. A study of 42 patients and review of 220 cases from literature. Oral Surg Oral Med Oral Pathol. 1992;74:610–619. 70. Hilz MJ. Assessment and evaluation of hereditary sensory and autonomic neuropathies with autonomic and neurophysiological examination. Clin Auton Res. 2002;12(suppl):I33–I43. 71. Menezes AH, Van Gilder JC. Anomalies of the craniovertebral junction. In: Youmans JR, ed. Neurological Surgery. Philadelphia, PA: WB Saunders; 1990:1359–1420. 72. Jones KL. Smith’s Recognizable Patterns of Human Malformations. Philadelphia, PA: WB Saunders; 1988:220–223.

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5

S E C T I O N

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The Airway David L. Mandell and Reza Rahbar

81

Developmental Anatomy and Physiology of the Larynx, Trachea, Esophagus, and Lungs

82

Physiology of the Larynx, Airways, and Lungs

83

Methods of Examination of the Pediatric Airway

84

Radiologic Evaluation of the Pediatric Airway

85

Cough

86

90

Congenital Malformations of the Trachea and Bronchi

91

Pediatric Upper Airway Infections

92

Acquired Disorders of the Larynx and Trachea

93 Pediatric Tracheotomy 94

Pediatric Airway Stenosis: Minimally Invasive Approaches

Stridor: Presentation and Evaluation

95

Airway Surgery: Open Approach

87

Aspiration: Etiology and Management

96

Foreign Bodies of the Larynx, Trachea, and Bronchi

88

Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease

97

Diagnosis and Management of Pediatric Laryngotracheal Trauma

89

Congenital Laryngeal Anomalies

98 Tumors of the Larynx, Trachea, and Bronchi

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C H A P T E R

Developmental Anatomy and Physiology of the Larynx, Trachea, Esophagus, and Lungs Glenn Isaacson

T

he evolving structure and physiology of the aerodigestive tract and lungs mirror the demands placed on them by development. In utero, the immature larynx has a single but important chore—to modulate fetal breathing in an aqueous medium, a function essential to orderly lung development. Suddenly, at birth, the lungs changes from passive organs and assume their vital role in gas exchange. The larynx takes on three difficult and contradictory tasks. It must control respiration, protect the lower airway from contamination, and produce the first cry. The esophagus must be ready to rhythmically contract to propel a food bolus toward the stomach during swallowing, yet maintain sufficient tone to prevent reflux between swallows. All this can be accomplished despite an immature central nervous system because of several remarkable structural adaptations. In childhood, the larynx permits eating, breathing, and speaking to proceed with ever greater efficiency. The trachea develops sufficient rigidity to resist collapse during inspiratory airflow while remaining flexible enough to stretch with negative intrathoracic pressure. The lungs rapidly grow gaining size and complexity with improving respiratory efficiency. This chapter highlights the events in human aerodigestive and lung development from these structures’ appearance in the embryo to their refined adult form. At each point, the interaction of structure and function helps explain how they succeed in health and how they fail in disease states.

esophagus (Fig. 81-2). At 33 days of life, the distal esophagus can be distinguished from the stomach, and the laryngeal primordia appear. The laryngeal aditus or slit is altered by the growth of three tissue masses: anteriorly, the primordium of the epiglottis (from the hypobranchial eminence, arches III and IV) and later ally from the precursors of the arytenoid cartilages (ventral ends of arch VI). The aditus is now T shaped. In the fifth and sixth weeks, the tracheoesophageal septum extends to the first tracheal ring. In the 13- to 17-mm embryo, laryngeal cartilage and muscle development is clearly identifiable, and lateral cricoid condensation is underway. By the seventh week of development, the cricoid ring is complete, and the cartilaginous hyoid is visible below the epiglottis (Fig. 81-3). Definitive tracheal cartilages appear at this stage, and the esophagus has four discrete layers. By the end of the embryonic period (27–31 mm crown-rump length), the larynx, trachea, and esophagus are well-formed organs (Fig. 81-4). In the fifth week, the lung bud has divided into two bronchial buds and is surrounded by a mass of splanchnic mesenchyme. These buds elongate to form primary bronchi. Even in this early phase, the right bronchus is

THE EMBRYO Development The embryology of the larynx, trachea, and esophagus was well studied during the first half of the 20th century as detailed by Soulie and Bardier,1 Lisser,3 Hast,4 Rahilly and Tucker,5 and Tucker and Tucker.6 In the 2-mm embryo, a median pharyngeal groove presages the first appearance of the respiratory tract (Fig. 81-1). The anlagen of the larynx, trachea, bronchi, and lungs arise from a ventromedial diverticulum of the foregut called the tracheobronchial groove at about 25 days of intrauterine life. The lining of the larynx and trachea is thus derived from the same endoderm as that of the gut. The cartilage of the trachea and the connective tissue and muscle of both the trachea and esophagus come from splanchnic mesenchyme. Lateral furrows develop on each side of the ventromedial diverticulum, deepen, and join to form the tracheoesophageal septum that will become the layers of tissue between the trachea and

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FIGURE 81-1. Section through the pharynx and the heart of a human embryo at 3 weeks’ gestational age, 1.38 mm in length. The median pharyngeal groove can be seen immediately dorsal to the heart. In the heart, the so-called epimyocardial mantle, the cardiac mesenchyme (“jelly”), and the endocardium can be identified. (From Tucker and O’Rahilly,44 Carnegie Collection, 5074.)

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FIGURE 81-2. Median section through the pharyngeal region at 5 weeks’ gestational age (4.5 mm). The respiratory diverticulum can be seen descending from its origin in the foregut. Its close relationship to the heart is evident. The site of the tracheoesophageal septum is clearly visible. (From Tucker and O’Rahilly,44 Carnegie Collection, 9297.)

FIGURE 81-3. Sagittal section near the median plane at 7 weeks’ gestational age (18 mm). The base of the skull and the vertebral center are evident. The forming epiglottis is evident. The cartilaginous hyoid is seen below the epiglottis. (From Tucker and O’Rahilly,44 Carnegie Collection, 8226.)

slightly larger than the left and more vertically oriented. On the right, these primary bronchi divide into secondary bronchi over the next few days. The superior bronchus defines the future right upper lobe. The intermediate

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FIGURE 81-4. (A) The greater horn of the hyoid and the thyroid lamina can be seen on each side. The laryngeal cavity is T shaped; that of the pharynx is U shaped. Behind the arytenoid cartilages, the transverse arytenoid muscle is evident. In the region between the hyoid and the thyroid, the ganglion is identifiable bilaterally. (B) The body of the hyoid, thyroid laminae, and cricoid cartilages are clearly visible, as are the laryngeal cavity and that of the laryngopharynx. The submandibular and thyroid glands can be seen bilaterally. The thyrohyoid and sternothyroid muscles and the oblique line of the thyroid cartilage are indicated, as is the posterior cricoarytenoid muscle. The blastema of the vocal ligament is marked. The internal jugular vein, vagus nerve, common carotid artery, and sympathetic trunk are identifiable on each side, and a parathyroid gland shows well on the left-hand side of the photomicrograph (;ts49). (C) Portions of the thyroid and cricoid cartilages, as well as the thyroid gland, are evident. On each side, the anterior branch of the inferior laryngeal nerve can be seen passing forward in the vicinity of the cricothyroid joint and ending in the thyroarytenoid muscle (silver preparation). (From Mauuller et al.45)

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CHAPTER 81 ❖ Developmental Anatomy and Physiology of the Larynx, Trachea, Esophagus, and Lungs

The complex structure of the larynx and its numerous folds and outpouchings predispose this region to congenital malformations. Congenital laryngoceles and saccular cysts arise in the region of the laryngeal ventricle. Laryngoceles are outpouching of saccular mucosa. They may remain within the confines of the cartilaginous larynx (internal laryngoceles) or extend through the thyrohyoid membrane to present as neck masses (combined laryngoceles). Saccular cysts occur in the laryngeal ventricle as well but are isolated from the interior of the larynx and do not contain air. They are submucosal and covered by normal mucous membrane.7 It has been theorized that failure of epithelial growth in the vestibule and subglottic regions results in laryngeal atresia. These atresias can be divided into three types. Type 1 consists of a supraglottic obstruction, absent vestibule, and

stenotic subglottis. Type 2 is a supraglottic obstruction that separates the primitive vestibule from the normal subglottis. In type 3, a perforated membrane partly obstructs the glottis.8, 9 Laryngeal atresia presents with asphyxia and death at the time of birth in most cases. Because the imperforate larynx cannot be intubated, emergent tracheotomy in the first minutes of life has accounted for the few reported survivors of this malformation. Failed fusion of the two lateral growth centers of the posterior cricoid cartilage at six to seven weeks of fetal life could result in a posterior laryngeal cleft. Further aborted development of the tracheoesophageal septum might result in a laryngotracheoesophageal cleft that could extend to the carina.10, 11 Several staging systems have been proposed for laryngotracheoesophageal clefts. Occult clefts can be appreciated only by palpation and measurement of the interarytenoid height. Type 1 clefts are limited to the supraglottic, interarytenoid area. Type 2 clefts show partial clefting of the posterior cricoid cartilage, sometimes with a mucosal bridge across the cartilaginous gap. Type 3 clefts involve the entire cricoid and the cervical portion of the tracheoesophageal membrane, stopping above the thoracic inlet. Type 4 clefts involve a major portion of the intrathoracic tracheoesophageal wall12 (Fig. 81-6). Three mechanisms have been proposed for the origin of tracheoesophageal fistulas: epithelial occlusion, in which occlusion of the esophageal lumen might occur; intraembryonic pressure, in which pressure from the heart, great vessels, or developing lung causes a disruption of esophageal growth; or differential growth, in which abnormalities of cellular proliferation cause the trachea to outgrow the esophagus in length. In each of these theoretic situations, the earlier the disruption, the more severe is the extent of the malformation.13, 14

FIGURE 81-5. Schematic of sagittal section of 5–6 week embryo. The bronchial buds and future trachea have formed. By the end of the sixth week, five secondary bronchial segments are present that will become the lobes of the lungs. RUL= right upper lobe, RML=right middle lobe, RLL=right lower lobe, LUL=left upper lobe, LLL=left lower lobe

FIGURE 81-6. Benjamin-Inglis classification of laryngotracheoesophageal clefts. (Modified after Benjamin and Inglis.12)

bronchus further divides to supply the middle and lower lobes. On the left, the secondary bronchi become the upper and lower lobe bronchi. Tertiary bronchi appear in the seventh week. During bronchial division, the surrounding mesenchyme is forming definitive masses that will become the lung parenchyma (Fig. 81-5). The pulmonary arteries arise from the right and left sixth aortic arches and become incorporated into the splanchnic mesenchyme. On the right, the distal portion of the sixth arch connecting the pulmonary artery and right dorsal aorta disappears; on the left it persists and becomes the ductus arteriosus. At the same time, the common pulmonary vein appears as an outgrowth of the atrium of the heart. The common vein divides and divides again to form the four pulmonary veins.

Malformations

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SECTION 5 ❖ The Airway

The upper aerodigestive tract forms in the embryonic period. In the fetal period, it grows, refines its structure, and develops the basic neurologic reflexes necessary for postnatal life. In the third month, the thyroid laminae fuse, the cartilaginous vocal processes of the arytenoids are seen, and the ventricle and saccule are identifiable. Fetal breathing movements have been visualized in utero by ultrasonography toward the end of the third month. Myenteric plexuses and ganglion cells are differentiated by 13 weeks of gestation, and the esophageal muscularis is well formed, suggesting the potential for peristalsis. Primitive swallowing movements have been observed in aborted fetuses of 75-mm length.15 Studies of radioactive colloidal gold or red blood cells injected into the amniotic fluid have shown that a 16-week fetus swallows 2–7 mL of fluid each day and that this amount in creases with gestational age. The role of fetal swallowing in the regulation of amniotic fluid volume is controversial, but polyhydramnios can complicate pregnancies in which fetal swallowing is impaired by neurologic disorders, mass lesions, or esophageal atresia.16 In the fourth month, goblet cells appear in the laryngeal submucosa and the trachea is fully ciliated. The esophageal lining cells are also ciliated at this point. Conversion to

mature squamous esophageal epithelium begins in the fifth month. Fibroelastic cartilage appears in the epiglottis in the fifth and sixth months, and the cuneiform and corniculate cartilages develop (Fig. 81-7). Bronchial division continues through the fetal period. Around 16 weeks of gestation, the terminal bronchioles divide into respiratory bronchioles. Each respiratory bronchiole forms three to six alveolar ducts. Capillaries from the mesenchyme surround the bulbous ends of alveolar ducts— the terminal sacs. These capillaries become the vascular bed of the pulmonary arteries and drain into the pulmonary veins. The thin epithelial cells that form the major part of the surface of the terminal sacs are call type I cells. Type II cells are thicker, maintaining their cuboidal shape. These cells produce surfactant. By 24 weeks, 17 orders of bronchi have formed (Fig. 81-8). During the second trimester, fetal breathing becomes a more mature activity, and laryngeal coordination and regulation are apparent. By use of antenatal ultrasonography with simultaneous color flow Doppler imaging, this activity can be seen and measured. Fetal diaphragmatic movements result in tracheal and laryngeal exchange of amniotic fluid with inspiratory and expiratory velocities in the order of 0.1 to 0.2 m/sec.17 The pharynx shows rhythmic expansion 200 ms before the onset of inspiration, stenting the tongue and pharynx open to allow the passage of fluid. Similarly, the larynx is seen to open 100 ms before the onset of inspiratory flow and

FIGURE 81-7. Sagittal section of formalin-fixed 20-week fetus. Note close approximation of the palate and epiglottis. The larynx is relatively large and the trachea short. The lungs are at the end of the canalicular period and are forming terminal sacs. e, epiglottis; l, larynx; t, trachea; l, lung; h, heart.

FIGURE 81-8. Transverse section of formalin-fixed 20-week fetus. The basic lung structure is complete. RML, right middle lobe; RLL, right lower lobe; LLL, left lower lobe; LUL, left upper lobe; RA, right atrium; LA, left atrium; e, esophagus; a, descending thoracic aorta.

THE FETUS

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CHAPTER 81 ❖ Developmental Anatomy and Physiology of the Larynx, Trachea, Esophagus, and Lungs

FIGURE 81-9. Coronal section through the posterior pharynx of a second-trimester fetus. Note close approximation of the uvula (u) and epiglottis (E), the prominent arytenoids (a), and the short epiglottic height. H, hyoid; T, thyroid cartilage; C, posterior cricoid lamina.

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to relax on expiration, narrowing the glottic chink and modulating expiratory flow and duration. The timing and duration of these activities are similar to those observed during air exchange after birth. The lungs are vulnerable to congenital malformations. Pulmonary agenesis is lethal when bilateral. When unilateral, the single lung is hypertrophied and extends into the opposite thoracic cavity. In congenital pulmonary hypoplasia the lungs are normally lobulated, but small in size. The condition is associated with prolonged oligohydramnios, thoracic cage abnormalities, aplasia of the diaphragm, and some severe neurological disorders.18 Abnormal lobulation is seen in lung sequestration,19 where lung tissue lacks normal communication with the tracheobronchial tree. Segments of the lung may communicate with the alimentary tract in bronchopulmonary foregut malformations.20 Congenital lobar emphysema21 results from overexpansion of the lung, either from extrinsic compression by vessels or by an intrinsic bronchial abnormality. Congenital cystic adenomatous malformation22 is a hamartomatous condition characterized by an increase in the density of structures resembling terminal bronchi. It may cause respiratory distress early in life or persist through life without symptoms, depending on its extent. Congenital pulmonary lymphangiectasis23 is often lethal. It is characterized by dilated lymphatics in the interlobar septa, the subpleural region, and in close association with bronchi. A third-trimester fetus is prepared for extrauterine life. Although the larynx is small, it is ready to perform its protective, respiratory, and phonatory functions (Figs. 81-9 and 81-10). The lungs are capable of respiration as the alveolarcapillary membrane is sufficiently thin and surfactant reduces surface tension to allow the first breath.

THE INFANT A neonate’s larynx is different in form and position from that of an adult (Figs. 81-11 to 81-13). The pharynx is vertically short, and the structures associated with it are high within the cervical area (Fig. 81-14). The inferior margin of the cricoid

FIGURE 81-10. Coronal histologic section through the anterior hyolaryngeal complex. Note the glandular elements in the submucosa of the aryepiglottic folds (E), laryngeal ventricles (V), and subglottis (S). These may give rise to congenital cysts in these locations. h, hyoid; t, thyroid cartilage; a, arytenoid; c, cricoid; Th, thyroid gland.

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FIGURE 81-11. Anterior view of the hyolaryngeal complex. (From Bosma, 1986, pp. 366–367.)

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FIGURE 81-12. Posterior view of the hyolaryngeal complex. (From Bosma, 1986, pp. 366–367.) FIGURE 81-14. Sagittal section of adult (A) and newborn (B) heads. Note apposition of the epiglottis and the soft palate, an adaptation that favors suckling without aspiration. (From Sasaki and Isaacson, 1988.)

FIGURE 81-13. Superior view of the hyolaryngeal complex. (From Bosma, 1986, pp. 366–367.)

cartilage is at the level of the fourth cervical vertebra (C4), and the tip of the epiglottis is at C1. The close apposition of the epiglottis and soft palate is thought to permit suckling and simultaneous respiration in the newborn and contributes to a baby’s obligate nasal breathing.24 The hyolaryngeal skeleton is vertically compact, compared with that of an adult. The thyroid cartilage is within the arch of the hyoid and slightly inferior to it. The vocal cords are oriented transversely in a newborn, the epiglottis is short, and the aryepiglottic folds are thick and bulky. The arytenoids are comparatively large and expanded by a thick areolar submucosa. All these features give a neonate’s larynx a different endoscopic appearance from that of an older child or adult.25 On introduction of a laryngoscope, the larynx appears anteriorly displaced, the arytenoids are prominent, and the membranous portion of the vocal folds is short. A newborn’s glottis is 7 mm in anteroposterior and 4 mm in lateral dimension. The subglottis is the narrowest portion of a newborn’s airway, with a diameter of 4 to 5 mm. It has a thick submucosa and is rich in mucus-producing glands. The relative resistance of a newborn’s subglottis to injury from prolonged intubation has been attributed to this high proportion of cross-sectional soft tissue. These mucus-producing glands can be injured during such a period of intubation and are thought to be the source of acquired subglottic cysts (see Fig. 81-10). Although the larynx of a healthy newborn can perform the basic protective, respiratory, and phonatory functions,

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these actions are inefficient. Immediately after birth, the closure reflex, which protects the lungs from contamination during eating, works poorly, leaving a neonate susceptible to aspiration. As time passes, the airway becomes more capable of excluding foreign matter. An infant’s glottis closes in response to tactile, thermal, or chemical stimulation of the laryngeal inlet or trachea. Furthermore, glottic closure can be triggered by irritation of distal esophageal afferents (as in reflux) or by stimulation of any of the major cranial nerves. The larynx should open again as soon as the stimulus disappears. In the immature larynx, glottic closure may continue long after the stimulus disappears—this is the phenomenon of laryngospasm.27 Laryngospasm that routinely terminates in adults as blood oxygen decreases and carbon dioxide increases may persist in a neonate and has been implicated in the etiology of sudden infant death syndrome.2,26 Two abnormal developmental conditions of the larynx, laryngomalacia and vocal cord paralysis, are worthy to mention here. Among the many causes of stridor in a newborn, these two abnormalities make up the bulk of diagnoses. Increasing evidence shows that laryngomalacia and vocal cord paralysis, when presenting in otherwise healthy children (i.e., those free of central nervous system diseases), represent maturational abnormalities in central nervous system control of laryngeal musculature. Laryngomalacia shows no histologic abnormalities in cartilage development, is frequently associated with swallowing difficulties, and routinely resolves with time, thus suggesting a neurologic cause. Furthermore, laryngomalacia can develop in previously normal patients after central nervous system lesions.28, 29 Likewise, many “idiopathic” vocal cord paralyses resolve spontaneously by the first year of life.30 Such paralyses may be intermittent, showing normal function on one inspiration and incoordinate or absent movement on other breaths.

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CHAPTER 81 ❖ Developmental Anatomy and Physiology of the Larynx, Trachea, Esophagus, and Lungs Electromyography may demonstrate abnormal rather than absent innervation.31 Thus, some vocal cord paralyses seem to represent incoordination of the opposing adductor and abductor function rather than an absence of innervation as is seen in acquired palsies. The trachea of a newborn tends to collapse easily. Its compliance is three times that of a 1-year-old’s trachea and six times that of an adult’s. The mechanical resistance of the trachea is partly due to the strength of its cartilages and partially attributable to the tone of the smooth muscle in its posterior wall.32 Resistance to airflow in animal preparations with compressed tracheas and in children with tracheomalacia decreases when smooth muscle tone is increased with methacholine.33 The common occurrence of postprandial regurgitation has focused much attention on the esophageal function in a newborn. About one third of infants demonstrate significant reflux on barium swallow, and this proportion may be higher with use of more sensitive techniques such as 24-hour pH probes and radionuclide milk scans. Esophageal motility in premature infants shows poor coordination with deglutition. Contractions are rapid and often not peristaltic, with simultaneous contractions along the entire esophagus. Lower esophageal sphincter pressure is low in newborns but increases with age, as does the coordination of peristalsis.15

THE CHILD The position, structure, and function of the larynx continue to change throughout childhood.34 By the age of 2 years, the lower border of the larynx has descended in the neck to the level of the fifth cervical vertebra (C5). It has reached C6 by age 5 years, and its definitive position (C6-7) is achieved at around 15 years.35 The thyroid cartilage and hyoid bone, which overlap in a newborn, separate during laryngeal descent. Growth of the larynx is rapid from birth to 3 years of age, then slows until puberty.36 Growth in the various laryngeal dimensions from birth to puberty is linear and proportional; thus, the general configuration of the larynx changes little during this time. Exceptions are the epiglottis and vocal folds. The epiglottis increases in curvature until age 3 years, then gradually flattens toward its adult configuration. Sixty to 75% of the vocal fold length is attributable to the vocal process of the arytenoid at birth. This configuration favors respiration over phonation and is similar to that seen in other mammals. By a child’s third birthday, the membranous portion of the vocal fold is dominant in size.37 The internal and external landmarks of the larynx maintain their relationships during this period of growth as well. Specifically, throughout childhood, the level of the true vocal folds is halfway between the thyroid notch and the lower border of the thyroid cartilage, the upper border of the cricoid maintains a 30° angle with the true cords, and the arytenoids are one-third the anterior height of the thyroid cartilage.38

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The growth of the larynx is accompanied by a gradual lowering of the vocal pitch. The fundamental frequency of a newborn’s cry is 500 Hz and descends to 286 Hz by 7 years of age. Until puberty, the vocal characteristics of males and females are similar. The trachea measures 4 cm in length in a newborn and increases to 12 cm by adulthood. Growth in childhood is divided proportionally between the tracheal cartilages and the annular ligaments that divide them. After puberty, growth is restricted to the annular ligaments, so the cartilages of a child are more closely approximated than are those of an adult. The upper edge of the trachea remains at the level of the sixth cervical vertebra throughout life.39 In the young child, increase in lung size is achieved by proliferation rather than enlargement. The bronchi continue to divide until 8 years of age when a full 24 orders exist. New alveoli are produced until age 3. From 3 to 8 years of age, the diameters of the alveoli increase to accommodate the growth of the thorax. Eventually the surface area of the alveolar-capillary membrane exceeds 70 m2. The membrane thins from 0.4 microns in the newborn to 0.2 microns in the adult.

THE TEENAGER The larynx undergoes remarkable changes in configuration in the second decade of life. The thyroid cartilage grows in size and changes its shape, producing the prominence of the Adam’s apple. The arytenoids grow slowly compared with the rest of the larynx, assuming adult proportions. The vocal folds elongate with only minor growth in the vocal processes of the arytenoids. In this way, the voice-producing membranous portion of the vocal fold comes to occupy six-tenths of the total length of the cord. This represents a compromise of respiratory function in favor of voice, as the 3:10 ratio of membranous/cartilaginous lengths has been shown to be optimal for respiration and is more closely approximated in a neonate.40 Ossification of the thyroid cartilage does not begin until the end of the second decade and is seen first near the inferior horn.41 The distribution of hyaline and elastic cartilage remains fairly constant through life.42 The most dramatic changes in the second decade are those associated with male voice mutation. Between the ages of 11 and 16 years, a clear sexual dimorphism is seen. Similar in appearance to the female larynx in prepuberty, the male larynx exceeds its counterpart in all dimensions by puberty. The angle of the thyroid laminae decreases from 120 to 90 degrees in both sexes as the anteroposterior length of the glottis increases, but the male thyroid eminence becomes much more prominent. Boys’ vocal folds grow twice as fast as girls’ in length during this period.43 This increase in length and mass of the vocal fold is thought to account for the drop in fundamental frequency from 286 Hz in the child to 207 Hz in the average woman and 120 to 130 Hz in the average man.

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Darwin’s evolutionary theories were questioned. How could a structure as complex as the eye, for instance, evolve and at each point in phylogeny represent a reproductive advantage for the creature that possessed it? If ontogeny recapitulates phylogeny, then the upper aerodigestive tract is a magnificent example of how evolving structures can successfully serve their host at all points of growth and development. This chapter is dedicated to the memories of James F. Bosma, M.D. (1916–2001) and Edmund S.Crelin, PhD. (1923–2004), whose exceptional contributions to the study of infant development enlightened us all.

Selected Readings Bosma JF. Anatomy of the Infant Head. Baltimore, MD: The Johns Hopkins University Press; 1986. Cardoso WV, Lü J. Regulation of early lung morphogenesis: questions, facts and controversies. Development. May 2006;133(9): 1611–24. Review. Crelin ES. Development of the upper respiratory system. Clin Symp. 1976;28:3. Crelin ES. Development of the lower respiratory system. Clin Symp. 1975;27:4. Kirchner JA. The vertebrate larynx: adaptations and aberrations. Laryngoscope. 1993;103:1197. Sasaki CT, Isaacson G. Functional anatomy of the larynx. Otolaryngol Clin North Am. 1988;21:595. Scholand MB, McDonald JA. Lung growth and development. In: Murray JF, Nadel JA, eds. Murray & Nadel’s Textbook of Respiratory Medicine. 4th ed. Philadelphia, PA: WB Saunders; 2005, Chapter 2.

References 1. Soulie A, Bardier E. Recherches sur le development du larynx chez l’homme. J Anat Physiol. 1907;43:137. 2. Bauman NM, Sandler AD, Schmidt C, et al. Reflex laryngospasm induced by stimulation of distal esophageal afferents. Laryngoscope. 1994;104:209. 3. Lisser H. Studies on the development of the human larynx. Am J Anat. 1911;12:27. 4. Hast MH. The developmental anatomy of the larynx. Otolaryngol Clin North Am. 1970;3:413. 5. O’Rahilly R, Tucker JA. Early development of the larynx in staged human embryos. Ann Otol Rhinol Laryngol. 1973;82:3. 6. Tucker JA, Tucker GF. Some aspects of fetal laryngeal development. Ann Otol Rhinol Laryngol. 1975;84:1. 7. Civantos FJ, Holinger LD. Laryngoceles and saccular cysts in infants and children. Arch Otolaryngol Head Neck Surg. 1992;118:296. 8. Walander A. The mechanisms of origin of congenital malformations of the larynx. Acta Otolaryngol (Stockh). 1955;45:426. 9. Zaw-Tun HIA. Development of congenital laryngeal atresias and cleft. Ann Otol Rhinol Laryngol. 1988;97:353. 10. Lim TA, Spanier SS, Kohut RI. Laryngeal clefts. A histopathologic study and review. Ann Otol. 1979;88:837. 11. Moungthong G, Holinger LD. Laryngotracheoesophageal clefts. Ann Otol Rhinol Laryngol. 1997;106:1002.

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12. Benjamin B, Inglis A. Minor congenital laryngeal clefts: diagnosis and classification. Ann Otol Rhinol Laryngol. 1989;98:41t7. 13. Holinger PH, Zimmermann AA, Parchet VN, Johnston KC. A correlation of the embryonic development of the trachea and lungs with congenital malformations. Adv Otorhinolaryngol. 1955;3:1. 14. Smith EI. The early development of the trachea and esophagus in relation to atresia of the esophagus and tracheoesophageal fistula. Contrib Embryol Carnegie Inst Wash. 1957;31:43. 15. Humphrey T. The development of mouth opening and related re flexes involving the oral area of human fetuses. Ala J Med Sci. 1968;5:126. 16. Grand RJ, Watkins JB, Torti FM. Development of the human gastrointestinal tract, a review. Gastroenterology. 1976; 70:790. 17. Isaacson G, Birnholz JC. Human fetal upper respiratory tract function as revealed by ultrasonography. Ann Otol Rhinol Laryngol. 1991;100:743. 18. Wigglesworth JS. Perinatal Pathology. Philadelphia, PA: W.B. Saunders; 1984:172–173. 19. Yildirim G, Güngördük K, Aslan H, Ceylan Y. Prenatal diagnosis of an extralobar pulmonary sequestration. Arch Gynecol Obstet. August 2008;278(2):181–186. 20. Singal AK, Srinivas M, Bhatnagar V. Bronchopulmonary foregut malformation in association with diaphragmatic eventration. J Pediatr Surg. July 2006;41(7):1329–1331. 21. Farrugia MK, Raza SA, Gould S, Lakhoo K. Congenital lung lesions: classification and concordance of radiological appearance and surgical pathology. Pediatr Surg Int. September 2008;24(9):987–991. 22. Lakhoo K. Management of congenital cystic adenomatous malformations of the lung. Arch Dis Child Fetal Neonatal Ed. January 2009;94(1):F73–F76. 23. Wilson RD, Pawel B, Bebbington M, et al. Congenital pulmonary lymphangiectasis sequence: a rare, heterogeneous, and lethal etiology for prenatal pleural effusion. Prenat Diagn. November 2006;26(11):1058–1061. 24. Crelin ES. Development of the upper respiratory system. Clin Symp. 1976;28:3. 25. Tucker G. The infant larynx: direct laryngoscopic observations. JAMA. 1932;99:1899. 26. Sasaki CT. Development of laryngeal function: etiologic significance in sudden infant death syndrome. Laryngoscope. 1979;3:420. 27. Suzuki M, Sasaki CT. Laryngeal spasm: a neurophysiologic redefinition. Ann Otol Rhinol Laryngol. 1977;86:1. 28. Archer SM. Acquired flaccid larynx: a case report supporting the neurologic theory of laryngomalacia. Arch Otolaryngol Head Neck Surg. 1992;118:654. 29. Woo P. Acquired laryngomalacia: epiglottis prolapse as a cause of airway obstruction. Ann Otol Rhinol Laryngol. 1992;101:314. 30. Isaacson G, Moya F. Hereditary congenital laryngeal abductor paralysis. Ann Otol Rhinol Laryngol. 1987;96:701. 31. Gartlan MG, Peterson KL, Hoffman HT, et al. Bipolar hookedwire electromyographic technique in the evaluation of pediatric vocal cord paralysis. Ann Otol Rhinol Laryngol. 1993;102:695. 32. Wailoo M, Emery JL. Structure of the membranous trachea in children. Acta Anat. 1980;106:254.

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CHAPTER 81 ❖ Developmental Anatomy and Physiology of the Larynx, Trachea, Esophagus, and Lungs 33. Panitch HB, Keklikian EN, Motley RA, et al. Effect of altering smooth muscle tone on maximal expiratory flows in patients with tracheomalacia. Pediatr Pulmonol. 1990;9:170. 34. Schwartz DS, Keller MS. Maturational descent of the epiglottis. Arch Otolaryngol Head Neck Surg. 1997;123:627. 35. Noback GJ. The developmental topography of the larynx, trachea and lungs in the fetus, newborn, infant and child. Am J Dis Child. 1923;26:515. 36. Klock LE, Beckwith JB. Appendix: dimensions of the human larynx during infancy and childhood. In: Bosma JF, ed. Anatomy of the Infant Head. Baltimore, MD: Johns Hopkins University Press; 1986:368–371. 37. Eckel HE, Keobke J, Sittel C, et al. Morthology of the human larynx during the first five years of life studied on whole organ serial sections. Ann Otol Rhinol Laryngol. 1999;108:232. 38. Isaacson G. Extraliminal arytenoid reconstruction: laryngeal frame work surgery applied to a pediatric problem. Ann Otol Rhinol Laryngol. 1990;99:616.

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39. Crelin ES. Functional Anatomy of the Newborn. New Haven, CT: Yale University Press; 1973:37–38. 40. Negus VE. The Comparative Anatomy and Physiology of the Larynx. London, UK: Heinemann; 1949. 41. Hately W, Evison G, Samuel E. The pattern of ossification in the laryngeal cartilages: a radiological study. Br J Radiol. 1965;38:585. 42. Sato K, Kurita S, Hirano M, Kiyokawa K. Distribution of elastic cartilage in the arytenoids and its physiologic significance. Ann Otol Rhinol Laryngol. 1990;99:363. 43. Kahane JC. A morphological study of the human prepubertal and pubertal larynx. Am J Anat. 1978;151:11. 44. Tucker JA, O’Rahilly R. Observations on the embryology of the human larynx. Ann Otol Rhinol Laryngol. 1972;81:520. 45. Mauuller F, O’Rahilly R, Tucker J. The human larynx at the end of the embryonic period proper. 2. The laryngeal cavity and the innervation of its lining. Ann Otol Rhinol Laryngol. 1985;94:607.

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82

C H A P T E R

Physiology of the Larynx, Airways, and Lungs Robert E. Wood

The larynx is composed of the cricoid, thyroid, and arytenoid cartilages; the epiglottis; the vocal cords; and associated muscles and ligaments. The details of laryngeal structure can be found in any standard anatomy text and in Chapter 74.

or the respiratory center in the brain, producing bradycardia, apnea, laryngospasm, and bronchoconstriction. In addition, systemic alterations, such as hypoxemia and hypercapnia, may reflexively alter laryngeal muscle tone. Many of the laryngeal reflexes may be abolished or modified by topical anesthetics or vagolytic drugs.

Intrinsic Laryngeal Musculature

Function

There are four important functions of the intrinsic laryngeal muscles. The glottis is opened by rotation of the arytenoid cartilages, which are moved by the posterior cricoarytenoid muscles. The glottis is closed by the action of the lateral cricoarytenoid muscles, which rotate the arytenoids in a direction opposite to that which opens the glottis. This action is supplemented by that of the arytenoid muscle, which approximates the arytenoids and shortens the posterior commissure. In addition, the cricothyroid muscle tenses the vocal cords and thus may also participate in glottic closure. Vocal cord tension is regulated by two sets of muscles. The cricothyroid muscle tilts the cricoid cartilage backward, tensing and lengthening the vocal cords. This is important in phonation as well as in glottic closure. The thyroarytenoid muscle relaxes the cords and shortens them. The vocal muscle, a part of the thyroarytenoid, “fine tunes” vocal cord tension and is thus important in phonation. The fourth muscle function of the larynx is that of lowering and raising the epiglottis. The aryepiglottic muscle lowers the epiglottis to cover the glottic orifice; the thyroepiglottic muscle, extending from the anterior portion of the epiglottis to the thyroid cartilage, raises the epiglottis, thus exposing the glottis.

The larynx serves three important functions: it acts as an airway, it serves as an instrument of phonation, and it protects the lower airways. The larynx is the narrowest portion of the entire airway system and therefore is particularly vulnerable to obstruction. The subglottic space is entirely surrounded by the cricoid cartilage, which serves a protective function but may also contribute to airway obstruction should mucosal edema occur, since the only direction in which the mucosa may swell is into the airway lumen. Complete or partial closure of the glottis during expiration results in increased intrathoracic pressure. This is essential for coughing or for forceful expulsion of abdominal contents (Valsalva maneuver) and may improve airway dynamics or gas exchange in pathologic conditions, as discussed later. The vocal function of the larynx is a complex subject that is not addressed here. The larynx protects the airway in several ways. Most important, it affects complete and automatic closure of the glottis during swallowing. The epiglottis, contrary to popular belief, is not essential for glottic closure or for prevention of aspiration. During swallowing, the vocal cords close completely, and the epiglottis is brought down over the glottis, deflecting the bolus of swallowed material to either side and posteriorly into the esophageal orifice. The other major protective function of the larynx is its role in the cough reflex, which is triggered by sensitive receptors in the larynx and the subglottic space. Stimulation of these receptors results in immediate closure of the glottis, which is followed by an explosive cough. This reflex mechanism is essential to life.

THE LARYNX

Innervation Innervation of the larynx, both motor and sensory, is from the tenth cranial nerve via the superior and inferior (recurrent) laryngeal nerves. Since there is bilateral cortical representation to each side, motor paralysis of the larynx is almost always due to a peripheral lesion. Innervation to all the intrinsic muscles of the larynx is by the recurrent laryngeal nerves, except for the cricothyroid muscle, which is innervated by the external branch of the superior laryngeal nerve. The sensory supply of the epiglottis, the aryepiglottic folds, and the laryngeal mucosa (including the subglottic space) comes from the internal branch of the superior laryngeal nerve. There are many laryngeal reflexes, some of which are poorly defined and understood. Reflexes arising in the larynx may affect the cardiovascular system, the lower airways,

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Important Physiologic Derangements in Laryngeal Function Vocal Cord Paralysis Paralysis of the vocal cords usually results from injury to the recurrent laryngeal nerves. Because of the longer course of the left recurrent laryngeal nerve (which passes around the aortic arch), it is more susceptible to injury than the right recurrent nerve, and it may also be involved by mediastinal lesions. Birth trauma is a relatively common cause of transient

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cord paralysis. Abductor paralysis (paralysis of the posterior cricoarytenoid muscles) leaves the cords in a paramedian position, with resulting airway obstruction. Phonation and cry are often fairly normal, although the patient usually has stridor, and older patients may complain of dyspnea. Adductor paralysis (paralysis of the lateral cricoarytenoid and arytenoid muscles) results in the inability to close the glottis, thus leading to aspiration, aphonia, and an ineffective cough. Unilateral adductor paralysis may lead to aspiration, whereas unilateral abductor paralysis is often relatively asymptomatic. Obstruction Laryngeal obstruction may result from abductor paralysis, as noted previously, or, more commonly, from infection or trauma leading to edema. Laryngeal edema may be generalized, as with thermal burns, or it may be localized to either the subglottic or the supraglottic region. Supraglottic edema is most often associated with acute infectious epiglottitis and is discussed elsewhere in this text. Subglottic edema may result from viral infections (croup) or mechanical trauma (such as intubation or bronchoscopy). Other causes of laryngeal obstruction include foreign bodies, congenital or acquired lesions (such as laryngeal webs, cysts, or other masses), and subglottic stenosis, which are discussed in other chapters of this text (see Chapters 83, 89, and 90). Laryngomalacia is an important laryngeal obstructive lesion in infancy, the physiology of which is instructive. This condition is usually benign and self-limited but may be severe enough to require surgical intervention to achieve an adequate airway. The most common findings associated with laryngomalacia are a floppy epiglottis, large redundant aryepiglottic folds, and large or redundant arytenoid processes. Any of these supraglottic structures may fall into the glottis during inspiration, thus causing obstruction; stridor associated with laryngomalacia is thus predominantly inspiratory. There is usually little obstruction during expiration, as the supraglottic structures are pushed out of the way during expiration. During crying, the stridor may decrease, because increased laryngeal muscle tone may stiffen the supraglottic structures. However, stridor due to subglottic obstruction (such as croup) is usually more severe when the rate and depth of respiration are increased, as in crying or with exercise. Two factors contribute to this phenomenon: (1) because of the Bernoulli effect (lateral pressure in a flowing stream decreases as the velocity of flow increases), the laryngeal structures tend to collapse inward, producing more obstruction as the airflow velocity increases; (2) higher flow velocity increases the turbulence of the flow and therefore the noise of respiration. During quiet breathing (as in sleep), flow velocities may be so low that no stridor may be apparent. Severe laryngeal obstruction leads to alveolar hypoxia. This, in turn, leads to pulmonary arteriolar constriction and elevation of pulmonary arterial pressure. Eventually, permanent changes may occur in the pulmonary arterial tree that

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lead to irreversible pulmonary hypertension, cor pulmonale, and death.

THE AIRWAYS One of the most important features of the structure of the airways is their ability to remain patent despite relatively large shifts in intrathoracic pressure during respiration. This characteristic is due to the fact that central airways have enough cartilage to maintain their shape. In the trachea and major bronchi, the cartilage is in the form of roughly C-shaped rings; but in more peripheral airways, the cartilage becomes more irregular and less prominent. Only in the subglottic space does the cartilage (cricoid) completely encircle the airway. Smaller airways are supported entirely by the elastic properties of the pulmonary parenchyma, and surfactant may play an important role in maintaining patency of airways smaller than about 2 mm. Larger airways are surrounded by strands of smooth muscle, particularly between the ends of the cartilaginous rings, contraction of which decreases the diameter of the airways and increases resistance to airflow. The epithelium of the respiratory mucosa from the posterior laryngeal commissure to the smaller airways is pseudostratified and ciliated. At the bronchiolar level, the epithelium becomes more cuboid in nature, and the number of cilia is decreased. No cilia are found in the respiratory bronchioles or smaller airways. Mixed seromucous glands are numerous in the larger airways (approximately one gland per square millimeter) but become sparse after the first several generations of airways. Goblet cells are numerous in the upper airway and extend further into the respiratory tree than do the glands; under normal circumstances, however, they are not present in the smaller airways. The airways are lined with a thin (perhaps discontinuous) layer of mucus that overlies the tips of the cilia on the epithelial cells. Secretion of mucus and fluid by the mucosal glands is under parasympathetic nervous control; goblet cells discharge their contents (mucus) primarily in response to irritative phenomena. Surrounding the cilia is a fluid the precise composition of which is unknown, but which, for hydrodynamic reasons, must have a low viscosity. The volume and the composition of the periciliary fluid are regulated by active ion transport at the apical surface of the airway epithelial cells.

Innervation Sensory innervation of the trachea and the airways is entirely via the vagus nerve. The receptors are primarily irritant receptors, stimulation of which results in effects similar to those seen with stimulation of the larynx. Motor innervation is both vagal and sympathetic, as is the nerve supply of the mucosal glands.

Function The major function of the airways is air conduction. The velocity of airflow at any point depends on respiratory

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CHAPTER 82 ❖ Physiology of the Larynx, Airways, and Lungs frequency, tidal volume, airway diameter, and difference in pressure between the atmosphere and the pleural space. In normal adults, tracheal airflow velocity is approximately 1.5 m/sec during quiet breathing. With an effective cough, the peak tracheal airflow velocity may approach two-thirds the speed of sound (more than 200 m/sec). The total crosssectional area of the airways increases dramatically with distal branching, and thus the linear airflow velocity decreases in peripheral airways. In the central airways (except perhaps the trachea), airflow patterns are turbulent or nearly so, and it is this turbulent flow that produces normal breath sounds. In smaller airways, airflow becomes laminar, and at the level of the alveolar ducts and alveoli, linear airflow velocity is so low that molecular diffusion may account for a significant proportion of gas movement. Inspiration occurs when intrathoracic pressure is lower than atmospheric pressure, and expiration occurs when intrathoracic pressure becomes greater than atmospheric pressure. The airways have some degree of compliance, increasing in diameter during inspiration and decreasing in diameter during expiration (Fig. 82-1). Because of this, the shear force exerted by the air on the secretions on the airway walls is greater during expiration than during inspiration, a fact that may play some role in keeping the airways clear of secretions. This phenomenon is exaggerated during hyperventilation, which helps explain the effectiveness of exercise in stimulating a productive cough. Narrowing of the lumen of the larger airways during coughing (by active muscle contraction as well as by increased intrathoracic pressure) increases the linear airflow velocity and thus leads to a more effective cough. The ventilatory function of the lung can be described in terms of volumes, flow rates, and airway resistance (the most common parameters of pulmonary function measured in the laboratory). Total lung capacity is divided into several components (Fig. 82-2). The reference point for all volume measurements is functional residual capacity: the volume of gas contained in the lung when all forces acting on the lung are in equilibrium. In practice, this occurs at the end of a quiet, relaxed, normal exhalation. Residual volume is the volume of gas remaining in the lung at the end of a maximal exhalation. Vital capacity (total lung capacity minus residual volume) and its subdivisions (inspiratory capacity and expiratory reserve volume) are usually measured with a simple spirometer. Measurements of absolute lung volumes (functional residual capacity, residual volume, and total lung capacity) require more sophisticated methods. The simplest technique for measurement of functional residual capacity is to have the patient rebreathe from a closed container of helium. After rebreathing and equilibration (usually for seven minutes), the volume of gas contained in the lungs can be calculated from the ratio of the initial and final helium concentrations and the initial volume of the container. Measurement of functional residual capacity with a body plethysmograph, although requiring more complex and expensive equipment, has the

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advantage of rapid measurement and is more accurate in patients with poor gas mixing in the lung (as with significant airway obstruction). Helium dilution will underestimate

FIGURE 82-1. (A) During inspiration, intrathoracic pressure is lower than atmospheric pressure, thus leading to distention of the intrathoracic airways. The extrathoracic portion of the trachea is surrounded by atmospheric pressure and may become narrower. (B) During expiration, intrathoracic pressure is higher than atmospheric pressure, and intrathoracic airways narrow, while the extrathoracic trachea may distend or remain at normal caliber. The dimensional changes on this diagram are exaggerated. The lower airways are not as well supported as the trachea, and their change in size with respiration may be more pronounced. This diagram illustrates that in the presence of partial bronchial obstruction (as by a foreign body), air may be able to enter the lung distal to the obstruction during inspiration but may not exit during exhalation, thus leading to air trapping and overinflation of that part of the lung (obstructive emphysema).

FIGURE 82-2. This spirogram indicates the subdivisions of lung volume. Tidal volume (TV), vital capacity (VC), expiratory reserve volume (ERV), and inspiratory capacity (IC) are relative volumes and can be measured with a simple spirometer. The absolute lung volumes, total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) cannot be determined by use of a simple spirometer but must be measured by gas dilution or plethysmographic techniques.

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functional residual capacity in the presence of airway obstruction; the difference between lung volumes measured by helium dilution and those measured by body plethysmography is the volume of “trapped” gas that does not participate in gas exchange. Flow rates are affected by the neuromuscular and mechanical components of ventilation. The most common measurement of flow is the forced expiratory volume in the first second (FEV1), which is measured with a spirometer (Fig. 82-3). Normally, the FEV1 is at least 80% of the vital capacity. Decreased FEV1 may be due to poor effort or muscle weakness but is usually a manifestation of airway obstruction. The FEV1 may not reflect significant increases in airflow resistance in airways less than about 2 mm in diameter. A spirometric tracing shows expired volume versus time. Plotting the first derivative of the spirometric tracing (i.e., volume per unit time) against expired volume yields the so-called flow/volume curve (Fig. 82-4). From this graphic presentation of the expiratory flow maneuver, inferences may be made about the state of the small and large airways. The slope of the flow/volume curve below approximately 50% of vital capacity is relatively independent of effort. In contrast, the FEV1 is highly effort dependent. Small airway obstruction is manifested primarily by lower flow rates at low lung volumes, thus giving a concave flow/volume curve. Obstruction at the larynx or in the trachea yields a curve with a truncated peak (see Fig. 82-4). Flow/volume curves are ordinarily generated with an electronic pneumotachometer in which flow rate is measured directly and is integrated against time to yield volume. Airway resistance is defined by the pressure required to produce a given flow rate and is expressed in units of centimeters of water pressure per liter per second of airflow. Airway resistance is measured in a body plethysmograph. Airway resistance at low lung volumes is higher than that measured

FIGURE 82-3. This spirogram shows forced expiratory maneuvers. Curve A represents a normal tracing, in which approximately 86% of the vital capacity (VC) is expelled in the first second (FEV1 [expiratory flow rate]/VC = 0.86). Curve B is an abnormal tracing recorded from a patient with airway obstruction (FEV1/VC = 0.49). The administration of a bronchodilator will usually result in an increase in FEV1 in a patient with physiologic airway obstruction.

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at high lung volumes owing to the increase in the diameter of the airways during inspiration. This can be taken into account by multiplying the airway resistance by the lung volume at which the measurements were taken; the resulting measurement is called the specific airway resistance. Measurements of airway resistance primarily reflect changes in the larger, central airways; the peripheral airways, although small, have a relatively large total cross-sectional area and contribute approximately one-fourth or less of the total pulmonary resistance. Another important function of the airways is humidification of inspired air. At 37°C, air saturated with water vapor contains 43 mg of water per liter; at room temperature, air contains only 10–15 mg of water per liter, depending on the relative humidity. Thus, a large amount of water must be added to the inspired air. During normal nasal breathing, a major portion of the humidification occurs in the upper airway (above the glottis), but further warming and humidification take place in the trachea and mainstem bronchi. When the nose is bypassed, by mouth breathing or an artificial airway, the lower airways must assume a much greater role in humidification and warming. Failure to achieve adequate humidification may result in airway obstruction by inspissated secretions.

Important Derangements in Airway Function Mechanical obstruction of the airways may be the result of extrinsic compression (as by mass lesions or enlarged great vessels) but more commonly is due to an intrinsic airway lesion. There are many causes of intrinsic airway obstruction,

FIGURE 82-4. The expiratory flow/volume curve presents the same data as are shown in a conventional spirogram but in a more easily interpreted form. Curve A is a normal tracing in which the peak flow is achieved after 10%–15% of the vital capacity has been exhaled; the remainder of the curve has a nearly constant slope. The tail of the curve is relatively effortindependent. Curve B is a tracing obtained from a patient with lower airway obstruction. Flow rates at low lung volumes are markedly decreased, while the peak flow is maintained at a near normal level. Curve C is a tracing obtained in a patient with high airway obstruction (tracheal or laryngeal) in which the expiratory flow is limited at high lung volumes but not at lower lung volumes. RV, residual volume; TLC, total lung capacity.

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CHAPTER 82 ❖ Physiology of the Larynx, Airways, and Lungs including endobronchial masses, airway stenosis (congenital or acquired), aspirated foreign body, mucosal edema, and increased tracheobronchial secretions. The single most common cause of chronic obstruction is increased secretions associated with decreased airway clearance (as in chronic bronchitis or cystic fibrosis). Physiologic obstruction is most often the result of increased bronchomotor tone (bronchospasm). This is usually transient and reversible but may be intractable and life-threatening (status asthmaticus). In an asthma attack, several mechanisms operate to produce obstruction, including increased bronchomotor tone, increased secretions, increased viscosity of secretions, mucosal edema, and impaired mucociliary transport. Bronchomotor tone is increased by parasympathetic effectors and may be decreased by beta-adrenergic-stimulating agents or by parasympatholytic agents such as atropine. Physiologic airway obstruction may also be the result of decreased bronchomotor tone, which may produce increased compliance of the airway walls. If the airways are too compliant, as in bronchiectasis or bronchomalacia, collapse may occur during exhalation, and air is trapped in the lung. Diffuse distal airway obstruction, as occurs with asthma or bronchiolitis, may lead to airway collapse with air trapping because of the increased intrathoracic pressure generated in the effort to overcome the expiratory resistance. This may to some extent be overcome by partial glottic closure during exhalation (“grunting”) or pursed-lip breathing so that the major pressure drop occurs at the glottis or lips. In much the same way and for the same reasons, an infant with surfactant deficiency grunts to maintain a higher intrathoracic pressure during exhalation. During mechanical ventilation of patients with distal airway obstruction or surfactant deficiency, elevation of the end-expiratory pressure may help maintain airway patency and improve gas exchange. The dynamics of the trachea are different from those of other airways, since part of the trachea lies outside the thorax. The extrathoracic trachea is, in effect, surrounded by atmospheric pressure, which remains constant, in contrast to the intrathoracic trachea, which is surrounded by the varying pressures of the intrathoracic space. The extrathoracic trachea tends to collapse during inspiration, whereas the intrathoracic trachea tends to collapse during expiration (see Fig. 82-1). Thus, a patient with tracheomalacia may have both inspiratory stridor and expiratory wheeze. Relaxation of the smooth muscle of the tracheal wall may increase the compliance of the membranous portion of the wall, which normally tends to invaginate when intrathoracic pressure is increased. Because of this, patients with tracheomalacia may have increased expiratory obstruction after administration of a bronchodilator, owing to loss of tracheal (and large airway) muscle tone.

THE PULMONARY PARENCHYMA The pulmonary parenchyma can be considered to consist of the terminal airways, alveoli, pulmonary capillary bed, and their supporting tissues. The functional unit of the lung is the

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alveolar/capillary interface, across which gas exchange takes place.

Structure Alveoli first appear as outpouchings in the walls of respiratory bronchioles; they are more numerous in the alveolar ducts, which terminate in a cluster of alveolar sacs. Each alveolus is a rough hexagon, with one side open to the alveolar duct. The number of alveoli increases about tenfold from birth to adulthood, when it averages 300–400 million, with a total surface area of 40–100 m2. The alveolar walls, or septa, are composed of two types of epithelial cells, reticular and elastic fibers, a thin basement membrane, and the capillary endothelium. Capillaries make up the majority of the septa. Small holes in the septa between adjacent alveoli (alveolar pores) provide an alternative route for movement of gases. Type I alveolar epithelial cells have a thin cytoplasm through which gases diffuse readily. Type II alveolar epithelial cells are rich in mitochondria and endoplasmic reticulum and actively synthesize and secrete surfactant. The patency of the smallest airways is dependent on the elastic properties of the lung parenchyma, since these airways have no cartilaginous support. When lung elasticity is reduced, as in old age or with emphysema, collapse of the smaller airways during exhalation may result in air trapping and impaired ventilation.

Function and Major Derangements of Pulmonary Parenchyma The major function of the lungs and respiratory system is gas exchange, for which there are three major requirements: pulmonary capillary blood flow, alveolar ventilation, and diffusion of gases across the alveolar capillary membrane. Perfusion Under normal circumstances, the entire right ventricular output passes through the pulmonary arteries before returning to the left atrium. The regional distribution of pulmonary blood flow is regulated by the pulmonary arterioles, which in turn respond to the partial pressure of oxygen in the adjacent alveoli. Alveolar hypoxia results in pulmonary arteriolar constriction, which helps maintain a uniform ratio of perfusion to ventilation. Gravitational effects may also be important, as blood flow to dependent portions of the lung is increased. Ventilation The diaphragm and the accessory muscles of respiration interact with the rigid chest wall to produce the negative intrathoracic pressure that is necessary for flow of air into the lungs. Relaxation of the muscles combined with elastic recoil of the lung parenchyma increases intrathoracic pressure and results in exhalation. Forced exhalation is accomplished by contraction of the abdominal muscles and the internal intercostal muscles. The regional distribution of ventilation depends on several factors: distribution of pressures, distribution of

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resistance and compliance, and rate and depth of respiration. In unilateral diaphragmatic paralysis, intrathoracic pressure on the paralyzed side is less negative, and therefore ventilation is impaired on that side. Areas of the lung with high airway resistance or low compliance are relatively poorly ventilated. At low respiratory frequencies, the distribution of ventilation is relatively even regardless of the distribution of airway resistance; however, as respiratory frequency increases, ventilation is shunted preferentially to the areas of the lung having the lowest airway resistance. Deeper inspirations not only result in a larger tidal volume but also tend to open relatively less compliant areas of lung, thus increasing their ventilation. Compliance is defined as the change in lung volume per unit change in transpulmonary pressure. In practice, compliance is more useful as a concept than as data, since its accurate measurement is relatively complex. Compliance is decreased by the normal elastic forces in the lung and by surface tension in the alveoli as well as by pathologic processes such as pneumonia, pulmonary edema, and interstitial fibrosis. Surfactant reduces surface tension, thus increasing pulmonary compliance. Because the alveoli are so small (the average diameter is approximately 0.25 mm), they have a significant amount of surface tension, which tends to make them collapse. This is countered by the presence of surfactant, which markedly reduces surface tension, especially during deflation of the lung. Surfactant is composed mostly of dipalmitoyl lecithin and a protein component and is synthesized in type II alveolar cells. The metabolic pathway matures at approximately 32–33 weeks in the human fetus, and infants born before that time usually have surfactant deficiency with the clinical syndrome of hyaline membrane disease (respiratory distress syndrome). The stress of birth or prolonged labor results in the induction of the enzymes of this pathway in the immature newborn, as does exogenous administration of corticosteroids. Approximately 24–48 hours are required for full induction of the pathway and synthesis of sufficient surfactant to prevent hyaline membrane disease. Hypoxia and metabolic acidosis interfere with both enzyme induction and surfactant production and may contribute to the development of surfactant deficiency in a mature infant. Surfactant deficiency increases alveolar surface tension and reduces pulmonary compliance, so more inspiratory effort is required to achieve adequate tidal volume. The functional residual capacity is decreased, and many alveoli may become completely atelectatic during expiration. Atelectasis and low functional residual capacity result in intrapulmonary shunting of blood and reduced arterial oxygen tension despite increased inspired oxygen concentrations. Alveolar collapse may be reduced or prevented by application of a constant positive distending pressure to the alveoli (continuous positive airway pressure or continuous negative pressure applied to the thorax). This increases pulmonary compliance and reduces the work of breathing. In patients whose ventilation is being assisted mechanically, positive end-expiratory pressure

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accomplishes the same goal. The maintenance of a constant distending pressure, regardless of the mechanism by which it is produced, has greatly reduced mortality due to neonatal respiratory distress. Constant distending pressure is also used effectively in patients beyond the neonatal period who for some reason have lost surfactant (e.g., as a result of shock lung) or who have poor compliance. Matching of perfusion and ventilation is a factor of major importance in gas exchange. “Wasted” ventilation occurs when areas of lung are ventilated but not perfused, but this does not contribute to arterial desaturation. Wasted perfusion (areas of the lung are perfused but not ventilated) results in arterial hypoxemia by mixing of the unoxygenated pulmonary arterial blood with the pulmonary venous return. Pulmonary arteriolar constriction in response to low alveolar oxygen tension is the most important mechanism for maintaining even distribution of perfusion and ventilation. Ventilation/perfusion mismatching due to uneven distribution of ventilation is the most common cause of hypoxemia. Another major factor in gas exchange is the ratio of anatomic or physiologic dead space to tidal volume. Physiologic dead space is the volume of air contained in the conducting airways that does not reach the alveoli and in the areas of the lung that are ventilated but not perfused. Normally, the dead space is approximately 30% of tidal volume. With disease that decreases the tidal volume or results in wasted ventilation, this ratio increases, and the per minute volume must be increased to maintain the same effective alveolar ventilation. Examples of conditions that may produce an increased ratio of dead space to tidal volume include restrictive lung disease, severe obstructive lung disease, chest trauma, pneumothorax, and hypoventilation due to depressant drugs. The regulation of respiration rate as well as tidal volume can be considered to have three major components: sensors (chemoreceptors and mechanical receptors), effectors (lungs and respiratory muscles), and the controller (the central nervous system). Arterial chemoreceptors in the carotid and aortic bodies respond to changes in the arterial oxygen tension by increasing their output when the arterial oxygen tension decreases. Likewise, acidosis or an increase in arterial carbon dioxide tension results in increased chemoreceptor activity. Central chemoreceptors in the medulla respond to changes in cerebrospinal fluid pH. Since the cerebrospinal fluid bicarbonate concentration equilibrates slowly with that in the blood, the medullary chemoreceptor is essentially a carbon dioxide sensor. With long-standing hypercapnia and metabolic compensation (increased bicarbonate), the response of this chemoreceptor may be blunted, leaving the oxygen receptors as the primary functioning sensor. Since the activity of the peripheral arterial oxygen sensor begins to fall off rapidly as the arterial oxygen tension rises above 100 Torr, it is evident that administering oxygen to chronically hypercapnic patients may deprive them of much of their respiratory drive.

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CHAPTER 82 ❖ Physiology of the Larynx, Airways, and Lungs Pulmonary stretch receptors within the airway smooth muscle are activated by inflation of the lungs and reflexively inhibit inspiration (the Hering–Breuer reflex). Central control of respiration may be a voluntary, cortical function, but automatic respiration is a brain stem function. A number of different nuclei and tracts are involved in the generation of respiratory rhythm, the integration of efferent and afferent signals, and the responses to various respiratory stimuli. Under normal circumstances, arterial carbon dioxide tension is the most important factor controlling overall ventilatory function; as it rises, so does minute ventilation. In most healthy subjects, minute ventilation increases by at least 1 L/min/Torr of carbon dioxide; the sensitivity to carbon dioxide is greater in younger subjects. The hypoxic respiratory drive is a nearly linear function of the desaturation of arterial hemoglobin, even though the chemoreceptors respond directly to changes in arterial oxygen tension. The individual response to hypoxia is variable and may be diminished in patients with chronic hypoxia. Diffusion The final essential component of effective gas exchange is diffusion. Both oxygen and carbon dioxide must diffuse across the alveolar capillary membrane. The rate of diffusion of carbon dioxide is much greater than that of oxygen (by approximately 20-fold) and is usually not limited by diffusion. On the other hand, diffusion of oxygen may be impaired when the alveolar capillary membrane is thickened by disease (e.g., interstitial pneumonitis or fibrosis, or pulmonary edema), and arterial hypoxemia may result. The diffusing capacity of the lung for oxygen (DLo2) is estimated by measuring the diffusing capacity for carbon monoxide (DLco).

PULMONARY DEFENSE MECHANISMS Pulmonary defense mechanisms can be divided into four different categories: mechanical, neurologic, humoral, and cellular.

Mechanical Defense Mechanisms Mechanical defense mechanisms begin at the nares, where the nasal hairs provide an important filtration function for large particulates. Turbulent airflow over the turbinates results in the deposition of many particles on the nasal mucosa. The particles that survive in the airstream beyond the nose (usually smaller than about 10 µm) are then trapped in the mucus layer lining the airways, either by impaction or (in peripheral airways) by sedimentation. The depth to which particles penetrate the lung is a function of the size and density of the particles. Particles trapped in the mucus layer are removed from the lung by mucociliary transport, coughing, or both. Particles that reach the alveolar spaces are removed by phagocytic cells. Another vitally important mechanical defense is cough, which may remove aspirated fluid as well as particles and secretions.

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1413

Mucociliary transport serves to remove not only inhaled particulate matter but also secretions and cellular debris from the airways. The importance of mucociliary transport in maintaining pulmonary homeostasis is emphasized by patients with immotile cilia, who have chronic bronchitis, sinusitis, and bronchiectasis at an early age. These patients also have chronic otitis because of failure of ciliary transport in the Eustachian tube. Effective mucociliary transport requires the concurrent function of a number of elements, including the number and distribution of cilia (or ciliated cells). Areas of squamous metaplasia may occur after various forms of insult and result in diminished mucus transport. Ciliary beat frequency (normally 15–20 beats per second) and the direction of coordinated ciliary beat are important aspects of effective mucociliary function. The mucus layer (sometimes referred to as the “gel” layer) floats on the periciliary fluid and is propelled along by the tips of the cilia. High viscosity and effective intermolecular cross-bridging between the adjacent mucous glycoprotein molecules are necessary for effective mucociliary transport. This has clinical relevance, since the administration of mucolytic agents such as N-acetylcysteine may liquefy mucus and result in pooling of secretions rather than normal clearance. The periciliary fluid must have appropriate viscoelastic properties and must be of the correct depth. If this layer is relatively dehydrated, the tips of the cilia may be crushed by the overlying mucus. If this layer is too deep, the mucus may float above the tips of the cilia. In either case, mucociliary transport is impaired. Many extrinsic factors may affect mucociliary transport. Trauma to the mucosa, as may occur with intubation or bronchoscopy, may impair transport until the mucosal damage has been repaired. Some viral infections, particularly influenza, produce a marked sloughing of ciliated cells, and many weeks may be required to achieve normal function again (which may explain the high incidence of bacterial superinfections associated with influenzal pneumonia). Bacterial infection or nonspecific inflammation may also interfere with mucus transport. Dehydration of the tracheobronchial secretions reduces mucociliary transport. Thus, it is important to provide additional humidification of inspired air when normal humidification is impaired (as during intubation). Cigarette smoking and many disease states also interfere with effective mucociliary function. These include chronic bronchitis, cystic fibrosis, asthma, vitamin A deficiency, and immotile cilia syndrome. Mucociliary function may be improved by the administration of beta-adrenergic-stimulating agents, by restoring normal humidification, by correcting nutritional or metabolic abnormalities, and by eliminating extrinsic factors such as cigarette smoking.

Neurologic Defense Mechanisms Neurologic pulmonary defense mechanisms primarily involve avoidance reflexes. A noxious odor stimulates bronchospasm

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or even apnea to reduce the penetration of the offending material into the lung. On a more integrated basis, an organism will attempt to remove itself from a noxious environment. Cough is also a neurologic defense mechanism in that it is a reflex involving the participation of the larynx, airways, and respiratory musculature and may be impaired by blocking of the sensory pathways.

Humoral Defense Mechanisms Humoral defense mechanisms in the lung involve both local and systemic immune responses. Secretory immunoglobulin, produced locally in the upper airways, does not fix complement, nor does it have much opsonizing activity, but it is important in neutralization of viruses and toxins. In addition, it may agglutinate bacteria and reduce bacterial attachment to tissue. Large amounts of lysozyme are secreted in the epithelium of the upper airways and may be important in antibacterial defenses. In the lower airways, IgG is the predominant immunoglobulin. There is both local production (mediated by the bronchial-associated lymphoid tissue) and transudation from the vascular bed. Other proteins, such as IgM and complement, are found in small quantities in the pulmonary secretions, but all proteins enter the secretions more readily in the presence of inflammation.

Cellular Defense Mechanisms The cellular defense mechanisms of the lung include alveolar macrophages, lymphocytes, and polymorphonuclear leukocytes. The alveolar macrophage is derived from blood monocytes, which are in turn derived from the bone marrow. The alveolar macrophage is a highly specialized cell and, in contrast to macrophages elsewhere in the body, is critically dependent on oxidative metabolism, becoming essentially nonfunctional at oxygen concentrations less than about 25 mm Hg. Alveolar macrophages are primarily responsible for removal of particulate debris, including dead or damaged cells, from the alveoli and terminal airways. Alveolar macrophages depend to a great extent on chemotactic factors produced by lymphocytes, which invite macrophages (and neutrophils) into the lung and then make them feel at home. Mechanical factors may also result

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in mobilization of macrophage-particulate loads (such as are produced with cigarette smoking), which leads to a great increase in the number of macrophages recoverable from the lung by saline lavage. Activation of macrophages by lymphocyte factors results in increased production of lysosomal enzymes, enhanced phagocytosis, and other phenomena. Alveolar macrophages may in turn stimulate lymphocytes by initial processing of antigens to which the lymphocytes then respond specifically. Macrophages are very important in killing intracellular organisms (such as Mycobacterium and Toxoplasma organisms) as well as fungi, bacteria, and viruses. Activated macrophages are capable of recognizing and killing tumor cells. Infections or other inflammatory reactions in the lung attract large numbers of polymorphonuclear leukocytes. These cells may be more important in dealing with established infection than are alveolar macrophages, since they are less dependent on oxygen and thus can operate within masses of secretions or hypoxic tissue.

Selected References Afzelius BA. The immotile-cilia syndrome: a microtubule-associated defect. Crit Rev Biochem. 1985;19:63. Berger AJ, Mitchell RA, Severinghaus JW. Regulation of respiration (three parts). N Engl J Med. 1977;29:194. Derene JPH, Macklem PT, Roussos CH. The respiratory muscles: mechanics, control, and pathophysiology (two parts). Am Rev Respir Dis. 1978;118:119. Ellis H, Feldman S. Anatomy for Anaesthetists. 3rd ed. Oxford, UK: Blackwell Scientific Publications; 1977. Proctor DF. The upper airways. I. Nasal physiology and defense of the lungs. Am Rev Respir Dis. 1977;115:97. Proctor DF. The upper airways. II. The larynx and trachea. Am Rev Respir Dis. 1977;115:315. Thurlbeck WM. Postnatal growth and development of the lung. Am Rev Respir Dis. 1975;111:803. Wanner A. Clinical aspects of mucociliary transport. Am Rev Respir Dis. 1977;116:73. Waterer GW. Airway defense mechanisms. Clin Chest Med 2012;33:199–209. West JB. Ventilation-perfusion relationships. Am Rev Respir Dis. 1977;116:919. Wilmott RW, Khurana-Hershey G, Stark JM. Current concepts on pulmonary host defense mechanisms in children. Curr Opin Pediatr. 2000;12:187.

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83

C H A P T E R

Methods of Examination of the Pediatric Airway David Albert and Peter Bull

OVERVIEW AND DEFINITIONS This chapter discusses the various methods that can be used to gain information about the pediatric airway depending on the context. As always, a thorough history and examination precede and determine the choice of special investigations. The chapter covers the airway from the supraglottis to the main bronchi and excludes the examination of the nasopharynx and distal airways. Though the definitive assessment remains a formal microlaryngosopy and tracheobronchoscopy, many other techniques of assessment are used. The chapter attempts to help with selection of the appropriate investigation in a logical sequence.

Historical Perspective Early attempts at examination of the living airway were impeded by inadequate oro-pharyngeal and laryngeal anesthesia and the absence of good lighting. In 1807, Bozzini published the description of a laryngeal speculum with two mirrors (one for lighting, the other for vision—quite unnecessary of course) with a candle for illumination, but there is no record of his having seen the larynx with this device. In 1829, still long before the days of electric lighting, Benjamin Babington of Guy’s Hospital, London, described the glottiscope, a laryngeal mirror with an attached tongue depressor, but he recorded no cases and had no pupils who took it up. It was not until 1854 that Manuel Garcia realized, having seen reflections in half-open windows while visiting Paris, that the same mirror could be used both to illuminate the throat and to inspect it. He used a dental mirror that had been shown unsuccessfully at the Great Exhibition in London in 1851 and because he was a professional singer with great control over his pharynx, he was able to place this mirror against his palate without gagging, with sunlight reflected onto his laryngeal mirror. He saw “to my great joy, the glottis wide open before me.” This discovery was rapidly accepted and used in Europe, particularly in Vienna and Budapest, though it was slower to gain acceptance in Britain. However, Morrell Mackenzie and his one-time protégé Felix Semon became expert in its use both diagnostically and therapeutically. By 1858, the use of the laryngoscope had spread to the USA with early pioneers being Krackowizer and J Solis Cohen. Chevalier Jackson in Philadelphia in the late 1880s designed a range of rigid instruments for direct examination

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of the larynx and bronchi, and these were subsequently modified by Sir Victor Negus and his colleague in London, Sir St. Clair Thomson. Developments of these early instruments still form the basis of modern laryngoscopes. The concept of laryngeal suspension by Kleinsasser in 1964 allowed the use of an operating microscope and bimanual surgery. It was the invention by Harold Hopkins of a telescope utilizing rod lenses that revolutionized endoscopy of all types and his first instrument, a cystoscope designed in collaboration with Karl Storz, was shown in 1967. Meanwhile, John Logie Baird had been working on the transmission of images through a fiber-optic bundle on which he took out a patent in 1928. He subsequently went on to develop an early form of television. This was superseded by increasingly sophisticated and miniaturized television systems that have led us to the present era of high definition TV and recording. Logie Baird’s early experiments in fiber-optic technology led ultimately to the high definition and small caliber flexible scopes in modern use.

SELECTION OF APPROPRIATE METHOD OF EXAMINATION Usually, a sequence of progressively invasive methods of examination will be used, determined by the working diagnosis based on the context of the child’s illness, the child’s history, and the findings at initial examination. The severity of the airway obstruction will to a large extent dictate what action needs to be taken and with what degree of urgency.

Context Many cases of acute airway obstruction will present to the emergency department and staff working in such an area must be completely familiar with airway assessment and management. It would be expected that all the necessary resuscitative equipment would be immediately available. Sometimes, problems will arise, either anticipated or unexpectedly, in other areas of clinical activity such as the inpatient ward or outpatient clinic and it is essential that the staff know how and when to call for expert help. Equipment may not be as immediately available as it would be in an emergency room or operating department. A neonatal intensive care unit (NICU) or special care baby unit (SCBU) would be expected to be adequately staffed, equipped, and trained to deal with airway management.

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Pattern of Stridor

HISTORY Perinatal History The obstetric and perinatal history is often relevant. This is particularly true if the child was born prematurely and required ventilation. Few neonates over 32 weeks’ gestation will require ventilation for respiratory distress syndrome. Ventilation is the norm for those delivered at 28 weeks or earlier, even with the administration of surfactant. Neonates admitted even for short periods to intensive care or special care baby units (SCBUs) may have had endotracheal intubation without the parents volunteering this important information. Beware the term “intubation,” as this may be mistaken for the passage of nasogastric tubes or suction for nasal and oral mucus extraction.

History of Stridor Stridor must be differentiated from stertor, which results from partial obstruction of the airway above the level of the larynx and has a snoring quality, lower pitched, and variable. Stridor results from turbulence within the more rigid air passages lower down the tract. Stridor that is present at birth with the child’s first breath is unusual. It generally denotes a fixed congenital narrowing such as a laryngeal web, subglottic stenosis or tracheal narrowing.1 Dynamic conditions such as laryngomalacia become evident in the first few weeks of life. The stridor in congenital vocal cord palsy is often present immediately postpartum. A gradual increase in severity of stridor or airway compromise implies growth of an obstruction that may be luminal as in a subglottic hemangioma or extrinsic as with a mediastinal mass.

Stridor is seldom constant. Any diurnal or other variation can help pinpoint the cause, though asking parents about the timing of stridor in the respiratory cycle is seldom profitable. Typically laryngomalacia is better with the child at rest and asleep but made worse by crying, feeding, and when the child is distressed. Airway obstruction with the baby supine can occur with a pedunculated laryngeal mass but more often is due at least in part to a degree of supralaryngeal obstruction such as micrognathia and resultant tongue base occlusion. Improvement in the airway with crying occurs in gross nasal obstruction such as bilateral choanal atresia.

Associated Features Airway obstruction produces a number of associated symptoms (Table 83-2) alongside stridor including recession, apnoeas, cyanosis, “dying spells,” dyspnoea, tachypnoea, cough, and hoarseness. Recession, even if quite severe, can be missed by parents but is a clear sign of inspiratory obstruction. Apnoeas with cyanosis are typical of severe tracheobronchomalacia and are sometimes termed “dying spells.” Parents will usually attempt resuscitation if the attacks are severe. It is often unclear how many of these attacks would otherwise be self-limiting. Tachypnoea and dyspnoea are not limited to upper airway obstruction but a clear description of exertional dyspnoea in an older child provides a useful functional assessment of severity. Cough is typical of tracheooesophageal fistula and of tracheomalacia. It may occur as a result of gastrooesophageal reflux, and is rarely due to “infant asthma.” Hoarseness clearly suggests a laryngeal lesion such as laryngeal papillomatosis but is also seen in vocal cord palsy.

TABLE 83-1. Nasopharyngeal Causes of Airway Obstruction Common

Acquired

Congenital

Neonates Neonatal rhinitis Choanal atresia/stenosis Craniofacial abnormalities Micrognathia

Neonates Syphillis Neonatal rhinitis

Children Allergic rhinitis Adenoiditis Adenotonsillar hypertrophy Foreign Bodies

Children Allergic rhinitis Adenoiditis Adenotonsillar hypertrophy Foreign bodies Nonallergic rhinitis NARES (Nonallergic rhinitis with eosinophilia) Retropharyngeal abscess Glandular fever Ludwig’s angina Thermal and caustic burns

Choanal atresia Choanal stenosis Mid nasal stenosis Piriform aperture stenosis Nasal glioma Encephalocoele Meningocoele Nasopharyngeal mass Hairy polyp/ Teratoma Craniofacial abnormalities with small nasopharynx Micrognathia Pierre Robin Treacher-Collins Macroglossia Downs Cystic hygroma Lingual thyroid

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CHAPTER 83 ❖ Methods of Examination of the Pediatric Airway 1417 TABLE 83-2. Laryngeal Causes of Airway Obstruction Common

Acquired

Congenital

Neonates Laryngomalacia Intubation trauma Reflux laryngitis Laryngotracheal stenosis Vocal cord palsy

Neonates Intubation trauma Surgical trauma e.g., laser Laryngotracheal stenosis Arytenoid fixation Reflux laryngitis

Laryngomalacia Posterior laryngeal cleft Vallecula cyst Laryngeal cysts Webs Laryngeal atresia Laryngotracheal stenosis Arytenoid fixation Vocal cord palsy

Children Croup Hemangiomas Papillomatosis Intubation trauma Vocal cord palsy Papillomatosis

Children Epiglottitis Croup Bacterial tracheitis Hereditary angioedema Epidemolysis bullossa Foreign bodies Dislocated arytenoid Intubation trauma Fracture Caustic and thermal burns Hemangiomas Cystic hygroma Papillomatosis Rhabdomyosarcoma Wegeners

TABLE 83-3. Tracheal Causes of Airway Obstruction Common

Acquired

Congenital

Neonates Tracheobronchomalacia Tracheal stenosis Vascular compression

Neonates Postintubation and endoscopy Tracheal stenosis Reflux tracheitis

Children Foreign bodies Tracheal stenosis

Children Laryngotracheitis Bacterial tracheitis Foreign bodies Localized malacia secondary to a tracheostomy or tracheo-esophageal fistula (TEF) repair Thyroid Cystic hygroma Mediastinal tumors

Stenosis Atresia Trapped first tracheal ring Complete cartilage rings Micro (stovepipe) trachea Tracheal cysts Hemangiomata Tracheobronchomalacia (with TEF) Vascular compression Aberrant innominate Pulmonary artery sling Double aortic arch

Feeding History Feeding is closely connected with breathing, particularly in the infant. An accurate picture of the feeding pattern must be obtained. Breast-fed babies with airway obstruction will characteristically “come up for air”; bottle-fed babies may require thickened feeds or a “slow teat” (i.e., one with small holes).

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Aspiration suggests a vocal cord palsy, tracheooesophageal fistula, or rarely a cleft larynx. Significant repeated aspiration may be associated with recurrent chest infections. Regurgitation (“posseting”) is common in neonates and by itself may not represent significant gastrooesophageal reflux. The end result of poor feeding may just be slow feeding that troubles the mother

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more than the child or there may be failure to thrive with demonstrably poor weight gain. A carefully plotted growth chart is invaluable in identifying a child who is sliding down the growth centiles. Even in the presence of laryngomalacia, it is important to consider other causes of failure to thrive.

General Medical Conditions Enquiry into the general medical history may explain a vocal cord palsy occurring as a result of neurological disease or cardiac surgery or may suggest vascular compression associated with congenital cardiac disease. Finally ask the parents about the presence of any vascular birthmarks, as they may be associated with a subglottic hemangioma.

EXAMINATION Observation Observing the child at rest before proceeding to formal examination provides not only an initial assessment of the degree of respiratory distress and the characteristics of any

stridor but also gives time to gain the child’s confidence. The characteristics of the stridor need to be observed as well as the effects of airway obstruction such as recession. Abnormal voice, wheeze, or cough are useful localizing signs. The pre-endoscopy assessment, though important, can only be a guide to the type and degree of pathology discovered at endoscopy. The combination of a thorough history, examination, and limited investigation can in some conditions (e.g., mild laryngomalacia) provide sufficient diagnostic probability to avoid initial endoscopy. The nature of the stridor may be characteristic of a particular pathology but is never diagnostic2; A second pathology may be present in up to 20% of cases though few will require treatment.3 The diagnosis can only be confirmed with certainty after endoscopy. This does not mean that every child with stridor requires endoscopy. In most children seen in a secondary or tertiary referral center, diagnostic endoscopy will be required and in most conditions is the definitive investigation. Dynamic conditions such as vocal cord palsy and tracheobronchomalacia often prove difficult to confirm or exclude at routine endoscopy.

TABLE 83-4. Symptoms Associated with Varying Causes of Airway Obstruction Symptoms

Typical Diagnoses

Stertor

Nasopharyngeal obstruction

E.g., Neonatal rhinitis

Inspiratory stridor

Laryngeal and subglottic obstruction

E.g., Laryngomalacia, subglottic stenosis

Biphasic stridor

High/mid tracheal obstruction

E.g., Tracheomalacia/stenosis

Prolonged expiratory phase

Tracheal and bronchial obstruction

E.g., Tracheobronchomalacia or stenosis

Cough

TEF Vocal cord palsy Cleft larynx Foreign body Tracheomalacia Reflux

Aspiration

TEF Vocal cord palsy Cleft larynx

Hoarseness

Laryngeal lesion

Acute airway obstruction

Retropharyngeal abscess Tonsillitis Glandular fever Foreign bodies Epiglottitis Croup Bacterial tracheitis

Dysphagia and feeding difficulties

Epiglottitis Tonsillitis Retropharyngeal abscess

Apneas Dying spells

Tracheobronchomalacia Reflex apnea

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E.g., Vocal cord palsy, papilloma

Feeding affected with many causes of severe airway obstruction and aspiration

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CHAPTER 83 ❖ Methods of Examination of the Pediatric Airway 1419

Characteristics of Stridor The characteristic sound of stridor even in a common condition such as laryngomalacia4 is so variable as to be of little diagnostic use on its own. The site of the abnormal vibration can rarely be tracked down with the aid of a stethoscope, because of the variable transmission of sound through the thorax. Auscultation is useful to detect heart murmurs and wheeze. If a baby is in an incubator, it is difficult to hear the stridor. A useful trick is to remove the end from a cheap stethoscope and listen through the open tubing. Typically, inspiratory stridor is due to an extra-thoracic obstruction (Fig. 83-1) in the larynx or high trachea. Bronchial or low tracheal obstruction produces an expiratory stridor. Biphasic stridor can occur with obstruction anywhere in the tracheobronchial tree. Even if expiratory stridor is absent, a prolonged expiratory phase may be present indicating an intrathoracic obstruction (Fig. 83-2). Laryngomalacia is said to have a “musical quality,” vocal cord palsy a “breathy quality.” The cough in tracheomalacia is said to be “barking.”

Associated Features Subcostal, intercostal, and suprasternal recession may occur separately or together and also be associated with “see-saw” respiration where there is paradoxical movement of the chest and abdomen. The severity of recession is a better indicator of the severity of airway compromise than the degree of stridor. The severity of stridor can paradoxically become less as obstruction worsens due to the diminishing airflow. No comfort should be taken from the fact that a child still looks pink. Cyanosis is a late event and suggests obstruction has been severe or prolonged. If a supralaryngeal component is suspected, nasal patency should be assessed with a mirror, a wisp of cotton wool, or using the bell end of a stethoscope. Make a conscious assessment of jaw and tongue size. Both stridor and recession will vary as the child rests, cries, or sleeps but it is rare to be able to demonstrate a similar

– ve

– ve – ve

Extra-thoracic

Intra-thoracic

Figure 83-1. Collapse and increasing obstruction on inspiration with extra-thoracic obstruction

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Extra-thoracic

Intra-thoracic

+ ve

+ ve

+ ve + ve

+ ve + ve

Figure 83-2. Collapse and increasing obstruction on expiration with intra-thoracic obstruction

repeatable change with position. However, stertor in cases of micrognathia will be relieved by holding the jaw forward. Observing the child feeding is very valuable particularly if there is poor feeding or aspiration. Examine the ears, nose, throat, and neck last, with the usual caution that you must not use any instrumentation to examine the throat of child in whom epiglottitis is suspected as this may trigger fatal laryngeal spasm.

INVESTIGATIONS Outpatient Assessment Flexible Endoscopy in the Office or Ward The introduction of ultrathin endoscopes15–17 with good optics and a diameter of less than 2 mm has allowed even neonates to be endoscoped (examined) without the need for a general anesthetic. Peroral passage of an endoscope using a finger between the child’s gums to protect the instrument is preferred by many to trans-nasal introduction, and is often better tolerated in the neonate. This is usually considered a screening procedure. The view particularly of the larynx is often suboptimal. No invasive diagnostic or therapeutic procedure can be undertaken and even if an abnormality is demonstrated (such as laryngomalacia) a second pathology more distally can easily be missed. Flexible endoscopy on the ward without anesthesia is particularly useful to assess dynamic abnormalities such as vocal cord palsy prior to a formal endoscopy in the operating room. Flexible endoscopy under sedation in an endoscopy suite is widely practiced by pediatricians and pulmonologists18–20 and is becoming more popular with otolaryngologists as an adjunct to rigid endoscopy.21 Informal Exercise Tests A simple but informative test of respiratory function is to observe the degree of dyspnoea, recession, or stridor after walking on the flat or climbing stairs.

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Imaging

Fitness to Fly Test

The value of radiological investigations has been reviewed retrospectively by Tostevin et al.5 A plain chest X-ray and a lateral view of the neck digitally enhanced to demonstrate the subglottis, oropharynx, and nasopharynx may be all the radiology required. The Cincinnati view (high kV filtered view) has been superseded by digital manipulation of the image. A plain chest X-ray may show the ground glass appearance of bronchopulmonary dysplasia or mediastinal shift with obstructive emphysema of a foreign body but it does not demonstrate the major airways well. If a foreign body is suspected in young children, diaphragmatic screening with videofluoroscopy is a more sensitive technique but exposes the child to a greater amount of ionizing radiation. In older children, inspiratory and expiratory films may demonstrate diaphragmatic immobility on the side of the obstruction. With experience, ultrasound of the vocal cords can be used to demonstrate vocal cord palsy with reasonable accuracy to complement the endoscopic findings.38 Computerized tomography and MRI8,9,10 are not usually sufficiently sensitive to characterize fully a stenotic segment, which can be more accurately assessed at endoscopy. If available, helical CT with multiplanar reconstruction may offer better definition of tracheal lesions.11,12 MRI and CT can demonstrate extrinsic compression, particularly by abnormal vasculature. Echocardiography can be used to screen for vascular compression demonstrating most but not all abnormal vasculature, as well as coincidental or symptomatic congenital heart disease. Videofluoroscopy is an excellent dynamic way of demonstrating tracheomalacia. It can be combined with a contrast swallow to look for vascular compression6,7 and aspiration. Bronchography is enjoying something of a renaissance after the introduction of safer nonionic contrast media. It is particularly useful for the lower airway demonstrating tracheobronchial stenosis and malacia. Opening pressures of the collapsed bronchi and lower trachea can be measured and used to determine the level of airway support needed.

The test measures cutaneous oxygen levels using pulse oximetry during controlled hypoxia to simulate conditions of a pressurized aircraft cabin. The usual indication would be in children with bronchopulmonary dysplasia.

Endoscopy The two essentials in pediatric airway endoscopy are safety and accuracy (Table 83-5). To achieve these requires not only a full range of specialized pediatric endoscopy equipment, but also most significantly a high level of experience in the endoscopist, anesthesiologist, and nursing staff. A systematic approach will provide a diagnosis in most cases.14 Laryngotracheobronchoscopy Laryngotracheobronchoscopy (LTB)22,23 (Fig. 83-3) using rigid Hopkin’s rod telescopes is the definitive investigation in the assessment of the stridulous child. It is now a highly technical procedure. The whole team (surgeon, anaesthetist, and nursing assistant) needs to work closely together to perform the examination safely, and to optimize the assessment. The advent of video and high-quality image reproduction on a viewing monitor has been invaluable in training. Assessment is now safer as the anaesthetist can see the image on screen and the team can be ready with equipment for the next stage. If the examination is for assessment, it is vital that accurate records are kept to allow comparison with future examinations. This is facilitated by using a standardized data capture form within a department.24 Use of a recognized staging system is important for publication of results. Prints from the video form a valid record for static conditions, whilst for dynamic conditions a video recording is unparalleled. The latest digital image recording TABLE 83-5. Indications for Airway Endoscopy • Known or suspected foreign body

Respiratory Function Tests

• Significant airway obstruction

Lung function tests such as flow-volume loops will help to localize the site of obstruction but require a degree of patient cooperation. Other lung function tests such as peak flows or more ventilation/perfusion scans are selected with the advice of a pulmonologist.

• Worsening airway obstruction

Sleep Studies Airway obstruction that worsens during sleep is usually a feature of pharyngeal obstruction such as adenotonsillar obstruction or a craniofacial anomaly. Occasionally however, laryngomalacia13 and indeed almost any laryngotracheal pathology can be worse during sleep and mimic snoring.

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• Hoarse voice • Diagnostic uncertainty • Associated features: • Dysphagia • Aspiration • Failure to thrive • Cyanotic attacks • Radiological abnormality

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CHAPTER 83 ❖ Methods of Examination of the Pediatric Airway 1421 anesthesia. The risk of this can be minimized by ensuring adequate depth of anesthesia or on occasion intravenous suxamethonium (0.5 mg/kg, max dose 100 mg) can be given if the patient is stable.

Figure 83-3. Laryngotracheobronchoscopy in progress.

systems allow multiple rapid images to be stored during the procedure with only a selected few being printed or converted to slide format. As computer memory becomes even more affordable, digital video recordings as well as still images can be saved and archived. This provides an invaluable source of information for sequential clinical comparisons, medico-legal purposes, and teaching. The latest high-definition television is unparalleled in clarity. Anesthesia for Airway Endoscopy AnesthesiA for AirwAy endoscopy Major units from around the world use different techniques, and it is probably more important that a team of surgeon, anaesthetist, and nurse work together than that one particular technique is followed. Practice varies between centers as to whether intubation is used at the start of the procedure but most units would now use spontaneous respiration rather than paralysis and jet ventilation. induction Some units will use an atropine premedication to facilitate a dry surgical field and improve the efficacy of topical anesthesia. Optimally, atropine (20 μg/kg, max dose 500 μg) should be given by intramuscular injection 30 minutes before surgery. Alternatively, it may be given orally (40 μg/ kg max. dose 500 μg) though variable absorption makes this route less reliable. Anticholinergic drugs (usually given IV) play a vital role in reducing vagally induced bradycardia and no surgical procedure should be started until venous access is secure. The administration of corticosteroids at induction (dexamethasone 250 μg/kg, max dose 8 mg) is a good safeguard if significant stenosis is suspected and have powerful antiemetic properties when combined with 5-HT receptor antagonists. Intravenous induction is preferable for older children though inhalational induction may be needed in infants, those with poor venous access and those with a precarious airway. Topical lidocaine spray (3–5 mg/kg, max dose 160 mg) to the larynx, subglottis, and trachea needs to be carefully measured as the concentrated preparations used for adults can easily result in overdosage.25,26 Laryngeal spasm is a potential hazard when administering topical local

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intubAtion This is rarely used as it is important to visualize the larynx prior to an instrumentation. However, once intubated, the child can be quickly ventilated down to a level of anesthesia, which allows the passage of endoscopes without gagging but maintains spontaneous respiration. The laryngoscope can be adjusted whilst the child is still intubated. Nasotracheal intubation allows the endotracheal tube to be withdrawn into the nasopharynx once the child is breathing spontaneously. It is useful to learn the technique of reinserting the tube without removing the surgical laryngoscope by using curved laryngeal forceps to guide the tube gently back into the glottis. nonintubAtion technique After induction, the child is breathed down to the same depth of anesthesia as above which in the presence of any obstruction can take some time. The advantage is that the endoscopist has a view of an airway that has not been altered by the passage of an endotracheal tube. At any time, airway control can be regained with intubation or the use of an endoscope. Jet VentilAtion This technique allows the child to be paralysed, thereby preventing any coughing or gagging, but gas exchange is maintained with short pulses of injected anesthetic gas, simulating normal respiration.27–29 The pressures required30 are higher than physiological levels with a risk in neonates and smaller children of a pneumothorax. Few centers now use this technique as dynamic conditions such as malacia and cord palsy cannot be identified. lAryngeAl MAsk This is useful for fiber-optic bronchoscopy particularly if the patient is difficult to intubate because of mandibular hypoplasia.31,32 trAcheotoMy tube AnesthesiA The tracheostomy tube is used to deliver inhalation agents during the examination of the larynx and subglottis. It is removed to allow examination of the stomal area and lower trachea. If necessary, inhalational anesthesia is maintained with a nasopharyngeal airway or a ventilating bronchoscope. MAintenAnce of AnesthesiA The ideal conditions for a surgeon to examine the airway is deep inhalational anesthesia with preservation of spontaneous respiration, as this allows a dynamic assessment. Overpressure using inhalational agents such as sevoflurane and halothane in oxygen can maintain a level of anesthesia that allows a thorough and prolonged examination of the airway without coughing, waking, or apnea. Halothane had the great advantage that it was relatively nonirritant to the airway but is no longer widely available.

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Sevoflurane33 is also nonirritant but has the advantage of rapid onset and no pungency allowing delivery of high concentrations quickly. Care needs to be taken during periods of relative hypoventilation or airway obstruction as there is a rapid termination of the anesthetic effect risking waking and coughing. The anaesthetist needs to be able to control anesthesia in response to surgical conditions and for this a video monitor is invaluable. Alternatively, total intravenous anesthesia may be employed using a combination of propofol and remifentanil by infusion. Peroperative SpO2 monitoring is now routine34 and in time CO2 monitoring is also becoming routine. Microlaryngotracheoscopy Technique The following description assumes that the patient has been intubated, a suspension laryngoscope is employed, and that the larynx is to be examined with a microscope or a rigid telescope. A small sandbag is usually required under the shoulders to prevent hyperextension of the neck, with sandbags laterally to support the long thin heads of ex-premature neonates. A Mayo table supports the laryngostat clear of the chest. Alternatively, for small infants, a flexible arm attached to the table supports the laryngoscope without any pressure on the still mobile premaxilla. It is important to prepare and check all equipment prior to the endoscopy so that the endoscopist is fully prepared for all eventualities. The range of Hopkins rod telescopes should include all lengths and diameters that could be needed and a 30° telescope to assess the supraglottic larynx without splinting. A microscope should be available though is often not used unless surgical intervention is required when two hands are needed for manipulation. If a microscope is used, a 400 mm lens allows the use of standard laryngeal instruments but a 350 mm lens brings the patient closer allowing easier manipulation of larynx, which is particularly important in small neonates. For routine examination, the telescope and camera can be held in the left hand with a probe used in the right. The view and images available are far superior to those through the microscope. Every unit should have a chart listing the appropriate sizes of bronchoscope for different ages. The age-appropriate bronchoscope needs to be checked and one at least a size smaller has to be instantly available as well. Antifog solution is only effective if freshly applied to the telescope lens. Laryngeal examination is usually begun without an endotracheal tube in place by gently inserting the lubricated suspension laryngoscope, taking care to protect the teeth and lips and to keep the tongue central to provide a well-centered view. Some surgeons prefer to use a hand held anesthetic laryngoscope. As in adults, it is important to check the overall appearance of the supraglottis and laryngopharynx during introduction of the laryngoscope. A probe is used to move the arytenoids independently assessing the mobility of each cricoarytenoid joint. If an

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interarytenoid scar is present, the arytenoids will not move independently. A posterior laryngeal cleft is excluded by passing the probe between the arytenoids, comparing the lower limit of the interarytenoid groove with that of the posterior commissure. Finally move the cords need to be gently moved apart to inspect the subglottis. The time available for the examination will depend on the airway. In a child breathing spontaneously with a normal airway and normal lung function, anesthesia can be maintained solely by the use of inhalational agents with the endotracheal tube withdrawn into the pharynx. In others, the time may be very limited and it is essential to be prepared to move ahead with bronchoscopy at any stage. If anesthesia is stable, a sucker can be placed in the laryngeal inlet to mimic laryngomalacia—the “Narcy test.” Photographs can be taken at this stage with a wide Storz photographic telescope. If there is significant subglottic stenosis, an ultrafine telescope passed through the laryngoscope will cause less trauma than a bronchoscope. Tracheobronchoscopy Traditionally, a ventilating bronchoscope (Fig. 83-4) has been used which provides a means of actively ventilating the patient if required. With spontaneous ventilation, a smaller diameter rigid Hopkins rod telescope can be used with less trauma and less splinting of the airway. An age-appropriate bronchoscope is used unless stenosis is suspected. Neonates pose particular problems if manipulation of the airway is required.35,36 An anesthetic laryngoscope can be used in the vallecula to lift the larynx forward whilst passing the bevel of the bronchoscope through the vocal cords under video control on the monitor. The main bronchi, the carina, the trachea, and the subglottis are all systematically examined and videographs or digital images recorded. Tracheomalacia should be observed with a small bronchoscope withdrawn from the area in question and without positive airways pressure to avoid splinting. The ratio of cartilage to membranous trachea

Figure 83-4. Ventilating bronchoscope.

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CHAPTER 83 ❖ Methods of Examination of the Pediatric Airway 1423 is significant in recording the type of malacia and in judging if aortopexy is likely to be successful. Dynamic Assessment of Larynx on Recovery from Anesthesia Typically, this can be achieved by withdrawing the bronchoscope to just posterior to the tip of the epiglottis. This affords a good view of the vocal cords to exclude a cord palsy and of the arytenoids to exclude the common posterior form of laryngomalacia, though anterior collapse of the epiglottis may be masked. In this case, a 30° or 70° telescope should be used. The anaesthetist should call the phase of respiration to check for paradoxical vocal cord movements. An excellent technique for dynamic assessment of the vocal cord movement is to insert a brain laryngeal mask airway with a fiber-optic bronchoscope passed through this to just above the laryngeal inlet.37 If a bilateral vocal cord palsy is suspected and structural abnormalities have been excluded with a full microlaryngoscopy and rigid bronchoscopy, it is sometimes necessary to reschedule the patient for a further examination in which a laryngeal mask and fiber-optic scope are used from the outset, reducing the influence of prolonged anesthesia on the cord function. An alternative is to use a 30° scope that gives a view of the larynx without splinting the supraglottis.

References 1. Pedraza Pena LR, Rodriguez Santana JR, Sifontes JE. Neonatal stridor: a life-threatening condition. P R Health Sci J. 1994;13(1):33–36. 2. Papsin BC, Abel SM, Leighton SE. Diagnostic value of infantile stridor: a perceptual test. Int J Pediatr Otorhinolaryngol. 1999;51(1):33–39. 3. Mancuso RF, Choi SS, Zalzal GH, Grundfast KM. Laryngomalacia. The search for the second lesion. Arch Otolaryngol Head Neck Surg. 1996;122(3):302–306. 4. Nussbaum E, Maggi JC. Laryngomalacia in children. Chest. 1990;98(4):942–944. 5. Tostevin PM, de Bruyn R, Hosni A, Evans JN. The value of radiological investigations in pre-endoscopic assessment of children with stridor. J Laryngol Otol. 1995;109(9):844–848. 6. Han MT, Hall DG, Manche A, Rittenhouse EA. Double aortic arch causing tracheoesophageal compression. Am J Surg. 1993;165(5):628–631. 7. Backer CL, Ilbawi MN, Idriss FS, DeLeon SY. Vascular anomalies causing tracheoesophageal compression. Review of experience in children [see comments]. J Thorac Cardiovasc Surg. 1989;97(5):725–731. 8. Hofmann U, Hofmann D, Vogl T, Wilimzig C, Mantel K. Magnetic resonance imaging as a new diagnostic criterion in paediatric airway obstruction. Prog Pediatr Surg. 1991;27: 221–230. 9. Vogl T, Wilimzig C, Hofmann U, Hofmann D, Dresel S, Lissner J. MRI in tracheal stenosis by innominate artery in children. Pediatr Radiol. 1991;21(2):89–93. 10. Vogl T, Wilimzig C, Bilaniuk LT, et al. MR imaging in pediatric airway obstruction. J Comput Assist Tomogr. 1990;14(2): 182–186.

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11. Whyte RI, Quint LE, Kazerooni EA, Cascade PN, Iannettoni MD, Orringer MB. Helical computed tomography for the evaluation of tracheal stenosis. Ann Thorac Surg. 1995;60(1):27–30. 12. Quint LE, Whyte RI, Kazerooni EA, et al. Stenosis of the central airways: evaluation by using helical CT with multiplanar reconstructions. Radiology. 1995;194(3):871–877. 13. Chetty KG, Kadifa F, Berry RB, Mahutte CK. Acquired laryngomalacia as a cause of obstructive sleep apnea. Chest. 1994;106(6):1898–1899. 14. Zalzal GH. Stridor and airway compromise. Pediatr Clin North Am. 1989;36(6):1389–1402. 15. de Blic J, Delacourt C, Scheinmann P. Ultrathin flexible bronchoscopy in neonatal intensive care units. Arch Dis Child. 1991;66(12):1383–1385. 16. Nussbaum E. Usefulness of miniature flexible fiberoptic bronchoscopy in children. Chest. 1994;106(5):1438–1442. 17. Arnold JE. Advances in pediatric flexible bronchoscopy. Otolaryngol Clin North Am. 1989;22(3):545–551. 18. Raine J, Warner JO. Fibreoptic bronchoscopy without general anaesthetic. Arch Dis Child. 1991;66(4):481–484. 19. Eber E, Zach M. [Flexible fiberoptic bronchoscopy in pediatrics—an analysis of 420 examinations] Flexible fiberoptische Bronchoskopie in der Padiatrie—Eine Analyse von 420 Untersuchungen. Wien Klin Wochenschr. 1995;107(8): 246–251. 20. Todres ID, Noviski N. Flexible fiberoptic bronchoscopy: a practical guide to examining infants and children. Mt Sinai J Med. 1995;62(1):36–40. 21. Handler SD. Direct laryngoscopy in children: rigid and flexible fiberoptic. Ear Nose Throat J. 1995;74(2):100–104,106. 22. Teitelbaum DH. Bronchoscopy and esophagoscopy in children. Curr Opin Pediatr. 1993;5(3):341–346. 23. Puhakka H, Kero P, Valli P, Iisalo E, Erkinjuntti M. Pediatric bronchoscopy. A report of methodology and results. Clin Pediatr Phila. 1989;28(6):253–257. 24. Hoeve LJ, Rombout J. Pediatric laryngobronchoscopy. 1332 procedures stored in a data base. Int J Pediatr Otorhinolaryngol. 1992;24(1):73–82. 25. Sitbon P, Laffon M, Lesage V, Furet P, Autret E, Mercier C. Lidocaine plasma concentrations in pediatric patients after providing airway topical anesthesia from a calibrated device. Anesth Analg. 1996;82(5):1003–1006. 26. Amitai Y, Zylber Katz E, Avital A, Zangen D, Noviski N. Serum lidocaine concentrations in children during bronchoscopy with topical anesthesia. Chest. 1990;98(6):1370–1373. 27. Shikowitz MJ, Abramson AL, Liberatore L. Endolaryngeal jet ventilation: a 10-year review. Laryngoscope. 1991;101(5): 455–461. 28. Depierraz B, Ravussin P, Brossard E, Monnier P. Percutaneous transtracheal jet ventilation for paediatric endoscopic laser treatment of laryngeal and subglottic lesions. Can J Anaesth. 1994;41(12):1200–1207. 29. Evans KL, Keene MH, Bristow AS. High-frequency jet ventilation--a review of its role in laryngology. J Laryngol Otol. 1994;108(1):23–25. 30. Janzen PR, Neasham J, Daniel M. Pressure reducing valve prevents barotrauma during jet ventilation for microlaryngeal surgery [letter]. Anaesthesia. 1995;50(9):831–832. 31. Baraka A, Choueiry P, Medawwar A. The laryngeal mask airway for fibreoptic bronchoscopy in children. Paediatr Anaesth. 1995;5(3):197–198.

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32. Watanabe I, Noguchi R, Morioka M, Waguri N, Shimoji K. [Anesthetic management for bronchofiberscopy and esophageal mannometric study in a patient with CHARGE association]. Masui. 1995;44(7):1010–1013. 33. Johannesson GP, Floren M, Lindahl SG. Sevoflurane for ENT-surgery in children. A comparison with halothane. Acta Anaesthesiol Scand. 1995;39(4):546–550. 34. Kessler G, Rauchfuss A, Werner C. [Pulse oximetry in surgery of the bronchial system] Pulsoximetrie bei Eingriffen im Bronchialsystem. HNO. 1989;37(5):216–219. 35. Holmes DK. Expanding the envelope of neonatal endoscopic tracheal and bronchial surgery. South Med J. 1995;88(5): 571–574.

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36. Lindahl H, Rintala R, Malinen L, Leijala M, Sairanen H. Bronchoscopy during the first month of life. J Pediatr Surg. 1992;27(5):548–550. 37. Wengen DF, Probst RR, Frei FJ. Flexible laryngoscopy in neonates and infants: insertion through a median opening in the face mask. Int J Pediatr Otorhinolaryngol. 1991;21(2): 183–187. 38. Vats A, Worley GA, de Bruyn R, et al. Laryngeal ultrasound to assess vocal fold paralysis in children. J Laryngology & Otology. 2004;118(6):429–431.

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84

C H A P T E R

Radiologic Evaluation of the Pediatric Airway Ammie White, Tamara Feygin, and Avrum N. Pollock

A

common adage among pediatric radiologists states that one thing that distinguishes them from adult radiologists is that they remember to look at the airway. Infants and young children have comparatively smaller, more compliant airways, which are more prone to obstruction than the airways of adults.1 Children are also subject to a variety of congenital, infectious or inflammatory, neoplastic, and accidental causes of airway obstruction, which are less likely to occur in older patients. Many of these etiologies will present with overlapping symptoms, most commonly stridor, wheezing, or varying degrees of dyspnea and respiratory distress. Clinical diagnosis may be difficult due to significant overlap in symptoms. A variety of imaging modalities may be used in the evaluation and differentiation of various pediatric airway disorders. Imaging work-up usually begins with screening radiographs of the airway or chest, which at times will be sufficient in making a definitive diagnosis, although evaluation may proceed to the use of computed tomography (CT) or magnetic resonance imaging (MRI) in certain clinical situations. Dynamic assessment with airway fluoroscopy, barium esophagography, or sleep fluoroscopy may also be used in selected cases. Due to its near universal availability and lack of ionizing radiation, ultrasound (US) may be used to screen for infectious collections or masses around the airway, although it has limited ability to assess the airway directly. CT or MRI may be helpful in selected cases, especially when there is concern for extrinsic compression of the airway by vascular anomalies or mass lesions.1,2 Newer technologies, including cine CT and cine MRI (including fetal MRI in addition to fetal US), as well as virtual bronchoscopy, may be valuable in the assessment of pediatric airway abnormalities in the future.

treated with supportive care and/or steroids in order to suppress airway inflammation. Croup is usually diagnosed clinically, although frontal and lateral radiographs of the airway may be obtained to assess for alternative causes of airway obstruction.4 These should be performed with a high kilovoltage (KV) filtered technique designed to diminish the conspicuity of the bones and soft tissues, making the airway stand out in sharper relief (Fig. 84-1). The frontal projection will classically show loss of the normal subglottic shoulder, likened to a sharp church steeple (the so-called “steeple sign”), although this “shoulder” is only seen when the vocal cords are closed (during crying or phonation). The lateral view may demonstrate mild circumferential narrowing of the trachea below the vocal cords and ballooning of the hypopharynx.2

AIRWAY EMERGENCIES AND ACUTE AIRWAY INFECTION

Prior to the introduction of the conjugate vaccines against Hib, invasive bacterial infection causing acute epiglottitis (supraglottitis) was not uncommon among young children between the ages of 1 and 5 years.2,5 The incidence of acute epiglottitis has decreased dramatically since the introduction of conjugate Hib vaccines in Western countries in the 1980s and 1990s, to such an extent that many clinicians trained in the past two decades have never seen a de novo clinical case.3–6 Occasional cases do still occur, and therefore continued familiarity with the clinical and imaging findings is necessary, as acute epiglottitis remains a life-threatening infection, which can rapidly progress to complete, fatal airway obstruction.7 Children with acute epiglottitis classically present with sore throat, odynophagia, high fever, drooling, respiratory difficultly, inspiratory stridor, and/or a muffled

Laryngotracheitis (Croup) Laryngotracheitis (croup) is the most common cause of acute upper airway obstruction in young children, with peak incidence among young children between the ages of 6 months and 3 years.3,4 It is generally caused by subglottic viral infection due to parainfluenza virus, influenza A or B virus, or respiratory syncytial virus (RSV). Children often present with a characteristic barking (croupy) cough, as well as with a low-grade fever, inspiratory stridor, respiratory distress, and hoarseness.2,3 Symptoms may last from days to weeks and are usually relatively mild and thus sufficiently

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Membranous Laryngotracheitis (Membranous Croup) Occasionally viral croup is complicated by secondary bacterial infection, most commonly with Staphylococcus aureus or Haemophilus influenzae type b (Hib), the latter usually in unvaccinated children.2,3 Patients will usually have several days of symptoms typical for viral croup, but with subsequent development of high fever, purulent sputum production, and persistent stridor. Patients with membranous croup appear toxic, distinguishing them from more benign appearing patients affected with viral croup. Frontal and lateral radiographs of the airway will show a normal epiglottis and subglottic narrowing, similar to findings seen in viral croup, but will also demonstrate debris and membranes as irregular nodularity/thickening along the tracheal walls (Fig. 84-2).2,3

Acute Epiglottitis

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FIGURE 84-2. Membranous croup. A 6-year-old male with hoarseness and difficulty breathing. Lateral soft tissue view of the neck demonstrates soft tissue thickening/undulation along the posterior wall of the trachea (arrows).

FIGURE 84-1. Croup. A 5-year-old male with stridor and noisy cough. High KV frontal view of the airway demonstrates narrowing of the subglottic airway, the so-called “steeple” sign (arrows).

or hoarse voice.2,4–6 Children usually appear quite toxic and may sit in a “tripod” or “sniffing” posture, breathing through their mouth with their jaw and tongue protruding in order to maintain patency of their airway.3 Lateral radiographs of the soft tissues of the neck remain the modality of choice in the evaluation of acute epiglottitis, as these are readily available and may be performed rapidly. As the patient’s clinical condition can deteriorate rapidly, utmost care must be taken when imaging children for whom there is strong suspicion of acute epiglottitis, including close monitoring by a clinician skilled in airway management, avoiding agitation, and not manipulating the neck, but rather allowing the patient to hold their neck in a position of comfort (passive), at times necessitating performance of the lateral neck radiograph

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with the patient in the seated position, resting their arms on a tray table, while the technologist performs the radiograph portably at the bedside.4 Characteristic imaging findings on lateral radiographs include thickening of the epiglottis, forming a rounded soft tissue mass at the level of the hyoid bone (i.e., the so-called “thumb sign”), thickening of the aryepiglottic folds, and ballooning of the hypopharynx (Fig. 84-3).2 Frontal radiographs may also demonstrate subglottic edema similar to the “steeple sign” seen with viral croup. Treatment is with antibiotics, and patients may require an artificial airway (endotracheal tube or tracheostomy in the most severe cases).6

Retropharyngeal and Peritonsillar Infection Retropharyngeal abscess most commonly occurs in children under 5 years of age, and is usually preceded by nasopharyngitis.2,3 Retropharyngeal infection in young children is believed to begin as spread of infection to draining retropharyngeal lymph nodes (nodes of Rouviere); these generally atrophy

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CHAPTER 84 ❖ Radiologic Evaluation of the Pediatric Airway 1427

FIGURE 84-3. Epiglottitis. A 5-year-old female with fever, stridor, and possible pharyngitis. Lateral soft tissue view of the neck demonstrates a thickened epiglottis (arrow) with the so-called “thumb sign.” In addition, the adenoids (A), palatine tonsils (PT), and lingual tonsils (LT) are enlarged.

by 4–5 years of age. Early swelling is related to edema and inflammation, which may subsequently progress to cellulitis or frank abscess formation.2–4 Patients present with fever, sore throat, neck pain, and stiffness, and usually appear toxic. If there is substantial swelling with encroachment on the airway, patients may also present with mouth breathing, and protrusion of their jaw and tongue, as may be seen with acute epiglottitis.2,3 Infants with retropharyngeal abscess may present with fever, drooling and stridor, or with just lethargy, making this clinical diagnosis more challenging.3 Initial imaging is performed using lateral radiographs of the soft tissues of the neck. Attention to meticulous technique is vital; the image should be acquired during inspiration with the neck somewhat extended. There may be spurious soft tissue thickening when the image is obtained during expiration or while the neck is in neutral or in a position of flexion. In patients with retropharyngeal cellulitis or abscess, lateral radiographs of the neck will show anterior displacement of the airway by abnormal prevertebral soft tissue swelling (Fig. 84-4), defined

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FIGURE 84-4. Retropharyngeal abscess. An 8-year-old female with sore throat and questionable foreign body. Lateral soft tissue view of the neck demonstrates marked thickening of the prevertebral soft tissues (arrows) with ventral displacement of the trachea.

as a width greater than the adjacent vertebral body at the C1 through C4 levels (in infants and young children), as well as effacement of the normal shelf of soft tissue that demarcates the upper extent of the cervical esophagus.2,4 Gas may rarely be seen within the prevertebral soft tissues, and when present in the absence of trauma, is highly suggestive of an abscess. If radiographs are concerning for retropharyngeal swelling, contrast-enhanced CT is typically performed to evaluate for the presence of a discrete abscess, and to help in the differentiation from that of a phlegmonous collection. Abnormalities

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can generally be accurately localized to the retropharyngeal space versus the parapharyngeal space by the direction of displacement of the parapharyngeal fat, which will be displaced anterolaterally by retropharyngeal abnormalities, but posteromedially by parapharyngeal abnormalities. Areas of swelling and heterogeneous enhancement may suggest developing phlegmon (Fig. 84-5), while a discrete ovoid rim enhancing fluid collection is more suggestive of an abscess (Fig. 84-6). It may be difficult to distinguish between a true abscess and

suppurative or necrotic retropharyngeal lymph nodes.4 It is common to see sterile (uninfected) retropharyngeal edema or effusions within the so-called “danger space,” the potential space (fascial compartment) posterior to the retropharyngeal soft tissues and anterior to the vertebral bodies, which is known to extend from the skull base to the mediastinum. It is crucial to distinguish these effusions from bona fide, contained, rim enhancing abscesses (Fig. 84-7).4

FIGURE 84-5. Retropharyngeal phlegmon. A 6-year-old male with fever and decreased p.o. intake. Contrast-enhanced CT of the neck at the level of the epiglottis demonstrates prevertebral soft tissue thickening and fullness (arrows) without a definable enhancing rim.

A

FIGURE 84-6. Retropharyngeal abscess. An 8-year-old female with sore throat and questionable foreign body (same patient as in Figure 84-4 above). Contrast-enhanced CT of the neck at the level of the vocal cords demonstrates retropharyngeal fullness, left greater than right, with an ovoid area of decreased attenuation and surrounding rim enhancement (arrows).

B

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C FIGURE 84-7. Retropharyngeal abscess extending into the mediastinum. An 8-month-old female with MRSA bacteremia and fever despite treatment with Vancomycin, now with question of abscess. Contrast-enhanced CT of the neck in the axial plane at the level of the epiglottis (A), at the level of the upper mediastinum (B), with coronal reformation at the cervicothoracic junction (C), demonstrates a rim-enhancing collection in the retropharyngeal region (asterisks) extending into the soft tissues of the neck laterally on the right (arrowheads) (A), and down into the upper mediastinum (M) (B,C), the so-called “danger space.” Note the associated leftward tracheal deviation (T).

Tonsillitis and acute pharyngitis are common infections seen in school aged children. These may result in sufficient swelling and mass effect to partially obstruct the oropharyngeal airway. Children will present with high fever and sore throat. While uncomplicated infections are diagnosed clinically, contrast-enhanced CT is the imaging modality of choice when there is concern for complications such as tonsillar (Fig. 84-8) or peritonsillar (Fig. 84-9) abscesses or for extension of infection into the deep soft tissues of the neck.2,4 Lateral radiographs of the airway are relatively insensitive in showing tonsillar or parapharyngeal swelling and abscesses, although the frontal view may demonstrate eccentric displacement of the aerated oropharynx and hypopharynx away from the more affected side, noting that tonsillitis is generally a bilateral process, and that findings may be subtle. Thrombophlebitis involving the internal jugular vein is an uncommon complication of pharyngitis; this may result in Lemierre syndrome with secondary septic pulmonary emboli (Fig. 84-10).4 Ludwig angina is a relatively uncommon acute cellulitis of the floor of the mouth, which may extend into the submandibular space or deep soft tissues of the neck and is most commonly secondary to odontogenic infection.4 Swelling elevates and displaces the tongue posteriorly and may lead to rapid airway compromise. Patients present with visible jaw and neck swelling and may also have stridor. US

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A

B FIGURE 84-8. Tonsillar abscess. A 10-year-old female immunocompromised patient who is status post liver transplantation, now with fever, strep throat, trismus, and voice changes. Contrast-enhanced CT of the neck in the axial plane at the level of the palatine tonsils (A), with coronal reformation (B), demonstrates fullness of the left tonsillar bed (arrowheads) associated with low attenuation and rim enhancement, with rightward deviation of the airway (arrows). There is persistent visualization of the fat lateral to the tonsillar pillar (curved arrow).

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A

FIGURE 84-10. Lemierre syndrome. A 12-year-old male with large left submandibular neck mass, sore throat, and fever. Contrastenhanced CT of the neck in the axial plane at the level of the palatine tonsils demonstrates a small retropharyngeal phlegmon within the midline (arrowheads), and a filling defect within the left internal jugular vein with surrounding rim enhancement (arrows), likely reflecting inflammatory enhancement of the vessel wall, some residual laminar flow within the jugular vein, or a combination of both. Findings are in keeping with infectious thrombophlebitis.

B FIGURE 84-9. Peritonsillar abscess. A 15-year-old female with right-sided palatal fullness and uvular deviation on examination. Contrast-enhanced CT of the neck in the axial plane at the level of the palatine tonsils (A), with coronal reformation (B), demonstrates fullness with decreased attenuation in the right peritonsillar region (arrowheads) with resultant leftward deviation of the airway (arrows), and obscuration of the fat lateral to the tonsillar bed, within the peritonsillar region. Note the normal fat on the left (asterisks).

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can be performed to assess for a discrete abscess or collection, but has limited utility in assessing the airway itself. CT may be performed to assess the degree of mass effect and airway compression, for the presence of an abscess, or for an underlying etiology, such as odontogenic disease, or less commonly submandibular sialadenitis. CT will show thickening and stranding along the skin and deep fascial planes as well as muscle swelling (Fig. 84-11). There may or may not be a discrete abscess, and gas may be seen within the soft tissues. MRI may be used in the assessment of any of these acute pharyngeal infections, but due to its relatively long imaging times, frequent need for sedation in young children, and the potential for rapid clinical deterioration in some instances, CT is still the preferred modality given its wider availability and rapid scan times with the newer generation of scanners, despite the relative risks of ionizing radiation.

Aspirated Foreign Bodies Foreign body aspiration is a leading cause of accidental injury in infants and young children, with 78%–89% of cases occurring under the age of 3 years.8 There are several

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A

factors placing infants and young children at increased risk for foreign body aspiration, particularly after 8–12 months of age, when they develop a pincer grasp and are able to more deftly manipulate small objects. A history of a choking episode is helpful, but these may have been unwitnessed or may not be remembered or deemed significant by the caregiver, especially in cases with delayed presentation. Patients may have symptoms of persistent cough, shortness of breath, persistent wheeze or sometimes fever, and may be misdiagnosed as having an upper respiratory infection, bronchiolitis, pneumonia, or asthma. Delay in diagnosis of greater than one month portends a much higher risk of complications, including pneumonia, bronchiectasis, or less commonly foreign body granuloma, bronchopulmonary or bronchoesophageal fistula, or pneumothorax.3,8 The majority of aspirated objects are organic and nonradioopaque, most commonly peanuts, popcorn, other nuts, seeds, hot dogs, and vegetables. Other less commonly aspirated objects include small toy parts, marbles, crayons, pen caps, tacks, pins, paper clips, nails, screws, bullets and casings (Fig. 84-12). Only about 15% of aspirated foreign bodies are radioopaque.8,9 Aspirated objects most commonly lodge in the main bronchi, with about 50%–55% of objects extending into the right main bronchus as compared to 19%–46% in the left main bronchus. Only between 3% and 17% of objects are found in the trachea, and the remaining small percentage are noted to be lodged within the larynx or hypopharynx.3,4,8,9 Air trapping with hyperinflation is thought to be related to a “ball-valve” mechanism, although there may be atelectasis or lobar collapse with complete obstruction.

B

C FIGURE 84-11. Ludwig’s angina. A 9-month-old female with submandibular swelling, evaluate for drainable fluid collection. Contrast-enhanced CT of the neck in the axial plane (A) at the level of the thyroid gland/submental region, with coronal (B) and sagittal (C) reformations, demonstrates marked thickening of the facial soft tissues (arrows) extending from the floor of the mouth and subcutaneous submental region to the level of the thoracic inlet.

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FIGURE 84-12. Foreign body in the airway (larynx). A 2-year-old male with stridor, thought to be croup, with no improvement despite steroids. Lateral soft tissue view of the neck demonstrates an omega-shaped partially radioopaque foreign body (arrows) within the subglottic airway, in keeping with an aspirated plastic toy piece.

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Initial imaging should be performed with standard chest radiographs (Fig. 84-13). These may appear normal, demonstrate unilateral hyperlucency due to a combination of hyperinflation and oligemia, or less commonly, will show

volume loss. Mediastinal shift, either away from or toward the affected side, may occur with severe air trapping or atelectasis, respectively. There may also be focal areas of pneumonia, pneumomediastinum, or pneumothorax. Air

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B

C

D

FIGURE 84-13. Foreign body (nonradioopaque) in the airway (bronchus). A 1-year-old female, swallowed a peanut, now with decreased breath sounds on the right. Frontal (A), lateral (B), right lateral decubitus (C), and left lateral decubitus (D) radiographs of the chest demonstrate hyperlucency of the right lung with appropriate left-sided atelectasis on the left lateral decubitus view, but with failure of collapse of the right lung on the right lateral decubitus view, in keeping with a nonradioopaque foreign body within the right airway. There is resultant air-trapping secondary to a ball-valve effect.

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CHAPTER 84 ❖ Radiologic Evaluation of the Pediatric Airway 1433 trapping on the affected side can be assessed with inspiratory and expiratory frontal views in cooperative older children or bilateral decubitus views in a younger child. These will show lack of change in volume (collapse/atelectasis) on the affected side on expiratory views or while imaging the patient in a dependent decubitus position.4,8 The normal contralateral lung will show increased attenuation and decreased volume by comparison. Care must be taken in positioning the patient on decubitus views, as excessive rotation will make it difficult to interpret the images in subtle cases. Although laryngotracheal foreign body is less common, when present, radiographs of the lateral soft tissues of the neck may demonstrate a filling defect in the air column.8 Airway fluoroscopy can also

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be used in the dynamic assessment for unilateral air trapping on the affected side. Sensitivity of radiography in diagnosing aspirated foreign bodies is reported to be between 66% and 88% in various series; thus normal radiographs cannot exclude this diagnosis. Recently, low-dose multidetector CT (MDCT), with new technology capable of isovolumetric imaging with high-quality 3-D reconstructions, as well as the capacity to perform virtual bronchoscopy, has been used as a noninvasive method in the assessment of foreign bodies within the airway, especially in clinically challenging/ problematic cases. CT may show intraluminal filling defects, consolidation, bronchiectasis, or air trapping, depending on the chronicity of the process (Fig. 84-14).8

C

D

FIGURE 84-14. Foreign body (opaque) in the airway (bronchus). A 7-year-old male with cerebral palsy, now with right lower lobe pneumonia, question possible aspiration. Noncontrast CT of the chest in the axial (A), coronal (B), and sagittal (C) planes on soft tissue algorithm and axial view on bone algorithm (D), demonstrate a radioopaque foreign body (arrows) within the right lower lobe bronchus, which upon further delineation using bone algorithm demonstrates the presence of a tooth obstructing the bronchus, with secondary atelectasis (arrowheads).

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CONGENITAL ABNORMALITIES AND MALFORMATIONS Choanal Atresia Choanal atresia is an uncommon congenital anomaly resulting in obstruction of the posterior nasal cavity by a bony or membranous septum that bridges the choana. The condition is most often bony (90%) and more commonly unilateral.1,2 Clinically, neonates may present with variable symptoms of upper airway obstruction, while the clinician will be unable to pass a small caliber catheter via the nares into the nasopharynx on the affected side. When the condition is bilateral, it may be life threatening, as neonates are “obligate nose breathers.” Patients with unilateral choanal atresia may present later in life with chronic unilateral rhinorrhea. Up to 75% of patients with choanal atresia may have other congenital anomalies, including CHARGE syndrome (colobomas, heart disease, choanal atresia, growth and mental retardation, genital hypoplasia, and ear anomalies with deafness).1,2 Uniform narrowing of both nasal cavities may be seen in craniofacial disorders that result in maxillary hypoplasia, such as is seen with Apert, Crouzon, and Pfeiffer syndromes. Imaging workup uses thin section CT (parallel to the hard palate), which can most clearly differentiate a bony from membranous septum, and is vital in aiding the clinicians with treatment and surgical planning. CT demonstrates narrowing of the posterior choanae to less than 3.4 mm, with an osseous or soft tissue septum occluding the posterior choanae, thickening of the vomer, and medial bowing of the posterior maxilla on the affected side (Fig. 84-15).1,2 Choanal stenosis will have similar imaging findings, but without a complete septum. Treatment depends on whether the septum is bony or membranous, complete or incomplete, and unilateral or bilateral, and includes endoscopic perforation, stent placement, or early versus delayed surgical resection and choanoplasty.

FIGURE 84-15. Choanal atresia. A 2-month-old female with double outlet left ventricle and nasal obstruction. Axial noncontrast CT of the head obtained parallel to the hard palate, at the level of the choana, demonstrates marked narrowing of the right posterior choana, associated with a bony bar (arrow), lateralization of the vomer (arrowhead) at the level of the bony bar (prominence of the pyramidal eminence), and an anterior fluid level, in keeping with bony choanal atresia.

Piriform Aperture Stenosis Piriform aperture stenosis is less common than, but clinically indistinguishable from, choanal atresia. The nasal fossae will appear narrow on physical examination. Piriform aperture stenosis results from overgrowth of the medial nasal process of the maxilla, thereby narrowing the anterior nasal cavities.1 Although this may be an isolated finding, it may also be associated with midfacial dysostosis, with a single central incisor, pituitary pathology, or other midline central nervous system (CNS) abnormalities along the holoprosencephaly spectrum. Imaging work-up primarily involves thin section CT, with the axial acquisition obtained parallel to the hard palate. CT shows thickening of the nasal processes of the maxilla and medial deviation of the anterior maxillae, resulting in a triangular shaped palate (Fig. 84-16). The anterior nasal (piriform) aperture will

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FIGURE 84-16. Piriform aperture stenosis. A 5-week-old former 34 week preemie female with persistent hypoxia and concern for abnormal bony facial anatomy. Axial noncontrast CT of the head obtained parallel to the hard palate demonstrates marked narrowing of the nasal inlet with close approximation of the nasal processes of the maxillae (arrows) with resultant critical narrowing of the nasal inlet, in keeping with nasal inlet/piriform aperture stenosis.

measure less than 11 mm in width in term neonates with this anomaly.1 Soft tissue may also extend across the anterior nares. As noted above, there may be a single central incisor and evidence of other midline CNS anomalies. Mild cases may be treated with supportive care, including humidification or decongestants, although in severe cases, stenting or surgical repair may be required.

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Cleft Palate and Velopharyngeal Incompetence Cleft lip and cleft palate may occur together or separately. These lesions are usually clinically obvious on examination (Fig. 84-17), but may be diagnosed antenatally (Fig. 84-18).

A

A

B

B FIGURE 84-17. Cleft lip and palate (postnatal). A 1-day-old female with multiple congenital anomalies and Opitz syndrome. Axial noncontrast CT (bone windows) of the maxillary region at the level of the upper lip (A) and maxilla (B), demonstrates a soft tissue defect within the left upper lip (arrowheads) and an obliquely oriented defect within the left maxilla (arrows) associated disorganized dentition.

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C FIGURE 84-18. Cleft lip and palate (prenatal). A 26-week fetus with congenital heart disease, cleft lip, and cleft palate. Coronal echo planar (EPI) MRI image of the fetus at the level of the palate (A), coronal fetal US at a similar level (B), and 3-D US (C) demonstrates a defect within the right hard palate (arrows), best appreciated on MRI, and a soft tissue defect within the right upper lip (arrowheads), best illustrated on US.

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Velopharyngeal incompetence (VPI) may occur in the setting of cleft palate, but can also be seen with Q22 syndrome (Velocardiofacial syndrome/DiGeorge syndrome), and may only be visible as a cleft in the soft palate. VPI will present with hypernasality (nasal speech) and is

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B

best assessed preoperatively with fluoroscopic evaluation after nasal placement of barium drops (Fig. 84-19) in conjunction with speech pathology, awake nasal endoscopy, or more recently using cine MRI (Fig. 84-20) in conjunction with speech pathology. The aim of these studies is

C

D

FIGURE 84-19. Velopharyngeal incompetence (VPI) (fluoroscopy). A 6-year-old male with velocardiofacial syndrome (22Q deletion), VPI, and unsuccessful attempt at nasal endoscopy. Lateral views of the nasopharynx (A) at rest and with phonation (B) (without administration of nasal barium), and submental vertex views of the nasopharynx at rest (C) and with speaking (D) after administration of barium nose drops, demonstrates touch closure (incomplete) with failure of complete elevation/apposition of the soft palate with the adenoid bed on the lateral view (arrowheads). On the submental vertex view, there is lack of complete circular closure/apposition of the pharyngeal walls with phonation (arrows) (D), from their position at rest (C). This leads to escape of air and resultant hypernasality of speech.

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C

B

D

FIGURE 84-20. VPI (Cine MRI). An 8-year-old male with velocardiofacial syndrome (22Q deletion), preoperative evaluation for posterior pharyngeal flap. Sagittal T2 HASTE (at the level of the nasopharynx) at rest (A) and with phonation (B) and axial T2 HASTE (at the level of the hard palate and below) at rest (C) and with phonation (D) demonstrate similar findings to those that would be expected on conventional fluoroscopic study obtained in Figure 84-19 above. Sagittal views demonstrate touch closure (incomplete) with failure of complete elevation/apposition of the soft palate with the adenoid bed (arrowheads), and axial views demonstrate lack of complete circular closure/apposition of the pharyngeal walls from their position at rest (arrows).

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to estimate (1) the degree of palatal elevation and closure against the adenoid bed, assessed in the lateral seated view, and (2) the degree of circular closure of the pharyngeal walls (lateral and posterior), best assessed on the submental vertex or equivalent view on fluoroscopic examination (prone or upright with the chin tucked into the chest). These maneuvers are performed while the child is instructed to say a string of phrases or say different vowels in order to stress/ activate the muscles noted above.

Enlarged Adenoids and Tonsils The lymphoid tissue of Waldyer’s ring (pharyngeal, palatine, and lingual tonsils) is typically more prominent in children than adults. The adenoids (pharyngeal tonsils) are usually absent at birth, but grow rapidly in infancy. Their absence in children older than 6 months of age can be seen in children with immunodeficiency, but is often seen in children on chemotherapy. The adenoids peak in size in early to middle childhood and regress in adolescence, after reaching a maximal normal size of 7–12 mm.1 Abnormal enlargement of the adenoids and palatine tonsils can lead to nasopharyngeal obstruction, otitis media, mouth breathing, snoring, and obstructive sleep apnea (OSA).1,10 While endoscopy is the gold standard for assessing pharyngeal lymphoid hyperplasia and subsequent obstruction, imaging may also be helpful. Screening radiographs of the lateral soft tissues of the neck are often obtained to assess size, shape, and position of the adenoids and palatine tonsils. These may be performed with the patient either in upright or supine position.1,2,10 Lateral radiographs demonstrate the adenoids as a convex soft tissue structure abutting the posterior nasopharyngeal roof and the palatine tonsils as superimposed ovoid structures overlapping the posterior aspect of the soft palate (Fig. 84-21). While assessment is often subjective, by convention, extension of the adenoids to the hard palate, extension of the palatine tonsils into the hypopharynx, and compression of the nasopharyngeal air column are considered abnormal.1,10 Video fluoroscopy in sedated patients, or cine MRI, has also been used to assess dynamic airway abnormalities related to adenoid and tonsillar hypertrophy.1,2 Treatment depends on severity of symptoms, with surgical resection performed when there is airway compromise, OSA, or recurrent infections.

Abnormalities of the Jaw and Tongue Although a detailed discussion is beyond the scope of this chapter, disorders of the jaw and tongue may lead to upper airway obstruction. These include micrognathia (mandibular hypoplasia), which may be idiopathic or related to various syndromes such as Treacher Collins, Nager or Goldenhar syndromes, hemifacial microsomia, trisomies 13 and 18, as well as other more rare trisomies, cri du chat, and Pierre Robin sequence.1 Micrognathia results in posterior

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FIGURE 84-21. Palatine tonsillar enlargement. A 2-year-old female with fever and neck pain. Lateral soft tissue of the neck demonstrates moderate to marked palatine tonsillar enlargement (arrows). In addition, incidentally noted is moderate enlargement of the adenoids (A) and mild enlargement of the lingual tonsils (arrowheads).

displacement of the tongue, which subsequently encroaches on the oropharyngeal airway. Depending on severity, patients may be treated with supportive care or may require surgery, including repair of the palate or mandibular distraction. Thin section CT with multiplanar reformations is helpful in preoperative planning (Fig. 84-22). Likewise, macroglossia may result in narrowing of the oropharynx. This may be seen in congenital hypothyroidism, idiopathic hyperplasia, the mucopolysaccharidoses, as well as chromosomal abnormalities including Down syndrome and Beckwith-Wiedemann syndrome.1 Occasionally, tongue enlargement may be due to the presence of a cystic or solid mass. The most common benign cystic etiologies include lingual thyroglossal duct cysts, dermoid cysts, duplication cysts, ranula, and lymphatic malformations (Fig. 84-23), while more common benign solid etiologies

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A

B B

C

C FIGURE 84-22. Mandibular hypoplasia. A 16-year-old male with mandibular hypoplasia, macroglossia, and bilateral temporomandibular joint (TMJ) ankylosis. Lateral scout view of the face (A) obtained at time of CT, sagittal reformation (B), and shaded surface reconstruction (C) demonstrate marked diminution in size of the mandible (arrows) associated with marked retrognathia.

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FIGURE 84-23. Venolymphatic malformation (neck) (pre- and postnatal). A 34-week gestational age male fetus with neck mass and postnatal MRI at 9 days of age for lymphatic malformation status post exit procedure and tracheostomy. Sagittal T2 HASTE view of the fetal head and chest region (A), axial T2 (B) and coronal T2 (C) from newborn imaging, demonstrate multi-cystic T2 bright areas in the submental region on the prenatal scan (arrows). On the postnatal scan, multiple fluid-fluid levels are seen on the axial T2 image (arrowheads), with corresponding bright T2 cystic lesions on the coronal view, with resultant rightward displacement of the airway (asterisks).

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include ectopic lingual thyroid (Fig. 84-24) and infantile hemangioma.1 Malignant lesions in the tongue are rare in children, although primary or metastatic sarcoma (including rhabdomyosarcoma), lymphoma, neuroblastoma, or rarely, granular cell tumors have been reported in the tongue.1 Patients may present with noisy breathing, drooling, dysphagia, and difficulty with speech. Radiographs of the lateral soft tissues of the neck will show prominent smooth or lobulated enlargement of the soft tissue shadow of the tongue and variable degrees of narrowing of the oropharyngeal airway. US can be used to assess for an underlying mass, and can distinguish between cystic from solid lesions, although it has limited ability in determining the full extent of some lesions, and cannot reliably assess effect on the airway. CT or MRI may also be used to assess for an underlying mass and the degree of airway encroachment. The degree of dynamic airway obstruction may be assessed with sleep fluoroscopy or cine MRI. Thyroid scintigraphy can be used to confirm suspected cases of ectopic thyroid. Masses may be seen on prenatal imaging, most commonly teratomas (Fig. 84-25) or lymphatic malformations (see Fig. 84-23 above). If there is significant airway obstruction, an EXIT procedure (Ex Utero Intrapartum Treatment) may be required in order to secure

A

the airway prior to disruption of fetal-placental circulation.1,11 Tracheostomy may be required in cases of symptomatic upper airway obstruction. Treatment otherwise depends on the etiology of the tongue enlargement and will range from treatment of the primary medical condition, cyst drainage, marsupialization, or sclerotherapy, resection or debulking of a mass, or reduction glossectomy.1 Glossoptosis is a condition in which the tongue “falls” posteriorly during sleep and may occlude the oropharyngeal airway resulting in OSA. This is most common in the setting of macroglossia, micrognathia, and/or hypotonia, including in children with cerebral palsy, Down syndrome, and Pierre Robin sequence.1 Glossoptosis can be assessed with sleep fluoroscopy or a cine MRI sleep study. Sagittal (lateral) images will show the tongue moving posteriorly, abutting the velum of the soft palate and posterior pharyngeal wall, leading to obstruction; in severe cases the tongue may also displace the soft palate, obstructing the nasopharynx as well.1 As above, treatment will depend on etiology, and may include conservative treatments such as repositioning or use of continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) during sleep, or in more severe cases may require surgery or tracheostomy.

B

FIGURE 84-24. Lingual thyroid. A 4-year-old female without normal thyroid and with mass at base of tongue, with occasional snoring, which is positional in nature. Noncontrast axial CT of the neck (A) at the level of the tongue base, and nuclear medicine I123 scan in the lateral projection (B) demonstrate a rounded area of marked increased attenuation within the tongue base on the CT (arrows) due to the high iodine content of the thyroid gland, similar to that of radiographic contrast material (not administered in the study). The thyroid gland avidly takes up the radiopharmaceutical and appears white/very intense (arrowheads) on this study against a relatively black background.

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FIGURE 84-25. Teratoma (pharyngeal) (pre- and postnatal). A 31-week gestational age male fetus with oropharyngeal mass and postnatal MRI at 9 days of age to assess for oropharyngeal teratoma. Sagittal T2 HASTE view of the fetal head region (A), and sagittal noncontrast T1 image (B) of the fetal facial region in the newborn period, demonstrates fullness in the region of the nasopharynx with absence of normal T2 brightness (arrowheads) normally seen with swallowed amniotic fluid on the fetal scan. On the postnatal scan the lesion is seen to extend from the oropharyngeal region out through the opening of the mouth and is markedly bright on T1 imaging (arrows) due to the presence of fat in this teratomatous lesion.

Atresia or Stenosis of the Upper Airway, Including Congenital High Airway Obstruction Syndrome Tracheal stenosis may be primary (congenital) or secondary (acquired). Secondary stenosis is far more common, frequently subglottic in location, and may result from prolonged intubation or prior tracheostomy, although may also be caused by prior trauma, infection or inflammation, or by extrinsic compression by anomalous mediastinal vessels or masses.12 Primary tracheal stenosis is a rare condition in which there is abnormal development of tracheal cartilage resulting in focal or diffuse complete cartilaginous rings and fixed tracheal narrowing.2,12 Complete cartilaginous rings may be an isolated finding but has been associated with pulmonary vascular sling, in which there is anomalous origin of the left main pulmonary artery from the right main pulmonary artery discussed further below; tracheoesophageal fistula (TEF) and calcified tracheal cartilage.2,12 Radiographs of the airway performed with a high KV filter (see Fig. 84-1 above) or dynamic airway fluoroscopy will show tracheal narrowing. Esophagography may be used to assess for focal areas

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of extrinsic mediastinal compression, such as occurs with anomalous vessels. CT or MRI can be used to demonstrate extent of stenosis, although the nonossified tracheal cartilage in children is not seen directly on these imaging modalities.2 Congenital high airway obstruction syndrome (CHAOS) is a phenotypic manifestation of various causes of complete or high-grade in utero upper airway obstruction, with the more common reported causes being laryngotracheal atresia, stenosis or webs, obstructing laryngeal cysts or other congenital intrinsic or extrinsic head and neck masses, which severely obstruct the upper airway.13,14 Laryngotracheal atresia is a very rare congenital abnormality believed to result from failure of recanalization of the primitive laryngotracheal tube to varying degrees early in gestation.13 Fluid normally produced by the developing fetal lungs is trapped in the setting of airway occlusion, resulting in the characteristic imaging findings (Fig. 84-26). The lungs are diffusely distended, resulting in flattening or frank inversion of the diaphragmatic leaves, and are abnormally echogenic on US, and diffusely hyperintense on fluid-sensitive MR sequences (Fig. 84-27).13,14 US findings may be mistaken for bilateral congenital pulmonary airway malformations (CPAMs) or other lung lesions seen on

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SECTION 5 ❖ The Airway diffuse subcutaneous edema and serous effusions in one or more body cavities (more commonly ascites than isolated pleural or pericardial effusion), as well as polyhydramnios and placental enlargement; this is thought to be due to compression of the heart by the distended lungs with resultant inhibition of systemic venous return.13,14 CHAOS is associated with other anomalies, and fetuses are at increased risk for intrauterine demise. Neonatal survival depends on delivery via EXIT procedure in order to ensure a secure airway prior to disruption of fetal-placental circulation (clamping of the umbilical cord).11,13,14

Disorders of Laryngotracheoesophageal and Tracheobronchial Formation

FIGURE 84-26. Congenital high airway obstruction syndrome (CHAOS) (postnatal). A 2-day-old male with laryngotracheal atresia. Frontal radiograph of the chest in the newborn period demonstrates marked inversion of the hemidiaphragms with marked hyperlucency of the lungs secondary to air trapping. A tracheostomy tube is in place, and there is bulging of the flanks secondary to anasarca.

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B

FIGURE 84-27. CHAOS (prenatal). A 22-week gestational age fetus with congenital airway obstruction. Coronal TruFisp (A) and coronal T2 HASTE (B) images of the chest and abdomen demonstrate marked inversion of the hemidiaphragms (arrows), increased signal of the lungs above, and marked ascites/anasarca below (asterisks).

screening fetal examinations if the radiologist or obstetrician performing the examination is unaware of this condition.13 The distal airway is abnormally dilated and fluid filled to the level of obstruction, which may occur anywhere from the larynx to the carina.13,14 A large percentage of fetuses with CHAOS show signs of nonimmune hydrops fetalis, including

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Laryngotracheoesophageal cleft is a spectrum of rare congenital anomalies resulting in a longitudinal cleft of variable length along the posterior wall of the upper airway, ranging from a tiny defect in the laryngeal submucosa, to the most severe form consisting of a continuous longitudinal cleft extending all the way from the larynx to a segment of the intrathoracic trachea.2,15 Depending on severity, patients may present with stridor, hoarse cry, swallowing difficulties and aspiration, cough, dyspnea, or cyanosis. Laryngotracheo-esophageal cleft has been associated with other anomalies, most commonly laryngomalacia, tracheobronchomalacia, and gastroesophageal reflux disease, although may also be associated with various syndromes.15 Radiographs are nonspecific but may show sequelae of aspiration. Barium swallow is likely to show free spillage of contrast into the airway, and the diagnosis may be suggested if the contrast appears to be entering the airway directly from the more inferior aspect of the pharynx or below (Fig. 84-28), although this may be difficult to distinguish from aspiration related to pharyngeal dysfunction.2 Communication between the trachea and esophagus has occasionally been reported on CT, but endoscopy/bronchoscopy is required for definitive assessment and diagnosis. Vallecular cysts (Fig. 84-29) are rare lesions that occur near the tongue base and are thought by some to be due to obstruction of minor salivary glands, much like a mucous retention cyst. Others believe that they may even represent a variant of the thyroglossal duct cyst. Abnormal development and separation of the lung buds from the primitive foregut may result in various manifestations of TEF, with or without esophageal atresia, or extremely rarely, one or more bronchi may originate directly from the esophagus.12 Esophageal atresia will be clinically evident shortly after birth, and discussion of this topic is beyond the scope of this chapter. The uncommon H-type TEF without esophageal atresia may be clinically occult, and result in symptoms of recurrent aspiration or pneumonia. This can be evaluated with fluoroscopic esophagography (Fig. 84-30), ideally via injecting nonionic, iso-osmolar water soluble contrast, or dilute barium under pressure through a catheter placed into the esophagus. The patient should be positioned in a prone-oblique to lateral position, such that the trachea

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B

FIGURE 84-28. Laryngeal cleft. A 15-year-old female with suspicion of recurrent type III laryngeal cleft 10 years post initial repair. Lateral fluoroscopic view obtained at the level of the cervical spine during swallowing, demonstrates a small area of focal outpouching (arrow) of barium into the region of the posterior airway at the level of C6.

C FIGURE 84-29. Vallecular cyst. A 14-day-old male with stridor and fullness anterior to the right saccule and right paraglottic region. Axial fat-saturated T2 (A), coronal fat-saturated T2 (B), and postcontrast fat saturated T1 images (C) of the neck demonstrate an ovoid area of T2 prolongation within the lateral airway (arrowheads) with resultant leftward deviation of the airway (asterisks). Note that on T1-weighted post contrast imaging, the lesion is purely cystic (arrows) with no evidence of rim enhancement.

A

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and esophagus are not superimposed, and the abnormal connection can be visualized as a thin tract traversing the posterior tracheal wall, with contrast subsequently spreading along the tracheal wall.12 This position will also allow the examining radiologist to benefit from the use of gravity in the filling of the more anterior trachea from the posterior esophagus, which is being opacified with radiographic contrast via pressure injection in order to try and stent open even the smallest of communications.

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SECTION 5 ❖ The Airway the tracheobronchial tree can be best demonstrated by CT, although MRI may also be used to assess the central airway (Fig. 84-32).2

Bronchial Atresia Occasionally, a cystic lesion in the lung of a fetus or newborn may be mistaken for a CPAM, previously referred to as a congenital cystic adenomatoid malformation (CCAM). These mimickers may be due to an area of obstructed lung distal to an atretic segment of bronchus, and actually represent an area of bronchial atresia (Fig. 84-33).

Laryngomalacia Laryngomalacia is the most common laryngeal disease of infancy and typically presents with inspiratory stridor at rest with normal cry. Laryngomalacia results from reduced laryngeal tone and/or abnormal pharyngeal laxity with resultant collapse of supraglottic structures during inspiration, leading to airway obstruction. Most cases are mild with symptoms resolving by the age of 12–24 months.16 Approximately 10% of cases are severe, manifesting symptoms such as poor weight gain, feeding difficulties, dyspnea or respiratory distress, OSA, or cardiopulmonary complications, and warrant further evaluation or more aggressive treatment.16 Infants with signs of severe disease have a higher prevalence of associated abnormalities,

FIGURE 84-30. Tracheoesophageal fistula (TEF) (H-type). A 7-day old female with history of imperforate anus, now with increased oral secretions. Prone oblique view of the chest at the time of pullback esophagram demonstrates a large tubular communication (arrows) between the posterior esophagus and the anterior trachea. Note the opacification of the tracheobronchial tree as outlined by barium due to the above noted anomalous communication between the esophagus and trachea. Opacification of the airway (arrowheads) cephalad to the TEF is noted, and is due to concomitant aspiration from above at the time of injection of barium into the upper most portion of the cervical esophagus (not shown).

Occasionally, an ectopic bronchus may originate directly from the trachea (termed “pig bronchus” or “bronchus suis” as this is the typical anatomy in the porcine species). The aberrant bronchus usually originates within 2 cm of the carina and is more common on the right (Fig. 84-31); this may replace a missing branch from one of the upper lobe bronchi or may be supernumerary.2,12 An ectopic tracheal bronchus may be associated with bronchomalacia or recurrent infections.12 Unilateral bronchopulmonary agenesis is rare, occurring in combination with absence of the ipsilateral pulmonary arteries and veins.2 Disorders of development of

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FIGURE 84-31. Pig bronchus. An 8-month-old male former 37-week preemie with history of giant omphalocele status post repair, pulmonary hypoplasia, and pulmonary hypertension. Shaded surface reconstruction image of the airway from contrast enhanced CT of the chest demonstrates an anomalous bronchus on the right (arrows), with the takeoff above the level of the right upper lobe bronchus (same patient as in Fig. 84-37 below).

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CHAPTER 84 ❖ Radiologic Evaluation of the Pediatric Airway 1445

A

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FIGURE 84-32. Pulmonary agenesis (right). A 3-day-old male with ambiguous genitalia and dextrocardia. Frontal radiograph of the chest (A) and coronal reformation (B) from contrast-enhanced CT of the chest demonstrate dextroposition of the cardiac apex due to negative mass effect on the right secondary to absence of the right lung. On the CT image, note is made of lack of visualization of the tracheobronchial tree on the right.

A

D

B

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E

F

FIGURE 84-33. Bronchial atresia (pre- and postnatal). A 28-week gestational age female fetus with left lung lesion for suspected CCAM or pulmonary sequestration, and postnatal CT of the chest performed at day 2 of life. Axial (A) and coronal (B) T2 HASTE images from fetal MRI, axial soft tissue images (C) from contrast-enhanced CT of the chest with coronal soft tissue windows (D) and two representative coronal images on lung/bone algorithm (E,F) demonstrate a fluid-filled structure within the region of the left hilum (arrowheads) (A–D) which is situated proximal to the expected takeoff of the left upper lobe bronchus. There is adjacent air trapping (asterisks) (E), and lack of visualization of the takeoff of the left upper lobe bronchus (arrow) (F).

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most commonly tracheomalacia (Fig. 84-34), vocal cord paralysis (Fig. 84-35), and subglottic stenosis.16 Laryngoscopy is the gold standard for diagnosis. Airway fluoroscopy has relatively low sensitivity, but may reveal findings of narrowing of the supraglottic portion of the larynx, abnormal downward, posterior movement of the epiglottis, and anterior displacement of the aryepiglottic folds during inspiration.1,2

Tracheomalacia and Bronchomalacia Tracheomalacia is the most common pediatric disease of the trachea, presenting with symptoms of expiratory stridor, wheezing, cough, recurrent respiratory tract infections, or cyanotic episodes, which may be exacerbated by cough, feeding, crying, or other activities that increase respiratory effort. However, due to impaired clearance of secretions, patients are at risk for recurrent infections, and in severe cases may develop bronchiectasis.17 The term tracheomalacia refers to softness or weakness of the trachea resulting in excessive collapse, usually involving the intrathoracic tracheal segment. If the extrathoracic segment of the trachea is involved, inspiratory or biphasic stridor may occur. Tracheobronchomalacia refers to excessive collapse of both the trachea and central bronchi (Fig. 84-36), although the term has occasionally been used interchangeably in the literature with tracheomalacia, a custom which will be continued in this text. Bronchomalacia refers to weakness and collapse of the central bronchi and is seen less commonly in isolation (Fig. 84-37).

A

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FIGURE 84-34. Tracheomalacia. A 4-month-old female with past history of repaired H-type TEF, now with cough and question of aspiration. Two lateral views of the esophagus obtained at the time of pullback esophagram and during vigorous crying, demonstrate marked change in caliber of the thoracic trachea (arrows) (open in A and closed in B) due to tracheal collapse, secondary to changes in intrathoracic pressure.

C

FIGURE 84-35. Vocal cord paralysis. A 2-year-old male, former 30-week preemie with prior history of endotracheal intubation and CPAP, now with concern for subglottic stenosis. Multiple frontal views of the airway obtained during high KV filtered fluoroscopic airway examination with the patient crying vigorously demonstrate abnormal motion of the left vocal cord as evidenced by adduction through all phases of crying (arrows) (cords opened in A at rest, partially closed in B, and closed in C when crying).

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CHAPTER 84 ❖ Radiologic Evaluation of the Pediatric Airway 1447

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D

FIGURE 84-36. Tracheobronchomalacia. A 4-year-old male with 1–2 month history of wheezing. Frontal and lateral radiographs of the airway obtained during high KV filtered fluoroscopic airway examination with the patient crying/phonating demonstrate the airway to be opened (arrows) and well visualized on the frontal (A) and lateral (B) views at rest, as opposed to complete intrathoracic tracheal airway collapse (arrows) on the frontal (C) and lateral (D) views obtained during maneuvers.

A

B

FIGURE 84-37. Bronchomalacia. An 8-month-old male former 37-week preemie with history of giant omphalocele status post repair, pulmonary hypoplasia, and pulmonary hypertension (same patient as in Fig. 84-31 above). Shaded surface reconstruction images of the airway from contrast enhanced CT of the chest during inspiration (A) and subsequently during expiration (B) demonstrate diffuse decrease in caliber of the bronchi during the expiratory phase of the respiratory cycle. Again note the pig bronchus as in Figure 84-31 above.

Tracheobronchomalacia can be focal or diffuse (localized or generalized) or result from primary or secondary causes (congenital or acquired). Primary tracheobronchomalacia is usually self-limited, with most infants outgrowing the condition by 2 years of age.1,17 Primary tracheobronchomalacia is more common in preterm infants, children born with TEF, and has been associated with diseases resulting in abnormal cartilage development, including chondromalacia and the mucopoly-

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saccharidoses.18 Secondary tracheobronchomalacia is more common than primary, often resulting from prolonged intubation, although may also be caused by prior trauma, infection or chronic inflammation, or long-standing extrinsic compression by such etiologies as vascular rings, slings or other anomalous vessels, thoracic cage deformities including scoliosis and cavus excavatum, or various mediastinal masses, similar to the etiologies causing tracheal stenosis.18 Tracheobronchomalacia

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has been associated with many other conditions, including gastroesophageal reflux disease, cardiovascular anomalies, chronic lung disease of prematurity (CLD) (formerly termed bronchopulmonary dysplasia [BPD]), subglottic stenosis, laryngo-malacia , vocal cord paralysis, and conditions associated with immature and autonomic nervous system including neurologic impairment and developmental delay.18 By definition, tracheomalacia is present when the central airway collapses by greater than 50% of its luminal diameter during expiration, although to our knowledge, there is currently no standard imaging grading system for severity that correlates with clinical symptomatology. Some degree of collapsibility is normal in infants due to immaturity of the airway.2,17 Direct visualization with laryngoscopy or bronchoscopy is the gold standard for diagnosis of laryngomalacia and tracheobronchomalacia. Plain radiography and airway fluoroscopy, using a high KV filter, can be used as a noninvasive means of evaluating the airway during inspiration and expiration, although both techniques have relatively low sensitivity in assessing airway collapse when compared with bronchoscopy.19 Low-dose MDCT with 3-D reconstructions of the airway, performed at end inspiration and during dynamic expiration in older children who are able to follow breathing instructions, versus at end expiration in infants and younger children via controlled ventilation (generally required for children under 5 years), has also been used to assess both diffuse and focal airway collapse and readily allows assessment of the relationship between the airway and adjacent structures. A decrease in cross-sectional area by more than 50% is diagnostic of tracheomalacia per CT criteria.17 Dynamic imaging during forced expiration or coughing is more sensitive than scanning at end expiration due to the higher intrathoracic pressures generated during active exhalation.17 Anterior bowing of the posterior tracheal membrane and some degree of tracheal narrowing occurs during expiration in normal infants, but there should be less than 50% decrease in luminal area.2,17 MDCT with contrast may be especially helpful when extrinsic compression by aberrant vessels or other mediastinal structures is suspected.

A

B

Bronchiectasis Bronchiectasis can be seen in many clinical settings, from the more common etiologies such as cystic fibrosis (CF) and CLD (Fig. 84-38), to the less common causes seen with heterotaxy syndromes (e.g., Kartagener syndrome). This can lead to bacterial overgrowth, which can then lead to further damage to the bronchial tree, leading to a viscous cycle of progressively worsening bronchiectasis.

Vascular Anomalies, Rings, and Sling The aortic arch and mediastinal great vessels develop from a series of six paired primitive arches, according to Edward’s hypothetical double aortic arch (DAA) system.20,21 Aberrant persistence or regression of various segments of these arches can result in anomalous course of the mediastinal great vessels, which may encircle or otherwise compress the airway

Ch84.indd 1448

C FIGURE 84-38. Bronchiectasis (CF and BPD). A 3-year-old male former 27-week preemie with chronic lung disease and 8-yearold female with exacerbation of cystic fibrosis. Frontal radiograph of the chest in a patient with CF (A) demonstrates multiple ring-like shadows (arrow) in keeping with bronchiectasis. Frontal radiograph of the chest in a 3-year-old patient with chronic lung disease of prematurity (B) demonstrates ring-like thickening of the bronchi (arrow) with associated right lower lobe air-trapping and scattered upper lobe atelectasis (arrowheads). The areas of bronchiectasis (arrows) are better appreciated on the coronal reformation from contrast-enhanced CT of the chest (C).

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CHAPTER 84 ❖ Radiologic Evaluation of the Pediatric Airway 1449 and esophagus. Depending on the location and degree of narrowing, patients can present with respiratory symptoms including stridor, respiratory distress, cough or recurrent infections, or alternatively with gastrointestinal symptoms such as dysphagia, gastroesophageal reflux, choking, or failure to thrive.21,22 Due to significant overlap of clinical symptoms, vascular rings may be misdiagnosed as asthma or reactive airways disease.21 Long-standing airway compression by anomalous vessels or other mediastinal structures can also result in focal tracheobronchomalacia.18,21 Patients with significant airway impingement tend to present at a younger age than those with compression primarily involving the esophagus.22 If assessed very carefully, vascular rings can be diagnosed on two view chest radiographs alone, as they will cause significant ventral bowing of the trachea on the lateral view, and will be associated with an additional soft tissue structure to the right of the trachea on the frontal view, either due to a right arch in a patient with an aberrant left subclavian artery, or due to the right arch in a patient with a DAA (Fig. 84-39). A vascular ring is formed when the trachea and esophagus are completely encircled by mediastinal vessels and their supporting structures. The most common symptomatic ring is a DAA (Fig. 84-40).2,20–22 In about 80% of cases the right arch is larger and more superiorly located than the left arch; in some cases a segment of the nondominant arch may be severely hypoplastic or atretic, forming a fibrous ligament that may only be well demonstrated on MRI.2,20 The other relatively common vascular ring is the right aortic arch with an aberrant left subclavian artery originating as the last branch from the arch, distal to the takeoff of the right subclavian artery (Fig. 84-41). This usually results in less compression of the airway and tends to present later on in life, with milder symptoms.2,21,22 The vascular ring in this case is completed by a left-sided ductus arteriosus or ligamentum arteriosum (the fibrous remnant of the fetal ductus arteriosus).2,20–22 In addition, the origin of the aberrant subclavian artery is often dilated, similar in caliber to the aorta (diverticulum of Kommerell), due to persistence of the dorsal segment of the primitive fourth aortic arch, and may result in symptoms related to esophageal compression (referred to as dysphagia lusoria). Although less common, if there is no diverticulum at the level of the proximal aberrant left subclavian artery, the ligamentum arteriosum may be right sided, absent or taking an anterior course relative to the left common carotid artery, and thus will not form a complete ring; however, these patients may still present with dysphagia.20 There is variable descent of the thoracic aorta with both double and right-sided aortic arch with aberrant left subclavian artery, which may be seen on the right, left, or in the midline on radiographs or crosssectional imaging.20 Other true vascular rings are rare.20 Note that the ligamentum arteriosum cannot be seen directly on imaging, but may be inferred by tethering of the arch. Left aortic arch with aberrant right subclavian artery is a relatively common arch anomaly (Fig. 84-42), occurring in about 1 in 200 individuals, but is not a true vascular ring, as the ligamentum arteriosum is almost always left-sided (and is hence considered a normal variant of aortic arch branching), and

Ch84.indd 1449

A

B FIGURE 84-39. Ventral tracheal bowing secondary to vascular ring. A 9-month-old male with cough. Frontal (A) and lateral (B) radiographs of the chest demonstrate leftward deviation of the trachea due to the right-sided vascular structure (arrows) and marked anterior displacement of the tracheal air column (arrowheads) due to the traversing posterior vascular structure (same patient as in Fig. 84-40).

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C

A

B

D

E

FIGURE 84-40. Double aortic arch (DAA). A 1-month-old male with rhinovirus bronchiolitis and inability to extubate (same patient as in Fig. 84-39 above). Frontal (A) and lateral (B) views of the esophagus from upper GI study, coronal reformation (C) from contrastenhanced CT of the chest, and axial CT images from the same study at the level of the mid chest/mediastinum (D) and upper chest/ mediastinum (E) confirm the findings noted in Figure 84-40 above. The esophagus is ventrally displaced by the posterior crossing vessel (arrowheads). The right component of the DAA is confirmed on both coronal and axial images (RAA-arrows). The trachea and esophagus are circumferentially constricted by the larger right and smaller left aortic arches (LAA-arrows). The sine qua non of this aortic branching abnormality on cross-sectional imaging is that of four arterial vessels seen within the superior mediastinum (right subclavian [RSCA-arrows], right common carotid [RCCA-arrows], left common carotid [LCCA-arrows], and left subclavian [LSCA-arrows]), as opposed to the normal branching pattern of the left-sided aortic arch (right innominate, left common carotid, left subclavian). The fifth vessel is a venous structure (innominate vein).

does not generally result in airway symptoms. However, as with a right arch with aberrant left subclavian artery, the origin of the aberrant artery may be dilated and cause symptoms of dysphagia.20,21 A pulmonary sling results from anomalous origin of the left main pulmonary artery from the right pulmonary artery (as opposed to the main pulmonary artery), whereby it must course between the trachea and esophagus just above the level of the carina, as it courses toward the left hemithorax (Fig. 84-43).2,21,22 This may compress the right main bronchus and trachea, leading to air trapping, atelectasis, or recurrent infections. Pulmonary sling is associated with abnormal tracheal development, including formation of complete tracheal rings, which can result in severe fixed tracheal stenosis. The right brachiocephalic (aka innominate) artery can also cause compression of the trachea at the level of the thoracic inlet in young children; this occurs more frequently when the artery originates from the aortic arch to the left of midline (Fig. 84-44).2,23 A higher incidence of innominate artery compression has been reported in patients with prior esophageal atresia.2

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If a vascular ring or other vascular compression syndrome is suspected, initial imaging work-up may include chest radiographs, echocardiography, fluoroscopic barium esophagography, and sometimes airway fluoroscopy. Proper diagnosis may ultimately require cross-sectional imaging with either contrast-enhanced CT or MRI (not requiring intravenous contrast administration). Chest radiographs may show variable degrees of unilateral or bilateral hyperinflation, atelectasis, or areas of consolidation, depending on the site and severity of compression or associated tracheobronchomalacia.21 Even in young infants whose normally prominent thymus may form most of the superior mediastinal contour, the side of the aortic arch can usually be inferred by extrinsic compression on the tracheal wall and slight deviation of the airway toward the contralateral side on the frontal radiographic or fluoroscopic evaluation of the chest.2,21 In DAA, there may be bilateral tracheal impressions on the frontal chest radiograph, with the right-sided impression usually slightly more cephalad; although midline trachea on a well-positioned frontal view should also raise suspicion for DAA. Lateral chest radiographs will show anterior bowing of the trachea in a more

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CHAPTER 84 ❖ Radiologic Evaluation of the Pediatric Airway 1451

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A

B

D

FIGURE 84-41. Right aortic arch with aberrant left subclavian artery (RAA, LSCA). A 2-year-old male with prior history of TEF repair at 6 weeks of age. Lateral esophagram image (A), sagittal reformation (B), axial (C), and coronal reformation (D) CT images from the same contrast-enhanced CT study demonstrate ventral displacement of the esophagus by the posterior crossing vessel (arrow). The airway is displaced ventrally by the crossing vessel, best demonstrated on the sagittal reformation (arrow). The right-sided aortic arch is confirmed on the coronal and axial images (RAA-arrows), and the posteriorly crossing aberrant vessel (left subclavian artery) (LSCA-arrows) is seen emanating from a diverticulum of Kommerell.

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E

FIGURE 84-42. Left aortic arch with aberrant right subclavian artery (LAA, RSCA). A 9-year-old male with velocardiofacial syndrome (22Q deletion) and possible vascular ring. Frontal (A) and lateral (B) views of the esophagus from an esophagram, axial source MRA images from the level the lower portion of the upper mediastinum (C) and upper mediastinum (D), as well as MIP (multiple intensity projection) (E) images from MRA confirm the position of the aberrantly coursing vessel posterior to the esophagus (arrows). The right subclavian artery (RSCA-arrows) is the last branch coming off of the aorta and passes/crosses posterior to the esophagus in order to ascend toward the level of the right axilla. As in most cases, there is no right-sided ductus arteriosus, and hence this is considered a normal vascular variant and not a vascular ring.

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FIGURE 84-43. Pulmonary sling. A 4-year-old female with trisomy 21 and tracheal stenosis. Contrast-enhanced CT angiogram of the chest obtained at the level of the main pulmonary artery demonstrates abnormal branching of the pulmonary artery as the left pulmonary artery (LPA-arrows) emanates from the right pulmonary artery (A) (RPA-arrows) and not the main pulmonary artery itself (MPA-arrows), and subsequently courses between the esophagus and the trachea in order to continue on into the left hemithorax (B).

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FIGURE 84-44. Airway compression from crossing innominate artery. A 1-month-old male status post repair of TEF, with segmental tracheomalacia, now with pronounced stridor and respiratory distress. Coronal (A) and sagittal (B) MIP images from contrast-enhanced CT of the chest demonstrate compression of the trachea (T-arrows) due to the crossing innominate artery (IA-arrows) on the right.

superior location with DAA (see Fig. 84-39 above) and with aberrant right or left subclavian arteries, and more distally with a pulmonary sling.2,21 Lateral views of the airway show narrowing or impression along the anterior wall of the trachea near the thoracic inlet in innominate artery compression syndrome.2 Barium esophagography will also show characteristic impression on the posterior wall of the upper thoracic esophagus (in Raider’s triangle) in the lateral projection with DAA and both right and left aberrant subclavian arteries coursing from a left or right aortic arch, respectively.2,21 Pul-

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monary sling is the only vascular anomaly which will result in impression on the posterior wall of the trachea and anterior margin of the esophagus on lateral chest radiographs or fluoroscopic contrast esophagography, although other subcarinal masses, cysts (Fig. 84-45), or lymph nodes may result in impression in a similar location.2,21 MRI with MR angiography (MRA) or CT angiography (CTA) is especially helpful when surgery is considered; both modalities can clearly delineate the vascular morphology and their relationship to the airway, as well as its effect on the airway and other medi-

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CHAPTER 84 ❖ Radiologic Evaluation of the Pediatric Airway 1453

A

FIGURE 84-45. Bronchogenic cyst. A 3-month-old female with respiratory distress, question mediastinal mass. Contrastenhanced CT in the immediate subcarinal region demonstrates a low-attenuation mass (asterisk) leading to ventral displacement of the airway with the mainstem bronchi (RMSB-arrow and LMSB-arrow) seen draping over the subcarinal lesion.

astinal structures, and have replaced invasive angiography for assessing mediastinal vascular anomalies.2,21

TUMORS AND TUMOR-LIKE CONDITIONS

B

Laryngotracheal Papillomatosis (Recurrent Respiratory Papillomatosis) Laryngotracheal papillomatosis is the most common benign neoplasm of the airway in children, resulting from chronic infection with human papilloma virus (HPV) 6 or 11 with recurrent growth of papillomas in the aerodigestive tract.24 When manifest in children, the disorder is most commonly related to vertical transmission from an infected mother during vaginal delivery, although there have been reports of in utero transmission.24 Only a small percentage of exposed infants will develop the disease.24 Children may present with hoarseness, voice change, stridor, or less commonly chronic cough, recurrent pneumonia, failure to thrive, dyspnea, dysphagia, or even acute respiratory distress if papillomas grow large enough to obstruct the airway. A worse prognosis occurs when the child presents at a younger age. Papillomas generally initially involve the larynx, with progression to extralaryngeal sites occurring in up to 30% of children and 16% of adults.24 These extralaryngeal sites include the oral cavity, trachea, bronchi, and esophagus in decreasing order of frequency. Radiographs of the airway may show lobulated soft tissue masses as nodules along the laryngotracheal air column. Pulmonary involvement is rare, but when it occurs, typically begins with small peripheral parenchymal nodules which slowly increase in size and then cavitate (Fig. 84-46); these may show air-fluid levels on radiographs

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C FIGURE 84-46. Laryngeal papillomatosis. An 8-year-old female with history of laryngotracheal papillomatosis on interferon therapy. Contrast-enhanced CT of the chest imaged on lung windows in the axial (A), coronal (B), and sagittal (C) planes demonstrates multiple cystic lesions (arrows) throughout the lung. Note is made of multiple soft tissue nodules (arrowheads) along the visualized trachea in keeping with papillomas.

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or CT, occurring in cysts or cyst-like lesions. To date, there is no cure for laryngotracheal papillomatosis, with many patients requiring intermittent surgery to debulk airway papillomas. Medical therapy may be used when frequent surgery is required, or if there is extralaryngeal spread. Patients may require tracheostomy if there is severe respiratory distress due to airway obstruction, although placement of an artificial airway has been associated with disease progression.24 There is hope that introduction of the multivalent vaccines against HPV will decrease the incidence of this disease in the future.

Other Intrinsic and Extrinsic Masses Affecting the Airway Various congenital, neoplastic, infectious, or traumatic abnormalities of the head, neck, and mediastinum can result in intrinsic obstruction or extrinsic compression of the airway, with differential diagnoses varying by age and location. More common masses in a neonate include infantile hemangioma, lymphatic malformation, or teratoma.2 Juvenile nasopharyngeal angiofibroma (JNAF) (Fig. 84-47) may occur in adolescent males, presenting with congestion and intermittent epistaxis. Normal structures in ectopic locations can result in airway obstruction, most commonly seen with ectopic thyroid tissue, which can arrest anywhere along its normal course of descent from the tongue base to the suprasternal notch, and may result in oropharyngeal airway obstruction when located at the base of the tongue as described above. Ectopic thymus has also been reported to occur within the trachea.2 Other airway tumors are rare, including laryngeal fibroma, chondroma, or neurofibroma, carcinoma, and carcinoid tumor (Fig. 84-48).2 Extrinsic anterior mediastinal abnormalities may compress or posteriorly displace the trachea. These include lymphoma

A

B

and leukemia, teratomas (Fig. 84-49), or less commonly, other germ cell neoplasms, thymic cysts, lipomas, venolymphatic malformations or occasionally, Langerhans cell histiocystosis involving the thymus. Middle mediastinal abnormalities which can compress the tracheobronchial tree include infectious or neoplastic adenopathy, including tuberculosis, foregut duplication cysts, and rare malignant tumors. Posterior mediastinal abnormalities may compress or anteriorly displace the trachea, and include tumors of neural or nerve sheath origin, such as tumors along the neuroblastoma/ ganglioneuroblastoma/ganglioneuroma spectrum, neurofibroma (Fig. 84-50), or schwannoma; and bronchopulmonary foregut duplication cysts and neurenteric cysts, the latter usually distinguishable by their association with vertebral body segmentation anomalies.2

LARYNGOTRACHEAL TRAUMA Laryngotracheal injury may result from either blunt or penetrating trauma, both of which occur relatively uncommonly in children.25 Blunt laryngotracheal trauma is more common than penetrating injury, and is most commonly due to bicycle or motor vehicle accidents, including impact to the neck by seatbelts or airbags, or due to a “clothesline type” injuries. Penetrating trauma tends to occur in slightly older children, with a mean age of 12 years at the time of occurrence as compared to a mean age of 10 years in patients subject to blunt trauma. Penetrating injury may be caused by gunshot wounds, stabbing injuries, or by impaling foreign bodies (e.g., glass).25 Clinical signs of airway injury include stridor, hoarseness, aphonia, cough, hemoptysis, respiratory distress, cyanosis, neck tenderness, tracheal deviation or step off, neck hematoma, and subcutaneous air with palpable crepitus.

C

FIGURE 84-47. Juvenile nasopharyngeal angiofibroma (JNAF). A 13-year-old male with large nasal mass. Contrast-enhanced axial CT of the head (A), MRI sagittal contrast-enhanced T1 MPRAGE (B), and lateral view of the nasopharyngeal region from digital subtraction angiogram (DSA) injection (C) via the left external carotid artery (patient’s nose is to the left of the image) demonstrates a large mass (M) in the nasopharyngeal region with typical involvement of the sphenopalatine region on the left (arrow) (A), and with avid uptake of radiographic contrast material (arrowheads) during angiographic study reflecting the marked increased vascularity of this lesion.

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CHAPTER 84 ❖ Radiologic Evaluation of the Pediatric Airway 1455

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D

FIGURE 84-48. Carcinoid tumor (bronchial). A 16-year-old male with asthma and persistent right upper lobe atelectasis. Patient is PPD negative. Frontal (A) and lateral (B) radiographs of the chest, axial (C) contrast-enhanced CT of the chest with coronal reformation (D) demonstrate right perihilar atelectasis (arrowheads), which upon closer inspection on cross-sectional imaging views is seen to be secondary to an endoluminal/endobronchial lesion (arrows).

Endoscopy may be performed to assess or confirm airway injury. Laryngotracheal separation and tracheobronchial rupture are rare in both children and adults, but have a high mortality.25 When this occurs, the site of tracheobronchial rupture more commonly occurs within the main bronchi, which may

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result in “fallen lung” sign and both pneumomediastinum and persistent large pneumothorax/pneumothoraces which does/ do not reduce despite the presence of a chest tube (Fig. 84-51). Imaging evaluation should begin with radiographs of the cervical spine and chest, which may demonstrate edema of

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A A

B

B

C FIGURE 84-49. Teratoma (chest). A 13-year-old female with intermittent cough and sputum changing in color from green to brown. Frontal radiograph of the chest (A), axial (B), contrast-enhanced CT of the chest with coronal reformation (C) demonstrates a large right-sided mediastinal mass (M) with calcifications seen along the lower aspect (arrowheads). On cross-sectional imaging, multiple tissue types can be identified including low attenuating fat (arrows), mildly attenuating soft tissue (the majority of the mass), and markedly attenuating calcium/bone (arrowheads), typical of the findings seen in a teratomatous lesion. Note the compression of the right mainstem bronchus (RMSB-arrows).

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C FIGURE 84-50. Neurofibromatosis type I (NF I) with airway compromise. A 15-year-old male with neurofibromatosis type I and multiple plexiform neurofibromas. Coronal (A), sagittal (B), and axial (C) STIR MRI images of the cervical region demonstrate innumerable plexiform neurofibromata (M) about the neck, right greater than left, with resultant marked leftward airway deviation/displacement and critical narrowing of the airway (arrows).

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CHAPTER 84 ❖ Radiologic Evaluation of the Pediatric Airway 1457

B

FIGURE 84-51. Tracheal laceration (conventional radiograph). Newborn male with hemoptysis after traumatic intubation. Portable frontal radiographic view of the chest obtained in the trauma bay, obscured at the lung bases by the hands of a restraining adult, demonstrates bilateral pneumothoraces (arrows) (probable tension on the right) and collapsed lungs in addition to pneumomediastinum (arrowheads) and subcutaneous emphysema (asterisks), all due to air leak secondary to tracheal laceration.

the airway or surrounding soft tissues or subcutaneous air. CT can assess for laryngotracheal injury in selected cases (Fig. 84-52). Water soluble contrast esophagram or CTA may be performed in cases of penetrating trauma.25

C FIGURE 84-52. Tracheal laceration (CT). A 7-year-old male with history of pneumomediastinum and seizures. Coronal (A) and sagittal (B) reformations and axial virtual bronchoscopy (C) images from CTA of the chest demonstrate a posterior lateral defect within the trachea on the right (arrows) secondary to tracheal laceration, thought to be due to traumatic intubation.

SUMMARY

A

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Neonates, infants, and children are at risk for a number of infectious, accidental, congenital, and neoplastic abnormalities potentially affecting patency of their airways. Although at times definitive diagnosis may be possible, there is often significant overlap in clinical symptoms among various etiologies which may preclude this from occurring. There are a number of noninvasive imaging modalities/techniques available that allow evaluation of pediatric airway disorders. In most cases, initial evaluation is performed with plain radiographs of the airway or chest. Meticulous attention to good

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technique is vital, as poor technical quality can simulate disease or limit diagnostic assessment. Dynamic assessment can be provided with airway fluoroscopy, although this is less sensitive than direct visualization with laryngoscopy and bronchoscopy for most airway disorders. Technological advances with CT and MRI allow for detailed static and dynamic evaluation of the airway, but should only be used in selected cases due to the risks of ionizing radiation with the former and relatively long scan times and frequent need for sedation with the latter.

References 1. Laya BF, Lee EY. Congenital causes of upper airway obstruction in pediatric patients: updated imaging techniques and review of imaging findings. Semin Roentgenol. 2012;47(2):147–158. 2. Mahboubi S, Kramer SS. The pediatric airway. J Thorac Imaging. 1995;10(3):156–170. 3. D’Agostino J. Pediatric airway nightmares. Emerg Med Clin N Am. 2010;28:119–126. 4. Chess MA, Chaturvedi A, Stanescu AL, Blickman JG. Emergency pediatric ear, nose and throat imaging. Semin Ultrasound CT MR. 2012;33(5):449–462. 5. Guldred LA, Lyhne D, Becker BC. Acute epiglottitis: epidemiology, clinical presentation, management and outcome. J Laryngol Otol. 2008;122:818–823. 6. Mayo-Smith MF, Spinale JW, Donskey CJ, Yukawa M, Li RH, Schiffman FJ. Acute epiglottitis: an 18-year experience in Rhode Island. Chest. 1995;108(6):1640–1647. 7. Garner D, Weston V. Effectiveness of vaccination for Haemophilus influenzae type B. Lancet. 2003;361:395–396. 8. Srivastava G. Airway foreign bodies in children. Clin Pediatr Emerg Med. 2010;11:67–72. 9. Kiyan G, Gocman B, Tugtepe H, Karakoc F, Dagli E, Dagli TE. Foreign body aspiration in children: the value of diagnostic criteria. Int Pediatr Otorhinolaryngol. 2009;73:963–967. 10. Feres MF, Hermann JS, Cappellette M Jr, Pignatari SS. Lateral X-ray view of the skull for the diagnosis of adenoid hypertrophy: a systematic review. Int J Pediatr Otorhinolaryngol. 2011;75(1):1–11. 11. Dighe MK, Peterson SE, Dubinsky TJ, Perkins J, Cheng E. EXIT procedure: technique and indications with prenatal

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12.

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15. 16.

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18.

19.

20.

21.

22.

23.

24. 25.

imaging parameters for assessment of airway patency. Radiographics. 2011;31:511–526. Berrocal T, Madrid C, Novo S, Gutiérrez J, Arjonilla A, Gómez-León N. Congenital anomalies of the tracheobronchial tree, lung, and mediastinum: embryology, radiology and pathology. Radiographics. 2003;24(1):e17. Epub 2003 Nov 10. Mong A, Johnson AM, Kramer SS, et al. Congenital high airway obstruction syndrome: MR/US findings, effect on management, and outcome. Pediatr Radiol. 2008;38:1171–1179. Saadai P, Jelin EB, Nijagal A, et al. Long-term outcomes after fetal therapy for congenital high airway obstructive syndrome. J Pediatr Surg. 2012;47:1095–1100. Leboulanger N, Garabédian E. Laryngo-tracheo-oesophageal clefts. Orphant J Rare Dis. 2011;6:81–90. Dickson JM, Richter GT, Meinzen-Derr J, Rutter MJ, Thompson DM. Secondary airway lesions in infants with laryngomalacia. Ann Otol Rhinol Laryngol. 2009;118(1):37–43. Lee EY, Boiselle PM. Tracheobronchomalacia in infants and children: multidetector CT evaluation. Radiology. 2009;252(1):7–22. Carden KA, Boiselle PM, Waltz DA, Ernst A. Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review. Chest. 2005;127(3):984–1005. Sanchez MO, Greer MC, Masters IB, Chang AB. A comparison of fluoroscopic airway screening with flexible bronchoscopy for diagnosing tracheomalacia. Pediatr Pulmonol. 2012;47(1):63–67. Ramos-Duran L, Nance JW, Schoepf UJ, Henzler T, Apfaltrer P, Hlavacek AM. Developmental aortic arch anomalies in infants and children assessed with CT angiography. AJR. 2012;198:W466–W474. Harty MP, Kramer SS, Fellows KE. Current concepts on imaging of thoracic vascular abnormalities. Curr Opin Pediatr. 2000;12:194–202. Shah RK, Mora BN, Bacha E, et al. The presentation and management of vascular rings: an otolaryngology perspective. Int J Pediatr Otorhinolaryngol. 2007;71(1):57–62. Vogl T, Wilimzig C, Bilaniuk LT, et al. MR imaging in pediatric airway obstruction. J Comput Assist Tomogr. 1990;14(2):182–186. Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryngoscope. 2008;118:1236–1247. Mandell DL. Traumatic emergencies involving the pediatric airway. Clin Pediatr Emerg Med. 2005;6:41–48.

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85

C H A P T E R

Cough Andrew J. Hotaling and James J. Jaber

The cough is the watchdog of the lungs. Chevalier Jackson, 1924 ough is a common, but frequently misunderstood, sign of illness. It is the most common symptom of respiratory tract disease, but it is not a diagnosis. Cough is the principal reason for more than 16 million physician office visits per year in the United States.1,2 The majority of diseases that occur in the first decade of life are respiratory in origin. It is estimated that respiratory illness causes one half of all illnesses and is responsible for two thirds of all infections in the first 5 years of life.3 The rational treatment of cough requires that a diagnosis be made, and the more accurate and precise the diagnosis, the greater the opportunity for accurate and precise therapy. Moreover, the differential diagnosis of cough in the pediatric population is quite different from that of adults, so evaluation and management should not be based on adult protocols. Adolescents 15 years and older may be evaluated using adult guidelines.4 The goals of this chapter are first to discuss the anatomy, mechanism, and pathophysiology of cough, then to review pertinent elements in the history and physical examination of cough in children, and finally to discuss the differential diagnosis of cough with attention to specific and more common etiologic causes in childhood and their respective management.

C

ANATOMY, MECHANISM, AND PATHOPHYSIOLOGY OF COUGH Coughing is an important physiologic defensive mechanism that allows clearance of secretions and particulates from the airway after a stimulus. In addition to this inherent airway protective mechanism, there are three other protective mechanisms for the respiratory system: (1) gag reflex, (2) mucociliary escalator, which is able to clear all parts of the lungs down to the alveolar ducts, and finally (3) the phagocytic and lymphatic systems, which are the only effective clearance mechanisms beyond the terminal bronchiole level. With these four protective measures in place, the body is well adapted to combat most pulmonary and extrapulmonary infiltrates. Coughing has two important defensive functions: to expel foreign material from the airway and to remove excessive secretions from the airway. Coughing is often a ubiquitous symptom even in healthy children, with a mean of 11 cough episodes every 24 hours. Therefore, it is imperative that the clinician has a working knowledge of the anatomy, mechanism, and pathophysiology of pediatric cough, so as to be able to differentiate those coughs that are pathologic versus those that are benign. In addition, the clinician must, through a good history, distinguish between acute (4 weeks), which will result in a different differential diagnosis. In a healthy person, the primary system for airway protection is the mucociliary escalator, a self-cleaning mechanism. Coughing becomes a factor only when there is an abnormal type or quantity of material to be removed or when the mucociliary system has become ineffective, such as in cystic fibrosis. The stimuli for cough can be classified into four groups: chemical, mechanical, thermal, and inflammatory. Examples of these stimuli are cigarette smoke, vascular ring, cold and/or dry air, and increased mucus secondary to inflammation, respectively. Each cough occurs through the stimulation of a complex reflex arc that has not been completely elucidated, but what is known is that each cough is initiated through the stimulation of cough receptors, that is, afferent pathways, that exist not only in the epithelium of the upper and lower respiratory tract, but also in the pericardium, esophagus, diaphragm, stomach, and external ear canal.1,5 An otolaryngologist cleaning cerumen from the external auditory canal typifies a wellknown example of this reflex arc. Inadvertent stimulation of ear canal and Arnold’s nerve, a branch of vagus nerve, causes an involuntary cough.6 Presumably, this complex neurosensory system with multiple points of innervations serves as an evolutionary airway advantage protecting the airway. The afferent pathway begins with receptors located in the upper levels of the respiratory tract and extending to the level of the terminal nonrespiratory bronchioles. Chemical receptors sensitive to acid, heat, and capsaicin-like compounds trigger the cough reflex via activation of the type 1 capsaicin receptor.7,8 In addition, mechanical cough receptors, which are the slow and rapid adapting receptors located at the level of the carina and larger bronchi, respond to mucosal tactile stimulation (i.e., tracheal suction). The proximal airways (larynx and trachea) are most sensitive to mechanical stimulation, and the distal airways are more sensitive to chemical stimulation. These receptors collectively are called the C-fiber receptors. Pulmonary stretch receptors are located in the smooth muscle of the respiratory tree and are stimulated by mechanical forces in the airway.9 Most receptors are highly concentrated in the larynx, carina, and at other airway bifurcations, and no receptors lie beyond the terminal bronchioles as these receptors are the guardians of the airway. Of these, the carina is the most sensitive.10 Afferent pathways from cranial nerve (CN) X and, to a lesser extent, CN IX and phrenic nerve carry impulses to the cough center in the medulla, which itself is under some control by higher cortical centers. However, no discrete cortical cough center has been identified. Once the stimulation is processed, the efferent pathway for cough is transmitted via CN X and spinal motor nerves C2 to

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S2, including the phrenic nerve to expiratory musculature to produce the cough. The efferent signals can result in stimulation of the diaphragmatic, pharyngeal, laryngeal, intercostal, abdominal wall, and pelvic muscle groups. Regardless of the mode or initial afferent stimulation, all coughs are generated by this efferent pathway. However, specific pattern and quality of a cough depend on the site and type of stimulation (see later). These afferent and efferent pathways are illustrated in Fig. 85-1.1 There is also a cortical input, and the cough can be initiated or suppressed by an awake patient. Voluntary suppression is common in adolescent patients with lung disease.11 The mechanics of a cough involve developing and then sustaining a high-velocity column of air to alleviate the irritation. The mechanism of cough production can be divided into four phases: (1) inspiratory, (2) contractive, (3) compressive, and (4) expiratory.11 The inspiratory phase usually begins with a deep inspiration that includes maximal abduction of the vocal cords with an increase in chest wall dimension, creating a more negative intrapleural pressure. This ensures that the lungs are filled with an adequate volume of air necessary to generate an effective cough. The second phase, the contractive phase, involves the various muscles of expiration receiving appropriate neural stimuli and subsequently contracting against closed glottic or supraglottic sphincters,

or both. These muscular contractions lead to the third phase, the compressive phase, in which there is a marked elevation of alveolar, pleural, and subglottic airway pressures. It is the closure of the false vocal cords that contributes to the greatest sphincter effect in preventing the flow of air during this phase. The final phase is expiratory, in which the glottis opens quickly, resulting in a release of trapped air at high flow rates, causing movement of secretions and foreign material from the larger airways into the pharynx or beyond. This sudden movement has been described as the bechic blast by Jackson.9 The peak flow approaches 25,000 cm/s, approximately Mach 0.75 (Mach 1 is the speed of sound).12 The peak flow continues after glottic opening, owing to dynamic collapse of the larger airways and continued intrathoracic compression of gas. With prolonged expiration, the subsequent compression of pulmonary parenchyma into airways squeezes more distal secretive material into larger airways, termed the tussive squeeze by Jackson. As mentioned earlier a similar pathway generates all coughs; however, specific patterns of cough depend on the site and type of stimulation. Mechanical laryngeal stimulation results in immediate expiratory stimulation, presumably to protect the airway from aspiration; stimulation distal to the larynx causes a more pronounced phase to generate the airflow necessary to remove the offending agent.

RECEPTORS

N

Higher centers

Paranasal sinuses

A

TS EN ER FF

External auditory canal Tympanic membrane

N —Higher centers —V Trigeminal —IX Glossopharyngeal —X Vagus —C3,4,5 Phrenic

Nose Pharynx Larynx Pleura Tracheobronchial tree Pericardium Diaphragm Peritoneum Esophagus, stomach Cough center of medulla

EFFERENTS

EFFECTORS

Vagus nerve

• Larynx • Tracheobronchial tree

Phrenic and other spinal motor nerves

• Expiratory musculature • Diaphragm • Abdominal muscles • Intercostal muscles • Peritoneal muscles

FIGURE 85-1. Afferent and efferent pathways of cough stimulation. (From Holinger and Sanders.1)

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CHAPTER 85 ❖ Cough It appears that increased secretions are necessary for an effective cough. In a study by Camner et al., small tagged particles were instilled in the airways of healthy patients.13 Coughing by healthy patients did not eliminate particles from the airway; however, patients with lung disease were able to eliminate the particles by coughing. It was concluded that increased tracheobronchial secretions are a necessary component for effective coughing, acting like a carrier. Glottic closure is not essential for coughing, and a suboptimal cough can occur in intubated patients. This is in part due to the peak flow rate occurring earlier and is submaximal in comparison with the cough in patients with a competent glottis. Furthermore, an endotracheal tube prevents tracheal compression, permitting high flow rates only after full inspiration and only in the initial phases of coughing. Thus, multiple elements are required for the generation of a cough, including an intact sensory apparatus, neural processing, timing and distribution of neuromuscular activity and an adequate musculoskeletal system. Cough is noted to be less vigorous in newborns than in older children. When stimulated by direct laryngoscopy, only 25% of premature infants cough, versus 50% of full-term infants. Children who do not cough effectively may be at risk for atelectasis, recurrent pneumonia, and chronic airway disease from aspiration and retention of secretions. Many disorders can impair a child’s ability to cough effectively, resulting in persistent, but ineffective, coughing (see Aspiration and Vocal Cord Paralysis sections).14

HISTORY, PHYSICAL EXAMINATION, AND LABORATORY STUDIES2,4 History Most illnesses associated with cough are caused by selflimited viral upper respiratory infections (vURIs). An accurate history may give the diagnosis, and if it does not lead to the specific diagnosis, the history will certainly narrow the differential diagnosis (Table 85-1). In some children, the quality of cough is recognizable and suggestive of a specific etiology, while in others, the diagnosis is much more elusive, requiring a more extensive laboratory and diagnostic work-up. The initial history should focus on several key elements such as age and circumstance at onset, quality of cough,

timing and triggers, associated symptoms, medical history, family history, and finally social history. Potential treatment is possible only after a precise diagnosis has been established that is guided by an excellent history. The age of the patient may suggest a diagnosis. Coughing in the neonatal group is unusual and suggests significant abnormality such as a congenital anomaly (e.g., tracheoesophageal fistula, tracheobronchomalacia), gastroesophageal reflux, cystic fibrosis, or chlamydial pneumonia. Attendance at a day-care center increases exposure to respiratory pathogens. Seasonal variation of cough in an older child may suggest an allergic etiology. Malabsorption, poor growth despite a large appetite, rectal prolapse, and nasal polyps raise the possibility of cystic fibrosis. Bordetella pertussis and pertussis-like viral infections can result in cough that has been described as the “100-day cough.”9 Infants with pertussis may not have the classic inspiratory whoop. Coughing associated with feeding suggests gastroesophageal reflux, aortic arch anomaly, unilateral vocal fold immobility, laryngeal cleft, or tracheoesophageal fistula. In any age group, particularly the toddler, a sudden acute cough which begins after playing may suggest the possibility of aspiration of a foreign body and must be investigated. Cough is the single most common symptom of a bronchial foreign body, present in up to 94% of cases.9 Recurrent viral upper respiratory infection is probably the most common cause of acute and chronic recurrent cough in children, with an average of eight or more episodes per year in preschool children.1,9 A habitual or psychogenic cough usually follows after resolution of a vURI. In some children, the quality of the cough is recognizable and suggestive of a specific etiology (Table 85-2).4 Classic recognizable coughs are important as barking or a brassy cough TABLE 85-2. Classic Recognizable Coughs in Children

Cough Quality

Croup, tracheomalacia, habit cough

Chronic “wet” cough

Suppurative process – bronchiectasis, CF, active infection, congenital malformations Postprandial GERD

Cough productive of casts

Bronchitis

Coughing with feeding Immunization status

Honking

Psychogenic

Malabsorption

Paroxymal cough (± whoop)

Pertusis and parapertusis

Staccato

Chlamydia in infants

TABLE 85-1. Key Historical Findings Of Cough Aspiration

Pollution Seasonal variation Wheezing

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Possible Differential Diagnosis or Contributing Factor

Barking or brassy cough

Choking episode (foreign body)

1461

Abbreviations: CF, cystic fibrosis; GERD, gastroesophgeal reflux. Source: Adapted and modified from Chang and Glomb.4

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may suggest a process that is occurring in the trachea or more proximal airway, whereas a loud Canadian goose-like “honking” cough that disappears at night is more reflective of a habitual cough. A chronic wet cough suggests a suppurative process that requires a more extensive work-up to rule out bronchiectasis, cystic fibrosis, active infection, immune deficiency, or congenital malformation. In a study of children presenting with a chronic cough, a “wet” quality to the cough was the most useful clinical marker of predicting a specific etiology (sensitivity of 96%, specificity was only 26%).15 A “seal-like bark” is typical of croup (laryngotracheobronchitis), and a paroxysmal cough with repeated coughs in quick succession, followed by a rapid inspiration (“whoop”), suggests pertussis. However, an infant with pertussis may present with no cough or a cough that leads to facial plethora or cyanosis. The paroxysm may terminate with vomiting or apnea. A whoop is uncommon in this age group. A staccato cough is heard in patients with Chlamydia pneumonia. The timing and triggers associated with cough can help guide the clinician. Gastroesophageal reflux is considered when the cough occurs postprandially or during sleep while lying supine. Coughing with feeding suggests an abnormal tracheoesophageal connection (i.e., laryngotracheoesophageal cleft and tracheoesophageal fistula), a unilateral vocal fold immobility, or an aortic arch anomaly. Cough-variant asthma is suggested by a cough occurring with exercise, cold exposure, laughing, or during sleep. The duration of the cough can be helpful. Often, it is difficult to distinguish between recurrent episodic coughing and persistent coughing. The most common causes of persistent coughing are reactive airway disease (asthma) and bronchitis, whereas recurrent episodic coughing is usually associated with recurrent upper respiratory infections. A productive cough usually occurs with a suppurative process, such as bacterial pneumonia. However, it is unusual for a young child to expectorate sputum, since the sputum is usually swallowed. If significant amounts of sputum are swallowed, vomiting may occur. A nonproductive or dry, hacking cough may be associated with a focal lesion in the airway. The association of coughing with hemoptysis is unusual in children. In such patients, one should consider bronchiectasis, cystic fibrosis, foreign bodies, pulmonary hemosiderosis, and tuberculosis. Sonorous breathing or snoring and rhinorrhea in the absence of upper respiratory infection suggest nasal obstruction. And, finally, a psychogenic cough is present during the day, especially most disruptive during school and typically disappears at night.4 Past medical history as well as family history may give insights into the etiology of the cough. Prematurity and a difficult neonatal course place children at a higher risk for asthma and atopy. Neonates who are small for their gestational age may have congenital infection. A family history of atopy or asthma increases the risk in offspring and suggests a diagnosis of either allergic rhinitis or asthma. Furthermore, a family history of cystic fibrosis or primary ciliary dyskinesia raises the suspicion for these familial inherited diseases.

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The possible effects of environmental pollution as well as exposure to indirect smoke must be considered when evaluating a child’s cough.16 It is important to ascertain where the child lives; epidemiology can have a dramatic impact on the diagnostic considerations, especially with respect to endemic fungal and parasitic infections. Residence in the inner cities of the United States is associated with exposure to pests such as cockroaches and mice, known allergens. Outdoor air pollution in inner cities is also associated with chronic cough. In a prevalence study of respiratory symptoms in secondary school children, the incidence of cough without cold was 14.8% in a high-pollution region versus 8.2% in a lowpollution region.17 Indoor air pollution due to biomass fuels is common in other countries. In an Italian study, with the use of cooking fuels other than natural gas and with heating appliances other than central heating, there appeared to be a mild adverse health effect in a general population sample, possibly predisposing children to respiratory infections.18 There is additional evidence that the experience of respiratory illness early in life is associated with increased respiratory morbidity later in childhood and in adulthood. Additionally, even mild illnesses such as coughs and colds can have a detrimental effect on cognitive performance.19 In a large study of more than 2000 infants followed for the first 5 years of life, the lowest incidence of pneumonia and bronchitis in the first year of life was recorded in the situation in which both parents were nonsmokers.20 In the first 12 months of life, exposure to cigarette smoke in the home doubled the risk of pneumonia and bronchitis for the infant. In an adolescent with coughing, the possibility that the child has been smoking must be considered. Another study demonstrated reduction of pulmonary function and increased frequency of cough in teenage athletes subjected to passive smoking. There was a fourfold increase in lower forced expiratory flow (FEF), 25%–75%, or cough in teenage athletes exposed to passive smoking. Boys were more often affected than girls, but girls were affected to a greater extent.21 A survey of respiratory symptoms in childhood was repeated 24 years after an initial survey.22 The prevalence of persistent wheezes, daytime and nighttime cough, and phlegm increased despite a substantial reduction in outdoor air pollution levels.

Physical Examination A complete physical examination includes special attention to the head and neck, respiratory passages, chest, and cardiovascular system. The physical examination begins with the vital signs, height, and weight. The presence of a fever usually indicates an infectious or inflammatory process. A growth delay or weight not meeting the expected level for a given height may suggest a chronic respiratory problem such as cystic fibrosis or uncontrolled asthma. The presence of a rash suggests an allergic or infectious cause. The presence of allergic shiners can indicate the venous congestion seen with a variety of upper respiratory tract disorders. Adenoidal facies

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CHAPTER 85 ❖ Cough can be seen with chronic upper airway obstruction, also seen in tonsillar hypertrophy. Asymmetry of the chest is found in congenital and destructive processes. Digital clubbing is seen in chronic suppurative lung diseases such as cystic fibrosis, hypersensitivity pneumonia, and bronchiectasis but is rarely, if ever, seen with reactive airway disease (asthma). Examination of the chest includes inspection, palpation, percussion, and auscultation. The rate, depth, and symmetry of breathing should be noted. Young children with pulmonary disease increase tidal volume by increasing the respiratory rate; thus, an increased respiratory rate is a sensitive indicator of pulmonary disease in the young population.12 The use of accessory muscles and nasal flaring is also noted. Percussion may indicate areas of dullness due to consolidation or due to pleural effusions. The normal inspiratory/expiratory ratio is 1:2.5 to 1:3. Most children 4–5 years of age or older and some younger children are able to cough on demand, and it is helpful to have the patient cough voluntarily to characterize that quality of the cough. The presence of wheezes, rales, and rhonchi is noted. A forced expiration may bring on wheezing, suggesting asthma. The presence of coughing with stridor suggests a partial upper airway obstruction. Auscultation of the neck is useful to locate more precisely the level of obstruction. The ear, nose, and throat examination can be very helpful, and indirect and direct inspection via a flexible nasopharnygoscopy of the nasophayrnx, hypopharynx, and larynx can be useful in diagnosis. The presence of a foreign body in the external auditory canal, excessive cerumen, or hair touching the tympanic membrane can stimulate Arnold’s nerve, a branch of the vagus nerve, producing an otogenic cough (vide infra). The nasal examination may suggest rhinitis of various forms, sinusitis, or polyps. The presence of nasal polyps in the pediatric patient mandates that a sweat test be performed to rule out cystic fibrosis. Sniffing, throat clearing, and hyponasal speech indicate chronic nasal, sinus, or adenoidal disease. A positive “99” test (hyponasality) indicates significant nasal obstruction. The word “nine” is one of the few words in the English language that is an obligate nasal sound. The child is instructed to say “ninety-nine.” The nose of the child is then occluded, and the child repeats the word. If there is no change in the nasality of the sound, there is a significant nasal obstruction. The allergic, or nasal, salute, usually made by passing the back of the hand across the tip of the nose, can result in a transverse nasal crease in the supratip region. The salute is found in patients with various chronic nasal disorders, including allergy. The oropharynx may demonstrate postnasal drip or signs of chronic irritation, including the presence of prominent lymphoid follicles on the posterior pharyngeal wall (known as cobblestoning). Acute pharyngitis can be associated with cough. Examination of the larynx indirectly with a mirror or a flexible nasopharyngoscope may show irritation consistent with aspiration or gastroesophageal reflux, a laryngeal cyst, or vocal cord paralysis. Sinusitis should be considered when palpation and percussion of the paranasal sinuses produce point tenderness.

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If the initial physical examination, including laboratory and radiologic studies (see later), is not diagnostic, the otolaryngologist may consider endoscopy. Although endoscopy is not as useful as in stridor or aspiration, it can be useful in difficult cases. Complete airway inspection includes the larynx and the tracheobronchial passages. Flexible nasopharyngoscopy or rigid larnygoscopy/bronchoscopy with general anesthesia is usually performed, and indications include the following: (1) suspicion of airway abnormality, (2) localized radiology changes, (3) suspicion of inhaled foreign body, (4) evaluation of aspiration lung disease, and (5) microbiological studies and lavage.4 In a European series, chronic cough was the indication for 11.6% of the 1233 pediatric bronchoscopies performed.23 Thomson et al. in a case series were able to document tracheobronchomalacia in 46% of patients.24 The most common endoscopic diagnosis includes congenital airway anomalies, neoplasms, and foreign bodies.

Imaging and Laboratory Studies Ancillary studies may be helpful but must be selected based on the history and physical examination. Radiographic studies include posteroanterior and lateral chest radiographs to assess for pathologic processes not apparent on physical examination. If the history suggests aspiration of a foreign body, comparing inspiratory and expiratory views may show hyperinflation caused by a radiolucent foreign body. In a study by Coren et al., a chest computed tomography (CT) of children with a history of chronic productive cough yielded 43% with documented brochiectasis.25 A screening sinus CT quickly and inexpensively evaluates for sinusitis. In a study by Tatli et al., 66% of children with a chronic cough who underwent imaging of their sinuses had some abnormal imaging.26 However, rhinorrhea, nasal congestion, sniffling, and postnasal drip had no significant relationship with paranasal sinus CT scan abnormality. Other imaging studies to consider are lateral soft tissue neck radiographs, barium swallow studies, and a milk scan or nuclear scintiscan reflux study. If the child can produce a sputum sample, gross and microscopic examination can be beneficial. For example, clear mucoid sputum is consistent with an allergic or asthmatic cause, in contrast to cloudy sputum, which is characteristic of a respiratory tract infection. The sputum in cystic fibrosis is frequently purulent but rarely foul smelling. The nasal smear is a simple, fast, reliable test to differentiate allergic rhinitis from vasomotor or infectious rhinitis. A Hansel stained slide showing greater than 5% eosinophils suggests allergic disease. Additional laboratory tests may include a sweat test, complete blood count with differential, eosinophil count, pulse oximetry or arterial blood gas test, erythrocyte sedimentation rate, tuberculin skin test, and a sputum culture and sensitivity test. Pulmonary function test including methacholine challenge, and flow volume loop examinations should be considered when a history suggests chronic obstructive or restrictive lung disease. In infants and small children, this test is often difficult to obtain. A therapeutic trial of albuterol can

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be used instead and can be diagnostic as well as therapeutic. All these tests are selected on the basis of history and physical examination findings.

culprit. In such cases, adenoidectomy is indicated and will control infection in the nose/nasopharynx in about two thirds of children.27

Differential Diagnosis

Aspiration

An approach to the diagnosis of cough must be systematic and logical as the potential etiologic causes are overwhelming. An illogical approach can be costly, ineffective, and can delay diagnosis leading to increased patient morbidity. We have proposed three different methods to assist in the differential diagnosis: (1) Table 85-3 gives the differential diagnosis by cause in five categories: congenital, inflammatory, infectious, neoplastic, and miscellaneous, (2) Table 85-4 gives the differential diagnosis by anatomic location, and finally (3) Table 85-5 lists the possible diagnosis by age. Children with chronic cough (>4 weeks) with a normal chest radiograph were evaluated for cough etiology.1 Cough from birth to 18 months is most commonly caused by gastroesophageal reflux disease (GERD), cough-variant asthma, or innominate artery compression of the trachea. The most frequent diagnosis between 1½ and 6 years of age was sinusitis (50%), followed by cough-variant asthma (27%). Cough between 6 and 16 years of age was caused by coughvariant asthma (45%), psychogenic/habit cough (32%), and sinusitis (27%).

Aspiration may be a cause of cough. However, aspiration is not a specific diagnosis but rather a sign of another problem. Infants are more prone to aspiration than adults because they have a relatively lax epiglottis, large arytenoids, and a wide aryepiglottic folds. Factors that can predispose an infant to aspiration include CNS disease, prematurity, mechanical barriers (tracheostomy), anatomic barriers (esophageal atresia/ stricture, vascular rings, type H tracheoesophageal fistula), gross gastroesophageal reflux, uncoordinated swallow, and disorders of the laryngeal innervation, including the internal and external branches of the superior laryngeal nerve and the recurrent laryngeal nerve.

SPECIFIC ETIOLOGIES Foreign Body Chest radiographs are often normal in the first 24 hours in patients with tracheobronchial foreign bodies. The sensitivity and specificity of inspiratory/expiratory and lateral decubitus films for foreign body aspiration are similar at 67%. The decision to perform an endoscopy is frequently based on the history, as there may not be physical or radiologic findings in the early postaspiration period. A child of any age can be suspected of having a foreign body; however, most frequently, the child is a toddler. Foreign bodies in the esophagus can present with airway symptoms, including cough, due to tracheal compression and are more common than airway foreign bodies.

Sinusitis Cough is often a presenting symptom in sinusitis. Adults usually have facial pain or headache, whereas children usually have nasal drainage without pain. The cough caused by sinusitis can be mediated by reflex mechanisms stimulated by a postnasal drip (see later) or can be associated with inflammatory mediators common to the respiratory tract. It is usually wet, nonproductive, and is worse when the child is lying supine at night. Acute bacterial sinusitis is treated with a course of antibiotics, but in those with refractory chronic sinusitis, adenoid hypertrophy is typically the

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Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) frequently presents with a cough in the neonate or infant. Other signs or complications of GERD include failure to thrive, vomiting, and recurrent aspiration pneumonia. One pediatric study estimates the incidence of GERD causing cough in the presence of a normal chest radiograph as 10%.28 A suspected diagnosis of GERD in a child must be systematically evaluated. Studies can include a barium esophagogram, a videofluoroscopic barium study to evaluate swallowing, esophageal manometry, direct laryngoscopy, bronchoscopy, esophagoscopy, esophageal biopsy, and staining of tracheal aspirate for lipid-laden macrophages. Initial conservative management includes parental reassurance, reverse Trendelenburg, and prone positioning after feeding. Medical management includes lower esophageal sphincter tone enhancing and prokinetic drugs such as metoclopramide, H2 blockers such as ranitidine, and proton pump inhibitors such as lansoprazole. These drugs can often be diagnostic as well as therapeutic. Eighty-five percent of children with GERD will spontaneously resolve by 18 months. If maximal medical management fails, and the infant persists with severe GERD with life-threatening symptoms, surgical intervention (i.e., fundoplication) may be indicated.

Laryngomalacia Laryngomalacia or, more appropriately, supraglottic laryngomalacia is the most common congenital diagnosis of the larynx. Ten percent of patients with laryngomalacia present with cough, although stridor is a more frequent sign. Usually, a positional history can be obtained in which the noise is exacerbated or is present only when the patient is in the supine position with increased activity. If there are no other airway anomalies, the patients usually do not require any treatment unless failure to thrive is present, and the parents

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TABLE 85-3. Differential Diagnosis of Cough by Cause Congenital Cause

Infectious Cause

Aberrant innominate artery

Adenoiditis

Achalasia

Adenovirus

Aspiration

Bronchiectasis

Bronchogenic cyst

Bronchitis, chronic

Bronchomalacia

Chlamydia trachomatis infection

Bronchopulmonary dysplasia (child also with wheeze)

Congenital rubella

Ciliary dyskinesia

Cryptococcus neoformans infection (immunocompromised host)

Congenital heart disease

Cytomegalovirus

Congenital subglottic stenosis

Human immunodeficiency virus

Cystic fibrosis

Measles (classic triad: cough, coryza, conjunctivitis)

Elongated uvula

Mycoplasma pneumonia infection

Esophageal duplication

Parasites35

Esophageal incoordination

Pertussis, parapertussis

Gastroesophageal reflux disease

Pharyngitis (chronic Waldeyer ring infection)

Immunodeficiency

Pneumonia

Kartagener syndrome (situs inversus, bronchiectasis, sinusitis)

Sinusitis

Laryngotracheomalacia

Tuberculosis

Lung cyst

Neoplastic Cause

Tracheal and bronchial stenosis

Primary benign

Tracheoesophageal fistula

Bronchial adenoma

Tracheolaryngoesophageal cleft

Cystic hygroma

Tracheomalacia

Mediastinal mass

Vascular ring

Recurrent respiratory papillomatosis

Vocal cord paralysis

Subglottic hemangioma

Inflammatory Cause

Teratoma

Allergy Asthma

Lymphoma

Bronchopulmonary fistula32

T cell leukemia

Cigarette smoking Environmental (indirect cigarette smoke, industrial pollutants) External auditory canal cerumen

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Primary malignant

Thymic neoplasm Metastatic malignant Hepatoblastoma

External auditory canal foreign body

Osteogenic sarcoma

External auditory canal hair on tympanic membrane

Wilms tumor

Foreign body

Miscellaneous Cause

Gastroesophageal reflux disease

Congestive heart failure

Laryngeal cyst

Drug (beta-adrenergic receptor antagonist, angiotensinconverting enzyme inhibitors)

Subacute thyroiditis22

Habit cough (psychogenic cough, cough tic)

Vallecular cyst

Mitral stenosis Ortner syndrome (cardiomegaly and recurrent laryngeal nerve paralysis) Rheumatic fever Vocal cord paralysis

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TABLE 85-4. Differential Diagnosis of Cough by Anatomic Location Ear

Small Airway

Acute otitis media

Asthma

Foreign body, cerumen, hair (Arnold reflex)

Bronchiolitis

Neoplasm

Congenital rubella

Nose and Nasopharynx

Cystic fibrosis

Adenoiditis Allergy (atopic upper airway disease) Environmental pollutants (active and passive cigarette smoke, industrial pollutants)

Cytomegalovirus infection Lung cyst

Parenchyma Alveolar disease (e.g., pulmonary hemosiderosis)

Foreign body

Pneumonia

Paranasal Sinus

Gastrointestinal Tract

Allergy

Esophageal foreign body

Environmental pollutants (cigarette smoke, industrial pollutants)

Gastroesophageal reflux disease Tracheoesophageal fistula (H-type)

Kartagener syndrome (complete situs inversus, chronic sinusitis, bronchiectasis)

Central Nervous System

Sinusitis

Arnold-Chiari malformation

Oropharynx

Gilles de la Tourette syndrome (20% with cough)

Elongated uvula

Habit cough (psychogenic cough, cough tic)

Pharyngitis

Mediastinum

Vallecular cyst

Cardiomegaly

Hypopharynx, Larynx

Cystic hygroma

Aspiration Croup (laryngotracheal bronchitis)

Hepatoblastoma Lymphoma

Foreign body

Ortner syndrome (cardiomegaly and recurrent laryngeal nerve paralysis)

Laryngeal cyst

Osteogenic sarcoma

Laryngomalacia

Sarcoidosis

Tracheolaryngoesophageal cleft

T cell leukemia

Vocal cord paresis or paralysis

Teratoma

Large Airway

Thymic neoplasm

Bronchiectasis

Wilms tumor

Bronchitis

Miscellaneous

Chlamydia trachomatis infection

Aortic arch anomaly

Cigarette smoking

Habit cough (psychogenic cough, cough tic)

Croup

Innominate arterial compression

Foreign body

Trauma

Kartagener syndrome (complete situs inversus, chronic sinusitis, bronchiectasis)

Vocal cord paralysis

Pertussis

Environmental

Tracheobronchomalacia

Low humidity

Tracheoesophageal fistula

Overheating Passive smoking, pollution

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TABLE 85-5. Differential Diagnosis of Cough by Age Newborn

School-Age Child

Adenoiditis

Adenoiditis

Aortic arch anomaly (vascular ring)

Allergy

Arnold-Chiari malformation

Asthma

Aspiration

Bronchiectasis

Bronchiectasis

Cigarette smoking

Bronchopulmonary dysplasia

Cystic fibrosis

Chlamydia trachomatis infection

Environmental (passive cigarette smoke, industrial pollutants)

Congenital rubella

Foreign body

Croup

Habit cough (psychogenic cough, cough tic)

Cystic fibrosis

Kartagener syndrome (complete situs inversus, chronic sinusitis, bronchiectasis)

Cytomegalovirus infection Environmental (passive cigarette smoke, industrial pollutants) Gastroesophageal reflux disease Kartagener syndrome (complete situs inversus, chronic sinusitis, bronchiectasis) Laryngotracheobronchomalacia Laryngotracheoesophageal cleft

Mycoplasma pneumoniae infection (most common age group) Pharyngitis Pneumonia Rhinitis Sinusitis Tuberculosis

Pertussis

Viral bronchitis

Pharyngitis

Uncommon Causes

Pneumonia

Alveolitis

Tracheoesophageal fistula (H-type)

Pulmonary fungal infections (Aspergillus)

Tuberculosis

Emphysema

Viral bronchiolitis

Alpha1 antitrypsin deficiency

Vocal cord paralysis

Ciliary dyskinesia

Preschooler

Pleural effusion

Adenoiditis

Pulmonary edema

Allergy (atopic upper airway disease)

Tuberculosis

Asthma Bronchiectasis Bronchitis (viral) Croup Cystic fibrosis Environmental (passive cigarette smoke, industrial pollutants) Foreign body Gastroesophageal reflux disease Pertussis Pharyngitis Pneumonia Rhinitis Sinusitis Tuberculosis

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can be reassured that the child will outgrow the process.29 However, 5% of children with laryngomalacia may have an associated subglottic stenosis.30 These disorders can sometimes be diagnosed with fluoroscopy but may require flexible fiberoptic nasopharyngoscopy or direct laryngoscopy and bronchoscopy.

Cough with Feeding In the neonate or young infant, cough with feeding suggests aortic arch anomalies, unilateral vocal fold immobility, or tracheoesophageal connections such as cleft larynx and tracheoesophageal fistula. Some of these disorders can be diagnosed with a barium esophagogram, but others require direct laryngoscopy.

Postnasal Drip Postnasal drip is a disputed cause of cough. Postnasal drip as a symptom commonly arises from rhinitis, sinusitis, and even GERD with reflux laryngitis. Dye studies performed in the 1930s showed that dye placed in the nasopharynx does not enter the larynx but enters the esophagus instead.31 However, many clinicians believe that postnasal drip can precipitate cough through the stimulation of receptors in the pharynx and endolarynx. Irwin et al. evaluated adult patients and found that 29% had postnasal drip as the sole cause of chronic persistent cough, and an additional 18% had postnasal drip combined with asthma as the cause of chronic persistent cough.32 In another study, 52% of 202 children with chronic cough had postnasal drip.33 Sources for the postnasal drip include the nose, paranasal sinuses, and adenoids. In a separate study, Irwin et al. examined nine patients with chronic cough secondary to postnasal drip. Flow volume loop studies demonstrated extrathoracic upper airway obstruction. The coughs resolved following specific therapy. Two theories are available to explain why postnasal drip causes cough. The first is that the postnasal drip into the hypopharynx irritates the larynx, stimulating the vagus nerve leading to cough. The second theory is that an irritated upper airway, the result of postnasal drip, causes cough from inflammatory changes in the larynx to the extent that edema occurs in the true vocal cords, leading to a partial obstruction.

Cough-Variant Asthma Reactive airway disease (asthma) is one of the most frequent causes of cough in the pediatric population. Cough-variant asthma is a term originally coined by observations in a handful of adults whom cough was the most prominent presenting symptom of asthma.34,35 Cough-variant asthma was first noted in an adult study and later in a pediatric study, and chronic cough was the only presenting manifestation of bronchial asthma in a second adult study.36 Initial work on coughvariant asthma in children was on subjects who also had other manifestations of airway obstruction. In those settings, cough

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responded to asthma therapy, which generally consisted of bronchodilators. Further investigations have suggested that asthma is an uncommon cause of cough in the absence of other asthmatic symptoms, particularly in children.4,24,37 Although the mechanism has not been completely elucidated, it has been suggested that the cough results from bronchoconstriction and direct stimulation of the bronchial rapidly acting stretch receptors or through mucous irritation of the C-fiber endings. The cough receptors become more reactive after changes in the tight junctions between epithelial surface cells due to conditions such as allergic exposure and infection. Because the cough receptors are primarily located in the large airways, the response to stimulation is cough, in contrast to the wheezing that occurs in small airway disease. However, Chang et al. note that bronchoconstriction and cough are mediated by different pathways, and while both can stimulated by common agents, inhibitors of cough do not inhibit bronchocontriction, with the converse being equally valid.38 Classically, the presentation of asthma is wheezing; however, cough-variant asthma presents as a nonproductive coughing without wheezing. Most asthmatic children develop asthma within the first 5 years of life.39 An epidemiologic study of wheeze, doctor-diagnosed asthma, and cough showed that 11% of children had been formally diagnosed as having asthma, with a somewhat higher prevalence of 13% in boys versus 9% in girls. The cumulative prevalence of asthma increased significantly with age. However, some children present with cough as the first sign. This cough typically is present with exertion and during sleeping, and frequently, such children do not have wheezing. In a detailed study by Hannaway and Hopper,40 32 pediatric patients with chronic cough were examined. These children had had cough for more than two months. The majority were younger than 10 years of age. In 23 of 32 patients, the cough was nocturnal, in 25 children, the cough was triggered with exercise, and finally 14 subjects had cough with exposure to cold air. Forty percent of the children had a positive family history of asthma, and 55% of the children had positive skin test reactions to two or more inhalants. On physical examination, approximately one third had subtle expiratory wheezes with prolonged expirations with 20 of these patients having normal pulmonary function tests. All the patients had a positive response to bronchodilator therapy, with resolution of cough. Of the 24 children followed long-term, 18 went on to develop classic asthma. Some authors advocate a methacholine challenge to identify patients likely to benefit from bronchodilator therapy for cough-variant asthma.41,42 Other disease processes can also give a positive methacholine challenge: a viral upper respiratory infection, allergic rhinitis, sarcoidosis, and congestive heart failure. A total eosinophil count has been advocated as an excellent screening device to predict patients who will benefit from bronchodilator therapy for cough variant asthma. However, peripheral blood smears are often normal, suggesting high specificity but low sensitivity. In addition,

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CHAPTER 85 ❖ Cough routine pulmonary function tests are normal.43 If all tests are negative or inconclusive, some practitioners advocate a diagnostic/therapeutic trial of systemic corticosteroids.44

Cystic Fibrosis Children with cystic fibrosis are another special group of patients. Chronic sinusitis is an almost universal problem in this population resulting from abnormal mucociliary clearance from the sinuses and lungs. Cough is the most constant symptom of pulmonary involvement in cystic fibrosis.45 Cystic fibrosis should be considered in any child with chronic cough. Additionally, there may be a history of malabsorption. A negative sweat test performed by the pilocarpine iontophoresis method of Gibson and Cooke in a hospital cystic fibrosis center is required to exclude this disease as a cause of cough. Genetic testing is also available.

Bronchitis Bronchitis usually exists in association with other respiratory diseases. Frequently, the trachea is involved concurrently. Acute tracheobronchitis is usually of viral origin. It can also occur with influenza, measles, typhoid, pertussis, diphtheria, and scarlet fever. Bacterial infections usually occur secondarily and may include infection with Streptococcus pneumoniae and Haemophilus influenzae. Chronic bronchitis is unusual in the absence of underlying pulmonary or systemic disease, such as cystic fibrosis or immotile cilia. Bronchitis presents with a chronic nonproductive or slightly productive cough following a respiratory infection (croup, pneumonia, mild upper respiratory infection). The cough may last for weeks and is exacerbated in a dry environment, such as winter months. Infectious bronchitis is very common and typically of viral origin. Seasonally, fall and winter are the times of highest incidence, with the infection occurring in children aged 5–7 years and usually resolving in fewer than 10 days. If the bronchitis persists more than 14 days, consideration should be given to bacterial cause, atelectasis, asthma, cystic fibrosis, immunodeficiency, and the presence of a foreign body.

Bronchiolitis Bronchiolitis is common in the lower respiratory tracts of children through the first 2 years of life. The cause is viral, with respiratory syncytial virus being the most common causative agent. The cough is described as paroxysmal and wheezy. Frequently, there is associated tachypnea of 80–90 respirations per minute, which may interfere with adequate feeding.

Bronchiectasis The term bronchiectasis describes dilatation of bronchi due to inflammatory changes of the bronchial wall, with accumulation of secretions. Rarely, the process is congenital.

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More commonly, the process is acquired, usually secondary to chronic pulmonary infections. Most commonly, the cause is cystic fibrosis. GERD can also produce bronchiectasis. A chronic productive cough is described, often with a history of repeated episodes of pneumonia involving the same lung segment, commonly the left lower lobe. Initially, the process may be insidious, with a normal initial physical examination. Hemoptysis may occur in approximately 50% of patients with bronchiectasis, and digital clubbing may be found.36 Bronchiectasis can be the sequela to pertussis, measles, cystic fibrosis, asthma, tuberculosis, pneumonia, foreign body, hypergammaglobulinemia, and congenital tracheobronchial malformations. It is one of the components of Kartagener syndrome, which also includes the situs inversus, otitis, and chronic sinusitis.

Allergy Allergy may be a predisposing factor for upper airway disease manifesting with cough. A response to antihistamine therapy indicates causative atopic upper airway disease. Cough or sneezing may be the presenting sign of a latex allergy in the spina bifida population, via an immunoglobulin E-mediated immediate hypersensitivity reaction that may progress to generalized anaphylaxis or cardiovascular collapse.46

Pertussis Because of poor compliance with recommended immunization schedules, pertussis outbreaks have occurred in many areas. The cough may begin without anticipation in an afebrile patient. There is a distinctive paroxysmal cough followed by a whoop. However, in an infant or in a patient older than 5 years, the typical whoop may not be present. Apnea may be a prominent feature in the infant.29 Typically, the child is red faced and occasionally cyanotic at the end of the paroxysm. The paroxysmal stage lasts two to four weeks or longer. Clinically, there is a repetitive series of 5–20 forceful coughs in the course of a single expiration. Frequently, vomiting occurs with the cough paroxysm. If a child presents with this history, pertussis must be considered. Infection occurs in epidemic cycles, at a frequency of two to four years. Paroxysmal coughing without whooping can be found in patients with pneumonia secondary to infection with adenovirus or Chlamydia.

Psychogenic or Habit Cough The majority of studies in the pediatric literature include habit cough, cough tic, and psychogenic cough under the same umbrella. Cough tic is thought to be a manifestation of Tourette’s syndrome which often presents with a spectrum of neurobehavioral disorders and has an organic etiology, whereas the literature is in general agreement that the diagnosis of either habit cough or psychogenic cough is one of exclusion and implies a nonorganic etiology. Consequently in children with chronic cough, the diagnoses of habit cough or psychogenic cough can only be made after tic disorders and

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Tourette’s syndrome have been excluded. The typical presentation is a bright-eyed child, worried parents, and a harassed physician.29 Classically, the cough is described as sounding like the honk of a Canada goose. Some studies also have reported that the typical psychogenic cough (i.e., honking) is recognizable and can often be heard even before the child is seen. The key feature of the cough is that it is not present while the child is asleep. The most common cause is thought to be a conversion or hysterical reaction to a school phobia. The posture is classically described as the chin placed on the chest with the hand held against the throat as if supporting the larynx. Clinical criteria that have been suggested in the pediatric literature to assist in diagnoses include and not limited to: (1) cough that disrupts normal activity or social activities; (2) cough that increases in frequency or severity with pleasurable social activities or exercise; (3) secondary gain that is acquired from the cough (e.g., parental attention or missing school); and (4) cough precipitated by emotional stress.47 Successful treatment has been reported with a variety of therapies utilizing a multidimensional approach. The cough can resolve immediately and long term with a single session of appropriate suggestion therapy using the distractor of diluted nebulized topical anesthesia.48 Other authors report successful treatment with 24–48 hours of bed sheet wrapping of the chest to support “weak chest muscles” as a face-saving but deceptive mechanism.5 Benign neglect with no parental reinforcement may also be beneficial. Frequently, one or both parents may resist the diagnosis. The pediatric literature recommends that in children with chronic cough associated with troublesome psychological manifestations, psychological counseling, or psychiatric intervention should be encouraged, after other causes have been ruled out.

Chlamydia Trachomatis Infection Chlamydial infection frequently presents as a pneumonia occurring in the first 6 months of life, usually associated with a prolonged afebrile illness featuring congestion, cough, tachypnea, rales, hyperinflated lungs with diffuse interstitial alveolar infiltrates, peripheral eosinophilia, and elevated levels of serum immunoglobulins.29 The cough is described as staccato and can cause cyanosis and emesis. There is a brief inspiration followed by a cycle of staccato cough and then a brief inspiration with the cycle repeating itself. There may be a preceding conjunctivitis.

Mycoplasma Pneumoniae Infection The initial presentation of Mycoplasma pneumoniae infection is a dry cough, but this cough rapidly progresses to become a mucoid or mucopurulent cough. Commonly, there are paroxysms of coughing while the patient is sleeping. School-age children are at highest risk.

Immunocompromised Host If the host is known to be immunocompromised, unusual causes should be sought, including infection with Pneumocystis carinii, Cryptococcus neoformans, and cytomegalovirus. With

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the last organism, the cough is often nonproductive or scantily productive. In cases in which no other cause of cough can be found, the possibility of an immunocompromised host should be considered. The differential diagnosis of immunocompromise includes immunoglobulin deficiency and human immunodeficiency virus infection and warrants further work-up.

Croup (laryngotracheobronchitis) Clinically, croup is characterized predominantly by inspiratory or biphasic stridor due to subglottic narrowing and is often accompanied by fever, hoarseness, and the characteristic “barking” cough. A child who presents with typical signs and symptoms usually requires no imaging, but plain films are done in order to exclude other possible diagnoses and can quickly confirm the diagnoses with the “steeple” sign. The most common pathogen is parainfluenza 1, and management is typically expectant but can be supplemented with humidified oxygen and racemic epinephrine.

Cough Syncope Coughing can lead to syncopal episodes, typically in children with asthma.49 The usual sequence is paroxysmal coughing, with facial congestion, turgidity, and cyanosis. Loss of consciousness occurs within seconds, with recovery in seconds to minutes. Pulmonary function tests demonstrate reversible bronchospasm.

Vocal Cord Paralysis The differential diagnosis of vocal cord paralysis includes Arnold–Chiari syndrome, Ortner syndrome, and idiopathic causes. Laryngeal penetration or aspiration associated with vocal cord paralysis may result in chronic cough.

CONCLUSION In general, the management of specific cough should be based on etiology. Patients with acute cough (3 h/d) oral feeding time, and are dependent on nasogastric tube feeding. Complications may arise as a result of gastrostomy placement and the development or worsening of GER has been widely reported. This has led to the frequent use of surgical antireflux treatment in the form of a fundoplication or other antireflux procedures.53–57 Underlying Structural Anomalies Treatment Patients with underlying treatable structural anomalies predisposing to aspiration such as severe laryngotracheal clefts and tracheoesophageal fistulae must be treated with corrective surgery first whenever possible. For mild laryngotracheal clefts, endoscopic treatment can be done. Severe laryngomalacia can be responsible for laryngeal penetration and aspiration in infants. A recent study reported an important improvement of laryngeal penetration and aspiration after cold knife supraglottoplasty in children treated for severe laryngomalacia; however, this treatment may not improve aspiration in patients with multiple medical comorbidities.58

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When bilateral, vocal fold immobility can cause aspiration. Vocal fold medialization can be realized in children either by injection laryngoplasty, thyroplasty, or nerve reinnervation.59 Cricopharyngeal achalasia can be efficiently treated either by conservative methods, botulinum toxin injection in the cricopharyngeus muscle and balloon dilatation,60 or by cricopharyngeal myotomy, preventing disruption of coordinated swallowing.61,62

Treatment of Aspiration Due to Gastroesophageal Reflux Conservative therapies are initially chosen for children with GER. Initial treatment involves positioning, the optimal position being upright or prone in infants; and thickening and fractioning of feedings. In most of the cases, these measures are not sufficient to treat GER and they must be associated with pharmacologic therapy. The advent of proton pump inhibitors (PPI) for use in children has had a significant impact on the treatment of GER disease, and PPI have been widely used to decrease acid reflux.63,64 Although the efficacy of PPIs has been established for esophagitis, it has not been established for CPA. It is important to remember that the predominant reflux in children is nonacid. Even if there is no objective evidence in the literature of the efficacy of PPIs on CPA, they are widely used. Prokinetic drugs, essentially domperidone, are also widely prescribed, but until now, no objective evidence of their efficacy in the treatment of GER has been provided. In case of severe respiratory symptoms that have not responded to conservative therapy deemed to be caused in part by GER, the antireflux procedure of choice is Nissen fundoplication.65–67 This procedure lengthens the intra-abdominal portion of the esophagus and attempts to create a one-way valve at the lower esophageal sphincter by wrapping the upper portion of the stomach around the lower portion of the esophagus. This procedure is highly effective in controlling GER, but it does not prevent aspiration of oral secretions. This procedure is effective in almost 90% of cases; unfortunately, there is a greater likelihood of failure of fundoplication (27%) in children with neurological impairment who are more likely to need this surgery because of the importance of their CPA related to GER.68

Treatment for Chronic Pulmonary Aspiration of Saliva In children, impaired salivary control manifests as drooling and aspiration. Various therapeutic options exist including oromotor training, drug therapies, and surgery.69 The first step is to correct the many situational factors that may worsen the drooling of the children: some medications or inflammation associated with dental and gingival disease may result in increased saliva production.70 When the treatment of underlying diseases is inadequate or impossible (e.g., as most neurological disorders), steps can be taken to minimize the aspiration or at least the damage done by the aspiration. In the setting of aspiration pneumonia, antibiotic coverage

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and pulmonary toilet measures are necessary. The choice of antibiotics depends on the suspected pathogens, with particular attention paid to whether the infection was acquired in the hospital or not. Broad anaerobic coverage is recommended. In a child with teeth, maintenance of good oral hygiene may help reduce the damage done by aspirated saliva. Drug Therapy Salivation is mainly mediated through parasympathetic stimulation. Acetylcholine is the active neurotransmitter, binding at muscarinic receptors in the salivary glands. Thus cholinergic muscarinic receptor antagonists such as atropine or scopolamine or glycopyrronium bromide can be used to reduce salivary secretion.71 Scopolamine transdermal therapeutic system is a selfadhesive dermal patch delivering scopolamine that must be changed every 72 hours. The use of scopolamine and other anticholinergic drugs to treat drooling has been repeatedly reported in the literature, and these drugs have proven to be effective in reducing the salivary flow.48,71,72,75 The disadvantages of systemic anticholinergic drugs are the many side effects that include behavioral changes and confusion, restlessness, blurred vision, urinary retention, flushing, nasal congestion, dry mouth and secretions, vomiting, and diarrhea. These side effects might be significant enough for ending the therapy. Forty percent of the patients experienced important side effects, 7% needing to stop the therapy in Jongerius et al trial.76 In other trials, treatment needed to be discontinued in 20% of patients.73,74 Minimally Invasive Methods Botulinum neurotoxin A injection into the salivary gland is an option to reduce the salivary flow rate. Botulinum toxin serotype A claves SNAP-25, an enzyme involved in the release of acetylcholine at the presynaptic membrane of parasympathetic nerves. In this way a temporary denervation of the target organ is established. Although only pilot studies with relatively small groups of patients are available, the outcome in these studies is uniformly favorable.76-79 The injection is made percutaneously, and ultrasound guidance is recommended to avoid side effects and improve efficacy and safety (Fig. 87.1). For young children, general anesthesia may be necessary. Parotid and submandibular glands are generally injected at two or three sites. In some studies, only the submandibular glands were injected because they produce a large part of resting saliva; however, parotids may be treated as well if necessary when there is excessive drooling when eating and drinking. Botulinum toxin is known to give clinically relevant results for 6 months. A near absence of side effects is reported across all studies. The reported side effects include weakness of adjacent muscles, facial weakness, and local infections. A controlled clinical trial studied the efficacy of both bilateral single-dose botulinum neurotoxin A injections into the submandibular glands and transdermal scopolamine on 45 children suffering from drooling and cerebral palsy.76 The effect on drooling by intraglandular injections was the

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The definitive treatments for the elimination of chronic life-threatening pulmonary aspiration are laryngotracheal separation or diversion.84–87 These procedures disconnect the upper trachea from the larynx eliminating all continuity between respiratory and digestive tracts. In laryngotracheal diversion, the proximal trachea is connected to the esophagus allowing the drainage of pooled secretions, while in laryngotracheal separation, the proximal trachea is simply closed and the secretions accumulate in the larynx before they are swallowed or orally expressed. The consequences of these procedures are the presence of a chronic tracheostomy and the loss of phonation. Successful reversal of these procedures has been reported in cases in which the patient regained laryngeal function. FIGURE 87-1. Ultrasound-guided botulinum toxin A injection in a right submandibular gland.

same magnitude as that of scopolamine; both treatments significantly reduced drooling compared with baseline. This outcome underlines that botulinum toxin has a strong anticholinergic effect in the target glands. Considering the side effects observed with scopolamine, botulinum neurotoxin injections seem to be more favorable when salivary flow reduction is needed. Although temporary, salivary flow reduction following botulinum neurotoxin injections is of satisfactory duration. Photocoagulation of salivary ducts by intraductal laser YAG photocoagulation has already been used in 48 cerebral palsied patients. Significant improvement in drooling severity and frequency was measured in the majority of cases with few complications.80 Surgery, providing a definite solution, also has to be considered as a potential alternative to reduce salivary secretion by submandibular gland excision or submandibular and parotid gland duct ligation.81–83 With the development of minimally invasive techniques such as botulinum toxin injections, surgery procedures will be less used. Definitive Treatments The approach is controversial and the attitude and treatment of chronic pulmonary aspiration depend on the centers where the children are managed. The controversy and position in favor of the conservative treatment have increased with the advent of minimally invasive modalities. In a small proportion of severely affected children with intractable pulmonary aspiration, when conservative measures have proven to be ineffective and when there is pulmonary function deterioration, more aggressive and definitive procedures might be used. Tracheotomy provides a simple means of increasing pulmonary toilet and may be helpful as a temporary measure for severe aspiration with pulmonary complications, the cuff preventing the secretions from penetrating the lower airways. For many authors, tracheotomy remains a temporary solution and they stress the need for more definitive surgical procedures.

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CONCLUSION Chronic pulmonary aspiration in children is often silencious and may be unrecognized until there is significant and definitive lung damage. Defining the cause of aspiration and the appropriate therapeutic options is challenging and requires a multidisciplinary approach. Different diagnostic procedures are available and must be chosen depending upon their relevance regarding the clinical status and impairments of the infant. With the improvement of the techniques and medications, conservative medical and surgical therapies are often effective enough to treat chronic pulmonary aspiration. For patients who continue to experience chronic life-threatening pulmonary aspiration, more definitive surgical procedures may still be proposed. More research and controlled clinical trials are needed to evaluate the accuracy of diagnostic methods and appropriateness of treatments and interventions.

References 1. Owayed AF, Campbell DM, Wang EEL. Underlying causes of recurrent pneumonia in children. Arch Pediatr Adolesc Med. 2000;154:190–194. 2. Lodha R, Puranik M, Natchu UCM, Kabra SK. Recurrent pneumonia in children: clinical profile and underlying causes. Acta Pediatr. 2002;91:1170–1173. 3. Colombo JL, Sammut PH. Aspiration syndromes. In: Taussig LM, Landau LI, eds. Pediatric Respiratory Medicine. St Louis, MO: Mosby; 1999:435–443. 4. Dunham ME, Holinger LD. Stridor, aspiration and cough. In: Bailey BJ, Johnson JT, Kohut RI, et al., eds. Head and Neck Surgery-Otolaryngology. Philadelphia, PA: JB Lippincott; 1993. 5. Ichord RN. Neurology of deglutition. In: Tuchman DN, Walter RS, eds. Disorders of Feeding and Swallowing in Infants and Children: Pathophysiology, Diagnosis and Treatment. San Diego, CA: Singular Publishing Group; 1993:37–52. 6. Derkay CS, Schechter GL. Anatomy and physiology of pediatric swallowing disorders. Otolaryngol Clin North Am. 1998;31:397–404.

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7. Fisher SE, Painter M, Milmoe G. Swallowing disorders in infancy. Pediatr Clin North Am. 1981;28:845–853. 8. Orenstein SR. An overview of reflux-associated disorders in infants: apnea, laryngospasm, and aspiration. Am J Med. 2001;111:60S–63S. 9. Harding SM. Recent clinical investigations examining the association of asthma and gastroesophageal reflux. Am J Med. 2003;115:39S–44S. 10. Rudolph CD. Supraesophageal complications of gastroesophageal reflux in children: challenges in diagnosis and treatment. Am J Med. 2003;115:150S–156S. 11. Morton RE, Wheatley R, Minford J. Respiratory tract infections due to direct and reflux aspiration in children with severe neurodisability. Dev Med Child Neurol. 1999;41:329–334. 12. Brodsky L. Dysphagia with respiratory/pulmonary presentation: assessment and management. Semin Speech Lang. 1997;18:13–22. 13. DeMatteo C, Matovich D, Hjartarson A. Comparison of clinical and videofluoroscopic evaluation of children with feeding and swallowing difficulties. Dev Med Child Neurol. 2005;47: 149–157. 14. Lefton-Greif MA, Mc-Grath-Morrow SA. Deglutition and respiration: development, coordination and practical implications. Semin Speech Lang. 2007;28:166–179. 15. Tutor JD, Schoumacher RA. Is aspiration causing your pediatric patient’s symptom? J Respir Dis. 2003;24:30–40. 16. Weir K, McMahon S, Barry L, Masters B, Chang AB. Clinical signs and symptoms of oropharyngeal aspiration and dysphagia in children. Eur Respir J. 2008;14 (Epub ahead of print). 17. Loughlin JM, Lefton-Greif MA. Dysfunctional swallowing and respiratory disease in children. Adv Pediatr. 1994;41:135–162. 18. Thach BT. Maturation and transformation of reflexes that protect the laryngeal airway from liquid aspiration from fetal to adult life. Am J Med. 2001;111:69S–77S. 19. Arvedson J, Rogers B, Buck G, Smart P, Msall M. Silent aspiration prominent in children with dysphagia. Int J Pediatr Otorhinolaryngol. 1994;28:173–181. 20. Morton RE, Bonas R, Fourie B, Minford J. Videofluoroscopy in the assessment of feeding disorders of children with neurological problems. Dev Med Child Neurol. 1993;35:388–395. 21. Rogers B, Arvedson B, Buck G, Smart P, Msall M. Characteristics of dysphagia in children with cerebral palsy. Dysphagia. 1994;9:69–73. 22. Friedman B, Fraziers JB. Deep laryngeal penetration as a predictor of aspiration. Dysphagia. 2000;15:153–158. 23. Martin-Harris B, Logemann JA, McMahon S, Schleicher M, Sandidge J. Clinical utility of the modified barium swallow. Dysphagia. 2000;15:136–141. 24. Logemann JA. Role of the modified barium swallow in management of patients with dysphagia. Otolaryngol Head Neck Surg. 1997;116:335–338. 25. Aviv JE, Kaplan ST, Thomson JE, Spitzer J, Diamond B, Close LG. The safety of flexible endoscopic evaluation of swallow with sensory testing (FEESST): an analysis of 500 consecutive evaluations. Dysphagia. 2000;15:39–44. 26. Hartnick CJ, Hartley BE, Miller C, Willging JP. Pediatric fiberoptic endoscopic evaluation of swallowing. Ann Otol Rhinol Laryngol. 2000;109:996–999. 27. Leder SB, Karas DE. Fiberoptic endoscopic evaluation of swallowing in the pediatric population. Laryngoscope. 2000;110:1132–1136.

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28. Link DT, Willging JP, Miller CK, Cotton RT, Rudolph CD. Pediatric laryngopharyngeal sensory testing during flexible endoscopic evaluation of swallowing: feasible and correlative. Ann Otol Rhinol Laryngol. 2000;109:899–905. 29. Willging JP, Thompson DM. Pediatric FEESST: fiberoptic endoscopic evaluation of swallowing with sensory testing. Curr Gastroenterol Rep. 2005;7:240–243. 30. Rees CJ. Flexible endoscopic evaluation of swallowing with sensory testing. Curr Opin Otolaryngol Head Neck Surg. 2006;14: 425–430. 31. Leder SB, Sasaki CT, Burrell MI. Fiberoptic endoscopic evaluation of dysphagia to identify silent aspiration. Dysphagia. 1998;13:19–21. 32. Langmore SE, Schatz K, Olson N. Endoscopic and videofluoroscopic evaluations of swallowing and aspiration. Ann Otol Rhinol Laryngol. 1991;100:678–681. 33. Aviv JE. Prospective, randomized outcome study of endoscopy versus modified barium swallow in patients with dysphagia. Laryngoscope. 2000;110:563–574. 34. Colodny N. Interjudge and intrajudge reliabilities in fiberoptic endoscopic evaluation of swallowing (FEES) using the penetration-aspiration scale: a replication study. Dysphagia. 2002;17:308–315. 35. Ahrens P, Noll C, Kitz R, Willigens P, Zielen S, Hofmann D. Lipid-laden alveolar macrophages (LLAM): a useful marker of silent aspiration in children. Pediatr Pulmonol. 1999;28:83–88. 36. Furuya ME, Moreno-Cordova V, Ramirez-Figueroa JL, et al. Cut-off value of lipid-laden alveolar macrophages for diagnosing aspiration in infants and children. Pediatr Pulmonol. 2007;42:452–457. 37. Kazachkov MY, Muhlebach MS, Livasy CA, Noah TL. Lipid laden macrophage index and inflammation in bronchoalveolar lavage fluids in children. Eur Repir J. 2001;18:790–795. 38. Brady SL, Hildner CD, Hutchins BF. Simultaneous videofluoroscopic swallow study and modified Evans blue dye procedure: an evaluation of blue dye visualization in cases of known aspiration. Dysphagia. 1999;14:146–149. 39. O’Neill-Pirozzi TM, Lisiecki DJ, Jack Momose K, Connors JJ, Milliner MP. Simultaneous modified barium swallow and blue dye tests: a determination of the accuracy of blue dye test aspiration findings. Dysphagia. 2003;18:32–38. 40. Donzelli J, Brady S, Wesling M, Craney M. Simultaneous modified Evans blue dye procedure and video nasal endoscopic evaluation of the swallow. Laryngoscope. 2001;111:1746–1750. 41. Wenzl TG, Moroder C, Trachterna M. Esophageal pH monitoring and impedance measurement: a comparison of two diagnostic tests for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2002;34:511–512. 42. Wenzl TG. Evaluation of gastroesophageal reflux events in children using multichannel intraluminal electrical impedance. Am J Med. 2003;115(suppl 1):161–165. 43. Wenzl TG, Silny J, Schenke S, et al. Gastroesophageal reflux and respiratory phenomena in infants: status of the intraluminal impedance technique. J Pediatr Gastroenterol Nutr. 1999;28:423–428. 44. Baikie G, South MJ, Reddihough DS. Agreement of aspiration tests using barium videofluoroscopy, salivagram, and milk scan in children with cerebral palsy. Dev Med Child Neurol. 2005;47:86–93.

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CHAPTER 87 ❖ Aspiration: Etiology and Management 45. Ravelli AM, Panarotto B, Verdoni L, Consolati V, Bolognini S. Pulmonary aspiration shown by scintigraphy in gastroesophageal reflux-related respiratory disease. Chest. 2006;130:1520–1526. 46. Rapp D. Drool control: long term follow up. Dev Med Child Neurol. 1980;22:448–453. 47. Johnson H. An Exploratory Study on Drooling Using a Frequency Method of Measuring in a Naturalistic Setting [Thesis/Dissertation]. Melbourne, Australia: La Trobe University; 1990. 48. Thomas-Stonell N, Greenberg J. Three treatment approaches and clinical factors in the reduction of drooling. Dysphagia. 1988;3:73–78. 49. Heyman S, Respondek M. Detection of pulmonary aspiration in children by radionuclide salivagram. J Nucl Med. 1989;30:697–699. 50. Bar-Sever Z, Connolly LP, Treves T. The radionuclide salivagram in children with pulmonary disease, a high risk of aspiration. Pediatr Radiol. 1995;25:S180–S183. 51. Boesch RP, Daines C, Willging JP, et al. Advances in the diagnosis and management of chronic pulmonary aspiration in children. Eur Respir J. 2006;28:847–861. 52. Dusick A. Investigation and management of dysphagia. Semin Pediatr Neurol. 2003;10:255–264. 53. Durkin ET, Schroth MK, Helin M, Schaaban AF. Early laparoscopic fundoplication and gastrostomy in infants with spinal muscular atrophy type I. J Pediatr Surg. 2008;43:2031–2037. 54. Partrick DA. Gastrointestinal tract feeding access and the role of fundoplication in combination with gastrostomy. Curr Opin Pediatr. 2007;19:333–337. 55. Vernon-Roberts A, Sullivan PB. Fundoplication versus post-operative medication for gastro-esophageal reflux in children with neurological impairment undergoing gastrostomy. Cochrane Database Syst Rev. 2007;24:CD006151. 56. Sulaeman E, Udall JN Jr, Brown RF. Gastroesophageal reflux and Nissen fundoplication following percutaneous endoscopic gastrostomy in children. J Pediatr Gastroenterol Nutr. 1998;26:269–273. 57. Puntis JW, Thwaites R, Abel G, Stringer MD. Children with neurological disorders do not always need fundoplication concomitant with percutaneous endoscopic gastrostomy. Dev Med Child Neurol. 2000;42:97–99. 58. Richter GT, Wootten CT, Rutter MJ, Thompson DM. Impact of supraglottoplasty on aspiration in severe laryngomalacia. Ann Otol Rhinol Laryngol. 2009;118:259–266. 59. Sipp JA, Kerschner JE, Braune N, Hartnick CJ. Vocal fold medialization in children: injection laryngoplasty, thyroplasty or nerve reinnervation. Arch Otolaryngol Head Neck Surg. 2007;133:767–771. 60. Leyden JE, Moss AC, MacMathuna P. Endoscopic pneumatic dilatation versus botulinum toxin injection in the management of primary achalasia. Cochrane Database Syst Rev. 2006;18:CD005046. 61. Pastor AC, Mills J, Marcon MA, Himidan S, Kim PC. A single center 26-year experience with treatment of esophageal achalasia: is there an optimal method? J Pediatr Surg. 2009;44:1349–1354. 62. Muraji T, Takamizawa S, Satoh S, et al. Congenital cricopharyngeal achalasia: diagnosis and surgical management. J Pediatr Surg. 2002;37:E12. 63. Gilger MA, Tolia V, Vandenplas Y, Youssef NN, Traxler B, Illueca M. Safety and tolerability of esomeprazole in children

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with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr. 2008;46:524–533. De Giacomo C, Bawa P, Franceschi M, Luinetti O, Fiocca R. Omeprazole for severe reflux esophagitis in children. J Pediatr Gastroenterol Nutr. 1997;24:528–532. Hassall E. Decisions in diagnosing and managing chronic gastroesophageal reflux disease in children. J Pediatr. 2005;146:S3–S12. Mattioli G, Bax K, Becmeur F, et al. European multicenter survey on the laparoscopic treatment of gastroesophageal reflux in patients aged less than 12 months with supraesophageal symptoms. Surg Endosc. 2005;19:1309–1314. Mattioli G, Sacco O, Repetto P, et al. Necessity for surgery in children with gastroesophageal reflux and supraoesophageal symptoms. Eur J Pediatr Surg. 2004;14:7–13. Kawahara H, Okuyama H, Kubota A, et al. Can laparoscopic antireflux surgery improve the quality of life in children with neurologic and neuromuscular handicaps? J Pediatr Surg. 2004;39:1761–1764. Crysdale WS, McCann C, Roske L, et al. Saliva control issues in the neurologically challenged: a 30 year experience in team management. Int J Pediatr Otorhinolaryngol. 2006;70:519–527. Meningaud JP, Pitak-Arnnop P, Chikhani L, et al. Drooling of saliva: a review of the etiology and management options. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101: 48–57. Jongerius PH, Van Tiel P, Van Limbeek J, et al. A systematic review for evidence of efficacy of anticholinergic drugs to treat drooling. Arch Dis Child. 2003;88:911–914. Bachrach SJ, Walter RS, Trzcinski K. Use of glycopyrrolate and other anticholinergic medications for sialorrhea in children with cerebral palsy. Clin Pediatr (Phila). 1998;37:485–490. Mier RJ, Bachrach SJ, Lakin RC, et al. Treatment of sialorrhea with glycopyrrolate: a double-blind, dose-ranging study. Arch Pediatr Adolesc Med. 2000;154:1214–1218. Blasco Pa, Stansbury JC. Glycopyrrolate treatment of chronic drooling. Arch Pediatr Adolesc Med. 1996;150:932–935. Lewis DW, Fontana C, Mehallick LK, Everett Y. Transdermal scopolamine for reduction of drooling in developmentally delayed children. Dev Med Child Neurol. 1994;36:484–486. Jongerius PH, Van den Hoogen F, Van Limbeek J, et al. Effect of botulinum toxin in the treatment of drooling: a controlled clinical trial. Pediatrics. 2004;114:620–627. Bothwell JE, Clarke K, Dooley JM, et al. Botulinum toxin A as a treatment of excessive drooling in children. Pediatr Neurol. 2002;27:18–22. Jongerius PH, Rotteveel JJ, Van Limbeek J, et al. Botulinum toxin effect on salivary flow rate in children with cerebral palsy. Neurology. 2004;63:1371–1375. Thevasagayam MS, Gan K, Eksteen E. Control of salivary secretions in esophageal atresia with laryngeal cleft using Botulinum toxin type A. Int J Pediatr Otorhinolaryngol. 2008;72:965–969. Chang CJ, Wong AMK. Intraductal laser photocoagulation of the bilateral parotid ducts for reduction of drooling in patients with cerebral palsy. Plast Reconstr Surg. 2001;107:907–913. Vijayasekaran S, Unal F, Schraff SA, et al. Salivary gland surgery for chronic pulmonary aspiration in children. Int J Pediatr Otorhinolayngol. 2007;71:119–123.

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82. Klem C, Mair EA. Four duct ligation: a simple and effective treatment for chronic aspiration from sialorrhea. Arch Otolaryngol Head Neck Surg. 1999;125:796–800. 83. Stern Y, Feinmesser R, Collins M, Shott SR, Cotton RT. Bilateral submandibular gland excision with parotid duct ligation for treatment of sialorrhea in children: long term results. Arch Otolaryngol Head Neck Surg. 2002;128:801–803. 84. Ninomiya H, Yasuoka Y, Inoue Y, et al. Simple and new surgical procedure for laryngotracheal separation in pediatrics. Laryngoscope. 2008;118:958–961. 85. Hafidh MA, Young O, Russell JD. Intractable pulmonary aspiration in children: which operation? Int J Pediatr Otorhinolayngol. 2006;70:19–25.

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86. Cook SP, Lawless ST, Kettrick R. Patient selection for primary laryngotracheal separation as treatment of chronic aspiration in the impaired children. Int J Pediatr Otorhinolayngol. 1996;38:103–113. 87. Takamizawa S, Tsugawa C, Nishijima E, Muraji T, Satoh S. Laryngotracheal separation for intractable aspiration pneumonia in neurologically impaired children: experience with 11 cases. J Pediatr Surg. 2003;38:975–977.

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C H A P T E R

Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease Dana Mara Thompson

P

hysiologic gastroesophageal reflux (GER) occurs daily in healthy infants and children without untoward outcomes. Regurgitation is the hallmark symptom. Infant GER symptoms peak by 4–6 months and usually resolve by 12–18 months of age.1 Gastroesophageal reflux disease (GERD) occurs when reflux of acid cause symptoms that affect the quality of life or lead to complications. As seen in Table 88-1, typical infant and toddler gastrointestinal (GI) symptoms include recurrent emesis, arching, irritability, dysphagia, feeding disorders, and failure to thrive. It was thought that most children outgrow GERD by 24–36 months of age. However, recent studies demonstrate that the presence of GERD symptoms through the first 3 years of life tend to recur in later childhood and adolescent years.2 GERD-related symptoms in older children include abdominal pain or discomfort, and morning nausea. Heartburn, the hallmark symptom of GERD in adults, does not manifest in until adolescence. For unexplained reasons, the incidence of childhood and adolescent GERD has increased, thereby potentially placing children at long-term risk of esophageal complications such as esophagitis or Barrett’s esophagus.3 When GER becomes extraesophageal and enters the larynx, it is referred to as laryngopharyngeal reflux (LPR) and causes the spectrum of diseases referred to as extraesophageal reflux disease (EERD).4–8 LPR is recognized as a clinical entity distinct from that of GERD. The prevalence of

LPR and EERD in children is not precisely known. However, it is estimated that 4%–10% of adult patients presenting to ear, nose, and throat (ENT) physicians have symptoms or problems that may be related to reflux.9 A variety of ENT symptoms have been described in association with reflux. However, results from published studies have been conflicting. A symptom survey showed that infants with reflux had no increase in the frequency of ear, sinus, or upper respiratory infections compared with a control population, although these infants were more likely to exhibit feeding refusal than control infants.10 On the contrary, a different study found that compared with controls, children with GERD were significantly more likely to have been diagnosed with sinusitis and laryngitis. However, it was unclear if those with EERD symptoms were at increased risk due to existing medical comorbidities.11 In the pediatric population, the consequences of LPR can cause airway obstruction and breathing problems, swallowing and feeding problems, or voice problems. Because regurgitation into the pharynx and vomiting are common events in infants, they are at increased risk for the EERD. As seen in Table 88-1, airway symptoms vary based on age. Chronic cough is the only consistent symptom of EERD that crosses the age spectrum from infants to adults. Typical upper airway symptoms of EERD in infants include infant apnea, cough and choking with feeding,

TABLE 88-1. Gastroesophageal Reflux Disease (GERD) and Laryngopharyngeal Reflux (LPR) Manifestations

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Infants

Toddlers/Preadolescents

Adolescents

Upper airway and laryngotracheal symptoms: Apnea or life-threatening events, croup, stridor, cough, sleep-disordered breathing

Upper airway and laryngotracheal symptoms: Recurrent croup, chronic cough, dyspnea, dysphonia/hoarseness, sleep-disordered breathing

Upper airway and laryngotracheal symptoms: dysphonia/hoarseness dyspnea, cough, laryngitis, croup, sleep-disordered breathing

Gastrointestinal symptoms: Regurgitation, recurrent emesis, feeding disorder, dysphagia, failure to thrive, colic, irritability, or torticollis (Sandifer’s syndrome)

Pharyngeal symptoms: Persistent sore throat, halitosis, throat clearing, dental erosion

Pharyngeal symptoms: Sore throat, halitosis, throat clearing, globus sensation

Chronic respiratory disease

Gastrointestinal symptoms: Regurgitation/vomiting, nausea, belching, dysphagia

Gastrointestinal symptoms: Belching, emesis, regurgitation chest or abdominal pain, heartburn, dysphagia, anorexia

Chronic respiratory disease

Chronic respiratory disease

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feeding difficulty, failure to thrive, wheezing, stridor, and recurrent croup. EERD symptoms in the toddler-aged and preadolescent child are similar to infants, but include more pharyngeal symptoms such as throat clearing, poor weight gain rather than food refusal, and obstructive apnea. This age group has usually outgrown physiologic regurgitation therefore these symptoms may occur in the presence or absence of regurgitation or emesis. Adolescent and older children will be able to describe their symptoms better, thus the clinical presentation is akin to adults with common symptoms that include globus, chronic cough, dysphagia, and hoarseness. Similar to adults, their airway symptoms often occur in the absence of typical GI symptoms of reflux disease. Otolaryngologist and other clinicians who care for children with airway disease understand the causal relationship between GERD and laryngotracheal disease. Utilization of test of esophageal function and ancillary test of airway function and airway protection in adult and pediatric patients with EERD has furthered our understanding of the relationship of reflux and airway symptoms and laryngotracheal disease. The clinical and basic science studies evaluating the role of reflux in pediatric laryngotracheal disease are limited to nonplacebo-controlled clinical studies, case series, and studies evaluating reflux testing modalities in children, thus the causal relationship between GERD and airway disease and laryngotracheal disease in children remains controversial. The evolving understanding of the role of nonacidic reflux in the etiology of airway and laryngotracheal disease likewise adds to the controversy of the association. This chapter will focus on the role of acidic reflux disease in the airway with mention of the role of nonacidic reflux and airway disease where appropriate.

PATHOPHYSIOLOGY There are two theories of how GERD causes airway symptoms and laryngotracheal disease. The first theory is that direct contact of acid and/or pepsin causes damage to the laryngeal epithelium resulting in inflammation and scarring. If the refluxed material is aspirated through the glottis, then it leads to inflammation of the subglottis, trachea, and distal airway. The second theory is that vagally mediated chemoreceptors found in the aerodigestive tract are stimulated or altered by acid, thereby affecting vagal nerve reflexes that lead to airway symptoms such as apnea and cough, poor airway protection, and aspiration. Most clinicians attribute EERD symptoms and disease to direct contact of acid and resultant damage. Our understanding of the role of vagal nerve function in upper airway disease is evolving. It is likely that a combination of both of these theories have a role in the clinical spectrum of pediatric laryngotracheal symptoms and complications of EERD, which is discussed below.

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In addition to the two proposed theories, infants and children have developmental anatomic, physiologic and neuromuscular factors, and medical comorbidities that are not present in adults which12 place them at risk for different complications EERD that are discussed in the following paragraphs.

Esophageal Factors Leading to Airway and Laryngotracheal Complications of EERD The small capacitance of the stomach and diminished clearance of the esophagus in infants and children compared with healthy adults increases the risk of the refluxate becoming extraesophageal. In addition, infants and children have a shorter esophageal length and spend more time in the supine position than adults, thereby decreasing the benefit of gravity, and a decreased travel time and length for reflux to reach the larynx. Esophageal motility must be functional to prevent retrograde reflux of regurgitated and swallowed contents to the larynx. The lower esophageal sphincter (LES) is the first line of defense against entry of reflux into the larynx. The LES maintains a tonic pressure between swallows, but relaxes to permit the advancing swallowed food bolus to enter the stomach. The high-pressure zone is designed to prevent reflux of stomach contents into the esophagus. Complex neurohormonal and neuromuscular mechanisms that are incompletely understood are responsible for control of the LES. In addition, neuromuscular function of the LES is not fully matured in infancy; therefore the multiple transient lower esophageal relaxation and regurgitation events that occur in infants place them at higher risk of complications of acid reflux. A child with generalized neuromuscular maturation delay or those who acquire neurologic disease are also at increased risk of reflux complications. The upper esophageal sphincter (UES) is the second line of defense against entry of reflux into the larynx. Like the LES, the UES maintains a tonic pressure except during swallowing, belching, and vomiting. A normally functioning UES prevents refluxed material from exiting the proximal esophagus to the hypopharynx and larynx. Unlike the LES, the UES loses its tone during sleep thereby increasing opportunity for extraesophageal events and complications. Increased amounts of time infants and children spend sleeping may place infants at an increased risk of reflux related complications compared with adults. The vagal nerve mediates the function of both the LES and UES, thereby further supporting the theory of vagal nerve function in the pathophysiology of GERD-related airway symptoms. Neuromuscular maturational delay or acquired conditions that cause vagal nerve dysfunction can alter LES, UES, and esophageal motility, thereby leading to increased risk of reflux in affected infants and children.

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CHAPTER 88 ❖ Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease

Upper Airway Factors Leading to Laryngotracheal Complications of EERD Unlike the mucosa of the esophagus, laryngotracheal mucosa is more sensitive to injury from acid reflux. Molecular studies postulate that the mechanisms of injury include altered mucosal responses and/or depletion of carbonic anhydrase isoenzymes, and a role of epithelial cadherin. These basic science studies support the notion that retrograde flow of gastric contents into the laryngopharynx creates debilitating of the mucosal responses to acid injury.13–15 Although not specifically studied in infants and children, similar mechanisms likely occur. Adequate airway protection is essential to prevent laryngotracheal complications of reflux disease. Airway protection is modulated through a vagally mediated neuromuscular reflex known as the laryngeal adductor reflex (LAR). LAR function can be altered by the untoward affects of acid reflux, thereby further supporting the theory of vagal-mediated responses in the pathophysiology of GERD-related airway symptoms and disease. The LAR is responsible for laryngeal tone, breathing, swallowing, and airway protection. This reflex is activated by sensory stimulation of the mechanoreceptors and chemoreceptors of the superior laryngeal nerve (SLN) located in the region of the aryepiglottic fold.16,17 Stimulation of these receptors transmits sensory afferent information by the SLN to brainstem nuclei that regulate respiration and swallowing. Information is then integrated between the nucleus tractus solitarius and nucleus ambiguus resulting in an involuntary efferent vagal motor response of adduction of the vocal folds and a swallow to clear any substance present, thereby protecting against aspiration.16,18–20 Dysfunction anywhere along the afferent, brainstem, or efferent pathway of the LAR can result in altered laryngeal function and tone and cause laryngotracheal signs and symptoms often associated or attributed to GERD and LPR such as cough, apnea, swallowing difficulty, and stridor. Developmental animal model studies and pediatric clinical studies show that short term acute exposure or application of acid directly to the larynx activates the LAR and can result in laryngospasm, apnea, and cough.21 The laryngospasm event ceases once the stimulus is swallowed and cleared.22,23 Chronic exposure of acid to the larynx has been shown to cause alteration in the afferent sensory limb of the LAR in adults and children, thereby implicating the role of acid reflux in laryngeal tone, function, airway protection, and swallowing. It is postulated that chronic LPR damages the nerve endings of the SLN, thereby altering the activation of the chemo and/ or mechanoreceptors. Decreased activation of SLN nerve ending receptors leads to diminished transmission of sensory vagal afferent information to the brainstem, thereby changing the neuromuscular resultant efferent response at the larynx.6,8,24–27 If laryngeal tone is altered, airway obstruction may occur. If vocal fold function and airway protection is altered, inflammation and aspiration may occur leading to cough, croup, stridor, wheezing, and long-term subglottic and tracheal consequences

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of scarring. Impaired swallow function and secretion clearance lead to feeding disorders, failure to thrive, and dysphagia. Similar to LES and UES function, the LAR function is affected by neuromuscular maturational delay or acquired conditions that cause vagal nerve dysfunction, thereby placing affected infants and children at a higher risk of airway symptoms. The anatomic size of the infant and pediatric larynx and trachea is much smaller than the adult; thereby the acid has a much smaller surface area to cause damage. With this smaller diameter, a minimal amount of mucosal swelling can lead to obstructive airway symptoms such as stridor, croup or wheezing. Chronic exposure to acid can cause damage to multiple surfaces leaving opposing raw surfaces the chance to scar leading to chronic obstructive disease such as laryngotracheal stenosis. Chronic upper airway obstruction is a promoter of reflux disease. Upper airway obstruction is common in pediatric population and is commonly caused by adenotonsillar hypertrophy, reactive airway disease, and asthma. Congenital or acquired laryngotracheal diseases can also cause upper airway obstruction. Breathing against an obstructed airway promotes reflux into the upper airway through the generating large negative intrathoracic pressures changes that push against the esophagus, thereby acting as a vacuum drawing the stomach contents into the esophagus28 by overcoming the antireflux barrier of the LES and the UES. Frequent LPR events result in inflammation and edema of the upper airway and laryngeal tissues potentiating further airway obstruction and compromise, which can lead to a vicious cycle of reflux and airway obstruction until one or the other or both are alleviated.5,7

Patient Factors Leading to Laryngotracheal Complications of EERD The pediatric population may present with additional medical comorbidities that increases their risk of complications of EERD. Premature infants have delayed maturation of neuromuscular function placing them at increased risk for GERD from multiple transient LES relaxation events, esophageal dysmotility, swallowing problems, and difficulty clearing reflux once it enters the pharynx and larynx. Premature infants and those born with multiple medial comorbidities have a much higher risk of prolonged intubation that alters the mucosal integrity of the larynx and trachea, thereby increasing the risk of edema and scarring if exposed to acid. This patient population is more likely to receive nasogastric feeding for nutrition, promoting posterior glottic edema, compromised laryngeal sensation and airway protection at the laryngeal level. The presence of a nasogastric tube promotes stimulation of distal esophageal afferent sensory mechanisms promoting reflux. Bolus feeding of the stomach can result in abnormal acid reflux events. Children with congenital or acquired neurologic disease are at increased risk of esophageal dysmotility, swallowing problems, and problems with airway protection, thereby increasing their chance of

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complications when the larynx is exposed to reflux. Children with upper airway obstruction from obesity, adenotonsillar disease, craniofacial dysmorphism, or other syndromic conditions also place them at higher risk of upper airway obstructive-induced GERD that is often not improved until the airway obstruction is often not improved until the airway obstruction is often not improved until the airway obstruction is addressed and managed..

EVALUATION OF GERD IN CHILDREN WITH AIRWAY SYMPTOMS AND LARYNGOTRACHEAL PATHOLOGY The most common studies used for the evaluation of acid reflux are an upper GI series/contrast esophagram, aerodigestive tract endoscopy, and 24-hour esophageal pH monitoring.

Because there is no clear consensus on which test predict and diagnose reflux as a cause of airway and laryngotracheal disease, the discussion will focus on common and recently introduced testing modalities and their strengths and inherent weaknesses in the evaluation of EERD. Most clinicians managing children with EERD will use a combination of clinical symptoms, physical examination findings, namely laryngoscopy and consider a trial of empiric therapy for 3 months, known as the “PPI test” to see if airway symptoms respond (Fig. 88-1).29,30 Indications for formal testing include inadequate symptom response to maximum dose empiric acid-suppression therapy, clinical examination findings symptoms suggestive of GERD complications despite adequate empiric acid-suppression therapy, such as laryngotracheal stenosis, or EERD symptoms or complications in need of objective confirmation of the diagnosis before antireflux surgery is performed.

Suspected LPR See Table 1 for symptoms

Laryngoscopy lingual tonsil hypertrophy

ventricular obliteration/obliteration

pseudosulcus vocalis

vocal fold cyst

Glottic or posterior glottic edema,

laryngeal hyperemia/erythema

Posterior commissure hypertrophy

Posterior wall cobblestoning

Empiric acid suppression therapy 3-month trial Symptoms + any laryngoscopy findings PPI 1-1.5 mg/kg q am + Ranatidine 6 mg/kg q HS Dietary and Lifestyle Modifications

Clinical improvement in symptoms

Continue acid suppression therapy

No improvement in symptoms

Diagnostic testing for GERD • Upper endoscopy with biopsy • Esophageal pH monitoring with impedance study if available (on therapy) • Bronchoscopy to look for evidence of aspiration • Laryngoscopy to look for evidence of GERD • Upper GI series (for evaluation of anatomy)

Inadequate acid suppression OR evidence of reflux-related damage

Maximize acid suppression therapy PPI 1-1.5 mg/kg BID + Ranatidine 6 mg/kg q HS

Evidence of non-acidic reflux or continued symptoms on maximal acid suppression

Consider adding a prokinetic

No clinical improvement

Consider Antireflux Surgery

FIGURE 88-1. Suggested evaluation and management algorithm for the child with suspected laryngopharyngeal reflux (LPR)

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CHAPTER 88 ❖ Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease

Empiric Trial—The “PPI Test” The “PPI test” is borrowed from adult practice. A patient with symptoms of EERD and laryngeal findings thought to be caused by reflux is started on a 3-month empiric trial of acid-suppression therapy. Symptom response is considered a diagnostic test of GERD as causation.31 If life-threatening complications or significant end organ damage of GERD are not present, many clinicians will use the PPI test before undergoing other invasive diagnostic tests.29,30 There is no clear consensus in medication dosage range or frequency. Initially, most otolaryngologists will use higher doses to treat EERD symptoms in order to determine symptom response and avoid the patient developing PPI resistance.32 Adult patients with EERD symptoms who took omeprazole 20 mg twice daily, the “PPI test” has a reported sensitivity range of 62.5%–81%.33,34 Symptom improvement with PPI therapy as a test of EERD and GERD ranges from — one to eight weeks.34,35 However, other studies have shown that patients with EERD may require higher doses of PPI and longer duration of treatment, up to six months, in order to obtain a satisfactory symptom response.36–43 There is neither current data for children, nor is there consensus regarding type or dose of acid-suppression medication used. The author’s preference is outlined in Fig. 88-1.

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laryngeal pathology. Microscopic magnification of the larynx during airway endoscopy under general anesthesia provides the best visualization of the larynx. Regardless of laryngoscopy technique, laryngeal findings of severe arytenoid edema, postglottic edema, pseudosulcus vocalis, and enlargement of lingual tonsil (Fig. 88-2A and B) are considered correlative laryngeal findings caused by GERD as determined by other diagnostic test of GERD.44,45 The finding of posterior wall cobblestoning effect (Fig. 88-2B and 88-3), although less specific, can be seen in children with reflux as a cause of airway symptoms and laryngotracheal pathology. The presence of at least one of the above findings has a sensitivity of 50% and a specificity of 100% for GERD. Finding at least two of these at a mild or severe level had a sensitivity of 87.5% and a specificity of 68%.44,45

Aerodigestive Tract Endoscopy Thorough examination of the pharynx, laryngotracheobronchial tree, esophagus, and stomach may provide a diagnostic assessment to determine if GERD is a causative factor in the etiology of airway symptoms and laryngotracheal pathology. In major centers, the trend is to evaluate children with EERD symptoms through a multidisciplinary team approach including pediatric otolaryngologist, pediatric pulmonologist, pediatric gastroenterologist, and other supporting services. In these centers, a child with refractory symptoms or laryngotracheal obstructive pathology will undergo aerodigestive tract endoscopy under anesthesia with all team members in attendance with each specialty evaluating their specific organ system. This approach also facilitates completion of ancillary test of GERD and EERD such as placement of intraluminal pH-monitoring catheters in children who may otherwise be noncooperative to placement when awake. Ultimately, this multidisciplinary approach fosters collaboration and crossfertilization of knowledge to best treat the child.

FIGURE 88-2A. Microdirect laryngoscopy showing LPR findings of pseudosulcus vocalis in a 2-year-old with stridor, chronic cough, and impedance pH proven GERD.

Laryngoscopic Findings Evaluation of the larynx can be accomplished by awake flexible laryngoscopy or by microlaryngoscopy under anesthesia. Fiberoptic flexible laryngoscopy with small diameter laryngoscopes has advanced our ability to examine the larynx in the awake child; however, the optics may limit delineation of subtle findings that could be correlative to GERD and LPR. The introduction of distal chip technology video laryngoscopes has improved our ability to observe fine details of

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FIGURE 88-2B. Flexible laryngoscopy showing LPR findings of lingual tonsil hypertrophy, posterior glottic erythema and posterior pharyngeal wall cobblestoning effect in a 9-year-old with biopsy-proven esophagitis.

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FIGURE 88-3. Flexible laryngoscopy showing LPR findings of posterior pharyngeal wall cobblestoning effect, and posterior glottic and arytenoid edema.

Bronchoscopy with Bronchoalveolar Lavage Examination of bronchoalveolar lavage (BAL) fluid for lipid-laden macrophages obtained during bronchoscopy can detect pulmonary aspiration of gastric contents. A lipid-laden macrophage index score of over 100 has greater than 90% sensitivity for diagnosing aspiration.46 The limitation of this test in the evaluation of EERD is that a high lipid-laden macrophage score cannot differentiate between the reflux of gastric contents and aspiration during swallowing. In addition, studies show that there is a low correlation between lipid-laden macrophages, GERD, and asthma or upper airway disorders.47,48 Therefore, examination of BAL fluid for lipid-laden macrophages only should be considered an adjunctive test and not a reliable indicator of GERD causing airway symptoms without other clinical substantiating data or examination findings. A recent study that examined BAL fluid for pepsin demonstrates that the detection of pepsin correlated with the finding of proximal acid reflux as determined by 24-hour intraluminal pH testing. A total of 65 of the 96 children (68%) had an extensive proximal acidic reflux index. Children with pathologic reflux had higher pepsin concentrations in their BAL fluid compared with children without reflux. This study suggests that pulmonary microaspiration as demonstrated by pepsin detection in BALF is common in children with chronic lung diseases and EERD symptoms, and may be more sensitive at detecting acid reflux than BAL examination for lipidladen macrophages alone.49

Esophageal Endoscopy With Biopsy Esophageal endoscopy enables both visualization and biopsy of the esophageal epithelium. Endoscopy, with histology evaluation of the esophageal epithelium is the most accurate method of demonstrating esophageal mucosal damage

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by reflux.50–52 The presence of erosions or ulcerations in the distal esophagus is indicative of GERD. Studies have shown that one-third of children with clinical evidence of GERD will have erosive esophagitis at the time of endoscopy.53 Those children with EERD symptoms or positive laryngeal findings suggestive of reflux between 30%–59% will have erosive esophagitis at the time of endoscopy.47,54–57 Microscopic evaluation of esophageal biopsies is important as histologic abnormalities can be seen even when there is no visual evidence of damage to the esophagus.58 Likewise, subtle mucosal changes of erythema and pallor may be observed in the absence of histopathological esophagitis. Histologic findings of intraepithelial eosinophils or neutrophils as well as morphometric measures of basal cell layer thickness and papillary height are valid indicators of reflux esophagitis.50 If histologic findings of reflux are demonstrated on biopsies in a child with airway symptoms or laryngotracheal pathology, then reflux is likely a causative factor. Because the esophageal lining is built to resist the untoward effects of acid and the larynx is not, a negative esophageal biopsy however does not eliminate reflux as a causative factor for airway symptoms and laryngotracheal pathology, a limitation of the use of esophagoscopy with biopsy in the evaluation of the child with EERD. An additional limitation of the use of esophageal biopsy findings in the evaluation of laryngopharyngeal disease is the discordance between positive pH studies and negative biopsy results in children with EERD symptoms and suggestive laryngoscopic findings.59

24-Hour Intraluminal Esophageal pH Monitoring and Impedance pH Monitoring Esophageal pH monitoring is a valid and reliable measure of acid reflux. Determination of acid reflux is accomplished by the use of specifically designed catheters that are passed through the nose of a child into the esophagus to determine acid events. To facilitate placement, the catheter is often placed at the time of aerodigestive tract endoscopy. Although it is considered the “gold standard’ in the determination of GERD in adults, the criteria to determine a positive test in infants and children for GERD, EERD, and LPR are still evolving.50 The sensitivity, specificity, and positive predictive value are superior to barium swallow with reported ranges from 31% to 86%, 21% to 83%, and 80% to 82%, respectively, when compared with esophageal pH monitoring.50 Over the past 20 years techniques for intraluminal esophageal pH monitoring have evolved from single channel to multichannel, and now multichannel intraluminal pH with impedance monitoring. Intraluminal Esophageal pH Monitoring Single-channel pH catheters have a pH sensor electrode at the terminal end of the catheter. Because the catheter can detect only distal esophageal acid exposure, this catheter design is limited in its usefulness to correlate proximal reflux events with laryngopharyngeal and airway symptoms and disease. Dual-channel catheters are designed to measure proximal and

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CHAPTER 88 ❖ Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease distal esophageal acid reflux to provide a better assessment of the correlation between the reflux event, reflux-related laryngeal symptoms, and EERD,60,61 which is considered by many to be the gold standard in diagnosing EERD.62 The proximal pH electrode is positioned in the esophagus just below the UES or in the pharynx. Positioning is verified by radiograph60 or flexible laryngoscopy.63 Pharyngeal pH monitoring has several limitations. The electrode must remain moist, free of mucus, and in contact with the mucosa to function properly. When the sensor is placed in the pharynx, it often dries out and is only intermittently in contact with mucosa,64 therefore the conditions of accurate and reliable detection of acid may not be maintained in the pharynx. Because of the limitations measuring pharyngeal pH, some clinicians will place the dual catheter so that the location of the proximal pH electrode is just below the UES. With dual-channel catheters, some clinicians will elect to place the second electrode in the stomach to assess intragastric pH to determine if there is adequate acid suppression on therapy. Triple-channel catheters have been designed to measure high esophageal, distal esophageal, and intragastric pH; however, the use in the pediatric population is limited as standard catheters designed for children are not readily available. Regardless of the number of electrodes in the catheter design, the esophageal luminal pH is monitored and recorded continuously for 18–24 hours and information is downloaded to the computer software to facilitate analysis. Parents are encouraged to keep a symptom diary for clinical correlation of reflux event and laryngopharyngeal symptom. A drop in esophageal pH < 4 has been the most widely accepted pH level considered pathologic.50 However, some studies suggest that pH ≤ 5 is correlative to LPR and EERD.6,65 Parameters evaluated include length of time that the esophageal pH < 4, the number of reflux episodes, the number of episodes that last longer than 5 minutes, and the distribution of episodes between the fasting and postprandial periods. No consensus exist as to which of these parameters is most correlative to LPR and EERD. In adults, the detection of acid at a proximal pH sensor located in the UES or esophageal inlet is sensitive and specific for LPR.4,66,67 However, studies to determine these correlations in children are inconclusive with some demonstrating correlation with LPR symptoms and laryngoscopy findings,68 whereas another study concludes that reflux to the proximal pH sensor cannot differentiate children with GERD from those with EERD.69 With documentation in a symptom log by the patient or observer, additional information can be gained with regard to the effects of sleep and sleeping position on reflux, and the temporal association of acid reflux with other symptoms, such as coughing, wheezing, irritability, choking, or stridor. However, lack of temporal-associated symptoms during the study period does not preclude acid reflux as a cause of EERD. Data on symptom correlation in children is lacking. Formal simultaneous multichannel studies of esophageal pH, heart rate, oxygen saturation (pulse oximetry), respiratory

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rate, and nasal airflow (nasal thermistor or end-tidal CO2) can be performed to establish the temporal relationship between esophageal acidification and apnea or other respiratory events. However the practicality of these modalities limits its use in clinical evaluation of GERD and EERD and have been employed mostly in clinical investigations.70–74 Despite being considered the gold standard, pH monitoring has several limitations. It allows detection of acid reflux at the position of the electrode only. The volume of refluxate and distance travelled from the stomach into the esophagus cannot be measured. The use of antacids, acid-suppressing medications, or prokinetic agents during the study will lead to a false-negative study result or true reflux. Because of the meal-to-meal and day-to-day variation in reflux, a child could be studied on a day when events are not occurring, thereby not completely eliminating the possibility of correlative reflux as a cause of symptoms. An additional limitation of pH monitoring is that it is sensitive but not specific for reflux. For example, a child with an obstructing pyloric stenosis which causes vomiting may also have a positive response. Intraluminal pH monitoring during acute respiratory illnesses with increased work of breathing, coughing, and wheezing may promote episodes of reflux therefore can produce a false-positive result. One of the greatest limitations of intraluminal pH monitoring in the evaluation infants and children with airway and laryngotracheal symptoms of reflux is the inability to determine the association of symptom causation by nonacid reflux events, which may play a major role in the etiology of atypical and airway symptoms and postprandial symptoms of reflux disease.68,75 Multichannel Intraluminal Impedance With pH Monitoring Multichannel intraluminal impedance (MII) is now the most widely used technique for evaluating esophageal function and GER. This technology addresses some of the limitations of the 24-hour intraluminal pH monitoring by being sensitive to bolus direction, differentiating between what is retrograde form and what is antegrade flow of the fluid and if acidic or not. This technique works by determining the changes in resistance to an alternating current between two metal electrodes produced by the presence of bolus inside the esophageal lumen. Through this bolus detection mechanism, this technology is sensitive enough to determine bolus direction. Retrograde detection of bolus movement is a reflux event, and antegrade detection of movement is a swallowed event. The impedance catheter has multiple metal electrodes spaced at interval distances. The most proximal electrode can be positioned at the UES or pharynx. When a retrograde reflux event occurs, the height of the reflux can be determined. When the impedance catheter design is combined with a pH sensor (MII–pH) at the distal end of the catheter, the height of the reflux event and the pH can be determined thereby making this technology ideal for correlating acidic and nonacidic reflux events with airway symptoms.76–79 It is postulated that nonacidic reflux events are likely involved in postprandial or atypical extraesophageal

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manifestations of GERD such as airway symptoms75 In infants, in particular, nearly 90% of the reflux events have been reported to be nonacidic because of the frequent neutralization of the gastric content following milk or formula feeding.80 A study comparing MII–pH with intraluminal pH monitoring in infants with EERD and airway symptoms showed that only 11.4% of the reflux episodes detected by impedance were detected by standard intraluminal pH monitoring, 85% of the episodes detected by impedance were associated with respiratory symptoms, but only 12% of these episodes were even detected by standard intraluminal pH monitoring.80 Another study with similar findings showed that children with persistent respiratory symptoms that included chronic cough, intractable asthma, recurrent respiratory infections, and chronic lung disease who underwent simultaneous impedance and pH monitoring, only 45% of reflux episodes were found to be nonacidic concluding that respiratory symptoms occurred more frequently when the reflux was nonacidic or mixed.78 These findings suggest that nonacidic reflux may be more contributory in respiratory disease than acid reflux, opening the door to pediatric otolaryngologist to question the role of acid alone in the etiology of airway diseases. A future direction may be to perform more Impedance pH studies in infants and children who present with respiratory disease or laryngotracheal pathology who have had persistent symptoms despite acid-suppression therapy. This may help us to determine better treatment modalities for nonresponders such as adding treatment modalities to increase esophageal transit time and motility such as promotility agents or erythromycin, or medications to decrease transient LES relaxations as to minimize the impact of nonacidic reflux on airway disease. It is possible that data obtained from MII–pH when a child is medically managed to the maximum, may better help predict which patients would benefit from fundoplication. Because MII–pH allows detection of reflux and definition of its chemical and physical composition (liquid, mixed, or gas), it has the ability to determine the proximal extent of the refluxate and the bolus presence time in the esophagus. It will likely replace 24-hour intraluminal pH monitoring as the gold standard for the detection of pathologic reflux in a child with airway and laryngotracheal disease.

Contrast Esophagram/Upper GI Series Contrast esophagram and upper GI series, also known as barium X-ray study has a limited role in the evaluation of reflux. The presence of reflux during the limited short testing time suggests that GERD occurs; however, it is unknown if the refluxate is acidic or nonacidic. A child may have reflux, but due to the brief duration of fluoroscopy exposure during the study the episode may be missed. Reflux may be seen during fluoroscopy even with asymptomatic children.50 This test is limited in sensitivity and specificity. Therefore, the test alone has low positive predictive value in the evaluation of children with airway disease and GERD without correlation with clinical symptoms and other examination findings.

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As this test requires the child to swallow contrast material, this test has no role in the child with EERD symptoms suspected to be due to reflux who is unable to eat or swallow. A contrast esophagram and upper GI series has a complementary role in the in the evaluation of children with recurrent emesis, dysphagia, and airway and other chronic respiratory symptoms. It is an effective method of evaluating the esophageal phase of swallowing as well as in investigating the GI tract for esophageal stenosis, malrotation, pyloric stenosis, tracheoesophageal fistula, stricture, or external compression from anomalous vascular structures that may be contributing factors in symptoms and disease etiology.50

Gastroesophageal Scintigraphy Although rarely utilized in children with airway disease, gastroesophageal scintigraphy is another radiographic test that can be used to demonstrate GER and may additionally confirm aspiration. During this test, the child is fed a technetium-99m (Tc99) sulfur colloid-labeled meal and postprandial images with a gamma camera are obtained. Images are repeated 4–18 hours to the following day to determine whether there is radionuclide scintigraphic activity in the lungs, indicating the aspiration occurred. The distinct advantage of this study compared with contrast esophagram is that it more accurately reflects the physiological conditions by showing whether the refluxate is aspirated during swallowing of the radionuclide, which will be detected on the postprandial images. If reflux with aspiration occurs later, then this is determined by finding the isotope in the lung fields on the delayed images. Scintigraphy is a low-sensitivity technique to diagnosis reflux is because of the brief duration of time of the study (only one meal is evaluated) and the fact that reflux and aspiration are episodic events therefore an event may be missed.50 Several studies have compared scintigraphy with pH monitoring in the detection of reflux and suggest that the two reveal different parameters of the same phenomenon and are not interchangeable in the diagnosis of reflux.81,82 Scintigraphy is felt to have limited usefulness in the evaluation and management of the child with airway symptoms, but may be useful if esophageal pH monitoring and endoscopy is normal in children where GERD is suspected to contribute to pulmonary aspiration and lower respiratory disease.83

TREATMENT AND MANAGEMENT Treatment of LPR and GER can be accomplished by a variety of strategies depending on age, nature, and severity of symptoms. The range of treatment options includes observation, lifestyle and dietary modifications, pharmacotherapy, and surgery (Fig. 88-1).

Lifestyle and Dietary Modification Efficacy of lifestyle and dietary modifications in the management of upper airway related reflux symptoms has not

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CHAPTER 88 ❖ Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease been studied. Data does exist showing conservative therapy interventions that can improve symptoms in 78% of infants with regurgitation and GERD84; however, those treated by conservative measures with improved symptoms may still develop esophagitis as demonstrated on histologic biopsy.85 Dietary options known to decrease the impact of GERD for infants include texture and formula type changes. Changing formula texture by adding a thickening agent increases its viscosity and calorie density. Thickened formula is still refluxed, but the number of emesis events diminishes. A recent Cochrane Database review found that thickened feeds are helpful conservative measure in reducing the symptoms of GER.86 Some infants may have milk or soy intolerance that induces emesis. Empirically, switching formula may improve reflux and regurgitation symptoms.87,88 An additional option for infants is small and frequent feedings. This dietary measure is based on the observation that pH-metric reflux decreases when feeding volume is decreased. Compliance with these options is difficult as frequent feedings disrupt parent schedules and reduced feeding volumes may also cause distress to the baby when hungry. In addition, some infants are “overfed,” therefore reducing volume may provide a simple solution. The above-described strategies are likely of little benefit for nonregurgitant reflux and may have a limited role in infants with airway symptoms outside of feeding problems, and aspiration.88 Dietary options for older children are similar to adults such as avoiding heavy meals before bedtime; however, the role in reducing airway symptoms is unknown. The role of dietary changes in the management of EERD and airway disease is likely adjunctive and complementary to pharmacotherapy. The role of body position in the treatment and management of EERD symptoms of reflux disease likewise has not been studied. Body positioning and its outcome in management of GERD, namely regurgitation has mixed conclusions. A Cochrane review showed that elevating the head of the crib in the supine position does not have any effect on the frequency of regurgitation and reflux events.86 Body position in the postprandial period however suggests that reflux is minimized when the child is placed in the prone or straight upright position and that postprandial supine positioning worsen reflux and should be avoided.84 Recent data gathered from intraluminal impedance pH testing have proved that placing infants in the prone or left lateral position in the postprandial period is a simple intervention to limit GER.89 Prone positioning must be used with caution because of the increased concern with sudden infant death syndrome (SIDS). For older children, elevation of the head of the bed and avoidance of snacks at bedtime, caffeine, and smoking are commonly recommended, but have not been formally studied. Elimination of smoke exposure is particularly important in managing children with EERD not only because that it worsens reflux,84 but also it causes upper airway inflammation. Increased smoke exposure predicts increased acid reflux in infants with apparent life-threatening events or wheezing90,91 and increased persistence of reflux symptoms from infancy to 9 years of age.92

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Medical Management Pharmacologic treatment for airway manifestations of reflux in children has been adapted from EERD treatment in adults in addition to strategies used to manage GERD in infants and children. Frequently employed pharmacologic treatment options for children include prokinetic agents, and acid-suppressing medications. The role and efficacy of acidneutralizing medications (magnesium hydroxide, aluminum hydroxide, magaldrate, and calcium carbonate) and mucosal protection agents (sucralfate) in the treatment of EERD is unknown. These medications are commonly used as an adjunct to H2RA (histamine2-receptor antagonist) or PPI.93 Prokinetic agents work by increasing LES pressure and accelerating gastric emptying.94 Cisapride and metoclopramide are options, however the side effect profile of irritability, acute extrapyramidal effects and tardive dyskinesia limit wide-spread use.95 The most widely used prokinetic in recent years is cisapride, but it is no longer available in North America because of the drug profile complication of developing a life-threatening prolonged QT interval.96 Cisapride is only available for use on compassionate-use grounds; therefore, risk benefit ratio must be carefully evaluated.96,97 Erythromycin is an underutilized option to improve motility. Using a much lower dose than is required for antibiotic use, erythromycin improves gastric emptying by stimulating motilin receptors to induce a strong propulsive wave from the antrum into the duodenum.98 Although it may increase LES pressure, early studies have not show consistent benefit in the treatment of reflux. The role of promotility agents for treatment of EERD and LPR is mostly adjunctive for cases refractory to symptom improvement with PPIs. Acid-suppression therapy has become the mainstay for treatment of airway and laryngotracheal manifestations despite clear evidence in full support or refute of their utility. The two classes of acid-reducing medications are H2RA therapy (cimetidine, ranitidine, famotidine) and PPI therapy. H2RA is a competitive H2-receptor antagonist that reversibly inhibits the action of histamine at the histamine H2-receptors, including receptors on the gastric cells. There is no US Food and Drug Administration (FDA) approved dosage guidelines for use of H2RA therapy for EERD in children. If using H2RA therapy alone for treatment of EERD and LPR, the author’s preference is ranitidine 3–5 mg/dose divided every eight hours.25 Although H2RA options are still used, PPIs are the most common medications utilized in the treatment of GERD, EERD, and LPR. Omeprazole and lansoprazole are currently FDA approved for use in children 1 year old and esomeprazole is approved for those 12 years old. The introduction of PPIs has revolutionized the approach to acid-related disorders in adults and children.99–106 Similar to adults, in children, these drugs have been proven to be effective and safe for the treatment of GERD-related symptoms and signs, including the most severe degrees of reflux esophagitis. Some studies have demonstrated better rates of healing of erosive esophagitis in

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children compared with studies in adults.101,104,106,107 Although the overall pharmacokinetic profiles of these agents are similar to those in adults, children differ significantly from adults in having an age-related enhanced metabolic capacity.108 Up to an age of 10, children often require higher doses on a perkilogram basis than adults. Dosage range for omeprazole for successful treatment of esophagitis in children ranges from 0.7 to 3.5 mg/kg/d.102,104 A starting dose of approximately 1.4 mg/kg/d omeprazole has been shown to effectively heal 75% of the children with severe esophagitis and also lead to resolution or significant improved GERD-related symptoms. Symptom relief with PPI therapy occurs within the first two weeks of treatment. Most children will need duration of two years from start of therapy.97 The most commonly reported error in PPI prescribing in children is underdosing, or splitting the total daily dose into twice-daily dosing. The optimal administration mode for PPIs is once per day, 30 minutes before the first meal of the day, since that is when acid pumps or proton pumps are generated, and can be efficiently blocked. For GERD, twice-daily PPI therapy is indicated for treatment of severe esophagitis, peptic stricture, esophageal motility disorders, and persistent nocturnal reflux symptoms. Adult studies suggest that EERD and LPR often require twice-daily PPI therapy to result in symptomatic relief.109–111 Even with twice-daily PPI therapy, there is nocturnal acid breakthrough.112–114 Adult studies have shown that the addition of a bedtime H2RA reduces the percentage time the intragastric pH is < 4 and nocturnal acid breakthrough. Nighttime H2RA should be considered as adjunct therapy in which greater suppression of gastric acid control is considered desirable.79,113,115 The data for the addition of H2RA for nocturnal acid breakthrough in patients with LPR is limited but suggest benefit.116 In adults, the present data for pharmacologic treatment of EERD and LPR are inconclusive. Studies assessing adequate dosing regimens and timeframe for symptom improvement in children with EERD are much in need. Based on available data in the efficacy of treatment of GERD-related disease in children along with the adaption of management strategies for adults, the author suggests starting PPI therapy at a dose of 1.5 mg/kg/d in the morning and the addition of nighttime H2RA at a dose of ranitidine 6 mg/kg for uncomplicated symptoms of EERD and LPR (Fig. 88-1). If symptoms are refractory after a 6–12-week trial, consider expanding to twice-daily PPI therapy. For “end stage” disease or complicated EERD and LPR such as laryngotracheal stenosis, feeding disorder with failure to thrive, reflux related apnea the author suggest twice daily PPI therapy and nighttime H2RA or antireflux surgery (Fig. 88-1). Reported side effects from PPI therapy are uncommon and include nausea, vomiting, skin rash, irritability and agitation. The children who are more commonly reported to have side effects also have an associated neuromuscular disorder.97

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Even though PPIs are reported safe in long-term management of adults117 and children with reflux disease,97 for up to 11 years, potent acid suppression resulting in achlorhydria may not be desirable, because gastric acid is an early line of protection against entry of pathogens into the gut as well being necessary for absorption of various nutrients. There is a possible but yet unproven altered vitamin B12118 and iron absorption, related to alteration of the gastric pH.119–121 Case reports describe the development of iron deficiency anemia associated with PPI therapy.119,120

Antireflux Surgery Surgical treatment of GERD by fundoplication is reserved for infants and children with severe, medically unmanageable complications of reflux. The most commonly associated upper airway problem managed by fundoplication is infant apnea. By using surrounding gastric fundus and fixing it to the distal esophagus, the goal of fundoplication surgery is to create a barrier to eliminate reflux of gastric contents into the esophagus, but still allow for unrestricted bolus propulsion into the stomach from the esophagus.122 There are a variety of types of fundoplication procedures out of which the Nissen fundoplication is the most commonly performed. Since the development of minimally invasive surgery, laparoscopic fundoplication for treatment for GERD has become very popular alternative to long-term medication use. Despite the appeal of a potentially curative operation, fundoplication surgery is not without caution and complications. Studies show that failure rates range between 5% and 70% and can occur as soon as 1–3 years.123 Findings suggest that the failure and complication rate is higher in children who have undergone esophageal atresia repair or neurologically impaired children compared with neurologically intact children.123,124 Others report good outcomes from fundoplication in neurologically impaired children.125,126 Some children develop postoperative symptoms that were not present before surgery that include abdominal bloating, increased flatus, difficulty with eructation and vomiting, and dysphagia.123,127–129 As the vagal nerve transverses between the trachea and esophagus, a risk of vagal nerve injury exist that could potentially worsen or exacerbate upper airway and laryngopharyngeal symptoms. In children, as in adults, experience of the surgeon and surgical center and appropriate case selection are key factors for determining surgical outcome.123 Relief from persistent airway symptoms after fundoplication has provided one of the strongest piece of evidence retrospectively linking the association of reflux disease and EERD.130–134 The role of fundoplication in the treatment of EERD and LPR is not clearly defined in adults or children. Over the past 12 years, an increasing number of studies have evaluated the role of fundoplication in EERD and LPR management in adults with mixed conclusion. Most current studies conducted by gastroenterologist conclude that surgical fundoplication is most effective in those who are

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CHAPTER 88 ❖ Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease responsive to acid-suppressive therapy.135 Studies conducted by otolaryngologist or collaborative multidisciplinary efforts show that fundoplication is an effective modality to treat EERD in selected cases.136–139 Laryngeal symptoms may take longer to resolve post fundoplication than esophageal symptoms, but an overall positive complete response rate of 65% and a subjective improvement response rate of 85%–97% have been reported.137,138 Benefits are reported within one to three months after surgery and persist for at least three years.137,139 The failure rate of fundoplication for those treated for EERD symptoms is unknown. Indications to consider fundoplication for treatment of EERD include individuals not responsive to PPI, incomplete clinical responders, and those who, in an informed manner, chose fundoplication over medication. Some otolaryngologists believe that patients with “end-stage” upper airway pathology (e.g., laryngotracheal stenosis, laryngeal cancer, leukoplakia, and so forth) are candidates for and do benefit from antireflux surgery.130,137,138 Pre- and postfundoplication analysis with multichannel intraluminal impedance suggest that there is more of a role of nonacidic disease in the causation of airway symptoms (Fig. 88-4A and B) and may further expand the utilization of fundoplication in airway disease.75–78

obstructive apnea, whereas the older infant, child, or adult coughs.140,141 Reflux may trigger apnea by stimulation of any of the laryngeal or esophageal chemoreflexes with the apneic response thought to be due to laryngospasm.142 Despite the physiological basis supporting a causal relation between apnea and reflux, studies have been unsuccessful in demonstrating a convincing temporal relationship between episodes of both acidic and nonacidic reflux and apnea.143 The association of GERD, LPR, and infant apnea is poorly understood despite multiple clinical and animal studies. It is confounded by conflicting data linking acid reflux to apnea70,144,145 and data that challenges the association.143,146–148 Acid stimulation of any of the laryngeal protective reflexes in infants and animal models can result in apnea,19,21,72,149,150 apnea–hypopnea events151 and apneahypoxic events.152 One of the most clinically accepted association is that, “awake apnea” episodes are triggered by acid reflux.144Recent studies using MII–pH technology demonstrate that 70% of GER episodes reach the pharynx in infants but only 12% of all reflux events are acidic and the remainder are nonacidic, thereby suggesting that nonacid reflux may play a greater role in the etiology of apnea.143 Another study that challenges the association between acid reflux and apnea suggest that GER may be present but does not contribute to apnea severity in preterm infants153 suggesting that other factors that may alter airway protective mechanisms may have a role. Airway protective mechanisms can be altered by chronic acid exposure.8,24–26,154,155 Chronic acid stimuli applied to the larynx in experimental and clinical models result in apnea not from the acid itself but from obstruction from secretions in the laryngeal inlet because of impaired ability to swallow to clear the stimulus and secretions in a timely manner.156,157 These investigative findings support the notion that apnea can

PEDIATRIC REFLUX AND LARYNGOTRACHEAL DISEASES Apnea GER is a potent stimulus of laryngeal protective reflexes. The response from stimulation in infants differs from those of toddlers, older children, and adults. The young infant may respond to laryngeal stimuli with central and/or

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FIGURE 88-4. (A) (B) Microdirect laryngoscopy and bronchoscopy showing bile staining of the posterior glottis, arytenoids, and subglottis in a 4-year-old child with impedance pH documented nonacidic reflux and refractory airway symptoms despite compliance with maximum acid-suppression therapy.

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occur because of alteration in the function airway protective by direct short lived application of acid to the larynx or by sensory denervation of the airway protective reflexes, namely the LAR, leading to difficulty swallowing secretions or a stimulus. Predilection to which mechanism occurs in the etiology of infant apnea or apparent life-threatening events remains yet to be elucidated. However, the data suggest that there is no causal relationship between the acid reflux event and the apnea event, yet many infants with apnea demonstrate pathologic reflux documented on pH monitoring.158 These findings imply that chronic acid exposure with poor clearance of stimulus or secretions is a plausible mechanism causing apnea140 that combines the data of acid disease as a contributing factor but other mechanisms contribute to the occurrence of the apneic event. This concept is supported by the findings of a study that tested laryngeal sensation counterintuitively found infants with apnea has less laryngopharyngeal sensation and more secretions compared with similarly aged comparison group.26 The apnea group also had a higher percentage with GERD. The investigators postulate that reflux causes a functional anesthesia of airway protective mechanisms leading to more secretions pooling in the hypopharynx and laryngeal inlet making it more difficult to swallow and clearing secretions that then enter or block the larynx likely leading to the cause of airway obstruction and apnea.26 The cause and effect relationship of GERD and obstructive sleep apnea (OSA) is likewise controversial despite a confirmed association between GERD and OSAS children as well as in adults. Treatment of GERD has been shown to improve OSA159 and OSA therapy with CPAP has been demonstrated to reduce GERD160 confirming a close association between these two conditions. Up to 50% of children with polysomnographic documented OSA will have pathologic GERD confirmed by pH monitoring; however, the temporal relationship between the reflux event and the apneic event has yet to be demonstrated.161 The role of upper airway sensorimotor impairment of the LAR has been studied in adults with significant OSA demonstrated on PSG. Adults with OAS who have a positive reflux finding score (RFS) demonstrated significant upper airway sensory impairment through finding elevated LPST thresholds of the LAR. These investigators concluded that laryngopharyngeal sensory impairment closely reflects LPR severity.162 In adults and children, further research is required to determine whether GERD and LPR precedes the development of OSA and contributes to its severity or whether the converse is true. Finally, it is also unknown whether successful treatment of OSA will affect the severity of the LPR.

Laryngomalacia Laryngomalacia is the most common cause of infant stridor and a common cause of upper airway obstruction in those under 18 months of age. In this condition, laryngeal tone is weak and stridor and upper airway obstruction occurs

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because of prolapse of upper supra-arytenoid tissue into the glottic inlet during inspiration. Up to 80% of infants with laryngomalacia will have GERD.7,25,163–167 The chronic nature of the upper airway obstruction likely promotes further reflux due to negative intrathoracic changes from breathing against an obstructed airway as previously discussed. Double pH monitoring has shown that infants with laryngomalacia will all have proximal reflux with a mean number of 15 events in 24 hours.7 The supra-arytenoid mucosa that is already redundant and prolapsing into the airway is likely worsened from the effects of LPR causing laryngeal edema. A histologic study of tissue removed at the time of supraglottoplasty demonstrates inflammatory changes similar to the histology seen in the esophagus due to reflux, furthering the association of GERD and LPR in laryngomalacia.168 By performing laryngopharyngeal sensory testing, a study showed that airway protective reflexes are altered in infants with laryngomalacia. This study showed that laryngeal sensation was significantly altered in infants with GERD and LPR compared to those who did not. Patients with feeding symptoms all had GERD and LPR likewise had significant laryngeal sensory deficits. The infants who are treated have significant improvement in symptoms and laryngeal sensation. Infants with severe symptoms requiring supraglottoplasty or tracheostomy had GERD, LPR, and even greater sensory deficits. The findings from this study imply that GERD and LPR has a role in laryngomalacia disease severity and likely affects the sensorimotor integrative function reflex of airway protection of the larynx leading to the findings of supraarytenoid prolapse, airway obstruction, feeding difficulty, cough and choking while feeding, aspiration, and apnea.25,169

Hoarseness and Vocal Fold Disease Hoarseness is the most common laryngeal-related symptom associated with GERD and LPR in children.170 Less commonly encountered symptoms are chronic cough or throat clearing and these symptoms may be absent in children with LPR and hoarseness. Hoarseness is the hallmark symptom of vocal fold cystic or nodular disease in children. The development of cystic (Fig. 88-5) or nodular disease is likely multifactorial for which GERD and LPR have been implied in the etiologic mechanism. Basic laryngeal molecular studies in children with documented reflux are however lacking. The relational implication of GERD, LPR in the etiology of hoarseness, and vocal fold disease in the pediatric population are from nonrandomized or noncontrolled prospective and retrospective studies that show laryngeal visual findings similarly seen in adults such as cyst, nodules, pseudocysts, and pseudosulcus vocalis that correlate with positive studies of GERD. Other studies suggest that extraesophageal clinical symptoms of GERD correlate with positive studies of GERD. The relationship has also been implied based on simply symptom improvement in children empirically treated for GERD.

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CHAPTER 88 ❖ Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease

FIGURE 88-5. Vocal fold cystic findings of LPR.

Reporting the prevalence of laryngeal changes consistent with reflux in children with GERD is a starting point; however, there are tremendous variations in clinicians consistently reporting findings and the perception differs of what is laryngeal finding of LPR versus what is not varies even among experienced clinicians.55,171 As in adults, there is a lack of consensus in defining a vocal fold nodule compared with cyst or a pseudocyst, but most will agree that LPR has a similar pathophysiologic dynamic in the etiology of some patients. A recent study evaluating hoarseness in children found that all children with vocal fold cyst/pseudocyst had an additional test that documented GERD. The same study found that laryngeal findings of LPR, including nodules and cyst that 74% children had a positive test for GERD. Nearly 70% children with LPR findings and positive GERD testing who were treated had symptom improvement or resolution.171 Laryngeal pseudosulcus refers to infraglottic edema resulting in the appearance of a fold parallel to the free edge of the vocal fold and is a clinically established finding of LPR in adults (Fig. 88-2A). A retrospective review of clinical photographs of 66 children undergoing direct laryngoscopy for airway symptoms for the presence of laryngeal pseudosulcus demonstrated that the presence correlated with positive reflux tests in 89% patients studied. When compared to children with pseudosulcus and a negative reflux study, these investigators found that the finding of pseudosulcus vocalis demonstrated a sensitivity and specificity of 89% and 70%, respectively, with having GERD.45 Other diffuse findings seen during airway endoscopy in children may correlate well with the diagnosis of GERD as determined by using other tests. One study described the triad of severe arytenoid edema, postglottic edema, and enlargement of lingual tonsil (Fig. 88-2B) as pathognomonic of GERD.44

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In contrast to the findings of the above-mentioned studies, through comparing pediatric voice outcome survey (PVOS) score, the RFS, and esophageal biopsy findings in children undergoing upper aerodigestive tract endoscopy, another group found that there were no significant correlations between RFS, esophageal biopsy results, PVOS, or RSI scores. However, they did find that the RFS was reliable in children as a means of evaluating laryngeal findings of reflux disease, but its validity could not be demonstrated due to the lack of correlation with the other scores. They concluded that further work is needed to refine and validate an objective pediatric laryngeal grading instrument to correlate symptoms with reflux disease.172 Duration and type of pharmacotherapy for the management of LPR-related hoarseness in children has yet to be determined. It has been suggested that laryngeal alterations and voice quality improve by 12 weeks of therapy with PPIs combined with prokinetic agent.173 Another study suggest that when pharmacotherapy is combined with voice/speech therapy, it may result in higher improvement and resolution rates.171

Dysphagia and Aspiration Like adults, there is a causal relationship between swallowing difficulty and GERD. Because infants and children will have difficulty expressing or articulating symptoms of dysphagia, the clinical presentation can differ from adults. Pediatric swallowing problems may present as coughing and choking during feeding, respiratory symptoms associated with feeding, failure to thrive, food refusal, recurrent emesis, pneumonia, or aspiration. The presence of these symptoms will often prompt the physician to investigate for GERD or empirically treat them. There are many reasons LPR can cause swallowing difficulty. LPR can cause pain. It causes alteration in the anatomy of the structures involved in swallowing and airway protection. As previously discussed, LPR causes sensory deficits in the LAR that modulates the swallow process in children and adults. The infant and pediatric swallowing process is a highly coordinated process that requires intact sensorimotor reflexes of the LAR to protect against aspiration. The high anatomic position of the larynx behind the nasopharynx during infancy along with an intact LAR swallow reflex allows the suck-swallow breath sequence to occur without compromise to respiration or increase risk of aspiration. As the child ages and matures, the larynx descends from its high position in the nasopharynx to its adult location in the neck. If the neuromuscular function of the airway protective reflexes (LAR) does not mature or if compromised by an acquired disease at the time of laryngeal descent, then the child is at risk for swallowing dysfunction and subsequent aspiration. Furthermore, the occurrence of microaspiration may lead to respiratory complications such as aspiration pneumonia, asthma exacerbation, or apnea. This may be the link that connects GERD and lower airway disease.

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It is theorized that gastric refluxate leads to edema of the posterior glottic region, causing decreased sensation and alterations in the laryngeal protective reflexes. The LAR results in glottic closure and cessation of respiration during swallowing and is triggered by exposure of the supraglottic mucosa to chemical or mechanical stimuli. This glottic closure prevents aspiration. When this reflex mechanism is disrupted by the deleterious effects of acid exposure, lack of appropriate laryngeal closure may in turn result in laryngeal penetration and aspiration. Children evaluated for swallowing problems who also had GERD demonstrate greater sensory deficits compared to children without GERD diagnosis.174 The same group of children with GERD had higher rates of pooling of secretions in the laryngeal inlet and recurrent pneumonia suggesting a connection between GERD and LPR, and an altered airway protection leading to lower airway disease. Another study demonstrates that if reflux is treated by either acid-suppression medication or fundoplication, the sensory deficits children, with dysphagia and aspiration, who do not have underlying neurologic disease will improve and result in better swallowing and airway protection.27 Increased vigilance is necessary in

identifying this group of children. An example of pre- and posttreatment improvement in laryngeal findings is demonstrated in Figures 88-6A and B of a child with multiple airway symptoms including dysphagia, aspiration, feeding disorder, LPR, and GERD. There are many esophageal diagnosis related to GERD that can cause dysphagia, but are beyond the scope of this chapter.

Recurrent Croup The etiology of recurrent or spasmodic croup is unclear. Recurrent croup occurs from inflammatory triggers in the upper airway and most episodes are attributed to viral illness and allergy. GERD has been studied and implicated in the cause of or exacerbation recurrent croup.175–179 Dual-pH monitoring demonstrating significant proximal sensor reflux events infers the cause and effect relationship between recurrent croup and GER.177 Up to 75% of patients with recurrent croup will have esophagitis seen on biopsy.51 Successful antireflux treatment leading to resolution of croup episodes, with recurrences after stopping medical

FIGURE 88-6A. Pretreatment laryngotracheal findings in a 5-year-old girl with aspiration, swallowing disorder, recurrent croup, and subglottic stenosis with impedance pH proven GERD and esophagitis.

FIGURE 88-6B. Improved laryngotracheal findings after fundoplication in the same 5-year-old with refractory symptoms despite balloon dilatation of subglottis and maximum medical treatment for acid suppression.

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CHAPTER 88 ❖ Airway and Laryngotracheal Manifestations of Gastroesophageal Reflux Disease management provides additional evidence of the role of GERD in disease etiology.176 The exact mechanism of GERD or LPR-associated croup is poorly understood. It is likely a combination of mucosal and structural disease in the subglottic region (Fig. 88-6A) Coexisting allergic or atopic disease with GERD increases the likelihood of recurrent croup. A recent study found that GERD was present in 62.5% of children with recurrent croup and that 17.2% had allergic disease or atopy.180 Another recent study found that greater than 60% of children with recurrent croup had coexisting diagnosis of asthma.181 The findings from these studies imply that those with allergies or asthma in addition to GERD are more likely to have recurrent croup events. Laryngopharyngeal changes consistent with GERD (Fig. 88-7) and LPR can be seen in up to 87% of children investigated by direct laryngoscopy and bronchoscopy. In this study, those diagnosed with LPR based on visual examination noted symptomatic improvement of respiratory symptoms after a six- to nine-month course of acid-suppression medications.181 Another study from the same institution showed that an underlying grade 1–2 subglottic stenosis is frequently present in patients with recurrent croup and laryngopharyngeal visual changes are consistent with LPR.182

Subglottic Stenosis The etiology of subglottic stenosis (SGS) is multifactorial; however, the causal relationship to GERD and LPR is well known to the practicing otolaryngologist,67,183,184 and some will treat aggressively before undertaking endoscopic (Fig. 88-6B) or open laryngotracheal airway reconstruction surgery.183 Our knowledge of pathophysiologic mechanism to the cause and effect relationship between GERD, LPR, and SGS is still evolving. Animal model studies show that inflammation induced in traumatized subglottis exposed to acid is significant and the added effect of pepsin is substantial.67,185 GERD is a frequent event in children with SGS. The frequency is likely exacerbated by the large negative intrathoracic pressure generated by breathing

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against an obstructed airway as discussed earlier. Likewise, any alteration of airway protection increases the risk of aspiration into the upper airway at the subglottic level, further exacerbating inflammatory changes that can lead to stenosis. Our understanding of the prevalence of GERD in patients with SGS is limited to case series mostly concluding that patients with uncontrolled GERD have higher rates of airway reconstruction failure for SGS, if the reflux is not identified and treated.186,187 Children with SGS are documented to have high rates of pathologic reflux,183 but it is unknown if these rates are any higher than other highrisk pediatric populations. These studies are challenged in concluding the causality of SGS and GERD because of the multiple other factors leading to GERD in this patient population.

Reflux and Paradoxical Vocal Fold Motion Paradoxical vocal fold motion (PVFM) is characterized by inappropriate adduction of the vocal folds during inspiration causing stridor. GER may occur in association with PVFM; however, a direct cause–effect relationship between these two disorders has not yet been established. The most widely accepted theory of GERD causation of PVFM is alteration in the response of vagally mediated reflexes by exposure of gastric fluids to the supraglottic chemoreceptors.188,189 Alternatively, PVFM may induce GER events by increasing the degree of negative inspiratory intrathoracic pressure. Stridor is the hallmark symptom. In infants and toddlers, the primary presentation is inspiratory stridor that occurs when calm, crying, or feeding.190 In older children and adolescents, related symptoms of PVFM include “choking episodes” during inspiration, throat and chest “tightness,” dysphagia, and “food sticking.” Varied success occurs with acid-suppression therapy alone.190,191 Biofeedback and respiratory retraining therapy are adjunctive measures191 that can be used for successful treatment outcomes in cooperative children and adolescents. When evaluating a child with PVFM, it is important not to overlook more serious causes that include brainstem compression, cortical or upper motor neuron injury, nuclear or lower motor neuron injury, or movement disorders. Other etiologies include drug-induced dystonic reactions, asthma, and psychogenic stridor presenting as malingering disorder or a conversion disorder.

CONCLUSIONS

FIGURE 88-7. Pseudosulcus vocalis in a 5-year-old child with pH proven GERD, hoarseness, and recurrent croup.

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In recent years, an association between GERD and laryngeal disorders has become the focus of intense study. Detailed history taking combined with laryngotracheal clinical examination findings suggestive reflux disease followed by empiric therapy with acid-suppression medication and monitoring symptom response remains the mainstay initial approach for nonlife-threatening airway

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symptoms and disease associated with GERD and LPR in children. Many children experience symptom relief from this approach. Life-altering, life-threatening or “endstage” airway disease associated with GERD and LPR may require several diagnosis tests to determine the severity to best direct treatment strategies. Because of the complexity, approaching the child with complicated EERD is best done by multidisciplinary teams. Recognizing that this approach lacks evidence-based retrospective or prospective data presents a ripe area for further clinical investigation. Future clinical investigation faces challenges as there is yet no consensus on the most practical and accurate technique for diagnosing GERD and LPR in children and prospective randomized controlled-clinical trials are ethically challenging to execute. Future research studies should seek standard reflux testing methods, clear comparison groups, and more rigorous statistical methods. Future investigation should also evaluate and clarify the role of nonacidic reflux in airway and laryngotracheal disease. Widespread use of impedance pH technology in the evaluation of children with airway disease should facilitate. Despite these potential limitations, future knowledge may come from molecular studies of the role of inflammatory neuropeptides and other cellular changes.

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89

C H A P T E R

Congenital Laryngeal Anomalies Mark E. Gerber and Judy L. Chen

T

he larynx functions as a breathing passage, provides airway protection during swallowing, aids in the clearance of secretions (cough), and allows for vocalization. It follows that symptoms of laryngeal anomalies are those of airway obstruction, difficulty in feeding, and abnormalities of phonation. These symptoms vary and are characteristic of individual anomalies. The signs and symptoms of a child with airway obstruction are usually different depending on the location and severity of obstruction. Being able to assess and localize the potential site and cause of the obstruction is essential. Airway obstruction at the level of the nasopharynx or oropharynx produces the inspiratory low-pitched sound called stertor or snoring. Dynamic supraglottic and glottic obstructions tend to produce inspiratory stridor due to collapse of these structures with negative inspiratory pressure. Intrathoracic airway lesions cause expiratory obstruction. Stridor caused by fixed subglottic laryngeal and cervical tracheal lesions is most often biphasic. Obstructive symptoms can vary from mild stridor to severe obstruction with increased work of breathing (retractions), tachypnea, episodes of apnea, and cyanosis. Feeding and swallowing issues arise due to a dysfunction at one or multiple levels of the laryngeal three-tiered system of “sphincters” that contribute to airway protection during swallowing: the epiglottis, aryepiglottic folds, and arytenoids (first level), the false vocal folds (second level), and the true vocal folds (third level). Anomalies that affect any of these protective barriers can result in aspiration. Symptoms of swallowing dysfunction and aspiration include coughing, choking and gagging episodes during and after feedings, stasis of secretions, and recurrent pneumonias. Phonatory abnormalities differ depending on the level of laryngeal anomaly present. A muffled cry is suggestive of supraglottic obstruction. A high-pitched or absent cry is associated with glottic abnormalities such as webs or atresia.

LARYNGOMALACIA Laryngomalacia is the most common congenital laryngeal anomaly and the most frequent cause of stridor in children. Sixty percent of congenital laryngeal anomalies in children with stridor result from laryngomalacia.1 Large series of congenital laryngeal anomalies cite a 50% to 75% incidence for laryngomalacia.2–4

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Terminology Laryngomalacia is a specific disease state with an ill-defined pathogenesis manifested by derangements of supraglottic anatomy, histology, or neurologic function. The term laryngomalacia was first used by Jackson and Jackson in 1942 to describe the inward collapse of supraglottic structures during inspiration.5 Prior to that, the general term congenital laryngeal stridor had been used.6 Laryngomalacia is a term that reflects the flaccidity of supraglottic laryngeal tissues without implying a specific pathophysiologic mechanism. However, stridor is a symptom, and not a specific disease state; and there are many congenital laryngeal disorders that can cause stridor.

Symptoms Intermittent, low-pitched inspiratory stridor is the hallmark of laryngomalacia. Symptoms usually appear within the first two weeks of life, although rarely onset occurs months after birth.8 This delay is interesting because laryngomalacia is presumed to be congenital. More recently, late-onset laryngomalacia has been described and classified by presenting symptoms: feeding-disordered laryngomalacia, sleep-disordered laryngomalacia, and exercise-induced laryngomalacia.77 An increase in the severity of stridor over the initial few months usually is followed by a gradual improvement. Symptoms usually are at their worst by 6 months of age, when they plateau and begin to resolve gradually. Although most patients are symptomfree by 18 to 24 months of age,9 stridor can persist for years.8 Typically, stridor is exacerbated by exertion: crying, agitation, feeding, or supine positioning. Substernal retractions indicate severe obstruction, and pectus excavatum is a complication of extreme chronic obstruction.10 Moderate to severe cases may be complicated by feeding difficulties, gastroesophageal reflux, failure to thrive, cyanosis, intermittent complete obstruction, or cardiac failure (as seen in obstructive sleep apnea).11–13

Pathophysiology Anatomic, neurologic, and inflammatory factors all may contribute to the development of laryngomalacia. Anatomic/ mechanical abnormalities are variable with one or more often occurring simultaneously with one aspect dominating (Fig. 89-1). Some consider the omega shape of the epiglot-

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A

A

B FIGURE 89-1. Direct laryngoscopy of a child with laryngomalacia under a general anesthetic with spontaneous ventilation. (A) During inspiration with collapse of the supraglottic larynx. (B) During expiration with passive opening of the supraglottic larynx.

tis a factor that contributes to stridor. However, the omega shape often is present in the absence of obstructive symptoms and is normal in infancy.15 The omega shape itself probably is not responsible for stridor,16 but may become a contributing factor when pathologically exaggerated. Regularly identified anatomic abnormalities include the following: 1. Inward collapse of the aryepiglottic folds, primarily the cuneiform cartilages, which often are enlarged. 2. A long tubular epiglottis (a pathologic exaggeration of the normal omega shape). 3. Anterior, medial collapse of the arytenoids cartilages. 4. Posterior inspiratory displacement of the epiglottis against the posterior pharyngeal wall or inferior collapse to the vocal folds. 5. Short aryepiglottic folds.13 Laryngeal cartilage immaturity, with resultant weakness and a tendency to collapse on inspiration, has been suggested as a contributing factor.10 However, this theory is

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B FIGURE 89-2. Laryngomalacia. (A) Prior to supraglottoplasty. (B) The improved view of the glottis after completion of the procedure.

weakened by the fact that the incidence of laryngomalacia is not increased in premature infants as compared to full-term infants.16 Conclusive evidence of histologic abnormalities has not been found.10 Keleman discerned no uniform differences between specimens of stridulous and normal infants.17 Histopathologic examination of specimens from patients with severe laryngomalacia requiring surgical intervention has revealed predominately normal microanatomy in one study of 10 patients11 or pervasive subepithelial edema in a more recent study of 9 patients.18 Because only a few reports document altered histologic structure,10,18,19 the evidence currently does not support microscopic structural pathology as the sole cause of laryngomalacia. Immature or defective neuromuscular control is another pathophysiologic mechanism thought to play a role in laryngomalacia. McSwiney and colleagues noticed delayed speech in 4 or 21 children with laryngomalacia.20 Associations among laryngomalacia, central apnea, hypotonia, mental retardation, and early speech problems have bee reported,

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CHAPTER 89 ❖ Congenital Laryngeal Anomalies 1519 adding further support to the theory of a delayed development in neuromuscular control. Belmont and Grundfast proposed that an active neuromuscular support system, comprised of the stylopharyngeus, palatopharyngeus, hyoglossus, and digastric muscles, is necessary to exert a dilatory effect on the supraglottic structures. They believe that hypotonia of these muscles, secondary to neuromuscular dysfunction, is manifested by stridor and varying degrees of airway obstruction and dysphagia.16 Even more specifically, Thompson describes laryngeal function and tone as a function of sensorimotor integration of peripheral sensory afferent reflexes, brainstem function, and the motor efferent response responsible for the vagal nerve-mediated reflex known as the laryngeal adductor reflex. Mechanoreceptors and chemoreceptors of the superior laryngeal nerve located in the region of the aryepiglottic fold send sensory afferent information to brainstem nuclei, which results in an involuntary efferent response through the vagus nerve of vocal fold adduction. Thompson demonstrates higher laryngopharyngeal sensory testing thresholds in infants with laryngomalacia, thus making plausible that, in laryngomalacia, the laryngeal sensorimotor integrative function between the brainstem and the peripheral afferent and efferent reflexes is altered.78 Gastroesophageal reflux is frequently associated with laryngomalacia. Prolonged laryngeal acid exposure can cause altered laryngeal sensation with subsequent dysfunction of the laryngeal adductor reflex as demonstrated by Thompson.78 The increased negative intrathoracic pressure generated on inspiration with a partially collapsed supraglottic larynx can increase the retrograde flow of gastric contents into the esophagus. The reverse may also occur with pharyngoesophageal reflux inducing posterior supraglottic edema. The edematous supraglottic mucosa collapses into the laryngeal introitus during inspiration.

Diagnosis The diagnosis of laryngomalacia is made with awake fiberoptic laryngoscopy identifying the pathologic features. When dysphagia is present, a fiberoptic endoscopic evaluation of swallowing or a videoflouroscopic swallow study can be obtained. Plain chest radiographs (PA and Lateral) and soft tissue neck radiographs (high kilovoltage (KV) anterior-posterior (AP) and Lateral) can be used to assist in evaluating the subglottic and tracheal airway. Based on the patterns of supraglottic collapse, laryngomalacia may be classified by type. Type 1 laryngomalacia is characterized by prolapse of redundant supraglottic mucosa; type 2 by shortened aryepiglottic folds; type 3 by posterior displacement of the epiglottis.7 When symptoms and findings are severe enough to warrant surgical intervention, a thorough endoscopic evaluation of the entire respiratory tract should be done at the time of surgery to evaluate for the possibility of synchronous lesions (which exist in up to 27% of patients with laryngomalacia21).

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Treatment Expectant observation is suitable for most cases of laryngomalacia. Most patients’ symptoms resolve spontaneously without intervention. However, a few patients have such severe symptoms that intervention becomes necessary. Severe symptoms necessitating intervention include apparent life threatenting events,12 cor pulmonale,11 failure to thrive, and feeding difficulties. Medical management includes treatment of any primary or secondary gastroesophageal reflux. Historically, tracheostomy was the standard therapy for the patient with severe laryngomalacia. This allowed for the pathology to be bypassed until the child outgrew it. However, the morbidity and mortality of tracheostomy are not inconsequential. Before the 1980s, there were only scattered case reports of alternative surgical approaches. Early efforts focused on modification of the obstructing the epiglottis. In 1922, Iglauer performed the first successful surgical alteration of the supraglottic larynx for laryngomalacia by amputating the redundant epiglottis with a wire snare resulting in resolution of the child’s severe cyanotic and apneic episodes.12 In 1944, Schwartz removed a V-shaped wedge of tissue from the epiglottis resulting in an immediate improvement in a patient.22 Fearon and Ellis successfully decannulated a patient with severe laryngomalacia shortly after suturing the epiglottis to the base of the tongue.23 Also in 1971, hyomandibulopexy (suspension of the hyoid bone to the symphysis of the mandible) was used successfully to create anterosuperior displacement of the obstructing epiglottis.24 The current management of severe laryngomalacia involves conservative excision of the obstructing supraglottic tissues. In 1984, Lane and associates first described the use of microcupped forceps and Bellucci scissors to remove obstructing structures of the posterior supraglottic region.10 In 1985, Seid and colleagues successfully treated three patients by dividing shortened aryepiglottic folds with the CO2 laser.13 Zalzal and colleagues subsequently described “epiglottoplasty,” the trimming of mucosa from the lateral edges of the epiglottis, the aryepiglottic folds, and the arytenoids and corniculate cartilages with microlaryngeal scissors.11 The term supraglottoplasty may be more appropriate as it can be used to describe any of these surgical procedures that modify the flaccid obstructing supraglottic tissues. The location and extent of resection are adapted to fit individual mechanical problems (Fig. 89-2). Both the CO2 laser and microlaryngeal scissors can be successfully used. Endoscopic supraglottoplasty with a laryngeal microdebrider has been described by Zalzal with the suction simulating negative pressure associated with inspiration, thus allowing better visualization and excision of redundant tissue.14

Complications Although complications of supraglottoplasty are unusual, an overly aggressive approach may lead to supraglottic stenosis or an exacerbation of dysphagia with aspiration.

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Conservative excision minimizes the probability of postoperative complications. If the excision proves inadequate, the child can always be returned to the operating room for additional removal of tissue. In rare cases, massive collapse of the entire supraglottic framework may require tracheotomy placement.

More mild to moderate stenosis may be asymptomatic until an upper respiratory tract infection results in additional subglottic edema narrowing the airway leading to symptoms of croup. These patients often have a history of recurrent and prolonged croup episodes.

CONGENITAL SUBGLOTTIC STENOSIS

Diagnosis

Congenital subglottic stenosis is the second most common cause of stridor in neonates, infants, and children.1 Congenital subglottic stenosis involved narrowing of the subglottic lumen in the absence of trauma (intubation). The normal full-term newborn larynx has a diameter of at least 5 mm. A subglottic lumen of less than 4 mm in a full-term newborn (3 mm in a premature infant) represents subglottic stenosis. The etiology of congenital subglottic stenosis is believed to be incomplete recanalization of the laryngeal lumen during embryogenesis. Congenital subglottic stenosis can be divided by histopathology into cartilaginous and membranous types. At endoscopy, the membranous type is usually circumferential and generally soft and dilatable. The mucosal lining is markedly thickened either secondary to an increase in the fibrous connective tissue layer in the submucosal or as a result of hyperplasia and dilation of the mucous glands in the subglottis.46,47 In contrast to the membranous type of stenosis, the cartilaginous variety is more variable in appearance. Mild stenoses usually have a normal shape but smaller than normal size. More commonly, the cricoid cartilage has an abnormal shape with prominent lateral shelves giving an elliptical appearance to the subglottic lumen (Fig. 89-6).47

The diagnosis of subglottic stenosis is made by rigid endoscopy under general anesthesia. The entire larynx is examined to determine the areas involved (supraglottis, glottis, subglottis) and the nature of the stenosis (soft—membranous, or firm—cartilaginous). The remainder of the tracheobronchial tree is then examined to assess for possible synchronous lesions. Thereafter, an objective measure of the stenosis severity is obtained. An endotracheal tube is passed (starting small so as to not unintentionally dilate the stenosis) through the stenosis and attached to the anesthetic circuit. The circuit is closed and pressure is permitted to rise gradually in the airway while the endoscopist is visualizing the subglottis with the endoscope. The pressure that causes a visible or audible leak is recorded. If there is a leak at less than 10 cm H2O pressure, then the next size endotracheal tube is passed and the procedure is repeated. The endotracheal tube size that permits a leak between 10 cm and 25 cm H2O pressure is considered as an accurate measure of the airway size. Comparison can then be made to the expected normal size for age in order to identify the percentage of the airway that is obstructed. The grading system most commonly utilized today is based on this endotracheal tube sizing: Grade I = 90% with a single procedure.55 Earlier reports for acquired 100% lesions using cartilage expansion were uniformly worse with decannulation rates of 37% to 50% after a single attempt, and up to 72% after multiple procedure.56

LARYNGOCELES AND SACCULAR CYSTS The laryngeal ventricle is a fusiform fossa bounded by the true vocal folds and false vocal folds. The anterior part of the roof of the ventricle leads up into a cecal pouch of mucous membrane called the saccule. The laryngeal saccule rises vertically between the false vocal fold, the base of the epiglottis, and the inner surface of the thyroid cartilage. Below the surface of its mucous membrane are delicate muscles that compress it to express its secretions on the vocal folds. A variety of abnormalities of the laryngeal saccule can occur (Fig. 89-3).25 A laryngocele is an abnormal dilation or herniation of the saccule. It communicates with the lumen of the larynx and is filled with air, but on occasion may be temporarily distended and filled with mucus. An internal laryngocele is confined to the interior of the larynx and extends posterosuperiorly into the area of the false vocal fold and aryepiglottic fold. An external laryngocele extends cephalad to protrude laterally into the neck through the thyrohyoid membrane. When an external laryngocele is combined with a symptomatic dilation of the internal portion, it is termed a combined laryngocele. The diagnosis of a laryngocele may be made when an ectatic, dilated saccule is symptomatic, palpable, or observed to extend above the superior margin of the thyroid cartilage by indirect or direct laryngoscopy, radiography, or dissection (at surgery or autopsy).25,26

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Laryngoceles become clinically perceptible only when distended by air or temporarily filled with a collection of fluid. In the latter situation, it is apparent that laryngoceles and saccular cysts are often indistinguishable from each other. Therefore, a fluid-filled, smooth mass distending the aryepiglottic fold may be a saccular cyst or a laryngocele. The pathogenesis of laryngoceles is variable. The extent to which congenital or acquired factors may be implicated must be assessed in each individual case. Laryngoceles observed in newborns are certainly congenital. The apparent increased incidence of laryngoceles observed in individuals whose occupations or hobbies involve prolonged periods of increased pressure within the laryngeal lumen (e.g., players of wind instruments) suggests that acquired factors contribute to laryngocele formation in some cases.27–30 In infants and children, a congenital defect or anatomic variation of the saccule must be implicated to a greater degree. A spectrum exists as follows: a laryngocele may be purely congenital (as in the newborn); may represent a congenital defect made apparent or exacerbated by habitual, increased intralaryngeal pressure; or may be acquired solely on the basis of prolonged increased intralaryngeal pressure. The saccular cyst (congenital cyst of the larynx, laryngeal mucocele) is distinguished from the laryngocele in that its lumen is isolated from the interior of the larynx and it does not contain air. Saccular cysts are distinctly submucosal and are covered with normal mucous membrane.26 There are two types of saccular cysts. The lateral saccular cyst extends posterosuperiorly into the false vocal fold and aryepiglottic fold from the nonpatent orifice of the saccule. The anterior saccular cyst extends medially and posteriorly from its origin at the nonpatent orifice of the saccule to protrude into the laryngeal lumen between the true and false vocal folds. Several mechanisms have been proposed to explain the formation of saccular cysts, but given their constant anatomic location, these cysts almost certainly result from a developmental failure to maintain patency of the saccular orifice.31 Saccular cysts can be congenital or acquired as inflammation, trauma, or tumors may occlude the saccular orifice with the same result. The laryngopyocele is an infected laryngocele, saccular cyst, or large saccule in which the orifice may have become occluded as a result of the infections process.26 The term first was coined and applied to an infected laryngocele, but it can describe any of the pus-containing saccular dilations, most of which are clinically similar in appearance.

Symptoms Symptoms of laryngoceles include intermittent hoarseness and dyspnea that may increase with crying. A weak cry or aphonia also may occur. Saccular cysts usually cause respiratory distress, typically with inspiratory stridor. An inaudible or muffled cry may also be present. Dysphagia is occasionally encountered.

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CHAPTER 89 ❖ Congenital Laryngeal Anomalies 1523

FIGURE 89-3. Coronal and sagittal views illustrate the anatomy and pathology of the laryngeal saccule and ventricle. Schematic coronal sections are taken through the anterior larynx at the level of the saccular orifice. (With permission from Holinger [Fig. 10.3, p. 143].76)

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Diagnosis The diagnosis of a laryngocele or saccular cyst is suggested by flexible laryngoscopy. Laryngoceles can be identified with high KV soft tissue radiographs of the neck. However, both with laryngoscopy and with radiography, if the laryngocele is not distended with air at the time of the evaluation, no significant abnormalities will be visualized. In the older child or adolescent, the diagnosis of a combined laryngocele is suspected by a mass in the neck produced with a modified Valsalva maneuver.

Treatment Needle aspiration of lateral saccular cysts confirms the diagnosis, but rarely obviates the need for more definitive therapy. Recurrence may be managed by aspiration or unroofing with a cup forceps or CO2 laser. However, repeated endoscopic procedures may be required.32 Therefore, if a cyst recurs after diagnostic aspiration, endoscopic excision is undertaken dissecting the cyst to its base at the orifice of the saccule, removing any remnants with the CO2 laser. Thereafter, if there is a recurrence, excision through a lateral cervical approach should be considered. Incising the thyrohyoid membrane along the superior margin of the thyroid cartilage while protecting the superior laryngeal nerve exposes the cyst allowing for its excision after dissection and ligating the base. It is rarely necessary to remove a portion of the thyroid cartilage. Tracheostomy can usually be avoided, but occasionally intubation will be needed for a few days until the perioperative edema subsides.

NEUROLOGIC LESIONS Neurologic lesions (vocal fold paralysis) are the third most common congenital laryngeal anomaly producing stridor in infants and children.33 Only laryngomalacia and congenital subglottic stenosis are more common. Unilateral and bilateral vocal fold paralysis occur with equal frequency. While congenital vocal fold paralysis is typically bilateral, the most common cause of unilateral vocal fold paralysis is iatrogenic.87–89 Of those with congenital vocal fold paralysis, approximately 50% are associated with other anomalies. Of those with acquired vocal fold paralysis, nearly 70% are secondary to congenital neurologic abnormalities (such as meningomyelocele, Arnold–Chiari malformation, and hydrocephalus) or the neurosurgical efforts to treat them.33 The etiology of unilateral vocal fold paralysis may be associated with cardiovascular anomalies or CNS anomalies, and the left side is more commonly affected.86

Symptoms Bilateral paralysis of the vocal folds typically produces high-pitched, inspiratory, or stridor: a phonatory sound or inspiratory cry. The cry may be normal. The vocal folds can appear to function as a one-way valve, being drawn

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during inspiration, but opening passively during expiration (paradoxical motion). Unilateral vocal fold paralysis produces much less prominent symptoms in the neonate. Stridor is uncommon. Usually, the cry is weak and occasionally breathy. Children with unilateral paralysis may have problems with feeding secondary to laryngeal penetration and aspiration.

Diagnosis The diagnosis of vocal fold paralysis is made by awake flexible laryngoscopy. Because of the rapid respiratory rate of infants, recording the endoscopy is helpful for slow motion replay to confirm the diagnosis. Once the diagnosis of paralysis of one or both vocal folds has been made, a thorough investigation for the underlying cause is carried out. Imaging of the head and chest is recommended to evaluate for possible associated cardiovascular or neurologic abnormalities. When an associated laryngeal lesion is suspected, it is important to completely evaluate the larynx and trachea under a general anesthetic in order to assess passive arytenoids mobility, and visualize any possible webbing or scarring.

Treatment If treated early, paralysis caused by increased intracranial pressure often responds to cerebrospinal shunting or posterior fossa decompression. Vocal fold paralysis in infants usually resolves within 6–18 months. However, function is unlikely to return if there is no sign of improvement within—two to three years. Because of this fact, a watchful waiting is appropriate management for the initial 2+ years. Unilateral vocal fold paralysis rarely requires surgical intervention. The occasional child with feeding difficulties is usually able to be managed with thickening of liquids. Rarely is airway support needed. With bilateral vocal fold paralysis, a temporary tracheotomy is usually, but not always necessary. When managing an infant without a tracheostomy, frequent reassessment to prevent failure to thrive is needed, as airway requirements will increase with growth of the child. A wide variety of possible surgical approaches to improve the airway in patients with bilateral vocal fold paralysis suggests that no one procedure is ideal. The goal is to restore the glottic airway by lateralizing one or both of the paralyzed vocal folds. Balancing a safe and patent airway with preservation of voice and swallowing functions is challenging. Reinnervation techniques are of unclear utility and are currently rarely employed. Surgical lateralization procedures for bilateral vocal fold paralysis are to some degree injurious to the developing larynx. Excisional procedures, in which tissue is removed from the posterior glottis, may be done in an open fashion or endoscopically utilizing the surgical laser. Experience with laser arytenoidectomy or posterior cordotomy has been good,34–37 with most patients being decannulated after a single treatment. Since the tissue excision is primarily within

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CHAPTER 89 ❖ Congenital Laryngeal Anomalies 1525 the posterior larynx, long-term voice results are typically acceptable. Also, if care is taken to avoid overly aggressive resection, aspiration is rarely a problem. The most common late complication is failure to achieve an adequate airway. More consistent results may be obtained using external approaches in children.38 Possible options include arytenoidectomy,38 arytenoidopexy,39 or laryngeal expansion with costal cartilage augmentation to the posterior cricoid plate.40 Of note, posterior cricoid grafting can be performed endoscopically with good outcome.84

CONGENITAL LARYNGEAL WEBS AND ATRESIA Congenital laryngeal webs are uncommon. Most are glottic and occur with extension into the subglottic larynx. The symptom complex and severity depend on where the webs are located and the degree of involvement. Virtually all infants and children with laryngeal webs have some degree of vocal dysfunction. When there is a thin anterior glottic web, the vocal folds are usually visible through these thin webs and there is little obstruction of the airway associated with mild hoarseness. As the webs become thicker and begin to extend into the subglottic larynx, there is increasing airway obstruction and the voice becomes weaker (Fig. 89-4). When more than 75% of the glottis is involved by a thick web, or with significant subglottic extension, the infant may be aphonic and airway obstruction severe, requiring tracheostomy soon after birth (Fig. 89-5).41 Isolated subglottic webs are less common than glottic webs. Supraglottic webs are also rare. Most supraglottic webs probably represent fusion of the ventricular bands anteriorly and typically cause mild symptoms of airway obstruction. When the larynx is difficult to visualize and vocal fold mobility is limited, the larynx needs to be assessed for the possibility of a posterior supraglottic or interarytenoid web.42,43 Complete congenital laryngeal atresia is incompatible with life unless an emergency tracheotomy is carried out in the delivery room. Laryngeal atresia can be diagnosed prenatally based on ultrasonographic evaluation by identifying signs of congenital high airway obstruction syndrome (CHAOS) including enlarged hyperechogenic lungs, flattened or inverted diaphragm, a dilated, fluid-filled airway distal to the obstruction, fetal hydrops, and polyhydramnios. Absence of flow in the trachea can be detected by color flow Doppler ultrasonography to help localize the level of obstruction. Prenatal diagnosis of CHAOS allows for the use of the ex utero intrapartum treatment (EXIT) procedure to evaluate and secure the airway at birth.85 Associated tracheal and esophageal anomalies are present in affected patients.44

Treatment Management of laryngeal webs is based on the extent of the lesion and the severity of symptoms. Goals of management include establishing a stable airway and providing a good

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A

B FIGURE 89-4. Anterior glottic web. (A) Prior to and (B) Following endoscopic division.

voice. A thin anterior glottic web may require only incision or dilation to realize a significant improvement in the voice. This may be done endoscopically by cold instrument or with CO2 or KTP laser. Mitomycin-C may also be applied to reduce scar formation. More significant webs that are still isolated to the glottis may respond adequately to dilation after incision along the margin of one vocal fold. However, in this case, revisions may be needed to obtain an optimal result. Keel placement is an option in these cases. When there is involvement of the subglottic larynx, the anterior cricoid plate is usually abnormal and needs to be addressed in order to achieve adequate results. This requires an external approach with division of web and the cricoid plate. Along with reorienting the rotated anterior cricoid plate, a cartilage graft can be utilized if expansion is needed or a laryngeal keel placed for 7–14

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A

goes undetected in three out of four until persistent aspiration in spite of successful tracheoesophageal fistula repair prompts further investigation.57 Laryngeal or laryngotracheoesophageal cleft is also part of the Pallister-Hall syndrome (autosomal dominant, hypothalamic hamartoblastoma, laryngeal cleft, hypopituitarism, imperforate anus, and polydactyly), as well as G syndrome/Opitz-Friaz syndrome (dysphagia, hypospadias, hypertelorism, cleft lip, and palate).58 The degree of clefting may be relatively minor, involving only a failure of interarytenoid muscle development, or can extend to the carina and even into the mainstem bronchi. Multiple classification systems have been used to describe laryngeal clefts. Independent from the numbering system used, it is useful to differentiate the length of the cleft as laryngeal (interarytenoid only, partial cricoid, or complete cricoid), and laryngotracheoesophageal clefts that extend into the cervical trachea, or the intrathoracic trachea.

Symptoms and Diagnosis

B FIGURE 89-5. Partial laryngeal atresia in a 5 year old that underwent tracheostomy placement immediately after birth. (A) View of supraglottis and glottis. (B) View of subglottis through anterior commissure laryngoscope which was used to separate the posterior aspect of the vocal folds, allowing visualization of the small pinhole posterior subglottic opening.

days. Occasionally, the anterior cricoid plate is not amenable to repositioning and can be resected submucosally followed by anterior costal cartilage augmentation45 or completing a partial cricotracheal resection in severe cases.

Patients with laryngeal or laryngotracheoesophageal clefts may present with inspiratory stridor, cyanotic attacks associated with feeding, aspiration, and recurrent pulmonary infections. As the length of the cleft increases, so does the severity of presenting symptoms with aspiration present in 100% of laryngotracheoesophageal clefts. While radiographic contrast studies may suggest aspiration, the best single study for identifying a laryngeal cleft is careful endoscopic examination. The arytenoids need to be parted in order to obtain adequate visualization, as the larynx may be obscured by redundant esophageal mucosa prolapsing into the glottic and subglottic lumen (Fig. 89-7). Measuring interarytenoid notch height relative to the vocal folds when a minor laryngeal cleft is suspected may be useful.59

Treatment Most clefts that are limited to the supraglottic larynx do not require surgical intervention. Treatment methods include evaluation and treatment of gastroesophageal reflux and

LARYNGEAL AND LARYNGOTRACHEOESOPHAGEAL CLEFTS Congenital laryngeal and laryngotracheoesophageal clefts are rare conditions that can be characterized by a posterior midline deficiency in the separation of the larynx and trachea from the hypopharynx and esophagus. The incidence is less than 0.1% and the majority of cases are sporadic. Recent publications report a higher incidence likely owing to better understanding and diagnosis of this disease.83 There is a strong association with other anomalies (56%), most commonly tracheoesophageal fistula in 20% to 27%.57 Of special interest is that over 6% of children with tracheoesophageal fistula have a coexisting laryngeal cleft. Of the children who present with tracheoesophageal fistula, the laryngeal cleft

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FIGURE 89-7. Laryngotracheoesophageal cleft through the cricoid and into the first two tracheal rings.

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CHAPTER 89 ❖ Congenital Laryngeal Anomalies 1527 swallowing therapy.57 When surgical intervention is required, endoscopic repair is successful in over 80%, with open repair reserved for endoscopic failures.57,60 In contrast to the interarytenoid clefts, surgical repair is required in nearly all laryngeal clefts that extend below the vocal folds. A complete discussion of the surgical options is beyond the scope of this chapter. However, an anterior approach through a laryngofissure is most commonly used. The advantage of this approach is excellent exposure of the entire defect without risk to laryngeal innervation. Complete laryngotracheoesophageal clefts that extend to the carina may require a posterolateral approach to allow for a two layer closure usually without requiring intraoperative extracorporeal circulation. In most circumstances, a tracheotomy is present prior to or placed at the time of reconstructive surgery. However, single-stage repair utilizing endotracheal intubation as a short-term stent is being increasingly utilized. The mortality of laryngeal clefts is usually from associated congenital anomalies, or an excessive delay in making the diagnosis, and has been reported to be between 11%57 and 46%61. The mortality associated with intrathoracic laryngotracheoesophageal clefts has been reported as high as 93%61. The incidence of requiring revision surgery also increases with the severity of the cleft57, with an overall incidence of 11%62. In addition to length of the cleft, insufficiently treated gastroesophageal reflux may also be associated with a decreased success rate.63

CONGENITAL NEOPLASMS Vascular Anomalies In 1982, Muliken and Glowacki presented a biologic systematic classification of vascular anomalies of infancy and childhood based on physical findings, clinical behavior, and cellular kinetics.64 It correctly describes two major types of pediatric vascular lesions: hemangiomas and vascular malformations. The suffix oma once referred to any swelling or tumor, but today denotes a tumor characterized by cellular hyperplasia. A subglottic hemangioma, there, is a tumor characterized by increased cell turnover of endothelium, mast cells, fibroblasts, and macrophages. In contrast, vascular malformations are not neoplastic lesions. They have a normal rate of endothelial turnover and are errors of vascular morphogenesis manifesting as various channel abnormalities.65 Vascular malformations are categorized by their predominant channel type (capillary, venous, arterial, lymphatic, or a combination thereof). Lesions such as arteriovenous malformations that have arterial components are termed fast-flow malformations. Slow-flow malformations are anomalies with capillary, lymphatic, or venous components. These formerly and incorrectly were called capillary hemangiomas, cystic hygromas or lymphangiomas, and cavernous hemangiomas, respectively.65 Hemangiomas are the most common tumors of infancy. They occur more commonly in females than males in a ratio of 3:1. Sixty percent occur in the head and neck region.

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Infants with multiple cutaneous lesions are suspect for associated visceral hemangiomas, the most common sites being the liver, lungs, and gastrointestinal tract.65 The hallmark of cutaneous lesions is rapid neonatal growth that begins in the first few weeks after birth. This proliferative phase usually lasts 6–10 months. A lesion in the superficial dermis becomes raised and bright red. When a lesion is located in the lower dermis or subcutaneous tissue, the skin may be only slightly raised, with a bluish hue. The involution phase begins after the 6–10 months of rapid growth, and the rate of growth slows to become proportional to the rate of growth of the child. By 5 years of age, most of the red color is gone. Complete resolution of the hemangioma occurs in 50% of the lesions by 5 years and 70% by 7 years of age, and the remaining lesions continue to diminish until 10–12 years of age.44 Subglottic and tracheal hemangiomas are benign congenital vascular neoplasms that are derived from mesodermal rests. The lesions are relatively uncommon, accounting for 1.5% of all congenital laryngeal anomalies, with a 2:1 female predominance.9 Patients are usually asymptomatic at birth but present with stridor within the first few months of life. A total of 85% present in the first 6 months and 50% have cutaneous hemangiomas present at the time of diagnosis.66 Asymmetric subglottic narrowing is the classic finding on soft tissue neck radiographs. Endoscopic diagnosis is usually made without biopsy because of the lesion’s typical appearance of a compressible, asymmetric, submucosal mass with bluish or reddish discoloration most often found in the posterolateral subglottis (Fig. 89-8). Subglottic and tracheal hemangiomas will have a rapid growth phase that slows by 12 months, followed by slow resolution over the subsequent months to years. Most will show complete resolution by five years. However, subglottic hemangiomas are associated with a 30% to 70% mortality when left untreated. The decision of what therapeutic measures to undertake needs to therefore be directed at maintaining the airway, while minimizing potential long-term sequelae of the treatment itself. Current management options include laser partial excision, open surgical resection, systemic or intralesional steroids, systemic interferon alfa-2A, propranolol, and tracheotomy. Open excision with anterior laryngotracheal reconstruction has gained popularity in recent years owing to increasing evidence suggesting that it is superior to other modalities in its ability to achieve decannulation or avoid tracheostomy altogether, often with fewer complications and fewer total procedures. Bypassing the obstructing lesion with a tracheotomy and waiting for the expected involution will provide for the optimal anatomical result, and it is considered by many to be the standard of care by which all other treatment options need to be measured. However, there are risks associated with a tracheotomy as well as the delay in speech and language that is routinely encountered when children acquire tracheotomy at a young age. Early methods of treatment that are no longer

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FIGURE 89-8. Anterior laryngotomy approach for laryngeal cleft repair. The U-shaped incision is made anteriorly on the right and posteriorly on the left at the margins of the cleft to offset the two lines of closure. Inserts A, B, and C illustrate the technique for the important offset two-layer closure. (With permission from Holinger [Fig. 10.13, p 159].76)

utilized because of the associated morbidity include external beam radiation, radium and gold implants, and sclerosing agents. Since their first documented use for subglottic hemangioma by Cohen in 1969,66 systemic corticosteroids have been frequently utilized both in isolation, and as adjuvant therapy. Steroids are thought to decrease hemangioma size by blocking estradiol induced growth,67 or by directly increasing capillary sensitivity to vasoconstrictors. Corticosteroid therapy with or without tracheotomy has been shown to be successful in 82% to 97.3% of cases. However, whether or not the time of tracheotomy cannulation is decreased is unknown. Risks of long-term steroid use include growth retardation and increased susceptibility to infection. These effects may be reduced by using an alternate day dosing regimen in the smallest possible doses. The successful use of intralesional injection of corticosteroids has been reported, avoiding a tracheotomy in 6/6 children using one to five injections with subsequent short-term intubation, and remains a beneficial adjuvant.68,92 Since its first reported use in the treatment of subglottic hemangiomas by Healy in 198069, the carbon dioxide laser remains a commonly used reliable tool when used carefully

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and in stages. It may be used alone or in combination with tracheotomy or steroids. In a report on 31 patients treated with laser partial resection with or without systemic corticosteroids, Sie et al. showed that over 75% were able to avoid a tracheotomy. However, use of the laser has been associated with a significant risk of inducing subglottic stenosis in up to 20%, particularly in cases of bilateral or circumferential disease.70 Surgical excision of a subglottic hemangioma was first reported by Sharp in 1949.71 More recently, there have been several reports of patients that underwent surgical excision through an open approach obtaining decannulation shortly after surgery or avoiding tracheotomy in 85% without laryngeal distortion or damage.72–74, 93–96 Use of interferon alfa-2A has been described in children with obstructing hemangiomas that were unresponsive to laser and/or corticosteroid therapy, achieving a 50% or greater regression of the lesion in 73%.75 Interferon alfa-2A requires prolonged therapy because it does not promote involution, but inhibits proliferation by blocking various steps in angiogenesis. The potential side effects that include neuromuscular impairment, skin slough, fever, and liver enzyme elevation limit its use.97,98

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FIGURE 89-9. Subglottic hemangioma.

Recently published case studies suggest a promising role for the use of propranolol in the treatment of subglottic hemangiomas.79–81 Denoyelle described two infants with subglottic hemangiomas treated with propranolol with good response, obviating the need for surgical intervention. One explanation for the therapeutic effect of a nonselective beta-blocker such as propranolol is vasoconstriction with associated color change and softening of the hemangioma. Down-regulation of the RAF-mitogen-activated protein kinase pathways and subsequent decreased expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) has also been proposed and may explain the progressive improvement that has been observed. In addition, propranolol may be triggering apoptosis of capillary endothelial cells.82 Common adverse side effects of propranolol include bradycardia and hypotension, thus requiring close monitoring during its use. Many treatment options still exist in the treatment of subglottic hemangioma because no one method has been shown to be superior. Long-term results of any therapeutic modality must gauge success based on a goal of obtaining an anatomically normal larynx after involution while maintaining a patent airway during the proliferative phase.

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7. Olney DR, Greinwald JH Jr, Smith RJ, Bauman NM. Laryngomalacia and its treatment. Laryngoscope. 1999 Nov;109(11):1770-5. 8. Smith G, Cooper D. Laryngomalacia and inspiratory obstruction in later childhood. Arch Dis Child. 1981;56:345. 9. Holinger P, Brown W. Congenital webs, cysts, laryngoceles, and other anomalies of the larynx. Ann Otol Rhinol Laryngol. 1967;76:744. 10. Lane R, Weider DJ, Steinem C, Marin-Padilla M. Laryngomalacia. A review and case report of surgical treatment with resolution of pectus excavatum. Arch Otolaryngol. 1984;110:546. 11. Zalzal G, Anon J, Cotton R. Epiglottoplasty for the treatment of laryngomalacia. Ann Otol Rhinol Laryngol. 1987;96:72. 12. Iglauer S. Epiglottidectomy for the relief of congenital laryngeal stridor. Laryngoscope. 1922;32:56. 13. Seid A, Park SM, Kearns MJ, Gugenheim S. Laser division of the aryepiglottic folds for severe laryngomalacia. Int J Pediatr Otorhinolaryngol. 1985;10:153. 14. Zalzal GH, Collins WO. Microdebrider-assisted supraglottoplasty. Int J Pediatr Otorhinolaryngol. 2005 Mar;69(3):305-9. Epub 2004 Dec 8. 15. McGill T. Congenital diseases of the larynx. Otolaryngol Clin North Am. 1984;17:57. 16. Belmont J, Grundfast K. Coongential laryngeal stridor (laryngomalacia). Etiologic factors and associated disorders. Ann Otol Rhinol Laryngol. 1984;93:430. 17. Keleman G. Congenital laryngeal stridor. Arch Otolaryngol. 1954;58:245. 18. Chandra R, Gerber M, Holinger L. Histological insight into the pathogenesis of severe laryngomalacia. Int J Pediatr Otorhinolaryngol. 2001;61:31. 19. Shulman J, Hollister DW, Thibeault DW, Krugman ME. Familial laryngomalacia. A case report. Laryngoscope. 1976;86:84. 20. McSwiney P, Cavanagh M, Languth P. Outcome in congenital stridor (laryngomalacia). Arch Dis Child. 1977;52:215. 21. Gonzalez, C, Reilly J, Bluestone C. Synchronous airway lesions in infancy. Ann Otol Rhinol Laryngol. 1987;96:77. 22. Schwartz L. Congenital laryngeal stridor (inspiratory laryngeal collapse). A new theory as to its underlying cause and the desirability of a change in terminology. Arch Otolaryngol. 1944;39:403. 23. Fearon B, Ellis D. The management of long term airway problems in infants and children. Ann Otol Rhinol Laryngol. 1971;80:669. 24. Cagnol C, Garcia M, Unal D. Un cas de stridor larynge congenital grave traite par hyomandibulopexie (A case of severe congenital laryngeal stridor treated by hyomandibulopexy). J Fr Otorhinolaryngol Audiophonol Chir Maxillofac. 1971;20:625. 25. Holinger L, Barnes D, Smid L. Laryngocele and saccular cysts. Ann Otol Rhinol Laryngol. 1978;87:675. 26. Desanto L, Devine K, Weiland L. Cysts of the larynx - classification. Laryngoscope. 1970;80:145. 27. Larrey D. Exercee particulirement dans les camps et les hopitaux militares depuis 1792 jusqu’en 1829 (Exercised particularly in the camps and military hospitals from 1792 to 1829). Clinique Chirugicale, Paris: Chef Gabon; 1829:81. 28. Holinger P, Steinem E. Congenital cysts of the larynx. Pract Otorhinolaryngol. 1947;9:129. 29. Pietrantoni L, Felisanti D, Finzi A. A laryngocele and laryngeal cancer. Ann Otol Rhinol Laryngol. 1959;68:100.

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30. MacFie W. Asymptomatic laryngoceles in wind-instrument bandsmen. Arch Otolaryngol. 1866;83:270. 31. Niparko J, Moran M, Baker S. Laryngeal saccular cyst. An unusual clinical presentation. Otolaryngol Head Neck Surg. 1987;97:576. 32. Civantos F, Holinger L. Laryngoceles and saccular cysts in infants and children. Arch Otolaryngol Head Neck Surg. 1992;118:296. 33. Holinger L, Holinger P, Holinger P. Etiology of bilateral abductor vocal cord paralysis. A review of 389 cases. Ann Otol Rhinol Laryngol. 1976;85:428. 34. Kashima H. Bilateral vocal fold motion impairment: pathophysiology and management by transverse cordotomy. Ann Otol Rhinol Laryngol. 1991;100:717. 35. Ossof R, Duncavage JA, Shapshay SM, Krespi YP, Sisson GA Sr. Endoscopic laser arytenoidectomy revisited. Ann Otol Rhinol Laryngol. 1994;99:764. 36. Ejnell H, Mansson I, Hallén O, Bake B, Stenborg R, Lindström J. A simple operation for bilateral vocal cord paralysis. Laryngoscope. 1984;94:954. 37. Remsen K, Lawson W, Patel N, Biller HF. Laser lateralization for bilateral vocal cord abductor paralysis. Otolaryngol Head Neck Surg. 1985;93:645. 38. Bower C, Choi S, Cotton R. Arytenoidectomy in children. Ann Otol Rhinol Laryngol. 1994;103:271. 39. Singer M, Haymaker R, Miller S. Restoration of the airway following bilateral recurrent laryngeal nerve paralysis. Laryngoscope. 1985;95:1204. 40. Gray S, Kelly S, Dove H. Arytenoid separation for impaired pediatric vocal fold mobility. Ann Otol Rhinol Laryngol. 1994;103:510. 41. Cohen S. Congenital glottic webs in children. Ann Otol Rhinol Laryngol. 1985;94(suppl 121):1. 42. Benjamin B, Mair E. Congenital inter-arytenoid web. Arch Otolaryngol Head Neck Surg. 1991;117:1118. 43. Cox D, Simmons F. Mid line vocal cord fixation. Arch Otolaryngol. 1974;100:219. 44. Holinger L, Tansek K, Tucker GJ. Congenital laryngeal anomalies associated with tracheal agenesis. Ann Otol Rhinol Laryngol. 1987;96:505. 45. Biavati M, Wood WE, Kearns DB, Smith RJ. One-stage repair of congenital laryngeal webs. Otolaryngol Head Neck Surg. 1995;112:447. 46. Tucker G, Ossoff RH, Newman AN, Holinger LD. Histopathology of the congenital subglottic stenosis. Laryngoscope. 1979;89:866. 47. Fearon B, Cotton R. Subglottic stenosis in infants and children: the clinical problem and experimental surgical correction. Can J Otolaryngol. 1972;1:281. 48. Myer CI, O’Connor D, Cotton R. Proposed grading system for subglottic stenosis based on endotracheal tube sizes. Ann Otol Rhinol Laryngol. 1994;108:319. 49. Kirchner F, Toledo P. Microcauterization in otolaryngology. Arch Otolaryngol. 1974;99(3):198. 50. Rodgers B, Talbert J. Clinical application of endotracheal cryotherapy. J Ped Surg. 1978;13(6D):662. 51. Cotton R, Myer CM 3rd, Bratcher GO, Fitton CM. Anterior cricoid split, 1977-1987. Evolution of a technique. Arch Otolaryngol Head Neck Surg. 1988;114(11):1300. 52. Holinger L, Stankiewicz J, Livingston G. Anterior cricoid split: the Chicago experience with an alternative to tracheotomy. Laryngoscope. 1987;97(1):19.

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53. Lusk R, Kang D, Muntz H. Auricular cartilage grafts in laryngotracheal reconstruction. Ann Otol Rhinol Laryngol. 1993;102(4):247. 54. Ochi J, Evans J, Bailey C. Pediatric airway reconstruction at Great Ormond Street: a ten-year review. I. Laryngotracheoplasty and laryngotracheal reconstruction. Ann Otol Rhinol Laryngol. 1992;101(6):465. 55. Stern Y, Gerber ME, Walner DL, Cotton RT. Partial cricotracheal resection with primary anastomosis in the pediatric age group. Ann Otol Rhinol Laryngol. 1997;106:891. 56. Cotton R, Gray S, Miller R. Update of the Cincinnati experience in pediatric laryngotracheal reconstruction. Laryngoscope. 1989;99(11):1111. 57. Evans K, Courteney-Harris R, Bailey CM, Evans JN, Parsons DS. Management of posterior laryngeal and laryngotracheoesophageal clefts. Arch Otolaryngol Head Neck Surg. 1995;121:1380. 58. Eriksen C, Zwillenberg D, Robinson N. Diagnosis and management of cleft larynx. Literature review and case report. Ann Otol Rhinol Laryngol. 1990;99(9):703. 59. Smith R, Neville M, Bauman N. Interarytenoid notch height relative to the vocal folds. Ann Otol Rhinol Laryngol. 1994;103:753. 60. Bent JP 3rd, Bauman NM, Smith RJ.Endoscopic repair of type IA laryngeal clefts. Laryngoscope. February 1997; 107(2):282-286. 61. Roth B. Laryngotracheoesophageal cleft, clinical features, diagnosis, and therapy. Eur J Pediatr. 1983;140:41. 62. Robie D, Pearl RH, Gonsales C, Restuccia RD, Hoffman MA. Operative strategy for recurrent laryngeal cleft: a case report and review of the literature. J Ped Surg. 1991;26(8):971. 63. Hof E, Hirsig J, Giedion A, Pochon JP. Deleterious consequences of gastroesophageal reflux in cleft larynx surgery. J Ped Surg. 1987;22(3):197. 64. Mulliken J, Glowacki J. Hemangioma and vascular malformation of infants and children. A classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69:412. 65. Fishman S, Mulliken J. Hemangiomas and vascular malformations of infancy and childhood. Pediatr Clin North Am. 1993;40:1177. 66. Cohen S. Unusual lesions of the larynx, trachea and bronchial tree. Ann Otol Rhinol Laryngol. 1969;78:476. 67. Hawkins D, Crockett DM, Kahlstrom EJ, MacLaughlin EF. Corticosteroid management of airway hemangiomas: longterm follow-up. Laryngoscope. 1984;94:633. 68. Meeuwis J, Bos CE, Hoeve LJ, van der Voort E. Subglottic hemangiomas in infants: treatment with intralesional corticosteroid injection and intubation. Int J Pediatr Otorhinolaryngol. 1990;19(2):145. 69. Healy G, Fearon B, French R, McGill T. Treatment of subglottic hemangioma with the carbon dioxide laser. Laryngoscope. 1980;90(5):809. 70. Sie K, McGill T, Healy G. Subglottic hemangioma: ten years’ experience with the carbon dioxide laser. Ann Otol Rhinol Laryngol. 1994;103(3):167. 71. Sharp H. Hemangioma of the trachea in an infant, successful removal. J Laryngol Otol. 1949;63:413. 72. Mulder J, van den Broek P. Surgical treatment of infantile subglottic hemangioma. Int J Pediatr Otorhinolaryngol. 1989;17(1):57. 73. Wiatrak B, Reilly JS, Seid AB, Pransky SM, Castillo JV. Open surgical excision of subglottic hemangioma in children. Int J Pediatr Otorhinolaryngol. 1996;34:191.

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CHAPTER 89 ❖ Congenital Laryngeal Anomalies 1531 74. Seid A, Pransky S, Kearns D. The open surgical approach to subglottic hemangioma. Int J Pediatr Otorhinolaryngol. 1991;22:85. 75. Ohlms L, Jones DT, McGill TJ, Healy GB. Interferon alfa-2a therapy for airway hemangiomas. Ann Otol Rhinol Laryngol. 1994;103:1. 76. Holinger L. Congenital laryngeal anomalies. In: Holinger L, Lusk R, Green C, eds. Pediatric Laryngology and Bronchoesophagology. Philadelphia, PA: Lippincott-Raven; 1997: 137–164. 77. Richter GT, Rutter MJ, deAlarcon A, Orvidas LJ, Thompson DM. Late-onset laryngomalacia: a variant of disease. Arch Otolaryngol Head Neck Surg. 2008;134:75–80. 78. Thompson DM. Abnormal sensorimotor integrative function of the larynx in congenital laryngomalacia: a new theory of etiology. Laryngoscope. 2007;117(6 Pt 2 suppl 114):1–33. 79. Denoyelle F, Leboulanger N, Enjolras O, Harris R, Roger G, Garabedian EN. Role of propranolol in the therapeutic strategy of infantile laryngotracheal hemangioma. Int J Pediatr Otorhinolaryngol. 2009;73:1168–1172. 80. Buckmiller L, Dyamenahalli U, Richter GT. Propranolol for airway hemangiomas: case report of novel treatment. Laryngoscope. 2009;119: 2051–2054. 81. Jephson CG, Manunza F, Syed S, Mills NA, Harper J, Hartley BE. Successful treatment of isolated subglottic haemangioma with propranolol alone. Int J Pediatr Otorhinolaryngol. September 29, 2009. [Epub ahead of print]. 82. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–2651. 83. Chien W, Ashland J, Haver K, Hardy SC, Curren P, Hartnick CJ. Type 1 laryngeal cleft: establishing a functional diagnostic and management algorithm. Int J Pediatr Otorhinolaryngol. 2006;70:2073–2079. 84. Inglis AF Jr, Perkins JA, Manning SC, Mouzakes J. Endoscopic posterior cricoid split and rib grafting in 10 children. Laryngoscope. 2003;113:2004–2009. 85. Shimabukuro F, Sakumoto K, Masamoto H, et al. A case of congenital high airway obstruction syndrome managed by ex utero intrapartum treatment: case report and review of the literature. Am J Perinatol. 2007;24:197–201.

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86. Emery PJ, Fearon B. Vocal cord palsy in pediatric practice: a review of 71 cases. Int J Pediatr Otorhinoloaryngol. 1984;8:147–154. 87. Rosin DF, Handler SD, Potsic WP, Wetmore RF, Tom LW. Vocal cord paralysis in children. Laryngoscope. 1990;100:1174– 1179. 88. Zbar RI, Smith RJ. Vocal fold paralysis in infants twelve months of age and younger. Otolaryngol Head Neck Surg. 1996;114:18–21. 89. Daya H, Hosni A, Bejar-Solar I, Evans JN, Bailey CM. Pediatric vocal fold paralysis: a long-term retrospective study. Arch Otolaryngol Head Neck Surg. 2000;126:21–25. 90. Durden F, Sobol SE. Balloon laryngoplasty as a primary treatment for subglottic stenosis. Arch Otolaryngol Head Neck Surg. 2007;133:772–775. 91. Lee KH, Rutter MJ. Role of balloon dilation in the management of adult idiopathic subglottic stenosis. Ann Otol Rhinol Laryngol. 2008;117:81–84. 92. Hoeve LJ, Kuppers GL, Verwoerd CD. Management of infantile subglottic hemangioma: laser vaporization, submucous resection, intubation, or intralesional steroids? Int J Pediatr Otorhinolaryngol. 1997;42:179–186. 93. Van Den Abbeele T, Triglia J-M, Lescanne E, et al. Surgical removal of subglottic hemangiomas in children. Laryngoscope. 1999;109:1281–1286. 94. Vijayasekaran S, White D, Hartley BEJ, Rutter MJ, Elluru RG, Cotton RT. Open excision of subglottic hemangiomas to avoid tracheostomy. Arch Otolaryngol Head Neck Surg. 2006;132:159–163. 95. Bajaj Y, Hartley BEJ, Wyatt ME, Albert DM, Bailey CM. Subglottic haemangioma in children: experience with open surgical excision. J Laryngol Otol. 2006;120:1033–1037. 96. O-Lee TJ, Messner A. Open excision of subglottic hemangioma with microscopic dissection. Int J Pediatr Otorhinolaryngol. 2007;71:1371–1376. 97. Bauman NM, Burke DK, Smith RJ. Treatment of massive or life-threatening hemangiomas with recombinant alpha(2a)interferon. Otolaryngol Head Neck Surg. 1997;117:99–110. 98. Pransky SM, Canto C. Management of subglottic hemangioma. Curr Opin Otolaryngol Head Neck Surg. 2004;12:509–512.

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90

C H A P T E R

Congenital Malformations of the Trachea and Bronchi Luv R. Javia, Brian P. Dunham, and Ian N. Jacobs

C

ongenital anomalies of the trachea and bronchi are due to either primary malformations of the cartilage or extrinsic compression from cardiovascular or gastrointestinal malformations. These malformations may present in the first few days of life with severe life threatening airway obstruction or may remain undetected and subclinical for many years. In the former situation, urgent diagnosis and intervention may be required. In addition, congenital malformations of the trachea and bronchi require close collaboration with other medical and surgical services such as anesthesiologists, cardiothoracic surgeons for surgical intervention, and pediatric intensivists for critical care management. An overview of congenital tracheal and bronchial anomalies is presented in Table 90-1.

TRACHEAL ANOMALIES Tracheomalacia Tracheomalacia is a weakness of the trachea with dynamic collapse during breathing, and represents the most common pathology of the trachea affecting both full-term and premature infants. It can affect a focal region of the trachea or the entire trachea with potentially more distal bronchial involvement as well. The trachea is composed of 16–20 arch-shaped cartilaginous rings with a soft posterior membranous wall composed of the trachealis muscle. Due to the differences between intraluminal and intrathoracic pressures, the tracheal lumen undergoes dynamic changes during normal phases of respiration. Specifically, the trachea dilates during inspiration and contracts during expiration. In fact, the transmural pressure gradients across the trachea will directly correlate with the degree of luminal change.1 A limited extent of motion is normal and has no impact on respiration. However, with tracheomalacia, these changes are more pronounced and become pathologic. The majority of cases of tracheomalacia are intrathoracic with luminal narrowing occurring most noticeably during forced expiration, cough, or Valsalva maneuver. Cervical tracheomalacia manifests with luminal collapse during inspiration due to the transmittance of negative intrapleural pressures to the extrathoracic trachea.2 Transient, mild tracheal luminal changes can also occur from the passage of a bolus through the adjacent esophagus. The normal trachea has a 4.5:1 ratio of the anterior tracheal ring to the posterior wall. With pathologic conditions of tracheomalacia, there is a 3:1 or 2:1 ratio with greater than 50% narrowing of the airway lumen (Fig. 90-1). Wailoo and Emery suggested that longitudinal muscle fibers

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of the membranous trachea may play an important structural role for the trachea.3 In addition, the cartilaginous rings themselves may be weakened due to either an abnormality in shape or constitution. Jamal et al. have suggested a possible direct neurologic etiology.4 They describe a child with clinically significant tracheomalacia that resolves subsequent to each treatment of recurring hydrocephalus. An initial classification scheme was proposed by Benjamin, with distinctions broadly divided between primary and secondary tracheomalacia.5 Whereas, primary tracheomalacia results from intrinsic cartilaginous defects, secondary tracheomalacia results from a variety of cardiovascular or gastrointestinal congenital malformations external to the trachea, compressive extratracheal neoplasms or cysts, dyschondroplasia, long-term tracheotomy tube placement, severe tracheobronchitis, or prolonged mechanical ventilation. Parsons devised the major airway collapse (MAC) classification system based on etiology.6 MAC type I is comprised of congenital tracheal collapse secondary to cartilage immaturity or abnormal composition, without external airway compression and includes patients with prematurity, esophageal atresia (EA), tracheoesophageal fistula (TEF), and genetic metabolic disorders such as mucopolysaccharidosis. MAC type II includes tracheal collapse secondary to extrinsic compression including patients with vascular anomalies, cysts, tumors, thymic enlargement, or goiter. MAC type III incorporates acquired malacia due to prolonged ventilation, tracheotomy, or severe tracheobronchial inflammation or infection. A variety of associated conditions can be present with tracheomalacia.2 Cardiovascular abnormalities have been seen in 20%–58% of patients with tracheomalacia and include patent ductus arteriosus, atrial or ventricular septal defects, aortic arch abnormalities, hypoplastic left or right heart, Tetralogy of Fallot, dextrocardia, and valvular stenosis. As many as 52% of patients with tracheomalacia have associated bronchopulmonary dysplasia. Patients with severe, lifethreatening tracheomalacia have associated gastroesophageal reflux as often as 78% of the time. Laryngeal abnormalities such as laryngomalacia, vocal cord paralysis, and subglottic stenosis have all been associated with tracheomalacia. A neurologic association has also been described with 8%–48% of patients with tracheomalacia having a neurologic impairment and 26% of patients having severe developmental delay. In addition, it can be found in patients with an immature autonomic nervous system. The true incidence of tracheomalacia is not clearly known. One recent study stated a conservative incidence estimate to be 1 in 2100 children.7 One challenge that leads to a delay

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TABLE 90-1. Classification of Congenital Malformations of the Trachea and Bronchi

I. Tracheal anomalies A. Tracheomalacia 1. Primary a. Term infants b. Premature infants 2. Secondary a. External compression i. Vascular anomalies a) Vascular rings b) Aberrant innominate artery c) Pulmonary artery sling d) Other vascular anomalies ii. Cardiac malformations iii. Congenital cysts iv. Neoplasms b. Tracheoesophageal fistula and esophageal atresia c. Bony thorax abnormality i. Pectus excavatum ii. Kyphoscoliosis iii. Thoracic dysplasia d. Dyschondroplasia B. Tracheal stenosis 1. Membranous tracheal webs 2. Congenital tracheal stenosis a. Complete tracheal rings b. Long-segmental c. Funnel-shaped d. Segmental 3. Tracheal cartilaginous sleeve 4. Tracheal agenesis and atresia II. Foregut cysts A. Bronchogenic cysts B. Esophageal duplications and enteric cysts III. Bronchial anomalies A. Bronchomalacia B. Tracheal bronchus C. High tracheal bifurcation D. Bronchial stenosis E. Bronchial agenesis and atresia

in diagnosis is the incorrect identification of this entity as asthma, tracheal obstruction, foreign body aspiration, or some other respiratory pathology. Symptoms are not specific for tracheomalacia and thus require a high index of suspicion. Symptoms can present shortly after birth, or they can manifest in the first few weeks to months of life. Diagnoses may also be made in children years after birth.7 The most common symptoms from involvement of the intrathoracic trachea include expiratory stridor and a barky cough. Conversely, extrathoracic tracheal involvement usually presents with inspiratory stridor. Additional symptoms include recurrent respiratory infections, wheezing, chronic cough, and cyanosis. If very severe, dying spells can occur which are reflex apneas initiated when the trachea is stimulated with secretions or a bolus of food in the esophagus. These can also

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FIGURE 90-1. Benjamin degrees of collapse.

occur during bronchoscopy.2 These dying spells can be lethal as they can lead to respiratory and cardiac arrest. A thorough history and physical examination is important in the diagnosis of tracheomalacia. Diagnosis may be suggested by airway caliber changes on airway fluoroscopy. Barium esophagography is useful in screening for vascular rings or TEF; it may also suggest reflux. Contrast computed tomography (CT) or magnetic resonance imaging (MRI) may be useful in the evaluation of tracheal compression by masses. MRI/MRA is the preferred modality for vascular abnormalities. Pulmonary function testing may show abnormal truncation of the expiratory limb of the flow volume loop.8 Definitive diagnosis is made by bronchoscopy under spontaneous ventilation demonstrating varying degrees of tracheal wall collapse (Fig. 90-2). Paralysis, heavy sedation, or positive-pressure ventilation can create false negatives as these maneuvers may mask malacia.

Primary Tracheomalacia Isolated primary tracheomalacia may occur in full-term and more commonly in premature infants and is thought to be due to immaturity of the tracheal cartilage or abnormal cartilage matrix. Primary tracheomalacia can be seen in patients with polychondritis, chondromalacia, mucopolysaccharidoses, Trisomy 21, or a myriad of syndromes (including Ehlers-Danlos, CHARGE, Pfeiffer, DiGeorge, Larsen, and Pierre-Robin sequence to name a few).2 In the case of the full-term infant with no known pulmonary disease, the flaccidity of the trachea is congenital with often no other isolated defects. In the majority of patients with tracheomalacia, an intervention is not needed as the patient will improve with time and maturation of the airway, usually resolving by 2 years of age. Bronchodilators may aggravate tracheomalacia as it may reduce tracheal muscular tone. Antireflux medication may be a valuable adjunctive treatment. Rarely, more severe tracheomalacia causing feeding difficulties, growth derangements, or refractory respiratory distress may require tracheotomy and positive pressure ventilation.

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tracheomalacia is aimed at addressing the underlying root cause of the external compression.

Congenital Vascular and Cardiac Anomalies

FIGURE 90-2. Rigid bronchoscopy showing anterior tracheomalacia.

Other surgical treatments such as external splinting of the malacic airway with synthetic mesh or rings fashioned from costal cartilage have not been satisfactory.8 Endotracheal and endobranchial stents made from metal have also been employed. However, due to complications such as bleeding, granulation tissue formation, extrusion, difficulty in their removal, migration, pneumonia, and even death, their use in the pediatric population should be restricted to only emergent situations where there are no other effective options.

Secondary Tracheomalacia Secondary tracheomalacia, which is usually more severe, may be caused by a number of compressive structures upon the airway including cardiovascular, gastrointestinal, musculoskeletal, or neoplastic sources (Table 90-1). A compressive etiology of tracheomalacia not only narrows the lumen, but also actually compromises the integrity of the tracheal wall. In addition, tracheotomy tubes often cause tracheomalacia around the level of the tracheotomy tube. Premature infants may develop tracheomalacia from a number of factors related to their chronic lung disease and prolonged intubation such as oxygen toxicity, positive pressure ventilation, increased work of breathing, and lower airway infections. Moreover, premature infants may have immature tracheal tissues. In most cases, respiratory support for chronic lung disease may alleviate the tracheomalacia symptoms. An unusual form of tracheomalacia can be seen in patients with unilateral pulmonary agenesis or after a pneumonectomy (especially the right side) in which a mediastinal shift compresses the airway between the aorta and pulmonary artery.9 Treatment of secondary

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Congenital vascular anomalies result from derangements in fourth or sixth branchial arch vessel development during embryogenesis. Paired dorsal and ventral aortae connected by paired aortic arches surround the pharyngeal foregut. Development of normal vasculature requires persistence of the left dorsal aorta, regression of the right dorsal aorta, and remodeling of the aortic arches. Anomalies of the sixth aortic arch can affect normal pulmonary artery development. In addition to compression by vascular anomalies, cardiac processes resulting in the enlargement of the left atrium of the heart can result in compression of the adjacent left mainstem bronchus.10,11 In addition to airway symptoms such as stridor, recurrent infections, reflex apneas, and chronic cough, there may be esophageal symptoms such as dysphagia. Whereas airway symptoms may present early, esophageal symptoms may present later in childhood. Evaluation should include frontal and lateral chest radiographs, barium esophagram, echocardiogram, a contrasted CT or MRI, and direct laryngoscopy and bronchoscopy. A normal chest radiograph in the setting of a symptomatic patient significantly decreases the probability of a vascular ring.11 Operative assessment of the airway is important for defining the severity, length, and location of airway compression. It is invaluable for evaluating other synchronous airway lesions such as laryngomalacia and tracheomalacia, and for evaluating vocal cord function prior to cardiac surgical intervention. The most common relevant vascular anomalies include (in decreasing frequency) double aortic arch, right aortic arch with left ligamentum arteriosum, and aberrant left subclavian artery, aberrant innominate artery, aberrant right subclavian artery, pulmonary artery sling, and aberrant left subclavian artery.11,12

Complete Vascular Rings Aortic arch anomalies may be present in 3% of people according to autopsy studies and most often are undiagnosed.13,14 Double aortic arch and right aortic arch with left ligamentum arteriosum and aberrant left subclavian artery are complete vascular rings that encircle and compress both the trachea and esophagus (Fig. 90-3) with the former being slightly more common. A double arch results from the persistence of both the right and left fourth aortic arches. Right aortic arch with left ligamentum arteriosum and aberrant left subclavian artery occurs with the disappearance of the left fourth arch and persistence of the left sixth arch.10 Symptoms include biphasic stridor, wheezing, cyanosis worsened by feeding, recurrent pneumonias, and lower airway infections. Dysphagia may occur from the esophageal compression. Symptoms present early in infancy with double aortic arch

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SECTION 5 ❖ The Airway

FIGURE 90-3. Double aortic arch forming a complete ring around the trachea and esophagus. (From Holinger et al.44)

and are typically more severe; patients with a right aortic arch with left ligmentum arteriosum and aberrant left subclavian artery are typically asymptomatic or present with symptoms later within the first few years of life.11,13 Diagnostic work-up includes barium esophagram and airway fluoroscopy (Fig. 90-4). This will often show an indentation into the esophagus. Bronchoscopy will show a pulsatile compression of both the anterior and posterior trachea. Definitive diagnosis is made by magnetic resonance angiography (MRA) that will delineate the vascular anatomy (Fig. 90-5). It is critical to identify the dominant arch preoperatively, as surgical correction involves division of the nondominant arch. Even with surgical correction of double aortic arch anomalies, about 30% of patients have residual symptoms. It is believed that this persistence of symptoms is from long-standing, severe compression that results in secondary tracheomalacia.15 Some have advocated that intraoperative endoscopic monitoring should be used for assessing the degree of airway decompression.16

FIGURE 90-4. Barium esophagram showing posterior indentation into the esophagus from a complete vascular ring.

Aberrant Innominate Artery An aberrant innominate artery originates more distally or leftward from the aortic arch and causes tracheal compression as it travels to the right, anterior to the trachea. It may cross over the trachea just above the carina and cause focal collapse. Diagnosis is confirmed by bronchoscopy, which reveals a focal, pulsatile, and asymmetric compression just above the carina and right mainstem bronchus. It often appears as an asymmetric triangular compression. Diagnosis is confirmed by MRA, which will reveal the aberrant innominate crossing in front of a narrowed trachea (Fig. 90-6). Coexistent secondary tracheomalacia may complicate matters, as it may actually be the real source of the symptoms. These children will have persistence of symptoms after surgical repair of the vascular anomaly. Some even believe that aberrant innominate artery may be overdiagnosed and overtreated.13 One study reports that 30% of children younger than 2-years-old have evidence of an anterior tracheal impression on lateral chest radiograph.17 In many cases, symptoms will improve with normal growth of the airway. With severe symptoms, surgical intervention is best accomplished by aortopexy with suspension of

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FIGURE 90-5. Magnetic resonance angiography showing complete vascular ring.

the innominate artery to the undersurface of the sternum (Fig. 90-7). Reimplantation or transection has been performed as well.18,19 Secondary tracheomalacia has been addressed surgically with external reinforcement of the malacic airway with autologous cartilage graft and a sternohyoid muscle flap suspension technique.18

Pulmonary Artery Sling A recent study reported the prevalence of pulmonary artery sling to be 59 per million school-aged children using

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CHAPTER 90 ❖ Congenital Malformations of the Trachea and Bronchi echocardiography.20 Malformation of the sixth aortic arch results in the left pulmonary artery arising from the right pulmonary artery and passing between the trachea and esophagus to get to the left lung hilum. The ligamentum arteriosum can create a vascular ring encircling the trachea, but not the esophagus. This vascular anomaly results in compression of the trachea, right mainstem bronchus, and anterior esophageal wall (Fig. 90-8). Associated lesions include congenital heart disease (50%), congenital anomalies (58%–83%), complete cartilaginous rings (50%), tracheomalacia, and abnormal pulmonary lobulation.10,13 Respiratory symptoms present early in life. Diagnosis is made by bronchoscopy and imaging (MRA, contrast CT, or echocardiography). Airway endoscopy will determine if the trachea is narrowed and if there are complete

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tracheal rings. There may be compression or atresia of the right bronchus from the pulmonary artery sling. Treatment includes observation or, if significant respiratory symptoms are present, a surgical translocation and reimplantation of the left pulmonary artery. Pulmonary artery sling often occurs in combination with complete tracheal rings and long segment tracheal stenosis in about half the instances (Fig. 90-9). This is the so-called “ring-sling” complex. When there are severe airway symptoms not alleviated solely by the repair of the pulmonary artery sling, a slide tracheoplasty may be performed at the same time under cardiopulmonary bypass to address the tracheal stenosis.13 Some believe, simultaneous repair of the sling and tracheal stenosis is thought to result in better prognosis,21 although others report early tracheoplasty (at < 3 months of age) in this setting may be associated with high mortality rates.22 A patient with “ring-sling” and an additional genetic syndrome may have additional postoperative morbidity and mortality due perhaps to coexistent cardiac and noncardiac abnormalities.23

FIGURE 90-8. Pulmonary artery sling.

FIGURE 90-6. Endoscopic view showing anterior lateral compression from an aberrant innominate artery.

FIGURE 90-7. Aortopexy. (From Othersen.45)

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FIGURE 90-9. Complete tracheal rings.

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Other Vascular Anomalies An aberrant right subclavian artery has an anomalous origin as the last aortic arch branch. This results in posterior compression of the esophagus. The majority is asymptomatic, but they can present with dysphagia. A cervical aortic arch is a rare abnormality in which the arch is above the level of the clavicles and can be as high as the C-2 vertebral body. Depending on the variant, symptoms may include pulsatile cervical mass, respiratory symptoms, or dysphagia.

Cardiac Malformations Cardiac-related compression of the airway with resultant respiratory distress is an important and often unrecognized entity. The carina, left mainstem bronchus, and trachea are in close proximity to various cardiac structures, specifically the left atrium, left pulmonary artery, and left pulmonary veins. Thus, various cardiac conditions that result in enlargement of these associated cardiac structures or massive cardiomegaly can result in compression of the airway. Acyanotic or cyanotic congenital heart disease with large left-to-right shunts (such as ventricular septal defects, patent ductus arteriosus, atrioventricular canal), Tetralogy of Fallot with absent pulmonary valve or pulmonary atresia, mitral regurgitation, truncus arteriosus, or dilated cardiomyopathy can all result in collateral airway compression. Elevated intracardiac filling pressures can result in mucosal edema from engorged intraluminal lymphatics and bronchial vessels. This edema can result in impaired clearance of pulmonary secretions and recurrent infections.10 Symptoms include wheezing, stridor, chronic cough, respiratory distress, and apnea in addition to other symptoms from the underlying cardiac abnormality. Diagnosis often requires radiographic imaging (MRI/MRA, CT with contrast, and/or echocardiography), bronchoscopy, and cardiac catheterization to clearly delineate the causative cardiac and airway issues. Treatment involves addressing the underlying cardiac defect, if feasible. In extreme cases, arteriopexy and or placement of bronchial stents may be required. Prompt diagnosis and treatment of children with cardiac defects and airway compression is necessary in order to avoid increased mortality and morbidity. Airway obstruction is often diagnosed after cardiac surgery in the setting of prolonged need for intubation.16 Tracheomalacia Associated with Tracheoesophageal Fistula (TEF), and Esophageal Atresia (EA) TEF and EA is a group of disorders characterized by an interruption of esophageal continuity with or without a tracheal communication. EA occurs relatively frequently, with one in 2500–3000 live births. The vast majority present sporadically with less than 1% being familial or syndromic. The classification scheme includes five types of TEF and EA. The most common type is III or C (86%) where there is a blind proximal esophageal pouch and a distal TEF, followed by Type I or A (8%) where there is EA and no TEF. Type V or E (TEF without atresia), Type II or B (EA with proximal TEF),

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and Type IV or D (EA with proximal and distal TEF) are less common (Fig. 90-10). Type V or E, also known as the H-type, may have more than one fistulous connection. The H-type fistula may present with copious tracheal secretions and chronic aspiration. Patients with TEF and EA may occur with other congenital anomalies in more than 50% of cases. A variety of systems may be affected, such as the cardiovascular (29%), anorectal (14%), genitourinary (14%), gastrointestinal (13%), vertebral/skeletal (10%), and respiratory (6%) systems.24 The diagnosis of TEF and EA may be suspected prenatally with the finding of a small or absent fetal stomach bubble on ultrasonography, especially in the setting of polyhydramnios. Prenatal MRI has also been performed to better characterize the anatomy. Shortly after birth affected patients may have excessive salivation; regurgitation, coughing, or choking with feeding; respiratory distress or cyanosis; or inability to pass a nasogastric tube. An air-filled abdomen on radiography suggests an EA with distal TEF (Type III or C). Pneumonia may be present on chest radiography with a distal TEF from aspiration of gastric reflux. An H-type fistula is diagnosed with a water-soluble contrast radiographic study. Endoscopic examination is vital in order to identify other abnormalities of the larynx and trachea, vocal cord mobility, and specifics of the anatomic abnormality of TEF/EA. These factors are important for surgical planning. Echocardiography should be done to identify concurrent cardiovascular anomalies and aid in finding the ideal surgical approach. Surgery involves a thoracotomy or thoracoscopic approach with division of the TEF and repair of the EA by primary anastomosis. The survival rate is 95% with current surgical practices and neonatal intensive care strategies.25 Survival is related to birth weight and the presence of other anomalies, especially cardiac defects. The Spitz classification correlates survival with birth weight and cardiac defects. Those with birth weight less than 1500 g and cardiac defects have a 22%–50% survival rate.24 Postoperative complications include esophageal stenosis, anastomotic leaks, recurrent fistulae, tracheomalacia, vocal cord paralysis, dysphagia, gastroesophageal reflux disease, and respiratory infections. Residual TEF pouches (Fig. 90-11) may become a source of

FIGURE 90-10. Classification of tracheoesophageal fistula. (A) Type A or I: Esophageal atresia without TEF; (B) Type B or II: Esophageal atresia with proximal TEF; (C) Type C or III: Esophageal atresia with distal TEF (86%); (D) Type D or IV: Esophageal atresia with both proximal and distal TEF; (E) Type E or V: H-type fistula; (F) Esophageal atresia alone. (From Holinger et al.44)

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CHAPTER 90 ❖ Congenital Malformations of the Trachea and Bronchi

FIGURE 90-11. Residual tracheoesophageal fistula pouch.

problems as they fill up with secretions and lead to recurrent pulmonary infections. Treatment involves endoscopic resection of the pouch walls using laparoscopic instruments. Tracheomalacia may be present in EA/TEF patients 75% of the time, but it is only clinically significant in 10%–20% of patients.25 Deficiency of the cartilage and increased length of the posterior trachealis muscle results in collapse of the airway during expiration. Moreover, the trachealis muscle may balloon inward due to weakness in the common parting wall and esophageal distention. Symptoms include biphasic or expiratory stridor, wheezing, persistent cough, recurrent pneumonias, and severe cyanosis (dying spells). Bronchoscopy aids in diagnosis and often shows collapse around the entry point of the TEF. The severity of the symptoms may require tracheotomy and positive pressure ventilation or aortopexy.

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lumen as compared to the normal trachea (Fig. 90-12). Children can develop tracheal stenosis from the disproportionate growth of the tracheal rings relative to the posterior membranous trachea. This results in near complete or complete tracheal rings with restricted growth of the enclosed tracheal lumen. There is a spectrum of lesions depending upon whether the pars membranacea is absent or decreased in size and a variety of inherent cartilaginous abnormalities (such as disorganized, ridge-like, or plates of cartilage). Additionally, diseased airway may range from involvement of just a few complete rings to most of the trachea. CTS can be divided into three general types: (1) long-segmental tracheal stenosis, (2) funnel-shaped narrowing, and (3) segmental narrowing. Type II can have variations in location of narrowing and length. Type III CTS is sometimes found distal to an anomalous right upper lobe bronchus.26 Clinically, children with CTS and complete tracheal rings are symptomatic and diagnosed mostly during infancy. They can present with a myriad of symptoms including severe expiratory or biphasic stridor, retractions, wet-sounding biphasic noise (washer machine, breathing), cyanosis, apneas, and chest congestion. Severity of symptoms is more affected by the degree of narrowing rather than the length of narrowing. Symptoms may not be noticed at birth, but may develop after a few months of age. Affected children may present with rapidly worsening symptoms in the face of their first upper respiratory tract infection. Children with CTS may have associated malformations, cardiac and pulmonary anomalies, Downs syndrome, and Pfeiffer syndrome. The association with the “ring-sling” complex has already been discussed. Imaging studies such as MRA or CTA may provide some information regarding airway narrowing and coexistent cardiac anomalies. Bronchoscopy is essential in clarifying the tracheal lesion, degree of narrowing, and length of narrowing. Decision for surgical intervention depends on the extent of stenosis, caliber of the airway, and condition of the patient. If the tracheal lumen is of very small caliber, then surgical intervention is necessary for survival. In contrast, larger

TRACHEAL STENOSIS Membranous Tracheal Webs Congenital soft tissue webs of the trachea are quite rare and certainly less common than cartilaginous obstructions or laryngeal webs. They can occur in the neonatal or juvenile periods sometimes at the level of the cricoid.26 The symptoms include wheezing and expiratory or biphasic stridor. The treatment includes incision and balloon dilation or endoscopic laser techniques for immediate relief of symptoms. Congenital Tracheal Stenosis and Complete Tracheal Rings Congenital tracheal stenosis (CTS) may range from short segment to extensive long segment tracheal stenosis, and it has been defined as at least 50% narrowing of the tracheal

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FIGURE 90-12. Types of tracheal stenosis. (From Graham.46)

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caliber rings may grow and require no surgical enlargement. Younger children at presentation are more likely to necessitate surgical intervention.27 For short segmental narrowing, tracheal resection and primary anastomosis may be all that is necessary (Fig. 90-13). This technique should only be used if the lesion involves no more than—four to five rings, totaling no more than 30% of the tracheal length. Beyond these limits, excessive tension on the anastomosis can result in postoperative morbidity from anastomotic leakage or restenosis.28 The trachea may be mobilized in a number of ways including laryngeal release maneuvers and distal mobilization in order to achieve a tension-free anastomosis. The suture line requires meticulous and precise approximation; suture preference varies and includes the use of polydioxanone (PDS), prolene or vicryl26 sutures. Complications include recurrent laryngeal nerve injury, dehiscence, and restenosis. Angioplasty balloon dilation of the reconstructed airway may be useful as an adjuvant treatment of postoperative restenosis. Longer segmental tracheal stenosis may require slide tracheoplasty and remains the preferred method of reconstruction over patch tracheoplasty (Fig. 90-14). Patch tracheoplasty can be fraught with complications such as severe tracheomalacia and graft failure. Originally described by Tsang et al. in 1989,29 slide tracheoplasty offers several advantages including the use of autologous trachea, earlier extubation, avoidance of a stent, and decreased granulation tissue formation. Slide tracheoplasty shortens the trachea by half of the involved stenotic segment and doubles the crosssectional area of the airway lumen. The patient is often placed on cardiopulmonary bypass and the trachea is exposed from the carina to the tracheal stenosis. The trachea is divided at the midpoint of the stenotic segment that is to be repaired. A posterior, longitudinal incision is made in the proximal segment through the stenotic area until normal trachealis muscle is encountered; similarly an anterior, longitudinal incision is made in the distal segment through the stenotic area until normal trachea or carina is encountered. The tracheal segments are slid over one another after trimming the corners, and a running polydioxanone suture (PDS) is performed. Some prefer mobilizing both the distal and proximal

tracheal segments with careful preservation of the lateral tracheal vascular supply,30 whereas others extensively mobilize the proximal segment and only partially mobilize distally in order to preserve the vascular supply through the distal tracheal segment.26 The slide tracheoplasty technique can be modified to incorporate abnormal tracheal arborization patterns and to treat mainstem bronchial stenosis.31 Growth of the trachea after slide tracheoplasty has been reported.28 A total cervical approach, avoiding a sternotomy and cardiopulmonary bypass, has been employed by the author in patients that have long segment tracheal stenosis extending as far distally as 1 cm above carina. Tracheal Cartilaginous Sleeve This rare congenital anomaly results from the formation of a long cartilaginous tracheal cylinder or sleeve without tracheal rings. The tracheal rings are fused to adjacent rings with little or no pars membranacea. Recent evidence suggests that tracheal stenosis may be related to increased proliferation of mesenchymal cells with upregulated expression of Fgf10, Tbx4, and Tbx5.32 The sleeve can extend into and beyond mainstem bronchi. It results in severe growth restriction of the tracheal caliber. It almost always occurs in conjunction with craniosynostosis syndromes, including Apert, Pfeiffer, and Crouzon syndromes. The incidence of tracheal cartilaginous sleeve may be underestimated in these patients due to the incorrect diagnosis of obstructive sleep apnea or hypopharyngeal obstruction, which can be present in this population. In one report, 90% of patients with both cartilaginous tracheal sleeves and craniosynostosis syndromes were dead by 2 years of age with 58% of the deaths directly related to airway pathology.33 The lumen diameter and length of an affected segment of trachea is nearly normal, however the rigidity of the cartilaginous sleeve disrupts effective cough airflow and mucous clearance mechanisms making patients more susceptible to infections, mucous plugging, and bronchospasms. In addition, cartilaginous sleeves are thought to be more predisposed to injury and granulation tissue.34 Mortality is increased in patients with sleeve extension to or beyond the carina. Symptoms include severe biphasic stridor, cyanosis, respiratory distress, recurrent croup, recurrent respiratory infections, and failure to thrive. Patients can present soon after birth, or after their first respiratory infection. Bronchoscopy is diagnostic and can be used in conjunction with CT or MRI to further clarify the lesion. Surgical treatment primarily includes tracheotomy for airway support employing a window technique in which a small rectangular area of the sleeve is resected. Tracheal cartilaginous sleeve resection is infrequently employed. Patients will likely require craniofacial surgery, such as midfacial advancement procedures, to address their associated midfacial abnormalities (Fig. 90-15).

Tracheal Agenesis and Atresia

FIGURE 90-13. Resection and end to end anastomosis.

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Tracheal agenesis is a very rare tracheal anomaly in which there is extensive hypoplasia or absence of the trachea, often with an airway and esophageal communication (Fig. 90-16).

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FIGURE 90-14. Slide tracheoplasty.

The incidence is believed to be 1 in 50,000 live births.35 Atresia is a congenital absence or closure of a normal opening, and agenesis is a developmental failure of an organ’s anlage. Twice as many males as compared to females are affected, 52% are premature, and up to 94% are thought to be associated with other congenital malformations.36 Floyd et al. established a classification scheme involving three types of tracheal agenesis.37 Type I has an absent proximal

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trachea with the distal trachea opening into the esophagus. Type II involves a complete absence of the trachea with the carina usually opening into the esophagus. Type III involves the origin of both mainstem bronchi directly from the esophagus. The relative incidence of all three are reported as 13%, 65%, and 22% respectively.35 Prenatally, polyhydramnios may be seen on ultrasonography. Prenatal MRI may give further characterization of

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FIGURE 90-15. Complete cartilaginous sleeve (Pfeiffers’s Syndrome).

Presence of other major neurological, cardiac, or other anomalies may preclude further aggressive intervention. Tracheal agenesis is almost uniformly fatal at this time due to the inadequacy of functionally suitable grafting material and reconstructive technology at this time. Some advise against reconstruction at all and instead support palliative measures. With reconstruction, the longest that a child with tracheal agenesis has survived is for 6 years.35 Congenital High Airway Obstruction Syndrome (CHAOS) is diagnosed when prenatal ultrasonography reveals bilaterally enlarged echogenic lungs, flattened or inverted diaphragms, airway dilation, and mediastinal compression. Prenatal MRI can give additional clarification of the anatomy. CHAOS can be due to tracheal agenesis/atresia or laryngotracheal cysts. Once an EXIT procedure is performed, occasionally laryngotracheoscopy and fetal tracheotomy can be performed to secure an airway.26 In instances of high, shortsegment tracheal atresia, we have successfully performed tracheal reconstruction at our institution following an initial fetal tracheotomy during an EXIT procedure.

FOREGUTS CYSTS Foregut cysts are an umbrella term for a spectrum of anomalies that may result from developmental aberrations of the embryonic foregut. This group encompasses bronchogenic cysts, esophageal duplications, enteric cysts, neurenteric cysts, pulmonary sequestration, and congenital cystic adenomatoid malformation to name a few.38

Bronchogenic Cysts

FIGURE 90-16. Tracheal agenesis.

the airway. A high index of suspicion is needed to avoid morbidity and mortality. Symptoms present immediately after birth, including absence of a cry, respiratory distress in the face of vigorous effort, minimal air exchange on auscultation, and difficulty with intubation. Positive pressure ventilation through an oropharyngeal airway may temporize the child if a fistula exists connecting the airway to the esophagus. A nasogastric tube will prevent soiling of the airway with gastric contents, and allows for the stomach to be decompressed during positive pressure ventilation. Intubation can be attempted through the esophagus under direct visualization. In addition, extracorporeal membrane oxygenation may provide support for several days while surgical plans developed and given consideration. If the diagnosis is suspected prenatally, ex-utero intrapartum therapy (EXIT) procedure may be an option to temporize an airway.

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Bronchogenic cysts occur when anomalous budding of the developing embryonic foregut and tracheobronchial tree becomes separated from the adjacent airways and develops independently. They are lined with respiratory epithelium, can contain cartilage and smooth muscle within the walls, and are filled with mucoid material and/or air. These cysts are more common in the mediastinum but can occur in the lower neck as well. When adherent to trachea, bronchi, or the esophagus, they can result in cough, recurrent pneumonia, fever, chest pain, wheezing, stridor, and respiratory distress. Most are believed to be asymptomatic and can be found incidentally on imaging. As they enlarge, they can cause airway obstruction and worsening of respiratory symptoms. Chest radiography may show these lesions, but CT and barium esophagram are often helpful in the diagnostic workup. These lesions do not enhance on contrasted CT. Surgical excision can result in relief of symptoms and a cure.39,40

Esophageal Duplications and Enteric Cysts Esophageal duplications are the second most common type of gastrointestinal tract duplications. These lesions have a wall comprised of smooth muscle and a mucosal lining that can be any gastrointestinal, respiratory, or squamous epithelium,

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CHAPTER 90 ❖ Congenital Malformations of the Trachea and Bronchi most often gastric mucosa. They are most commonly seen in the posterior mediastinum. Symptoms include respiratory symptoms, dysphagia, and vomiting. Barium esophagram shows esophageal displacement by a mass or an intramural, extramucosal mass. Esophageal duplications do not enhance on contrasted CT, and a variety of associated vertebral anomalies can be seen on imaging. Treatment of lesions involves surgical resection.39,40

BRONCHIAL ANOMALIES Bronchomalacia Bronchomalacia is the dynamic collapse of one or both mainstem bronchi and/or their distal lobar or segmental divisions that can occur due to inherent defects in the cartilage or from extrinsic compression (Fig. 90-17). Bronchomalacia more often presents with tracheomalacia as opposed to an isolated lesion. Bronchomalacia is seen predominantly on the left side (35.7%) as compared to the right (22%). Bronchomalacia is most commonly seen in the left mainstem bronchus, left upper lobe bronchus, right middle lobe bronchus, and right mainstem bronchus, in descending order of prevalence. There is also a male predominance to these lesions.41 Primary bronchomalacia involves defects in the cartilage. This can be from prematurity, inherent cartilage structural defects, or from a congenital absence of cartilaginous rings in the subsegmental bronchi as is seen with Williams-Campbell syndrome. Distal airway collapse in Williams-Campbell syndrome can lead to bronchiectasis. Secondary bronchomalacia occurs from external compression by an enlarged cardiac structure or vascular anomaly,

FIGURE 90-17. Left bronchomalacia.

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similar to secondary tracheomalacia. Bronchomalacia may also be associated with congenital lobar emphysema causing hyperinflation of the affected tissues. Symptomatically, patients present with a similar picture to tracheomalacia. Patients can have stridor, wheezing, persistent cough, recurrent respiratory infections, respiratory distress, and cyanosis. They often present in infancy with their first respiratory infection. Bronchomalacia is often misdiagnosed as asthma and thus there can be delay in diagnosis. Diagnosis and differentiation from asthma is done by bronchoscopy with spontaneous breathing in which the dynamic characteristics of the airway can be witnessed. Treatment is often conservative, as many of these children will improve as their airway matures and grows with time. When bronchomalacia is severe and progresses to respiratory compromise, tracheotomy and positive pressure ventilation may be indicated. Moreover, surgical treatment of the inciting source of external compression, such as with aortopexy, may be helpful.36 Stents can also be used, as discussed with tracheomalacia, but they have serious complications including erosion, difficult removal, granulation tissue formation, and death; as such these should be reserved for emergent situations and not for long-term therapy at this time.

Tracheal Bronchus A tracheal bronchus, also called pig bronchus, is not an uncommon incidental finding on bronchoscopy. It occurs when the right upper lobe bronchus joins the distal trachea instead of the right mainstem bronchus (Fig. 90-18). The tracheal bronchus can be segmental (apical segment of the right upper lobe), lobar (the entire right upper lobe), or

FIGURE 90-18. Tracheal bronchus.

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supernumerary (segmental or lobar bronchial duplication).40 A tracheal bronchus can also be left-sided and supply the left upper lobe; although the right side is more likely.42 Patients with tracheal bronchus are most often asymptomatic. However, they can be symptomatic if associated with other anomalies or if drainage is compromised by inflammation or infection. Patients have presented with recurrent respiratory infections, chronic cough, stridor, hemoptysis, and acute respiratory distress. Tracheal bronchus can be associated with bronchiectasis, atelectasis, chronic bronchitis, focal emphysema, and cystic lung malformations.39,42 One should suspect this entity if there are decreased breath sounds on auscultation in the upper lobe distribution despite a correctly placed endotracheal tube. Many of these bronchial anomalies may be seen on CT as a small area of hypoattenuation coming directly off of the trachea.39 Bronchoscopy allows for direct visualization of the tracheal bronchus. Most patients with tracheal bronchus do not require an intervention and can be conservatively managed. Severe respiratory symptoms or unrelenting infections may necessitate surgical excision.

High Tracheal Bifurcation High tracheal bifurcation results from a reduced number of cartilaginous rings. Frontal chest radiography may demonstrate the bifurcation at a high thoracic level (T3 or above). This entity has been associated with DiGeorge syndrome, skeletal dysplasia, congenital heart disease, brevicollis, and myelomeningocele. Endotracheal intubation may result in mainstem intubation as the bifurcation is higher than anticipated.40

Bronchial Stenosis Similar to tracheal stenosis, bronchial stenosis can be a result of compressive vascular, cardiac, or soft tissue lesions, or they can be due to inherent cartilaginous abnormalities resulting in airway narrowing. The site of obstruction, degree of obstruction, cause of stenosis, presence of cardiovascular abnormalities, and overall health of the patient will dictate the symptoms and overall management strategy. Interestingly, airway stenosis that involves not only the trachea, but extending into the bronchial airway has been managed with slide tracheoplasty.31

Bronchial Agenesis and Atresia Bronchial agenesis is the congenital absence of a bronchus and is not uniformly fatal in contradistinction to tracheal agenesis. Bronchial atresia is characterized by mucus filled bronchocele resulting from a blind-terminating segmental or lobar bronchus. Collateral airways supply the distal alveoli that become hyperinflated due to air trapping. Age at presentation significantly affects the clinical picture. In young adults, this anomaly is usually asymptomatic, an incidental finding in about 50% of cases, usually affects the upper lobes,

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and afflicts predominantly males. This is in contradistinction to its presence in young children and infants. In the neonatal period, bronchial atresia may be seen as a mass due to trapping of fetal lung liquid. Symptoms may include dyspnea, recurrent pneumonia, cough, respiratory distress, fever, and asthma. In children or infants, it usually is symptomatic, affects the lower more than upper lobes, and has a female predominance. Infants present with respiratory distress and young children usually present with recurrent pneumonia by 3 years of age. Bronchoscopy and CT imaging is helpful in the diagnosis of these lesions. Severity of symptoms may dictate the necessity of surgical intervention such as lobectomy or segmentectomy.39,43

References 1. Panitch HB, Talmaciu I, Heckman J, Wolfson MR, Shaffer TH. Quantitative bronchoscopic assessment of airway collapsibility in newborn lamb tracheae. Pediatr Res. 1998;43:832–839. 2. Carden KA, Boiselle PM, Waltz DA, Ernst A. Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review. Chest. 2005;127:984–1005. 3. Wailoo MP, Emery JL. The trachea in children with tracheooesophageal fistula. Histopathology. 1979;3:329–338. 4. Jamal N, Bent JP, Vicencio AG. A neurologic etiology for tracheomalacia? Int J Pediatr Otorhinolaryngol. 2009;73: 885–887. 5. Benjamin B. Tracheomalacia in infants and children. Ann Otol Rhinol Laryngol. 1984;93:438–442. 6. Mair EA, Parsons DS. Pediatric tracheobronchomalacia and major airway collapse. Ann Otol Rhinol Laryngol. 1992; 101:300–309. 7. Boogaard R, Huijsmans SH, Pijnenburg MW, Tiddens HA, de Jongste JC, Merkus PJ. Tracheomalacia and bronchomalacia in children: incidence and patient characteristics. Chest. 2005;128:3391–3397. 8. McNamara VM, Crabbe DC. Tracheomalacia. Paediatr Respir Rev. 2004;5:147–154. 9. Jaquiss RD. Management of pediatric tracheal stenosis and tracheomalacia. Semin Thorac Cardiovasc Surg. 2004;16: 220–224. 10. Kussman BD, Geva T, McGowan FX. Cardiovascular causes of airway compression. Paediatr Anaesth. 2004;14:60–74. 11. Shah RK, Mora BN, Bacha E, et al. The presentation and management of vascular rings: an otolaryngology perspective. Int J Pediatr Otorhinolaryngol. 2007;71:57–62. 12. Woods RK, Sharp RJ, Holcomb GW 3rd, et al. Vascular anomalies and tracheoesophageal compression: a single institution’s 25-year experience. Ann Thorac Surg. 2001;72:434–438; discussion 8–9. 13. McLaren CA, Elliott MJ, Roebuck DJ. Vascular compression of the airway in children. Paediatr Respir Rev. 2008;9:85–94. 14. McLaughlin RB Jr, Wetmore RF, Tavill MA, Gaynor JW, Spray TL. Vascular anomalies causing symptomatic tracheobronchial compression. Laryngoscope. 1999;109:312–319. 15. Fleck RJ, Pacharn P, Fricke BL, Ziegler MA, Cotton RT, Donnelly LF. Imaging findings in pediatric patients with persistent airway symptoms after surgery for double aortic arch. Am J Roentgenol. 2002;178:1275–1279.

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CHAPTER 90 ❖ Congenital Malformations of the Trachea and Bronchi 16. Sebening C, Jakob H, Tochtermann U, et al. Vascular tracheobronchial compression syndromes - experience in surgical treatment and literature review. Thorac Cardiovasc Surg. 2000;48:164–174. 17. Strife JL, Baumel AS, Dunbar JS. Tracheal compression by the innominate artery in infancy and childhood. Radiology. 1981;139:73–75. 18. Tatekawa Y, Tojo T, Hori T, et al. A new technique for treatment of tracheal compression by the innominate artery: external reinforcement with autologous cartilage graft and muscle flap suspension. Pediatr Surg Int. 2008;24:431–435. 19. Tsugawa C, Ono Y, Nishijima E, Takamizawa S, Satoh S, Muraji T. Transection of the innominate artery for tracheomalacia caused by persistent opisthotonus. Pediatr Surg Int. 2004;20:55–57. 20. Yu JM, Liao CP, Ge S, et al. The prevalence and clinical impact of pulmonary artery sling on school-aged children: a largescale screening study. Pediatr Pulmonol. 2008;43:656–661. 21. Elliott M, Roebuck D, Noctor C, et al. The management of congenital tracheal stenosis. Int J Pediatr Otorhinolaryngol. 2003;67(suppl 1):S183–S192. 22. Oshima Y, Yamaguchi M, Yoshimura N, et al. Management of pulmonary artery sling associated with tracheal stenosis. Ann Thorac Surg. 2008;86:1334–1338. 23. Fiore AC, Brown JW, Weber TR, Turrentine MW. Surgical treatment of pulmonary artery sling and tracheal stenosis. Ann Thorac Surg. 2005;79:38–46; discussion 38–46. 24. Spitz L. Oesophageal atresia. Orphanet J Rare Dis. 2007;2:24. 25. Achildi O, Grewal H. Congenital anomalies of the esophagus. Otolaryngol Clin North Am. 2007;40:219–244, viii. 26. Sandu K, Monnier P. Congenital tracheal anomalies. Otolaryngol Clin North Am. 2007;40:193–217, viii. 27. Rutter MJ, Willging JP, Cotton RT. Nonoperative management of complete tracheal rings. Arch Otolaryngol Head Neck Surg. 2004;130:450–452. 28. Anton-Pacheco JL, Cano I, Comas J, et al. Management of congenital tracheal stenosis in infancy. Eur J Cardiothorac Surg. 2006;29:991–996. 29. Tsang V, Murday A, Gillbe C, Goldstraw P. Slide tracheoplasty for congenital funnel-shaped tracheal stenosis. Ann Thorac Surg. 1989;48:632–635. 30. Rutter MJ, Cotton RT, Azizkhan RG, Manning PB. Slide tracheoplasty for the management of complete tracheal rings. J Pediatr Surg. 2003;38:928–934.

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31. Beierlein W, Elliott MJ. Variations in the technique of slide tracheoplasty to repair complex forms of long-segment congenital tracheal stenoses. Ann Thorac Surg. 2006;82:1540–1542. 32. Tiozzo C, De Langhe S, Carraro G, et al. FGF10 (Fibroblast Growth Factor 10) plays a causative role in the tracheal cartilage defects in a mouse model of Apert syndrome. Pediatr Res. 2009. Epub ahead of print. 33. Noorily MR, Farmer DL, Belenky WM, Philippart AI. Congenital tracheal anomalies in the craniosynostosis syndromes. J Pediatr Surg. 1999;34:1036–1039. 34. Scheid SC, Spector AR, Luft JD. Tracheal cartilaginous sleeve in Crouzon syndrome. Int J Pediatr Otorhinolaryngol. 2002;65:147–152. 35. Haben CM, Rappaport JM, Clarke KD. Tracheal agenesis. J Am Coll Surg. 2002;194:217–222. 36. Ho AS, Koltai PJ. Pediatric tracheal stenosis. Otolaryngol Clin North Am. October 2008;41(5):999–1021, x. 37. Floyd J, Campbell DC Jr, Dominy DE. Agenesis of the trachea. Am Rev Respir Dis. 1962;86:557–560. 38. Azzie G, Beasley S. Diagnosis and treatment of foregut duplications. Semin Pediatr Surg. 2003;12:46–54. 39. Berrocal T, Madrid C, Novo S, Gutiérrez J, Arjonilla A, Gómez-León N. Congenital anomalies of the tracheobronchial tree, lung, and mediastinum: embryology, radiology, and pathology. Radiographics. 2004;24:e17. 40. Chen JC, Holinger LD. Congenital tracheal anomalies: pathology study using serial macrosections and review of the literature. Pediatr Pathol. 1994;14:513–537. 41. Masters IB, Chang AB, Patterson L, et al. Series of laryngomalacia, tracheomalacia, and bronchomalacia disorders and their associations with other conditions in children. Pediatr Pulmonol. 2002;34:189–195. 42. Ghaye B, Szapiro D, Fanchamps JM, Dondelinger RF. Congenital bronchial abnormalities revisited. Radiographics. 2001;21:105–119. 43. Morikawa N, Kuroda T, Honna T, et al. Congenital bronchial atresia in infants and children. J Pediatr Surg. 2005;40:1822–1826. 44. Holinger LD, Lusk RP, Green CG, eds. Pediatric Laryngology and Bronchoesophagology. Philadelphia, PA: Lippincott/ Williams Wilkins; 1997. 45. Othersen Jr HB, ed. The Pediatric Airway. Philadelphia, PA: WB Saunders; 1991. 46. Graham JM, Scadding GK, Bull PD, eds. Pediatric ENT. New York, NY: Springer; 2007.

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91

C H A P T E R

Pediatric Upper Airway Infections David L. Mandell

S

tridor, a sign of airway obstruction, is common in children with upper respiratory disease. There are many potential causes of stridor in children, ranging from congenital anomalies, neurological conditions, neoplasms, chemical and thermal injuries, foreign bodies, inflammation, and infection. This chapter will discuss some of the classic infectious causes of pediatric stridor, including viral laryngotracheobronchitis (e.g., croup), bacterial tracheitis, and acute supraglottitis.

CROUP Croup (also known as viral laryngotracheobronchitis) refers to the barking cough present with infectious narrowing of the pediatric subglottis.1 Croup is the most common cause of infectious airway obstruction in young children, with an annual incidence in the United States of 18 per 1000 children.2,3 The disease has a peak incidence of 60 per 1000 children among those 1–2 years of age.2,3 The typical age range affected by croup is 6 months–3 years.4 The disease is more common in early fall and winter, although sporadic cases are seen throughout the year.2,3 The most common etiologic agent is parainfluenza virus type I, although other pathogens have also been implicated (including parainfluenza types 2 and 3, influenza A and B, respiratory syncytial virus, adenovirus, Mycoplasma pneumoniae, herpes simplex type I, measles, and varicella).5–7 Croup typically begins with a several-day history of nonspecific viral upper respiratory tract symptoms, with progression to hoarseness, a barky (seal-like) cough, and stridor.4 The stridor associated with croup usually begins as inspiratory, but then progresses to become biphasic as the subglottic mucosa becomes increasingly edematous. On chest auscultation, breath sounds are usually clear, although transmitted stridor from the subglottis may be noted.1 The clinician must be aware of signs of impending respiratory collapse, such as loud biphasic stridor, nasal flaring, intercostal and suprasternal retractions, tachypnea, and arterial desaturation.4 Children with croup commonly present with a low-grade fever. The complete blood count, if obtained, will inconsistently show mild leukocytosis.4 The diagnosis of croup is usually made clinically, and in clinical practice, the diagnosis is only incorrect in about 2% of patients.8 A scoring system for the clinical severity of croup does exist, and is used primarily for clinical research purposes. The Westley scoring system uses five categories (level of consciousness, cyanosis, stridor, air entry, and retractions) and assigns a grade to each of them using a numerical scale, with the final total score ranging from 0 (no symptoms) to 17 (severe symptoms).9

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Although the diagnosis of croup is typically made based solely upon clinical signs and symptoms, ancillary studies can be considered. A classic finding seen on antero-posterior cervical plain film radiography is the “steeple sign,” indicative of a narrowed subglottis.4 The subglottic narrowing is dynamic and can be accentuated during inspiration.10 One problem with plain film radiography is that half of children with a clinical diagnosis of croup will still have a normal cervical X-ray7 (Fig. 91-1). Endoscopy is usually not required in the work-up of an uncomplicated case of croup.4 Most children with croup are treated as outpatients, with hospitalization rates ranging from 1.5% to 15%.11,12 Endotracheal intubation is uncommon, occurring in only about 2% of hospitalized children with croup.3 The need for intubation is believed to have dropped over the years due to improvements in medical therapy protocols.13

FIGURE 91-1. Antero-posterior cervical plain radiograph of a child with croup. Note the narrowed subglottis (steeple sign).

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Since croup symptoms are expected to be self-limited, traditional treatment has mainly consisted of supportive care. One popular, simple treatment has been exposing the patient to a humidifier or a steam shower. The rationale for humidification is that it may soothe the inflamed airway mucosa, decrease coughing, and liquefy the secretions for easier clearance.14 However, it has not been definitively shown that humidified air has any measurable effect on the subglottic mucosa, or that it influences patient outcome.15 Despite the lack of strong evidence regarding efficacy, humidified air is still routinely used for children with croup in general clinical practice, mainly based upon anecdotal evidence.4 Racemic epinephrine is an effective treatment option for croup. The medication is given by nebulizer, and consists of levo (L) and dextro (D) epinephrine isomers. The L-form is the active component, exerting a vasoconstrictive adrenergic effect on the mucosal vasculature and effectively reducing airway edema.9,16 The inactive D-isomer is added to reduce the risk of side effects. Nebulized racemic epinephrine leads to rapid clinical improvement in children with croup within 10–30 minutes and significantly decreases the need for endotracheal intubation.17 However, the effect of this medication is transient, wearing off within 2 hours. When racemic epinephrine was first used for croup, children who received it would be admitted for fear of a rebound effect once the medication wore off.4 In modern practice, however, most children with croup can be discharged home from the Emergency Department after a 2–3 hour observation period following racemic epinephrine treatment.18 The medication does have some potential cardiovascular side effects, and should generally be reserved for severely ill patients with croup who do not respond to more conservative interventions. Corticosteroids are one of the most commonly used treatments for croup, although the degree of severity of croup required for such therapy to be given remains subjective.19 The medication has an anti-inflammatory effect by inhibiting the synthesis and release of inflammatory mediators such as IL-1, IL-2, TNF(, and arachadonic acid metabolites, and also decreases the permeability of capillary endothelium while stabilizing lysosomal membranes—all of which decrease the inflammatory reaction and reduce submucosal edema.19 Corticosteroids have a relatively slow onset and can take up to 3 hours to exert their maximal effect. Their potential adverse effects include GI bleeding oral candidiasis and precipitation of bacterial tracheitis.19 Hospitalization rates have been shown to be lower in children with croup treated with nebulized and/or intramuscular corticosteroids versus controls.20 Oral steroids have been shown to be as effective as nebulized steroids in most cases of croup.21 Another treatment for croup that can be useful during an acute episode is heliox, a mixture of helium and oxygen.22 Helium is a light, odorless, noncombustible, physiologically inert gas with a very low gas density compared to air in the room.22 The mixture of helium and oxygen creates respirable gas with a lower density than room air or supplemental oxygen

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alone. The low density of heliox reduces gas turbulence in the airway, thus easing breathing. The usual ratio of the gas mixture is 80% helium and 20% oxygen. If the patient requires greater than a 40% proportion of inspired O2, heliox cannot be used.1 A recent review has suggested that the beneficial effect of heliox compared to other techniques may be more anecdotal than scientifically proven.23 For severe cases of croup in which the symptoms do not respond to humidified air, steroids, heloix, or racemic epinephrine, intubation may become necessary. It is generally recommend that the endotracheal tube should be smaller than expected for the age, so as not to further exacerbate subglottic edema.4 Patients can then be extubated when an air leak is detected (usually 2–3 days later).1 If no air leak is identified after about 5 days, endoscopy is indicated. Endoscopy may also be indicated in cases of recurrent croup, in which case endoscopy is ideally delayed 3–4 weeks after an acute episode of croup to allow the edema to subside, since the edema may mask an underlying anatomic abnormality.4 However, in the acute setting, endoscopy may still be indicated for atypical presentations or uncharacteristic clinical courses, in which case the clinician may want to rule out other entities, such as bacterial tracheitis or an airway foreign body. In cases of recurrent croup, it is generally advisable to search for underlying predisposing factors. One such factor may be gastroesophageal reflux disease and laryngopharyngeal reflux. In one study of eight children with recurrent croup, esophageal pH was less than 6 for 4.1% of the 23–24 hour study time, whereas the pH was less than six for only 1.25% of the study time in six controls. In addition, the pharyngeal pH was less than 6 for 4.1% of the study time, versus 0.8% for the control group.24 In another study of 32 children with recurrent croup, it was determined with retrospective review that 15 children (47%) were felt to have gastroesophageal reflux disease (based upon a variety of studies), and another 8 (25%) had an anatomic abnormality (either subglottic stenosis or laryngomalacia).25 It was also noted that patients with gastroesophageal reflux disease presented with recurrent croup at a younger mean age (6 months vs. 9 months) and had smaller intervals between croup episodes (3 months vs. 11 months) than recurrent croup children without gastroesophageal reflux disease.25 In summary, croup is traditionally defined as a viral laryngotracheobronchitis and is a very common childhood illness. The disease is typically diagnosed by history and physical examination alone. Treatment is usually on an outpatient basis, with less than 10% of the patients being hospitalized. For uncomplicated cases, management usually involves humidification and oral steroids. For more severe cases with failure to respond to more conservative measures, interventions such as racemic epinephrine, heliox, and intubation are considered. In cases of recurrent croup, endoscopy should be considered to rule out an underlying structural anomaly (such as subglottic stenosis), and clinicians should consider a work-up and/or empiric treatment for gastroesophageal reflux disease and laryngopharyngeal reflux.

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BACTERIAL TRACHEITIS Bacterial tracheitis is traditionally defined as a rare, lifethreatening cause of infectious airway obstruction in children.26 The disease is thought to occur due to bacterial superinfection in the setting of a predisposing viral laryngotracheitis. Bacterial tracheitis is associated with thick membranous tracheal secretions that do not clear effectively with coughing (Fig. 91-2). The tracheal membranes may occlude the airway, leading to respiratory collapse and death. Bacterial tracheitis is a disease with multiple names, including bacterial laryngotracheobronchitis, membranous laryngotracheobronchitis, pseudomembranous croup, and exudative tracheitis.27 The first detailed description of bacterial tracheitis was by Jones et al. in 1979.26 This paper described 8 children hospitalized with symptoms of a viral upper respiratory tract infection that progressed to a “brassy cough,” fever, and toxicity. The differential diagnosis included severe croup and also epiglottitis, but the patients demonstrated no response to traditional therapies for croup (e.g., mist, racemic epinephrine), and patients had a normal-appearing epiglottis on endoscopy. Purulent secretions were found in the trachea, and the term “bacterial tracheitis” was coined.26 The typical clinical presentation of bacterial tracheitis begins with a several-day history of symptoms that may suggest a viral upper respiratory tract infection (e.g., fever, cough, and stridor similar to croup). The average prodrome lasts 2.5 days,27 but can range from 1 hour to 5 days.28 The prodrome is then followed by a rapid onset of high fever, respiratory distress, and an overall toxic appearance. Typically, there is no substantial cough, and no odynophagia or drooling. The child typically appears comfortable when lying supine. Marked leukocytosis with a left shift is often present, and the patient usually appears more ill than a patient with a typical case of croup. Patients with bacterial tracheitis typically fail to respond to typical croup treatments such as racemic epinephrine and steroids. Traditionally, the average age of patients who present with bacterial tracheitis is 4 years,29 with a range of 3 weeks to

FIGURE 91-2. Rigid endoscopic view of proximal trachea filled with thick, purulent secretions in a child with bacterial tracheitis.

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11.5 years.26,30 The male-to-female ratio has been reported to be approximately 2:1.29 Most cases occur in winter,27 although occasional cases have been reported in the fall and spring.31,32 Most cases of bacterial tracheitis occur in previously healthy children, although cases have been reported in children with other pre-existing upper airway disorders and associated underlying clinical features, such as subglottic hemangioma, laryngomalacia, tracheobronchomalacia, Down’s syndrome, prior tracheoesophageal fistula repair, and immunosuppression due to leukemia and aplastic anemia.29,32 In the majority of patients with bacterial tracheitis, a high fever is noted, and patients are frequently described as “toxic.”26,28,31,33 However, fever is not necessarily a consistent finding in every patient.30 The white blood cell count was traditionally described as being very elevated (as high as 28,700 × 103 cells/mm3),26 but subsequent reports suggest that the mean white blood cell count is 12–13,000 × 103 cells/mm3,28,29 and may be within the normal range in some patients.30 The most commonly isolated bacterium from tracheal secretions in patients with bacterial tracheitis is Staphyloccocus aureus, which is found in approximately 65% of cases (33%–75%).26,29,30 Other bacteria that have been isolated from tracheal secretions in these cases include: H. influenzae, Group A Streptococcus, S. pneumoniae, S. viridans, Klebsiella, E. coli, and Neisseria species.26,28–31,33 When plain film radiographs are obtained, subglottic narrowing has been seen in 32%–100% of cases of bacterial tracheitis, and diffuse haziness suggestive of tracheal membranes is seen in 23%–87% (Fig. 91-3).29,33 It has been

FIGURE 91-3. Lateral cervical plain radiograph of a child with bacterial tracheitis. Note the hazy appearance of the trachea, suggestive of membranous tracheal secretions.

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suggested that plain film radiographs are not particularly valuable in these patients, and bronchoscopy is considered the definitive method of diagnosis, especially in a child in acute respiratory distress.30 Rigid endoscopy not only confirms the diagnosis but is also therapeutic. To perform rigid tracheobronchoscopy in patients with suspected bacterial tracheitis, anesthesia with spontaneous ventilation is preferred. Typical findings during endoscopy include edema of the subglottis, ulceration and pseudomembrane formation in the trachea, and thick inflammatory exudate with sloughed mucosa that obstructs the lumen of trachea and mainstem bronchi. The thick material should be removed with a suction and optical forceps, and tracheal specimens should be sent for Gram stain, culture, and sensitivities. Repeat endoscopy to remove the re-accumulated material is sometimes necessary.29 Many children with bacterial tracheitis require endotracheal intubation and ventilatory support; the decision to intubate is made on a case-by-case basis. The reported intubation rate for bacterial tracheitis is 75%–91%.26,30,33 In a large review of 161 cases of bacterial tracheitis, an artificial airway was required in 83% of the patients, with tracheotomy being performed in 11% of the patients.29 The duration of intubation is typically 3–7 days, and the decision to extubate is guided by evidence of clinical improvement, including decreased tracheal secretions, defervescence, and an air leak developing around the endotracheal tube.29 The mean duration of hospitalization is 8.7 days (4–24 days).29 Complications of bacterial tracheitis include pneumonia (54% of patients),29,33 respiratory arrest (11% of patients),29 death (3.7% of patients),29 cardiopulmonary arrest,26,28,29,31 toxic shock syndrome,32,34 septic shock,34 anoxic encephalopathy,29 and acute respiratory distress syndrome.30,34 In addition to endoscopy and the removal of tracheal secretions, antibiotics are a mainstay of treatment for bacterial tracheitis. Choices include a semisynthetic penicillin (i.e., nafcillin) with the intent to treat S. aureus, or a thirdgeneration cephalosporin (e.g., ceftriaxone, cefotaxime) for expanded gram-negative coverage. Other antibiotics options that have been used include cefuroxime and ampicillin/ sulbactam.27 The antibiotic therapy is adjusted based upon the results from the Gram stain and culture and sensitivity results. After hospital discharge, oral amoxicillin-clavulanate is often prescribed for a total duration of antibiotic therapy of 10–14 days.27 Some more recent reports have suggested that the clinical presentation of bacterial tracheitis has been changing. In 1998, Bernstein et al. reported on 46 patients with bacterial tracheitis, defined as symptoms, including at least two of the following three features: (radiographic evidence of tracheal membranes, mucopurulent tracheal secretions on endoscopy, or tracheal aspirate with positive leukocytes or positive bacterial culture).35 Patients in this series demonstrated an older mean age (5.75 years) than earlier reports and were less likely to appear toxic. High fever (≥40°C) was noted in only eight patients (17%). All patients underwent rigid tracheobronchoscopy, but only 26 of them (57%) were intubated, and only

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one patient underwent tracheotomy. There were no deaths in the series. The most commonly isolated bacteria were M. catarrhalis (27%) and S. aureus (22%). In addition, influenza A virus was isolated from 18 of the 25 cases (72%), for which viral cultures were obtained.35 In a follow-up study from the same institution, 94 patients with bacterial tracheitis were reviewed over a 10-year period.27 The mean age at presentation had increased to 8 years. Those patients who required endotracheal intubation were younger (average: 7 years) than those who were not intubated (average: 9 years). Only 9.5% of cases were described as toxic, and only 6.4% demonstrated severe respiratory distress. Oxygen saturation below 92% was described in only one case. Most patients in the series (60%) were not febrile, and the mean white blood cell count was just 10.8 × 103 cells/mm3. There were no deaths in the series, and no patients underwent tracheotomy. Rigid tracheobronchoscopy was performed in all patients, and membranes or thick secretions were found in 89%.27 In this more recent series, the most common bacterial isolates were S. aureus (21%), S. pneumoniae (11%), H. influenzae (11%), M. catarrhalis (9%), Group A Streptococcus (6%), and normal oropharyngeal flora (41%).27 It was found that patients with M. catarrhalis were more likely to have a severe clinical course; 83% required intubation (vs. 49% for patients without M. catarrhalis cultured), and patients with M. catarrhalis infections happened to be younger than those without this bacterium. Viral cultures were obtained in 34 patients, of which 65% were positive, including viruses such as influenza A (77%), influenza B (14%), and respiratory syncytial virus (9%).27 Another study has found viral isolates from tracheal secretions including influenza, parainfluenza, and enterovirus.33 In summary, bacterial tracheitis was initially described as a rare, life-threatening infectious airway emergency. Bacterial tracheitis may be part of a continuum with croup. The typical case requires prompt rigid airway endoscopy in the operating room. Recent reports have suggested that the severity of the disease may be decreasing, with patients presenting at an older age, with less virulent pathogens. The decreased rate of intubation and tracheotomy and improved survival may also indicate increased physician comfort and experience with the disease process.27

ACUTE EPIGLOTTITIS Acute epiglottitis, also known as acute supraglottitis, is a lifethreatening infection of the supraglottic airway (Fig. 91-4). It classically occurs between the ages of 2–5 years, and the most common causative organism has traditionally been Haemophilus influenzae type B.36 H. influenzae Type B (HIB) has been considered the leading cause of invasive bacterial disease in children in the United States, being responsible for illness such as meningitis, septic arthritis, cellulitis, pneumonia, and supraglottitis.36 The first HIB vaccine (a purified capsular polysaccharide) was introduced in the United States in 1985, and was given

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CHAPTER 91 ❖ Pediatric Upper Airway Infections

FIGURE 91-4. Rigid endoscopic view of erythematous, edematous epiglottis in a child with acute epiglottitis.

to children 2 years of age and older.36 The first conjugate (polysaccharide-protein) HIB vaccine in the United States was licensed in 1987.36 The conjugate vaccine is considered to be more immunogenic, leading to the creation of anticapsular defense antibodies in the host. The conjugate vaccine can be given to younger infants, and the United States Centers for Disease Control recommends vaccination at 2, 4, and 6 months, with a booster at 12–15 months.37 Use of the conjugate HIB vaccine has led to a significant decrease in the incidence of H. influenzae disease. Universal HIB vaccination led to a decrease in the incidence of acute epiglottitis in children under the age of 5 in the United States, from 41 cases per 100,000 in 1987 to 1.3 per 100,000 in 1997.38 Acute epiglottitis does still exist, but because it has become much less common, the diagnosis requires a high level of suspicion. Also, due to the widespread use of the HIB vaccine, organisms other than HIB account for a greater percentage of cases today, and the disease may present with atypical features. The classic clinical presentation of acute epiglottitis is that of a 2–5 year old child with high fever, irritability, throat pain, airway obstruction, respiratory distress—all of which progress rapidly over several hours. The patient typically appears toxic and anxious, and maintains a tripod position (sitting upright, leaning forward, supported by the hands, with the chin up and the mouth open). Patients usually exhibit “the 4 D’s”—drooling, dyspnea, dysphagia, and dysphonia.39 The diagnosis of acute epiglottitis is confirmed by the direct inspection of the epiglottis, but this should be done in the operating room setting. It is generally recommended that the pharynx not be examined in the Emergency Department, due to the fear of precipitating complete airway obstruction.1 Anxiety-provoking procedures (such as phlebotomy) should generally be avoided until after the airway is secured. Patients often have an elevated white blood cell count with a left shift. Radiographs are useful with regards to suggesting the diagnosis and helping to rule out croup, retropharyngeal abscess, or a foreign body.1 A lateral neck radiograph with

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hyperextension during inspiration may show the classic “thumb sign,” with thickening of the epiglottis and the aryepiglottic folds and loss of the shadow of the vallecula (Fig. 91-5).1 The primary goal of management of acute epiglottitis is to obtain and maintain an adequate airway. Patients typically require emergency endoscopy in the operating room. The set-up should include a variety of endotracheal tubes, rigid bronchoscopes, and tracheotomy supplies. During induction, spontaneous breathing is preferred, and the patient should be intubated, after which cultures should be taken from the epiglottis, along with blood cultures. A nasotracheal tube can be considered for greater stability. Antibiotics (usually a second or third generation cephalosporin, or ampicillin/sulbactam) should be started and the patient should be transferred to the Intensive Care Unit. Antibiotics should be adjusted as culture results return. The patient should remain intubated until there is evidence of clinical improvement, which can be assessed by monitoring vital signs, as well as checking for an air leak around the endotracheal tube and examining the supraglottis with bedside direct laryngoscopy or flexible nasolaryngoscopy. A dose of intravenous dexamethasone can be considered to reduce postextubation stridor. Based on data from the Children’s Hospital of Pittsburgh, the average duration of intubation for acute epiglottitis is 2.8 days

FIGURE 91-5. Lateral cervical plain radiograph of a child with acute epiglottitis. Note the thickened epiglottis (e.g., “thumb sign”) (arrow).

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(range: 1–6 days), the average length of stay in the Intensive Care Unit is 3.6 days (range: 2–17 days), and the average length of hospitalization is 5.5. days (range: 3–22 days).40 In the United States, the HIB vaccine has had a profound impact on the incidence of acute epiglottitis. In one study, it was found that the rate of acute epiglottitis in the state of Rhode Island dropped from 6.1 cases per 100,000 children per year to 0.3 cases per 100,000 children per year when comparing three prevaccination years (1975–1977) to 3 postvaccination years (1990–1992).41 Similar dramatic decreases in the incidence of acute epiglottitis in response to vaccination programs have been reported in Canada42 and the United Kingdom.43 In Australia, the conjugate HIB vaccine became available in 1993, and in the 3 years prior to use of the vaccine (1990–1992), there were 107 cases of acute epiglottitis in Australia, compared to only 19 cases over a similar time frame postvaccination (1998–2000).44 Not all countries worldwide seem to have a need for universal HIB vaccination programs. In Singapore, invasive HIB disease naturally occurs in only 3.3 per 100,000 children under age 5 per year, with only two pediatric cases of acute epiglottitis reported from 1992–2001.45 The reason for the low incidence of invasive HIB disease is unknown, but this phenomenon has led Singapore to conclude that a universal HIB vaccination program is not justified in that country.45 Prior to widespread HIB vaccination, H. influenzae type B accounted for 90% of cases of acute epiglottitis.46 In the postvaccination age, H. influenzae type B now accounts for 32% to 63% of cases.46,47 Other causative organisms that have been reported include S. pneumoniae, S. viridans, S. pyogenes, S. aureus, nontypeable H. influenzae, H. parainfluenzae, K. pneumoniae, and even Candida albicans.40,44,46 Vaccine failure can occur with the HIB vaccine, and failure is defined as the occurrence of invasive HIB disease despite previous vaccination, most likely due to an inadequate serum concentration of antibodies directed against the organism’s capsular polysaccharide.48 In a study from the United Kingdom, 115 HIB vaccine failures were reported in over 5 million vaccinated children from 1992– 1998, with a failure rate of 2.2 per 100,000 vaccinees.48 Of the failures, 61% of the cases presented with meningitis, and 19% with epiglottitis. Clinical risks factors (former premature delivery, malignancy, developmental delay, Down’s syndrome) and/or immunodeficiency were found in 45 (44%) of vaccine failures.48 The most common immunological deficiency was that of IgG2, followed by IgA. After HIB infection, 70% of those with vaccine failure do have a satisfactory antibody response to the disease.48 Of the 30% who do not have a satisfactory antibody response to disease, the majority do respond to a further booster dose of the conjugate vaccine.48 One effect of universal HIB vaccination has been that the average age of patients presenting with acute epiglottis has increased. The reason for this phenomenon is that adult cases of acute epiglottitis have traditionally not been closely linked to H. influenzae type B infection. Thus, while

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the HIB vaccine has dramatically decreased the number of pediatric cases of acute epiglottitis, the number of adult cases has remained essentially unchanged.43,44 In a study at Boston Children’s Hospital, the mean age of patients presenting with acute epiglottis rose from 5.8 years (1992–1997) to 14.6 years (1999–2002).46 Other studies have shown that among all cases of acute epiglottitis, the percentage of adult cases rose from 17%–31% (prevaccination) to 84%–97% (postvaccination).41,44 HIB typically accounts for only 11%–20% of cases of acute epiglottitis in adults.41,43,44 Other causative organisms seen in adult cases of acute epiglottitis include α-hemolytic streptococcus, S. pneumoniae, β-hemolytic streptococcus, Propionibacterium species, and S. aureus.41,44 Blood cultures in adult cases are negative in as many as 85% of patients.41 The clinical manifestations of acute epiglottitis in adults is often different than that of children. In adults, the disease has a slower onset, more oropharyngeal symptoms, less localization to the epiglottis (e.g., more diffuse pharyngeal and supraglottic involvement), and less risk of acute airway occlusion. Adults are also less likely than younger children to require intubation,46 with an artificial airway being required in 68% of children and only 21% of adults with acute epiglottitis in one study.41

CONCLUSIONS Croup, bacterial tracheitis, and acute epiglottitis represent different manifestations of infectious obstruction of the pediatric airway—each with its own distinct clinical features and management protocols. Changing management options and epidemiological factors have led to changes in how these diseases are diagnosed and managed, and clinicians must maintain a high level of suspicion for these disorders and try to distinguish between them when faced with pediatric infectious airway obstruction.

References 1. Rotta AT, Wiryawan B. Respiratory emergencies in children. Respir Care. 2003;48:248–260. 2. Geelhoed GC, Macdonald WB. Oral and inhaled steroids in croup: a randomized, placebo-controlled trial. Pediatr Pulmonol. 1995;20:355–361. 3. Yates RW, Doull IJ. A risk-benefit assessment of corticosteroids in the management of croup. Drug Saf. 1997;16:48–55. 4. Stroud RH, Friedman NR. An update on inflammatory disorders of the pediatric airway: epiglottitis, croup, and tracheitis. Am J Otolaryngol. 2001;22:268–275. 5. Denny FW, Murphy TF, Clyde WA, et al. Croup: an 11-year study in a pediatric practice. Pediatrics. 1983;71:871–876. 6. Baugh R, Gilmore BB. Infectious croup: a critical review. Otolaryngol Head Neck Surg. 1986;95:40–46. 7. Cunningham MJ. The old and new of acute laryngotracheal infections. Clin Pediatr. 1992;31:56–64. 8. Mauro RD, Poole SR, Lockhart CH. Differentiation of epiglottitis from laryngotracheitis in the child with stridor. Am J Dis Child. 1988;142:679–682.

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CHAPTER 91 ❖ Pediatric Upper Airway Infections 9. Westley CR, Cotton EK, Brooks JG. Nebulized racemic epinephrine by IPPB for the treatment of croup: a double-blind study. Am J Dis Child. 1978;132:484–487. 10. Swishchuk LE. Upper airway, nasal passages, sinuses, and mastoids. In: Swishchuk LE, ed. Emergency Radiology of the Acutely Ill and Injured Child. 2nd ed. Baltimore, MD: Williams & Wilkins; 1986:127–140. 11. Henrickson KH, Kuhn SM, Savatski LL. Epidemiology and cost of infection with human parainfluenza virus types 1 and 2 in young children. Clin Infect Dis. 1997;18:770–779. 12. Duncan NO, Sprecher RC. Infections of the airway. In Cummings CW, ed. Otolaryngology-Head & Neck Surgery. 3rd ed. St. Louis, MO: Mosby; 1998:388–400. 13. Geelhoed GC. Sixteen years of croup in a Western Australian teaching hospital: effects of routine steroid treatment. Ann Emerg Med. 1996;28:621–626. 14. Skolnik NS. Treatment of croup: a critical review. Am J Dis Child. 1989;143:1045–1049. 15. Bourchier D, Dawson KP, Fergusson DM. Humidification in viral croup: a controlled trial. Aust Pediatr J. 1984;20:289–291. 16. Kristjansson S, Berg-Kelly K, Winso E. Inhalation of racemic adrenaline in the treatment of mild and moderately severe croup: clinical symptom score and oxygen saturation measurements for evaluation of treatment effects. Acta Paediatr. 1994;83:1156–1160. 17. Landau LI, Geelhoed GC. Aerosolized steroids for croup. N Engl J Med. 1994;33:322–323. 18. Prendergast M, Jones JS, Hartman D. Racemic epinephrine in the treatment of laryngotracheitis: can we identify children for outpatient therapy? Am J Emerg Med. 1994;12:613–616. 19. Cressman WR, Myer CM III. Diagnosis and management of croup and epiglottitis. Pediatr Clin North Am. 1994;41: 265–276. 20. Johnson DW, Jacobson S, Edney PC, et al. A comparison of nebulized budesonide, intramuscular dexamethasone, and placebo for moderately severe croup. N Engl J Med. 1998;339: 498–503. 21. Klassen TP, Craig WR, Moher D, et al. Nebulized budesonide and oral dexamethasone for treatment of croup: a randomized controlled trial. JAMA. 1998;279:1629–1632. 22. McGee DL, Wald DA, Hinchliffe S. Helium-oxygen therapy in the emergency department. J Emerg Med. 1997;15:291–296. 23. Vorwerk C, Coats TJ. Use of helium-oxygen mixtures in the treatment of croup: a systematic review. Emerg Med J. 2008;25:547–550. 24. Contencin P, Narcy P. Gastroesophageal reflux in infants and children. A pharyngeal pH monitoring study. Arch Otolaryngol Head Neck Surg. 1992;118:1028–1030. 25. Waki EY, Madgy DN, Belenky WM, Gower VC. The incidence of gastroesophageal reflux in recurrent croup. Int J Pediatr Otorhinolaryngol. 1995;32:223–232. 26. Jones R, Santos JI, Overall JC Jr. Bacterial tracheitis. JAMA. 1979;242:721–726. 27. Salamone FN, Bobbitt DB, Myer III CM, Rutter MJ. Bacterial tracheitis reexamined: is there a less severe manifestation? Otolaryngol Head Neck Surg. 2004;131:871–876. 28. Liston SL, Gehrz RC, Siegel LG, Tilelli J. Bacterial tracheitis. Am J Dis Child. 1983;137:764–767. 29. Gallagher PG, Myer CM III. An approach to the diagnosis and treatment of membranous laryngotracheobronchitis in infants and children. Pediatr Emerg Care. 1991;7:337–342.

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30. Eckel HE, Widemann B, Damm M, Roth B. Airway endoscopy in the diagnosis and treatment of bacterial tracheitis in children. Int J Pediatr Otorhinolaryngol. 1993;27:147–157. 31. Mahajan A, Alvear D, Chang C, et al. Bacterial tracheitis, diagnosis and treatment. Int J Pediatr Otorhinolaryngol. 1986; 10:271–277. 32. Donaldson JD, Maltby CC. Bacterial tracheitis in children. J Otolaryngol. 1989;18:101–104. 33. Han BK, Dunbar JS, Striker TW. Membranous laryngotracheobronchitis (membranous croup). AJR. 1979;133:53–58. 34. Britto J, Habibi P, Walters S, et al. Systemic complications associated with bacterial tracheitis. Arch Dis Child. 1996;74:249–250. 35. Bernstein T, Brilli R, Jacobs B. Is bacterial tracheitis changing? A 14-month experience in a pediatric intensive care unit. Clin Infect Dis. 1998;27:458–462. 36. Wenger JD. Epidemiology of Haemophilus influenzae type b disease and impact of Haemophilus influenzae type b conjugate vaccines in the United States and Canada. Pediatr Infect Dis J. 1998;17:S132–S136. 37. Advisory Committee on Immunization Practices (ACIP). Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. Recommendations of the ACIP. MMWR Morb Mortal Wkly Rep. 1991;40(RR01):1–7. 38. Centers for Disease Control and Prevention. Progress toward eliminating Haemophilus influenzae type b disease among infants and children—United States, 1987–1997. MMWR Morb Mortal Wkly Rep. 1998;47(46):993–998. 39. Blackstock D, Adderley RJ, Steward DJ. Epiglottitis in young infants. Anesthesiology. 1987;67:97–100. 40. Valdapeña HG, Wald ER, Rose D, et al. Epiglottitis and Haemophilus influenzae immunization: the Pittsburgh experience—a five-year review. Pediatrics. 1995;96:424–427. 41. Mayo-Smith MF, Spinale JW, Donskey CJ, et al. Acute epiglottitis: an 18-year experience in Rhode Island. Chest. 1995;108:1640–1647. 42. Scheifele DW. Recent trends in pediatric Haemophilus influenzae type B infections in Canada. Immunization Monitoring Program, Active (IMPACT) of the Canadian Paediatric Society and the Laboratory Centre for Disease Control. CMAJ. 1996;154:1041–1047. 43. McVernon J, Slack MPE, Ramsay ME. Changes in the epidemiology of epiglottitis following introduction of Haemophilus influenzae type b (Hib) conjugate vaccines in England: a comparison of two data sources. Epidemiol Infect. 2006;134:570–572. 44. Wood N, Menzies R, McIntyre P. Epiglottitis in Sydney before and after the introduction of vaccination against Haemophilus influenzae type b disease. Intern Med J. 2005;35:530–535. 45. Low YM, Leong JL, Tan HK. Paediatric acute epiglottitis re-visited. Singapore Med J. 2003;44:539–541. 46. Shah RK, Roberson DW, Jones DT. Epiglottitis in the Haemophilus influenzae type b vaccine era: changing trends. Laryngoscope. 2004;114:557–560. 47. McEwan J, Giridharan W, Clarke RW, Shears P. Paediatric acute epiglottitis: not a disappearing entity. Int J Pediatr Otorhinolaryngol. 2003;67:317–321. 48. Heath PT, Booy R, Griffiths H, et al. Clinical and immunological risk factors associated with Haemophilus influenzae type b conjugate vaccine failure in childhood. Clin Infect Dis. 2000;31:973–980.

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92

C H A P T E R

Acquired Disorders of the Larynx and Trachea Nicolas Leboulanger and Eréa Noël Garabedian

A

cquired laryngotracheal stenoses in children are essentially due to an endoluminal trauma caused by an intubation tube. They may also occur following an external trauma, a heat-related lesion, infection, inflammation, or a chemical burn. Because of anatomical peculiarities, these traumas primarily involve the subglottic region. Indeed, the physiological narrowness of this region, in conjunction with the small size of the upper airways in a neonate or infant, makes the region particularly vulnerable (Table 92-1). Occurring more frequently than congenital stenoses, acquired laryngotracheal stenoses are usually more difficult to treat because of their severity and the cicatricial nature of the lesions. The diagnosis, as implied during the initial interview, is usually easy, thanks to endoscopic assessment, which is the gold standard of examinations. However, the evaluation of the physical characteristics of the stenosis—including, in particular, its location and its extent—is often difficult.

TABLE 92-1. Age/Weight/Intubation Tube/ Bronchoscopes Correspondence Table

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Age

Weight (kg)

Tube

Bronchoscope

Premature

10 y

13.5 (Benjamin)

16

6.0

8.2

Sizes indicate length of blade in centimeter.

a

laryngoscope, the bronchoscope is selected on the basis of patient age and size (Table 96.2). As a general rule, it is wise to use the largest bronchoscope which can be passed without resistance; this permits use of a larger telescope for better visualization and increase the likelihood that the object can be withdrawn through the bronchoscope. Two laryngoscopes and two bronchoscopes are lighted and ready; should a light fail or a forceps become jammed in a scope, a backup will be available immediately. An additional bronchoscope is also useful in cases of fragmented foreign bodies, so that the airway may be rapidly reestablished and the procedure continued after the equipment from the initial pass is handed off to the scrub technician. Positive-action (center-action) forceps are most commonly used in extraction of airway foreign bodies, owing to the popularity of the optical forceps system fitted with the Hopkins rod-lens telescope (Karl Storz, Fig. 96.8C). The optical forceps are manufactured in appropriate lengths for the bronchoscopes with which they are used, and are available in the peanut-grasping, forward-grasping (“alligator”), and cup forceps varieties. Other “nonoptical” types are also available (Fig. 96.8B), and are used with distal illumination through light carriers (Pilling) or proximal illumination using a glass prism (Storz). Positive-action forceps may be particularly helpful in dilating the bronchial wall to create forceps spaces when a foreign body is wedged in a distal bronchus. Passive-action forceps offer a greater range of blades for the various types of mechanical problems. A specific forceps of one of the four major types (forward-grasping, rotation, ball bearing, or hollow object forceps) can be selected in most cases (Fig. 96.8A). No fewer than 60 variations of these four have been designed. For a particular foreign body, the forceps are selected and tried with a duplicate object on a mannequin board or lung model. The forceps should be smooth in operation, and the blades adjusted so they close completely when the handles are closed. The shaft of the forceps must be straight to provide proper visualization, and to prevent friction between the forceps and the lumen of the tube. Two varieties of forceps are made available for removal of any foreign body. Although a forceps may

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A

B

C FIGURE 96-8. Technique of foreign body extraction. (A) The blades of the forceps must pass beyond the equator of the object to avoid stripping off. (B) The object is dislodged and the bronchoscope tip is advanced to the foreign body to stabilize it. (C) The foreign body, scope, and forceps are removed as a unit.

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CHAPTER 96 ❖ Foreign Bodies of the Larynx, Trachea, and Bronchi be chosen that is apparently best suited for the job, unexpected circumstances may arise after the procedure is under way and may require the use of a second variety of forceps. The Fogarty embolectomy catheter is another instrument which has found its way into the foreign body armamentarium at some institutions.77 This small catheter fitted with a balloon may be passed through a bronchoscope, positioned distal to the foreign body, inflated with saline, and withdrawn to trap the presenting part of the object within the lumen of the bronchoscope. The bronchoscope, catheter, and foreign body are then removed from the patient as a single unit. This technique, however, compromises control of the object. The Surgical Team A team approach to foreign body removal cannot be overemphasized. The anesthesiologist, the scrub technician, the circulating nurse, and the endoscopist must all have experience with extraction of foreign bodies. If this is not the case, consideration is given to delaying the procedure until experienced personnel are available. A plan for orderly removal of the object is discussed with each member of the team and his or her role in that plan clearly delineated. The procedure is not begun until all members of the team are prepared and positioned appropriately.

Anesthesia In cases of severe airway obstruction, foreign bodies are usually located in the larynx or upper trachea. In such cases, the child may be mummified, and the object removed through a laryngoscope placed without anesthesia. Oxygenation may be supported intraoperatively by insufflation through a nasal catheter. For most foreign body extractions, however, general anesthesia provides a more controlled setting. Spontaneous ventilation is generally preferable to apneic technique, particularly for laryngeal and tracheal foreign bodies, since the patient has already demonstrated that he can ventilate himself by generating negative intrathoracic pressure. Although some studies suggest a higher likelihood of coughing and bucking with this technique during extraction,78 it is still prudent to begin the procedure this way to be certain that the airway is not occluded by laryngotracheal or bilateral bronchial foreign bodies. In such cases, use of positive pressure ventilation under apneic conditions may render the patient impossible to ventilate due to obstruction by the foreign body. Once the airway is deemed sufficiently patent, either technique can likely be used safely. While spontaneous ventilation technique precludes use of the rapid sequence induction, no cases of aspiration on induction have been reported. Preoperative sedation, which can potentially depress the patient’s respiratory drive, is avoided. During induction in the operating suite, standard monitoring is initiated, including an electrocardiogram, a precordial stethoscope, a blood pressure cuff, a pulse oximeter, an end tidal carbon dioxide monitor, and a thermometer. An anticholinergic agent (usually glycopyrrolate) is administered intravenously prior to the

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procedure to reduce secretions and the risk of bradycardia. Induction of anesthesia is by mask, usually using sevoflurane and oxygen. Nitrous oxide may be used to facilitate a smooth induction, but should be discontinued prior to the procedure so that the patient may remain adequately saturated with oxygen during the foreign body extraction. Following induction, the laryngoscope is passed by the endoscopist to ensure that no foreign body is present in the larynx. If the laryngeal inlet is clear, the larynx is sprayed with a solution of 2% lidocaine in order to desensitize the larynx and reduce the risk of laryngospasm. The bronchoscope is then inserted, and the tracheobronchial tree is inspected while the patient is ventilated and anesthetized through the bronchoscope side arm. Spontaneous ventilation is maintained through a closed system created using an eyeglass or telescope to occlude the proximal end of the bronchoscope. The inhaled agent is supplemented with intravenous propofol as needed. Positive pressure ventilation is avoided, since this tends to drive the foreign body further peripherally. Use of the rod-lens system within the bronchoscope reduces the lumen through which the patient is ventilated and may result in transient desaturation. When this occurs, the telescope may be temporarily replaced with an eyeglass with the lips compressed against the bronchoscope and the nares pinched to ensure a closed system for positive pressure ventilation. Lightening the level of anesthesia may sometimes be useful in inducing a cough that actually helps move the foreign body toward the bronchoscope.

Endoscopic Technique Endoscopic extraction of foreign bodies in children is a gentle, delicate procedure. Adequate protection is applied to the eyes and superior alveolar ridge. The laryngoscope is placed atraumatically into the right side of the mouth, with the tongue gently pushed to the left. The tip of the scope is positioned in the vallecula. The bronchoscope is inserted with care not to injure the laryngeal structures. One must never force a scope, forceps, or foreign body. Once the bronchoscope has been advanced into the upper trachea, ventilation through the side arm is established and confirmed by the endoscopist. The tracheobronchial tree is completely inspected, as multiple foreign bodies may be present. Inspection begins with the normal bronchus, and all secretions are removed in order to ensure optimal respiratory function when the involved side is inspected. When a foreign body is seen, its shape, position, and forceps spaces are assessed. The suction is used to remove secretions from around the foreign body, but is inadequate to hold foreign bodies and is not used for attempted removal. The presentation of the foreign body is studied, with special attention to the location of unseen parts such as sharp points which may be buried deep within the mucosa. Prior to extraction, the orientation of the object may be modified with the tip of the scope, a technique especially

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helpful when establishing forceps spaces between the object and lumen walls. When possible, the foreign body is rotated into the sagittal plane, since this is the largest diameter of the laryngeal lumen. One must be cautious not to drive the foreign body further down. Forceps spaces, the spaces where the blades of the forceps may be safely placed, may be obliterated if granulations are present or if the surrounding mucosa is swollen. If granulations are present proximal to the foreign body, the bronchoscope may be pushed past the granulations, or the granulations may be dilated using an airway balloon carefully positioned proximal to the foreign body. Some clinicians prefer to remove the granulation tissue; if bleeding results making manipulation unsafe, topical epinephrine diluted 1:30,000 or topical oxymetazoline may be applied with a sponge carrier. When the foreign body is grasped, an effort is made to place the tips strategically. In grasping globular foreign bodies, the blades must pass beyond the equator of the object to avoid stripping off (Fig. 96.9A). Vegetable foreign bodies such as peanuts are grasped lightly to avoid fragmentation. Use of a peanut forceps with light, delicate blades facilitates such gentle handling. Once firmly within the forceps, the object is dislodged and gently withdrawn. The scope is then advanced to the foreign body, and the object anchored against the tube mouth to protect the grasp (Fig. 96.9B). The foreign body, scope, and forceps are then removed as a unit (Fig. 96.9C). Rarely, the foreign body will not pass through the subglottis and will require a tracheotomy for removal. In such cases, the foreign body may have originated in the esophagus and migrated through the party wall into the trachea. Such patients should undergo esophagoscopy to look for evidence of a fistula. Immediately following removal of the foreign body, the laryngoscope is reinserted and a second pass made with the bronchoscope. This procedure ensures that there is no retained foreign body in the airway, and allows for reassessment of airway patency in the region previously occupied by the object. Bleeding may be controlled with topical vasoactive agents, granulation tissue may be resected as necessary, and purulent secretions may be more effectively cleared. Postoperative use of antibiotics is indicated in patients with fever, and when evidence of pneumonia is present. Steroids are not usually necessary unless there has been significant trauma to the airway. In one study, their routine use was associated with a higher incidence of persistent pneumonia and atelectasis.25 In cases where granulation tissue causes significant narrowing of the airway, steroids may reduce the risk of permanent bronchial stenosis.

Special Situations Stripping Off Several factors may cause the foreign body to be stripped from the forceps’ grasp. Three of these are related to the forceps, including: (1) faulty application of forceps, (2) improper forceps for the problem, and (3) mechanically imperfect forceps (poorly adjusted or poorly constructed). Three additional

Ch96.indd 1620

A

B FIGURE 96-9. Optical foreign body forceps. The three common types illustrated in (A) are (top to bottom): alligator forceps, peanut forceps, and serrated cup forceps. (B) The forceps are assembled with an internal telescope. The light cord attaches opposite the operator’s grip to provide room for finger movement. A rubber stopper placed over the forceps seals the forceps within the bronchoscope.

factors are related to the foreign body, and include: (1) improper orientation of the object, (2) failure to anchor the foreign body against the tube mouth, and (3) a foreign body that is too large for the lumen. In the latter situation, it may

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1621

be necessary to fragment the foreign body, or to remove it through a tracheotomy. If a foreign body is stripped off in the larynx, the airway is reestablished immediately either by removing the object or by pushing it down into one bronchus (preferably the one in which it had been lodged). The faulty technique is corrected, and the object is relocated. A foreign body lost in the trachea will most probably enter the opposite bronchus. This occurs because a previously obstructed lung or lobe moves little air and the foreign body will be carried into the normal bronchus. If the foreign body cannot be located readily, it may be found next to the scope below the vocal folds or in the mouth, hypopharynx, or nasopharynx.

technique. As previously mentioned, flexible fiberoptic bronchoscopy may be used for this purpose, preferably via an indwelling open-tube bronchoscope or endotracheal tube. Fluoroscopic guidance is also useful in these cases79 In particular, the use of simultaneous biplane fluoroscopy in the angiography suite results in rapid and precise localization of the object. One must proceed cautiously, however, since the fluoroscope does not visualize the tissues that lie between the forceps blades and the foreign body. Bronchography, topical vasoconstrictors (oxymetazoline), and Fogarty catheter extraction have also been used successfully in managing inaccessible foreign bodies.80 A wire with a magnetic tip may be useful in extracting distal ferromagnetic foreign bodies.81

Pointed Objects The first priority in removing pointed objects from the airway is to locate the point, and then release and sheath it within the scope (Fig. 96.10A, B). This is accomplished by advancing the scope over the foreign body, rather than by pulling the foreign body into the tube. Double-pointed objects can be bent and converted to a single point for extraction; alternatively a wide (staple) forceps, scope, or both can be used to protect both points simultaneously during the extraction maneuver (Fig. 96.10C). The point is released, then sheathed by advancing the scope over it. The forceps, foreign body, and scope are removed as a unit. If the point cannot be sheathed, the foreign body may be withdrawn with the point trailing. Rotation forceps may be used to allow points to rotate and trail, thus avoiding perforation (Fig. 96.10D). Peripheral and Upper Lobe Foreign Bodies Peripheral and upper lobe foreign bodies are occasionally difficult to visualize and access by standard bronchoscopic

Unsuccessful Endoscopic Removal Employing the techniques described above, endoscopic extraction of foreign bodies is successful on the first attempt in the vast majority of cases. In cases involving significant granulation tissue and bleeding or multiple small fragments that migrate distally, a second procedure may be required to complete the extraction. Similarly, complicated foreign bodies such as grass heads and crab claws may not be expeditiously removed. If the foreign body cannot be removed within about 60 minutes, the procedure should be temporarily aborted. Inflammation of the airway is proportional to the time the bronchoscope is in the larynx, the trauma of the procedure, and the size of the bronchoscope in relation to the size of the child’s larynx. When stridor and dyspnea result from the endoscopy, treatment with humidity, high-dose intravenous steroids (dexamethasone, 1–1.5 mg/kg, up to a 30 mg bolus), racemic epinephrine, and elevation of the head is usually

FIGURE 96-10. Techniques for endoscopic removal of sharp and penetrating foreign bodies: (A) Long axis traction is particularly important for pointed objects with large heads. The point may be easily located (1), but the greater hazard lies in the risk of tearing the bronchial wall with the head of the tack (2). Positioning the patient’s head toward the opposite side straightens the axis of the airway, permitting relatively safe, slow, steady withdrawal of the object (3). (B) An inward rotation method is used for pins or needles with an embedded point. Side-grasping forceps capture the pin near its point. A corkscrew motion is used to push the pin distally whiled rotating it clockwise, feeing the point and aligning it with the long axis of the forceps (1). The scope is advanced over the point to sheathe it (2) for extraction (3). (C) Double-pointed objects can be converted to a single point, then sheathed for extraction. (D) Demonstration of rotation forceps. In (1), typical forward grasping forceps fix the foreign body, increasing the likelihood of laceration. When the rotation forceps is used (2), its two pointed and opposing blades allow the foregn body to rotate (3), so hazardous parts trail harmlessly during extraction (4). (From Holinger LD, Lusk RP, Green CG. Pediatric Laryngology and Bronchoesophagology. Philadelphia, PA: Lippincott, Williams & Wilkins, 1997, p.248.)

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effective within 24 hours. Repeat bronchoscopy may be attempted once residual laryngeal symptoms have resolved. Should a second attempt at extraction fail, thoracotomy with bronchotomy or segmental lobectomy may be necessary.

COMPLICATIONS Complications associated with airway foreign bodies have been defined by Inglis and Wagner10 as conditions or actions before or during bronchoscopy leading to ongoing postoperative morbidity. Of 119 patients treated by these authors between 1984 and 1989, minor complications, such as postoperative atelectasis, wheezing, and stridor from subglottic trauma, were present in 12%. Major complications, defined as those requiring more than one week of hospitalization postoperatively or those requiring open surgery, were present in 3%. This overall complication rate of 15% represented a significant improvement over that of 44% identified in a similar group of patients 20 years earlier. The authors attributed this change to the development of the rod-lens optical system, which led to a reduction in missed or incompletely removed foreign bodies. In addition, the authors identified an increased risk of complications with increasing duration of the foreign body in situ. Complication rates in other recent reports range from 0% to 25%.27,49,50 Laryngeal edema and traumatic laryngitis are common sequelae of airway foreign bodies and their removal. Stridor resulting from foreign body extraction may be treated with steroids and racemic epinephrine as previously described. Persistent pneumonia and atelectasis are most common following removal of long-standing tracheobronchial foreign bodies. In one series, 20.2% of patients with tracheobronchial foreign bodies had preoperative chest X-rays consistent with inflammation; these individuals demonstrated a mean pulmonary recovery time of 3.8 days.82 Intravenous antibiotics, bronchodilators, and chest physical therapy may be useful for several days postoperatively in such cases. Bronchospasm and postobstructive pulmonary edema, which occur less frequently, may also require aggressive medical management. Further surgical intervention may be required in cases of persistent granulation tissue, laryngotracheal or bronchial stenosis, bronchial hemorrhage, pneumothorax, pneumomediastinum, bronchial fistula, and lung abscess. Fatal complications of airway foreign bodies include complete obstruction of the airway and cardiac arrest induced by prolonged hypoxia. Fortunately, these are exceedingly rare.

Otolaryngology, and individual providers of pediatric medical services is essential if such accidents are to be reduced in frequency. Well-child visits are an ideal opportunity to advise parents and caretakers to avoid feeding nuts, popcorn, seeds, and spherical candies to children under 4 or 5 years of age. Hot dogs and grapes should be cut into tiny pieces before being fed to young children. Children should also be supervised during playtime, since they may obtain dangerous objects from a sibling or from a location in the home which has not been childproofed. Balloons are a significant airway risk in children of all ages. Federal regulations enacted over the last 25 years have been directed at controlling the size and shape of objects intended for use by children. In 1979, the Consumer Product Safety Commission (CPSC) established the minimum size criteria for manufacture of new toys used by children under age 3 [16 CFR Section 1500 18(a)(9)]. Based on modeling of the pediatric airway and historical data, these dimensions were established at 31.7 mm in diameter and 25.4–57.1 mm in length.83 These measurements were used to create the Small Parts Test Fixture (SPTF), a truncated plastic cylinder into which the product or any of its detachable parts must not fit (Fig. 96.11).83 In a series

PREVENTION Avoidance of objects which are easily aspirated or readily lodge in the pediatric airway is the ultimate prevention against all foreign body accidents. However, it is impractical to assume that even the most vigilant parents and caretakers can make all such objects inaccessible to children. Continuing education through child advocates such as the American Academy of Pediatrics, the American Society of Pediatric

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FIGURE 96-11. Small Parts Test Fixture. (Courtesy of James Reilly, MD.)

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CHAPTER 96 ❖ Foreign Bodies of the Larynx, Trachea, and Bronchi of 534 aerodigestive tract foreign body events accumulated by Reilly et al.84 over the two year period 1988–1989, 99% of the involved objects failed the small parts test and just 6% were toys or toy parts, supporting the continued use of the test device. However, 37% of the events in this study, and 31% in another recent series by Rimell et al.13 occurred in children over the age of 3, suggesting the age group considered at risk should be expanded. The latter study also included computer analysis of 101 objects causing asphyxiation, of which 5 had diameters larger than the SPTF and 9 had dimensions longer than the SPTF. All five with passing diameters and one with a passing length were toys with at least one spherical part. In addition, a CPSC review of choking events occurring between 1973 and 1983 identified 195 choking events in children aged 3 months to 4 years due to items which would have passed the small parts test.83 Of these, 37 (19%) died as a result of the event. Spherical objects were recovered in 66%. A 2008 study, reviewing data from 48 children’s hospitals from 1989 to 2004, demonstrated that 23% of fatalities from choking events passed the small parts test, and that many objects involved in both fatal and nonfatal injuries passed because of the slanted bottom.85 Based on these data and the sizes of the offending objects, it has been recommended that two test gauges be developed, one measuring 44.5 mm in diameter for spherical objects and one measuring 36.8 mm for nonspherical foreign bodies, both incorporating an open bottom design.13,85,86

References 1. Killian G. Direct endoscopy of the upper air-passages and oesophagus; its diagnostic and therapeutic value in the search for and removal of foreign bodies. J Laryngol Rhinol Otol. 1902;17:461. 2. National Safety Council. Accident Facts. Chicago, IL: 1968. 3. National Safety Council. Injury Facts. Itasca, IL: 2011. 4. Clerf LH. Historical aspects of foreign bodies in the air and food passages. South Med J. 1975;68:449–454. 5. Weist JR. Foreign bodies in the air passages. Trans Am Surg Assoc. 1890;12:10. 6. Jackson C. Foreign bodies in the trachea, bronchi and oesophagus - the aid of oesophagoscopy, bronchoscopy, and magnetism in their extraction. Laryngoscope. 1905;15:257. 7. Jackson C, Jackson CL. Diseases of the Air and Food Passage of Foreign Body Origin. Philadelphia, PA: WB Saunders Co.; 1936. 8. Marsh BR. Historic development of bronchoesophagology. Otolaryngol Head Neck Surg. 1996;114:689–716. 9. Hopkins HH. Endoscopy. New York, NY: Appleton Century Crofts; 1976:17. 10. Inglis AF, Wagner DV. Lower complication rates associated with bronchial foreign bodies over the last 20 years. Ann Otol Rhinol Laryngol. 1992;101:61–66. 11. Clerf LH. Historical notes on foreign bodies in the air passages. Am Med Hist. 1936;8:547. 12. Lifschultz BD, Donoghue ER. Deaths due to foreign body aspiration in children: the continuing hazard of toy balloons. J Forensic Sci. 1996;41:247–251. 13. Rimell FL, Thome A Jr, Stool S, et al. Characteristics of objects that cause choking in children. JAMA. 1995;274: 1763–1766.

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14. Ryan CA, Yacoub W, Paton T, Avard D. Childhood deaths from toy balloons. Am J Dis Child. 1990;144:1221–1224. 15. Altkorn R, Chen X, Milkovich S, et al. Fatal and non-fatal food injuries among children (aged 0–14 years). Int J Pediatr Otorhinolaryngol. 2008;72:1041–1046. 16. Heimlich HJ. A life-saving maneuver to prevent food choking. JAMA. 1975;234:398–401. 17. Andazola JJ, Sapien RE. The choking child: what happens before the ambulance arrives? Prehosp Emerg Care. 1999;3:7. 18. American Heart Association in collaboration with International Liaison Committee on Resuscitation. Guidelines 2005 for cardiopulmonary resuscitation and emergency cardiovascular care: international consensus on science, part 11: pediatric basic life support. Circulation. 2005;112 [Suppl I]: IV-156-IV-166. 19. Black RE, Choi KJ, Syme WC, Johnson DG, Matlak ME. Bronchoscopic removal of aspirated foreign bodies in children. Am J Surg. 1984;148:778–781. 20. Black RE, Johnson DG, Matlak ME. Bronchoscopic removal of aspirated foreign bodies in children. J Pediatr Surg. 1994;29:682–684. 21. Hughes CA, Baroody FM, Marsh BR. Pediatric tracheobronchial foreign bodies: historical review from the Johns Hopkins Hospital. Ann Otol Rhinol Laryngol. 1996;105:555–561. 22. Lemberg PS, Darrow DH, Holinger LD. Aerodigestive tract foreign bodies in the older child and adolescent. Ann Otol Rhinol Laryngol. 1996;105:267–271. 23. Linegar AG, Von Oppell UO, Hegemann S, de Groot M, Odell JA. Tracheobronchial foreign bodies: experience at Red Cross Children’s Hospital, 1985–1990. S Afr Med J. 1992;82: 164–167. 24. Mantel K, Butenandt I. Tracheobronchial foreign body aspiration in childhood: a report on 224 cases. Eur J Pediatr. 1986;145:211–216. 25. McGuirt WF, Holmes KD, Feehs R, Browne JD. Tracheobronchial foreign bodies. Laryngoscope. 1988;98:615–618. 26. Mu L, He P, Sun D. Inhalation of foreign bodies in Chinese children: a review of 400 cases. Laryngoscope. 1991;101: 657–660. 27. Oguz F, Citak A, Unuvar E, Sidal M. Airway foreign bodies in childhood. Int J Pediatr Otorhinolaryngol. 2000;52:11–16. 28. Ortega M, Sifontes JE, Rosa O, Mayol PM, Rivera R. Foreign body aspiration in Puerto Rican children: report of 83 cases. Bol Asoc Med P R. 1986;78:282–286. 29. Pasaoglu I, Dogan R, Demircin M, Hatipoğlu A, Bozer AY. Bronchoscopic removal of foreign bodies in children: retrospective analysis of 822 cases. Thorac Cardiovasc Surg. 1991;39:95–98. 30. Puhakka H, Svedstrom E, Kero P, Valli P, Iisalo E. Tracheobronchial foreign bodies: a persistent problem in pediatric patients. Am J Dis Child. 1989;143:543–546. 31. Steen KH, Zimmermann T. Tracheobronchial aspiration of foreign bodies in children: a study of 94 cases. Laryngoscope. 1990;100:525–530. 32. Svensson G. Foreign bodies in the tracheobronchial tree: special references to experience in 97 children. Int J Pediatr Otorhinolaryngol. 1985;8:243–251. 33. Wiseman NE. The diagnosis of foreign body aspiration in childhood. J Pediatr Surg. 1984;19:531–535. 34. Morley RE, Ludemann JP, Moxham JP, Kozak FK, Riding KH. Foreign body aspiration in infants and toddlers: recent trends in British Columbia. J Otolaryngol. 2004;33:37–41.

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35. Foods and Choking in Children, A Report to the U.S. Food and Drug Administration and the U.S. Department of Agriculture by the Committee on Nutrition, American Academy of Pediatrics, December 1993. 36. DeRowe A, Massick D, Beste DJ. Clinical characteristic of aero-digestive foreign bodies in neurologically impaired children. Int J Pediatr Otorhinolaryngol. 2002;62:243–248. 37. Hsu W, Sheen Ts, Lin C, Tan C, Yeh T, Lee S. Clinical experiences of removing foreign bodies in the airway and esophagus with a rigid bronchoscope: a series of 3217 cases from 1970 to 1996. Otolaryngol Head Neck Surg. 2000;122:450–454. 38. Pyman C. Radiolucent foreign bodies. Aust Paediatr J. 1972;8:166. 39. Bloom DC, Christenson TE, Manning SC, et al. Plastic laryngeal foreign bodies in children: a diagnostic challenge. Int J Pediatr Otorhinolaryngol. 2005;69:657–662. 40. Garcia-Iriarte MT, Munoz M, O’Connor C, et al. Small parts of ballpoint pens: choking hazard in children. Pediatrics. 1998;102:160. 41. Bhana BD, Gunaselvam JG, Dada MA. Mechanical airway obstruction caused by accidental aspiration of part of a ball point pen. Am J Forensic Med Pathol. 2000;21:362–365. 42. Banerjee A, Subba Rao KSVK, Khanna SK, et al. Laryngotracheo-bronchial foreign bodies in children. J Laryngol Otol. 1988;102:1029–1032. 43. Halvorson DJ, Merritt RM, Mann C, Porubsky ES. Management of subglottic foreign bodies. Ann Otol Rhinol Laryngol. 1996; 105:541–544. 44. Mantor PC, Tuggle DW, Tunell WP. An appropriate negative bronchoscopy rate in suspected foreign body aspiration. Am J Surg. 1989;158:622–624. 45. Vane DW, Pritchard J, Colville CW, West KW, Eigen H, Grosfeld JL. Bronchoscopy for aspirated foreign bodies in children: experience in 131 cases. Arch Surg. 1988;123: 885–888. 46. Losek JD. Diagnostic difficulties of foreign body aspiration in childhood. Am J Emerg Med. 1990;8:348–350. 47. Lowe D, Russell RI. Tracheobronchial foreign bodies-the position of the carina. J Laryngol Otol. 1984;98:499–501. 48. Even L, Heno N, Talmon Y, Samet E, Zonis Z, Kugelman AC. Diagnostic evaluation of foreign body aspiration in children: a prospective study. J Pediatr Surg. 2005;40:1122–1127. 49. Baharloo F, Veyckemans F, Francis C, Biettlot MP, Rodenstein DO. Tracheobronchial foreign bodies: presentation and management in children and adults. Chest. 1999;115:1357–1362. 50. Metrangelo S, Monetti C, Meneghini L, Zadra N, Giusti F. Eight years’ experience with foreign body aspiration in children: what is really important for a timely diagnosis? J Pediatr Surg. 1999;34:1229–1231. 51. Barrios-Fontoba JE, Gutierrez C, Lluna J, Vila JJ, Poquet J, Ruiz-Company S. Bronchial foreign body: should bronchoscopy be performed in all patients with a choking crisis? Pediatr Surg Int. 1997;12:118–120. 52. McCrae T. Lumleian lectures on the clinical features of foreign bodies in the bronchi. Lancet. 1924;(5250):735, (5251):787, (5252):838. 53. Tomaske M, Gerber AC, Stocker S, Weiss M. Tracheobronchial foreign body aspiration in children – diagnostic value of symptoms and signs. Swiss Med Wkly. 2006;136:533–538. 54. Parsons DS, Kearns D. The two-headed stethoscope: its use for ruling out airway foreign bodies. Int J Pediatr Otorhinolaryngol. 1991;22:181.

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55. Tan HK, Brown K, McGill T, Kenna MA, Lund DP, Healy GB. Airway foreign bodies (FB): a 10-year review. Int J Pediatr Otorhinolaryngol. 2000;56:91–99. 56. Choi SJ, Choi BK, Kim HJ, et al. Lateral decubitus HRCT: a simple technique to replace expiratory CT in children with air trapping. Pediatr Radiol. 2002;32:179–182. 57. Hong SJ, Goo HW, Rob JL. Utility of spiral and cine CT scans in pediatric patients suspected of aspirating radiolucent foreign bodies. Otolaryngol Head Neck Surg. 2008;138:576–580. 58. Huang HJ, Fang HY, Chen HC, Wu CY, Cheng CY, Chang CL. Three-dimensional computed tomography for detection of tracheobronchial foreign body aspiration in children. Pediatr Surg Int. 2008;24:157–160. 59. Applegate KE, Dardinger JT, Lieber, ML, et al. Spiral CT scanning technique in the detection of aspiration of LEGO foreign bodies. Pediatr Radiol. 2001;31:836–840. 60. Cevizci N, Dokucu AI, Baskin D, et al. Virtual bronchoscopy as a dynamic modality in the diagnosis and treatment of suspected foreign body aspiration. Eur J Pediatr Surg. 2008;18:398–401. 61. Jones CM, Athanasiou T. Is virtual bronchoscopy an efficient diagnostic tool for the thoracic surgeon? Ann Thorac Surg. 2005;79:365–374. 62. Kocaoglu M, Bulakbasi N, Soylu K, Demirbag S, Tayfun C, Somuncu I. Thin-section axial multidetector computed tomography and multiplanar reformatted imaging of children with suspected foreign-body aspiration: is virtual bronchoscopy overemphasized? Acta Radiol. 2006;47:746–751. 63. Karnwal A, Ho EC, Hall A, Molony N. Lateral soft tissue neck X-rays: are they useful in management of upper aero-digestive tract foreign bodies? J Laryngol Otol. 2007;122:845–847. 64. Silva AB, Muntz HR, Clary R. Utility of conventional radiography in the diagnosis and management of pediatric airway foreign bodies. Ann Otol Rhinol Laryngol. 1998;107: 834–838. 65. Esclamado RM, Richardson MA. Laryngotracheal foreign bodies in children: a comparison with bronchial foreign bodies. Am J Dis Child. 1987;141:259–262. 66. Mu L, Sun D, He P. Radiological diagnosis of aspirated foreign bodies in children: review of 343 cases. J Laryngol Otol. 1990;104:778–782. 67. Zerella JT, Dimler M, McGill LC, Pippus KJ. Foreign body aspiration in children: value of radiography and complications of bronchoscopy. J Pediatr Surg. 1998;33:1651–1654. 68. White DR, Zdanski CJ, Drake AF. Comparison of pediatric airway foreign bodies over fifty years. South Med J. 2004;97: 434–436. 69. Svedstrom E, Puhakka H, Kero P. How accurate is chest radiography in the diagnosis of tracheobronchial foreign bodies in children? Pediatr Radiol. 1989;19:520–522. 70. Assefa D, Amin N, Stringel G, Dozor AJ. Use of decubitus radiographs in the diagnosis of foreign body aspiration in young children. Pediatr Emerg Care. 2007;23:154–157. 71. Burrington JD, Cotton EK. Removal of foreign bodies from the tracheobronchial tree. J Pediatr Surg. 1972;7:119–122. 72. Ritter FN. Questionable methods of foreign body treatment. Ann Otol. 1974;83:729. 73. Cotton EK, Abrams G, Vanhoutte J, Burrington J. Removal of aspirated foreign bodies by inhalation and postural drainage: a survey of 24 cases. Clin Pediatr. 1973;12:270–276. 74. Campbell DN, Cotton EK, Lilly JR. A dual approach to tracheobronchial foreign bodies in children. Surgery. 1982;91: 178–182.

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CHAPTER 96 ❖ Foreign Bodies of the Larynx, Trachea, and Bronchi 75. Deutsch ES, Dixit D, Curry J, et al. Management of aerodigestive tract foreign bodies: innovative teaching concepts. Ann Otol Rhinol Laryngol. 2007;166:319–323. 76. Holinger LD. Foreign bodies of the larynx, trachea, and bronchi. In: Bluestone CD, Stool SE, eds. Pediatric Otolaryngology. 2nd ed. Philadelphia, PA: WB Saunders Co.; 1990:1210. 77. Kosloske AM. Tracheobronchial foreign bodies in children: back to the bronchoscope and a balloon. Pediatrics. 1980;66:321–323. 78. Soodan A, Pawar D, Subramanium R. Anesthesia for removal of inhaled foreign bodies in children. Paediatr Anaesth. 2004;14:947–952. 79. Yuksel M, Ozyurtkan MO, Lacin T, Yildizeli B, Batirel HF. The role of fluoroscopy in the removal of tracheobronchial pin aspiration. Int J Clin Pract. 2006;60:1451–1453. 80. Hight DW, Philippart AI, Hertzler JH. The treatment of retained peripheral foreign bodies in the pediatric airway. J Pediatr Surg. 1981;16:694–699.

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81. Mayr J, Dittrich S, Triebl K. A new method for removal of metallic-ferromagnetic foreign bodies from the tracheobronchial tree. Pediatr Surg Int. 1997;12:461–462. 82. Roh JL, Hong SJ. Lung recovery after rigid bronchoscopic removal of tracheobronchial foreign bodies in children. Int J Pediatr Otorhinolaryngol. 2008;72:635–641. 83. Reilly JS. Prevention of aspiration in infants and young children: federal regulations. Ann Otol Rhinol Laryngol. 1990;99:273–276. 84. Reilly JS, Walter MA, Beste D, et al. Size/shape analysis of aerodigestive foreign bodies in children: a multi-institutional study. Am J Otolaryngol. 1995;16:190–193. 85. Milkovich SM, Altkorn R, Chen X, et al. Development of the small parts cylinder: lessons learned. Laryngoscope. 2008;118:2082–2086. 86. Reilly JS, Cook SP, Stool D, Rider G. Prevention and management of aerodigestive foreign body injuries in childhood. Pediatr Clin North Am. 1996;43:1403–1411.

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97

C H A P T E R

Diagnosis and Management of Pediatric Laryngotracheal Trauma Robert J. Tibesar, Susan E. Pearson, Frank L. Rimell, and James D. Sidman

B

lunt and penetrating laryngotracheal trauma is rare in adults and even more unusual in children. The reported incidence is between 0.00003% and 0.0001% of all pediatric emergency room trauma patients and 0.5% of admitted pediatric trauma patients.1,2 Although it is rare, when it does occur, it frequently results in significant morbidity or in mortality. This is due to the fact that minor direct trauma to the larynx or trachea, in the pediatric population, usually results in serious injury.3 Pediatric laryngotracheal injuries are different from the commonly observed adult injuries. This is because of the unique anatomic features of the pediatric larynx. Some protective features of the pediatric larynx include relatively soft, pliable cartilages and a high position of the larynx in the neck, shielded by the mandible (Fig. 97-1).4 These differences result in fewer laryngeal injuries, especially fractures. The unfavorable characteristics of the pediatric larynx include its size and shape and the immaturity of the membranes. The pediatric larynx has a decreased cross-sectional area compared to the adult larynx.3 It is funnel-shaped and is narrowest at the subglottic region. The epiglottis is narrower and has an omega-like shape, and there is a posterior tilt to the cricoid. These differences bring the aryepiglottic folds closer to the midline and result in a narrowed laryngeal inlet. The intercartilaginous fibers and membranes are weaker and thus more susceptible to rupture in the pediatric population. The mucosa is loosely attached to the cartilage and there is extensive elasticity of the cartilaginous framework. Injury to the pediatric larynx tends to result in increased soft-tissue damage and less cartilaginous fractures and disruption.5

FIGURE 97-1. Differences in upper airway anatomy between the adult and the child. E, epiglottis; H, hyoid; T, thyroid cartilage; C, cricoid cartilage.

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Because of these differences, similar injuries have more severe consequences in children.

TYPES OF INJURIES Laryngeal trauma is classified as either blunt or penetrating. Blunt injuries are more common than penetrating injuries. Bicycle accidents account for the majority of the blunt injuries in children, whereas penetrating injuries are caused by gunshot wounds, knife or scissor stab wounds, or falls onto sharp objects. Although the use of seat belts and air bags has resulted in lower fatality rates associated with motor vehicle accidents, there is a growing amount of literature on injuries caused by seat belt restraint or air bag deployment. Most automobile passengers sustain minor injuries, but there are reported adult and child fatalities.6

Blunt Injuries Blunt laryngotracheal trauma in a child is typically sustained while the child is riding a bicycle or a motorbike. Falling onto the handlebars with the neck extended causes compression of the larynx and trachea against the cervical vertebral column.1 Injuries resulting from riding a motorbike or an all-terrain vehicle into a clothesline have also occurred. The force of such a blow is imparted on the laryngotracheal complex. An extensive variety of injuries can result, including hyoid fractures (Fig. 97-2), vocal cord avulsion or paralysis, laryngeal fractures, arytenoid cartilage dislocation, thyroepiglottic ligament disruption, posterior tracheal lacerations, mucosal edema, submucosal hematoma, tracheobronchial ruptures, and laryngotracheal separation.1 Other mechanisms of injury include child abuse, suicide attempts by hanging, and athletic injuries.7 Children of all ages are involved in blunt laryngotracheal injuries, with a mean age of approximately 10 years, and boys are affected more frequently than girls are.1 Presenting complaints may be quite minimal with blunt airway injuries. Frequent symptoms include neck pain and some degree of respiratory distress. Children may also present with odynophagia, dysphagia, voice change, hemoptysis, cervical or mediastinal subcutaneous emphysema, and ecchymosis.4 Laryngotracheal separations and tracheobronchial ruptures are uncommon, but are more common in children than in adults. Mortality rates of up to 30% have been reported. Half of the children who die do so within one hour of the trauma event.8 The elasticity of the chest wall in children allows massive external forces directly onto the mediastinum

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FIGURE 97-2. Computed tomographic scan of a hyoid fracture.

without disruption of the integrity of the chest wall. Rib fractures, present in approximately 90% of adults with tracheobronchial injury, are present in only approximately 24% of children with similar injuries.8 Thus, absence of rib fractures does not rule out major intrathoracic injuries in children. The pathogenesis of tracheobronchial rupture is a rapidly increased intrabronchial pressure caused by compression of the chest against a closed glottis.9 Air dissects through the rupture and into the retropharynx and mediastinum.10 Other explanations include shear forces, traction, and crush of the airway between the chest and the vertebrae.9 Successful management of airway disruptions is based on prompt recognition of airway compromise along with rapid treatment to maintain effective ventilation. Traumatic pneumothorax or pneumomediastinum is usually present. Continued air leak despite decompression of the pneumothorax with a chest tube is the key to suspecting possible tracheobronchial disruption.8 The location of tracheobronchial injuries has been found to be relatively consistent: 80% involve the main stem bronchi, 15% involve the trachea, and 5% involve the distal bronchi.11,12 Blunt trauma to the laryngotracheal complex may also result in tears of the esophagus. Hypopharyngeal and esophageal tears can occur without disruption of the laryngeal skeleton. The greater cornu of the thyroid cartilage can lacerate the pharyngeal mucosa.13 The morbidity and mortality associated with blunt neck injuries are most often related to a delay in diagnosis. A possible reason for the delay in diagnosis of laryngotracheal injury is the fact that the relatively stiff cervical fascia and tracheal cartilage may initially preserve the airway continuity until soft-tissue swelling or hematoma formation leads to signs and symptoms of airway compromise.14 The astute clinician must be aware of the possibility that the patient with blunt laryngeal injury may initially be quite stable but could rapidly deteriorate as soft-tissue injury and edema worsens.

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FIGURE 97-3. Twelve-year-old male suffered penetrating neck and laryngotracheal trauma from a timber cutting accident. Immediate surgical exploration and foreign body removal revealed injury to posterior tracheal wall and esophagus.

Penetrating Injuries Penetrating laryngotracheal injuries in children are even less common than blunt injuries; however, these injuries are associated with significant morbidity and mortality rates. Boys are injured more frequently than girls are, and the children tend to be older than those affected by blunt trauma injury, with a mean age of 12 years15 (Fig. 97-3). The mechanisms of injury include gunshot wounds, knife or scissors stab wounds, and glass injuries.15,16 Predominant clinical findings on presentation include air bubbling through the wound, subcutaneous crepitus, respiratory distress or stridor, shock or hemorrhage, neurologic signs, hemoptysis, hematemesis, dysphonia or hoarseness, and expanding hematoma. Unlike blunt laryngotracheal trauma, associated chest, digestive tract, and vascular injuries are common.17 Approximately 10% of these patients must have emergency surgery secondary to instability.18 Typical indications for emergency surgery include bleeding, open airway, and expanding hematoma. Airway compromise and exsanguination from major vascular injury are the major factors contributing to early mortality in patients with penetrating neck injuries. Late mortality is generally secondary to undiagnosed esophageal injuries. Esophageal injuries are rare but are the most commonly missed associated injury.19 There is an associated digestive tract injury in 15%–50% of these patients. Esophageal injuries have significant associated morbidity and a mortality rate reaching 19.5%.20 Associated esophageal injuries are difficult to diagnose because they may be 3–4 cm away from the tracheal injury. This is because of the extensive esophageal mobility.21 Odynophagia, hematemesis, and subcutaneous emphysema are the most common findings of esophageal injury.

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CHAPTER 97 ❖ Diagnosis and Management of Pediatric Laryngotracheal Trauma 1629

HISTORY AND PHYSICAL EXAMINATION Any child sustaining anterior cervical injury should be examined for the presence of laryngotracheal injury. Symptoms of injury include increasing airway obstruction with stridor or dyspnea, cough, dysphonia or aphonia, dysphagia or odynophagia, hemoptysis or hematemesis, and neck pain.22 A thorough and careful history should be obtained and an accurate physical examination performed, including determining the mechanism of injury. The patient should be quickly but meticulously examined for respiratory difficulty, stridor, loss or change in voice, and swallowing abnormalities. The child’s voice may initially be muffled, hoarse, or aphonic or may be normal and deteriorate gradually. Neurologic deficits, especially cervical spine

injuries, should be ruled out. The neck should be inspected for palpable laryngeal cartilage fractures, obliteration of external laryngeal anatomic landmarks, tenderness, crepitus, hematoma formation, and swelling. Once it is determined that laryngotracheal injury is suspected based on history and physical examination, a sequential algorithm is recommended in the evaluation and management of such patients (Fig. 97-4).

DIAGNOSTIC TESTS Several diagnostic tests contribute to the diagnosis of these injuries. It must be underscored that if respiratory distress symptoms are progressive, securing a safe airway is the first priority, followed by an orderly evaluation.

History and physical exam suspicious for Laryngotracheal trauma Airway stable

Airway unstable

Direct laryngoscopy, rigid bronchoscopy, tracheotomy in OR

Flexible exam

Abnormal, but airway still stable

Normal

CT scan, delineate extent of laryngotracheal injury

Inpatient observation & monitoring

CT scan normal

CT scan shows fractures

Serial flexible exams

Definitive operative exploration, repair mucosal damage, reduce and fixate cartilage fractures

Discharge when stable, continue long-term follow up

FIGURE 97-4. Flow chart demonstrating sequential diagnostic evaluation and management of pediatric laryngotracheal trauma. (Adapted in part from Schaeffer.39)

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The definitive diagnostic step for discerning the extent of the injury and determining the necessity for open exploration and repair is endoscopy.23,24 In experienced hands, flexible laryngoscopy is a very valuable tool for evaluating laryngeal anatomy and function. A 2- to 3-mm pediatric flexible scope can easily identify vocal cord mobility, mucosal tears, hematoma, or arytenoid dislocations without endangering the cervical spine. One must remember, however, that in an already traumatized larynx, irreversible laryngospasms may occur if the scope is advanced too close to the larynx. Direct laryngoscopy may be needed to further evaluate the larynx but requires a general anesthetic and may exacerbate mucosal tears or miss a dislocated epiglottis.25 The patient with dyspnea, hemoptysis, subcutaneous emphysema, or a pneumothorax refractory to the insertion of chest tubes needs an immediate bronchoscopy, with possible control of the distal airway if a tracheobronchial separation is found.26,27 In children, who have smaller airways, fiberoptic bronchoscopy has been invaluable in the diagnosis of tracheal and bronchial injuries. A fiberoptic bronchoscope may be inserted through the endotracheal tube and is helpful in aspirating material, mucous plugs, and thick secretions.28 Fiberoptic bronchoscopy also allows the selective stenting of the transected or lacerated trachea or selective intubation of the right or left main stem bronchus, allowing controlled ventilation prior to an immediate thoracotomy by a thoracic surgeon.24 Minor airway lesions may be overlooked unless the endoscopy is completed by an examination with increased intratracheal pressure, thus stenting open the airway. This additional maneuver is recommended whenever a tracheal wall lesion is suspected but is not seen by endoscopy.29 Bronchoscopy is the most reliable means of establishing the diagnosis and determining the site, nature, and extent of tracheobronchial injury.11 Esophagoscopy is the procedure of choice in the evaluation of a possible concomitant esophageal injury. The presence of a hematoma or blood usually suggests an underlying injury, and visualization of the perforation confirms the diagnosis. When the procedure is performed under general anesthesia with positive-pressure breathing, bubbles often form in the field, making it easier to detect small perforations. Although a negative esophagoscopic finding does not definitively rule out a perforation, the addition of an esophagram improves the yield.17 The initial radiologic examination may include the lateral soft-tissue radiograph of the neck, cervical spine series, and a chest radiograph. It is best to obtain portable films in the emergency department. These are low cost, straightforward, rapidly obtainable, and highly useful diagnostic procedures that have long been regarded as standard of airway examination.30 They may provide valuable information about fractured or displaced laryngeal cartilages, soft-tissue swelling or emphysema, pneumothorax or pneumomediastinum, and cervical spine injuries. Unfortunately, the cartilage of the

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airway in children is not ossified, and thus, these studies may provide an inadequate evaluation of cartilaginous damage. Computed tomography (CT) adds a three-dimensional component to the understanding of the laryngeal and tracheal anatomy. Only hemodynamically stable patients without airway compromise should undergo CT evaluation. In the acute setting, at most institutions, CT of the neck is used to evaluate for possible bony and cartilaginous fractures and soft-tissue injuries (Fig. 97-5). This is especially needed when laryngoscopic examination is difficult. Indications for CT usually include neck trauma with signs and symptoms of cervical and laryngeal injury or a mechanism of trauma known to cause such injuries.31 Helical CT represents a recent major improvement in the evaluation of trauma patients. Scanning time through the neck is substantially reduced, because data are continuously collected. Short scan times, in turn, reduce the likelihood of motion artifacts and result in the higher quality of reformatted images.32 Often, three-dimensional CT provides significant additional information for patients with suspected laryngotracheal injury. It can confirm subtle injuries suggested on two-dimensional CT and may reveal additional unsuspected pathologic lesions. Thus, it tends to increase diagnostic accuracy and may be helpful in preoperative planning.33 The results obtained by spiral CT with colorcoded three-dimensional reconstruction have recently been compared to those obtained with magnetic resonance angiography and are as informative yet less costly, with a shorter examination period.34 Magnetic resonance imaging (MRI) studies of children with laryngotracheal trauma are generally not performed in the acute setting because of the sensitivity of MRI to motion and the longer examination time. Yet, in the evaluation of subacute or chronic laryngotracheal injuries, MRI is capable of better soft-tissue contrast than CT and can offer coronal and sagittal views.35 A gastrografin swallow study may need to be performed to rule out an esophageal tear. The sensitivity of a swallow study alone is reportedly between 50% and 90%.24,36 Water-soluble contrast agents should be used to help prevent barium sulfate–induced mediastinitis. The use of fluoroscopy with multiple views in addition to the standard anteroposterior and lateral projections increase the yield of esophagography.17

TREATMENT The literature is limited in reports of the management of pediatric laryngotracheal trauma, although it generally parallels adult management. Immediate airway management followed by timely diagnosis of associated injuries is essential for the effective treatment and the avoidance of complications. The goal of the treatment should be the restoration of a normal airway and voice.3,37 Management of laryngeal trauma is based on the degree of injury suspected during the initial assessment.

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CHAPTER 97 ❖ Diagnosis and Management of Pediatric Laryngotracheal Trauma 1631

FIGURE 97-5. Computed tomographic scan of varying degrees of laryngeal fractures, from nondisplaced to severely comminuted (A–C). Note the subcutaneous air in each of the fractures, regardless of the severity.

Management of the Airway Securing the airway is the most important first step in the management of victims of penetrating or blunt laryngotracheal trauma, yet there is controversy regarding the best method. Some authors avoid intubation because of concern about further iatrogenic injury by converting a small tear or partial transection into a complete transection. Furthermore, endotracheal intubation may interfere with subsequent evaluation of the larynx and the trachea. They cite possible neck manipulation during intubation with exacerbation of a cervical spine injury and the danger of persistent airway edema and suggest a tracheotomy.38,39 Also, the failure to establish an airway would mean that an urgent airway could become an emergent airway and necessitate immediate tracheotomy performed under less than ideal conditions. In the adult population, it is generally accepted that the safest method of securing the airway is with the tracheotomy performed under local anesthesia with the patient fully awake. However, this option requires a high degree of self-control and cooperation by the patient and is not feasible in the pediatric population. Additionally, due to the limited pulmonary reserve, time is of the essence when securing the airway in children. If possible, children should have their airways secured in an operating room after induction with inhalation general anesthesia. The

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first step is rigid bronchoscopy with cannulation of the airway under direct visualization. The tracheotomy is then performed over the rigid bronchoscope.5,40 In contrast, other authors recommend endotracheal intubation by a skilled physician, preferably over a flexible bronchoscope, especially in infants and small children.14,41 In this patient population, with a smaller and less defined airway, there is an increased rate of tracheotomy complications. Other disadvantages of tracheotomy include possible further damage to the posterior tracheal wall by the rigid nature of most tracheotomy tubes.10 If endotracheal intubation is attempted, one should always be prepared to perform an emergency tracheotomy if the airway becomes compromised.

Management of Laryngeal Injuries Endoscopic examination of the larynx should be performed to look for exposed or fractured cartilage, injury to vocal cords, or other signs of damage to the larynx. This will help determine if surgical versus nonsurgical management is indicated. Children with isolated laryngeal injury, such as minor mucosal lacerations with no exposed cartilage, or nondisplaced thyroid cartilage fractures, can be managed conservatively, provided they are closely monitored until the soft-tissue edema resolves. Medical management, including

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humidification of the inspired air, elevation of the head of the bed, broad-spectrum antibiotics, H2 blockers, and intravenous steroids, is most effective during the acute phase.42 A patient with laryngeal trauma that is managed conservatively should be reevaluated in 7–14 days when the swelling subsides. Subtle cricoarytenoid joint dysfunction may then become more evident. Vocal cord hematomas (Fig. 97-6) and edema are slower to resolve and may cause persistent dysphonia. Surgical exploration and repair is indicated for the following types of laryngeal injuries: compromise of the anterior commissure, mucosal disruption with exposed underlying cartilage, multiple displaced fractures of the thyroid or cricoids cartilages, and injury causing vocal cord paralysis.39 Exposed laryngeal cartilage should be covered with mucosa to decrease the likelihood of chondritis.23 The avulsed mucosa can usually be sutured back to its normal anatomic position. Otherwise, local mucosal flaps should be rotated. Closure should be performed with absorbable sutures, with the knots buried to prevent granulation formation and possible obstruction.42 Typically this is done with a standard laryngofissure open technique, although endoscopic management of blunt pediatric laryngeal trauma has been reported.43 Fractures need to be reduced and secured, usually with absorbable plates and screws or sutures, as soon as possible.44 A crushed larynx, although rare, requires meticulous reduction and airway maintenance. A stent may be inserted to ensure the reduction and is usually kept in place for 2–6 weeks. The stent maintains the lumen of the larynx, helps prevent adhesions, and helps maintain the scaphoid shape of the anterior commissure, all of which are essential for normal vocalization.39 Laryngeal repair within 24–48 hours of injury avoids prolonged cartilage exposure to a contaminated field and has been shown to improve the outcome.42,45 Dislocated, subluxed, or avulsed arytenoids should be positioned back onto the cricoarytenoid facet. Early endoscopic

FIGURE 97-6. Vocal fold hematoma.

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reduction is preferred, although delayed reduction should still be attempted, despite the possibility of suboptimal return of function.46 The completely avulsed arytenoid should be preserved and repositioned to provide bulk for the posterior glottis and help prevent aspiration.23

Management of Tracheal Injuries After properly attending to the laryngeal injuries, the trachea can be addressed. The treatment of tracheal injuries is primarily surgical. However, lesions less than one-third the circumference of the trachea may be associated with the full expansion of the lung and early cessation of the air leak after chest tube placement, and nonoperative medical management may be sufficient. This is especially true if the laceration is of the posterior wall and has well-opposed edges with no soft-tissue loss (Fig. 97-7).11,47 Endoscopically, the wound edges can be sealed with fibrin glue, provided the wound edges can be reapproximated without tension.29 Alternatively, an endotracheal tube placed distal to a tracheal lesion for 48 hours may help seal the wound, although this is not standard practice.21 These nonsurgical treatment options are important because lower tracheal injuries often require a thoracotomy, which has a higher rate of complications.29 Larger lacerations of the trachea should be repaired with absorbable suture material using the interrupted technique. Local muscle flaps can be used to reinforce these suture lines. Placement of a tracheotomy tube through a simple anterior laceration should be avoided, unless long-term intubation is expected. In managing extensive tracheal wounds, it is imperative to acquire a tension-free, well-vascularized anastomosis. The blood supply to the trachea enters primarily from the lateral aspects; thus, mobilization should be performed by anterior and sometimes posterior dissection with preservation of the adjacent lateral tissues.21 Extensive tracheal injuries require debridement of devitalized tissue. Conservation of viable tracheal tissue is essential. Careful end-to-end anastomosis is done using interrupted absorbable suture. Interrupted absorbable sutures are used exclusively to allow growth and to avoid the granuloma problems associated with nonabsorbable sutures.8 Sutures are placed around the cartilage at a submucosal level, with the knots tied outside the lumen. Complete tracheal separations are often closed by passing of an endotracheal tube across the lacerated trachea. The repair is then completed over the endotracheal tube.23 Lung or laryngeal mobilization to reduce anastomotic tension is rarely needed in children.8 Traumatic esophageal perforation carries high rates of morbidity and mortality, although there is a better prognosis for children than adults. Esophageal injuries should be closed in two layers with a vascularized flap of tissue interposed between the trachea and the esophagus.18 This will help prevent tracheoesophageal fistulas.18

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CHAPTER 97 ❖ Diagnosis and Management of Pediatric Laryngotracheal Trauma 1633

FIGURE 97-7. Tracheal tears. Note the presence of subcutaneous air.

COMPLICATIONS

CONCLUSION

Severe injuries or those that are improperly managed may lead to significant complications. These include glottic or subglottic stenosis, glottic webs, scarring, vocal cord paralysis, esophageal stricture or stenosis, or tracheoesophageal fistulas. Stridor or dyspnea on exertion may indicate stenosis. Dysphonia or aphonia may result from glottic webs or scarring, vocal cord paralysis, or arytenoid damage. Dysphagia and weight loss may signal an esophageal stricture or stenosis. Tracheoesophageal fistula, vocal cord paralysis, or arytenoid damage may be diagnosed after a child has repeated bouts of aspiration pneumonia. The formation of granulation tissue at areas of exposed cartilage or anastamotic repair can be a difficult postoperative complication. It is best prevented by achieving adequate mucosal coverage of cartilage at the time of initial repair. If stents are used, it is advisable they be removed as soon as possible. Granulation tissue that causes symptoms of airway compromise can be serially reduced with endoscopic techniques, although recurrence is common. The surgical treatment of vocal cord paralysis is usually delayed for a year. This allows adequate time for the return of vocal cord function. During this period of time, electromyography can be used to follow any nerve progress. The paralyzed vocal cord can be temporarily injected with Gelfoam or fat to help reduce the chance of aspiration. If the paralysis continues after one year, thyroplasty or laryngeal reinnervation can be performed.

Laryngotracheal trauma is rare in the pediatric population but extremely challenging because of the size of the airway and the potential threat to life. Early diagnosis and careful, aggressive, individualized treatment are the key elements of a successful outcome.

PROGNOSIS The prognosis after laryngotracheal trauma depends primarily on the extent of initial injury. The outcome is typically excellent for patients whose injuries were minor enough to be managed nonsurgically. Most of these patients experience a full return of function.39 For those with more extensive injuries requiring operative management, the goal of decannulation and an adequate to good voice is often achieved eventually.2

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References 1. Gold SM, Gerber ME, Shott SR, Myer CM III. Blunt laryngotracheal trauma in children. Arch Otolaryngol Head Neck Surg. 1997;123:83. 2. Schaeffer SD. The treatment of acute external laryngeal injuries. Arch Otolaryngol Head Neck Surg. 1991;117:35. 3. Kadish H, Schuck J, Woodward GA. Blunt pediatric laryngotracheal trauma: case reports and review of the literature. Am J Emerg Med. 1994;12:207. 4. Humar A, Pitters C. Emergency department management of blunt cervical tracheal trauma in children. Pediatr Emerg Care. 1991;7:291. 5. Myer CM, Orobello P, Cotton RT, Bratcher GO. Blunt laryngeal trauma in children. Laryngoscope. 1987;97:1043. 6. Grisoni ER, Pillai SB, Volsko TA, et al. Pediatric airbag injuries: the Ohio experience. J Pediatr Surg. 2000;35:160. 7. Paluska, SA, Lansford CD. Laryngeal trauma in sport. Curr Sports Med Rep. 2008;7:16–21. 8. Grant WJ, Meyers RL, Jaffe RL, Johnson DG. Tracheobronchial injuries after blunt chest trauma in children-hidden pathology. J Pediatr Surg. 1998;33:1707. 9. Gaebler C, Mueller M, Schramm W, Eckersberger F, Vécsei V. Tracheobronchial ruptures in children. Am J Emerg Med. 1996;14:279. 10. Schoem SR, Choi SS, Zalzal GH. Pneumomediastinum and pneumothorax from blunt cervical trauma in children. Laryngoscope. 1997;107:351. 11. Hancock BI, Wiseman NE. Tracheobronchial injuries in children. J Pediatr Surg. 1991;26:16. 12. Mordehai J, Kurzbart E, Kapuller V, Mares AJ. Tracheal rupture after blunt trauma in a child. J Pediatr Surg. 1997;32:104. 13. Lusk RP. The evaluation of minor cervical blunt trauma in the pediatric patient. Clin Pediatr. 1986;25:445.

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14. Ford HR, Gardner ML, Lynch JM. Laryngotracheal disruption from blunt pediatric neck injuries: impact of early recognition and intervention on outcome. J Pediatr Surg. 1995;30:1–5. 15. Hall JR, Reyes HM, Meller JL. Penetrating zone-II neck injuries in children. J Trauma. 1991;3:1614. 16. Cooper A, Barlow B, Niemirska M, Gandhi R. Fifteen years’ experience with penetrating trauma to the head and neck in children. J Pediatr Surg. 1987;22:24. 17. Grewal H, Rao PM, Mukerji S, Ivatury RR. Management of penetrating laryngotracheal injuries. Head Neck. 1995;17:494. 18. McConnell DB, Trunkey DD. Management of penetrating trauma to the neck. Adv Surg. 1994;27:97. 19. Shama DM, Odell J. Penetrating neck trauma with tracheal and esophageal injuries. Br J Surg. 1984;71:534. 20. Mulder DS, Barkun JS. Injury to the trachea, bronchus and esophagus. Trauma. 1991:343–345. 21. Corneille MG, Stewart RM, Cohn SM. Upper airway injury and its management. Sem Thorac Cardiovasc Surg. 2008;20:8–12. 22. Mace SE. The unstable occult cervical spine fracture: a review. Am J Emerg Med. 1992;10:611. 23. Lee WT, Eliashar R, Eliachar I. Acute external laryngotracheal trauma: diagnosis and management. Ear Nose Throat J. 2006;85:179–184. 24. Bhojani RA, Rosenbaum DH, Dikmen E, et al. Contemporary assessment of laryngotracheal trauma. J Thorac Cardiovasc Surg. 2005;130:426–432. 25. O’Keeffe LI, Maw AR. The dangers of minor blunt laryngeal trauma. J Laryngol Otol. 1992;106:372. 26. Atkins BZ, Abbate S, Fisher SR, Vaslef SN. Current management of laryngotracheal trauma: case report and literature review. J Trauma. 2004;56:185–190. 27. Bell RB, Verschueren DS, Dierks EJ. Management of laryngeal trauma. Oral Max Surg Clin N Am. 2008;20:415–430. 28. Becmeur F, Donato L, Horta-Geraud P, et al. Rupture of the airways after blunt chest trauma in two children. Eur J Pediatr Surg. 2000;10:133. 29. Hager J, Gunkel AR, Riccabona U. Isolated longitudinal rupture of the posterior tracheal wall following blunt neck trauma. Eur J Pediatr Surg. 1999;9:104. 30. Herdman RC, Saeed SR, Hinton EA. The lateral soft tissue neck X-ray in accident and emergency medicine. Arch Emerg Med. 1992;9:149. 31. Maceri DR, Mancuso AA, Canalis RF. Value of computed axial tomography in severe laryngeal injury. Arch Otolaryngol. 1982;108:449.

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32. Alexander AE Jr, Lyons GD, Fazekas-May MA, et al. Utility of helical computed tomography in the study of arytenoid dislocation and arytenoid subluxation. Ann Otol Rhinol Laryngol. 1997;106:1020. 33. Meglin AJ, Biedlingmaier JF, Mirvis SE. Three-dimensional computerized tomography in the evaluation of laryngeal injury. Laryngoscope. 1991;101:202. 34. Katz M, Konen E, Rozenman J, Szeinberg A, Itzchak Y. Spiral CT and 3D image reconstruction of vascular rings and associated tracheobronchial anomalies. J Comput Assist Tomogr. 1995;19:564. 35. Chui L, Lufkin R, Hanafee W. The use of MRI in the identification of post-traumatic laryngeal deformities. Clin Imaging. 1990;14:127. 36. Jurkovich GJ, Zingarelli W, Wallace J, Curreri PW. Penetrating neck trauma: diagnostic studies in the asymptomatic patient. J Trauma Injury Infect Crit Care. 1985;25:819. 37. Butler AP, Wood BP, O’Rourke AK, Porubsky ES. Acute external laryngeal trauma: experience with 112 patients. Ann Otol Rhinol Laryngol. 2005;114:361–368. 38. Merritt RM, Bent JP, Porubsky ES. Acute laryngeal trauma in the pediatric patient. Ann Otol Rhinol Laryngol. 1998;107:104. 39. Schaeffer SD. The acute management of external laryngeal trauma: a 27-year experience. Arch Otolaryngol Head Neck Surg. 1992;118:598. 40. Kurien M, Zachariah N. External laryngotracheal trauma in children. Int J Pediatr Otorhinolaryngol. 1999;49:115. 41. Gussack GS, Jurkovich GJ, Luterman A. Laryngotracheal trauma: a protocol approach to a rare injury. Laryngoscope. 1986;96:660. 42. Bent JP, Porubsky ES. The management of blunt fractures of the thyroid cartilage. Otolaryngol Head Neck Surg. 1994;110:195. 43. Elmaraghy CA, Tanna N, Wiet GJ, Kang DR. Endoscopic management of blunt pediatric laryngeal trauma. Ann Otol Rhinol Laryngol. 2007;116:192–194. 44. Woo P. Laryngeal framework reconstruction with miniplates. Ann Otol Rhinol Laryngol. 1990;99:772. 45. Leopold DA. Laryngeal trauma: a historical comparison of treatment methods. Arch Otolaryngol. 1983;109:106. 46. Sataloff RT, Rao VM, Hawkshaw M, Lyons K, Spiegel JR. Cricothyroid joint injury. J Voice. 1998;12:112. 47. Kielmovitch IH, Friedman WH. Lacerations of the cervical trachea in children. Int J Pediatr Otorhinolaryngol. 1988;15:73.

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98

C H A P T E R

Tumors of the Larynx, Trachea, and Bronchi Dale A. Tylor and Seth M. Pransky

T

umors of the larynx, trachea, and bronchi are rare in children. By virtue of their location, these lesions can lead to significant morbidity and mortality by mechanical obstruction of the airway. Symptoms include stridor, cough, dysphonia, wheezing, or dyspnea. With increasing airway obstruction, life-threatening respiratory distress can develop. Distal obstruction of the airways can result in hyperexpansion of the lung, atelectasis, or pneumonia.

TUMORS OF THE LARYNX (TABLE 98-1) Recurrent Respiratory Papillomatosis Introduction Recurrent respiratory papillomatosis (RRP) is the most common benign neoplasm of the larynx in children. This disease is often difficult and frustrating to manage because of its known

TABLE 98-1. Tumors of the Larynx

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Type of Tumor

Benign

Malignant

Epithelial

Squamous papilloma Adenoma Oncocytoma Pleomorphic adenoma

Squamous cell carcinoma Verrucous carcinoma Spindle cell carcinoma Squamous cell carcinoma Adenosquamous carcinoma Basal cell carcinoma Malignant melanoma Adenoid cystic carcinoma Adenocarcinoma Malignant mixed tumor Mucoepidermoid carcinoma

Mesenchymal

Fibroma Chondroma Chondroblastoma Hemangioma Leiomyoma Lipoma Rhabdomyoma Lymphangioma Fibrous histiocytoma

Fibrosarcoma Rhabdomyosarcoma Chondrosarcoma Liposarcoma Angiosarcoma Spindle cell sarcoma Leiomyosarcoma Malignant fibrous histiocytoma

Neuroendocrine

Neurofibroma Schwannoma Paraganglioma Granular cell tumor

Malignant granular cell tumor Carcinoid tumor

Hematopoietic

Plasmacytoma Reticulocytoma Hemangioendothelioma

Lymphoma Leukemia Malignant hemangioendothelioma

Miscellaneous

Hamartoma Adenolipoma Teratoma Amyloidosis

Malignant teratoma Metastatic carcinoma

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local persistence and recurrence and potential for spread throughout the respiratory tract. The toll of RRP relates to its recurrent nature, significant airway morbidity, psychological and financial concerns created by multiple operative procedures, and emotional strain associated with chronic disease. The most common symptoms of RRP are related to varying degrees of laryngeal airway involvement and usually begin with hoarseness, abnormal cry, or voice change and progress to stridor as the airway is increasingly obstructed. True acute respiratory distress is fortunately uncommon because papillomas tend to gradually encroach upon the airway and generate symptoms and lead to medical evaluation before overt respiratory collapse. It is not uncommon for the condition to initially be misdiagnosed as asthma, recurrent croup, or bronchitis, and symptoms may be present for over a year before the correct diagnosis is ultimately made. In any infant or young child with symptoms of voice change, obstructive airway symptoms, or recurrent croup, laryngoscopy is indicated to rule out the presence of RRP. Flexible laryngoscopy in the office may reveal a mass involving the larynx, and operative microsuspension laryngoscopy with biopsy is indicated for definitive diagnosis and treatment. Epidemiology RRP can have its onset in either childhood, termed juvenile onset recurrent respiratory papillomatosis (JORRP), or as adult-onset recurrent respiratory papillomatosis (AORRP); age at diagnosis ranges from 1 day to 84 years. Although the actual incidence and prevalence of disease are not known, incidence in the United States has been estimated at 4.3 per 100,000 children and 1.8 per 100,000 adults. Annual projections exist for 2354 new diagnoses and 5970 active cases of JORRP and 3623 new diagnoses and 9015 active cases of AORRP in the United States.1 Average and median ages at diagnosis of JORRP are 3.8 and 2.8 years, respectively, and mean duration of disease has been reported as 4.4 years.2 Children of teenage mothers and first-born progeny are at higher risk of JORRP. There does not appear to be any gender preponderance in JORRP. Etiology Human papillomavirus (HPV) is well established as the cause of RRP. HPV is a nonenveloped, icosahedral-shaped virion capsid that is 55 nm in diameter with circular, double projections, or the virus can become latent in which the mucosa is normal-appearing both grossly and histologically.3 Although over 100 different types of HPV have been identified, HPV-6 and HPV-11 are found most often in laryngeal papillomatosis. Pediatric infection with HPV type 11 portends an elevated risk of obstructive laryngeal and distal airway disease and ultimate need for tracheotomy.4 HPV types 16 and 18 have been identified much less commonly and are clearly related to a greater oncologic risk. HPV has been identified in clinically nondiseased epithelium in both active RRP patients and those in clinical remission. One study detected HPV DNA in nondiseased sites

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almost as frequently as in gross papillomas—40% versus 50%.5 Sites of predilection for RRP are at squamociliary junctions: the nasal vestibule, nasopharynx, palate, epiglottis, larynx, trachea, bronchi, and lung. HPV has not been demonstrated in ciliated epithelium. Traumatized ciliated epithelium may heal as nonciliated epithelium and undergo metaplasia to cuboidal or squamous epithelium. Thus, injury to the tracheal mucosa by surgical instrumentation (suction tip, forceps, microdebrider, or laser) or by an endotracheal tube can create mucosal change explaining the recognized phenomenon of papillomas occurring at sites of epithelial injury. Similarly, tracheostomy leads to epithelial injury and to squamous metaplasia and the commonly observed development of tracheal papillomas after tracheotomy. There appears to be an immune-related predisposition to the development of RRP, particularly with respect to diminished cell-mediated immunity. In evaluating the immunologic status of 20 children with RRP, Stern et al.6 noted that CD4/ CD8 ratios as well as the lymphocyte response to stimulation by mitogens were reduced significantly when compared to normal children. Lesser responses of lymphocytes to the mitogens portended greater number of sites of disease and more frequent recurrences. Impaired natural killer function correlated strongly with more frequent recurrences as well. It has been presumed that hormones have some influence on the disease process of RRP. This notion is based on the observation that the growth rate of genital condylomas is increased during pregnancy and that some cases of spontaneous regression have been observed during puberty. To date, the onset of puberty with altered levels of hormones has not conclusively been proven to have significant effect on remission. Pathology Grossly, papillomas appear as irregular, exophytic, pedunculated nodular masses, although they may also be found to be sessile in nature. They are usually pink but can vary from white to red in color and can range from a velvety to firm consistency. They may be singular but are more often multiple and can be recognized in various sizes. Histologically, papillary-like projections of fibrovascular connective tissue cores are found to be covered by stratified squamous epithelium. Abnormal squamous keratinization is the rule. Although a benign neoplasm histologically, malignant transformation in chronic invasive papillomatosis has been described by many authors and is an important reason for sending specimen for pathologic evaluation in patients with recurrent disease. The larynx is affected in almost 100% of cases, with involvement of the glottis most commonly, followed by the supraglottis and then the subglottis. Distal spread to the trachea is the next common site, followed by the bronchus and then the lung.7 Tracheal involvement has been reported to range from 17% to 26%, and pulmonary involvement is estimated between 1% and 6%. Irwin et al.8 reported that papilloma had spread from the original site of the lesion in 78% of cases. Distal spread is particularly distressing because of the difficulty of adequately removing the papillomas and ensuring a

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CHAPTER 98 ❖ Tumors of the Larynx, Trachea, and Bronchi patent airway. Tracheotomy greatly increases the chance for the development of tracheal disease, and avoidance of tracheotomy is recommended if possible. With pulmonary spread, small homogeneous nodules and cavitary lesions of various thicknesses with a diameter of up to several centimeters are characteristic. Lung involvement that leads to restrictive lung disease carries significant morbidity, and the incidence of cancer with pulmonary involvement has been found to be 16%.

1637

Many staging systems for RRP have been proposed as a means to facilitate assessment of the clinical course of the disease and the efficacy of treatment. In 1998, a staging system was proposed that accounts for disease both inside and outside of the larynx as well as functional components, and software that is capable of encrypting such data is available to allow for a secure database of patients from around the world (see Figs. 98-1 and 98-2).3

FIGURE 98-1. RRP staging assessment sheet. (Reproduced with permission from Derkay.1)

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1638

SECTION 5 ❖ The Airway ANTERIOR

Lingual epiglottis

Laryngeal epiglottis

Anterior commissure

Aryepiglottic fold False vocal cord

Ventricle True vocal cord

Arytenoid Posterior commissure POSTERIOR

FIGURE 98-2. RRP laryngeal involvement diagram. (Reproduced with permission from Derkay.1)

Transmission of Disease A strong association between RRP and the presence of maternal genital warts (condylomata acuminata) during childbirth has been noted; over half of the affected children are born to mothers with active genital condyloma. Vertical transmission of HPV to the newborn oropharynx can occur at delivery. The lack of a higher correlation between maternal condylomata acuminata, and RRP in children may be due to the lack of documentation of papillomas and the finding that 20% of normal-appearing cervices without overt exophytic lesions may harbor HPV. Furthermore, it is estimated that 25% of all women of childbearing age have HPV in their genital tracts, which argues for other cofactors assisting in disease transmission. The risk of RRP developing in neonates born to infected mothers should be as high as 1 in 32 but is generally estimated to be9 only 1 in 400.Siblings of children with RRP do not seem to have an increased risk for RRP. However, there does appear to be an underlying genetic susceptibility for RRP, and studies are currently ongoing to assess the specific genetics of RRP to help identify targets for rational drug development. Cesarean section delivery, which bypasses the area of maternal infection, seems to lessen risk of RRP, but RRP has been identified in infants delivered through Cesarean section. Consequently, controversy exists regarding recommending routine Cesarean section delivery in pregnant women with active genital warts. It is the general feeling in the pediatric otolaryngology community that due to the increased risk of transmission of disease to the newborn in woman with active cervical and/or genital papilloma (especially the young primiporous woman), Cesarean section should be offered as an option.

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Clinical Course The clinical course of RRP is characteristically unpredictable (see Figs. 98-3 to 98-5): papilloma may respond to 1 or 2 treatments, recur chronically for many years, spontaneously regress after years of treatment or rarely, progress to terminal disease. Distinguishing between JORRP and AORRP has prognostic merit, as JORRP patients tend to suffer from a more aggressive disease process. Even among children with RRP, those diagnosed before age 3 are 3.6 times more likely to require more than four surgeries per year and have almost double the risk of having two or more affected anatomic subsites. The average number of procedures a child with JORRP undergoes2 is 20.3, with a median of 12. AORRP more commonly affects males, and tends to be less extensive and less aggressive, although malignant degeneration is possible in a minority of cases. Factors associated with spontaneous remission of RRP are not well understood. It is likely that HPV becomes dormant rather than being eradicated, as RRP can recur as long as 47 years after clinical clearing of the airway. Dysplastic changes in a bed of papilloma can occur, particularly in those with AORRP. Likewise, squamous cell carcinoma can arise within RRP, either in the larynx, trachea, or the lungs, and distant metastatic spread is possible. Cocarcinogens, host immunocompetence, the type of HPV infection (types 16 and 18), and the duration of infection all play a role, but exact understanding of the interaction of these factors is limited. When RRP behaves in an extremely aggressive fashion, termed “invasive papillomatosis,” spread of papilloma can occur into the pulmonary parenchyma, soft tissue of the neck, and even the regional lymph nodes.

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A FIGURE 98-3. Severe RRP involving entire larynx.

B FIGURE 98-4. Focal papilloma involving anterior commissure region.

In RRP, there is no known single or combination treatment that reliably eradicates HPV, the etiologic agent of this disease. Therapeutic regimens for RRP stress maintenance of a patent airway and acceptable voice while preventing spread of disease and complications. Often, multimodality therapy is required to manage this disease. Medical Therapy Various attempts at the medical control of this disease reflect the difficulty in finding a definitive curative therapy for this disease process. Previous unsuccessful therapeutic trials to control the underlying viral infection have included antibiotics, hormones, steroids, the topical antiviral agent podophyllin, antimetabolites (5-fluorouracil and methotrexate), and transfer factors. Radiation therapy has the potential for malignant transformation and is contraindicated. Ongoing adjunct therapeutic trials include HPV vaccines, gene therapies, reflux management, cidofovir, acyclovir, ribavirin, cis-retinoic

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C FIGURE 98-5. A, Severe papilloma at first encounter. B, same larynx 1 year later after 11 procedures. C, same larynx 2 weeks later after first injection with cidofovir.

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acid, mumps vaccine, interferon-α, indole-3-carbinol (I3C)/ diindolylmethane (DIM), photodynamic therapy (PDT), bevamiczumab, and COX-2 inhibitors. The introduction of the quadrivalent HPV vaccination, Gardasil® (Merck & Co, Whitehouse Station, NJ), which consists of HPV subtypes 6, 11, 16 and 18, as well as other polyvalent vaccines in development, has led to excitement about a possible preventative modality for RRP.10 Therapeutic benefit of the vaccination in patients already affected with RRP has not yet been demonstrated, although serological studies are being carried out to provide insights as to the viability of a therapeutic role for the vaccine (Ferrel Buchinsky, MD, personal communication). Achieving adequate vaccination levels across the population will be critical in both preventing individual development of maternal condylomata and generating enough herd immunity to decrease transmission in general. The vaccine has been approved for use in females and males from age 9 to 26 years for the prevention of genital warts in both genders and cervical, vulvar and vaginal cancers in women. Cidofovir (Vistide®, Gilead, Foster City, CA) is an antiviral agent with a broad spectrum of activity against a wide variety of DNA viruses, including HPV. The US Food and Drug Administration (FDA) has approved intravenous use in patients with HIV who have infection with cytomegalovirus. Cidofovir has a propensity to be selectively absorbed by cells with HPV. The cell converts it into active agents that cause apoptosis and gene upregulation, with early death of the cell. Initially reported as a case report in 1995 as a successful treatment for hypopharyngeal-esophageal papillomas, a larger series of adult with severe laryngeal papillomatosis was described in 1998, describing a dramatic response to intralesional injection in 14 of 17 patients.11 Subsequent reports of malignancy in 2 of 36 adult patients raised significant concern about the safety of this agent, but subsequent review at the Armed Forces Institute revealed evidence of carcinoma before initiation of treatment with cidofovir. Pransky et al.12 reported good results with cidofovir in five children with severe disease requiring very frequent surgical procedures. Four of the five patients were significantly improved or disease free. A follow-up report with a total of 11 children over a 6-year period continued to reveal good response. In a more recent 13-year follow-up report on the use of cidofovir in 21 patients with severe disease followed between 18 months and 13 years, 52% achieved durable remission (followed greater than 5 years), 33% had significant improvement in disease and considerable lengthening of the intersurgical interval, and 15% had no significant response to the injections (Mullin and Pransky, unpublished study). No toxicity had occurred, and biopsy specimens have not revealed any malignant transformation.13 Other reports have shown that cidofovir is quite effective in improving or bringing about remission of RRP.14 The ideal frequency and dose of cidofovir has yet to be determined. Currently, our group employs a solution of 5–7.5 mg/mL with an interval of injection generally between 2 and 3 weeks until clinical clearing of disease is seen.

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Patients managed with cidofovir should be well hydrated, and monitored by a complete blood count, urinalysis, blood urea nitrogen, creatinine, and liver function tests. Some reports have indicated that cidofovir injection results in regression of papillomas without surgical removal; there has been particular interest in utilizing this benefit in the region of the glottis, where repeated surgical intervention may lead to severe scarring of the lamina propria with resultant vocal worsening. The concern of dysplasia and/or carcinomatosis continues to be an issue in the use of this drug. Broekema and Dikkers,15 in a review of the literature, found a 2.7% rate of dysplasia with cidofovir use, which subsequently cleared, and there were no cases of malignant degeneration. Nevertheless, this suggests that cidofovir use should be limited to disease of moderate to severe extent and mandates extensive counseling, including the discussion of the rare possibility for malignant change, when obtaining informed consent. Furthermore, serial pathologic evaluation of papillomas is reasonable in patients receiving intralesional cidofovir to ensure that dyplastic changes are not developing. Interferons are a class of proteins manufactured by cells in response to various stimuli, including viral infection. Interferons bind to specific membrane receptors and then alter cell metabolism. They have antiviral, antiproliferative, antitumor, and immunomodulatory effects. The exact mechanism of an interferon’s action on laryngeal papillomatosis is not known, but it is thought that it affects the production of enzymes such as protein kinase and endonuclease, thereby leading to the inhibition of viral protein synthesis and to breakdown of viral DNA. Preliminary reports in the early 1980s were quite encouraging, although prospective studies using interferon in association with the CO2 laser found a mixed response. Patients who did benefit experienced either a complete eradication of the disease or a decrease in tumor growth and a resultant reduction in the number of surgical procedures necessary to control the disease. Unfortunately, many patients experienced a “rebound” regrowth of papilloma after discontinuation of the interferon. More recent studies from Europe have shown approximately 42% remission rate (predominantly in adults after several years of treatment). There seems to be better results16 in patients with HPV type 6 than 11. A dose-related response of RRP to interferons has been demonstrated. Toxicity associated with interferon includes the acute reactions of fever and generalized influenza-like symptoms (chills, headache, myalgias, and nausea), which diminish over time, and the chronic effects of a decrease in the growth rate of children (although catchup growth is noted when therapy is ceased). Neurologic disorders, transient increases in transaminase levels, leukopenia, and thrombocytopenia have been reported, as have rashes, dry skin, alopecia, generalized pruritus, and autoimmune problems such as systemic lupus erythematosus. Fatigue, which can be extreme, is one of the most noteworthy of the adverse reactions. Spastic diplegia has been reported in those who received interferon before gross motor development, which mandates precautions when using this agent in infants. Neurologic and developmental assessment, especially in

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CHAPTER 98 ❖ Tumors of the Larynx, Trachea, and Bronchi infants, should be performed before beginning therapy. Interferon manufacture has undergone changes, and currently, a longer lasting preparation recombinant interferon-α2a (Pegasys®, Roche, Basel, Switzerland) is being utilized as a subcutaneous injection once weekly. It has been utilized to treat hepatitis C in adults and is not FDA approved for the treatment of RRP. Monitoring by complete blood count, platelets, urinalysis, and liver function studies should be performed before beginning therapy and every 1–2 months while receiving therapy. If a response is followed by latent recurrence, another therapeutic trial may be instituted. I3C is derived from cruciferous vegetables (cabbage, broccoli, Brussels sprouts, and cauliflower) and appears to have some effect in controlling the growth of new laryngeal papillomas. I3C is thought to affect papilloma growth through its effect on estrogen metabolism. Rosen et al.17 found that a third of RRP patients who received oral I3C had complete arrest of new papilloma growth, another third had a reduced papilloma growth rate, and the rest did not have any benefit. A high correlation was noted between the urinary estrogen metabolite ratio (2-hydroxylestrone to 16α-hydroxylestrone) and response. Interestingly, most (5 of 6) of the complete response group were adults, whereas most (5 of 6) of the nonresponders were children. DIM is a natural product of I3C acid digestion in the stomach and is thought to be the active metabolite of I3C. Animal studies have demonstrated that I3C, when injected intravenously to bypass stomach acid digestion, does not produce an estrogen metabolite effect, whereas DIM is equally effective when administered by direct injection or ingestion. 13C seems to be relatively safe, although with long-term use, there is concern for risk of diminished bone density; low bone density in children who have been maintained on high-dose 13C is fortunately rare. The main side effects appear to be disequilibrium and possible elevated liver enzymes associated with higher doses. Larger studies of I3C/DIM with prolonged follow-up are needed. Although papillomaviridae do not code for the enzyme thymidine kinase, and acyclovir is an antiviral that depends on the presence of virally coded thymidine kinase, there have been some reports of successful use of acyclovir in treating RRP. It has been postulated that it is more effective in settings of concomitant viral infections such as herpes simplex type 1 or cytomegalovirus or Epstein–Barr virus. Another antiviral agent, ribavirin, which is utilized to treat respiratory syncytial virus in infants, has been tried in an aerosol form as well as orally (at doses of 23 mg/kg/day divided four times daily) after loading IV dose, with some impact on increasing the intervals required between the procedures. Direct injection of mumps vaccine or measles-mumps-rubella vaccine into papillomas has been utilized, has been reported to show some effectiveness in decreasing the rate of recurrence after direct injection into papillomas, but the data have not been reproducible.3 Gene therapies are increasingly attractive as they predominantly target genes being produced in pathologically affected tissues, sparing normal cells and tissues. A number of early genes

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of HPV type 6 and 11, namely E2, E5, E6, and E7, are current gene therapy targets. Furthermore, inhibitors of EGF receptor kinase are a promising therapy, as high levels of EGF receptors have been found in RRP. Gefitinib (AstraZenaca, Wilmington, DE) is an EGF receptor tyrosine kinase inhibitor and has been reported that it has been utilized in a particularly severe case of RRP.18 Bevacizumab (Avastin ®, Genentech, South San Francisco CA) is a human monoclonal antibody targeting VEGF, resulting in an anti-angiogenic response in some patients with RRP who receive intralesional injections. Rogers et al. recently published their experience using intralesional bevacizumab in children with RRP and found increased duration of time between procedures, decreased number of procedures per year, improved burden of disease and improved quality of life measures in children with aggressive disease receiving the medication.19 Thus far, these therapies are largely experimental. Treatment of gastroesophageal reflux disease should be considered in all patients with RRP. Pignatari et al.20 noted that 90% of children with RRP had extraesophageal reflux present. There does appear to be a significantly decreased recurrence rate of disease and risk of postoperative laryngeal webbing in those children treated with antireflux therapy. Trials have been carried out that show treatment with HPV 16 heat-shock protein fusion product in children with severe RRP lead to increase intersurgical intervals.3 PDT with dihematoporphyrin ether (DHE) uses the propensity of this substance to concentrate in papillomas versus surrounding normal tissue. When activated by light with the appropriate wavelength (630 nm), DHE produces cytotoxic agents that selectively destroy cells containing the DHE. The proposed mechanism of cell destruction is through the production of toxic oxygen radicals that cause disruption of the cell membrane by lipid or protein sulfhydryl oxidation. Vascular damage in the form of microcirculatory disruption of rapidly dividing tissue also occurs, in a dose-dependent fashion. Photosensitivity can occur, usually within 2 weeks of instituting therapy. m-tetrahydroxyphenylchlorin (mTHPC), which has a much shorter period of photosensitivity, has shown good responses in the majority of patients who have been monitored for 12–18 months. Unfortunately, the PDT response is not as apparent in tracheal lesions, and it has no effect on parenchymal lesions or on the persistence of HPV DNA.21 PDT in general has some beneficial effect in modifying the RRP disease process but is rarely utilized currently. Retinoids, which are vitamin A analogs and metabolites, act to modulate the proliferation and differentiation of cell lines. Within the airway and gut, the lack of vitamin A has been found to result in squamous metaplasia and hyperkeratinization, whereas high levels of vitamin A can suppress squamous differentiation and may result in mucous metaplasia.3 Trials of 13-cis-retinoic acid (Accutane®) with a dose of 1–2 mg/kg/day until side effects develop or 6 months have passed, have been undertaken. Results to date have been inconclusive, and the significant risk of teratogenicity in a sexually reproductive population of patients as well as psychiatric adverse effects has led to some hesitancy in consideration of this as a standard therapy of RRP.

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Current research into the effectiveness of cyclo-oxygenase (COX)-2 inhibitors in treating RRP is ongoing, as the medication Celebrex® (Pfizer, New York, NY) has demonstrated antipapilloma activity in a rabbit model. Surgical Therapy The aim of therapy in extensive disease should be to create a safe and patent airway, reduce tumor burden, decrease the spread of disease, improve voice quality, and increase the time intervals between surgical procedures. Surgical therapy should be based on the principle of preservation of nondiseased tissue to prevent the complication of laryngeal scarring or stenosis while attempting removal of visible papilloma. In areas where removal of the lesion would cause long-term iatrogenic damage (such anterior commissure webbing), incomplete excision of papillomas is preferred. Surgical treatment in the past has included the use of thermal cautery, cryosurgery, ultrasound, and removal of papillomas with cup forceps. Presently, the most widely used procedure is microsuspension laryngoscopy with the CO2 laser or angiolytic lasers (KTP/PDL) alone or in combination with the microdebrider or cup forceps to remove papillomas. Given the great variability of the disease presentation with both pedunculated and sessile areas and portions of the larynx that may be difficult to easily visualize or access, it is best for the surgeon to be prepared with various surgical modalities for individualized and optimal management of RRP. The advantage of the laser is its superior precision and inherent hemostatic properties. Thorough knowledge of laser application has resulted in fewer operative complications such as airway fires, pneumothorax, and anesthetic complications. Reports of delayed local tissue damage have ranged from a low of 13% to as high as 35%, however. The majority of problems involve the delayed formation of laryngeal webs, most commonly at the anterior commissure, posterior commissure and interarytenoid region. Data suggests that the number of laser procedures and the severity of disease have a linear relationship to the frequency and severity of complications. Using a microspot CO2 laser at lower settings and shorter bursts, as well as accepting residual disease at anatomically vulnerable locations, can reduce the frequency of complications. In addition, the introduction of the newer flexible fiberoptic CO2 laser has provided an advantage in reaching difficult areas of the larynx with precise excision of papilloma. Overaggressive use of the laser may result in injury to unaffected tissue and create an environment suitable for the implantation of viral particles. These concerns, as well as an animal study demonstrating that CO2 laser ablation causes a greater delay in healing and denser fibrosis than is the case with microforceps, have led to the pursuit of other lasers to use. The photoangiolytic 585 nm pulsed dye laser, with a fiber that must be placed adjacent to the lesions, has been utilized both in children and adults, and can be performed awake in the clinic on cooperative patients to photocoagulate the affected tissue. In a similar manner, the 532 nm pulsed KTP laser is also increasingly being utilized as alternatives to the traditional CO2 laser.

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For lesion debulking, microforceps are used for biopsy, and either microforceps or a powered microdebrider can be used to address the bulk of the disease. The laryngeal microdebrider is an adaptation of endoscopic sinus instruments. Microdebrider removal of papilloma has become the standard treatment for controlled removal of large, pedunculated airway lesions with minimal risk to normal tissue. It has been shown to provide a safe and rapid means of removal with less postoperative pain and good postoperative voice results. Bleeding is usually minimal and easily controlled with topical application of vasoconstrictive medications. Other technologies, such as Coblation® or that of controlled radiofrequency, are being studied as an adjunctive surgical treatment of RRP.

Subglottic Hemangioma Introduction Infantile hemangiomas are the most common tumor of the head and neck in the pediatric population. These congenital, vascular lesions typically proliferate rapidly in the first several months of life after which time they involute slowly over many years. Presence of hemangioma in the subglottic region, however, is rare and makes up only 1.5% of all congenital anomalies of the larynx.22 Because of the lifethreatening nature of subglottic obstruction, a high index of suspicion is necessary in evaluating young infants with noisy breathing, feeding difficulties, or respiratory distress. Epidemiology This entity is seen almost exclusively in infants, with 85% being diagnosed before 6 months of age. A female to male preponderance of 2.5 to 1 has been noted in many series. Fairskinned children also tend to be more commonly affected than their darker-skinned counterparts. Fifty percent of children with subglottic hemangiomas are found to have cutaneous hemangiomas, often located in the facial region. As a corollary, a high association is noted between facial hemangiomas with a “beard” distribution and symptomatic hemangiomas of the upper airway. One series found that 63% of children with multiple facial hemangiomas had symptomatic airway hemangiomas. PHACES syndrome requires special mention with respect to subglottic hemangioma. Abnormalities present in this syndrome include posterior fossa malformations, hemangiomas that usually are segmental in nature and involve the face and/or head and neck, arterial anomalies, cardiac malformations, eye anomalies, and sternal defects (see Fig. 98-6). Arterial anomalies can be found throughout the body, but intracranial vascular anomalies can lead to cerebrovascular events, and thus a screening MRI of the brain in these patients is necessary.22 Pathology Histologically, the tumor shows tubules of plump, proliferating endothelial cells surrounding narrow vessels and an abundance of mast cells. The composition of infantile hemangiomas also includes fibroblasts, pericytes, and

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FIGURE 98-6. Two-month-old female with PHACE syndrome and extensive head and neck hemangiomatosis.

interstitial cells. More recently, the expression of GLUT1, an erythrocyte-type glucose transporter that can be found in endothelium at the blood–brain barrier, has been identified in infantile hemangiomas but not in other vascular malformations or vascular lesions. Furthermore, it has been found to be expressed in placental tissue, fueling speculation of the etiology of infantile hemangiomas to be embolized placental cells or perhaps angioblastic differentiation toward a placental phenotype.23 Clinical Course Classically, symptoms of airway obstruction with inspiratory or biphasic stridor are present and can progress to acute respiratory distress. Such symptoms do not normally begin at birth but instead occur within the first few weeks to months of life. The stridor is frequently exacerbated by excitement or crying, which causes vascular engorgement, and is reduced with rest. These patients often present with “croup” at 6–8 weeks of life. Upper respiratory tract infections worsen the symptoms, and episodic exacerbations may result in an erroneous diagnosis of “recurrent croup.” Other symptoms include feeding problems, cough, cyanosis, and rarely, dysphonia. Slow and progressive growth of the lesion can lead to almost complete obstruction of the subglottic airway. Subglottic hemangiomas behave similarly to cutaneous hemangiomas. The natural history of these lesions is variable, but many lesions appear to spontaneously involute after 12–18 months. Cutaneous hemangiomas are said to have two involutional rates—early and late. With early involution, the proliferation phase occurs during the first 6–12 months, and then the lesions rapidly resolve. Late involuters do not complete their involution for 3–5 years, and some of the lesions do not involute completely. Unfortunately, unlike cutaneous lesions, which may be largely asymptomatic with time afforded to observe until involution, subglottic hemangiomas often require treatment given their life-threatening nature.

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Work Up In an infant with obstructive airway symptoms such as stridor, dyspnea, cyanotic episodes, or feeding problems, endoscopy is performed to establish the diagnosis. Flexible fiberoptic laryngoscopy on the awake patient may fail to visualize the subglottic region, and the absence of other obvious lesions above the vocal folds mandates operative endoscopic evaluation. Adjunctive radiographic measures that are helpful preoperatively include high-kilovoltage anteroposterior neck films, which may demonstrate asymmetric subglottic narrowing in up to 50% of patients, and an esophagram, which helps rule out other congenital vascular anomalies. After bronchoscopy has confirmed that the only airway lesion present is in the subglottis, microsuspension laryngoscopy will confirm the diagnosis. The classic appearance is one of an asymmetric, smooth, submucosal, pink or blue compressible subglottic mass (see Fig. 98-7). Most authorities report a left-sided predominance, although the lesion may occur on the right or can be bilateral. Hemangiomas have also been reported to extend into the posterior commissure and to the upper part of the trachea. Hemangiomas that exhibit a “blush” or staining of the supraglottic, glottic, or tracheal mucosa suggest a significant extent of disease. Postcricoid hemangioma can be present and has been reported to cause failure to thrive. Biopsy is controversial; while it is the only way of providing histological diagnosis, there is a small risk of uncontrolled airway hemorrhage. In actuality, the diagnosis is frequently based on the history and endoscopic findings alone. To provide maximal evidence for the diagnosis and document progession of disease, photographic documentation of the lesion at each endoscopic procedure should be obtained. Contrasted computerized tomography (CT) or magnetic resonance imaging (MRI) of the neck and mediastinum can be considered for larger subglottic hemangiomas, especially those associated with cutaneous hemangiomas in the head and neck area. Certain lab testing has been suggested for use in a research capacity to distinguish hemangiomas from other vascular or lymphatic malformations, including GLUT1, basic fibroblast growth factor, proliferating cell nuclear antigen, vascular endothelial growth factor, type IV collagenase, and urokinase.

A

B

FIGURE 98-7. Typical smooth submucosal subglottic hemangioma.

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Treatment Many different therapies have been advocated as treatment of subglottic hemangioma. Mild cases that cause few symptoms can be closely observed, often with an adjunct of reflux management to limit additional edema in the airway and occasional use of corticosteroids when respiratory symptoms are intermittent and mild. The bulk of these patients have larger symptomatic lesions, however, that require some form of intervention until involution occurs. Treatment options historically have included systemic and intralesional corticosteroids, debulking surgery, tracheotomy, open or endoscopic surgical excision, interferon-α and vincristine. In recent years, the β-blocker propranolol has been serendipitously identified as very successful in managing these lesions without need for interventional surgery, and it has rapidly become a mainstay of therapy of cosmetically or functionally deforming head and neck hemangiomas. Former treatments that have been abandoned include radiation therapy, radioactive gold implantation, injection of sclerosing agents, and cryotherapy. Medical Therapy Systemic steroid therapy has frequently been used during the proliferative stage, with a good initial response. The mechanism of the effect of steroids on hemangiomas is not clear. Steroids occupy estradiol receptor sites, and it is theorized that they inhibit some supportive function of estradiol on the hemangioma. On the basis of the experimental observation that cortisone and hydrocortisone inhibit angiogenesis in the presence of a fragment of heparin, prednisone is thought to have an effect on the hemangioma during the proliferative stage. Some suggest that corticosteroids may increase the sensitivity of vessels to other natural vasoconstrictors that can result in the shrinkage of the vascular mass. It should be noted that only 25% of case of subglottic hemangioma resolve with systemic steroid administration alone.22 Prednisone can be given at doses as high as 4 mg/kg per day or 8 mg/kg every other day for 6–12 weeks and then tapered slowly. A second course can be used after a few weeks in those with resumption of hemangioma growth. If long-term steroid use is contemplated, treatment should be administered every other day, at a lower dose of 1 mg/kg per day, to decrease the possibility of untoward effects of the steroid. Steroids can play an additional beneficial role of reducing inflammation in acute respiratory infections or in milder cases with only intermittent respiratory distress. Caution should be exercised because the hemangioma may recur after withdrawal of the steroids. The use of systemic steroids is not without risks; known complications of prolonged steroid use can be seen with this therapy, such as growth suppression, immune compromise, and the development of cataracts and cushingoid features. Consultation from pediatric endocrinology is often beneficial when using long-term steroid therapy. Intralesional steroids are an alternative to oral steroids and seem to have a higher percentage of cure; however, when

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utilized as the sole treatment modality, the local inflammation from manipulation of the hemangioma can result in prolonged periods of intubation and mechanical ventilation. Intralesional injection of steroids may best be utilized as an adjunct with other forms of therapy such as laser therapies or debulking procedures. Findings that recombinant interferon-α was effective in managing Kaposi sarcoma and pulmonary hemangiomatosis, as well as the in vitro observation of inhibition of capillary endothelium locomotion by interferon-α, led to a trial of this drug for hemangiomas. Empiric doses of interferon-α2a of 2–3 million units/m2 utilized subcutaneously for 6–12 months has proven modestly effective, with a majority demonstrating at least 50% regression. It does seem to be help at preventing the need for tracheotomy or achieving earlier decannulation in those infants with prior tracheotomy. Side effects of interferon, which include fever, neutropenia, and skin necrosis, were typically transient and minimal. The reports of spastic diplegia in young infants after the use of interferon as presented in the previous papillomatosis section is especially relevant in the treatment of subglottic hemangioma, as most of these patients are infants. Interferon should be considered only when traditional therapeutic modalities fail and especially when subglottic hemangioma is part of a massive lifethreatening cervicofacial hemangioma. Vincristine is a vinca alkaloid chemotherapeutic agent that has been found useful in some cases of steroid-resistant hemangiomatosis.24 It inhibits mitosis by acting on cell microtubules and is hypothesized to be effective in hemangiomas as these lesions may have an elevated tubulin content. Much of the experience of this medication with hemangioma has been in children with Kassabach–Merritt syndrome. Although adverse effects are somewhat less common in children than adults with vincristine, they should be considered; neurotoxicity is the main concern, with manifestations of constipation, ileus, and abdominal pain as well as bone pain. Oncologists, given their expertise in managing dosing and complications of this medication, should administer the vincristine. The most exciting treatment modality in the armamentarium against hemangioma is that of the β-blocker, propranolol. It was noted to decrease cutaneous hemangiomas in children receiving the drug for cardiac complications of steroid therapy for aggressive hemangiomas, and was subsequently applied to otherwise healthy children with hemangiomas, often with dramatic results.25 There have been multiple reports of success with propranolol shrinking subglottic hemangioma and obviating any other form of intervention such as debulking or open surgical resection (see Fig. 98-8). Indeed, propranolol has become a mainstay of therapy for pediatric dermatologists managing cutaneous hemangioma. Adverse effects have been limited, with rare cases of hypoglycemia, somnolence, bronchospasm, hypotension, and failure to thrive noted. Present doses vary but are typically in the range of 2–3mg/kg divided in 2–3 daily doses. Duration of therapy is also not fully elucidated, but

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FIGURE 98-8. Same lesion 5 days after the treatment with propranolol.

many use it for a period of over 1 year; typically once the lesions are not symptomatic and cease to be improved by the medication, it can be weaned. A small subset of patients may not respond completely or may develop recurrent hemangioma after weaning from the propranolol, and they pose a dilemma in treatment, often necessitating other medical or surgical therapy to completely address the disease. Surgical Therapy The first decision that needs to be made in symptomatic cases is the necessity of tracheotomy. If the lesion is recognized early, a tracheotomy can be avoided and the hemangioma can be treated by other means, thus obviating the known morbidity associated with infantile tracheotomy. In severe, life-threatening cases, tracheotomy can be performed to establish an airway. In these cases, the hemangioma should still be treated aggressively to shorten the time until decannulation. Laser treatments have long been used for the treatment of subglottic hemangioma. The CO2 laser was the workhorse until the recent introduction of angiolytic lasers; both types of laser are acceptable modalities. Although it has a very high rate of success of 89%, multiple laser procedures are the norm owing to persistence of the hemangioma and regrowth related to an ongoing period of proliferation.26 The rate of subglottic stenosis can be considerable, at 6%–25%, most commonly when disease is bilateral or circumferential. Temporary tracheotomy is sometimes necessary. Many authors have suggested guidelines that treatment to decrease the tumor size must be performed in a manner that leaves the larynx functionally normal. The use of intense

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postoperative humidification to avoid crust formation is critical. CO2 laser should only be used on capillary-type lesions as cavernous lesions have vascular spaces too large for the hemostatic properties of the laser. It should be utilized in patients with exclusively subglottic lesions and not in those with diffuse hemangioma extending to the trachea. Staged resection of large subglottic lesions is also preferable to prevent the apposition of raw mucosal surfaces. When these precautions are observed, CO2 laser therapy is thought to be a safe, effective treatment of isolated subglottic hemangiomas. Both the neodymium:yttrium-aluminum-garnet (Nd-YAG) and the argon lasers have been used to treat subglottic hemangiomas but with limited success and a relatively high rate of complications. Other lasers have shown more promise. Potassium titanyl phosphate (KTP) laser and the pulsed dye laser have the advantage of an absorption spectrum corresponding to blood. Furthermore, each of these utilizes fiberoptic delivery methods. These advantages allow more direct delivery of laser energy than offered by a traditional CO2 laser, especially to distal subglottic hemangiomas and distal tracheobronchial tumors. A more focused delivery of lower energy laser could theoretically lead to less damage to the adjacent mucosa and thus possibly lessen the chance of the development of subglottic stenosis after laser therapy. The newer fiber optic CO2 laser also offers a more direct and controlled application of the laser energy. An endoscopic approach involving debulking of the hemangioma with a microdebrider has been described by the senior author, and it offers the ability to precisely excise defined amounts of the lesion with excellent visualization and an ability to preserve large amounts of mucosa and perichondrium. Staging of the procedure may be preferable in some larger lesions to decrease the risk of postoperative stenosis. Early extubation is the rule with this technique. Care should be taken in cavernous hemangioma cases where the risk of bleeding is higher. In general, topical vasoconstrictors suffice to maintain hemostasis intraoperatively. Open surgical excision, which is often thought to be associated with greater morbidity and postoperative scarring, does have its supporters. It offers the ability to completely excise the lesion and to simultaneously enlarge the subglottic laryngeal framework if cartilage grafting is performed in conjunction with the procedure. This procedure does require longer surgery times and longer intensive care unit stays than the other alternatives. Its greatest benefit is with bilateral or circumferential or otherwise large hemangiomas that would otherwise necessitate tracheotomy.22 In summary, multiple modalities are available for the treatment of subglottic hemangiomas, and frequently, a combination of therapies is used. With small or medium sized lesions, oral propranolol, oral or intralesional corticosteroids, and endoscopic debulking procedures with microdebrider and/or a laser should be considered. More extensive lesions, in addition to the above, can be considered for open excision, vincristine, or tracheotomy.

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SECTION 5 ❖ The Airway

Neurogenic Tumors of the Larynx Neurogenic tumors of the larynx are rare, with fewer than 200 cases reported in both children and adults. They occur in all age groups and are slightly more common in female patients. They tend to occur in the supraglottic region or the posterior larynx. Most of the benign neoplasms can be removed by transoral excision. Some of the more common neurogenic tumors that have been reported to occur in the larynx include neurofibroma, neurilemoma, granular cell tumor, and carcinoid tumor.27 Neurofibroma and neurilemoma are neoplasms of Schwann cell origin. Although they are similar in their clinical features, some characteristics may be used to distinguish between neurofibroma and neurilemoma. Neurilemomas are typically solitary and encapsulated, whereas neurofibromas are nonencapsulated and are more frequently multiple, especially in association with neurofibromatosis (von Recklinghausen disease). Histologically, neurilemoma, also known as benign schwannoma or neurinoma, has two characteristic cellular patterns: Antoni A and B. The Antoni A pattern designates cellular areas composed of a compact arrangement of bipolar cells whose nuclei occasionally line up in vertical palisades (Verocay body), whereas the Antoni B pattern consists of loosely organized nonaligned cells in a myxoid matrix. Complete excision, either endoscopically or in an open fashion, is recommended. Endolaryngeal neurofibromas may be solitary endolaryngeal lesions or may occur in association with systemic neurofibromatosis. The systemic association seems to be more common in children. The youngest patient reported had the diagnosis made at 3 months of age. The incidence of multiple neurofibromatosis has been estimated at 1 in 3000 births. Symptoms of laryngeal neurofibroma are dyspnea, voice change or hoarseness, cough, noisy sleeping or stridor, and less commonly, dysphagia. Nearly all the tumors described involve the arytenoids or the aryepiglottic folds. Although they often appear to be well encapsulated, microscopic extension along nerve roots is the rule. If a submucosal mass is discovered in the larynx, especially in a patient with other manifestations of neurofibromatosis, a biopsy specimen should be obtained for diagnosis. Complete surgical excision of the lesion is recommended but, in reality, may be difficult to achieve. For complete excision, a radical open surgical procedure is often required, and recurrence is frequent. Thus, multiple procedures may be necessary to completely excise the tumor. This problem is especially apparent in plexiform neurofibromas, which differ from nonplexiform lesions in that the former are highly infiltrating, more diffuse, and poorly localized and involve multiple nerves. Total removal may not be possible, even with total laryngectomy. Repeated local excisions may be necessary as the lesion begins to encroach on the airway. It is important to remember that this lesion is benign (albeit with malignant potential) and that

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judicious subtotal removal is indicated when vital structures are involved. Granular cell tumor in the pediatric larynx is very rare, with fewer than three dozen cases having been reported in the literature. Granular cell tumor occurs more commonly in the fourth to sixth decade of life and can develop in any part of the body.28 The most common site of involvement is the tongue. The larynx is reported to be involved in approximately 7%–10%. It was originally thought to be a neoplasm of muscular origin, but most experts presently believe the origin of the tumor to be neurogenic, either Schwann cell or primitive neuroectodermal cell. Histologically distinctive, the cells are polymorphic with abundant acidophilic and granular cytoplasm. Nuclei are small, vesicular, and centrally located. Mitosis is rare. The common unique phenomenon of pseudoepitheliomatous hyperplasia in adult laryngeal granular cell tumor (50%–60%) has not been found in pediatric cases. In adults, superficial biopsy of tumors with this phenomenon can lead to the misdiagnosis of squamous cell carcinoma. In pediatric patients, the initial symptoms are usually hoarseness, stridor, and respiratory difficulty. The sites of origin in children are principally confined to the glottis and subglottis, in contrast to adults, in whom subglottic involvement is rare. Clinically, the lesions appear as a polypoid or sessile mass that may be solitary or multiple. A 10%–15% rate of multicentricity is reported. This tumor generally takes a benign course, and most pediatric patients have responded well to the treatment of choice, local endoscopic excision. The recurrence rate is low, 2%–8%, even in those with incomplete excision. Some patients had extensive enough tumor to require laryngectomy. Although malignant granular cell tumors have a reported incidence of 1%–3%, only one tumor has been reported in the larynx, and none of the pediatric cases have been malignant.

Miscellaneous Benign Laryngeal Tumors Fibrous histiocytoma is a mesenchymal neoplasm that is extremely rare in the larynx. Just 18 cases have been reported; only two of which have involved children. Controversy exists regarding the cell of origin in this tumor, as reflected by the confusing and variable nomenclature used. Most authorities believe that the histiocyte is the cell of origin, whereas some think that the cell of origin is a primitive, undifferentiated mesenchymal stem cell. The confusion is underscored by Blitzer et al.,29 who list 21 different synonyms for fibrous histiocytoma. The differential diagnosis includes other benign and malignant mesenchymal neoplasms such as fibromatosis, fibrosarcoma, myoblastoma, and pleomorphic rhabdomyosarcoma. Differentiating these various diseases can be quite difficult, and electron microscopy is usually necessary to confirm the diagnosis. Given the rarity of this disease and difficulty in differentiating between benign and malignant disease, complete excision followed by long-term follow-up is recommended, with routine repeat endoscopy and biopsy.

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CHAPTER 98 ❖ Tumors of the Larynx, Trachea, and Bronchi Recurrence of the lesion would then demand more aggressive surgical extirpation. Inflammatory pseudotumor of the larynx has been reported in several children, and typically causes obstructive upper airway symptoms.30 Histologically, this lesion is composed of mesenchymal and inflammatory infiltrates. Involvement of the airway with this lesion is usually in the pulmonary parenchyma. When the upper airway is involved, endoscopic removal or open surgical excision of the lesion should be performed.

Malignant Laryngeal Tumors Malignant tumors of the larynx are uncommon in children. Barnes et al.31 reviewed the literature in 2001 and noted a total of 63 cases of laryngeal or laryngopharyngeal malignancies in children and adolescents. Laryngeal malignancies in children are mainly of mesenchymal origin. Indeed, mesenchymal histologies make up over two-thirds of all such malignancies, in contrast to adult laryngeal cancer that is primarily epithelial in nature. In children, rhabdomyosarcomas, predominantly of the embryonal type, are most commonly noted. Squamous cell carcinomas are the next most common. The remainder of cases include synovial sarcoma, malignant fibrous histiocytoma, non-Hodgkin lymphoma, chondrosarcoma, Ewing sarcoma, fibrosarcoma, malignant schwannoma, mixed sarcoma, mucoepidermoid carcinoma, and primitive neuroectodermal tumor. Ferlito et al.32 did not find that children with laryngeal cancer had the usual risk factors such as exposure to radiation therapy, chemicals, or active/passive smoking. The male– female ratio was approximately 3:1. The average age for the development of rhabdomyosarcoma was younger than that for squamous cell carcinoma, 9 versus 12 years. The most frequent site was supraglottic at 37%, followed by glottic at 22%. The most common symptoms were dyspnea, hoarseness, and dysphagia. Direct laryngoscopy and bronchoscopy with biopsy are essential in establishing the type of malignancy, as well as defining its extension. A metastatic work-up, including a skeletal survey, bone scan, and bone marrow biopsy, as well as chest CT, is important, particularly for rhabdomyosarcomas. The choice of treatment depends on the histologic type, clinical stage, and available treatment regimen. For rhabdomyosarcoma, a combination of radiation and multiagent chemotherapy is usually recommended, surgery generally being reserved for biopsy and debulking only. For squamous cell carcinoma, treatment with radiation with or without chemotherapy, or surgery, or both, is indicated. When radiation therapy is used in children, the possibility of growth arrest and radiation-induced malignancy must be factored into selection of the method of treatment. Unlike younger adults, pediatric laryngeal squamous carcinomas are well-differentiated keratinizing carcinomas, and survival is relatively good. Using both CT and MRI preoperatively enhances one’s ability to more

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accurately determine the extent of extirpation necessary. The overall survival of children seems to be at least as good as that of adults. In all these pediatric laryngeal malignancies, the principle of early identification of unusual laryngeal findings in children with hoarseness or voice change is stressed. Prompt recognition plus treatment of any abnormal laryngeal mass in a young child with hoarseness is critical.

TUMORS OF THE TRACHEA (TABLE 98-2) Primary tumors of the trachea are rare, with limited literature available. Only 6% of primary tracheal tumors occur in the pediatric population. Desai et al.33 reviewed the literature for the period from 1965 to 1995 and found that 36 primary neoplasms of the trachea were reported in children and adolescents. Some differences were noted in the occurrence of the various types of tracheal neoplasms in children in comparison with the previous review by Gilbert et al.34 who found 42 tracheal tumors in children reported between 1908 and 1952. Desai et al. found that only 64% of the tracheal tumors were benign, whereas Gilbert et al. reported that over 90% were benign. In Desai et al.’s series, the predominant benign tracheal tumors were hemangiomas, granular cell tumors, and benign fibrous tumors (benign fibrous histiocytoma and mesenchymoma), whereas Gilbert et al. noted that papilloma, followed by fibroma and angioma were most common. Tracheal papillomas accounted for almost 60% (23/39) of the benign tracheal tumors in Gilbert et al.’s review and only 13% (3/23) in Desai et al.’s report. This significant change may be more a reflection of a change in reporting bias and not a true change in histopathology. Malignant tracheal tumors in children include malignant fibrous histiocytoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, rhabdomyosarcoma, squamous cell carcinoma, and carcinoid. Gilbert et al. reported only three tracheal malignancies, all sarcomas. The wider histopathology found in the more recent literature probably represents evolution of the pathologic classification. Desai et al. found that tracheal tumors occur most frequently in the cervical trachea and that malignant tumors occur distally, in the intrathoracic trachea. The available data showed that the tracheal tumors most commonly originated from the posterior wall of the trachea. Malignant tumors tended to develop later, with 11 of the 13 malignancies occurring during adolescence. The initial symptoms were most commonly wheezing (56%), stridor (36%), cough (33%), and dyspnea (9%). Other symptoms include hemoptysis, especially in malignant lesions, hoarseness, and dysphagia. Symptoms from tracheal obstruction are not generally manifested until significant obstruction is present, at least 50%; hence, a delay in the diagnosis of tracheal neoplasms is expected. Desai et al. found that lesions

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TABLE 98-2. Tumors of the Trachea Type of Tumor

Benign

Malignant

Epithelial

Squamous papilloma Papillomatosis Oncocytoma Pleomorphic adenoma Mucous gland adenoma Myoepithelioma

Squamous carcinoma in situ Squamous cell carcinoma Adenocarcinoma Large cell undifferentiated carcinoma Adenoid cystic carcinoma Mucoepidermoid carcinoma Malignant mixed tumor

Mesenchymal

Fibroma Fibromatosis Chondroma Chondroblastoma Hemangioma Leiomyoma Lipoma Rhabdomyoma Lymphangioma Benign fibrous histiocytoma

Fibrosarcoma Rhabdomyosarcoma Chondrosarcoma Liposarcoma Angiosarcoma Spindle cell sarcoma Leiomyosarcoma Malignant fibrous histiocytoma

Neuroendocrine

Neurofibroma Schwannoma Paraganglioma Granular cell tumor

Carcinoid tumor—typical and atypical Large-cell neuroendocrine tumor Small-cell neuroendocrine tumor

Hematopoietic

Plasmacytoma Reticulocytoma Hemangioendothelioma Hemangiopericytoma

Malignant hemangioendothelioma Lymphoma Leukemia

Miscellaneous

Hamartoma Adenolipoma Teratoma Amyloidosis

Metastatic carcinoma Malignant teratoma

obstructed 50%–95% of the lumen by the time that they were diagnosed. The diagnostic work-up should begin with radiographs of the airway, neck, and chest, possibly followed by contrasted CT or MRI (or both) of the neck and chest, to evaluate intraluminal and extraluminal spread of the disease. Other tests that can be of assistance include barium swallow, especially for those with dysphagia, angiography, and pulmonary function tests (flow–volume curve). A definitive diagnosis requires direct laryngoscopy, bronchoscopy, and possibly esophagoscopy to determine the extent of disease, obtain a biopsy specimen for tissue diagnosis, and ensure an adequate airway. The rarity and the variety of the tumors limit the experience in treating pediatric tracheal tumors. In general, surgical excision appears to be the mainstay of therapy and may be performed either endoscopically or open through a tracheal fissure or by tracheal resection. As dictated by histopathology, radiotherapy and/or chemotherapy may be added. Close

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follow-up with CT/MRI, as well as serial bronchoscopy, is necessary.

Other Rare Tumors of the Trachea Fibrous histiocytoma of the trachea is very rare, with only 10 patients being reported, 7 of whom were younger than 18 years. Just as for fibrous histiocytoma of the larynx, histologic identification can be difficult. The histologic criteria differentiating malignant from benign lesions are not well demarcated. Localization of the tumor in the lower part of the trachea is more commonly reported, with symptoms being related to this region (i.e., noisy breathing, progressive dyspnea, and hemoptysis). This location causes difficulty in airway management inasmuch as tracheotomy may not bypass the obstruction. Laser bronchoscopy offers the most efficacious means of debulking. Local resection, frequently under bronchoscopic control, is the preferred method of treatment; however, recurrence is common. In malignant cases, tracheal resection is mandated.

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CHAPTER 98 ❖ Tumors of the Larynx, Trachea, and Bronchi

TUMORS OF THE BRONCHUS Although primary bronchial tumors in children are rare, they are more common than primary tracheal neoplasms. Unlike tracheal tumors, the majority of bronchial neoplasms are malignant. A large variety of benign lesions have been identified.

Benign Tumors Inflammatory Pseudotumor Inflammatory pseudotumor is the most common benign bronchial tumor in children. It consists of a proliferation of reticuloendothelial cells that arise from an inflammatory response to a previous insult, such as infection or trauma. Approximately 50 cases have been reported in children younger than 16 years. The youngest child was 1 year of age at diagnosis, although most lesions are identified in children older than 5 years. Symptoms are usually rare and nonspecific, such as fever or cough. Occasionally, pain, hemoptysis, or pneumonitis is encountered. The natural history is slow growth with a tendency to local invasiveness. Treatment generally requires excisional surgery with bronchoplasty. Hamartomas These lung lesions consist of an abnormality in the proportion or arrangement of normal pulmonary elements. Approximately 15 cases have been reported in children. The lesion is mostly parenchymal in nature, is often quite large, and causes significant symptoms or severe respiratory distress. A triad of tumors consisting of pulmonary hamartoma, extra-adrenal paraganglioma, and gastric smooth muscle tumors has been identified in young women. In a setting of any young female who is identified as having any one of these three lesions, the clinician must search for the other two.

Malignant Tumors Bronchial Adenomas The term bronchial adenoma is a misnomer that unfortunately misleads clinicians into believing that they are dealing with a benign disease. This term refers to a heterogeneous group of lesions with significant malignant potential. Included in this category are bronchial carcinoids, mucoepidermoid carcinoma, and adenoid cystic carcinoma. They are generally slow growing, and symptoms include recurrent pneumonia, hemoptysis, wheezing, chest pain, pleural effusion, persistent cough, and dyspnea. The differential diagnosis includes asthma, foreign bodies, tuberculosis, aspergillosis, hamartoma, bronchiectasis, and cystic fibrosis. Bronchial carcinoids are the most commonly reported bronchial tumors in children. Of these, approximately 10%–15% are found to have metastatic disease. Carcinoid syndrome develops in exceedingly few patients with metastatic disease. Typical bronchial carcinoids have low malignant potential, whereas atypical carcinoids are much more

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aggressive lesions that are capable of lymphatic invasion and distant metastases. They are in the amine uptake and decarboxylase group of tumors and are derived from multipotential neural crest cells known as Kulchitsky cells. Signs and symptoms in children are wheezing and atelectasis, in addition to the classic triad of cough, pneumonitis, and hemoptysis described in adults. The diagnosis is made by endoscopy, and the tumor appears as a polypoid mass that is either partially or totally obstructing the bronchus. Biopsy is necessary but may cause significant bleeding. Because of concern for recurrence (60%–75% recurrence rate with endobronchial excision), as well as metastatic spread, endoscopic resection is not recommended. Conservative surgical resection with removal of any involved lymphatics is the treatment of choice. Follow-up is performed with repeat bronchoscopy and CT/ MRI examination. The prognosis after complete excision is good, with a reported survival rate of 90%. Mucoepidermoid Carcinoma Mucoepidermoid carcinoma occurs less frequently than bronchial carcinoids, with just over two dozen cases reported in children. These lesions are histologically identical to the more common mucoepidermoid carcinomas of the salivary glands and can be classified into low-, intermediate-, and high-grade tumors. Recurrent pneumonia is the most common initial symptom. These tumors tend to be of low malignancy in children, and only one case of metastatic spread to the regional lymph nodes has been reported. The tumor is noted to arise from the main stem bronchus or the proximal portion of the lobar bronchus. The lesions are usually covered with normal mucosa; hence, bronchial washings are not useful in diagnosis. Conservative surgical resection is the treatment of choice, and no recurrence has been reported after complete resection. Adjuvant chemotherapy or radiation therapy is not necessary if the resection is complete. Adenoid Cystic Carcinoma Only a handful of cases of adenoid cystic carcinoma have been noted in children. These tumors are locally aggressive lesions, and they disseminate through lymphatic and perineural channels. En-bloc resection with hilar lymphadenectomy appears to be the best approach to these tumors. Postoperative radiation may be required, with indefinite follow-up for distant metastatic disease. Bronchogenic Carcinoma Bronchogenic carcinoma has been identified in children, with approximately 50 cases noted in the literature. Undifferentiated carcinoma and adenocarcinoma account for 80% of the lesions. Unfortunately, the disease is frequently disseminated at the time of diagnosis, and such dissemination is the reason for its poor prognosis. If the lesion is identified early, surgical and adjunctive therapies can be curative. Two cases of bronchogenic carcinoma have been noted in congenital cystic malformations. This finding is somewhat

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disturbing; hence, it is recommended that patients with asymptomatic congenital cystic malformations who do not undergo surgical resection be closely monitored. Miscellaneous Tumors Various other malignant lesions have been identified in the tracheobronchial tree of children, including pulmonary blastoma, leiomyosarcoma, rhabdomyosarcoma, hemangiopericytoma, malignant teratoma, plasmacytoma, and myxosarcoma. Symptomatic children are more likely to have a malignant lesion than those who have their tumor identified by routine screening. If it is suspected that a lesion is present, bronchoscopy can reveal most tumors and thus allow for earlier diagnosis and treatment. An improved prognosis depends on early identification and prompt surgical intervention.

References 1. Derkay CS. Task force on recurrent respiratory papillomas. A preliminary report. Arch Otolaryngol Head Neck Surg. 1995;121:1386–1391. 2. Armstrong LR, Derkay CS, Reeves WC, the RRP Task Force. Initial results from the national registry for juvenile onset recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg. 1999;125:743–748. 3. Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryngoscope. 2008;118:1236–1247. 4. Rimell FL, Shoemaker DL, Pou AM, Jordan JA, Post JC, Ehrlich GD. Pediatric respiratory papillomatosis: prognostic role of viral typing and cofactors. Laryngoscope. 1997;107:915–918. 5. Pignatari S, Smith EM, Gray SD, Shive C, Turek LP. Detection of human papillomavirus infection in diseased and nondiseased sites of the respiratory tract in recurrent respiratory papillomatosis patients by DNA hybridization. Ann Otol Rhinol Laryngol. 1992;101:408–412. 6. Stern Y, Felipovich A, Cotton RT, Segal K. Immunocompetency in children with recurrent respiratory papillomatosis: prospective study. Ann Otol Rhinol Laryngol. 1997;116:169–171. 7. Kashima H, Mounts P, Leventhal B, Hruban RH. Sites of predilection in recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol. 1993;102:580–583. 8. Irwin BC, Hendrickse WA, Pincott JR, Bailey CM, Evans JN. Juvenile laryngeal papillomatosis. J Laryngol Otol. 1986;100:435–445. 9. Shah K, Kashima H, Polk BF, Shah F, Abbey H, Abramson A. Rarity of cesarean delivery in cases of juvenile-onset respiratory papillomatosis. Obstet Gynecol. 1986;68:795–799. 10. Gallagher TQ, Derkay CS. Recurrent respiratory papilloma: update 2008. Curr Opin Otolaryngol Head Neck Surg. 2008;16:536–542. 11. Snoeck R, Wellens W, Desloovere C, et al. Treatment of severe laryngeal papillomatosis with intralesional injections of cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine]. J Med Virol. 1998;54:219–225. 12. Pransky SM, Magit AE, Kearns DB, Kang DR, Duncan NO. Intralesional cidofovir for recurrent respiratory papillomatosis

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14. 15.

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22. 23.

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28.

29. 30.

in children. Arch Otolaryngol Head Neck Surg. 1999;125: 1143–1148. Pransky SM, Albright JT, Magit AE. Long-term follow-up of pediatric recurrent respiratory papillomatosis managed with intralesional cidofovir. Laryngoscope. 2003;113:1583–1587. Soma MA, Albert DM. Cidofovir: to use or not to use? Curr Opin Otolaryngol Head Neck Surg. 2008;16(1):86–90. Broekema F, Dikkers FG. Side Effects of cidofovir in the treatment of recurrent respiratory papillomatosis. Eur Arch Otorhinolaryngol. 2008;265:871–879. Gerein V, Rastorguev E, Gerein J, Jecker P, Pfister H. Use of interferon-alpha in recurrent respiratory papillomatosis: 20-year follow-up. Ann Otol Rhinol Laryngol. 2005;114: 463–471. Rosen CA, Woodson GE, Thompson JW, Hengesteg AP, Bradlow HL. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg. 1998;118:810–815. Bostrom B, Sidman J, Marker S, Lander T, Drehner D. Gefitinib therapy for life-threatening laryngeal papillomatosis. Arch Otolaryngol Head Neck Surg. 2005;131:64–67. Rogers DJ, Ojha S, Maurer R, Hartnick CJ. Use of adjuvant intralesional bevacizumab for aggressive respiratory papillomatosis in children. JAMA Otolaryngol Head Neck Surg. 2013;139:496–501. Pignatari SS, Liriano RY, Avelino MA, Testa JR, Fujita R, De Marco EK. Gastroesophageal reflux in patients with recurrent laryngeal papillomatosis. Braz J Otorhinolaryngol. 2007;73:210–214. Basheda SG, Mehta AC, De Boer G, Orlowski JP. Endobronchial and parenchymal juvenile laryngotracheobronchial papillomatosis. Effect of photodynamic therapy. Chest. 1991;100:1458–1461. O-Lee TJ, Messner A. Subglottic hemangioma. Otolaryngol Clin N Am. 2008;41:903–911. North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001;137:559–570. Perez J, Pardo J, Gomez C. Vincristine—an effective treatment of corticoid-resistant life-threatening infantile hemangiomas. Acta Oncologica. 2002;41:197–199. Léauté-Labrèze C, Dumas de la Roque E, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–2651. Bitar MA, Moukarbel RV, Zalzal GH. Management of congenital subglottic hemangioma: trends and success over the past 17 years. Otolaryngol Head Neck Surg. 2005;132:226–231. Stanley RJ, Scheithauer BW, Weiland LH, Neel HB. Neural and neuroendocrine tumors of the larynx. Ann Otol Rhinol Laryngol. 1987;96:630–638. Amar YG, Nguyen LHN, Manoukian JJ, Nguyen VH, O'Gorman A, Shapiro R. Granular cell tumor of the trachea in a child. Int Pediatr Otorhinolaryngol. 2002;62:75–80. Blitzer A, Lawson W, Biller HF. Malignant fibrous histiocytoma of the head and neck. Laryngoscope. 1977;87:1479–1499. Bouchène M, Fouchet M, Frachon-Collardeau S, Pignat JC, Merrot O. Inflammatory pseudotumor of the larynx in children [Article in French]. Ann Otolaryngol Chir Cervicofac. 2009;126:14–17.

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CHAPTER 98 ❖ Tumors of the Larynx, Trachea, and Bronchi 31. Barnes C, Sexton M, Sizeland A, Tiedemann K, Berkowitz RG, Waters K. Laryngo-pharyngeal carcinoma in childhood. Int J Pediatr Otorhinolaryngol. 2001;61:83–86. 32. Ferlito A, Renaldo A, Marioni G. Laryngeal malignant neoplasms in children and adolescents. Int J Pediatr Otorhinolaryngol. 1999;49:1–14.

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33. Desai DP, Holinger LD, Gonzalez-Crussi F. Tracheal neoplasms in children. Ann Otol Rhinol Laryngol. 1998;107:790–796. 34. Gilbert JG, Mazzarella LA, Feit LJ. Primary tracheal tumors in the infant and adult. Arch Otolaryngol. 1953;58:1–9.

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6

S E C T I O N

The Head and Neck Trevor J. McGill and Robert F. Yellon

99 Laser Surgery

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108

Malignant Tumors of the Head and Neck

100 The Neck: Embryology and Anatomy

109 Thyroid

101

Methods of Examination of the Head and Neck

110

102

Imaging of Pediatric Neck Masses

103

Neck Masses

111 Cranofacial Development and Congential Anomaly: A Contemporary Review of Processes and Pathogenesis

104

Congenital Cysts and Sinuses of the Head and Neck

105

Cervical Adenopathy

106

Head and Neck Space Infections

107

Benign Tumors of the Head and Neck

Injuries of the Neck

112

Primary Care of Infants and Children with Cleft Palate

113

Pediatric Plastic Surgery of the Head and Neck

114

Hemangiomas and Vascular Malformations

115

Pediatric Skull Base Surgery

26/02/14 1:10 PM

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99

C H A P T E R

T

Laser Surgery Jay Werkhaven

he development of laser applications in pediatric otolaryngology has paralleled that in general otolaryngology. As newer applications have been developed, they have been extended to use within the pediatric population. Engineering advances have allowed the application of lasers to procedures in pediatrics which would not have been previously possible owing to size limitations. A unique application of lasers within the field of pediatric otolaryngology would be for the treatment of vascular malformations, which in general manifests in the younger age group rather than in adults. The acceptance of lasers within the subspecialty has mandated that the surgeon be familiar with multiple laser systems and procedures. The common use of the carbon dioxide (CO2) laser is part of most every residency programs. In addition, education and the use of other wave lengths such as neodymium: yttrium-aluminum-garnet (Nd:YAG), potassium–titanium–phosphate (KTP), and flashlampexcited dye lasers has been incorporated into most training programs as well. Knowledge of each of these systems and of the differences between these lasers is important because safety protocols vary depending upon the wave lengths. In most hospitals clinical privileges for use of lasers are, therefore, given on an individual wave length basis after demonstrating proficiency in knowledge and safety issues. The application of lasers within otolaryngology in general can be traced to 1967, when Sataloff1 first used the neodymium: glass laser against otosclerotic stapes. Unfortunately, his results were less than optimal, and the otologic applications of lasers were delayed. The first endoscopic application of the CO2 laser was described by Jako2 and, since his initial report, this laser has become the workhorse within the field. Other lasers operating at different wavelengths have been developed and have found specific applications to which they are most suited, new lasers are in various stages of developmental testing, and newer delivery systems have been developed to extend the use of existing lasers. Although the criticism was made, with some accuracy, that the laser was a technology in search of an application, this is no longer the case. Initially, the laser represented a new modality for delivering a thermal effect to tissue. Although there are some unique advantages to the delivery systems of the laser, the tissue response is basically similar in most surgical laser applications (i.e., a thermal vaporization or coagulation). However, the development of lasers for specific applications has been demonstrated by the flashlamp-excited dye laser. This laser was the first for which the proposed clinical application was identified before the development of the specific parameters

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of the laser.3 The future of lasers may be represented by the experimental investigations provided by the free electron laser. This is a research laser capable of providing wavelengths between 2 and 10 μm and is continuously tunable within this range to allow experimental studies of specific wavelengths and pulse parameters. Investigations with this laser have identified a potentially useful wavelength at 6.45 μm. This wavelength falls on the amide II absorption band of protein and allows cutting of tissue and bone with extreme precision and minimal thermal effect lateral to the cut.4 It is the goal of this chapter to outline the basic physics, safety, and potential clinical applications of each laser. An understanding of the physics of lasers enables the surgeon to select the appropriate laser for various clinical applications on the basis of desired and anticipated tissue effects. Safety considerations are obviously important, not only for the surgeon and the patient but also for operating room personnel, and the controversy regarding the hazards of laser plume and potential viral transmission should be appreciated. Each of the surgical lasers in common use has been tried in an extensive variety of applications. Each laser has demonstrated itself to be especially useful in certain applications. The discussion of laser applications focuses on those applications generally accepted in common use and applicable to the pediatric population.

PHYSICS The basic premise for the generation of laser energy was formulated by Einstein5 in 1917. The concept of the stimulated emission of a photon from an excited system was the basis for the development of the first operating laser in 1958.6 Current surgical lasers operate in a narrow wavelength region around the visible light spectrum, but experimental lasers have been developed that operate in the X-ray and the far infrared wavelengths. As an engineering device, the laser can be considered to be composed of a lasing medium, a resonant cavity, and an excitation energy source. The lasing medium can be composed of free electrons, semiconductor materials, ions, atoms, or molecules. For brevity in discussion, the atom is used as a basic example. Atoms are composed of electron shells in discrete or quantitized energy states. Transition between states from a lower to a higher level requires the input of energy; conversely, transition from a higher to a lower state results in the emission, or yield, of energy. This energy is typically in the form of electromagnetic radiation. The quantitized amount of electromagnetic radiation is termed a photon.

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When a population of atoms is in their lowest energy transition state, it is called the ground state. An atom in the ground state can interact with a photon, absorb energy, and be promoted to a higher energy state, or an excited state. Once this atom is in the higher energy state, it can undergo transition back to the ground state with the spontaneous release of electromagnetic radiation (or photon), a process called spontaneous emission. Stimulated emission occurs in a system where this photon then interacts with another atom that already exists in a higher energy state. This photon can cause the transition from a higher energy level to a lower energy level with the emission of a second photon from the second atom. For this process to occur, the potential transition state of the second atom must exactly match the energy state of the incident photon. Thus, two photons are released from the system, the original photon and the second, emitted photon. These two photons are of equivalent wavelength and are coherent (coordinated in space and time). Coordination in space and time means that both the incident and the emitted photons are traveling in the same direction with their wavelengths in phase.7 Within a laser, an external energy source must be applied to the lasing medium to raise the atoms within the medium to the excited energy state. For the process of developing a laser beam to proceed, more than half the population of atoms within the lasing medium must be in the excited state, a phenomenon called population inversion. The energy can be input into the lasing medium in several ways. Typically, an electric current, radiofrequency energy source, or flashlamp is used to deliver energy into the lasing medium. With many of the atoms in the lasing medium in a higher energy state, spontaneous emission occurs frequently and in a random spacial orientation. The last requirement for a surgical laser, therefore, is an optical cavity to redirect, focus, and amplify the spontaneous emission of photons into a concentrated, usable output. To accomplish this, the lasing medium is placed inside an optical cavity. Typically, the optical cavity is a space between two special mirrors. One mirror is completely reflecting, and the other mirror is only partially reflecting, therefore allowing a portion of the generated laser beam to pass through the mirror and thus be available for use. The cascade effect begins when a photon is spontaneously emitted along the axis of the optical cavity. Photons are reflected between the two mirrors, and, as the photons interact with other excited atoms, another photon is generated that is coherent with the incident photon. Thus, one photon generates two, two generate four, and so on. This cascade effect would rapidly deplete the atoms existing in a stimulated state were it not for the constant input of energy from the electric current, radiofrequency excitation, or flashlamp. For the laser to function in a continuous mode, energy must be continuously applied to the lasing medium to keep the medium in a state of population inversion.8 Another important characteristic of the optical cavity is that its length must be an integer or multiple of the wavelength that is desired. This is necessary to create a standing wave within the cavity, allowing the photons to propagate.

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A nonintegral wavelength of the optical cavity would allow cancellation of energy by destructive interference of the wavelengths. The energy that is released through the partially reflective mirror is termed the laser beam. This energy is coherent (i.e., the photons are all in phase with one another and parallel in direction). This results in the unique characteristics of the laser beam, which are monochromaticity, intensity, collimation, and coherence. Once the beam exits the optical cavity, it may then be redirected into delivery devices that are specific for each surgical application. The mid-infrared wavelength of the CO2 laser is not transmitted through an optical fiber but is redirected by a series of mirrors down a hollow articulated arm system. This maintains the beam’s coherence, collimation, and intensity. At the end of the articulated arm assembly, the beam may then be passed through a lens, which serves to focus the beam to an extremely small spot size. Laser-visible and near-infrared wavelengths are capable of being transmitted through flexible optical fibers. The bending and flexing of the fiber result in the internal reflection of the beam within the fiber and the loss of the collimation of the beam. This loss of collimation is seen as beam divergence as it exits the fiber tip; the quality of the fiber determines the degree of divergence, typically between 8 and 30 degrees. Surgical lasers allow the operator to select power (watts) and exposure time (seconds). In addition, through manipulation of the fiber or the end-stage delivery device of an articulated arm (microspot micromanipulator or bronchoscopic coupler), the surgeon may also control the spot size. The surgical tissue effects of the laser are dependent on the amount of energy delivered to the tissue and the absorption of that particular wavelength within the tissue. Power density is a measure of the concentration of laser energy and is represented as power (watts) per square centimeter. Radiant exposure is expressed as power density × time and is represented as joules per centimeter squared (joules = power [watts] × time). Power density can vary linearly, as the power output of the laser is changed, or logarithmically, as the size of the laser spot is changed. Laser spot size may be changed by defocusing the fiber or pulling it away from the surgical field or by changing the site of focus of a micromanipulator or bronchoscopic coupler. Radiant exposure is a measure of the total energy delivered to the tissue and allows comparison of tissue effects for individual wavelengths at different energy exposures. As a general rule, the concept of power density (watts/cm2) is a more useful measurement for the surgeon. Generally, the higher the power density, the faster the vaporization of tissue occurs; conversely, the lower the power density, the slower vaporization or coagulation occurs.9

TISSUE EFFECTS The photons of light or laser energy can interact with tissue in one of several possible reactions. First, the photons may be reflected from the surface of the tissue and have no further

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CHAPTER 99 ❖ Laser Surgery interaction. Second, another reaction may be transmission through tissue. This can be compared with the phenomenon seen when a flashlight is used to shine through a patient’s fingers or hands to localize superficial veins. A potential application of this concept of transmission is diaphanography, in which a bright pulse of light is directed through breast tissue to localize breast masses that are more dense than surrounding fibrofatty tissue. Third, photons of light may be scattered within tissue, either by individual atoms or by variations in tissue structure such as sheets of collagen or muscle fibers. This scattering can redirect the photons of light back out of the tissue (indirect reflectance) or may allow further transmission through the tissue (indirect transmission). Finally, the photon of light may be absorbed by various chromophores within the tissue. Chromophores may be specific atoms, molecules, or macromolecular structures. Once a photon of light energy is absorbed, it elevates the chromophore to a higher energy level. Either a thermal effect is caused by the higher kinetic energy of the chromophore or the reemission of energy of a lower wavelength results in a phenomenon named fluorescence. It is the absorption of energy by chromophores within the tissue, with the resultant increase in kinetic energy that is the basis for application of most surgical lasers. The absorption of kinetic energy results in coagulation or vaporization of tissue. The absorption of energy by a chromophore is wavelength dependent. This concept results in the various specific tissue thermal effects from lasers of different wavelengths. The CO2 laser operating at 10,600 nm is absorbed well by one of the bending modes of the water molecule. Therefore, its tissue effects are best in tissues with high water content and are correspondingly less in tissues with low water content, such as bone. The Nd:YAG laser is poorly absorbed by most tissues in the body and, therefore, has one of the deepest optical penetration depths. The 1064-nm wavelength is not absorbed well by any specific chromophore but is absorbed in a nonspecific fashion by multiple compounds within tissue, and this results in a deep thermal coagulative effect. The argon laser with its main output wavelengths at 488 nm and 514 nm is absorbed by tissue proteins, melanin, and hemoglobin. The strong absorption by melanin and hemoglobin results in an intermediate optical penetration depth and good coagulation. The KTP/532 laser operating at 532 nm is absorbed less specifically by proteins, melanin, and hemoglobin but has an optical penetration depth and a thermocoagulation similar to those of the argon laser. The flashlamp-excited dye laser at 585 nm and the argon yellow dye laser of the same wavelength represent the first lasers designed to be absorbed by a specific chromophore. The wavelength was selected to be high enough to minimize protein and melanin absorption while still allowing adequate absorption by the chromophore hemoglobin. This results in specific absorption in vascular tissue.10 In summary, the surgical effect of a laser is due to the absorption of specific wavelengths of light, and the rate of surgical effect is determined by the power density or the rate at which energy is directed into the tissue.

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LASERS IN COMMON SURGICAL APPLICATION The common surgical lasers, in order of increasing wavelength, are the argon laser, KTP/532 laser, flashlampexcited dye laser, argon pump dye laser, diode laser, Nd:YAG laser, and CO2 laser. Each of these lasers has been around for many years and has demonstrated its usefulness for specific clinical applications. New applications and new lasers such as the Ho:YAG and Er:YAG lasers are constantly being developed and evaluated, and this list is subject to future change. The following sections discuss some lasers with potential clinical applications.

Argon Laser The argon laser uses a direct-current energy source to excite argon ions. The energy requirement to create argon ions from atoms and then stimulate them to a high energy state is relatively inefficient. These lasers generally need a flowing water cooling system because of the high heat generated. The argon ion laser is a multiple wavelength output laser with its two main output wavelengths at 488 nm and 514 nm in the blue and blue-green region of the visible spectrum. This laser can operate in a continuous mode with a fiber-optic delivery system. Early argon ion lasers had a power output limitation of less than 5 watts and initially found application only in dermatology. Newer argon ion lasers now have power output capabilities up to 20 watts for tissue vaporization and cutting.

KTP/532 Laser The KTP/532 laser uses a crystal matrix of Nd:YAG, whose laser output is directed through a KTP frequency-doubling crystal to decrease the wavelength from 1064 to 532 nm. This laser was initially developed in response to the low power output available with older-generation argon ion lasers. The 532-nm wavelength was shown to be well absorbed by hemoglobin and nonspecifically absorbed by melanin to a lesser extent than the argon laser. The output is through a fiberoptic delivery system. The high peak powers, up to 20 watts, allow coagulation and vaporization of tissue, which initially were not possible with the argon laser. Since the development of the KTP/532 laser, specific improvements to the device have expanded its potential applications. Modifications to the device itself allow the surgeon to operate not only with the 532-nm wavelength but also with the 1064-nm wavelength of the central Nd:YAG crystal. Beam delivery devices have been optimized for use with this laser for dermatologic applications, and a dye module, which may be added to the laser, allows production of other wavelengths dependent on the dye selected.

Flashlamp-Excited Dye Laser The flashlamp-excited dye laser represents the first laser designed for a specific application. Dermatologic applications of the argon laser especially demonstrated some long-term

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complications of pigmentation changes owing to melanin absorption and textural changes owing to nonspecific thermal coagulation effects within the dermis. The flashlampexcited dye laser was specifically designed for absorption by the chromophore hemoglobin. The wavelength was determined to be 585 nm for maximal absorption, and the optimal duration of the beam was experimentally determined to be 400 μsec.11 The tissue effect resulting from the use of this laser is coagulation of small vascular structures. This laser has found widespread application and acceptance in the treatment of cutaneous vascular lesions, such as port-wine stains and hemangiomas. Delivery output is through a fiber-optic cable directed into a handpiece with a fixed 3- or 5-mm spot size.

Argon Pumped-Dye Laser The argon pumped-dye laser was first used as a research tool. An argon laser is directed into a dye module, and the dye is excited to emit a laser output. Because of the macromolecular design of the dye, the output is tunable over a limited range, which is specific for each type of dye. Although this laser began as a research tool to allow investigation of tissue effects of various wavelengths, it found clinical applications in photodynamic therapy. An exogenous chromophore, such as hematoporphyrin derivative, is given to a patient and allowed to localize within target tissues. The absorption of ultraviolet wavelengths of light by this dye results in the fluorescence of the dye, allowing localization of the dye within the target tissue. Stimulation of a hematoporphyrin derivative at 633 nm in the red visible wavelengths results in absorption by the dye and production of singlet oxygen. The singlet oxygen results in a chemical cascade reaction, causing cell death of the target tissue.12 The laser itself, because of its use of an argon-exciting source, has high power and cooling requirements and can be delivered through a fiber-optic cable.

Diode Laser The diode laser has seen applications within Otolaryngology recently. This laser produces an 808 or 980 nm wavelength output that is delivered through a fiber-optic delivery system. The absorption of the diode laser is therefore slightly less than that seen for the Nd:YAG laser and deeper than that seen with the KTP/532 laser. This device is housed in a small unit making it portable and facile for use in a clinical office. Current applications include nasal, oral, and oropharyngeal procedures.

ND:YAG Laser The Nd:YAG laser is a flashlamp-excited crystalline matrix laser. The Nd atom is embedded in a YAG crystal and emits a wavelength at 1064 nm. The earliest Nd:glass laser emitted a wavelength at 1060 nm, and this variation in laser output illustrates the effect that surrounding environment may have on constraining the quantum states available to an atom and crystal lattice. As noted earlier, the absorption of the 1064-nm

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wavelength is nonspecific in tissue, resulting in a deep thermocoagulation. The delivery output from this laser is through a fiber-optic cable.

Carbon Dioxide Laser The CO2 laser has become the general-purpose laser within the field of Otolaryngology-Head and Neck Surgery. Since its initial endoscopic laryngeal applications by Jako2 in 1972, this laser has found widespread applications, both endoscopically and macroscopically. The output wavelength of 10,600 nm is produced by direct current or radiofrequency excitation of a gas mixture of CO2, nitrogen, and helium. The output of the laser is coupled to an articulated arm system, which, in turn, may be attached to a microspot micromanipulator for the microscope, a bronchoscopic coupler for the bronchoscope, or a handpiece. Output devices of a waveguide nature with outside diameters as small as 1 mm have been developed, and while they have a limited bend radius and are limited to 2 m in length, endoscopic and otologic applications are now practical with wave guides. An FDAacceptable fiber-optic cable is now available.13,14 Endoscopic applications with the microspot micromanipulator have been facilitated with the development of smaller spot sizes. The newer units available have spot sizes as small as 250 μm at 400-mm focal length and afford greater precision in the larynx than do older units.15 Macroscopic applications using fiber delivery and laser handpiece have found acceptance in oral cavity, head, and neck surgery. At the author’s institution, the CO2 laser is employed for almost 90% of all cases in which a laser is used.

LASER SAFETY AND ANESTHETIC CONSIDERATIONS Each type of laser has a unique wavelength and tissue effect. Therefore, it is the responsibility of the surgeon to obtain training in the safe use of the equipment as well as in the potential clinical applications. Courses exist to train the surgeon in the safe use of the laser and to give hands-on experience in the tissue effects. The courses that are offered cover various types of lasers and, as a mandate, include instruction in basic laser physics and in tissue interaction and safety. Safety considerations include those for the patient, the surgeon, and all operating room personnel. Safety issues encompass the hazards of stray laser exposure to all personnel within the operating room; the hazards of exposure to laser by-products, such as the laser smoke plume; and the hazards of laser exposure to anesthetic instruments, such as the endotracheal tube with the potential for fires. The highest principle of medicine holds that no untoward harm befalls the patient. To this end, the patient should be protected against any stray laser exposure. Eye protection varies by laser and, at a minimum, includes lubricating the eyes with a water-soluble lubricant (oil-based lubricants may have the potential for ignition), taping the eyes closed, and

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CHAPTER 99 ❖ Laser Surgery then protecting the eyes with saline-soaked gauze pads. This ocular exposure protection is adequate for the CO2 laser, but for visible-wavelength lasers and the Nd:YAG laser, which may penetrate easily through water, the added protection of aluminum foil over the eye pads is required. The operative field should be draped as well as possible and surrounded with moist towels; in appropriate circumstances, aluminum foil protection from stray laser exposure may also be required. All personnel within the operating room should wear protective eye shields that are specific for the laser wavelength being used. All laser-safe eye shields are imprinted with the optical density at the appropriate wavelength; if the glasses or goggles are not specifically marked as such, they are generally not acceptable. Ocular protection should include side shields to protect from stray laser exposure laterally. The windows in the operating room should be covered with an opaque material whenever visible-wavelength lasers are used, but the glass in a window will stop transmission of a CO2 mid-infrared laser. An official sign should be posted outside the operating room warning that laser operations may occur within the confines of the operating room. In addition, a spare set of safety glasses is usually left outside the door for operating personnel who wish to come inside the room while the laser is in operation. Although the fiber-optic transmission of certain laser beams have been said to be generally safe when within a body cavity, it is still prudent to be cautious. Although remote, the possibility does exist for accidental breakage of the optical fiber between the coupler and the operating field, with subsequent unplanned exposure to operating personnel. The hazards of exposure to the laser smoke plume have been recognized as a concern. When surgical lasers are used in the vaporization mode, the initial velocity of material ejected from the wound may be as high as several meters per second.16 The smoke plume can be seen to rise high above the operative field to the level of the surgeon’s and assistant’s heads, and, therefore, they may be exposed directly to laser plume products. Special laser masks with extremely small pores should be worn to minimize exposure to this laser plume. Studies have examined the contents of the laser plume, and although the studies were unable to demonstrate viable cells, intact fragments of DNA were demonstrated.17,18 The remote theoretical possibility exists for these fragments to be inhaled by operating room personnel. A survey of more than 2000 laser users was unable to conclusively demonstrate transmission of papilloma virus to operating otolaryngologists, gynecologists, or podiatrists, but the prudent approach dictates caution. A high-volume smoke evacuator should be used in the operating field to collect the laser plume. Other studies have looked at the effects of the plume itself in causing pulmonary inflammation and have demonstrated that the plume from use of the electrosurgical unit is at least as inflammatory as that from use of the surgical lasers.19 In light of all these facts, it appears that the most judicious course would also be to use smoke evacuation whenever an electrosurgical unit is in use.

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ANESTHESIA FOR LASER PROCEDURES The otolaryngologist, by virtue of the site of the specialty, must share access to the patient with the anesthesiologist. Use of lasers in the head and neck region is accompanied by the risk of accidental laser exposure to anesthetic equipment and endotracheal tubes. The early use of the CO2 laser resulted in some unfortunate cases in which the endotracheal tube was ignited, with a resultant fire and blowtorch effect within the patient’s airway. Some of these cases had disastrous outcomes. Whenever the laser is to be used within the region of the anesthetic equipment, laser-safe endotracheal tubes should be used and the anesthetic equipment as best as possible should be shielded with aluminum foil to prevent stray laser exposure. In the oral cavity, oropharynx, and glottis, a laser-resistant endotracheal tube must be used that is specific for the wavelength of laser that is being applied. Situations do occur, however, in which the endotracheal tube is too large or obstructs exposure to the operative field, and alternatives must be considered. Appropriate alternatives include the use of jet ventilation in the glottis, spontaneous ventilation, as well as the apneic technique, whereby the endotracheal tube is removed intermittently and work is performed while the patient’s oxygen saturation is monitored.20 It is an interesting counterpoint, and one of concern, that hospitals that require surgeons to have demonstrated instruction in safety and use of lasers do not require anesthesiologists to be likewise informed. Basins filled with water should be immediately available for all laser procedures to douse fires. The concentration of inspired oxygen should be 30% or below during use of the laser and nitrous oxide should not be used since these gasses are flammable. Fire extinguishers are required.

CLINICAL APPLICATIONS OF LASERS IN PEDIATRIC OTOLARYNGOLOGY It is a true axiom that children are not just “small adults.” Many laser applications initially developed for use on adult patients require reduction in size and modification of certain delivery instruments to make them available for use in pediatric patients. This is not the only difference. Because of reduced size, vital structures may be closer or more adjacent to each other and thus be at greater risk from scattered laser illumination. Healing and potential scarring are also often different compared with those of the adult patient. Examples of all these differences are illustrated in the following paragraphs; these differences serve to emphasize the justifiably conservative application of lasers within the pediatric population until all the data and effects are well known.

OTOLOGIC APPLICATIONS The argon, KTP, and diode lasers are used for otologic applications in the general adult population. The most common application of lasers is for stapedotomies and revision

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stapedotomy procedures. Several papers have analyzed the thermal effects of the various lasers, and some controversy still exists over which is the ideal unit to use for this procedure.21,22 In theory, the visible wavelengths of the argon and the KTP and diode lasers may be transmitted through a stapedotomy hole and damage structures within the vestibule.23 In practice, this has not been noted, which may in part be due to the divergence of the laser beam once it leaves the end of the fiber. From an engineering standpoint, it is somewhat more convenient for the surgeon to use the fiber-optic handpieces of the argon, CO2, and the KTP lasers versus the microspot micromanipulator of the CO2 laser, but all four units have their advocates. For the occasional stapedotomy surgeon, it appears that the learning curve for a laser-assisted stapedotomy is easier than that for classic techniques, and, therefore, this procedure allows the occasional surgeon more consistent results.24 No independent studies dedicated to the use of these lasers for stapedotomy in the pediatric population have been published, but many otologists have anecdotal reports of performing this procedure in older children and teenagers with good results. These lasers have also been used in middle-ear exploration work to remove scar and granulation tissue. They have proved a valuable adjunct to chronic ear surgery by the atraumatic and hemostatic removal of fibrosis and granulation tissue to allow better visualization. Again, the experience in children is limited, and concerns about laser exposure to the facial nerve and to the promontory must be considered. Various lasers, most especially the CO2 laser, KTP laser and the Nd:YAG laser have been used for performing myringotomy.25–27 In theory, the vaporization of the tympanic membrane with cauterization of the edges should allow a myringotomy hole to be performed hemostatically and quickly. It was originally thought that laser-performed myringotomy incisions would stay open an intermediate length of time between a cold steel myringotomy and a pressure equalization tube insertion (i.e., 30–60 days). Results have not shown that laser-performed myringotomy incisions stay open any appreciable length of time, which has significantly limited the usefulness of this procedure.28 Reports in the literature on the use of the laser for tympanoplasty welding have not documented its use in children. In this technique, a low-power argon, KTP, or CO2 laser is used to thermally fuse the graft to the edges of the perforation. The reports have indicated that although this technique is successful, the overall graft success rate is not significantly different from that for conventional techniques. Therefore, it appears that there is minimal benefit to be obtained from the use of lasers for tympanomeatal flap or tympanic membrane welding.29

RHINOLOGIC APPLICATIONS The rhinologic applications of lasers in the pediatric population have closely paralleled those in adults. In addition, the use of lasers for repair of choanal atresia has been investigated for many years. The limited exposure available

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in the pediatric nose encourages the development of less invasive techniques, for which the laser is of great potential benefit. However, especially in children, there may be significant disadvantages related to the proximity of vital structures to each other as well as to the thinness of tissue, which allows deeper optical scattering with potential harm to the orbit. Choanal stenosis has traditionally been repaired with a transpalatal or transnasal approach. The use of small sinus endoscopy telescopes has significantly reduced the number of patients who undergo transpalatal repair. Soft tissue stenosis may be repaired straightforwardly either by elevation of mucosal flaps and removal of soft tissue or by serial dilation and placement of indwelling stents. Lasers have been used to vaporize soft tissue choanal stenosis, with significant reduction in blood loss and with no difference in success or in morbidity. The argon, KTP, and CO2 micromanipulator systems lasers have all been used to perform vaporization of the soft tissue component of choanal stenosis. For the microscope and micromanipulator, the advantages of high magnification are somewhat offset by the inconvenience of delivery of the CO2 beam to the posterior aspect of the nose.30 The success rates for repair of soft tissue stenosis by the three types of lasers are roughly equivalent. Potential difficulties arise when the choanal stenosis is of a bony nature. In these cases, the three lasers have been demonstrated to be less beneficial in the removal of the bone. The holmium:YAG laser at 2.1 μm and the newer fiber-optic CO2 laser delivery systems, however, have shown initial benefit in these cases. The holmium:YAG laser can ablate both soft tissue and bone with a minimum of thermal char to the bone. Lasers may be effective for bone removal in choanal atresia, but there have been reports of fatal air embolism.31 The argon, KTP, Nd:YAG, and CO2 lasers have all been used for inferior turbinate reduction. The lasers are used in their coagulation or minimal vaporization mode to reduce the soft tissue hypertrophy over the inferior turbinate.32 Care must be taken in the use of these lasers to leave islands of normal mucosa to allow remucosalization, or the development of exposed bone and bony sequestrations may result. In addition, technical care must be exercised to avoid reflectance from the tissue surface with potential coagulation of septal mucosa. Microdebrider and coblator turbinate reduction are also good alternatives.33,34 The KTP/532 laser has been extensively promoted for use in endoscopic sinus surgery. The potential advantages of hemostasis with improved visualization and decreased tissue trauma have been promoted on the basis of procedures performed in adults. There are no reported ocular injuries in adults owing to transmission of the beam through the lamina papyracea. However, in children, there are anecdotal reports of diplopia resulting from medial rectus edema, presumably owing to the optical penetration of the beam through normal lamina papyracea. Because of the relative thinness of tissue in children and the proximity of vital structures to each other, it appears that the prudent and conservative approach would be to withhold application of the laser for endoscopic sinus

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CHAPTER 99 ❖ Laser Surgery surgery. The holmium:YAG laser, with its relatively shallow optical penetration depth, may have some potential applications, but studies have not yet been performed in children.35 The same is true for the fiber-optic CO2 laser.

ORAL/OROPHARYNGEAL APPLICATIONS Within the oral cavity and oropharynx, the surgical lasers have found application for removal of tongue lesions and floor of mouth lesions, glossal reductions, and lingual tonsil and lingual thyroid resections. The operative exposure in this region is such that any of the lasers can be used with their handpieces, including the CO2 laser. The Nd:YAG laser in contact mode has been found to be especially useful, but all surgical lasers are beneficial because of their hemostasis and decrease of muscular injury compared with resection with an electrosurgical unit. Tongue lesions, such as granulomas and small hemangiomas, can be removed completely. In operations on the tongue, the laser avoids the distortion the electrosurgical unit causes by contraction of the muscle. If the resection area is small, the area may be left to heal secondarily, whereas large resections may require primary closure. Vascular malformations and lymphangiomas may be photocoagulated with superficial illumination from the Nd: YAG laser because of its deep coagulative effect. Multiple treatments may be required, but hemiglossectomy or tongue resection may not be an option. The contact Nd: YAG laser has been especially useful in resection of ranulas of the floor of the mouth. Marsupialization results in an unacceptably high recurrence rate. The contact Nd: YAG laser allows resection of the cyst by allowing the surgeon to stay close to the cyst with good hemostasis and less than 1 mm of thermal coagulation surrounding the vaporization. Noncontact argon and KTP/532 laser use may result in 2–3 mm of thermal coagulation and, if the cyst extends deep, has the potential for lingual nerve injury. Although the CO2 laser with micromanipulator has been used for resections of ranulas, the tactile control of the newer fiber-optic CO2 and the contact Nd:YAG laser makes this procedure slightly easier technically. All the surgical lasers can be used efficaciously for glossal reduction in Beckwith-Wiedemann or Down syndrome. Either a stellate or a keyhole pattern resection is done in the midline of the tongue. In this resection, the lasers are especially useful because they do not cause muscular artifact that would be seen with electrosurgical units and therefore allow a more precise resection pattern. Hemostasis is generally good, and the wound is closed primarily. Incidence of chronic lingual tonsillitis is uncommon in younger children but presents with increasing frequency throughout the teens. Occasional lingual tonsil hypertrophy may result in airway obstruction and sleep apnea. Endoscopic removal of lingual tonsils may be performed with the CO2 laser and microspot micromanipulator, or with the fiber-optic CO2 laser. With the patient in suspension, the beam is defocused, and the lingual tonsils are ablated rather than resected.

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This results in much better hemostasis than would incision and resection.36 Another acceptable technique for resection of lingual tonsils is transoral resection using of the argon, KTP, or contact Nd:YAG laser with the tongue retracted far inferiorly. Exposure is usually adequate. Lingual thyroid has been removed when it has caused obstruction and dysphagia and is unresponsive to thyroid suppression.37 Hemostasis is generally good with all the surgical laser systems.

TONSILLECTOMY No other procedure within the field of otolaryngology has generated as much controversy as the performance of tonsillectomy using laser. All commonly used surgical lasers have been promoted at one time or another for this procedure. The argon, CO2, KTP, Nd:YAG lasers (in both contact and noncontact modes), and diode lasers have been used to perform tonsillectomy. Proponents have claimed decreased blood loss with better hemostasis, faster operating times, and decreased pain as beneficial effects of using laser. Each of the lasers being used is employed for its thermocoagulation properties and its simultaneous vaporization of tissue. The technique is to place the tonsil under tension and, staying carefully on the tonsil capsule, to vaporize the areolar tissue holding the tonsil to the underlying constrictor muscle. Depending on the laser used, as the perforating vessels are encountered, the laser may need to be defocused to cauterize these vessels, or electrocautery must be employed for the larger vessels. Unfortunately, lasers have been marketed as “painless” surgery, and some patients request the use of the laser for tonsillectomy in the misguided belief that their procedure will be completely without pain. The depth of thermocoagulation for the CO2 laser is on the order of 200 μm. The thermocoagulation depth of the contact KTP and Nd:YAG lasers is slightly deeper. Only when the argon or KTP/532 laser is used in a noncontact mode are thermocoagulation depths on the order of 1–2 mm approached with consistent sealing of blood vessels and minimal bleeding. Clinical situations exist, such as von Willebrand disease and hemophilia, in which this is desirable. This deeper thermocoagulation is associated with a delayed healing time, however, because the tissue takes 7–10 days longer to slough than in a standard cold steel or electrosurgical tonsillectomy. The delayed eschar slough occasionally results in postoperative bleeding as late as 14–20 days, but the incidence of postoperative bleeding is less. Proponents of decreased pain with laser tonsillectomy cite the sealing of nerves with resultant lack of axoplasmic leakage as the reason for reduced postoperative pain. Patients’ subjective reports of pain comparing a standard tonsillectomy on one side with laser tonsillectomy on the other side have yielded inconsistent trends. Objective measurements of oral intake of patients having laser tonsillectomy compared with patients having standard treatment have not shown statistically significant differences. Many of the studies comparing the laser techniques with traditional techniques of

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tonsillectomy are flawed by the numbers of patients who are too small to generate statistically significant data. The cost of the use of the laser is often passed on to the patient as an amortization cost. In addition, the use of an optical fiber or waveguide is often charged to the patient as a direct cost. This results in an increase in the overall cost of the procedure to the patient, which, in the current era of negotiated global prices for procedures, must be absorbed by the hospital and cannot be passed on to the patient. Current recommendations take into consideration the small potential benefit for increased hemostasis and decreased blood loss with the concomitant increased cost to the patient. The use of the KTP/532 or argon laser appears justified in those patients with a documented bleeding disorder, such as hemophilia or von Willebrand disease. In addition, the laser may be used for those patients in whom the surgeon wishes to avoid the potential electromagnetic interference with cardiac pacing units associated with use of electrosurgical units.38 The coblator is another good option.

GLOTTIC AND TRACHEAL APPLICATIONS The CO2 laser was the first surgical laser to be used for endoscopic applications, beginning with Jako’s report2 of laryngeal surgery in 1972. Since that time, the CO2 laser has become the most commonly used surgical laser in OtolaryngologyHead and Neck Surgery, and most CO2 laser procedures are performed endoscopically within the larynx or trachea. The laser is uniquely beneficial in endoscopic applications because of its hemostasis, precision, and hands-off approach. Other surgical lasers have specific, although limited, applications, but newer applications are being investigated. Despite all the potential advantages of the laser for endoscopic applications, most procedures can still be performed with cold steel techniques. The CO2 laser has been demonstrated to be the treatment of choice for palliation for recurrent laryngeal papillomatosis.39 The advantages of the CO2 laser of precision, hemostasis, and minimal thermal effect have resulted in a decrease in surgical complications, such as anterior glottic webs and scarring.40 There have been reports of the use of the KTP/532 laser for palliation of papilloma, but the depth of thermocoagulation lateral to the impact is a theoretical concern. Clinical trials of photodynamic therapy are very promising.41,42 Excision of glottic lesions can easily be performed with the CO2 laser. Epiglottic, glottic, and subglottic cysts may be either excised or marsupialized if they are exceedingly large. Hemorrhagic polyps may be removed avascularly.43 Vocal nodules are rarely removed in children; when strong indications exist for their removal, they may be shave-excised with the CO2 laser, but cold steel techniques with microflaps are probably more appropriate and result in less scarring. The microtrapdoor flap to preserve overlying mucosa is useful in the treatment of anterior and posterior glottic webs as well as of subglottic stenosis. With this technique, the laser is used to make an incision in the scar, and dissection raises a

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mucosal flap. The laser is then used to vaporize the substance of the scar tissue, and the flap is replaced to give immediate coverage and prevent reformation of scar. This has been successfully used in the treatment of anterior and posterior glottic webs as a one-stage procedure and in a serial fashion for sequential repair of subglottic stenosis of Cotton grades I and II.44,45 Subglottic hemangiomas present a difficult challenge. Many of these hemangiomas are capillary hemangiomas; therefore, the thermal coagulation afforded by the CO2 laser is adequate. The depth of the hemangioma is sometimes difficult to determine, and it may extend through the cricothyroid membrane or may have destroyed some of the cartilaginous support of the cricoid. Sequential excision with the CO2 laser is the conservative approach to spare lateral tissue, but vessels with significant vascular engorgement may be beneficially treated with the KTP/ 532 or argon laser. The 3- to 4-mm thermocoagulation depth from the Nd:YAG laser may cause unwanted damage to the underlying cricoid cartilage. Open surgical excision and propranolol treatment are also options.46,47 Excision of suprastomal granulation tissue after tracheotomy can be performed with the CO2 laser under direct vision and relatively avascularly. Excision of granuloma is usually not performed until the patient is ready to be decannulated because the routine excision of granulomas does not prevent their recurrence owing to the indwelling tracheotomy tube’s tendency to cause reformation. Excision of granuloma can be performed with the subglottiscope or the ventilating CO2 laser bronchoscope.48 A standard bronchoscope and CO2 laser fiber are an excellent newer option. Tracheal applications of surgical lasers are infrequently done but can be performed safely with the CO2, argon, and KTP/532 lasers. Obstructing endotracheal or endobronchial tumors may be ablated with surgical laser. When lesions are especially vascular, the KTP laser with a small fiber may be useful for vaporization with coagulation lateral to the impact point. For greatest thermal precision, the CO2 laser is the laser of choice. Historically, excision of scar tissue and granulation tissue is best performed with the CO2 laser ventilating bronchoscope.49 One difficulty with the use of this instrument is that the smallest size requires the trachea to be large enough to admit a 7-mm diameter bronchoscope. Currently, the fiber-optic delivery of CO2, KTP/532, or argon lasers may be achieved through the side channel of standard ventilating bronchoscopes.

CUTANEOUS APPLICATIONS Hemangiomas and vascular malformations are common in children. The clinical distinction between these two entities is related to the rate of growth. Vascular malformations grow proportionately with the child. Many common hemangiomas demonstrate spontaneous involution in early childhood. Early results with ruby and argon lasers in children (especially those younger than 12 years) were disappointing. Textural

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CHAPTER 99 ❖ Laser Surgery irregularities, scarring, and hyper- and hypopigmentation were potential complications. In theory, they were due to nonspecific absorption by melanin and proteins in the dermis.50 To overcome these problems, the flashlamp-excited dye laser was developed with a peak operating wavelength of 585 nm and a 400-μsec pulse duration to allow a compromise between coagulation and thermal diffusion. The flashlamp-excited dye laser is especially effective for decolorizing hemangiomas and superficial vascular malformations. The optical depth of penetration for this laser precludes its use in the deep dermis. It is especially useful for superficial cutaneous hemangiomas of the port-wine-stain type. The method of action is absorption of thermal energy by hemoglobin, with damage to the endothelium, and subsequent fibrosis of the vascular spaces, with decolorization of the hemangioma. Because of the selective absorption by hemoglobin, the overlying epidermis and the underlying dermis are spared with minimal structural changes. It is important to perform a test spot with exposure at various power densities to determine the optimal exposure for each patient, because skin type and melanin concentration vary from patient to patient.51 Good results from the use of this laser have extended its applications to treatment of strawberry hemangiomas at a young patient age. Even though many of these hemangiomas will demonstrate spontaneous involution, preliminary data suggest that early treatment with the flashlamp-excited dye laser slows the rate of growth. Rapidly growing hemangiomas can be also treated medically with propranolol.52 Vascular malformations that are not amenable to surgical excision or those that would result in an unacceptable cosmetic defect may be photocoagulated with the Nd: YAG or the KTP/532 laser. A needle is inserted lateral to the vascular malformation, and the fiber from the laser is introduced through the lumen of the needle. Photocoagulation is then carried out throughout the substance of the vascular malformation in a pattern similar to that used for liposuction. As the laser coagulates the tissue, the fiber is advanced to expose new regions, thus spreading the tunnel of coagulation surrounding the path of the optical fiber. This technique has been used successfully for extensive vascular malformations involving the eyebrows and eyelids with no damage to superficial or deep structures. Near the eye, an aluminum scleral shield is used to protect the globe.

CONCLUSIONS With the exception of specific cutaneous applications, as noted, most surgical lasers operate as thermal instruments. Knowledge of the tissue characteristics and the absorption of specific wavelengths allow the surgeon to predict the clinical effects of each of the surgical lasers. It is the responsibility of the surgeon to have obtained instruction in the use of the lasers as well as in all safety considerations regarding the individual laser units employed. Finally, unless the laser is the most appropriate instrument for a particular application,

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or the application cannot be performed without the laser, it should not be used.

References 1. Sataloff J. Experimental use of laser in otosclerotic stapes. Arch Otolaryngol. 1967;85:58. 2. Jako GJ. Laser surgery of the vocal cords. Laryngoscope. 1972;82:2204. 3. Vincent R, Bitterman AJ, Oates J, Sperling N, Grolman W. KTP versus CO2 laser fiber stapedotomy for primary otosclerosis: results of a new comparative series with the otologyneurotology database. Otol Neurotol. 2012;33(6):928–933. 4. Desai SC, Sung CK, Jang DW, Genden EM. Transoral robotic surgery using a carbon dioxide flexible laser for tumors of the upper aerodigestive tract. Laryngoscope. 2008;118(12): 2187–2189. 5. Tan OT, Kershmann R, Parrish JA. The effect of epidermal pigmentation on selective vascular effects of pulsed laser. Lasers Surg Med. 1984;4:365. 6. Edwards G, Logan R, Copeland M, et al. Tissue ablation by a free electron laser tuned to the amide II band. Nature. 1994;371:416. 7. Einstein A. Zur quanten theorie der Strahlung (The quantum theory of radiation). Phys Zeit. 1917;18:121. 8. Schawlow AL, Townes CH. Infrared and optical lasers. Phys Rev. 1958;112:1940. 9. Polanyi TG. Laser physics. Otolaryngol Clin North Am. 1983;16:753. 10. Fuller TA. The physics of surgical lasers. Lasers Surg Med. 1980;1:5. 11. Fuller TA. Fundamentals of lasers in surgery and medicine. In: Dixon JA, editor. Surgical Applications of Lasers. Chicago, IL: Year Book; 1983:11–28. 12. Sliney DH. Laser-tissue interactions. Clin Chest Med. 1985;6:203. 13. Tan OT, Morrison P, Kurban AK. 585 nm for the treatment of port-wine stains. Plast Reconstr Surg. 1991;88:547. 14. Wenig BL, Kurtzman DM, Grossweiner LI, et al. Photodynamic therapy in the treatment of squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1990;116:1267. 15. Shapshay SM, Wallace RA, Kveton JF, Hybels RL, Setzer SE. New microspot micromanipulator for CO2 laser application in otolaryngology-head and neck surgery. Otolaryngol Head Neck Surg. 1988;98:179. 16. Mihashi S, Jako GJ, Incze J, Strong MS, Vaughan CW. Laser surgery in otolaryngology: interaction of CO2 laser and soft tissue. Ann N Y Acad Sci. 1976;267:263. 17. Bellina JH, Stjernholm RL, Kurpel JE. Analysis of plume emissions after papovavirus irradiation with the carbon dioxide laser. J Reprod Med. 1982;27:268. 18. Garden JM, O’Banion MK, Shelnitz LS, et al. Papillomavirus in the vapor of carbon dioxide laser-treated verrucae. JAMA. 1988;259:1199. 19. Wenig BL, Stenson KM, Wenig BM, Tracey D. Effects of plume produced by the Nd: YAG laser and electrocautery on the respiratory system. Lasers Surg Med. 1993;13:242. 20. Ossoff RH. Laser safety in otolaryngology - head and neck surgery: anesthetic and educational considerations for laryngeal surgery. Laryngoscope. 1989;99:1.

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21. Lesinski GS, Palmer A. Lasers for otosclerosis: CO2 vs. argon and KTP-532. Laryngoscope. 1989;99:1–8. 22. Lesinski GS, Palmer A. Lasers for otosclerosis: CO2 vs. argon and KTP-532. Laryngoscope. 1989;99:9–12. 23. Vollrath M, Schreiner C. Influence of argon laser stapedotomy on inner ear function and temperature. Otolaryngol Head Neck Surg. 1983;91:521. 24. Pillsbury HC. Comparison of small fenestra stapedotomies with and without KTP-532 laser. Arch Otolaryngol Head Neck Surg. 1989;115:1027. 25. Jang CH, Cho YB, Choi CH, Song CH, Kim SH, Park SY. Cochlear tolerance of Nd: YAG laser myringotomy. In Vivo. 2007 Sept-Oct;21(5):913–916. 26. Rahman A, Von Unge M, Olivius P, Dirclex J, Hultcrantz M. Healing time, long term result and effects of stem cell treatment in acute tympanic membrane perforations. Int J Ped Otorhinolaryngology. 2007 July;71(7):1129–1137. 27. Lin SH, Lai CC, Shiao AS. CO2 laser myringotomy in children with otitis media with effusion. J. Laryngol Otol. 2006;120(3): 188–192. 28. Goode RL. CO2 laser myringotomy. Laryngoscope. 1982;92:420. 29. Hanna E, Eliachar I, Cothren R, Ivanc T, Hughes G. Laser welding of fascial grafts and its potential application in tympanoplasty: an animal model. Otolaryngol Head Neck Surg. 1993;108:356. 30. Healy GB, McGill T, Jako GJ, Strong MS, Vaughan CW. Management of choanal atresia with the carbon dioxide laser. Ann Otol Rhinol Laryngol. 1978;87:658. 31. Ramsden JD, Campisi P, Forte V. Choanal atresia and choanal stenosis. Otolaryngol Clin N Am. 2009;42:339–352. 32. McCombe AW, Cook J, Jones AS. A comparison of laser cautery and submucosal diathermy for rhinitis. Clin Otolaryngol. 1992;17:297. 33. Jiang ZY, Pereira KD, Friedman NR, Mitchell RB. Inferior turbinate surgery in children: a survey of practice patterns. Laryngoscope. 2012;122:1620–1623. 34. Simeon R, Soufflet B, Delacour IS. Coblation turbinate reduction in childhood allergic rhinitis. Eur Ann Otorhinolaryngol Head Neck Dis. 2010;127:77–82. 35. Shapshay SM, Rebeiz EE, Pankratov MM. Holmium:yttrium alumi num garnet laser-assisted endoscopic sinus surgery: clinical experience. Laryngoscope. 1992;102:1177. 36. Wouters B, van Overbeek JJ, Buiter CT, Hoeksema PE. Laser surgery in lingual tonsil hyperplasia. Clin Otolaryngol. 1989;14:291. 37. Maddern BR, Werkhaven JA, McBride TP. Lingual thyroid in a young infant presenting as airway obstruction: report of a case. Int J Pediatr Otorhinolaryngol. 1988;16:77.

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38. Oas RE Jr, Bartels JP. KTP-532 laser tonsillectomy: a comparison with standard technique. Laryngoscope. 1990;100:385. 39. Simpson GT, Strong MS. Recurrent respiratory papillomatosis: the role of the carbon dioxide laser. Otolaryngol Clin North Am. 1983;16:887. 40. Ossoff RH, Werkhaven JA, Dere H. Soft-tissue complications of laser surgery for recurrent respiratory papillomatosis. Laryngoscope. 1991;101:1162. 41. Zeitels SM, Lopez-Guerra G, Burns JA, Lutch M, Friedman AM, Hillman RE. Microlaryngoscopic and officebased injection of bevacizumab (Avastin) to enhance 532-nm pulsed KTP laser treatment of glottal papillomatosis. Ann Otol Rhinol Laryngol. 2009;118(9 Suppl 201):1–13. 42. Zeitels SM, Barbu AM, Landau-Zemer T, et al. Local injection of bevacizumab (Avastin) and angiolytic KTP laser treatment of recurrent respiratory papillomatosis of the vocal folds: a prospective study. Ann Otol Rhinol Laryngol. 2011;120(10): 627–634. 43. Karlan MS, Ossoff RH. Laser surgery for benign laryngeal disease. Conservation and ergonomics. Surg Clin North Am. 1984;64:981. 44. Beste DJ, Toohill RJ. Microtrapdoor flap repair of laryngeal and tracheal stenosis. Ann Otol Rhinol Laryngol. 1991;100:420. 45. Werkhaven JA, Weed DT, Ossoff RH. Carbon dioxide laser serial microtrapdoor flap excision of subglottic stenosis. Arch Otolaryngol Head Neck Surg. 1993;119:676. 46. Denoyelle F, Leboulanger N, Enjolras O, Harris R, Roger G, Garabedian EN. Rolf of Propranolol in the therapeutic strategy of infantile Laryngotracheal hemangioma. Int J Pediatr Otorhinolaryngol. 2009;73:1168–1172. 47. Fuchsmann C, Quintal MC, Giguere C, et al. Propranolol as first-line treatment of head and neck hemangiomas. Arch Otolaryngol Head Neck Surg. 2011;137(5):471–478. 48. Werkhaven J, Maddern BR, Stool SE. Posttracheotomy granulation managed by carbon dioxide laser excision. Ann Otol Rhinol Laryngol. 1989;98:890. 49. Ossoff RH. Bronchoscopic laser surgery: which laser when and why. Otolaryngol Head Neck Surg. 1986;94:378. 50. Cosman B. Experience in the argon laser therapy for port-wine stains. Plast Reconstr Surg. 1980;65:119. 51. Tan OT, Carney JM, Margolis R, et al. Histologic responses of port- wine stains treated by argon, carbon dioxide, and tunable dye lasers. A preliminary report. Arch Dermatol. 1986;122:1016. 52. Bingham MM, Saltzman B, Vo NJ, Perkins JA. Propranolol reduces infantile hemangioma volume and vessel density. Otolaryngol Head Neck Surg. 2012;147:338–344.

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100 C H A P T E R

The Neck: Embryology and Anatomy Mark A. Richardson and Kathleen C. Y. Sie

T

he neck is the passageway for communication between the head and the trunk. The tremendous variety of pathologic conditions affecting this region makes an understanding of the embryology and anatomy of the neck a vital part of the otolaryngologist’s knowledge. This chapter emphasizes the embryology of the major vessels, nerves, muscles, thyroid, and parathyroid glands as they relate to clinical problems. The surface anatomy of the neck with reference to the triangles of the neck and lymphatic drainage are discussed, as are the fascial planes and related spaces.

EMBRYOLOGIC DEVELOPMENT OF ARTERIES OF THE NECK Symmetry is a fundamental principle in embryologic development. In accordance with this principle, the arteries start as a paired symmetric system that is altered during the development by the fusion or atrophy of their various parts. As the heart is displaced caudally and the pharyngeal arches are formed, six pairs of pharyngeal arteries develop in succession. Not all six pairs of pharyngeal vessels are present at the same time. The mandibular and hyoid arch vessels (first and second pharyngeal arch vessels) disappear before the fifth and sixth pharyngeal arch vessels have differentiated. Fig. 100-1 shows the pharyngeal arch arteries arising ventrally from the aortic sac and terminating laterally in the dorsal aorta of the corresponding side. At a more caudal level, the two dorsal aortas fuse to form a single midline dorsal aorta. The initial arrangement of the arch vessels is subsequently transformed during development. The first and second pharyngeal arch vessels disappear at about the time the third and fourth arch vessels mature and increase in size. The remnant of the first arch artery is the maxillary artery, and the stapedial artery (when present) represents a remnant of the second arch. The ventral portions of the first and second arch vessels may also contribute to the development of the external carotid artery (see Fig. 100-1).1,2 The third pharyngeal arch vessels differentiate into the internal carotid arteries. The fourth arch vessels form the arch of the aorta on the left side and contribute to the proximal aspect of the subclavian artery on the right. The left subclavian artery arises by hypertrophy of a branch of the left dorsal aorta (see Fig. 100-1).3 Abnormalities of the great vessels are among the most common developmental anomalies. With the growth of the body and changes in the vascular patterns, certain channels may persist that normally undergo regression, or vessels that normally persist may disappear. In most cases, these

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variations have little effect on function, and circulation is not impaired. In some cases, however, variations in the aortic arch development may be of greater clinical significance. For instance, persistence of the right and left fourth arches and dorsal aortic root results in an “aortic ring,” which may compress the trachea and esophagus. The resulting interference with swallowing may require ligation of one of the two arches. Another arch abnormality that produces clinical symptoms and signs is the aberrant right subclavian artery. In this case, the vessel passes from the dorsal aortic root across the midline behind the esophagus. It may then exert enough pressure to interfere with swallowing, although usually not as great a pressure as occurs with aortic ring malformation. Other abnormalities in the development of the branchial arch vessels are discussed in major embryologic texts.4,5 Hematoma formation within the stapedial artery stem in mouse embryos results in varying degrees of ear (outer and middle), mandibular, parotid, and facial nerve anomalies. This vascular phenomenon results in craniofacial microsomia in animal models and is the presumed cause in nongenetic human craniofacial microsomia.7

VEINS OF THE NECK The superficial veins, subcutaneous veins, and external and anterior jugulars are especially variable in size and course, and their connections between the deep veins also vary.

External Jugular The external jugular vein begins in the substance of the parotid gland where it is most often formed by the union of the posterior facial and posterior auricular veins. In this region of the parotid gland, it may receive a communication from the internal jugular vein. The external jugular vein runs vertically downward across the superficial surface of the sternocleidomastoid muscle and courses inferiorly to pierce the fascia of the posterior triangle of the neck, just above the clavicle. It also receives the transverse cervical, the suprascapular, and, frequently, the anterior jugular veins. The external jugular vein usually terminates in the subclavian vein but, in onethird of instances, may terminate in the internal jugular vein.

Anterior Jugular The anterior jugular vein usually begins in the suprahyoid region, through the confluence of variable superficial veins, or it may arise more laterally. It has variable communications

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FIGURE 100-1. (A) Aortic arches before transformation into a definitive vascular pattern. (B) Aortic arches after transformation. (C) The great arteries in the adult. (After Langman.3)

with the internal jugular or the facial vein and descends on the infrahyoid musculature. In the lower portion of the neck above the sternum, the two veins are commonly united by a transversely disposed jugular venous arch, which is one of the vessels that may be encountered in a tracheostomy incision. Below this jugular venous arch, each anterior jugular vein courses laterally to empty into the terminal portion of the external jugular vein or into the subclavian vein between the external and internal jugulars.

Internal Jugular The right internal jugular vein is usually the larger of the jugular veins, and it begins at the jugular foramen as the continuation of the sigmoid and inferior petrosal sinuses. This confluence forms the jugular bulb in the floor of the tympanic cavity. The jugular bulb is usually covered by bone and generally lies inferior to the level of the annulus. A high jugular bulb may extend into the mesotympanum and can be

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dehiscent or covered with bone. It is usually seen as a bluish mass in the posterior tympanum on otoscopic examination. These lesions can cause tinnitus and hearing loss or can be asymptomatic. Inadvertent puncture of a high jugular bulb during middle-ear surgery or myringotomy can cause significant hemorrhage.8 Chemoreceptor tissue, from which tumors may arise, is located against the jugular bulb. The jugular vein lies posterior to the internal carotid artery, from which it is separated by the 9th, 10th, and 11th cranial nerves as they emerge from the anterior portion of the jugular foramen. At its superior end, the internal jugular vein receives the inferior petrosal sinus, which passes through the anterior aspect of the jugular foramen. The middle meningeal veins and the vein of the cochlear aqueduct also enter it here. As the jugular vein courses into the neck, it lies lateral to the internal and common carotid arteries. As the vein assumes the position lateral to the artery, the vagus nerve lies posterior and between the two vessels. The internal jugular vein is intimately related to the deep cervical lymph nodes that are

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CHAPTER 100 ❖ The Neck: Embryology and Anatomy 1667 embedded in that portion of the carotid sheath surrounding the vein. At about the level of the hyoid bone, the internal jugular vein receives the facial vein and a part of the posterior facial vein. As it courses inferiorly, the internal jugular vein typically receives the superior thyroid vein and, often, the pharyngeal and lingual veins (Fig. 100-2). Its termination joins the subclavian vein to form the brachiocephalic, or innominate, vein on each side. The thoracic duct on the left and the right lymphatic duct or its constituent vessel on the right open between the internal jugular and subclavian vessels. The subclavian vein lies anterior to the corresponding artery and at a slightly lower level. Anteriorly, the vein passes deep to the clavicle and superficial to the anterior scalene muscle. The subclavian artery passes deep to the scalene muscle. (Normally, the phrenic nerve passes deep to it, but sometimes the accessory phrenic nerve courses anterior to the vein.)

THORACIC AND RIGHT LYMPHATIC DUCTS

Right Lymphatic Duct

Thoracic Duct As the thoracic duct enters the most inferior portion of the neck, it lies somewhat to the right of the subclavian artery and behind the left common carotid artery (Fig. 100-3). From this position between the esophagus and the left pleura and deep to the left common carotid artery and left vagus nerve, it

Median thyrohyoid lig. Hyoid B.

arches anterosuperiorly and laterally. In so doing, the thoracic duct emerges between the left common carotid and the left subclavian artery. As the thoracic duct arches above the level of the subclavian artery, it passes between the internal jugular vein and the anterior scalene musculature, generally to terminate near the junction of the internal jugular vein on the left and the subclavian vein. Typically, the thoracic duct drains both lower limbs, most of the abdomen and its contents, and the left side of the head and neck. The actual termination of the thoracic duct varies, and it may terminate in the subclavian vein, the internal jugular vein, or the innominate vein. It appears that there is at least a potential anastomosis between the thoracic duct and the right lymphatic duct. If the thoracic duct becomes obstructed in the neck, the anastomosis may have a functional significance. Surgical injuries to the thoracic duct can frequently be treated by temporary pressure. Ligation may be necessary if the leak does not stop with pressure.

The right lymphatic duct receives lymph from the right side of the head and neck, from the right upper extremity, and from the right side of the thorax. This duct usually terminates into the angle of union between the subclavian and the internal jugular veins or directly into one of these veins. Like the thoracic duct, the right lymphatic duct has two valves at its

Thyrohyoid membrane Thyrohyoid cartilage Strenothyroid M. (Inserting on oblique line of thyroid cartilage) Lingual A.

Omohyoid M. External carotid A.

Thyrohyoid M.

Internal carotid A.

Inferior pharyngeal constrictor M.

Vagus N. Superior thyroid A., V.

Cricothyroid M.

Internal jugular V. Anterior branch of thyroid A.,V.

Middle thyroid V.

Thyroid gland (Left lobe) (Isthmus)

Inferior thyroid Vs.

inferior thyroid A. Common carotid A.

Sternothyroid M. Sternothyroid M. Trachea

Thymus gland

FIGURE 100-2. Deep veins and thymus. (From Crelin.20)

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Jugular sacc

Superficial Su lymphatics lym

or vena Superior cava

J Jugular lymph sac s Subclavian lymph sac

Thoracic duct Thorac

Lymph node D Deep lymphatics Th Thoracic duct

Retroperitonial sac Retrop

Cisterna chyli

Retroperitoneal Retro lymph sac lymp Cisterna chyli chy Posterior lymph ssac Superficial lymphatics

Lymph node A

Posterior ior sac

B

FIGURE 100-3. Development of the lymphatic vessels. (A) Human embryo at nine weeks, showing the primitive lymph sacs and the developing vessels. (After Sabin FR. The origin and development of the lymphatic system. Johns Hopkins Hosp Reports monograph vol 5 1913.) (B) Ventral view of formation of the single thoracic duct from the primitive paired lymphatic plexus. (B, from Arey.1)

opening into the venous system to prevent retrograde mixing of venous blood. Lymphatic channels are thought to originate by endothelial buds derived from the lining of jugular sacs. Disorders of the formation of the lymphatic system can lead to lymphatic malformations. Although the term “-oma” suggests a tumor, these malformations are not tumors and include a spectrum of lesions ranging from cystic hygromas to lymphangiomas. The cystic hygroma is a purely lymphatic channel entity in which there is anomalous lymphatic drainage. The sequestered lymphatic tissue gives rise to cysts lined with endothelium that enlarge when infected. The close relationship of the developing lymphatic and venous systems sometimes leads to lymphaticovenous malformations. Grossly, lymphatic malformations consist of multiloculated cysts containing serous fluid. They are commonly located in the neck but may appear in the axilla, thorax, groin, or abdomen. Large posterior cervical cystic hygromas have been associated with Turner syndrome.9,10 Treatment requires surgical management or schlerotherapy.

EMBRYOLOGIC DEVELOPMENT OF NECK MUSCLES The muscles of the body develop from mesoderm. Segmentation of the para-axial mesoderm into somites is

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followed by subsequent differentiation into the myotome (which gives rise to muscle mass), dermatome (which gives rise to integumentary tissues), and sclerotome (which gives rise to the axial skeleton). Unlike the voluntary musculature of other parts of the body, most of the segmental musculature of the neck is formed by the differentiation of branchial arch mesenchyme, with some contributions from the cervical somites. The extensor musculature of other parts of the body and most of the segmental musculature of the neck is formed from the epaxial divisions of the cervical myotomes. The hypaxial portions of these myotomes form the scalene, prevertebral, geniohyoid, and infrahyoid muscles.5 In general, the muscles of branchiomeric origin retain the innervation characteristic of the arch. Therefore, the muscles that are derived from the mesenchyme of the mandibular, or first, arch are supplied by fibers of the trigeminal nerve. This group includes the muscles of mastication, the mylohyoid muscle, and the anterior belly of the digastric muscle as well as the tensor veli palatini and tensor tympani muscles. The second arch is associated with the hyoid and the ossicular chain lateral to the stapes footplate. The muscles of the second arch include the muscles of facial expression, the platysma, and the anterior portion of the base of tongue. The artery and nerve of this arch are the stapedial artery and facial nerve, respectively. The third arch gives rise to the stylopharyngeus and part of the pharyngeal constrictor

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CHAPTER 100 ❖ The Neck: Embryology and Anatomy 1669 muscles. They are innervated by the glossopharyngeal nerve. The primordial muscle masses of the fourth and fifth arches give rise to the muscles of the larynx and part of the pharyngeal constrictors. These muscles are innervated largely by the vagus nerve. Anomalies of the branchial apparatus can result from incomplete closure of the branchial clefts, failure of obliteration of the cervical sinus of His, or entrapment of epithelial rests within lymph nodes. These developmental anomalies can result in the formation of a sinus, a fistula, or a cyst. These are discussed in Chapter 98. Third and fourth branchial pouch anomalies may rarely manifest as recurrent thyroiditis resulting from an intrathyroid cyst that communicates with the piriform sinus.11 The precise development of the sternocleidomastoid and trapezius muscles is difficult to establish. Most researchers think that this muscle group is formed primarily from branchiomeric tissue but that the migration of muscle cells from the occipital somites contributes to part of this development. The innervation of these muscles is from the spinal accessory nerve. The infrahyoid muscles of the anterior aspect of the

neck are of somitic origin. These muscles are innervated by a branch of the hypoglossal nerve with fibers from the first and second cervical nerves, the ansa cervicalis. Early in embryonic development, the infrahyoid muscle mass was closely associated with the mass that gives rise to the diaphragmatic musculature. This helps explain the origin of the innervations of the infrahyoid muscles from the cervical nerves.3

EMBRYOLOGY OF THYROID AND PARATHYROID GLANDS AND THYMUS Thyroid Gland The thyroid gland originates early in embryonic development as a thickening of the endoderm of the floor of the pharynx in the midline between the first and second pouches, near the portion that becomes the tuberculum impar. This tissue mass forms a diverticulum with a bilobed, flasklike appearance. This thyroid primordium (Fig. 100-4) soon begins to descend, but a thin connection, the stalklike thyroglossal duct, remains attached to the oropharynx. This point of

FIGURE 100-4. Stages in the development of the thyroid gland. (A) 1, The thyroid primordium and pharyngeal epithelium of a 4.5-mm human embryo; 2, Section through the same structure, showing raised central portion. (B) 1, Thyroid primordium of a 6.5-mm embryo; 2, Section through the same structure. (C) 1, Thyroid primordium of an 8.2-mm embryo, beginning to descend; 2, Lateral view of the same structure. (D) Thyroid primordium of an 11-mm embryo. The connection with the pharynx is broken, and the lobes are beginning to grow laterad. (E) Thyroid gland of a 13.5-mm embryo. The lobes are thin sheets curving around the carotid arteries. Several lacunae are present in the sheets, which are not to be confused with follicles. (From Weller.21)

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attachment marks the origin of the thyroid gland and may be seen in the adult as the foramen caecum. When the thyroid primordium descends, it consists of two lobes extending to either side of the midline, with a narrow isthmus of tissue joining them medially. This tissue mass reaches the level of the laryngeal primordium at about the seventh week of gestation. The thyroglossal tract is normally obliterated but, when it persists, may increase the likelihood of the formation of thyroglossal duct cysts (Fig. 100-5). A persistent thyroglossal duct may track medial to the central portion of the hyoid cartilage as it descends toward the thyroid gland.12 Furthermore, the superior portion of the persistent duct may have several finger-like projections to the tongue base, predisposing to recurrent lesions.13 Accessory thyroid tissue may be found along the path of migration of the thyroid gland. When the primordial thyroid fails to descend, it may persist in the tongue musculature as a lingual thyroid (Fig. 100-6).3,5

Parathyroid Glands Two pairs of parathyroid glands develop from separate pouches. The inferior pair is derived from the third and the superior from the fourth pharyngeal pouch. They are frequently designated as parathyroids 3 and parathyroids 4. At the seventh week of development, the parathyroid primordia free themselves from the pouches and move caudally. Although they initially move in close association with each other, parathyroids 3 remain attached to the thymus and migrate farther caudally than do parathyroids 4. Occasionally during their migration, fragmentation of the parathyroid tissue takes place, resulting in the formation of accessory parathyroid glands. Parathyroids 4 usually adhere to the thyroid capsule and may become embedded in the substance of the thyroid gland (see Fig. 100-6). Further details of the

embryology and developmental abnormalities of the thyroid and parathyroid are discussed in Chapter 98.

Thymus The thymus is also derived from the third pharyngeal pouch and moves caudally with parathyroids 3 to a level lower than the thyroid tissue, eventually migrating to the superior mediastinum. Remnants of thymus tissue can remain in the neck to form thymic cysts or accessory lobes of thymus; these usually lie below the thyroid cartilage.

ANATOMY OF THE NECK Surface Anatomy of the Neck The neck may be divided into an anterior region, or the cervix, and a posterior region, or the nucha. The nuchal division is more properly related to the back and is represented by the vertebral column with its paravertebral musculature. The cervical division is of greater interest to the otolaryngologist. When viewed from the lateral aspect, it has a quadrilateral outline. It is bounded superiorly by the mandible and mastoid process, inferiorly by the clavicle, anteriorly by the midline of the neck, and posteriorly by the anterior border of the trapezius muscle.

Triangles of the Neck The sternocleidomastoid muscle is a prominent landmark in the neck and divides it into anterior and posterior parts, or triangles, as it courses from the mastoid tip to the medial aspect of the clavicle (Fig. 100-7).

The Posterior Triangle The posterior triangle is bounded posteriorly by the trapezius muscle, anteriorly by the sternocleidomastoid muscle,

Genioglossus muscle Genihyoideus muscle Mylohyoideus muscle Hyoid bone Thyro-hyoid membrane

Foramen caecum Epiglottis

Thyroid cartilage Fascia colli Pretracheal fascia Cricoid cartilage Thyroid gland Sternum

FIGURE 100-5. Various locations of thyroglossal duct cysts. (A) In front of the foramen caecum; (B) at the foramen caecum; (C) above the hyoid bone; (D) below the hyoid bone; (E) in the region of the thyroid gland; (F) at the suprasternal notch. Approximately 50% of the cysts are at D, below the hyoid bone. (From Ward.22 By permission of Surgery, Gynecology, and Obstetrics.)

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CHAPTER 100 ❖ The Neck: Embryology and Anatomy 1671 Pedicle of left 3rd pharyngeal pouch

Laryngeal epithelium Right internal carotid artery Right parathyroid III

Left thymus u us Th Left para Thyroid III External Carotid a artery

Right thymus Right 4th aortic arch us caroticus Residuum of right ductus

l Left lateral lobe of thyroid phar Left 4th pharyngeal pouch

External caotid art artery Layngeal epithelium

Right lateral lobe of thyroid Thyroid istmu istmus Innominate artery arter

Trachea sophagus descending aorta Oesophagus Right parathyroid IV

Right internall carotid artery y

Aortic trunk Pulmonary trunk Ventral portion of right 4th pharyngeal pouch

Left parathyroid III

A

Right parathyroid d III

Laryngeal ep epithelium otid artery Right internal carotid

Left parathyroid IV

Light thymic stalk

Right ht lobe of thyroid oid gland

Trachea

Right ight common carotid artery

id artery Right external carotid

Right thymus

Left external caroti carotid artery Left parathyroid III

Left thymus

an atery Right subclavian

hyroid III Right parathyroid Left IVth pouch (vent, par part) Left parathyroid IV Thyroid gland

Ascending aorta

Oeso eso sophagus Oesophagus

us gland Right thymus Left thymus gland Left common carotid arter artery

Left 6th aortic arch artery (Pulmonary artery)

Vth arch Right IVth Innominate artery

Ascending aorta Ductus arteriosus ery Right subclavian artery

Pulmonary trunk Trachea Oesophagus

C

B

FIGURE 100-6. Reconstruction of the pharyngeal pouches, their derivatives, and related aortic arches. (A) At 13.5 mm (beginning of seventh week); (B) at 16.8 mm (beginning of eighth week). (C) At 23 mm (end of eighth week). (From Hamilton,23 after Weller.21)

and inferiorly by the middle third of the clavicle. Its floor is formed by the deep layer of the deep cervical fascia, which covers the scalene muscle, the levator muscle of the scapula, and the splenius capitis muscle. The roof of the triangle is the superficial layer of the deep cervical fascia (see Fig. 100-7). The most important contents of the posterior triangle are the subclavian artery, brachial plexus, spinal accessory nerve, and posterior cervical lymph nodes. The omohyoid muscle crosses the posterior triangle and divides it into a superior occipital triangle and an inferior subclavian triangle.14,15

muscle. The anterior triangle is crossed by the digastric, stylohyoid, and omohyoid muscles, which subdivide this area into smaller triangles: the submandibular, carotid, submental, and inferior carotid triangles. The chief contents of the anterior triangle are the common, external, and internal carotid arteries; the internal jugular vein; the laryngeal, pharyngeal, vagal, and recurrent laryngeal nerves; the submandibular gland; and lymphatic tissue (see Fig. 100-7).

The Anterior Triangle

The lymph nodes of the neck include five main groups: submandibular, submental, superficial cervical, anterior cervical, and deep cervical nodes (Fig. 100-8).14,16 The submandibular nodes, which are inferior to the body of the mandible in the submandibular triangle, are chiefly superficial to the submandibular gland. Small lymph nodes are sometimes found on the undersurface of the submandibular gland. These nodes drain the cheek, the medial canthal region, the lateral aspect of the nose, the upper lip, the teeth,

The anterior triangle is bounded posteriorly by the sternocleidomastoid muscle, anteriorly by the midline of the neck, and superiorly by the lower border of the mandible. Its floor (deep border) is formed by the mylohyoid and hyoglossus muscles and by parts of the thyrohyoid and pharyngeal constrictor muscles. Its roof (superficial border) is formed by the superficial layer of the deep cervical fascia and the platysma

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Lymph Nodes of the Neck

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FIGURE 100-7. Triangles of the neck.

the gingiva, and the anterolateral aspect of the tongue. The submandibular nodes drain subsequently into the superior deep cervical nodes. The submental nodes are between the anterior bellies of the digastric muscles. These nodes drain the central aspect of the lower lip and floor of the mouth and the mobile tongue. The submental nodes drain subsequently into the submandibular nodes and into the deep cervical node group at the level of the hyoid cartilage. The superficial cervical nodes lie adjacent to the external jugular vein and superficial to the sternocleidomastoid muscle. These nodes drain the inferior aspects of the auricular and parotid regions and drain subsequently into the superior deep cervical nodes (Figs 100-8 and 100-9). The anterior cervical nodes lie ventral to the larynx and trachea and drain the lower part of the larynx, the thyroid gland, and the cervical aspect of the trachea. Efferents from this node group pass deeper into the deep cervical nodes, which are larger, more numerous, and lie along the carotid sheath. The deep cervical nodes are frequently divided into

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two groups: the superior deep cervical nodes and the inferior deep cervical nodes. The superior deep cervical nodes lie deep to the sternocleidomastoid muscle and in close association with the internal jugular vein and spinal accessory nerve. These nodes drain the occipital region, the back of the neck, the auricle, most of the tongue, the larynx, thyroid gland, trachea, nasopharynx, nasal cavities, palate, and esophagus. They also receive efferent vessels from a major portion of the other nodes of the head and neck. The inferior deep cervical nodes lie deep to the sternocleidomastoid muscle in the supraclavicular area and are in proximity to the brachial plexus and subclavian vein. This inferior node group drains the back of the scalp and neck as well as part of the pectoral region. The inferior deep cervical nodes receive lymphatic drainage from the superior deep cervical nodes. The deep cervical node groups on the right side form a large lymphatic vessel, the jugular trunk, which joins the venous system at the junction of the internal jugular and subclavian veins. On the left side, the jugular trunk joins the thoracic duct.

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Superficial temporal vein, artery (Parietal branches)

Epicranial aponeurosis (galea aponeurotica) Temporal fascia Superior auricular muscle

(Frontal branches) Occipitofrontal muscle (frontal belly)

Posterior auricular vein, artery

Supratrochlear vein

Posterior auricular muscle

supraorbital vein

Occipitofrontal muscle (occipital belly)

Auriculotemporal nerve vein

Greater occipital nerve

Anterior Auricular muscle

Occipital vein, artery

Angular artery, vein

Retroauricular lymph node

Transverse facial artery

Lesser occipital nerve branches (C.2, 3 of cervical plexus) Great auricular nerve (C.2, 3 of cerical plexus) Prevertebral fascia

Parotid dcut Superficial fascia overlying buccal fat pad Facial artery, vein Mandibular lymph node

Accessory nerve. XI

Superficial layer of parotid fascia overlying parotid gland

Trapezius muscle

Cut end of facial cranial nerve VII branch emerging from parotid gland Superficial parotid lymph node

Omohyoid muscle (Inferior belly)

External jugular vein

Sternocleidomastoid muscle

Superficial cervical lymph node Transverse cervical nerve (C. 2, 3 of cervical plexus)

Supraclavicular ns (C.3, of cervical plexus)

FIGURE 100-8. Superficial veins and muscles of the neck. (From Crelin.20)

The retropharyngeal nodes are an important nodal chain in the pediatric patient. Infection and subsequent suppuration in these nodes cause retropharyngeal abscesses. These nodes lie deep to the buccopharyngeal fascia, between the posterior pharynx and the cervical vertebrae. They drain the nasal cavities, the nasopharynx, and Waldeyer’s ring. Efferents from this group pass to the superior deep cervical nodes (Fig. 100-10) (see Chapter 99).

Fascial Layers of the Neck It is important to understand the position of the lymph nodes relative to the fascial layers and compartments of the head and neck. The lymphatic system drains three areas of infection in the head and neck. Subsequent suppuration and necrosis in the involved node may lead to the accumulation of purulent material, which may spread through one or more continuous fascial compartments. Thus, infections that originate from one site in the skin or in the pharynx may subsequently spread to involve specific lymphatics of the neck with subsequent deep neck infection. Knowledge of the anatomy of the cervical fascia is essential to the understanding of the pathophysiology and treatment of infectious and noninfectious diseases of the head and neck.

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Cervical Fascia The neck is enveloped by two basic fascial layers, the superficial and deep cervical fascias. These fascial layers both unite and separate various important structures. In so doing, certain fascial planes and compartments are formed. By understanding the contents of these spaces together with their position in the neck and their relationships to other structures, the differential diagnosis of a neck mass may be made more easily, and potential complications from deep neck infections may be anticipated. The surgeon must be fully familiar with these structures and their relationships if the surgical approach to and drainage of deep neck infections is to be effective.16 The superficial cervical fascia surrounds the neck and is continuous with the superficial fascia of the pectoral, deltoid, and back regions inferiorly and the fascia of the muscles of facial expression superiorly. Within this layer are the thin sheets of platysma muscle as well as the external jugular vein and superficial lymph nodes. The more important deep cervical fascia is in three layers: a superficial investing layer, a middle layer, and a prevertebral layer (Fig. 100-11). The superficial layer of the deep cervical fascia completely surrounds the neck like a stocking. Posteriorly, it is attached to the spinal processes of the cervical vertebra and to the ligamentum nuchae. It passes forward and divides to ensheathe

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1674

SECTION 4 ❖ The Head and Neck Submental lymph node Mandible

Mylohyoid muscle Chin (Mentum) elevated

Anterior belly of right digastric muscle

Mylohyoid artery, nerve Submental artery Submandibular gland

Superficial layer of cervical fascia sheathing submandibular gland

Submandibular lymph node Thyrohyoid muscle Jugulodigastric lymph node Carotid sheath Superior deep cervical lymph nodes Ansa cervicalis Juguloomohyoid lymph node

Hyoid bone

Inferior deep cervical lymph nodes Omohyoid muscle (Inferior belly) (Superior Belly)

Fascia of infrahyoid ms Sternocleidomastoid muscle (Clavicular head) (Sternal head)

Sternothyroid muscle Sternohyoid muscle

Superficial layer of cervical fascia enclosing belly of sternocleidomastoid muscle

FIGURE 100-9. Deep lymph nodes. (From Crelin.20)

Pharyngeal branches Retropharyngeal lymph node Skull

Posterior surface of superior cervical sympathetic ganglion Rami communicantes

Cut edges of left half of alar fascia Posterior surface of visceral fascia (Buccopharyngeal part)

Sympathetic trunck

Visceral fascial sheath of thyroid gland

Inferior thyroid artery

Carotid sheath Right half of alar fascia (Fused to carotid sheath laterally and visceral fascia along the midline. Extends from skull to fuse with visceral fascia about the level of 7th cervical vertebra.)

FIGURE 100-10. Retropharyngeal nodes. (From Crelin.20)

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FIGURE 100-11. Transverse section of the neck at the level of the larynx, showing fascial layers. (After Hollinshead.16)

the trapezius muscle and then forms a single layer as it passes over the posterior triangle of the neck. After dividing again to ensheathe the sternocleidomastoid muscle, the fascia continues across the neck as a single layer to join the corresponding layer of the opposite side in the anterior midline. The superficial layer is attached to the hyoid bone in the anterior triangle and is divided into suprahyoid and infrahyoid portions. The suprahyoid portion splits to envelop the submandibular and parotid glands. Between these two glands, the fascia unites to form the stylomandibular ligament, which attaches to the lingual surface of the angle of the mandible and to the styloid process. Thus, the superficial layer of the deep cervical fascia separates the submandibular and parotid glands from each other and from the rest of the neck. The superficial layer continues superiorly to ensheathe the posterior body of the mandible. Its medial extension ensheathes the internal and external pterygoid muscles. The infrahyoid portion of the superficial layer of the deep cervical fascia splits inferiorly to attach to the anterior and posterior aspects of the manubrium, where it forms the suprasternal space of burns. This space contains the anterior jugular veins with their communicating veins and a few lymph nodes (see Fig. 100-11). The middle, or pretracheal, layer of the deep cervical fascia is composed of two layers: a superficial muscular layer and a deep visceral layer. The more superficial muscular layer ensheathes the strap muscles—the sternohyoid, sternothyroid, thyrohyoid, and omohyoid muscles. The deeper visceral layer surrounds the trachea, thyroid gland, and esophagus; this is called the visceral space. Both layers are attached to the thyroid cartilage superiorly and extend inferiorly to the posterior aspect of the sternum, where they blend with the tissue between the pericardial sac and great vessels and with that of the sternum. The lateral aspect of this layer contributes to the formation of the carotid sheath before fusing with the outer superficial fascial layer. The posterosuperior portion of this visceral fascial layer envelops the constrictor muscles and attaches to the base of the skull, forming the anterior aspect of the retropharyngeal

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space. This portion of the visceral layer is also referred to as the buccopharyngeal fascia (see Fig. 100-11).17 The deep, or prevertebral, layer of the deep cervical fascia, like the superficial layer, begins in the posterior midline and completely surrounds the neck. As the fascial layer proceeds forward from the ligamentum nuchae and the cervical spine, it covers the prevertebral musculature, forming the floor of the posterior cervical triangle, and covers the brachial plexus and subclavian artery. After attaching to the transverse process of the cervical vertebrae, this fascial layer splits into two layers in front of the vertebral column, forming the “danger space.” Both layers of this prevertebral fascia originate at the base of the skull, but the anterior layer fuses with the fascia of the esophagus in the superior mediastinum, forming the posterior wall of the retropharyngeal space. The posterior lamina continues further down through the mediastinum and retroperitoneum to the coccyx. An anterior extension of this layer to the carotid sheath, called the alar fascia, separates the retropharyngeal space from the parapharyngeal space (see Fig. 100-11).

The Carotid Sheath The carotid sheath is the condensation of fascia that invests the carotid artery, internal jugular vein, and vagus nerve. It has contributions from all three layers of the deep cervical fascia. The cervical sympathetic trunk lies behind the sheath superficial to the prevertebral fascia. The carotid sheath extends from the base of the skull through the parapharyngeal space, superficial to the deep layer of the deep cervical fascia, into the superior mediastinum (see Fig. 100-11).

Potential Neck Spaces Although the interfascial spaces of the neck are shown as anatomically absolute and distinct, almost all these spaces may communicate with each other by way of defects in fascial integrity produced by perforating vessels and nerves, developmental aberrations, or destruction secondary to a disease

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process. For this reason, variations in the clinical behavior of certain diseases of the head and neck may take place.16,18 The hyoid bone serves as a point of attachment for the fascial layers and, as such, divides the fascial spaces into a suprahyoid and infrahyoid group. Those spaces whose ensheathing fascia are not bound to the hyoid run through the entire length of the neck. Insofar as these fascial layers limit the spread of infection, the hyoid bone represents an important structure in the control of certain diseases, such as Ludwig’s angina.

SPACES EXTENDING THROUGH THE ENTIRE LENGTH OF THE NECK Retropharyngeal Spaces The retropharyngeal space may be divided anatomically into three separate spaces: the retroesophageal, prevertebral, and danger spaces (Figs 100-11 and 100-12). The retroesophageal space lies between the middle or buccopharyngeal layer of the deep cervical fascia anteriorly and the prevertebral layer of the deep cervical fascia posteriorly. It extends from the base of the skull superiorly into the superior mediastinum to the level of T1 where the middle and deep layers fuse. This space contains the retropharyngeal lymph nodes, which are typically present in children younger than 4 years of age. Infection in the adenoids, nasal cavities, nasopharynx, and posterior ethmoid sinuses may spread through lymphatics to involve these nodes. Nodal necrosis may result in abscess formation within this retroesophageal space. Infection in this space is usually unilateral because of facial attachment to the midline raphe. Infection in this space may be associated with vertebral osteomyelitis. The prevertebral space is located between the prevertebral layer of the deep cervical fascia and the bodies of the cervical vertebrae. Extending from the base of the skull along the spinal column to the coccyx, this potential space allows for

the spread of infection from the neck to the psoas muscle. Tuberculosis involving the cervical vertebrae with extension into this space was seen before the development of effective tuberculosis therapy (see Figs 100-11 and 100-12). The danger space lies within the two layers of the prevertebral fascia and extends from the base of the skull downward through the mediastinum. Infection within this space may spread as far inferiorly as the diaphragm. The close relationship of this potential space to the prevertebral, retroesophageal, and lateral pharyngeal spaces may allow for infection in the pharynx to spread into the mediastinum or beyond. The potential danger of infection in this area is great.

The Vascular Space The visceral vascular space is the potential space within the carotid sheath and extends from the base of the skull into the superior mediastinum. Because all three layers of the deep cervical fascia contribute to the formation of this space, infection in any other fascial space may ultimately involve this space. Thrombosis of the internal jugular vein and erosion of the carotid artery represent serious complications of infection within the carotid sheath; it is thus most important that the clinician recognize and treat carotid space infections (see Figs 100-11 and 100-12).

Suprahyoid Spaces Submandibular Space The submandibular space is divided by the mylohyoid muscle into the sublingual space superiorly and the submaxillary space inferiorly. The submandibular gland extends into and communicates with both of these spaces. The central compartment of the submaxillary space, which is medial to the anterior belly of the digastric muscle, is termed the submental space (Fig. 100-13). The entire submandibular space is bounded superiorly by the mucosa of the floor of the mouth, laterally and anteriorly by the mandible, posteriorly and inferiorly by the intrinsic

FIGURE 100-12. Longitudinal section through the neck showing spaces and fascial layers. (After Hollinshead.16)

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FIGURE 100-13. Oblique section through the neck. (From Everts and Echevarria.6)

muscles of the base of the tongue and hyoid bone, and inferiorly by the superficial layer of the deep cervical fascia. The submandibular gland protrudes around the posterior border of the mylohyoid muscle to enter and become a passageway between the superior sublingual compartment and the submaxillary space. Infection in the submental space may spread freely beneath the anterior belly of the digastric muscle and into the submaxillary space and then via the submandibular gland into the sublingual space. Because of this free intercommunication, these spaces should be considered as a single unit. This concept was discussed by Ludwig, and multispace infection is the hallmark of Ludwig angina (see Fig. 100-13) (see Chapter 65).

Paraphayngeal Space The parapharyngeal space is also called the pharynomaxillary, peripharyngeal, or lateral pharyngeal space. This lateral, cone- shaped potential space has its base along the sphenoid bone at the base of the skull and its apex at the hyoid bone. It is bounded medially by the buccopharyngeal fascia, which covers the superior constrictor muscle. Its lateral limit is formed by the superficial layer of the deep cervical fascia covering the mandible, by the internal pterygoid muscle, and by the deep lobe of the parotid. The pterygomandibular raphe limits it anteriorly, and the prevertebral fascia limits it posteriorly. The styloid process and its attachments divide this space

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into two compartments: an anterior muscular compartment and a posterior neurovascular compartment. The posterior compartment contains the carotid sheath and cranial nerves IX through XII. The anterior compartment contains no vital structures and extends upward between the lateral wall of the pharynx and the medial surface of the internal pterygoid muscle (Fig. 100-14). Penetrating trauma of the oropharynx, lateral to the tonsil, may violate the carotid sheath in this space. The parapharyngeal space communicates with several other spaces in the neck. The inferomedial submandibular space, the posteromedial retropharyngeal space, the lateral parotid and masticator spaces, and the posterior carotid sheath all communicate with the parapharyngeal space and, in so doing, may influence the spread of infection in the head and neck. The adenoids, tonsils, nasal cavities, and paranasal sinuses represent sources of infection in this space. Mastoid infection may progress to a coalescent mastoiditis and erode through the mastoid tip at the digastric ridge, producing a Bezold abscess (see Fig. 100-14) (see Chapters 26 and 99).

Masticator Space The masticator space is anterior and lateral to the parapharyngeal space. It contains the masseter muscle, the internal and external pterygoid muscles, the ramus of the mandible, the tendon of the temporalis muscle, and the inferior alveolar neurovascular bundle. The masticator space is bounded by

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Anterior Visceral Space The anterior visceral space is the pretracheal portion of the visceral compartment and is bounded by the visceral fascia, which surrounds the trachea from the thyroid gland superiorly to the anterior portion of the mediastinum at the level of the arch of the aorta inferiorly. This space communicates freely with the posterior visceral space. Penetration of the cervical esophagus by instruments or a foreign body may cause infection in this space, with subsequent extension into the mediastinum (see Figs 100-11 and 100-12).

SUMMARY

FIGURE 100-14. Coronal section through the head. (From Everts and Echevarria.6)

the superficial layer of the deep cervical fascia, which divides around the mandible. The outer layer surrounds the masseter muscle and attaches to the zygoma. The inner layer ensheathes the internal and external pterygoid muscles. These two layers then reunite around the posterior and anterior bodies of the mandibular ramus. Infections in this space most commonly arise from molar teeth, but infection in the region of the zygoma, temporal bone, or mandible may also spread to this space (see Fig. 100-13) (see Chapters 99 and 100).

Parotid Space The parotid space is formed by the superficial layer of the deep cervical fascia as it splits to enclose the parotid gland. The space is separated from the submandibular space inferiorly by the stylomandibular ligament. Connective tissue septa radiate from the surface of the capsular sheath into the surrounding connective tissue. Similar septa perforate the gland itself and internally bind the gland to its capsule. The medial aspect of this parotid capsule is incomplete and allows direct communication of the parotid space with the parapharyngeal space. Therefore, infections in the parotid space pose a significant threat because they may spread readily into the parapharyngeal space and then to the retropharyngeal space (see Fig. 100-14) (see Chapter 65).3,19

Peritonsillar Space The peritonsillar space lies between the capsule of the faucial tonsil medially, the superior constrictor muscle laterally, and the tonsillar pillars anteriorly and posteriorly. Infection in this space may spread into the parapharyngeal space, and involvement of the carotid sheath with subsequent thrombosis of the internal jugular vein may occur (see Fig. 100-14) (see Chapter 61).

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The fascial layers and compartments in the infant do not differ significantly in anatomy from those of the adult. The fascia of the infant may be somewhat thinner and less well developed than that of the adult, but the fascial layers and compartments contain the same structures and have the same anatomic relationships as do those of the adult. The less well-developed neck musculature of the infant and child may not supply the same degree of support as is found in the adult and so may be more prone to displacement and distortion from disease processes. Therefore, infection in the deep neck spaces may interfere with breathing and swallowing to a greater degree in the small child than in the adult. Fascial layers may become quite thickened and well defined in response to chronic infection, so what may represent a flimsy layer of fascia in the uninfected neck may become a thickened fascial layer that serves as an effective barrier to the spread of infection in response to chronic infection in this area. See also Chapter 99 for treatment of deep neck space infections. An understanding of the embryology of the neck is helpful in generating a differential diagnosis of neck masses in both children and adults. Every otolaryngologist must also develop a strong working knowledge of neck anatomy in order to minimize surgical risk and optimize patient outcomes.

Selected References Anson BJ, McVay CB. Surgical Anatomy. 5th ed. Philadelphia, PA: WB Saunders; 1971. A surgical anatomy text with fine illustrations and a discussion of the anatomy of the neck that relates well to the surgical approach to pathologic processes in this region. Crelin ES. Development of the upper respiratory system. Clin Symp. 1976;28:4. Clear and concise review that covers comparative anatomy as well as embryology of the head and neck. Also instructive drawings by Dr. Frank Netter. Levitt GW. Cervical fascia and deep neck infections. Laryngoscope. 1970;80:409. Patten BM. Human Embryology. 3rd ed. NewYork, NY: McGraw-Hill; 1968. A clear presentation of human embryology with fine illustrations.

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References 1. Arey LB. Developmental Anatomy: A Textbook and Laboratory Manual of Embryology. 7th ed. Philadelphia, PA: WB Saunders; 1974. 2. Crelin ES. Development of the upper respiratory system. Clin Symp. 1976;28:4. 3. Langman J. Medical Embryology: Human Development— Normal and Abnormal. 2nd ed. Baltimore, MD: Williams & Wilkins; 1969. 4. Jaffe BF. The branchial arches—normal development and abnormalities. In: Ferguson CF, Kendig EL, eds. Pediatric Otolaryngolog. Vol. 2. Philadelphia, PA: WB Saunders; 1972. 5. Patten BM. Human Embryology. 3rd ed. New York, NY: McGraw-Hill; 1968. 6. Everts EC, Echevarria J. The pharynx and deep neck infections. In: Paparella MM, Shumrick DA, eds. Otolaryngology. Vol 3. Philadelphia, PA: WB Saunders; 1973. 7. Poswillo DE. Etiology and pathogenesis of first and second branchial arch defects: the contribution of animal studies. In: Converse JM, McCarthy JG, WoodSmith D, eds. Symposium on Diagnosis and Treatment of Craniofacial Anomalies. Vol 20. New York, NY: New York University; 1976:86-99. 8. Suarez PA, JG Batsakis. Nonneoplastic vascular lesions of the middle ear. Ann Otol Rhinol Laryngol. 1993;102:738. 9. Edwards MJ, Graham JM Jr. Posterior nuchal cystic hygroma. Clin Perinatalol. 1990;17:611. 10. van der Putte SC. Lymphatic malformation in human fetuses. A study of fetuses with Turner’s syndrome or status Bonnevie Ullrich. Virchows Arch ;obPathol Anat;cb. 1977;376:233.

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11. Miller D, Hill JL, Sun CC, O'Brien DS, Haller JA Jr. The diagnosis and management of pyriform sinus fistulae in infants and young children. J Pediatr Surg. 1983;18:377. 12. Horisawa M, Niinomi N, Ito T. Anatomical reconstruction of the thyroglossal duct. J Pediatric Surg. 1991;26:776. 13. Kim MK, Pawel BR, Isaacson G. Central neck dissection for the treatment of recurrent thyroglossal duct cysts in childhood. Otolaryngol Head Neck Surg. 1999;121:543. 14. Gray H. Anatomy of the Human Body. 27th ed. Philadelphia, PA: Lea & Febiger; 1959. 15. Pernkopf E. Atlas of Topographical and Applied Human Anatomy. Vol 1. Philadelphia, PA: WB Saunders; 1963. 16. Hollinshead WH. Textbook of Anatomy. 3rd ed. Hagerstown, MD: Harper & Row; 1974. 17. Anson BJ, McVay CB. Surgical Anatomy. 5th ed. Philadelphia, PA: WB Saunders; 1971. 18. Levitt GW. Cervical fascia and deep neck infections. Laryngoscope. 1970;80:409. 19. Beck AL. Surgical approaches to deep neck infection. Ann Otol Rhinol Laryngol. 1955;64:91. 20. Crelin ES. Anatomy of the Newborn: An Atlas. Philadelphia, PA: Lea & Febiger, 1969. 21. Weller GL. Development of the thyroid, parathyroid, and thymus glands in man. Contrib Embryol Carnegie Inst Wash. 1933;24:93. 22. Ward GE. Thyroglossal tract abnormalities. Cysts and fistulas. Surg Gynecol Obstet. 1949;89:727. 23. Hamilton WJ, Mossman HW. Human Embryology. 4th ed. Baltimore, MD: Williams & Wilkins; 1972.

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101

C H A P T E R

T

Methods of Examination of the Head and Neck Joseph Haddad Jr., Sarah E. Keesecker, and David T. Kent

he neck of a child changes during the first decade of life. Fat accumulations in the superficial fascial compartments are initially prominent but begin to resorb at 9 months of age. The cartilaginous framework of the infantile larynx is not prominent and is located higher in the neck. As the child grows and the neck elongates, anatomic structures such as the sternocleidomastoid muscle become more reliable landmarks (Fig. 101-1). A careful history and physical

examination should guide the physician in choosing among a wide array of diagnostic procedures.

HISTORY A careful history combines information taken from the patient, family, and referring physician and includes the onset of the problem and its duration, location, severity, and progression.

FIGURE 101-1. Maturational differences in neck examination and imaging. (A) shows an infected branchial cleft cyst in a 2-year-old child; (B) shows a computed tomographic (CT) scan in the same child. It is difficult to diagnose the neck mass in this child on the basis of neck landmarks. In the teenager shown in (C) the landmarks are prominent, and a large branchial cleft cyst is seen anterior to the sternocleidomastoid muscle; CT demonstrates the large cystic lesion in (D).

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The information should lead to a differential diagnosis chosen from the basic types of pathologic conditions found in the neck. Congenital lesions may be symptomatic at birth or, like branchial cleft cysts, may become obvious with infection or slow filling with mucus. Acute inflammatory processes may occur with fever, pain, and swelling; chronic inflammatory processes, such as with granulomatous disease, have varying symptoms and signs. Neoplastic neck masses may slowly enlarge without causing significant symptoms. Interference with air or food passage or neural involvement may be late symptoms. Temporal associations should be considered. Neck pain or swelling during meals suggests salivary duct obstruction by stricture or stones. Neck mass enlargement with exercise, straining, or crying may indicate a vascular or lymphatic abnormality or a laryngocele. Environmental exposures should be determined. In a child with a neck mass, previous contact with a cat suggests cat-scratch disease. Medications such as diphenylhydantoin (Dilantin) may promote cervical lymphadenopathy. Radiation therapy to the head and neck is associated with an increased risk of thyroid carcinoma in later years. Children on cyclosporine or FK506 therapy after organ transplantation are at risk for lymphoproliferative disorders, with diffuse cervical lymphadenopathy.

PHYSICAL EXAMINATION Examination is begun when the child is comfortable with the physician. The young patient may sit in the parent’s lap to be examined. Most examiners divide the neck into anatomic areas for better definition of a differential diagnosis and to facilitate description of the problem among physicians. For example, midline neck lesions may represent a congenital problem (Fig. 101-2). Landmarks are outlined in Chapter 103, Figures 103-6 and 103-7.

INSPECTION In good light, the following normal landmarks should be identified: the jaw, the sternocleidomastoid muscles, the clavicles, and the cartilaginous larynx and trachea. Asymmetry, vascular marks, skin discolorations, scars, fistulas, and abnormal pulsations should be recorded. If a neck mass is present, its location and size should be noted, as should changes with swallowing, tongue protrusion, and head lowering. Thyroglossal duct cysts are attached to the hyoid muscle, usually in the midline, and may move with tongue protrusion. Head lowering causes venous congestion, which may cause cavernous hemangiomas to increase in size. Transillumination of a neck mass is sometimes helpful in superficial, cystic, or fluid-filled masses. Many neck masses change in size and appearance over time, and serial examinations may be necessary for adequate evaluation. Photographs may be useful.

PALPATION Using both hands, the examiner gently palpates the areas of the neck. Notable features include mobility, consistency, tenderness, pulsation, and crepitus. Sebaceous cysts are attached to the epidermis; benign lymph nodes are rubbery, well defined, and mobile; hemangiomas and lymphangiomas have a “bag of worms” consistency due to the presence of loculated fluid chambers (Fig. 101-3). Palpation should include careful evaluation of the following structures in the neck: salivary glands, lymph nodes, sternocleidomastoid muscle, thyroid gland, and larynx. The laryngeal examination is discussed in Chapter 83.

SALIVARY GLANDS The parotid glands are usually not palpable in normal children. The Stensen duct should be examined since pus may be expressed in acute parotitis. Bilateral parotid enlargement is common in mumps; when recurrent, it may represent benign parotitis of childhood. Most parotid masses in children are benign lymphangiomas and hemangiomas; they are usually soft and diffuse. Cystic masses have been reported in children and adolescents infected with human immunodeficiency virus. Solid masses in children carry a higher risk for neoplasm. Cat-scratch disease may manifest with intraparotid lymphadenopathy. The submandibular and sublingual glands are best examined with bimanual palpation (Fig. 101-4). Palpation of the submandibular gland may reveal the presence of stones. Oral cavity examination is discussed in Chapter 62.

LYMPH NODES FIGURE 101-2. Midline neck lesions often represent congenital problems. A congenital midline cervical cleft is shown, with a characteristic nipple-like projection over the cleft opening.

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Lymphadenopathy is common in children and usually represents inflammation after an upper respiratory tract infection or other infectious process. Persistent enlargement of a node after antibiotic therapy raises the suspicion for

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FIGURE 101-3. (A) Large lymphangioma of the neck in a 1-year-old child. (B) CT scan demonstrates septated, fluid-filled areas within the mass.

FIGURE 101-4. Bimanual palpation of the submandibular gland is performed with gloves. The right index finger palpates the contents of the submandibular triangle intraorally while gentle external pressure is exerted by the left hand. Stones in the parenchyma of the gland or in the ductal system are easily felt by the examining finger in this manner.

neoplasm. Large lymph nodes in the posterior triangle have a higher incidence of malignancy; the upper respiratory and digestive tracts should be examined for the primary source of a metastatic neoplasm. Multiple matted lymph nodes or the presence of a draining sinus is suggestive of granulomatous, fungal, or tuberculous disease (Fig. 101-5). Midline, pretracheal (Delphian) nodes may be associated rarely with thyroiditis or thyroid carcinoma.

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FIGURE 101-5. Nonhealing wound of the right neck after excisional biopsy in a young boy with bilateral neck masses. Subsequent evaluation led to the diagnosis of chronic granulomatous disease.

STERNOCLEIDOMASTOID MUSCLE In a neonate, asymmetry of the sternocleidomastoid muscle that is associated with torticollis and a hard mass within the muscle suggests fibromatosis colli. This may result from a hematoma after a difficult delivery, but the cause is often uncertain.

THYROID GLAND The thyroid gland consists of two lobes connected by the isthmus, which lies in front of the second or third tracheal

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ring. In approximately one third of children, a pyramidal lobe extends upward from the isthmus. This lobe is a remnant of the thyroglossal duct. The normal thyroid is not easily palpable, but a small goiter or thyroid nodule can frequently be felt by the examiner. The thyroid gland is best palpated with the patient sitting and the examiner standing behind the patient. The isthmus is normally palpable 1 cm below the cricoid cartilage. The lobes are lateral to the trachea and medial to the sternocleidomastoid muscle. A slight retraction of this muscle with one hand permits the fingertips of the other hand to outline the surface of the lobe (Fig. 101-6). When the patient swallows, the gland moves upward. Nodules inside the gland likewise move upward with swallowing. In general, diffuse enlargement of the thyroid gland in children represents thyroiditis, particularly Hashimoto disease.1 Thyroid cancer is uncommon in children, except after radiation exposure; however, when a discrete thyroid mass is present in a child, it is much more likely to be a malignancy (see Chapter 108).

AUSCULTATION Auscultation of the neck is important in evaluating the child with upper airway obstruction. The character of the stridor and the quality of the voice and cry can help to determine the location and cause of the obstruction. Vascular sounds in the neck in children most often represent transmitted cardiac murmurs. Rarely, diffuse toxic goiter may cause a systolic bruit in the thyroid area. A bruit may also be audible in the presence of an arteriovenous malformation.

ANCILLARY METHODS OF EXAMINATION

thyroid lesions in children,2 but is not as well accepted for evaluating other pediatric neck lesions. It requires a cooperative child and a willing parent. It also requires a pathologist experienced in examining the cytologic specimens obtained. One method for obtaining a specimen by fine-needle aspiration is shown in Fig. 101-7. A fine (18- to 22-gauge) needle attached to a disposable syringe (10 or 20 mL) in a syringe holder is used to obtain the specimen. As the mass is punctured by the needle, the syringe piston is withdrawn slightly to create a vacuum inside the syringe. The needle is then moved back and forth within the mass. The vacuum in the syringe is then released before the needle is withdrawn from the lesion. A small amount of sterile saline may be aspirated into the syringe to retrieve the specimen from the needle. Then, the specimen may be divided into several samples for bacteriologic studies and cytologic smears. The cytologic smears are prepared and stained by the Papanicolaou method. Fine-needle aspiration is generally useful for diagnosis in thyroid disease. It may be contraindicated in children with suspected atypical mycobacteria because it may lead to development of a draining fistulous tract. Small or deep lesions of the neck and large, solid nonvascular tumors may be aspirated or biopsy specimens can be removed with a cutting needle under guidance by computed tomography (CT).

Imaging Techniques In choosing an imaging technique, the physician must consider the patient’s age and the ability of the patient to

Needle Aspiration and Biopsy Fine-needle aspiration is widely used in adults and may be useful in differentiating between benign and malignant

FIGURE 101-6. Palpation of the thyroid gland is usually performed with the examiner standing behind the patient. A slight retraction of the sternocleidomastoid muscle away from the midline with one hand permits the other hand to outline the surface of the lobe.

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FIGURE 101-7. Technical aspects of the aspiration biopsy technique. (A) The needle is introduced into the mass, which is firmly grasped by the fingers. (B) Vacuum pressure is applied to the syringe. (C) The needle is moved back and forth within the mass and in different directions without being completely withdrawn. (D) With the needle still in the mass, the vacuum in the syringe is released, and the needle containing the specimen is then withdrawn. (Modified from Frable, 1976.)

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CHAPTER 101 ❖ Methods of Examination of the Head and Neck 1685 cooperate. Many techniques require sedation of a child for adequate examination, so the desirability and ease of performing these tests must be considered.

Plain Film The plain film radiograph of the neck is a useful base line study in children. It can confirm the presence of a radiopaque foreign body in the airway or soft tissues of the neck; it can demonstrate soft tissue compression of the airway caused by, for example, a retropharyngeal abscess or large neck mass. Calcifications, such as in papillary carcinoma of the thyroid or tuberculous lymphadenitis, can be documented and localized. Radiopaque stones within the submandibular gland or duct are well demonstrated on a submental view plain film. Persistent retention of gas in the cervical esophagus may indicate an esophageal foreign body. Air in the soft tissues of the neck is seen after trauma or esophageal perforation, or it may represent an incidental, benign finding in some children after swimming or vigorous exercise. Plain films include a lateral projection, with the chin in a slightly extended position, and a frontal projection, with the chin superimposed on the occiput with the mouth closed. The radiographs are exposed during inspiration to obtain a reproducible anatomic pattern.3 Certain techniques enhance the diagnostic use of plain films. Magnification views allow more accurate visualization of small cervical structures and small foreign bodies. High kilovoltage filters (which may be made of a combination of tin, copper, and aluminum) decrease the radiation absorption of the ossified cervical spine, thereby enhancing delineation of the airway (Fig. 101-8). Maturational differences in children should be considered in evaluating cervical radiographs. The larynx and cricopharyngeus muscle migrate inferiorly during growth, from the level of C2 to approximately C5 in adults. No structures aside from the hyoid bone are ossified in the pediatric larynx, and no sexual dimorphism is detectable in the first 6 years of life.4 The retropharyngeal space is relatively thicker in children, and the prevertebral tissues are expandable. The normal thickness is less than the size of one vertebral body, but it can expand to the width of three vertebral bodies during forceful expiration or crying with the neck flexed. By adolescence, the upper limit of normal decreases to one-third the width of the vertebral body. Ambiguity about prevertebral tissue thickening on lateral cervical X-ray film often can be resolved by fiberoptic examination or with more advanced imaging studies. CT scanning with contrast may provide additional information to help differentiate abscesses from other spaceoccupying lesions, but clinical findings must be considered as well when evaluating for surgery.5-7

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FIGURE 101-8. Magnification airway view of a neck in the anteroposterior projection reveals asymmetric swelling of the subglottic airway in a young child with stridor and hemangiomas of the skin. A diagnosis of subglottic hemangioma was confirmed on bronchoscopy.

body can be confirmed, and accumulation of contrast medium in the soft tissue of the neck or prevertebral space may indicate a fistula, congenital lesion, or posttraumatic lesion from a foreign body. The study is often included when evaluating stridor in an infant or to rule out gastroesophageal reflux or a tracheoesophageal fistula. (See Chapters 74, 75, 78–80 for swallowing disturbances and esophageal lesions.)

Esophagography

Ultrasonography

The barium swallow demonstrates pathologic conditions of the esophagus. Indirect high-speed filming techniques give less radiation exposure than they did in the past. The esophagram may demonstrate displacement caused by tumors, inflammatory masses, and abscesses. An intraluminal foreign

Ultrasound has many advantages in evaluating neck problems in children, and is especially useful for evaluating superficial cysts.8 No sedation is required and no radiation is involved. The machines are portable, and the hand-held transducer allows for evaluation in any plane. Its main limitation in

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evaluating neck problems is its lack of specificity, especially in deeply located structures.8 Ultrasound is most useful in determining the organ of origin of a neck mass and in helping to differentiate a cystic from a solid mass. US can be useful for locating hypoechogenic areas associated with abscesses, but contrast-enhanced CT may be required to detect the hallmark sign of ring enhancement.8 Ultrasound can also be useful in evaluating thyroid disease. A thyroid nodule may have cystic, solid, or mixed echogenic properties. After the echogenicity is determined, the lesion may be aspirated or a biopsy specimen may be obtained. Color Doppler ultrasound supplements conventional ultrasound to assess vascularity and blood supply, but may not be useful for flow evaluation in low-flow lesions such as venous malformations.8 Ultrasound may be helpful in the preoperative evaluation of a thyroglossal duct cyst to confirm the presence of a thyroid gland in the normal position; however, only a thyroid scan demonstrates function. A lymphangioma in the neck may demonstrate characteristic anechoic or mixed echogenic patterns; septations are sometimes demonstrated, and the margins are poorly defined. MR is most useful for differentiating lymphatic malformations from surrounding soft tissues.8

Computed Tomography (CT) CT reconstructs a tomographic image from multiple attenuation readings with a highly collimated radiation beam. The contiguous slices (usually 3 mm thick in pediatric neck scans)9 provide excellent information about neck anatomy and pathologic conditions. CT has many advantages in evaluating the pediatric neck for such problems as parapharyngeal abscess, brachial cleft anomaly, or other nonthyroid masses (see Fig. 101-1B and D), but should always be correlated with clinical findings when evaluating for surgical management.5-7 CT provides information on the extent of a neck mass and the presence of calcifications; it can define adjacent soft tissue planes and normal anatomic structures. Nonpalpable enlarged nodes in the neck may be shown. When contrast is used, information is obtained about vascularity, local inflammatory processes, and the location of the carotid artery. The power of CT scanning to differentiate phlegmon and cellulitis from abscesses is limited and clinical correlation is necessary when evaluating for such lesions.5,6 CT is a superior technique for demonstrating bone conditions, such as fracture and erosion, and has evolved to the point where scans can typically be completed in a very short time, occasionally obviating the need for sedation in children.9 Rapid collection of axial slices on a continuously moving table, called helical, spiral, or volumetric CT scanning, is a continually developing technology that provides for less sedation and radiation exposure in the pediatric patient while maintaining image quality.9 CT angiography can be used with helical CT as a way to obtain information on vascularity and anatomy with only a bolus injection of contrast. This can be especially helpful in pediatric patients in whom

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the administration of intravenous contrast by bolus and drip technique can be difficult. The drawbacks of using CT in children are the possible need for sedation in young children, the use of ionizing radiation and the need for intravenous contrast agent to evaluate vascularity. Ionizing radiation has recently become a significant concern among parents and healthcare providers, as it is energetic enough to cause strand breaks and base damage in DNA that increase the risks of radiation-induced carcinogenesis. Children are especially vulnerable to this damage, as they are inherently more radiosensitive and have a greater remaining lifespan in which a radiation-induced cancer may develop. No large-scale epidemiologic studies have yet been conducted, but studies based on available data indicate that 0.4%–2% of all US cancers may be attributable to CT study radiation exposure. The incidence of fatal CT radiation-induced cancer has been estimated as high as 1 in 1000 CT scans for a young child. It is important to note that the risk for any one individual is small, and is likely greatly outweighed by the positive benefit of an appropriate CT scan. Application of the ALARA principle (“as low as reasonably possible”) should be used when making decisions regarding a CT imaging study. The cautious physician will justify its necessity and be confident of its benefit to the patient. Methods for reducing the overall radiation dose from CT include avoiding unnecessary scans, using alternative imaging methods when available, and reducing the CT-related dose in the individual patient through adjustment of the scanner’s exposure control.10-12 Other factors affecting the choice of CT include the age of the child, the availability of alternative imaging techniques, and the clinician’s experience.

Magnetic Resonance Imaging Magnetic resonance imaging (MRI) has become an accepted modality of evaluation of the head and neck. It is founded on the principle that atoms with a net nuclear spin placed in a strong magnetic field process, absorb, and release energy at specific frequencies when stimulated with radio frequency electromagnetic energy. The energy released from the hydrogen nuclei generates signals that are sensed by an antenna and processed by a spectrometer. A computer system can then construct images displaying anatomic structures.13 The standard high-field magnet strength is 1.5 T. MRI does not use ionizing radiation, but, like CT, it may require sedation, especially in children under 6 years of age.8 Vascular structures can be visualized without contrast. MRI can generate images in three planes: coronal, sagittal, and axial (Fig. 101-9). These can provide an added dimension in evaluating the neck. With a thyroglossal duct cyst, a sagittal view can demonstrate a midline tract. MRI is superior to CT in providing soft tissue contrast resolution and is therefore especially useful in the evaluation of vascular anomalies14; it is inferior in delineating osseous structures, calcifications, and airways. In general, CT is the preferred imaging modality

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Nuclear Scintigraphy

FIGURE 101-9. Sagittal view on magnetic resonance imaging demonstrating a large thymus in an infant with a suprasternal mass.

for evaluation of deep neck infections due to the consistently better quality, lower price, and quicker scan times. However, MRI can be useful when CT evaluation of difficult abscesses is equivocal.14 Magnetic resonance angiography (MRA) uses special (gradient echo) pulse sequences to obtain multiple images of moving sources (protons in flowing blood) without the injection of a contrast agent, and can be useful for evaluating vascular complications such as internal carotid artery narrowing or venous thrombosis.14 The images may be stacked and rotated in a computer display to obtain a threedimensional representation of the larger, faster flowing vessels. The lesion, however, may not be visualized unless it is coarsely vascular and has a high flow. Since the vessels, along with the lesion, can usually be discerned on conventional MRI slices, MRA is not often necessary. MRA is sensitive to motion artifacts, especially swallowing, and is likely to require sedation in children (Fig. 101-10). Gadolinium (Gd) injection usually enhances (brightens) the signal of a neck mass on MRI. Because adjacent fat planes are already bright, especially on the most frequently obtained (T1-weighted) pulse sequences, enhancement may actually decrease the conspicuousness of a lesion. Conspicuousness increases when gadolinium is used in conjunction with a “fat suppression” pulse sequence that darkens fat planes adjacent to the lesion. These sequences are exquisitely sensitive to motion artifact, however, and for most neck masses in children, conventional T1-weighted images in multiple planes, supplemented by a T2-weighted sequence for further characterization of the lesion, may be sufficient. Some sedation may be necessary even in these cases. Diffusion-weighted MRI has recently been shown to be effective in differentiating between benign and malignant head and neck masses, but larger studies are needed to confirm these promising initial findings.15

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The thyroid gland is easily evaluated by nuclear medicine procedures using isotopes. Even though thyroid masses are rare in children, when they do occur, they are more likely to be malignant than they are in adults, and nuclear imaging plays an important role in their detection. In the past decade, technetium-99m (99mTc) has replaced radioactive iodine for scanning the thyroid gland. Sodium pertechnetate 99mTc is concentrated within the thyroid gland by the same trapping mechanism that stores iodine, but this isotope is not incorporated into the precursors of thyroxine. Nonfunctioning (cold) nodules are demonstrated as filling defects within the image of the gland; functioning (hot) nodules are demonstrated as areas of increased activity. If only the nodules concentrate the radioactive isotope, then the thyroid gland must be stimulated by thyroid-stimulating hormone (TSH) and the patient is scanned again. After TSH stimulation, a normal thyroid gland is seen, with the autonomous thyroid nodule evident in the normal tissue. Scintigraphy is also useful for the detection of ectopic thyroid tissue.14 The same techniques can be used to evaluate the salivary glands, but the results are nonspecific. Degenerative diseases such as Sjögren disease show decreased uptake of radioisotope. Neoplastic or inflammatory masses that destroy or replace the gland display focally decreased uptake. Warthin tumor and oncocytoma, rare in children, may concentrate the isotope. 99mTc diphosphonate is a bone-imaging agent that is normally taken up in the cervical spine. This agent may also be absorbed in areas of necrosis or calcification within the soft tissues of the neck. Neuroblastomas take up bone-scanning agents, even when calcification of this tumor cannot be demonstrated radiographically. Iodine 123 metaiodobenzylguanidine scintigraphy is useful in confirming the neural crest origin and staging of cervical neuroblastoma due to its high sensitivity.8 The use of gallium for evaluation of neck masses requires a relatively high radiation dose and is discouraged in children.

Arteriography The use of angiography has diminished dramatically with the widespread use of CT. Its main uses are limited to the diagnosis of vascular neck masses and cervical trauma with vascular injury. The vascular neck masses include chemodectomas and nasopharyngeal angiofibromas, which show numerous enlarged arteries and staining in the capillary phase of the study. Arteriovenous malformations are characterized by large feeding vessels and show prompt filling of large draining veins during the arterial phase. Cavernous hemangiomas have a slow flow and are rarely demonstrated. Digital subtraction angiography is widely used and employs a digital format for computer image enhancement. With this modality, exposure to contrast and radiation is usually reduced.

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FIGURE 101-10. Magnetic resonance imaging of a 4-month-old infant with a right neck mass. (A) Mass adjacent to the carotid on an axial view. (B) Magnetic resonance angiographic reconstruction of the neck vessels, with deviation of the carotid. Excisional biopsy revealed ectopic thymus of the right neck.

Arteriography has taken on an important role in preoperative evaluation and embolization of vascular malformations in the neck. A variety of embolic materials has been employed, including plastic, Gelfoam, metal, coils, absolute alcohol, blood clots, and muscle. Vascular thrombosis distal to the embolic material reduces vascularity and flow of the malformation and operative blood loss.

With the advent of CT scanning, sialography is rarely used in children. MR sialography is another acceptable substitute for standard sialography, as the latter can be a painful procedure.8 Xeroradiography exposes the child to approximately four times the radiation of conventional neck radiography and is not routinely used in children.16

Friedman AP, Haller JO, Goodman JD, Nager H. Sonographic evaluation of noninflammatory neck masses in children. Radiology. 1983;147:693. Gatenby RA, Mulhern CB Jr, Strawitz J. CT-guided percutaneous biopsies of head and neck masses. Radiology. 1983;146:717. Harnsberger HR, Mancuso AA, Muraki AS, et al. Branchial cleft anomalies and their mimics: computed tomographic evaluation. Radiology. 1984;152:739. Leboeuf G, Ducharme JR. Thyroiditis in children. Diagnosis and management. Pediatr Clin North Am. 1966;13:19. Solbiati L, Cioffi V, Ballarati E. Ultrasonography of the neck. Radiol Clin North Am. 1992;30:941. Swartz JD, Yussen PS, Popky G. Imaging the soft tissues of the neck: nonnodal acquired disease. Crit Rev Diagn Imaging. 1991;31:471. Yousem DM. Dashed hopes for MR imaging of the head and neck: the power of the needle. Radiology. 1992;184:25.

Selected References

References

Other Imaging Techniques

The following articles provide background information to the topic discussed in this chapter. Cole DR, Bankoff M, Carter BL. Percutaneous catheter drainage of deep neck infections guided by CT. Radiology. 1984;152:224. Fiori-Ratti L, DeCampora E, Senin U. Sequence scintigraphy: a morphological and functional study of the salivary glands. Laryngoscope. 1977;87:1086. Frable WJ. Thin needle aspiration biopsy. Am J Clin Pathol. 1976;65:168.

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1. Gould LV, Cummings CW, Rabuzzi DD, Reed GF, Chung CT. Use of computerized axial tomography of the head and neck region. Laryngoscope. 1977;87:1270. 2. Corrias A, Cassio A, Weber G, et al. Thyroid nodules and cancer in children and adolescents affected by autoimmune thyroiditis. Arch Pediatr Adolesc Med. 2008;162(6):526–531. 3. Brodeur AE, Silberstein MD, Graviss ER. Direct microfocus magnification: its many advantages in pediatrics. Am J Dis Child. 1980;134:245.

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11. Rice HE, Frush DP, Farmer D, Waldhausen JH. APSA Education Committee. Review of radiation risks from computed tomography: essentials for the pediatric surgeon. J Pediatr Surg. 2007;42(4):603–607. 12. Brenner DJ, Hall EJ. Computed Tomography—An Increasing Source of Radiation Exposure. N Engl J Med. 2007;357: 2277–2284. 13. Stark D, Moss A, Gamsu G, Clark OH, Gooding GA, Webb WR. Magnetic resonance imaging of the neck. Radiology. 1984;150:447. 14. Gujar S, Gandhi D, Mukherji SK. Pediatric head and neck masses. Top Magn Reson Imaging. 2004;15(2):95–101. 15. Abdel Razek AA, Gaballa G, Elhawarey G, Megahed AS, Hafez M, Nada N. Characterization of pediatric head and neck masses with diffusion-weighted MR imaging. Eur Radiol. 2009:19(1):201–208. 16. Smith C, Ramsey RG. Xeroradiography of the lateral neck. Radiographics. 1982;2:306.

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102 C H A P T E R

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Imaging of Pediatric Neck Masses Kalliopi Petropoulou and Barton F. Branstetter IV

neck mass in a child elicits a differential diagnosis that is starkly different from the differential for an adult neck mass. Although most neck masses reflect benign pathology arising in the neck itself, the neck is often the site of presentation for systemic diseases or aggressive malignancies. Occasionally, the etiology of a pediatric neck mass will be evident clinically, but the majority of patients will undergo imaging to narrow the differential diagnosis and to more completely define the extent of the lesion. There are three cross-sectional imaging modalities currently employed to evaluate head and neck pathology: ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI).1 When imaging children, criteria for selecting the most appropriate modality include availability, cost-effectiveness, modality sensitivity, and patient risk. Radiation exposure is a major concern in the pediatric population as is the duration of imaging, because longer studies may require sedation or even general anesthesia. Each imaging modality has relative advantages and disadvantages. MRI has superior soft tissue resolution, allows direct multiplanar imaging, and evaluates bone marrow signal, which is of critical importance in the imaging of the skull base and face. Sedation or even general anesthesia is frequently required for the completion of the study especially when dealing with patients younger than 7 years of age. In addition to the inherent risks of sedation or anesthesia, they contribute to increased costs. MRI of the skull base, head, and neck in older children and adolescents can be seriously compromised by the artifacts generated by dental braces. When MRI is the imaging modality of choice, the dental braces may have to be removed (Fig. 102-1). CT allows better assessment of the periosteum and bone matrix. With the advent of 16- and 64-channel CT scanners, imaging time has been reduced dramatically, and the reformatted sagittal and coronal images are of excellent diagnostic quality. CT imaging protocols are now completed within fractions of a minute, resulting in less radiation exposure and significant reduction in the need for sedation. Special efforts have been made in recent years to design and decorate CT and MRI suites in a way that the child’s attention is distracted from the examination process. Since the implementation of sedation distraction techniques, the percentage of patients receiving sedation for CT imaging has dropped to 1% and for MRI from 70% to 2 cm) can be the manifesting sign of leukemia, lymphoma, or metastatic disease, and although less common, a neck mass can be only manifesting sign of pediatric thyroid carcinoma. Although primary neuroblastoma of the head and neck can occur,109 over 90% of cases represent metastatic disease.110 In young children, LCH (formerly known

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CHAPTER 105 ❖ Cervical Adenopathy as histiocytosis X) is more common than the lymphomas.111 It is not a true malignancy, but a reactive process characterized by proliferation of the monocyte/macrophage line. Because of its invasive nature, it is included in the discussion on neoplastic disorders. Cunningham, Myers, and Bluestone112 noted the following distribution of tumor types: Hodgkin disease and NHL (60%), rhabdomyosarcoma (15%), thyroid tumors (10%), neuroblastoma (5%), and nasopharyngeal carcinoma (5%). Lymphoma HodgKiN disease Clinical findings and diagnosis: Hodgkin disease commonly manifests with asymptomatic cervical or supraclavicular lymphadenopathy which may fluctuate over time.113 Two-thirds of patients also have mediastinal node involvement, but constitutional symptoms (fever, night sweats, weight loss) occur in only 25%–30%. An infectious etiology has been suggested.114 Lymph node microscopy reveals large bi-nucleated malignant cells known as Reed– Sternberg cells (RSC), in combination with a population of inflammatory cells (Fig. 105-9). Flow cytometry is a technique that examines microscopic particles suspended in a stream of fluid, enabling identification of specific cell types. While considered a standard for diagnosing leukemia, flow cytometry performed on needle aspiration samples from suspected lymphoma is diagnostic if positive, but is not sensitive.115 Flow cytometry is combined with other diagnostic techniques for definitive diagnosis of lymphoma, including IHC in situ hybridization and gene rearrangement studies.116 Hodgkin disease is staged using the Ann Arbor staging classification,117 which utilizes biopsy findings, CT scan, and PET scan, to determine the anatomical areas of the body that are affected. Based on the degree of involvement ranging from single lymph node region involvement to dissemination, the tumor is staged from I to IV. Stage I is involvement of a single lymph node region (I) or single extralymphatic site (Ie); Stage II is involvement of two or more lymph node regions on the same side of the diaphragm (II) or of one lymph node region and a contiguous extralymphatic site (IIe); Stage III is involvement of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIs) and/or limited contiguous extralymphatic organ or site (IIIe, IIIes); Stage IV is disseminated involvement of one or more extralymphatic organs.

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Treatment: In general, early stage Hodgkin disease (IA or IIA) is treated with either chemotherapy or radiation therapy alone, while more extensive disease (III, IVA, or IVB) is treated with combination therapy. Chemotherapy typically involves a combination of Adriamycin, Bleomycin, Vinblastine, and Dacarbazine (ABVD regimen), although newer regimens are being developed and utilized including the Stanford V regimen.118 Certain prognostic factors are associated with better survival including young age, lower stage disease, and lower lymphocyte and white blood cell counts.119 Non-Hodgkin Lymphoma Clinical findings and diagnosis: NHL manifests less often with cervical adenopathy,120,121 but when adenopathy does occur (50%–80% of patients), it is often exclusively supradiaphragmatic (i.e., involving the neck, supraclavicular regions, and axillae). Because there are varied types of NHL, there is no specific pathologic biopsy finding. The typical pathologic types are lymphoblastic, small noncleaved cell, and large cell. There are various clinical staging systems for NHL, of which some are used for adults and some for children. Because the terms are often confusing, the paradigm for staging NHL is by aggressiveness. Although adult NHL can be prognostically classified by aggressiveness into low grade, intermediate grade, or high grade (with each having either a diffuse or nodular pattern), pediatric NHL is usually high grade and diffuse. Treatment: Chemotherapy is used for treating all stages of NHL, with many protocols in the literature that utilize up to five drugs in various schedules. Allogenic and autologous stem cell transplants may be used based on the patient’s response to chemotherapy.122 Monoclonal antibody therapy (Rituxan®) is also being used to treat some types and stages of NHL.123 Although the major cancer-reporting agencies still use the historic Hodgkin vs. non-Hodgkin classification for statistical reporting, the recent classifications (1994 REAL and 2001 WHO) have abandoned the HL vs. NHL grouping and instead list 43 different forms of lymphoma based on clinical, pathologic and prognostic factors.124 The recent 2008 revision of the WHO classification uses recent developments in the diagnosis and recognition of tumors of the hematopoietic and lymphoid tissues, including the lymphomas.125

Langerhans Cell Histiocytosis

FIGURE 105-9. A, Photomicrograph of a Langerhans cell (from Table 105-2). B, Electron microscopic view of a Birbeck granule.

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LCH is a proliferation of Langerhans cells with extensive infiltration. Langerhans cells are histiocytes that function as antigen presenting cells, derive from the bone marrow, and migrate from skin to the lymph nodes. LCH can manifest from isolated lesions to diffuse disease. Previous names for this disease include Hand–Schüller–Christian disease, Letterer–Siwe disease, and histiocytosis X. Clinical findings and diagnosis: LCH typically manifests with unifocal or multifocal bony lesions, and only a small number patients initially have isolated cervical nodes.126

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Based on location and systemic involvement, LCH is classified into unifocal; multifocal unisystem, and multifocal multisystem. Neonatal presentation can be life-threatening.127 Biopsy of affected lymph nodes or skin is diagnostic. Light microscopy using Hematoxylin-eosin staining will show sheets of cells with features of Langerhans cells including a folded coffee-bean shaped nucleus, discrete nucleolus, and a moderate amount of eosinophilic cytoplasm (Fig. 105-10A). Electron microscopy will show the presence of Birbeck granules (membrane-bound rod or racquet-shaped structures with a central linear density) (Fig. 105-10B), and iummunocytochemistry will show CD1 positivity. Treatment: Treatment consists primarily of surgical excision for localized lesions and of chemotherapy, with or without irradiation and surgery, for multifocal disease.128 The deoxyadenosine analogs (Cladribine and clofarabine) are used in leukemia and may have some benefit in refractory LCH.129 Bone marrow transplant has been described for severe refractory disease.130

Iatrogenic Disorders Serum sickness is usually caused by an allergic reaction to an ingested or injected drug. Systemic antigen-antibody

A

complexes provoke cervical and generalized lymphadenitis.131 Other symptoms include malaise, fever, urticaria, swollen joints, arthralgias, and hepatosplenomegaly. The symptoms usually subside 1–2 weeks after cessation of the offending agent. Bacille Calmette–Guérin (BCG) vaccination against tuberculosis produces lymphadenopathy in 1% of children.132 It is more common in immunocompromised neonates infected with HIV,133 as well as children with immune disorders such as chronic granulomatous disease.134 Diagnosis is suggested by axillary (97%), cervical (2%), or clavicular (1%) adenitis ipsilateral to the vaccine site with no other detectable cause; a cutaneous sinus drainage tract may be present at the site of injection. Mean age at presentation is seven months, with onset of adenitis weeks to months following inoculation. Treatment is supportive, with needle aspiration for suppurative nodes, and excisional biopsy reserved for large nodes (3 cm or greater) or those that show rapid enlargement and induration during follow-up.135 Diptheria, tetanus, and pertussis (DTP)-induced cervical lymphadenitis is a rare complication of DTP inoculation. Spontaneous resolution generally occurs within several weeks.136 Drug-induced cervical adenopathy has been reported with phenytoin, isoniazid, pyrimethamine, allopurinol, and phenylbutazone. Anticonvulsant hypersensitivity syndrome refers to a spectrum of symptoms including lymphadenopathy, and can develop after carbamazepine, phenytoin, and lamotrigine. Valproic acid and benzodiazepines do not cause this syndrome137 Immunosuppressive agents such as cyclosporine and FK 506 may produce cervical adenopathy as part of posttransplant lymphoproliferative disease.138 Epstein–Bar infection may be the cause.139 Once biopsy has established the diagnosis, discontinuation of immunosuppressive therapy and the use of rituximab will generally reverse the disease progression.140 Intravenous drug abuse without HIV is associated with multiple soft tissue complications in the head and neck, including lymphadenopathy.141

EVALUATION AND DIAGNOSIS

B FIGURE 105-10. Photomicrograph of an atypical lymphocyte.

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Because there are so many different causes of lymphadenopathy in children, diagnosis requires an organized stepwise approach of history, physical examination, diagnostic testing, imaging studies, and needle or open biopsy until the diagnosis is made (Table 105-8). The duration and laterality of the adenopathy provide important diagnostic clues. Acute unilateral adenitis is generally caused by bacterial adenitis while less likely etiologies include nontuberculous adenitis and toxoplasmosis. When a bacterial etiology is suspected for acute adenitis, 7–10 days of an oral cephalosporin or semisynthetic penicillin should be prescribed as a diagnostic trial. Conversely, acute bilateral adenitis is most often a response to systemic infection

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TABLE 105-8. Evaluation and Diagnosis of Lymphadenopathy in Children History of duration and laterality of the lymphadenopathy Acute unilateral lymphadenopathy • Bacterial adenitis; nontuberculous adenitis; toxoplasmosis Acute bilateral lymphadenopathy • Viral adenitis; pharyngitis; EBV; CMV; HSV-6; mycoplasma Subacute or chronic lymphadenopathy • Cat scratch; tuberculosis; AIDS; malignancy,; non-infectious lymphadenopathy syndromes History of the child’s overall state of health Associated Infectious symptoms (fever, pain, irritability) • Bacterial adenitis; viral adenitis Associated constitutional symptoms: (change in appetite, weight loss, night sweats, fevers) • Tuberculosis:; lymphoma; unrecognized infection or malignancy A more focused history Recent pharyngitis or viral respiratory infection: bacterial adenitis; viral adenitis Recent travel: • USA (AZ, CA, TX, NM): coccidiomycosis • USA (southeastern or central): histoplasmosis • Tropical countries: parasitic infection • Developing countries: tuberculous adenitis Dental problems: actinomycosis Exposure to cats: cat scratch; toxoplasmosis Ingestion of uncooked meats: toxoplasmosis Contact with rabbits: tularemia Other family members with systemic infection: tuberculosis Unpasteurized dairy products: brucellosis Other systemic infections: AIDS; fungal infection Medication usage: drug-induced lymphadenopathy Physical Exam Overall appearance of the child • Sick appearing child: more likely an infectious etiology • Nontoxic appearing child: suspicious for a neoplasm

such as EBV or CMV, or a localized reaction to nonspecific viral pharyngitis. Other etiologies include HSV-6 and mycoplasma. The most common causes of subacute or chronic adenitis are cat scratch, tuberculous adenitis, and noninfectious lymphadenopathy syndromes. AIDS must also be considered in an at-risk child. Nontender adenopathy of any duration is suspicious for malignancy. The history of the child’s overall state of health is helpful: acute infectious symptoms suggest viral or bacterial adenitis; more chronic constitutional symptoms such as weight loss, sweats, and prolonged fevers suggest either a more systemic infectious process or malignancy such as lymphoma. A more focused history will identify certain diagnostic clues. Recent pharyngitis or viral respiratory infection suggests bacterial or viral adenitis. Recent travel to certain areas can suggest specific less common infectious processes: travel within the United States to Arizona, California, Texas and New Mexico (cocciodiomycosis); travel to southeastern or central

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Nature of the lymphadenopathy itself • Tenderness and rapid erythema: acute bacterial infection • Slow progression to erythema: chronic bacterial infection • Mild tenderness and no erythema: viral infection • Large, firm and rubbery: neoplastic Associated findings on the skin and mucous membranes • Viral syndrome • Kawasaki disease • PFAPA Fine Needle Aspiration for either suspected infectious or non-inflammatory etiology Stains: gram, CSD, AFB Bacterial culture Mycobacterial culture Fungal culture Flow cytometry Diagnostic Testing if no diagnosis from all of above CBC and peripheral smear Mononucleosis testing: heterophile or monospot PPD testing Serology (antibody titers): EBV; CSD; HSV; CMV; HHV-6; toxoplasmosis; tularemia; brucella; fungal infection HIV testing Imaging Studies if no diagnosis from all of above Chest x-ray: tuberculosis; sarcoidosis Neck Ultrasound: evaluate for congenital cyst or abscess formation Neck CT Neck MRI Open Biopsy if no definitive diagnosis from all of above If lymphadenopathy does not regress and diagnosis is unsure If lymph nodes are hard or fixed If location is posterior cervical or supraclavicular If history of constitutional symptoms

United States (histoplasmosis); travel to tropical countries (parasitic infection); and travel to developing countries (tuberculous adenitis). Other historical clues include the following: a history of dental infection (actinomycosis); exposure to cats (cat scratch or toxolasmosis); ingestion of uncooked meats (toxoplasmosis); contact with rabbits (tularemia); other family members with systemic infection (tuberculosis); ingestion of unpasteurized dairy products (brucellosis); the presence of other systemic infections (AIDS; fungal infection); medication usage(drug-induced lymphadenopathy). The physical examination should focus on the overall appearance of the child (a sick appearing child is more likely to have an infectious etiology, while a non-toxic-appearing child is suspicious for a neoplastic disorder); the nature of the lymphadenopathy itself including tenderness, erythema, nature of progression, and the nature of the lymph nodes or palpation; and associated findings on the skin and mucous membranes that can suggest viral infection, Kawasaki disease, and PFAPA.

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FNA is indicated for acute adenitis that persists or progresses despite antimicrobial therapy, and for subacute or chronic adenopathy of unknown cause. To identify a presumed infectious etiology in acute adenitis, the largest and/or most fluctuant node is selected for aspiration. After cleansing with betadine and alcohol, the overlying skin is anesthetized with 2% lidocaine or procaine. Aspiration for identification of organism is performed with an 18- or 20-gauge needle attached to a 20- mL syringe. The aspirate is inoculated directly onto appropriate media for aerobes, anaerobes, fungi, and mycobacteria; Gram stain, CSD stain, and acid-fast stains are also performed. Early use of FNA to evaluate subacute or chronic presumed noninflammatory adenopathy can help guide additional diagnostic tests, including imaging studies and excisional biopsy. Aspiration is performed with a 22-gauge needle attached to a 10-mL syringe. The plunger is withdrawn to 1 mL before insertion and moved using a rapid in-and-out motion within the lesion. The aspirate is spread on two prelabeled slides placed directly in ethanol or sprayed with fixative. Diagnostic testing is performed if the FNA does not provide a definitive diagnosis. A complete blood count with differential blood cell count and reticulocyte count will suggest viral or bacterial infection. Leukemia is suggested by blast cells on the peripheral smear and by unexplained anemia, especially if accompanied by reticulocytopenia or abnormalities of platelets or leukocytes. Intradermal skin tests for tuberculosis are recommended early in the diagnostic evaluation, including NTM antigens when available. Persistent undiagnosed adenopathy warrants more specific tests including a heterophile count or monospot, antistreptolysin O (ASO) titers, and serologic evaluation. Serologic tests are available for EBV (monospot or viral antibody titers), CSD, herpes simplex virus, CMV, HHV-6, HIV, toxoplasmosis, tularemia, Brucella, histoplasmosis, and coccidiodomycosis. Imaging studies include chest X-ray, neck ultrasound, neck CT, and neck magnetic resonance imaging (MRI). A chest X-ray is helpful in diagnosing MTB, sarcoidosis (hilar adenopathy), M. pneumoniae, and AIDS (30%–50% of AIDS patients have lymphoid interstitial pneumonitis). CT and MRI offer similar information, but MRI is slightly more sensitive for soft tissue abnormalities. In general,142,143 normal nodes are up to 10 mm with a longitudinal to transverse diameter ratio of 2:1 or higher, whereas larger nodes are abnormal, particularly if the ovoid shape is not preserved. Other suggestive imaging findings are central nodal necrosis with a rim of irregular enhancement (tumor infiltration); lymph node enhancement (acute infection, lymphoma, tuberculosis, and less common causes such as Kikuchi-Fujimoto disease, Kimura disease, and GLH); multiple, low-density nodes with thick rims of peripheral rim enhancement and possible calcification (tuberculous adenitis); calcifications in lymph nodes (tuberculous adenitis and other forms of granulomatous adenopathy, lymphoma after irradiation or chemo-

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therapy, and following healed viral or bacterial infection); diffuse cervical lymphadenopathy with multiple parotid cysts (HIV infection). Compared with MRI and CT, ultrasound offers the advantages of lower cost and portability, but provides inferior soft tissue details. Nonetheless, ultrasound can determine if a lesion is cystic or solid, help monitor disease progression, and serve as a guide for FNA. Early open biopsy is indicated for144 (1) supraclavicular or low neck adenopathy; (2) prolonged systemic symptoms, such as fever, weight loss, night sweats; (3) hard or fixed mass; (4) abnormal chest X-ray; and (5) rapid or progressive growth in the absence of inflammation. Biopsy is also indicated for a persistent mass of unknown cause following the previous studies described here. In general, the largest node should be removed, but specimens from the lower neck and supraclavicular areas provide the highest diagnostic yield. Excised nodes are submitted fresh in saline, not formalin, for bacteriologic studies, routine histologic examination, and for Giemsa, acid-fast, Warthin-Starry, periodic acid-Schiff (PAS), and methenamine silver stains. Table 105-8 is a succinct stepwise approach to the evaluation and diagnosis of the child with lymphadenopathy of acute, subacute or chronic nature.

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51. Edginton ME, Rakgokong L, Verver S, et al. Tuberculosis culture testing at a tertiary care hospital: options for improved management and use for treatment decisions. Int J Tuberc Lung Dis. 2008;12(7):786–791. 52. Zhou Y, Li HP, Li QH, et al. Differentiation of sarcoidosis from tuberculosis using real-time PCR assay for the detection and quantification of Mycobacterium tuberculosis. Sarcoidosis Vasc Diffuse Lung Dis. 2008;25(2):93–99. 53. Jackson LA, Perkins BA, Wenger JD. Cat scratch disease in the United States: an analysis of three national databases. Am J Public Health. 1993;83(12):1707–1711. 54. Florin TA, Zaoutis TE, Zaoutis LB. Beyond cat scratch disease: widening spectrum of Bartonella henselae infection. Pediatrics. 2008;121(5):e1413–e1425. 55. Bass JW, Vincent JM, Person DA. The expanding spectrum of Bartonella infections: II. Cat-scratch disease. Pediatr Infect Dis J. 1997;16(2):163–179. 56. Kaplan SL, Mason EO Jr, Wald ER, et al. Pneumococcal mastoiditis in children. Pediatrics. 2000;106(4):695–699. 57. Caponetti GC, Pantanowitz L, Marconi S, Havens JM, Lamps LW, Otis CN. Evaluation of immunohistochemistry in identifying Bartonella henselae in cat-scratch disease. Am J Clin Pathol. 2009;131(2):250–256. 58. Munson PD, Boyce TG, Salomao DR, Orvidas LJ. Cat-scratch disease of the head and neck in a pediatric population: surgical indications and outcomes. Otolaryngol Head Neck Surg. 2008;139(3):358–363. 59. Windsor JJ. Cat-scratch disease: epidemiology, aetiology and treatment. Br J Biomed Sci. 2001;58(2):101–110. 60. Nordahl SH, Hoel T, Scheel O, Olofsson J. Tularemia: a differential diagnosis in oto-rhino-laryngology. J Laryngol Otol. 1993;107(2):127–129. 61. Jacobs RF. Tularemia. Adv Pediatr Infect Dis. 1996;12:55–69. 62. Oztoprak N, Celebi G, Hekimoglu K, Kalaycioglu B. Evaluation of cervical computed tomography findings in oropharyngeal tularaemia. Scand J Infect Dis. 2008;40(10):811–814. 63. From the Centers for Disease Control and Prevention. Plague— United States, 1992. JAMA. 1992;268(21):3055. 64. Mantur BG, Amarnath SK. Brucellosis in India - a review. J Biosci. 2008;33(4):539–547. 65. Queipo-Ortuno MI, Colmenero JD, Bravo MJ, GarciaOrdonez MA, Morata P. Usefulness of a quantitative real-time PCR assay using serum samples to discriminate between inactive, serologically positive and active human brucellosis. Clin Microbiol Infect. 2008;14(12):1128–1134. 66. Friduss ME, Maceri DR. Cervicofacial actinomycosis in children. Henry Ford Hosp Med J. 1990;38(1):28–32. 67. Hong IS, Mezghebe HM, Gaiter TE, Lofton J. Actinomycosis of the neck: diagnosis by fine-needle aspiration biopsy. J Natl Med Assoc. 1993;85(2):145–146. 68. Brook I. Actinomycosis: diagnosis and management. South Med J. 2008;101(10):1019–1023. 69. Meijer JA, Sjogren EV, Kuijper E, Verbist BM, Visser LG. Necrotizing cervical lymphadenitis due to disseminated Histoplasma capsulatum infection. Eur J Clin Microbiol Infect Dis. 2005;24(8):574–576. 70. Mazzoni A, Ferrarese M, Manfredi R, Facchini A, Sturani C, Nanetti A. Primary lymph node invasive aspergillosis. Infection. 1996;24(1):37–42.

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71. Gustafson KS, Feldman L. Cryptococcal lymphadenitis diagnosed by fine-needle aspiration biopsy. Diagn Cytopathol. 2007;35(2):103–104. 72. Montoya JG, Remington JS. Studies on the serodiagnosis of toxoplasmic lymphadenitis. Clin Infect Dis. 1995;20(4): 781–789. 73. Jayaram N, Ramaprasad AV, Chethan M, Sujay AR. Toxoplasma lymphadenitis. Analysis of cytologic and histopathologic criteria and correlation with serologic tests. Acta Cytol. 1997;41(3):653–658. 74. Montoya JG, Berry A, Rosso F, Remington JS. The differential agglutination test as a diagnostic aid in cases of toxoplasmic lymphadenitis. J Clin Microbiol. 2007;45(5):1463–1468. 75. Kayhoe DE, Jacobs L, Beye HK, Mc CN. Acquired toxoplasmosis; observations on two parasitologically proved cases treated with pyrimethamine and triple sulfonamides. N Engl J Med. 1957;257(26):1247–1254. 76. Yoskovitch A, Tewfik TL, Duffy CM, Moroz B. Head and neck manifestations of Kawasaki disease. Int J Pediatr Otorhinolaryngol. 2000;52(2):123–129. 77. Harnden A, Takahashi M, Burgner D. Kawasaki disease. BMJ. 2009;338:b1514. 78. Rowley AH, Baker SC, Orenstein JM, Shulman ST. Searching for the cause of Kawasaki disease—cytoplasmic inclusion bodies provide new insight. Nat Rev Microbiol. 2008;6(5):394–401. 79. Onouchi Y, Gunji T, Burns JC, et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet. 2008;40(1):35–42. 80. Chen SY, Wan L, Huang YC, et al. Interleukin-18 gene 105A/C genetic polymorphism is associated with the susceptibility of Kawasaki disease. J Clin Lab Anal. 2009;23(2):71–76. 81. Yu HR, Kuo HC, Sheen JM, et al. A unique plasma proteomic profiling with imbalanced fibrinogen cascade in patients with Kawasaki disease. Pediatr Allergy Immunol. 2009;20(7): 699–707. 82. Park AH, Batchra N, Rowley A, Hotaling A. Patterns of Kawasaki syndrome presentation. Int J Pediatr Otorhinolaryngol. 1997;40(1):41–50. 83. Shinohara M, Sone K, Tomomasa T, Morikawa A. Corticosteroids in the treatment of the acute phase of Kawasaki disease. J Pediatr. 1999;135(4):465–469. 84. Duval M, Nguyen VH, Daniel SJ. Rosai-Dorfman disease: an uncommon cause of massive cervical adenopathy in a twoyear-old female. Otolaryngol Head Neck Surg. 2009;140(2): 274–275. 85. Raveenthiran V, Dhanalakshmi M, Hayavadana Rao PV, Viswanathan P. Rosai-Dorfman disease: report of a 3-year-old girl with critical review of treatment options. Eur J Pediatr Surg. 2003;13(5):350–354. 86. Konca C, Ozkurt ZN, Deger M, Aki Z, Yagci M. Extranodal multifocal Rosai-Dorfman disease: response to 2-chlorodeoxyadenosine treatment. Int J Hematol. 2009;89(1):58–62. 87. Ifeacho S, Aung T, Akinsola M. Kikuchi-Fujimoto disease: a case report and review of the literature. Cases J. 2008;1(1):187. 88. Lerosey Y, Lecler-Scarcella V, Francois A, Guitrancourt JA. A pseudo-tumoral form of Kikuchi’s disease in children: a case report and review of the literature. Int J Pediatr Otorhinolaryngol. 1998;45(1):1–6.

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CHAPTER 105 ❖ Cervical Adenopathy 89. Pace-Asciak P, Black MA, Michel RP, Kost K. Case series: raising awareness about Kikuchi-Fujimoto disease among otolaryngologists: is it linked to systemic lupus erythematosus? J Otolaryngol Head Neck Surg. 2008;37(6):782–787. 90. Hoyt DJ, Fisher SR. Kikuchi's disease causing cervical lymphadenopathy. Otolaryngol Head Neck Surg. 1990; 102(6):755–758. 91. Feder HM Jr. Cimetidine treatment for periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis. Pediatr Infect Dis J. 1992;11(4):318–321. 92. Padeh S, Brezniak N, Zemer D, et al. Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr. 1999;135(1):98–101. 93. Tasher D, Stein M, Dalal I, Somekh E. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatr. 2008;97(8):1090–1092. 94. Burton MJ, Pollard AJ, Ramsden JD. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Revi. 2010;(9). Art.No.:CD008669. DOI: 10.1002/14651858.CD008669. 95. Armstrong WB, Allison G, Pena F, Kim JK. Kimura’s disease: two case reports and a literature review. Ann Otol Rhinol Laryngol. 1998;107(12):1066–1071. 96. Asma A, Maizaton AA. Kimura’s disease: an unusual cause of cervical tumor. Med J Malaysia. 2005;60(3):373–376. 97. Sun QF, Xu DZ, Pan SH, et al. Kimura disease: review of the literature. Intern Med J. 2008;38(8):668–672. 98. Mroz RM, Korniluk M, Stasiak-Barmuta A, Chyczewska E. Increased levels of interleukin-12 and interleukin-18 in bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis. J Physiol Pharmacol. 2008;59(suppl 6):507–513. 99. Drake W. Infectious antigens may play a role in the pathogenesis of sarcoidosis. Medscape J Med. 2008;10(12):288. 100. Shetty AK, Gedalia A. Sarcoidosis: a pediatric perspective. Clin Pediatr (Phila). 1998;37(12):707–717. 101. Valeyre D, Uzunhan Y, Bouvry D, Naccache JM, Nunes H. Up-to-date in pulmonary and extrapulmonary sarcoidosis. Acta Clin Belg. 2008;63(6):408–413. 102. Hoffmann AL, Milman N, Byg KE. Childhood sarcoidosis in Denmark 1979-1994: incidence, clinical features and laboratory results at presentation in 48 children. Acta Paediatr. 2004;93(1):30–36. 103. Gedalia A, Molina JF, Ellis GS Jr, Galen W, Moore C, Espinoza LR. Low-dose methotrexate therapy for childhood sarcoidosis. J Pediatr. 1997;130(1):25–29. 104. Liang J, Newman JG, Frank DM, Chalian AA. Cervical unicentric Castleman disease presenting as a neck mass: case report and review of the literature. Ear Nose Throat J. 2009;88(5):E8–E11. 105. Buesing K, Perry D, Reyes C, Abdessalam S. Castleman disease: surgical cure in pediatric patients. J Pediatr Surg. 2009;44(1):e5–e8. 106. Miltenyi Z, Toth J, Gonda A, Tar I, Remenyik E, Illes A. Successful immunomodulatory therapy in Castleman disease with paraneoplastic pemphigus vulgaris. Pathol Oncol Res. 2009;15(3):375–381. 107. Leach DB, Hester TO, Farrell HA, Chowdhury K. Primary amyloidosis presenting as massive cervical lymphadenopathy with severe dyspnea: a case report and review of the literature. Otolaryngol Head Neck Surg. 1999;120(4):560–564.

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108. Rapkiewicz A, Thuy Le B, Simsir A, Cangiarella J, Levine P. Spectrum of head and neck lesions diagnosed by fine-needle aspiration cytology in the pediatric population. Cancer. 2007;111(4):242–251. 109. Moukheiber AK, Nicollas R, Roman S, Coze C, Triglia JM. Primary pediatric neuroblastic tumors of the neck. Int J Pediatr Otorhinolaryngol. 2001;60(2):155–161. 110. Haase GM. Head and neck neuroblastoma. Semin Pediatr Surg. 1994;3(3):194–202. 111. Robinson LD, Smith RJ, Rightmire J, Torpy JM, Fernbach DJ. Head and neck malignancies in children: an age-incidence study. Laryngoscope. 1988;98(1):11–13. 112. Cunningham MJ, Myers EN, Bluestone CD. Malignant tumors of the head and neck in children: a twenty-year review. Int J Pediatr Otorhinolaryngol. 1987;13(3):279–292. 113. Bonadonna G. Historical review of Hodgkin’s disease. Br J Haematol. 2000;110(3):504–511. 114. Hjalgrim H, Engels EA. Infectious aetiology of Hodgkin and non-Hodgkin lymphomas: a review of the epidemiological evidence. J Intern Med. 2008;264(6):537–548. 115. Morse EE, Yamase HT, Greenberg BR, et al. The role of flow cytometry in the diagnosis of lymphoma: a critical analysis. Ann Clin Lab Sci. 1994;24(1):6–11. 116. Kaleem Z. Flow cytometric analysis of lymphomas: current status and usefulness. Arch Pathol Lab Med. 2006;130(12): 1850–1858. 117. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the committee on Hodgkin’s disease staging classification. Cancer Res. 1971;31(11):1860–1861. 118. Abuzetun JY, Loberiza F, Vose J, et al. The Stanford V regimen is effective in patients with good risk Hodgkin lymphoma but radiotherapy is a necessary component. Br J Haematol. 2009;144(4):531–537. 119. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International prognostic factors project on advanced Hodgkin’s disease. N Engl J Med. 1998;339(21): 1506–1514. 120. al-Talib RK, Sworn MJ, Ramsay AD, Hitchcock A, Herbert A. Primary cervical lymphoma: the role of cervical cytology. Cytopathology. 1996;7(3):173–177. 121. Shad A, Magrath I. Non-Hodgkin's lymphoma. Pediatr Clin North Am. 1997;44(4):863–890. 122. Prochazka V, Faber E, Raida L, et al. Prolonged survival of patients with peripheral T-cell lymphoma after first-line intensive sequential chemotherapy with autologous stem cell transplantation. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2009;153(1):63–66. 123. White CA. Rituxan immunotherapy and zevalin radioimmunotherapy in the treatment of non-Hodgkin’s lymphoma. Curr Pharm Biotechnol. 2003;4(4):221–238. 124. Fisher RI, Miller TP, Grogan TM. New REAL clinical entities. Cancer J Sci Am. 1998;4(suppl 2):S5–S12. 125. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the WHO classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5): 937–951. 126. Kilborn TN, Teh J, Goodman TR. Paediatric manifestations of Langerhans cell histiocytosis: a review of the clinical and radiological findings. Clin Radiol. 2003;58(4): 269–278.

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127. Mosterd K, van Marion A, van Steensel MA. Neonatal Langerhans’ cell histiocytosis: a rare and potentially lifethreatening disease. Int J Dermatol. 2008;47(suppl 1):10–12. 128. Satter EK, High WA. Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society. Pediatr Dermatol. 2008;25(3):291–295. 129. Rodriguez-Galindo C, Jeng M, Khuu P, McCarville MB, Jeha S. Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer. 2008;51(5):703–706. 130. Caselli D, Arico M. The role of BMT in childhood histiocytoses. Bone Marrow Transplant. 2008;41(suppl 2):S8–S13. 131. Ghiringhelli P, Ghiringhelli L. Lymphadenopathies and diseases with manifestations of autoimmunity. Minerva Med. 1988;79(9):761–774. 132. Mori T, Yamauchi Y, Shiozawa K. Lymph node swelling due to bacille Calmette-Guerin vaccination with multipuncture method. Tuber Lung Dis. 1996;77(3):269–273. 133. Karpelowsky JS, Alexander AG, Peek SD, Millar AJ, Rode H. Surgical complications of bacille Calmette-Guerin (BCG) infection in HIV-infected children: time for a change in policy. S Afr Med J. 2008;98(10):801–804. 134. Kusuhara K, Ohga S, Hoshina T, et al. Disseminated Bacillus Calmette-Guerin lymphadenitis in a patient with gp91phox (-) chronic granulomatous disease 25 years after vaccination. Eur J Pediatr. 2009;168(6):745–747. 135. Oguz F, Mujgan S, Alper G, Alev F, Neyzi O. Treatment of Bacillus Calmette-Guerin-associated lymphadenitis. Pediatr Infect Dis J. 1992;11(10):887–888. 136. Omokoku B, Castells S. Post-DPT inoculation cervical lymphadenitis in children. N Y State J Med. 1981;81(11): 1667–1668.

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137. Mansur AT, Pekcan Yasar S, Goktay F. Anticonvulsant hypersensitivity syndrome: clinical and laboratory features. Int J Dermatol. 2008;47(11):1184–1189. 138. Katz BZ, Pahl E, Crawford SE, et al. Case-control study of risk factors for the development of post-transplant lymphoproliferative disease in a pediatric heart transplant cohort. Pediatr Transplant. 2007;11(1):58–65. 139. Burns DM, Crawford DH. Epstein-Barr virus-specific cytotoxic T-lymphocytes for adoptive immunotherapy of post-transplant lymphoproliferative disease. Blood Rev. 2004;18(3):193–209. 140. Gallego S, Llort A, Gros L, et al. Post-transplant lymphoproliferative disorders in children: The role of chemotherapy in the era of rituximab. Pediatr Transplant. 2010;14(1):61–66. 141. Theodorou SJ, Theodorou DJ, Resnick D. Imaging findings of complications affecting the upper extremity in intravenous drug users: featured cases. Emerg Radiol. 2008;15(4):227–239. 142. Ishikawa M, Anzai Y. MR imaging of lymph nodes in the head and neck. Magn Reson Imaging Clin N Am. 2002;10(3): 527–542. 143. Kaji AV, Mohuchy T, Swartz JD. Imaging of cervical lymphadenopathy. Semin Ultrasound CT MR. 1997;18(3):220–249. 144. Soldes OS, Younger JG, Hirschl RB. Predictors of malignancy in childhood peripheral lymphadenopathy. J Pediatr Surg. 1999;34(10):1447–1452.

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106 C H A P T E R

Head and Neck Space Infections Robert F. Yellon, Todd Falcone, and David W. Roberson

I

nfections of the deep spaces of the head and neck have been reported since the time of Hippocrates, Galen, and other authors, under the names morbus strangulatorius, cynanche (Greek for suffocation), and angina maligna.1,2 It is reported that George Washington died after suffering a type of deep neck infection called cynanche trachealis.3 Substantial progress has been made since Wilhelm Fredrick von Ludwig recommended the application of leeches and a piece of silver nitrate to the middle of the area of swelling during a case of the deep neck infection that bears his name (Ludwig angina).4 However, even in this era of antibiotic therapy, thorough knowledge of the important anatomic, etiologic, bacteriologic, and clinical factors, as well as the diagnostic and therapeutic modalities required for the proper care of deep head and neck space infections in children, is essential to ensure rapid resolution and avoid complications. The following discussions on the anatomy of fascial planes and deep head and neck spaces are adapted from the classic textbook by Hollinshead,5 with more recent critical reviews by Som and Curtin6 and Myers and Johnson (Jonas Johnson, personal communication, 2010). This chapter describes the typical clinical features of deep head and neck space infections, medical versus surgical management, and important complications of these infections. Previous treatment of deep head and neck space infections with antimicrobial agents and the increasing prevalence of immunocompromised patients may have led to atypical manifestations and pathogens; thus, the clinician must be vigilant in making the correct diagnosis and prescribing the correct treatment.

The tonsils and adenoids are a source of infection of the lateral pharyngeal space. Infection of the temporal bone with extension of infection from the inferior aspect of the petrous apex into the lateral pharyngeal space may occur. A Bezold abscess (Fig. 106-1) develops when infection in the mastoid tip erodes through the mastoid cortex, usually on its medial side, and occupies the space between the mastoid tip and the mandible. This infection may also extend medially into the lateral pharyngeal space (Fig. 106-2) or anteriorly into the submandibular space (see Chapter 38). Tonsillar infection can lead to peritonsillar space infection. Peritonsillar infection, in turn, can extend through the pharyngeal constrictor muscle into the lateral pharyngeal space. Iatrogenic causes of lateral pharyngeal space infections include local anesthesia given for tonsillectomy and superior alveolar nerve block (see Chapter 67). Dental and gingival infections can lead to deep head and neck infections spontaneously or iatrogenically. Infection of the mandibular teeth usually leads to infection of the mandibular, submandibular, masseteric, parotid, and lateral pharyngeal spaces.7 Infection of the maxillary teeth generally spreads to the masticator space. Buccal space infection may occur secondary to infection of the maxillary or mandibular

ETIOLOGY OF HEAD AND NECK SPACE INFECTIONS Knowledge of the most common sources of head and neck space infections is important so that infection in the fascial space, as well as at the original site, can be eradicated. Retropharyngeal space infection frequently originates from an infection in the nose, paranasal sinuses, or nasopharynx that drains to the retropharyngeal lymph nodes. These nodes may undergo suppurative adenitis with the subsequent formation of a retropharyngeal abscess. Trauma to the pharynx can also provide a portal of entry for infection of the retropharyngeal and lateral pharyngeal spaces. Tuberculous infection of the vertebral bodies (Pott abscess), as well as nontuberculous infection, can lead to prevertebral (retropharyngeal) space infections.

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FIGURE 106-1. Computed tomographic scan of the right temporal bone showing erosion of the mastoid cortex in a child with a Bezold abscess.

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SECTION 6 ❖ The Head and Neck become infected by extension from adjacent deep neck spaces and suppurative adenitis. Intravenous (IV) drug abuse and iatrogenic causes, such as central venous catheter placement, may lead to infection within the carotid sheath or other spaces. Deep neck space infections may also arise secondary to anatomic connections with abscesses in the mediastinum.

BACTERIOLOGY OF HEAD AND NECK SPACE INFECTIONS

FIGURE 106-2. Computed tomographic scan of the neck showing an abscess in the right lateral pharyngeal space associated with the Bezold abscess seen in Figure 106-1.

teeth, parotid gland, or skin overlying the buccal space or from adenitis of the nodes overlying the adjacent masseter muscle. In children younger than 3 years, buccal space infection may arise secondary to bacteremia from Haemophilus influenzae type B in the absence of another locus of infection. These children often have a high fever for 24 hours before clinical signs of buccal space infection become apparent. This is now rare in the postvaccination era. Canine space infection results from maxillary canine tooth infection as its root abscess erodes through the anterior cortex of the maxilla into the canine space. Infection of the parotid space and space of the submandibular gland can result from infection of the glands themselves or be secondary to suppurative adenitis of the lymph nodes within these spaces. Parotid space infection may also be a complication of the acute parotitis that can occur postoperatively after major surgery, or it may result from calculi or tumors encroaching on the lumina of the ductal system. Trauma or infection of the tonsils, laryngotracheal complex, hypopharynx, and esophagus can provide a source of infection for the visceral and pretracheal spaces. Infection of cystic hygromas and branchial cleft remnants can extend into the adjacent deep neck spaces and may be recurrent. The structures of the carotid sheath may

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Both aerobic and anaerobic pathogenic bacteria have been isolated from head and neck space infections. Many of these abscesses are polymicrobial, and many of these organisms produce β-lactamase.8,9 Gas-forming bacteria may cause emphysema and crepitus. Buccal space infections with or without preseptal cellulitis of the orbit secondary to H. influ­ enzae type B may occasionally occur in children younger than 3 years in the absence of a previous locus of infection. Of the gram-positive aerobic pathogens in our series of 117 children (N = 78 cultures obtained) treated for head and neck space infections at the Children’s Hospital of Pittsburgh from 1986 to 1992 (Table 106-1), β-hemolytic streptococci (18%) and Staphylococcus aureus (18%) were most prevalent. Of the anaerobic pathogens, Bacteroides melaninogenicus (16.7%) and Veillonella species (14%) predominated.10 The gram-negative pathogen Haemophilus parainfluenzae was found in 14% of cultures. If all gram-negative pathogens are included, these organisms were present in 17.9% of cultures. Two papers point out an increasing incidence of group A β-hemolytic strep,11,12 but several authors have reported that S. aureus is the most common pathogen.13,14 Ossowski and others, Thomason and others, and Inman and others found an increase in methicillin-resistant Staphylococcus aureus (MRSA) isolates.14–16 Mycobacterium tuberculosis, atypical mycobacteria, and cat-scratch disease can cause infection of cervical nodes with adenopathy and occasional abscess and fistula formation.17–19 Infections caused by atypical mycobacteria and the cat-scratch disease bacillus Rochalimaea henselae tend to differ from infections caused by the other typical pathogens already listed in that fever and pain are usually absent.20,21 The fever and massive adenopathy that can be associated with Kawasaki disease (mucocutaneous lymph node syndrome) may simulate bacterial deep neck space infection. Kawasaki disease may be differentiated from bacterial deep neck space infection by the associated findings of conjunctivitis, strawberry tongue, rash, desquamation of the skin of hands and feet, and coronary artery vasculitis. Other causes of adenopathy in children include infection with viruses (Epstein-Barr virus and human immunodeficiency virus), fungi, brucellosis, plague, tularemia, and lymphogranuloma venereum. Noninfectious causes of adenopathy in children include sarcoidosis, drug reaction (phenytoin), and malignancy (see Chapter 105).22

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CHAPTER 106 ❖ Head and Neck Space Infections TABLE 106-1. Bacteriology of Head and Neck Space

Infections in 78 Infants and Children at the Children’s Hospital of Pittsburgh: January 1986 Through June 1992

Number of Cases β-hemolytic Streptococcus

14 (18)

Staphylococcus aureus

14 (18)

Bacteroides melaninogenicus

13 (16.7)

Veillonella species

11 (14)

Haemophilus parainfluenzae

11 (14)

Bacteroides intermedius

6 (7.7)

Micrococcus species

6 (7.7)

Peptostreptococcus species

4 (5)

Fusobacterium species

4 (5)

Candida albicans

4 (5)

Staphylococcus coagulase negative

2 (2.6)

Beta Streptococcus group C

2 (2.6)

Haemophilus haemolyticus

2 (2.6)

Haemophilus influenzae (nontypable)

2 (2.6)

Bacteroides bivius

2 (2.6)

Eikenella corrodens

2 (2.6)

Escherichia coli

1 (1.3)

α-Hemolytic Streptococcus

34 (44)

Neisseria speciesa

17 (22)

Diphtheroid species

9 (11.5)

Other

16 (20.5)

a

b

No growth

7(9)

a

Normal oropharyngeal flora.

b

Other organisms consisted of 16 species considered to be normal oropharyngeal flora (one isolate of each species).

ANTIMICROBIAL THERAPY FOR HEAD AND NECK SPACE INFECTIONS After appropriate cultures are obtained (when possible), antimicrobials are indicated for infection of the head and neck spaces. Oral antibiotics may be adequate in selected patients, such as adolescents with adequately drained peritonsillar abscesses, minimal trismus, and good oral intake. Penicillin was previously used most frequently to treat these infections; but because β-lactamase-producing bacteria are common, agents that are β-lactamase stable or those that inhibit β-lactamase are more desirable. We have had considerable success with the use of clindamycin plus cefuroxime for initial empirical therapy in such patients. Clindamycin is an appropriate choice for gram-positive organisms and

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anaerobes. However, clindamycin is not recommended as monotherapy if gram-negative organisms are suspected, in which case the combination of clindamycin and cefuroxime is preferred. In our series (see Table 106-1), gram-negative aerobic pathogens were found in 17.9% of cultures from children with head and neck space infections.10 H. parainfluenzae was found in 14% and H. influenzae (nontypable) in 2.6% of 78 cultures from 117 children. More recently, the combination ampicillin–sulbactam has been recommended for its excellent in vitro activity against the usual pathogens.11,23–25 Our experience with ampicillin–sulbactam has been excellent. The optimal duration of antimicrobial therapy has not been formally studied, but a minimum of 10–14 days is recommended. When the patient has improved sufficiently to change from IV to oral therapy, amoxicillin–clavulanate is an appropriate agent. Cefuroxime axetil, cefdinir, and clindamycin are other good choices. For children with allergy to penicillin or cephalosporin, clindamycin and the combination of erythromycin and sulfisoxazole are alternatives.

DIAGNOSTIC STUDIES Studies appropriate for most patients with head and neck space infections include a complete blood count with differential, prothrombin time, partial thromboplastin time, electrolytes, and possibly urine specific gravity. Throat, blood, and sputum cultures may be needed. Fungal and acid-fast cultures may be indicated for immunocompromised patients. Cultures should be obtained before antibiotic therapy is begun if practical. Anteroposterior and lateral soft tissue radiographs of the neck and pharynx are almost always indicated if a neck infection is suspected. The lateral soft tissue neck and pharyngeal film should be taken with the child’s neck in extension and during inspiration. If this film is taken with the child’s neck in flexion or during expiration, spurious thickening of the retropharyngeal and retrotracheal spaces may be seen, especially in young children. If the retropharyngeal space measures >7 mm and the retrotracheal space measures >13 mm, an infection in these spaces is probable.26 In cases when a younger child cannot cooperate with appropriate positioning and inspiration, an airway fluoro may clarify what findings are “real” and what are artifacts of positioning and exhalation. The presence of a retropharyngeal abscess usually causes loss of normal cervical spine curvature with resultant straightening. A gas–fluid level confirms the presence of an abscess. A lateral neck radiographic film may also demonstrate a radiopaque foreign body. Gas-forming bacteria (Fig. 106-3) and penetrating lesions of the upper aerodigestive tract may produce emphysema in the soft tissue. Sialoliths that cause obstruction may be identified in the salivary glands. Lesions that erode bone, such as a Bezold abscess eroding the mastoid tip, may be observed (see Fig. 106-1). Panorex films may identify areas of osteomyelitis of the mandible with bone erosion, as well as dental infection, abscesses, or granulomas. A chest radiograph may identify concomitant pneumonia or mediastinal involvement.

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FIGURE 106-3. A lateral neck film of a child with an abscess in the retropharyngeal space shows significant thickening of the prevertebral soft tissues and gas in the retropharyngeal space.

If the aforementioned studies are not diagnostic and it is possible that an abscess is present rather than cellulitis or adenopathy, further imaging techniques may be indicated. In some cases, needle aspiration of inflammatory head or neck masses may be diagnostic of an abscess if frank pus is aspirated. Needle aspiration is particularly useful for differentiating between peritonsillar abscess and cellulitis in selected, cooperative patients. Computed tomography (CT) is by far the most widely used imaging procedure. Axial CT should be performed with 4- to 5-mm sections from the base of the cranium to the upper portion of the mediastinum. The lateral pharyngeal space, oral cavity, and submandibular and submental spaces may also require examination with 4-mm coronal sections.27 Advantages of CT include delineation of both osseous and soft tissue structures. IV contrast may help to identify an abscess as a “rim-enhancing lesion” with a low-density center. Gas–fluid levels or gas bubbles are also diagnostic

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of an abscess. Multilocular abscesses may be present. IV contrast also helps to delineate vascular structures, thrombosis of the jugular vein, and lymph node anatomy. The use of contrast, however, carries the risk of occasional allergic reaction and renal insult. The sensitivity and specificity of CT scan in determining the presence of edema, mass effect, and lymphadenopathy has not been formally studied but is presumably very high. The sensitivity and specificity of CT (Table 106-2) for predicting the presence of pus has been reported by many workers to be in the range of 60%–90%.11,28–29,32,34–37,39 Findings that are reported to be more predictive of the presence of pus are rim enhancement, “scalloping” or irregularity of the wall of the mass, size of the mass > 2.0 cm, and total volume of the mass > 4.0 cm3. It is clear from the literature that although CT is very effective in identifying the lesion, its ability to distinguish frank pus from phlegmon is only fair. This is not surprising when one considers the natural history of the disease in children, which is a suppurative adenitis that liquefies in a gradual process over several days.11,35,38 The imaging characteristics of a partially liquefied mass and a fully liquefied mass are, of course, very similar. Some authors have recommended the use of magnetic resonance imaging (MRI) to help differentiate head and neck abscesses from cellulitis. The use of MRI has the advantage of examination in multiple planes, including the axial, coronal, and sagittal planes. Five-millimeter sections using T1-weighted sequences help delineate the major anatomic structures, whereas the inflammatory tissue has low to intermediate signal intensity. T2-weighted images can characterize inflammatory tissue and abscess cavities because these tissues have high-intensity signals. The use of gadolinium contrast may help identify abscess cavities by demonstrating rim enhancement. Sagittal MRI sections may be particularly valuable for the evaluation of retropharyngeal and lateral pharyngeal space infections.27 However, MRI is often not available as an emergency study and almost always requires intubation in an ill child, particularly in a child with TABLE 106-2. Sensitivity and Specificity of CT Scans in

Distinguishing Cellulitis Versus Abscesses in Head and Neck Space Infections in 16 Infants and Children at Children’s Hospital of Pittsburgh: January 1986 Through June 1992

Abscess Found at Surgery CT scan

Positive

Yes

No

10

2

1

3

Negative Sensitivity = 10/11 = 91% Specificity = 3/5 = 60% Positive predictive value = 10/11 = 91% Negative predictive value = 3/4 = 75%

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CHAPTER 106 ❖ Head and Neck Space Infections a potential airway issue. Therefore, its practical value would seem to be limited. Ultrasonography (US) has also been recommended as a method to differentiate between cellulitis or adenopathy and abscesses in head and neck space infections (Fig. 106-4). One study in children compared the efficacy of US and CT in the diagnosis of retropharyngeal adenopathy or cellulitis versus abscess.39 All 10 patients in this study had CT scans that were interpreted as showing abscesses. Real-time US identified only 3 of 10 of these patients as having abscesses. In patients who had US evidence of abscess, intraoperative US guidance allowed surgical drainage of three abscess cavities. Two additional children who had CT evidence of abscess but only adenopathy on US examination underwent US-guided needle aspiration of the center of the mass, and no pus could be aspirated. A study in adults compared physical examination and US for differentiation between deep neck adenopathy and abscess.40 Of the 40 patients in this study, 34 underwent surgical exploration and 24 were found to have abscesses. Physical examination had a sensitivity of 33% and a specificity of 81% in detecting the presence of an abscess; US had a sensitivity of 95% and a specificity of 75%. The authors

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point out that false-positive results may occur with US because inflammatory or lymphomatous adenopathy can occasionally appear to be cystic on US. False-negative US examinations for abscesses can occur because a truly cystic lesion may appear solid with US if the fluid within the cyst is atypical and contains crystals or proteinaceous debris. One study reported correct identification of retropharyngeal adenitis or cellulitis by US in seven children whose infections all resolved with antibiotic therapy alone.41 In a series of 12 children, US correctly differentiated between abscess and adenopathy/cellulitis.42 Intraoral US was recently used to identify peritonsillar abscesses in 12 patients.43 Thus, the role of US in the evaluation of head and neck space infections in children has not been fully determined. If CT or MRI are not available, US is indicated to aid in the diagnosis. US may also be valuable when CT, MRI, or the clinical picture is not clear regarding the presence of an abscess versus cellulitis or adenopathy. Finally, US appears to be useful for intraoperative localization of abscesses.39,44 US has the limitation that it does not localize concurrent abscesses. In some cases, children have more than one abscess in noncontiguous locations.11 Therefore, it appears that for the foreseeable future CT, despite its limitations, is the best imaging study available. In some patients, such as older cooperative children with head and neck space infections (e.g., peritonsillar space infection), needle aspiration is faster and more costeffective than imaging studies in determining the presence of an abscess.

CLINICAL FEATURES OF HEAD AND NECK SPACE INFECTIONS Certain signs and symptoms are common in children with head and neck space infections. In the series of 117 children with head and neck space infections evaluated at our institution, the most common symptom was fever (73%), followed by sore throat (47%), dysphagia (37.6%), trismus (36%), decreased appetite (22.2%), and voice change (18%).10 Because many of these patients may have previously been treated with antimicrobials, the clinical manifestations may be atypical.

AIRWAY MANAGEMENT FOR HEAD AND NECK SPACE INFECTIONS

FIGURE 106-4. Ultrasound examination of the retropharyngeal space in a child with a retropharyngeal abscess.

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In children with any type of head and neck space infection, a stable airway must be maintained. Airway stability may be accomplished when necessary by endotracheal intubation or tracheostomy. If trismus or massive soft tissue edema precludes endotracheal intubation, tracheotomy is necessary. Establishment of an artificial airway in a child with a tenuous airway should be strongly considered before the child depletes all respiratory reserve or progresses to complete obstruction or respiratory failure, which necessitates a more risky emergency tracheotomy. In extreme circumstances, cricothyroidotomy may be required. Securing the airway by

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initial endotracheal intubation or with a rigid bronchoscope followed by conversion to a tracheotomy is important in patients at risk for postoperative extubation and difficult reintubation. Unsuccessful attempts at intubation may also precipitate acute airway obstruction, and thus tracheotomy under local anesthesia has occasionally been performed. A nasopharyngeal or oral airway may be useful to avoid intubation or tracheotomy and may be a helpful temporizing measure in selected cases (see Chapter 93).

arises from the vertebral spinous processes and ligamentum nuchae on both sides of the neck (Fig. 106-5). It then travels between and encircles the trapezius muscle, sternocleidomastoid muscle (SCM), and omohyoid muscle and subsequently travels anterior to and between the strap muscles. It is attached to the hyoid bone superiorly. This fascial layer splits inferiorly to attach to both the anterior and the posterior surfaces of the sternum, thereby creating the suprasternal space (of Burns) between the inferior portions of the SCMs.

SUPERFICIAL FASCIA OF THE NECK

Middle Layer

Superficial fascia of the neck is composed of subcutaneous tissue. This fascial layer contains fat, and in its deep portion it covers voluntary muscles such as the platysma and the muscles of the head and face.

Anterolaterally, the middle, pretracheal, or visceral layer of the deep cervical fascia is continuous with the superficial layer of the deep cervical fascia at the lateral borders of strap muscles. The middle layer then passes posterior to the strap muscles and anterior to the trachea and thyroid gland, hence the name pretracheal fascia (see Fig. 106-5). This fascial layer travels posteriorly to envelop the pharynx and esophagus, hence the name visceral fascia. The middle layer of the deep cervical fascia is continuous with the buccopharyngeal fascia. Superiorly, the middle cervical fascia fuses with the hyoid bone and thyroid cartilage. Inferiorly, this layer travels deep to the sternum and extends over

DEEP FASCIA OF THE NECK Superficial Layer The superficial or anterior layer of the deep cervical fascia is distinct from the superficial fascia of the neck because it is a deeper structure. The superficial layer of the deep cervical fascia

FIGURE 106-5. Major fascial layers and anatomic structures seen in an axial section of the lower part of the neck. Note the carotid sheath and visceral space.

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CHAPTER 106 ❖ Head and Neck Space Infections the fibrous pericardium and great vessels in the superior mediastinum.

Posterior Layer Similar to the superficial and middle layers, the posterior or prevertebral layer of the deep cervical fascia arises on the vertebral spinous processes and ligamentum nuchae. It then passes deep to the trapezius muscles and covers the scalene muscles, levator scapulae, longus coli, brachial plexus, and phrenic nerve. This layer also covers the vertebral column and attaches to the clavicles inferiorly. The portion of this fascia that covers the vertebral bodies and longus coli muscles is described as being composed of two distinct layers5,38 (Figs. 106-6 and 106-7). The more posterior prevertebral portion is directly applied to the vertebral bodies and muscles, whereas the more anterior portion is called the alar fascia. Other researchers question the existence of the alar layer and instead describe a fascial structure called the cloison sagittale (see Fig. 106-6), which is discussed further in the section Danger Space and Cloison Sagittale.6,45 In contrast, more contemporary head and neck anatomists state that the fascia in this region is

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composed of only a single layer of prevertebral fascia with no alar fascia or cloison sagittale (Jonas Johnson, personal communication, 2010).

FASCIA OF THE UPPER PART OF THE NECK, FACE, AND HEAD Superficial Layer Above the hyoid bone, the superficial layer of the deep cervical fascia extends from the hyoid bone inferiorly to the mandible and zygomatic arch superiorly (see Fig. 106-7). This fascia, which lies deep to the platysma muscle, splits to cover both the medial and the lateral surfaces of the mandible. Anteriorly, it covers the mylohyoid muscle and anterior belly of the digastric muscle. At the level of the submandibular gland, it divides to form a capsule around this structure. Posteriorly, it divides to cover the lateral aspect of the masseter muscle, and it splits to form a capsule on the medial and lateral surfaces of the parotid gland on its way to the zygoma. It also sends a lamina to cover the medial aspect of the internal pterygoid muscle on its way to the pterygoid plate.

FIGURE 106-6. Major fascial layers and anatomic structures seen in an axial section through the level of the nasopharynx. Note the relationship of the parapharyngeal and retropharyngeal spaces. Contemporary authorities report that the alar fascia and cloison sagittale do not exist and that “retropharyngeal” and “danger” spaces are synonymous. In their view, this space lies between the single layer of prevertebral fascia and the buccopharyngeal fascia on the posterior wall of the pharynx. BPF, buccopharyngeal fascia; CN, cranial nerve; DS, danger space; PVS, prevertebral space; RPS, retropharyngeal space. (From Jonas Johnson, personal communication, 2010.)

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FIGURE 106-7. Fascial layers and deep neck spaces seen in a midline sagittal section. (From Thomason et al.16; Behrman et al.22; Eugene Myers and Jonas Johnson, personal communication, 2000.)

Buccopharyngeal Fascia The buccopharyngeal fascia covers the pharynx and is continuous with the tunica adventitia or visceral fascia (middle layer of the deep cervical fascia) covering the esophagus. It also covers the lateral surface of the buccinator muscle and attaches to the mandible at the pterygomandibular raphe.

ANATOMY, CLINICAL MANIFESTATIONS OF INFECTIONS, AND OPEN SURGICAL PROCEDURES Peritonsillar Space Lying between the capsule of the palatine tonsil and the pharyngeal muscles, the peritonsillar (or paratonsillar) space is the most common site of head and neck space infections. This space is filled with loose connective tissue. It extends anterior and posterior to the tonsillar pillars. Superiorly, it may extend to the level of the hard palate or torus tubarius. Inferiorly, it may extend as low as the piriform fossa. Although the anatomic boundaries of the peritonsillar space do not include the lateral pharyngeal space, peritonsillar infection often extends into the lateral pharyngeal space with involvement of the internal pterygoid muscle, a combination that results in trismus. In the Children’s Hospital of Pittsburgh series, 63% of 61 children with peritonsillar space infection were reported to have had trismus.10 Clinical findings in children with peritonsillar space infections include pain, fever, dysphagia, and cervical adenopathy. An oropharyngeal examination is important to make the diagnosis. The hallmark of peritonsillar space infection is swelling of the tissues lateral and superior to the tonsil, with

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consequent medial and anterior displacement of the tonsil. Displacement of the uvula to the contralateral side of the pharynx may also occur. The tonsils may be erythematous, enlarged, and covered with exudate. The breath may be fetid. If an abscess is present, it usually forms at the superior pole of the tonsil. In the management of peritonsillar infections, cellulitis should be differentiated from abscess. Some abscesses may be clinically obvious; others are less obvious, and clinical distinction is more difficult. An initial 12- to 24-hour trial of appropriate IV antibiotics is reasonable in selected patients with peritonsillar infection and no clear evidence of abscess, airway compromise, septicemia, severe trismus, or other complications.46 When extension of infection from the peritonsillar space to the adjacent deep neck spaces is suspected, CT may be indicated (Fig. 106-8). If improvement does not occur after a trial of IV antimicrobial therapy, needle aspiration may be attempted to identify an abscess. Intraoral US evaluation correctly identified 12 of 12 cases of peritonsillar abscess in 10 adults and 2 children and was a useful guide for needle aspiration.43 The use of needle aspiration versus incision and drainage for definitive treatment of a peritonsillar abscess is controversial. The traditional treatment of peritonsillar abscess has been incision and drainage via a curvilinear incision through the anterior tonsillar pillar, followed by blunt dissection into the abscess cavity with a hemostat or tonsil clamp. If indicated, interval tonsillectomy is then performed 4–12 weeks later.47 Some surgeons advocate immediate tonsillectomy (“quinsy tonsillectomy,” “tonsillectomy à chaud”) as definitive treatment to ensure complete drainage of the abscess and to obviate the need for a second hospitalization to perform an interval tonsillectomy.5,18,35,47 The incidence of bleeding after

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series including adults and children ranged from 6% to 36%, with an overall incidence of 17% in 526 patients from six studies (Table 106-4).48,50,52,55–57 Rates of recurrent tonsillitis occurring before or after peritonsillar abscess ranged from 7% to 50%, with an overall incidence of 29% in 364 patients from five studies (see Table 106-4).48,55–58 In one study, the incidence of recurrent peritonsillar abscess or recurrent tonsillitis after incision and drainage of the initial peritonsillar abscess was 63% in 27 patients younger than 30 years.57 In the treatment of peritonsillar abscess, quinsy tonsillectomy, incision and drainage with or without interval tonsillectomy, and needle aspiration are all safe and effective. Each therapeutic modality has advantages in TABLE 106-3. Incidence of Perioperative or Delayed Hemorrhage Associated With Quinsy Tonsillectomy

Reference

Number of Patients

Grahne (1958)

725

0 (0)

Beeden and Evans (1970)

100

5 (5)

28

2 (7)

119

2 (2)

55

0 (0)

1027

9 (1)

McCurdy (1977) Templer et al. (1977) Richardson and Birck (1981) Total FIGURE 106-8. Computed tomographic scan showing a right peritonsillar abscess. Note the “rim enhancement” of the abscess with intravenous contrast material.

quinsy tonsillectomy in adults and children ranged from 0% to 7% with an overall incidence of 1% in 1027 patients from five series (Table 106-3).48–52 In a study involving 55 children who underwent quinsy tonsillectomy, no patient had postoperative or delayed bleeding.51 In a military population, essentially no difference was noted in the amount of intraoperative or postoperative bleeding in patients treated with quinsy tonsillectomy and those treated with interval tonsillectomy.50 Needle aspiration has been successfully used as definitive treatment of peritonsillar abscesses. In one study, 90% of 41 patients (age not specified) were successfully managed with needle aspiration of peritonsillar abscesses at the point of maximum bulging or, if the first aspiration was unsuccessful, 1 cm lower.53 In a second series of 74 patients (adults and children) with peritonsillar infections who underwent needle aspiration of the superior, middle, and inferior peritonsillar areas, pus was aspirated in 70% of cases. A second series of aspirations was required for seven patients (10%) on the following day.54 In a series of 29 children, the incidence of recurrent peritonsillar abscess and recurrent tonsillitis after peritonsillar abscess was 7% each.55 Recurrence rates for peritonsillar abscess in a

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Number with Hemorrhage (%)

TABLE 106-4. Incidence of Prior or Subsequent Recurrent

Tonsillitis or Recurrent Peritonsillar Abscess Associated With Peritonsillar Abscess

Reference

Number PTA

Number Recurrent PTA (%)

Number Recurrent Tonsillitis (%)

Beeden and Evans (1970)

111

18 (16)

56 (50)

McCurdy (1977)

62

4 (6)

Templer et al (1977)

119

11 (9)

Herbild and Bonding (1981)

161

36 (22)

32 (20)

Holt and Tinsley (1981)

29

2 (7)

6 (21)

Nielsen and Greisen (1981)

44

16 (36)

3 (7)

Schraff et al. (2001)

83

Total

609

10 (19) 87/526 (17)

107/364 (29)

Abbreviation: PTA, peritonsillar abscess.

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certain situations. In patients with peritonsillar abscess and significant airway obstruction and in those who have associated complications such as lateral pharyngeal space abscess, quinsy tonsillectomy is appropriate. If incision and drainage or needle aspiration fail to adequately drain an abscess, quinsy tonsillectomy is also indicated. Additionally, for patients with a previous history of recurrent peritonsillar abscess or recurrent tonsillitis severe enough to warrant tonsillectomy, quinsy tonsillectomy should be considered. In this last scenario, incision plus drainage followed by interval tonsillectomy (four to six weeks later) is also a reasonable choice. For a child in whom tonsillectomy is indicated on the basis of recurrent peritonsillar abscess, recurrent tonsillitis, or chronic airway obstruction secondary to tonsillar hypertrophy, quinsy tonsillectomy may be the most cost-effective treatment because it obviates a second period of hospitalization, anesthesia, and morbidity. Needle aspiration of peritonsillar abscesses, when successful, is the least invasive and least painful of the various treatment modalities. In older and cooperative children without associated complications, needle aspiration of peritonsillar abscesses is safe and effective. For children with a bleeding diathesis who are not allowed blood transfusion for religious reasons or whose general condition is too poor to tolerate a general anesthetic, needle aspiration is the treatment of choice.

Retropharyngeal Versus Parapharyngeal Infections Although the surgeon should always be aware of the anatomy of the neck, some authors maintain that there is little, if any, practical clinical distinction between retro- and parapharyngeal infections. These infections almost always arise as a suppurative adenitis and are initially contained within the capsule of the lymph node; the node is typically at the junction of the retro- and parapharyngeal spaces.11,38,68 In the pre-CT era, these infections would eventually escape the nodal wall and erode into the retropharyngeal or parapharyngeal space, possibly entering the danger space and causing very significant mortality.59 In the current era, these infections are usually diagnosed by CT scan when they are still contained within the suppurating node and thus not truly within either the retropharyngeal or the parapharyngeal spaces.

Retropharyngeal Space The retropharyngeal space is the superior continuation of the retrovisceral space. According to Grodinsky and Holyoke38 and Hollinshead,5 it lies posterior to the buccopharyngeal fascia (middle layer of the deep cervical fascia) covering the pharynx and anterior to the prevertebral fascia (alar layer) (see Figs. 106-6 and 106-7). Many contemporary head and neck anatomists consider the retropharyngeal space to be synonymous with the danger space; they report that these two spaces do not exist as separate entities and

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that the alar layer of the prevertebral fascia does not exist (Jonas Johnson, personal communication, 2010). The superior limit of the retropharyngeal space is the cranial base. Inferiorly, the retrovisceral space extends into the mediastinum to approximately the level of the tracheal bifurcation. The buccopharyngeal fascia is adherent to the prevertebral fascia in the midline, so infections in the retropharyngeal space are unilateral. Lateral neck films (see Fig. 106-3), CT (Fig. 106-9), MRI, or US (see Fig. 106-4) may help ascertain whether cellulitis or a true abscess is present. Two chains of lymph nodes are present on either side of the midline in the retropharyngeal space. They receive drainage from the nose, paranasal sinuses, pharynx, and Eustachian tube. These lymph nodes may be prominent in children, and some may persist into adulthood. In the interpretation of Grodinsky and Holyoke,38 Hollinshead,5 and Johnson (personal communication, 2010), infections in the prevertebral space (between the vertebral bodies and the prevertebral layer of fascia) bulge in the midline and are bilateral. Children with an infection in the retropharyngeal space are usually irritable and have fever, dysphagia, muffled speech or cry, noisy breathing, a stiff neck, and cervical lymphadenopathy. As the infection progresses, stridor and drooling develop. In the Pittsburgh series of 27 children with retropharyngeal infections, 9 (33%) had torticollis.10 The most important diagnostic sign has been stated to be the presence of unilateral posterior pharyngeal swelling when the child’s pharynx is inspected; but this finding was more often present in the pre-CT era, when diagnosis was often delayed for several weeks. Kirse and Roberson11 reported that none of the 73 patients had this sign recorded on examination in the Emergency Department or by the otorhinolaryngology service, and Page and others34 reported it in less than 25% of cases. A child who is uncooperative or unable to cooperate may need to be restrained; however, caution should be exercised in restraining the child who may have an infection compromising the airway. In some cases, the child should be intubated in the operating room and examined under anesthesia prior to CT scan. The differential diagnosis for many of these children includes an atypical supraglottitis, so a high index of concern for airway loss must be maintained. In current practice, it is not uncommon to see children present with deep neck infections having no specific physical findings.11,34 A transoral approach is recommended for incision and drainage of abscesses in the retropharyngeal space, unless the abscess cannot be approached safely transorally (e.g., has extension lateral to the great vessels). The patient must be intubated orally, which can be performed safely by introducing the tube on the side opposite the abscess. To avoid aspiration of purulent material if the abscess ruptures during intubation, the patient should be in the head-down Trendelenburg position. The position and mouth gag used to perform tonsillectomy are preferred for adequate exposure and to secure the endotracheal tube. Before incision and drainage, needle aspiration of the abscess should be performed to prevent tracheal aspiration of pus during the incision and to obtain material for Gram stain, culture, and antimicrobial sensitivity

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FIGURE 106-9. Computed tomographic scans showing, A, left retropharyngeal cellulitis without an abscess and, B, a left retropharyngeal abscess.

studies, and to rule out a carotid pseudoaneurism. After the aspiration procedure identifies the location of the abscess, a vertical incision is made directly over the abscess and the space opened gently with a hemostat to drain the abscess and avoid injury to the great vessels. No drain is placed because it could potentially be aspirated or swallowed postoperatively. If the infection has extended lateral to the great vessels, the procedure should be performed through an external neck incision, as described in the section Open Surgical Approach to Deep Neck Space Infections.11,31 On rare occasions, both transoral and external neck approaches are needed to provide adequate drainage. If the child has early recurrence of the abscess or if the abscess does not resolve rapidly after a transoral drainage procedure, an external cervical approach should be considered.

Danger Space and Cloison Sagittale As described by Grodinsky and Holyoke38 and cited by Hollinshead,5 the portion of the deep layer of the cervical fascia that covers the vertebral bodies and longus coli muscles is composed of two distinct layers. The anterior portion is called the alar fascia, and the more posterior portion that is in direct contact with the vertebral bodies is called the prevertebral fascia. The space between the two layers is called the danger space38 (see Figs. 106-6 and 106-7). This space extends from the cranial base to the diaphragm.

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The existence of the danger space and the alar layer of the prevertebral fascia is debated. Some authorities argue that the danger space and the alar layer do not exist and that a structure called the cloison sagittale is the important fascial structure in this region.22,45 The cloison sagittale is described as a thin layer of fascia that runs in an anterior– posterior plane from the pterygoid plate to the prevertebral fascia and separates the lateral aspects of the retropharyngeal space from the lateral pharyngeal space on either side of the neck (see Fig. 106-6). Thus, the cloison sagittale prevents the spread of infection from the retropharyngeal space to the lateral pharyngeal space. Contemporary authorities report that based on dissections in pharyngeal cancer patients the alar fascia and cloison sagittale do not exist and the retropharyngeal, danger, and prevertebral spaces are synonymous. In their view, this space lies between the single layer of prevertebral fascia and the buccopharyngeal fascia on the posterior wall of the pharynx (Jonas Johnson, personal communication, 2010).

Prevertebral Space In the opinion of Grodinsky and Holyoke38 and Hollinshead,5 the prevertebral space lies posterior to the prevertebral fascia and anterior to the vertebral bodies and is the most posterior of the spaces (see Figs. 106-6 and 106-7). Infection in this space is seen as a bulging mass in

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the midline of the pharynx, with extension to both sides of the pharynx because of the absence of a midline raphe. The prevertebral space extends from the base of the cranium to the diaphragm. Infection in this space is best approached surgically, as described in the section Open Surgical Approach to Deep Neck Infections, rather than the transoral approach because the external approach avoids the possibility of a persistent draining fistula in the pharynx with the potential for aspiration. Needle aspiration via the transoral route may be useful for localization of an abscess. These infections may require prolonged antimicrobial therapy for associated osteomyelitis or tuberculous infection of the vertebral bodies.60

Mandibular Space Filled with loose connective tissue, the space of the body of the mandible is an actual space rather than a potential one. This space is formed by the splitting of the two leaflets of the superficial layer of the deep cervical fascia. These two leaflets attach to the inferior border of the mandible on its lateral surface and the medial surface of the mandible at the level of the mylohyoid muscle. This space is limited anteriorly by the attachment of the anterior belly of the digastric muscle and posteriorly by the attachment of the medial pterygoid muscle to the mandible. Mandibular space infections usually follow dental infection, trauma, or surgery. The suppurative dental process erodes through the lingual cortex of the mandible to create an abscess between the mandible and the inner leaflet of the superficial layer of the deep cervical fascia. This intraoral swelling lies more anteriorly than the swelling that occurs during infection of the medial portion of the masticator space. Pain and intraoral swelling are present, but not external facial swelling unless the process extends to involve the dependent lymphatics in the submandibular space. Mandibular space abscesses may be drained via an intraoral incision along the medial surface of the body of the mandible.

Masticator Space The masticator space is created by the splitting of the superficial layer of the deep cervical fascia around the masseter and internal pterygoid muscles (Fig. 106-10). Also contained in this space are the ramus of the mandible, the temporalis muscle, fat, and loose connective tissue. This space extends anteriorly as the fascia covers the buccal fat pad and then ends as the fascia attaches to the maxilla and buccinator muscle fascia. The space ends posteriorly as the two laminae of the fascia fuse along the posterior border of the mandible. Superiorly, the medial aspect of the masticator space is limited by the origin of the temporalis muscle from the skull; laterally, it is limited by the temporalis fascia. It extends medially to include the pterygopalatine fossa. The mandibular nerve and the internal maxillary artery are also found in this space. Infection in the masticator space most commonly arises from the mandibular teeth but may also

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extend from infection in the temporal or zygomatic bones. Infection in this space may be limited to the portion of the space that lies medial to the mandible or in the portion that lies lateral to the mandible, or both. The superior portion of the masticator space is sometimes referred to as the temporal space, with compartments both medial and lateral to the temporalis muscle. Infections of the masticator space are usually related to dental infection, trauma, or surgery. Localized osteomyelitis or subperiosteal abscess of the mandible may be present, as may cellulitis of the gingiva. The major symptom of masticator space infection is deep pain along the ascending ramus of the mandible. Trismus is an early and prominent finding. Sore throat, dysphagia, and pain on moving the tongue are often present. Signs depend on whether the medial compartment, lateral compartment, or both compartments of the masticator space are involved. Swelling is present in the area of the retromolar trigone if the medial compartment is involved. This swelling may be mistaken for a peritonsillar abscess. If the lateral compartment is involved, swelling will be present externally, overlying the masseter muscle and mandible. Infection may also extend superiorly and lie medial or lateral to the temporalis muscle. When masticator space infections require incision and drainage, the approach depends on whether the medial or the lateral portion is involved. If the lateral portion is involved, an incision may be made below and parallel to the body of the mandible, with incision of the platysma and fascial capsule of the submandibular gland. The facial vein and possibly the facial artery are then identified and ligated, and the vessels along with the fascial capsule of the gland, platysma, and marginal mandibular nerve are carefully elevated to the level of the inferior border of the mandible. The tendon of the masseter muscle is then detached from the mandible, and the lateral portion of the masticator space is entered and drained. Iodophor-impregnated packing is placed. The medial portion of the masticator space is approached via an intraoral incision medial to the ascending ramus of the mandible in the area of the retromolar trigone. In some instances, both intraoral and external drainages may be required. Superior extension of masticator space infections into the temporal portion of the masticator space that require drainage may be approached in the following manner: incisions are made along the hairline through the temporalis fascia to reach abscesses lateral to the temporalis muscle. To reach medially located abscesses, incisions are made through the temporalis fascia and muscle. Packing is placed.

Buccal Space Lateral to the buccinator muscle lies the buccopharyngeal fascia, which forms the medial wall of the buccal space. The skin

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FIGURE 106-10. Major structures seen in a coronal section of the head at the level of the soft palate, along with the anatomic relationships of the masticator space.

of the cheek is the lateral boundary. Limiting the buccal space inferiorly is the lower border of the mandible; the posterior limit is the pterygomandibular raphe. The buccal space contains the buccal fat pad, Stensen duct, and facial artery.61 Infections in the buccal space are characterized by marked swelling of the cheek, which is warm, tender, and red. Trismus from inflammation of the adjacent masseter muscle is often observed. Subcutaneous fluctuation may be found with an abscess. Usually, little intraoral swelling is evident. Buccal space infections may occasionally extend to involve the maxillary sinus, orbit, preseptal orbital tissues, or cavernous sinus. Buccal space abscesses usually occur subcutaneously in the cheek. These abscesses may be drained by a skin incision, followed by blunt dissection in a direction parallel to the branches of the facial nerve. Packing may be placed.

infection may be mistaken for dacryocystitis. The infection may occasionally drain just inferior to the medial canthus of the eye. If the infection extends inferior to the origin of the levator anguli oris muscle, swelling is also present in the labial sulcus. Abscesses in the canine space may be approached by an incision in the maxillary labial sulcus down through the periosteum. Blunt dissection is then performed superiorly to enter and drain the abscess. Treatment of the associated dental infection may include apicoectomy and curettage of purulent granulation tissue from the bony defect over the canine root, pulp extirpation, or extraction, for which dental consultation is recommended.61

Canine Space

An apical abscess of the roots of any tooth can erode through the inner or outer bony cortices of the mandible or maxillary alveolus and cause a subperiosteal abscess. The location depends on the involved tooth. Toothache, local swelling, and possibly fever and fluctuation may be present. Surgical treatment of an abscess in these areas requires incision and drainage, followed by appropriate dental care, as described in the section Canine Space (see also Chapter 67).

The canine space is a potential space anterior to the maxillary canine fossa, superior to the origin of the levator anguli oris muscle and inferior to the origin of the levator labii superioris muscle on the face of the maxilla. A toothache usually precedes canine space infection. Swelling is present lateral to the nares; thus, canine space

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Other Dental Infections

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Parotid Space Similar to the space of the submandibular gland, the parotid space is formed by the splitting of the superficial layer of the deep cervical fascia to cover the medial and lateral surfaces of the parotid gland. The parotid space also contains the periparotid lymph nodes and the facial nerve and may contain the auriculotemporal nerve, external carotid and superficial temporal arteries, and retromandibular vein. In contrast to the thick fascia covering the lateral surface of the parotid gland, the fascia covering the medial surface of the gland is thin, thus allowing parotid space infection to extend into the adjacent lateral pharyngeal space. Pain, redness, and edema over the parotid area are typical of parotid space infection. Even when an abscess is present, the tough, tense fascia covering the lateral aspect of the gland prevents the palpation of fluctuation in the parotid space. It is nearly always unilateral. Parotid space abscesses may be approached through a standard parotidectomy-type incision, including an incision around the base of the lobule, or via a “hockey-stick” incision in a preauricular crease, with extension of the incision below the angle of the mandible toward the tip of the hyoid bone. Anterior and posterior flaps are elevated for a short distance in the plane of the parotid capsule superiorly and in the subplatysmal plane inferiorly. The parotid fascia is then detached from the anterior surface of the tragal cartilage and SCM and is superficially incised to drain the parotid space. If necessary, the dissection anterior to the tragus and bony external auditory canal is carefully continued in a medial direction until the main trunk of the facial nerve is identified. Blunt dissection can then be used to drain an abscess that lies in the posterosuperomedial aspect of the parotid space above the main trunk of the nerve. The parotid gland may then be detached from the posterior belly of the digastric muscle. Blunt medial dissection superior to the posterior belly of the digastric muscle and posterior to the mandible allows drainage of the lateral pharyngeal space, which may be secondarily involved because of the propensity for parotid space infection to traverse the thin layer of fascia on the medial surface of the gland. When necessary, the lateral pharyngeal space may also be approached via blunt dissection inferior to the posterior belly of the digastric muscle and anterior to the SCM. Abscesses within the parenchyma of the gland may be drained by gentle blunt dissection in a direction parallel to the branches of the facial nerve (see Chapter 39).

peripharyngeal, pharyngomaxillary, pterygopharyngeal, pterygomandibular, and pharyngomasticatory space. This space is shaped like an inverted pyramid. Superiorly, the parapharyngeal space extends to the cranial base. The inferior limit of this space is the place where the hyoid bone joins the fascia of the submandibular gland and the sheaths of the stylohyoid muscle and the posterior belly of the digastric muscle. It lies lateral to the buccopharyngeal fascia on the pharynx and medial to the pterygoid muscles and fascia on the medial surface of the parotid gland. The parapharyngeal space extends anterosuperiorly to the pterygomandibular raphe and posteriorly to the posterior surface of the carotid sheath. Infection may spread to the lateral pharyngeal space from the tongue, retropharyngeal space, teeth, submandibular gland, parotid gland, masticator space, tonsils, and peritonsillar areas. The styloglossus and stylopharyngeus muscles cross the parapharyngeal space. The styloid process and attached fascia of the tensor veli palatini muscle divide the parapharyngeal space into a prestyloid compartment that contains the internal maxillary artery, maxillary nerve, and tail of the parotid gland and a poststyloid compartment that contains the carotid artery; internal jugular vein; cervical sympathetic chain; and cranial nerves IX, X, XI, and XII (see Fig. 106-6). Pain, fever, and a stiff neck are the usual initial complaints of a child with a parapharyngeal space infection. Trismus is present when the anterior (prestyloid) compartment is involved because of inflammation of the internal pterygoid muscle, but trismus may be absent when only the posterior (poststyloid) compartment is involved. Perimandibular edema occurs frequently and can involve the parotid and submandibular areas. As described, oropharyngeal examination can be helpful in making the diagnosis in those with parapharyngeal wall swelling, which is frequently posterior to the tonsil. The tonsil is usually medially and anteriorly displaced. CT, MRI, or US may help differentiate an abscess from cellulitis in the lateral pharyngeal space (Figs. 106-2 and 106-11). When infection is severe and extensive, airway obstruction may be present. One or more of the cranial nerves or the cervical sympathetic chain (Horner syndrome) in the posterior compartment may be involved. Because other potential spaces of the head and neck may be primarily or secondarily involved, the examination must include these areas. Infections in which pus has escaped the confines of the purulent node and is free within the lateral pharyngeal space requiring surgical intervention are best drained by an open surgical approach.

Parapharyngeal Space

Carotid Sheath

According to the descriptions of Hollinshead, the parapharyngeal space is continuous with the retropharyngeal space in its lateral aspect. In contrast, reports by Som and Curtin6 and Charpy45 describe the existence of a fascial band called the cloison sagittale that separates the retropharyngeal space from the parapharyngeal space (see Fig. 106-6). The parapharyngeal space has also been called lateral pharyngeal, 5

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Within the carotid sheath are the carotid artery, internal jugular vein, and vagus nerve. The anterolateral wall of the carotid sheath is derived from the anterior layer of the deep cervical fascia. A contribution from the middle layer of the deep cervical fascia is present anteriorly. The medial and posterior walls are derived from the anterior layer of the deep cervical fascia as it sends a lamina medial to the

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CHAPTER 106 ❖ Head and Neck Space Infections

FIGURE 106-11. Computed tomographic scan of the neck of a child with left parapharyngeal space cellulitis and no abscess.

great vessels, and then posterior to them, to overlie the posterior layer of the deep cervical fascia. Posteromedially, a portion of the carotid sheath is attached to a lamina from the posterior layer (see Fig. 106-5). Infections in adjacent deep neck spaces, suppurative adenitis, tumor masses, hypercoagulable states, IV drug abuse, and iatrogenic causes such as placement of a central venous catheter may lead to infection of the structures within the carotid sheath. Stiffness and swelling of the anterolateral aspect of the neck and torticollis are present. With thrombosis of the internal jugular vein, spiking (“picket fence” pattern) fevers may occur as septic emboli seed the pulmonary circulation. The open surgical approach to this deep neck space infections is described below.

Visceral Space Contents of the visceral space include the thyroid gland, trachea, and esophagus (see Fig. 106-5). It is divided into pretracheal and retrovisceral spaces, which are in continuity superiorly. Above the level where the inferior thyroid artery enters the thyroid gland there is only one visceral compartment, and it is surrounded by the middle layer of the deep cervical fascia anteriorly, fascia of the carotid sheath laterally, and posterior layer of the deep cervical fascia posteriorly. Below the level where the inferior thyroid artery enters the thyroid gland, dense connective tissue attaches the lateral aspect of the esophagus to the prevertebral layer, thus creating the anterior portion of the visceral space or the pretracheal space anterior to the esophagus and the retrovisceral space posteriorly. The pretracheal portion

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extends superiorly to the attachments of the strap muscles to the thyroid cartilage and hyoid bone. Inferiorly, the pretracheal portion of the visceral space extends to the anterior mediastinum at the level of the arch of the aorta and fibrous pericardium. The retrovisceral portion extends superiorly to become the retropharyngeal space, which continues to the cranial base. Inferiorly, the retrovisceral space extends into the mediastinum to approximately the level of the tracheal bifurcation, a common pathway for neck infection to spread into the mediastinum. The esophagus is enclosed in a tunica adventitia that is continuous with the middle layer of the deep cervical fascia (buccopharyngeal fascia) covering the pharynx. Infections in the visceral space are serious. Early symptoms include sore throat, dysphagia, and a hoarse or muffled quality of the voice. The sore throat is a manifestation of edema and inflammation of the pharyngeal structures. Changes in vocal quality are due to laryngeal or supraglottic edema. This edema may progress to aphonia and airway obstruction. Perforation of viscera can lead to emphysema and crepitus in the neck, as well as mediastinal emphysema and pneumothorax. Dyspnea, possibly related to bronchopneumonia, may be prominent. Tenderness may be present over the lateral aspects of the hyoid bone and larynx. Neck swelling, with or without fluctuation, may occur. Open surgical therapy is required as described below.

SUBMANDIBULAR SPACE INFECTIONS AND LUDWIG ANGINA In continuity with the parapharyngeal space at its most anterior extent is the submandibular space. The limits of the submandibular space are the mucosa of the floor of the mouth, the tongue superiorly, and the superficial layer of the deep cervical fascia as it runs from the hyoid bone inferiorly to the mandible superiorly (Figs. 106-12 and 106-13). According to Hollinshead,5 the portion of the submandibular space that lies below the level of the mylohyoid muscle is referred to as the submaxillary space. This space is further divided into the submental space, which lies medial to the anterior bellies of the digastric muscles, and the subsidiary submaxillary space, which lies lateral and posterior to these muscles. The sublingual space is superior to the mylohyoid muscle in the submandibular space and contains the sublingual glands, the lingual and hypoglossal nerves, and a portion of the submandibular gland and duct. Contemporary head and neck anatomists consider some of these terms to be outdated. Instead, they divide the submandibular space into a supramylohyoid portion (equivalent to the sublingual space) and an inframylohyoid portion, which contains the structures in the submandibular triangle lateral to the digastric muscle and medial to the mandible and also contains the submental space medial to the anterior bellies of the digastric muscles (Jonas Johnson, personal communication, 2010). The supramylohyoid and inframylohyoid

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FIGURE 106-12. Selected structures seen in an anteroinferior oblique view of the submandibular space. Note how the supramylohyoid portion of the submandibular space is in continuity with the inframylohyoid portion and how the submandibular duct passes posterior to the mylohyoid muscle.

FIGURE 106-13. Anterior view of the submandibular space showing the relationships of the supramylohyoid, inframylohyoid, and submental portions of the submandibular space.

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CHAPTER 106 ❖ Head and Neck Space Infections portions are in continuity posterior to the mylohyoid muscle (see Fig. 106-12). The space of the submandibular gland lies within the submandibular triangle. Infections in this area often arise from mandibular dental disease; but they may also result from sialoadenitis, suppurative adenitis, or tonsillar disease. Early in the course, the infection is localized to the gingiva, floor of the mouth, and tongue. Later, infection may extend to involve all portions of the submandibular space on one side. Induration and edema of the floor of the mouth are noted with infection of the supramylohyoid portion of the submandibular space. If the inframylohyoid portion of the submandibular space is involved, induration and edema are palpable inferior and medial to the mandible. Infections in these spaces may progress to abscess formation (Fig. 106-14), with or without fluctuation, or persist as cellulitis. Trismus may be present as the infection extends to involve the suprahyoid musculature and internal pterygoid muscle. Bilateral involvement of the submandibular spaces can lead to massive edema of the tongue and floor of the mouth, with posterior displacement of the tongue. Trismus from involvement of the internal pterygoid muscles combines with edema of the floor of the mouth and tongue to cause respiratory compromise. The patient has halitosis and difficulty handling secretions. The tissues of the supramylohyoid and inframylohyoid portions of the submandibular

FIGURE 106-14. Computed tomographic scan of the neck in a child with a large abscess involving the left submandibular triangle area of the inframylohyoid portion of the submandibular space.

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spaces are extremely indurated. This constellation of signs and symptoms is called Ludwig angina. Bilateral involvement is always present in Ludwig angina. Laryngeal or supraglottic edema may occur and lead to vocal changes or airway obstruction. In a true case of Ludwig angina, cellulitis with tension on soft tissues are noted; an abscess may or may not be present. In Ludwig angina, release of tension is the basic surgical principle.64 However, it is important to perform adequate exploration for abscesses and drain them. Even if imaging studies do not show an abscess, open surgical intervention is recommended in all but an exceptionally mild, early case. Again, early control of the airway should be strongly considered in all but exceptionally mild, early cases. Tracheotomy is preferred. The surgical approach to Ludwig angina includes a generous horizontal incision approximately 1 cm above the hyoid bone (Fig. 106-15). This incision may be extended laterally to explore the space of the submandibular gland, with incision of the capsule if an abscess is suspected. The platysma is divided horizontally, whereas the superficial layer of the deep cervical fascia is incised vertically in the midline from the mandibular symphysis to the hyoid bone (Fig. 106-16). The digastric muscles, the mylohyoid muscles, and a variable portion of the tongue muscles are divided in the midline sagittal plane to decompress the floor of the mouth. Blunt or finger dissection between the layers of muscles in a lateral direction is useful to identify and drain any abscesses. Iodoform-impregnated packing is placed for several days, and the wounds are left open.

FIGURE 106-15. Incision for the surgical approach to Ludwig angina. Note that the central incision (solid line) can be extended laterally (dotted lines) to allow exploration and drainage of the space of the submandibular gland if an abscess in this space is suspected.

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FIGURE 106-16. Surgical approach to Ludwig angina. After horizontal division of the platysma, the superficial layer of the deep cervical fascia, the mylohyoid, and a portion of the tongue muscles are divided in the midline. Blunt dissection is performed between the muscle layers in a lateral direction to drain any abscesses that may be present.

SPACE OF THE SUBMANDIBULAR GLAND As the superficial layer of the deep cervical fascia splits to form a capsule around the submandibular gland, the space of the submandibular gland is formed. This space contains the submandibular gland as well as lymph nodes. On its medial surface, the fascia is perforated by the submandibular duct, which allows easy spread of infection to the supramylohyoid portion of the submandibular space (see Fig. 106-12). The space of the submandibular gland is part of the larger inframylohyoid portion of the submandibular space and is contained within the submandibular triangle, medial to the mandible and lateral to the digastric muscle. It may be drained by the open surgical approach described earlier.

a small horizontal incision over the anterior border of the SCM. The SCM is retracted posteriorly, vascular control is obtained of the great vessels, and blunt finger dissection immediately posterior to the great vessels is used to enter the abscess. Although this approach sounds too “blind,” when the author Roberson used it it was very simple and effective. Mosher’s first recommendation was to make a large T-shaped incision, which has been modified by most contemporary surgeons so that the horizontal limb is slightly lower in relation to the body of the mandible and the vertical limb is omitted entirely (Fig. 106-17). The remainder of Mosher’s technique is unchanged. After making a horizontal neck incision through the skin and platysma, dissection is carried out between the anterior border of the SCM and the posterior and inferior aspects of the submandibular gland. The fascial layers may be extremely thickened. The facial artery should be avoided or ligated during the elevation of the submandibular gland. If the abscess is limited to the space of the submandibular gland, the fascial capsule of the gland can simply be incised along its lower border for drainage, or the entire gland may be excised. The carotid sheath structures are identified opposite to the tip of the greater horn of the hyoid bone, and the sheath may require incision and drainage if an abscess is present. Finger dissection superiorly along the carotid sheath allows drainage of the parapharyngeal space up to the cranial base. Blunt dissection medial to the carotid sheath in an inferior direction allows drainage of both the pretracheal and the retrovisceral portions of the visceral space (Fig. 106-18).

Open Surgical Approach to Deep Neck Space Infections Achieving and maintaining adequate drainage of loculated collections of pus are the goals of open surgical procedures for the treatment of deep head and neck space infections. Associated foci of infection such as abscesses of tooth roots or infections of the temporal bone must also be identified and treated by the surgeon. The classic descriptions of the open surgical approach to deep pus in the neck written by Dean62 in 1919 and Mosher63 in 1929 are useful today with minor modifications. This approach is useful for drainage of visceral, submandibular, parapharyngeal, and prevertebral space infections; infections of the carotid sheath; and selected infections of the retropharyngeal space. Most uncomplicated retropharyngeal abscesses may be drained transorally, as described in the section Retropharyngeal Space. Dean,62 when discussing focal retropharyngeal infections (in his study, due to tuberculosis in most cases), advocated

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FIGURE 106-17. The incision for open surgical procedures to drain deep neck space infections is shown by the solid line. The outdated T incision of Mosher with an unnecessary vertical limb is shown by the dotted line.

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CHAPTER 106 ❖ Head and Neck Space Infections

FIGURE 106-18. Lateral neck anatomy seen with posterolateral retraction of the sternocleidomastoid muscle. Arrows show how the carotid sheath and retropharyngeal, lateral pharyngeal, and visceral spaces can be approached.

Iodophor-impregnated packing is placed for several days, and the wounds are closed loosely. The packing is slowly removed over a period of several days. Head and neck space abscesses that are obviously pointing may be surgically managed by simple skin and subcutaneous tissue incision, evacuation of purulent material, and blunt or digital exploration of the abscess cavity to open and drain any areas of loculated pus. Packing is then placed.

SURGICAL VERSUS NONSURGICAL THERAPY Debate continues regarding the need for and timing of surgical intervention in head and neck space infections. With the availability of newer antimicrobial agents, some clinicians advocate withholding surgical intervention in patients with an abscess and providing treatment with a prolonged course of antimicrobial therapy. In our opinion, antimicrobial therapy is effective in treating most patients who have uncomplicated cellulitis or adenopathy in the head and neck spaces and who lack the signs and symptoms of airway obstruction. When patients have a compromised airway or fail to rapidly improve after antimicrobial therapy, incision and drainage are indicated, despite the lack of evidence from imaging that an abscess is present. If no improvement is seen over a reasonable period, such as 24–72 hours, and antimicrobial therapy is continued without surgical intervention, catastrophic events can occur (see the section Complications). For patients with

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obvious abscesses, as determined by clinical examination and imaging studies, incision and drainage should be performed in the operating room. Several studies have shown that small abscesses can be treated with IV antibiotics alone in some cases.65–68 Of course, in the absence of surgical drainage, it is not possible to be completely certain that pus is present. Nonetheless, enough cases have been reported of treatment of lesions that were considered by experienced radiologists to be abscesses that we consider it proven that IV antibiotics alone can cure some abscesses. None of these papers have attempted, however, to make a cost-benefit analysis suggesting that IV antibiotic therapy is superior from the standpoint of either patient morbidity or cost. The morbidity of transoral drainage approaches 0%, and in our institutions we have found that when a child is afebrile and nontoxic 24 hours after drainage they may be safely converted to oral antibiotics and discharged to home. The morbidity to the patient and the cost of rapid drainage and discharge are low. Conversely, a child who responds to IV antibiotics but who is believed to have pus collection will certainly be monitored in hospital on IV antibiotics for several days, and up to 50% of children who have a trial of IV antibiotics will ultimately require surgery.34,46 Thus, if the surgeon feels that pus is present, it would seem that the child’s recovery is hastened, morbidity reduced, and cost reduced by prompt surgical drainage. When imaging studies are negative or equivocal for the diagnosis of an abscess, an initial trial of medical management is appropriate. Repeated imaging studies during the course of medical treatment can be helpful, especially in a child who is not rapidly improving.11 The initial imaging studies may have been negative or equivocal, but the follow-up study may be positive. The most effective method to determine the causative organisms and select the most appropriate antimicrobial agents is to obtain material for culture during fine-needle aspiration of the inflammatory mass or during incision and drainage in the operating room. Incision and drainage are indicated when the child fails to rapidly improve after empirical treatment; when complications such as airway compromise occur; or when an unusual organism is suspected, such as in a patient who is immunocompromised. Needle aspiration in an awake infant or a young child is not feasible and can be dangerous. However, needle aspiration for diagnosis and for evacuating purulent material can be performed in selected older children and adolescents. In one study, the combination of one or two needle aspirations plus IV antimicrobial therapy for neck abscesses in children was successful in 56% of 18 abscesses in 17 children.30 Children with unilocular and small abscesses had a higher response rate to needle aspiration than did those with multilocular and large abscess cavities, which more often required incision and drainage. Needle aspiration has also been reported to be successful in the treatment of nonperitonsillar head and neck abscesses in adults.53

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For abscesses associated with airway obstruction, septicemia, or complications and for those that fail to respond to needle aspiration, incision and drainage are indicated. For uncomplicated head and neck space abscesses, the choice of using IV antibiotics alone versus needle aspiration or incision and drainage plus IV antibiotics is up to the clinician, although we strongly recommend incision and drainage.

COMPLICATIONS Complications of head and neck space infections include airway obstruction, septicemia, carotid artery rupture, thrombosis of the internal jugular vein, mediastinitis (with potential mediastinal abscess and rupture of the great vessels in the chest), Lemierre syndrome, and rupture of an abscess into the pharynx, all of which can be fatal.69,70 Sentinel bleeding from the pharynx or ear may be a harbinger of arterial erosion and massive hemorrhage. Arteriography may be indicated to identify the bleeding vessel if the clinical course allows time for such an examination. Obtaining access to the great vessels for ligation to control hemorrhage is critical in this situation. Reisner et al.71 reported that internal carotid pseudoaneurysm complicated a staphylococcal parapharyngeal space abscess. Symptoms included a pulsatile neck mass, Horner syndrome, hemoptysis, and hemorrhagic shock. The pseudoaneurysm was managed by angiography and endovascular occlusion. Britt et al.72 reviewed the literature from the last 30 years and found that 29 cases of Ludwig angina in children were reported. Five of the 29 (17%) children died of causes that included airway obstruction, mediastinitis, empyema, pneumonia, and sepsis. Complications that occur during the course of a head and neck space infection require an open surgical approach for drainage of the space. An intrathoracic complication during the course of a head and neck space infection requires consultation with a chest surgeon. A more complicated clinical course was predicted by the presence of multiple abscesses or airway obstruction associated with deep neck space infections.73 Thrombosis of the internal jugular vein is characterized by spiking fevers, chills, and facial and orbital swelling, with evidence of septic emboli in the pulmonary circulation and, occasionally, the systemic circulation. The diagnosis of internal jugular vein thrombosis may be made on the basis of the typical clinical picture plus evidence of thrombosis as detected by CT with contrast, US, or MRI with flow-sensitive pulse sequences.74,75 Arteriography and venography appear to be unnecessarily invasive for the diagnosis of most cases of internal jugular vein thrombosis because the previously listed methods are reliable and safer. Internal jugular vein thrombosis in the course of head and neck space infection may require systemic anticoagulation or even ligation with possible excision of the vein.74 Lemierre syndrome begins with infection in the oropharynx, followed by thrombosis of the tonsillar veins

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and internal jugular vein, infection in the parapharyngeal space, with septicemia and septic emboli. Surgical drainage, antibiotics, and jugular vein ligation may be required.76 An abscess may rupture into the pharynx or trachea and cause asphyxiation, pneumonia, lung abscess, or empyema. Inflammatory torticollis with cervical vertebral subluxation requiring cervical traction and fusion to prevent spinal cord injury has been reported to occur during head and neck space infections.77 Neuropathies involving the cranial nerves IX, X, XI, and XII may complicate parapharyngeal space infections.78 Horner syndrome may occur during parapharyngeal space infections.79 Because life-threatening complications can develop, the clinician must make the diagnosis as rapidly as possible and institute the most effective methods of management.

CONCLUSIONS The morbidity and mortality from pediatric neck space infections can be devastating; however, the early use of antibiotics and CT scan imaging over recent years has led to better outcomes in this disease and in this population. Despite better outcomes, an increase in the incidence of head and neck space abscesses in the pediatric population over the last decade has been described by several authors. Also common to these studies is the awareness of the ongoing debate as to whether medical or surgical therapy is the best management for these infections. There is agreement within the field that neck infections presenting with severe symptoms or airway compromise should have immediate definitive surgical drainage; however, a considerable amount of research has been published in an effort to identify subpopulations that may benefit from IV antibiotic treatment alone. Moreover, the role of CT in the diagnosis and management of neck infections is a matter of continual debate. Studies are looking at the utility of CT scans for every child presenting with signs and symptoms of neck space infections versus identifying subsets of children who, based on their presentation and risk factors, may not need an initial CT to decide the best course of treatment. For those who do undergo CT imaging, factors used to accurately identify and differentiate abscesses from phlegmons or presuppurative lymphadenitis are being contested in the modern literature. Overall conclusions at this point do favor the utility of CT scan in the diagnosis of neck infections, although the most sensitive and specific clinical predictor of true abscess amenable to surgical drainage is still a matter of debate.

Selected References Hollinshead W, ed. Anatomy for Surgeons. Vol. 1. 3rd ed. Philadelphia, PA: Harper & Row; 1982: 269–289. An excellent description of the fascia and fascial spaces of the head and neck. This chapter should be studied by all physicians involved in the care of patients with head and neck space infections. Weber AL, Baker AS, Montgomery WW. Inflammatory lesions of the neck, including fascial spaces-evaluation by computed

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CHAPTER 106 ❖ Head and Neck Space Infections tomography and magnetic resonance imaging. Isr J Med Sci. 1992;28:241. A concise description of the anatomy of the fascial spaces of the head and neck is provided along with pertinent CT and MRI criteria that help identify cellulitis, abscesses, and internal jugular vein thrombosis. Kirse DJ, Roberson DW. Surgical management of retropharyngeal space infections in children. Laryngoscope. 2001;111:1413– 1422. One of the largest studies to date in the current medical literature focusing on RPA, role of CT in predicting pus and one of the few papers identifying surgical exploration/drainage as the gold standards for management. Most other papers over the last decade use this article as a reference. McClay JE, Murray AD, Booth T. Intravenous antibiotic therapy for deep neck abscesses defined by computed tomography. Arch Otolaryngol Head Neck Surg. 2003;129:1207–1212. Although a small study, this article is referenced several times among the modern literature citing evidence for medical management of abscesses diagnosed by CT. There is no good explanation as to why the CT findings did not correlate with an abscess in need of surgical management, but it certainly contributes to the ongoing debate/controversy that exists between medical and surgical management of deep space neck infections in the pediatric population. Page NC, Bauer EM, Lieu JE. Clinical features and treatment of retropharyngeal abscess in children. Otolaryngol Head Neck Surg. 2008;138:300–306. In the constant debate over which signs on CT can best predict abscess and positive pus at drainage, this large series identifies cross-sectional area > 2.0 cm2 as significant. Author is optimistic that subgroups may exist that benefit from initial IV antibiotic therapy versus drainage but at this point concludes, like Kirse and Roberson, that surgical drainage within the first 24 hours of presentation for patients presenting with signs/symptoms and CT findings suggestive of true abscess should be the initial therapy of choice. Meyer AC, Kimbrough TG, Finkelstein M, Sidman JD. Symptom duration and CT findings in pediatric deep neck infection. Otolaryngol Head Neck Surg. 2009;140:183–186. There currently seems to be a lot of effort to identify a subgroup of children who do not need a CT scan to identify an abscess. Duration of symptoms or varying demographic data have been studied alongside CT-diagnosed abscesses in an effort to localize a group of children who may not need imaging upon presentation. This study comes right out and suggests CT for each child since there was no significant identifier that could statistically predict abscess on CT. Thomason TS, Brenski A, McClay J, Ehmer D. The rising incidence of methicillin-resistant Staphylococcus aureus in pediatric neck abscesses. Otolaryngol Head Neck Surg. 2007;137: 459–464. MRSA in pediatric neck abscesses is notably increasing. Historically, MRSA infections were mainly nosocomial, but this does not seem to be true anymore. Community-acquired MRSA is now a significant contributor to pediatric neck space infections. MRSA/methicillin-sensitive Staphylococcus aureus (MSSA) seems to be more commonly found in the lateral region of the deep neck (non-retropharyngeal or non-parapharyngeal spaces) compared to the medial regions, and it also appears to affect younger children (average age close to 19 months) compared to older children. Shefelbine SE, Mancuso AA, Gejewski BJ, Ojiri H, Stringer S, Sedwick JD. Pediatric retropharyngeal lymphadenitis: differentiation from retropharyngeal abscess and treatment

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implications. Otolaryngol Head Neck Surg. 2007;136:182–188. Yet another study looking retrospectively at possible clinical indicators or CT signs that could predict successful surgical drainage of pus from neck space infections in children. A volume greater than 4 cm3 seemed to be the number pointing to successful drainage, whereas 2 cm3 pointed to medical management. There exists a “gray zone” in between 2 and 4 cm3 in which treatment guidelines are not clear. However, the numbers are quite low to generalize here (10/18 surgical abscesses drained pus). There are also good illustrations and descriptions of lymph node changes leading from the presuppurative phase to abscess as purulence extends through the lymph node capsule. In the discussion, it does a decent job of comparing many of the recently cited articles (Kirse, McClay, etc.) in terms of lymph node anatomy and pathophysiology. Malloy KM, Christenson T, Meyer JS, et al. Lack of association of CT findings and surgical drainage in pediatric neck abscesses. Int J Pediatr Otorhinolaryngol. 2008;72:235–239.

References 1. McCaskey CH. Ludwig’s angina. Arch Otolaryngol. 1942; 36:467. 2. Templer JW, Holinger LD, Wood RP, 2nd, Tra NT, DeBlanc GB. Immediate tonsillectomy for the treatment of peritonsillar abscess. Am J Surg. 1977;134:596. 3. Muckleston HS. Angina ludovici and kindred affections: an historical and clinical study. Ann Otol Rhinol Laryngol. 1928;37:711. 4. Burke J. Angina ludovici: a translation, together with a biography of Wilhelm Fredrick von Ludwig. Bull Hist Med. 1939;7:115. 5. Hollinshead W, ed. Anatomy for Surgeons. Vol 1. 3rd ed. Philadelphia, PA: Harper & Row; 1982:269–289. 6. Som P, Curtin H. The fasciae and spaces of the head and neck: an analysis of the confusion in the literature with new anatomic correlation. Unpublished manuscript, 1993. 7. Weber AL, Baker AS, Montgomery WW. Inflammatory lesions of the neck, including fascial spaces—evaluation by computed tomography and magnetic resonance imaging. Isr J Med Sci. 1992;28:241. 8. Asmar BI. Bacteriology of retropharyngeal abscess in children. Pediatr Infect Dis J. 1990;9:595. 9. Brook I. Microbiology of abscesses of the head and neck in children. Ann Otol Rhinol Laryngol. 1987;96:429. 10. Tschiassny K. Ludwig’s angina—a surgical approach based on anatomical and pathological criteria. Ann Otol Rhinol Laryngol. 1947;56:937. 11. Kirse DJ, Roberson DW. Surgical management of retropharyngeal space infections in children. Laryngoscope 2001;111:1413–1422. 12. Cabrera CE, Deutsch ES, Eppes S, et al. Increased incidence of head and neck abscesses in children. Otolaryngol Head Neck Surg. 2007;136:176–181. 13. Coticchia JM, Getnick GS, Yun RD, Arnold JE. Age-, site-, and time-specific differences in pediatric deep neck abscesses. Arch Otolaryngol Head Neck Surg. 2004;130:201–207. 14. Inman JC, Rowe M, Ghostine M, Fleck T. Pediatric neck abscesses—changing organisms and empiric therapies. Laryngoscope 2008;118:2111–2114.

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15. Ossowski K, Chun RH, Suskind D, Baroody FM. Increased isolation of methicillin-resistant Staphylococcus aureus in pediatric head and neck abscesses. Arch Otolaryngol Head Neck Surg. 2006;132(Suppl 11):1176–1181. 16. Thomason TS, Brenski A, McClay J, Ehmer D. The rising incidence of methicillin-resisitant Staphylococcus aureus in pediatric neck abscesses. Otolaryngol Head Neck Surg. 2007;137:459–564. 17. Alvi A. Mycobacterium chelonei causing recurrent neck abscess. Pediatr Infect Dis J. 1993;12:617. 18. Carithers HA. Cat-scratch disease: an overview based on a study of 1200 patients. Am J Dis Child. 1985;139:1124. 19. Kennedy TL. Curettage of nontuberculous mycobacterial cervical lymphadenitis. Arch Otolaryngol Head Neck Surg. 1992;118:759. 20. Yonetsu K, Izumi M, Nakamura T. Deep facial infections of odontogenic origin: CT assessment of pathways of space involvement. AJNR Am J Neuroradiol. 1998;19:123. 21. Zangwill KM, Jamilton DH, Perkins BA, et al. Cat scratch disease in Connecticut: epidemiology, risk factors, and evaluation of a new diagnostic test. N Engl J Med. 1993;329:8. 22. Behrman R, Vaughan V, Nelson W, eds. Nelson Textbook of Pediatrics. 13th ed. Philadelphia, PA: WB Saunders; 1987:529, 632, 638–639, 710–711. 23. Reinhardt JF, Johnston L, Ruane P, et al. A randomized, doubleblind comparison of sulbactam/ampicillin and clindamycin for the treatment of aerobic and aerobic–anaerobic infections. Rev Infect Dis. 1986;8(Suppl 5):569. 24. Retsema JA, English AR, Girard A, et al. Sulbactam/ampicillin in vitro spectrum, potency, and activity in models of acute infection. Rev Infect Dis. 1986;8(Suppl 5):528. 25. Sichel J, Gomori JM, Saah D, Elidan J. Parapharyngeal-space abscess in children: the role of CT for diagnosis and treatment. Int J Pediatr Otorhinolaryngol. 1996;35:213. 26. Haug RH, Wible RT, Lieberman J. Measurement standards for the prevertebral region in the lateral soft-tissue radiograph of the neck. J Oral Maxillofac Surg. 1991;49:1149. 27. Varghese S, Hengerer AS, Putnam T, Colgan MT. Neck abscess causing Horner’s syndrome. NY State J Med. 1982;82:1855. 28. Holt GR, McManus K, Newman RK, Potter JL, Tinsley PP. Computed tomography in the diagnosis of deep-neck infections. Arch Otolaryngol. 1982;108:693. 29. Nyberg DA, Jeffrey RB, Brant-Zawadzki M, Federle M, Dillon W. Computed tomography of cervical infections. J Comput Assist Tomogr. 1985;9:288. 30. Brodsky L, Belles W, Brody A, Squire R, Stanievich J, Volk M. Needle aspiration of neck abscesses in children. Clin Pediatr (Phila). 1992;31:71. 31. Choi S, Vezina L, Grundfast K. Relative incidence and alternative approaches for surgical drainage of different types of deep neck abscesses in children. Arch Otolaryngol Head Neck Surg. 1997;123:1271. 32. Lazor JB, Cunningham MJ, Eavey RD, Weber AL. Comparison of computed tomography and surgical findings in deep neck infections. Otolaryngol Head Neck Surg. 1994;111:746. 33. Schechter GL, Sly DE, Roper AL, Jackson RT. Changing face of treatment of peritonsillar abscess. Laryngoscope. 1982;92:757. 34. Page NC, Bauer EM, Lieu JE. Clinical features and treatment of retropharyngeal abscess in children. Otolaryngol Head Neck Surg. 2008;138:300–306.

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35. Meyer AC, Kimbrough TG, Finkelstein M, Sidman JD. Symptom duration and CT findings in pediatric deep neck infection. Otolaryngol Head Neck Surg. 2009;140:183–186. 36. Malloy KM, Christenson T, Meyer JS, et al. Lack of association of CT findings and surgical drainage in pediatric neck abscesses. Int J Pediatr Otorhinolaryngol. 2008;72:235–239. 37. Vural C, Gungor A, Comerci S. Accuracy of computerized tomography in deep neck infections in the pediatric population. Am J Otolaryngol. 2003;24(3):143–148. 38. Grodinsky M, Holyoke E. The fasciae and fascial spaces of the head, neck and adjacent region. Am J Anat. 1938;63:367. 39. Glasier CM, Stark JE, Jacobs RF, et al. CT and ultrasound imaging of retropharyngeal abscesses in children. AJNR Am J Neuroradiol. 1992;13:1191. 40. Kreutzer EW, Jafek BW, Johnson ML, Zunkel DE. Ultrasonography in the preoperative evaluation of neck abscesses. Head Neck Surg. 1982;4:290. 41. BenAmi T, Yousefzadeh DK, Aramburo MJ. Presuppurative phase of retropharyngeal infection: contribution of ultrasonography in the diagnosis and treatment. Pediatr Radiol. 1990;21:23. 42. Kraus R, Han BK, Babcock DS, Oestreich AE. Sonography of neck masses in children. Am J Radiol. 1986;146:609. 43. Haeggstrom A, Gustafsson O, Engquist S, Engstrom CF. Intraoral ultrasonography in the diagnosis of peritonsillar abscess. Otolaryngol Head Neck Surg. 1993;108:243. 44. Lewis GJS, Leithiser RE, Glasier CM, Igbal V, Stephanson CA, Seibert JJ. Ultrasonography of pediatric neck masses. Ultrasound Q. 1989;7:315. 45. Charpy A. Aponeuroses of the neck. In Poirier P, Charpy A, eds. Traite de Anatomic Humaine. Vol. 2, f. 1. Paris: Masson; 1912:258–280. 46. Blotter JW, Yin L, Glynn M, Wiet GJ. Otolaryngology consultation for peritonsillar abscess in the pediatric population. Laryngoscope. October 2000;110(10 Pt 1):1698–1701. 47. Paparella MM, Shumrick DA, Meyerhoff WL, Seid AB, eds. Oto Laryngology. Vol. 3. 2nd ed. Philadelphia, PA: WB Saunders; 1980:2272–2273. 48. Beeden AG, Evans JNG. Quinsy tonsillectomy—a further report. J Laryngol Otol. 1970;84:443. 49. Grahne B. Abscess tonsillectomy. Arch Otolaryngol. 1958; 68:332. 50. McCurdy JA. Peritonsillar abscess: a comparison of treatment by immediate tonsillectomy and interval tonsillectomy. Arch Otolaryngol. 1977;103:414. 51. Richardson KA, Birck H. Peritonsillar abscess in the pediatric population. Otolaryngol Head Neck Surg. 1981;89:907. 52. Syriopoulou V, Bitsi M, Theodoridis C, Saroglou I, Krikos X, Tzanetou K. Clinical efficacy of sulbactam/ampicillin in pediatric infections caused by ampicillin-resistant or penicillin-resistant organisms. Rev Infect Dis. 1986;8 (Suppl 5):630. 53. Herzon FS. Permucosal needle drainage of peritonsillar abscesses. Arch Otolaryngol. 1984;110:104. 54. Robson CD, Hazra R, Barnes PD, Robertson RL, Jones D, Husson RN. Nontuberculous mycobacterial infection of the head and neck in immunocompetent children. AJNR Am J Neuroradiol. 1999;20:1829. 55. Holt GR, Tinsley PP. Peritonsillar abscesses in children. Laryngoscope. 1981;91:1226.

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CHAPTER 106 ❖ Head and Neck Space Infections 56. Herbild O, Bonding P. Peritonsillar abscess: recurrence rate and treatment. Arch Otolaryngol. 1981;107:540. 57. Nielsen VM, Greisen O. Peritonsillar abscess. I. Cases treated by incision and drainage: a follow-up investigation. J Laryngol Otol. 1981;95:801. 58. Schraff S, McGinn JD, Derkay CS. Peritonsillar abscess in children: a 10-year review of diagnosis and management. Int J Pediatr Otorhinolaryngol. 2001;57(3):213–218. 59. Richards L. Retropharyngeal abscess. NEJM. 1936; 215:1120–1130. 60. Battista RA, Baredes S, Krieger A, Fieldman R. Prevertebral space infections associated with cervical osteomyelitis. Otolaryngol Head Neck Surg. 1993;108:160. 61. Thompson JW, Cohen SR, Reddix P. Retropharyngeal abscess in children: a retrospective and historical analysis. Laryngoscope. 1988;98:589. 62. Dean LW. The proper procedure for external drainage of retropharyngeal abscess secondary to caries of the vertebrae. Ann Otol Rhinol Laryngol. 1919;28:566–572. 63. Mosher H. The submaxillary fossa approach to deep pus in the neck. Trans Am Acad Ophthalmol Otolaryngol. 1929;34:19. 64. Topazian R, Goldberg M, eds. Management of Infections of the Oral and Maxillofacial Regions. Philadelphia, PA:WB Saunders; 1981:196–199. 65. Morrison JE, Pashley NRT. Retropharyngeal abscesses in children: a 10-year review. Pediatr Emerg Care. 1988;4:9. 66. Thomas TT. Ludwig’s angina: an anatomical, clinical and statistical study. Univ Pennsylvania Med Bull. 1908;21:2. 67. McClay JE, Murray AD, Booth T. Intravenous antibiotic therapy for deep neck abscesses defined by computed tomography. Arch Otolaryngol Head Neck Surg. 2003;129:1207–1212. 68. Shefelbine SE, Mancuso AA, Gejewski BJ, Ojiri H, Stringer S, Sedwick JD. Pediatric retropharyngeal lymphadenitis: differentiation from retropharyngeal abscess and treatment implications. Otolaryngol Head Neck Surg. 2007;136:182–188.

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69. Bakshi R, Grover G. Retropharyngeal abscess with mediastinal extension in an infant—still existing? Pediatr Emerg Care. 2009;25(3):181–183. 70. Wright CT, Stocks RM, Armstrong DL, Arnold SR, Gould HJ. Pediatric mediastinitis as a complication of methicillinresistant Staphylococcus aureus retropharyngeal abscess. Arch Otolaryngol Head Neck Surg. April 2008;134(4):408–413. 71. Reisner A, Marshall G, Bryant K, Postel GC, Eberly SM. Endovascular occlusion of a carotid pseudoaneurysm complicating deep neck-space infection in a child. Case report. J Neurosurg 91:510, 1999. 72. Britt J, Josephson G, Gross C. Ludwig’s angina in the pediatric population: report of a case and review of the literature. Int J Pediatr Otorhinolaryngol. 2000;52:79. 73. Elsherif AM, Park AH, Alder SC, Smith ME, Muntz HR, Grimmer F. Indicators of a more complicated clinical course for pediatric patients with retropharyngeal abscess. Int J Pediatr Otorhinolaryngol. December 4, 2009;74(2):198–201. 74. Bach MC, Roediger JH, Rinder HM. Septic anaerobic jugular phlebitis with pulmonary embolism: problems in management. Rev In fect Dis. 1988;10:424. 75. Merhar GL, Colley DP, Clark RA, Herwig SR. Computed tomographic demonstration of cervical abscess and jugular vein thrombosis. Arch Otolaryngol. 1981;107:313. 76. Ridgway JM, Parikh DA, Wright R, et al. Lemierre syndrome: a pediatric case series and review of literature. Am J Otola­ ryngol. 2010;31(1):38–45. 77. Bredenkamp JK, Maceri DR. Inflammatory torticollis in children. Arch Otolaryngol Head Neck Surg. 1990;116:310. 78. Langenbrunner DJ, Dajani S. Pharyngomaxillary space abscess with carotid artery erosion. Arch Otolaryngol. 1971;94:447. 79. Ungkanont K, Yellon R, Weissman J, Casselbrant ML, González-Valdepeña H, Bluestone CD. Head and neck space infections in infants and children. Otolaryngol Head Neck Surg. 1995;112:375.

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107

C H A P T E R

Benign Tumors of the Head and Neck Karen F. Watters, Reza Rahbar, and Trevor J. McGill

B

enign tumors of the head and neck, excluding congenital and inflammatory lesions, are relatively rare in the pediatric age group. They are represented by a small group of tumors that arise from a variety of tissue types including the peripheral nervous system, vascular tissue, muscle, tissue of mesenchymal origin, and salivary tissue.

CLINICAL EXAMINATION The child with a suspected head and neck neoplasm requires a complete clinical history and physical examination. Salient points in the history should include the age of the child, the duration and nature of onset of the mass, associated symptoms such as pain, epistaxis, and neurological deficits, whether the child has a known mutation or syndrome associated with the development of neoplasms, and if there is a significant family history of disorders or tumors. Otologic, oral, nasal, and neck examinations can be easily performed in children of all ages. The findings that assist clinical diagnosis include location of the mass, whether it is superficial or deep, color and vascularity, the presence of pulsations or bruits, the consistency (solid or cystic),whether it is tethered to overlying skin or underlying tissue, and the presence of cranial nerve palsies or functional deficits. Flexible fiberoptic nasolaryngoscopy permits direct visualization of the nasopharynx, hypopharynx, and larynx in children of all ages. This examination is very important if a nasopharyngeal lesion such as a juvenile nasopharyngeal angiofibroma (JNA) is suspected, or if symptoms such as dysphonia or dysphagia are present suggestive of a vocal cord paralysis.

DIAGNOSTIC WORK UP The majority of head and neck tumors require further diagnostic evaluation. Characteristic findings on imaging can provide clues to a specific diagnosis. The choice of imaging modality depends on the nature and location of the tumor as well as proposed treatment options. Ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) can be very helpful in confirming clinically suspected diagnoses and also establishing a baseline size for those lesions that will be monitored conservatively, such as neurofibromas. US can be useful to identify size and echogenic patterns of the lesion—distinguish solid lesions from cystic lesions and detect vascularity, venous, or arterial. It has the advantage of being ready availability, low cost, does not expose the child to ionizing radiation, and sedation or anesthesia

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is rarely required in young children. CT is helpful in characterization of bone involvement (erosion, remodeling, and sclerosis), delineating between solid and cystic lesions, defining location and relationship of the lesion to surrounding anatomic structures, and detecting intralesional calcification. An MRI is the modality of choice for demonstrating the soft-tissue characteristics of tumors. It has the benefit of no radiation exposure; however, sedation or general anesthesia is generally required in young children. In some situations, both CT and MRI are performed, for example, JNA—bony erosion is identified on CT, and intracranial extension of the tumor is further defined on MRI. In specific conditions, especially presumed vascular lesions, angiography can supply additional information; for example, a JNA has a characteristic “tumor blush” on angiography.

BIOPSY If the histologic diagnosis of a lesion is required, excisional biopsies are performed for lesions that are amenable to surgical resection. In larger lesions, that are not amenable to surgical resection and the diagnosis is unclear on clinical and radiological findings, a core biopsy can be performed under US or CT guidance. If this is not possible, an open biopsy can be obtained. Fine-needle aspiration is may be performed in the pediatric population if there is a cytopathologist with sufficient skill and training to interpret the specimen.

MANAGEMENT Management of benign neoplasms includes both conservative and surgical treatment. Surgical resection or excisional biopsy may be indicated when the diagnosis is uncertain, there is a concern for malignant transformation, or there are significant functional deficits or significant deformity secondary to mass effect or infiltration by the neoplasm. For example, a neurofibroma may be safely followed with serial clinical examination and interval MRI for a number of years. However, surgical resection is indicated if there is a rapid increase in size, with a concern for malignant degeneration or upper aerodigestive or neural symptoms secondary to mass effect and compression by the neurofibroma. Unlike congenital lesions, such as hemangiomas, benign neoplasm tumors typically do not regress or spontaneously resolve, and surgical resection is the treatment of choice in most cases.

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CLASSIFICATION Benign head and neck neoplasms can be classified into the following categories based on tissue of origin: neural, vascular, muscular, salivary, and mesenchymal and fibrous (Table 107-1).

Neural Tumors/Tumors of the Peripheral Nervous System Benign tumors of the peripheral nervous system that occur in the head and neck in children include neurofibromas, schwannomas, and paragangliomas (PG). Neurofibromas are benign tumors of the peripheral nervous system that can involve any cranial, peripheral, or autonomic nerve (Fig. 107-1A–C). They occur either sporadically or in association with neurofibromatosis type 1 (NF1; or von Recklinghausen disease), an autosomal dominant condition. NF1 has an incidence of 1 in 3000 live births. It is the result of a defect in the tumor suppressor gene, neurofibromin 1, resulting in an increased incidence of both benign and malignant tumors. Neurofibromas generally appear during late adolescence, being preceded by the presence of multiple café-au-lait macules, which supports the diagnosis of NF1.1 Histologically, neurofibromas are composed of Schwann cells, fibroblasts, mast cells, and vascular elements.1,2 TABLE 107-1. Classification of Benign Tumors in the Head and Neck in Children

Tissue of Origin

Benign Neoplasm

Malignant Counterpart

Neural

Neurofibromas Schwannomas Paragangliomas (carotid body tumors)

Malignant peripheral sheath nerve tumors

Vascular

Juvenile angiofibroma (JNA) Pyogenic granuloma

Muscular

Smooth muscle (leiomyoma, Leiomyosarcoma angiomyoma, epithelioid Angiosarcoma leiomyoma) Rhabdomyosarcoma Skeletal muscle (rhabdomyoma)

Salivary

Pleomorphic adenoma

Mesenchymal

Lipomas Myxomas Pilomatrixomas Harmatomas Chordomas Mesenchyomas

Fibrous

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Infantile myofibromatosis Desmoid Benign fibrous histiocytomas

Liposarcoma

FIGURE 107-1. A solitary peripheral nerve sheath tumor in the floor of the right nasal vestibule in a 12-year-old boy. (A) Completion excision was performed by a sublabial approach. (B) The operative site following complete excision. (C) The resected tumor approximately 1.5 cm in size. Histologic examination confirmed this to be an atypical peripheral nerve sheath tumor.

The majority of neurofibromas are relatively small, solitary or multiple, rubbery tumors involving the skin and superficial subcutaneous tissue. However, both solitary neurofibromas and plexiform neurofibromas occur in children with NF1. Plexiform neurofibromas tend to appear as sausage-shaped masses extending along peripheral nerves or nerve roots and are often located in multiple fascial compartments. More than 50% of plexiform neurofibromas occur in the head and neck.3 Large deep plexiform neurofibromas can infiltrate surrounding tissue and cause disfiguring deformity and functional deficits from mass effect. Plexiform neurofibromas appear hypointense on CT and hyperintense T2-weighted MRI (Fig. 107-2A and B). A central area of hyperintensity on CT and hypointensity on MRI, the so-called “target sign,” is often seen and is characteristic of benign plexiform neurofibromas. This helps to distinguish plexiform neurofibromas from lymphatic malformations.4 Surgical resection is the mainstay of treatment, but this can be challenging because of the infiltrating nature of these tumors and their tendency to recur5,6 (Fig. 107-2C). The risk of significant neurovascular morbidity is often associated with complete resection, and thus, it is often not possible. Indications for surgical resection include the following: 1. The mass effect from the neurofibroma is causing upper aerodigestive tract compromise. 2. To exclude malignancy in a rapidly enlarging neurofibroma or in a neurofibroma where radiographic findings are atypical and suggestive of malignancy. 3. Severe cosmetic deformity. 4. Where surgery may improve functional deficits or alleviate symptoms caused by compression of neural structures.

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CHAPTER 107 ❖ Benign Tumors of the Head and Neck 1793

FIGURE 107-2. A large plexiform neurofibroma in a patient with neurofibromatosis type 1. (A) Axial CT scan showing a large hypointense left neck mass compressing the trachea and deviating the trachea to the left. (B) Coronal T2-weighted MRI with a hyperintense mass infiltrating multiple fascial planes. Areas of hypointensity, “target sign,” are seen in the center, which are characteristic of benign plexiform neurofibromas. (C) The operative field showing the carotid artery (red vessel loop) and the jugular vein (blue vessel loop) following complete resection. The resected lesion was greater than 11.5 cm in diameter.

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Regrowth of a partially resected tumor frequently necessitates additional surgical procedures. Neurofibromas are followed clinically and by imaging, usually MRI, at least annually. Any child presenting for the first time with a neurofibroma should be referred to a multidisciplinary team of geneticists, pediatricians, and neurologists, specialized in the management of neurofibromatosis. Once diagnosed, these children require lifelong assessments to detect the numerous manifestations of the disease. Malignant peripheral nerve sheath tumor (MPNST) is usually seen in patients with NF1. MPNST is suggested by a rapid increase in size, alteration in enhancement characteristics on MRI, or the development of metastatic disease. Fluorodeoxyglucose (FDG)-positive emission tomography (PET) imaging is useful in the evaluation of suspected MPNST.7 Schwannomas are solitary benign tumors that derive from the schwann cells of the nerve sheath. Approximately 40%–50% of all schwannomas arise in the head and neck, most commonly the lateral cervical region, arising from the vagus nerve and sympathetic nerves.8 Schwannomas occur sporadically and in patients with neurofibromatosis type 2 (NF2). Schwannomas are sharply demarcated and of variable signal on T1- and T2-weighted images. Cystic foci can also be seen in schwannomas.4 NF2 has an incidence of 1 in 50,000 live births. It is caused by a defect in the “Merlin or Schwannomin” gene located on chromosome 22. The defect can result in either a failure to synthesize Merlin or the production of a defective peptide that lacks the normal tumor-suppressive effect. NF2 is characterized by bilateral schwannomas or acoustic neuromas of the eighth cranial nerve.9 Complete surgical excision is recommended with careful preservation of the associated nerve, if possible. Although most PG take the form of adrenal primary tumors within the pediatric population, head and neck tumors are an extremely rare occurrence. Carotid body tumors (CBTs) are the most frequent PG in the head and neck, accounting for almost 60% of head and neck PGs.10 They arise from glomus bodies (paraganglia) located at the carotid bifurcation. Carotid paraganglia are composed of chemoreceptor cells derived from the carotid primitive neural crest. CBTs are extremely uncommon in the pediatric population, typically occurring in older children and adolescents. Among 90 patients with CBTs, Shamblin et al.11 reported only one case in a 12-year-old child. Other sites in the head and neck include the jugular body, along the glossopharyngeal nerve and its tympanic branch, and the vagus nerve. CBT may be sporadic, familial (autosomal dominant inheritance with variable penetrance diseased gene localized to 11q23), or hyperplastic (resulting from the chronic hypoxia seen at high altitudes). Although histologically benign, CBTs can cause significant morbidity due to their location. Ten percent of cases have more than one paraganglioma and metastases occur in approximately 6% of patients.12,13

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Clinical manifestations of CBT include a slow growing pulsatile upper cervical mass with possible vagal or hypoglossal neuropathy in large tumors. Larger tumors possibly appear more often in children as smaller ones are often mistaken for cervical lymphadenopathy. Occasionally a bruit is heard over the lesion suggesting significant compression of the carotid arteries. Shamblin classified CBTs into three groups based on tumor size and involvement of the carotid vessels: group I tumors are localized and do not involve the surrounding major vessel; group II tumors are adherent or partially surround the vessels; and group III tumors are large and encase the vessels. The size of tumor positively correlates with the Shamblin’s classification. The major concerns with PG in the head and neck region are as follows:

Treatment Complete surgical resection is the treatment of choice.14 Preoperative selective angiographic embolization to decrease tumor vascularity is an important adjunct in restricting blood flow during surgery and diminishing blood requirements. According to the Shamblin classification, the risk for cranial nerve injury and vascular injury increases, as the disease progresses and CBT enlarges.11 In group I and II tumors, subadventitial resection is performed; great care is taken to preserve associated vessels and nerves (Fig. 107-3B–D). A team experienced in carotid shunting and vascular reconstruction should be present when a type III tumor is being resected. Radiotherapy is reserved for inaccessible PG and inadequate excision in adults and is not used in children. Chemotherapy is ineffective in treating these tumors.

1. Catecholamine hypersecretion. Symptoms of catecholamine secretion (hyperthermia, tachycardia, and hypertension) may exist at presentation or develop intraoperatively following tumor manipulation. 2. Progressive invasion of the major vessels and nerves of the neck and skull base. 3. Metastases to the lymph nodes, lungs, and bones; these occur in 6% of patients.

Vascular Tumors

Diagnostic Work Up Children found to have head and neck PG should have urine sent for free catecholamines, to detect catecholamine hypersecretion or an undiagnosed pheochromocytoma. The most specific test to detect this is a 24-hour urinary metanephrine measurement. The rich vascular supply of CBT is of diagnostic importance on imaging. CT, MRI, and arteriography remain the imaging modalities of choice. On CT with contrast, CBT is easily identified as a hypervascular mass located at the carotid bifurcation, widening the angle between the internal and external carotid artery, creating “a saddle.” The anatomy of carotid vessels and their relationship to an enhancing lesion can also be evaluated by CT angiography. An MRI is the most important imaging modality in evaluating CBTs in relation to surrounding soft tissue and vascular structures. Axial T1- and T2-weighted MR images reveal a well-defined carotid space lesion (Fig. 107-3A). In children, MRI may be more helpful for evaluation and characterization of CBTs, because small tumors may be less easily depicted in angiographic or CT studies. An MRI is also more sensitive in evaluating possible invasion of the skull base. Octreotide scintigraphy has also been investigated in the head and neck, which shown great promise in its ability to identify occult PGs and to detect metastases in patients with malignant tumors. Newer evidence suggests that FDG PET imaging may be more accurate than MRI in detecting primary tumors less than 1 cm in size.

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JNA is a relatively uncommon benign but locally aggressive neoplasm that occurs almost exclusively in the nasopharynx of adolescent males. Although the etiology of JNA is unknown, a variety of growth factors and androgens, and genetic alterations are thought to have a role in tumor biology.15 Presentation is typically with epistaxis and nasal obstruction. Other symptoms include hyponasal speech, facial swelling, proptosis, and diplopia. Symptoms are typically present for at least 6–12 months before the diagnosis is established.16 Examination reveals a vascular lesion with prominent submucosal blood vessels arising along the posterolateral wall of the nasal cavity at the sphenopalatine foramen, and frequently spreading anteriorly into the nasal cavity and posteriorly into the nasopharynx. The tumor characteristically grows laterally through the pterygopalatine fissure into the pterygomaxillary fossa. Tumor extension into the sphenoid, maxillary and ethmoidal sinuses, orbit, parasellar region, and middle cranial fossa is common. Erosion of the posterior wall of the maxillary sinus is secondary to extension from the infratemporal fossa. Intracranial extension, which is usually extradural, can occur secondary to tumor extension through the roof of the infratemporal fossa or through the superior orbital fissure, with subsequent extension into the cavernous sinus. These patients present with the classic signs of superior orbital fissure syndrome: paralysis of extraocular motions, exophthalmos, and ptosis. Approximately 20% of patients have evidence of skull base invasion at the time of diagnosis.16 It is important to note that angiofibromas invade the skull base through relentless expansion unlike malignant tumors that cause bone destruction through cellular infiltration. There is no universally accepted staging space system for JNAs. The most recent staging system was proposed by Radkowski et al.17 in 1996 (Table 107-2). The purpose of a staging system is to stratify tumor extent in an attempt to predict outcome. Tumor extent is important to the surgeon for ascertaining the likelihood of complete excision and the risk of complications.

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CHAPTER 107 ❖ Benign Tumors of the Head and Neck 1795 TABLE 107-2. Staging System for Juvenile Angiofibromas17

FIGURE 107-3. Carotid body tumor. (A) Coronal contrast enhanced T1-weighted MRI showing a hyperintense tumor at the left carotid artery bifurcation. (B) The operative field prior to resection of the tumor showing the internal jugular vein (blue and red vessel loop) and the internal carotid artery (red vessel loop only). (C) The tumor has been removed. “Saddling” of the internal and external carotid arteries is seen. (D) The resected tumor is over 2.5 cm in size.

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IA

Limited to nose and/or nasopharynx

IB

Extension into ≥1 sinus

IIA

Minimal extension into pterygomaxillary fossa

IIB

Full occupation of pterygomaxillary fossa (± erosion of orbital bones

IIC

Extension posterior to pterygoid plates

IIIA

Erosion of skull base with minimal intracranial extension

IIIB

Erosion of skull base with extensive intracranial extension ± cavernous sinus extension

Histologically JNA is a biphasic tumor, consisting of vascular and fibroblastic components. The fibrous stroma has characteristic uniformly distributed irregular slit-like vascular channels with a “staghorn” appearance that lack contractile elements and often result in massive hemorrhage following biopsy or manipulation. Evaluation Both CT and MRI are vital to enable correct staging of the JNA and appropriate surgical planning. JNAs appear as hyperintense lesions on CT with contrast. The exact location of the tumor as well as bony erosion and extension of the tumor into the skull base can be clearly identified (Fig. 107-4A). Bowing of the posterior wall of the maxillary sinus, the “antral bowing” sign is highly suggestive of a JNA.4 MRI characteristics depend on the relative combination of vascular fibrous components and tissue edema. JNAs are markedly enhanced on contrast-enhanced T1-weighted MRI with multiple flow-related signal voids and have a lobulated appearance of variable signal intensity on T2-weighted MR images (Fig. 107-4B and C). Inspissated secretions in obstructed sinuses must be distinguished from tumor to prevent upstaging of the tumor. Angiography is performed in all cases. The angiographic “tumor blush” supplied via branches of the internal maxillary and ascending pharyngeal and palatine arteries is characteristic of JNA (Fig. 107-4D). Biopsy is almost never required prior to surgical intervention. The characteristic age, clinical presentation, and imaging features usually permit a confident preoperative diagnosis of JNA. The pattern of bony erosion and prominent vascularity are the key features that distinguish JNA from others tumors found in this site including rhabdomyosarcoma and lymphoma. Treatment Surgery is the primary mode of treatment of JNA. The surgical approach depends on the stage of the tumor. Preoperative angiography with embolization of the tumor should be performed at least 24 hours prior to surgical resection, regardless of surgical approach. Traditionally, open surgical approaches,

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FIGURE 107-4. Juvenile angiofibroma in a 15-year-old boy who presented with epistaxis. (A) Coronal CT scan (bony windows) showing a well-defined tumor, which extends laterally into the pterygopalatine fossa, mildly expanding it. Superiorly the tumor erodes the floor of the sphenoid sinus, completely filling the sphenoid sinus. Medially the lesion crosses the midline, and inferiorly it fills the nasopharynx. (B) Coronal T1-weighted MRI showing a homogenous enhancing tumor, which appears separate from the floor of the sella and the anterior cranial fossa. Expansion into the pterygopalatine fossa is again seen. Flow voids are also evident. (arrow) (C) Saggital T1-weighted MRI showing no evidence of intracranial extension. (D) Angiogram of the external carotid artery showing the characteristic angiographic “tumor blush” arising from the internal maxillary artery.

such as lateral rhinotomy and mid-facial degloving, were used for all stages of JNA, with endoscopic approaches being used in stage I disease only. However, as endoscopic techniques have improved, along with image-guided navigation system and individual endoscopic surgical skills, the indications for endoscopic removal for JNA have expanded. Stage IIc tumors can now be safely removed endoscopically. Angiofibromas that have evidence of intracranial or orbital

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extension are not ideal for endoscopic resection and typically require an open approach. The endoscopic approach has the advantage of no facial incision or disruption of the facial skeleton and also significantly decreases hospital stay and the recovery period. During endoscopic excision, partial removal of the middle turbinate or the vomer is often necessary to gain circumferential access to the tumor. Powered tools including the microdebrider and

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CHAPTER 107 ❖ Benign Tumors of the Head and Neck 1797 radiofrequency coblator can be used to debulk the tumor, and bipolar diathermy is useful for hemostasis. The sphenopalatine artery should be clearly identified at the sphenopalatine foramen and ligated with clips. Frequently the tumor can be removed en-bloc via the oral cavity. Endoscopic drills can be used in sites where the tumor is adherent to bone, such as the root or the pterygoids or the face of the sphenoid. Open surgical approaches include lateral rhinotomy and mid-facial degloving. A lateral rhinotomy allows for excellent exposure in patients with bulky stage II disease, but leaves a scar. The midfacial degloving technique also provides excellent surgical exposure with the advantage of no facial incisions. To access tumors that are invading the pterygopalatine and infratemporal fossae, removal of the posterior wall of the maxillary sinus may be necessary; the tumor is then peeled off the endosteum of the anterior skull base. The management of tumors with intracranial extension continues to be debated. A combined otolaryngology/neurosurgical approach is recommended in such cases; extension into the middle cranial fossa should be resected in continuity with the nasopharyngeal component, which is approached from below in a separate operative field. Radiation therapy is used in the past for tumors with extensive intracranial extension, but it is no longer recommended due to the concern for radiation-induced malignancies. Interferon is used in select cases that are not amenable to surgical resection or have extensive intracranial involvement. The likelihood of local control after surgery varies with tumor extent and the procedure that is performed. Recurrence does not appear to be increased in the endoscopic approach, although studies are limited by the length of follow-up and criteria for selection in the endoscopic group.18 Pyogenic granulomas are acquired benign, vascular tumors of unknown etiology that are uncommon in children. They arise in response to a variety of stimuli, including minor trauma, chronic irritation, growth factors, and hormonal influences. They rapidly appear and are discrete, bright red, and often very friable with a tendency to bleed. In children, they are often mistaken for hemangiomas, both clinically and histologically. Pyogenic granulomas are characterized histologically by a lobular capillary arrangement within a fibromyxomatous stroma. As a result, they have been given the misleading term “lobular capillary hemangioma.”19 Although spontaneous involution has been reported, the majority of pyogenic granulomas require removal by cautery, curettage, shave excision, laser, or surgical excision. Surgical excision is recommended in children as it has the lowest rate of recurrence and provides a specimen to rule out more serious diagnoses.

Muscular Tumors Leiomyomas are benign myogenic tumors that may develop wherever smooth muscle is present. Histologically they are distinguished into solid leiomyoma, angiomyoma, and epithelioid leiomyoma. They are extremely rare in children.

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Solid leiomyomas are typically found in the buccal mucosa and esophageal smooth muscle. They can be associated with Alport’s syndrome.20 Angiomyomas are composed of mature smooth muscle cells and numerous blood vessels. In the head and neck, they occur primarily in the larynx and nasal turbinates, and in addition, in the oral cavity (lip, hard palate, and tonsil), nose, ear, cheek, parotid gland, and submandibular region. In the oropharynx, they typically occur in or on the tongue, presenting as a slowly enlarging, painless nodule, which may eventually reach a couple of centimeters in size. In most cases, leiomyoma and angiomyoma can be completely treated by simple resection. Histologically it is important to differentiate angiomyoma from angiosarcoma and vascular leiomyosarcoma. Rhabdomyomas are rare benign tumors arising from striated muscle. They are divided topographically into cardiac and extracardiac. Extracardiac rhabdomyomas are classified into three subtypes: adult, fetal, and genital type. The head and neck region is the principle site of involvement in 95% of cases of extracardiac rhabdomyomas.21 Fetal rhabdomyomas, which are thought to arise from fetal rests, are the least common of all rhabdomyomas types. They usually present as a solitary mass in male infants less than 3 years of age. Presenting symptoms are related to their site and may include feeding difficulties, hoarseness, or respiratory distress.22 Classic and intermediate variants exist. The classic type, described only during the first year of life, is usually found in the preauricular and postauricular regions as a well-circumscribed mass. The intermediate type tends to occur in mucosal sites, such as the tongue, nasopharynx and larynx, and the soft tissue of the neck. Diagnosis is made histologically via core biopsy (under radiographic guidance), open biopsy, or excisional biopsy of the lesion. Fetal rhabdomyomas do not usually invade adjacent tissue. Rhabdomyomas appear as well-defined homogenous masses on CT with contrast. On T2-weighted MRI, the lesion is hyperintense. Cytological features of rhabdomyomas include cohesive clusters of spindle cells and rhabdomyoblasts with abundant eosinophilic granular cytoplasm, often peripherally located nuclei, cross-striations, elongated intracytoplasmic inclusions, and absence of mitotic figures. On immunohistochemistry they express desmin, muscle-specific actin, and myoglobin. These findings are important to distinguish rhabdomyomas from rhabdomyosarcomas. Complete excision of a rhabdomyoma is usually curative. Metastases are rare. Recurrence is associated with incomplete resection; however, rhabdomyosarcoma must be carefully excluded in all cases of recurrence.23 Chemotherapy and radiotherapy do not have a role to play in the treatment of rhabdomyomas.

Salivary Gland Tumors Salivary gland tumors can arise from any of the major or minor salivary glands. The most common benign tumor of

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salivary glands in children is a pleomorphic adenoma. A study by Luna et al.,24 based on data of six centers comprising 9823 patients, showed that 3.3% of all salivary neoplasms were found in persons younger than 16 years, with 79% localized in the parotid gland and a predominance of pleomorphic adenomas in 60%. Pleomorphic adenomas appear as wellcircumscribed hypointense tumors on CT (Fig. 107-5A). On T2-weighted MRI, they are homogeneously hyperintense, and the relationship of the tumor to the deep and superficial lobes of the gland can be clearly identified (Fig. 107-5B). The majority of pleomorphic adenomas are located in the superficial lobe of the parotid. Superficial parotidectomy with preservation of the facial nerve is indicated (Fig. 107-5C and D). The tumor is removed intact with a cuff of tissue around it to prevent recurrence. Facial nerve monitoring should be used during the surgery. Enucleation is not recommended as it can result in tumor spillage, increasing recurrence rates, and

can also lead to damage of the facial. Pleomorphic adenomas located in the deep lobe are removed in a similar fashion.

Tumors of Mesenchymal Tissue Lipomas are the most common tumor of mesenchymal cell origin. They are rare in children and present as nontender, slowly enlarging soft lobulated subcutaneous masses (Fig. 107-6A and B). Lipomas appear hyperintense on T2-weighted MRI (Fig. 107-6D). Treatment is complete surgical excision. Recurrence is very rare. Histologically, it is important to distinguish lipoma from liposarcoma, specifically pleomorphic lipoma and spindle cell lipoma, which can have similar histological characteristics to liposarcoma. Multiple cutaneous lipomas in a child should alert one to a rare autosomal disorder known as Bannayan–Riley–Ruvalcaba syndrome.25 This condition is characterized by cutaneous

FIGURE 107-5. Pleomorphic adenoma. (A) Axial CT scan showing a hypointense lobular tumor with circumscribed borders in the left parotid. (B) Axial T2-weighted MRI showing a homogenous hyperintense tumor with evidence of compression of the deep lobe of the parotid gland. (C) The tumor was resected completely, in the operative field. (D) The main trunk and branches of the facial nerve were dissected and preserved during tumor resection.

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CHAPTER 107 ❖ Benign Tumors of the Head and Neck 1799

FIGURE 107-6. Lipoma. (A) and (B) A soft nontender tumor in the posterolateral neck of an 18-month-old boy. (C) Axial T1-weighted MRI scan showing a hyperintense tumor.

lipomas, macrocephaly, intestinal polyps, and developmental delay, and is associated with PTEN gene mutations. Myxomas are rare, locally infiltrative, benign, connective tissue tumors that are found in bone and somatic soft tissues. These tumors most frequently occur in the myocardium. In the head and neck region, the most commonly affected sites are the maxilla and mandible; however, myxomas have also been reported in the tongue, nose, cheek, neck musculature, pharynx, larynx, and parotid gland. Nevertheless, myxoma is a very uncommon lesion of the midface, particularly in the pediatric population; 8% of myxomas occurred in children less than 16 years of age.26 Most myxomas are asymptomatic. Tumors in the maxilla may grow undetected for a considerable duration as they expand silently into the maxillary sinus. Midfacial myxoma most commonly presents as a slowly growing, painless mass of the mandible or maxilla. Symptoms and signs of nasal obstruction, malocclusion, tooth instability, pain, and diplopia herald advanced disease. A delay in diagnosis often occurs with an average of one to five years between disease onset and clinical presentation.27 On CT, myxomas have a variable appearance but typically demonstrate a multilocular radiolucency with well-defined margins. Myxomas present great difficulties in management because of their tendency to recur. Treatment of choice is complete surgical resection with negative margins. Recurrence occurs in approximately 33% of cases and has been reported 15 years after initial surgery.28 Careful long-term follow-up is essential to aid in early detection of recurrent lesions.

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Pilomatrixomas, also called calcifying epitheliomas of Malherbe, are rare benign tumors arising from hair follicle matrix cells. They are more common in children and young adults; 40% of patients are under 10 years of age. Females have a higher incidence.29 Pilomatrixoma usually occur as a single neoplasm, but familial and multiple cases have been reported. Associations with myotonic dystrophy, Turner syndrome, Gardner syndrome, and Rubinstein–Taybi syndrome have been reported.30–33 The characteristic cytologic feature of pilomatrixomas include the presence of calcium deposits and varying amounts of basaloid and pathognomonic ghost cells. Sixty percent of pilomatrixomas occur in the head and neck, and over 20% of cases occur in the cheek region.34 Other sites include the preauricular region, neck, periorbital region, and scalp. Pilomatrixomas frequently mimic of salivary gland lesions and are commonly misdiagnosed. They present as nontender, slow-growing, rock-hard subcutaneous masses, which are typically adherent to the skin but not fixed to the underlying tissue (Fig. 107-7A). As they grow more superficial, a blue hue may be noted in the overlying epidermis, which occasionally may become ulcerated. Diagnosis is usually made on the basis of history and clinical examination alone. CT imaging demonstrates intralesional calcification and can also help to assess the depth of tissue involvement (Fig. 107-7B). Although there is no evidence that pilomatrixomas undergo malignant transformation, they do not spontaneously regress, and surgical excision is recommended29 (Fig. 107-7C). Recurrence is rare with complete excision.

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SECTION 6 ❖ The Head and Neck

FIGURE 107-7. Pilomatrixoma. (A) A pilomatrixoma in the preauricular region of a 3-year-old girl. Note the lesion is adherent to the overlying skin and the bluish hue. (B) Axial CT scan demonstrates a well-circumscribed lesion in the left preauricular region, not involving the parotid gland. The intralesional calcifications are characteristic of pilomatrixoma. (C) The resected tumor, 2 cm in size.

Hamartomas are benign lesions resulting from an abnormal growth of tissue, which is native to its site, but grows in a disorganized mass. They can be found on the neck, face, ears, and oral cavity, and are very uncommon in young children. They are usually asymptomatic but can cause disfigurement due to their location. They rarely invade or compress surrounding structures significantly. In Cowden’s disease, hamartomas are found at multiple body sites.35 Complete surgical excision is recommended. Recurrence is rare. Chordomas arise from notochord remnants. They typically present as skull base neoplasms. Extranotochordal chordomas presenting as neck masses have been reported but are extremely rare.

Fibrous Tumors Infantile myofibromatosis (IM) is classically described in children younger than 2 years. It is the most common fibrous tumor of infancy, characterized by proliferation of myofibroblastic cells. Two-thirds of patients have lesions present at birth. Eighty percent of patients have a solitary lesion involving skin, muscle, viscera, or bone; however, lesions can also be multicentric, scattered throughout the body. Fifty percent of lesions occur in the head and neck: infratemporal fossa, skull base, tongue base, and neck.36 Both multicentric and solitary lesions can be inherited as an autosomal dominant or recessive disorder with variable penetrance. The morbidity of IM is entirely dependent on the site of the lesion. They can often show rapid growth, local invasion, spontaneous necrosis, and regression. Because of this, they are often mistaken for malignant lesions. As a minimum, biopsy is recommended for diagnosis.

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Treatment of IM is controversial. The treatment of choice is complete surgical excision; however, because of the possibility of spontaneous regression and low recurrence rate, some recommend conservative surgery or no management at all.36 The prognosis following complete surgical resection is excellent. Chemotherapy has been used in unresectable lesions causing significant morbidity. Desmoid tumors or musculoaponeurotic fibromatosis are benign fibrous neoplasms of spindle-shaped fibroblasts and collagen that infiltrates muscle and can become adherent to surrounding structures. The term desmoid means “tendon-like.” Desmoids are rare, accounting for only 0.03% of all neoplasms. Head and neck desmoids have been shown to constitute 12%–15% of all desmoids throughout the body. Twenty-five percent of all desmoid tumors occur in children under 15 years of age.37 The etiology of desmoid tumors remains unclear; a genetic defect in the regulation of connective tissue growth, trauma, and pregnancy have been proposed as causes. When present in patients with Gardner syndrome and familial adenomatous polyposis, the prevalence of desmoids increases to 13%.37,38 Despite their nonmetastatic nature, these tumors present a great challenge to their management. No clear consensus for the most appropriate clinical management of the pediatric desmoid tumors exists. Although spontaneous regression has been reported, desmoids tumors can be generally locally aggressive and have tendency to recur. Complete surgical resection with clear margins is the primary treatment modality, which can be often difficult as the tumor may encase major vessels and nerves. Adjuvant chemotherapy and/or radiotherapy have been used, although results are not consistent. It is

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CHAPTER 107 ❖ Benign Tumors of the Head and Neck 1801 important to differentiate desmoid tumors histologically from fibrosarcomas. Benign fibrous histiocytomas are very rare tumors in children. They are characterized by proliferation of both fibroblasts and histiocytes. They typically present as slowgrowing, painless noninvasive masses in the cervical region. Surgical excision is recommended.

References 1. Riccardi VM. VonRecklinghausen neurofibromatosis. N Engl J Med. 1981;305:1617–1627. 2. Khanna G, Sato Y, Smith RJ, Bauman NM, Nerad J. Causes of facial swelling in pediatric patients: correlation of clinical and radiologic findings. Radiographics. 2006;26:157–171. 3. Neville H, Corpron C, Blakely ML, Andrassy R. Pediatric neurofibrosarcoma. J Pediatr Surg. 2003;38(3):343–346; discussion 343–346. 4. Robson CD. Imaging of head and neck neoplasms in children. Pediatr Radiol. 2010;40(4):499–509. 5. Wise JB, Patel SG, Shah JP. Management issues in massive pediatric facial plexiform neurofibroma with neurofibromatosis type 1. Head Neck. 2002;24:207–211. 6. Needle MN, Cnaan A, Dattilo J, et al. Prognostic signs in the surgical management of plexiform neurofibroma: the Children’s Hospital of Philadelphia experience, 1974–1994. J Pediatr. 1997;131:678–682. 7. Benz MR, Czernin J, Dry SM, et al. Quantitative F18-fluorodeoxyglucose positron emission tomography accurately characterizes peripheral nerve sheath tumors as malignant or benign. Cancer. 2010;116(2):451–458. 8. de Campora E, Radici M, de Campora L. Neurogenic tumors of the head and neck in children. Int J Pediatr Otorhinolaryngol. 1999;49(suppl 1):S231–S233. 9. Evans GR, Lloyd SK, Ramsden RT. Neurofibromatosis type 2. Adv Otorhinolaryngol. 2011;70:91–98. 10. Georgiadis GS, Lazarides MK, Tsalkidis A, Argyropoulou P, Giatromanolaki A. Carotid body tumor in a 13-year-old child: case report and review of the literature. J Vasc Surg. 2008;47(4):874–880. 11. Shamblin WR, ReMine WH, Sheps SG, Harrison EG Jr. Carotid body tumor (chemodectoma). Clinicopathologic analysis of ninety cases. Am J Surg. 1971;122(6):732–739. 12. Fennessy BG, Kozakewich HP, Silvera M, et al. The presentation and management of multiple paraganglioma in head and neck. Ir J Med Sci. 2011;180(3):757–760. 13. Zaupa P, Höllwarth ME. Carotid body paraganglioma: rare tumor in a 15-year-old adolescent boy. J Pediatr Surg. 2007;42(4):E13–E17. 14. Patetsios P, Gable DR, Garrett WV. Management of carotid body paragangliomas and review of a 30-year experience. Ann Vasc Surg. 2002;16(3):331–338. 15. Coutinho-Camillo CM, Brentani MM, Nagai MA. Genetic alterations in juvenile nasopharyngeal angiofibromas. Head Neck. 2008;30(3):390–400. 16. Mendenhall WM, Werning JW, Hinerman RW, Amdur RJ, Villaret DB. Juvenile nasopharyngeal angiofibroma. J HK Coll Radiol. 2003;6:15–19. 17. Radkowski D, McGill T, Healy GB, Ohlms L, Jones DT. Angiofibroma. Changes in staging and treatment. Arch Otolaryngol Head Neck Surg. 1996;122:122–129.

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18. Huang J, Sacks R, Forer M. Endoscopic resection of juvenile nasopharyngeal angiofibroma. Ann Otol Rhinol Laryngol. 2009;118(11):764–768. 19. Mills SE, Cooper PH, Fechner RE. Lobular capillary hemangioma: the underlying lesion of pyogenic granuloma. A study of 73 cases from the oral and nasal mucous membranes. Am J Surg Pathol. 1980;4:470–479. 20. Uliana V, Marcocci E, Mucciolo M, et al. Alport syndrome and leiomyomatosis: the first deletion extending beyond COL4A6 intron 2. Pediatr Nephrol. 2011;26(5):717–724. 21. Helliwell TR, Sissons MC, Stoney PJ, Ashworth MT. Immunochemistry and electron microscopy of head and neck rhabdomyoma. J Clin Pathol. 1988;41(10):1058–1063. 22. Cacciari A, Predieri B, Mordenti M, et al. Rhabdomyoma of a rare type in a child: case report and literature review. Eur J Pediatr Surg. 2001;11:66–68. 23. Valdez TA, Desai U, Volk MS. Recurrent fetal rhabdomyoma of the head and neck. Int J Pediatr Otorhinolaryngol. 2006;70(6):1115–1118. 24. Luna MA, Batsakis JG, el-Naggar AK. Salivary gland tumors in children. Ann Otol Rhinol Laryngol. 1991;100:869. 25. Buisson P, Leclair MD, Jacquemont S, et al. Cutaneous lipoma in children: 5 cases with Bannayan-Riley-Ruvalcaba syndrome. J Pediatr Surg. 2006;41:1601–1603. 26. KeszlerA, Dominguez FV, Giannunzio G. Myxoma in childhood: an analysis of 10 cases. J. Oral Maxillofac Surg. 1995;53:518–521. 27. Stout AP. Myxoma: the tumor of primitive mesenchyme. Ann Surg. 1948;127:706–719. 28. Wachter BG, Steinberg MJ, Darrow DH, McGinn JD, Park AH. Odontogenic myxoma of the maxilla: a report of two pediatric cases. Int J Pediatr Otorhinolaryngol. 2003;67(4):389–393. 29. Yencha MW. Head and neck pilomatricoma in the pediatric age group: a retrospective study and literature review. Int J Pediatr Otorhinolaryngol. 2001;57:123–128. 30. Geh JL, Moss AL. Multiple pilomatrixomata and myotonic dystrophy: a familial association. Br J Plast Surg. 1999;52:143–145. 31. Noguchi H, Kayashima K, Nishiyama S, Ono T. Two cases of pilomatrixoma in Turner’s syndrome. Dermatology. 1999;199:338–340. 32. Pujol RM, Casanova JM, Egido R, Pujol J, de Moragas JM. Multiple familial pilomatricomas: a cutaneous marker for Gardner syndrome? Pediatr Dermatol. 1995;12:331–335. 33. Cambiaghi S, Ermacora E, Brusasco A, Canzi L, Caputo R. Multiple pilomatricomas in Rubinstein-Taybi syndrome: a case report. Pediatr Dermatol. 1994;11:21–25. 34. Agarwal RP, Handler SD, Matthews MR, Carpentieri D. Pilomatrixoma of the head and neck in children. Otolaryngol Head Neck Surg. 2001;125:510–515. 35. Eng C. Genetics of Cowden syndrome: through the looking glass of oncology. Int J Oncol. 1998;12(3):701–710. 36. Beck JC, Devaney KO, Weatherly RA, Koopmann CF Jr, Lesperance MM. Pediatric myofibromatosis of the head and neck. Arch Otolaryngol Head Neck Surg. 1999;125(1):39–44. 37. Zampieri N, Cecchetto M, Zorzi MG, Pietrobelli A, Ottolenghi A, Camoglio F. An unusual case of extra-abdominal desmoid tumour. Eur J Cancer Care (Engl). 2010;19(3):410–412. 38. Sinno H, Zadeh T. Desmoid tumors of the pediatric mandible: case report and review. Ann Plast Surg. 2009;62(2): 213–219.

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108 C H A P T E R

M

Malignant Tumors of the Head and Neck Kenneth R. Whittemore Jr. and Michael J. Cunningham

alignant neoplasms rank second only to trauma as a cause of mortality in children 1–14 years of age.1 The incidence of head and neck malignancies among children, based upon the National Cancer Institute’s Surveillance, Epidemiology and End Results tumor database, appears to be increasing, reflective of a greater rate of childhood cancer in general.2 Estimates as to the percentage of primary malignant tumors in children originating in the head and neck vary from 5% to 12%, depending upon whether retinoblastoma is included.2,3 This figure increases to approximately 50% in infants inclusive of retinoblastoma.4 It has been stated that one of every four malignancies in the pediatric age group eventually involves the head and neck region.5 Three extensive reviews of head and neck malignancies in the pediatric population have been published in the past 25 years.2,5,6 Tumor pathologic characteristics from one of these series are listed in Table 108-1. The most striking observation made is the rarity of epidermoid carcinoma in children in comparison with adults. Lymphomas, both Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), are the predominant neoplasms of the head and neck region. Soft tissue sarcomas, specifically rhabdomyosarcomas, are the next most common, whereas skeletal sarcomas are comparatively rare. Thyroid carcinomas and, to a lesser degree, salivary gland malignancies are also common, with papillary carcinoma and mucoepidermoid carcinoma being the most prevalent in each gland, respectively. Nasopharyngeal squamous cell carcinoma (SCC) is the principal epithelial malignancy; melanoma and other skin cancers are rare. Neurogenic and germ cell neoplasms may occur as either primary or metastatic cervicofacial lesions. Childhood cancer incidence rates vary significantly according to age, gender, race, ethnicity and geography; this is true of malignancies within the head and neck region as well.2,7 Age-specific presentation patterns are listed in Table 108-2. Malignant teratomas are primarily congenital lesions. Neuroblastomas tend to occur in infants. Sarcomatous neoplasms span the entire pediatric age range, with the majority of rhabdomyosarcomas occurring in the preschool years. The NHLs likewise demonstrate a broad age range, predominantly clustered slightly later in childhood during the school-age years. HL usually occurs in early adolescence and rarely in children younger than 5 years of age. Thyroid carcinoma, nasopharyngeal carcinoma (NPC), and salivary gland neoplasms also occur predominantly in adolescents. Thyroid carcinoma is far more prevalent in girls, whereas HL and NHL demonstrate a slight male predilection.2,6

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The survival rate of children with head and neck cancer, particularly those with lymphoma and sarcoma, has improved significantly over the last 30 years (Table 108-3).1 This improvement can be attributed to a combination of earlier disease recognition, the evolution of coherent and aggressive clinicopathologic staging systems, the establishment of multimodality treatment protocols, and the improvement in craniofacial resection techniques for previously unresectable neoplasms. Early recognition requires knowledge of those historical factors known or strongly suspected to increase the risk of malignancy in a child. Examples of such include a family history of childhood cancer, a previous primary neoplasm, a known systemic cancer predisposition, and exposure to radiation therapy or to carcinogenic or immunosuppressive drugs.8–10 The most common manifestation of a malignancy of the head and neck in the pediatric age group is an asymptomatic mass. The neck is the most common anatomic presentation site (Table 108-4). The oropharynx and nasopharynx, orbit and paranasal sinuses, salivary glands, face and scalp, and auricular region follow in descending order of frequency. Early signs and symptoms such as lymphadenopathy, otalgia, otorrhea, rhinorrhea, nasal obstruction, and headache are also common to the benign illnesses affecting this age group. More recognizable symptoms heralding upper aerodigestive tract compromise include voice change, hoarseness, stridor, dysphagia, and hemoptysis. These typically occur late in the course of malignant disease. Clinical factors that increase the risk that a mass may be malignant include onset in the neonatal period, history of rapid or progressive growth, skin ulceration, fixation to underlying structures, or a firm mass greater than 3 cm in diameter.11 Despite the comparatively high frequency of reactive cervical lymphadenopathy, congenital lesions, and benign neoplasms in the pediatric age group, a firm neck mass in a child without the usual signs of inflammation should be considered possibly malignant until proven otherwise. A child suspected of having a malignancy in the head and neck region requires a complete otolaryngologic and systemic evaluation. Particular attention during the physical examination should be directed at the abdominal, axillary, and inguinal areas owing to the frequency with which head and neck malignancy is part of a generalized process involving these regions. Otologic, nasal, oral, and neck examinations are easily performed in most children. Visualization of the nasopharynx, hypopharynx, and larynx

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SECTION 6 ❖ The Head and Neck

TAblE 108-1. Pediatric Head and Neck Malignanciesa Number of Malignancies Pathologic Diagnosis

Total

boys

Girls

Mean Age (yr)

Acinar cell carcinoma

36

16

20

Adenocarcinoma

34

14

20

13.4

8

2

6

14.1

18

6

12

2.9

Adenoid cystic carcinoma Germ cell neoplasms Lymphoma

14.3

816

504

312

12.6

Hodgkin lymphoma

515

285

230

13.8

Non-Hodgkin lymphoma

301

219

82

10.5

Melanoma

32

73

59

13.8

Mucoepidermoid carcinoma

82

31

51

13.6

Neural malignancies

706

351

355

2.3

Neuroblastoma

48

17

31

2.7

Retinoblastoma

497

247

250

1.4

Other neural malignancies

161

87

74

5.9

62

35

27

11.9

Osteosarcoma

21

11

10

12.5

Chondrosarcoma

13

7

6

12.5

Ewing sarcoma

20

12

8

10.5

Skeletal sarcomas

Other skeletal sarcomas Soft tissue sarcomas Rhabdomyosarcoma (RMS) Parameningeal RMS

8

5

3

12.9

366

191

175

8.5

239

125

114

7.4

67

28

39

8.0

Nonparameningeal RMS

172

97

75

7.2

Non-RMS soft tissue sarcomas

127

66

61

10.5

54

36

18

13.4

Squamous cell carcinoma Thyroid carcinoma

652

131

521

15.3

Follicular

69

13

56

15.3

Medullary

46

19

27

12.5

537

99

438

15.5

84

42

42

14.3

3050

1432

1618

10.4

Papillary Other malignancies Total

National Cancer Institute Seer Tumor Database (1973–1996): National Cancer Institute’s Surveillance, Epidemiology and End Results tumor registry.

a

Source: From Albright et al.2

may be accomplished by flexible fiberoptic nasopharyngoscopy in children of all ages. Laryngoscopy and pharyngoscopy under general anesthesia are required for those children who cannot be examined satisfactorily in the outpatient setting. Axial and coronal computed tomography (CT) and magnetic resonance imaging (MRI) are the radiologic

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studies of choice in evaluating suspected neoplasms of the head and neck.12 CT can help differentiate between solid and cystic masses; it also allows documentation of bone erosion, invasion of contiguous structures, and intracranial extension. The advantages of MRI include better contrast of tissues of similar densities, better delineation of neoplasms from surrounding soft tissue structures, the ability

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CHAPTER 108 ❖ Malignant Tumors of the Head and Neck TAblE 108-2. Age Distribution of 411 Children With Head and Neck Malignancies Average Age (yr)

Age Range (yr)

— 1.9 6.4 8.0 8.1 11.8 12.4 14.4 15.2

NB NB–5 NB–17 2–18 NB–18 4–19 6–18 9–18 7–8

Malignant teratoma Neuroblastoma Rhabdomyosarcoma Non-Hodgkin lymphoma Other sarcomas Hodgkin lymphoma Thyroid carcinoma Nasopharyngeal carcinoma Salivary gland malignancies Abbreviation: NB, newborn. Source: From Cunningham et al.368

TAblE 108-3. Trends in Five-Year Relative Survival Rates2 (%) for Children Under Age 15, United States (1975–2003) Site All sites Acute lymphocytic leukemia Acute myeloid leukemia Bone and joint Brain and other nervous system Hodgkin lymphoma Neuroblastoma Non-Hodgkin lymphoma Soft tissue Wilms’ tumor

1975– 1977

1978– 1980

1981– 1983

1984– 1986

1987– 1989

1990– 1992

1993– 1995

1996– 2003

58 58 19 51 57 81 52 43 61 73

63 66 26 49 58 88 57 53 75 79

67 71 27 57 56 88 55 67 69 87

68 73 31 59 62 91 52 70 74 91

71 78 37 67 64 87 62 71 65 92

76 83 41 67 64 97 76 76 80 92

77 84 42 74 70 95 67 81 77 92

80 87 54 72 74 95 69 87 72 92

Survival rates are adjusted for normal life expectancy and are based on follow-up of patients through 2004.

a

Source: From Jemal et al.1

to obtain multiplanar images, and the avoidance of ionizing radiation or intravenous iodinated contrast material. The disadvantages of an MRI include prolonged imaging times with the need to keep children restrained and sometimes sedated, high sensitivity to motion, poor distinction of bone, and imaging prohibition resulting from the presence of metallic foreign bodies or implants. Radionuclide scan and uptake studies may be warranted in the evaluation of suspected thyroid neoplasms. Systemic neoplastic evaluation may require skeletal survey, bone scan, liver spleen scan, or intravenous pyelogram. Positron emission tomography (PET) has also recently been used to evaluate primary tumors, tumor response to treatment, and evidence of local disease recurrence.13 The primary goals of the radiologic assessment are to more precisely define the primary lesion and to detect metastatic disease for accurate clinical staging. Examination under general anesthesia complements radiographic studies in defining the extent of the primary tumor and allowing for adequate tissue sampling for

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histopathologic diagnosis. Biopsy of pharyngeal and laryngeal lesions is performed under direct visualization at the time of operative examination. Biopsy of external head and neck lesions is done in either an excisional or incisional fashion, depending on the size and location of the mass. An excisional biopsy may be therapeutic and diagnostic. Fineneedle aspiration (FNA) for cytologic study is useful in the assessment of suspected thyroid gland lesions, salivary gland lesions, and additional selected neck masses.14–17 The reliability of FNA is highly dependent on the expertise of the cytopathologist. The use of monoclonal antibody techniques and DNA amplification with polymerase chain reaction has improved the reliability, sensitivity, and specificity of making an accurate cytopathologic diagnosis.17,18 Nondiagnostic needle biopsies require open biopsy for confirmation if there is a high index of suspicion. Other histopathologic studies of potential benefit include bone marrow and cerebral spinal fluid evaluations, blood assays for tumor-produced substances such as α-feto protein and β-human chorionic gonadotropin in suspected germ cell tumors, and genetic testing for markers

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SECTION 6 ❖ The Head and Neck TAblE 108-4. Anatomic Locations of 411 Pediatric Head and Neck Malignancies Site

Pathologic Diagnosis

Subtotal No. Children

Neck Hodgkin lymphoma Non-Hodgkin lymphoma Thyroid carcinoma Neuroblastoma Rhabdomyosarcoma Other sarcomas Teratoma Parathyroid adenoma

70.0

71

17.0

21

5.0

14

3.0

10

2.5

6

1.5

3

1.0

33 18 18 2

Orbit/paranasal sinuses Rhabdomyosarcoma Chondrosarcoma

286 131 78 38 203 5 10 3 1

Oronasopharynx Non-Hodgkin lymphoma Nasopharyngeal carcinoma Rhabdomyosarcoma Fibrohistiocytoma

Total (%)

19 2

Parotid Mucoepidermoid carcinoma Non-Hodgkin lymphoma Adenocarcinoma Rhabdomyosarcoma

5 5 2 2

Facial region Rhabdomyosarcoma Synovial sarcoma Osteogenic sarcoma Chondrosarcoma Non-Hodgkin lymphoma

3 2 2 2 1

Ear/temporal bone Rhabdomyosarcoma Squamous cell carcinoma

5 1

Tongue Mucoepidermoid carcinoma Adenocarcinoma Total

2 1 411

100

Fifteen neuroblastomas were likely cervical metastases from the abdomen.

a

Source: From Cunningham et al.368

such as n-mycin suspected neuroblastomas.19 Communication between the surgeon and the pathologist regarding the clinical presentation is essential for establishing the correct diagnosis.20 The treatment of malignant neoplasms of the head and neck in the pediatric age group is dictated by the histopathologic diagnosis and the extent or stage of the disease. Coordination of treatment often requires the interaction of many pediatric specialties and support services because most solid

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malignancies require multimodality therapy.19,21 Radiation therapy and multidrug chemotherapy are the two primary treatment modalities for the lymphoid and sarcomatous pediatric malignancies. Surgical resection is the primary treatment of glandular neoplasms and has a primary therapeutic role for mesenchymal tumors that are accessible to complete excision. Surgical biopsy is required for initial diagnostic purposes and sometimes for staging. Surgery may additionally be required for debulking and salvage procedures, airway maintenance,

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CHAPTER 108 ❖ Malignant Tumors of the Head and Neck follow-up endoscopic or operative examination purposes, and routine and specialized otolaryngologic care.

HODGKIN lYMPHOMA HL is a malignant neoplasm of the lymphoreticular system with a bimodal distribution; one peak occurs in adolescence and young adulthood, and another occurs at age older than 50 years. In contrast to NHL, HL is uncommon in preadolescent children and rarely occurs in children younger than 5 years of age.22,23 Although no definitive causal factors are known, there is an association between Epstein-Barr virus (EBV) infection and HL. Increased titers of EBV-induced antibodies have been documented in patients with HL, and there is an epidemiologically confirmed increased risk of developing HL following a confirmed bout of infectious mononucleosis.24,25 HL is distinguished histopathologically by the diagnostic presence of Reed–Sternberg (RS) cells admixed within the appropriate pleomorphic cellular background. Such RS cells are multinucleated with large nucleoli and a halo or clear zone around the nucleolus; although they represent the common malignant component of the diverse histologic subtypes of HL, their cellular origin remains an enigma.26 The most widely used HL classification system is the Rye classification system.27 The Rye classification system recognizes four HL subtypes based upon the cellular background: lymphocyte predominant, lymphocyte depletion, nodular sclerosis, and mixed cellularity. The lymphocyte predominant category is characterized by an abundance of mature lymphocytes with only occasional RS cells and most closely resembles reactive hyperplasia. The lymphocyte depletion group demonstrates few lymphocytes in association with an abundance of pleomorphic RS cells, disorderly fibrosis, or both. In the nodular sclerosis variant, broad bands of collagen divide the involved lymph node into cellular nodules. The cellular proliferation within these nodules is characterized by the presence of lacunar cells, variant RS cells with well-defined cellular borders surrounded by a clear space. In the mixed cellularity subtype, the lymph node is obliterated by a heterogeneous population of cells including lymphocytes, plasma cells, eosinophils, neutrophils, and frequent RS cells. Adolescent and young adult patients with HL are more likely to have nodular sclerosis disease at the time of presentation; lymphocyte predominant and mixed cellularity disease are relatively more common in children aged 10 years or younger; the mixed cellularity HL subtype has been particularly associated with human immunodeficiency virus (HIV) infection.26,28 Immunophenotypic analysis has shown heterogenous antigenic profiles on RS cells with no convincing evidence of RS cell-specific antigens.29 A combination of several markers including activation antigens, human leukocyte antigen–related molecules, T and B cell–associated antigens, and leukocyte common antigen is currently employed for the immunodiagnosis of HL in routine

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1807

pathology practice.30 Recognition that nodular lymphocyte predominant HL (NLPHL) differs both morphologically and immunophenotypically from the other classical subtypes of HL has led to an alternative pathologic classification, called the Revised European-American Lymphoma classification system, which divides HL into two broad categories: classical HL and NLPHL (Table 108-5).31,32 Further rationale for this classification system is documentation that NLPHL has different virologic features and is clinically less aggressive than classic HL.26 HL arises within lymph nodes in more than 90% of childhood, adolescent, and young adult cases.33,34 The typical patient with HL has asymmetric lymphadenopathy that is firm, rubbery, and nontender. The cervical, supraclavicular, and mediastinal lymph nodes are the most frequent sites of presentation. Mediastinal node involvement has been particularly associated with right supraclavicular nodal disease. Obstruction of the superior vena cava or tracheobronchial tree may occur as a complication of mediastinal lymphadenopathy. Axillary, inguinal, and generalized lymphadenopathy are uncommon. Extranodal primary sites, including Waldeyer’s ring, are rare. Extranodal involvement does occur with disease progression; the spleen, liver, lung, bone, and bone marrow being the common organ systems affected. At presentation, children with HL have nonspecific systemic symptoms, termed B-symptoms, in 25%–30% of cases; these may include unexplained fever, night sweats, weight loss, weakness, anorexia, and pruritus.25 The diagnosis of HL is made by lymph node biopsy. An excisional nodal biopsy, preferably with the capsule intact, is ideal. Once the diagnosis is established, it is essential to define the full extent of disease in each patient before TAblE 108-5. Revised European-American Lymphoma (REAL) Classification System— Morphologic, Immunophenotypic, and Virologic Feautres of NLPHL Hodgkin Disease Versus Classic HD

NlPHl

Diagnostic RS or lacunar cells CD15 CD30 CD20 CD45 EMA EBV (in large cells)

“Classical” Hodgkin lymphomaa

Rare to absent

Present

Negative Usually negative Usually positive Positive Positive Usually negative

Positive Positive Usually negative Usually negative Negative Often positive (20%–70%)

Abbreviations: RS, Reed-Sternberg; EMA, epithelial membrane antigen; EBV, Epstein-Barr Virus; NLPHL, nodular lymphocyte predominant Hodgkin lymphoma. a Subtypes of classical Hodgkin lymphoma: nodular sclerosis, mixed cellularity, and lymphocyte depletion

Source: Adapted from Carbone et al.26

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SECTION 6 ❖ The Head and Neck

instituting specific treatment. The Ann Arbor staging system (Table 108-6) is used to stratify risk for patients with HL. This staging system is based on the premise that HL arises in a unifocal lymph node site, spreads via lymphatics to contiguous lymph node groups, and involves extralymphatic sites, including the spleen, principally by hematogenous dissemination.35 The system recognizes that localized extralymphatic spread may occur and that such patients do as well as comparable patients of the same stage without local extralymphoidal disease. Such involvement is denoted by the letter E after the stage designation. Constitutional symptoms of unexplained fever, night sweats, and weight loss are also considered significant in the staging of the disease and are designated A when absent and B when present. The staging of patients with HL has historically consisted of a combination of clinical and surgical staging. Clinical staging is based upon history, physical examination, radiologic procedures, and laboratory tests. The gold standard of surgical staging has been laparotomy.36 The current quality of imaging techniques, however, as well as the more routine use of systemic chemotherapy for early stage disease, has lessened the need for surgical staging. CT, MRI, and 2-[F-18]–fluoro-2-deoxy-d-glucose PET provide anatomic and physiologic data rivaling that obtained from staging laparotomy.37–40 Bone marrow aspirate and biopsy remains necessary for patients with clinical stage III or IV disease and for patients of any stage with B-symptoms.25 TAblE 108-6. Ann Arbor Staging Classification of Hodgkin Diseasea

Stage

Definition

I

Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE)

II

Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (IIE). An optional recommendation is that the numbers of node regions involved be indicated by a subscript (e.g., II3)

III

Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIS), or both (IIISE).

IV

Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement. The reason for classifying the patient as stage IV should be identified further by defining site by symbols.

a Each stage is subdivided into A and B categories indicating the absence or presence, respectively, of documented unexplained fever, night sweats, or weight loss (>10% of body weight in the prior six months).

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The treatment of HL varies according to stage. In children, the trend is to treat in multimodality fashion so as to reduce the morbidity and mortality associated with the higher doses of chemotherapy or radiation therapy required for single modality therapy. Stage IA and IIA disease is routinely treated with a combination of low-dose multiagent chemotherapy and radiation therapy to the involved field; the event-free survival rate in these patients is generally greater than 90%.25,36 Current efforts are directed at tailoring treatments to minimize morbidity while maintaining this excellent prognosis. One such potential area to reduce treatment morbidity is to hold adjuvant radiation therapy in stage IA and IIA patients who are complete responders after chemotherapy. Intermediate-risk patients include those with stage IIIA disease or stages I or II disease with B-symptoms, bulky disease, or spleen involvement. These patients require an increased number of cycles of chemotherapy and either increased dose or volume of radiation therapy.36 Total nodal irradiation had been the historical therapeutic choice for patients with stages IB and IIB disease; localized radiotherapy supplemented with chemotherapy, however, appears to offer the same therapeutic advantages of total nodal irradiation without the deleterious side effects.41 For patients with high-risk advanced stages IIIB and IV HL, multiagent chemotherapy alone or in combination with radiation therapy is used.36 The recent management of HL distinguishes between children who have obtained full growth and those who are still growing in an attempt to limit the high doses and extended fields of radiation therapy that cause considerable long-term morbidity for children and young adolescents. Similarly, chemotherapeutic regimens have been changed to reduce the risks of sterility, pulmonary toxicity, and secondary malignancies.25,42 Patients with HL who relapse may be candidates for autologous stem cell transplantation.43 With current treatments, greater than 90% of all patients with HL, regardless of stage, initially achieve a complete remission. Prolonged remission and cure is achieved in approximately 90% of patients with early stage I and II disease and in 35%–60% of patients with advanced stage III and IV disease.25,28,36 Histopathologic findings also have prognostic implications; patients with lymphocyte predominant lesions have the most favorable survival statistics, followed in prognostic order by the nodular sclerosis, mixed cellularity, and unfavorable lymphocyte depletion subtypes.28 The long-term survival of successfully treated patients with HL has resulted in additional problems. Older children and adolescents subjected to radiation therapy and chemotherapy have experienced growth arrest, hypothyroidism, sterility, and pulmonary fibrosis.25,42 Sepsis is a risk in patients after undergoing splenectomy or stem cell transplantation.43 All HL survivors, particularly those treated in multimodality fashion, are at risk for the development of second malignancies involving the lung, gastrointestinal tract, breast, and thyroid, as well as both acute lymphoblastic leukemia and NHL.44–47

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CHAPTER 108 ❖ Malignant Tumors of the Head and Neck

NON-HODGKIN lYMPHOMA NHL designates a heterogeneous group of solid primary neoplasms of the lymphoreticular system. In children, NHL most commonly occurs between the ages of 2 and 12 years and, as in HL, demonstrates a male predilection.48,49 Both congenital and acquired immunodeficiency disorders predispose to the development of NHL. Such disorders include common and combined variable immunodeficiency, ataxia-telangiectasia, Wiskott–Aldrich syndrome, X-linked lymphoproliferative disorder, immunosuppression for transplantation, and acquired immunodeficiency syndrome (AIDS).50–52 The classification of the NHLs has been both confusing and controversial. Older classification systems used the categories of lymphocytic lymphosarcoma, lymphoblastic lymphosarcoma, reticulum cell sarcoma, and follicular lymphoma. These terms were used to differentiate the lymphomas on a morphologic basis, with lymphosarcomas being small cell differentiated lymphomas, reticulum cell sarcomas being large cell undifferentiated lesions, and follicular lymphomas reflecting a nodular histological pattern recognized to have a more favorable prognostic significance.53 Rappaport and associates modified the older classification systems by recognizing the resemblance of malignant lymphoma cells to their benign lymphocytic or histiocytic counterparts.54 In the lymphocytic category, the importance of cellular differentiation was retained, as was the distinction between nodular and diffuse histological patterns. Categories were created to encompass lesions with more than one cell type and lesions whose cells appeared undifferentiated. Clinicopathologic studies demonstrated the Rappaport classification (Table 108-7) to be a useful guide to the management and prognosis of NHL.55 Subsequent advances in the development of immunologic markers for lymphocytic subtypes led to further changes in NHL classification. Immunophenotyping allowed separation of NHL into categories of B cell, T cell, and true histiocytic origins, and the B- and T-cell lymphomas were further subdivided based on their morphologic appearance and degree of lymphocytic transformation.56 A working formulation for clinical usage has been developed in which the NHLs are now grouped not only on a basis of their morphology and function but also according to their natural histories and responsiveness to therapy (Table 108-8).57 Such groupings clearly represent a spectrum of disease, and new subgroups arise that challenge current classification schema. Over 90% of children with NHL have high-grade disease consisting of one of three following types: small noncleaved cell lymphoma, large cell lymphoma, and lymphoblastic lymphoma.49 Small noncleaved cell lymphoma is of B-cell origin; lymphoblastic lymphoma is generally of T-cell origin; large cell lymphoma may express B- or T-cell markers or both.

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TAblE 108-7. Rappaport Classification Nodular • Lymphocytic, well differentiated • Lymphocytic, poorly differentiated • Mixed, lymphocytic and histiocytic • Histiocytic Diffuse • Lymphocytic, well differentiated • Lymphocytic, poorly differentiated • Mixed, lymphocytic and histiocytic • Histiocytic • Undifferentiated Others • Composite lymphoma • Immunoblastic lymphadenopathy • Non-Hodgkin’s lymphoma, unclassified • Non-Hodgkin’s lymphoma, material insufficient for subtype classification Source: Adapted from Ersboll et al.424

TAblE 108-8. Working Formulation Classification Low grade • Malignant lymphoma, small lymphocytic • Malignant lymphoma, follicular, predominantly small cleaved cell • Malignant lymphoma, follicular, mixed small cleaved and large cell Intermediate grade • Malignant lymphoma, follicular, predominantly small cleaved cell • Malignant lymphoma, diffuse, small cleaved cell • Malignant lymphoma, diffuse, mixed small and large cell • Malignant lymphoma, diffuse, large cell High grade • Malignant lymphoma, immunoblastic • Malignant lymphoma, lymphoblastic • Malignant lymphoma, small noncleaved cell Miscellaneous • Composite lymphoma • Mycosis fungoides • Histiocytic • Extramedullary • Unclassifiable Others • Immunoblastic lymphadenopathy • Non-Hodgkin’s lymphoma, material insufficient for subtype classification Source: Adapted from Ersboll et al.424

The clinical features of NHL reflect the site of origin of the primary tumor and the extent of local and systemic disease. Asymptomatic lymphadenopathy is the most common initial

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SECTION 6 ❖ The Head and Neck

presentation, with approximately 45% of patients found to have head and neck involvement at diagnosis.58,59 Inguinal, axillary, and generalized nodal presentations are comparatively less frequent. Nodal growth may be rapid, but insidious presentations more often occur. The more atypical presentations of NHL result from extranodal involvement. Such extranodal involvement occurs far more frequently in children than adults.49,60 Extranodal sites in the head and neck include Waldeyer’s ring of the oropharynx and nasopharynx, the nose and paranasal sinuses, the orbit, and the maxilla and mandible. The signs and symptoms attributable to extranodal cervicofacial NHL are quite variable and site specific; such may include facial swelling, epistaxis, nasal blockage, and other manifestations of upper airway obstruction, rhinorrhea, dysphagia, facial pain, and other neurologic findings including cranial nerve deficits or central nervous system (CNS) symptoms.58,59 Nasal–paranasal–oronasopharyngeal primary sites account for between 60% and 90% of extranodal head and neck NHL and appear to be at a greater risk for secondary CNS involvement.61,62 Furthermore, the early detection of NHL involving Waldeyer’s ring may be difficult because it may mimic benign adenotonsillar hypertrophy. A biopsy through adenoidectomy or tonsillectomy may be warranted if there is asymmetry, discoloration, or evidence of systemic symptoms.63,64 Childhood NHL additionally differs from that in adults in that it has a diffuse rather than a nodular histological presentation, a greater likelihood of being composed of prognostically unfavorable cell types as mentioned above, and a tendency toward leukemic transformation and hematogenous dissemination in addition to CNS involvement.49,60 Constitutional signs and symptoms that correlate with advanced disease include fever, weight loss, malaise, pancytopenia resulting from bone marrow infiltration, and neurologic manifestations. The Ann Arbor staging classification for HL (Table 108-6) is often still applied to patients with NHL.65 Alternatively the St. Jude’s classification system (Table 108-9)66 has been utilized. The St. Jude’s classification system attempts to account for the characteristic extranodal presentations and tendency toward hematogenous dissemination, bone involvement, and CNS involvement in childhood NHL.60,66,67 The clinical staging of NHL of the head and neck requires a comprehensive history and physical examination, serologic testing such as a complete blood count and lactate dehydrogenase level, chest radiograph, skeletal survey or bone scan, bone marrow biopsy, and cerebrospinal fluid analysis in addition to appropriate head and neck imaging by means of typically CT and often MRI.62,68 Abdominal CT with contrast or ultrasound may be used to assess for mesenteric lymph node involvement. More recently, gallium-67 scanning and PET with 18-F-fluoro-2-deoxy-d-glucose have been used for disease staging and for following disease progression during treatment.69 Laparotomy is not a routine procedure in the staging of patients with NHL.

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TAblE 108-9. St. Jude’s Classification System Stage

Criteria for Extent of Disease

I

A single tumor (extranodal) or single anatomic area (nodal), with the exclusion of mediastinum or abdomen

II

A single tumor (extranodal) with regional node involvement Two or more nodal areas on the same side of the diaphragm Two single (extranodal) tumors with or without regional node involvement on the same side of the diaphragm A primary gastrointestinal tract tumor, usually in the ileocecal area, with or without involvement of associated mesenteric nodes only

III

Two single tumors (extranodal) on opposite sides of the diaphragm Two or more nodal areas above and below the diaphragm All the primary intrathoracic tumors (mediastinal, pleural, thymic) All extensive primary intraabdominal disease All paraspinal or epidural tumors, regardless of other tumor site(s)

IV

Any of the above with initial CNS and/or bone marrow involvement

Abbreviation: CNS, central nervous system.

The aim of staging and subsequent classification is to define disease extent and adapt treatment accordingly. Unfortunately none of the NHL classification uniformly take into account other factors shown to have prognostic importance, such as the maximum diameter of the largest tumor, immunologic characteristics of the lymphoma, specific extranodal sites of involvement, tumor proliferation rate, the patient’s performance status, and serum lactate dehydrogenase concentrations.48,70 The diagnosis of NHL requires biopsy; typically excisional biopsy for nodal disease and incisional biopsy for extranodal disease, unless adenotonsillectomy is indicated. Surgery plays little additional role in NHL treatment with the exceptions of surgical debulking in selected cases of aerodigestive tract compression or when reduction of tumor load may lower the risk of development of tumor lysis syndrome.70 The latter is particularly true for Burkitt lymphoma (BL). For the reasons previously outlined, stage I NHL is infrequently diagnosed in the pediatric age group; approximately 80% of children with NHL have advanced stage II, III, or IV disease.66,67 The principal treatment for near all stages of pediatric head and neck NHL is systemic chemotherapy; the rapid doubling time of high-grade NHL makes it very chemoresponsive.58,59 However, there are exceptions to this rule such as stage I follicular lymphoma.71,72 Radiation therapy has a limited role in the treatment of NHL. CNS prophylaxis

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CHAPTER 108 ❖ Malignant Tumors of the Head and Neck in children with high-grade NHL can be achieved with intrathecally administered chemotherapy alone. Treatment for relapse consists of high-dose chemotherapy; bone marrow transplantation may be considered.49 Both early and late complications can arise secondary to chemotherapy. Early complications are generally the result of the rapid lysis of tumor cells. The most significant longterm complications relate to the development of secondary malignancies. Current efforts in the treatment of NHL are directed at limiting chemotherapeutic exposure to that necessary to obtain excellent cure rates while attempting to reduce the incidence of such secondary malignancies.73 Prognosis is principally associated with disease stage and response to initial therapy. The current overall fiveyear disease-free survival rate for NHL of the head and neck approximates 70%–76%.58,59 The event-free survival rate for NHL irrespective of site of origin is 85%–95% for stage I and II disease and 50% to 85% for stage III and IV disease, respectively, depending on the histological type.49 The potential role of immunotherapy, given the observation that most childhood NHL is characterized by T- or B-cell differentiation, remains speculative.

bURKITT lYMPHOMA BL is a non-Hodgkin B-cell lymphoma that has distinct epidemiologic and clinical features.74,75 Epidemiologic differences separate BL into an endemic (previously termed African) and a nonendemic or sporadic (previously termed American) type. The limited geographic distribution of endemic BL suggests an infectious etiology, with serologic evidence supporting a role for the EBV. Almost all patients with endemic BL demonstrate high antibody titers to EBV determinant antigens, and 80%–90% of their tumor cells contain copies of the EBV DNA genome; in contrast, only 15%–20% of patients with the sporadic form of BL demonstrate this serologic and histopathologic EBV association.76 At the molecular level, BL is characterized by a c-myc proto-oncogene translocation. Colonization of B cells with EBV may optimize the likelihood for c-myc translocation events and malignant transformation.77 Furthermore, distinct translocation patterns appear to exist between endemic and sporadic BL, suggesting that sporadic or nonendemic BL derives from cells more advanced along the B cell differentiation pathway than those of the endemic variety. Histopathologically both variants of BL are characterized by small- to medium-sized monomorphic lymphoid cells with prominent basophilic cytoplasm. These cells are usually interspersed with scattered benign macrophages containing cellular debris from apoptotic neoplastic cells, yielding the classic “starry sky” appearance when examined under low magnification.78 Mitotic figures are typically abundant. Immunophenotypically, BL is a B cell lymphoma expressing cell surface immunoglobulins or B cell lineage markers.79

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BL is a disease almost exclusively afflicting children with a predilection for males.74,75 The clinical presentation characteristics of endemic BL, however, differ greatly from that of the sporadic form. Endemic BL is diagnosed at an average age of 9 years and characteristically occurs as a facial mass originating from the jaw.80,81 The maxilla is more frequently involved than the mandible. Loose dentition, facial distortion, trismus, and proptosis are common manifestations. Abdominal masses, when present, are typically of renal or gonadal origin. Splenic and lymph node involvement is rare. Sporadic BL, in contrast, is associated with slightly older children (average age 12 years) and usually presents in the abdomen; such abdominal lymphoma is usually of mesenteric lymph node or ileocecal origin.82 Approximately onequarter of sporadic BL cases involve the head and neck. Asymptomatic cervical lymph node enlargement is the most common presentation; jaw involvement as seen in endemic BL is comparatively rare. Waldeyer’s ring origin with nasopharyngeal, oropharyngeal, and parapharyngeal mass presentations has also been reported.83–85 Bone marrow involvement is more common in sporadic BL, and CNS involvement may potentially occur with comparative equal frequency in both endemic and sporadic forms.80,81 BL has rapid proliferative potential, and tumors may increase in size quickly. Rapid diagnosis, staging, and treatment are advocated. Staging work up is similar to that used in other NHLs, with perhaps even a greater emphasis on CT and MRI scanning in sporadic BL to localize and define head and neck masses. Gallium scans and lactate dehydrogenase levels are useful to quantitate tumor burden and to follow up patients serially.75,80 A distinct clinical staging system is used for BL (Table 108-10), based on the premise that the anatomic sites of predilection of BL do not conform readily to the conventional Ann Arbor NHL staging classification.75,82 The primary treatment modality for both endemic and sporadic BL is multidrug chemotherapy. Because of the high proliferative rate of BL and the abundance of cells in various stages of the cell cycle, successive chemotherapy cycles result in greater cytotoxicity than do traditional fixed dose regimens.86 Surgery has a limited role, principally for diagnostic biopsy purposes, in the management of BL. In endemic abdominal BL disease, however, the surgical reduction of tumor bulk has been shown to improve survival.81,87 A similar role for tumor debulking or resection of head and neck BL has not been defined. Three- and five-year event-free survival rates for both endemic and sporadic BL are 85%–95% for limited disease and 75%–85%, respectively, for advanced disease; relapse rates are lower and survival rates are significantly higher in patients with a smaller tumor burden at presentation.88 For localized disease limited to the head and neck, a 90% longterm survival is reported.73 Children younger than 12 years of age do significantly better than older patients, and high

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SECTION 6 ❖ The Head and Neck

TAblE 108-10. Clinical Staging Classification of Burkitt Lymphoma

Stage

Extent of Tumor

I

Single tumor mass (extra abdominal IA or abdominal IB)

II

Two separate tumor masses either above or below the diaphragm

III

More than two separate tumor masses or disease above and below the diaphragm

IV

Pleural effusion, ascites, or involvement of central nervous system (malignant cells in cerebrospinal fluid) or bone marrow

anti-EBV antigen titers in sporadic BL patients appear to be associated with a more favorable prognosis.82,88

Rhabdomyosarcoma Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in the pediatric age group, accounting for 50%– 70% of all childhood sarcomas.89–91 There is an incidence of diagnosis of RMS at a rate of 4.5 per million children per year.92 According to the first and second Intergroup Rhabdomyosarcoma Studies (IRS I and IRS II), 35% of pediatric RMSs occur in the head and neck. Approximately 70% of these children manifest their disease before 12 years of age, and 43% present at age younger than 5 years. There is no apparent sex predilection; however, RMS is four times more common in white children than in any other racial group.93 Although most cases of RMS are sporadic, there appear to be both environmental and genetic risk factors for developing RMS. Implicated environmental exposures include parental smoking, in utero radiation exposure, advanced maternal age, the child preceded by prior spontaneous abortions, use of antibiotics by mother or child, and recreational drug use by the mother.94–98 A genetic predisposition is suggested by syndromes that appear to have a higher risk for pediatric RMS such as neurofibromatosis, Li–Fraumeni syndrome, Beckwith–Wiedemann syndrome, and Costello syndrome.99–101 A higher incidence of congenital malformations has also been reported in children with RMS (32%) in comparison with the general population (3%).102 RMS has a wide spectrum of histopathologic subtypes. The IRS histopathologic classification lists embryonal, alveolar, botryoid, spindle cell, and undifferentiated.103–104 In IRS III, the frequency of occurrence of the histopathologic subtypes is as follows: embryonal, 54%; alveolar, 18.5%; undifferentiated, 6.5%; and botryoid, 4.5%; spindle cell was not included.105 The characteristic microscopic appearance of embryonal RMS is that of small, dark, spindle-shaped cells in a loose myxoid background. Round cells resembling lymphocytes are also occasionally seen. Cytologic structures indicative of rhabdomyoblasts may be identified but are

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not considered necessary for histopathologic confirmation. Botryoid RMS is a variant of embryonal RMS that occurs when the growth of embryonal RMS is unrestricted in a body cavity such as the nasopharynx; it tends to become polyploid, resembling a bunch of grapes, so-called sarcoma botryoids. These histopathologic subtypes have been found to have prognostic significance, categorized as favorable prognosis (botryoid, spindle cell), intermediate prognosis (embryonal), and unfavorable prognosis (alveolar and undifferentiated). 103–104 Alveolar RMS is described histopathologically as having small cells with little cytoplasm that are in a number of aggregates divided by fibrovascular septae.106 RMSs of the head and neck region are anatomically categorized as orbital, parameningeal, and nonparameningeal.106,107 Parameningeal sites include the nasopharynx, paranasal sinuses, middle ear, and infratemporal fossa. Nonparameningeal sites include all other “superficial” areas of the head and neck.108 Within the head and neck region, the most common sites of origin, in descending order of frequency, are the orbit, nasopharynx, middle ear-mastoid region, and sinonasal cavities.109 Orbital RMS is the most frequent neoplasm of the orbit in children.110,111 Rapidly progressive, unilateral proptosis in a child younger than 10 years of age is the typical presentation. Localized orbital disease is common. CNS extension with associated pain, headache, and irreversible visual loss is infrequent. RMS of the nasopharynx tends to occur in preschool children in less obvious fashion with symptoms of unilateral otitis media, rhinorrhea, and nasal obstruction. A delay in diagnosis of several months after onset of symptoms is common.112 In one series, only 4 of 20 primary RMSs of the nasopharynx remained confined to the nasopharynx at diagnosis. RMS of the paranasal sinuses may have manifestations analogous to either nasopharyngeal or orbital RMS. Headache and pain are the more common symptoms and are often mistaken for those of sinusitis. Other signs and symptoms include nasal obstruction, facial edema, and epistaxis.112 Patients with RMS of the ear typically have unilateral otorrhea and a hemorrhagic, soft tissue mass in the external auditory meatus, middle ear, or both. An initial diagnosis of otitis media or otitis externa is often mistakenly made.113 Approximately 50% of patients with aural RMS have neurologic findings by the time the proper diagnosis is determined, with the facial nerve being most commonly involved.114 Multiple cranial nerve palsies suggest extension of disease to the base of the skull or CNS.115 This is also true of nasopharyngeal and sinonasal sites of origin.116 All head and neck RMSs arising in parameningeal sites require CT and MRI radiologic evaluation, as well as lumbar puncture with cerebrospinal fluid cytologic study to assess for skull base erosion or CNS involvement.117–119 Metastatic spread of RMS occurs by lymphatic and hematogenous routes.91,118,120 The incidence of cervical lymph node metastases varies with the primary site, being notably rare with orbital RMS. In IRS I and IRS II, no patients with orbital primary lesions presented with clinically positive neck nodes, whereas 7% of patients with other head and neck primary tumors had positive

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CHAPTER 108 ❖ Malignant Tumors of the Head and Neck nodes.121 The most common sites of hematogenous metastatic disease are the lung, bone, and bone marrow. About 13% of patients with RMSs of the head and neck present with distant metastases, except for orbital primary lesions, which have a comparatively low 4% incidence.122 Lesions arising in parameningeal sites have an additional increased incidence of meningeal extension.115,123 Skeletal survey, bone scan, and bone marrow aspirate or biopsy are necessary for complete systemic evaluation. The treatment of patients with RMS is determined by the primary site of involvement and the clinicopathologic stage of disease as established by the IRS (Table 108-11). This clinical staging system is based on extent of disease (localized, regional, or systemic) at presentation and whether excision of local-regional disease is accomplished.124 A recurring problem with this essentially postoperative staging system is that surgical definitions of disease resectability differ between institutions; hence, the IRS grouping of any particular lesion may also vary. An alternative preoperative TNM (tumor, node, metastasis) staging has been proposed (Table 108-12).125,126 This system places emphasis on local invasiveness as opposed to size criteria in determining the tumor stage. The TNM staging system is prospectively being evaluated in the IRS IV with preliminary results in extremity RMS revealing it to have prognostic significance.90,127,128 A similar study of head and neck RMS shows that multiple parameters such as primary lesion size, local invasiveness, nodal metastasis, and distant metastasis have prognostic significance.129 Independent of the clinical characteristics of the disease, adults do worse compared with children in the treatment of RMS.130 Treatment guidelines have been established by the IRS, most importantly the superiority of multimodality therapy— TAblE 108-11. Staging of Rhabdomyosarcoma According to the Intergroup Rhabdomyosarcoma Study

Group I

Localized disease with tumor completely resected and regional nodes not affected Confined to muscle or organ of origin Contiguous involvement-infiltration outside the muscle or organ of origin

Group II

Localized disease with microscopic residual disease or regional disease with no residual or with microscopic residual disease Grossly resected tumor with microscopic residual disease (nodes negative) Regional tumor completely resected (nodes positive or negative) Regional disease with involved nodes grossly resected but with evidence of microscopic residual disease

Group III

Incomplete resection or biopsy with gross residual disease

Group IV

Metastatic disease present at onset

Source: From Barnes.109

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1813

TAblE 108-12. TNM Classification of Rhabdomyosarcoma Modified by the Intergroup Rhabdomyosarcoma Study Group

Stage Site

T

Size

N

M

Any N0

M0

M0

I

T1 or T2 A or B Orbit, head, and neck, excluding parameningeal sites, genitourinary but not bladder or prostate

II

Bladder, prostate, T1 or T2 extremity, cranial parameningeal sites, other

T1 or T2 A

N0 or Nx

III

Bladder, prostate, T1 or T2 extremity, cranial parameningeal sites, other

T1 or T2 A or B

N1 Any N M0

IV

All

T1 or T2 A or B

N0 or N1

M1

Where tumor, nodes, metastasis (TNM) and size of tumor defined as: T1, confined to site of origin T2, extension or fixation to surrounding structures A, tumor ≤5 cm B, tumor > cm N0, no clinically involved lymph nodes N1, regionallly involved lymph nodes Nx, unknown clinical status of nodes M0, no distant metastasis M1, metastasis present Source: Adapted from Pappo et al.

surgery, radiotherapy, and chemotherapy—over single modality therapy in treating this disease. Before the IRS, the five-year survival rate for RMS of the head and neck, all sites considered, ranged from 8% to 20%. The average survival rate was 15 months for orbital RMS, 7–12 months for middle ear-mastoid RMS, and 17 months for RMS arising in the soft tissues of the face and the neck.108 In IRS I using multimodality treatment principles, the three-year relapse-free survival rates increased to 91% for orbital primary disease, 46% for parameningeal (middle ear-mastoid, sinonasal, nasopharyngeal, and infratemporal fossa) primary disease, and 75% for other head and neck sites.122 Surgical extirpation of the primary tumor is indicated when such removal imposes no major functional disability and when excision of the primary tumor permits either the elimination of postoperative radiation therapy or a reduction in radiation dose. This is true of many of the nonorbital and nonparameningeal head and neck sites.130 Biopsy alone

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is advocated for orbital RMS because combined radiotherapy and chemotherapy have resulted in excellent longterm survival with limited morbidity.122 When only partial tumor resection is possible, as is often true of parameningeal sites, initial surgery is limited to biopsy. Some institutions advocate complete resection of some parameningeal tumors if surgically feasible, for example, in the occipital and infratemporal fossa regions, to obviate the need for radiotherapy; possible complications of such surgical management include cranial nerve injury, cosmetic deformity, and trismus.106 A study comparing the role of surgical biopsy versus a debulking procedure in patients with IRS group III RMS showed no difference in outcome, and therefore, biopsy alone is warranted in extensive disease.132 Surgery may also play a role in categorizing patients as partial or complete responders for possible additional therapy.105 For example, in IRS III, patients in group III confirmed to be partial responders at the time of a “second-look” surgical procedure received additional chemotherapy with prophylactic benefit.92,104,105 A review examining multimodality therapy for RMS suggests that patients with group III nonalveolar RMS, even when completely resected as confirmed by a second-look procedure, may benefit from the use of follow-up radiotherapy.133 Another study looking at the prognostic significance of RMS response in general at the end of primary therapy suggests that there is no improvement in disease recurrence or mortality whether the patients were a complete responder or a partial or nonresponder suggesting that in this group of patients, aggressive follow-up therapy may not be necessary.134 Because the anatomic location of many RMSs of the head and neck precludes complete resection, radiation therapy is commonly required, and almost all patients with head and neck RMS, regardless of respectability, receive systemic chemotherapy. Chemotherapy is typically administered postoperatively to patients with small resectable lesions. Preoperative chemotherapy is given initially to patients with larger lesions to decrease tumor volume before local treatment. Such local treatment may require a combination of surgical resection and radiation. Radiation therapy is also indicated for group II, III, and IV tumors. Radiotherapy is directed at the primary site. Wide portals are determined by the extent of tumor on pretreatment clinical and roentgenographic examination.135 A clinically negative neck requires no treatment beyond chemotherapy and observation. Children with a clinically positive neck benefit from neck dissection with additional radiation therapy.124 Chemotherapy protocols vary principally with the stage of disease.136,137 Complications of radiotherapy in the treatment of head and neck RMS include osteoradionecrosis, xerostomia, maxillofacial hypoplasia, malocclusion, dental disease, and the development of secondary malignancies, particularly additional sarcomas.112,129 Chemotherapy has both shortand long-term complications including anemia, neutropenia, thrombocytopenia, neural and cardiac toxicity, and the potential development of acute myeloid leukemia.50 One of

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the main goals of further investigation of RMS therapy is to modify treatment so as to minimize deleterious side effects, especially the development of secondary malignancies, without compromising survival. The primary site is a very important prognostic indicator for several reasons. First, the location of the primary tumor determines the signs and symptoms that lead to diagnosis or delay thereof. Second, the likelihood of lymphatic spread and hematogenous dissemination varies with primary site.121 Third, the location has implications concerning resectability. The histopathologic subtype is also an important variable. Children with alveolar RMS and undifferentiated sarcoma have a poor survival rate compared with those with embryonal RMS.139 A number of chromosomal abnormalities in RMS have been identified and are being investigated to determine their significance as prognostic indicators.139 For example, in alveolar RMS, the PAX3-FKHR fusion associated with the translocation t(2;13)(q35;q14) was found to be a negative prognostic factor.139,141 Spontaneous occurrence of RMS has been associated with a mutation of the PTCH gene (abnormality in 9q22.3 locus)139,142,143 and may imply that environmental exposure in utero may play a role. The most meaningful prognostic variable is the response to treatment because those children who do not achieve complete response will not survive.140 In IRS I, patients with distant metastases (group IV) or evidence of base of skull and CNS extension as with parameningeal sites with gross residual disease (group III) did particularly poorly. Survival in these groups was typically less than 12 months.137 The meninges also proved to be the most common site of tumor recurrence (relapse), whether there was initial evidence of CNS disease.122 These observations led to protocol changes in the second IRS (IRS II) in which an attempt was made to protect the CNS in highrisk patients with parameningeal disease by the addition of prophylactic cranial irradiation and intrathecal tripledrug chemotherapy.138 This approach proved to be efficacious.141 In IRS III, patients with parameningeal tumors without obvious intracranial extension were found to have a similar survival outlook whether they received solely radiotherapy to the tumor with a 2-cm margin or prophylactic CNS treatment. Therefore, the use of intrathecal chemotherapy and whole brain radiation therapy has been limited to those children with parameningeal RMS who also have intracranial extension, evidence of cerebrospinal fluid involvement, bony erosion, or cranial nerve deficits.105 Control of disease in patients with distant metastases remains difficult. The IRS IV protocol addresses this distant metastases problem with trials of pairs of chemotherapeutic agents before the introduction of standard chemotherapy and radiation therapy.142 Early results from IRS IV show an increased survival rate compared with IRS III with the use of increased doses of alkylating agents in patients with stage I embryonal tumors of the head and neck.143 The failure-free survival was 90% in IRS IV compared with 53% in IRS III.

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CHAPTER 108 ❖ Malignant Tumors of the Head and Neck Children with orbital RMS and those with localized disease have the best outcome.149 The overall five-year survival rate in IRS III was 71%, which has improved from IRS II by a statistically significant 8%.105 This overall improvement was attributed principally to the benefit of intensification of chemotherapy in patients in group III, not including special pelvic, orbit, and nonparameningeal sites. The five-year survival rate in IRS-III for select groups is as follows: group I favorable histology, 93%; group I unfavorable histology and group II, 54%–81%; group III, 74%; and group IV, 27%–31%.105,144 Individuals who are free of recurrence two years after treatment are probably cured.145 Time to relapse appears to have prognostic significance that is independent of histology or tumor site.150 Children who recurred less than 6 months, between 6 and 12 months, and after 12 months had 4-year survival rates of 12%, 21%, and 41%, respectively.150 Currently, the use of immunotherapy is being investigated as a novel therapy for RMS.151 T-helper cells that have been exposed to RMS antigens have been shown to be able to recognize tumor antigens on a variety of tumor types, suggesting their potential future use as an anticancer vaccine.151

Soft Tissue Sarcomas Other Than Rhabdomyosarcoma Soft tissue sarcomas other than RMS account for between 3% and 5% of all malignant neoplasms in children.91,152 A bimodal age distribution curve with one incidence peak in children younger than 4–5 years of age, and another peak in adolescence is characteristic of almost all these lesions.153 The soft tissue sarcomas of infants and young children primarily occur in the head and neck region, whereas lesions in adolescents predominantly arise in the trunk and extremities. Nonrhabdomyosarcomas sarcomas are considered separate from RMSs because of the variety of different tumor types and their variable response to standard RMS treatment protocols. Most patients with a non-RMS present with a nontender mass lesion that can occur anywhere in the body. Patients with larger tumors are more likely to have metastatic disease preferentially to the lungs, brain, and bone marrow.154,155 When evaluating a child with a suspected sarcoma, a complete history and physical examination is essential. Radiographic studies may include CT and MRI of the primary site and areas of possible metastatic disease. A tissue diagnosis may be made by tru-cut needle biopsy or alternatively by incisional biopsy. Excisional biopsy is infrequent and may be contraindicated for fear of disrupting tissue planes thus compromising more definitive surgery. Many sarcomas have specific translocations that can aid in diagnosis once tissue is obtained.156 The following translocations have been associated with the corresponding sarcomas: congenital fibrosarcoma, t(12;15)(p13;q25) with fusion product ETV6-NTRK3; Ewing sarcoma/PNET,

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1815

t(11;22)(q24;q12) with fusion product EWS-FLI1, (t21;22) (q22;q12) with fusion product EWS-ERG, t(7;22)(p22;q12) with fusion product EWS-ETV1, t(17;22)(q12;q12) with fusion product EWS-E1AF, and t(2;22)(q33;q12) with fusion product EWS-FEV; synovial sarcoma, t(X,18) (p11;q11) with fusion products SYT-SSX1, SYT-SSX2, and SYT-SSX4.157 Because of their relative rarity, the study of the natural history of these neoplasms and the development of effective treatment regimens require multiinstitution collaboration. In general, with the exception of fibrosarcoma, soft tissue sarcomas demonstrate a tendency toward both local recurrence and metastatic hematogenous spread. This behavior dictates a multimodality therapeutic approach similar to that used in patients with RMS.158–161 In general, complete surgical excision is the treatment of choice with radiation and chemotherapy reserved for cases of incomplete resection.162 In a study of 33 cases of non-rhabdomyosarcoma sarcomas of the head and neck, prognostic factors included extent of resection, grade of the tumor, disease bulk, and location; tumors of the oral cavity and pharynx, for example, have the most favorable prognosis.162 In another study of 88 pediatric patients with non-RMSs not limited to the head and neck, a margin of greater than 1 cm was found to correlate with decreased risk of local recurrence; this was noted to be independent of tumor grade.163 In regards to metastatic disease to lymph nodes, not enough data exist to make definitive recommendations except when the primary disease is in an extremity. Sampling of clinically suspicious nodes should be performed by regional dissection, excision, or FNA.164 The use of radiotherapy in patients with nonrhabdomyosarcoma sarcomas is less effective compared to patients with RMS. Despite this, postoperative radiation therapy was efficacious in those non-RMS cases in which surgical margins were less than 1 cm and the tumor was high grade.155 This observation is of particular importance in the head and neck region where it may be difficult to obtain a 1-cm margin without extensive morbidity. Chemotherapy is generally reserved for those patients who have metastatic or unresectable disease. A variety of agents are currently being evaluated.165–167 A five-agent combination chemotherapeutic regimen including vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is showing promising results.168

Fibrosarcoma Fibrosarcoma is the most common sarcomatous neoplasm after RMS, accounting for 11% of all soft tissue sarcomas of childhood.91,169 Although fibrosarcoma is primarily a malignancy of the extremities in adolescents, approximately 15%–20% of fibrosarcomas occur in the head and neck region, predominantly in infants and young children.153 The most common time of presentation in childhood is within the first 6 months of life.148 Fibrosarcoma may also arise in

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SECTION 6 ❖ The Head and Neck

older children as a secondary neoplasm following radiation therapy.170 Histopathologically, fibrosarcomas consist of malignant fibroblasts associated with variable collagen or reticulin production. Demonstrative evidence of local infiltration distinguishes well-differentiated fibrosarcoma from nonmalignant juvenile fibromatosis. However, this distinction can sometimes be difficult.109,171 Fibrosarcoma of infancy histologically appears the same as in older patients but is less aggressive.148 Such infantile fibrosarcomas can mimic hemangiomas both in terms of time of presentation and physical characteristics.172 The etiology of fibrosarcoma in children is speculative.173 Dermatofibrosarcoma protuburans is a low-grade sarcoma that can transform into a fibrosarcoma.174 The sites of occurrence of fibrosarcoma in the head and neck include the neck, oral cavity, scalp, auriculoparotid region, nose and paranasal sinuses, larynx, face, cheek, and hypopharynx.109 A slowly enlarging, painless, firm mass is the typical presentation. Symptoms result from local extension and pressure on surrounding structures. Plain radiographs reveal a soft tissue density, frequently with associated bone destruction. Tracheobronchial lesions may manifest with various airway signs and symptoms including stridor, recurrent pneumonia, cough, and hemoptysis.175,176 CT evaluation of fibrosarcomas in parameningeal locations is important to assess for base of skull erosion and intracranial extension.177 Fibrosarcoma is unique among the soft tissue sarcomas in that metastatic disease in infants and young children is infrequent. The incidence of local recurrence varies greatly with reported rates between 17% and 43%.148 Lymph node metastases occur in less than 10% of patients. The incidence of hematogenous metastasis to lung and bone is reported to be less than 10% for children younger than 10 years of age, whereas rates approach 50% in patients older than 15 years.178,179 Therapy is primarily directed at local disease control. Complete surgical excision, when possible, is advocated. Maintenance of function at the expense of inadequate margins or incompletely resected disease is often necessary in childhood head and neck cases. In such situations, gross tumor resection is followed by local radiation therapy or treatment with vincristine, actinomucin-D, and cyclophosphamide.172 Adjuvant chemotherapy in the setting of distant metastases is of uncertain value and is not used routinely because of the low incidence of metastatic disease. Preoperative chemotherapy may be used to decrease the size of the tumor in an attempt to make it completely resectable.148 The five-year survival rate of infants and young children with fibrosarcoma is between 80% and 90%.

Synovial Sarcoma Synovial sarcomas account for approximately 5% of all pediatric soft tissue sarcomas. Synovial sarcoma is primarily a malignancy of the extremities; the occurrence of this tumor in the head and neck is rare, with fewer than 50 cases

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reported.109,180,181 There is a slight female predominance.180 Synovial sarcoma is thought to arise from synovioblastic differentiation of mesenchymal stem cells; this derivation accounts for the presence of synovial sarcomas in head and neck sites, which have no normal synovial structures.177 Cervicofacial synovial sarcomas have been reported in the larynx, pharynx, tongue, tonsil, and orofacial soft tissues. The most common location is the neck, where they present as firm, gradually enlarging parapharyngeal or retropharyngeal masses that become symptomatic by compromising contiguous structures. Delay in diagnosis of up to one year is common.180 Synovial sarcomas appear on plain film radiography as soft tissue masses, usually without adjacent bone erosion; the presence of multiple foci of calcification can be a helpful diagnostic feature. The recommended initial imaging of the primary tumor is MRI as it demonstrates good contrast between the tumor and surrounding structures and highlights the cystic appearance and sharp margins characteristic of this lesion.182 Chest CT and a bone scan with 99mTc-labeled methyl diphosphonate are used to evaluate for metastatic disease. Treatment of local disease consists of the widest possible surgical excision followed by radiation therapy.183 Five-year survival rates following combined surgical and radiation treatment regimens approximate 50%; children with small localized lesions have the best outcome.91,184 Local recurrence and metastases to lymph nodes, bone marrow, and lung occur in approximately 50% of patients.185 Because of the documented tumor regression following chemotherapy and because of the poor prognosis associated with systemic, particularly lung, metastases, multimodality treatment regimens similar to those used for childhood RMS are advocated to treat this disease.186 In a study of 31 patients with synovial sarcoma treated by surgical resection followed by both chemotherapy and radiation therapy, the five-year survival rate was improved to 74%; the anatomic location of these lesions was not limited to the head and neck.180 A retrospective study of children with synovial sarcomas suggests that complete resection with gross disease-free margins followed by radiotherapy is the treatment of choice in group I (complete resection) and group II patients (microscopic disease remains); the addition of chemotherapy to these groups did not improve outcome.187 Similarly in another study assessing the role of chemotherapy in children with grossly resected synovial sarcoma, patients considered low risk (group I with a size of the tumor